CN105017231B - Polysubstituted fluorine-containing trim of indoles statin and application thereof - Google Patents

Polysubstituted fluorine-containing trim of indoles statin and application thereof Download PDF

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CN105017231B
CN105017231B CN201510364691.8A CN201510364691A CN105017231B CN 105017231 B CN105017231 B CN 105017231B CN 201510364691 A CN201510364691 A CN 201510364691A CN 105017231 B CN105017231 B CN 105017231B
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acid
compound
fluoro
indoles
carbon atom
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CN105017231A (en
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汪忠华
吴范宏
李兵
俞晓东
吕倩倩
吴闯
苏飞飞
巫辅龙
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SHANGHAI HUALI BIOMEDICAL Co.,Ltd.
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SHANGHAI HUALI BIOPHARMACEUTICAL CO Ltd
Shanghai Institute of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

The invention belongs to medicinal chemistry art, provide a kind of phthalein CoA-reductase inhibitors of 3 methylpent of 3 hydroxyl two, it is a kind of fluorine-containing trim of poly-substituted miazines statin containing the hydroxypentanoic acid of 1 fluorine 3 and its salt or ester that are formed after 3 fluorine caprolactone fragments and its lactone open loop, its structural formula is described below：

Description

Polysubstituted fluorine-containing trim of indoles statin and application thereof
Technical field
The invention belongs to medicinal chemistry art, more particularly to a kind of statins, a kind of specifically polysubstituted Yin Fluorine-containing trim of diindyl class statin and application thereof.
Background technology
High fat of blood is the inducement of various cardiovascular and cerebrovascular diseases, and population epidemiology investigation shows, for Chinese male crowd For, low-density lipoprotein (lipid forms lipoprotein with albumin combination mostly and existed in blood of human body) concentration often raises 1mmol/L can make Incidence of CHD rise 36%, and ischemic cerebral apoplexy risk increases by 31%, in world today's " three high " (high fat of blood, hypertension, hyperglycaemia) is the risk factors or its direct illness of various diseases.Various medical science and biological metabolism Research has shown that, the phthalein CoA-reductase of 3- hydroxy-3-methyls penta 2 in blood of human body in the content and liver of blood fat (lipoprotein) (3-Hydroxy-3-methylglutaryl-CoA Reductase, HMGR) activity has conclusive association：The same bottom of HMGR enzymes The phthalein coacetylase (3-Hydroxy-3-methylglutaryl-CoA, HMG-CoA) of thing 3- hydroxy-3-methyls penta 2, which combines, occurs two It is secondary be related to four electronics transfer reduction reaction and generate the critical materials 3,5- dihydroxy-acids of human body lipid synthesis.3- hydroxyls- The phthalein CoA-reductase inhibitors of 3- methylpents two (i.e. commercially available statins) are main flow hypolipidemics on the market Thing, wherein by Pfizer Inc.'s development and sale Atorvastatin calcium preparation by 2008 annual sales amounts be 12,400,000,000 dollars, may Claim " cookle " in medical history.The type medicine through metabolism in human body due to that can expose same HMGR enzymes bound substrates HMG-CoA identicals 3,5- dihydroxy-acid structures, while it will be far longer than normal substrate with HMGR binding ability HMG-coA (the K that HMG-CoA combines with HMGRmFor the umol/L orders of magnitude, and the IC of statins50In the nmol/L orders of magnitude, So statins can fight for HMGR active site after entering human body, and then prevent knots of the HMGR with HMG-coA Close, that is, inhibit conversions of the HMG-CoA to 3,5- dihydroxy-acids, and then the final synthesis for inhibiting people's body lipid.
The Fluvastatin of statins from its proto-drug the most is found to first generation Lovastatin in the U.S. by writing from memory Since the exploitation list marketing of gram company, it has been subjected to natural fermented statin, artificial synthesized statin, third generation superstatin three Stage.With the research and development that deepens continuously of the mechanism of action to statins and Computeraided drug design, Recognize that fluorine atom is introduced in the appropriate site of existing statins or its analog to be pressed down to the HMGR enzymes for improving drug molecule System activity or the toxic side effect for reducing medicine have effect.Foreign patent such as United States Patent (USP) US5409820, US4965200, US5622985, US5691173, US20020183527, US4681893, US5354772, USRE37314, US685868, US6465447, US5753675, US5856336, US7022713, US5854259 and Canadian Patent CA1323836, The Chinese patent such as CA2072945 CN101580497A, CN101230055A, CN1539417A and document (Science, 2001 (292):3S all directly or indirectly 1160-1164) etc. is asserted, 5R-3,5- dihydroxy-acid structures are the 3- hydroxy-3-methyls The active necessary structure of penta 2 phthalein CoA-reductase inhibitors (statins), thus the Statins listed on the market Lipidemia medicine is all the class formation, and existing patent also all remains this must structure
However, statins also has adverse reaction, such as：Hepatopathy, carcinogenic toxicity, particularly muscle side reaction, band Myolysis, just because of this serious toxic side effect so that cerivastatin (cerivastatin) removes city.
The content of the invention
For above-mentioned technical problem of the prior art, the invention provides a kind of polysubstituted fluorine-containing modification of indoles statin Thing and application thereof, the described this polysubstituted fluorine-containing trim of indoles statin and application thereof will solve statin of the prior art Class medicine easily produces disease of the liver, carcinogenic toxicity, muscle side reaction, the technical problem of rhabdomyolysis.
The invention provides a kind of compound, its structural formula as shown in formula I,
Wherein, R1, R2 be hydrogen, the straight chain saturation of 1-10 carbon atom or unsaturated alkyl, cyclopropyl, phenyl, methoxyl group, Or ethyoxyl, R3, R4 be hydrogen, the straight chain saturation of 1-10 carbon atom or unsaturated alkyl, cyclopropyl, phenyl, methoxyl group or Person's ethyoxyl, R5, R6, R7, R8, R9, R10 are respectively hydrogen, hydroxyl, hydroxyl with being taken containing carboxylate formed by 1-3 carbon atom It is former for 1-10 carbon of group, hydrocarbyl ether, the halogen of 1-3 carbon atom, or the halogenated hydrocarbons of 1-3 carbon atom, straight or branched The hydrocarbyl group of son, the cycloalkane of 3-7 carbon atom, substituted aroma ring, the straight chain saturation of 1-10 carbon atom or unsaturated alkane Base, cyclopropyl, phenyl, methoxyl group or ethyoxyl.
Further, in the hydrocarbyl group of 1-10 carbon atom of straight or branched, optionally substituted by one or more Group substitutes, and the substituent is selected from：The simple substitution for including 1-3 carbon atom of halogen atom, hydroxyl or straight or branched Group.
Further, in the cycloalkane of 3-7 carbon atom, optionally substituted by one or more substituted radicals, it is described to take Dai Ji is selected from：The simple substituted radical for including 1-3 carbon atom of halogen atom, hydroxyl or straight or branched.
Further, in substituted aroma ring, substituted radical includes the alkyl or hydrocarbyl ether of halogen, 1-3 carbon atom.
Further, described indole ring quilt Five yuan or hexa-atomic full Substituted with the rigid heterocyclic of, insatiable hunger and/or fragrance.
Further, compound name of the invention is the fluoro- 6- of (4S, 6S) -4- (2- (3- (4- fluorophenyls) -1- isopropyls Base -1H- indoles -2- bases) vinyl) tetrahydrochysene -2H- pyran-2-ones, its structural formula as shown in 001,
Further, compound name of the invention is the fluoro- 6- of (4S, 6R) -4- (2- (3- (4- fluorophenyls) -1- isopropyls Base -1H- indoles -2- bases) ethyl) tetrahydrochysene -2H- pyran-2-ones, its structural formula as shown in 002,
Present invention also offers a kind of pharmaceutical composition, the compound of above-mentioned (I) (001), (002) containing effective dose, Or its salt or its ester, stereoisomer or optical isomer.
Present invention also offers the compound of above-mentioned (I) (001), (002) to prepare for treating reduction blood lipid level Application in medicine.
Present invention also offers above-mentioned (I) (001), (002) compound prepare be used for treat coronary heart disease, high fat of blood draws Application in the medicine for the high fat of blood that the atherosclerosis or diabetes of hair trigger.
Present invention also offers a kind of compound, its structural formula as shown in formula I I,
Wherein, R1, R2 be hydrogen, the straight chain saturation of 1-10 carbon atom or unsaturated alkyl, cyclopropyl, phenyl, methoxyl group, Or ethyoxyl, R3, R4 be hydrogen, the straight chain saturation of 1-10 carbon atom or unsaturated alkyl, cyclopropyl, phenyl, methoxyl group or Person's ethyoxyl, R5, R6, R7, R8, R9, R10 are respectively hydrogen, hydroxyl, hydroxyl with being taken containing carboxylate formed by 1-3 carbon atom It is former for 1-10 carbon of group, hydrocarbyl ether, the halogen of 1-3 carbon atom, or the halogenated hydrocarbons of 1-3 carbon atom, straight or branched The hydrocarbyl group of son, the cycloalkane of 3-7 carbon atom, substituted aroma ring, the straight chain saturation of 1-10 carbon atom or unsaturated alkane Base, cyclopropyl, phenyl, methoxyl group or ethyoxyl, X are straight or branched alkyl, straight chain or the branch of hydrogen, 1-10 carbon atom The unitary or polynary acyl group of 1-20 carbon of chain, the cyclic hydrocarbon radical of 3-7 carbon atom, the fragrant acyl that is substituted by 0 to 5 substituents Base or inorganic oxacid acyl group, M are sodium ion, potassium ion, ammonium ion, calcium ion or magnesium ion.
Further, in the hydrocarbyl group of 1-10 carbon atom of straight or branched, optionally substituted by one or more Group substitutes, and the substituent is selected from：The simple substitution for including 1-3 carbon atom of halogen atom, hydroxyl or straight or branched Group.
Further, in the cycloalkane of 3-7 carbon atom, optionally substituted by one or more substituted radicals, it is described to take Dai Ji is selected from：The simple substituted radical for including 1-3 carbon atom of halogen atom, hydroxyl or straight or branched.
Further, in substituted aroma ring, substituted radical includes the alkyl or hydrocarbyl ether of halogen, 1-3 carbon atom.
Further, described indole ring quilt Five yuan or hexa-atomic full Substituted with the rigid heterocyclic of, insatiable hunger and/or fragrance.
Further, compound name of the invention be the fluoro- 7- of (3S, 5S) -3- (3- (4- fluorophenyls) -1- isopropyls - - 2-vinyl of 1H- indoles)-5- hydroxyl-6- enanthic acid sodium, its structural formula as shown in 003,
Further, compound name of the invention be the fluoro- 7- of (3S, 5S) -3- (3- (4- fluorophenyls) -1- isopropyls - - 2-ethyl of 1H- indoles)-5- hydroxyl-6- enanthic acid sodium, its structural formula as shown in 004,
Further, compound name of the invention be the fluoro- 7- of (3S, 5S) -3- (3- (4- fluorophenyls) -1- isopropyls - - 2-vinyl of 1H- indoles)-5- hydroxyl-6- Semi-Heptanoic Acid Calcium Salts, its structural formula as shown in 004,
Further, compound name of the invention be the fluoro- 7- of (3S, 5S) -3- (3- (4- fluorophenyls) -1- isopropyls - - 2-ethyl of 1H- indoles)-5- hydroxyl-6- Semi-Heptanoic Acid Calcium Salts, its structural formula as shown in 006,
Present invention also offers a kind of pharmaceutical composition, above-mentioned (I I), (003), (004), (005) containing effective dose, (006) compound or its salt or its ester, stereoisomer or optical isomer.
Present invention also offers the compound of above-mentioned (I I), (003), (004), (005), (006) to prepare for treating Reduce the application in the medicine of blood lipid level.
Present invention also offers the compound of above-mentioned (I I), (003), (004), (005), (006) to prepare for treating Application in the medicine for the high fat of blood that the atherosclerosis or diabetes that coronary heart disease, high fat of blood trigger trigger.
Present invention also offers a kind of compound, its structural formula as shown in formula III,
Wherein, R1, R2 be hydrogen, the straight chain saturation of 1-10 carbon atom or unsaturated alkyl, cyclopropyl, phenyl, methoxyl group, Or ethyoxyl, R3, R4 be hydrogen, the straight chain saturation of 1-10 carbon atom or unsaturated alkyl, cyclopropyl, phenyl, methoxyl group or Person's ethyoxyl, R5, R6, R7, R8, R9, R10, R11 are respectively hydrogen, hydroxyl, hydroxyl with containing carboxylic acid formed by 1-3 carbon atom Hydrocarbyl ether, the halogen of ester substituted radical, 1-3 carbon atom, or 1-10 of the halogenated hydrocarbons of 1-3 carbon atom, straight or branched The hydrocarbyl group of carbon atom, the cycloalkane of 3-7 carbon atom, substituted aroma ring, the straight chain saturation of 1-10 carbon atom or insatiable hunger With alkyl, cyclopropyl, phenyl, methoxyl group or ethyoxyl, X is straight or branched alkyl, the straight chain of hydrogen, 1-10 carbon atom Or the unitary of 1-20 carbon of side chain or polynary acyl group, the cyclic hydrocarbon radical of 3-7 carbon atom, the fragrance that is substituted by 0 to 5 substituents Acyl group or inorganic oxacid acyl group.
Further, in the hydrocarbyl group of 1-10 carbon atom of straight or branched, optionally substituted by one or more Group substitutes, and the substituent is selected from：The simple substitution for including 1-3 carbon atom of halogen atom, hydroxyl or straight or branched Group.
Further, in the cycloalkane of 3-7 carbon atom, optionally substituted by one or more substituted radicals, it is described to take Dai Ji is selected from：The simple substituted radical for including 1-3 carbon atom of halogen atom, hydroxyl or straight or branched.
Further, in substituted aroma ring, substituted radical includes the alkyl or hydrocarbyl ether of halogen, 1-3 carbon atom.
Further, described indole ring quilt Five yuan or hexa-atomic full Substituted with the rigid heterocyclic of, insatiable hunger and/or fragrance.
Further, compound name of the invention be the fluoro- 7- of (3S, 5S) -3- (3- (4- fluorophenyls) -1- isopropyls - - 2-vinyl of 1H- indoles)-5- hydroxyl-6- methyl heptanoates, its structural formula as shown in 007,
Further, compound name of the invention be the fluoro- 7- of (3S, 5S) -3- (3- (4- fluorophenyls) -1- isopropyls - - 2-yl of 1H- indoles)-5- hydroxyl-6- methyl heptanoates, its structural formula as shown in 008,
Further, compound name of the invention be the fluoro- 7- of (3S, 5S) -3- (3- (4- fluorophenyls) -1- isopropyls - 1H- indoles -2- bases) -5- (formyloxy) -6- enyl-heptanoic acids, its structural formula as shown in 009,
Further, compound name of the invention be the fluoro- 7- of (3S, 5R) -3- (3- (4- fluorophenyls) -1- isopropyls - 1H- indoles -2- bases) -5- (formyloxy) enanthic acid, its structural formula as shown in 010,
Further, compound name of the invention be the fluoro- 7- of (3S, 5S) -3- (3- (4- fluorophenyls) -1- isopropyls - 1H- indoles-2- bases)-5-nicotinoyl-6- enyl-heptanoic acids, its structural formula as shown in 011,
Further, compound name of the invention be the fluoro- 7- of (3S, 5S) -3- (3- (4- fluorophenyls) -1- isopropyls - 1H- indoles-2- bases)-5-nicotinoyl-6- enanthic acid, its structural formula as shown in 012,
Further, compound name of the invention is (3S, 5S- ((3S, 3AR, 6S, 6AS) -6- (nitre epoxide) hexahydro furan Mutter simultaneously [3,2-b] furans -3- bases) the fluoro- 7- of -3- (3- (4- fluorophenyls) -1- isopropyl -1H- indoles -2- bases) -5- hydroxyls -6- Alkene-heptanoate, its structural formula as shown in 013,
Further, compound name of the invention is (3S, 5S- ((3S, 3AR, 6S, 6AS) -6- (nitre epoxide) hexahydro furan Mutter simultaneously [3,2-b] furans -3- bases) the fluoro- 7- of -3- (3- (4- fluorophenyls) -1- isopropyl -1H- indoles -2- bases) -5- hydroxyls -6- heptan Acid esters, its structural formula as shown in 014,
Present invention also offers a kind of pharmaceutical composition, above-mentioned (III), (007), (008), (009) containing effective dose, (010), (011), (012), (013), the compound of (014) or its salt or its ester, stereoisomer or optical isomerism Body.
Present invention also offers above-mentioned (III), (007), (008), (009), (010), (011), (012), (013), (014) compound is preparing the application in being used to treat the medicine for reducing blood lipid level.
Present invention also offers above-mentioned (III), (007), (008), (009), (010), (011), (012), (013), (014) compound is preparing the height for treating coronary heart disease, the atherosclerosis that high fat of blood triggers or diabetes trigger Application in the medicine of blood fat.
The present invention's contains the fluoro- 3- hydroxypentanoic acids of 1- formed after the fluoro- caprolactone fragments of 3- and its lactone open loop and its salt Or the fluorine-containing trim of polysubstituted indoles statin of ester or its active metabolite, its structure is as shown in IV：
Such compound or its active metabolite are the phthalein CoA-reductase (3-Hydroxy-3- of 3- hydroxy-3-methyls penta 2 Methylglutaryl-CoA Reductase, HMGR) 3, the 5- dihydroxy-acids of inhibitor its six-membered cyclic lactone forms 3- Hydroxyl be replaced by fluorine atoms after derivative.Its structural formula such as formula I, wherein：
Part A is the fluoro- 3- hydroxypentanoic acid of 1- and its salt or ester formed after the fluoro- caprolactone fragments of 3- or its lactone open loop；
As shown in the V of formula I, when its structure is the fluoro- caprolactone fragments of 3-, its substituted radical R1, R2 be hydrogen, methyl, ethyl, The straight chain saturation or unsaturated alkyl or cyclopropyl of the 1-10 carbon atom such as propyl group, vinyl, substituted-phenyl and methoxyl group, ethoxy The small size substituted radicals such as the straight or branched alkyl of the 1-10 carbon atom such as base, R1 and R2 are preferably hydrogen or methyl.
When its structure is the carboxylate of open loop form, its substituted radical R1, R2 are hydrogen, methyl, ethyl, propyl group, ethene The straight chain such as base saturation or unsaturated alkyl or cyclopropyl, substituted-phenyl and methoxyl group, ethyoxyl etc. small size substituted radical, R10 is preferably hydrogen.R10 substituted radicals with carboxylic acid into ester can be the 1-10 carbon atom such as methyl, ethyl, propyl group straight chain or Branched hydrocarbyl either other organic acid esters, preferably methyl esters or ethyl ester.
Equally, hydroxy-acid group can also include sodium salt, the potassium of monovalence with alkali metal or alkaline-earth metal M into salt, M metal salts Salt or ammonium salt, calcium salt, the magnesium salts of divalence, particular certain cancers and calcium salt.
Organic or inorganic acid ester can be formed with group X additions for the alcoholic extract hydroxyl group exposed after lactone open loop, its implication It is as follows：
A) organic acid esters
The unitary of 1-20 carbon of-straight or branched or multi-carboxylate, preferably 1-10 carbon, it is optionally one or more Substituted radical substitutes, and the substituent is selected from：Halogen atom, hydroxyl or straight or branched it is simple comprising 1-3 carbon atom Substituted radical
The substituent can also be the cyclic hydrocarbon radical of 3-7 carbon atom, preferably 3-5 carbon atom.
- substituent the aromatic carboxylic acids containing aromatic ring structure, such as substituted aroma carboxylic acid：
Wherein n be 0-20 integer, preferably 1-3；
X, Y represent substituent, are selected from：1-3 the simple of carbon atom that include of halogen atom, hydroxyl or straight or branched takes For group
B) inorganic acid ester
Inorganic acid ester includes various oxygen-containing inorganic acid esters, can be sulfuric acid, phosphoric acid, nitric acid, sulfurous acid, phosphorous acid, nitrous Acid or pyrosulfuric acid, pyrophosphoric acid etc., preferably sulfuric acid phosphoric acid and nitric acid.
C portion is the polysubstituted indolyl radical of rigid plane of lipophilic, and structure such as following formula shows
Specific definition is as follows in formula：
A) female ring structure
- poly-substituted quinoline or other coplanar split heterocycles, selected from indoles, poly-substituted quinoline etc.
- following five yuan or hexa-atomic of saturation, insatiable hunger and/or aromatic heterocycle, comprising one or more selected from nitrogen, oxygen, sulphur Hetero atom, and a part of structure of poly-substituted quinoline is the same as above-mentioned five yuan or hexa-atomic of saturation, insatiable hunger and/or aromatic heterocycle split Ring structure, it is selected from：
It is preferred that following female ring structure：
B) substituent in female ring structure
R5, R6, R7, R8, R9, R10 are defined as following substituted radicals：
- unsubstituted, a hydrogen atom is directly connected to,
- hydroxyl, or hydroxyl is with containing carboxylate, preferably hydroxyl or hydroxy carboxylic acid ester, acetic acid formed by 1-3 carbon atom Ester,
The hydrocarbyl ether of -1-3 carbon atoms, the preferably methoxyl group of S spatial configurations, ethyoxyl.
- halogen, or the halogenated hydrocarbons of 1-3 carbon atom, preferably fluorine or chloromethyl.
The hydrocarbyl group of 1-10 carbon atom of-straight or branched, is optionally substituted by one or more substituted radicals, described Substituent is selected from：The simple substituted radical for including 1-3 carbon atom of halogen atom, hydroxyl or straight or branched, it is preferably different Propyl group.
The cycloalkane of -3-7 carbon atoms, is optionally substituted, the substituent is selected from by one or more substituted radicals：Halogen The simple substituted radical for including 1-3 carbon atom of atom, hydroxyl or straight or branched, preferably cyclopropyl.
- substituted aroma ring, substituted radical include the alkyl of halogen, 1-3 carbon atom.Preferably align substituted fluorophenyl Or phenyl.
Part B is the attachment structure of A and C portion
- for the carbochain of two carbon atoms, can be vinyl or ethyl, preferably ethyl.
The Drug combination of the compound of the present invention and at least one treatment angiocardiopathy, the medicine are selected from ACE Inhibitor, Angiotensin Ⅱ receptor antagonist, beta adrenergic blocker, calcium ion channel blocker, antithrombotic agent Deng medicine.
Suitable Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, Angiotensin Ⅱ receptor antagonist, beta adrenergic blocker, calcium channel resistance Stagnant dose, the medicine such as antithrombotic agent its detailed description can be found in such as clinical medicine handbook.
The preparation flow of the compound of the present invention is as follows：
It is raw material to include but is not limited to the carboxylic metallic salt of commercially available Statins bulk drug (mainly calcium salt, sodium salt), It is free through the acidifying of certain density hydrochloric acid, and be concentrated in vacuo after appropriate organic solvent extraction and obtain crude carboxylic acid.This crude product Without refining, that is, carry out lactonizing for next step.
The DMAP of above-mentioned crude carboxylic acid and catalytic amount, appropriately sized magnetic stir bar are added to suitable in the lump When reaction vessel in, organic solvent dissolving after.A certain amount of dicyclohexylcarbodiimide solution is added dropwise, at room temperature stirring reaction Overnight.After thin-layer chromatography monitoring reaction completely, filter, filtrate anhydrous sodium sulfate drying, concentration, column chromatography for separation (PE/EA ladders Degree elutes) obtain lactone.
A certain amount of organic solvent and diethylin sulfur trifluoride is added in reaction vessel, low temperature stirring certain time Afterwards, a certain amount of lactone solution is added.After a period of time, natural temperature reaction is stayed overnight.After thin-layer chromatography monitoring reaction completely, Add water quenching to go out, liquid separation extraction, anhydrous sodium sulfate drying, concentrate, column chromatography for separation (PE/EA gradient elutions) obtains of the present invention contain Fluorine derivative.
By the lactone form of above-mentioned fluorine-containing derivant, 1- can be obtained with open loop under suitable aqueous slkali and organic solvent Fluoro- 3- hydroxypentanoic acids form, so as to expose carboxylic acid and alcoholic OH groups, further with acid, alkali addition into salt, ester, acid amides etc. Addition product.
This kind of compound synthesis method of the present invention is simple, and it is raw material to be especially available with existing procucts bulk drug, warp The simply reaction of several steps is crossed to can be prepared by.Relative to the statin analog (referring to HMGR enzyme inhibitors) of business development, it suppresses Enzymatic activity IC50Value is compared or the same order of magnitude or has the lower order of magnitude, and which show this kind of compound of the present invention Can be as the medicinal application for reducing blood fat.It is external large-scale pharmacy giant patent particularly in whole statinses on the market In the case of monopolization, fluorine-containing statins antilipemic medicine of the exploitation with independent intellectual property right, there is certain meaning.
Compound of the present invention is the phthalein CoA-reductase (3-Hydroxy-3- of 3- hydroxy-3-methyls penta 2 Methylglutaryl-CoA Reductase, HMGR) inhibitor.
The present invention includes stereoisomer and optical isomer, such as corresponding isomers or diastereoisomer, and it is produced The reason for raw be selection such compound in possessed asymmetry in structure.The same with most drug, it can also With crystal formation, different crystal forms possessed by each single chemical substance are also included in class of the present invention in such compound.
This kind of compound of the present invention can also be the form of solvation, especially methanol, ethanol, the larger polarity such as water Small molecule solvent.Its solvation can occur in the production process of the composition in the compound or inclusion compound, Huo Zheyou In the hygroscopicity that compound has, solvation can occur by certain time.
Compound of the present invention and its active metabolite are known as the derivative of prodrug or metabolic activity thing.
The fluoro- 3- hydroxypentanoic acids of 1- formed after compound lactone open loop of the present invention have hydroxyl and hydroxy-acid group, Can the reaction conversion in organic solvent (ethanol, acetone, dichloromethane, tetrahydrofuran etc.) with corresponding organic base and inorganic base Into corresponding salt.
Inorganic base into salt include sodium salt, calcium salt, sylvite, ammonium salt etc..Particular certain cancers and calcium salt.
There is the fluoro- 3- hydroxypentanoic acids of 1- after the compounds of this invention lactone open loop, can containing hydroxy-acid group and alcoholic OH groups To form ester with suitable oxyacid and alcohol compound addition.
By the lactone form of above-mentioned fluorine-containing derivant, 1- can be obtained with open loop under suitable aqueous slkali and organic solvent Fluoro- 3- hydroxypentanoic acids form, so as to expose carboxylic acid and alcoholic OH groups, hydroxyl therein can same chlorosulfonic acid/pyridine, POCl3/N(Et)3, wait reaction to generate inorganic sulfuric ester, phosphate, nitrate etc..
Hydroxyl can obtain carboxylate with oxyacid addition after the compounds of this invention lactone open loop, these esters include with it is organic Or the ester that the addition of inorganic oxacid institute obtains (these acid are reacted into ester with the alcoholic extract hydroxyl group exposed after lactone hydrolysis).These Oxygen-containing inorganic acid includes but is not limited to (Asia) sulfuric acid, (Asia) phosphoric acid, nitric acid, carbonic acid, (original) silicic acid, and correspondingly (Asia) hydrogen sulfate Ester, (Asia) hydrogen phosphate etc..Organic acid includes simple alkyl acid such as formic acid, acetic acid, propionic acid, adipic acid, alginic acid, aspartic acid Deng amino acid, benzoic acid, benzene sulfonic acid, butyric acid, citric acid, camphoric acid, camphorsulfonic acid, cyclopentyl propionic acid, glucosulfone acid, dodecane Base sulfuric acid, ethyl sulfonic acid, fumaric acid, glucoheptonic acid, phosphoglycerol, enanthic acid, caproic acid, 2- ethylenehydrinsulfonic acids, lactic acid, maleic acid, first Sulfonic acid, 2- naphthalene sulfonic acids, oxalates, flutter acid, pectinic acid, 3- phenylpropionic acids, picric acid, neopentanoic acid, butanedioic acid, tartaric acid, first The organic carboxyl acid that can be used for hydroxyl into ester of the parmacodynamics-less activities such as benzene sulfonic acid, palmitic acid and undecanoic acid.
Carboxylic acid can form carboxylate with suitable alcohol addition after the compounds of this invention lactone open loop.Organic Alcohol includes simple Alkylol such as methanol, ethanol, propyl alcohol, hexylene glycol, the alcohols that can be used for carboxylic acid into ester of the parmacodynamics-less activity such as glycerine.
Meaning of the present invention is that compound and its active metabolite are including but not limited to same by the compound in claims Existing known related drugs carry out split, and these splits include but is not limited into ester including covalently bound, into acid amides into again Miscellaneous salt or the splicing by the part A in formula I with other related drugs progress fragment.It is all by the A portions in structural formula Divide and carry out split with other medicine and the compound with suppression HMGR enzymatic activitys is all in patent claims 1 of the present invention Signified analog and its active metabolite.
Related drugs in above-mentioned include but is not limited to be used to prevent and treat all kinds of of three high (high fat of blood, hypertension, hyperglycaemia) Medicine.For patient clinically, one of three senior middle schools is not individually to go out item, and often two or three go out simultaneously The different phase of present patient disease, thus drug combination is necessary, this helps to reduce dose and mitigates medication treatment Toxic side effect.
Above-mentioned middle related drugs include but is not limited to phenoxy acetic acid class, the nicotinic acid class for treating high fat of blood.
Above-mentioned middle related drugs include but is not limited to Mg-ATP enzyme inhibitors class (such as reserpine), the α for treating hypertension2By Body activator (such as clonidine, ethyldopa), beta-blocker (atenolol in such as Luo Er classes), angiotensin-converter Enzyme inhibitor (benazepil in such as pril), angiotensinⅡantagonist (such as the Telmisartan of husky smooth class), an oxidation Nitrogen donor medicine (Isosorbide Mononitrates of such as nitrate esters), these medicines all contain amido or alcoholic extract hydroxyl group, carboxylic acid group Group, the medicine splicing object of correlation can be obtained into salt into acid amides, soda acid by being dehydrated into ester with compound of the present invention.
The present invention utilizes model prediction result in Computer-Aided Drug Design, and design has synthesized a series of fluoro- containing 3S- The statins fluorine-containing derivant of caprolactone fragment structure, it is clear that such compound can expose 3S, 5R-3,5- after hydrolysis Dihydroxy-acid structure, by HMGR enzyme inhibition activity experiment tests, it is found that the series compound has with commercial type The IC of statins same order or lower quantity50Test value, it can be used as lipidemia medicine.
The HMGR inhibitor (statins being commonly called as) of the present invention, will not exclusively eliminate or at least weaken this kind of medicine The toxicity that thing is brought, and pharmacological activity value is improved.Pharmacology test result shows, in claim compound phase for Not derivative statin is on the whole to HMGR enzyme inhibition activities IC50Test value tool is significantly improved.
Embodiment：
The following example illustrates the method and composition being not intended to limit the present invention.Other of different condition and product are suitable When modification and adjustment are normal and approved.It will be apparent to one skilled in the art that also within the scope of the present invention.
The compound of the present invention can be prepared according to general approach as described below using appropriate material as raw material, and And by latter embodiments come concrete example explanation.Certainly, the condition of the citing compound producing step in embodiment and side The various known rational changes of method can be used for preparing these compounds.Unless otherwise indicated, it is used organic in embodiment Solvent and reagent (dichloromethane, ethyl acetate, petroleum ether and triethylamine etc.) are the routine that commercial reagent is approved through this area A small amount of Non-aqueous processings is done except water process or done using the molecular sieve after activation to method.Described analytical and testing instrument and condition removes It is non-to be otherwise noted, otherwise：HRMS high resolution mass spectrums are Brooker,Switzerland company solanX-70FT-MS, H-NMR nucleus magnetic hydrogen spectrum Volance III 500M, test solvent CDCl3.Spectral data is attached.
The Fluvastatin lactone of embodiment 1 and the preparation of Fluvastatin lactone reduction
5.00g Fluvastatin sodium salt is weighed, is added in 250ml eggplant-shape bottle, adds 100ml dichloromethane peace treaty The watery hydrochloric acid of 10ml 20 times of concentrated hydrochloric acids dilution, acutely shaking, stratification.Upper strata aqueous phase is taken, the detection control of pH test paper is in 2-3 When, you can think free complete.Liquid separation, 100ml dichloromethane equivalent extract three times, merge lower floor's organic phase, 20ml water backwashes Once, organic phase anhydrous sodium sulfate drying.45 DEG C of vacuum are spin-dried for, and oil pump, which is evacuated to, white foaming material occurs, cooling, smashs to pieces White powder 4.23g is obtained, this Fluvastatin crude carboxylic acid is not refined to be used in next step.
4.00g above-mentioned Fluvastatin crude carboxylic acid is weighed, is added in 250ml three-necked flask, adds 5g powder The stirrer of molecular sieve, 0.05g p dimethylamino pyridine and suitable size, displaced air are simultaneously protected with nitrogen, add 100ml Dichloromethane.Reaction vessel is inserted in ice bath and stirred, the dicyclohexylcarbodiimide for being slowly injected into 5.0g is dissolved in 20ml bis- Chloromethanes solution.It is added dropwise within about 10 minutes, reaction unit is removed into reaction at room temperature overnight.Monitor and react through thin-layer chromatography After completely, filter, after filtrate anhydrous sodium sulfate drying, vacuum is spin-dried for, and rapid column chromatography separation (PE/EA gradient elutions) obtains fluorine and cut down He is statin lactone 2.18g.MP 65.7-66.8 DEG C, HRMS (ESI):C24H24FNO3,394.18549(M+H)+Theoretical value 394.18185；1H-NMR:7.53 (dd, J=13.0,8.2Hz, 2H), 7.42-7.35 (m, 2H), 7.21 (t, J=7.3Hz, 1H), 7.15-7.06 (m, 3H), 6.76 (d, J=16.1Hz, 1H), 5.68 (dd, J=16.0,6.0Hz, 1H), 5.30-5.23 (m, 1H), 4.83 (dt, J=13.7,6.7Hz, 1H), 4.36 (s, 1H), 2.76 (dd, J=17.8,4.8Hz, 1H), 2.70- 2.61(m,1H),2.00–1.89(m,1H),1.68–1.64(m,6H)
Above-mentioned Fluvastatin lactone is weighed into 500mg, is added in 25ml reaction tubes, adds stirrer and about 5ml methanol About 1ml tetrahydrofuran and the 10% of 20mg Pt/c catalytic hydrogenation catalysts, displaced air, room temperature normal pressure catalytic hydrogenation. After 12 hours, thin-layer chromatography monitoring reaction is complete.Pt/C is filtered out, after anhydrous sodium sulfate drying, vacuum is spin-dried for filtrate, post Chromatography (PE/EA gradient elutions) obtains Fluvastatin lactone reduzate 355mg, HRMS (ESI)：C24H26FNO3, 396.20059(M+H)+, theoretical value 396.19750；H-NMR:7.55 (dd, J=23.9,8.0Hz, 2H), 7.42-7.34 (m, 2H), 7.15 (dd, J=18.0,8.8Hz, 3H), 7.08 (t, J=7.3Hz, 1H), 4.70-4.60 (m, 1H), 3.94 (s, 1H), 2.79 (t, J=7.4Hz, 2H), 2.54-2.35 (m, 2H), 1.69 (t, J=11.7Hz, 6H), 1.56-1.32 (m, 3H)
The preparation of the compound 001,002 of embodiment 2
Appropriately sized magnetic stir bar is added in 50ml reaction tube, and displaced air is simultaneously protected with nitrogen, injection Reaction vessel is inserted in low temperature stirring reaction bath (less than -65 DEG C) after 30ml dichloromethane, injects and adds under low temperature 0.75ml diethylin sulfur trifluoride, stir about are dissolved in 10ml dichloromethane solutions after 15 minutes, by 1.50g Fluvastatin It is slowly added to.After stirring reaction about 30 minutes, injection adds about 0.3ml triethylamine, and after 2 hours, natural temperature reaction is stayed overnight. After thin-layer chromatography monitoring reaction completely, filter, filtrate anhydrous sodium sulfate drying, be spin-dried for, silver nitrate complexing silica gel column chromatography point Fluvastatin fluoro product (001) 0.76g is obtained from (isopropanol/petroleum ether gradient elution).Same method can obtain 002.
The preparation of the compound 003,004,005,006 of embodiment 3
Fluvastatin fluoro thing (001) 1.00g is taken, with ice bath after tetrahydrofuran 6ml dissolvings, the LiOH for adding 1mol/L is molten After liquid 1.5ml is stirred 2 hours, when with 10% hydrochloric acid, to be acidified to pH be 2-3, solvent is evaporated off in 45 DEG C of decompression, adds acetone about After 10ml dissolvings, 10% Na is slowly added dropwise while stirring2CO3The aqueous solution, it is seen that have floccule and muddy appearance, be added dropwise to Untill no longer there is floccule.Muddy thing dissolving is heated to, is stood, slow cooling is overnight.Next day obtains acicular crystal 0.68g, i.e., Fluvastatin fluoro sodium salt (003).Same method can obtain reducing fluoro sodium salt 004.
Fluvastatin fluoro thing (001) 1.00g is taken, ice bath after being dissolved with tetrahydrofuran 6ml, adds 1mol/L LiOH After solution 1.5ml is stirred 2 hours, when with 10% hydrochloric acid, to be acidified to pH be 7-8, solvent is evaporated off in 45 DEG C of decompression, adds ethanol about After 10ml dissolvings, 10% CaCl is slowly added dropwise while stirring2The aqueous solution, it is stirred overnight, separates out solid, filters, obtain half calcium Salt crude product.With the methanol/water mixed solution of 50% volume ratio, the refined calcium salt of Fluvastatin fluoro half (005) of recrystallization 0.75g.Same method can obtain the Fluvastatin reduction calcium salt 006 of fluoro half.
The preparation of the compound 007,008 of embodiment 4
Fluvastatin fluoro thing (001) 1.00g is taken, with ice bath after tetrahydrofuran 6ml dissolvings, the LiOH for adding 1mol/L is molten After liquid 2.5ml is stirred 2 hours, this water oil mixture is washed into (5 × 3) three times with ether, it is organic to discard upper strata after washing every time Phase.Aqueous phase with 10% hydrochloric acid to be acidified to pH be 2-3 when, add water and ethyl acetate liquid separation extraction three times (6 × 3), organic phase Anhydrous sodium sulfate drying, 45 DEG C of decompression are evaporated off solvent and produce Fluvastatin fluoro lactone open loop crude carboxylic acid 0.89g.
Above-mentioned crude carboxylic acid is dissolved in 25ml absolute methanol, after adding the p dimethylamino pyridine of catalytic amount, adds under ice bath Enter 1.2gDCC (dicyclohexylcarbodiimide) and be dissolved in 5ml methanol resulting solutions.Ice bath is removed, stirring reaction is overnight, through thin layer After analysis monitoring reaction completely, filter, be concentrated under reduced pressure, silica gel column chromatography separating purification obtains Fluvastatin fluorocarboxylic acid methyl esters (007)0.75g.Same method can obtain compound 008.
The preparation of the compound 009,010 of embodiment 5
The open loop crude carboxylic acid of Fluvastatin fluoro lactone described in Example 5 0.65g is dissolved in formic acid and dichloromethane 1:1 in the mixed solvent, adding 1.2gDCC after adding the p dimethylamino pyridine of catalytic amount, under ice bath, (dicyclohexyl carbon two is sub- Amine) it is dissolved in the 1 of 5ml formic acid and dichloromethane:1 mixed solvent resulting solution.Ice bath is removed, stirring reaction is overnight, through thin layer After chromatography monitoring reaction completely, filter, be concentrated under reduced pressure, silica gel column chromatography separating purification obtains Fluvastatin fluorocarboxylic acid formic acid esters (009)0.57g.Same method can obtain compound 010.
The preparation of the compound 011,012 of embodiment 6
Open loop crude carboxylic acid 0.65g and the 2g nicotinic acid of Fluvastatin fluoro lactone described in Example 5 is dissolved in the two of 15ml 1.2gDCC (dicyclohexylcarbodiimide) is added in chloromethanes, after adding the p dimethylamino pyridine of catalytic amount, under ice bath to be dissolved in 5ml dichloromethane resulting solutions.Ice bath is removed, stirring reaction is overnight, and back flow reaction monitors after about 1 hour through thin-layer chromatography Reaction is complete, filters, and filtrate decompression concentration, silica gel column chromatography separating purification obtains Fluvastatin fluoro nicotinate (011) 0.57g.Same method can obtain compound 012.
The preparation of the compound 013,014 of embodiment 7
Open loop crude carboxylic acid 0.65g and the 2.5g Isosorbide Mononitrate of Fluvastatin fluoro lactone described in Example 5 It is dissolved in 50ml acetonitrile, after adding the p dimethylamino pyridine of catalytic amount, 1.2gDCC (dicyclohexyl carbon two is added under ice bath Imines) it is dissolved in 5ml acetonitrile resulting solutions.Recession is added dropwise and removes ice bath, heating water bath back flow reaction is stayed overnight, supervised through thin-layer chromatography It is complete to survey reaction, filters, filtrate decompression concentration, silica gel column chromatography separating purification obtains Fluvastatin fluoro Isosorbide Mononitrate (013)0.26g.Same method can obtain compound 014.
The compound activity of embodiment 8 is tested
Following description of test the compounds of this invention are tested former to the inhibitory action of the enzymatic activity of HMG-CoA reductase (HMGR) Reason
3- hydroxy-3-methyl glutaryls coenzyme (HMG-CoA) reductase is internal catalysis acetyl coenzyme A synthesis mevalonic acid This metabolic pathway key enzyme, it is catalyzed following reaction under physiological environment：
HMG-CoA+NADPH+2H+→mevalonic acid+2NADP++CoASH
Because NADPH has absworption peak at 340nm, therefore the activity of HMG-CoA reductase can pass through spectrophotometric The reduction speed of light absorbs is completed at method measure 340nm.
Material and instrument:(this kit includes HMG-CoA Reductase Assay Kit:HMGR,HMG-CoA, NADP-H, buffer solution, Pitavastatin solution), other auxiliary materials be 96 orifice plates, ultra-pure water, accurate pipettor (2-20ul and Each one of 0.5-2ul) and its supporting disposable pipette tips, spectrophotometer or ELIASA
Medicament is prepared and prepared
10ml 5 times of concentration buffer liquid are diluted to 1 times of buffer solution (i.e. the 5 of 10ml times of liquid add 40ml ultra-pure water), In the case of 96 orifice plates, 1ml 1 times of liquid can carry out the test of 5 samples, be stored in stand-by in ice, remaining 5 times of buffer solutions In -20 DEG C of preservations.25mg NADPH requires supplementation with 1.5ml 1 times of buffer solution, is well mixed -20 DEG C of preservations.
Method and flow
Thaw：Defrosting enzyme needs on ice or keep surrounding environment cooling again, try not enzyme being placed on ice more than 60 points Clock, because the standing time long activity reduction that can cause enzyme.Other defrostings can be carried out at room temperature, once thawing to be stored in On ice.
Instrument adjustment:Test and temperature is adjusted to 37 DEG C before starting, absorbing wavelength 340nm, get out dynamic routine.96 holes Plate sample reads a number in every 20 seconds, amounts to 10 minutes.
The reaction solution of suitable volumes is added according to the kit forms provided and flow
Form
Reagent Standard entertion mode
Flow:A, 1 times of quantitative buffer solution is added in each hole；
B, add testing sample in the hole in addition to blank and positive control
C, add the NADPH for supplementing buffer solution in each hole
D, add substrate HMG-CoA in each hole
E, enzyme-added HMGR is in the hole in addition to blank
F, reaction solution is well mixed, especially with least strongly being stirred before first time extinction ground is surveyed during 96 orifice plate test sample Mix 10 seconds
G, dynamic routine is opened, observes the change of absorbance
The method introduced according to kit carries out active testing, obtains absorbance decline curve, the slope of decline indicates difference Sample carries out Mathematical treatment and fitting to the inhibitions of HMGR enzymes to the slope curve of gained, according to kit technical support, Activity data is calculated by below equation
Wherein:Parameter 12.44 represents 12.44mM/cm, because attenuation coefficients of the NADPH under 340nm is 6.22mM/cm, Not twice of the NADPH in reaction mechanism, therefore be 12.44
TV is the cumulative volume of reaction solution, and 96 orifice plates are 0.2ml
V represents the volume of reductase, concentration of the enzyme in enzyme-grams of albumen of milli, 0.55-0.65mg/ml
LP represents optical path width, and 96 orifice plates are 0.55cm
The NADPH that Unit is defined as the 1umol per minute at 37 DEG C is converted into NADP+, concrete unit umol/min/mg Protein
A340 represents absorbance of the sample in 340 nano wave lengths, absorbance change value corresponding to Δ A340 expressions
MinssampleThe time used in sample test is represented, unit is minute, corresponding MinsblankRepresent that blank sample is surveyed Examination time used, the same Mins of its numerical valuesampleIt is equal.
It is overall to represent experienced MinssampleThe change of sample absorbance under 340 nanometers of wavelength in time Rate, unit min-1, sameRepresent the rate of change of blank sample.
Test result
Defining inhibiting rate is
Wherein activity dataActivityRepresent the Activity activity values correspondingly tested and calculated according to formula, active number According toSempleRepresent the activity value added after inhibitor sample.

Claims (4)

  1. A kind of 1. compound, it is characterised in that：Its compound name is the fluoro- 6- of (4S, 6R) -4- (2- (3- (4- fluorophenyls) -1- Isopropyl -1H- indoles -2- bases) ethyl) tetrahydrochysene -2H- pyran-2-ones, its structural formula as shown in 002,
    Or its compound name is the fluoro- 7- of (3S, 5R)-3- (- 2-yl of 3- (4- fluorophenyls)-1- isopropyl-1H- indoles)-5- Hydroxyheptanoic acid sodium, its structural formula as shown in 004,
    Or its compound name is the fluoro- 7- of (3S, 5R)-3- (- 2-yl of 3- (4- fluorophenyls)-1- isopropyl-1H- indoles)-5- Hydroxyheptanoic acid methyl esters, its structural formula as shown in 008,
    Or its compound name is the fluoro- 7- of (3S, 5R) -3- (3- (4- fluorophenyls) -1- isopropyl -1H- indoles -2- bases) -5- (formyloxy) enanthic acid, its structural formula as shown in 010,
    Or its compound name is (3S, 5R- ((3S, 3AR, 6S, 6AS) -6- (nitre epoxide) hexahydro furyl simultaneously [3,2-b] furan Mutter -3- bases) the fluoro- 7- of -3- (3- (4- fluorophenyls) -1- isopropyl -1H- indoles -2- bases) -5- hydroxyheptanoates, its structural formula is such as Shown in 014,
  2. 2. a kind of pharmaceutical composition, any described compound or its salt in the claim 1 containing effective dose.
  3. 3. any described compound is preparing the application in being used to treat the medicine for reducing blood lipid level in claim 1.
  4. 4. any described compound is preparing the Atherosclerosis for treating coronary heart disease, high fat of blood triggers in claim 1 Application in the medicine for the high fat of blood that change or diabetes trigger.
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