CN105147659A - Application of acid lovastatin hydroxyl compound - Google Patents
Application of acid lovastatin hydroxyl compound Download PDFInfo
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- CN105147659A CN105147659A CN201510490570.8A CN201510490570A CN105147659A CN 105147659 A CN105147659 A CN 105147659A CN 201510490570 A CN201510490570 A CN 201510490570A CN 105147659 A CN105147659 A CN 105147659A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/297—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Abstract
The invention discloses application of acid lovastatin hydroxyl compound in preparing a medicine for treating hyperlipidemia. The acid lovastatin hydroxyl compound can significantly reduce toxicity, and can be used for treating hyperlipidemia without metabolism in body.
Description
The divisional application that the parent application that the application is aimed at that December in 2013 is submitted to Patent Office of the People's Republic of China on the 24th, application number is 201310722852.7, denomination of invention is " preparation method of a kind of preparation method of lovastatin acid compound, compositions, compositions and application thereof " is made, the content of above-mentioned parent application is incorporated herein in the mode introduced.
Technical field
The present invention relates to technical field of pharmaceuticals, particularly relate to a kind of application of lovastatin acid compound.
Background technology
Statins is HMG-CoA reductase inhibitor, this type of medicine prepares rate-limiting enzyme HMG-CoA reductase by competitive inhibition endogenous cholesterol, block hydroxyl first valeric acid metabolic pathway in cell, prepared by intracellular cholesteryl reduce, thus surperficial low density lipoprotein, LDL (LDL) acceptor quantity of feedback irritation cell film and activity increase, make serum cholesterol remove increase, level reduces; Statins also can suppress liver to prepare Apolipoprotein B-100, thus reduces and be rich in triglyceride AV, the preparation method of lipoprotein and secretion.
Lovastatin is the medicine for the treatment of hyperlipidemia conventional at present, clinical research shows, lovastatin is the prodrug of inactive lactone structure, must metabolism in vivo, hydrolysis, forming the lovastatin acid compound with active structure could suppress HMG-CoA reductase; The structure of lovastatin acid compound is extremely similar to pravastatin sodium, and pravastatin sodium is marketed drug, has good DEVELOPMENT PROSPECT; And lovastatin acid compound only controls as related substances in the research of lovastatin drug quality at present, there is not the research being directly used in treatment hyperlipidemia aspect.
Summary of the invention
For solving problems of the prior art, the invention provides a kind of application of lovastatin acid compound.
The invention provides the application of a kind of lovastatin acid compound in the medicine for the preparation for the treatment of hyperlipidemia.
Preferably, described application, comprises the following steps:
1) preparation is such as formula the compound lovastatin ammonia propyl ester shown in B
Get such as formula the compound lovastatin shown in A, add ethanol and propylamine carries out ring-opening reaction, obtained such as formula the compound lovastatin ammonia propyl ester shown in B;
2) preparation is such as formula the compound lovastatin acid compound shown in C
Get step 1) obtained such as formula the compound lovastatin ammonia propyl ester shown in B, add hydrochloric acid and carry out acidification hydrolization reaction, recrystallization, obtained such as formula the compound lovastatin acid compound shown in C;
3) by such as formula the compound lovastatin acid compound shown in C for the preparation for the treatment of hyperlipidemia medicine.
Preferably, described step 1) under 30 DEG C ~ 50 DEG C condition, add propylamine carry out ring-opening reaction.
Preferably, described step 1) in add propylamine reaction 1h ~ 5h.
Preferably, described step 2) in use re-crystallizing in ethyl acetate.
In above-mentioned preparation method, such as formula the compound lovastatin shown in A, its chemistry 8-(2-(4-hydroxyl-6-oxygen-tetrahydrochysene-2H-pyrans-2-base) ethyl)-7-methyl isophthalic acid by name, 2,3,7,8,8a-hexahydro naphthalene-1-base-2-methylbutyl butenoate, its English be expressed as 8-(2-(4-hydroxy-6-oxo-tetrahydro-2H-pyran-2-yl) ethyl)-7-methyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl2-methylbutanoate; Such as formula the compound lovastatin ammonia propyl ester shown in B, its chemistry 8-by name (3,5-dihydroxy-7-oxygen-7-(propylcarbamic) heptyl)-7-methyl isophthalic acid, 2,3,7,8,8a-hexahydro naphthalene-1-base 2-methylbutyl butenoate, its English is expressed as: 8-(3,5-dihydroxy-7-oxo-7-(propylamino) heptyl)-7-methyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl2-methylbutanoate; Such as formula the compound lovastatin acid compound shown in C; its chemistry by name 3; 5-dihydroxy-7-(2-methyl-8-(2-methylbutyryl base oxygen base)-1,2,6,7,8,8a-hexahydro naphthalene-1-base) enanthic acid; its English is expressed as: 3,5-dihydroxy-7-(2-methyl-8-(2-methylbutanoyloxy)-1,2,6,7,8,8a-hexahydronaphthalen-1-yl) heptanoicacid; this is those skilled in the art is easy and way that is that generally adopt, and those of ordinary skill in the art can grasp completely.
Lovastatin is the prodrug of inactive lactone structure, must metabolism in vivo, hydrolysis, and forming the lovastatin acid compound with active structure could suppress HMG-CoA reductase; And lovastatin acid compound provided by the invention, do not need metabolism to be in vivo used for the treatment of hyperlipidemia.
The preparation method of lovastatin acid compound in the present invention, its beneficial effect is as follows:
1. preparation method of the present invention is simple, and raw material is easy to get, and is conducive to suitability for industrialized production;
2. the present invention uses reagent toxicity lower, is conducive to environmental conservation;
3. yield of the present invention is higher, reaches more than 97%.
The invention provides the application of a kind of lovastatin acid compound in the medicine for the preparation for the treatment of hyperlipidemia, its beneficial effect is as follows:
1. toxicity of the present invention significantly reduces;
2. lovastatin acid compound of the present invention does not need metabolism to be in vivo used for the treatment of hyperlipidemia.
Accompanying drawing explanation
Fig. 1 lovastatin acid compound structural formula;
Fig. 2 lovastatin acid compound synthetic route chart;
Fig. 3 lovastatin acid compound 3D schemes;
Fig. 4 simvastatin hydroxy acid compound 3D schemes;
Fig. 5 pravastatin sodium 3D schemes;
Figure 61 dqa3D schemes;
Fig. 7 lovastatin acid compound docks result with 1dqa;
Fig. 8 simvastatin hydroxy acid compound docks result with 1dqa;
Fig. 9 pravastatin sodium docks result with 1dqa;
Figure 10 lovastatin acid compound and 1dqa combination;
Figure 11 simvastatin hydroxy acid compound and 1dqa combination;
Figure 12 pravastatin sodium and 1dqa combination;
Figure 13 pravastatin sodium (the 50%-outsourcing phase-48hpf administration) toxicity (3dpf) to zebrafish embryo;
Figure 14 lovastatin administration (the 50%-outsourcing phase-48hpf administration) toxicity (3dpf) to zebrafish embryo;
Figure 15 simvastatin administration (the 50%-outsourcing phase-48hpf administration) toxicity (3dpf) to zebrafish embryo;
Figure 16 lovastatin places 0h Solution H PLC chromatogram;
Figure 17 lovastatin places 24h Solution H PLC chromatogram;
Figure 18 pravastatin sodium 500ug/ml3dpf acts on the deformity of zebrafish embryo;
Figure 19 pravastatin sodium 500ug/ml3dpf acts on the deformity of zebrafish embryo;
Figure 20 pravastatin sodium 1000ug/ml3dpf acts on the deformity of zebrafish embryo;
Figure 21 pravastatin sodium 1000ug/ml3dpf acts on the deformity of zebrafish embryo;
Figure 22 pravastatin sodium 1000ug/ml3dpf acts on the deformity of zebrafish embryo;
Figure 23 pravastatin sodium wild type control (Wt) 3dpf acts on the deformity of zebrafish embryo;
Figure 24 pravastatin sodium 1500ug/ml2dpf acts on the deformity of zebrafish embryo;
Figure 25 pravastatin sodium Wt3dpf acts on the deformity of zebrafish embryo;
Figure 26 pravastatin sodium Wt2dpf acts on the deformity of zebrafish embryo;
Figure 27 lovastatin 0.01ug/ml1dpf acts on the deformity of zebrafish embryo;
Figure 28 lovastatin 0.005ug/ml1dpf acts on the deformity of zebrafish embryo;
Figure 29 lovastatin 0.0005ug/ml3dpf acts on the deformity of zebrafish embryo;
Figure 30 lovastatin 0.001ug/ml2dpf acts on the deformity of zebrafish embryo;
Figure 31 lovastatin 0.001ug/ml3dpf acts on the deformity of zebrafish embryo;
Figure 32 lovastatin Wt2dpf acts on the deformity of zebrafish embryo;
Figure 33 lovastatin Wt3dpf acts on the deformity of zebrafish embryo;
Figure 34 simvastatin 0.005ug/ml3dpf acts on the deformity of zebrafish embryo;
Figure 35 simvastatin 0.03ug/ml3dpf acts on the deformity of zebrafish embryo;
Figure 36 simvastatin 0.05ug/ml1dpf acts on the deformity of zebrafish embryo;
Figure 37 simvastatin 0.01ug/ml3dpf acts on the deformity of zebrafish embryo;
Figure 38 simvastatin 0.03ug/ml3dpf acts on the deformity of zebrafish embryo;
Figure 39 simvastatin 0.01ug/ml2dpf acts on the deformity of zebrafish embryo;
Figure 40 simvastatin Wt3dpf acts on the deformity of zebrafish embryo.
Detailed description of the invention
Embodiment one
Such as formula a preparation method for the compound lovastatin acid compound shown in C, comprise the following steps:
1) preparation is such as formula the compound lovastatin ammonia propyl ester shown in B
Get such as formula the compound lovastatin 40.4g shown in A, add 400ml ethanol, add propylamine 29.5g under 30 DEG C of conditions and carry out ring-opening reaction 1h, TLC detects to reacting completely, frozen water drops to 10 DEG C and terminates reaction, and decompression steams ethanol, obtained such as formula the compound lovastatin ammonia propyl ester shown in B;
2) preparation is such as formula the compound lovastatin acid compound shown in C
Get step 1) obtained such as formula the compound lovastatin ammonia propyl ester shown in B, add 2mol/L hydrochloric acid solution 300ml stirring at room temperature 1h and carry out acidification hydrolization reaction, by re-crystallizing in ethyl acetate, obtained such as formula the compound lovastatin acid compound 38.1g shown in C, yield 94.3% (the compound lovastatin in shown in formula A).
Embodiment two
Such as formula a preparation method for the compound lovastatin acid compound shown in C, comprise the following steps:
1) preparation is such as formula the compound lovastatin ammonia propyl ester shown in B
Get such as formula the compound lovastatin 40.4g shown in A, add 400ml ethanol, add propylamine 29.5g under 40 DEG C of conditions and carry out ring-opening reaction 5h, TLC detects to reacting completely, frozen water drops to 10 DEG C and terminates reaction, and decompression steams ethanol, obtained such as formula the compound lovastatin ammonia propyl ester shown in B;
2) preparation is such as formula the compound lovastatin acid compound shown in C
Get step 1) obtained such as formula the compound lovastatin ammonia propyl ester shown in B, add 2mol/L hydrochloric acid solution 300ml stirring at room temperature 1h and carry out acidification hydrolization reaction, by re-crystallizing in ethyl acetate, obtained such as formula the compound lovastatin acid compound 38.7g shown in C, yield 95.6% (the compound lovastatin in shown in formula A).
Embodiment three
Such as formula a preparation method for the compound lovastatin acid compound shown in C, comprise the following steps:
1) preparation is such as formula the compound lovastatin ammonia propyl ester shown in B
Get such as formula the compound lovastatin 40.4g shown in A, add 400ml ethanol, add propylamine 29.5g under 50 DEG C of conditions and carry out ring-opening reaction 3h, TLC detects to reacting completely, frozen water drops to 10 DEG C and terminates reaction, and decompression steams ethanol, obtained such as formula the compound lovastatin ammonia propyl ester shown in B;
2) preparation is such as formula the compound lovastatin acid compound shown in C
Get step 1) obtained such as formula the compound lovastatin ammonia propyl ester shown in B, add 2mol/L hydrochloric acid solution 300ml stirring at room temperature 1h and carry out acidification hydrolization reaction, by re-crystallizing in ethyl acetate, obtained such as formula the compound lovastatin acid compound 39.3g shown in C, yield 97.3% (the compound lovastatin in shown in formula A).
Embodiment four
A compositions for lovastatin acid compound, by weight, comprises following component:
Table 1 embodiment Four composition proportioning
| Component | Weight (part) |
| Lovastatin acid compound | 5 |
| Polyoxyethylene sorbitan monoleate | 0.3 |
| Hyprolose | 3 |
| Cross-linking sodium carboxymethyl cellulose | 9 |
| Mannitol | 40 |
| Microcrystalline Cellulose | 30 |
| Magnesium stearate | 0.6 |
| Opadry film coating pre-mix dose | In right amount |
A preparation method for the compositions of lovastatin acid compound, comprises the following steps (each amounts of components is by described in table 1):
1) lovastatin acid compound, polyoxyethylene sorbitan monoleate, hyprolose, cross-linking sodium carboxymethyl cellulose, mannitol and microcrystalline Cellulose is taken, wet granulation;
2) magnesium stearate is taken, tabletting;
3) Opadry film coating pre-mix dose is taken, film coating.
Embodiment five
A compositions for lovastatin acid compound, by weight, comprises following component:
Table 2 embodiment five component proportion
| Component | Weight (part) |
| Lovastatin acid compound | 20 |
| Polyoxyethylene sorbitan monoleate | 0.3 |
| Hyprolose | 3 |
| Cross-linking sodium carboxymethyl cellulose | 9 |
| Mannitol | 40 |
| Microcrystalline Cellulose | 30 |
| Magnesium stearate | 0.6 |
| Opadry film coating pre-mix dose | In right amount |
A preparation method for the compositions of lovastatin acid compound, comprises the following steps (each amounts of components is by described in table 2):
1) lovastatin acid compound, polyoxyethylene sorbitan monoleate, hyprolose, cross-linking sodium carboxymethyl cellulose, mannitol and microcrystalline Cellulose is taken, wet granulation;
2) magnesium stearate is taken, tabletting;
3) Opadry film coating pre-mix dose is taken, film coating.
Embodiment six
A compositions for lovastatin acid compound, by weight, comprises following component:
Table 3 embodiment six component proportion
| Component | Weight (part) |
| Lovastatin acid compound | 10 |
| Polyoxyethylene sorbitan monoleate | 0.3 |
| Hyprolose | 3 |
| Cross-linking sodium carboxymethyl cellulose | 9 |
| Mannitol | 40 |
| Microcrystalline Cellulose | 30 |
| Magnesium stearate | 0.6 |
| Opadry film coating pre-mix dose | In right amount |
A preparation method for the compositions of lovastatin acid compound, comprises the following steps (each amounts of components is by described in table 3):
1) lovastatin acid compound, polyoxyethylene sorbitan monoleate, hyprolose, cross-linking sodium carboxymethyl cellulose, mannitol and microcrystalline Cellulose is taken, wet granulation;
2) magnesium stearate is taken, tabletting;
3) Opadry film coating pre-mix dose is taken, film coating.
One, the comparison in drug effect
Lovastatin acid compound, simvastatin hydroxy acid compound are respectively the activity in vivo product of lovastatin and simvastatin, the two is HMG-CoA reductase inhibitor, do not need through metabolism in vivo, can be directly used in treatment hyperlipidemia, its drug effect compares in table 4, table 5.
Table 4 lovastatin compares with lovastatin acid compound drug effect
As can be seen from Table 4, compared with lovastatin, lovastatin acid compound has more excellent bioavailability, stronger hypolipemic function and more long-acting therapeutical effect.
Table 5 simvastatin compares with simvastatin hydroxy acid compound drug effect
As can be seen from Table 5, compared with simvastatin, simvastatin hydroxy acid compound has more excellent bioavailability, stronger hypolipemic function and more long-acting therapeutical effect.
Two, utilize docking assay lovastatin acid compound, simvastatin hydroxy acid compound and pravastatin sodium to the inhibitory action of HMG-CoA reductase albumen (1dqa).
1, part is selected
PUMBEDLINE searches lovastatin acid compound, simvastatin hydroxy acid compound, pravastatin sodium information are shown in Fig. 3, Fig. 4, Fig. 5 and table 6.
Table 6 part information
Remarks: 1. CID is compound information code, to be numbered according to data message date created by PUMBEDLINE and to obtain.
2. XLogP3 represents hydrophobic parameter value of calculation, is used for evaluating the fat water partition coefficients of medicine, have employed the legal conversion of atom adding.
2, acceptor selection
By the information of inquiring about in PDB protein pool in table 7, delivered 8 kinds of data at present, respectively corresponding inhomogeneous statin and substrate-binding site, according to this research purpose, select 1dqa as receptor, the 3D figure of 1dqa is shown in Fig. 6.
Table 7PDB protein pool Query Information table
3, docking prepares
First optimal treatment is carried out to the conformation of 1dqa, CHARm molecular field is applied to 1dqa, adopt MM calculation optimization 1dqa energy; After carrying out hydrogenation to 1dqa, removing invalid conformation, residue, select No. 1 avtive spot as docking pocket, its radius is 15.0 dusts; According to the character of part and 1dqa, DockLigands program is adopted to carry out half flexible docking.
4, result
Docking the results are shown in Figure 7, Fig. 8 and Fig. 9; The combination of part and 1dqa is shown in Figure 10, Figure 11, Figure 12, and visible lovastatin acid compound, simvastatin hydroxy acid compound have similar combination with pravastatin sodium to 1dqa; The combination of pravastatin sodium, lovastatin acid compound and simvastatin hydroxy acid compound and 1dqa avtive spot 1 mainly relies on the hydrogen atom in part to form hydrogen bond with LYS606, HIS635, SER637 aminoacid in 1dqa respectively; Another pravastatin sodium and simvastatin hydroxy acid compound also can form Pi-Pi conjugated bonds with aminoacid LYS62; The matching degree of assay lovastatin acid compound, simvastatin hydroxy acid compound and pravastatin sodium and 1dqa, thus evaluate it further to the rejection ability of HMG-CoA reductase, the results are shown in Table 8.
The matching degree of table 8 three kinds of compounds and 1dqa
| Index | Number | -PLP1 | -PLP2 | PMF | RMSD |
| 2 | Lovastatin acid compound | 105.880 | 109.980 | 161.920 | 1.101990 |
| 26 | Simvastatin hydroxy acid compound | 82.330 | 91.070 | 149.000 | 1.092800 |
| 12 | Pravastatin sodium | 114.250 | 123.460 | 157.340 | 1.148210 |
Remarks: 1. Index: index.
2. Number: number, title.
3. PLP:(Piecewiselinearpotential) adopt piecewise linearity potential energy add and calculate; Score higher expression part and receptor affinity stronger.Whether participate according to hydrogen bond in docking operation, can be divided into PLP1 and PLP2 two kinds of functions, PLP1 does not consider the impact that hydrogen bond docks; PLP2 considers the impact of hydrogen bond on docking.
4. PMF:(Potentialofmeanforce), adopt adding and calculating of the average energy of intermolecular distance; Score higher expression part and receptor affinity stronger.
5. RMSD: the docking conformation of compound and the root-mean-square deviation of parent crystal conformation, characterize the difference degree on position and conformation that to predict the outcome with actual value, unit is dust.
In molecular docking process, the normal scoring functions that adopts is used for evaluating in docking procedure (LigandFit), the power of compound and receptor protein associativity.For specific protein research system, generally often need multiple different scoring functions to check docking result; To avoid single scoring functions by the Preference of the training set molecule selected when it is set up, lack the shortcoming of universality; As can be seen from above-mentioned table 8, lovastatin acid compound, simvastatin hydroxy acid compound and pravastatin sodium dock in conformation with receptor protein 1dqa's, and the score value of PLP1, PLP2 and PMF is all higher, and between each compound, difference is less; RMSD is all less than 2.0 dusts simultaneously, represents that LigandFit docking result is accurate; The above results shows: lovastatin acid compound, simvastatin hydroxy acid compound and pravastatin sodium suppress HMG-CoA reductase effect similar, and namely they have similar biological activity.
Three, statins toxicity ratio comparatively
In toxicologic study, Brachydanio rerio is usually used in the acute and chronic toxicity test of various medicine, and the transparent feature of its embryo is more conducive to the Structure and form change observing embryo's different phase; In its juvenile stage, each tissue system (nervous system, cardiovascular system, blood system, muscle skeleton motor system, secretion, absorption and Excretory system etc.) of body is close to ripe and perfect, start the physiological function of bringing into normal play, be similar to adult.Therefore, zebrafish embryo stage and juvenile stage can be used for studying the fetal development toxicity of compound and the target toxicity of each histoorgan fast.This research and utilization Brachydanio rerio model animal comparative study toxicity of multiple statins to fetal development, especially on the impact that muscular tissue is grown.
1, the medication of zebrafish embryo
Treat the state of fetal development to the 50%-outsourcing phase after collecting embryo, select normotrophic embryo by often organizing 30 groupings, be placed in the statin medicinal liquid of variable concentrations, wild matched group is all established in each test.
Lovastatin, simvastatin dimethyl sulfoxide prepare mother solution, and diluting with artificial seawater before using is desired concn, and because mother solution is dimethyl sulfoxide configuration, for avoiding dimethyl sulfoxide to have an impact to embryo, mother solution at least dilutes more than 100 times; Test fluid artificial seawater dilutes, and after administration, every day observes the developmental condition of embryo, number dead and lopsided in statistics embryo, and takes pictures.After embryo's contamination, every day changes a medicinal liquid, administration process continues to the embryo 48dpf phase, and (48hpf is from the outsourcing phase to hatching administration in 48 hours, other are by that analogy), by medicinal liquid sucking-off, rinse embryo and be again placed in artificial seawater for several times and make it to continue to grow.
2, experimental result
1) comparison of lovastatin, simvastatin and pravastatin sodium fetal toxicity
Lovastatin and simvastatin are the prodrug of inactive lactone structure, must distinguish metabolism open loop in vivo and form lovastatin acid compound and simvastatin hydroxy acid compound and could suppress HMG-CoA reductase; Pravastatin sodium then exists with the form of hydroxy acid compound; Pravastatin sodium, lovastatin, simvastatin act on zebrafish embryo (50%-outsourcing phase-48hpf) at 3dpf teratogenesis lethal range as shown in Figure 13, Figure 14, Figure 15 (3dpf for from the outsourcing phase to hatching administration in 3 days, other by that analogy).
Table 9 three kinds of compound impacts on zebrafish embryo are compared
Three kinds of statinses are that concentration dependent rises gradually to embryo's teratogenesis within the scope of respective concentration; From the concentration range that teratogenesis is lethal, the a little higher than lovastatin of activity of simvastatin, the activity of pravastatin sodium is then far above simvastatin and lovastatin, namely the toxicity of pravastatin sodium is far below simvastatin and lovastatin, thus lovastatin acid compound can be described, the drug toxicity of simvastatin hydroxy acid compound is less than the prodrug of inactive lactone structure.
By table 9, 10 can find out, from the lethal order of severity display of teratogenesis that three kinds of statinses act on zebrafish embryo in early days, lovastatin is the most serious, next is simvastatin, least seriously pravastatin sodium, and the difference of concentration is fairly obvious when different classes of statins reaches identical teratogenesis or lethal effect to zebrafish embryo, such as 100% fatal dose of 100% fatal dose of the maximum lovastatin of the early stage zebrafish embryo toxicity pravastatin sodium minimum with toxicity is differed and reach 100,000 times, and pravastatin sodium, lovastatin, the molecular weight differences of simvastatin three kinds of medicines is apart from less, three kinds of statinses recommendation dosage clinically also differs less, but but differ greatly in the toxicity acting on early stage zebrafish embryo.
Table 10. six kinds of statinses act on zebrafish embryo teratogenesis lethasl concentration and compare
Chemically structure compares pravastatin sodium, lovastatin, simvastatin, its relative molecular mass closely; Pravastatin sodium exists with tool activated hydroxy acid compound structure, but lovastatin and simvastatin are the existence of inactive lactone version; Pravastatin sodium to zebrafish embryo teratogenesis lethal effect much smaller than lovastatin and simvastatin; Its plasma protein binding rate of pravastatin sodium, much smaller than lovastatin and simvastatin, is about 50% of lovastatin and simvastatin, show its main medicine existence in a free form in vivo, but toxicity is far smaller than lovastatin and simvastatin; The lovastatin acid compound formed after the above results display open loop, the toxicity of simvastatin hydroxy acid compound are compared with the inactive lactone structure of simvastatin with lovastatin respectively, and its toxic action obviously alleviates.
2) fetal toxicity of lovastatin acid compound, simvastatin hydroxy acid compound is compared
Carry out HPLC after lovastatin, simvastatin solution 24h and detect analysis, as can be seen from testing result, all basic after lovastatin, simvastatin 24h exist with lovastatin acid compound, simvastatin hydroxy acid solvate forms.
Table 11 lovastatin and simvastatin comparative result
Remarks: WT is wild contrast type, namely the embryo not adding medicine in contrast.
As can be seen from Table 11, when administration concentration increases to 0.01ug/ml, lovastatin and simvastatin 0, the normal chick embryo of 24h digital display work of surviving declines, when concentration increases to 0.1ug/ml, total survival of lovastatin and simvastatin and normal chick embryo number of surviving is 0; Result shows that administration concentration reaches more than 0.01ug/ml, and lovastatin and simvastatin all show fetal toxicity.
3) statins acts on the teratogenecity of zebrafish embryo
After statins is contaminated to Brachydanio rerio, every day observes once, and the record main lopsided form of statistics is also taken pictures; Although can find out that the concentration range that these three kinds of statinses of pravastatin sodium, lovastatin, simvastatin act on early stage zebrafish embryo differs greatly by the picture of Figure 18 ~ Figure 39, but the phenotype form affecting the early development of embryo is comparatively similar, the toxic reaction phenotype caused to lovastatin acid compound, simvastatin hydroxy acid compound is also similar, mainly concentrates on the following aspects:
1. the overall body of embryo is long shortens, and yolk sac extension shortens thick, and caudal style bends towards side, left and right; The motor capacity of high concentration group reduces, responsive not as Normal group with headband touching reaction;
2. in embryo development procedure, pigment is influenced, and entirety weakens;
3. embryo has congestion to occur, occurs that the position of congestion mainly concentrates on the caudal style position of head, trunk back and yolk sac extending end;
4. zebrafish embryo all finds pericardium enlargement phenomenon under finite concentration, occurs the banded deformity of heart simultaneously;
5. all there is exception in processed group embryo trunk place muscular tissue, and body segment is unintelligible, has the trend of parallelization at the maximum concentration group body segment of each group.
3, conclusion is analyzed
1) statins acts on zebrafish embryo teratogenesis lethasl concentration scope: the six kinds of statinses giving variable concentrations concentration at zebrafish embryo early development 50%-outsourcing phase-48hpf act on, result shows that the concentration range that six kinds of statins effect body early embryo teratogenesis are lethal is widely different, and what difference was maximum reaches up to ten thousand times; The lethal order of severity of teratogenesis that three kinds of statinses act on zebrafish embryo is followed successively by: lovastatin is the most serious, and being secondly simvastatin, is thirdly the hydroxy acid compound of lovastatin acid compound, simvastatin, least seriously pravastatin sodium.
2) toxicity: lovastatin and the open loop of SV key form lovastatin acid compound, simvastatin hydroxy acid compound respectively, and toxicity at least reduces 50 times; But owing to also creating other related substanceses after degraded, therefore the toxicity ratio of lovastatin acid compound and simvastatin hydroxy acid compound mensuration is lower.
3) deformity: although statins to act on early stage zebrafish embryo concentration difference very large, the deformity caused is consistent substantially, mainly contains that the overall body of embryo longly shortens, yolk sac extends thick, the caudal style of shortening and bend; Pigment weakens; The caudal style position congestion of head, trunk back and yolk sac extending end; Pericardium enlargement phenomenon, there is the banded deformity of heart simultaneously; All there is exception in embryo's trunk place muscular tissue, has the trend of parallelization at the maximum concentration group body segment of each group.
More than detailed description of the invention in conjunction with embodiment; only for technical conceive of the present invention and feature are described; its object is to allow person skilled in the art understand content of the present invention and to be implemented; protection scope of the present invention can not be limited with this; all equivalences done according to spirit of the present invention change or modify, and all should be encompassed in protection scope of the present invention.
Claims (2)
1. the application of lovastatin acid compound in the medicine for the preparation for the treatment of hyperlipidemia.
2. apply as claimed in claim 1, it is characterized in that, comprise the following steps:
1) preparation is such as formula the compound lovastatin ammonia propyl ester shown in B
Get such as formula the compound lovastatin shown in A, add ethanol and propylamine carries out ring-opening reaction, obtained such as formula the compound lovastatin ammonia propyl ester shown in B;
2) preparation is such as formula the compound lovastatin acid compound shown in C
Get step 1) obtained such as formula the compound lovastatin ammonia propyl ester shown in B, add hydrochloric acid and carry out acidification hydrolization reaction, recrystallization, obtained such as formula the compound lovastatin acid compound shown in C;
3) by such as formula the compound lovastatin acid compound shown in C for the preparation for the treatment of hyperlipidemia medicine.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310722852.7A CN103755562B (en) | 2013-12-24 | 2013-12-24 | The preparation method of a kind of preparation method of lovastatin acid compound, composition, composition and application thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5098931A (en) * | 1989-08-31 | 1992-03-24 | Merck & Co., Inc. | 7-substituted HMG-CoA reductase inhibitors |
| CN103172603A (en) * | 2011-12-22 | 2013-06-26 | 北大方正集团有限公司 | High-selectivity lovastatin extraction method by esterifying lovastatin acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1102588C (en) * | 1997-01-24 | 2003-03-05 | 兰贝克赛实验室有限公司 | Process for manufacturing simvastatin from lovastatin or mevinolinic acid |
| NO991045L (en) * | 1998-03-05 | 1999-09-06 | Synthon Bv | Process for the preparation of simvastatin and / or its derivatives |
| WO2002009697A1 (en) * | 2000-07-27 | 2002-02-07 | Plus Chemicals, B.V | Highly purified simvastatin compositions |
| CN1255398C (en) * | 2004-06-09 | 2006-05-10 | 山东鲁抗医药股份有限公司 | Synthesis of cinvastatin |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5098931A (en) * | 1989-08-31 | 1992-03-24 | Merck & Co., Inc. | 7-substituted HMG-CoA reductase inhibitors |
| CN103172603A (en) * | 2011-12-22 | 2013-06-26 | 北大方正集团有限公司 | High-selectivity lovastatin extraction method by esterifying lovastatin acid |
Non-Patent Citations (3)
| Title |
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| ANA MORNAR等: "Development of a Rapid LC/DAD/FLD/MSn Method for the Simultaneous Determination of Monacolins and Citrinin in Red Fermented Rice Products", 《JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY》 * |
| 李安良: "《生物利用度控制-前药和药物靶向作用》", 29 February 2008, 化学工业出版社 * |
| 陆彬: "《药剂学》", 31 January 2003, 中国医药科技出版社 * |
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| CN103755562A (en) | 2014-04-30 |
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