CN104529971A - HMG-GoA reductase inhibitor - Google Patents
HMG-GoA reductase inhibitor Download PDFInfo
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- CN104529971A CN104529971A CN201410843872.4A CN201410843872A CN104529971A CN 104529971 A CN104529971 A CN 104529971A CN 201410843872 A CN201410843872 A CN 201410843872A CN 104529971 A CN104529971 A CN 104529971A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D309/30—Oxygen atoms, e.g. delta-lactones
Abstract
The invention relates to a compound, in particular to an HMG-GoA reductase inhibitor. The HMG-GoA reductase inhibitor is ester formed by naphthol and Cn polyhydroxyalkanoate or Cn olefine acid of the compound in the formula I, wherein n is an integer from six to fourteen. The compound can be effectively used for treating or preventing dyslipidemia, for example, the compound can effectively treat or prevent hypercholesteremia or mixed type hyperlipidemia.
Description
This application claims the right of priority of the Chinese Patent Application No. 201410046605.4 that on January 30th, 2014 submits to, its full content is incorporated to herein by reference.
Technical field
The invention belongs to medical art, relate to hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin derivative, and their preparation method and its usage.
Background technology
Statin (statins) class medicine is hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor of exploitation in nearly twenties years, is a secondary prevention medicine of coronary heart disease, hypertension and cerebro-vascular diseases.This type of medicine is by competitive inhibition endogenous cholesterol synthesis rate-limiting enzyme (HMG-CoA) reductase enzyme, block hydroxyl first valeric acid pathways metabolism in cell, intracellular cholesteryl is synthesized reduce, thus feedback irritation cell film surface (being mainly liver cell) low-density lipoprotein (low density lipoprotein, LDL) acceptor quantity and activity increase, make serum cholesterol remove increase, level reduces.
The mechanism of action of statins can be divided into effect for reducing fat and non-effect for reducing fat, effect for reducing fat is that the structure of itself or its meta-bolites is similar to HMG-CoA, can be active in the commitment competitive inhibition HMG-CoA reductase of cholesterol biosynthesis, mevalonic acid is made to form obstacle, hinder the synthesis of liver endogenous cholesterol, and compensatory add the synthesis of low-density lipoprotein on liver plasma membrane (LDL) acceptor, LDL a large amount of in blood plasma is ingested, be that bile acide is got rid of external through the metabolism of ldl receptor approach, reduce plasma LDL levels; This medicine heavy dose also slightly can reduce plasma triglyceride (TG) level, and hinders synthesis and the release of vldl (VLDL) because liver cell synthetic cholesterol decreases; In addition owing to adding the synthesis of ldl receptor on liver plasma membrane, apolipoprotein B (apoB-100) and apo E (apoE) can also be distinguished, also strengthen the removing of LDL precursor VLDL, also slightly can increase high density lipoprotein cholesterol (HDL-C) level.In a word, statins plays the effect of adjusting blood lipid by above several link.
Non-effect for reducing fat is embodied in anti-inflammatory action; Improve function of vascular endothelium effect; Suppress smooth muscle cell proliferation effect; Stablize atherosclerotic plaque; Platelet aggregation-against, reduces the effects such as thrombosis.
Statins is mainly used in coronary heart disease clinically, cerebral apoplexy, diabetic angiopathy, atrial fibrillation, hypertension and alzheimer disease.Its toxic side effect is mainly reflected in liver toxicity, musclar toxicity, these three aspects of neurotoxicity; Other discomforts mainly contain slight gastrointestinal reaction, and main manifestations has nauseating, stomachache, constipation, flatulence etc.Some patient applies statins can there is the phenomenons such as weak, gastrointestinal symptom, headache, fash, can disappear after decrement or drug withdrawal.
Within 1979, find and be extracted lovastatin, within 1987, obtaining FDA approval listing as first statins.After this, the Statins new drug such as Simvastatin, Pravastatin, fluvastatin, Rosuvastatin, Zarator, Cerivastatin is constantly pushed out.
Mevastatin, has another name called ML236B (Compactin), ML-236B, molecular formula C
23h
34o
5, chemistry is by name: (S)-2-Methyl Butyric Acid-(1S, 7S, 8S, 8aR)-1,2,3,7,8,8a-six hydrogen-7-methyl-8-{2-[(2R, 4R)-4-hydroxyl-6-oxo-2H-THP trtrahydropyranyl]-ethyl } and-1-naphthalene ester.Under structure is shown in:
For white or off-white color crystalline powder.Dissolve in acetone, slightly molten in ethanol, ethyl acetate, insoluble in water.Mevastatin is the competitive inhibitor of 3-hydroxyl 3-methyl glutaryl coenzyme A reductase (HMG-CoA reductase), HMG-CoA reductase is the rate-limiting enzyme of Biosynthesis of cholesterol initial stage, reversibly suppress HMG-CoA reductase, thus suppress the biosynthesizing of cholesterol.Mevastatin has carboxylic acid and lactone two kinds of chemical specieses, two kinds of chemical specieses can transform mutually, open can salify for lactonic ring in the basic conditions, and mevastatin salt forms beta-hydroxy acid in acid condition, and acid type can change the lactone form of closed loop into gradually through processed.
Mevastatin is the secondary metabolite of a kind of fungi, is found, and separated separately from Penicillium brvicompactum by A.G.Brown in 1976 in 1976 by Akira Endo from fungi Penicillium Citrinum.
Lovastatin (Lovastatin) is otherwise known as mevinolin, Teroltrat (Mevacor), monacolin K.Its chemical name is: (S)-2-Methyl Butyric Acid (4R, 6R)-6-[2-[(1S, 2S, 6R, 8S, 8aR)-1,2,6,7,8,8a--hexahydro-8-hydroxy-2,6-dimethyl-1-naphthyl] ethyl] tetrahydrochysene-4-hydroxyl-2H-pyran-2-one-8-ester.Its structure is as follows:
Lovastatin is a kind of secondary metabolite produced by filamentous fungus fermentation.Its main producing strains comprises: terreus (Aspergillus terreus), monascus (Monascus ruber) etc.Akira Endo in 1979 isolates again and suppresses the active stronger monacolin K of HMG-CoA reductase from monascus Monascusruber nutrient solution.Alberts etc. isolate the material mevinolin identical with monacolin K in 1980 from terreus Aspergills terreus, rear called after lovastatin.
Although there has been the medicine of many treatment hyperlipemias available clinically, but this area still expects to have the medicine being used for the treatment of hyperlipemia with more excellent biology, physics and/or chemical feature available.
Summary of the invention
The object of this invention is to provide the medicine being used for the treatment of hyperlipemia with more excellent biology, physics and/or chemical feature.
First aspect present invention provides a kind of compound, and it is with the naphthalene nucleus hydroxyl of compounds of Formula I and C
nalkanoic acid or C
nthe ester that olefin(e) acid is formed,
The wherein integer of n=6 ~ 14, such as n is 6,7,8,9,10,11,12,13 or 14.
Compound according to a first aspect of the present invention, wherein said C
nalkanoic acid is the C of straight chain
nalkanoic acid.
Compound according to a first aspect of the present invention, wherein said C
nalkanoic acid is the C of straight chain
6 ~ 12alkanoic acid.
Compound according to a first aspect of the present invention, wherein said C
nalkanoic acid is the C of straight chain
6 ~ 10alkanoic acid.
Compound according to a first aspect of the present invention, wherein said C
nolefin(e) acid is the C of straight chain
nolefin(e) acid.
Compound according to a first aspect of the present invention, wherein said C
nolefin(e) acid is the C of straight chain
6 ~ 12olefin(e) acid.
Compound according to a first aspect of the present invention, wherein said C
nolefin(e) acid is the C of straight chain
6 ~ 10olefin(e) acid.
Compound according to a first aspect of the present invention, wherein forms the C of ester with the naphthalene nucleus hydroxyl of formula I
nalkanoic acid is alkanoic acid, and it is selected from: n-caproic acid, positive enanthic acid, n-caprylic acid, pelargonic acid, n-capric acid, positive undeeanoic acid, positive laurostearic acid, positive TETRADECONIC ACID.
Compound according to a first aspect of the present invention, wherein forms the C of ester with the naphthalene nucleus hydroxyl of formula I
nalkanoic acid is selected from: n-caproic acid, positive enanthic acid, n-caprylic acid, pelargonic acid, n-capric acid.
Compound according to a first aspect of the present invention, wherein said C
nolefin(e) acid is the C of straight chain
nolefin(e) acid, and this straight chain C
nolefin(e) acid comprises 1 to n-2 double bond, such as, comprising 1 to n-3 double bond, such as, comprising 1 to n-4 double bond.
Compound according to a first aspect of the present invention, wherein said C
nolefin(e) acid is the hexenoic acid of straight chain, comprising 1 ~ 2 double bond; Further, it is selected from: 2-hexenoic acid, 3-hexenoic acid, 4-hexenoic acid, 5-hexenoic acid, 2,4-Sorbic Acids, 3,5-Sorbic Acids.
Compound according to a first aspect of the present invention, wherein said C
nolefin(e) acid is the heptenoic acid of straight chain, comprising 1 ~ 3 double bond; Further, it is selected from: 2-heptenoic acid, 3-heptenoic acid, 4-heptenoic acid, 5-heptenoic acid, 6-heptenoic acid, 2,4-heptadienoic acids, 2,5-heptadienoic acids, 2,6-heptadienoic acids, 3,5-heptadienoic acids, 3,6-heptadienoic acids, 2,4,6-heptantriene acids.
Compound according to a first aspect of the present invention, wherein said C
nolefin(e) acid is the octylenic acid of straight chain, comprising 1 ~ 4 double bond; Further, it is selected from: 2-octylenic acid, 3-octylenic acid, 4-octylenic acid, 5-octylenic acid, 6-octylenic acid, 2,4-octadienoic acids, 2,5-octadienoic acids, 2,6-octadienoic acids, 3,5-octadienoic acids, 3,6-octadienoic acids.
Compound according to a first aspect of the present invention, wherein said C
nolefin(e) acid is the nonenoic acid of straight chain, comprising 1 ~ 5 double bond; Further, it is selected from: 2-nonenoic acid, 3-nonenoic acid, 4-nonenoic acid, 5-nonenoic acid, 6-nonenoic acid, 2,4-nonadienoic acids, 2,5-nonadienoic acids, 2,6-nonadienoic acids, 3,5-nonadienoic acids, 3,6-nonadienoic acids.
Compound according to a first aspect of the present invention, wherein said C
nolefin(e) acid is the decylenic acid of straight chain, comprising 1 ~ 6 double bond.
Compound according to a first aspect of the present invention, wherein said C
nolefin(e) acid is the undecylenic acid of straight chain, comprising 1 ~ 6 double bond.
First aspect present invention provides a kind of compound, wherein said C
nolefin(e) acid is the lauroleic acid of straight chain, comprising 1 ~ 6 double bond.
Compound according to a first aspect of the present invention, wherein said C
nolefin(e) acid is the tridecylenic acid of straight chain, comprising 1 ~ 6 double bond.
Compound according to a first aspect of the present invention, wherein said C
nolefin(e) acid is the tetradecenoic acid of straight chain, comprising 1 ~ 6 double bond.
Compound according to a first aspect of the present invention, it is selected from:
formula Ia (i.e. formula I chemical combination naphthalene nucleus hydroxyl and n-caprylic acid ester are formed ester),
formula Ib (i.e. formula I chemical combination naphthalene nucleus hydroxyl and 2-hexenoic acid are formed ester),
And their pharmaceutical salts, solvate, ester, prodrug.
Further, second aspect present invention provides the method preparing compound described in any one of first aspect present invention, and it comprises the following steps:
I) hydroxyl on following formula: compound pyranoid ring and TERT-BUTYL DIMETHYL CHLORO SILANE (TBDMSCl) is made to react
Obtain following formula: compound:
Ii) make
with C
nalkanoic acid or C
nolefine acid reaction (such as reacting in DCC and dicyclohexylcarbodiimide), forms the ester cpds shown in following formula:
r is C
n-1alkyl or C
n-1thiazolinyl, (that is, R group forms the present invention C mentioned above to the implication that n has described in the arbitrary embodiment of first aspect present invention together with carboxyl
nalkanoic acid or C
nolefin(e) acid);
Iii) make
react (such as reacting in THF) to remove TBDMS group with TBAF (tetrabutyl ammonium fluoride), obtain target compound shown in following formula:
In an example of method described in second aspect present invention, wherein said compound
can be prepared through hydrolysis (being such as hydrolyzed in the basic conditions) by lovastatin.
Further, third aspect present invention provides the purposes of compound described in any one of first aspect present invention in the medicine for the preparation for the treatment of or prevention hyperlipemia.
Further, third aspect present invention provides the purposes of compound described in any one of first aspect present invention in the medicine for the preparation for the treatment of or prevention hypercholesterolemia or combined hyperlipidemia familial.
Further, fourth aspect present invention provides a kind of pharmaceutical composition, it comprises compound described in any one of first aspect present invention, be selected from following carbohydrate: glucose, sucrose, lactose, N.F,USP MANNITOL, sorbyl alcohol and combination thereof, and optional pharmaceutical excipient (carbohydrate except above-mentioned).To have been surprisingly found that when the compounds of this invention and described carbohydrate are combined with pharmaceutical compositions, contribute to the chemical stability keeping described compound especially.Especially, described carbohydrate is selected from lactose, N.F,USP MANNITOL and combination thereof.
Pharmaceutical composition according to a fourth aspect of the present invention, the weight ratio of wherein said compound and described carbohydrate is 1:1 ~ 10.
Further, fifth aspect present invention provides the method making stability of compounds, the method comprises the step making compound mix to make mixture with carbohydrate, described carbohydrate is selected from: glucose, sucrose, lactose, N.F,USP MANNITOL, sorbyl alcohol and combination thereof, and described compound is as described in any one of first aspect present invention.
Method according to a fifth aspect of the present invention, wherein said stablizing makes described compound maintain chemical stability.
Method according to a fifth aspect of the present invention, wherein said compound and carbohydrate mix to make mixture with the ratio of weight ratio 1:1 ~ 10.
In one embodiment, the compounds of this invention prepares by following schematic reaction process:
Wherein R has C of the present invention
nalkanoic acid or C
nthe implication of the alkyl or alkenyl part of olefin(e) acid; In an example, R is
or
wherein * represents the position be connected with acyl group.
In one embodiment, such as, described in above-mentioned reaction process, the synthesis of the compounds of this invention is generally through several step below:
(1) lovastatin obtains intermediate (2) through hydrolysis deacylated tRNA radical reaction in the basic conditions;
(2), in two hydroxyls of intermediate (2), the hydroxyl on cyclic lactone optionally generates silicon ether and intermediate (3) with TERT-BUTYL DIMETHYL CHLORO SILANE reaction;
(3) the 1-hydroxyl in intermediate (3) and carboxylic acid direct polycondensation under DCC effect are obtained by reacting esterification products and intermediate (4);
(4) intermediate (4) in acid condition deprotection obtain such as formula the target compound shown in (5).
In the present invention, term " naphthalene nucleus hydroxyl " refers to, such as, and the hydroxyl on the 8-position of the hexahydro naphthalene ring of following formula structural compounds.Thus ester cpds of the present invention is by this hydroxyl and of the present invention and C
nalkanoic acid or C
nthe carboxyl of olefin(e) acid is formed.
The present invention has been found that the compounds of this invention can effectively be used for the treatment of or prevent hyperlipemia, such as, can effectively treat or prevent hypercholesterolemia or combined hyperlipidemia familial.In addition, optionally, also find that the compounds of this invention has the biological property of one or more aspects desirable.
Accompanying drawing explanation
Fig. 1 is the schematic diagram that some compounds reduce the effect of plasma triglyceride.
Embodiment
the preparation of A, compound
embodiment 1:preparation (1S, 3R, 7S, 8S, 8aR)-8-(2-((2R, 4R)-4-hydroxyl-6-oxo tetrahydrochysene-2H-pyranyl-2-base] ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro naphthalene-1-base octanoates
Step 1: the preparation of intermediate 2
By 20 grams of lovastatins (2) (0.05mmol) and by 28 grams of KOH, 140ml methanol-water (6:1, V/V) the solution mixing formed, stirring is warming up to back flow reaction 8 hours stopped reaction, be cooled to room temperature and add 110ml water, then underpressure distillation removing methyl alcohol, add 400ml water and 100ml methylene dichloride in residue, be added dropwise to 6M hydrochloric acid under stirring to PH=2.Stirred at ambient temperature 4.5 hours; add saturated sodium bicarbonate solution and be neutralized to neutrality; stratification; water layer uses 100ml dichloromethane extraction once again; combined dichloromethane extracting solution adds anhydrous magnesium sulfate drying 3 hours, and filtration, concentrating under reduced pressure obtain deacylated tRNA based products intermediate (2) (orange oil) and be directly used in next step reaction.
Step 2: the preparation of intermediate 3
The intermediate (2) previous step be obtained by reacting and 19.3 grams of TERT-BUTYL DIMETHYL CHLORO SILANE (128.7mmol), 19.6 grams of imidazoles (286.9mmol), 180ml methylene dichloride react 5.5 hours under being mixed in room temperature, add water agitator treating twice (100ml × 2 time), anhydrous magnesium sulfate drying, filter, be evaporated to dry, crude product is through column chromatography purification (silica gel, ethyl acetate/normal hexane=2:8) obtain (3) 12.5 grams, intermediate, yield 58%, fusing point 142 DEG C.
1HNMR(CDCl
3，400MHz)δ5.99(1H,d,J＝9.6Hz),5.77-5.84(1H,m),5.56(1H,brs),4.67-4.72(1H,m),4.28-4.30(1H,m),4.23-4.25(1H,m),2.55-2.67(2H,m),2.34-2.47(2H,m),2.16-2.18(1H,m),1.68-1.92(7H,m),1.43-1.55(2H,m),1.14(3H,d,J＝7.6Hz),0.87-0.92(12H,m),0.08(6H,d,J＝1.6Hz)；
13CNMR(CDCl
3,100MHz)170.5，133.4，131.0，129.7，128.5，76.3，65.2，63.6，39.3，38.6，36.8，36.3，35.7，32.9，30.7，27.3，25.6(×3)，24.2，23.7，17.9，13.9，5.0(×2)。
Step 3: the preparation of intermediate 4
Under nitrogen protection; 4.34 grams of intermediates (2) (10mmol) and 2.16 grams of n-caprylic acid (15mmol), 3.09 grams of DCC are mixed in 100ml methylene dichloride, add 4-pyrollidinopyridine 0.22 gram (1.5mmol) under stirring in stirred at ambient temperature 3 days.Decompression steams methylene dichloride, and residue adds 100ml ether and stirs rear filtration, and filtrate evaporate to dryness obtains crude product, obtains intermediate 4,4.66 grams, yield 83% through column chromatography purification (ethyl acetate-hexane=1:1.5).
Step 4: target product (1S, 3R, 7S, 8S, 8aR)-8-(2-(and (2R, 4R)-4-hydroxyl-6-oxo tetrahydrochysene-2H-pyranyl-2-base] ethyl]-3,7-dimethyl-1,2, the preparation of 3,7,8,8a-hexahydro naphthalene-1-base octanoate:
Compound (4) (2.3mmol) that 1.29 grams of upper steps obtained under stirring and the solution of 20mlTHF composition are added to 0.682 gram of HAc (9.6mmol) and 2.26 grams of Bu
4n
+f
-3H
2in the mixing solutions of O (7.2mmol), 20mlTHF, finish stirring at room temperature 18 hours.Add the dilution of 100ml ether, then successively wash with hydrochloric acid, water, the saturated brine (2 times) of 2%, organic phase drying (anhydrous magnesium sulfate), filtration, evaporated under reduced pressure obtain faint yellow solid, white solid (1S is obtained through recrystallization, 3R, 7S, 8S, 8aR)-8-(2-((2R, 4R)-4-hydroxyl-6-oxo tetrahydrochysene-2H-pyranyl-2-base] ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro naphthalene-1-base monooctyl ester 0.75 gram, yield 73%.
1H NMR(CDCl
3,400MHz):δ5.97(d,1H),5.70(d,1H),5.63(dd,1H),5.53,(br,1H)4.53(m,1H),4.25 (m,1H),4.03(m,1H),2.93(m,1H),2.77(m,1H),2.26–2.43(m,4H),1.85-2.01(m,5H),1.54-1.69(m,8H),1.21-1.36(m,9H),1.01(d,3H),0.89(d,3H),0.77(t,3H).
13C NMR(CDCl
3,400MHz):δ175.691,169.332,141.225,135.534,132.553,127.267,77.093,72.237,63.902,45.971,40.322,39.671,38.132,35.702,34.113,33.321,31.732,31.091,30.115,29.101,29.102,25.433,25.012,23.167,20.745,20.432,19.557。MS-EI,(m/z):461(M+H)。
embodiment 2:preparation (1S, 3R, 7S, 8S, 8aR)-8-(2-((2R, 4R)-4-((1,1-dimethyl ethyl) dimethyl is silica-based) oxo)-6-oxo tetrahydrochysene-2H-pyranyl-2-base) ethyl)-3,7-dimethyl-1,2,3,7,8,8a-hexahydro naphthalene-1-base-2-hexene acid esters
Substantially with reference to the method for embodiment 1, different is only changed by n-caprylic acid in step 3 to make 2-hexenoic acid, obtains target product.
1H NMR(CDCl
3,400MHz):δ6.83(m,1H),5.96(d,1H),5.81(d,1H),5.77(d,1H),5.62(dd,1H),5.56,(br,1H)4.55(m,1H),4.35(m,1H),4.03(m,1H),2.92(m,1H),2.78(m,1H),2.36–2.45(m,4H),1.86-2.02(m,5H),1.54-1.69(m,5H),1.21-1.33(m,6H),1.03(d,3H),0.87(d,3H),0.76(t,3H)。
13C NMR(CDCl
3,400MHz):δ175.665,169.332,148.522,142.355,136.134,132.334,126.267,122.578,77.115,72.097,64.002,45.871,40.132,39.671,37.932,35.802,34.103,32.421,31.752,31.091,30.115,25.512,23.167,20.845,20.532,19.587。MS-EI,(m/z):431(M+H)。
b, biological test
Below biology investigation is carried out to the compounds of this invention (when using embodiment 1 or embodiment 2 gained end product as tester, they are designated as embodiment 1 product or embodiment 2 product or similar statement).
test example 1:
Test the IC50 value of some compounds to institute's support methods such as [0130] section and embodiments 1 with reference to CN102387800B (Chinese Patent Application No. 201080016152.0) specification sheets [0100], result is as follows:
| Compound | Embodiment 1 product | Embodiment 2 product | Simvastatin | Mevastatin | Pravastatin |
| IC50(nM) | 0.05 | 0.1 | 4 | 2 | 8 |
Have been found that, the compounds of this invention demonstrates excellent effect in the hydroxymethyl glutaryl CoA reductase inhibitor medicaments model trial of classics, show and can treat or prevent hyperlipemia, such as be used for the treatment of or prevent the biologic activity of hypercholesterolemia or combined hyperlipidemia familial, and its activity is better than existing analogue significantly.
test example 2:
Test to institute's support methods such as [0153] section and embodiments 4 effect that some compounds reduce plasma triglyceride with reference to CN102387800B (Chinese Patent Application No. 201080016152.0) specification sheets [0140].The dosage of each medicine is 25mg/kg, po.Result as shown in Figure 1.Result shows, and the compounds of this invention has the effect of excellent reduction plasma triglyceride.
test example 3: biological test (mensuration of LD50)
With reference to the document (Li Yinchao that Li Yin is superfine, Deng, the mensuration of rabdosia rubescens diterpene constituents medium lethal dose, Journal of Chinese Hospital Pharmacy, 2011,31 (2): 163) described method, use Bliss method design experiment, to mouse single oral gavage, observe toxic reaction and the death condition of mouse in 14d, with death of mice rate for index, measure the compounds of this invention to 95% fiducial limit of LD50 and LD50 of mouse.Result: the LD50 of embodiment 1 product single oral gavage administration is 27.23g/kg body weight, 95% of LD50 is crediblely limited to 26.43 ~ 28.67g/kg body weight; The LD50 of embodiment 2 product single oral gavage administration is 33.61g/kg body weight, and 95% of LD50 is crediblely limited to 31.48 ~ 35.06g/kg body weight; The LD50 of Simvastatin single oral gavage administration is 18.22g/kg body weight, and 95% of LD50 is crediblely limited to 17.03 ~ 19.83g/kg body weight; The LD50 of mevastatin single oral gavage administration is 15.83g/kg body weight, and 95% of LD50 is crediblely limited to 14.16 ~ 17.08g/kg body weight.Visible, from Drug safety angle, the compounds of this invention is obviously better than the security of prior art compound.
c, composition example
composition example 1:
The compound of embodiment 1 is fully mixed through lapping mode with weight ratio 1:5 ratio with glucose, sucrose, lactose, N.F,USP MANNITOL, sorbyl alcohol, starch, Microcrystalline Cellulose, dextrin respectively, obtains 8 kinds of compositions.These compositions are packed respectively in vial, place 3 months at 45 DEG C of temperature, use HPLC method measure these different compositions 0 month time embodiment 1 compounds content and in March time embodiment 1 compounds content, calculate each composition when March relative to the relative content of said composition 0 month time.
HPLC method measuring method is: be weighting agent with octadecylsilane chemically bonded silica; With acetonitrile-0.01% phosphoric acid (60:40) for moving phase; Determined wavelength is 238nm; Number of theoretical plate calculates by object peak and is not less than 3000; Get the composition be equivalent to containing 20mg target compound appropriate, accurately weighed, put in 100ml measuring bottle, add acetonitrile and make dissolving and be diluted to scale, shake up.Precision measures 1 μ l, injection liquid chromatography, record color atlas.Separately get target compound reference substance (chromatographic purity is greater than 99.8%), be measured in the same method.By external standard method with calculated by peak area, to obtain final product.
Result: two kinds of compositions that use lactose, both N.F,USP MANNITOL obtain, relative content during March is in 97.7 ~ 99.8% scopes, use each composition that other 6 kinds of carbohydrates obtain, relative content during March is in 88.2 ~ 92.6% scopes, lower than lactose, N.F,USP MANNITOL significantly.
In addition, according to aforesaid method, unlike compound medical compounds being changed into embodiment 2.Result: two kinds of compositions that use lactose, both N.F,USP MANNITOL obtain, relative content during March is in 97.5 ~ 99.4% scopes, and use each composition that other 6 kinds of carbohydrates obtain, relative content during March is in 87.5 ~ 92.1% scopes.
In other supplementary test, make lovastatin and fully mix through lapping mode with weight ratio 1:5 ratio with glucose, sucrose, lactose, N.F,USP MANNITOL, sorbyl alcohol, starch, Microcrystalline Cellulose, dextrin respectively, obtain eight kinds of compositions; Measure the relative content of these eight kinds of compositions after 45 DEG C of process during March with above method, result shows them all in 94.6 ~ 97.3% scopes, and without obvious or regular difference.
composition example 2:
1 parts by weight of example 1 compound is fully mixed through lapping mode with 5 parts by weight of lactose, then glucose, sucrose, sorbyl alcohol, starch, Microcrystalline Cellulose, each 1 weight part of dextrin is added respectively, fully mix through lapping mode, obtain composition 21.The formula of reference group compound 21 and method, different is only that lactose is wherein replaced with N.F,USP MANNITOL, obtains composition 22.
1 parts by weight of example 2 compound is fully mixed through lapping mode with 5 parts by weight of lactose, then glucose, sucrose, sorbyl alcohol, starch, Microcrystalline Cellulose, each 1 weight part of dextrin is added respectively, fully mix through lapping mode, obtain composition 23.The formula of reference group compound 23 and method, different is only that lactose is wherein replaced with N.F,USP MANNITOL, obtains composition 24.
The method of reference group compound example 1 measures the relative content of the target compound of above four kinds of compositions after placing process in March through 45 DEG C, result shows four kinds of compound relative contents all in 97.6 ~ 99.1% scopes, show when adding lactose or N.F,USP MANNITOL, when adding other auxiliary material again, target compound still keeps excellent stability.
composition example 3:
1 parts by weight of example 1 compound is fully mixed through lapping mode with 1 weight part, 2.5 weight parts, 7.5 weight parts or 10 parts by weight of lactose, obtains composition 31, composition 32, composition 33, composition 34.The formula of reference group compound 31 ~ 34 and method, different is only that lactose is wherein replaced with N.F,USP MANNITOL, obtains composition 35, composition 36, composition 37, composition 38.
The method of reference group compound example 1 measures the relative content of the target compound of above eight kinds of compositions after placing process in March through 45 DEG C, result shows in eight kinds of compositions, target compound relative content, all in 97.3 ~ 99.5% scopes, shows all to make target compound keep excellent stability when adding relative quantity 1 ~ 10 parts by weight of lactose or N.F,USP MANNITOL.
composition example 4:
20 parts by weight of example 1 compounds are fully mixed through lapping mode with 100 parts by weight of lactose (usually can be regarded as thinner), 10 weight part sodium starch glycolatees (usually can be regarded as disintegrating agent), 5 weight part PVP K30s (usually can be regarded as tackiness agent agent), 1 weight part Magnesium Stearate, be pressed into tablet, every sheet, containing embodiment 1 compound 20mg, obtains composition 41.The formula of reference group compound 41 and method, different is only that embodiment 1 compound is wherein replaced with embodiment 2 compound, obtains composition 42.
The formula of difference reference group compound 41 and composition 42 and method, different is only N.F,USP MANNITOL lactose wherein being replaced with equivalent, obtains two compositions and is respectively composition 43 and composition 44.
The respectively formula of reference group compound 41 and composition 42 and method, different is only by the half of wherein lactose replaces with the N.F,USP MANNITOL of equivalent, namely uses 1:1 lactose/N.F,USP MANNITOL combination, obtains two compositions and be respectively composition 45 and composition 46.
The method of reference group compound example 1 measures the relative content of the target compound of above six kinds of compositions after placing process in March through 45 DEG C, and result shows in six kinds of compositions, and target compound relative content is all in 97.6 ~ 99.2% scopes.
industrial applicability
Hydroxymethyl glutaryl coenzyme A (HMG-CoA) the reductase inhibitor lovastatin derivative that the present invention relates to can be treated or prevent hyperlipemia, such as be used for the treatment of or prevent hypercholesterolemia or combined hyperlipidemia familial, and these compounds have excellent performance.
Claims (10)
1. a compound, it is with the naphthalene nucleus hydroxyl of compounds of Formula I and C
nalkanoic acid or C
nthe ester that olefin(e) acid is formed,
The wherein integer of n=6 ~ 14, such as n is 6,7,8,9,10,11,12,13 or 14.
2. compound according to claim 1, wherein said C
nalkanoic acid is the C of straight chain
nalkanoic acid, such as C
6 ~ 12alkanoic acid, such as C
6 ~ 10alkanoic acid; And/or, described C
nolefin(e) acid is the C of straight chain
nolefin(e) acid, such as C
6 ~ 12olefin(e) acid, such as C
6 ~ 10olefin(e) acid.
3. compound according to claim 1, wherein said C
nalkanoic acid is selected from: n-caproic acid, positive enanthic acid, n-caprylic acid, pelargonic acid, n-capric acid, positive undeeanoic acid, positive laurostearic acid, positive TETRADECONIC ACID; Described straight chain C
nolefin(e) acid comprises 1 to n-2 double bond, such as, comprising 1 to n-3 double bond, such as, comprising 1 to n-4 double bond; Described C
nolefin(e) acid is the hexenoic acid of straight chain, comprising 1 ~ 2 double bond; Such as be selected from: 2-hexenoic acid, 3-hexenoic acid, 4-hexenoic acid, 5-hexenoic acid, 2,4-Sorbic Acids, 3,5-Sorbic Acids; Described C
nolefin(e) acid is the heptenoic acid of straight chain, comprising 1 ~ 3 double bond; Such as be selected from: 2-heptenoic acid, 3-heptenoic acid, 4-heptenoic acid, 5-heptenoic acid, 6-heptenoic acid, 2,4-heptadienoic acids, 2,5-heptadienoic acids, 2,6-heptadienoic acids, 3,5-heptadienoic acids, 3,6-heptadienoic acids, 2,4,6-heptantriene acids; Described C
nolefin(e) acid is the octylenic acid of straight chain, comprising 1 ~ 4 double bond; Such as be selected from: 2-octylenic acid, 3-octylenic acid, 4-octylenic acid, 5-octylenic acid, 6-octylenic acid, 2,4-octadienoic acids, 2,5-octadienoic acids, 2,6-octadienoic acids, 3,5-octadienoic acids, 3,6-octadienoic acids; Described C
nolefin(e) acid is the nonenoic acid of straight chain, comprising 1 ~ 5 double bond; Such as be selected from: 2-nonenoic acid, 3-nonenoic acid, 4-nonenoic acid, 5-nonenoic acid, 6-nonenoic acid, 2,4-nonadienoic acids, 2,5-nonadienoic acids, 2,6-nonadienoic acids, 3,5-nonadienoic acids, 3,6-nonadienoic acids.
4. compound according to claim 1, it is selected from:
And their pharmaceutical salts, solvate, ester, prodrug.
5. prepare the method for compound described in any one of claim 1-4, it comprises the following steps:
I) hydroxyl on following formula: compound pyranoid ring and TERT-BUTYL DIMETHYL CHLORO SILANE (TBDMSCl) is made to react
Obtain following formula: compound:
；
Ii) make
with C
nalkanoic acid or C
nolefine acid reaction, forms the ester cpds shown in following formula:
Iii) make
react to remove TBDMS group with TBAF, obtain target compound shown in following formula:
Wherein, R is C
n-1alkyl or C
n-1thiazolinyl, n has implication as claimed in claim 1.
6. the purposes of compound described in any one of claim 1-4 in the medicine for the preparation for the treatment of or prevention hyperlipemia.
7. the purposes of compound described in any one of claim 1-4 in the medicine for the preparation for the treatment of or prevention hypercholesterolemia or combined hyperlipidemia familial.
8. a pharmaceutical composition, it comprises compound described in any one of claim 1-4, is selected from following carbohydrate: glucose, sucrose, lactose, N.F,USP MANNITOL, sorbyl alcohol and combination thereof, and optional pharmaceutical excipient.
9. pharmaceutical composition according to claim 8, the weight ratio of wherein said compound and described carbohydrate is 1:1 ~ 10.
10. make the method for stability of compounds, the method comprises the step making compound mix to make mixture with carbohydrate, described carbohydrate is selected from: glucose, sucrose, lactose, N.F,USP MANNITOL, sorbyl alcohol and combination thereof, and described compound is as described in any one of claim 1-4; Further, described stablizing makes described compound maintain chemical stability; Further, described compound and carbohydrate mix to make mixture with the ratio of weight ratio 1:1 ~ 10.
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| CN108558805A (en) * | 2018-05-30 | 2018-09-21 | 日照市普达医药科技有限公司 | A kind of lipid regulating agent and its application in preventing myocardial ischemia |
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| US4444784A (en) * | 1980-08-05 | 1984-04-24 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
| US6002021A (en) * | 1998-06-29 | 1999-12-14 | Industrial Technology Research Institute | Process for preparing 6(R)-{2-8'(S)-2",2"-dimethylbutyryloxy-2'(S)-6'(R)-dimethyl-1',2',6'7',8' 8'A(R)-hexahydronapthyl-1'(S)-ethyl}-4(R)-hydroxy-3,4,5,6-tetrahydro-2H- pyran-2-one |
| CN102245178A (en) * | 2008-10-15 | 2011-11-16 | 神经元生物制药股份公司 | Biosynthesis of derivatives of monacolin J |
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2014
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4444784A (en) * | 1980-08-05 | 1984-04-24 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
| US6002021A (en) * | 1998-06-29 | 1999-12-14 | Industrial Technology Research Institute | Process for preparing 6(R)-{2-8'(S)-2",2"-dimethylbutyryloxy-2'(S)-6'(R)-dimethyl-1',2',6'7',8' 8'A(R)-hexahydronapthyl-1'(S)-ethyl}-4(R)-hydroxy-3,4,5,6-tetrahydro-2H- pyran-2-one |
| CN102245178A (en) * | 2008-10-15 | 2011-11-16 | 神经元生物制药股份公司 | Biosynthesis of derivatives of monacolin J |
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| CN108558805A (en) * | 2018-05-30 | 2018-09-21 | 日照市普达医药科技有限公司 | A kind of lipid regulating agent and its application in preventing myocardial ischemia |
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