CN106938979B - A kind of NO donator type statin derivative, preparation method and application - Google Patents
A kind of NO donator type statin derivative, preparation method and application Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Abstract
The present invention provides a kind of compounds with structural formula shown in general formula (I), the compound has preferable NO release activity, with good application prospect, can be used for anti-inflammatory, antithrombus formation, anti-platelet activity, reduce cholesterol and triglyceride levels and/or improve hdl level, treatment periphery ischaemic, the vascular complication of diabetes patient or atherosclerosis etc..The present invention also provides the methods for preparing the compound.
Description
Technical field
The present invention relates to pharmacy and field of medicinal chemistry, it is related to a kind of NO donator type statin derivative, preparation method and answers
With, and in particular to a kind of N- aryl-N '-hydroxyl guanidine NO donator type statin derivative and its preparation method and application.
Background technique
Nitric oxide (Nitric oxide, NO), which is the eighties in last century, a kind of executes letter what is found in the mammalian body
The important gas molecules for making effect, are chosen as annual star molecule by U.S.'s Science magazine in 1992.From last century 80
Age end starts, and people mainly have studied the physiological function of N0.It was found that its can vasodilator, participate in blood pressure control；It is small to reduce blood
The aggregation of plate has the function of antithrombotic；It can also inhibit vascular smooth muscle cell proliferation, there is study of anti-atherogenic effect；It can shadow
Ring the release of central nervous system nerve mediator；Non-specific killing intracellular bacteria, helminth and malignant cell etc. can be passed through
And enhance the non-specific immune function of body；It can be by inhibiting the proliferation of T lymphocyte to inhibit the specific immunity of body；
And the physiological action that can protect digestive system etc..
Statins, that is, hydroxy-3-methylglutaryl CoA reductase inhibitor be presently the most effectively, clinical application it is most extensive
Regulating plasma lipid drug.Total plasma cholesterol (TC) and low density lipoprotein cholesterol can be effectively reduced in statins
(LDL-C) triglycerides (TG) and increasing high density lipoprotein cholesterol (HDL-C) water can also be greatly lowered in level
It is flat.Some clinical tests reduce coronal move it has been proved that hydroxy-3-methylglutaryl CoA reductase inhibitor, that is, statins have
Effect [the .The Journal of Pharmacology such as the Izzat NN and of arteries and veins disease and stroke risk
Experimental Therapeutics, 2000,293:315；The such as Gotto JrAmerican Journal of Cardiology, 2005,96:34F-38F.].But this protective effect needs higher dosage and needs ability after a couple of days to several weeks
Show, which limits its applications in this respect.And statins also have certain security risk.Muscle poison is statin
The main adverse reaction of class drug, the clinical manifestation of muscle poison is myalgia, flesh tenderness, myasthenia, and is increased with creatine kinase,
Most serious is rhabdomyolysis, but this adverse reaction is extremely rare.Cerivastatin is because inappropriate medication causes sternly
Weight rhabdomyolysis and in 2001 quit listing.
Therefore, develop it is a kind of also have while adjusting blood lipid anti-inflammatory, antithrombus formation, anti-platelet activity and
The drugs of the functions such as muscle poison is reduced or eliminated by great market prospects.NO donor and existing statins are passed through into certain companies
It connects base a pair of horses going side by side and synthesizes twin medicine, make it into after body while playing raw medicine and the collective effect of NO, reach synergistic purpose.Root
According to this theory, NicOx company has synthesized a variety of twin medicines, including NO donator type Pravastatin (NCX-6550), NO donor
Type Fluvastatin (NCX-6553), NO donator type Atorvastatin (NCX-6560).The hypolipidemic activity of these new drugs and corresponding
Statins it is suitable or stronger, some new functions have been provided simultaneously with, as NCX-6550 is shown than Pravastatin more
Strong anti-inflammatory activity, NCX-6550 and NCX-6553 can inhibit the proliferation of aortal smooth muscle.According to the publication of NicOx company
Information claims NCX-6560 to have safety more better than Atorvastatin and tolerance (http://www.nicox.com/asp/
NCX6560.asp), and there are anticoagulation and anti-inflammatory properties.
N- N-Hydroxyguanidine is another effective N0 donor.The study found that N- N-Hydroxyguanidine is in vivo
There are leukemia cell and anti-tumor activity, the NO that this kind of compound discharges in vivo is cell growth inhibition and cytotoxicity
Reason.It has also been found that this kind of compound has antihypertensive active, some compounds are marked with protective effect to Ischemia Reperfusion for research.
NitroMed company, which declares that N- N-Hydroxyguanidine is taken simultaneously in proportion with other vasoactive agents, to be made
For the new treatment to tuberculosis, sexual dysfunction, anoxic, cardiovascular disease, the even diseases such as memory loss.The country has expanded
The application study of N- aryl-N '-hydroxyl guanidine NO compound donator, obtains some split medicines with preferable physiological activity
Object.Zhang Zhiguo etc. [the Acta Pharmaceutica Sinica such as Zhang Zhiguo, 2004,39 (9): 705-710.] is by N- aryl-N '-N-Hydroxyguanidine
With antasthmatic Seratrodast split, obtained split drug antiasthmatic activity is significantly stronger than plug song Si Site.[the kings such as Wang Weidong
The China such as non-east journal of Medicinal Chemistry, 2004,14 (1): 1-8] by N- aryl-N '-hydroxyl guanidine NO compound donator with it is anti-inflammatory
Medicine flobufen phase split, obtained split drug significantly reduce the gastrointestinal side effect of flobufen.[the Chen such as Chen
L.et al.Chinese Journal of Natural Medicines 2010,8 (6): 436-440] by N- aryl-N '-hydroxyl
Base guanidine NO compound donator and the split of antihepatitis drug oleanolic acid, obtained split drug have stronger suppression to human liver cancer cell
System activity.N- aryl-N '-N-Hydroxyguanidine and Chrysin [Peng Shengming University Of Xiangtan Ph.D. Dissertation .2009] split
The noval chemical compound with anti-diabetic activity is obtained.N- aryl-N '-hydroxyl guanidine NO compound donator is replaced with blood-pressure drug
Meter Sha Tan [the .2006 Nian Liujie such as stone soldier Chinese Pharmaceutical Association Annual Conference meeting paper, 4145-4152] split, obtains
Has the noval chemical compound of preferable vasodilator activity.
But, if can be had N- aryl-N '-hydroxyl guanidine NO donor medicine and statins split
The noval chemical compound of more preferable technical effect, is not yet shown in relevant report at present.
Summary of the invention
In view of the shortcomings of the prior art and technological gap, one of the objects of the present invention is to provide one kind to have logical formula (I)
The compound of shown structural formula, the compound are the nitric oxide donator type statin derivative of brand new, can be used for treating height
Pionemia, treats the vascular complication and atherosclerosis of periphery ischaemic, diabetes patient, while having anti-inflammatory, anti-blood
Bolt formation, anti-platelet activity.
Wherein, R1For statin residue；R2For acyl group；R3Represent H orX represents F, Cl, Br, H, CH3、
OCH3、N3Or carbon atom number is less than 3 alkoxies.
Preferably, R1It is stood including Lovastatin, Simvastatin, Pravastatin, Fluvastatin, Atorvastatin, west and cuts down him
The residue in spit of fland, Rosuvastatin or Pitavastatin, structural formula are one of following:
It is furthermore preferred that R1For one of such as flowering structure:
R2ForPreferably
Preferably, R3For
For example, compound of the present invention includes but is not limited to following compound:
Preferably, compound of the present invention is following compound:
Another of this hair is designed to provide the preparation method of above compound, with R2ForR3ForFor, the method includes the steps:
(1) arylamine, ammonium thiocyanate and chlorobenzoyl chloride react in organic solvent obtains intermediate 2；
(2) 2 alkaline condition of intermediate hydrolyzes to obtain intermediate 3；
(3) intermediate 3 and CH3I reacts in organic solvent obtains intermediate 4；
(4) intermediate 4 and NH2OHHCl reacts in alkaline solution obtains NO compound donator 1；
(5)Boc2O protects compound 1, obtains intermediate 5；
(6) intermediate 5 reacts to obtain intermediate 6 with 4- chloromethyl benzoic acid chlorides under triethylamine catalysis；
(7) intermediate 6 reacts to obtain object I with the salt of statin in organic solvent under KI catalysis；
Another object of the present invention is that providing above compound has anti-inflammatory, antithrombus formation, anti-blood in preparation
Platelet activity, reduce cholesterol and triglyceride levels and/or improve hdl level, treatment periphery ischaemic,
Purposes in terms of the drug that at least one in the vascular complication or atherosclerosis of diabetes patient acts on.
A further object of the invention is to provide above compound in drug and its physiologically acceptable solvation
Object or polymorph.
Beneficial effects of the present invention:
Gained compound of the invention has preferable NO release activity, with good application prospect, can be used for anti-inflammatory, anti-
Thrombosis, anti-platelet activity reduce cholesterol and triglyceride levels and/or improve hdl level, treatment
Periphery ischaemic, the vascular complication of diabetes patient or atherosclerosis etc..
Detailed description of the invention
Fig. 1 is NO release in vitro standard curve and regression equation figure used in the present invention.
Specific embodiment
The present invention is specifically described below by embodiment, it is necessary to which indicated herein is that following embodiment is only used
It is further detailed in the present invention, should not be understood as limiting the scope of the invention, which is skilled in technique
Some nonessential modifications and adaptations that personnel are made according to foregoing invention content, still fall within protection scope of the present invention.
Embodiment 1:(3R, 5R) -7- [5- isopropyl -3- phenyl -2- (4- fluorophenyl) -4- (anilino- formoxyl) pyrroles -
1-] -3,5- dihydroxy enanthic acid-{ 4- { N '-[(tertbutyloxycarbonyl) oxygroup]-N- (4- chlorphenyl) carbonamidine base } carbamoyl } benzyl
Ester
Step 1:N- (4- chlorphenyl)-N '-benzoylthioureas, that is, compound 2a
At room temperature, 18.42g NH4SCN is dissolved in 250ml acetone, 29.5g PhCOCl is disposably added in stirring, risen
Temperature stops heating, is cooled to room temperature, is slowly added to 20.58g 4- chloroaniline in batches, continue stirring extremely to back flow reaction 15min
Fully reacting is cooled to room temperature.It in the 700g trash ice that reaction solution is poured into, is filtered after ice-out, discards filtrate, filter cake acetone
Recrystallization, it is dry, white is obtained to off-white color acicular crystal 41.5g, yield 88.5%.Mp:144.5-145.4
Step 2:1- (4- chlorphenyl)-thiocarbamide, that is, compound 3a
41.0g 2a is added in 10% sodium hydroxide solution of 500ml, is warming up to 80 DEG C, stirring to TLC, which detects, reacts
Complete fully reacting.Reaction solution is poured into the 1200g trash ice containing 92ml concentrated hydrochloric acid, with concentrated ammonia liquor tune pH8-9 under stirring, is stirred
It is filtered after mixing to ice-out, discards filtrate, filter cake is washed with deionized, and reduced vacuum is dry, then by desciccate with third
Ketone/petroleum ether 1: 3 recrystallizes, and obtains Off-white product 25.6g, yield 97.3%.Mp:176.9-177.6
Step 3:S- methyl-N- (4- chlorphenyl) amidino groups thioether, that is, compound 4a
By 24.0g 3a and 24.0g CH3I is suspended in the anhydrous EtOH of 240ml, is warming up to be back to TLC and detect and reacted
Entirely.Concentration removes EtOH and obtains solid product, with ethyl acetate washing concentrating product, obtains off-white powder product 24.6g, produces
Rate 95.5%.
M+1:201.0
Step 4:1- (4- chlorphenyl) -2- hydroxyl guanidine, that is, compound 1a
24.0g 4a is dissolved in 240ml EtOH, 16.6g NH is added2OH.HCl is cooled to 0-10 DEG C, with 10%
NaOH solution tune pH10-11.It is stirred at this temperature to TLC and detects fully reacting, concentration removes EtOH and obtains white solid.To
Ether and deionized water is added in the solid, stirs, and filtering, filter cake washs to obtain product 20.4g, yield 91.0% with ether.
M+1:186.1,1H-NMR (DMSO-d6,400MHz): δ 8.44 (s, 1H), 7.78 (s, 1H), 7.25 (dd, 4H),
5.10 (s, 2H).
Step 5:2- [(tertbutyloxycarbonyl) oxygroup] -1- (4- chlorphenyl) guanidine, that is, compound 5a
2.8g 1a is dissolved in dioxane/water mixed solvent at room temperature, is added at one time 4.2ml triethylamine, is stirred,
It is cooled to 0 DEG C, by 3.9g Boc2O is dissolved in 5ml dioxane, is slowly dropped into reaction solution.Concentration of reaction solution after reaction 0.5h
To doing, cold ether is added, stirs, filtering, concentration filtrate no longer reduces to volume, cold ether is added again, stirring, filtering.It closes
And 2 filter cakes, it is crystallized with acetone/water system, obtains product 2.0g, yield 46.5%.
1H-NMR (DMSO-d6,400MHz): δ 8.11 (s, 1H), 7.32 (dd, 4H), 5.76 (s, 2H), 1.45 (s, 9H)
Step 6:N- { N '-[(tertbutyloxycarbonyl) oxygroup]-N- (4- chlorphenyl) amidino groups } -4- chloromethylbenzene formamide is changed
Close object 6a
Under nitrogen protection, 2.0g 5a is dissolved in 100ml anhydrous methylene chloride, is cooled to -10 DEG C, tri- second of 1.5ml is added
Then the dichloromethane solution of 15ml 1.5g 4- chloromethyl benzoic acid chlorides is slowly dropped into reaction solution, stir about 0.5h by amine,
Fully reacting.Washed reaction liquid 1 time, organic layer then is washed 2-3 times with saturated sodium bicarbonate solution, then washed with saturated common salt
Wash organic layer 1-2 times, last organic layer dries, filters removing filter cake with anhydrous magnesium sulfate, and concentration filtrate obtains crude product.Silica gel column layer
Analyse isolated target product 6a 0.4g.
Step 7:(3R, 5R) -7- [5- isopropyl -3- phenyl -2- (4- fluorophenyl) -4- (anilino- formoxyl) pyrroles -
1-] -3,5- dihydroxy enanthic acid-{ 4- { N '-[(tertbutyloxycarbonyl) oxygroup]-N- (4- chlorphenyl) carbonamidine base } carbamoyl } benzyl
The synthesis of ester, that is, object NO-6a-Ato
0.4g 6a and 1.2g Atorvastatin calcium are dissolved in 10ml DMF, KI 0.8g is added, 48h is stirred at room temperature.It will
Reaction solution is poured into 50ml deionized water, then ethyl acetate extraction uses EA layers of saturated common salt water washing, then use anhydrous magnesium sulfate
It is dry, it is then filtered to remove filter cake, concentration filtrate obtains crude product.Column chromatography for separation obtains target product NO-6a-Ato
M+1:960.2,1H-NMR (DMSO-d6,400MHz): 9.79 (s, 1H), 8.05 (d, 2H), 7.60 (d, 2H),
7.52-7.48 (m, 4H), 7.40 (d, 2H), 7.26-7.15 (m, 6H), 7.10-7.07 (m, 4H), 7.02-6.96 (m, 2H),
5.21 (s, 2H), 4.83 (d, 1H), 4.67 (d, 1H), 3.93 (m, 2H), 3.76 (m, 1H), 3.53 (m, 1H), 3.23 (m, 1H),
2.52 (dd, 1H), 2.36 (dd, 1H), 1.63 (m, 1H), 1.50 (m, 1H), 1.44 (s, 9H), 1.40 (m, 1H), 1.35 (d,
6H), 1.31 (m, 1H)
Embodiment 2:(3R, 5S) -7- [2- cyclopropyl -4- (4- fluorophenyl) quinoline -3-] -3,5- dihydroxy -6 (E)-heptene
Acid-{ 4- { N '-[(tertbutyloxycarbonyl) oxygroup]-N- (4- chlorphenyl) carbonamidine base } carbamoyl } benzyl ester, that is, compound N O-6a-
Pita
0.4g 6a and 0.8g Pitavastatin Calcium are dissolved in 10ml DMF, KI 0.8g is added, 48h is stirred at room temperature.It will be anti-
Liquid is answered to be poured into 50ml deionized water, then ethyl acetate extraction uses EA layers of saturated common salt water washing, then dry with anhydrous magnesium sulfate
It is dry, it is then filtered to remove filter cake, concentration filtrate obtains crude product.Column chromatography for separation obtains target product NO-6a-Pita
M+1:823.1,1H-NMR (DMSO-d6,400MHz): δ 8.02 (d, 2H, J=8.4), 7.85 (d, 1H, J=
8.4), 7.64 (d, 1H), 7.60 (d, 2H, J=8.4), 7.50 (d, 2H, J=8.8), 7.41 (d, 2H, J=8.8), 7.37-
7.23 (m, 6H), 6.51 (d, 1H), 5.61 (dd, 1H), 5.22 (s, 2H), 4.88 (d, 1H), 4.81 (d, 1H), 4.13 (m,
1H), 3.82 (m, 1H), 2.49 (dd, 1H), 2.36 (dd, 1H), 1.51 (m, 2H) 1.44 (s, 9H), 1.23 (m, 2H), 1.16
(m, 1H), 1.02 (m, 2H)
Embodiment 3:(3R, 5S) [6- isopropyl -2- (N- methyl-N-methyl sulfonic acid amido) -4- (4- chlorphenyl) is phonetic by -7-
Pyridine -5-] -3,5- dihydroxy -6 (E)-heptenoic acid-{ 4- { N '-[(tertbutyloxycarbonyl) oxygroup]-N- (4- chlorphenyl) carbonamidine base } ammonia
Base formoxyl } benzyl ester, that is, compound N O-6a-Rosu
0.4g 6a and 0.8g rosuvastain calcium are dissolved in 10ml DMF, KI 0.8g is added, 48h is stirred at room temperature.It will
Reaction solution is poured into 50ml deionized water, then ethyl acetate extraction uses EA layers of saturated common salt water washing, then use anhydrous magnesium sulfate
It is dry, it is then filtered to remove filter cake, concentration filtrate obtains crude product.Column chromatography for separation obtains target product NO-6a-Ato
M+1:883.3,1H-NMR (DMSO-d6,400MHz): δ 8.03 (d, 2H), 7.70 (dd, 2H) 7.59 (d, 2H),
7.50 (d, 2H), 7.41 (d, 2H), 7.26 (dd, 2H), 6.52 (d, 1H), 5.51 (dd, 1H), 5.21 (s, 2H), 4.97 (d,
1H), 4.85 (d, 1H), 4.20 (m, 1H), 3.90 (m, 1H), 3.55 (s, 3H), 3.44 (s, 3H), 2.56 (dd, 1H), 2.38
(dd, 1H), 1.58 (m, 2H), 1.44 (s, 9H), 1.33 (q, 1H), 1.22 (d, 6H)
Embodiment 4:(3R, 5R) -7- [(1S, 2S, 6R, 8S, 8aR) -2,6- dimethyl -8- (2,2- dimethyl butyrate acyl-oxygens
Base) -1,2,6,7,8,8a- hexahydro -1- naphthalenes] -3,5- dihydroxy enanthic acid -- { 4- { N '-[(tertbutyloxycarbonyl) oxygroup]-N- (4-
Chlorphenyl) carbonamidine base } carbamoyl } benzyl ester, that is, compound
NO-6a-Sim
0.4g 6a and 0.8g Simvastatin sodium are dissolved in 10ml DMF, KI 0.8g is added, 48h is stirred at room temperature.It will be anti-
Liquid is answered to be poured into 50ml deionized water, then ethyl acetate extraction uses EA layers of saturated common salt water washing, then dry with anhydrous magnesium sulfate
It is dry, it is filtered to remove filter cake, concentration filtrate obtains crude product.Column chromatography for separation obtains target product NO-6a-Sim
M+1:838.2,1H-NMR (DMSO-d6,400MHz): 8.05 (d, 2H), 7.61 (d, 2H), 7.50 (d, 2H),
7.40 (d, 2H), 5.94 (d, 1H), 5.75 (dd, 1H), 5.48 (brs, 1H), 5.21 (s, 2H), 5.15 (brs, 1H), 4.81
(d, 1H), 4.48 (d, 1H), 4.02 (m, 1H), 3.45 (m, 1H), 2.54 (dd, 1H), 2.38 (m, 2H), 2.29 (m, 1H),
2.23 (m, 1H), 1.99-1.91 (m, 2H), 1.84-1.81 (m, 1H), 1.55-1.46 (m, 4H), 1.44 (s, 9H), 1.40-
1.33 (m, 2H), 1.26-1.23 (m, 5H), 1.03 (s, 3H), 1.02 (s, 3H), 0.80 (d, 3H), 0.74 (t, 3H)
Embodiment 5:(3R, 5R) -7- [5- isopropyl -3- phenyl -2- (4- fluorophenyl) -4- (anilino- formoxyl) pyrroles -
1-] -3,5- dihydroxy enanthic acid-{ 4- { N '-[(tertbutyloxycarbonyl) oxygroup]-N- (4- fluorophenyl) carbonamidine base } carbamoyl } benzyl
Ester, that is, compound N O-6b-Ato
Step 1:N- (4- fluorophenyl)-N '-benzoylthioureas, that is, compound 2b
At room temperature, by 27.0g NH4SCN is dissolved in 500ml acetone, and 42.6g PhCOCl is disposably added in stirring, is risen
Temperature stops heating, is cooled to room temperature, is slowly added to 34.0g 4- fluoroaniline in batches, continue to stir to anti-to back flow reaction 15min
Room temperature should be cooled to completely.It in the 1200g trash ice that reaction solution is poured into, is filtered after ice-out, discards filtrate, filter cake is with third
Ketone recrystallization, it is dry, white is obtained to off-white color acicular crystal 65.0g, yield 77.4%.Mp:131.6-132.3 DEG C.
Step 2:1- (4- fluorophenyl)-thiocarbamide, that is, compound 3b
65.0g 2b is added in 10% sodium hydroxide solution of 700ml, is warming up to 80 DEG C, stirring to TLC, which detects, reacts
Completely.Reaction solution is poured into the 1200g trash ice containing 140ml concentrated hydrochloric acid, with concentrated ammonia liquor tune pH8-9, stirring to ice under stirring
It is filtered after thawing, discards filtrate, filter cake is washed with deionized, and reduced vacuum is dry, then by desciccate acetone/petroleum
Ether 1: 3 recrystallizes, and obtains Off-white product 38.0g, yield 94.2%.Mp:168.3-168.5
Step 3:S- methyl-N- (4- chlorphenyl) amidino groups thioether, that is, compound 4b
By 43.0g 3b and 53.8g CH3I is suspended in the anhydrous EtOH of 500ml, is warming up to be back to TLC and detect and reacted
Entirely.Concentration removes EtOH and obtains solid product, with ethyl acetate washing concentrating product, obtains off-white powder product 44.0g, produces
Rate 96.6%.
Step 4:1- (4- fluorophenyl) -2- hydroxyl guanidine, that is, compound 1b
24.0g 4b is dissolved in 240ml EtOH, 18.4g NH is added2OH.HCl is cooled to 0-10 DEG C, with 10%
NaOH solution tune pH10-11.It is stirred at this temperature to TLC and detects fully reacting, concentration removes EtOH and obtains white solid.To
Ether and deionized water is added in the solid, stirs, and filtering, filter cake washs to obtain product 18.6g, yield 82.4% with ether.
M+1:170.1
Step 5:2- [(tertbutyloxycarbonyl) oxygroup] -1- (4- fluorophenyl) guanidine, that is, compound 5b
3.0g 1b is dissolved in dioxane/water mixed solvent at room temperature, is added at one time 5.0ml triethylamine, is stirred,
It is cooled to 0 DEG C, by 4.0g Boc2O is dissolved in 5ml dioxane, is slowly dropped into reaction solution.Concentration of reaction solution after reaction 0.5h
To doing, cold ether is added, stirs, filtering, concentration filtrate no longer reduces to volume, cold ether is added again, stirring, filtering.It closes
And 2 filter cakes, it is crystallized with acetone/water system, obtains product 2.2g, yield 46.1%.
M+1:270.1, H-NMR (DMSO-d6,400MHz): δ 7.95 (s, 1H), 7.38 (dd, 2H), 7.05 (t, 2H),
5.69 (s, 2H), 1.46 (s, 9H)
Step 6:N- { N '-[(tertbutyloxycarbonyl) oxygroup]-N- (4- fluorophenyl) amidino groups } -4- chloromethylbenzene formamide is changed
Close object 6b
Under nitrogen protection, 2.0g 5b is dissolved in 100ml anhydrous methylene chloride, is cooled to -10 DEG C, tri- second of 1.5ml is added
Then the dichloromethane solution of 15ml 1.5g 4- chloromethyl benzoic acid chlorides is slowly dropped into reaction solution, stir about 0.5h by amine,
Fully reacting.Washed reaction liquid 1 time, organic layer then is washed 2-3 times with saturated sodium bicarbonate solution, then washed with saturated common salt
Wash organic layer 1-2 times, last organic layer dries, filters removing filter cake with anhydrous magnesium sulfate, and concentration filtrate obtains crude product.Silica gel column layer
Analyse isolated target product 6b 0.5g.
M+1:422.0
Step 7:(3R, 5R) -7- [5- isopropyl -3- phenyl -2- (4- fluorophenyl) -4- (anilino- formoxyl) pyrroles -
1-] -3,5- dihydroxy enanthic acid-{ 4- { N '-[(tertbutyloxycarbonyl) oxygroup]-N- (4- fluorophenyl) carbonamidine base } carbamoyl } benzyl
Ester, that is, compound N O-6b-Ato
0.4g 6b and 1.2g Atorvastatin calcium are dissolved in 10ml DMF, KI 0.8g is added, 48h is stirred at room temperature.It will
Reaction solution is poured into 50ml deionized water, then ethyl acetate extraction uses EA layers of saturated common salt water washing, then use anhydrous magnesium sulfate
Removing filter cake is dried, filtered, concentration filtrate obtains crude product.Column chromatography for separation obtains target product NO-6b-Ato
M+1:944.4, δ 9.82 (s, 1H), 8.04 (d, 2H), 7.60 (d, 2H), 7.51 (d, 2H), 7.43 (m, 2H),
7.29-7.15 (m, 8H), 7.10-7.06 (m, 4H), 7.01-6.97 (m, 2H), 5.21 (s, 2H), 4.84 (d, 1H), 4.66 (d,
1H), 3.92 (m, 2H), 3.77 (m, 1H), 3.54 (m, 1H), 3.22 (m, 1H), 2.53 (dd, 1H), 2.35 (dd, 1H), 1.62
(m, 1H), 1.51 (m, 1H), 1.43 (s, 9H), 1.37 (m, 1H), 1.36 (d, 6H), 1.32 (m, 1H)
Embodiment 6:(3R, 5S) -7- [2- cyclopropyl -4- (4- fluorophenyl) quinoline -3-] -3,5- dihydroxy -6 (E)-heptene
Acid-{ 4- { N '-[(tertbutyloxycarbonyl) oxygroup]-N- (4- fluorophenyl) carbonamidine base } carbamoyl } benzyl ester, that is, compound N O-6b-
Pita
0.4g 6b and 0.8g Pitavastatin Calcium are dissolved in 10ml DMF, KI 0.8g is added, 48h is stirred at room temperature.It will be anti-
Liquid is answered to be poured into 50ml deionized water, then ethyl acetate extraction uses EA layers of saturated common salt water washing, then dry with anhydrous magnesium sulfate
It is dry, it is filtered to remove filter cake, concentration filtrate obtains crude product.Column chromatography for separation obtains target product NO-6b-Pita
M+1:807.3,1H-NMR (DMSO-d6,400MHz): δ 8.01 (d, 2H), 7.85 (d, 1H), 7.64 (d, 1H),
7.60 (d, 2H), 7.43 (m, 2H), 7.39-7.23 (m, 8H), 6.51 (d, 1H), 5.61 (dd, 1H), 5.22 (s, 2H), 4.87
(d, 1H), 4.80 (d, 1H), 4.12 (m, 1H), 3.81 (m, 1H), 2.46 (dd, 1H), 2.36 (dd, 1H), 1.51 (m, 2H),
1.43 (s, 9H), 1.23 (m, 2H), 1.18 (m, 2H), 1.02 (d, 4H)
Embodiment 7:(3R, 5S) [6- isopropyl -2- (N- methyl-N-methyl sulfonic acid amido) -4- (4- chlorphenyl) is phonetic by -7-
Pyridine -5-] -3,5- dihydroxy -6 (E)-heptenoic acid-{ 4- { N '-[(tertbutyloxycarbonyl) oxygroup]-N- (4- fluorophenyl) carbonamidine base } ammonia
Base formoxyl } benzyl ester, that is, compound N O-6b-Rosu
0.4g 6b and 0.8g rosuvastain calcium are dissolved in 10ml DMF, KI 0.8g is added, 48h is stirred at room temperature.It will
Reaction solution is poured into 50ml deionized water, then ethyl acetate extraction uses EA layers of saturated common salt water washing, then use anhydrous magnesium sulfate
Removing filter cake is dried, filtered, concentration filtrate obtains crude product.Column chromatography for separation obtains target product NO-6b-Rosu
M+1:807.3,1H-NMR (DMSO-d6,400MHz): δ 8.02 (d, 2H), 7.70 (dd, 2H), 7.59 (d, 2H),
7.44 (dd, 2H), 7.27 (q, 4H), 6.52 (d, 1H), 5.51 (dd, 1H), 5.21 (s, 2H), 4.97 (brs, 1H), 4.85
(brs, 1H), 4.21 (brs, 1H), 3.90 (brs, 1H), 3.56 (s, 3H), 3.44 (s, 3H), 2.55 (dd, 1H), 2.39 (dd,
1H), 1.61 (m, 2H), 1.57 (m, 2H), 1.43 (s, 9H), 1.40 (m, 1H), 1.20 (d, 6H)
Embodiment 8:(3R, 5R) -7- [(1S, 2S, 6R, 8S, 8aR) -2,6- dimethyl -8- (2,2- dimethyl butyrate acyl-oxygens
Base) -1,2,6,7,8,8a- hexahydro -1- naphthalenes] -3,5- dihydroxy enanthic acid -- { 4- { N '-[(tertbutyloxycarbonyl) oxygroup]-N- (4-
Fluorophenyl) carbonamidine base } carbamoyl } benzyl ester, that is, compound N O-6b-Sim
0.4g 6b and 0.8g Simvastatin sodium are dissolved in 10ml DMF, KI 0.8g is added, 48h is stirred at room temperature.It will be anti-
Liquid is answered to be poured into 50ml deionized water, then ethyl acetate extraction uses EA layers of saturated common salt water washing, then dry with anhydrous magnesium sulfate
It is dry, it is filtered to remove filter cake, concentration filtrate obtains crude product.Column chromatography for separation obtains target product NO-6b-Sim.
M+1:822.4,1H-NMR (DMSO-d6,400MHz): 8.06 (d, 2H), 7.60 (d, 2H), 7.43 (dd, 2H),
7.27 (t, 2H), 5.93 (d, 1H), 5.75 (dd, 1H), 5.48 (brs, 1H), 5.20 (s, 2H), 5.15 (br, 1H), 4.78 (d,
1H), 4.44 (dd, 1H), 4.00 (brs, 1H), 3.46 (brs, 1H), 2.54 (dd, 1H), 2.39 (m, 2H), 2.30 (m, 1H),
2.23 (dd, 1H), 1.99-1.91 (m, 2H), 1.84-1.81 (m, 1H), 1.55-1.46 (m, 4H), 1.43 (s, 9H), 1.36-
1.32 (m, 2H), 1.24 (brs, 5H), 1.03 (s, 3H), 1.02 (s, 3H), 0.80 (d, 3H), 0.74 (t, 3H)
Embodiment 9:(3R, 5R) -7- [5- isopropyl -3- phenyl -2- (4- fluorophenyl) -4- (anilino- formoxyl) pyrroles -
1-] -3,5- dihydroxy enanthic acid-{ 4- { N '-[(tertbutyloxycarbonyl) oxygroup]-N- phenyl formamidine base } carbamoyl } benzyl ester i.e. change
Close object NO-6c-Ato
Step 1:N- phenyl-N '-benzoylthioureas, that is, compound 2c
At room temperature, 57.1g NH4SCN is dissolved in 500ml acetone, 91.4g PhCOCl is disposably added in stirring, risen
Temperature stops heating, is cooled to room temperature, is slowly added to 46.5g 4- chloroaniline in batches, continue to stir to anti-to back flow reaction 15min
Room temperature should be cooled to completely.It in the 1500g trash ice that reaction solution is poured into, is filtered after ice-out, discards filtrate, filter cake acetone
Recrystallization, it is dry, white is obtained to off-white color acicular crystal product 120.0g, yield 93.75%
Mp:150.0-150.4 DEG C
Step 2:1- phenylthiourea, that is, compound 3c
120g 2c is added in 10% sodium hydroxide solution of 800ml, is warming up to 80 DEG C, stirring to TLC, which detects, reacts
Complete fully reacting.Reaction solution is poured into the 1500g trash ice containing 160ml concentrated hydrochloric acid, with concentrated ammonia liquor tune pH8-9 under stirring,
It is filtered after stirring to ice-out, discards filtrate, filter cake is washed with deionized, and reduced vacuum is dry, then uses desciccate
Acetone/petroleum ether 1: 3 recrystallizes, and obtains Off-white product 64.5g, yield 92.2%.
Mp:172.3-173.6
Step 3:S- Methyl-N-phenyl amidino groups thioether, that is, compound 4c
By 62.0g 3c and 86.7g CH3I is suspended in the anhydrous EtOH of 5000ml, is warming up to and is back to TLC detection reaction
Completely.Concentration removes EtOH and obtains solid product, with ethyl acetate washing concentrating product, obtains off-white powder product 63.6g,
Yield 93.9%.
Step 4:2- hydroxyl -1- guanidines, that is, compound 1c
33.5g 4c is dissolved in 500ml EtOH, 30.8g NH is added2OH.HCl is cooled to 0-10 DEG C, with 10%
NaOH solution tune pH10-11.It is stirred at this temperature to TLC and detects fully reacting, concentration removes EtOH and obtains white solid.To
Ether and deionized water is added in the solid, stirs, and filtering, filter cake washs to obtain product 25.4g, yield 83.6% with ether.
Step 5:2- [(tertbutyloxycarbonyl) oxygroup] -1- guanidines, that is, compound 5c
25.0g 1c is dissolved in dioxane/water mixed solvent at room temperature, 21.0ml triethylamine is added at one time, stirs
It mixes, is cooled to 0 DEG C, by 32.7g Boc2O is dissolved in 50ml dioxane, is slowly dropped into reaction solution.It is concentrated after reaction 0.5h
Reaction solution to dry, addition cold ether, stirring, filtering, concentration filtrate no longer reduces to volume, and cold ether is added again, stirs, mistake
Filter.Merge 2 filter cakes, is crystallized with acetone/water system, obtain product 10.3g, yield 24.8%.
M+1:252.5,1H-NMR (DMSO-d6,400MHz): δ 7.94 (s, 1H), 7.36 (d, 2H), 7.20 (t, 2H),
6.84 (t, 1H), 5.71 (s, 2H), 1.45 (s, 9H)
Step 6:
N- { N '-[(tertbutyloxycarbonyl) oxygroup]-N- phenyl amidino groups } -4- chloromethylbenzene formamide, that is, compound 6c
Under nitrogen protection, 2.0g 5c is dissolved in 100ml anhydrous methylene chloride, is cooled to -10 DEG C, tri- second of 2.0ml is added
Then the dichloromethane solution of 20ml 2.0g 4- chloromethyl benzoic acid chlorides is slowly dropped into reaction solution, stir about 0.5h by amine,
Fully reacting.Washed reaction liquid 1 time, organic layer then is washed 2-3 times with saturated sodium bicarbonate solution, then washed with saturated common salt
Wash organic layer 1-2 times, last organic layer dries, filters removing filter cake with anhydrous magnesium sulfate, and concentration filtrate obtains crude product.Silica gel column layer
Analyse isolated target product 6c 0.4g.
Step 7:(3R, 5R) -7- [5- isopropyl -3- phenyl -2- (4- fluorophenyl) -4- (anilino- formoxyl) pyrroles -
1-] -3,5- dihydroxy enanthic acid-{ 4- { N '-[(tertbutyloxycarbonyl) oxygroup]-N- phenyl formamidine base } carbamoyl } benzyl ester i.e. change
Close object NO-6c-Ato
0.4g 6c and 1.2g Simvastatin sodium Atorvastatin calcium are dissolved in 10ml DMF, KI0.8g is added, room temperature is stirred
Mix 48h.Reaction solution is poured into 50ml deionized water, then ethyl acetate extraction uses EA layers of saturated common salt water washing, then use nothing
Water magnesium sulfate dries, filters removing filter cake, and concentration filtrate obtains crude product.Column chromatography for separation obtains target product NO-6c-Ato.
M+1:926.3 1H-NMR (DMSO-d6,400MHz): δ 9.83 (s, 1H), 8.05 (d, 2H), 7.60 (d, 2H),
7.51 (d, 2H), 7.42 (d, 2H), 7.35 (d, 3H), 7.22-7.15 (m, 6H), 7.10-7.06 (m, 4H), 7.01-6.96 (m,
2H), 5.21 (s, 2H), 4.84 (d, 1H), 4.66 (d, 1H), 3.92 (m, 2H), 3.76 (m, 1H), 3.53 (br, 1H), 3.21
(m, 1H), 2.50 (m, 1H), 2.35 (m, 1H), 1.62 (m, 1H), 1.54 (m, 1H), 1.43 (s, 9H), 1.37 (m, 1H), 1.36
(d, 6H), 1.30 (m, 1H)
Embodiment 10:(3R, 5S) -7- [2- cyclopropyl -4- (4- fluorophenyl) quinoline -3-] -3,5- dihydroxy -6 (E)-heptan
Olefin(e) acid-{ 4- { N '-[(tertbutyloxycarbonyl) oxygroup]-N- phenyl formamidine base } carbamoyl } benzyl ester, that is, compound N O-6c-Pita
0.4g 6c and 0.8g Pitavastatin Calcium are dissolved in 10ml DMF, KI 0.8g is added, 48h is stirred at room temperature.It will be anti-
Liquid is answered to be poured into 50ml deionized water, then ethyl acetate extraction uses EA layers of saturated common salt water washing, then dry with anhydrous magnesium sulfate
It is dry, it is filtered to remove filter cake, concentration filtrate obtains crude product.Column chromatography for separation obtains target product NO-6c-Pita.
M+1:789.4,1H-NMR (DMSO-d6,400MHz): δ 8.02 (d, 2H), 7.85 (d, 1H), 7.64 (d, 1H),
7.60 (d, 2H), 7.43 (d, 2H), 7.37-7.23 (m, 8H), 6.51 (d, 1H), 5.60 (dd, 1H), 5.22 (s, 2H), 4.88
(d, 1H), 4.82 (d, 1H), 4.13 (m, 1H), 3.81 (m, 1H), 2.47 (dd, 1H), 2.36 (dd, 1H), 1.56-1.48 (m,
2H), 1.43 (s, 9H), 1.23 (m, 2H), 1.16 (m, 1H), 1.02 (m, 2H)
Embodiment 11:(3R, 5S) [6- isopropyl -2- (N- methyl-N-methyl sulfonic acid amido) -4- (4- chlorphenyl) is phonetic by -7-
Pyridine -5-] -3,5- dihydroxy -6 (E)-heptenoic acid-{ 4- { N '-[(tertbutyloxycarbonyl) oxygroup]-N- phenyl formamidine base } carbamyl
Base } benzyl ester, that is, compound N O-6c-Rosu
0.4g 6c and 0.8g rosuvastain calcium are dissolved in 10ml DMF, KI 0.8g is added, 48h is stirred at room temperature.It will
Reaction solution is poured into 50ml deionized water, then ethyl acetate extraction uses EA layers of saturated common salt water washing, then use anhydrous magnesium sulfate
Removing filter cake is dried, filtered, concentration filtrate obtains crude product.Column chromatography for separation obtains target product NO-6c-Rosu.
M+1:849.3,1H-NMR (DMSO-d6,400MHz): δ 8.03 (d, 2H), 7.70 (m, 2H), 7.59 (d, 2H),
7.44 (m, 2H), 7.36 (d, 2H), 7.25 (t, 3H), 6.52 (d, 1H), 5.51 (dd, 1H) 5.21 (s, 2H), 4.95 (d, 1H),
4.83 (d, 1H), 4.20 (m, 1H), 3.90 (m, 1H), 3.54 (s, 3H), 3.44 (s, 3H), 2.54 (q, 1H), 2.39 (q, 1H),
1.55 (m, 2H), 1.43 (s, 9H), 1.33 (m, 1H), 1.19 (d, 6H)
Embodiment 12:(3R, 5R) -7- [(1S, 2S, 6R, 8S, 8aR) -2,6- dimethyl -8- (2,2- dimethyl butyrate acyl-oxygens
Base) -1,2,6,7,8,8a- hexahydro -1- naphthalenes] -3,5- dihydroxy enanthic acid -- { 4- { N '-[(tertbutyloxycarbonyl) oxygroup]-N- benzene
Base carbonamidine base } carbamoyl } benzyl ester, that is, compound N O-6c-Sim
0.4g 6c and 0.8g Simvastatin sodium are dissolved in 10ml DMF, KI 0.8g is added, 48h is stirred at room temperature.It will be anti-
Liquid is answered to be poured into 50ml deionized water, then ethyl acetate extraction uses EA layers of saturated common salt water washing, then dry with anhydrous magnesium sulfate
It is dry, it is filtered to remove filter cake, concentration filtrate obtains crude product.Column chromatography for separation obtains target product NO-6c-Sim.
M+1:804.5,1H-NMR (DMSO-d6,400MHz): 8.05 (d, 2H), 7.61 (d, 2H), 7.43 (q, 2H),
7.36-7.34 (m, 3H), 5.94 (d, 1H), 5.75 (dd, 1H), 5.48 (brs, 1H), 5.21 (s, 2H), 5.15 (br, 1H),
4.82 (d, 1H), 4.49 (d, 1H), 4.02 (m, 1H), 3.45 (br, 1H), 2.54 (dd, 1H), 2.38 (m, 2H), 2.29 (m,
1H), 2.26 (m, 1H), 1.97-1.91 (m, 2H), 1.84-1.81 (m, 1H), 1.55-1.47 (m, 4H), 1.43 (s, 9H),
1.39-1.34 (m, 2H), 1.23 (brs, 5), 1.03 (s, 3H), 1.02 (s, 3H), 0.78 (d, 3H), 0.74 (t, 3H)
Experimental example 1: the NO extracorporeal releasing test of compound TM
Laboratory apparatus: UV-2450 ultraviolet-uisible spectrophotometer (Shimadzu Corporation)；AE163 electronic analytical balance (Switzerland
MITTLER)
Experiment reagent: sulfanilamide (SN) (AR Sinopharm Chemical Reagent Co., Ltd.)；Sodium nitrite (the Chengdu AR section dragon chemical industry examination
Agent factory)；Horseradish peroxidase (AR)；Hydrogen peroxide (30% Chengdu Ke Long chemical reagent factory)；N-1- naphthyl ethylenediamine salt
Hydrochlorate (AR Sinopharm Chemical Reagent Co., Ltd.)；Disodium hydrogen phosphate (Chengdu AR Ke Long chemical reagent factory)；Trifluoroacetic acid
(Chengdu AR Ke Long chemical reagent factory)；Methylene chloride (Chengdu AR Ke Long chemical reagent factory).Griess test solution (takes sulfanilamide (SN)
4.0g, N-1- naphthyl ethylenediamine hydrochloride 0.125g, 85% phosphoric acid 6.25ml are codissolved in 250ml deionized water, shake up i.e.
)；80 μ g/ml horseradish peroxidase solution are (by 20mg horseradish peroxidase, the H of 0.15ml 30%2O2And 0.0931g
Disodium ethylene diamine tetraacetate (EDTA) be codissolved in 250ml deionized water to get)
Experimental drug: the target product TM prepared according to embodiment 1-12 method
Experimental method:
Precision weighs the dry sodium nitrite of 0.069g, is dissolved in 1L deionized water, forms the sodium nitrite solution of 1mM.
Precision measures the 2.00ml solution, and 0.50ml Griess test solution is added, and is diluted to 25ml, and shaking is uniform.The solution is taken respectively
4.00ml, 3.00ml, 2.50ml, 2.00ml, 1.50ml, 1.00ml in 25.0ml volumetric flask, constant volume to 25.0ml to get
0.32×10-5mol/L-1.28×10-5The sodium nitrite series standard solution of mol/L.Each concentration is measured under 548nm wavelength
The absorbance of solution, and standard curve is drawn according to the data obtained, with absorbance A to the concentration C of sodium nitrite standard solution into
Row, which returns, to be calculated.
Precision weighs 12 each 5.0mg of target compound respectively, uses 5ml dmso solution respectively, is separately added into
50%TFA-DCM solution each 5.00ml stirs 1h at 25 DEG C, and concentration removes DCM, uses the Na of 1.0mol/L respectively2HPO4It neutralizes
pH 7.4.It is then respectively adding each 5.00ml of horseradish peroxidase solution, is incubated at room temperature 30min, then be separately added into Griess
Test solution 5.00ml is uniformly mixed, is finally diluted to 100.0ml respectively.Respective dilution is taken to measure absorbance at 548nm, it will
Absorbance value substitutes into the concentration that regression equation calculation goes out NO in solution.And the release percentage of TM is calculated by formula I.TM's releases
It puts percentage and represents the NO release in vitro activity of the donor medicine.
Wherein, W represents NO release percentage
C represents the NO concentration of release
V represents the volume (i.e. 100.0ml, 0.1000L) after dilution
M represents the molecular weight of NO compound donator TM
The taken compound donator quality of m representative (i.e. 5.0mg, 5.0 × 10-3g)
Experimental result:
According to experimental method, the standard solution absorbance of various concentration is as shown in Table I:
The standard solution absorbance of the various concentration of Table I
Recurrence calculating is carried out with concentration C of the absorbance A to sodium nitrite standard solution, draws standard curve, as a result such as Fig. 1
It is shown.
According to experimental method, the NO extracorporeal releasing quantity for measuring 12 target compounds is as shown in Table II.
Table II target compound release in vitro NO correlation absorbance
The absorbance value of each object TM is substituted into regression equation, the concentration of NO release in vitro can be obtained, as shown in Table III.
Table III target compound release in vitro NO concentration
The numerical value of Table III is substituted into formula I, the NO release percentage of each compound donator TM can be obtained, as shown in table IV.
The NO of Table IV target compound discharges percentage
Data can be seen that compound N O-6b-Ato under these experimental conditions and compound N O-6b- from table IV
The NO release in vitro ability of Pita is most strong, followed by compound N O-6b-Sim, compound N O-6a-Ato, NO-6a-Pita, NO-
The NO release in vitro ability of 6a-Rosu, NO-6b-Rosu, NO-6c-Sim are general, NO-6c-Ato, NO-6c-Pita, NO-6c-
The NO release in vitro ability of Rosu, NO-6a-Sim are worst.Result is believed that compound N O-6b-Ato, NO-6b- accordingly
Pita, NO-6b-Sim have preferable NO release activity, may there is preferable application prospect.
Conclusion:
Under this experiment condition, it is found that all target compound TM have NO release activity, wherein the NO of 3 compounds
Release activity is stronger, there is preferable application prospect.
Claims (8)
1. the compound that one kind has structural formula shown in general formula (I):
Wherein, R3Represent H orX represents F, Cl, Br, H, CH3、OCH3、N3Or carbon atom number is less than 3 alcoxyls
Base；R1For statin residue and for such as one of flowering structure:
,
R2For
2. compound according to claim 1, which is characterized in that R2For
3. compound according to claim 1 or 2, which is characterized in that R3For
4. compound according to claim 3, which is characterized in that the compound is such as one of flowering structure:
5. any one of Claims 1 to 4 compound acceptable salt in pharmacy or physiologic meaning.
6. compound according to claim 1, which is characterized in that X F, Cl or H.
7. the preparation method of compound as described in claim 1, which is characterized in that R2ForR3ForThe method includes the steps:
(1) arylamine, ammonium thiocyanate and chlorobenzoyl chloride react in organic solvent obtains intermediate 2；
(2) 2 alkaline condition of intermediate hydrolyzes to obtain intermediate 3；
(3) intermediate 3 and CH3I reacts in organic solvent obtains intermediate 4；
(4) intermediate 4 and NH2OHHCl reacts in alkaline solution obtains NO compound donator 1；
(5)Boc2O protects compound 1, obtains intermediate 5；
(6) intermediate 5 reacts to obtain intermediate 6 with 4- chloromethyl benzoic acid chlorides under triethylamine catalysis；
(7) intermediate 6 reacts to obtain object I with the salt of statin in organic solvent under KI catalysis；
8. any one of claim 1~6 compound has anti-inflammatory, antithrombus formation, anti-platelet activity, reduction in preparation
Cholesterol and triglyceride levels and/or the blood vessel for improving hdl level, treating periphery ischaemic, diabetes patient
Purposes in terms of the drug that at least one in complication or atherosclerosis acts on.
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| CN1794987A (en) * | 2003-05-27 | 2006-06-28 | 尼科克斯公司 | Nitrooxyderivatives of fluvastatin, pravastatin, cerivastatin, atorvastatin and rosuvastatin as cholesterol-reducing agents with improved anti-inflammatory, antithrombotic and antiplatelet activity |
| CN101580497A (en) * | 2009-06-26 | 2009-11-18 | 四川抗菌素工业研究所有限公司 | Statins antilipemic drugs furazan nitroxides derivates and preparation method thereof |
| CN101613284A (en) * | 2009-06-26 | 2009-12-30 | 四川抗菌素工业研究所有限公司 | NItroxyderivatives of lovastatin, Simvastatin and simvastatin-6-oxide and preparation method thereof |
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| CN1794987A (en) * | 2003-05-27 | 2006-06-28 | 尼科克斯公司 | Nitrooxyderivatives of fluvastatin, pravastatin, cerivastatin, atorvastatin and rosuvastatin as cholesterol-reducing agents with improved anti-inflammatory, antithrombotic and antiplatelet activity |
| CN101580497A (en) * | 2009-06-26 | 2009-11-18 | 四川抗菌素工业研究所有限公司 | Statins antilipemic drugs furazan nitroxides derivates and preparation method thereof |
| CN101613284A (en) * | 2009-06-26 | 2009-12-30 | 四川抗菌素工业研究所有限公司 | NItroxyderivatives of lovastatin, Simvastatin and simvastatin-6-oxide and preparation method thereof |
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