# US 2018/0022688 A1 · Compound, and separation method, synthesis method and use thereof

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- Number: US 2018/0022688 A1
- Document ID: US20180022688A1
- Status: Published application
- Kind: A1
- Application number: 15/548,760
- Filed: 2016-01-27
- Published: 2018-01-25
- Earliest claimed: 2015-02-04
- Assignees: Beijing Peking University WBL Biotech Co., Ltd.
- Applicants: Beijing Peking University Wbl Biotech Co., Ltd.
- Inventors: Zhenwen Duan; Shuren Guo; Xuemei Li
- Web page: https://patentgrep.com/patent/US20180022688A1

## CPC

- C07C 69/73: of unsaturated acids
- A61P 3/06: Antihyperlipidemics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 67/03: by reacting an ester group with a hydroxy group
- C07C 67/12: from asymmetrical anhydrides
- C07C 67/56: by solid-liquid treatment; by chemisorption
- C07C 69/732: of unsaturated hydroxy carboxylic acids
- A61K 31/216: of acids having aromatic rings, e.g. benactizyne, clofibrate
- C07C 67/48: Separation; Purification; Stabilisation; Use of additives
- C07C 2602/10: the other ring being six-membered, e.g. tetraline
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## 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

### Claim 1

A compound of Formula (I), or a stereoisomer, tautomer,
racemate, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof:
R1 is selected from H, C1-C6 alkyl, halo C1-C6 alkyl, (CH2)1-6OH, C3-C7 cycloalkyl, halo C3-C7 cycloalkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C1-C6 alkylthio, halo C1-C6 alkylthio, halogen, nitro, amino and cyano;
R2 is selected from H, C1-C6 alkyl, halo C1-C6 alkyl, (CH2)1-6OR6, C3-C7 cycloalkyl, halo C3-C7 cycloalkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C1-C6 alkylthio, halo C1-C6 alkylthio, halogen, nitro, amino and cyano;
R3 is selected from H, C1-C6 alkyl;
R4 and R5 each are independently selected from: H, —COR7, —SO2R8, and —SiR9R10R11;
wherein, R7 is selected from C1-C6 alkyl and halo C1-C6 alkyl; R8 is selected from C1-C6 alkyl, optionally substituted C1-C6 alkyl, C6-C10 aryl, and optionally substituted C6-C10 aryl; R9, R10 and R11 are independently selected from C1-C6 alkyl;
wherein, R6 has the same definition as R4 and R5;
wherein, the compound of Formula (I) wherein R1 is (CH2)OH, R2 is methyl, and R3, R4 and R5 are H, is excluded.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein,
R1 is selected from H, C1-C3 alkyl, halo C1-C3 alkyl, (CH2)1-3OH, C3-C6 cycloalkyl, halo C3-C6 cycloalkyl, C1-C3 alkoxy, halo C1-C3 alkoxy, C1-C3 alkylthio, halo C1-C3 alkylthio, halogen, nitro, amino and cyano.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein,
R1 is selected from H, C1-C3 alkyl, halo C1-C3 alkyl, (CH2)1-3OH, halogen, nitro, amino and cyano.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein
R1 is selected from H, C1-C3 alkyl, and (CH2)1-3OH.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein
R2 is selected from H, C1-C3 alkyl, halo C1-C3 alkyl, (CH2)1-3OR6, C3-C6 cycloalkyl, halo C3-C6 cycloalkyl, C1-C3 alkoxy, halo C1-C3 alkoxy, C1-C3 alkylthio, halo C1-C3 alkylthio, halogen, nitro, amino and cyano;
wherein, R6 is selected from H, —COR7, —SO2R8, and —SiR9R10R11;
wherein, R7 is selected from C1-C6 alkyl, and halo C1-C6 alkyl; R8 is selected from C1-C6 alkyl, optionally substituted C1-C6 alkyl, C6-C10 aryl, and optionally substituted C6-C10 aryl; R9, R10 and R11 are independently selected from C1-C6 alkyl.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein
R2 is selected from H, C1-C3 alkyl, halo C1-C3 alkyl, (CH2)1-3OR6, C3-C6 cycloalkyl, halo C3-C6 cycloalkyl, C1-C3 alkoxy, halo C1-C3 alkoxy, C1-C3 alkylthio, halo C1-C3 alkylthio, halogen, nitro, amino and cyano;
wherein, R6 is selected from: H, —COR7, —SO2R8, and —SiR9R10R11;
wherein, R7 is selected from C1-C3 alkyl, and halo C1-C3 alkyl; R8 is selected from C1-C3 alkyl, optionally substituted C1-C3 alkyl, C6-C10 aryl, and optionally substituted C6-C10 aryl; R9, R10 and R11 are independently selected from C1-C6 alkyl.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein
R2 is selected from H, C1-C3 alkyl, halo C1-C3 alkyl, (CH2)1-3OR6, C3-C6 cycloalkyl, halo C3-C6 cycloalkyl, C1-C3 alkoxy, halo C1-C3 alkoxy, C1-C3 alkylthio, halo C1-C3 alkylthio, halogen, nitro, amino and cyano;
wherein, R6 is selected from: H, —COR7, —SO2R8, and —SiR9R10R11;
wherein, R7 is selected from —CH3; R8 is selected from —CF3 and p-methylphenyl; R9, R10 and R11 are independently selected from methyl and tert-butyl.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein
R2 is selected from H, C1-C3 alkyl, halo C1-C3 alkyl, (CH2)1-3OR6, halogen, nitro, amino and cyano;
wherein, R6 is selected from H, —COR7, —SO2R8, and —SiR9R10R11;
wherein, R7 is selected from C1-C6 alkyl, and halo C1-C6 alkyl; R8 is selected from C1-C6 alkyl, optionally substituted C1-C6 alkyl, C6-C10 aryl, and optionally substituted C6-C10 aryl; R9, R10 and R11 are independently selected from C1-C6 alkyl.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein
R2 is selected from H, C1-C3 alkyl, halo C1-C3 alkyl, (CH2)1-3 OR6, halogen, nitro, amino and cyano;
wherein, R6 is selected from: H, —COR7, —SO2R8, and —SiR9R10R11;
wherein, R7 is selected from C1-C3 alkyl and halo C1-C3 alkyl; R8 is selected from C1-C3 alkyl, optionally substituted C1-C3 alkyl, C6-C10 aryl, and optionally substituted C6-C10 aryl; R9, R10 and R11 are independently selected from C1-C6 alkyl.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein
R2 is selected from H, C1-C3 alkyl, halo C1-C3 alkyl, (CH2)1-3OR6, halogen, nitro, amino and cyano;
wherein, R6 is selected from: H, —COR7, —SO2R8 and —SiR9R10R11;
wherein, R7 is selected from —CH3; R8 is selected from —CF3 and p-methyl phenyl; R9, R10 and R11 are independently selected from methyl and tert-butyl.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein
R2 is selected from H, C1-C3 alkyl and (CH2)1-3OR6;
wherein, R6 is selected from H, —COR7, —SO2R8 and —SiR9R10R11;
wherein, R7 is selected from C1-C6 alkyl and halo C1-C6 alkyl; R8 is selected from C1-C6 alkyl, optionally substituted C1-C6 alkyl, C6-C10 aryl, and optionally substituted C6-C10 aryl; R9, R10 and R11 are independently selected from C1-C6 alkyl.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein
R2 is selected from H, C1-C3 alkyl, and (CH2)1-3OR6;
wherein, R6 is selected from H, —COR7, —SO2R8, and —SiR9R10R11;
wherein, R7 is selected from C1-C3 alkyl and halo C1-C3 alkyl; R8 is selected from C1-C3 alkyl, optionally substituted C1-C3 alkyl, C6-C10 aryl, and optionally substituted C6-C10 aryl; R9, R10 and R11 are independently selected from C1-C6 alkyl.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein
R2 is selected from H, C1-C3 alkyl, and (CH2)1-3OR6;
wherein, R6 is selected from H, —COR7, —SO2R8, and —SiR9R10R11;
wherein, R7 is selected from —CH3; R8 is selected from —CF3 and p-methyl phenyl; R9, R10 and R11 are independently selected from methyl and tert-butyl.

### Claim 14 (depends on 1)

The compound according to claim 1, wherein
R3 is selected from H and C1-C3 alkyl.

### Claim 15 (depends on 1)

The compound according to claim 1, wherein
R3 is C1-C3 alkyl.

### Claim 16 (depends on 1)

The compound according to claim 1, wherein
R4 and R5 each are independently selected from: H, —COR7, —SO2R8, and —SiR9R10R11;
wherein, R7 is selected from C1-C3 alkyl, and halo C1-C3 alkyl; R8 is selected from C1-C3 alkyl, optionally substituted C1-C3 alkyl, C6-C10 aryl, and optionally substituted C6-C10 aryl; R9, R10 and R11 are independently selected from C1-C6 alkyl.

### Claim 17 (depends on 1)

The compound according to claim 1, wherein
R4 and R5 each are independently selected from: H, —COR7, —SO2R8, and —SiR9R10R11;
wherein, R7 is selected from —CH3; R8 is selected from —CF3, and p-methyl phenyl; R9, R10 and R11 are independently selected from methyl, and tert-butyl.

### Claim 18

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

### Claim 19 (depends on 1)

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

### Claim 20 (depends on 1)

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

### Claim 21 (depends on 1)

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.

### Claim 22

A method for extracting Compound 5 from Monascus-fermented rice or extract thereof, comprising the following steps of:
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.

### Claim 23 (depends on 22)

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 solution˜100% (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

### Claim 24 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)

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),
wherein, in Formula (II), R1, R2 and R4 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).

### Claim 25

A method for synthesizing compound 5:

### Claim 26

A method for synthesizing Compound 5:

### Claim 27 (depends on 1)

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.