CN104356118B - Polysubstitution pyrroles pitavastatin lactone dewatering compound and application thereof - Google Patents
Polysubstitution pyrroles pitavastatin lactone dewatering compound and application thereof Download PDFInfo
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- CN104356118B CN104356118B CN201410553313.XA CN201410553313A CN104356118B CN 104356118 B CN104356118 B CN 104356118B CN 201410553313 A CN201410553313 A CN 201410553313A CN 104356118 B CN104356118 B CN 104356118B
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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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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- 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
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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 statinses, a kind of specifically polysubstituted pyrrole
Cough up class his statin lactone anhydro compounds and application thereof.
Background technology
Hyperlipidemia is the inducement of various cardiovascular and cerebrovascular diseases, and population epidemiology investigation shows, for Chinese male crowd
For, low density lipoprotein, LDL (lipid forms lipoprotein with albumin bound mostly and exists 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 "
(hyperlipidemia, hypertension, hyperglycemia) is the risk factor of various diseases or its direct disease.Various medical science and biological metabolism
Research has shown that, the penta 2 phthalein CoA-reductase of 3- hydroxy-3-methyls 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
Penta 2 phthalein coenzyme A (3-Hydroxy-3-methylglutaryl-CoA, HMG-CoA) of thing 3- hydroxy-3-methyls is combined occurs two
The secondary reduction reaction for being related to four electron transfers and generate the critical materialses 3 of human body lipid synthesis, 5- dihydroxy-acids.3- hydroxyls-
Two phthalein CoA-reductase inhibitors of 3- methylpent (i.e. commercially available statinses) is main flow hypolipidemic on the market
Thing, is 12,400,000,000 dollars wherein by the atorvastatin calcium preparation of Pfizer Inc.'s development and sale by 2008 annual sales amounts, 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 which 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 statinses50In the nmol/L orders of magnitude,
So statinses 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, HMG-CoA is inhibited to the conversion of 3,5- dihydroxy-acids, and then finally inhibit the synthesis of people's body lipid.
Statinses are 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, which has been subjected to natural fermented statin, synthetic statin, third generation superstatin three
Stage.With the research and development that deepens continuously of the mechanism of action to statinses and Computeraided drug design,
Recognize fluorine atom is introduced to improving the HMGR enzymes suppression of drug molecule in the appropriate site of existing statinses or its analog
The toxic and side effects of system activity or reduction 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 CN101580497A such as CA2072945, CN101230055A, CN1539417A and document (Science, 2001
(292):3S is all directly or indirectly asserted 1160-1164) etc., 5R-3,5- dihydroxy-acid structure is the 3- hydroxy-3-methyls
The active necessary structure of penta 2 phthalein CoA-reductase inhibitors (statinses), 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, statinses also have not
Good reaction, such as：Hepatopathy, carcinogenic toxicity, particularly muscle side reaction, rhabdomyolysises, 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 statinses derivant of segment structure, through HMGR enzyme inhibition activity experiment tests, it is found that the series compound has same city
The statinses 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 polysubstituted pyrrole class he statin lactone be dehydrated
Compound and application thereof, described his statin lactone anhydro compounds of this polysubstituted pyrrole class and application thereof prior art to be solved
In statins derivative there are toxic and side effects, and treat the limited technical problem of the effect of hyperlipidemia.
The invention provides a kind of compound, its structural formula is as follows,
Wherein,
R6, R10, R11 be hydrogen, the straight chain saturation of 1-10 carbon atom or unsaturated alkyl or cyclopropyl, substituted-phenyl,
Or the small size substituted radical such as the straight or branched alkyl of 1-10 carbon atom, M is sodium ion, potassium ion, ammonium ion, calcium
Ion or magnesium ion, R9 is straight or branched alkyl or the organic acid esters of hydrogen or 1-10 carbon atom, Z for straight chain or
The unitary or polycarboxy of 1-20 carbon of side chain, wherein, R1, R2, R3, R4, R5, R7, R8 be respectively hydrogen, hydroxyl, hydroxyl with
Containing carboxylate substituent groups, the hydrocarbyl ether of 1-3 carbon atom, halogen, or 1-3 carbon atom formed by 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.
Further, take with one or more on the unitary or polycarboxy of 1-20 carbon of described straight or branched
For group, simple substituted radical comprising 1-3 carbon atom of the substituent group for halogen atom, hydroxyl or straight or branched.
Further, the substituent group can also be the cycloalkyl of 3-7 carbon atom.
Further, Z is the substituent group 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 R6, R10, R11 are hydrogen, methyl, ethyl, propyl group, vinyl, methoxyl group or ethyoxyl.
Further, described R9 substituted radicals are methyl, ethyl, propyl group, methyl ester or ethyl ester.
Further, described R1, R2, R3, R4, R5, R7, R8 are hydroxyl, hydroxy carboxylic acid ester, acetass, S spatial configurations
Methoxyl group, ethyoxyl, fluorine, chloromethyl, isopropyl, cyclopropyl, the fluorophenyl of para-orientation.
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 substituent groups
Group replaces, simple substituent group comprising 1-3 carbon atom of the substituent group 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, the following structure of described pyrrole structure is replaced,
Further, present invention also offers a kind of a kind of preferred compound, its compound name is (S) -5- (4- fluorine
Phenyl) -2- isopropyl -1- (2- (6- oxo -3,6- dihydro -2H- pyrans -2- bases) ethyl)-N, 4- diphenyl -1H pyrroles -3-
Methanamide, its structural formula is
Further, present invention also offers a kind of a kind of preferred compound, its compound name is (Z) -7- (2-
(4- fluorophenyls) -5- isopropyl -3- phenyl -4 (phenylcarbamoyl) -1H- pyrroles's -1- bases) -5- hydroxyl -2- olefin(e) acid sodium, its
Structural formula is
Further, present invention also offers a kind of a kind of preferred compound, its compound name is (Z) -7- (2-
(4- fluorophenyls) -5- isopropyl -3- phenyl -4 (phenylcarbamoyl) -1H- pyrroles's -1- bases) -5- hydroxyls hept-2-ene" acid half
Calcium salt, its structural formula is
Further, present invention also offers a kind of a kind of preferred compound, its compound name is (Z)-methyl 7-
The acid of (2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4 (phenylcarbamoyl) -1H- pyrroles's -1- bases) -5- hydroxyls hept-2-ene"
Methyl ester, its structural formula is
Further, present invention also offers a kind of a kind of preferred compound, its compound name is (Z) -7- (2-
(4- fluorophenyls) -5- isopropyl -3- phenyl -4 (phenylcarbamoyl) -1H- pyrroles's -1- bases) -5- (formyloxy) heptyl -
2- olefin(e) acids, its structural formula is
Further, present invention also offers a kind of a kind of preferred compound, its compound name is (Z) -7- (2-
(4- fluorophenyls) -5- isopropyl -3- phenyl -4 (phenylcarbamoyl) -1H- pyrroles's -1- bases) -5- (cigarette) heptyl -2- olefin(e) acids,
Its structural formula is
Further, present invention also offers a kind of a kind of preferred compound, its compound name be (Z)-(3AR,
6S, 6AS) -6 (nitrooxy) hexahydro furyl simultaneously [3,2-b] furan -3- base 7- (2- (4- fluorophenyls) -5- isopropyl -3- phenyl -
4- (phenylcarbamoyl) -1H- pyrroles's -1- bases) -5- hydroxyl hept-2-ene" acid esters, its structural formula is
Present invention also offers a kind of Pharmaceutical composition, the compound in any of the above described containing effective dose or pharmaceutically
Acceptable salt, ester and pharmaceutically acceptable carrier or complex.
Present invention also offers compound in any of the above described one and the like, its prodrug 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 caused by flat or prevention and treatment of coronary heart disease, the atherosclerosiss of hyperlipidemia initiation, diabetes.
Further, described reduction blood fat level refers to the high density lipoprotein of reduction blood fat, low-density albumen, very
Low density lipoprotein, LDL, triglyceride, in TL 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 hyperlipidemia, hypertension, hyperglycemia
The soda acid of the groups such as hydroxyl, carboxylic acid, amido is answered into salt, into ester, into amide, into splicing objects such as ethers.
The invention provides a kind of new HMGR inhibitor (statinses being commonly called as), to not exclusively 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 derivant 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 HMGR inhibitor (statinses being commonly called as) of the present invention, will not exclusively eliminate or at least weaken this kind of medicine
The toxicity that thing brings, and pharmacologically active value is improved.Pharmacology test result shows that such many hydrogen described in invention are luxuriant and rich with fragrance
After the fluorine-containing trim of ring class statin and its lactone open loop, carboxylic acid and its ester are relative to the HMGR enzymes suppression on the whole of not derivative statin
System activity IC50Test value is with raising or quite.
Therefore the purpose of the present invention is the 2- formed after a kind of structure shown in formula I contains 2- hexenolactones fragment and its lactone open loop
The polysubstituted pyrrole class statin derivant of alkene -3- hydroxypentanoic acids and its salt or ester or its active metabolite：
Such compound or its active metabolite are penta 2 phthalein CoA-reductase (3-Hydroxy-3- of 3- hydroxy-3-methyls
Methylglutaryl-CoA Reductase, HMGR) inhibitor 3,5- dihydroxy-acids its six-membered cyclic lactone forms 3-
Hydroxyl be replaced by fluorine atoms after derivant.Its structural formula such as formula I, wherein：
Part A is the 2- alkene -3- hydroxypentanoic acid and its salt or ester formed after 2- hexenolactones fragment or its lactone open loop；
As shown in formula I, when its structure is 2- hexenolactone fragments, its substituted radical R6, R10, R11 are hydrogen, methyl, second
The straight chain saturation of the 1-10 carbon atoms such as base, propyl group, vinyl or unsaturated alkyl or cyclopropyl, substituted-phenyl and methoxyl group,
The small size substituted radical such as straight or branched alkyl of the 1-10 carbon atoms such as ethyoxyl, R6, R10, R11 are preferably hydrogen or first
Base.
When its structure for open loop form carboxylate when, its substituted radical R6, R10, 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
Group, R6, R10, R11 are preferably hydrogen.Can be that 1-10 carbon such as methyl, ethyl, propyl group is former with carboxylic acid into the R9 substituted radicals of ester
The straight or branched alkyl of son or other organic acid esters, preferably methyl ester or ethyl ester
Equally, hydroxy-acid group can also be with alkali metal or alkaline-earth metal M into salt, and M slaines include the sodium salt of monovalence, potassium salt
Or ammonium salt, the calcium salt of bivalence, magnesium salt, 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, preferably 1-10 carbon, optionally by one or more
Substituted radical replaces, and the substituent group is selected from：Halogen atom, hydroxyl or straight or branched comprising the simple of 1-3 carbon atom
Substituted radical
The substituent group can also be the cycloalkyl of 3-7 carbon atom, preferably 3-5 carbon atom.
- substituent group the aromatic carboxylic acids containing aromatic ring structure such as substituted aroma carboxylic acid：
Integers of the wherein n for 0-20, preferably 1-3；
X, Y represent substituent group, 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 sulphuric 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 rigid plane polysubstituted pyrrole ring or other nitrogen heterocyclic rings for lipophilic, structure such as following formula are shown
In formula, specific definition is as follows：
A) female ring structure
- pyrrole ring or substituted azole ring or other coplanar nitrogenous five-ring heterocycles, selected from pyrroles, pyrazoles etc.
It is preferred that following female ring structure：
B) substituent group in female ring structure
R1, R2, R3, R4, R5, R7, R8 are defined as following substituted radicals：
- unsubstituted, is directly connected to a hydrogen atom
- hydroxyl, or hydroxyl with contain carboxylate substituent groups formed by 1-3 carbon atom
The hydrocarbyl ether of -1-3 carbon atom
- halogen, or the halogenated hydrocarbons of 1-3 carbon atom
The hydrocarbyl group of 1-10 carbon atom of-straight or branched, is optionally replaced by one or more substituted radicals, described
Substituent group is selected from：The simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched, it is preferably different
Propyl group
The cycloalkane of -3-7 carbon atom, is optionally replaced by one or more substituted radicals, and the substituent group is selected from：Halogen
The simple substituted radical comprising 1-3 carbon atom of atom, hydroxyl or straight or branched, preferably cyclopropyl.
- substituted aroma ring, substituted radical include halogen, the alkyl of 1-3 carbon atom or hydrocarbyl ether, and preferably para-position takes
The fluorobenzene group in generation.
Part B is the attachment structure of A and C portion
- for two carbon atoms carbochain, 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 cardiovascular disease
With the medicine is selected from ACE inhibitor, Angiotensin Ⅱ receptor antagonist, beta adrenergic blocker, calcium channel resistance
Stagnant dose, the medicine such as antithrombotic agent.
Suitable ACE inhibitor, Angiotensin Ⅱ receptor antagonist, beta adrenergic blocker, calcium channel resistance
Stagnant dose, the medicine such as antithrombotic agent can find its detailed description in such as clinical medicine handbook.
This kind of compound synthesis method of the present invention is simple, is especially available with existing procucts crude drug for raw material, Jing
Cross the simply reaction of several steps can be prepared by.Statin analog (referring to HMGR enzyme inhibitors) relative to 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 penta 2 phthalein CoA-reductase (3-Hydroxy-3- of 3- hydroxy-3-methyls
Methylglutaryl-CoA Reductase, HMGR) inhibitor.
The present invention includes stereoisomer and optical isomer, for example, correspond to isomer or diastereomer, its product
The unsymmetry possessed in structure in such compound for the reason for raw being selection.The same with most drug, which 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 methanol, ethanol, the larger polarity such as water
Small molecule solvent.Its solvation can occur in the production process of the compositionss 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 derivant of prodrug or metabolic activity 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, potassium salt, ammonium salt etc..Particular certain cancers and calcium salt.
There is after the compounds of this invention lactone open loop 2- alkene -3- hydroxypentanoic acids, containing hydroxy-acid group and alcoholic OH groups, can
To form ester with suitable oxyacid and alcohol compound addition.
After the compounds of this invention lactone open loop, hydroxyl can obtain carboxylate with oxyacid addition, 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) sulphuric 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, propanoic acid, adipic acid, alginic acid, aspartic acid
Deng aminoacid, benzoic acid, benzenesulfonic acid, butanoic acid, citric acid, dextrocamphoric acid., camphorsulfonic acid, cyclopentyl propionic acid, glucosulfone acid, dodecane
Base sulphuric acid, ethyl sulfonic acid, fumaric acid, glucoheptonic acid, phosphoglycerol, enanthic acid, caproic acid, 2- ethylenehydrinsulfonic acids, lactic acid, maleic acid, first
Sulfonic acid, 2- LOMAR PWA EINECS 246-676-2, oxalates flutter acid, pectinic acid, 3- phenylpropionic acids, picric acid, neopentanoic acid, succinic acid, tartaric acid, first
The parmacodynamics-less activities such as benzenesulfonic acid, Palmic acid and undecanoic acid can be used for same hydroxyl into the organic carboxyl acid of ester.
After the compounds of this invention lactone open loop, carboxylic acid can form carboxylate with suitable alcohol addition.Organic Alcohol includes simply
Alkylol such as methanol, ethanol, propanol, hexanediol, the parmacodynamics-less activity such as glycerol can be used for same carboxylic acid into the alcohols of ester.
Indication of the present invention is that compound and its active metabolite including but not limited to will be the compound in claims same
Existing known related drugs carry out split, these splits include it is covalently bound include but is not limited to into ester, into amide into answering
Miscellaneous salt or the part A in formula I is carried out with other related drugs the splicing of fragment.The all of A portions by structural formula
Point split is carried out with other medicine and there is the compound for suppressing HMGR enzymatic activitys to be all patent claims of the present invention 1
The analog and its active metabolite of indication.
Related drugs in above-mentioned are including but not limited to used for preventing and treating all kinds of of three-hypers (hyperlipidemia, hypertension, hyperglycemia)
Medicine.For patient clinically, of three senior middle schools is not individually to go out item, is often two or three while going out
The different phase of present patient disease, thus drug combination is necessary, this contributes to reducing dose and mitigates medication treatment
Toxic and side effects.
Above-mentioned middle related drugs including but not limited to treat phenoxy acetic acid class, the nicotinic acid class of hyperlipidemia.
Above-mentioned middle related drugs including but not limited to treat Mg-ATP enzyme inhibitor classes (such as Reserpine), the α of hypertension2Receive
Body agonist (such as clonidine, methyldopa), beta-blocker (such as the Atenolol of Luo Er apoplexy due to endogenous wind), angiotensin-converter
Enzyme inhibitor (such as the benazepril in pril), angiotensinⅡantagonist (such as the telmisartan of husky smooth class), an oxidation
Nitrogen donor medicine (the such as isosorbide mononitrates of nitrate esters) etc., these medicines all contain amido or alcoholic extract hydroxyl group, carboxylic acid group
Group, can be with compound of the present invention by being dehydrated into ester into amide, and soda acid obtains the medicine splicing object of correlation into salt.
The present invention includes stereoisomer and optical isomer, for example, correspond to isomer or diastereomer, its product
The unsymmetry possessed in structure in such compound for the reason for raw being selection.The same with most drug, which 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 compositionss.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 as raw material using appropriate material according to the general approach of described below, 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 does the Non-aqueous processing for doing a small amount of except water process or using the molecular sieve after activation.Described analytical and testing instrument and condition are 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
III 500M of volance, 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 crude 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 are added to suitable in the lump
When reaction vessel in, organic solvent dissolving after.A certain amount of dicyclohexylcarbodiimide solution of Deca, stirring reaction under room temperature
Overnight.Jing after thin layer chromatography monitoring reaction completely, sucking filtration, filtrate anhydrous sodium sulfate drying, concentration, (PE/EA is terraced for column chromatography for separation
Degree eluting) 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%3Aqueous 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) obtain the fragment of hexenolactone containing 2- of the present invention
Statin derivant.
By the lactone form of the above-mentioned fragment statin derivant 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, amide.
Specific embodiment：
The preparation of 1 atorvastatin lactone of embodiment
Weigh the atorvastatin calcium salt of 5.00g, be added in the eggplant-shape bottle of 250ml, add 100ml dichloromethane and
The dilute hydrochloric acid of 20 times of dilutions of about 10ml, acidifying, point liquid, 100ml dichloromethane equivalent are extracted three times, merge lower floor's organic faciess,
Anhydrous sodium sulfate drying.Concentration, oil pump evacuation obtain white powder 4.54g, i.e. atorvastatin crude carboxylic acid
Weigh 4.00 above-mentioned atorvastatin crude carboxylic acid, be added in there-necked flask, add 0.05g to dimethylamine
Yl pyridines, 50ml dichloromethane and stirrer.The dicyclohexylcarbodiimide for being slowly injected into 5.0g under ice bath is dissolved in 20ml dichloros
Methane resulting solution.After completion of dropping, remove ice bath and react at room temperature overnight.Jing after thin layer chromatography monitoring reaction completely, take out
Filter, filtrate anhydrous sodium sulfate drying, vacuum are spin-dried for, and rapid column chromatography separates (PE/EA gradient elutions) and obtains atorvastatin lactone
2.78g.MP:81.5-83.2 DEG C, HRMS (ESI):C33H33FN2O4, 541.25169 (M+H)+Theoretical value 541.25026；H-
NMR：δ 7.24-7.13 (m, 9H), 7.07 (d, 2H, J=7.5Hz), 7.03 (t, 3H, J=8.1Hz), 6.90 (s, 1H), 4.54
(t, 1H, J=9.7Hz), 4.31 (s, 1H), 4.27-4.17 (m, 1H), 4.10-3.99 (m, 1H), 3.61-3.51 (m, 1H),
2.66 (dd, 1H, J=17.7,4.7Hz), 2.57 (d, 1H, J=17.6Hz), 1.95-1.84 (m, 1H), 1.75 (s, 1H),
1.73 (s, 1H), 1.54 (t, 6H, J=7.5Hz)
The preparation of 2 compound 001 of embodiment
Appropriately sized magnetic stir bar is added in two mouthfuls of reaction bulbs of 50ml, adds the p-methyl benzenesulfonic acid of 0.50g
(PBSA) and 1.50g atorvastatin lactone 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, the NaHCO for plus 5%3
Aqueous solution shakes, and point liquid removes a layer organic facies, and anhydrous sodium sulfate drying, concentration, column chromatography for separation (PE/EA gradient elutions) obtain this
Atorvastatin lactone derivatives (001) 0.76g of the fragment of hexenolactone containing 2- described in invention.
The preparation of 3 compound 002,003 of embodiment
Atorvastatin derivant (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, the slow Na of Deca 10% while stirring2CO3Aqueous 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 cotton-shaped crystallization 0.57g i.e.
Atorvastatin derivant sodium salt (002).
Atorvastatin derivant (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 7-8,45 DEG C of decompression is evaporated off solvent, adds ethanol about
After 10ml dissolvings, the slow CaCl of Deca 10% while stirring2Aqueous solution, is stirred overnight, and separates out solid, and sucking filtration obtains half calcium
Salt crude product.With the methanol/water mixed solution of 50% volume ratio, refined half calcium salt of atorvastatin derivant of recrystallization
(003)0.83g。
The preparation of 4 compound 004 of embodiment
Atorvastatin derivant thing (001) 1.00g is taken, with ice bath after tetrahydrofuran 6ml dissolvings, adds 1mol/L's
After LiOH solution 2.5ml is stirred 2 hours, this water oil mixture ether is washed into three times (5 × 3), is discarded after washing every time
Layer organic facies.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 faciess anhydrous sodium sulfate drying, 45 DEG C of decompression are evaporated off solvent and obtain final product atorvastatin derivant lactone open loop crude carboxylic acid
0.79g。
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 methanol resulting solutions.Remove ice bath, stirring reaction overnight, Jing thin layers
After analysis monitoring reaction completely, sucking filtration, concentrating under reduced pressure, silica gel column chromatography separating purification obtain atorvastatin derivant carboxylate methyl ester
(004)0.75g。
The preparation of 5 compound 005 of embodiment
Open loop crude carboxylic acid 0.65g of atorvastatin derivant lactone described in Example 4 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 under ice bath, is added
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, sucking filtration, concentrating under reduced pressure, silica gel column chromatography separating purification obtain atorvastatin derivant carboxylic
Sour formic acid esters (005) 0.57g.
The preparation of 6 compound 006 of embodiment
Atorvastatin fluoro lactone open loop crude carboxylic acid 0.65g described in Example 5 and 2g nicotinic acid are dissolved in 15ml's
In dichloromethane, after adding the p dimethylamino pyridine of catalytic amount, under ice bath, add 1.2gDCC (dicyclohexylcarbodiimide) molten
In 5ml dichloromethane resulting solutions.Remove ice bath, overnight, and back flow reaction is after about 1 hour, Jing thin layer chromatographies prison for stirring reaction
Survey reaction complete, sucking filtration, filtrate reduced in volume, silica gel column chromatography separating purification obtain atorvastatin derivant nicotinate
(006)0.57g。
The preparation of 7 compound 007 of embodiment
Atorvastatin fluoro lactone open loop crude carboxylic acid 0.65g described in Example 4 and the different Pyrusussuriensiss of 2.5g single nitric acids
Ester is dissolved in the acetonitrile of 50ml, after adding the p dimethylamino pyridine of catalytic amount, adds 1.2gDCC (dicyclohexyl carbon under ice bath
Diimine) it is dissolved in 5ml acetonitrile resulting solutions.Completion of dropping recession except ice bath, heating in water bath back flow reaction overnight, Jing thin layer chromatographies
Monitoring reaction is complete, sucking filtration, filtrate reduced in volume, and it is different that silica gel column chromatography separating purification obtains atorvastatin derivant single nitric acid
Pyrusussuriensiss ester (073) 0.26g.
8 compound activity of embodiment 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 S-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
As 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 test kit includes HMG-CoA Reductase Assay Kit:HMGR, HMG-CoA,
NADP-H, buffer, 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 microplate reader
Medicament is prepared and is prepared
5 times of concentration buffer liquid of 10ml are diluted to into 1 times of buffer (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, remaining 5 times of buffer in ice
Preserve in -20 DEG C.The NADPH of 25mg requires supplementation with 1 times of buffer of 1.5ml, -20 DEG C of preservations of mix homogeneously.
Method and flow process
Thaw：Defrosting enzyme needs on ice or keep surrounding cooling again, try not enzyme is 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 thaw to be stored in
On ice.
Instrument adjustment:Temperature is adjusted to 37 DEG C before starting by experiment, 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 in each hole；
B, plus testing sample in the hole in addition to blank and positive control
C, plus supplemented the NADPH of buffer in each hole
D, plus substrate HMG-CoA is in each hole
E, enzyme-added HMGR are in the hole in addition to blank
F, reactant liquor mix homogeneously especially at least will be strongly stirred before first time absorbance 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, carries out Mathematical treatment and fitting to the slope curve of gained, according to the explanation of test kit, makes
Activity data is calculated with equation below
Wherein:Parameter 12.44 represents 12.44mM/cm, as attenuation coefficients of the NADPH under 340nm is 6.22mM/cm,
The NADPH of twice in reaction mechanism, therefore be 12.44
Cumulative volumes of the TV for reactant liquor, 96 orifice plates are 0.2ml
V represents the volume of reductase, i.e., the volume of the enzyme used by testing every time
0.6 represents using the concentration under mg-Protein units (mgP)/ml, generally 0.50-0.70, here test 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 are min-1, it is sameRepresent the rate of change of blank sample.
Then under certain concentration, the suppression ratio of certain sample is：
Wherein activity dataActivityRepresent the Activity activity values tested and calculated according to formula correspondence, active number
According toSampleRepresent the activity value after adding inhibitor sample.
Measure suppression ratio 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 (4)
1. his statin lactone anhydro compounds of a kind of polysubstituted pyrrole class, it is characterised in that：Its structural formula is
Or
Or
Or
。
2. a kind of Pharmaceutical composition, it is characterised in that：Compound described in the claim 1 containing effective dose or its can pharmaceutically connect
The salt received and pharmaceutically acceptable carrier.
3. compound described in claim 1 or its pharmaceutically acceptable salt or the drug regimen described in claim 2
Thing is caused in preparation treatment reduction blood fat level or prevention and treatment of coronary heart disease, the atherosclerosiss of hyperlipidemia initiation, diabetes
High blood cholesterol drug in purposes.
4. purposes as claimed in claim 3, it is characterised in that：Described reduction blood fat level refers to the high density of reduction blood fat
Lipoprotein, low-density albumen, triglyceride, one or more in TL.
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| CN105085497B (en) * | 2015-06-26 | 2017-12-26 | 上海应用技术学院 | Polysubstituted pyrrole class statin fluorine-containing derivant and application thereof |
| CN105017231B (en) * | 2015-06-26 | 2018-01-26 | 上海应用技术学院 | Polysubstituted fluorine-containing trim of indoles statin and application thereof |
| CN108299405A (en) * | 2018-02-12 | 2018-07-20 | 李化绪 | 3- is to N, N diethylaminos phenylimino class compound and its application in hyperlipidemia |
| CN108299406A (en) * | 2018-02-12 | 2018-07-20 | 李化绪 | Hmg-coa reductase inhibitor |
| CN108164517A (en) * | 2018-02-12 | 2018-06-15 | 李化绪 | (2- hexahydrotoluene -1- bases) imido base class compound and its application in hyperlipidemia |
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