COMPOUND, AND SEPARATION METHOD, SYNTHESIS METHOD AND USE THEREOF

Abstract

The invention relates to new compounds as well as a separation method, a synthetic method and use thereof. It is demonstrated by an assay on activity that the compound has an activity of inhibiting an HMG-CoA reductase. In addition, the invention also relates to a derivative of the compound.

Claims

1. A compound of Formula (I), or a stereoisomer, tautomer, racemate, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof: ##STR00016## R.sub.1 is selected from H, C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl, (CH.sub.2).sub.1-6OH, C.sub.3-C.sub.7 cycloalkyl, halo C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy, halo C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, halo C.sub.1-C.sub.6 alkylthio, halogen, nitro, amino and cyano; R.sub.2 is selected from H, C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl, (CH.sub.2).sub.1-6OR.sub.6, C.sub.3-C.sub.7 cycloalkyl, halo C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy, halo C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, halo C.sub.1-C.sub.6 alkylthio, halogen, nitro, amino and cyano; R.sub.3 is selected from H, C.sub.1-C.sub.6 alkyl; R.sub.4 and R.sub.5 each are independently selected from: H, COR.sub.7, SO.sub.2R.sub.8, and SiR.sub.9R.sub.10R.sub.11; wherein, R.sub.7 is selected from C.sub.1-C.sub.6 alkyl and halo C.sub.1-C.sub.6 alkyl; R.sub.8 is selected from C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 aryl, and optionally substituted C.sub.6-C.sub.10 aryl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from C.sub.1-C.sub.6 alkyl; wherein, R.sub.6 has the same definition as R.sub.4 and R.sub.5; wherein, the compound of Formula (I) wherein R.sub.1 is (CH.sub.2)OH, R.sub.2 is methyl, and R.sub.3, R.sub.4 and R.sub.5 are H, is excluded.

2. The compound according to claim 1, wherein, R.sub.1 is selected from H, C.sub.1-C.sub.3 alkyl, halo C.sub.1-C.sub.3 alkyl, (CH.sub.2).sub.1-3OH, C.sub.3-C.sub.6 cycloalkyl, halo C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.3 alkoxy, halo C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkylthio, halo C.sub.1-C.sub.3 alkylthio, halogen, nitro, amino and cyano.

3. The compound according to claim 1, wherein, R.sub.1 is selected from H, C.sub.1-C.sub.3 alkyl, halo C.sub.1-C.sub.3 alkyl, (CH.sub.2).sub.1-3OH, halogen, nitro, amino and cyano.

4. The compound according to claim 1, wherein R.sub.1 is selected from H, C.sub.1-C.sub.3 alkyl, and (CH.sub.2).sub.1-3OH.

5. The compound according to claim 1, wherein R.sub.2 is selected from H, C.sub.1-C.sub.3 alkyl, halo C.sub.1-C.sub.3 alkyl, (CH.sub.2).sub.1-3OR.sub.6, C.sub.3-C.sub.6 cycloalkyl, halo C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.3 alkoxy, halo C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkylthio, halo C.sub.1-C.sub.3 alkylthio, halogen, nitro, amino and cyano; wherein, R.sub.6 is selected from H, COR.sub.7, SO.sub.2R.sub.8, and SiR.sub.9R.sub.10R.sub.11; wherein, R.sub.7 is selected from C.sub.1-C.sub.6 alkyl, and halo C.sub.1-C.sub.6 alkyl; R.sub.8 is selected from C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 aryl, and optionally substituted C.sub.6-C.sub.10 aryl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from C.sub.1-C.sub.6 alkyl.

6. The compound according to claim 1, wherein R.sub.2 is selected from H, C.sub.1-C.sub.3 alkyl, halo C.sub.1-C.sub.3 alkyl, (CH.sub.2).sub.1-3OR.sub.6, C.sub.3-C.sub.6 cycloalkyl, halo C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.3 alkoxy, halo C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkylthio, halo C.sub.1-C.sub.3 alkylthio, halogen, nitro, amino and cyano; wherein, R.sub.6 is selected from: H, COR.sub.7, SO.sub.2R.sub.8, and SiR.sub.9R.sub.10R.sub.11; wherein, R.sub.7 is selected from C.sub.1-C.sub.3 alkyl, and halo C.sub.1-C.sub.3 alkyl; R.sub.8 is selected from C.sub.1-C.sub.3 alkyl, optionally substituted C.sub.1-C.sub.3 alkyl, C.sub.6-C.sub.10 aryl, and optionally substituted C.sub.6-C.sub.10 aryl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from C.sub.1-C.sub.6 alkyl.

7. The compound according to claim 1, wherein R.sub.2 is selected from H, C.sub.1-C.sub.3 alkyl, halo C.sub.1-C.sub.3 alkyl, (CH.sub.2).sub.1-3OR.sub.6, C.sub.3-C.sub.6 cycloalkyl, halo C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.3 alkoxy, halo C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkylthio, halo C.sub.1-C.sub.3 alkylthio, halogen, nitro, amino and cyano; wherein, R.sub.6 is selected from: H, COR.sub.7, SO.sub.2R.sub.8, and SiR.sub.9R.sub.10R.sub.11; wherein, R.sub.7 is selected from CH.sub.3; R.sub.8 is selected from CF.sub.3 and p-methylphenyl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from methyl and tert-butyl.

8. The compound according to claim 1, wherein R.sub.2 is selected from H, C.sub.1-C.sub.3 alkyl, halo C.sub.1-C.sub.3 alkyl, (CH.sub.2).sub.1-3OR.sub.6, halogen, nitro, amino and cyano; wherein, R.sub.6 is selected from H, COR.sub.7, SO.sub.2R.sub.8, and SiR.sub.9R.sub.10R.sub.11; wherein, R.sub.7 is selected from C.sub.1-C.sub.6 alkyl, and halo C.sub.1-C.sub.6 alkyl; R.sub.8 is selected from C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 aryl, and optionally substituted C.sub.6-C.sub.10 aryl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from C.sub.1-C.sub.6 alkyl.

9. The compound according to claim 1, wherein R.sub.2 is selected from H, C.sub.1-C.sub.3 alkyl, halo C.sub.1-C.sub.3 alkyl, (CH.sub.2).sub.1-3 OR.sub.6, halogen, nitro, amino and cyano; wherein, R.sub.6 is selected from: H, COR.sub.7, SO.sub.2R.sub.8, and SiR.sub.9R.sub.10R.sub.11; wherein, R.sub.7 is selected from C.sub.1-C.sub.3 alkyl and halo C.sub.1-C.sub.3 alkyl; R.sub.8 is selected from C.sub.1-C.sub.3 alkyl, optionally substituted C.sub.1-C.sub.3 alkyl, C.sub.6-C.sub.10 aryl, and optionally substituted C.sub.6-C.sub.10 aryl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from C.sub.1-C.sub.6 alkyl.

10. The compound according to claim 1, wherein R.sub.2 is selected from H, C.sub.1-C.sub.3 alkyl, halo C.sub.1-C.sub.3 alkyl, (CH.sub.2).sub.1-3OR.sub.6, halogen, nitro, amino and cyano; wherein, R.sub.6 is selected from: H, COR.sub.7, SO.sub.2R.sub.8 and SiR.sub.9R.sub.10R.sub.11; wherein, R.sub.7 is selected from CH.sub.3; R.sub.8 is selected from CF.sub.3 and p-methyl phenyl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from methyl and tert-butyl.

11. The compound according to claim 1, wherein R.sub.2 is selected from H, C.sub.1-C.sub.3 alkyl and (CH.sub.2).sub.1-3OR.sub.6; wherein, R.sub.6 is selected from H, COR.sub.7, SO.sub.2R.sub.8 and SiR.sub.9R.sub.10R.sub.11; wherein, R.sub.7 is selected from C.sub.1-C.sub.6 alkyl and halo C.sub.1-C.sub.6 alkyl; R.sub.8 is selected from C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 aryl, and optionally substituted C.sub.6-C.sub.10 aryl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from C.sub.1-C.sub.6 alkyl.

12. The compound according to claim 1, wherein R.sub.2 is selected from H, C.sub.1-C.sub.3 alkyl, and (CH.sub.2).sub.1-3OR.sub.6; wherein, R.sub.6 is selected from H, COR.sub.7, SO.sub.2R.sub.8, and SiR.sub.9R.sub.10R.sub.11; wherein, R.sub.7 is selected from C.sub.1-C.sub.3 alkyl and halo C.sub.1-C.sub.3 alkyl; R.sub.8 is selected from C.sub.1-C.sub.3 alkyl, optionally substituted C.sub.1-C.sub.3 alkyl, C.sub.6-C.sub.10 aryl, and optionally substituted C.sub.6-C.sub.10 aryl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from C.sub.1-C.sub.6 alkyl.

13. The compound according to claim 1, wherein R.sub.2 is selected from H, C.sub.1-C.sub.3 alkyl, and (CH.sub.2).sub.1-3OR.sub.6; wherein, R.sub.6 is selected from H, COR.sub.7, SO.sub.2R.sub.8, and SiR.sub.9R.sub.10R.sub.11; wherein, R.sub.7 is selected from CH.sub.3; R.sub.8 is selected from CF.sub.3 and p-methyl phenyl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from methyl and tert-butyl.

14. The compound according to claim 1, wherein R.sub.3 is selected from H and C.sub.1-C.sub.3 alkyl.

15. The compound according to claim 1, wherein R.sub.3 is C.sub.1-C.sub.3 alkyl.

16. The compound according to claim 1, wherein R.sub.4 and R.sub.5 each are independently selected from: H, COR.sub.7, SO.sub.2R.sub.8, and SiR.sub.9R.sub.10R.sub.11; wherein, R.sub.7 is selected from C.sub.1-C.sub.3 alkyl, and halo C.sub.1-C.sub.3 alkyl; R.sub.8 is selected from C.sub.1-C.sub.3 alkyl, optionally substituted C.sub.1-C.sub.3 alkyl, C.sub.6-C.sub.10 aryl, and optionally substituted C.sub.6-C.sub.10 aryl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from C.sub.1-C.sub.6 alkyl.

17. The compound according to claim 1, wherein R.sub.4 and R.sub.5 each are independently selected from: H, COR.sub.7, SO.sub.2R.sub.8, and SiR.sub.9R.sub.10R.sub.11; wherein, R.sub.7 is selected from CH.sub.3; R.sub.8 is selected from CF.sub.3, and p-methyl phenyl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from methyl, and tert-butyl.

18. The following compound, selected from: ##STR00017## and diacetate, bis(4-methylbenzenesulfonate), bis(trifluoromethanesulfonate), and bis(tert-butyldimethylsilyl ether) of Compound 5; ##STR00018## and triacetate, tri(4-methylbenzenesulfonate), tri(trifluoromethanesulfonate), and tri(tert-butyldimethylsilyl ether) of Compound 5a.

19. A pharmaceutical composition, comprising the compound according to claim 1 and optionally, a pharmaceutically acceptable excipient.

20. A method for inhibiting HMG-CoA reductase activity comprising contacting the compound according to claim 1 with HMG-CoA reductase.

21. A method for preventing and/or treating dyslipidemia, hyperlipemia, or atherosclerosis in a patient, comprising administering a therapeutically effective amount of the compound according to claim 1 to the patient in need of treatment.

22. A method for extracting Compound 5 from Monascus-fermented rice or extract thereof, comprising the following steps of: ##STR00019## 1) extracting Monascus-fermented rice or extract thereof with ethyl acetate (or dichloromethane or methanol or ethanol, or methanol/ethanol aqueous solution) as a solvent; 2) separating the ethyl acetate (or dichloromethane or methanol or ethanol, or methanol/ethanol aqueous solution) extract obtained in Step 1) by silica gel column chromatography, and carrying out gradient elution with petroleum ether, ethyl acetate and methanol, to obtain the ethyl acetate eluting fraction; 3) separating the ethyl acetate eluting fraction obtained in Step 2) by silica gel column chromatography, carrying out elution with dichloromethane-ethyl acetate-methanol, detecting and combining the fractions, to obtain the fractions in Step 3); 4) separating the second fraction obtained in Step 3) by C18 column chromatography, and carrying out gradient elution with acetonitrile-methanol-water, to obtain 82% (acetonitrile-methanol 1:1) aqueous solution eluting fraction; 5) further separating the 82% (acetonitrile-methanol 1:1) aqueous solution eluting fraction obtained in Step 4) by sephadex LH-20 column chromatography using dichloromethane-methanol as a mobile phase, analyzing and combining the fractions, to obtain the fractions in Step 5); and 6) purifying the third fraction obtained in Step 5) by chromatographic method, to obtain Compound 5.

23. The method according to claim 22, wherein, 1) extracting Monascus-fermented rice or extract thereof with 2-6-fold volume of ethyl acetate (or dichloromethane or methanol or ethanol, or methanol/ethanol aqueous solution) as a solvent for three times, 20-40 min for each time, combining the extracting solution, and concentrating it under reduced pressure to recover the solvent, and to obtain the ethyl acetate extract; 2) separating the ethyl acetate (or dichloromethane or methanol or ethanol, or methanol/ethanol aqueous solution) extract obtained in Step 1) by silica gel column chromatography, and carrying out gradient elution with petroleum ether, ethyl acetate and methanol or ethanol, or methanol/ethanol aqueous solution, to obtain the ethyl acetate eluting fraction; 3) separating the ethyl acetate eluting fraction obtained in Step 2) by silica gel column chromatography, carrying out elution with dichloromethane-ethyl acetate-methanol (30:30:1), and combining the fractions, to obtain 5 fractions; 4) separating the second fraction obtained in Step 3) by C18 column chromatography, and carrying out gradient elution with 82% (acetonitrile-methanol 1:1) aqueous solution100% (acetonitrile-methanol 1:1), to obtain 82% (acetonitrile-methanol 1:1) aqueous solution eluting fraction; 5) further separating the 82% (acetonitrile-methanol 1:1) aqueous solution eluting fraction obtained in Step 4) by sephadex LH-20 column chromatography using dichloromethane-methanol (2:1) as a mobile phase, and combining the fractions, to obtain 6 fractions in Step 5); and 6) purifying the third fraction obtained in Step 5) by chromatography using acetonitrile-methanol-water as a mobile phase and using C18 chromatographic column as a stationary phase, to obtain Compound 5 ##STR00020##

24. A method for synthesizing the compound of Formula (I) according to claim 1, and Compound 5 and Compound 5a according to claim 18: reacting a compound of Formula (II) under alkaline condition, or adding an esterification reagent under alkaline condition, to prepare the compound of Formula (I), ##STR00021## wherein, in Formula (II), R.sub.1, R.sub.2 and R.sub.4 have the same meanings as defined in Formula (I) according to any one of claims 1-17, the pH range of the alkaline condition is 7.5-14, and optionally, an alkaline reagent such as sodium hydroxide, potassium hydroxide, ammonia water and sodium carbonate, or a solvent may be added; the esterification reagent may be selected from lower alcohol such as methanol and ethanol; anhydride (acetic anhydride, sulfonic anhydride, trifluormethanesulfonic anhydride, etc.), acyl chloride (toluenesulfonyl chloride), and chlorosilane (tert-butyldimethylchlorosilane).

25. A method for synthesizing compound 5: ##STR00022## ##STR00023##

26. A method for synthesizing Compound 5: ##STR00024## ##STR00025##

27. A method for preventing and/or treating hypercholesterolemia, combined hyperlipidemia in a patient, comprising administering a therapeutically effective amount of the compound according to claim 1 to the patient in need of treatment.

Description

DESCRIPTION OF THE DRAWINGS

[0041] FIG. 1 shows the .sup.1H-.sup.1H COSY() (FIG. 1A) and HMBC signals () (FIG. 1B) of Compound 5 according to the invention.

SPECIFIC MODES FOR CARRYING OUT THE INVENTION

[0042] The invention relates to a compound of Formula (I), or a stereoisomer, tautomer, racemate, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof:

##STR00004##

[0043] R.sub.1 is selected from H, C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl, (CH.sub.2).sub.1-6OH, C.sub.3-C.sub.7 cycloalkyl, halo C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy, halo C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, halo C.sub.1-C.sub.6 alkylthio, halogen, nitro, amino and cyano;

[0044] R.sub.2 is selected from H, C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl, (CH.sub.2).sub.1-6OR.sub.6, C.sub.3-C.sub.7 cycloalkyl, halo C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy, halo C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, halo C.sub.1-C.sub.6 alkylthio, halogen, nitro, amino and cyano;

[0045] R.sub.3 is selected from H and C.sub.1-C.sub.6 alkyl;

[0046] R.sub.4 and R.sub.5 each are independently selected from: H, COR.sub.7, SO.sub.2R.sub.8, and SiR.sub.9R.sub.10R.sub.11;

[0047] wherein, R.sub.7 is selected from C.sub.1-C.sub.6 alkyl and halo C.sub.1-C.sub.6 alkyl; R.sub.8 is selected from C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 aryl, and optionally substituted C.sub.6-C.sub.10 aryl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from C.sub.1-C.sub.6 alkyl;

[0048] wherein, R.sub.6 has the same definition as R.sub.4 and R.sub.5;

[0049] wherein, the compound of Formula (I) wherein R.sub.1 is (CH.sub.2)OH, R.sub.2 is methyl, and R.sub.3, R.sub.4 and R.sub.5 are H, is excluded.

[0050] In one embodiment, the invention relates to a compound of Formula (I), wherein, R.sub.1 is selected from H, C.sub.1-C.sub.3 alkyl, halo C.sub.1-C.sub.3 alkyl, (CH.sub.2).sub.1-3OH, C.sub.3-C.sub.6 cycloalkyl, halo C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.3 alkoxy, halo C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkylthio, halo C.sub.1-C.sub.3 alkylthio, halogen, nitro, amino and cyano.

[0051] In one embodiment, the invention relates to a compound of Formula (I), wherein, R.sub.1 is selected from H, C.sub.1-C.sub.3 alkyl, halo C.sub.1-C.sub.3 alkyl, (CH.sub.2).sub.1-3OH, halogen, nitro, amino and cyano.

[0052] In one embodiment, the invention relates to a compound of Formula (I), wherein, R.sub.1 is selected from H, C.sub.1-C.sub.3 alkyl, and (CH.sub.2).sub.1-3OH.

[0053] In one embodiment, the invention relates to a compound of Formula (I), wherein

[0054] R.sub.2 is selected from H, C.sub.1-C.sub.3 alkyl, halo C.sub.1-C.sub.3 alkyl, (CH.sub.2).sub.1-3OR.sub.6, C.sub.3-C.sub.6 cycloalkyl, halo C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.3 alkoxy, halo C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkylthio, halo C.sub.1-C.sub.3 alkylthio, halogen, nitro, amino and cyano;

[0055] wherein, R.sub.6 is selected from H, COR.sub.7, SO.sub.2R.sub.8, and SiR.sub.9R.sub.10R.sub.11;

[0056] wherein, R.sub.7 is selected from C.sub.1-C.sub.6 alkyl and halo C.sub.1-C.sub.6 alkyl; R.sub.8 is selected from C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 aryl, and optionally substituted C.sub.6-C.sub.10 aryl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from C.sub.1-C.sub.6 alkyl.

[0057] In one embodiment, the invention relates to a compound of Formula (I), wherein

[0058] R.sub.2 is selected from H, C.sub.1-C.sub.3 alkyl, halo C.sub.1-C.sub.3 alkyl, (CH.sub.2).sub.1-3OR.sub.6, C.sub.3-C.sub.6 cycloalkyl, halo C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.3 alkoxy, halo C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkylthio, halo C.sub.1-C.sub.3 alkylthio, halogen, nitro, amino and cyano;

[0059] wherein, R.sub.6 is selected from: H, COR.sub.7, SO.sub.2R.sub.8 and SiR.sub.9R.sub.10R.sub.11;

[0060] wherein, R.sub.7 is selected from C.sub.1-C.sub.3 alkyl and halo C.sub.1-C.sub.3 alkyl; R.sub.8 is selected from C.sub.1-C.sub.3 alkyl, optionally substituted C.sub.1-C.sub.3 alkyl, C.sub.6-C.sub.10 aryl, and optionally substituted C.sub.6-C.sub.10 aryl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from C.sub.1-C.sub.6 alkyl.

[0061] In one embodiment, the invention relates to a compound of Formula (I), wherein

[0062] R.sub.2 is selected from H, C.sub.1-C.sub.3 alkyl, halo C.sub.1-C.sub.3 alkyl, (CH.sub.2).sub.1-3OR.sub.6, C.sub.3-C.sub.6 cycloalkyl, halo C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.3 alkoxy, halo C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkylthio, halo C.sub.1-C.sub.3 alkylthio, halogen, nitro, amino and cyano;

[0063] wherein, R.sub.6 is selected from: H, COR.sub.7, SO.sub.2R.sub.8 and SiR.sub.9R.sub.10R.sub.11;

[0064] wherein, R.sub.7 is selected from CH.sub.3, R.sub.8 is selected from CF.sub.3 and p-methyl phenyl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from methyl and tert-butyl.

[0065] In one embodiment, the invention relates to a compound of Formula (I), wherein

[0066] R.sub.2 is selected from H, C.sub.1-C.sub.3 alkyl, halo C.sub.1-C.sub.3 alkyl, (CH.sub.2).sub.1-3OR.sub.6, halogen, nitro, amino and cyano;

[0067] wherein, R.sub.6 is selected from H, COR.sub.7, SO.sub.2R.sub.8 and SiR.sub.9R.sub.10R.sub.11;

[0068] wherein, R.sub.7 is selected from C.sub.1-C.sub.6 alkyl and halo C.sub.1-C.sub.6 alkyl; R.sub.8 is selected from C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 aryl, and optionally substituted C.sub.6-C.sub.10 aryl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from C.sub.1-C.sub.6 alkyl.

[0069] In one embodiment, the invention relates to a compound of Formula (I), wherein

[0070] R.sub.2 is selected from H, C.sub.1-C.sub.3 alkyl, halo C.sub.1-C.sub.3 alkyl, (CH.sub.2).sub.1-3OR.sub.6, halogen, nitro, amino and cyano;

[0071] wherein, R.sub.6 is selected from: H, COR.sub.7, SO.sub.2R.sub.8 and SiR.sub.9R.sub.10R.sub.11;

[0072] wherein, R.sub.7 is selected from C.sub.1-C.sub.3 alkyl, and halo C.sub.1-C.sub.3 alkyl; R.sub.8 is selected from C.sub.1-C.sub.3 alkyl, optionally substituted C.sub.1-C.sub.3 alkyl, C.sub.6-C.sub.10 aryl, and optionally substituted C.sub.6-C.sub.10 aryl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from C.sub.1-C.sub.6 alkyl.

[0073] In one embodiment, the invention relates to a compound of Formula (I), wherein

[0074] R.sub.2 is selected from H, C.sub.1-C.sub.3 alkyl, halo C.sub.1-C.sub.3 alkyl, (CH.sub.2).sub.1-3OR.sub.6, halogen, nitro, amino and cyano;

[0075] wherein, R.sub.6 is selected from: H, COR.sub.7, SO.sub.2R.sub.8 and SiR.sub.9R.sub.10R.sub.11;

[0076] wherein, R.sub.7 is selected from CH.sub.3, R.sub.8 is selected from CF.sub.3 and p-methyl phenyl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from methyl and tert-butyl.

[0077] In one embodiment, the invention relates to a compound of Formula (I), wherein

[0078] R.sub.2 is selected from H, C.sub.1-C.sub.3 alkyl, and (CH.sub.2).sub.1-3OR.sub.6;

[0079] wherein, R.sub.6 is selected from H, COR.sub.7, SO.sub.2R.sub.8, and SiR.sub.9R.sub.10R.sub.11;

[0080] wherein, R.sub.7 is selected from C.sub.1-C.sub.6 alkyl, and halo C.sub.1-C.sub.6 alkyl; R.sub.8 is selected from C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 aryl, and optionally substituted C.sub.6-C.sub.10 aryl; R.sub.9, R.sub.10, and R.sub.11 are independently selected from C.sub.1-C.sub.6 alkyl.

[0081] In one embodiment, the invention relates to a compound of Formula (I), wherein

[0082] R.sub.2 is selected from H, C.sub.1-C.sub.3 alkyl and (CH.sub.2).sub.1-3OR.sub.6;

[0083] wherein, R.sub.6 is selected from H, COR.sub.7, SO.sub.2R.sub.8 and SiR.sub.9R.sub.10R.sub.11;

[0084] wherein, R.sub.7 is selected from C.sub.1-C.sub.3 alkyl and halo C.sub.1-C.sub.3 alkyl; R.sub.8 is selected from C.sub.1-C.sub.3 alkyl, optionally substituted C.sub.1-C.sub.3 alkyl, C.sub.6-C.sub.10 aryl, and optionally substituted C.sub.6-C.sub.10 aryl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from C.sub.1-C.sub.6 alkyl.

[0085] In one embodiment, the invention relates to a compound of Formula (I), wherein

[0086] R.sub.2 is selected from H, C.sub.1-C.sub.3 alkyl and (CH.sub.2).sub.1-3OR.sub.6;

[0087] wherein, R.sub.6 is selected from H, COR.sub.7, SO.sub.2R.sub.8 and SiR.sub.9R.sub.10R.sub.11;

[0088] wherein, R.sub.7 is selected from CH.sub.3; R.sub.8 is selected from CF.sub.3 and p-methyl phenyl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from methyl, and tert-butyl.

[0089] In one embodiment, the invention relates to a compound of Formula (I), wherein, R.sub.3 is selected from H and C.sub.1-C.sub.3 alkyl.

[0090] In one embodiment, the invention relates to a compound of Formula (I), wherein, R.sub.3 is C.sub.1-C.sub.3 alkyl.

[0091] In one embodiment, the invention relates to a compound of Formula (I), wherein

[0092] R.sub.4 and R.sub.5 each are independently selected from: H, COR.sub.7, SO.sub.2R.sub.8, and SiR.sub.9R.sub.10R.sub.11;

[0093] wherein, R.sub.7 is selected from C.sub.1-C.sub.3 alkyl, and halo C.sub.1-C.sub.3 alkyl; R.sub.8 is selected from C.sub.1-C.sub.3 alkyl, optionally substituted C.sub.1-C.sub.3 alkyl, C.sub.6-C.sub.10 aryl, and optionally substituted C.sub.6-C.sub.10 aryl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from C.sub.1-C.sub.6 alkyl.

[0094] In one embodiment, the invention relates to a compound of Formula (I), wherein

[0095] R.sub.4 and R.sub.5 each are independently selected from: H, COR.sub.7, SO.sub.2R.sub.8, and SiR.sub.9R.sub.10R.sub.11;

[0096] wherein, R.sub.7 is selected from CH.sub.3; R.sub.8 is selected from CF.sub.3, and p-methyl phenyl; R.sub.9, R.sub.10 and R.sub.11 are independently selected from methyl, and tert-butyl.

[0097] In one embodiment, the invention relates to a compound of Formula (I), which is selected from:

##STR00005##

[0098] and diacetate, bis(4-methylbenzenesulfonate), bis(trifluoromethanesulfonate), and bis(tert-butyldimethylsilyl ether) thereof,

##STR00006##

[0099] and triacetate, tris(4-methylbenzenesulfonate), tris (trifluoromethanesulfonate), and tris (tert-butyldimethylsilyl ether) thereof.

[0100] As used herein, the term C.sub.1-C.sub.6 alkyl refers to a linear or branched alkyl having 1-6 carbon atoms. Examples of C.sub.1-C.sub.6 alkyl include, but are not limited to methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

[0101] Similarly, the term C.sub.1-C.sub.3 alkyl refers to a linear or branched alkyl having 1-3 carbon atoms. Examples of C.sub.1-C.sub.3 alkyl include, but are not limited to methyl, ethyl, n-propyl, and isopropyl.

[0102] The term C.sub.1-C.sub.6 alkoxy refers to OC.sub.1-C.sub.6 alkyl.

[0103] The term C.sub.1-C.sub.6 alkylthio refers to SC.sub.1-C.sub.6 alkyl.

[0104] Similarly, C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3 alkylthio have similar meanings.

[0105] The term C.sub.3-C.sub.7 cycloalkyl refers to an alkyl having a saturated 3-7 membered monocyclic system, wherein C.sub.3-C.sub.7 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0106] Similarly, the term C.sub.3-C.sub.6 cycloalkyl refers to an alkyl having a saturated 3-6 membered monocyclic system, wherein C.sub.3-C.sub.6 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0107] The term halogen refers to F, Cl, Br or I.

[0108] The term halo-XX group refers to a halogenated XX group. For example, halo C.sub.1-C.sub.6 alkyl refers to halogenated C.sub.1-C.sub.6 alkyl. The term halo C.sub.3-C.sub.7 cycloalkyl refers to halogenated C.sub.3-C.sub.7 cycloalkyl. Similarly, the term halo C.sub.1-C.sub.6 alkylthio, halo C.sub.1-C.sub.6 alkoxy, halo C.sub.3-C.sub.6 cycloalkyl, halo C.sub.1-C.sub.3 alkoxy, halo C.sub.1-C.sub.3 alkylthio have similar meanings as described above.

[0109] The term C.sub.6-C.sub.10 aryl refers to a monovalent aromatic alkyl having 6-10 carbon atoms. Examples of aryl include, but are not limited to phenyl, tolyl, ethylphenyl, naphthyl, etc.

[0110] As used herein, the term a pharmaceutically acceptable salt of the compound of Formula (I) refers to an organic acid addition salt formed by a pharmaceutically acceptable anion (such as methylbenzenesulfonate radical, methanesulfonate radical, malate radical, acetate radical, citrate radical, malonate radical, tartrate radical, succinate radical, benzoate radical, ascorbate radical, -ketoglutarate radical, and -glycerophosphate) of an organic acid. It may also form a suitable inorganic salt, including, but not limited to hydrochlorate, sulfate, nitrate, bicarbonate and carbonate, phosphate, hydrobromate, hydriodate, etc.

[0111] A pharmaceutically acceptable salt can be obtained by the standard processes well known in the art, for example, by reacting a sufficient amount of an alkaline compound with a suitable acid providing a pharmaceutically acceptable anion.

[0112] Monascus-fermented rice or extract thereof according to the invention may be the commercially available Monascus-fermented rice (Monascus-fermented rice dry powder, fermentation products of Monascus-fermented rice, red kojic rice), or extract of Monascus-fermented rice (such as Xuezhikang capsule, Xuezhikang tablet or raw material thereof).

[0113] The extract of Monascus-fermented rice according to the invention may be prepared by the following method (but not limited to the following method):

[0114] 1) to 1 part of Monascus-fermented rice by weight, adding 2-10 parts of 50-100% (v/v) ethanol or methanol or methanol/ethanol aqueous solution, or ethyl acetate (or other organic solvent) by volume each time, heating the resultant mixture to reflux for 1-3 h, and performing the extraction for 2-3 times;

[0115] 2) filtrating the extracting solution, combining the filtrate, and optionally recovering the solvent; and

[0116] 3) concentrating the filtrate obtained in the step 2) to a thick paste.

[0117] As used herein, the term solvate may be formed by a common organic solvent: hydrocarbon solvent such as benzene or toluene; chlorinated solvent such as chloroform and dichloromethane; alcohol solvent such as methanol, ethanol or isopropanol; ether solvent such as diethyl ether or tetrahydrofuran, or ester solvent such as ethyl acetate. Alternatively, the solvate of the compound of Formula (I) may be formed by water, and in this case, it is a hydrate.

[0118] As used herein, the term hydrate refers to the compound or a salt thereof according to the invention further comprising a stoichiometric or non-stoichiometric water bound via a non-covalent intermolecular force.

[0119] As used herein, unless otherwise specified, the term prodrug refers to a derivative which can be hydrolyzed, oxidized or subjected to other reactions under biological conditions (in vitro or in vivo) to provide a compound according to the invention. A prodrug is only reacted in the reaction under biological conditions to form an active compound, or has activity in its unreacted form. In general, a prodrug can be prepared by well-known methods, for example, the methods described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (edited by Manfred E. Wolff, the 5.sup.th edition).

[0120] The stereochemical definitions and principles used herein generally follow MCGRAW-HILL DICTIONARY OF CHEMICAL TERMS (S. P. Parker, Ed., McGraw-Hill Book Company, New York, 1984); and ELIEL, E. and WILEN, S., STEREOCHEMISTRY OF ORGANIC COMPOUNDS (John Wiley & Sons, Inc., New York, 1994). Many organic compounds are present in their optically active forms, i.e., have the ability of rotating the plane of polarization of linearly polarized light.

[0121] As used herein, the term treatment generally refers to the acquirement of a desired pharmacological and/or physiological effect. The effect may be preventive depending on complete or partial prevention of a disease or symptoms thereof; and/or may be therapeutic depending on partial or complete stabilization or cure of a disease or side effects caused by the disease. The treatment used herein covers any treatment of a disease in a patient, comprising: (a) preventing a disease or a symptom in a patient who is susceptible to the disease or the symptom but has not been diagnosed to suffer from the disease yet; (b) inhibiting the symptom of a disease, i.e., preventing the progress thereof; or (c) alleviating the symptom of a disease, i.e., resulting in degeneration of the disease or the symptom.

[0122] The compound of the invention can be prepared by conventional organochemical synthetic methods. For example, the invention relates to a method for preparing a compound of Formula (I):

##STR00007##

[0123] reacting a compound of Formula (II) under alkaline condition, or adding an esterification reagent under alkaline condition, to prepare the compound of Formula (I), wherein, in Formula (II), R.sub.1, R.sub.2 and R.sub.4 have the same meanings as defined above in Formula (I).

[0124] The pH range of the alkaline condition is 7.5-14, and optionally, an alkaline reagent such as sodium hydroxide, potassium hydroxide, ammonia water and sodium carbonate, or a solvent may be added; the esterification reagent may be selected from lower alcohol such as methanol and ethanol; anhydride (acetic anhydride, sulfonic anhydride, trifluormethane sulfonic anhydride, etc.), acyl chloride (toluene sulfonyl chloride), and chlorosilane (tert-butyldimethylchlorosilane).

[0125] Conventional chemical conversion may be used to carry out the invention. A person skilled in the art can determine suitable chemical agents, solvents, protective groups and reaction conditions for use in the chemical conversions. Relevant information can be found in, for example, R. Larock, Comprehensive Organic Transformations, VCH publisher (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, the 3.sup.rd edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and John Wiley and Sons, Encyclopedia of Reagents for Organic Synthesis, edited by L. Paquette (1995) and the later editions.

[0126] A protective group refers to a group which can prevent an active moiety (such as hydroxyl or amino) from being disturbed in the subsequent reactions upon conjugation to the active moiety, and can be removed by conventional methods after the reactions. Examples of hydroxyl protective groups include, but are not limited to, alkyl, phenylmethyl (benzyl), allyl, trityl (i.e., triphenylmethyl), acyl (such as, benzoyl, acetyl or HOOCXCO, X is alkylidene group, alkenylene group, cycloalkylidene group or arylene group), silyl (e.g., trimethylsilyl, triethylsilyl and tert-butyldimethylsilyl), alkoxycarbonyl, aminocarbonyl (e.g., dimethylaminocarbonyl, methylethylaminocarbonyl and phenylaminocarbonyl), alkoxymethyl, phenylmethoxymethyl and alkylmercapto-methyl. Examples of amino protective groups include, but are not limited to, alkoxycarbonyl, alkanoyl, aryloxycarbonyl, aryl-substituted alkyl, etc. Hydroxyl and amino protective groups have been discussed in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, the second edition, John Wiley and Sons (1991). Both hydroxyl and amino protective groups can be removed by conventional methods after the reaction.

[0127] Another object of the invention is to provide a method for separating a compound. In particular, another object of the invention is to provide a method for extracting Compound 5 from Monascus-fermented rice or extract thereof, the method comprising the following steps:

##STR00008##

[0128] 1) extracting Monascus-fermented rice or extract thereof with ethyl acetate (or dichloromethane or methanol or ethanol, or methanol/ethanol aqueous solution) as a solvent;

[0129] 2) separating the ethyl acetate (or dichloromethane or methanol or ethanol, or methanol/ethanol aqueous solution) extract obtained in Step 1) by silica gel column chromatography, and carrying out gradient elution with petroleum ether, ethyl acetate and methanol/ethanol, to obtain the ethyl acetate eluting fraction;

[0130] 3) separating the ethyl acetate eluting fraction obtained in Step 2) by silica gel column chromatography, carrying out elution with dichloromethane-ethyl acetate-methanol, detecting and combining the fractions, to obtain 5 fractions in Step 3);

[0131] 4) separating the second fraction obtained in Step 3) by C18 column chromatography, and carrying out gradient elution with acetonitrile-methanol-water, to obtain 82% (acetonitrile-methanol 1:1) aqueous solution eluting fraction;

[0132] 5) further separating the 82% (acetonitrile-methanol 1:1) aqueous solution eluting fraction obtained in Step 4) by sephadex LH-20 column chromatography using dichloromethane-methanol as a mobile phase, analyzing and combining the fractions, to obtain 6 fractions in Step 5); and

[0133] 6) purifying the third fraction obtained in Step 5) by chromatographic method using acetonitrile-methanol-water as a mobile phase and using C18 chromatographic column as a stationary phase, to obtain Compound 5.

[0134] In an embodiment, a method for extracting Compound 5 from Monascus-fermented rice or extract thereof, the method comprising the following steps:

[0135] 1) extracting Monascus-fermented rice or extract thereof with 2-6-fold volume of ethyl acetate (or dichloromethane or methanol or ethanol, or methanol/ethanol aqueous solution) as a solvent for three times, 20-40 min for each time, combining the extracting solution, and concentrating it under reduced pressure to recover the solvent, and to obtain the ethyl acetate extract;

[0136] 2) separating the ethyl acetate (or dichloromethane or methanol or ethanol, or methanol/ethanol aqueous solution) extract obtained in Step 1) by silica gel column chromatography, and carrying out gradient elution with petroleum ether, ethyl acetate and methanol or ethanol, to obtain the ethyl acetate eluting fraction;

[0137] 3) separating the ethyl acetate eluting fraction obtained in Step 2) by silica gel column chromatography, carrying out elution with dichloromethane-ethyl acetate-methanol (30:30:1), analyzing and combining the fractions, to obtain 5 fractions in Step 3);

[0138] 4) separating the second fraction obtained in Step 3) by C18 column chromatography, and carrying out gradient elution with 82% (acetonitrile-methanol 1:1) aqueous solution100% (acetonitrile-methanol 1:1), to obtain 82% (acetonitrile-methanol 1:1) aqueous solution eluting fraction;

[0139] 5) further separating the 82% (acetonitrile-methanol 1:1) aqueous solution eluting fraction obtained in Step 4) by sephadex LH-20 column chromatography using dichloromethane-methanol (2:1) as a mobile phase, analyzing and combining the fractions, to obtain 6 fractions in Step 5); and

[0140] 6) purifying the third fraction obtained in Step 5) by chromatography using acetonitrile-methanol-water as a mobile phase and using C18 chromatographic column as a stationary phase, to obtain Compound 5

##STR00009##

[0141] The invention further provides a pharmaceutical composition comprising the compound of Formula (I) according to the invention. The invention provides such a pharmaceutical composition, comprising at least one the compound of Formula (I) as described above, and optionally, a pharmaceutically acceptable excipient.

[0142] Methods for preparing a pharmaceutical composition comprising a certain amount of an active ingredient, are known or are obvious for a person skilled in the art according to the contents as disclosed in the invention. For example, as described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, E. W., ed., Mack Publishing Company, 19th ed. (1995), methods for preparing a pharmaceutical composition comprising incorporating a suitable pharmaceutically acceptable excipient, carrier, diluent, etc.

[0143] The known methods for preparing a pharmaceutical preparation according to the invention include the conventional mixing, dissolving or freeze-drying methods. The compound according to the invention can be used to prepare a pharmaceutical composition, which is administered to a patient by various routes suitable for the selected administration mode, for example, oral, or parenteral route (intravenous, intramuscular, topical, or subcutaneous route).

[0144] Therefore, the compound of the invention in combination with a pharmaceutically acceptable carrier (such as an inert diluent or an assimilable edible carrier) can be administered systemically, e.g., orally. They can be encapsulated into a hard or soft shell gelatin capsule, and pressed into a table. For the treatment by oral administration, an active compound may be combined with one or more excipients, and be used in a form of a deglutible tablet, a buccal tablet, a troche, a capsule, an elixir, a suspension, a syrup, a wafer, etc. The composition and preparation shall comprise at least 0.1% of an active compound. The ratio of the composition to the preparation can be varied certainly, and the active compound may account for about 1 wt % to about 99 wt % of a given unit dosage form. In such a therapeutically active composition, the active compound is in an amount sufficient to obtain an effective dosage level.

[0145] A tablet, a troche, a pill, a capsule, and the like may include: a binder, such as tragacanth gum, arabic gum, maize starch or gelatin; an excipient, such as dicalcium phosphate; a disintegrant, such as maize starch, potato starch, and alginic acid etc; a lubricant, such as magnesium stearate; and a sweeting agent, such as sucrose, fructose, lactose or aspartame; or a flavoring agent, such as peppermint, winter green oil or cherry flavor. When the unit dosage form is a capsule, in addition to the above types of materials, it may comprise a liquid carrier, such as vegetable oil or polyethylene glycol. Various other materials may be present as a coating or change the physical form of a solid unit dosage form in other manners. For example, a tablet, a pill or a capsule may be coated with gelatin, wax, shellac or sugar etc. A syrup or elixir may comprise an active compound, sucrose or fructose as a sweeting agent, methyl p-hydroxybenzoate or propyl p-hydroxybenzoate as preservative, a dye and a flavoring agent (such as a cherry flavor or an orange flavor). Certainly, any material for preparing any unit dosage form should be pharmaceutically acceptable and be substantively not toxic in its applied amount. In addition, an active compound may be incorporated into a sustained release preparation and a sustained release device.

[0146] An active compound may also be administered intravenously or intraperitoneally by infusion or injection. An aqueous solution of an active compound or a salt thereof may be prepared, optionally, by mixing it with a non-toxic surfactant. A dispersing agent in glycerol, liquid polyethylene glycol, glycerin triacetate and a mixture thereof and in oil may also be prepared. Under the common conditions of storage and use, the preparations may comprise a preservative in order to suppress the growth of microbes.

[0147] A pharmaceutical dosage form suitable for injection or infusion may include a sterile aqueous solvent or a dispersing agent or a sterile powder comprising an active ingredient (optionally encapsulated into a liposome) of an immediate preparation such as a solution or a dispersing agent suitable for sterile injection or infusion. Under all the conditions, the final dosage form shall be sterile, liquid or stable under the production and storage conditions. A liquid carrier may be a solution or a liquid disperse medium, including, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid macrogol, etc), vegetable oil, a non-toxic glyceride and a suitable mixture thereof. A suitable fluidity may be retained, for example, by the formation of liposome, by retaining the desired particle size in the presence of a dispersing agent, or by using a surfactant. The effect of suppressing microbes can be obtained by various antibacterial agents and antifungal agents (such as paraben, chlorbutol, phenol, sorbic acid, and thiomersal, etc). In many conditions, an isotonizing agent, such as sugar, buffer or NaCl, is preferably comprised. By the use of a composition of delayed absorbents (e.g., aluminium monostearate and gelatin), an extended absorption of an injectable composition can be obtained.

[0148] A sterile injectable solution can be prepared by mixing a desired amount of an active compound in a suitable solvent with the desired various other ingredients as listed above, and then performing filtration and sterilization. In the case of a sterile powder for the preparation of a sterile injectable solution, the preferred preparation method is vacuum drying and freeze drying techniques, which will result in the production of the active ingredient and the powder of any other desired ingredient present in the previous sterile filtration solution.

[0149] A useful solid carrier includes crushed solid (such as talc, clay, microcrystalline cellulose, silicon dioxide, and aluminum oxide etc). A useful liquid carrier includes water, ethanol or ethylene glycol or water-ethanol/ethylene glycol mixture, in which the compound of the invention may be dissolved or dispersed in an effective amount, optionally, with the aid of a non-toxic surfactant. An adjuvant (such as a flavor) and an additional antimicrobial agent may be added to optimize the property for a given use.

[0150] A thickener (such as synthetic polymer, fatty acid, fatty acid salt and ester, fatty alcohol, modified cellulose or modified inorganic material) may also be used with a liquid carrier to form a coatable paste, gel, ointment, soap and the like, and be directly applied to the skin of a user.

[0151] A therapeutically effective amount of a compound or an active salt or derivative thereof not only depends on the specific salt selected, but also depends on the administration mode, the nature of the disease to be treated and the age and state of a patient, and finally depends on the decision made by an attending physician or a clinical physician.

[0152] Above preparation may be present in a unit dosage form, which is a physical dispersion unit comprising a unit dose, suitable for administration to a human body and other mammalian body. A unit dosage form may be capsule(s) or tablet(s). Depending on the particular treatment involved, the amount of an active ingredient in a unit dose may be varied or adjusted between about 0.1 and about 1000 mg or more.

[0153] The invention further provides use of the compound according to the invention or a pharmaceutical composition comprising the compound in the manufacture of a medicament, in particular a medicament for inhibiting HMG-CoA reductase. Correspondingly, the invention provides a method for preventing and/or treating dyslipidemia, hyperlipemia, or atherosclerosis in a patient, comprising administering a therapeutically effective amount of at least one compound of the invention to the patient in need of treatment. Dyslipidemia refers to a condition in which one or more blood lipid-associated indexes of human body do not fall into the corresponding normal ranges, including elevated total cholesterol, elevated low density lipoprotein cholesterol, elevated apolipoprotein B, elevated triglyceride, and the like. The invention provides a method for preventing and/or treating hypercholesterolemia, combined hyperlipidemia in a patient, comprising administering a therapeutically effective amount of at least one compound of the invention to the patient in need of treatment.

[0154] The invention provides a method for treating an increase in total cholesterol, an increase in low density lipoprotein cholesterol, an increase in apolipoprotein B, an increase in triglyceride and the like when the effect of a lifestyle intervention therapy (such as diet adjustment, body weight control, more exercise, and quitting smoking) is not satisfactory.

[0155] In above uses, the compound of the invention can be used alone, or in combination with an effective amount of additional lipid-regulatory drug(s). The additional lipid-regulatory drug includes cholesterol synthesis inhibitors (statins or salts thereof, such as lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, and pitavastatin, etc), cholesterol absorption inhibitors (Ezetimibe and the like), fibrates (Lopid, lipanthyl ciprofibrate, bezafibrate, fenofibrate and gemfibrozil), nicotinic acids (nicotinic acid, inositol nicotinate, Dongzhiping, and niceritrol, etc), bile acid sequestrants, and phenoxy aromatic acids.

[0156] The compound according to the invention or a pharmaceutically acceptable salt thereof (such as acetate, malonate, tartrate, succinate, hydrochlorate, sulfate, and nitrate), may be used to prevent or treat above diseases.

[0157] In the following examples, the invention is explained more specifically. However, it should be understood that the following examples are provided for the purpose of illustrating the invention, rather than limiting the scope of the invention.

[0158] The chemical raw materials used in the following examples are either commercially available or prepared by the synthetic methods well known in the art.

Example 1

[0159] The inventor further studied the ingredients of Monascus-fermented rice, and separated and purified a new statins compound (Compound 5).

##STR00010##

[0160] 1. Monascus-Fermented Rice

[0161] 1) 6 kg Monascus-fermented rice dry powder (produced by WBL PEKING UNIVERSITY BIOTECH CO., LTD), was ultrasonically extracted with 2-6-fold volume of ethyl acetate (or dichloromethane or methanol or ethanol, or methanol/ethanol aqueous solution) as a solvent for three times, 20-40 min for each time, and the extracting solution was combined, and concentrated under reduced pressure to recover solvent, and obtain the ethyl acetate extract (240 g).

[0162] 2) The ethyl acetate extract was separated by silica gel column chromatography, and gradient elution was carried out by using petroleum ether, ethyl acetate and methanol, to obtain the ethyl acetate eluting fraction (72 g).

[0163] 3) The ethyl acetate eluting fraction was separated by silica gel column chromatography; dichloromethane-ethyl acetate-methanol (30:30:1) was used for elution; and 110 fractions were obtained, 10 ml for each fraction. After the tracking detection with TLC (or HPLC), the fractions having the same or similar chromatographic behavior were combined, and 5 fractions were obtained (i.e., the first 1-35; 36-50; 51-65; 66-89; 90-110 fractions were combined, respectively).

[0164] 4) The second fraction (the combined first 36-50 fractions, 16 g) in Step 3) was separated by C18 column chromatography, and gradient elution was carried out by using 82% (acetonitrile-methanol 1:1) aqueous solution to 100% (acetonitrile-methanol 1:1), to obtain the 82% (acetonitrile-methanol 1:1) aqueous solution eluting fraction (3.2 g, collecting 900 ml in total).

[0165] 5) The 82% (acetonitrile-methanol 1:1) aqueous solution eluting fraction was further separated by sephadex LH-20 column chromatography using dichloromethane-methanol 2:1 as a mobile phase, and 120 fractions in total were collected, 5 ml for each fraction. After the tracking detection with TLC (or HPLC), the fractions having the same or similar chromatographic behavior were combined, and 6 fractions were obtained (i.e., the first 1-40; 41-65; 66-80; 81-95; 96-110; 111-120 fractions were combined, respectively).

[0166] 6) The third fraction (the combined first 66-80 fractions, 256 mg) in Step 5) was finally purified by semi-preparative high performance liquid chromatography, using 66% (acetonitrile-methanol 1:1) aqueous solution as a mobile phase, at a flow rate of 4 ml/min, and using C18 semi-preparative chromatographic column (10250 mm, 5 m) as a stationary phase, wherein the wavelength of DAD detector was 247 nm, and the fraction of the chromatographic peak at 22.8 min (21.5-23.5 min) was collected. After enrichment and concentration for several times, about 13 mg new compound (Compound 5) was obtained.

[0167] 2. Xuezhikang

[0168] 1) 3 kg of dry content powder of Xuezhikang capsule (WBL PEKING UNIVERSITY BIOTECH CO., LTD), was ultrasonically extracted with 2-6-fold volume of ethyl acetate (or dichloromethane or methanol) as a solvent for three times, 20-40 min for each time, and the extracting solution was combined, and concentrated under reduced pressure to recover the solvent, and to obtain the ethyl acetate extract (200 g).

[0169] 2) The ethyl acetate extract was separated by silica gel column chromatography, and gradient elution was carried out by using petroleum ether, ethyl acetate and methanol, to obtain ethyl acetate eluting fraction (60 g).

[0170] 3) The ethyl acetate eluting fraction was separated by silica gel column chromatography; dichloromethane-ethyl acetate-methanol (30:30:1) was used for elution; and 110 fractions were collected, 10 ml for each fraction. After the tracking detection with TLC (or HPLC), the fractions having the same or similar chromatographic behavior were combined, to obtain the 5 fractions (the first 1-35; 36-50; 51-65; 66-89; 90-110 fractions were combined, respectively) in Step 3).

[0171] 4) The second fraction (the combined first 36-50 fractions, 14 g) in Step 3) was separated by C18 column chromatography, and gradient elution was carried out by using 82% (acetonitrile-methanol 1:1) aqueous solution100% (acetonitrile-methanol 1:1), to obtain the 82% (acetonitrile-methanol 1:1) aqueous solution eluting fraction (2.8 g).

[0172] 5) The 82% (acetonitrile-methanol 1:1) aqueous solution eluting fraction was further separated by sephadex LH-20 column chromatography using dichloromethane-methanol 2:1 as a mobile phase, and 120 fractions in total were collected, 5 ml for each fraction. After the tracking detection with TLC (or HPLC), the fractions having the same or similar chromatographic behavior were combined, and 6 fractions (i.e., the first 1-40; 41-65; 66-80; 81-95; 96-110; 111-120 fractions were combined, respectively) in Step 5) were obtained.

[0173] 6) The third fraction (the combined first 66-80 fractions, 208 mg) in Step 5), was finally purified by semi-preparative high performance liquid chromatography, using 66% (acetonitrile-methanol 1:1) aqueous solution as a mobile phase, at a flow rate of 4 ml/min, and using C18 semi-preparative chromatographic column (10250 mm, 5 m) as a stationary phase, wherein the wavelength of DAD detector was 247 nm, and the fraction of the chromatographic peak at 22.8 min (21.5-23.5 min) was collected. After enrichment and concentration for several times, about 11.5 mg new compound (Compound 5) was obtained.

[0174] In the invention, other raw materials or preparations of Monascus-fermented rice may also be used as raw materials, such as Xuezhikang tablet (WBL PEKING UNIVERSITY BIOTECH CO., LTD).

Example 2: Synthesis and Identification of Compound 5

Method A:

[0175] ##STR00011## ##STR00012##

[0176] 1. Synthesis of Compound 2

[0177] 20.9 g (0.05 mol) of Compound 1 (Simvastatin, purchased from sigma) was dissolved in 500 ml dichloromethane, and 12 g (0.07 mol) of meta chloro perbenzoic acid was added. After stirring at room temperature for 40 min, the reaction was completed. Saturated sodium bicarbonate solution was added. After standing and delamination, the organic phase was washed sequentially with saturated sodium bicarbonate and saturated NaCl aqueous solution, dried and concentrated, and used in the next reaction without further separation.

[0178] 2. Synthesis of Compound 3

[0179] To 250 ml of tetrahydrofuran, 0.085 mol of diethyl amine and 0.075 mol of tert-butyl alcohol were added. Under stirring in an ice bath, 0.15 mmol n-butyl lithium was added. After stirring for 20 min, the synthesized mixture in the above step was added in the reaction, and reacted under stirring in an ice bath. TLC was used to monitor the reaction. After the reaction was completed, the reaction was washed sequentially with water and saturated NaCl aqueous solution, and the organic phase was dried with anhydrous sodium sulfate, and concentrated. The resultant mixture was separated by column chromatography, to obtain 4.36 g of Compound 3, with a yield of 21%.

[0180] 3. Synthesis of Compound 4

[0181] 13 g of Compound 3 (0.03 mol) was dissolved in 60 ml chloroform, and the pH of the solution was adjusted to be acidic with hydrochloric acid. After stirring at room temperature overnight, the resultant mixture was washed sequentially with 10% sodium thiosulfate, water, and saturated NaCl aqueous solution. The organic solvent was removed under reduced pressure to obtain the crude product. After separation by column chromatography, 5.96 g of Compound 4 was obtained, with a yield of 62%.

[0182] 4. Synthesis of Compound 5

[0183] Under the protection of N.sub.2 gas, 7 g of Compound 4 was dissolved in 150 ml of methanol, and 0.3 mol of tetrabutylammonium hydrogen sulfate was added. The reaction was carried out under stirring and heating. TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was dissolved in 150 ml of mixed solution (water:heptane=1:1). After stirring for 2 h, the organic phase was separated, dried with anhydrous sodium sulfate, filtrated, and concentrated to obtain 6.82 g of Compound 5 of interest, with a yield of 88%.

[0184] Alternatively Method B:

##STR00013## ##STR00014##

[0185] 1. Synthesis of Compound 2b

[0186] 20.2 g (0.05 mol) of Compound 1 (lovastatin, purchased from sigma) was dissolved in 500 ml of dichloromethane, and 12 g (0.07 mol) of meta chloro perbenzoic acid was added. The resultant mixture was stirred at room temperature for 40 min. After the reaction was completed, saturated sodium bicarbonate solution was added. After standing and delamination, the organic phase was washed sequentially with saturated sodium bicarbonate and saturated NaCl aqueous solution, dried and concentrated, and used in the next reaction without separation.

[0187] 2. Synthesis of Compound 3b

[0188] To 250 ml of tetrahydrofuran, 0.085 mol of diethyl amine and 0.075 mol of tert-butyl alcohol were added. Under stirring in an ice bath, 0.15 mmol of n-butyl lithium was added. After stirring for 20 min, the mixture synthesized in the above step was added in the reaction, and reacted under stirring in an ice bath. TLC was used to monitor the reaction. After the reaction was completed, the reaction was washed sequentially with water and saturated NaCl aqueous solution, and the organic phase was dried with anhydrous sodium sulfate, and concentrated. The resultant mixture was separated by column chromatography, to obtain 4.22 g of Compound 3b, with a yield of 21%.

[0189] 3. Synthesis of Compound 4

[0190] 12.6 g of Compound 3b (0.03 mol) was dissolved in 60 ml chloroform, and the pH of the solution was adjusted to be acidic with hydrochloric acid. After stirring at room temperature overnight, the resultant mixture was washed sequentially with 10% sodium thiosulfate, water, and saturated NaCl aqueous solution. The organic solvent was removed under reduced pressure to obtain the crude product. After separation by column chromatography, 5.96 g of Compound 4 was obtained, with a yield of 62%.

[0191] 4. Synthesis of Compound 5

[0192] Under the protection of N.sub.2 gas, 7 g of Compound 4 was dissolved in 150 ml of methanol, and 0.3 mol of tetrabutylammonium hydrogen sulfate was added. The reaction was carried out under stirring and heating. TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was dissolved in 150 ml of mixed solution (water:heptane=1:1). After stirring for 2 h, the organic phase was separated, dried with anhydrous sodium sulfate, filtrated, and concentrated to obtain 6.82 g of Compound 5 of interest, with a yield of 88%.

[0193] Method for identifying the structure of Compound 5 was as follows:

[0194] 1. Physical-Chemical Data of the Compound

[0195] Light Yellow Oil.

[0196] The three maximum absorption peaks in UV spectrum: .sub.max(CH.sub.2Cl.sub.2)=226.8 nm, 265.4 nm, and 301.2 nm, respectively.

[0197] FT-IR (KBr, cm.sup.1) spectrum: 3422 (OH), 3013, 2952 (hydrogen on saturated carbon), 1732 (carbonyl).

[0198] HR-ESI-MS: m/z 355.1886 [M+Na].sup.+ (the calculated value was 355.1885, C.sub.20H.sub.28O.sub.4Na).

[0199] 2. Identification of its Formula

[0200] It could be found by analysis of the carbon spectrum of the compound (.sup.13C-NMR and DEPT) that the compound included 20 carbon atoms, which were 3 methyl groups (1 of which was methoxy, and 1 of which was linked to sp.sup.2 carbon), 4 methylene groups, 9 methyne groups (5 of which were sp.sup.2 carbons), and 4 quaternary carbon atoms (1 of which was the carbon atom of carbonyl), and it could also be found that there were 8 carbon atoms ( 126.9, 126.9, 127.2, 127.5, 133.4, 134.6, 135.9, 136.1) in the olefinic carbon region. It could be deduced from .sup.1H-.sup.1H COSY correlated spectrum (FIG. 1A) that the bold line represents the C2-C4 fragment and the C7-C8 fragment. It could be deduced from the 8 carbon atoms in the olefinic carbon region that the compound had 4 CC bonds. It could be found by further analysis of HMBC correlated signal that there were correlated signals between 6-Me and C5, C7; between H-5 and C6, C7; between H-4 and C5, C8a; between H-3 and C4a; between H-1 and C8a, C4a; between H-8 and C8a, C4a, and the like, and therefore, it could be deduced that the compound has a statin nuclear structure of 1, 2-dihydronaphthalene ring moiety. It could also be found from HMBC spectrum (FIG. 1AB) that there were correlated signals between the methyl of methoxy ( 3.69), H-2 ( 2.46/2.48) & H-3 ( 2.45) and C1 ( 173.0), indicating that methoxy was linked to C1. Therefore, it could be deduced that the compound was a methyl-esterified statin derivative. Further based on the HR-ESI-MS result, it was deduced that the compound was: methyl 7-(2,6-dimethyl-1,2-dihydronaphthalen-1-yl)-3,5-dihydroxyheptanoate. The formula was shown in FIG. 1.

[0201] 3. NMR Data on Compound 5

TABLE-US-00001 TABLE 1 NMR data on Compound 5 (600 MHz, CDCl.sub.3, is expressed as ppm, J is expressed as Hz) .sup.1H-.sup.1H HMBC Position .sup.13C-NMR .sup.1H-NMR COSY (H.fwdarw.C) 1 42.2 2.57 (1H, m) 7a, 7b, 2 7, 2, 4a, 8a 2 32.7 2.68 (1H, m) 2-Me, 3 1 3 134.6 5.76 (1H, dd, 9.6, 3.0) 4, 2 4a 4 126.9 6.35 (1H, dd, 9.6, 2.4) 3 8a, 5 4a 133.4 5 126.9 6.85 (1H, s) 6, 7 6 136.1 7 127.2 6.93 (1H, d, 7.8) 8 5, 8 8 127.5 6.99 (1H, d, 7.8) 7 7, 4a, 8a 8a 135.9 1 173.0 2 41.7 2.46 (1H, m) a 3 4, 3, 1 2.48 (1H, m) b 3 69.2 2.45 (1H, m) 2a, 2b, 4 1, 4 4 42.4 1.51 (1H, m) a 5, 3 6, 2, 3, 5 1.52 (1H, m) b 5 72.9 3.76 (1H, m) 4a, 4b 3 6 36.0 1.31 (1H, m) a 7a, 7b, 5 1, 5 1.45 (1H, m) b 7 22.9 1.57 (1H, m) a 1, 6a, 6b 8a, 2, 6, 1, 5 1.66 (1H, m) b 2-Me 15.0 1.03 (3H, d, 7.2) 2 1, 2, 3 6-Me 21.1 2.29 (3H, s) 6, 5, 7 1-OMe 51.9 3.69 (3H, s) 1

Example 3: Synthesis of Compound 5a

[0202] ##STR00015##

[0203] 1. Synthesis of Compound 5a

[0204] Under the protection of N.sub.2 gas, 7.4 g of Compound 4a was dissolved in 150 ml of methanol, and 0.3 mol of tetrabutylammonium hydrogen sulfate was added. The reaction was carried out under stirring and heating. TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was dissolved in 150 ml of mixed solution (water:heptane=1:1). After stirring for 2 h, the organic phase was separated, dried with anhydrous sodium sulfate, filtrated, and concentrated to obtain 6.91 g of Compound 5a of interest, with a yield of 85%.

Example 4

[0205] Assay on HMG-CoA Reductase-Inhibiting Activity

[0206] 1. Experimental Materials

[0207] 1.1 Drugs

[0208] Compound 5prepared by the inventor

[0209] Lovastatin standard substancepurchased from Sigma Company

[0210] 1.2 Enzyme

[0211] Rat liver microsomes (HMG-CoA reductase) were commercially purchased, or were prepared by reference to the following method: the male rat liver was removed and rinsed with KESD buffer, and then centrifuged at 12,000 g for 15 min. The supernatant was taken. After centrifugation at 105,000 g for 90 min twice, the centrifuged pellets resulted from centrifugation were collected. To the centrifuged pellets, 8.3% glycerol was added, and the resultant mixture was heated in a 37 C. warm bath for 1 h. The crude product of the rat liver microsomes was purified with saturated ammonium sulfate, and the 35-50% purified fraction was collected. The rat liver microsomes obtained were stored in 80 C. refrigerator.

[0212] 1.3 Reagents

[0213] Potassium chloride, potassium dihydrogen phosphate, ethylenediamine tetra acetic acid, dithiothreitolpurchased from Beijing Chemical Reagent Company

[0214] nicotinamide-adenine dinucleotide phosphate (NADPH)purchased from Merck Company

[0215] 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)purchased from Sigma Company

[0216] 2. Experimental Method

[0217] Compound 5 was dissolved in 75% ethanol solution, at an initial concentration of 8.6 mg/ml, and was subjected to stepwise dilution to obtain 4.3 mg/ml, 2.15 mg/ml. The total volume of the test system was 250 l, and the concentrations of various ingredients were as follows: 200 mM potassium chloride, 160 mM potassium dihydrogen phosphate, 4 mM ethylenediamine tetra acetic acid, 10 mM dithiothreitol, and the concentrations for the two substrates nicotinamide adenine dinucleotide and 3-hydroxy-3-methylglutaryl-coenzyme A were 200 M and 50 M, pH6.8, respectively, wherein 30 l was added for enzyme, 5 l was added for the test group, and 5 l (solvent for dissolving the sample) was added for the control group. The dynamic change in OD.sub.340 was determined at 37 ELISA Microplate Reader. The decreasing rate of OD.sub.340 (represented by slope) was measured within 5 min, to evaluate the HMG-CoA reductase activity, and to further evaluate the enzyme-inhibiting activity. The results were shown in Table 2.

[0218] 3. Experiment Results

[0219] The experimental results show that Compound 5 inhibited the HMG-CoA reductase activity, and exhibited a dose-response relationship, indicating that the compound had a good inhibitory effect on the HMG-CoA reductase activity.

TABLE-US-00002 TABLE 2 The detection results on activity of enzyme inhibitors Concen- Final Inhibi- tration of Volume of concen- tion Sample the inhibitor the inhibitor tration rate name (mg/ml) (l) (g/ml) Slope (%) blank 13.5 control lovastatin 4.0 5 80 8.2 39.2 Compound 5 8.6 5 172 7.8 42.2 4.3 5 86 9.0 33.3 2.15 5 43 10.9 19.2 * blank control is a solvent Lovastatin is a positive control.