CN108299405A - 3- is to N, N diethylaminos phenylimino class compound and its application in hyperlipidemia - Google Patents
3- is to N, N diethylaminos phenylimino class compound and its application in hyperlipidemia Download PDFInfo
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- CN108299405A CN108299405A CN201810144999.5A CN201810144999A CN108299405A CN 108299405 A CN108299405 A CN 108299405A CN 201810144999 A CN201810144999 A CN 201810144999A CN 108299405 A CN108299405 A CN 108299405A
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- C07—ORGANIC CHEMISTRY
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention discloses one kind 3 couples of N, N diethylamino phenylimino class compound, structural formula is：
Description
Technical field
The invention belongs to research field before pharmaceutical synthesis and clinical drug, it is related to a kind of 3- to N, N diethylamino phenyl
Imido base class compound and its application in hyperlipidemia.
Technical background
Hyperlipidemia（hyperlipidemia）It refer to the total cholesterol in blood plasma（Total Cholesterol, TC）With
（Or）Triglycerides（Triglyceride, TG）Level increases.Hyperlipidemia is to endanger the elderly's body and mind in aging society to be good for
The serious systemic metabolic disorder disease of health, it is the heart and brain blood such as cerebral apoplexy, coronary heart disease, myocardial infarction and atherosclerosis
Pipe disease（Cardiovascular disease, CVD）One of Major Risk Factors.The report of the World Health Organization also refers to
Go out, the raising of cholesterol levels is one of big main cause of death in the whole world five, and hyperlipidemia has become a getting worse at present
Social public health problem.With the development of the social economy, continuous improvement and the behavior and life style of living standards of the people
Variation, Chinese population average serum total cholesterol level are being stepped up.Therefore, novel blood lipid-lowering medicine is found to control to improve
Level is treated for improving the elderly's quality of life, improving disease present situation has great realistic meaning.
3- hydroxyl 3- methyl glutaryl coenzyme A reductases（HMG-CoA reductase）It is Biosynthesis of cholesterol initial stage
Rate-limiting enzyme, HMG-CoA reductase inhibitor can inhibit the biosynthesis of cholesterol, can also stimulate LDL receptor
Synthesis, increase intake to low-density lipoprotein particle, finally make total cholesterol in blood plasma, low-density lipoprotein and carry fat egg
The horizontal of nB reduces, and raises simultaneously High-density Lipoprotein-cholesterol and moderate reduction serum triglyceride level.In addition,
Statins further include other pleiotropic effects to the treatment of the angiocardiopathy based on atherosclerosis, such as improve blood
Endothelial tube function inhibits vascular smooth muscle cell curing and migration, the stability for maintaining focal plaque, inhibits the shape of foam cells
At etc..There is also some adverse reactions such as myalgia, hepatic injuries for statins（Blood cretinephosphokinase is set to increase, striated muscle is molten
Solution）, currently, the research of HMG-CoA reductase inhibitor is more deepened, seek completely new active more preferable, the lower structure of toxicity
Or optimization is transformed to existing structure, to obtain a kind of new structural HMG-CoA reductase inhibitor for controlling
Treat hyperlipidemia.
Invention content
One of the objects of the present invention is to provide a kind of 3- to N, N diethylamino phenylimino class compounds, knot
Structure formula is as follows：
。
It is pre- in disease as HMG-CoA reductase inhibitor that another object of the present invention is to provide a kind of compounds
Application in anti-and/or treatment.
Another object of the present invention is to provide the compounds in preparing prevention and/or treatment hyperlipidemia
Application.
Further, the compound reduces total cholesterol, triglycerides and improves high-density lipoprotein and contains in preparation
Measure the application in drug.
Another object of the present invention is to provide a kind of synthetic method of the compound, synthetic route is：
。
Further, synthesis step is：
1) aminating reaction of carbonyl alpha-position occurs in organic solvent for compound 1 and compound 2, generates compound 3；
2) in the presence of acid binding agent, the amino in compound 3 occurs acylation reaction and generates compound 4；
3) under compound 4 and 6- (tertiary butyl) -2- (3- phenylpropionyls amido) benzo [b] thiophene -3- carboxylic acid, ethyl ester heating conditions
Cyclization occurs and generates compound 5；
4) hydrolysis generation compound 6 occurs for compound 5；
5) for the carbonyl of compound 6 again with to N, N diethylamino aniline reactions generate final (E) -6- (tertiary butyl) -2- (1-
(3- is to N, N diethylaminos phenylimino) butyl) -2,5- diisopropyl -4- phenyl -1H- pyrroles -3- formamido groups) benzene
And [b] thiophene -3- carboxylic acid, ethyl esters (compound 7).
Further, organic solvent can be dichloromethane in step 1)（It is preferred that 1,2- dichloroethanes）, acetonitrile, N, N- bis-
Methylformamide (DMF), ethyl acetate, toluene, one or several kinds of mixing in dimethylbenzene, preferably acetonitrile.
Further, the acid binding agent in step 2) can be the organic bases, preferably triethylamine such as triethylamine, pyridine.
Further, heating condition is 40 DEG C-reflux in step 3), is preferably flowed back.
Obviously, the above according to the present invention is not departing from this hair according to the ordinary technical knowledge and means of this field
Under the premise of bright above-mentioned basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.
Specific implementation mode
Embodiment 1：(2- (penta ring -2- bases of 2- methyl-1,3-dioxies) ethyl) valinate（Structural formula is as follows）Conjunction
At：
At room temperature, first by 2- (2- methyl-1s, 3- dioxolanes -2- bases) second -1- amine (compound 2) (28.86g, 220mmol)
It is dissolved in acetonitrile, above-mentioned solution is then added to the bromo- 4- ethyoxyls -2- methyl -4- oxos butyl- 1- bases of 3- under stiring
In acetonitrile (350mL) solution of (compound 1) (41.61g, 200mmol) and triethylamine (42mL, 302mmol).By the mixed of gained
It closes object to be stirred at room temperature overnight, pour into 500mL ether.Gained suspension 300mL water is extracted, then with 300mL concentration
It is extracted twice for the hydrochloric acid of 2mol/L.25% sodium hydrate aqueous solution of mass fraction, which is added, makes combined extract alkalize, and uses
The ethyl acetate of 500mL × 2 is extracted twice.Extract is merged, water and saturated common salt water washing is used successively, uses anhydrous magnesium sulfate
It is dry.After being filtered to remove drier, solvent volatilization crystallization obtains (2- (2- methyl-1s, the 3- dioxolanes -2- of 45.54g yellow
Base) ethyl) valinate (compound 3), yield 87.8%.1H-NMR (400 MHz, CDCl3) δ:0.95(s, 3H),
0.97(s, 3H), 1.21(t, 3H), 1.27(s, 3H), 1.76(t, 2H), 2.23(s, 1H), 2.39(m, 1H),
2.57(t, 2H), 2.83(d, 1H), 3.75-3.96(m, 4H), 4.11(q, 2H). 13C-NMR (125 MHz,
CDCl3) δ: 14.68, 19.04, 24.25, 29.10, 41.17, 44.55, 61.74, 64.62, 65.78,
110.10,172.92.LC-MS(ESI, pos, ion) m/z: 260[M+1].
Embodiment 2：N- isobutyryls-N- (2- (penta ring -2- bases of 2- methyl-1,3-dioxies) ethyl) valine（Structural formula is as follows）
Synthesis：
The compound 3 (25.94g, 100mmol) synthesized in embodiment 1 is dissolved in dichloromethane (200mL) and triethylamine
In the solution of (28.6mL, 205mmol), obtained mixture is then cooled to 0 DEG C under dry nitrogen atmosphere.Under stirring
Dichloromethane (50mL) solution of isobutyryl chloride (11mL, 106mmol) is slowly added dropwise.After being added dropwise to complete, mixture is continued to stir
It mixes 80 minutes, is subsequently poured into the ether of 100mL.Obtained ethereal solution is used into water, the hydrochloric acid of 2mol/L, unsaturated carbonate hydrogen successively
Sodium water solution and saturated common salt water washing, then dried with anhydrous magnesium sulfate.25g crude product N- isobutyryls-are obtained after evaporation solvent
N- (2- (penta ring -2- bases of 2- methyl-1,3-dioxies) ethyl) valine (compound 4).By crude Compound 4 (25g,
82.95mmol) be added to sodium hydroxide (12g, 300mmol) methanol aqueous solution (480mL, 5:1) it is heated to reflux in 3 hours.
Obtained solution is cooled to room temperature, after methanol is concentrated, the water for adding 500mL is diluted.Then the solution that will be obtained
It is extracted with ether, with the hydrochloric acid Acidified aqueous layer of 0 DEG C of 6mol/L, is extracted twice with the ethyl acetate of 300mL × 2.It will close
And extract saturated common salt water washing, anhydrous magnesium sulfate be dried and evaporated obtain after solvent 20g it is refined after N- isobutyryls
Base-N- (2- (2- methyl-1s, 3- dioxolanes -2- bases) ethyl) valine (compound 4), yield 66.4%.1H-NMR (400
MHz, CDCl3) δ:0.95(s, 3H), 0.97(s, 3H), 1.08(s, 3H), 1.11(s, 3H),1.26(s, 3H),
1.88(t, 2H), 2.60-2.81(m, 2H), 3.33-3.43(m, 2H), 3.74-3.95(m, 4H), 4.90(d,
1H). 13C-NMR (125 MHz, CDCl3) δ: 19.18, 19.33, 24.25, 30.05, 32.74, 42.37,
43.16, 61.21, 64.62, 109.38, 173.70,177.47.LC-MS(ESI, pos, ion) m/z: 302[M+
1].
Embodiment 3：6- (tertiary butyl) -2- (2,5- diisopropyls -1- (2- (penta ring -2- bases of 2- methyl-1,3-dioxies) ethyl) -
- 3 formamido of 4- phenyl -1H- pyrroles) benzo [b] thiophene -3- carboxylic acid, ethyl esters（Structural formula is as follows）Synthesis：
Embodiment 2 is synthesized into obtained compound 4 (20g, 66.36mmol) and 6- (tertiary butyl) -2- (3- phenylpropionyls amido)
The mixture of benzo [b] thiophene -3- carboxylic acid, ethyl esters (38g, 93.71mmol) is heated at 90 DEG C and is stirred 2 hours.Then it will mix
It closes object to be cooled to room temperature, by silica gel chromatograph, (eluant, eluent is hexane：Ethyl acetate=4:1) it purifies twice, you can divide from raw material
From obtaining 6- (tertiary butyl) -2- (2,5- diisopropyls -1- (2- (penta ring -2- bases of 2- methyl-1,3-dioxies) ethyl) -4- phenyl -
- 3 formamido of 1H- pyrroles) benzo [b] thiophene -3- carboxylic acid, ethyl esters (compound 5), then with isopropyl ether recrystallize again
To the compound 5 of 18.40g white crystallines, yield 43%.1H-NMR (400 MHz, CDCl3) δ:1.27(s, 3H),
1.29-1.31(m, 15H), 1.32(s, 9H), 2.15(t, 2H), 3.44(m, 4H), 3.76-3.95(m, 4H),
4.03(q, 2H), 4.16(t, 2H),7.39-7.53(m, 6H), 7.69(d, 1H),8.01(s, 1H). 13C-NMR
(125 MHz, CDCl3) δ: 14.68, 21.52, 24.25, 25.31, 25.40, 31.36, 35.35, 42.06,
47.56, 61.45, 64.62, 109.38, 110.29, 120.28, 123.44, 124.00, 124.86, 125.07,
126.28, 127.20, 128.18, 129.27, 131.23, 136.27, 137.60, 146.98, 152.06,
153.26, 160.84,166.73.LC-MS(ESI, pos, ion) m/z: 645[M+1].
Embodiment 4：(tertiary butyl) -2- (2,5- diisopropyls -1- (3- oxos butyl) -4- phenyl -1H- pyrroles's -3- formyl ammonia
Base) benzo [b] thiophene -3- Ethyl formates（Structural formula is as follows）Synthesis：
Embodiment 3 is synthesized to the absolute ethyl alcohol of obtained compound 5 (18.40g, 28.53mmol) and concentrated hydrochloric acid (0.4mL)
(120mL) solution is heated to reflux 20 hours.Reaction mixture is cooled to room temperature, after concentration, then obtained mixture is dissolved in
Acetone：Water=3:In the solution of 1 (120mL), the PTSA of 5g is added（Para toluene sulfonamide）.Solution is heated to reflux and is stirred
Two days, solution is cooled to room temperature after the completion of reaction, adds 500mL ether and 200mL saturated salt solutions, it is organic after liquid separation
Layer uses saturated sodium bicarbonate aqueous solution and saturated common salt water washing, anhydrous magnesium sulfate drying concentration successively.The grease that will be obtained
It is dissolved in the isopropyl ether of heat of minimum, after cooling, filtering obtains 11.91g off-white colors (tertiary butyl) -2- (2,5- diisopropyls
Base -1- (3- oxos butyl) -4- phenyl -1H- pyrroles -3- formamido groups) benzo [b] thiophene -3- Ethyl formates (compound 6),
Yield 69.5%.1H-NMR (400 MHz, CDCl3) δ:1.28-1.31(m, 15H), 1.32(s, 9H), 2.10(s,
3H), 2.93(t, 2H),3.44(m, 2H), 4.03(q, 2H), 4.29(t, 1H),4.63(t, 1H),7.39-7.53
(m, 6H), 7.69(d, 1H),8.03(s, 1H). 13C-NMR (125 MHz, CDCl3) δ: 14.68, 21.52,
25.31, 25.40, 28.59, 31.36, 35.35, 43.46, 49.38, 61.45, 110.29, 120.28,
123.44, 124.00, 124.86, 125.07, 126.28, 127.20, 128.18, 129.27, 131.23,
136.27, 137.60, 146.98, 152.06, 153.26, 160.84, 166.73,209.08.LC-MS(ESI, pos,
ion) m/z: 601[M+1].
Embodiment 5：(E) -6- (tertiary butyl) -2- (1- (3- is to N, N diethylaminos phenylimino) butyl) -2,5- diisopropyls
Base -4- phenyl -1H- pyrroles -3- formamido groups) benzo [b] thiophene -3- carboxylic acid, ethyl esters（Structural formula is as follows）Synthesis：
Stirring rod will be housed, the 250mL round-bottomed flasks of Dean-Stark water knockout drums and reflux condenser take out from baking oven, true
The lower cooling of sky, is used in combination argon gas to backfill.Under argon gas stream, by toluene (100mL), embodiment 4 synthesizes obtained compound 6
(11.91g, 19.82mmol), to N, N diethylaminos aniline (3.26g, 19.82mmol) and p-methyl benzenesulfonic acid monohydrate
(1-2mol%) is introduced into reaction flask.Then it flows back under stiring, until being collected into Dean-Stark pipeline bottoms
The water of a certain amount of (about 0.36g).Then reaction mixture is filtered by diatomite, and evaporated volatile organic
Then object obtains 11.55g products (E) -6- (tertiary butyl)-by Kugelrohr distillations (boiling point is 105 DEG C of about 1 millitorrs of pressure)
2- (1- (3- is to N, N diethylaminos phenylimino) butyl) -2,5- diisopropyl -4- phenyl -1H- pyrroles's -3- formyl ammonia
Base) benzo [b] thiophene -3- carboxylic acid, ethyl esters (compound 7) are yellow crystals, yield 78%.1H-NMR (400 MHz, CDCl3)
δ:1.12(t, 6H), 1.21(t, 3H), 1.32(m, 21H), 2.17(s, 3H), 2.99(t, 2H), 3.23(m,
4H), 3.48(m, 1H), 3.78(m, 1H), 4.14-4.18(m, 4H), 6.74(m, 2H), 7.06(m, 2H),
7.28-7.40(m, 6H), 7.76(d, 1H), 7.81(d, 1H).13C-NMR (125 MHz, CDCl3) δ:12.99,
14.68, 18.95, 21.52, 25.31, 25.4, 31.36, 35.35, 37.11, 46.42, 50.24, 61.45,
110.29, 112.43, 120.28, 123.44, 124, 124.86, 125.07, 125.54, 126.28, 127.2,
128.18, 129.27, 131.23, 136.27, 137.6, 144.22, 146.86, 146.98, 152.06,
153.26, 160.84, 166.73, 178.5.LC-MS(ESI, pos, ion) m/z: 747.4[M+1].
Test example：To the inhibiting effect of the HMG-CoA reductase of hyperlipemia in mice
One, the preparation of fat emulsion
Take 2g propylthiouracil (PTU)s finely ground in mortar, it is spare.It takes 25g lards to melt in 40 DEG C of heating water baths, sets in mortar, be added
15g cholesterol, 2g propylthiouracil (PTU)s, 1g sugar, are sufficiently stirred, dissolve.A concentration of 10% cholic acid sodium water solution is added slowly again
20ml, and be stirred continuously, Tween 80 10ml, propylene glycol 30ml is then added, grinding emulsification is uniform, finally adds distilled water extremely
100ml.Be fitted into closed container, refrigerate, when use prior to 37 DEG C water-baths melt.
Two, hyperlipemia in mice modeling and grouping
Male ICR mouse, 18~22g of weight are randomly divided into several groups according to weight, randomly select 1 group and are set as Normal group, just
It often feeds, every morning distilled water（10mL·kg-1）Gavage；Remaining animal is used to modeling, gavage fat emulsion（10mL·
kg-1）, continuous five weeks, freely absorb conventional feed during gavage, fasting 12h after last gavage（It can't help water）, mouse orbit is quiet
Arteries and veins takes blood, detaches serum, modeling animal equilibrium is divided into 15 groups by serum triglyceride level using randomized blocks, respectively
For：Model group, positive controls（Simvastatin group）, test group（The corresponding compound of the embodiment of the present invention）.
Three, the administration of different grouping
Each group continues in every morning distilled water（Normal group）Or fat emulsion（Model group, positive controls and test group）
Gavage, dosage 10mLkg-1；Afternoon, each group gave agents, successive administration 3 weeks respectively.
Normal group：10mL·kg-1Distilled water；
Model group：10mL·kg-1Distilled water；
Positive controls：Simvastatin group 1mgkg-1；
Test group：The corresponding compound 1mgkg of the embodiment of the present invention-1。
Four, blood and Indexs measure are taken
Fasting 12h after the last administration（It can't help water）, mouse orbit venous blood sampling, 20~30min of standing, centrifugation 20 minutes or so
（2000~3000 revs/min）, serum is taken, HMG-CoA reductase activity is measured according to corresponding reagent box specification, according to mutually taking an entrance examination
Agent box specification measures total cholesterol（TC）, triglycerides（TG）And high-density lipoprotein（HDL-C）.
Measurement result see the table below：
Note：Compared with positive controls, * P<0.05
The above results show the compounds of this invention test group HMG-CoA reductase activity, total cholesterol compared with model group（TC）、
Triglycerides（TG）And high-density lipoprotein（HDL-C）The significant difference of content（P<0.05）, the compounds of this invention with sun
Property control group test group compare HMG-CoA reductase activity, total cholesterol（TC）And triglycerides（TG）Significant difference
（P<0.05）, illustrate that the compounds of this invention can reduce HMG-CoA reductase activity, reduce TC, TG level, increase HDL-C water
Flat, the pharmacological activity with reducing blood lipid can be used as HMG-CoA reductase inhibitor class drug, be carried out in hyperlipidemia field
More deep exploration, exploitation.
The above is only a preferred embodiment of the present invention, it is noted that come for those of ordinary skill in the art
It says, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications also should be regarded as
The content that the present invention is covered.
Claims (4)
1. a kind of 3- is to N, N diethylamino phenylimino class compounds, which is characterized in that its structural formula is as follows：
。
2. compound as described in claim 1 answering in disease prevention and/or treatment as HMG-CoA reductase inhibitor
With.
3. compound as described in claim 1 is preparing the application in preventing and/or treating hyperlipidemia.
Contain 4. compound as described in claim 1 reduces total cholesterol, triglycerides and improve high-density lipoprotein in preparation
Measure the application in drug.
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Application publication date: 20180720 |