WO2016124087A1 - 化合物、其分离方法、合成方法及用途 - Google Patents

化合物、其分离方法、合成方法及用途 Download PDF

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WO2016124087A1
WO2016124087A1 PCT/CN2016/072306 CN2016072306W WO2016124087A1 WO 2016124087 A1 WO2016124087 A1 WO 2016124087A1 CN 2016072306 W CN2016072306 W CN 2016072306W WO 2016124087 A1 WO2016124087 A1 WO 2016124087A1
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alkyl
group
methanol
compound
halo
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PCT/CN2016/072306
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English (en)
French (fr)
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段震文
郭树仁
李雪梅
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北京北大维信生物科技有限公司
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Priority to MYPI2017702865A priority Critical patent/MY188671A/en
Priority to KR1020177024626A priority patent/KR102160471B1/ko
Priority to SG11201706353WA priority patent/SG11201706353WA/en
Priority to AU2016214849A priority patent/AU2016214849B2/en
Priority to US15/548,760 priority patent/US10099998B2/en
Priority to JP2017541085A priority patent/JP6686032B2/ja
Priority to EP16746082.3A priority patent/EP3255031B1/en
Priority to CN201680007999.XA priority patent/CN107207404B/zh
Publication of WO2016124087A1 publication Critical patent/WO2016124087A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/12—Preparation of carboxylic acid esters from asymmetrical anhydrides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/56—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/58—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/62—Use of additives, e.g. for stabilisation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives

Definitions

  • the invention relates to a novel compound isolated from red yeast rice, a separation method, a synthesis method and a use thereof, and the compound has the HMG-CoA reductase inhibition effect by an activity test; and another compound having a similar structure and a synthesis method thereof.
  • Monascus-fermented rice is a purple-red rice koji made from rice as a raw material and fermented by Monascus. The use of red yeast rice in China can be used.
  • Monascus-fermented rice is a purple-red rice koji made from rice as a raw material and fermented by Monascus. The use of red yeast rice in China can be used.
  • Monascus ruber In the 1970s, Professor Endo of Japan first isolated the physiologically active substance monacolin K from Monascus ruber.
  • Many domestic and foreign scholars have continuously found physiologically active substances in the metabolites of Monascus. Including monacolin compounds, Monascus pigment, antihypertensive component GABA and antioxidant component dimerumic acid and so on. There is still a large research potential and development space in the red song.
  • Xuezhikang capsule or tablet
  • Xuezhikang is a listed Chinese-made lipid-regulating Chinese medicine red yeast preparation developed by the applicant. It is rich in various active ingredients such as statins, and has fewer adverse reactions than the existing lipid-lowering pharmaceuticals.
  • Xuezhikang is rich in natural statins.
  • Xuezhikang also contains isoflavones, sterols, more than 20 kinds of amino acids, unsaturated fats Acid and a variety of trace elements.
  • the isoflavones mainly include genistein, daidzein and glycyrrhizin, all of which are soy isoflavones.
  • Phytosterols are substances similar to cyclic alcohol structures, widely distributed in nature and represent the end products of plant metabolism.
  • the sterols in Xuezhikang include ergosterol, stigmasterol and sitosterol.
  • Xuezhikang has more than 20 kinds of amino acid components such as glycine, proline, serine, aspartic acid, glutamic acid, arginine, histidine, taurine and ⁇ -aminobutyric acid (GABA).
  • amino acid components such as glycine, proline, serine, aspartic acid, glutamic acid, arginine, histidine, taurine and ⁇ -aminobutyric acid (GABA).
  • Xuezhikang contains a lot of fatty acids. Gas chromatography and mass spectrometry were used to study the methyl esterified derivatives of fatty acids in Xuezhikang. Fourteen fatty acid components were identified, among which palmitic acid, linoleic acid and oleic acid were abundant.
  • Xuezhikang mainly contains trace elements such as magnesium and selenium, among which the content of magnesium is relatively high.
  • R 1 is selected from the group consisting of H, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, (CH 2 ) 1-6 OH, C 3 -C 7 cycloalkyl, halogenated C 3 -C 7 ring Alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halo C 1 -C 6 alkylthio, halogen, nitro, amino and Cyano group
  • R 2 is selected from the group consisting of H, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, (CH 2 ) 1-6 OR 6 , C 3 -C 7 cycloalkyl, halogenated C 3 -C 7 Cycloalkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halogenated C 1 -C 6 alkylthio, halogen, nitro, amino And cyano;
  • R 3 is selected from the group consisting of H, C 1 -C 6 alkyl
  • R 4 and R 5 are each independently selected from the group consisting of: H, -COR 7 , -SO 2 R 8 , -Si R 9 R 10 R 11 ;
  • R 7 is selected from C 1 -C 6 alkyl, halo C 1 -C 6 alkyl
  • R 8 is selected from C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkyl, C 6 - a C 10 aryl, optionally substituted C 6 -C 10 aryl group
  • R 9 , R 10 , R 11 are independently selected from C 1 -C 6 alkyl
  • R 6 is the same as defined above for R 4 and R 5 ;
  • R 1 is (CH 2 )OH
  • R 2 is a methyl group
  • R 3 , R 4 and R 5 are H.
  • Another object of the invention is to provide a process for the preparation of a compound of formula (I) according to the invention:
  • the compound (I) is obtained by reacting a compound of the formula (II) under basic conditions or by adding an ester-forming reagent under basic conditions.
  • R 1 , R 2 , and R 4 in the formula (II) are the same as defined above in the formula (I).
  • the pH range of the alkaline condition is 7.5-14, and an alkaline reagent such as sodium hydroxide, potassium hydroxide, ammonia water or sodium carbonate or a solvent may be optionally added.
  • the ester-forming reagent may be selected from lower alcohols such as methanol and ethanol; acid anhydrides (acetic anhydride, sulfonic anhydride, trifluoromethanesulfonic anhydride, etc.), acid chlorides (toluenesulfonyl chloride), and chlorosilanes (tert-butyldimethylchlorosilane).
  • Another object of the present invention is to provide a method for extracting Compound 5 from red yeast or an extract thereof, the method comprising the steps of:
  • step 2) The ethyl acetate (or dichloromethane or methanol or ethanol, or methanol/ethanol aqueous solution) extract of step 1) is subjected to silica gel column chromatography, and eluted with petroleum ether, ethyl acetate and methanol to obtain a gradient elution. Ethyl acetate elution fraction;
  • step 3 The eluted portion of the ethyl acetate in step 2) was subjected to silica gel column chromatography, eluted with dichloromethane-ethyl acetate-methanol, and the fractions were analyzed and combined to obtain step 3) 5 fractions. ;
  • step 5 The eluted portion of the 82% (acetonitrile-methanol 1:1) aqueous solution of step 4) was further separated by sephadex LH-20 column chromatography using dichloromethane-methanol as a mobile phase, and the fractions were analyzed and combined. Obtaining step 5) 6 fractions;
  • the third fraction of the step 5) was purified by chromatography, using acetonitrile-methanol-water as the mobile phase and the C18 column as the stationary phase to obtain the compound 5.
  • Another object of the invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, said pharmaceutical composition comprising at least one compound of the invention, and optionally a pharmaceutically acceptable excipient.
  • Another object of the present invention is to provide a use of a compound of the present invention or a pharmaceutical composition comprising the same for the preparation of a medicament, particularly a medicament for inhibiting HMG-CoA reductase.
  • the invention provides a method of preventing and/or treating dyslipidemia, hyperlipidemia, or atherosclerosis comprising administering to a patient in need of treatment a therapeutically effective amount of at least one compound of the invention.
  • Dyslipidemia one or more of the human body's indicators associated with blood lipids, is not within normal values, including elevated total cholesterol, low-density lipoprotein cholesterol Elevation, elevated apolipoprotein B, elevated triglycerides, etc.
  • the present invention provides a method for preventing and/or treating hypercholesterolemia, mixed hyperlipidemia, comprising administering to a patient in need of treatment a therapeutically effective amount of at least one compound of the present invention.
  • the invention provides an improvement of total cholesterol, low density lipoprotein cholesterol, and apolipoprotein B liter in the treatment of lifestyle intervention (such as adjusting diet structure, controlling body weight, increasing exercise, and quitting smoking). High, elevated triglycerides, etc.
  • lifestyle intervention such as adjusting diet structure, controlling body weight, increasing exercise, and quitting smoking.
  • lipid-lowering drugs include: cholesterol synthesis inhibitors (statins or their salts, such as lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, etc.), cholesterol absorption inhibitors (Yibu Maibu, etc.), fibrates (Nuoheng, Liping aliprofen, bezafibrate, fenofibrate and gemfibrozil), niacin drugs (nicotinic acid, niacin muscle) Alcohol ester, East fat, pentaerythritol, etc.), bile acid sequestrant drugs, phenoxy acids.
  • cholesterol synthesis inhibitors such as lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, etc.
  • cholesterol absorption inhibitors Yibu Maibu, etc.
  • fibrates Nuoheng, Liping aliprofen, bezafibrate, fen
  • the compound of the present invention or a pharmaceutically acceptable salt thereof (for example, acetate, malonate, tartrate, succinate, hydrochloride, sulfate, nitrate, etc.) can be used for the prevention or treatment of the above diseases .
  • Figure 1 shows 1 H- 1 H COSY of Compound 5 of the present invention. (Fig. 1A) and HMBC related signals (Fig. 1B).
  • the present invention relates to a compound of the following formula (I) or a stereoisomer, tautomer, racemate, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof:
  • R 1 is selected from the group consisting of H, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, (CH 2 ) 1-6 OH, C 3 -C 7 cycloalkyl, halogenated C 3 -C 7 ring Alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halo C 1 -C 6 alkylthio, halogen, nitro, amino and Cyano group
  • R 2 is selected from the group consisting of H, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, (CH 2 ) 1-6 OR 6 , C 3 -C 7 cycloalkyl, halogenated C 3 -C 7 Cycloalkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halogenated C 1 -C 6 alkylthio, halogen, nitro, amino And cyano;
  • R 3 is selected from the group consisting of H, C 1 -C 6 alkyl
  • R 4 and R 5 are each independently selected from the group consisting of: H, -COR 7 , -SO 2 R 8 , -Si R 9 R 10 R 11 ;
  • R 7 is selected from C 1 -C 6 alkyl, halo C 1 -C 6 alkyl
  • R 8 is selected from C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkyl, C 6 - a C 10 aryl, optionally substituted C 6 -C 10 aryl group
  • R 9 , R 10 , R 11 are independently selected from C 1 -C 6 alkyl
  • R 6 is the same as defined above for R 4 and R 5 ;
  • R 1 is (CH 2 )OH
  • R 2 is a methyl group
  • R 3 , R 4 and R 5 are H.
  • the invention relates to a compound of formula (I), wherein R 1 is selected from H, C 1 -C 3 alkyl, halo C 1 -C 3 alkyl, (CH 2 ) 1-3 OH, C 3 -C 6 cycloalkyl, halogenated C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy, C 1 -C 3 alkylthio , halogenated C 1 -C 3 alkylthio, halogen, nitro, amino and cyano.
  • R 1 is selected from H, C 1 -C 3 alkyl, halo C 1 -C 3 alkyl, (CH 2 ) 1-3 OH, C 3 -C 6 cycloalkyl, halogenated C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy, C 1 -C 3 al
  • the invention relates to a compound of formula (I), wherein R 1 is selected from H, C 1 -C 3 alkyl, halo C 1 -C 3 alkyl, (CH 2 ) 1-3 OH, halogen, nitro, amino and cyano.
  • the invention relates to compounds of formula (I), wherein R 1 is selected from the group consisting of H, C 1 -C 3 alkyl, (CH 2 ) 1-3 OH.
  • the invention relates to a compound of formula (I), wherein
  • R 2 is selected from H, C 1 -C 3 alkyl, halo C 1 -C 3 alkyl, (CH 2 ) 1-3 OR 6 , C 3 -C 6 cycloalkyl, halogenated C 3 -C 6 Cycloalkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, halogenated C 1 -C 3 alkylthio, halogen, nitro, amino And cyano;
  • R 6 is selected from the group consisting of H, -COR 7 , -SO 2 R 8 , and -Si R 9 R 10 R 11 ;
  • R 7 is selected from C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, and R 8 is selected from C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkyl, C 6 - C 10 aryl, optionally substituted C 6 -C 10 aryl, R 9 , R 10 , R 11 are independently selected from C 1 -C 6 alkyl.
  • the invention relates to a compound of formula (I), wherein
  • R 2 is selected from H, C 1 -C 3 alkyl, halo C 1 -C 3 alkyl, (CH 2 ) 1-3 OR 6 , C 3 -C 6 cycloalkyl, halogenated C 3 -C 6 Cycloalkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, halogenated C 1 -C 3 alkylthio, halogen, nitro, amino And cyano;
  • R 6 is selected from the group consisting of: H, -COR 7 , -SO 2 R 8 , -SiR 9 R 10 R 11 ;
  • R 7 is selected from C 1 -C 3 alkyl, halo C 1 -C 3 alkyl, and R 8 is selected from C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkyl, C 6 - C 10 aryl, optionally substituted C 6 -C 10 aryl, R 9 , R 10 , R 11 are independently selected from C 1 -C 6 alkyl.
  • the invention relates to a compound of formula (I), wherein
  • R 2 is selected from H, C 1 -C 3 alkyl, halo C 1 -C 3 alkyl, (CH 2 ) 1-3 OR 6 , C 3 -C 6 cycloalkyl, halogenated C 3 -C 6 Cycloalkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, halogenated C 1 -C 3 alkylthio, halogen, nitro, amino And cyano;
  • R 6 is selected from the group consisting of: H, -COR 7 , -SO 2 R 8 , -SiR 9 R 10 R 11 ;
  • R 7 is selected from -CH 3
  • R 8 is selected from -CF 3
  • R 9 , R 10 and R 11 are independently selected from methyl and tert-butyl.
  • the invention relates to a compound of formula (I), wherein
  • R 2 is selected from the group consisting of H, C 1 -C 3 alkyl, halo C 1 -C 3 alkyl, (CH 2 ) 1-3 OR 6 , halogen, nitro, amino and cyano;
  • R 6 is selected from the group consisting of H, -COR 7 , -SO 2 R 8 , and -SiR 9 R 10 R 11 ;
  • R 7 is selected from C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, R 8 is selected from C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkyl, C 6 - C 10 aryl, optionally substituted C 6 -C 10 aryl, R 9 , R 10 , R 11 are independently selected from C 1 -C 6 alkyl.
  • the invention relates to a compound of formula (I), wherein
  • R 2 is selected from the group consisting of H, C 1 -C 3 alkyl, halo C 1 -C 3 alkyl, (CH 2 ) 1-3 OR 6 , halogen, nitro, amino and cyano;
  • R 6 is selected from the group consisting of: H, -COR 7 , -SO 2 R 8 , -SiR 9 R 10 R 11 ;
  • R 7 is selected from C 1 -C 3 alkyl, halo C 1 -C 3 alkyl, and R 8 is selected from C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkyl, C 6 - C 10 aryl, optionally substituted C 6 -C 10 aryl, R 9 , R 10 , R 11 are independently selected from C 1 -C 6 alkyl.
  • the invention relates to a compound of formula (I), wherein
  • R 2 is selected from the group consisting of H, C 1 -C 3 alkyl, halo C 1 -C 3 alkyl, (CH 2 ) 1-3 OR 6 , halogen, nitro, amino and cyano;
  • R 6 is selected from the group consisting of: H, -COR 7 , -SO 2 R 8 , -SiR 9 R 10 R 11 ;
  • R 7 is selected from -CH 3
  • R 8 is selected from -CF 3
  • R 9 , R 10 and R 11 are independently selected from methyl and tert-butyl.
  • the invention relates to a compound of formula (I), wherein
  • R 2 is selected from the group consisting of H, C 1 -C 3 alkyl, (CH 2 ) 1-3 OR 6 ;
  • R 6 is selected from the group consisting of H, -COR 7 , -SO 2 R 8 , and -Si R 9 R 10 R 11 ;
  • R 7 is selected from C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, R 8 is selected from C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkyl, C 6 - C 10 aryl, optionally substituted C 6 -C 10 aryl, R 9 , R 10 , R 11 are independently selected from C 1 -C 6 alkyl.
  • the invention relates to a compound of formula (I), wherein
  • R 2 is selected from the group consisting of H, C 1 -C 3 alkyl, (CH 2 ) 1-3 OR 6 ;
  • R 6 is selected from the group consisting of H, -COR 7 , -SO 2 R 8 , and -Si R 9 R 10 R 11 ;
  • R 7 is selected from C 1 -C 3 alkyl, halo C 1 -C 3 alkyl, and R 8 is selected from C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkyl, C 6 - C 10 aryl, optionally substituted C 6 -C 10 aryl, R 9 , R 10 , R 11 are independently selected from C 1 -C 6 alkyl.
  • the invention relates to a compound of formula (I), wherein
  • R 2 is selected from the group consisting of H, C 1 -C 3 alkyl, (CH 2 ) 1-3 OR 6 ;
  • R 6 is selected from the group consisting of H, -COR 7 , -SO 2 R 8 , and -Si R 9 R 10 R 11 ;
  • R 7 is selected from -CH 3
  • R 8 is selected from -CF 3
  • R 9 , R 10 and R 11 are independently selected from methyl and tert-butyl.
  • the invention relates to compounds of formula (I), wherein R 3 is selected from H, C 1 -C 3 alkyl.
  • the invention relates to compounds of formula (I), wherein R 3 is C 1 -C 3 alkyl.
  • the invention relates to a compound of formula (I), wherein
  • R 4 and R 5 are each independently selected from the group consisting of: H, -COR 7 , -SO 2 R 8 , -SiR 9 R 10 R 11 ;
  • R 7 is selected from C 1 -C 3 alkyl, halo C 1 -C 3 alkyl, and R 8 is selected from C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkyl, C 6 - C 10 aryl, optionally substituted C 6 -C 10 aryl, R 9 , R 10 , R 11 are independently selected from C 1 -C 6 alkyl.
  • the invention relates to a compound of formula (I), wherein
  • R 4 and R 5 are each independently selected from the group consisting of: H, -COR 7 , -SO 2 R 8 , -SiR 9 R 10 R 11 ;
  • R 7 is selected from -CH 3
  • R 8 is selected from -CF 3
  • R 9 , R 10 and R 11 are independently selected from methyl and tert-butyl.
  • the invention relates to a compound of formula (I) selected from the group consisting of
  • di-p-toluenesulfonate bis(trifluoromethanesulfonate), di(tert-butyldimethylsilyl ether),
  • C 1 -C 6 alkyl refers to a straight or branched hydrocarbon group containing from 1 to 6 carbon atoms.
  • Examples of C 1 -C 6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, t-butyl, n-pentyl, and n-hexyl.
  • C 1 -C 3 alkyl refers to a straight or branched hydrocarbon group containing from 1 to 3 carbon atoms.
  • Examples of C 1 -C 3 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl.
  • C 1 -C 6 alkoxy refers to -OC 1 -C 6 alkyl.
  • C 1 -C 6 alkylthio refers to -SC 1 -C 6 alkyl.
  • C 3 -C 7 cycloalkyl refers to a hydrocarbon of a 3-7 membered monocyclic system having a saturated ring, and the C 3 -C 7 cycloalkyl group may be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a ring. Hexyl, cycloheptyl.
  • C 3 -C 6 cycloalkyl refers to a hydrocarbon of a 3-6 membered monocyclic system having a saturated ring
  • the C 3 -C 7 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentane.
  • Base cyclohexyl.
  • halogen means fluoro, chloro, bromo or iodo.
  • halo XX group refers to a halogen substituted XX group.
  • halo C 1 -C 6 alkyl refers to a halogen-substituted -C 1 -C 6 alkyl group.
  • halo C 3 -C 7 cycloalkyl refers to a halogen-substituted -C 3 -C 7 cycloalkyl.
  • the C 1 -C 3 alkylthio group has a meaning similar to the above.
  • C 6 -C 10 aryl refers to a monovalent aromatic hydrocarbon group of 6 to 10 carbon atoms.
  • aryl groups include, but are not limited to, phenyl, tolyl, ethylphenyl, naphthyl, and the like.
  • the term "pharmaceutically acceptable salts of the compounds of formula (I)" is exemplified by the formation of pharmaceutically acceptable anions such as tosylate, mesylate, malate, acetate, citrate, An organic acid addition salt formed from an organic acid of malonate, tartrate, succinate, benzoate, ascorbate, ⁇ -ketoglutarate, and ⁇ -glycerophosphate.
  • Suitable inorganic salts can also be formed including, but not limited to, hydrochlorides, sulfates, nitrates, bicarbonates and carbonates, phosphates, hydrobromides, hydroiodides, and the like.
  • compositions can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of a basic compound with a suitable acid that provides a pharmaceutically acceptable anion.
  • the red yeast rice or extract of the present invention may be commercially available red yeast rice (red yeast rice powder, red yeast rice fermentation product, red yeast rice), or red yeast rice extract (such as Xuezhikang Capsule, Xuezhikang Tablet or its raw material).
  • the red yeast extract of the present invention can be obtained by the following method (not limited to the following method):
  • solvate can be formed using a common organic solvent: a hydrocarbon solvent such as benzene or toluene, such as a chlorinated solvent of chloroform, dichloromethane, an alcohol solvent such as methanol, ethanol or isopropanol, for example Ether or ether solvent of tetrahydrofuran or an ester solvent such as ethyl acetate.
  • a hydrocarbon solvent such as benzene or toluene
  • an alcohol solvent such as methanol, ethanol or isopropanol
  • Ether or ether solvent of tetrahydrofuran or an ester solvent such as ethyl acetate.
  • solvates of the compounds of formula (I) may be formed using water, in which case they are hydrates.
  • hydrate refers to a compound of the invention or a salt thereof, further comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • prodrug refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the invention. Prodrugs undergo this reaction to become active compounds only under biological conditions, or they are active in their unreacted form. Prodrugs can generally be prepared using well-known methods, such as those described in 1 Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, ed., 5th Edition).
  • treating generally refers to obtaining the desired pharmacological and/or physiological effects.
  • the effect may be prophylactic according to the prevention of the disease or its symptoms in whole or in part; and/or may be therapeutic according to the partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • treatment encompasses any treatment for a patient's condition, including: (a) prevention of a disease or condition in a patient who is susceptible to an infectious disease or condition but has not yet diagnosed the disease; (b) inhibition of the symptoms of the disease, That is, to prevent its development; or (c) to alleviate the symptoms of the disease, that is, to cause the disease or symptoms to degenerate.
  • the compounds of the present invention can be prepared according to conventional organic chemical synthesis methods.
  • the invention relates to a process for the preparation of a compound of formula (I):
  • the compound (I) is obtained by reacting a compound of the formula (II) under basic conditions or by adding an ester-forming reagent under basic conditions.
  • R 1 , R 2 , and R 4 in the formula (II) are the same as defined above in the formula (I).
  • the pH range of the alkaline condition is 7.5-14, and an alkaline reagent such as sodium hydroxide, potassium hydroxide, ammonia water or sodium carbonate or a solvent may be optionally added.
  • the ester-forming reagent may be selected from lower alcohols such as methanol and ethanol; acid anhydrides (acetic anhydride, sulfonic anhydride, trifluoromethanesulfonic anhydride, etc.), acid chlorides (toluenesulfonyl chloride), and chlorosilanes (tert-butyldimethylchlorosilane).
  • Protecting groups are those which, once attached to an active moiety (e.g., a hydroxyl or amino group), prevent these moieties from being interfered by subsequent reactions and which can be removed by conventional methods after the reaction.
  • hydroxy protecting groups include, but are not limited to, alkyl, benzyl (benzyl), allyl, trityl (ie, triphenylmethyl), acyl (eg, benzoyl, acetyl or HOOC-X"-CO-, X" is an alkylene, alkenylene, cycloalkylene or arylene group, a silyl group (for example, trimethylsilyl, triethylsilyl and Tert-butyldimethylsilyl), alkoxycarbonyl, aminocarbonyl (for example, dimethylaminocarbonyl, methylethylaminocarbonyl and phenylaminocarbonyl), alkoxymethyl, benzyloxymethyl and Alkyl hydr
  • amino protecting groups include, but are not limited to, alkoxycarbonyl, alkanoyl, aryloxycarbonyl, aryl substituted alkyl, and the like. Hydroxy and amino protecting groups have been discussed in T. W. Greene and P. G.. M. Wuts, Protective Groups in Organic Synthesis, 2nd Edition, John Wiley and Sons (1991). Both the hydroxy group and the amino protecting group can be removed by a conventional method after the reaction.
  • Another object of the invention is to provide a method of separating a compound.
  • step 2) The ethyl acetate (or dichloromethane or methanol or ethanol, or methanol/ethanol aqueous solution) extract of step 1) is subjected to silica gel column chromatography, and washed with petroleum ether, ethyl acetate and methanol/ethanol. Destaining, obtaining an elution portion of ethyl acetate;
  • step 3 The eluted portion of the ethyl acetate in step 2) was subjected to silica gel column chromatography, eluted with dichloromethane-ethyl acetate-methanol, and the fractions were analyzed and combined to obtain step 3) 5 fractions. ;
  • step 5 The eluted portion of the 82% (acetonitrile-methanol 1:1) aqueous solution of step 4) was further separated by sephadex LH-20 column chromatography using dichloromethane-methanol as a mobile phase, and the fractions were analyzed and combined. Obtaining step 5) 6 fractions;
  • step 5 The third fraction of step 5) was purified by chromatography using acetonitrile-methanol-water as the mobile phase and the C18 column as the stationary phase to obtain compound 5.
  • a method of extracting Compound 5 from red yeast or an extract thereof comprising the steps of:
  • step 2) The ethyl acetate (or dichloromethane or methanol or ethanol, or methanol/ethanol aqueous solution) extract of step 1) is subjected to silica gel column chromatography, and eluted with petroleum ether, ethyl acetate and methanol/ethanol. , obtaining an elution portion of ethyl acetate;
  • Step 3 The eluted portion of the ethyl acetate in step 2) was subjected to silica gel column chromatography, eluted with dichloromethane-ethyl acetate-methanol (30:30:1), and the fractions were analyzed and combined to obtain Step 3) 5 points;
  • step 5 The eluted portion of the 82% (acetonitrile-methanol 1:1) aqueous solution of step 4) was further separated by sephadex LH-20 column chromatography using dichloromethane-methanol (2:1) as a mobile phase. After analyzing and merging the fractions, step 5) 6 fractions are obtained;
  • step 5 The third fraction of step 5) is purified by chromatography, using acetonitrile-methanol-water as the mobile phase and C18 column as the stationary phase to obtain compound 5
  • the invention also provides a pharmaceutical composition comprising a compound of formula (I) of the invention.
  • the invention provides a pharmaceutical composition comprising at least one compound of formula (I) of the invention as described above, and optionally a pharmaceutically acceptable excipient.
  • a method of preparing the pharmaceutical composition comprises incorporating a suitable pharmaceutical excipient, carrier, diluent, and the like.
  • the pharmaceutical preparations of the invention are prepared in a known manner, including conventional methods of mixing, dissolving or lyophilizing.
  • the compounds of the present invention can be formulated into pharmaceutical compositions and administered to a patient in a variety of ways suitable for the chosen mode of administration, for example, orally or parenterally (by intravenous, intramuscular, topical or subcutaneous routes).
  • the compounds of the invention may be administered systemically, for example, orally, in association with a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules and can be compressed into tablets.
  • a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules and can be compressed into tablets.
  • the active compound may be combined with one or more excipients and in the form of swallowable tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. use.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the ratio of such compositions and formulations may of course vary and may range from about 1% to about 99% by weight of a given unit dosage form.
  • the amount of active compound is such that an effective dosage level can be obtained.
  • Tablets, lozenges, pills, capsules and the like may also contain: a binder such as tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, Potato starch, alginic acid, etc.; a lubricant such as magnesium stearate; and a sweetener such as sucrose, fructose, lactose or aspartame; or a flavoring agent such as mint, wintergreen or cherry.
  • a binder such as tragacanth, acacia, corn starch or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrating agent such as corn starch, Potato starch, alginic acid, etc.
  • a lubricant such as magnesium stearate
  • a sweetener such as sucrose, fructose, lactose or aspartame
  • a flavoring agent such as mint, wintergreen or cherry
  • any material used to prepare any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound can be incorporated into sustained release formulations and sustained release devices.
  • the active compound can also be administered intravenously or intraperitoneally by infusion or injection.
  • An aqueous solution of the active compound or a salt thereof can be prepared, optionally mixed with a non-toxic surfactant.
  • Dispersing agents in glycerol, liquid polyethylene glycols, triacetin and mixtures thereof, and oils can also be prepared. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions of the active ingredient (optionally encapsulated in liposomes) containing the immediate formulation of a suitable injectable or injectable solution or dispersing agent. Or sterile powder. In all cases, the final dosage form must be sterile, liquid, and stable under the conditions of manufacture and storage.
  • the liquid carrier can be a solvent or liquid dispersion medium including, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, non-toxic glycerides, and suitable mixtures thereof.
  • Proper fluidity can be maintained, for example, by liposome formation, by maintaining the desired particle size in the case of a dispersing agent, or by the use of a surfactant.
  • the action of preventing microorganisms can be produced by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents such as sugars, buffers or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use of compositions that delay the absorbent (for example, aluminum monostearate and gelatin).
  • Sterile injectable solutions are prepared by combining the required active compound in a suitable solvent with the various other ingredients enumerated above, followed by filter sterilization.
  • the preferred preparation methods are vacuum drying and lyophilization techniques which result in a powder of the active ingredient plus any additional ingredients present in the previously sterile filtration solution. .
  • Useful solid carriers include comminuted solids (e.g., talc, clay, microcrystalline cellulose, silica, alumina, etc.).
  • Useful liquid carriers include water, ethanol or ethylene glycol or a water-ethanol/ethylene glycol mixture, and the compounds of the present invention may be dissolved or dispersed in an effective amount, optionally with the aid of a non-toxic surfactant.
  • Adjuvants such as fragrances
  • additional antimicrobial agents can be added to optimize the properties for a given use.
  • Thickeners can also be used with liquid carriers to form coatable pastes, gels, ointments , soap, etc., used directly on the user's skin.
  • the therapeutic requirements of a compound or an active salt or derivative thereof depend not only on the particular salt selected, but also on the mode of administration, the nature of the disease to be treated, and the age and condition of the patient, ultimately depending on the attending physician or clinician decision.
  • unit dosage form is a unit dispersion unit containing a unit dosage unit suitable for administration to humans and other mammalian bodies.
  • the unit dosage form can be a capsule or tablet, or a plurality of capsules or tablets.
  • the amount of unit dose of the active ingredient may vary or be adjusted between about 0.1 and about 1000 mg or more, depending on the particular treatment involved.
  • the invention also provides the use of a compound of the invention or a composition comprising the same for the preparation of a medicament, in particular for the inhibition of HMG-CoA reductase.
  • the present invention provides a method of treating a patient for preventing and/or treating dyslipidemia, hyperlipidemia, or atherosclerosis comprising administering to a patient in need of treatment a therapeutically effective amount of at least one compound of the present invention.
  • Dyslipidemia one or more of the human body indicators associated with blood lipids, is not within the normal range of values, including elevated total cholesterol, elevated LDL cholesterol, elevated apolipoprotein B, and elevated triglycerides.
  • the present invention provides a method for preventing and/or treating hypercholesterolemia, mixed hyperlipidemia patients, including administering a patient in need of treatment A therapeutically effective amount of at least one compound of the invention.
  • the invention provides an improvement of total cholesterol, low density lipoprotein cholesterol, and apolipoprotein B liter in the treatment of lifestyle intervention (such as adjusting diet structure, controlling body weight, increasing exercise, and quitting smoking). High, elevated triglycerides, etc.
  • lifestyle intervention such as adjusting diet structure, controlling body weight, increasing exercise, and quitting smoking.
  • lipid-lowering drugs include: cholesterol synthesis inhibitors (statins or their salts, such as lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, etc.), cholesterol absorption inhibitors (Yibu Maibu, etc.), fibrates (Nuoheng, Liping aliprofen, bezafibrate, fenofibrate and gemfibrozil), niacin drugs (nicotinic acid, niacin muscle) Alcohol ester, East fat, pentaerythritol, etc.), bile acid sequestrant drugs, phenoxy acids.
  • cholesterol synthesis inhibitors such as lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, etc.
  • cholesterol absorption inhibitors Yibu Maibu, etc.
  • fibrates Nuoheng, Liping aliprofen, bezafibrate, fen
  • the compound of the present invention or a pharmaceutically acceptable salt thereof (for example, acetate, malonate, tartrate, succinate, hydrochloride, sulfate, nitrate, etc.) can be used for the prevention or treatment of the above diseases .
  • the present inventors isolated and purified a novel statin compound (Compound 5) by further study on the composition of red yeast rice.
  • step 5 The third step (combined 66-80 fraction, 256 mg) of step 5) was fractionated, and finally purified by semi-preparative high-performance liquid phase, using 66% (acetonitrile-methanol 1:1) aqueous solution as mobile phase, flow rate For 4ml/min, the C18 semi-preparative column (10 ⁇ 250mm, 5 ⁇ m) is the stationary phase, the DAD detector wavelength is 247nm, and the chromatographic peak fraction of 22.8min (21.5-23.5min) is collected and enriched and concentrated several times to obtain new The compound (Compound 5) was about 13 mg.
  • step 3 The eluted fraction of ethyl acetate was subjected to silica gel column chromatography, and eluted with dichloromethane-ethyl acetate-methanol (30:30:1). A total of 110 fractions were received, and each stream was divided into 10 ml. After TLC (or HPLC) tracking and detection of the same or similar fractions of the combined chromatographic behavior, step 3) 5 fractions were obtained (dimensions 1-35; 36-50; 51-65; 66-89 before combining; 90-110 points).
  • the present invention can also use other red yeast raw materials or preparations as raw materials, such as Xuezhikang tablets (Beijing Beida Weixin Biotechnology Co., Ltd.).
  • compound 1 (simvastatin, purchased from sigma) was dissolved in 500 ml of dichloromethane, 12 g (0.07 mol) of m-chloroperoxybenzoic acid was added, and stirred at room temperature for 40 min.
  • the sodium hydrogencarbonate solution was allowed to stand for stratification, washed successively with saturated sodium hydrogencarbonate and saturated brine, and the organic layer was dried and concentrated, and the next reaction was carried out without isolation.
  • the structure identification method of compound 5 is as follows:
  • HMBC-related signals revealed 6-Me and C5, C7; H-5 and C6, C7; H-4 and C5, C8a; H-3 and C4a; H-1 and C8a, C4a; H-8 and From the correlation signal between C8a, C4a, etc., it can be inferred that the compound has a statin core of the 1,2-dihydronaphthalene ring moiety. From the HMBC map (Fig. 1AB), methyl groups of methoxy groups ( ⁇ 3.69), H-2' ( ⁇ 2.46/2.48) and H-3' ( ⁇ 2.45) and C1' ( ⁇ 173) were also found.
  • Lovastatin standard - purchased from Sigma
  • Rat liver microsomes (HMG-CoA reductase) were commercially available or prepared as follows: The liver of male rats was taken out, washed with KESD buffer, centrifuged at 12,000 g for 15 min, and the supernatant was taken. After centrifugation at 105,000 g for another 90 min, the pellet was collected. 8.3% glycerol was added to the centrifuge and heated in a 37 ° C warm bath for 1 h. Rat liver microsomes were purified by saturated ammonium sulfate and 35-50% purified fractions were collected. The obtained rat liver microsomes were stored in a -80 ° C refrigerator.
  • Nicotinamide adenine dinucleotide (NADPH) purchased from Merck
  • Compound 5 was dissolved in 75% ethanol solution at an initial concentration of 8.6 mg/ml and diluted stepwise to obtain 4.3 mg/ml, 2.15 mg/ml; the total volume in the assay system was 250 ⁇ l, and the concentration of each component was: potassium chloride.
  • Lovastatin is a positive control.

Abstract

本发明涉及新化合物、其分离方法、合成方法及用途，经活性实验证明该化合物具有HMG-CoA还原酶抑制作用；另外还涉及其衍生物。

Description

化合物、其分离方法、合成方法及用途 技术领域
本发明涉及从红曲中分离出的新化合物、分离方法、合成方法及用途，经活性实验证明该化合物具有HMG-CoA还原酶抑制作用；以及另外的与其结构相似的化合物及其合成方法。
背景技术
我国的中医药具有悠久的使用和研究历史，红曲(Monascus-fermented rice)是以大米为原料，经红曲霉(Monascus)发酵制成的一种紫红色米曲，红曲在我国的使用可追溯到汉代。上世纪70年代，日本Endo教授首次从红色红曲霉(Monascus ruber)中分离出生理活性物质莫纳克林K(monacolin K)以来，众多国内外学者在红曲霉代谢产物中不断发现生理活性物质，包括monacolin类化合物,红曲色素,降压成分GABA及抗氧化成分dimerumic acid等等。红曲中仍有较大的研究潜力和开发空间。
血脂康(胶囊或片)是申请人研制的上市国产调脂中药红曲制剂，富含他汀等多种活性成分，相比已有的调脂药物化药，不良反应少。适应症为高脂血症及动脉粥样硬化引起的心脑血管疾病的治疗。除湿祛痰，活血化淤，健脾消食。用于脾虚痰淤阻滞症的气短、乏力、头晕、头痛、胸闷、腹胀、食少纳呆等；高脂血症；也可用于由高脂血症及动脉粥样硬化引起的心脑血管疾病的辅助治疗。
现有技术经过对于血脂康的研究，从其中分离发现了以下成分：
他汀成分
血脂康中富含系列天然他汀类物质。
异黄酮成分
血脂康中还含有异黄酮、甾醇类物质、20余种氨基酸、不饱和脂肪 酸及多种微量元素。异黄酮成分主要包括染料木素、大豆苷元、黄豆黄素,均属于大豆异黄酮。
甾醇成分
植物甾醇是一种类似于环状醇结构的物质,广泛分布于自然界,代表了植物代谢的终产物。
血脂康中的甾醇包括麦角甾醇、豆甾醇及谷甾醇等。
氨基酸成分
血脂康中具有甘氨酸、脯氨酸、丝氨酸、天门冬氨酸、谷氨酸、精氨酸、组氨酸、牛磺酸、γ-氨基丁酸(GABA)等20余种氨基酸成分。
不饱和脂肪酸成分
血脂康中含大量的脂肪酸成分。采用气相色谱与质谱联用技术对血脂康中脂肪酸类成分的甲酯化衍生物进行研究,鉴定出14种脂肪酸类成分，其中棕榈酸、亚油酸及油酸,含量丰富。
微量元素成分
血脂康中主要含有镁、硒等微量元素,其中镁的含量相对较高。
发明内容
本发明的一个目的是提供下式(I)的化合物或其立体异构体、互变异构体、外消旋物、代谢产物、前药、药学上可接受的盐或溶剂化物：
Figure PCTCN2016072306-appb-000001
R1选自H、C1-C6烷基、卤代C1-C6烷基、(CH2)1-6OH、C3-C7环烷基、卤代C3-C7环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基、卤素、硝基、氨基和氰基；
R2选自H、C1-C6烷基、卤代C1-C6烷基、(CH2)1-6OR6、C3-C7环 烷基、卤代C3-C7环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基、卤素、硝基、氨基和氰基；
R3选自H、C1-C6烷基；
R4和R5各自独立地选自：H、-COR7、-SO2R8、-Si R9R10R11；
其中，R7选自C1-C6烷基、卤代C1-C6烷基，R8选自C1-C6烷基、任意取代的C1-C6烷基、C6-C10芳基、任意取代的C6-C10芳基，R9、R10、R11独立地选自C1-C6烷基；
其中，R6与上述对于R4和R5的定义相同；
其中，排除以下式(I)的化合物：R1为(CH2)OH，R2为甲基，R3、R4和R5为H。
本发明的另一个目的是提供制备本发明式(I)化合物的方法：
Figure PCTCN2016072306-appb-000002
化合物(I)由式(II)化合物，在碱性条件下反应制得，或在碱性条件下加入成酯试剂反应制得。式(II)中R1、R2、和R4与上文在式(I)中的定义相同。
碱性条件的pH范围为7.5-14，可选加入氢氧化钠、氢氧化钾、氨水、碳酸钠等碱性试剂或溶剂。成酯试剂可选甲醇、乙醇等低级醇；酸酐(醋酸酐、磺酸酐、三氟甲磺酸酐等)、酰氯(甲苯磺酰氯)、氯硅烷(叔丁基二甲基氯硅烷)。
本发明的另一个目的是提供从红曲或其提取物提取化合物5的方法，所述方法包括下列步骤：
Figure PCTCN2016072306-appb-000003
1)对于红曲或其提取物使用乙酸乙酯(或二氯甲烷或甲醇或乙醇、或甲醇/乙醇水溶液)为溶剂进行提取；
2)对于步骤1)的乙酸乙酯(或二氯甲烷或甲醇或乙醇、或甲醇/乙醇水溶液)提取物进行硅胶柱层析分离，用石油醚、乙酸乙酯及甲醇进行梯度洗脱，得到乙酸乙脂洗脱部分；
3)对于步骤2)的乙酸乙脂洗脱部分进行硅胶柱层析分离，用二氯甲烷-乙酸乙脂-甲醇洗脱，将流分进行分析、合并后，得到步骤3)5个流分；
4)对于步骤3)的第2流分进行C18柱层析分离，用乙腈-甲醇-水梯度洗脱，得到82％(乙腈-甲醇1：1)水溶液洗脱部分；
5)对于步骤4)的82％(乙腈-甲醇1：1)水溶液洗脱部分进一步用二氯甲烷-甲醇为流动相进行sephadex LH-20柱层析分离，将流分进行分析、合并后，得到步骤5)6个流分；
6)对于步骤5)的第3流分利用色谱纯化，以乙腈-甲醇-水为流动相，C18色谱柱为固定相，得到化合物5。
本发明的另一个目的是提供包含本发明化合物的药物组合物，所述药物组合物包括至少一种本发明化合物，和任选的药学上可以接受的赋形剂。
本发明的另一个目的是提供本发明化合物或包含该化合物的药物组合物在制备药物、特别是用于抑制HMG-CoA还原酶的药物中的用途。相应地，本发明提供一种预防和/或治疗血脂异常、高血脂症、或动脉粥样硬化患者的方法，包括给予需要治疗的患者治疗有效量的至少一种本发明的化合物。血脂异常即一种或多种与血脂相关的人体指标不在正常数值范围内，包括总胆固醇升高、低密度脂蛋白胆固醇 升高、载脂蛋白B升高、甘油三酯升高等。本发明提供一种预防和/或治疗高胆固醇血症、混合型高脂血症患者的方法，包括给予需要治疗的患者治疗有效量的至少一种本发明的化合物。
本发明提供一种在生活方式干预治疗(如：调整饮食结构、控制体重、增加运动、戒烟)效果不理想时，治疗其总胆固醇升高、低密度脂蛋白胆固醇升高、载脂蛋白B升高、甘油三酯升高等。
本发明化合物的上述用途，可单独使用，或与有效剂量的其他调脂药物联合使用。其他调脂药物包括：胆固醇合成抑制剂(他汀类或其盐类，如洛伐他汀、普伐他汀、辛伐他汀、氟伐他汀、阿托伐他汀、匹伐他汀等)、胆固醇吸收抑制剂(依折麦布等)、贝特类(诺衡、力平脂环丙贝特、苯扎贝特、非诺贝特及吉非贝齐)、烟酸类药物(烟酸、烟酸肌醇酯、东脂平、戊四烟酯等),胆酸螯合剂药物、苯氧芳酸类。
本发明的化合物或其药学上可接受的盐(例如醋酸盐、丙二酸盐、酒石酸盐、琥珀酸盐、盐酸盐、硫酸盐、硝酸盐等)，可用于上述疾病的预防或治疗。
附图说明
图1表示本发明的化合物5的1H-1H COSY
Figure PCTCN2016072306-appb-000004
(附图1A)和HMBC相关信号
Figure PCTCN2016072306-appb-000005
(附图1B)。
具体实施方式
本发明涉及下式(I)的化合物或其立体异构体、互变异构体、外消旋物、代谢产物、前药、药学上可接受的盐或溶剂化物：
Figure PCTCN2016072306-appb-000006
R1选自H、C1-C6烷基、卤代C1-C6烷基、(CH2)1-6OH、C3-C7环烷基、卤代C3-C7环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基、卤素、硝基、氨基和氰基；
R2选自H、C1-C6烷基、卤代C1-C6烷基、(CH2)1-6OR6、C3-C7环烷基、卤代C3-C7环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基、卤素、硝基、氨基和氰基；
R3选自H、C1-C6烷基；
R4和R5各自独立地选自：H、-COR7、-SO2R8、-Si R9R10R11；
其中，R7选自C1-C6烷基、卤代C1-C6烷基，R8选自C1-C6烷基、任意取代的C1-C6烷基、C6-C10芳基、任意取代的C6-C10芳基，R9、R10、R11独立地选自C1-C6烷基；
其中，R6与上述对于R4和R5的定义相同；
其中，排除以下式(I)的化合物：R1为(CH2)OH，R2为甲基，R3、R4和R5为H。
在一种实施方式中，本发明涉及式(I)的化合物，其中，R1选自H、C1-C3烷基、卤代C1-C3烷基、(CH2)1-3OH、C3-C6环烷基、卤代C3-C6环烷基、C1-C3烷氧基、卤代C1-C3烷氧基、C1-C3烷硫基、卤代C1-C3烷硫基、卤素、硝基、氨基和氰基。
在一种实施方式中，本发明涉及式(I)的化合物，其中，R1选自H、C1-C3烷基、卤代C1-C3烷基、(CH2)1-3OH、卤素、硝基、氨基和氰基。
在一种实施方式中，本发明涉及式(I)的化合物，其中，R1选自H、C1-C3烷基、(CH2)1-3OH。
在一种实施方式中，本发明涉及式(I)的化合物，其中
R2选自H、C1-C3烷基、卤代C1-C3烷基、(CH2)1-3OR6、C3-C6环烷基、卤代C3-C6环烷基、C1-C3烷氧基、卤代C1-C3烷氧基、C1-C3烷硫基、卤代C1-C3烷硫基、卤素、硝基、氨基和氰基；
其中，R6选自H、-COR7、-SO2R8、-Si R9R10R11；
其中，R7选自C1-C6烷基、卤代C1-C6烷基，R8选自C1-C6烷基、 任意取代的C1-C6烷基、C6-C10芳基、任意取代的C6-C10芳基，R9、R10、R11独立地选自C1-C6烷基。
在一种实施方式中，本发明涉及式(I)的化合物，其中
R2选自H、C1-C3烷基、卤代C1-C3烷基、(CH2)1-3OR6、C3-C6环烷基、卤代C3-C6环烷基、C1-C3烷氧基、卤代C1-C3烷氧基、C1-C3烷硫基、卤代C1-C3烷硫基、卤素、硝基、氨基和氰基；
其中，R6选自：H、-COR7、-SO2R8、-SiR9R10R11；
其中，R7选自C1-C3烷基、卤代C1-C3烷基，R8选自C1-C3烷基、任意取代的C1-C3烷基、C6-C10芳基、任意取代的C6-C10芳基，R9、R10、R11独立地选自C1-C6烷基。
在一种实施方式中，本发明涉及式(I)的化合物，其中
R2选自H、C1-C3烷基、卤代C1-C3烷基、(CH2)1-3OR6、C3-C6环烷基、卤代C3-C6环烷基、C1-C3烷氧基、卤代C1-C3烷氧基、C1-C3烷硫基、卤代C1-C3烷硫基、卤素、硝基、氨基和氰基；
其中，R6选自：H、-COR7、-SO2R8、-SiR9R10R11；
其中，R7选自-CH3，R8选自-CF3、对甲苯基，R9、R10、R11独立地选自甲基、叔丁基。
在一种实施方式中，本发明涉及式(I)的化合物，其中
R2选自H、C1-C3烷基、卤代C1-C3烷基、(CH2)1-3OR6、卤素、硝基、氨基和氰基；
其中，R6选自H、-COR7、-SO2R8、-SiR9R10R11；
其中，R7选自C1-C6烷基、卤代C1-C6烷基，R8选自C1-C6烷基、任意取代的C1-C6烷基、C6-C10芳基、任意取代的C6-C10芳基，R9、R10、R11独立地选自C1-C6烷基。
在一种实施方式中，本发明涉及式(I)的化合物，其中
R2选自H、C1-C3烷基、卤代C1-C3烷基、(CH2)1-3OR6、卤素、硝基、氨基和氰基；
其中，R6选自：H、-COR7、-SO2R8、-SiR9R10R11；
其中，R7选自C1-C3烷基、卤代C1-C3烷基，R8选自C1-C3烷基、 任意取代的C1-C3烷基、C6-C10芳基、任意取代的C6-C10芳基，R9、R10、R11独立地选自C1-C6烷基。
在一种实施方式中，本发明涉及式(I)的化合物，其中
R2选自H、C1-C3烷基、卤代C1-C3烷基、(CH2)1-3OR6、卤素、硝基、氨基和氰基；
其中，R6选自：H、-COR7、-SO2R8、-SiR9R10R11；
其中，R7选自-CH3，R8选自-CF3、对甲苯基，R9、R10、R11独立地选自甲基、叔丁基。
在一种实施方式中，本发明涉及式(I)的化合物，其中
R2选自H、C1-C3烷基、(CH2)1-3OR6；
其中，R6选自H、-COR7、-SO2R8、-Si R9R10R11；
其中，R7选自C1-C6烷基、卤代C1-C6烷基，R8选自C1-C6烷基、任意取代的C1-C6烷基、C6-C10芳基、任意取代的C6-C10芳基，R9、R10、R11独立地选自C1-C6烷基。
在一种实施方式中，本发明涉及式(I)的化合物，其中
R2选自H、C1-C3烷基、(CH2)1-3OR6；
其中，R6选自H、-COR7、-SO2R8、-Si R9R10R11；
其中，R7选自C1-C3烷基、卤代C1-C3烷基，R8选自C1-C3烷基、任意取代的C1-C3烷基、C6-C10芳基、任意取代的C6-C10芳基，R9、R10、R11独立地选自C1-C6烷基。
在一种实施方式中，本发明涉及式(I)的化合物，其中
R2选自H、C1-C3烷基、(CH2)1-3OR6；
其中，R6选自H、-COR7、-SO2R8、-Si R9R10R11；
其中，R7选自-CH3，R8选自-CF3、对甲苯基，R9、R10、R11独立地选自甲基、叔丁基。
在一种实施方式中，本发明涉及式(I)的化合物，其中，R3选自H、C1-C3烷基。
在一种实施方式中，本发明涉及式(I)的化合物，其中，R3为C1-C3烷基。
在一种实施方式中，本发明涉及式(I)的化合物，其中
R4和R5各自独立地选自：H、-COR7、-SO2R8、-SiR9R10R11；
其中，R7选自C1-C3烷基、卤代C1-C3烷基，R8选自C1-C3烷基、任意取代的C1-C3烷基、C6-C10芳基、任意取代的C6-C10芳基，R9、R10、R11独立地选自C1-C6烷基。
在一种实施方式中，本发明涉及式(I)的化合物，其中
R4和R5各自独立地选自：H、-COR7、-SO2R8、-SiR9R10R11；
其中，R7选自-CH3，R8选自-CF3、对甲苯基，R9、R10、R11独立地选自甲基、叔丁基。
在一种实施方式中，本发明涉及式(I)的化合物，其选自：
Figure PCTCN2016072306-appb-000007
及其二乙酸酯、二对甲苯磺酯、二(三氟甲磺酸酯)、二(叔丁基二甲基硅醚)，
Figure PCTCN2016072306-appb-000008
及其三乙酸酯、三对甲苯磺酯、三(三氟甲磺酸酯)、三(叔丁基二甲基硅醚)。
如本文所使用，术语“C1-C6烷基”是指含有1-6个碳原子的直链或支链烃基。C1-C6烷基的例子包括但不限于甲基、乙基、正丙基、异丙基、叔丁基、正戊基和正己基。
类似地，术语“C1-C3烷基”是指含有1-3个碳原子的直链或支链烃基。C1-C3烷基的例子包括但不限于甲基、乙基、正丙基、异丙基。
术语“C1-C6烷氧基”是指-O-C1-C6烷基。
术语“C1-C6烷硫基”是指-S-C1-C6烷基。
类似地，“C1-C3烷氧基”、“C1-C3烷硫基”具有类似的含义。
术语“C3-C7环烷基”是指具有饱和环的3-7元单环系统的烃，C3-C7环烷基可以为环丙基、环丁基、环戊基、环己基、环庚基。
类似地，术语“C3-C6环烷基”是指具有饱和环的3-6元单环系统的烃，C3-C7环烷基可以为环丙基、环丁基、环戊基、环己基。
术语“卤素”是指氟、氯、溴或碘。
术语“卤代XX基团”是指卤素取代的XX基团。例如，“卤代C1-C6烷基”是指卤素取代的-C1-C6烷基。术语“卤代C3-C7环烷基”是指卤素取代的-C3-C7环烷基。类似地，术语卤代C1-C6烷硫基、卤代C1-C6烷氧基、卤代C3-C6环烷基、卤代C1-C3烷氧基、卤代C1-C3烷硫基具有类似于以上的含义。
术语“C6-C10芳基”是指6-10个碳原子的单价芳香烃基。芳基的例子包括但不限于苯基、甲苯基、乙苯基、萘基等。
如本文所使用，术语“式(I)化合物的药学上可以接受的盐”的例子是由形成药学上可以接受的阴离子(如甲苯磺酸根、甲磺酸根、苹果酸根、醋酸根、柠檬酸根、丙二酸根、酒石酸根、琥珀酸根、苯甲酸根、抗坏血酸根、α-酮戊二酸根和α-甘油磷酸根)的有机酸形成的有机酸加合盐。也可形成合适的无机盐，包括但不限于盐酸盐、硫酸盐、硝酸盐、碳酸氢盐和碳酸盐、磷酸盐、氢溴酸盐、氢碘酸盐等。
药学上可以接受的盐可使用本领域熟知的标准程序获得，例如，通过将足量的碱性化合物和提供药学上可以接受的阴离子的合适的酸反应。
本发明的红曲或提取物可以为市售的红曲(红曲干粉、红曲发酵产物、红曲米)、或红曲提取物(如血脂康胶囊、血脂康片或其原料)。
本发明所述红曲提取物可通过如下方法(并不限于如下方法)制得：
1)取红曲1重量份，每次加入2－10体积份的50－100％(v/v)的乙醇或甲醇或甲醇/乙醇水溶液，或乙酸乙酯(或其它有机溶剂)加热回流1－3小时，提取2－3次；
2)提取液过滤，合并滤液；可选地，回收溶剂，
3)将步骤2)中得到的滤液浓缩成稠膏。
如本文所使用，术语“溶剂化物”可以使用常见的有机溶剂形成：例如苯或甲苯的烃溶剂，例如氯仿、二氯甲烷的氯化溶剂，例如甲醇、乙醇或异丙醇的醇溶剂，例如乙醚或四氢呋喃的醚溶剂，或例如乙酸乙酯的酯溶剂。或者，式(I)化合物的溶剂化物可以使用水形成，在这种情况下，它们为水合物。
如本文所使用，术语“水合物”是指本发明的化合物或其盐，其进一步包含通过非共价分子间力结合的化学计量的或非化学计量的量的水。
如本文所使用，除非另外说明，术语“前药”是指可以在生物学条件(体外或体内)下水解、氧化或进行其他反应以提供本发明的化合物的衍生物。前药仅在生物学条件下经过该反应成为活性化合物，或者它们在它们不反应的形式中具有活性。通常可以使用公知的方法制备前药，例如1Burger's Medicinal Chemistry and Drug Discovery(1995)172-178,949-982(Manfred E.Wolff编,第5版)中描述的那些方法。
本文使用的立体化学的定义和约定一般遵循MCGRAW-HILL  DICTIONARY OF CHEMICAL TERMS(S.P.Parker,Ed.,McGraw-Hill Book Company,New York,1984)；和ELIEL,E.和WILEN,S.,STEREOCHEMISTRY OF ORGANIC COMPOUNDS(John Wiley&Sons,Inc.,New York,1994)。许多有机化合物以光学活性形式存在，即它们具有旋转平面偏光的平面的能力。
本文使用的术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据完全或部分地预防疾病或其症状，可以是预防性的；和/或根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)预防易感染疾病或症状但还没诊断出患病的患者所发生的疾病或症状；(b)抑制疾病的症状，即阻止其发展；或(c)缓解疾病的症状，即，导致疾病或症状退化。
本发明的化合物可以按照常规的有机化学合成方法制备。例如，本发明涉及一种制备式(I)化合物的方法：
Figure PCTCN2016072306-appb-000009
化合物(I)由式(II)化合物，在碱性条件下反应制得，或在碱性条件下加入成酯试剂反应制得。式(II)中R1、R2、和R4与上文在式(I)中的定义相同。
碱性条件的pH范围为7.5-14，可选加入氢氧化钠、氢氧化钾、氨水、碳酸钠等碱性试剂或溶剂。成酯试剂可选甲醇、乙醇等低级醇；酸酐(醋酸酐、磺酸酐、三氟甲磺酸酐等)、酰氯(甲苯磺酰氯)、氯硅烷(叔丁基二甲基氯硅烷)。
常规的化学转换可用于实施本发明。本领域的技术人员可以决定用于这些化学转换的适当的化学剂、溶剂、保护基和反应条件。相关信息描述于，例如，R.Larock，Comprehensive Organic  Transformations，VCH出版商(1989)；T.W.Greene和P.G.M.Wuts，Protective Groups in Organic Synthesis，第3版，John Wiley and Sons(1999)；L.Fieser和M.Fieser，Fieser and Fieser’s Reagents for Organic Synthesis，John Wiley and Sons(1994)；及L.Paquette编辑的Encyclopedia of Reagents for Organic Synthesis，John Wiley and Sons(1995)及其后来的版本。
保护基指那些一旦连接活性部分(例如，羟基或氨基)，防止这些部分被后来的反应干扰并可在反应后通过常规的方法去除的基团。羟基保护基的例子包括但不限于，烷基、苯甲基(苄基)、烯丙基、三苯甲基(即，三苯基甲基)、酰基(例如，苯甲酰基、乙酰基或HOOC-X”-CO-，X”为亚烷基、亚链烯基、亚环烷基或亚芳基)、甲硅烷基(例如，三甲基甲硅烷基、三乙基甲硅烷基和叔丁基二甲基甲硅烷基)、烷氧基羰基、氨基羰基(例如，二甲基氨基羰基、甲基乙氨基羰基和苯基氨基羰基)、烷氧甲基、苯甲氧甲基和烷基巯甲基。氨基保护基的例子包括但不限于，烷氧基羰基、烷酰基、芳氧基羰基、芳基取代的烷基等。羟基和氨基保护基已在T.W.Greene和P.G..M.Wuts，Protective Groups in Organic Synthesis，第2版，John Wiley and Sons(1991)中讨论。羟基和氨基保护基都可在反应后通过常规的方法去除。
本发明的另一个目的是提供化合物的分离方法。具体地说，本发明的另一个目的是提供从红曲或其提取物提取化合物5的方法，所述方法包括下列步骤：
Figure PCTCN2016072306-appb-000010
1)对于红曲或其提取物使用乙酸乙酯(或二氯甲烷或甲醇或乙醇，或甲醇/乙醇水溶液)为溶剂进行提取；
2)对于步骤1)的乙酸乙酯(或二氯甲烷或甲醇或乙醇，或甲醇/乙醇水溶液)提取物进行硅胶柱层析分离，用石油醚、乙酸乙酯及、甲醇/乙醇进行梯度洗脱，得到乙酸乙脂洗脱部分；
3)对于步骤2)的乙酸乙脂洗脱部分进行硅胶柱层析分离，用二氯甲烷-乙酸乙脂-甲醇洗脱，将流分进行分析、合并后，得到步骤3)5个流分；
4)对于步骤3)的第2个流分进行C18柱层析分离，用乙腈-甲醇-水梯度洗脱，得到82％(乙腈-甲醇1：1)水溶液洗脱部分；
5)对于步骤4)的82％(乙腈-甲醇1：1)水溶液洗脱部分进一步用二氯甲烷-甲醇为流动相进行sephadex LH-20柱层析分离，将流分进行分析、合并后，得到步骤5)6个流分；
6)对于步骤5)的第3个流分利用色谱方法纯化，以乙腈-甲醇-水为流动相，C18色谱柱为固定相，得到化合物5。
在一个实施方式中，从红曲或其提取物提取化合物5的方法，所述方法包括下列步骤：
1)对于红曲或其提取物使用2-6倍体积的乙酸乙酯(或二氯甲烷或甲醇或乙醇，或甲醇/乙醇水溶液)为溶剂提取3次，每次20-40分钟，合并提取液，减压浓缩并回收溶剂，得乙酸乙脂提取物；
2)对于步骤1)的乙酸乙酯(或二氯甲烷或甲醇或乙醇，或甲醇/乙醇水溶液)提取物进行硅胶柱层析分离，用石油醚、乙酸乙酯及甲醇/乙醇进行梯度洗脱，得到乙酸乙脂洗脱部分；
3)对于步骤2)的乙酸乙脂洗脱部分进行硅胶柱层析分离，用二氯甲烷-乙酸乙脂-甲醇(30：30：1)洗脱，将流分进行分析、合并后，得到步骤3)5个流分；
4)对于步骤3)的第2个流分进行C18柱层析分离，用82％(乙腈-甲醇1：1)水溶液～100％(乙腈-甲醇1：1)梯度洗脱洗脱，得到82％(乙腈-甲醇1：1)水溶液洗脱部分；
5)对于步骤4)的82％(乙腈-甲醇1：1)水溶液洗脱部分进一步用二氯甲烷-甲醇(2：1)为流动相进行sephadex LH-20柱层析分离， 将流分进行分析、合并后，得到步骤5)6个流分；
6)对于步骤5)的第3个流分利用色谱纯化，以乙腈-甲醇-水为流动相，C18色谱柱为固定相，得到化合物5
Figure PCTCN2016072306-appb-000011
本发明还提供了包含本发明式(I)化合物的药物组合物。本发明提供了这样的药物组合物，其包含至少一种如上所述的本发明的式(I)化合物，和任选的药学上可以接受的赋形剂。
制备各种含有一定量的活性成分的药物组合物的方法是已知的，或根据本发明的公开内容对于本领域技术人员是显而易见的。如REMINGTON’S PHARMACEUTICAL SCIENCES,Martin,E.W.,ed.,Mack Publishing Company,19th ed.(1995)所述，制备所述药物组合物的方法包括掺入适当的药学赋形剂、载体、稀释剂等。
以已知的方法制造本发明的药物制剂，包括常规的混合、溶解或冻干方法。本发明的化合物可以制成药物组合物，并向患者以适于选定的施用方式的各种途径施用，例如，口服或肠胃外(通过静脉内、肌内、局部或皮下途径)。
因此，本发明的化合物结合药学上可以接受的载体(如惰性稀释剂或可同化的可食用的载体)可以全身施用，例如，口服。它们可以封闭在硬或软壳的明胶胶囊中，可以压为片剂。对于口服治疗施用，活性化合物可以结合一种或多种赋形剂，并以可吞咽的片剂、颊含片剂、含片、胶囊剂、酏剂、悬浮剂、糖浆、圆片等的形式使用。这种组合物和制剂应该包含至少0.1％的活性化合物。这种组合物和制剂的比例当然可以变化，可以占给定的单位剂型重量的大约1％至大约99％。在这种治疗有用的组合物中，活性化合物的量使得能够获得有效剂量水平。
片剂、含片、丸剂、胶囊剂等也可以包含：粘合剂，如黄蓍胶、阿拉伯胶、玉米淀粉或明胶；赋形剂，如磷酸氢二钙；崩解剂，如玉米淀粉、马铃薯淀粉、藻酸等；润滑剂，如硬脂酸镁；和甜味剂，如蔗糖、果糖、乳糖或阿司帕坦；或调味剂，如薄荷、冬青油或樱桃香味。当单位剂型是胶囊时，除了上面类型的材料，它还可以包含液体载体，如植物油或聚乙二醇。各种其他材料可以存在，作为包衣，或以其他方式改变固体单位剂型的物理形式。例如，片剂、丸剂或胶囊剂可以用明胶、蜡、虫胶或糖等包衣。糖浆或酏剂可以包含活性化合物，蔗糖或果糖作为甜味剂，对羟苯甲酸甲酯或对羟苯甲酸丙酯作为防腐剂，染料和调味剂(如樱桃香料或桔子香料)。当然，用于制备任何单位剂型的任何材料应该是药学上可以接受的且以应用的量基本上无毒。此外，活性化合物可以掺入缓释制剂和缓释装置中。
活性化合物也可以通过输注或注射来静脉内或腹膜内施用。可以制备活性化合物或其盐的水溶液，任选地混和无毒的表面活性剂。也可以制备在甘油、液体聚乙二醇、甘油三乙酸酯及其混合物以及油中的分散剂。在普通的储存和使用条件下，这些制剂包含防腐剂以防止微生物生长。
适于注射或输注的药物剂型可以包括包含适于无菌的可注射或可输注的溶液或分散剂的即时制剂的活性成分(任选封装在脂质体中)的无菌水溶液或分散剂或无菌粉末。在所有情况下，最终的剂型在生产和储存条件下必须是无菌的、液体的和稳定的。液体载体可以是溶剂或液体分散介质，包括，例如水、乙醇、多元醇(例如，甘油、丙二醇、液体聚乙二醇等)、植物油、无毒的甘油酯及其合适的混合物。可以维持合适的流动性，例如，通过脂质体的形成，通过在分散剂的情况下维持所需的粒子大小，或通过表面活性剂的使用。可以通过各种抗细菌剂和抗真菌剂(如对羟苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等)产生预防微生物的作用。在许多情况下，优选包括等渗剂，如糖、缓冲剂或氯化钠。通过使用延缓吸收剂的组合物(例如，单硬脂酸铝和明胶)可以产生可注射的组合物的延长吸收。
通过将合适的溶剂中的需要量的活性化合物与需要的上面列举的各种其他成分结合，然后进行过滤灭菌，制备无菌可注射溶液。在用于制备无菌注射溶液的无菌粉末的情况下，优选的制备方法是真空干燥和冷冻干燥技术，这会产生活性成分加上任何另外需要的以前无菌过滤溶液中存在的成分的粉末。
有用的固体载体包括粉碎的固体(如滑石、粘土、微晶纤维素、二氧化硅、氧化铝等)。有用的液体载体包括水、乙醇或乙二醇或水-乙醇/乙二醇混合物，本发明的化合物可以任选在无毒的表面活性剂的帮助下以有效含量溶解或分散在其中。可以加入佐剂(如香味)和另外的抗微生物剂来优化对于给定用途的性质。
增稠剂(如合成的聚合物、脂肪酸、脂肪酸盐和酯、脂肪醇、改性纤维素或改性无机材料)也可和液体载体用于形成可涂覆的糊剂、凝胶、软膏、肥皂等，直接用于使用者的皮肤上。
化合物或其活性盐或衍生物的治疗需要量，不仅取决于选择的特定的盐，而且取决于施药方式、待治疗的疾病的本质和患者的年龄和状态，最终取决于在场医师或临床医生的决定。
上述制剂可以以单位剂型存在，该单位剂型是含有单位剂量的物理分散单元，适于向人体和其它哺乳动物体给药。单位剂型可以是胶囊或片剂，或是很多胶囊或片剂。根据所涉及的具体治疗，活性成分的单位剂量的量可以在大约0.1到大约1000毫克或更多之间进行变化或调整。
本发明还提供本发明的化合物或包含该化合物的组合物在制备药物、特别是用于抑制HMG-CoA还原酶的药物中的用途。相应地，本发明提供一种治疗预防和/或治疗血脂异常、高血脂症、或动脉粥样硬化患者的方法，包括给予需要治疗的患者治疗有效量的至少一种本发明的化合物。血脂异常即一种或多种与血脂相关的人体指标不在正常数值范围内，包括总胆固醇升高、低密度脂蛋白胆固醇升高、载脂蛋白B升高、甘油三酯升高等。本发明提供一种预防和/或治疗高胆固醇血症、混合型高脂血症患者的方法，包括给予需要治疗的患者治 疗有效量的至少一种本发明的化合物。
本发明提供一种在生活方式干预治疗(如：调整饮食结构、控制体重、增加运动、戒烟)效果不理想时，治疗其总胆固醇升高、低密度脂蛋白胆固醇升高、载脂蛋白B升高、甘油三酯升高等。
本发明化合物的上述用途，可单独使用，或与有效剂量的其他调脂药物联合使用。其他调脂药物包括：胆固醇合成抑制剂(他汀类或其盐类，如洛伐他汀、普伐他汀、辛伐他汀、氟伐他汀、阿托伐他汀、匹伐他汀等)、胆固醇吸收抑制剂(依折麦布等)、贝特类(诺衡、力平脂环丙贝特、苯扎贝特、非诺贝特及吉非贝齐)、烟酸类药物(烟酸、烟酸肌醇酯、东脂平、戊四烟酯等),胆酸螯合剂药物、苯氧芳酸类。
本发明的化合物或其药学上可接受的盐(例如醋酸盐、丙二酸盐、酒石酸盐、琥珀酸盐、盐酸盐、硫酸盐、硝酸盐等)，可用于上述疾病的预防或治疗。
在下列实施例中，将更加具体地解释本发明。但应理解，下列实施例旨在说明本发明而不对本发明的范围构成任何限制。
以下实施例中所用的化学原料均为商购获得或通过本领域熟知的合成方法获得。
实施例1
本发明人通过对于红曲进一步的成分研究，分离纯化得到了一种新的他汀类化合物(化合物5)。
Figure PCTCN2016072306-appb-000012
1.红曲
1)取红曲干粉(北京北大维信生物科技有限公司生产)6kg，用2-6 倍体积的乙酸乙酯(或二氯甲烷或甲醇或乙醇，或甲醇/乙醇水溶液)为溶剂超声提取3次，每次20-40分钟，合并提取液，减压浓缩并回收溶剂，得乙酸乙脂提取物(240g)。
2)取乙酸乙酯提取物进行硅胶柱层析分离，用石油醚、乙酸乙酯及甲醇进行梯度洗脱，得到乙酸乙脂洗脱部分(72g)。
3)取乙酸乙脂洗脱部分进行硅胶柱层析分离，用二氯甲烷-乙酸乙脂-甲醇(30：30：1)洗脱共接收了110个流分，每流分为10ml。经TLC(或HPLC)跟踪检测后，合并色谱行为相同或相似的流分，合并后得到5个流分(分别为合并前的第1-35；36-50；51-65；66-89；90-110流分)。
4)对步骤3)的第2个(合并前36-50流分,16g)流分进行C18柱层析分离，用82％(乙腈-甲醇1：1)水溶液100％(乙腈-甲醇1：1)梯度洗脱，得到82％(乙腈-甲醇1：1)水溶液洗脱部分(3.2g，共接收900ml)。
5)82％(乙腈-甲醇1：1)水溶液洗脱部分进一步用二氯甲烷-甲醇2：1为流动相进行sephadex LH-20柱层析分离,共接收了120个流分，每流分为5ml。经TLC(或HPLC)跟踪检测合并色谱行为相同或相似的流分，合并后得到6个流分(分别为合并前的第1-40；41-65；66-80；81-95；96-110；111-120流分)。
6)将步骤5)的第3个(合并前66-80流分，256mg)流分，最后利用半制备高效液相纯化，以66％(乙腈-甲醇1：1)水溶液为流动相，流速为4ml/min，C18半制备色谱柱(10×250mm,5μm)为固定相，DAD检测器波长为247nm，收集22.8min(21.5-23.5min)的色谱峰流分，多次富集浓缩得到新化合物(化合物5)约13mg。
2.血脂康
1)取血脂康胶囊(北京北大维信生物科技有限公司)内容物干粉3kg，用2-6倍体积的乙酸乙酯(或二氯甲烷或甲醇)为溶剂超声提取3次，每次20-40分钟，合并提取液，减压浓缩并回收溶剂，得乙酸乙脂提取物(200g)。
2)取乙酸乙酯提取物进行硅胶柱层析分离，用石油醚、乙酸乙酯及甲醇进行梯度洗脱，得到乙酸乙脂洗脱部分(60g)。
3)取乙酸乙脂洗脱部分进行硅胶柱层析分离，用二氯甲烷-乙酸乙脂-甲醇(30：30：1)洗脱，共接收了110个流分，每流分为10ml。经TLC(或HPLC)跟踪检测合并色谱行为相同或相似的流分后，得到步骤3)5个流分(分别为合并前的第1-35；36-50；51-65；66-89；90-110流分)。
4)对步骤3)第2个(合并前36-50流分,14g)流分进行C18柱层析分离，用82％(乙腈-甲醇1：1)水溶液～100％(乙腈-甲醇1：1)梯度洗脱，得到82％(乙腈-甲醇1：1)水溶液洗脱部分(2.8g)。
5)82％(乙腈-甲醇1：1)水溶液洗脱部分进一步用二氯甲烷-甲醇2：1为流动相进行sephadex LH-20柱层析分离，共接收了120个流分，每流分为5ml。经TLC(或HPLC)跟踪检测合并色谱行为相同或相似的流分，合并后得到步骤5)6个流分(分别为合并前的第1-40；41-65；66-80；81-95；96-110；111-120流分)。
6)对步骤5)第3个(合并前66-80流分，208mg)流分，最后利用半制备高效液相纯化，以66％(乙腈-甲醇1：1)水溶液为流动相，流速为4ml/min，C18半制备色谱柱(10×250mm,5μm)为固定相，DAD检测器波长为247nm，收集22.8min(21.5-23.5min)的色谱峰流分，多次富集浓缩得到新化合物(化合物5)约11.5mg。
本发明也可使用其他红曲原料或制剂为原料，如血脂康片(北京北大维信生物科技有限公司)。
实施例2：化合物5的合成与鉴定
方法A：
Figure PCTCN2016072306-appb-000013
1.化合物2的合成
20.9g(0.05mol)的化合物1(辛伐他汀，购自sigma)溶于500ml二氯甲烷中，加入12g(0.07mol)的间氯过氧苯甲酸，室温搅拌40min，反应结束后，加入饱和碳酸氢钠溶液，静置分层，依次用饱和碳酸氢钠、饱和食盐水洗涤，有机层干燥浓缩，不经分离直接进行下一步反应。
2.化合物3的合成
在250ml四氢呋喃中加入0.085mol的二乙胺和0.075mol的叔丁醇，冰浴搅拌下，加入0.15mmol的正丁基锂，搅拌20min，将上述步骤合成的混合物加入反应中，继续冰浴搅拌反应，TLC监测，反应结束后依次用水和饱和食盐水洗涤，有机层用无水硫酸钠干燥，浓缩，所得混合物经柱层析分离，得4.36g化合物3，收率21％。
3.化合物4的合成
将13g化合物3(0.03mol)溶于60ml氯仿中，盐酸调节溶液PH至酸性，室温搅拌过夜，依次用10％的硫代硫酸钠、水、饱和食盐水洗 涤，减压蒸除有机溶剂得粗品，经柱层析分离得5.96g化合物4，收率62％。
4.化合物5的合成
氮气保护下，7g化合物4溶于150ml甲醇中，加入0.3mol的四丁基胺硫酸氢盐，加热搅拌反应，TCL监测反应，反应结束后减压除去溶剂，剩余物溶于150ml混合溶液(水：庚烷＝1:1)中，搅拌2小时。分离有机层，无水硫酸钠干燥，抽滤，浓缩得6.82g目标化合物5，收率88％。
或方法B：
Figure PCTCN2016072306-appb-000014
1.化合物2b的合成
20.2g(0.05mol)的化合物1(洛伐他汀，购自sigma)溶于500ml二氯甲烷中，加入12g(0.07mol)的间氯过氧苯甲酸，室温搅拌40min，反应结束后，加入饱和碳酸氢钠溶液，静置分层，依次用饱和碳酸氢钠、饱和食盐水洗涤，有机层干燥浓缩，不经分离直接进行下一 步反应。
2.化合物3b的合成
在250ml四氢呋喃中加入0.085mol的二乙胺和0.075mol的叔丁醇，冰浴搅拌下，加入0.15mmol的正丁基锂，搅拌20min，将上述步骤合成的混合物加入反应中，继续冰浴搅拌反应，TLC监测，反应结束后依次用水和饱和食盐水洗涤，有机层用无水硫酸钠干燥，浓缩，所得混合物经柱层析分离，得4.22g化合物3b，收率21％。
3.化合物4的合成
将12.6g化合物3b(0.03mol)溶于60ml氯仿中，盐酸调节溶液PH至酸性，室温搅拌过夜，依次用10％的硫代硫酸钠、水、饱和食盐水洗涤，减压蒸除有机溶剂得粗品，经柱层析分离得5.96g化合物4，收率62％。
4.化合物5的合成
氮气保护下，7g化合物4溶于150ml甲醇中，加入0.3mol的四丁基胺硫酸氢盐，加热搅拌反应，TCL监测反应，反应结束后减压除去溶剂，剩余物溶于150ml混合溶液(水：庚烷＝1:1)中，搅拌2小时。分离有机层，无水硫酸钠干燥，抽滤，浓缩得6.82g目标化合物5，收率88％。
化合物5的结构鉴定方法为：
1.化合物的理化数据
淡黄色油状物，
UV光谱中有三个最大吸收峰，分别为λmax(CH2Cl2)＝226.8nm,265.4nm,301.2nm。
FT-IR(KBr,cm-1)光谱：3422(-OH)，3013，2952(饱和碳氢)，1732(羰基)。
HR-ESI-MS：m/z 355.1886[M+Na]+(计算值为355.1885，C20H28O4Na)。
2.结构式的确定
分析该化合物的碳谱(13C-NMR及DEPT)，有20个碳原子,分别为甲基3个(其中甲氧基1个，与sp2碳相连的甲基1个)，亚甲基4个，次甲基9个(其中5个为sp2碳)及季碳为4个(其中一个为羰基碳)，同时也可以发现烯碳区有8个碳原子(δ126.9,126.9,127.2,127.5,133.4,134.6,135.9,136.1)。从1H-1H COSY相关信号图(附图1A)中可以推断出用粗线表示的C2’到C4的片段和C7-C8片段。从烯碳区的8个碳原子可以推断该化合物有4个C＝C。进一步分析HMBC相关信号，可以发现6-Me与C5，C7；H-5与C6，C7；H-4与C5，C8a；H-3与C4a；H-1与C8a，C4a；H-8与C8a，C4a等之间的相关信号，从此可以推断该化合物具有1，2-二氢萘环部分的他汀母核。从HMBC图谱(附图1AB)中，还发现甲氧基的甲基(δ3.69)，H-2’(δ2.46/2.48)和H-3’(δ2.45)与C1’(δ173.0)之间有相关信号，这表明甲氧基与C1’相连，从而可以推断该化合物是甲酯化的他汀类似物。进一步结合HR-ESI-MS结果，推断该化合物为：7-(2,6-二甲基-1,2-二氢萘-1-基)-3,5-二羟基庚酸甲酯(methyl 7-(2,6-dimethyl-1,2-dihydronaphthalen-1-yl)-3,5-dihydroxyheptanoate)。结构式为图1中所表示。
3.化合物5的NMR数据
表1.化合物5的NMR数据(600MHz,CDCl3,δ以ppm表示,J以Hz表示)
Figure PCTCN2016072306-appb-000015
Figure PCTCN2016072306-appb-000016
实施例3：化合物5a的合成
Figure PCTCN2016072306-appb-000017
1.化合物5a的合成
氮气保护下，7.4g化合物4a溶于150ml甲醇中，加入0.3mol的四丁基胺硫酸氢盐，加热搅拌反应，TCL监测反应，反应结束后减压除去溶剂，剩余物溶于150ml混合溶液(水：庚烷＝1:1)中，搅拌2小时。分离有机层，无水硫酸钠干燥，抽滤，浓缩得6.91g目标化合物5a，收率85％。
实施例4
HMG-CoA还原酶抑制活性实验
1实验材料
1.1药品
化合物5---自制
洛伐他汀标准品---购于Sigma公司
1.2酶
大鼠肝脏微粒体(HMG-CoA还原酶)商购，或者参照下述方法制备：取出雄性大鼠的肝脏，用KESD缓冲液冲洗之后，12,000g离心15min，取上清液。再用105,000g离心90min两次之后，收集离心沉淀。离心沉淀里加入8.3％甘油，用37℃温浴加热1h。大鼠肝脏微粒体粗体物用饱和硫酸铵纯化并收集35-50％纯化部分即得。得到的大鼠肝脏微粒体存放在-80℃冰箱中。
1.3试剂
氯化钾，磷酸二氢钾,乙二胺四乙酸,二硫苏糖醇---购于北京化学试剂公司
烟酰胺腺嘌呤二核苷酸(NADPH)---购于Merck公司
3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)----购于Sigma公司
2实验方法
将化合物5用75％乙醇溶液溶解，初浓度为8.6mg/ml并逐级稀释，得4.3mg/ml，2.15mg/ml；测定体系中总体积为250μl，各成分的浓度为：氯化钾200mM,磷酸二氢钾160mM,乙二胺四乙酸4mM，二硫苏糖醇10mM，两个底物烟酰胺腺嘌呤二核苷酸和3-羟基-3-甲基戊二酰辅酶A的浓度分别为200μM和50μM,pH6.8,酶加30μl,试验组加5μl，对照组加5μl(溶解样品溶剂)，在Versamax酶标仪上37℃条件下检测OD340的动态变化。通过检测OD340在5分钟内下降的快慢(以斜率值表示)，来评价HMG-CoA还原酶活性的强弱，进而评价酶抑制剂活性的强弱，结果见表2。
3实验结果
实验结果表明，化合物5对HMG-CoA还原酶的活性有抑制作用，且呈浓度-效应关系。表明该化合物对HMG-CoA还原酶的活性有较好的抑制作用。
表2.酶抑制剂活性检测结果
Figure PCTCN2016072306-appb-000018
*空白对照为溶剂
洛伐他汀是阳性对照。

Claims (26)

  1. 下式(I)的化合物或其立体异构体、互变异构体、外消旋物、代谢产物、前药、药学上可接受的盐或溶剂化物：
    Figure PCTCN2016072306-appb-100001
    R1选自H、C1-C6烷基、卤代C1-C6烷基、(CH2)1-6OH、C3-C7环烷基、卤代C3-C7环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基、卤素、硝基、氨基和氰基；
    R2选自H、C1-C6烷基、卤代C1-C6烷基、(CH2)1-6OR6、C3-C7环烷基、卤代C3-C7环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基、卤素、硝基、氨基和氰基；
    R3选自H、C1-C6烷基；
    R4和R5各自独立地选自：H、-COR7、-SO2R8、-Si R9R10R11；
    其中，R7选自C1-C6烷基、卤代C1-C6烷基，R8选自C1-C6烷基、任意取代的C1-C6烷基、C6-C10芳基、任意取代的C6-C10芳基，R9、R10、R11独立地选自C1-C6烷基；
    其中，R6与上述对于R4和R5的定义相同；
    其中，排除以下式(I)的化合物：R1为(CH2)OH，R2为甲基，R3、R4和R5为H。
  2. 根据权利要求1的化合物，其中，
    R1选自H、C1-C3烷基、卤代C1-C3烷基、(CH2)1-3OH、C3-C6环烷基、卤代C3-C6环烷基、C1-C3烷氧基、卤代C1-C3烷氧基、C1-C3烷硫基、卤代C1-C3烷硫基、卤素、硝基、氨基和氰基。
  3. 根据权利要求1的化合物，其中，
    R1选自H、C1-C3烷基、卤代C1-C3烷基、(CH2)1-3OH、卤素、硝基、氨基和氰基。
  4. 根据权利要求1的化合物，其中
    R1选自H、C1-C3烷基、(CH2)1-3OH。
  5. 根据权利要求1－4中任一项的化合物，其中
    R2选自H、C1-C3烷基、卤代C1-C3烷基、(CH2)1-3OR6、C3-C6环烷基、卤代C3-C6环烷基、C1-C3烷氧基、卤代C1-C3烷氧基、C1-C3烷硫基、卤代C1-C3烷硫基、卤素、硝基、氨基和氰基；
    其中，R6选自H、-COR7、-SO2R8、-Si R9R10R11；
    其中，R7选自C1-C6烷基、卤代C1-C6烷基，R8选自C1-C6烷基、任意取代的C1-C6烷基、C6-C10芳基、任意取代的C6-C10芳基，R9、R10、R11独立地选自C1-C6烷基。
  6. 根据权利要求1－4中任一项的化合物，其中
    R2选自H、C1-C3烷基、卤代C1-C3烷基、(CH2)1-3OR6、C3-C6环烷基、卤代C3-C6环烷基、C1-C3烷氧基、卤代C1-C3烷氧基、C1-C3烷硫基、卤代C1-C3烷硫基、卤素、硝基、氨基和氰基；
    其中，R6选自：H、-COR7、-SO2R8、-SiR9R10R11；
    其中，R7选自C1-C3烷基、卤代C1-C3烷基，R8选自C1-C3烷基、任意取代的C1-C3烷基、C6-C10芳基、任意取代的C6-C10芳基，R9、R10、R11独立地选自C1-C6烷基。
  7. 根据权利要求1－4中任一项的化合物，其中
    R2选自H、C1-C3烷基、卤代C1-C3烷基、(CH2)1-3OR6、C3-C6环烷基、卤代C3-C6环烷基、C1-C3烷氧基、卤代C1-C3烷氧基、C1-C3烷硫基、卤代C1-C3烷硫基、卤素、硝基、氨基和氰基；
    其中，R6选自：H、-COR7、-SO2R8、-SiR9R10R11；
    其中，R7选自-CH3，R8选自-CF3、对甲苯基，R9、R10、R11独立地选自甲基、叔丁基。
  8. 根据权利要求1－4中任一项的化合物，其中
    R2选自H、C1-C3烷基、卤代C1-C3烷基、(CH2)1-3OR6、卤素、硝基、氨基和氰基；
    其中，R6选自H、-COR7、-SO2R8、-Si R9R10R11；
    其中，R7选自C1-C6烷基、卤代C1-C6烷基，R8选自C1-C6烷基、任意取代的C1-C6烷基、C6-C10芳基、任意取代的C6-C10芳基，R9、R10、R11独立地选自C1-C6烷基。
  9. 根据权利要求1－4中任一项的化合物，其中
    R2选自H、C1-C3烷基、卤代C1-C3烷基、(CH2)1-3OR6、卤素、硝基、氨基和氰基；
    其中，R6选自：H、-COR7、-SO2R8、-SiR9R10R11；
    其中，R7选自C1-C3烷基、卤代C1-C3烷基，R8选自C1-C3烷基、任意取代的C1-C3烷基、C6-C10芳基、任意取代的C6-C10芳基，R9、R10、R11独立地选自C1-C6烷基。
  10. 根据权利要求1－4中任一项的化合物，其中
    R2选自H、C1-C3烷基、卤代C1-C3烷基、(CH2)1-3OR6、卤素、硝基、氨基和氰基；
    其中，R6选自：H、-COR7、-SO2R8、-SiR9R10R11；
    其中，R7选自-CH3，R8选自-CF3、对甲苯基，R9、R10、R11独立地选自甲基、叔丁基。
  11. 根据权利要求1－4中任一项的化合物，其中
    R2选自H、C1-C3烷基、(CH2)1-3OR6；
    其中，R6选自H、-COR7、-SO2R8、-Si R9R10R11；
    其中，R7选自C1-C6烷基、卤代C1-C6烷基，R8选自C1-C6烷基、任意取代的C1-C6烷基、C6-C10芳基、任意取代的C6-C10芳基，R9、R10、R11独立地选自C1-C6烷基。
  12. 根据权利要求1－4中任一项的化合物，其中
    R2选自H、C1-C3烷基、(CH2)1-3OR6；
    其中，R6选自H、-COR7、-SO2R8、-Si R9R10R11；
    其中，R7选自C1-C3烷基、卤代C1-C3烷基，R8选自C1-C3烷基、任意取代的C1-C3烷基、C6-C10芳基、任意取代的C6-C10芳基，R9、R10、R11独立地选自C1-C6烷基。
  13. 根据权利要求1－4中任一项的化合物，其中
    R2选自H、C1-C3烷基、(CH2)1-3OR6；
    其中，R6选自H、-COR7、-SO2R8、-Si R9R10R11；
    其中，R7选自-CH3，R8选自-CF3、对甲苯基，R9、R10、R11独立地选自甲基、叔丁基。
  14. 根据权利要求1－13中任一项的化合物，其中
    R3选自H、C1-C3烷基。
  15. 根据权利要求1－13中任一项的化合物，其中
    R3为C1-C3烷基。
  16. 根据权利要求1－15中任一项的化合物，其中
    R4和R5各自独立地选自：H、-COR7、-SO2R8、-SiR9R10R11；
    其中，R7选自C1-C3烷基、卤代C1-C3烷基，R8选自C1-C3烷基、任意取代的C1-C3烷基、C6-C10芳基、任意取代的C6-C10芳基，R9、R10、R11独立地选自C1-C6烷基。
  17. 根据权利要求1－15中任一项的化合物，其中
    R4和R5各自独立地选自：H、-COR7、-SO2R8、-SiR9R10R11；
    其中，R7选自-CH3，R8选自-CF3、对甲苯基，R9、R10、R11独立地选自甲基、叔丁基。
  18. 以下化合物，其选自：
    Figure PCTCN2016072306-appb-100002
    及其二乙酸酯、二对甲苯磺酯、二(三氟甲磺酸酯)、二(叔丁基二甲基硅醚)；
    Figure PCTCN2016072306-appb-100003
    及其三乙酸酯、三对甲苯磺酯、三(三氟甲磺酸酯)、三(叔丁基二甲基硅醚)。
  19. 一种药物组合物，其包含权利要求1－18中任一项的化合物和任选的药学上可以接受的赋形剂。
  20. 权利要求1－18中任一项的化合物用于制备药物的用途，其中所述药物用于抑制HMG-CoA还原酶活性。
  21. 权利要求1－18中任一项的化合物用于制备药物的用途，其中所述药物用于抑制胆固醇合成。
  22. 从红曲或其提取物提取化合物5的方法，所述方法包括下列步骤：
    Figure PCTCN2016072306-appb-100004
    1)对于红曲或其提取物使用乙酸乙酯(或二氯甲烷或甲醇或乙醇、或甲醇/乙醇水溶液)为溶剂进行提取；
    2)对于步骤1)的乙酸乙酯(或二氯甲烷或甲醇或乙醇、或甲醇/乙醇水溶液)提取物进行硅胶柱层析分离，用石油醚、乙酸乙酯及甲醇进行梯度洗脱，得到乙酸乙脂洗脱部分；
    3)对于步骤2)的乙酸乙脂洗脱部分进行硅胶柱层析分离，用二氯甲烷-乙酸乙脂-甲醇洗脱，对流分进行检测、合并，合并后得到步骤3)流分；
    4)对于步骤3)第2个流分进行C18柱层析分离，用乙腈-甲醇-水梯度洗脱，得到82％(乙腈-甲醇1：1)水溶液洗脱部分；
    5)对于步骤4)的82％(乙腈-甲醇1：1)水溶液洗脱部分进一步用二氯甲烷-甲醇为流动相进行sephadex LH-20柱层析分离，对流分分析、合并，合并后得到步骤5)流分；
    6)对于步骤5)的第3个流分利用色谱方法纯化，得到化合物5。
  23. 根据权利要求22的方法，其中，
    1)对于红曲或其提取物使用2-6倍体积的乙酸乙酯(或二氯甲烷或甲醇或乙醇、或甲醇/乙醇水溶液)为溶剂提取3次，每次20-40分钟，合并提取液，减压浓缩并回收溶剂，得乙酸乙脂提取物；
    2)对于步骤1)的乙酸乙酯(或二氯甲烷或甲醇或乙醇、或甲醇/乙醇水溶液)提取物进行硅胶柱层析分离，用石油醚、乙酸乙酯及甲醇或乙醇、或甲醇/乙醇水溶液进行梯度洗脱，得到乙酸乙脂洗脱部分；
    3)对于步骤2)的乙酸乙脂洗脱部分进行硅胶柱层析分离，用二氯甲烷-乙酸乙脂-甲醇(30：30：1)洗脱、合并流分，合并后得到5个流分；
    4)对于步骤3)合并后的第2个流分进行C18柱层析分离，用82％(乙腈-甲醇1：1)水溶液～100％(乙腈-甲醇1：1)梯度洗脱洗脱，得到82％(乙腈-甲醇1：1)水溶液洗脱部分；
    5)对于步骤4)的82％(乙腈-甲醇1：1)水溶液洗脱部分进一步用二氯甲烷-甲醇(2：1)为流动相进行sephadex LH-20柱层析分离，合并后得到步骤5)6个流分；
    6)对于步骤5)的第3个流分利用色谱纯化，以乙腈-甲醇-水为流动相，C18色谱柱为固定相，得到化合物5
    Figure PCTCN2016072306-appb-100005
  24. 合成前述权利要求1－17中任一项中的式(I)化合物以及权利要求18中的化合物5和化合物5a的方法：
    将式(II)化合物在碱性条件下反应，或在碱性条件下加入成酯试剂反应，制得式(I)的化合物，
    Figure PCTCN2016072306-appb-100006
    其中，式(II)中R1、R2和R4与前述权利要求1－17中任一项中的式(I)中的定义相同，
    碱性条件的pH范围为7.5-14，可选加入氢氧化钠、氢氧化钾、氨水、碳酸钠等碱性试剂或溶剂；成酯试剂可选自甲醇、乙醇等低级醇；酸酐(醋酸酐、磺酸酐、三氟甲磺酸酐等)、酰氯(甲苯磺酰氯)、氯硅烷(叔丁基二甲基氯硅烷)。
  25. 化合物5的合成方法：
    Figure PCTCN2016072306-appb-100007
  26. 化合物5的合成方法：
    Figure PCTCN2016072306-appb-100008
PCT/CN2016/072306 2015-02-04 2016-01-27 化合物、其分离方法、合成方法及用途 WO2016124087A1 (zh)

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JP2017541085A JP6686032B2 (ja) 2015-02-04 2016-01-27 化合物、その分離方法、合成方法及び使用
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