CN104974116B - Vibralactone amide derivatives and preparation method and application - Google Patents
Vibralactone amide derivatives and preparation method and application Download PDFInfo
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- SLYAZNPNEYAOHC-FSPLSTOPSA-N C[C@H]([C@H](C1)OC)C=C1C(O)=O Chemical compound C[C@H]([C@H](C1)OC)C=C1C(O)=O SLYAZNPNEYAOHC-FSPLSTOPSA-N 0.000 description 1
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Abstract
The invention belongs to technical field of pharmaceuticals, and in particular to（Formulas I）Shown vibralactone（Vibralactone）Amide derivatives, using the formula I compounds represented or its pharmaceutically acceptable salt as the pharmaceutical composition of active component, their preparation method, and their applications in the medicine for preventing and treating fat and other metabolic diseases such as diabetes is prepared.
Description
Technical field
The invention belongs to drug field, and in particular to vibralactone amide derivatives are as a kind of potent pancreatic lipase
Inhibitor, by being combined the activity and inhibitory enzyme with pancreatic lipase, prevention triglyceride hydrolysis is absorbable free fatty
And monoacylglycerol, it is not absorbed, so as to reduce energy intake, control body weight.
Background technology
Obesity is a kind of disease as caused by appetite, caloric intake, Metabolism regulation disorder, with diabetes, angiocardiopathy,
Fatty liver, some tumours have obvious correlation, it has also become endanger one of primary killers of human health.Therefore how effectively
Reducing obesity becomes the important subject that many countries face.Fat regimen in diet is the main reason for causing obesity
One of, the major lipids composition in food is triglycerides, before this kind of fat is absorbed, is first hydrolyzed into corresponding monoglyceride
And aliphatic acid.And in this process, the 50%-70% of pancreatic lipase hydrolyzable amount of total fat (Drug Discov Today, 2007,
12,879).Monoglyceride caused by hydrolysis and aliphatic acid can form micella with cholate, cholesterol and lysophosphatidic acid, so as to
Absorbed by intestinal epithelial cell, part oxidation generation carbon dioxide and water, and release energy, a part is closed again in cell
Into triglycerides, and then chylomicron is formed, into blood.Therefore, suppressing the vigor of pancreatic lipase effectively can suppress in meals
Fat absorption, so as to reach the fat purpose (Drugs, 2006,66,1625) for the treatment of.
Weibel in 1987 etc. (The Journal of Antibiotics, 1987,40,1081) is in Streptomyces
Separation is found that pancreatic lipase inhibitor lipstatin in toxytricini（1）, compound 1 is one cis with two
The β lactone compounds of double bond.Weibel etc. also reported the derivative of some compounds 1 simultaneously, including lipstatin's
Saturated derivatives tetrahydrolipstatin（2）, and it is suppression to study the β lactones found in lipstatin class compound structures
The activity institute of lipase processed is necessary.Due to lipstatin structural instability, final Switzerland Hoffmann-La Roche companies
Compound 2 is developed as a kind of non-systemic slimming medicine listing, also known as trade name Xenical, orlistat
（Orlistat）, entitled (3S, 4S) -3- hexyls -4- [(2S) -2- hydroxy tridecyls base] -2- oxetanone-N- formyls of chemistry
Base-L-Leu ester.Orlistat is the slimming drugs that FDA ratifies as a kind of potent gastrointestinal lipases inhibitor.It is made
It is by forming covalent bond with the active ser position of pancreatic lipase, causing enzyme to inactivate, so as to block human body pair with mechanism
Fatty absorption in food.But orlistat has certain side effect, predominantly gastrointestinal discomfort, including abdominal distension is vented, had to go to the toilet, fat
Fat rushes down etc. (Drugs, 1998,56,241).In addition, orlistat（Orlistat）Except leucyl- carries a chirality in structure
Outside center, its Ester groups also has 3 chiral centres to need to build in building-up process, and the difficulty of asymmetric syntheses is larger, existing
The orlistat clinically used at present（Orlistat）Most of bulk drug was still also prepared originally by natural lipstatin,
Cost is still very high (Organic Letters, 2008,10,1401).
Therefore, finding safely and effectively lipase inhibitor turns into a focus of Bariatric.
The applicant is to the brown tough lead fungi of lid【The brown tough lead fungi of lid（Boreostereum vibrans）Belong to tough lead fungi section
（Stereaceae）, Stereum fungi】A structure novel compound is found that during the chemical constitution study of zymotic fluid
(Organic Letters, 2006,8,5749.) --- vibralactone（Vibralactone）, it has the characteristics that：Structure
Uniqueness, the β containing 4/5 ring fused system-lactone type structure, functional group's highly dense, except containing active function groups β-lactone,
The also hydroxyl of exocyclic double bond, cyclic olefinic bond and an allylic.Content is higher, is easier to accumulate.To the brown tough lead fungi of lid
（Boreostereum vibrans）Zymotic fluid carries out separation and Extraction, obtains vibralactone（Vibralactone）.
So far, vibralactone amide derivatives and its report of activity are had no in the prior art.
The content of the invention
The mesh of the present invention be to provide it is a kind of have good suppress lipase active effect and low new tough of toxic side effect
Lead fungi element amide derivatives, pharmaceutical composition and pancreatic lipase inhibitor using them as active component.There is provided them simultaneously
Preparation method, and they in the medicine of fat prevention and treatment and other metabolic diseases such as diabetes is prepared should
With.
In order to realize the above-mentioned purpose of the present invention, the invention provides following technical scheme：
Following structural formula（I）Shown vibralactone（Vibralactone）Amide derivatives,
Wherein：
R1And R2Represent straight chain（C3–C13）Alkyl, can be with identical or different.
The compounds of this invention shows good pancreatic lipase inhibitory activity and less by porcine pancreatic lipase experimental study
Toxicity, can further it develop to treat and prevent the medicine of fat and other metabolic disease such as diabetes.
Currently preferred compound is：
Compound of the invention preferred is：
Preferred compounds of the invention by porcine pancreatic lipase experimental study, have more obvious pancreatic lipase inhibitory activity and
Less toxicity.
Present invention also offers the method for preparing vibralactone amide derivatives, comprise the following steps：
Vibralactone is corresponding carboxylic acid by Jones reagent oxidations first, is then reacted with oxalyl chloride and generates acyl chlorides, then with
Amine reacts to obtain vibralactone amide derivatives,
Wherein R1And R2Represent straight chain（C3–C13）Alkyl, it is identical or different.
The embodiment of the present invention 1 teaches the preparation method of compound in detail.
Present invention also offers include at least one formula（I）Representative vibralactone amide derivatives are above-mentioned tough
Its pharmaceutically acceptable salt of lead fungi element amide derivatives individually or with reference to one or more pharmaceutically may be used as active component
The pharmaceutical composition of the carrier of receiving.
Described vibralactone amide derivatives are still further provides to prepare prevention and/or treating fat and other
Application in metabolic disease such as the medicine of diabetes.
And pharmaceutical composition is preparing prevention and/or is treating the medicine of fat and other metabolic disease such as diabetes
In application.
The pancreatic lipase inhibitor using described vibralactone amide derivatives as active component is provided simultaneously.
And the vibralactone amide derivatives described in are used as pancreatic lipase inhibitor.
The present invention, by the product and diamine reactant after oxidation reaction, obtains 13 derivatives using vibralactone as parent, from
Middle acquisition its pancreatic lipase inhibitory activity of one derivative and prototype compound（Vibralactone）Compare, improve three quantity
Level, its IC50Reach nanomole level（14nM）.The compound has similar drug effect with currently marketed OTC medicines Orlistat
Group and mechanism of action.
It when the compounds of this invention is used as on medicine, can directly use, or be used in the form of pharmaceutical composition.The medicine
Compositions contain 0.1~99%, and preferably 0.5~90% the compounds of this invention, remaining is pharmaceutically acceptable, to people
Nontoxic and inert with animal pharmaceutical acceptable carrier and/or excipient.
Described pharmaceutical carrier or excipient be it is one or more selected from solid, semisolid and liquid diluent, filler with
And pharmaceutical preparation assistant agent.Described pharmaceutical composition is used in the form of per weight dose.The medicine of the present invention can be through
Oral and injection（Intravenous, intramuscular injection）Two kinds of form administrations.
It orally can use its solid or liquid preparation, such as pulvis, tablet, sugar-coat agent, capsule, solution, syrup, pill.
Injection can use its solid or liquid preparation, such as powder-injection, solution type injection.
Embodiment
Further the substantive content of the present invention is illustrated with reference to embodiment, but present disclosure is not limited to
In this.
1H- and13C-NMR is determined by Bruker AVANCE III-600, DRX-500 or AM-400, is inside designated as TMS, its
In1H NMR are determined under 400MHz, 500MHz and 600MHz,13C NMR are determined under 100MHz, 125MHz and 150MHz；Matter
Spectrum HREI-MS and EI-MS is determined by Finnigan-MAT90 mass spectrographs；HRESI-MS and ESI-MS is by API QSTAR Pulsar
I mass spectrographs determine；Rotary Evaporators：Buchi R-200、R-201；DLSB5110 type low-temp reaction coolant recirculation pumps, IKA
RCTbasic (security control type) heats magnetic stirring apparatus.
Column chromatography material：Column chromatography silica gel (80-100 mesh and 200-300 mesh) and prefabricated GF254TLC plates are Qing Daohai
Foreignize plant produced；Sephadex LH-20 are Sweden's Amersham Biosciences Products；Chromatorex C-
18 (40-75 μm) be Japanese Fuji Silysia chemical companies product.HPLC：Agilent1100, Zorbax SB-
C18column, 5 μm, 4.6mm × 150mm；Prep-HPLC：Agilent1200, Zorbox SB-C18column, 5 μm,
9.4mm×150mm.Coloration method is wavelength 254 under fluorescent lamp, observes fluorescence, I at 365nm2Steam develops the color, 10% sulfuric acid vanilla
Colour developing is heated after aldehyde processing.
Other reagents come from Sigma Aldrich, J＆K lark prestige, or Beijing Yi Nuokai companies, are point of commercialization
Analyse pure or chemically pure reagent, anhydrous reagent (such as anhydrous THF, DCM, Toluene, DMF) used by this paper experimental section
Prepared by anhydrous solvent standard handler.
1st, vibralactone（Vibralactone）Prepare
The brown tough lead fungi (Boreosterum vibrans) of lid picks up from Kunming plant institute, and Saving specimen is in Kunming plant research
Institute.Turn the brown tough lead fungi of lid of method culture of triangular flask Liquid Culture using inclined-plane.Culture medium：Peeled potatoes 200g (to boil water), Portugal
Grape sugar 20g, MgSO41.5g, KH2PO43g, VB110mg, pork protein peptone 1.0g, deionized water 1000mL, pH is adjusted with citric acid
To 6.0~6.5；Condition of culture：24 DEG C, rotating speed 150r/min of temperature, camera bellows culture 25 days.Culture gained zymotic fluid acetic acid second
Ester is extracted three times, and medicinal extract, upper silica gel post separation, with petroleum ether-ethyl acetate system gradient elution are concentrated under reduced pressure to give after filtering
Vibralactone (vibralactone) can be obtained.
2nd, (1R, 5S) -3- (N- heptyl-N- octyl groups formamide) -1- (3- methyl-2-butene -1- bases) -6- oxabicyclos
[3.2.0] hept-2-ene" -7- ketone（Compound 1）Preparation：
Step A：The preparation of vibralactone acid
25mL round-bottomed flasks are taken, are sequentially added（208mg,1.0mmol）Vibralactone vibralactone, 5mL acetone,
It is added dropwise under frozen water cooling（0.8mL,2mmol,2.5M）Jones reagents, after reacting 10 minutes, add a small amount of water quenching and go out instead
Should, it is extracted with ethyl acetate 3 times (20mL × 3), after merging organic layer, is washed to saturated common salt colourless, then uses anhydrous Na2SO4
Dry, be evaporated under reduced pressure and remove solvent, with 3:1 petroleum ether and ethyl acetate eluent rapid column chromatography obtains colourless grease
199mg yields 90%.
HR-ESI-MS m/z222.0902[M]+(Calc.for C12H14O4,222.0892).1H-NMR(CDCl3,
400MHz)δ(ppm):6.72(1H,s),5.10(1H,t,J=7.5Hz),4.85(1H,d,J=5.2Hz),2.99(2H,m),
2.68(1H,dd,J1=7.4Hz,J2=15.0Hz),2.52(1H,dd,J1=7.4Hz,J2=15.0Hz),1.73(3H,s),1.64
(3H,s).13C-NMR(CDCl3,100MHz)δ(ppm):170.5,168.4,140.3,137.0,137.0,116.3,78.1,
76.5,36.4,27.3,25.8,18.0.
Step B：The preparation of compound 1
25mL round-bottomed flasks are taken, (111mg, 1mmol) acid (Tetrahedron2005,61,11132) are added, in anhydrous nothing
5mL anhydrous methylene chlorides are added under conditions of oxygen, 0 DEG C is cooled to, it is anhydrous that (0.17mL, 2mmol) oxalyl chloride, 7 μ L is added dropwise
DMF, be concentrated under reduced pressure reaction system after reaction half an hour, obtains sticky product, and it is standby to add the dissolving of 5mL anhydrous methylene chlorides.
It is another to take a 25mL round-bottomed flasks to add (340mg, 1.5mmol) amine, 5mL anhydrous methylene chlorides, under frozen water cooling, add
（0.29mL, 2mmol）The triethylamine steamed again, the anhydrous methylene chloride solution of freshly prepared acyl chlorides is added dropwise, room is risen to after adding
Temperature, reaction is overnight.Then add a small amount of water quenching to go out reaction, be extracted with ethyl acetate 3 times (20mL × 3), after merging organic layer,
1M HCl (1x10mL), H are used successively2O(1x10mL),1M NaHCO3, (2x10mL), saturated common salt water washing and then with nothing
Water Na2SO4Dry, be evaporated under reduced pressure and remove solvent, the grease 229mg yields 55% of brown are obtained through column chromatography for separation.
HR-ESI-MS m/z454.3289[M+Na]+(Calc.for C27H45NNaO3,454.3297).1H-NMR
(CDCl3,400MHz)δ(ppm):5.69(1H,br s),5.13(1H,t,J=7.4Hz),4.81(1H,d,J=5.6Hz),3.36
(2H,t),3.22(2H,m),3.13(1H,ddd),2.97(1H,dd),2.63(1H,dd),2.49(1H,dd),1.73(3H,
s),1.64(3H,s),1.27(22H,br s),0.88(6H,t,J=6.6Hz).13C-NMR(CDCl3,100MHz)δ(ppm):
171.8,166.7,140.3,136.5,126.5,116.9,76.2,48.6,44.9,39.5,31.7,29.7,29.2,29.0,
27.4,27.3,27.0,26.7,25.8,22.6,22.58,18.0,14.07,14.05.
Compound 2-13 synthesis step is the same as compound 1.Used different substrates（Diamines）Purchased from Sigma
Aldrich, J＆K lark prestige, or Beijing Yi Nuokai Science and Technology Ltd.s etc..
The compound 1-13 prepared with the aforedescribed process structural formula is as follows：
Compound 1-13 spectral data is：
Compound 1:HR-ESI-MS m/z454.3289[M+Na]+(Calc.for C27H45NNaO3,454.3297).1H-
NMR(CDCl3,400MHz)δ(ppm):5.69(1H,br s),5.13(1H,t,J=7.4Hz),4.81(1H,d,J=5.6Hz),
3.36(2H,t),3.22(2H,m),3.13(1H,ddd),2.97(1H,dd),2.63(1H,dd),2.49(1H,dd),1.73
(3H,s),1.64(3H,s),1.27(22H,br s),0.88(6H,t,J=6.6Hz).13C-NMR(CDCl3,100MHz)δ
(ppm):171.8,166.7,140.3,136.5,126.5,116.9,76.2,48.6,44.9,39.5,31.7,29.7,29.2,
29.0,27.4,27.3,27.0,26.7,25.8,22.6,22.58,18.0,14.07,14.05.
Compound 2:HR-EI-MS m/z:445.3564[M]+(Calcd.for C28H47NO3:445.3556).1H NMR
(400MHz,CDCl3)δ(ppm):5.69(1H,s),5.14(1H,t,J=6.5Hz),4.81(1H,d,J=5.6Hz),3.34
(2H,m),3.22(2H,m),3.16-3.09(2H,m),2.63(1H,m),2.48(1H,m),1.73(3H,s),1.64(3H,
s),1.52(4H,s),1.26(20H,s),0.89(6H,t,J=4.0Hz).13C NMR(100MHz,CDCl3)δ(ppm):
171.8,166.7,140.3,136.5,126.5,116.9,77.6,76.2,50.0,48.7,39.5,31.8,29.7,29.5,
29.2,27.5,27.3,27.0,26.8,25.8,22.6,18.1,14.1.
Compound 3:HR-EI-MS m/z:417.3257[M]+(Calcd.for C26H43NO3:417.3243).1H NMR
(400MHz,CDCl3)δ(ppm):5.71(1H,s),5.15(1H,m),4.83(1H,d,J=5.6Hz),3.36(2H,m),3.26
(2H,m),3.18-3.10(1H,m),3.01(1H,m),2.66(1H,m),2.51(1H,m),1.73(3H,s),1.64(3H,
s),1.52(4H,m),1.26(16H,m),0.89(6H,t,J=6.8Hz).13CNMR(100MHz,CDCl3)δ(ppm):171.7,
166.7,140.3,136.5,126.5,116.9,77.6,76.2,48.6,44.9,39.5,31.7,29.7,29.2,29.0,
28.9,27.5,27.3,27.0,26.7,25.8,22.6,18.0,14.1.
Compound 4:HR-EI-MS m/z:403.3094[M]+(Calcd.for C25H41NO3:403.3086).1H NMR
(400MHz,CDCl3)δ(ppm):5.69(1H,s),5.14(1H,m),4.81(1H,d,J=5.6Hz),3.35(2H,m),3.24
(2H,m),3.16-3.10(1H,m),2.96(1H,m),2.64(1H,m),2.48(1H,m),1.73(3H,s),1.64(3H,
s),1.50(4H,m),1.26(14H,m),0.89(6H,t,J=6.8Hz).13CNMR(100MHz,CDCl3)δ(ppm):171.7,
166.7,140.3,136.5,126.5,116.9,77.6,76.2,48.7,44.9,39.5,31.8,29.2,28.9,27.4,
27.3,27.1,27.0,26.7,25.8,22.6,22.4,18.0,14.1.
Compound 5:HR-EI-MS m/z:473.3871[M]+(Calcd.for C30H51NO3:473.3869).1H NMR
(400MHz,CDCl3)δ(ppm):5.69(1H,s),5.14(1H,m),4.81(1H,d,J=5.6Hz),3.35(2H,m),3.23
(2H,m),3.16-3.10(1H,m),2.99(1H,m),2.64(1H,m),2.48(1H,m),1.73(3H,s),1.64(3H,
s),1.50(4H,m),1.26(24H,m),0.89(6H,t,J=6.8Hz).13CNMR(100MHz,CDCl3)δ(ppm):171.8,
166.7,140.3,136.5,126.5,116.9,77.6,76.2,48.7,44.9,39.5,31.9,29.7,29.6,29.4,
29.2,27.4,25.8,22.6,18.0,14.1.
Compound 6:HR-EI-MS m/z:389.2923[M]+(Calcd.for C24H39NO3:389.2930).1H NMR
(400MHz,CDCl3)δ(ppm):5.69(1H,s),5.13(1H,m),4.81(1H,d,J=5.6Hz),3.35(2H,m),3.24
(2H,m),3.16-3.10(1H,m),2.96(1H,m),2.64(1H,m),2.48(1H,m),1.72(3H,s),1.63(3H,
s),1.50(4H,m),1.26(12H,m),0.89(6H,t,J=6.8Hz).13CNMR(100MHz,CDCl3)δ(ppm):171.8,
166.7,140.3,136.5,126.5,116.9,77.6,76.2,48.7,44.9,39.5,31.9,29.7,29.6,29.4,
29.2,27.4,25.8,22.6,18.0,14.1.
Compound 7:HR-EI-MS m/z:501.4168[M]+(Calcd.for C32H55NO3:501.4182).1H NMR
(400MHz,CDCl3)δ(ppm):5.69(1H,s),5.13(1H,m),4.81(1H,d,J=4.0Hz),3.35(2H,m),3.26
(3H,m),3.16-3.09(1H,m),2.99(1H,m),2.65(1H,m),2.48(1H,m),1.73(3H,s),1.64(3H,
s),1.52(4H,s),1.26(28H,s),0.89(6H,t,J=8.0Hz).13CNMR(100MHz,CDCl3)δ(ppm):171.8,
166.7,140.3,136.5,126.5,116.9,77.6,76.2,57.9,48.7,44.9,39.5,31.9,29.6,29.5,
29.3,27.5,27.3,27.0,26.8,25.8,22.6,18.1,14.1.
Compound 8:HR-EI-MS m/z:361.2627[M]+(Calcd.for C22H35NO3:361.2617).1H NMR
(400MHz,CDCl3)δ(ppm):5.70(1H,s),5.13(1H,m),4.81(1H,d,J=5.6Hz),3.36(2H,m),3.26
(2H,m),3.16-3.09(1H,m),3.01(1H,m),2.68(1H,m),2.50(1H,m),1.73(3H,s),1.64(3H,
s),1.52(4H,m),1.26(8H,m),0.89(6H,t,J=6.8Hz).13CNMR(100MHz,CDCl3)δ(ppm):171.8,
166.7,140.3,136.5,126.5,116.9,77.6,76.2,49.9,48.6,44.9,39.5,32.9,29.2,28.8,
28.6,27.3,27.1,25.8,22.3,18.0,14.0.
Compound 9:HR-EI-MS m/z:529.4467[M]+(Calcd.for C34H59NO3:529.4495).1H NMR
(600MHz,CDCl3)δ(ppm):5.70(1H,s),5.13(1H,m),4.81(1H,d,J=5.6Hz),3.35(2H,m),3.24
(2H,m),3.16-3.11(1H,m),3.10(1H,m),2.65(1H,m),2.48(1H,m),1.73(3H,s),1.64(3H,
s),1.52(4H,m),1.26(32H,m),0.89(6H,t,J=8.0Hz).13CNMR(150MHz,CDCl3)δ(ppm):171.8,
166.7,140.2,136.6,126.5,116.9,77.6,76.2,50.1,48.6,44.9,39.5,31.9,29.7,29.6,
29.5,29.4,29.3,29.2,27.7,27.4,27.3,27.0,26.8,25.8,22.7,18.1,14.1.
Compound 10:ESI-MS m/z:581[M+Na]+.1H NMR(400MHz,CDCl3)δ(ppm):5.70(1H,s),
5.13(1H,m),4.81(1H,d,J=5.6Hz),3.33(2H,m),3.26(2H,m),3.16-3.09(1H,m),2.99(1H,
m),2.65(1H,m),2.48(1H,m),1.73(3H,s),1.64(3H,s),1.52(4H,m),1.26(36H,m),0.89
(6H,t,J=8.0Hz).13C NMR(100MHz,CDCl3)δ(ppm):171.8,166.7,140.3,136.5,126.5,
116.9,77.6,76.2,48.7,44.9,39.5,31.9,29.6,29.5,29.4,27.3,27.0,26.8,25.8,22.7,
18.1,14.1.
Compound 11:HR-EI-MS m/z:585.5109[M]+(Calcd.for C38H67NO3:585.5121).1HNMR
(400MHz,CDCl3)δ(ppm):5.69(1H,s),5.15(1H,m),4.81(1H,d,J=5.6Hz),3.35(2H,m),3.23
(2H,m),3.16-3.10(1H,m),3.00(1H,m),2.64(1H,m),2.48(1H,m),1.73(3H,s),1.64(3H,
s),1.50(4H,m),1.26(40H,m),0.89(6H,t,J=6.8Hz).13C NMR(100MHz,CDCl3)δ(ppm):
171.7,166.7,140.3,136.5,126.5,116.9,77.6,76.2,48.7,44.9,39.5,31.9,29.7,29.6,
29.4,29.2,27.5,27.3,27.0,26.7,25.8,22.6,18.0,14.1.
Compound 12:HR-EI-MS m/z:319.2146[M]+(Calcd.for C19H29NO3:319.2147).1HNMR
(400MHz,CDCl3)δ(ppm):5.72(1H,s),5.15(1H,m),4.82(1H,d,J=5.6Hz),3.35(2H,m),3.25
(2H,m),3.18-3.11(1H,m),2.98(1H,m),2.66(1H,m),2.50(1H,m),1.75(3H,s),1.66(3H,
s),1.50(4H,m),1.26(2H,m),0.86(6H,m).13CNMR(100MHz,CDCl3)δ(ppm):171.8,166.8,
140.3,136.5,126.5,116.9,77.6,76.2,48.4,44.7,39.5,31.3,29.6,27.3,25.8,22.4,
20.2,18.0,14.1.
Compound 13:ESI-MS m/z:356[M+Na]+.1H NMR(400MHz,CDCl3)δ(ppm):5.70(1H,s),
5.13(1H,m),4.81(1H,d,J=5.6Hz),3.35(2H,m),3.26(2H,m),3.16-3.09(1H,m),2.99(1H,
m),2.65(1H,m),2.48(1H,m),1.73(3H,s),1.64(3H,s),1.52(4H,m),1.26(4H,m),0.89(6H,
m).13C NMR(100MHz,CDCl3)δ(ppm):171.8,166.7,140.3,136.5,126.5,116.9,77.6,76.2,
48.7,44.6,39.5,31.9,29.5,28.5,27.3,25.8,21.8,19.9,18.1,13.6.
The pharmacological evaluation of the compounds of this invention:
Embodiment 2：
Suppress pancreatic lipase experiment in vitro：
First, medicine and compound are determined
Measure compound is the gained vibralactone vibralactone amide derivatives of embodiment 1, totally 12 compounds；
Positive drug is orlistat（Orlistat,N-Formyl-L-leucine(1S)-1-[[(2S,3S)-3-hexyl-4-oxo-
2-oxetanyl]methyl]dodecyl ester）Purchased from Sigma companies；Compound and Orlistat are dissolved in dimethyl Asia
Sulfone（DMSO）In, 4 DEG C of preservations.2nd, reagent and solution
（1）Reagent
Porcine pancreatic lipase（PPL）Purchased from Aladdin Reagent Company；p-nitrophenyl butyrate（p-NPB）、Tris
Purchased from Sigma companies；D-PBS is purchased from Hyclone companies；Anhydrous calcium chloride is Chengdu Ke Long chemical reagents factory product.
（2）Solution
Tris buffer solutions contain 100mM Tris, 5mM CaCl2, 7.0,4 DEG C of preservations of pH value；PPL solution is matched somebody with somebody with D-PBS
1000U/mL storage liquid is made, dispenses, -80 DEG C of preservations；P-NPB solution is with dimethylformamide（DMF）It is configured to 10mM's
Solution, -20 DEG C of preservations.
3rd, preferred compound 1-5 detects to PPL inhibitory action
In 96 hole elisa Plates, by the μ L of testing compound 185 of various concentrations and PPL solution（250U/mL）5 μ L are fully mixed
Close, each concentration sets 3 repeating holes, 37 DEG C, 15min；Add p-NPB（10mM）10 μ L, it is well mixed, 37 DEG C,
15min；BioTek PowerWave XS ELIASAs determine OD400nm/630nmValue, Detection wavelength 400nm, reference wavelength are
630nm.Experiment sets blank control wells and Orlistat Positive control wells simultaneously, tests and carries out altogether three times.The IC of calculating50Value
（50%Concentration of Inhibition）, that is, suppress the active compound concentrations of PPL50%.It is calculated as follows：PPL lives
Property inhibiting rate（%）=（1-sample OD values/experiment contrast hole OD values）×100%
As a result：
The present invention for parent, has synthesized 13 derivatives with vibralactone (vibralactone), therefrom obtains one and derives
Its pancreatic lipase inhibitory activity of thing and prototype compound（Vibralactone）Compare, improve three orders of magnitude, its IC50Reach
Nanomole rank（14nM）.The compound has similar pharmacophore and effect machine with currently marketed OTC medicines Orlistat
System.
Currently marketed OTC medicines Orlistat and vibralactone（Vibralactone）Structural formula be：
The IC of the control compound of table 1 and vibralactone amide derivatives of the present invention50Value
| Compound | IC50（μM） |
| Orlistat | 0.004 |
| Vibralactone | 47.260 |
| 1 | 0.014 |
| 2 | 0.017 |
| 3 | 0.027 |
| 4 | 0.089 |
| 5 | 0.198 |
| 6 | 0.216 |
| 7 | 2.236 |
| 8 | 3.251 |
| 9 | 3.439 |
| 10 | 4.789 |
| 11 | 5.477 |
| 12 | 7.245 |
| 13 | 10.508 |
Conclusion：
Compared with prior art, the present invention has following outstanding features：
1. the compound of the present invention belongs to the pancreatic lipase inhibitor of a new type, suppress with now all of pancreatic lipase
Agent has different structures.
It is never 2. the compound of the present invention has significant pancreatic lipase inhibitory activity, and derives from natural products
Isolated in the mushroom fermentation of toxicity, relative safety is higher, imply that the compound has preferable prospect in medicine.
3. the raw material of substance abundance, inexpensive of the present invention, preparation technology is simple, by being fermented to the brown tough lead fungi of lid
Culture can obtain parent compound, and the source of raw material of substance is guaranteed.
4. the present invention, by the product and diamine reactant after oxidation reaction, obtains 13 derivatives using vibralactone as parent,
Therefrom obtain its pancreatic lipase inhibitory activity of a derivative and prototype compound（Vibralactone）Compare, improve three numbers
Magnitude, its IC50Reach nanomole level（14 nM）.
The Formulation Example of the compounds of this invention
Embodiment 3：
Compound is made by embodiment 1, by compound crystal and excipient weight than 1：1 ratio adds excipient, system
Grain tabletting.
Embodiment 4：
Compound is made by embodiment 1, routinely capsule is made in capsule preparations method.
Embodiment 5：
Compound is made by embodiment 1, by compound crystal and excipient weight than 1：2 ratio adds excipient, system
Grain tabletting.
Embodiment 6：
Compound is made by embodiment 1, by compound crystal and excipient weight than 1：3 ratio adds excipient, system
Grain tabletting.
Embodiment 7：
Tablet：Compound 100mg is made in embodiment 1
Starch 100mg
Corn steep liquor 17% is appropriate
Magnesium Stearate proper quantity
Embodiment 8：
Capsule：Compound 100mg is made in embodiment 1
Starch 100mg
Magnesium Stearate proper quantity
Preparation method：Embodiment 1 is made into compound to mix with auxiliary agent, sieves, is uniformly mixed in suitable container,
Obtained mixture loads hard gelatin capsule.
Embodiment 9：
Ampulla：Compound 50mg is made in embodiment 1
Preparation method：Embodiment 1 is made into compound to be dissolved in 2 milliliters of propane diols, filtering resulting solution is in sterile bar
It is fitted under part in ampoule bottle.
Claims (8)
1. the vibralactone amide derivatives shown in following structural formula (1),
2. preparing the method for vibralactone amide derivatives in claim 1, comprise the following steps：
Vibralactone is corresponding carboxylic acid by Jones reagent oxidations first, and generation acyl chlorides is then reacted with oxalyl chloride, then anti-with amine
Vibralactone amide derivatives should be obtained,
3. pharmaceutical composition, comprising the vibralactone amide derivatives shown in claim 1 Chinese style (1) or its can pharmaceutically connect
The salt received is as active component, individually or with reference to one or more of pharmaceutically acceptable carriers.
4. the vibralactone amide derivatives described in claim 1 are preparing prevention and/or are treating fat and other metabolism
Application in the medicine of property disease.
5. the vibralactone amide derivatives described in claim 1 are in the medicine for preparing prevention and/or treatment diabetes
Using.
6. the pharmaceutical composition of claim 3 is in preparing prevention and/or treating the medicine of fat and other metabolic diseases
Application.
7. application of the pharmaceutical composition of claim 3 in the medicine for preparing prevention and/or treatment diabetes.
8. using the vibralactone amide derivatives described in claim 1 as the pancreatic lipase inhibitor of active component.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1907978A (en) * | 2006-08-17 | 2007-02-07 | 中国科学院昆明植物研究所 | Vibralactone, preparation method and medicinal application thereof |
| WO2009123164A1 (en) * | 2008-04-02 | 2009-10-08 | 塩野義製薬株式会社 | Heterocyclic derivative having inhibitory activity on endothelial lipase |
| CN103338636A (en) * | 2010-12-07 | 2013-10-02 | 好时公司 | Compounds influencing fatty acid uptake and metabolism and the production of inflammatory agents and methods of isolating them from cocoa products |
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2014
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1907978A (en) * | 2006-08-17 | 2007-02-07 | 中国科学院昆明植物研究所 | Vibralactone, preparation method and medicinal application thereof |
| WO2009123164A1 (en) * | 2008-04-02 | 2009-10-08 | 塩野義製薬株式会社 | Heterocyclic derivative having inhibitory activity on endothelial lipase |
| CN103338636A (en) * | 2010-12-07 | 2013-10-02 | 好时公司 | Compounds influencing fatty acid uptake and metabolism and the production of inflammatory agents and methods of isolating them from cocoa products |
Non-Patent Citations (1)
| Title |
|---|
| Vibralactone as a Tool to Study the Activity and Structure of the ClpP1P2 Complex from Listeria monocytogenes;Evelyn Zeiler，等;《ANGEWANDTE CHEMIE》;20111222;第50卷(第46期);第11001页右栏第1-2段、第11002页图1 * |
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