CN104356119B - Polysubstitution miazines pitavastatin lactone dewatering compound and application thereof - Google Patents
Polysubstitution miazines pitavastatin lactone dewatering compound and application thereof Download PDFInfo
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- CN104356119B CN104356119B CN201410553927.8A CN201410553927A CN104356119B CN 104356119 B CN104356119 B CN 104356119B CN 201410553927 A CN201410553927 A CN 201410553927A CN 104356119 B CN104356119 B CN 104356119B
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
Abstract
The invention belongs to the chemical field of medicaments, and provides a compound. The structural formula of the compound is as shown in the specification. A test shows that the compound has an effect of suppressing the activity of HMG-coA reductase and can serve as a new generation of potential HMG-coA reductase inhibitors.
Description
Technical field
The invention belongs to medicinal chemistry art, more particularly to a kind of statins, it is specifically a kind of polysubstituted phonetic
Pyridine class his statin lactone anhydro compounds 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 and exists with albumin combination mostly in blood of human body) concentration is often raised
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 of various diseases or its direct illness.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 of blood fat (lipoprotein) and liver
(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 is combined occurs two
The secondary reduction reaction for being related to four electro transfers 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 being 12,400,000,000 dollars by 2008 annual sales amounts by the Atorvastatin calcium preparation of Pfizer Inc.'s development and sale, bears
Claim " cookle " in medical history.The type medicine due in human body Jing metabolism 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 the binding ability of HMGR
HMG-coA (the K that HMG-CoA is combined with HMGRmFor the umol/L orders of magnitude, and the IC of statins50In the nmol/L orders of magnitude,
So statins can fight for the active site of HMGR into after human body, and then prevent HMGR with the knot of HMG-coA
Close, that is, inhibit HMG-CoA to the conversion of 3,5- dihydroxy-acids, and then finally inhibit the synthesis of people's body lipid.
Statins is found to first generation Lovastatin in the U.S. by writing from memory from the mevastatin of its proto-drug the most
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 and introduce fluorine atom to improving the HMGR enzymes suppression of drug molecule in the appropriate site of existing statins or its analog
The toxic and side effect of system activity or reduction medicine has 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 CN101580497A such as CA2072945, CN101230055A, CN1539417A and document (Science, 2001
(292):1160-1164) etc. 3S is all directly or indirectly 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 for listing on the market
Lipidemia medicine is all the class formation, and existing patent also all remains this must structure.However, statins also has not
Good reaction, such as：Hepatopathy, carcinogenic toxicity, particularly muscle side reaction, rhabdomyolysis, just because of this secondary work of serious poison
With so that cerivastatin (cerivastatin) removes city.
Predicted the outcome using model in Computer-Aided Drug Design, design has synthesized a series of containing 2- hexenolactone pieces
The statins derivative of segment structure, through HMGR enzyme inhibition activity experiment tests, it is found that the series compound has same city
The statins same order sold on face or the IC of lower quantity50Test value, can use as lipidemia medicine.
The content of the invention
For above-mentioned technical problem of the prior art, the invention provides a kind of poly-substituted miazines his statin lactone dehydrations
Compound and application thereof, described his statin lactone anhydro compounds of this poly-substituted miazines and application thereof will solve prior art
In statins derivative there is toxic and side effect, and treat the limited technical problem of the effect of high fat of blood.
The invention provides a kind of compound, its structural formula is as follows,
Wherein, R1, R2, R11 are hydrogen, the straight chain saturation of 1-10 carbon atom or unsaturated alkyl or cyclopropyl, substituted benzene
The small size substituted radicals such as the straight or branched alkyl of base or 1-10 carbon atom, M be sodium ion, potassium ion, ammonium root from
Son, calcium ion or magnesium ion, R9 is the straight or branched alkyl or organic acid esters of hydrogen or 1-10 carbon atom, and Z is
The unitary or polycarboxy of 1-20 carbon of straight or branched, wherein, R3, R4, R5, R6, R7, R8 are respectively hydrogen, hydroxyl, hydroxyl
With hydrocarbyl ether, halogen containing carboxylate substituent groups formed by 1-3 carbon atom, 1-3 carbon atom, or 1-3 carbon atom
Halogenated hydrocarbons, the hydrocarbyl group of 1-10 carbon atom of straight or branched, the cycloalkane of 3-7 carbon atom, substituted aroma ring or
Hydrophilic radical.
Further, take with one or more on the unitary or polycarboxy of 1-20 carbon of described straight or branched
For group, the substituent is the simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched.
Further, the substituent can also be the cycloalkyl of 3-7 carbon atom.
Further, Z is the substituent aromatic carboxylic containing aromatic ring structure,
Wherein n for 0-20 integer, X, Y be respectively halogen atom, hydroxyl or straight or branched comprising 1-3 carbon atom
Simple substituted radical.
Further, described R1, R2, R11 are hydrogen, methyl, ethyl, propyl group, vinyl, methoxyl group or ethyoxyl.
Further, described R9 substituted radicals are methyl, ethyl, propyl group, methyl esters or ethyl ester.
Further, described R3, R4, R5, R6, R7, R8, R9 are hydroxy carboxylic acid ester, acetic acid esters, the first of S spatial configurations
Fluorophenyl, methyl substituted sulfuryl group or phenyl that epoxide, ethyoxyl, fluorine, chloromethyl, cyclopropyl, contraposition replace.
Further, described Z is sulfate ion, phosphate anion, nitrate ion, sulfite ion, phosphorous
Acid ion, nitrite ion, pyrosulfuric acid radical ion or pyrophosphate ion.
Further, in the hydrocarbyl group of 1-10 carbon atom of straight or branched, optionally by one or more substituents
Group replaces, simple substituent comprising 1-3 carbon atom of the substituent selected from halogen atom, hydroxyl or straight or branched
Group.
Further, in the cycloalkane of 3-7 carbon atom, optionally replaced by one or more substituted radicals, the replacement
Base is selected from：The simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched.
Further, described hydrophilic radical be replace sulfuryl, sulfoxide group, ketone carboxyl or acid amides, substituent is hydroxyl
The simple substituted radical comprising 1-3 carbon atom of base or straight or branched.
Further, described pyrimidine structure is by five yuan or rigid heterocyclic institute's generation of hexa-atomic saturation, insatiable hunger and/or fragrance
Replace, described five yuan or the rigid heterocyclic of hexa-atomic saturation, insatiable hunger and/or fragrance are comprising one or more selected from nitrogen, oxygen, sulphur
Hetero atom.
Further, the rigid heterocyclic of described five yuan or hexa-atomic saturation, insatiable hunger and/or fragrance is
Further, the invention provides a preferred compound, its compound name is (R, E)-N- (4- (4- fluorine
Phenyl) -6- isopropyls -5 (2- (6- oxo -3,6- dihydro -2H- pyrans -2- bases) vinyl)-pyrimidine -2-base)-N- methyl first
Sulfonamide, its structural formula is
Further, the invention provides a preferred compound, its compound name is (S)-N- (4- (4- fluorobenzene
Base) -6- isopropyls -5 (2- (6- oxo -3,6- dihydro -2H- pyrans -2- bases) ethyl) pyrimidine -2-base)-N- methyl methylsulfonyls
Amine, its structural formula is
Further, the invention provides a preferred compound, its compound name is (R, 2Z, 6E) -7- (4-
(4- fluorophenyls)-6- isopropyl-2-N- methyl methanesulfonamidos) pyrimidine-5- bases)-5-hydroxyl hept- 2,6-2- olefin(e) acid sodium salts, its
Structural formula is
Further, the invention provides a preferred compound, its compound name is (S, Z) -7- (4- (4- fluorine
Phenyl) -6- isopropyl -2- (N- methyl methanesulfonamidos) pyrimidine -5- bases) -5- hydroxyl hept-2-ene" acid sodium-salts, its structural formula is
Further, the invention provides a preferred compound, its compound name is (R, 2Z, 6E) -7- (4-
(4- fluorophenyls)-6- isopropyl-2- (N- methyl methanesulfonamidos) pyrimidine-5- bases)-5-hydroxyl-2,6-2- enoic acid hemicalcium salts, its
Structural formula is
Further, the invention provides a preferred compound, its compound name is (S, Z) -7- (4- (4- fluorine
Phenyl) -6- isopropyl -2- (N- methyl methanesulfonamidos) pyrimidine -5- bases) -5- hydroxyls hept-2-ene" half calcium salt of acid, its structural formula
For
Further, the invention provides a preferred compound, its compound name is (R, 2Z, 6E)-methyl (4-
(4- fluorophenyls) -6- isopropyl -2- (N- methyl methanesulfonamidos) pyrimidine -5- bases) -5- hydroxyl -2,6-2- e pioic acid methyl esters, its knot
Structure formula is
Further, the invention provides a preferred compound, its compound name is (S, Z)-methyl (4- (4-
Fluorophenyl) -6- isopropyl -2- (N- methyl methanesulfonamidos) pyrimidine -5- bases) -5- hydroxyls hept-2-ene" acid methyl esters, its structural formula
For
Further, the invention provides a preferred compound, its compound name is (R, 2Z, 6E) -7- (4-
(4- fluorophenyls) -6- isopropyl -2- (N- methyl methanesulfonamidos) pyrimidine -5- bases) -5- (formyloxy) hept- 2,6-2- olefin(e) acids,
Its structural formula is
Further, the invention provides a preferred compound, its compound name is (S, Z) -7- (4- (4- fluorine
Phenyl) -6- isopropyl -2- (N- methyl methanesulfonamidos) pyrimidine -5- bases) -5- (formyloxy) heptyl -2- olefin(e) acids, its structure
Formula is
Further, the invention provides a preferred compound, its compound name is (S, Z) -7- (4- (4- fluorine
Phenyl) -6- isopropyl -2- (N- methyl methanesulfonamidos) pyrimidine -5- bases) -5- (cigarette) heptyl -2- olefin(e) acids, its structural formula is
Further, the invention provides a preferred compound, its compound name is (R, 2Z, 6E) -7- (4-
(4- fluorophenyls) -6- isopropyl -2- (N- methyl methanesulfonamidos) pyrimidine -5- bases) -5- (cigarette) hept- 2,6-2- olefin(e) acids, its structure
Formula is
Further, the invention provides a preferred compound, its compound name be (2Z, 5R, 6E)-(3AR,
6S, 6AS) -6 (nitrooxy) hexahydro furyls simultaneously [3,2-b] furans -3- bases (4- (4- fluorophenyls) -6- isopropyl -2- (N- methyl
Methanesulfonamido) pyrimidine-5- bases)-5-hydroxyl-2,6-2- olefin(e) acid esters, its structural formula is
Further, the invention provides a preferred compound, its compound name be (5S, Z)-(3AR, 6S,
6AS) -6 (nitrooxy) hexahydro furyls simultaneously [3,2-b] furans -3- bases (4- (4- fluorophenyls) -6- isopropyl -2- (N- methyl first
Sulfonamido) pyrimidine -5- bases) -5- hydroxyl hept-2-ene" acid esters, its structural formula is
Present invention also offers a kind of Pharmaceutical composition, the compound or pharmacy in any of the above described containing effective dose
Upper acceptable salt, ester and pharmaceutically acceptable carrier or compound.
Present invention also offers compound in any of the above described and the like, its pro-drug and active metabolism
Thing and aforesaid compound pharmaceutically acceptable salt, ester or above-mentioned Pharmaceutical composition are preparing treatment reduction blood fat water
Purposes in the high blood cholesterol drug that flat or prevention and treatment of coronary heart disease, the atherosclerotic of high fat of blood initiation, diabetes are caused.
Further, described reduction blood fat level refers to five indexs (HDL, low-density of reduction blood fat
Albumen, very low-density lipoprotein, triglycerides, TL) in one or any several.
Present invention also offers a kind of be based on compound obtained in medicine principle of hybridization, including using above-mentioned described change
The hydroxyl of compound, hydroxy-acid group is same to prevent and treat the right of the relevant disease medicine main component compound such as high fat of blood, hypertension, hyperglycaemia
The soda acid of the groups such as hydroxyl, carboxylic acid, amido is answered into salt, into ester, into acid amides, into splicing objects such as ethers.
The invention provides a kind of new HMGR inhibitor (statins being commonly called as), not exclusively to eliminate or extremely
Weaken the toxicity that this kind of medicine brings less, and pharmacologically active value is improved.Pharmacology test result shows, described in invention
Such polysubstituted indoles statin derivative and its lactone open loop after carboxylic acid and its ester relative to not derivative statin in totality
Upper HMGR enzyme inhibition activities IC50Test value tool is significantly improved.
The present invention is that a kind of structure shown in formula I contains the 2- alkene -3- formed after 2- hexenolactones segments-segment and its lactone open loop
The poly-substituted miazines statin derivative or its active metabolite of hydroxypentanoic acid and its salt or ester：
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 be the 2- alkene -3- hydroxypentanoic acids and its salt that are formed after 2- hexenolactones segments-segment or its lactone open loop or
Ester；
As shown in formula I, when its structure is 2- hexenolactone segments-segments, its substituted radical R1, R2, R11 are hydrogen, first
The straight chain saturation or unsaturated alkyl of the 1-10 carbon atom such as base, ethyl, propyl group, vinyl or cyclopropyl, substituted-phenyl and first
The small size substituted radicals such as the straight or branched alkyl of the 1-10 carbon atom such as epoxide, ethyoxyl, R1 and R2, R11 are preferably hydrogen
Or methyl.
When its structure for open loop form carboxylate when, its substituted radical R1, R2, R11 be hydrogen, methyl, ethyl, propyl group,
The straight chain such as vinyl saturation or unsaturated alkyl or cyclopropyl, substituted-phenyl and methoxyl group, ethyoxyl etc. small size substituent
Group, R1 and R2, R11 are preferably hydrogen.Can be methyl, ethyl, propyl group into R9, R10 substituted radical of ester with carboxylic acid or alcoholic extract hydroxyl group
Deng the straight or branched alkyl or other organic acid esters of 1-10 carbon atom, preferably methyl esters or ethyl ester.
Equally, hydroxy-acid group can also be with alkali metal or alkaline-earth metal M into salt, and M slaines include sodium salt, the sylvite of monovalence
Or ammonium salt, the calcium salt of divalence, magnesium salts, particular certain cancers and calcium salt.
For the alcoholic extract hydroxyl group exposed after lactone open loop can form organic or inorganic acid ester with group X additions, its implication
It is as follows：
A) organic acid esters
The unitary of 1-20 carbon of-straight or branched or multi-carboxylate, preferred 1-10 carbon, optionally by one or more
Substituted radical replaces, 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 cycloalkyl of 3-7 carbon atom, preferred 3-5 carbon atom.
- substituent the aromatic carboxylic acids containing aromatic ring structure such as substituted aroma carboxylic acid：
Wherein n for 0-20 integer, preferred 1-3；
X, Y represent substituent, are selected from：Simply the taking comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched
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 many hydrogen phenanthrene rings of rigid plane of lipophilic or many hydrogen phenanthrene rings or other condensed ring of substituent group, and structure is as follows
Formula is shown
Specific definition is as follows in formula：
A) female ring structure
- polysubstituted pyrimidine ring
- following five yuan or the rigid heterocyclic of hexa-atomic saturation, insatiable hunger and/or fragrance, comprising one or more selected from nitrogen, oxygen,
The hetero atom of sulphur, is selected from：
B) substituent in female ring structure
R3, R4, R5, R6, R7, R8 are defined as following substituted radicals：
As formula is shown, substituted organic amine is connected in female ring
- unsubstituted, is directly connected to a hydrogen atom
- hydroxyl, or hydroxyl with contain carboxylate formed by 1-3 carbon atom,
The hydrocarbyl ether of -1-3 carbon atom, 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 replaced by one or more substituted radicals, described
Substituent is selected from：The simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched, preferred isopropyl
Base.
The cycloalkane of -3-7 carbon atom, is optionally replaced by one or more substituted radicals, and the substituent is selected from：Halogen
The simple substituted radical comprising 1-3 carbon atom of plain atom, hydroxyl or straight or branched, preferred cyclopropyl.
- substituted aroma ring, substituted radical includes the alkyl of halogen, 1-3 carbon atom, preferably aligns substituted fluorophenyl
Or phenyl.
- hydrophilic radical, the sulfuryl for such as replacing, sulfoxide group or ketone carboxyl, acid amides, these substituents are generally hydroxyl or straight
The simple substituted radical comprising 1-3 carbon atom of chain or side chain.Preferably methyl substituted sulfuryl group.
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.
Another aspect of the present invention is to provide for type I compound to be made with least one treatment the medication combined of angiocardiopathy
With the medicine is selected from 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.
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.
This kind of compound synthesis method of the present invention is simple, is especially available with existing procucts bulk drug for raw material, Jing
Cross the simply reaction of several steps can be prepared by.Relative to the statin analog (referring to HMGR enzyme inhibitors) of business development, its suppression
Enzymatic activity IC50Value is compared or the same order of magnitude or with the lower order of magnitude, which show this kind of compound of the present invention
Can be used as the medicinal application of reduction blood fat.It is external large-scale pharmacy giant patent particularly in whole statinses on the market
In the case of monopolization, statins antilipemic of the exploitation with independent intellectual property right is wanted, with 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, for example, correspond to isomers or diastereoisomer, its product
The asymmetry possessed in structure in such compound for the reason for raw being selection.The same with most drug, it can also
With crystal formation, the different crystal forms that each single chemical substance has in such compound are also included in class of the present invention.
This kind of compound of the present invention can also be the form of solvation, especially methyl alcohol, 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 through certain hour.
Compound of the present invention and its active metabolite are known as the derivative of prodrug or metabolic activity thing
Thing.
2- alkene -3- the hydroxypentanoic acids 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 2- alkene -3- hydroxypentanoic acids after the compounds of this invention lactone open loop, containing hydroxy-acid group and alcoholic OH groups, can
Ester is shaped as to add with suitable oxyacid and alcohol compound.
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 is obtained (these acid react 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 correspondence (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 flutters acid, pectinic acid, 3- phenylpropionic acids, picric acid, neopentanoic acid, butanedioic acid, tartaric acid, first
The parmacodynamics-less activities such as benzene sulfonic acid, palmitic acid and undecanoic acid can be used for same hydroxyl into the organic carboxyl acid of ester.
Carboxylic acid can add with suitable alcohol and be shaped as carboxylate after the compounds of this invention lactone open loop.Organic Alcohol includes simple
Alkylol such as methyl alcohol, ethanol, propyl alcohol, hexylene glycol, the parmacodynamics-less activity such as glycerine can be used for same carboxylic acid into the alcohols of ester.
Indication 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 to into ester including covalently bound, into acid amides into again
Miscellaneous salt or the part A in formula I is carried out into the splicing of fragment with other related drugs.The all of A portions by structural formula
Divide carries out split and there is the compound of suppression HMGR enzymatic activitys to be all in patent claims of the present invention 1 with other medicine
The analog and its active metabolite of indication.
Related drugs in above-mentioned are including but not limited to used for all kinds of of preventing and treating three high (high fat of blood, hypertension, hyperglycaemia)
Medicine.For patient clinically, 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 contributes to reducing dose and mitigation medication treatment
Toxic and side effect.
Above-mentioned middle related drugs including but not limited to treat phenoxy acetic acid class, the nicotinic acid class of high fat of blood.
Above-mentioned middle related drugs including but not limited to treat Mg-ATP enzyme inhibitor classes (such as reserpine), the α of hypertension2Receive
Body activator (such as clonidine, ethyldopa), beta-blocker (such as the atenolol in Luo Er classes), angiotensin-converter
Enzyme inhibitor (such as the benazepil in pril), angiotensinⅡantagonist (such as the Telmisartan of husky smooth class), an oxidation
Nitrogen donor medicine (the such as Isosorbide Mononitrates of nitrate esters), these medicines are all containing amido or alcoholic extract hydroxyl group, carboxylic acid group
Group, can be with compound of the present invention by being dehydrated into ester into acid amides, and soda acid obtains the medicine splicing object of correlation into salt.
The present invention includes stereoisomer and optical isomer, for example, correspond to isomers or diastereoisomer, its product
The asymmetry possessed in structure in such compound for the reason for raw being selection.The same with most drug, it can also
With crystal formation, the different crystal forms that each single chemical substance has in such compound are also included in class of the present invention.
The following example illustrates rather than the restriction method of the present invention and composition.Other of different condition and product are fitted
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 using appropriate material according to the general approach of described below 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 change of method can be used for preparing these compounds.Unless otherwise stated, it is used organic in embodiment
Solvent and reagent (dichloromethane, ethyl acetate, petroleum ether and triethylamine etc.) are the routine of commercial reagent Jing this areas accreditation
Method is done and does the Non-aqueous processing of a small amount of except water process or using the molecular sieve after activation.Described analytical and testing instrument and condition is removed
It is non-to be otherwise noted, otherwise：HRMS high resolution mass spectrums be Brooker,Switzerland company solanX-70 FT-MS, H-NMR nucleus magnetic hydrogen spectrums
The 500M of volance III, test solvent is CDCl3.Spectral data is attached.
The generalized flowsheet for preparing such compound is described below：
To include but is not limited to the carboxylic metallic salt (mainly calcium salt, sodium salt) of commercially available Statins bulk drug for raw material,
The acidifying of Jing certain density hydrochloric acid is free, and concentrated in vacuo Jing after appropriate organic solvent extraction obtains crude carboxylic acid.This crude product
Without refined, that is, carry out lactonizing for next step.
The DMAP of above-mentioned crude carboxylic acid and catalytic amount, appropriately sized magnetic stir bar is added in the lump suitable
When reaction vessel in, organic solvent dissolving after.A certain amount of dicyclohexylcarbodiimide solution, stirring reaction under room temperature is added dropwise
Overnight.Jing after thin-layer chromatography monitoring reaction completely, suction filtration, filtrate anhydrous sodium sulfate drying, concentration, (PE/EA is terraced for column chromatography for separation
Degree is eluted) obtain lactone.
A certain amount of organic solvent and p-methyl benzenesulfonic acid and a certain amount of lactone are added in reaction vessel, are refluxed anti-
Should.After a period of time, Jing after thin-layer chromatography monitoring reaction completely, the NaHCO for plus 5%3The aqueous solution shakes, and it is organic that point liquid removes layer
Phase, anhydrous sodium sulfate drying, concentration, column chromatography for separation (PE/EA gradient elutions) obtains the fragment of hexenolactone containing 2- of the present invention
Statin derivative.
By the lactone form of the above-mentioned fragment statin derivative of hexenolactone containing 2-, in suitable aqueous slkali and organic solvent
Under 2- alkene -5- hydroxypentanoic acid forms can be obtained with open loop, so as to expose carboxylic acid and alcoholic OH groups, further with acid, alkali adds
Into into addition products such as salt, ester, acid amides.
Specific embodiment：
Embodiment 1：The preparation of RSVL
Weigh the rosuvastatin sodium salt of 5.00g, in being added to the eggplant-shape bottle of 250ml, add 100ml dichloromethane and
The watery hydrochloric acid of 20 times of dilutions of about 10ml, acidifying, point liquid, 100ml dichloromethane equivalent is extracted three times, merges lower floor's organic phase,
Anhydrous sodium sulfate drying.Concentration, oil pump is vacuumized, and obtains white powder 4.87g, i.e. rosuvastatin crude carboxylic acid weighs 4.50
Above-mentioned Pravastatin crude carboxylic acid, in being added to there-necked flask, adds p dimethylamino pyridine, the 50ml dichloromethane of 0.05g
And stirrer.The dicyclohexylcarbodiimide that 5.0g is slowly injected under ice bath is dissolved in 20ml dichloromethane resulting solutions.Drip
Bi Hou, removes ice bath and reacts at room temperature overnight.Jing after thin-layer chromatography monitoring reaction completely, suction filtration, filtrate anhydrous sodium sulfate is done
Dry, vacuum is spin-dried for, and rapid column chromatography separates (PE/EA gradient elutions) and obtains pravastatin lactone 3.78g.MP:132.2-132.5
DEG C, HRMS (ESI):C22H26FN3O5S,464.16970(M+H)+Theoretical value 464.16107；H-NMR:δ7.62(dd,2H,J
=8.0,5.6Hz), 7.10 (t, 2H, J=8.4Hz), 6.71 (d, 1H, J=16.1Hz), 5.48 (dd, 1H, J=16.1,
5.9Hz), 5.28-5.19 (m, 1H), 4.33 (s, 1H), 3.57 (s, 3H), 3.52 (s, 3H), 3.32 (dt, 1H, J=13.2,
6.6Hz), 2.75-2.64 (m.2H), 1.91 (d, 1H, J=14.1Hz), 1.69-1.61 (m, 1H), 1.26 (dd, 6H, J=
6.3,3.6Hz)
Embodiment 2：The preparation of RSVL reduzate
Above-mentioned RSVL is weighed into 500mg, in being added to 25ml reaction tubes, stirrer and about 5ml is added
The tetrahydrofuran of methyl alcohol and about 1ml and the 10% of 20mg Pt/C catalytic hydrogenation catalysts, displaced air, room temperature normal pressure catalysis hydrogen
Change.After 12 hours, thin-layer chromatography monitoring reaction is complete.Filtration filters Pt/C, and filtrate Jing after anhydrous sodium sulfate drying, revolve by vacuum
Dry, column chromatography for separation (PE/EA gradient elutions) obtains RSVL reduzate 360mg, HRMS (ESI)：C24H28FNO3,
466.18565(M+H)+, theoretical value 466.18119；H-NMR:7.63 (dd, 2H, J=8.6,5.5Hz), 7.45 (dd, 1H, J=
), 8.5,5.4Hz 7.13 (t, 1H, J=8.6Hz), 7.07 (t, 2H, J=8.6Hz), 6.34 (d, 1H, J=16.0Hz), 5.46
(dt, 1H, J=15.8,6.9Hz), 3.90 (s, 1H), 3.55 (s, 3H), 3.51 (s, 2H), 3.35 (dt, 1H, J=13.3,
6.6Hz), 2.60 (t, 1H, J=7.3Hz), 2.50-2.40 (m, 2H), 2.24 (m, 2H), 1.25 (d, 3H, J=0.8Hz),
1.24(s,3H)。
Embodiment 3:The preparation of compound 001,002
Appropriately sized magnetic stir bar is added in two mouthfuls of reaction bulbs of 50ml, adds the p-methyl benzenesulfonic acid of 0.45g
(PBSA) and 1.50g RSVL displaced air and with nitrogen protect, inject 30ml tetrahydrofuran after will reaction
Container is heated to reflux, Jing after thin-layer chromatography monitoring reaction completely, Jing after thin-layer chromatography monitoring reaction completely, and the NaHCO for plus 5%3
The aqueous solution shakes, and point liquid removes a layer organic phase, and anhydrous sodium sulfate drying, concentration, column chromatography for separation (PE/EA gradient elutions) obtains this
Rosuvastatin derivative (001) 0.65g of the invention fragment of hexenolactone containing 2-.
Embodiment 4:The preparation of compound 003,004,005,006
Rosuvastatin derivative (001) 1.00g is taken, with ice bath after tetrahydrofuran 6ml dissolvings, the LiOH of 1mol/L is added
After solution 1.5ml is stirred 2 hours, when with 10% hydrochloric acid, to be acidified to pH be 2-3,45 DEG C of decompression is evaporated off solvent, 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, drop to
Till 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.,
Rosuvastatin derivative sodium salt (003).Same method can obtain compound 004.
Rosuvastatin derivative (001) 1.00g is taken, with ice bath after tetrahydrofuran 6ml dissolvings, adds 1mol/L's
After LiOH solution 1.5ml is stirred 2 hours, when with 10% hydrochloric acid, to be acidified to pH be 7-8,45 DEG C of decompression is evaporated off solvent, adds second
After alcohol about 10ml dissolvings, 10% CaCl is slowly added dropwise while stirring2The aqueous solution, is stirred overnight, and separates out solid, and suction filtration is obtained
Half calcium salt crude product.With the methanol/water mixed solution of 50% volume ratio, the refined calcium of rosuvastatin derivative half of recrystallization
Salt (005) 0.75g.Same method can obtain compound 006.
Embodiment 5:The preparation of compound 007,008
Rosuvastatin derivative (001) 1.00g is taken, with ice bath after tetrahydrofuran 6ml dissolvings, the LiOH of 1mol/L is added
After solution 2.5ml is stirred 2 hours, this water oil mixture ether is washed into three times (5 × 3), upper strata is discarded after washing every time to be had
Machine phase.10% hydrochloric acid of water is acidified to pH when being 2-3, adds water and ethyl acetate point liquid to extract three times (6 × 3), organic
Phase anhydrous sodium sulfate drying, 45 DEG C of decompression is evaporated off solvent and obtains final product rosuvastatin derivative lactone open loop crude carboxylic acid 0.89g.
Above-mentioned crude carboxylic acid is dissolved in the absolute methanol of 25ml, after adding the p dimethylamino pyridine of catalytic amount, adds under ice bath
Enter 1.2gDCC (dicyclohexylcarbodiimide) and be dissolved in 5ml methyl alcohol resulting solutions.Remove ice bath, stirring reaction overnight, Jing thin layers
After analysis monitoring reaction completely, suction filtration, reduced pressure concentration, silica gel column chromatography separating purification obtains rosuvastatin derivative carboxylate methyl ester
(007)0.53g.Same method can obtain compound 008.
Embodiment 7:The preparation of compound 009,010
Open loop crude carboxylic acid 0.65g of rosuvastatin derivative lactone described in Example 5 is dissolved in formic acid and dichloromethane
The 1 of alkane:In 1 mixed solvent, after adding the p dimethylamino pyridine of catalytic amount, 1.2gDCC (dicyclohexyl carbon is added under ice bath
Diimine) it is dissolved in the 1 of 5ml formic acid and dichloromethane:1 mixed solvent resulting solution.Remove ice bath, stirring reaction overnight, Jing
After thin-layer chromatography monitoring reaction completely, suction filtration, reduced pressure concentration, silica gel column chromatography separating purification obtains rosuvastatin derivative carboxylic
Sour formic acid esters (009) 0.57g.Same method can obtain compound 010.
Embodiment 8:The preparation of compound 011,012
Rosuvastatin derivative lactone open loop crude carboxylic acid 0.65g described in Example 5 and 2g nicotinic acid are dissolved in 15ml
Dichloromethane in, add catalytic amount p dimethylamino pyridine after, under ice bath add 1.2gDCC (dicyclohexylcarbodiimide)
It is dissolved in 5ml dichloromethane resulting solutions.Remove ice bath, overnight, and back flow reaction is after about 1 hour, Jing thin-layer chromatographies for stirring reaction
Monitoring reaction is complete, and suction filtration, filtrate reduced in volume, silica gel column chromatography separating purification obtains rosuvastatin derivative nicotinate
(012)0.57g.Same method can obtain compound 011.
Embodiment 10:The preparation of compound 013,014
Rosuvastatin derivative lactone open loop crude carboxylic acid 0.65g described in Example 5 and the different mountain of 2.5g single nitric acids
Pear ester is dissolved in the acetonitrile of 50ml, after adding the p dimethylamino pyridine of catalytic amount, 1.2gDCC (dicyclohexyls is added under ice bath
Carbodiimide) it is dissolved in 5ml acetonitrile resulting solutions.Completion of dropping recession remove ice bath, heating water bath back flow reaction overnight, Jing thin layers
Analysis monitoring reaction is complete, and suction filtration, filtrate reduced in volume, silica gel column chromatography separating purification obtains rosuvastatin derivative single nitric acid
Soquad (013) 0.26g.Same method can obtain compound 014.
Compound activity is tested
Inhibitory action of following description of test the compounds of this invention to the enzymatic activity of HMG-CoA reductase (HMGR)
Experimental principle
3- hydroxy-3-methyl glutaryl coenzyme (HMG-CoA) reductases are to be catalyzed acetyl coenzyme A synthesis mevalonic acid in vivo
This metabolic pathway key enzyme, its be catalyzed under physiological environment below react：
HMG-CoA+NADPH+2H+→mevalonic acid+2NADP++CoASH
Because NADPH has absworption peak at 340nm, therefore the activity of HMG-CoA reductase can be by luminosity of dividing the work
The reduction yield of light absorbs at 340nm is determined completing.
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
0.5-2ul is each one) and its supporting disposable pipette tips, spectrophotometer or ELIASA
Medicament is prepared and prepared
5 times of concentration buffer liquid of 10ml are diluted to into 1 times of buffer solution (i.e. the 5 of 10ml times liquid add the ultra-pure water of 40ml),
In the case of 96 orifice plates, 1 times of liquid of 1ml 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.The NADPH of 25mg requires supplementation with 1 times of buffer solution of 1.5ml, is well mixed -20 DEG C of preservations.
Method and flow process
Thaw：Defrosting enzyme needs on ice or keep surrounding environment cooling again, try not that enzyme is placed on ice more than 60 points
Clock because standing time it is long can cause enzyme activity reduction.Other defrostings can be carried out at room temperature, once thaw to be stored in
On ice.
Instrument adjustment:Temperature is adjusted to 37 DEG C by experiment before starting, and absorbing wavelength is 340nm, gets out dynamic routine.96 holes
Plate sample read a number per 20 seconds, amounted to 10 minutes.
The form provided according to kit and flow process add the reactant liquor of suitable volumes
Form
Reagent Standard entertion mode
Flow process:A, adds quantitative 1 times buffer solution in each hole；
B, plus testing sample in the hole in addition to blank and positive control
C, plus supplemented the NADPH of buffer solution in each hole
D, plus substrate HMG-CoA is in each hole
E, enzyme-added HMGR is in the hole in addition to blank
F, reactant liquor is well mixed, and especially at least strongly to be stirred before first time extinction ground is surveyed with during 96 orifice plate test sample
Mix 10 seconds
G, opens dynamic routine, observes the change of absorbance
Active testing is carried out according to the method that kit is introduced, absorbance decline curve is obtained, the slope of decline indicates difference
Inhibition of the sample to HMGR enzymes, to the slope curve of gained Mathematical treatment and fitting are carried out, and according to the explanation of kit, are made
Activity data is calculated with equation below
Wherein:Parameter 12.44 represents 12.44mM/cm, because attenuation coefficients of the NADPH under 340nm is 6.22mM/cm,
The NADPH of twice in reaction mechanism, therefore for 12.44
TV is the cumulative volume of reactant liquor, and 96 orifice plates are 0.2ml
V represents the volume of reductase, i.e., the volume of enzyme used in test every time
0.6 represents using the concentration under mg-Protein units (mgP)/ml, generally 0.50-0.70, here kit
The concentration of offer is 0.6
LP represents optical path width, and 96 orifice plates are 0.55cm
Unit is defined as the NADPH of the 1umol per minute at 37 DEG C and is converted into NADP+, and concrete unit is umol/min/mg
Protein
A340 represents absorbance of the sample in 340 nano wave lengths, and Δ A340 represents corresponding absorbance change value
MinssampleThe time used by 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.
Overall expression experienced MinssampleSample absorbance under 340 nanometers of wavelength in time
Rate of change, unit is min-1, it is sameRepresent the rate of change of blank sample.
Then the inhibiting rate of certain sample is under certain concentration：
Wherein activity dataActivityThe Activity activity values tested and calculated according to formula correspondence are represented,
Activity dataSampleRepresent and add the activity value after inhibitor sample.
Measure inhibiting rate data of the same sample under variable concentrations, you can draw the compound to 3- hydroxy-3-methyls
The half-inhibition concentration IC of pentanedioyl acyl coenzyme (HMG-CoA) reductase50。
Claims (11)
1. a kind of compound, its structural formula is as follows,
Or, wherein, R1, R2, R3, R4, R11 be hydrogen, M be sodium ion,
Potassium ion, ammonium ion, calcium ion or magnesium ion, R5 be isopropyl, R6 for p-fluorophenyl, R7 and R8 be respectively methyl or
The methyl substituted sulfuryl of person.
2. a kind of compound according to claim 1, it is characterised in that：Its compound name is（R, E）-N-（4-（4 -
Fluorophenyl）- 6-isopropyl-5（2 -（6-oxo-3,6-dihydro-2H--2-bases of pyrans）Vinyl）- pyrimidine -2
- base）- N- methylmethanesulfonamides, its structural formula is
。
3. a kind of compound according to claim 1, it is characterised in that：Its compound name is（S）-N-（4-（4-fluorine
Phenyl）- 6-isopropyl-5（2 - （6-oxo-3,6-dihydro-2H--2-bases of pyrans）Ethyl）Pyrimidine-2-
Base）- N- methylmethanesulfonamides, its structural formula is
。
4. a kind of compound according to claim 1, it is characterised in that：Its compound name is（R, 2Z, 6E）-7-（4-
（4- fluorophenyls）- 6- isopropyl -2-（N- methyl methanesulfonamidos）Pyrimidine -5- bases）- 5-hydroxyl hept- 2,6- diene acid sodium-salts, its
Structural formula is
。
5. a kind of compound according to claim 1, it is characterised in that：Its compound name is（S, Z）-7 - （4-（4-
Fluorophenyl）- 6-isopropyl-2-（N- methyl methanesulfonamidos）Pyrimidine-5-base）- 5-hydroxyl hept-2-ene" acid sodium
Salt, its structural formula is。
6. a kind of compound according to claim 1, it is characterised in that：Its compound name is（R, 2Z, 6E）-7-（4-
（4- fluorophenyls）- 6- isopropyl -2-（N- methyl methanesulfonamidos）Pyrimidine -5- bases）The calcium of-5-Hydroxyheptyl-2,6- dienoic acids half
Salt, its structural formula is
。
7. a kind of compound according to claim 1, it is characterised in that：Its compound name is (S, Z）-7 - （4-（4
- fluorophenyl）- 6-isopropyl-2-（N- methyl methanesulfonamidos）Pyrimidine-5-base）- 5-hydroxyl hept-2-ene" acid half
Calcium salt, its structural formula is
。
8. a kind of Pharmaceutical composition, it is characterised in that：Compound or pharmacy in the claim 1 ~ 7 containing effective dose in any one
Upper acceptable salt and pharmaceutically acceptable carrier.
9. the compound and aforesaid compound in claim 1 ~ 7 in any one pharmaceutically in preparation control by acceptable salt
Treat the high fat of blood medicine that reduction blood fat level or prevention and treatment of coronary heart disease, the atherosclerotic of high fat of blood initiation, diabetes are caused
Purposes in thing.
10. the pharmaceutical composition described in claim 8 is preparing treatment reduction blood fat level or prevention and treatment of coronary heart disease, high fat of blood
Purposes in the high blood cholesterol drug that the atherosclerotic of initiation, diabetes are caused.
11. purposes as described in claim 9 or 10, it is characterised in that：Described reduction blood fat level refers to reduction blood fat
HDL, low-density albumen, very low-density lipoprotein, triglycerides, one or more in TL.
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