CN104367575B - A kind of Bouchardatine and Bouchardatine derivatives and its preparation method and application - Google Patents
A kind of Bouchardatine and Bouchardatine derivatives and its preparation method and application Download PDFInfo
- Publication number
- CN104367575B CN104367575B CN201410738124.XA CN201410738124A CN104367575B CN 104367575 B CN104367575 B CN 104367575B CN 201410738124 A CN201410738124 A CN 201410738124A CN 104367575 B CN104367575 B CN 104367575B
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- Prior art keywords
- bouchardatine
- compound
- derivatives
- steps
- piperidyl
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
A kind of application of Bouchardatine and Bouchardatine derivatives in preparing anti-obesity and mitigating the medicine of fatty liver generation；Shown in Bouchardatine the and Bouchardatine derivant structures formula such as formula (I)：The R is (CH2)n R1, R1For substituted-phenyl, heterocyclic radical or substituted-amino；N=0,1,2 or 3.Bouchardatine the and Bouchardatine derivatives that the present invention is provided can significantly inhibit PECTORAL LIMB SKELETON 3T3 L1 differentiation, so as to reduce the lipid accumulation in 3T3 L1 fat cells；And the accumulation of the human liver cancer cell inner lipid of enuatrol induction can be reduced, the effect with reduction zooblast triglyceride levels and anti-obesity and mitigation fatty liver generation.
Description
Technical field
The present invention relates to Bouchardatine technical fields, more particularly, to a kind of Bouchardatine and
Bouchardatine derivatives and its preparation method and application.
Background technology
Obesity, as the metabolic class disease of a class, the generation development with a variety of other metabolism class diseases exists close
Cutting link, such as diabetes B, atherosclerosis, hypertension.Research shows that the formation of obesity is due to body external source
Property Energy intaking consumed more than human body energy, energy more than needed stored in the form of triglycerides, mediates organism metabolism disorderly
Random process.At present, the World Health Organization fat judgement is all based on body-mass index (Body Mass Index,
BMI), i.e. BMI >=30kg/m2Shi Ze is defined as obesity.With the development of global economy, obesity and its complication have turned into tight
Ghost image rings the worldwide public health problem of human health.
Counted according to world health health tissues, whole world population of being obese ratio in 2011 is up to 30%, wherein teenager (18 years old
Population support accounts for 10% up to 1,200,000,000 below)；2012, Adolescent Obesity population then increased to 1,500,000,000；, the item number in 2013
Value then rises to 1,700,000,000.And in China, the rate of rise of China's population of being obese is equal to the national Past 30 Years such as America and Europe nearly ten years
Rate of rise.In the case of world's population of being obese increasing number, researched and developed then for effective medicine of obesity
Relatively lag behind.Alternative anti-obesity medicine is seldom in current world wide.Current clinical practice mainly has first kidney
Upper parathyrine reuptaking inhibitor phentermine hydrochloride/phentermine hydrochloride-Topiramate compound capsule, lipase inhibitor orlistat,
And nervous centralis class medicine hydrochloric acid Lao Kaselin etc..In use, anti-fat effect is limited, and side effect is bright for said medicine
It is aobvious, limit the use of antiadipositas drug thing.Therefore, more preferably, the higher antiadipositas drug thing of security has turned into research and development drug effect
One of current study hotspot.
Research shows that the formation of obesity consumes reduced capability mainly due to fatty excessive formation and fat oxidation
It is caused.The formation of fat is mainly the two coefficient results of aspect factor：1) multipotency/unipotent stem cell is in particular growth factor
Induction under directed differentiation formation fat cell；2) triglycerides is constantly accumulated in fat cell, forms ripe fat cell.
Therefore, suppress Adipocyte Differentiation or promote fat oxidation consumption, be development anti-obesity medicine so as to reduce lipid accumulation
Elementary tactics.
Natural products Bouchardatine is as a class β-indole quinazoline ketone alkaloid, and its structure is quinazolinone
The 2- compositions that are connected with the 2- positions of indoles.Bouchardatine is isolated from Bouchardatia neurococca, modern
Research shows that Bouchardatine has the multiple biological activities such as anticancer, antiviral, treating tuberculosis, but has no it in anti-obesity
And the application in mitigation fatty liver.
The content of the invention
The purpose of the present invention be for it is of the prior art it is not enough there is provided a kind of Bouchardatine and
Bouchardatine derivatives.
Present invention also offers the preparation method of above-mentioned Bouchardatine and Bouchardatine derivatives and should
With, Bouchardatine and Bouchardatine derivatives of the present invention have good anti-fat effect, small toxicity, can
The advantages of reducing lipid within endothelial cells accumulation, reduction zooblast triglyceride levels, is preparing prevention and treatment and anti-obesity
And have wide application space on the medicine of mitigation fatty liver relevant disease.
Inventor has found that natural products Bouchardatine has certain work for suppressing Adipocyte Differentiation and accumulation
Property, it is an anti-obesity drug leads structure with latency development prospect.Inventor is in Bouchardatine architecture basics
On carried out modification and optimizing research.Mainly the amido with chain structure feature is introduced from No. 5 positions, it is therefore an objective to improve target
The interaction ability and the chemical tampering effect to related pathways of compound and action target spot, improve compound water solubility and
The patent medicine property such as bioavilability.
The present invention realizes above-mentioned technical purpose by following technical scheme：
The invention provides a kind of Bouchardatine and Bouchardatine derivatives, the Bouchardatine
With Bouchardatine derivant structures formula such as formula (I) Suo Shi：
Wherein：R is-(CH2)nR1, n=0,1,2 or 3；
The R1Independently selected from：
(1) by one or more R2Substituted substituted-phenyl；
(2) morpholine base or piperidyl；
(3) N, N- dimethylamino or N, N- diethylamino；
R2Independently selected from：
(1) it is fluorine-based；
(2) methoxyl group；
(3) nitro.
The R1For N, N- dimethyl, N, N- diethyl, morpholine base, piperidyl, p-nitrophenyl, p-methoxyphenyl
Etc. aromatics group.
Bouchardatine and Bouchardatine derivatives building-up process of the present invention is as follows：
Specific synthesis step is as follows：
S1：Anthranilamide and triethyl orthopropionate reaction are obtained into compound 1
S2：Compound 2 will be obtained after the bromination of compound 1 obtained by previous step
S3：Compound 2 obtained by previous step and phenylhydrazine are substituted, imines is first generated after elimination reaction, then regenerationization
Compound 3
S4：By previous step gained compound 3 be catalyzed through PPA Fischer reaction obtain containing indole ring structures feature
Compound 4
S5：By compound 4 obtained by previous step and DMSO-H2O and ammonium acetate reaction, and introduce formoxyl in the 3- positions of indoles
Obtain compound 5, i.e. natural products Bouchardatine
S6：The carbonyl of quinazolinone in compound 5 obtained by previous step is subjected to chloro, compound 6 is obtained
S7：Compound 6 obtained by previous step is reacted from different aminated compounds, Bouchardatine derivatives are obtained.
Preferably, compound 2 and the mol ratio that phenylhydrazine reacts are 1 in the S3 steps:3~5.
Preferably, reaction protects progress using nitrogen in the S5 steps.
Preferably, ammonium acetate and the mol ratio that compound 4 is reacted are 2~6 in the S5 steps：1, the DMSO-H2O is molten
DMSO and H in liquid2O volume ratio is 10~20:1.
Present invention also offers a kind of Bouchardatine and Bouchardatine derivatives prepare anti-obesity and
Mitigate the application in the medicine of fatty liver generation；
Further, medicine of the present invention also includes and its pharmaceutically acceptable salt or carrier.
Further, the medicine is injection, tablet, pill, capsule, suspending agent or emulsion.
Cellular level test result indicates that, Bouchardatine the and Bouchardatine derivatives that provide of the present invention are not
Content of triglyceride in 3T3-L1 mouse adipocytes can only be significantly decreased, additionally it is possible to reduce the human liver cancer of enuatrol induction
Cell line HepG-2 intracellular triglycerides are accumulated.As compound SYS-B3 suppress it is lipogenetic activity for EC50=0.78 ±
0.13μM；And the activity for suppressing the accumulation of human hepatoma cell strain HepG-2 intracellular triglycerides is EC50=14.44 ± 0.52 μM,
Show Bouchardatine the and Bouchardatine derivatives by suppressing intracellular fat generation to reduce fatty shape
Into, and may be absorbed by suppressing ectogenous fat acid and promote endogenous lipid mobilization to reduce accumulation of fat, reach treatment
Obesity and the effect for mitigating fatty liver generation.
By being found to compound SYS-B3 lipid-loweringings Mechanism Study, compound SYS-B3 can effectively suppress Adipose Differentiation
The expression (such as PPAR γ, C/EBP α, SREBP-1c) of related regulatory factors and regulate and control lipogenetic associated metabolic enzyme (ACC,
FAS, SCD-1).Secondly, it has been found that compound SYS-B3 can activate AMPK paths and suppress unfolded protein response
Path (unfolded protein response, UPR), these results are consistent with the therapeutic action effect of its anti-obesity.
The Bouchardatine derivatives and natural products Bouchardatine fat suppressions provided the present invention is provided
Effect carries out contrast discovery, and Lipid-lowering activities of the present invention are significantly improved, especially, compound SYS-B3 Lipid-lowering activities ratios
Bouchardatine natural products Lipid-lowering activities improve about 23 times.
Results of animal shows that the IC50 of the anxious malicious toxicity of compound SYS-B3 is more than 80mg/kg, than effective dose window
It is high more than 100 times.And compound SYS-B3 can effectively reduce white adipose tissue weight under the conditions of not influenceing mouse to ingest
Amount, and can triglycerides and free fatty acid content in the reduction blood plasma of conspicuousness, this experimental result and cellular level are ground
Study carefully result to be consistent.In addition, compound SYS-B3 pharmaceutical properties are stable, membrane permeability is good, and bioavailability is higher, shows
SYS-B3 has good druggability.
Present invention also offers a kind of antiadipositas drug thing, such medicine, which has, to be reduced Fat Accumulation, mitigates fat, alleviation fat
The effects such as fat liver.Such compound can be used for the related disease such as treatment obesity and fat caused diabetes, angiocardiopathy
Disease.Such medicine contains Bouchardatine the and Bouchardatine derivatives of the invention provided and pharmaceutically acceptable
Adjuvant.The form that injection, tablet, pill, capsule, suspending agent or emulsion can be made in the medicine is used.It is administered
Approach can be it is oral, percutaneously, vein or intramuscular injection.
Pharmacology and animal level are it is demonstrated experimentally that Bouchardatine provided by the present invention and Bouchardatine spread out
Biology, with anti-obesity and mitigation fatty liver generative capacity, especially by the Bouchardatine derivatives of structure of modification
The druggability Bouchardatine that compares significantly improve, with the prospect for being developed into anti-obesity new drug.
Compared with prior art, the present invention has advantages below and beneficial effect：
Bouchardatine the and Bouchardatine derivatives that the present invention is provided can substantially reduce 3T3-L1 fat
Intracellular lipid accumulation, and the accumulation of the human liver cancer cell inner lipid of enuatrol induction can be reduced, with reduction animal
Cell triglyceride levels and anti-obesity and the effect for mitigating fatty liver generation, and it is safe, and druggability is good.
Brief description of the drawings
Fig. 1：Bouchardatine the and Bouchardatine derivatives that the present invention is provided are to 3T3-L1 fat cell fat
The influence of fat accumulation (compound concentration is 1 μM)；
Fig. 2：The Bouchardatine derivatives SYS-B3 and Bouchardatine natural products that the present invention is provided is with dense
The mode of degree gradient dependence reduces the lipid accumulation comparison diagram of 3T3-L1 cells；
Fig. 3：Bouchardatine the and Bouchardatine derivatives that the present invention is provided to 3T3-L1 cell differentiations and
The cellular morphology comparison diagram of Basal control group BM and DMSO differentiation control group processing；(cellular morphology is the 6th day, 40 times of microscope
Observed under the visual field)
Fig. 4：Bouchardatine the and Bouchardatine derivatives that the present invention is provided induce human liver cancer to enuatrol
The influence of cell HepG-2 lipid accumulations (compound concentration is 1 μM).
Fig. 5：Bouchardatine the and Bouchardatine derivatives that the present invention is provided induce human liver cancer to enuatrol
The influence (compound concentration is 1 μM) of cell HepG-2 lipid accumulations, through oil red O stain, 4 times of mirrors of microscope take pictures gained scheme
Piece.
Embodiment
With reference to specific embodiment to Bouchardatine and Bouchardatine derivatives of the present invention and its preparation
The present invention is further described in methods and applications.Unless stated otherwise, the reagent of the invention used, apparatus and method is this skills
Conventional reagent, equipment and the conventional use of method purchased in market in art field.
Embodiment 1：The synthesis of compound 1
1.36g anthranilamides are put into 50mL single port bottles, triethyl orthopropionate 10mL is added, temperature is adjusted to
155 DEG C of reaction 19h, thin-layered chromatography monitoring reaction is complete.Reaction solution is cooled to room temperature, a small amount of white solid is separated out, then put
Put refrigerator and separate out a large amount of solids, filtering, ethanol washing after mother liquor is spin-dried for, then with ethanol dissolving wherein impurity, is refiltered, closed
And filter cake, dry and 1.51g white needles 1 are obtained.
Yield 89.5%；1H NMR (400MHz, CDCl3) δ 11.39 (s, 1H), 8.31 (d, J=7.9Hz, 1H), 7.83-
7.67 (m, 2H), 7.48 (t, J=7.4Hz, 1H), 2.85 (q, J=7.5Hz, 2H), 1.46 (t, J=7.6Hz, 3H)；ESI-MS
m/z:175.2[M+H]+.
Embodiment 2：The synthesis of compound 2
1.5g compounds 1 are added in 90mL acetic acid, 705mg sodium acetates are added, 60 DEG C are heated to, stirred for a moment,
Until reaction solution clarification.Take 0.5mL bromines to be dissolved into 10mL acetic acid, be added dropwise to constant pressure funnel in reaction solution, reacted
Liquid is changed into white opacity from brown, reacts or so 10 hours, reaction solution is poured into water, a large amount of white solids of precipitation, suction filtration,
Massive laundering.Dried under infrared lamp, obtain 1.93g white solids 2.
Yield 88.7%；1H NMR (400MHz, DMSO) δ 12.49 (s, 1H), 8.12 (d, J=8.0Hz, 1H), 7.86
(t, J=7.8Hz, 1H), 7.70 (t, J=8Hz, 1H), 7.56 (d, J=8.0Hz, 1H), 5.10 (m, 1H), 2.01 (d, J=
8.0Hz,3H)；ESI-MS m/z:255.0[M+H]+, 253.0 [M-H]-.
Embodiment 3：The synthesis of compound 3
14.87g compounds 2 are added in 450mL ethanol, 20.2mL phenylhydrazines is added, is heated to reflux, reaction is stayed overnight,
Discovery in second day has a large amount of faint yellow solids suspended.Stop reaction, cooling and standings, filtering is washed, then use ethanol with a small amount of ethanol
Recrystallization, drying obtains the frivolous solid 3 of the faint yellow cotton like of 12.4g.
Yield 76%；1H NMR (400MHz, DMSO) δ 11.50 (s, 1H), 9.88 (s, 1H), 8.13 (d, J=7.9Hz,
1H), 7.81 (t, J=7.6Hz, 1H), 7.68 (d, J=8.1Hz, 1H), 7.60 (d, J=7.8Hz, 2H), 7.49 (t, J=
7.5Hz, 1H), 7.28 (t, J=7.9Hz, 2H), 6.89 (t, J=7.3Hz, 1H), 2.35 (s, 3H)；ESI-MS m/z:279.2
[M+H]+, 277.2 [M-H]-.
Embodiment 4：The synthesis of compound 4
200mL PPA is added in 500mL three-necked bottle, oil bath heating opens mechanical agitation to 180 DEG C.By 12.4gization
Compound 3 is added in PPA.2h is reacted, reaction solution gradually becomes bronzing.Stop reaction, a large amount of frozen water are poured into cooling and standings
In, pH is adjusted to neutrality with KOH, is separated out and is dried under a large amount of greenish yellow solids, filtering, infrared lamp, obtains 9.5g greenish yellow solids 4.
Yield 82.1%；1H NMR (400MHz, DMSO) δ 11.71 (s, 1H), 8.13 (d, J=7.8Hz, 1H), 7.80
(t, J=7.5Hz, 1H), 7.70 (d, J=8.0Hz, 1H), 7.63 (d, J=7.9Hz, 1H), 7.58 (s, 1H), 7.53 (d, J=
8.2Hz, 1H), 7.45 (t, J=7.5Hz, 1H), 7.21 (t, J=7.6Hz, 1H), 7.05 (t, J=7.5Hz, 1H)；ESI-MS
m/z:262.1[M+H]+, 260.1 [M-H]-.
Embodiment 5：The synthesis of compound 5
1.8g compounds 4,2.1g ammonium acetates are added in three-necked bottle, mixed solvent DMSO-H is used2O (50mL/2.7mL) is molten
Solution, N2Protection, reacts 24 hours in 150 DEG C.Reaction solution is poured into a large amount of frozen water, is stirred continuously, a large amount of solids is separated out, will analyse
Dried under the brown solid filtering gone out, infrared lamp, DCM crosses post purifying, obtains 1.2g faint yellow solids 5.
Yield 61%；1H NMR(400MHz,DMSO)δ13.62(s,1H),13.11(s,1H),10.49(s,1H),8.28
(d, J=8.0Hz, 1H), 8.22 (d, J=7.1Hz, 1H), 7.92 (dd, J=11.1,4.1Hz, 1H), 7.86 (d, J=
7.8Hz, 1H), 7.70 (d, J=8.1Hz, 1H), 7.61 (t, J=6.9Hz, 1H), 7.43 (t, J=7.1Hz, 1H), 7.36 (t,
J=7.1Hz, 1H)；ESI-MS m/z:290.1[M+H]+, 288.0 [M-H]-.
Embodiment 6：The synthesis of compound 6
1.1g compounds 5,2mL POCl are added in single port bottle3, 0.3mL DMAs, back flow reaction 6
Hour, reaction solution is poured into frozen water, is stirred continuously, a large amount of solids are separated out, the faint yellow solid of precipitation is filtered, under infrared lamp
Drying, EA:PE=1：3 cross post purifying, obtain 0.67g faint yellow solids 6.
Yield 57%；1H NMR (400MHz, DMSO) δ 10.68 (s, 1H), 8.28 (d, J=6.6Hz, 2H), 7.94 (t, J
=7.6Hz, 1H), 7.87 (d, J=7.8Hz, 1H), 7.74 (d, J=7.8Hz, 1H), 7.66 (t, J=7.6Hz, 1H), 7.55
(s, 1H), 7.50 (t, J=7.9Hz, 1H), 7.43 (t, J=7.8Hz, 1H)；ESI-MSm/z:308.1[M+H]+, 306.0 [M-
H]-.
Embodiment 7：Compound SYS-B1 synthesis
127mg compounds 6 are added in 15mL toluene, 0.1mL triethylamines, and 0.4mLN, N- diethyl is drawn
Ethylenediamine, 12h is reacted in 110 DEG C, and reaction solution is in golden yellow, and point plate display reaction is complete.Post processing：By reaction solution in 75 DEG C of water
Solvent and a small amount of triethylamine are spin-dried in bath, then uses CHCl3, saturated aqueous common salt extraction product and separate a small amount of impurity.Drying has
Machine phase, is spin-dried for solvent, uses chloroform：Methanol：Ammoniacal liquor=15：1：0.5%, which makees eluant, eluent, crosses post and purifies to obtain pale red solid.
Yield 57%；1H NMR(400MHz,CDCl3) δ 11.45 (s, 1H), 10.56 (s, 1H), 8.51 (d, J=5.1Hz,
1H), 7.77 (t, J=9.8Hz, 2H), 7.71-7.65 (m, 1H), 7.44 (d, J=7.9Hz, 1H), 7.41-7.37 (m, 1H),
7.27 (dd, J=5.3,1.9Hz, 2H), 7.14 (s, 1H), 3.66 (d, J=4.1Hz, 2H), 2.76 (t, J=5.7Hz, 2H),
2.63 (dd, J=14.4,7.2Hz, 4H), 1.08 (t, J=7.1Hz, 6H)13C NMR(101MHz,CDCl3)δ191.1,
159.3,154.3,149.3,142.9,135.1,133.0,128.3,127.0,126.5,124.9,123.2,123.0,
121.4,117.5,114.3,111.6,50.9,46.8,38.3,11.4.HRMS(ESI)m/z:calcd for C23H25N5O,[M
+H]+388.2132,found 388.2119.
Embodiment 8：Compound SYS-B2 synthesis
127mg compounds 6 are added in 15mL toluene, 0.1mL triethylamines, and excessive amine chain aminopropyl is drawn
Morpholine 0.3mL.12h is reacted in 110 DEG C, reaction solution is in light red, point plate display reaction is complete.Post processing：By reaction solution in
Solvent and a small amount of triethylamine are spin-dried in 75 DEG C of water-baths, then uses CHCl3, saturated aqueous common salt extraction product and separate a small amount of impurity.
Organic phase is dried, solvent is spin-dried for, uses chloroform：Methanol：Ammoniacal liquor=20：1：0.5%, which makees eluant, eluent, crosses post and purifies to obtain faint yellow solid.
Yield 51%；1H NMR(400MHz,CDCl3) δ 11.48 (s, 1H), 10.09 (s, 1H), 8.53 (d, J=8.2Hz,
1H), 8.30 (s, 1H), 7.85 (d, J=8.5Hz, 2H), 7.76 (t, J=7.1Hz, 1H), 7.48 (dd, J=13.4,7.1Hz,
2H), 7.35 (d, J=7.1Hz, 1H), 7.30 (t, J=8.5Hz, 1H) .3.87 (t, J=7.8Hz, 4H), 3.82 (dd, J=
10.3,5.7Hz, 2H), 2.69 (t, J=7.9Hz, 2H), 2.62 (s, 4H), 1.97 (dd, J=10.8,5.6Hz, 2H)13C
NMR(101MHz,CDCl3)δ191.0,159.7,154.5,149.3,142.7,134.8,132.9,128.5,127.1,
126.1,124.9,123.3,123.0,121.4,117.6,114.4,111.3,67.0,59.3,54.0,43.1,23.1.HRMS
(ESI)m/z:calcd for C24H25N5O2,[M+H]+416.2081,found 416.2080.
Embodiment 9：Compound SYS-B3 synthesis
150mg compounds 6 are added in 15mL toluene, 0.1mL triethylamines, and excessive amine chain aminoethyl is drawn
Piperidines 0.3mL.11h is reacted in 110 DEG C, reaction solution is in light red, point plate display reaction is complete.Post processing：By reaction solution in 75
Solvent and a small amount of triethylamine are spin-dried in DEG C water-bath, then uses CHCl3, saturated aqueous common salt extraction product and separate a small amount of impurity.It is dry
Dry organic phase, is spin-dried for solvent, uses chloroform：Methanol：Ammoniacal liquor=20：1：0.5%, which makees eluant, eluent, crosses post and purifies to obtain pale red solid.
Yield 53%；1H NMR(400MHz,CDCl3) δ 11.49 (s, 1H), 10.16 (s, 1H), 8.53 (d, J=8.4Hz,
1H), 7.86 (d, J=9.5Hz, 1H), 7.80-7.71 (m, 2H), 7.51 (d, J=8.2Hz, 1H), 7.49-7.44 (m, 1H),
7.35 (d, J=5.7Hz, 1H), 7.32-7.28 (m, 1H), 7.05 (s, 1H), 3.75 (dd, J=10.5,5.6Hz, 2H), 2.73
(t, J=5.9Hz, 2H), 2.52 (s, 4H), 1.72-1.62 (m, 4H), 1.53 (d, J=4.8Hz, 2H)13C NMR(101MHz,
CDCl3)δ191.0,159.4,154.4,149.4,142.7,134.9,132.9,128.4,127.1,126.4,124.9,
123.3,123.0,121.2,117.6,114.3,111.4,56.3,54.1,37.9,26.1,24.3.HRMS(ESI)m/z:
calcd for C24H25N5O,[M+H]+400.2132,found 400.2131.
Embodiment 10：Compound SYS-B4 synthesis
150mg compounds 6 are added in 15mL toluene, 0.1mL triethylamines are drawn, and excessive 215mg is to nitre
Base aniline.11h is reacted in 110 DEG C, reaction solution is in light red, point plate display reaction is complete.Post processing：By reaction solution in 75 DEG C of water
Solvent and a small amount of triethylamine are spin-dried in bath, then uses CHCl3, saturated aqueous common salt extraction product and separate a small amount of impurity.Drying has
Machine phase, is spin-dried for solvent, uses chloroform：Methanol：Ammoniacal liquor=35：1：0.5%, which makees eluant, eluent, crosses post and purifies to obtain red brown solid.
Yield 50%；1H NMR (400MHz, DMSO) δ 10.48 (s, 1H), 8.27 (d, J=7.9Hz, 1H), 8.21 (d, J
=7.8Hz, 1H), 7.95 (d, J=2.0Hz, 1H), 7.93 (d, J=1.8Hz, 1H), 7.92-7.89 (m, 1H), 7.85 (d, J
=7.9Hz, 1H), 7.69 (d, J=8.1Hz, 1H), 7.61 (t, J=6.9Hz, 1H), 7.42 (t, J=7.6Hz, 1H), 7.35
(t, J=7.5Hz, 1H), 6.70 (s, 1H), 6.64-6.60 (m, 1H), 6.59 (d, J=3.2Hz, 1H)
13C NMR(101MHz,DMSO)δ187.49,161.73,156.78,153.88,145.29,135.82,134.85,
134.63,128.83,127.58,127.35,126.79,126.34,126.07,125.34,125.03,123.21,122.43,
122.23,121.74,120.11,113.23,112.34.ESI-MS m/z:410.2[M+H]+, 408.1 [M-H]-.
Embodiment 11：Compound SYS-B5 synthesis
117mg compounds 6 are added in 15mL toluene, 0.1mL triethylamines, and excessive amine chain aminopropyl is drawn
Piperidines 0.3mL.11h is reacted in 110 DEG C, reaction solution is in light red, point plate display reaction is complete, post processing：By reaction solution in 75
Solvent and a small amount of triethylamine are spin-dried in DEG C water-bath, then uses CHCl3, saturated aqueous common salt extraction product and separate a small amount of impurity.It is dry
Dry organic phase, is spin-dried for solvent, uses chloroform：Methanol：Ammoniacal liquor=15：1：0.5%, which makees eluant, eluent, crosses post and purifies to obtain pale red solid.
Yield 58%；1H NMR (400MHz, DMSO) δ 9.08 (s, 1H), 8.18 (d, J=7.4Hz, 1H), 8.07 (d, J
=7.7Hz, 1H), 7.84 (dd, J=14.4,7.5Hz, 2H), 7.70 (d, J=7.8Hz, 1H), 7.53 (t, J=8.2Hz,
1H), 7.37 (t, J=8.0Hz, 1H), 7.25 (t, J=7.1Hz, 1H), 3.86 (s, 2H), 2.43 (s, 4H), 2.03 (s, 2H),
1.50(s,4H),1.37(s,2H),1.21(s,2H).13C NMR(101MHz,DMSO)δ188.17,162.2,156.4,
135.9,134.3,133.9,128.7,127.2,126.2,126.0,124.9,122.8,121.9,121.5,120.4,
119.0,113.2,56.8,56.1,53.8,27.2,25.3,23.9.HRMS(ESI)m/z:calcd for C25H27N5O,[M+
H]+414.2288,found 414.2274.
Embodiment 12：Compound SYS-B6 synthesis
117mg compounds 6 are added in 15mL toluene, 0.1mL triethylamines are drawn, and 101mg is to methoxybenzene
Amine.13h is reacted, point plate display reaction is complete, post processing：Reaction solution is spin-dried for solvent and a small amount of three second in 75 DEG C of water-baths
Amine, then use CHCl3, saturated aqueous common salt extraction product and separate a small amount of impurity.Organic phase is dried, solvent is spin-dried for, uses chloroform：First
Alcohol：Ammoniacal liquor=35：1：0.5%, which makees eluant, eluent, crosses post and purifies to obtain dark brown solid.
Yield 54%；1H NMR(400MHz,DMSO)δ12.72(s,1H),10.48(s,1H),9.45(s,1H),8.33
(d, J=8.1Hz, 1H), 8.20 (d, J=6.8Hz, 1H), 7.91 (d, J=8.9Hz, 2H), 7.85 (d, J=7.9Hz, 2H),
7.70 (t, J=8.2Hz, 1H), 7.55 (t, J=7.3Hz, 1H), 7.39 (t, J=7.9Hz, 1H), 7.29 (t, J=7.4Hz,
1H), 7.10 (d, J=8.9Hz, 2H), 3.84 (s, 3H)13C NMR(101MHz,DMSO)δ187.4,162.1,158.7,
150.2,149.1,146.6,140.3,135.9,134.8,134.5,131.2,129.0,127.6,127.2,126.4,
125.9,125.1,123.2,122.8,121.8,121.6,120.1,119.8,114.6,113.2,55.4.HRMS(ESI)m/
z:calcd for C24H18N4O2,2[M+H]+395.1503,found 395.1491.
Embodiment 13：Compound SYS-B7 synthesis
117mg compounds 6 are added in 15mL toluene, 0.1mL triethylamines are drawn, and 94.45mg amine chains are to fluorine
Aniline.11h is reacted, point plate display reaction is complete, post processing：Reaction solution is spin-dried for solvent and a small amount of three second in 75 DEG C of water-baths
Amine, then use CHCl3, saturated aqueous common salt extraction product and separate a small amount of impurity.Organic phase is dried, solvent is spin-dried for, uses chloroform：First
Alcohol：Ammoniacal liquor=35：1：0.5%, which makees eluant, eluent, crosses post and purifies to obtain dark yellow solid.
Yield 57%；1H NMR(400MHz,DMSO):δ 12.80 (s, 1H), 9.48 (s, 1H), 8.34 (d, J=7.8Hz,
1H), 8.20 (d, J=7.6Hz, 1H), 7.98-7.90 (m, 2H), 7.87 (dd, J=13.9,7.4Hz, 2H), 7.71 (d, J=
8.1Hz, 1H), 7.56 (t, J=7.2Hz, 1H), 7.39 (dd, J=15.2,7.1Hz, 3H), 7.30 (t, J=7.3Hz, 1H)
.13C NMR(101MHz,DMSO):δ187.4,162.0,159.9,152.7,149.0,146.3,143.8,135.9,134.5,
131.6,129.0,127.3,126.5,125.9,125.2,123.4,123.3,121.8,119.7,116.2,116.0,
113.0,112.9；HRMS(ESI)m/z:calcd for C23H15FN4O,[M+H]+383.1303,found 383.1287.
Embodiment 14：Application mouse PECTORAL LIMB SKELETON 3T3-L1 cell differentiation models, using oil red O stain and with reference to micro-
Mirror is taken pictures, and evaluates Bouchardatine and Bouchardatine derivatives to content of triglyceride shadow in fat cell
Ring.
Experimental procedure
The 3T3-L1 PECTORAL LIMB SKELETONs of exponential phase, 5.0*104Cells/well, is uniformly seeded to 48 orifice plates, cell culture
Case quiescent culture, changes a nutrient solution in every two days.Treat that cell growth, close to 80% fusion, changes nutrient solution, continue to cultivate 2
It merges (Day0) to cell completely, changes the DMEM complete culture solutions containing induction liquid I (dual anti-containing 10%FBS and 1%
DMEM nutrient solutions), 37 DEG C of 5%CO2Quiescent culture 3 days (Day3).After 3 days, the DMEM containing induction liquid II is changed complete
Full nutrient solution continues to cultivate 3 days (Day6).For pharmaceutical intervention group, using the DMEM complete culture solutions of the liquid containing induction as dilution
Liquid, dilution drug solution to finite concentration, in Day0 and Day3, is together added.Blank control group and differentiation control group, respectively
Add isometric DMSO solution.In Day6, carry out oil red O stain and take pictures and content of triglyceride analysis.
(1) induction liquid is prepared
Induction liquid I：Containing 500 μM of 3- isobutyl group -1- methyl-xanthines, 100ng/mL dexamethasone, 2 μ g/mL pancreas islet
The DMEM complete culture solution inductions liquid II of element：DMEM complete culture solutions containing 2 μ g/mL insulin
(2) oil red O stain
When cell induction is broken up to Day6, the pre-cooled PBS rinses of cell 1 time, 4% frost paraformaldehyde fixer room temperature is consolidated
Determine 60min.0.3% oil red O stain working solution room temperature dyes 30min.The deionized water of room temperature is rinsed 2-3 times, inverted microscope
Take pictures (40 ×).
300uL aqueous isopropanols are separately added into per hole, shaking table gently shakes room temperature extraction oil red O dyestuff 30mins, respectively
Pipette 100 μ L dye liquors and carry out 510nm absorbance detections.
(3) content of triglyceride is analyzed
After cell differentiation terminates, most PBS is removed in precooling PBS rinses 2 times, adds the deionization of the X-100 containing 0.2%Triton
Solution, is stored at room temperature 1h, collects cell suspension, and ultrasonication 10min makes cell fully crack, supernatant is collected by centrifugation, according to
Triglycerides detection kit specification determines content of triglyceride.
(4) interpretation of result
Content of triglyceride analysis represents using breaking up control group for " 100% compare ", i.e., compound content of triglyceride/point
Change control group content * 100%.Experimental result is the average value of three independent experiments, is as a result entered according to " mean+SD "
Row statistical analysis.
(5) experimental result
As shown in figure 1, DM groups represent differentiation control group, the cell of normal differentiation is represented, there is substantial amounts of lipid accumulation.
Bouchardatine is natural products, and compound SYS-B1 etc. is Bouchardatine derivatives.Compared with DM, 1 μM
SYS-B1, SYS-B2, SYS-B3 and SYS-B5 can effectively suppress fat generation (*, p<0.05；*, p<0.01)；Wherein with
Compound SYS-B1 and SYS-B3 inhibition are most obvious.
As Fig. 2 shows that Bouchardatine and SYS-B3 can reduce 3T3-L1 in the way of concentration gradient dependence
Lipid within endothelial cells content (*, p<0.05；*, p<0.01；* *, p<0.001), and compound SYS-B3 activity is stronger.Can by figure
Know, the cell treated by 5 μM of Bouchardatine and SYS-B3, content of triglyceride reduces 18% respectively,
65%；We obtain Bouchardatine and SYS-B3 EC by calculating50Value is respectively 22.59 μM, 1.1 μM, compound
SYS-B3 Lipid-lowering activities improve about 23 times.
In Fig. 3, BM represents Basal control group, represents undifferentiated cell, intracellular without lipid accumulation；DM represents differentiation pair
According to group, intracellular high-visible substantial amounts of lipid；And the intracellular lipid content of compound treatment group is with compound concentration
Raise and gradually decrease.Such as compound SYS-B3 0.1, under 0.5,1,5,10 μM of concentration, content of triglyceride is respectively control
73%, 56%, 47%, 28%, the 15% of group.
Embodiment 15：Using human hepatoma cell strain HpeG-2, using content of triglyceride assay kit and BCA albumen
Concentration measuring kit, the human liver cancer that in-vitro evaluation Bouchardatine and Bouchardatine derivative are induced enuatrol
The influence of cell line HpeG-2 cell content of triglyceride.
Experimental procedure：
The Setup Experiments blank control group (being not added with enuatrol), enuatrol induction group (containing enuatrol), and various concentrations
Pharmaceutical intervention group.Concrete operations are as follows：
Human liver cancer cell HepG-2 is uniformly seeded to 48 orifice plates, quiescent culture 24h.Replacing contains 0.5mM enuatrols
DMEM complete culture solutions (contain the dual anti-DMEM nutrient solutions of 10%FBS and 1%), the final concentration of 1mM of enuatrol.37 DEG C of 5%CO2
24h is incubated under environment altogether.In this experiment, compound intervention group is compound through the DMEM complete culture solutions dilution containing enuatrol
To required concentration.And blank control group is separately added into the DMSO of equivalent with enuatrol control group.
(1) oil red O stain and spectrophotometric analysis
Cell pre-cooled PBS (PH7.4) rinse 2 times, 4% frost paraformaldehyde fixer room temperature fixes 60min.0.3%
Oil red O stain liquid room temperature dyes 30mins.Deionized water is rinsed 2-3 times, and inverted microscope is taken pictures (40 ×)
(2) content of triglyceride is analyzed with protein content
Most PBS is removed in treated cell, PBS rinses 2 times, and the deionization for adding the X-100 containing 0.2%Triton is molten
Liquid, is stored at room temperature 1h, and piping and druming repeatedly makes cell fully crack, and collects cell suspension to centrifuge tube, ultrasonication 10min, centrifugation
Supernatant is collected, glycerine three is determined according to triglycerides detection kit specification and BCA protein quantifications detection kit respectively
Ester content and protein concentration.Last content of triglyceride is represented in " nmol/mg albumen " form.For the ease of with control group ratio
Compared with using control group as " 100% ", convert (treatment group content of triglyceride (nmol/mg albumen)/control group triglycerides respectively
Content ((nmol/mg albumen) * 100%).Experimental result is the average value of three independent experiments, as a result according to " average value ± mark
It is accurate poor " carry out statistical analysis.
(3) experimental result
In Fig. 4, compared with blank control Blank groups, enuatrol induction group intracellular triglyceride content is notable
Raise (#, p<0.01).And compound intervention then can effectively reduce intracellular triglyceride content, at such as 1 μM, compound
SYS-B1, SYS-B2, SYS-B3 group content of triglyceride reduce 43%, 28%, 54% respectively, with compound SYS-B3 effects
It is best.
Fig. 5 shows that Blank groups are represented without enuatrol processing, intracellular without obvious lipid accumulation；Control groups
Represent enuatrol induction processing, intracellular high-visible substantial amounts of lipid accumulation.And Bouchardatine is in 10 μM of concentration
Lipid within endothelial cells accumulation is without significant change, and lipid within endothelial cells accumulation is significantly reduced during 1 μM of Bouchardatine derivatives,
Wherein with compound SYS-B1 effects preferably, the experiment illustrates again, by structure of modification, Bouchardatine derivatives
Lipid-lowering activities are significantly improved.
Claims (8)
1. a kind of application of Bouchardatine derivatives in preparing anti-obesity and mitigating the medicine of fatty liver generation, its
It is characterised by, shown in the Bouchardatine derivant structures formula such as formula (I)：
Wherein：R is-(CH2)nR1, n=0,1,2 or 3；
The R1Independently selected from：
(1) morpholine base or piperidyl；
(2) N, N- diethylamino；
As the R1During selected from morpholine base or piperidyl, nitrogen-atoms and-(CH on morpholine base or piperidyl2)n- connection；
Work as R1During selected from morpholine base, n=3；
Work as R1During selected from piperidyl, n=2；
Work as R1Selected from N, during N- diethylaminos, n=2.
2. a kind of preparation method of Bouchardatine derivatives according to claim 1, it is characterised in that synthesis step
It is rapid as follows：
S1：Anthranilamide and triethyl orthopropionate reaction are obtained into compound 1S2：By S1 steps
Compound 2 is obtained after the middle bromination of gained compound 1
S3：Gained compound 2 and phenylhydrazine in S2 steps are substituted, imines is first generated after elimination reaction, chemical combination is then regenerated
Thing 3
S4：The Fischer reactions that gained compound 3 in S3 steps is catalyzed through PPA obtain the change containing indole ring structures feature
Compound 4
S5:By gained compound 4 and DMSO-H in S4 steps2O and ammonium acetate reaction, and obtained in the 3- positions introducing formoxyl of indoles
To compound 5, i.e., described Bouchardatine
S6:The carbonyl of quinazolinone in gained compound 5 in S5 steps is subjected to chloro, compound 6 is obtained
S7:Gained compound 6 in S6 steps is reacted from different aminated compounds, the Bouchardatine is obtained and derives
Thing.
3. the preparation method of Bouchardatine derivatives as claimed in claim 2, it is characterised in that in the S3 steps
Compound 2 is 1 with the mol ratio that phenylhydrazine reacts:3~5.
4. the preparation method of Bouchardatine derivatives as claimed in claim 2, it is characterised in that in the S5 steps
Reaction is protected using nitrogen and carried out.
5. the preparation method of Bouchardatine derivatives as claimed in claim 2, it is characterised in that in the S5 steps
Ammonium acetate is 2~6 with the mol ratio that compound 4 is reacted：1, the DMSO-H2DMSO and H in O solution2O volume ratio be 10~
20:1。
6. a kind of Bouchardatine derivatives, it is characterised in that the Bouchardatine derivant structures formula such as formula
Shown in ((I))：
Wherein：R is-(CH2)nR1, n=0,1,2 or 3；
The R1Independently selected from：
(1) morpholine base or piperidyl；
(2) N, N- diethylamino；
As the R1During selected from morpholine base or piperidyl, nitrogen-atoms and-(CH on morpholine base or piperidyl2)n- connection；
Work as R1During selected from morpholine base, n=3；
Work as R1During selected from piperidyl, n=2；
Work as R1Selected from N, during N- diethylaminos, n=2.
7. application according to claim 1, it is characterised in that the medicine also includes its pharmaceutically acceptable salt or load
Body.
8. application according to claim 1, it is characterised in that the medicine is injection, tablet, pill, capsule, outstanding
Floating agent or emulsion.
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| Alkaloids and limonoids from Bouchardatia neurococca: systematic significance;C. Wattanapiromsakul et al.;《Phytochemistry》;20031231(第64期);609-615 * |
| Rutaecarpine Analogues Reduce Lipid Accumulation in Adipocytes via Ihibiting Adipogenesis/Lipogenesis with AMPK Activation and UPR Suppression;Ying-Chun Chen et al.;《ACS Chemical Biology》;20130820(第8期);2301-2311 * |
| Rutecarpine ameliorates bodyweight gain through the inhibition of orexigenic neuropeptides NPY and AgRP in mice;Su-Jin Kim et al.;《Biochemical and Biophysical Research Communications》;20090902(第389期);437–442 * |
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