CN110183329B - Nitrate NO donor type statin derivative and preparation method thereof - Google Patents

Nitrate NO donor type statin derivative and preparation method thereof Download PDF

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CN110183329B
CN110183329B CN201910531093.3A CN201910531093A CN110183329B CN 110183329 B CN110183329 B CN 110183329B CN 201910531093 A CN201910531093 A CN 201910531093A CN 110183329 B CN110183329 B CN 110183329B
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statin
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CN110183329A (en
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陈宇瑛
邹云
艾林
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Sichuan Industrial Institute of Antibiotics
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/02—Preparation of esters of nitric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C203/00—Esters of nitric or nitrous acid
    • C07C203/02—Esters of nitric acid
    • C07C203/04—Esters of nitric acid having nitrate groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom

Abstract

The invention discloses a nitrate NO donor type statin derivative and a preparation method thereof, belonging to the technical field of pharmaceutical chemical synthesis and having a structural formula shown as the following general formula:
Figure DDA0002099778030000011
wherein R is a statin residue; and includes three types of linkage, ortho, meta and para; the invention selects the statins to be hybridized with the NO donor, and both the NO and the statins have good treatment effect on atherosclerosis, thereby effectively avoiding the problem of unmatched action mechanisms of the NO and the statins; according to the invention, 4-coumaric acid is selected as a linking group, so that the curative effect of the medicine can be effectively enhanced, preliminary tests on the in vitro release activity of the NO donor type statin derivatives prove that the nitrate type NO donor type statin derivatives can effectively release NO, and the NO can reach more than 1.0mg/L in 4 h; beneficial attempts are made to develop anti-atherosclerotic drugs for NO donors.

Description

Nitrate NO donor type statin derivative and preparation method thereof
Technical Field
The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to nitrate NO donor type statin derivatives and a preparation method thereof.
Background
Atherosclerosis (AS) is the main pathological basis of cardiovascular and cerebrovascular diseases, and the research shows that Nitric Oxide (NO) and statins have positive effects on improving atherosclerosis.
NO plays an important physiological role as a messenger substance and an effector molecule in cardiovascular, immune, nervous, etc. systems. NO has biological activities such as inhibiting platelet aggregation, inhibiting smooth muscle cell proliferation, and regulating immunity, in addition to vasodilating activity. Therefore, the preparation has important significance for treating cardiovascular diseases such as hypertension, atherosclerosis and the like.
Statins are a class of drugs that lower LDL cholesterol by inhibiting the reductase activity of hydroxymethylglutaryl-coenzyme a (HMG-CoA). The medicine has Pleiotropic effects (Pleiotropic effects), and has the functions of improving vasodilation function, reducing vascular inflammation and oxidative stress injury, inhibiting thrombosis and platelet aggregation, preventing adhesion of platelets and leukocytes to vascular endothelium, stabilizing atherosclerotic vulnerable plaque, and promoting neovascularization besides the lipid-lowering effect.
NO donor type medicines are a hot spot of new medicine development in recent years, a molecular 'hybridization' (Hybrids) technology is mainly adopted in the development process, the NO donor and a certain medicine are combined into a molecule in an ester forming or amide forming mode, and the obtained 'Hybrids' compound can simultaneously have two action sites, so that the medicine effect is enhanced.
At present, NO donor type medicaments mainly relate to cardiovascular system medicaments, non-steroidal anti-inflammatory drugs, anti-tumor medicaments, anti-allergic medicaments and the like, 1 NO donor type anti-heart failure medicament Bidil is marketed in the United states in 2005, more than 10 NO donor type anti-heart failure medicaments are in different clinical research stages, and the research reports on the aspects of blood fat regulating and anti-atherosclerosis medicaments are less.
The research on NO donor type drugs has been encouraging. Nitrate NO donor type drugs are the earliest developed NO donor type drugs, and BiDil (bye-DILL) is a drug sold on the market.
However, studies of the hybrid of statins and nitrate NO donors have been reported, for example, Chinese patent with publication No. CN1794987A, but NO report on NO release rate is found at present.
For this type of drug, the design of the drug requires attention to the balance between the two dual acting drugs, and the release of NO must be precisely matched to the other mechanism of action in order to exert their greatest pharmacokinetic and pharmacodynamic advantages. How to balance the two drug effects to achieve the optimal curative effect is also a challenging problem facing the present, and is a problem which is always attempted to be solved but not solved in the field.
Disclosure of Invention
It is an object of the present invention to provide a nitrate NO-donor statin derivative to solve the above problems.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a nitrate NO donor statin derivative having a structural formula shown in the following general formula:
Figure BDA0002099778010000021
wherein R is a statin residue; and includes three types of linkage, ortho, meta and para.
As a preferred technical scheme: the statin residue is selected from simvastatin residue, atorvastatin residue, pitavastatin residue and rosuvastatin residue, and respectively has the following structures:
Figure BDA0002099778010000031
specifically, the above preferred compounds are of the formula:
Figure BDA0002099778010000032
Figure BDA0002099778010000041
it is well known to those skilled in the art that the above-mentioned o, m, and p represent ortho-, meta-, and para-positions, respectively.
The second purpose of the invention is to provide pharmaceutically acceptable salts, esters, solvate compounds or crystal forms of the derivatives.
The third purpose of the invention is to provide a preparation method of the derivative, which adopts the technical scheme that the preparation method comprises the following steps:
(1) taking 4-coumaric acid to react with 1, 4-dihalogenated butane to obtain an intermediate A;
(2) reacting the intermediate A obtained in the step (1) with nitrate to obtain an intermediate B;
(3) carrying out etherification reaction on the intermediate B obtained in the step (2) and dihalogenated benzyl to obtain an intermediate C, wherein the dihalogenated benzyl comprises an ortho-position structure, a para-position structure and a meta-position structure;
(4) preparing statin compounds into statin metal salts;
(5) and (4) reacting the intermediate C obtained in the step (3) with the statin metal salt obtained in the step (4) to obtain the intermediate.
As a preferred technical scheme: in the step (1), the 4-coumaric acid is dissolved by acetone, and alkali is added.
As a preferred technical scheme: in the step (2), the intermediate A is firstly dissolved in acetonitrile, and the nitrate is silver nitrate.
As a preferred technical scheme: and (3) the dichlorobenzyl in the step (3) is dichlorobenzyl.
As a preferred technical scheme: in the step (3), the intermediate B is firstly dissolved in acetonitrile, and weak base and catalyst are added.
As a further preferable technical scheme: the weak base is potassium carbonate.
As a further preferable technical scheme: the catalyst is potassium iodide
The preparation process of the invention is as follows:
Figure BDA0002099778010000051
compound 4 in the above formula is intermediate a, compound 5 is intermediate B, and compound 6/7/8 is intermediate C.
Compared with the prior art, the invention has the advantages that: the invention selects the statins to be hybridized with the NO donor, and both the NO and the statins have good treatment effect on atherosclerosis, thereby effectively avoiding the problem of unmatched action mechanisms of the NO and the statins.
In addition, 4-coumaric acid is selected as a linking group, so that the curative effect of the medicine can be effectively enhanced;
preliminary tests on the in-vitro release activity of the NO donor type statin derivatives show that the nitrate type NO donor type statin derivatives can effectively release NO, and the NO can reach more than 1.0mg/L in 4 hours; beneficial attempts are made to develop anti-atherosclerosis drugs for NO donors.
Drawings
FIG. 1 is a mass spectrum of Prodrug-I;
FIG. 2 is a hydrogen spectrum of Prodrug-I;
FIG. 3 is a mass spectrum of Prodrug-II;
FIG. 4 is a hydrogen spectrum of Prodrug-II;
FIG. 5 is a mass spectrum of Prodrug-III;
FIG. 6 is a hydrogen spectrum of Prodrug-III.
Detailed Description
The invention will be further explained with reference to the drawings.
Example 1
Preparation of intermediate 4-coumaric acid derivatives
1.1 preparation of E-4-hydroxy-phenylacrylic acid-4' -bromobutyl ester (4):
4.9g (FW164, 30mmol) of 4-coumaric acid was dissolved in 200ml of acetone, and after the dissolution, 24ml of triethylamine and 12ml (100mmol) of 1, 4-dibromobutane were added, and the mixture was reacted under reflux for 6 hours (60 ℃). Filtering, concentrating the filtrate to obtain oily substance, performing column chromatography [ PE/EA is 3:1(v: v) elution ], and performing post-treatment to obtain white solid E-4-hydroxy-phenylpropenoic acid-4' -bromobutyl ester (4)4.8 g.
Preparation of E-4-hydroxy-phenylacrylic acid-4' - (nitrooxy) butyl ester (5):
4.8g (16mmol) of compound (4) was dissolved in 100ml of acetonitrile and AgNO was added 3 6.9g (41mmol), refluxing for 5h (85 deg.C), cooling to room temperature, filtering, concentrating the filtrate to oil, and performing column chromatography [ PE/EA: 3:1(v: v) ]]And then 11.2g of crude product E-4-hydroxy-phenylacrylic acid-4' - (nitrooxy) butyl ester (5) is obtained through post-treatment.
1.3 preparation of E-4- (2-chloromethyl) benzyloxyphenylpropenoic acid-4' - (nitrooxy) butyl ester (6):
0.5g of the crude compound 5 was dissolved in 100ml of acetonitrile, and 0.7g (4mmol) of o-dichlorobenzyl, K, were added thereto 2 CO 3 0.2g (1.4mmol), catalytic amountKI, stirring for 24h at room temperature, filtering to remove precipitate, concentrating the filtrate to oil, and eluting by column chromatography [ PE/EA ═ 3:1(v: v) ]]And then the mixture is post-treated to obtain a yellow-white oily substance E-4- (2-chloromethyl) benzyloxy-phenylpropenoic acid-4' - (nitrooxy) butyl ester (6) of 0.4 g.
1.4 preparation of E-4- (3-chloromethyl) benzyloxyphenylacrylic acid-4' - (nitrooxy) butyl ester (7):
0.5g of the crude compound 5 was dissolved in 100ml of acetonitrile, and 0.7g (4mmol) of m-chlorobenzyl chloride, K, were added thereto 2 CO 3 0.2g (1.4mmol), catalytic amount of KI, stirring at room temperature for 24h, filtering off the precipitate, concentrating the filtrate to an oil, and column chromatography [ PE/EA ═ 3:1(v: v) elution]And then the mixture is post-treated to obtain 0.6g of a yellow-white oily substance E-4- (3-chloromethyl) benzyloxy phenylpropenoic acid-4' - (nitrooxy) butyl ester (7).
1.5 preparation of E-4- (4-chloromethyl) benzyloxyphenylacrylic acid-4' - (nitrooxy) butyl ester (8):
0.5g of the crude compound 5 was dissolved in 100ml of acetonitrile, and 0.7g (4mmol) of p-dichlorobenzene (K) was added thereto 2 CO 3 0.2g (1.4mmol) of KI with catalytic amount, stirring at room temperature for 24h, filtering off precipitate, concentrating filtrate to obtain oil, and eluting with column chromatography [ PE/EA is 3:1(v: v) ]]And then the yellow white solid E-4- (4-chloromethyl) benzyloxy phenylpropenoic acid-4' - (nitrooxy) butyl ester (8)0.6g is obtained by post-treatment.
Example 2
Preparation of metal salts of statins
Figure BDA0002099778010000081
2.1 preparation of simvastatin sodium (1):
dissolving 10g (24mmol) of simvastatin in 20ml of acetone (room temperature), adding 24.0ml (24mmol) of 4% NaOH, reacting at room temperature for 4h, evaporating the solvent to dryness to obtain a yellow brown viscous solid, adding acetone to dissolve the yellow brown viscous solid, decoloring with activated carbon, filtering, and evaporating the solvent to dryness to obtain a yellow white solid, namely the simvastatin sodium (1).
Figure BDA0002099778010000082
2.2 preparation of sodium pirvastatin (2):
dissolving 10g (19.3mmol) of pitavastatin protective substance in 200ml of ethanol (55 ℃), adding 37.4ml (44.9mmol) of 10% HCl after complete dissolution, dropwise adding 25ml (250mmol) of 40% NaOH after half an hour, cooling to room temperature after complete reaction (PE/EA is 1:3) by TLC detection, filtering, adjusting the pH to 7-8 by using 2NHCl, extracting by using 120ml of n-hexane by 3, and concentrating an aqueous layer until the aqueous layer is dried to obtain a white sodium salt, namely the pitavastatin sodium (2).
Figure BDA0002099778010000091
2.3 preparation of rosuvastatin sodium (3): dissolving 10g (17.3mmol) of the rosuvastatin protective substance in 250ml of ethanol (60 ℃), adding 41.7ml (50mmol) of 10% HCl after complete dissolution, dropwise adding 27.9ml (279mmol) of 40% NaOH after half an hour, cooling to room temperature after complete reaction (PE/EA is 1:3) by TLC detection, filtering, adjusting the pH to 7-8 by using 2NHCl, extracting by using 120ml of n-hexane by 3, and concentrating a water layer until the water layer is dried to obtain white sodium salt, namely the rosuvastatin sodium (3).
Example 3
Preparation of the target Compound
Preparation of (3R,5R) -7- [ (1S,2S,6R,8S,8aR) -8- (2, 2-dimethylbutyryloxy) -1,2,6,7,8,8 a-hexahydro-2, 6-dimethyl-1-naphthyl ] -3, 5-dihydroxyheptanoic acid-2' - [4- [ (E) -3- [4- (nitrooxy) -butoxy ] -3-oxopropenyl-phenoxymethyl ] -benzyl ester (Prodrug-I):
0.6g (1.4mmol) of compound (6) was dissolved in 10ml of DMF, and a solution of simvastatin sodium (1) (1.3g, 2.8mmol, FW ═ 458.57) in DMF was added dropwise, and a catalytic amount of KI was added and the mixture was stirred at room temperature for 24 hours. Adding 20ml of water into the system, extracting with EA 20ml of x 3, washing the EA layer with saturated salt water, concentrating the EA layer to obtain a yellow transparent oily substance, performing column chromatography [ PE/EA is 3:1(v: v) elution ], and performing post-treatment to obtain 0.4g of a pale yellow oily substance Prodrug-I;
MS：820.4(M+1) + (see FIG. 1);
1 H-NMR(CDCl 3 )δ(ppm)：7.62-7.66(d,1H),7.46-7.50(d,2H),7.36-7.45(m,4H),6.97-6.99(d,2H),6.28-6.32(d,1H),5.96-5.99(d,1H),5.74-5.78(dd,1H),5.48-5.50(m,1H),5.39-5.40(m,1H),5.27-5.30(d,2H),5.20(s,2H),4.50-4.53(t,2H),4.22-4.25(m,3H),3.70-3.75(m,1H),2.48-2.50(m,2H),2.43-2.45(m,1H),2.31-2.36(m,1H),2.20-2.24(dd,1H),1.81-1.95(m,6H),1.43-1.67(m,6H), 1.20-1H (m,1H), 1.27-2.78 (m,1H), 3.39-0.09 (d,3H), 3.0-3.0 (d,1H), 3H), (see FIG. 2).
Preparation of (3R,5R) -7- [ (1S,2S,6R,8S,8aR) -8- (2, 2-dimethylbutyryloxy) -1,2,6,7,8,8 a-hexahydro-2, 6-dimethyl-1-naphthyl ] -3, 5-dihydroxyheptanoic acid-3' - [4- [ (E) -3- [4- (nitrooxy) -butoxy ] -3-oxopropenyl-phenoxymethyl ] -benzyl ester (Prodrug-II):
0.6g (1.4mmol) of compound (7) was dissolved in 10ml of DMF, and a solution of simvastatin sodium (1) (1.3g, 2.8mmol, FW ═ 458.57) in DMF was added dropwise, and a catalytic amount of KI was added and the mixture was stirred at room temperature for 24 hours. Adding 20ml of water into the system, extracting with EA 20ml of x 3, washing the EA layer with saturated salt water, concentrating the EA layer to obtain a yellow transparent oily substance, performing column chromatography [ PE/EA is 3:1(v: v) elution ], and performing post-treatment to obtain 0.4g of a pale yellow oily substance Prodrug-II;
MS：820.3(M+1) + (see FIG. 3);
1 H-NMR(CDCl 3 ) δ (ppm): 7.62-7.66(d,1H),7.45-7.50(d,2H),7.37-7.42(m,3H),7.32-7.35(m,1H),6.97-6.99(d,2H),6.28-6.32(d,1H),5.96-5.99(d,1H),5.75-5.79(dd,1H),5.49-5.50(m,1H),5.39-5.40(m,1H),5.17(s,2H),5.09(s,2H),4.50-4.53(t,2H),4.28-4.29(m,1H),4.22-4.25(t,2H),2.53-2.54(d,2H),2.40-2.44(m,1H), 2.33-2.33 (m,1H), 1.81 (m,1H), 1.31-1H), 1.25 (t,2H), 2H, 2.53-2.54(d,2H),2.40-2.44(m,1H), 1.81-1H, 1H, 1, 3H) 1.13(s,3H),1.07-1.11(d,3H),0.85-0.87(d,3H),0.79-0.83(t.3H), (see FIG. 4).
Preparation of (3R,5R) -7- [ (1S,2S,6R,8S,8aR) -8- (2, 2-dimethylbutyryloxy) -1,2,6,7,8,8 a-hexahydro-2, 6-dimethyl-1-naphthyl ] -3, 5-dihydroxyheptanoic acid-4' - [4- [ (E) -3- [4- (nitrooxy) -butoxy ] -3-oxopropenyl-phenoxymethyl ] -benzyl ester (Prodrug-III):
0.6g (1.4mmol) of compound (8) was dissolved in 10ml of DMF, and a solution of simvastatin sodium (1) (1.3g, 2.8mmol, FW ═ 458.57) in DMF was added dropwise, and a catalytic amount of KI was added and the mixture was stirred at room temperature for 24 hours. Adding 20ml of water into the system, extracting with EA 20ml of x 3, washing the EA layer with saturated salt water, concentrating the EA layer to obtain yellow transparent oily matter, performing column chromatography [ PE/EA is 1:1(v: v) elution ], and performing post-treatment to obtain 0.6g of light yellow oily matter Prodrug-III;
MS：820.4(M+1) + (see FIG. 5);
1 H-NMR(CDCl 3 ) δ (ppm): 7.61-7.65(d,1H),7.46-7.49(d,2H),7.35-7.44(dd,4H),6.95-6.98(d,2H),6.28-6.32(d,1H),5.96-5.99(d,1H),5.75-5.79(dd,1H),5.48-5.51(m,1H),5.39-5.41(m,1H),5.16(s,2H),5.11(s,2H),4.50-4.53(t,2H),4.30-4.35(m,1H),4.22-4.27(t,2H),3.77-3.79(m,1H),2.53-2.55(d,2H),2.38-2.43(m,1H),2.33-2.36(m,1H), 1.65 (1H), 1.75-6.32 (d,1H), 1.17-5.6.6 (d,1H), 5.6 (s,1H), 5.50-4.53 (t,2H), 2H, 4.35(m,1H), 3H) 1.14(s,3H),1.09-1.13(d,3H),0.85-0.90(d,3H),0.80-0.83(t,3H), (see FIG. 6).
Preparation of 4- (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (anilinocarbonyl) pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid-2' - [4- [ (E) -3- [4- (nitrooxy) -butoxy ] -3-oxopropenyl-phenoxymethyl ] -benzyl ester (Prodrug-IV):
0.3g (0.7mmol) of the compound (6) is dissolved in 10ml of DMF, atorvastatin calcium (1.7g, 1.4mmol) solution in DMF is added dropwise, KI with catalytic amount is added, and the mixture is stirred at room temperature for 24 hours. Adding 20ml of water into the system, extracting with EA 20ml of x 3, washing the EA layer with saturated salt water, concentrating the EA layer to obtain a yellow transparent oily substance, performing column chromatography [ PE/EA is 1:1(v: v) elution ], and performing aftertreatment to obtain 0.3g of Prodrug-IV which is a light yellow solid.
MS：942.3(M+1) + (ii) a (not shown in the figure);
1 H-NMR(CDCl 3 ) δ (ppm): 7.62-7.66(d,1H),7.46-7.49(d,2H),7.37-7.43(m,4H),7.13-7.19(m,8H),7.05-7.07(d,2H),6.96-7.00(t,5H),6.86(s,1H),6.28-6.32(d,1H),5.27(s,2H),5.14(s,2H),4.50-4.53(t.2H),4.07-4.14(dd,2H),3.91-3.96(m,1H),3.71-3.73(m,1H),3.52-3.58(m,1H),2.40-2.42(d,2H),1.81-1.89(m,4H),1.54(s,3H),1.52(s,3H), 1.39-1H), (1.39-2H), (27H), (2H, 27.27H), (m,1H), (2H), (m, 2H).
Preparation of 5- (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (anilinocarbonyl) pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid-3' - [4- [ (E) -3- [4- (nitrooxy) -butoxy ] -3-oxopropenyl-phenoxymethyl ] -benzyl ester (Prodrug-V):
0.3g (0.7mmol) of the compound (7) is dissolved in 10ml of DMF, atorvastatin calcium (1.7g, 1.4mmol) solution in DMF is added dropwise, KI with catalytic amount is added, and the mixture is stirred at room temperature for 24 hours. Adding 20ml of water into the system, extracting with EA 20ml of 3, washing the EA layer with saturated salt water, concentrating the EA layer to obtain yellow transparent oily matter, performing column chromatography [ PE/EA is 1:1(v: v) elution ], and performing post-treatment to obtain yellow crystal Prodrug-V0.2 g;
MS：942.3(M+1) + (not shown);
1 H-NMR(CDCl 3 ) δ (ppm): 7.62-7.66(d,1H),7.47-7.49(d,2H),7.38-7.41(M,3H),7.31-7.33(M,1H),7.16-7.19(M,8H),7.05-7.07(d,2H),6.96-7.01(M,5H),6.85(s,1H),6.28-6.32(d,1H),5.16(s,2H),5.10(s,2H),4.50-4.53(t,2H),4.22-4.25(t,2H),4.09-4.17(M,2H),3.91-3.97(M,1H),3.71-3.75(M,1H),3.55-3.58(M,1H),2.45-2.46(d,2H), 1.81-3.81 (M,1H), (1H, 27.49H), (27, 2H), (49-1H), (49-4.25, 2H).
Preparation of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (anilinocarbonyl) pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid-4' - [4- [ (E) -3- [4- (nitrooxy) -butoxy ] -3-oxopropenyl-phenoxymethyl ] -benzyl ester (Prodrug-VI):
0.3g (0.7mmol) of the compound (8) is dissolved in 10ml of DMF, atorvastatin calcium (1.7g, 1.4mmol) solution in DMF is added dropwise, KI with a catalytic amount is added, and the mixture is stirred at room temperature for 24 h. Adding 20ml of water into the system, extracting with EA 20ml of 3, washing the EA layer with saturated salt water, concentrating the EA layer to obtain a yellow transparent oily substance, performing column chromatography [ PE/EA is 1:1(v: v) for elution ], and performing aftertreatment to obtain 0.3g of yellow solid Prodrug-VI;
MS：942.3(M+1) + (not shown);
1 H-NMR(CDCl 3 )δ(ppm)：7.61-7.65(d,1H),7.46-7.48(d,2H),7.35-7.44(dd,4H),7.14-7.26(m,8H),7.05-7.06(d,2H),6.94-7.05(m,5H),6.86(s,1H),6.28-6.32(d,1H),5.15(s,2H),5.09(s,2H),4.50-4.53(t,3H),4.22-4.25(t,2H),4.08-4.21(m,2H),3.93-3.96(m,1H),3.73-3.74(m,1H),3.55-3.59(m,1H),2.45-2.46(d,2H),1.83-1.90(m,4H),1.54(s,3H),1.52(s,3H),1.43-1.49(m,2H),1.24-1.27(m,2H), (scheme omitted).
Preparation of 7- (3R,5R,6E) -7- [ 2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl ] -3, 5-dihydroxy-6-heptenoic acid-2' - [4- [ (E) -3- [4- (nitrooxy) -butoxy ] -3-oxopropenyl-phenoxymethyl ] -benzyl ester (Prodrug-VII):
0.6g (1.4mmol) of the compound (6) was dissolved in 10ml of DMF, and a solution of pivastatin sodium (2) (1.3g, 2.8mmol, FW ═ 483) in DMF was added dropwise, and a catalytic amount of KI was added thereto, followed by stirring at room temperature for 24 hours. Adding 20ml of water into the system, extracting with EA 20ml of x 3, washing the EA layer with saturated salt water, concentrating the EA layer to obtain a yellow transparent oily substance, carrying out column chromatography [ PE/EA is 1:1(v: v) elution ], and carrying out aftertreatment to obtain 0.6g of a light yellow oily substance Prodrug-VII;
MS：805.3(M+1) + (not shown).
1 H-NMR(CDCl 3 ) δ (ppm): 7.93-7.95(d,1H),7.61-7.65(d,1H),7.56-7.60(m,1H),7.47-7.49(d,2H),7.36-7.45(m,4H),7.28-7.34(m,2H),7.09-7.20(m,4H),6.97-6.99(d,2H),6.58-6.22(d,1H),6.27-6.31(d,1H),5.52-5.58(dd,1H),5.28(s,2H),5.16(s,2H),4.48-4.51(t,2H),4.33-4.37(m,1H),4.20-4.23(t,2H),4.09-4.12(m,1H), 2.41-2.41 (t,2H), 2.33-4.37 (m,1H),4.20-4.23(t,2H),4.09-4.12(m,1H), 2H), 1.19-4.34 (m,1H), 1.79-0.42 (m,1H), 2H) (not shown).
Preparation of (3R,5R,6E) -7- [ 2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl ] -3, 5-dihydroxy-6-heptenoic acid-3' - [4- [ (E) -3- [4- (nitrooxy) -butoxy ] -3-oxopropenyl-phenoxymethyl ] -benzyl ester (Prodrug-VIII):
0.6g (1.4mmol) of the compound (7) was dissolved in 10ml of DMF, and a solution of pivastatin sodium (2) (1.3g, 2.8mmol, FW ═ 483) in DMF was added dropwise, and a catalytic amount of KI was added thereto, followed by stirring at room temperature for 24 hours. Adding 20ml of water into the system, extracting with EA 20ml of x 3, washing the EA layer with saturated salt water, concentrating the EA layer to obtain a yellow transparent oily substance, performing column chromatography [ PE/EA is 1:1(v: v) for elution ], and performing post-treatment to obtain 0.8g of a light yellow oily substance Prodrug-VIII;
MS：805.3(M+1) + (not shown);
1 H-NMR(CDCl 3 ) δ (ppm): 7.93-7.95(d,1H),7.60-7.65(d,1H),7.56-7.59(m,1H),7.45-7.47(d,2H),7.34-7.43(m,4H),7.27-7.32(m,2H),7.10-7.21(m,4H),6.95-6.97(d,2H),6.59-6.63(d,1H),6.27-6.31(d,1H),5.54-5.60(dd,1H),5.17(s,2H),5.08(s,2H),4.49-4.52(t,2H),4.36-4.41(m,1H),4.21-4.24(t,2H),4.10-4.14(m,1H), 2.47-2.47 (m,2H), 2.45-1H), 1.45-1H, 1.50-6.31 (d,1H), 2H) (not shown in the figure).
Preparation of (3R,5R,6E) -7- [ 2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl ] -3, 5-dihydroxy-6-heptenoic acid-4' - [4- [ (E) -3- [4- (nitrooxy) -butoxy ] -3-oxopropenyl-phenoxymethyl ] -benzyl ester (Prodrug-IX):
0.6g (1.4mmol) of the compound (8) was dissolved in 10ml of DMF, and a solution of pivastatin sodium (2) (1.3g, 2.8mmol, FW ═ 483) in DMF was added dropwise, and a catalytic amount of KI was added thereto, followed by stirring at room temperature for 24 hours. Adding 20ml of water into the system, extracting with EA 20ml of x 3, washing the EA layer with saturated salt water, concentrating the EA layer to obtain yellow transparent oily substance, performing column chromatography [ PE/EA is 1:1(v: v) elution ], and performing post-treatment to obtain 0.8g of Prodrug-IX of pale yellow oily substance;
MS：805.3(M+1) + (not shown).
1 H-NMR(CDCl 3 ) δ (ppm): 7.93-7.95(d,1H),7.57-7.64(d,1H),7.43-7.46(d,2H),7.33-7.41(dd,4H),7.25-7.32(m,2H),7.09-7.20(m,4H),6.92-6.94(d,2H),6.58-6.62(d,1H),6.27-6.31(d,1H),5.53-5.59(dd,1H),5.16(s,2H),5.06(s,2H),4.48-5.13(t,2H),4.36-4.40(m,1H),4.20-4.23(t,2H),4.10-4.13(m,1H),2.47-2.55(m,2H), 2.35-2.35 (m, 44.35-4.35, 4.35(m,1H), (1H, 2H, 45-5.5.7H), (2H, 2H), (7.45-5.4.7H), (1H, 2H).
Preparation of (3R,5R,6E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonamido) -5-pyrimidine ] -3, 5-dihydroxy-6-heptenoic acid-2' - [4- [ (E) -3- [4- (nitrooxy) -butoxy ] -3-oxopropenyl-phenoxymethyl ] -benzyl ester (Prodrug-X):
0.6g (1.4mmol) of the compound (6) is dissolved in 10ml of DMF, and rosuvastatin sodium (3) (1.5g, 2.8mmol, FW ═ 543) solution in DMF is added dropwise, KI is added in a catalytic amount, and the mixture is stirred at room temperature for 24 hours. Adding 20ml of water into the system, extracting with EA 20ml of x 3, washing the EA layer with saturated salt water, concentrating the EA layer to obtain yellow transparent oily substance, performing column chromatography [ PE/EA is 1:1(v: v) elution ], and performing post-treatment to obtain pale yellow oily substance Prodru g-X0.4 g;
MS：865.3(M+1) + (not shown);
1 H-NMR(CDCl 3 ) δ (ppm): 7.63-7.65(d,1H),7.60-7.62(m,2H),7.37-7.49(m,6H),7.04-7.08(t,2H),6.97-6.99(d,2H),6.58-6.63(d,1H),6.28-6.32(d,1H),5.40-5.45(dd,1H),5.28(s,2H),5.16(s,2H),4.49-4.52(t,2H),4.41-4.42(m,1H),4.21-4.24(t,2H),4.17-4.19(m,1H),3.56(s,3H),3.51(s,3H),3.32-3.36(m,1H),2.46-2.49(m,2H), 1.81-4.55 (m,1H), (1H, 6H, 1H), (4.55-6H).
Preparation of (3R,5R,6E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonamido) -5-pyrimidine ] -3, 5-dihydroxy-6-heptenoic acid-3' - [4- [ (E) -3- [4- (nitrooxy) -butoxy ] -3-oxopropenyl-phenoxymethyl ] -benzyl ester (Prodrug-XI):
0.6g (1.4mmol) of the compound (7) is dissolved in 10ml of DMF, rosuvastatin sodium (3) (1.5g, 2.8mmol, FW ═ 543) solution in DMF is added dropwise, KI in catalytic amount is added, and stirring is carried out at room temperature for 24 h. Adding 20ml of water into the system, extracting with EA 20ml of x 3, washing the EA layer with saturated salt water, concentrating the EA layer to obtain a yellow transparent oily substance, performing column chromatography [ PE/EA is 1:1(v: v) elution ], and performing post-treatment to obtain 0.4g of a pale yellow oily substance Prodrug-XI;
MS：865.3(M+1) + (not shown);
1 H-NMR(CDCl 3 ) δ (ppm): 7.65-7.72(m,4H),7.58-7.62(d,1H),7.45(s,1H),7.32-7.40(m,3H),7.23-7.27(t,2H),7.02-7.05(d,2H),6.46-6.54(t,2H),5.49-5.54(dd,1H),5.15(s,2H),5.11(s,2H),4.55-4.58(t,2H),4.21-4.22(m,1H),4.14-4.19(t,2H),3.89-3.90(m,1H),3.55(s,3H),3.45(s,3H),2.48-2.52(m,2H),1.71-1.79(m,4H), 1.39-1.39 (m,1H), 1.25-1H), (1H, 1H), (15H ), (FIGS.
Preparation of (3R,5R,6E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonamido) -5-pyrimidine ] -3, 5-dihydroxy-6-heptenoic acid-4' - [4- [ (E) -3- [4- (nitrooxy) -butoxy ] -3-oxopropenyl-phenoxymethyl ] -benzyl ester (Prodrug-XII):
0.6g (1.4mmol) of the compound (8) is dissolved in 10ml of DMF, rosuvastatin sodium (3) (1.5g, 2.8mmol, FW ═ 543) solution in DMF is added dropwise, KI in catalytic amount is added, and stirring is carried out at room temperature for 24 h. Adding 20ml of water into the system, extracting with EA 20ml of x 3, washing the EA layer with saturated salt water, concentrating the EA layer to obtain a yellow transparent oily substance, performing column chromatography [ PE/EA is 1:1(v: v) elution ], and performing post-treatment to obtain 0.6g of a light yellow oily substance Prodrug-XII;
MS：865.3(M+1) + (not shown);
1 H-NMR(CDCl 3 ) δ (ppm): 7.61-7.65(m,3H),7.44-7.48(d,2H),7.37-7.42(dd,4H),7.05-7.09(t,2H),6.95-6.97(d,2H),6.60-6.64(d,1H),6.28-6.32(d,1H),5.42-5.47(dd,1H),5.16(s,2H),5.09(s,2H),4.50-4.53(t,2H),4.44-4.46(m,1H),4.22-4.25(t,2H),4.12-4.15(m,1H),3.56(s,3H),3.51(s,3H),3.34-3.37(m,1H),2.50-2.53(m,2H),1.81 (m, 88H), 1.58-4.58 (d,1H), (FIGS. (d,1H), 4.22-4.25H), (2H), (FIGS.
Example 4
Determination of Compound NO in vitro Release
The method comprises the following steps: in this example, Griess method in spectrophotometry was used to detect the in vitro NO-releasing ability of the synthesized compound;
1. preparation of griiss reagent
4g of sulfanilamide and 0.2g of N-naphthyl ethylenediamine hydrochloride are taken, 10mL of 85% phosphoric acid is added, and the mixture is diluted to 100mL by distilled water. Placing in dark place for later use;
2. drawing of Standard Curve
Preparation of a standard stock solution: 0.15g of dried sodium nitrite (dried at 110 ℃ for 1 hour) is weighed precisely, placed in a 100mL volumetric flask, dissolved with distilled water and diluted to the mark. A0.1 mL to 100mL volumetric flask was measured precisely and diluted to the mark with water. Thus obtaining the standard stock solution of 1.5mg/L sodium nitrite.
Preparation of standard working solution: precisely measuring 1,2, 4, 6 and 8ml of standard stock solution to prepare 0.15-1.2 mg/L sodium nitrite series standard working solution.
Respectively measuring 8mL of the working solution, fully and uniformly mixing the working solution with 2mL of the Grice reagent, standing at room temperature for 10min, and measuring the absorbance at 540 nm. And drawing a standard curve according to the obtained data, and performing regression calculation on the concentration C of the sodium nitrite standard solution by using the absorbance value A.
3. Determination of nitric oxide Release amount in vitro
Preparation of a phosphate buffer solution (pH 7.4) containing excess L-cysteine (5 mmol): 6.8g of potassium dihydrogen phosphate was weighed precisely, and 395mL of 0.1mol/L sodium hydroxide solution and 0.6g of L-cysteine were added, dissolved in water and diluted to 1000 mL. This gave a pH7.4 phosphate buffer solution containing excess L-cysteine (5 mmol).
Preparing a test solution:
accurately weighing a compound Prodrug-I-Prodrug-XII, dissolving and diluting the compound with dimethyl sulfoxide to 10mL, and shaking up to obtain a solution with the concentration of 0.01 mol/L;
all samples were precisely measured as 1.0mL of a dimethylsulfoxide solution (0.01mol/L) and diluted to 100mL with a pH7.4 phosphate buffer solution containing an excess of L-cysteine (5 mmol/L). Finally, the concentration of the test solution was 10 － 4 mol/L. Incubating the solution at 37 deg.C, mixing 8mL of the reaction solution with 2mL of Grignard reagent at different time points, standing at room temperature for 10min, and measuring absorbance at 540nm wavelength.
Nitric oxide release as Nitrite Oxide (NO) 2 － ) Is expressed in terms of the amount of (A);
TABLE 1 Compound NO in vitro Release data I (A)
Figure BDA0002099778010000191
TABLE 2 Compound NO in vitro Release data II (C)
Figure BDA0002099778010000192
Figure BDA0002099778010000201
As can be seen from the release data in Table 2, the release curves of the compounds Prodrug-I, Prodrug-II, Prodrug-VI, Prodrug-VII and Prodrug-IX were consistent, and the release tended to be stable after 4 hours.
The release curves of the compounds Prodrug-III, Prodrug-IV, Prodrug-V, Prodrug-VIII, Prodrug-X, Prodrug-XI and Prodrug-XII are consistent and any sustained release is carried out at 4 h.
TABLE 3 in vitro release of Compound NO
Figure BDA0002099778010000202
Figure BDA0002099778010000211
As seen by the percent release of the compounds of table 3: all target compounds can achieve more than 16% of NO release, wherein the lowest NO release rate of target compounds Prodrug-I and Prodrug-II Prodrug-III with simvastatin as a parent nucleus is 16% -26%, the highest NO release rate of target compounds Prodrug-X, Prodrug-XI and Prodrug-XII with rosuvastatin as the parent nucleus is 27% -38%, wherein the highest NO release rate of meta-substituted Prodrug-XI is 38.22%, and the NO release rate of target compounds with atorvastatin and pitavastatin as the parent nucleus is intermediate; in addition, the target NO release is slightly higher in the meta position than in the ortho and para positions, except that the parent nucleus is the target of simvastatin.
The above description is intended to be illustrative of the preferred embodiment of the present invention and should not be taken as limiting the invention, but rather, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.

Claims (8)

1. A nitrate NO donor statin derivative, wherein the derivative has a structural formula shown by the following general formula:
Figure FDA0003763575200000011
r is a statin residue, and the statin residue is one of a simvastatin residue, an atorvastatin residue, a pitavastatin residue and a rosuvastatin residue;
wherein, when R is selected as simvastatin residue, the derivative is connected in para position;
when R is selected as an atorvastatin residue, the derivative is connected in an ortho-position and a meta-position;
when R is selected as pitavastatin residue, the derivative is ortho-linked;
when R is selected as a rosuvastatin residue, the derivatives are connected in ortho, meta and para positions;
the simvastatin residue, the atorvastatin residue, the pitavastatin residue and the rosuvastatin residue respectively have the following structures:
Figure FDA0003763575200000012
2. a process for the preparation of the derivative according to claim 1, comprising the steps of:
(1) taking 4-coumaric acid to react with 1, 4-dihalogenated butane to obtain an intermediate A;
(2) reacting the intermediate A obtained in the step (1) with nitrate to obtain an intermediate B;
(3) carrying out etherification reaction on the intermediate B obtained in the step (2) and dihalogenated benzyl to obtain an intermediate C, wherein the dihalogenation comprises ortho-position, para-position and meta-position structures;
(4) preparing statin compounds into statin metal salts;
(5) and (4) reacting the intermediate C obtained in the step (3) with the statin metal salt obtained in the step (4) to obtain the intermediate.
3. The method of claim 2, wherein: in the step (1), the 4-coumaric acid is dissolved by acetone, and alkali is added.
4. The method of claim 2, wherein: in the step (2), the intermediate A is firstly dissolved in acetonitrile, and the nitrate is silver nitrate.
5. The method of claim 2, wherein: and (3) the dihalogenated benzyl in the step (3) is dichlorobenzyl.
6. The method of claim 2, wherein: in the step (3), the intermediate B is firstly dissolved in acetonitrile, and weak base and catalyst are added.
7. The method of claim 6, wherein: the weak base is potassium carbonate.
8. The method of manufacturing according to claim 6, characterized in that: the catalyst is potassium iodide.
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