CN107325149B - A kind of radix glycyrrhizae gadoleic acid derivative and preparation method thereof and purposes - Google Patents
A kind of radix glycyrrhizae gadoleic acid derivative and preparation method thereof and purposes Download PDFInfo
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Abstract
The invention discloses a kind of radix glycyrrhizae gadoleic acid derivative, its structure is as shown in the formula in Figure of abstract；The present invention discloses the preparation method of the radix glycyrrhizae gadoleic acid derivative.The invention also discloses the radix glycyrrhizae gadoleic acid derivative as a kind of purposes of anti-inflammatory drug, specifically can apply to treatment and prevention ALI, chronic obstructive pulmonary disease, septicopyemia etc. has in medicine or the pharmaceutical composition of related disorders.
Description
Technical field
The present invention relates to a kind of radix glycyrrhizae gadoleic acid derivative and preparation method thereof and the purposes as anti-inflammatory, belong to newization
The it is proposed of compound, preparation and application technical field.
Background technology
Inflammation is the basic defense mechanism of immune system, can prevent from being caused by noxious stimulus (such as pathogen and poison)
Injury.However, inflammatory process may cause tissue damage in itself and cause many diseases even cancer (R.Medzhitov,
Nature,2008,454,428-435).Inflammation is that the biological tissue with vascular system (wound, infection, lacks to damage factor
Blood, poisoning or autoimmune lesions) complicated defense reaction (Hsu CC, Lien JC. etc., Biochemical for being occurred
Pharmacology, 2013,85,385-395), appropriate inflammatory reaction is host defense destructive stimulus and the weight for starting healing
Process is wanted, but acute inflammation may cause the lesions such as tissue damage, pyemia, cancer and shock (Heiss E, Herhaus C.
Deng, J BiolChem, 2001,276,32008-32015).When exposed to inflammatory factor or other stimulations, monocyte transfer
To extravascular tissue, macrophage is divided into.After activation, macrophage can produce nitric oxide (NO), prostaglandin E2
And cell factor (such as factor such as interleukins (IL-1 β, IL-6) and TNF (TNF-α)) (PGE2).These because
Sub- great expression meeting Human Umbilical Vein Endothelial Cells, epithelial cell produce profound influence, and carry out place in the mesenchymal cell of local microenvironment
(Yona S, Jung S. etc., CurrOpinHematol, 2010,17,53-59) such as main defence, tissue reconstruction or reparations.
NSAIDs (NSAIDs) accounts for critical role, but NSAIDs long-term use in treatment pain and aspect of inflammation
Relevant with intestines and stomach adverse events incidence height (T.Narsinghani, R.Sharma, Chem.Biol.Drug Des, 2014,
84,1-23).Therefore, still there is an urgent need to find the medicine with improvement result and reduce the novel anti-inflammatory drug of adverse reaction.
Because therapeutic efficiency and side effect are less, natural products occupies weight in the medicine of many research and development early stage recruit's entities (NMEs)
Want status, nearly half NMEs be all natural products or derivatives thereof (E.Patridge, P.Gareiss. etc., Drug Discov,
2016,21,204-207)；Find new type natural product antiinflammatory drugs and have more theory value and practical significance.
The content of the invention
It is an object of the invention to provide a kind of radix glycyrrhizae gadoleic acid derivative and preparation method thereof and purposes；The present invention another
Purpose is to provide a kind of anti-inflammatory drug, and it is relevant to be applied to treatment and prevention ALI, chronic obstructive pulmonary disease, septicopyemia etc.
In the medicine or pharmaceutical composition of disease.
The present invention is achieved by the following technical solutions：
A kind of radix glycyrrhizae gadoleic acid derivative is provided, shown in its structure such as general formula (I)：
Wherein R is the amino containing one or more substituents, alcohol/phenolic group, mercaptan/thiophenol group, diazanyl, the substituent
Selected from different substituted alkyl, aromatic radical, heterocyclic radical one or more.
Preferably, described R is that monosubstituted/disubstituted amino or diazanyls of C1~C6, C1~C6 of hydroxyl or halogen are mono-
Substitution/disubstituted amino, C1~C6 substituted alcohols/phenolic group, C1~C6 substitutions mercaptan/thiophenol group, C0~C3 containing aryl or heterocycle
Substituted-amino, the nafoxidine base or piperazinyl or homopiperazine base of C0~C3 substitutions.
Invention also provides the preparation method of above-mentioned radix glycyrrhizae gadoleic acid derivative, comprise the following steps：
Step (1)：Compound (I) and phosphonoacetate feed intake to react according to the ︰ 1~2 of mol ratio 1 is made compound
(ⅱ)；
Reaction dissolvent is aprotic solvent；Reaction temperature is -10 DEG C~40 DEG C；
Preferably, reaction dissolvent is tetrahydrofuran；Reaction temperature is 0 DEG C~30 DEG C.
Step (2)：Compound (II) and caustic alkali feed intake to react according to the ︰ 1~3 of mol ratio 1 is made compound (III)；
Reaction dissolvent is that polarity dipole solvent mixes with aprotic solvent；Reaction temperature is -10 DEG C~100 DEG C；
Preferably, reaction dissolvent is ethanol, chloroform mixing；Catalysts are sodium hydroxide；Reaction temperature is 0 DEG C
~30 DEG C.
Step (3)：Compound (III) and corresponding amine, alcohols or thio-alcohol feed intake reaction according to the ︰ 1~10 of mol ratio 1
Radix glycyrrhizae gadoleic acid derivative (I) is made；
Reaction dissolvent is aprotic solvent；Reaction reagent is condensing agent；Reaction temperature is -20 DEG C~100 DEG C；
Preferably, reaction dissolvent is dichloromethane；Reaction reagent is that 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne two is sub-
The condensing agent such as amine hydrochlorate (EDCHCl)/I-hydroxybenzotriazole (HOBt), dicyclohexylcarbodiimide (DCC)；Reaction temperature
Spend for -5 DEG C~30 DEG C.
Step (4)：The reaction such as compound (III) and alcohols, thio-alcohol be made glycyrrhizin derivative according to the ︰ 1 of mol ratio 1~
10, which feed intake, reacts obtained radix glycyrrhizae gadoleic acid derivative (I)；
Reaction dissolvent is aprotic solvent；Catalysts are dehydration catalyst；Reaction temperature is -20 DEG C~100 DEG C；
Preferably, reaction dissolvent is dichloromethane；Reaction reagent is the concentrated sulfuric acid, phosphorus pentachloride, thionyl chloride, boron trifluoride
Deng catalyst；Reaction temperature is -5 DEG C~30 DEG C.
It is highly preferred that the preparation method of the radix glycyrrhizae gadoleic acid derivative, comprises the following steps：
Step (1)：Sodium hydride is added in anhydrous tetrahydro furan, stirred under the conditions of 0 DEG C~5 DEG C, nitrogen protection, is slowly dripped
Add phosphonoacetate, after adding, continue stirring 1 hour；Compound (I) is dissolved in THF, under condition of ice bath slowly
It is added drop-wise in above-mentioned mixed reaction solution, is stirred at room temperature 2~3 hours, TLC monitorings, after compound (I) reaction completely, stops anti-
Should；By reacting liquid filtering, ethyl acetate washes twice, merging filtrate, and extraction, organic phase is washed twice with water, anhydrous sodium sulfate
Dry, filtering is concentrated under reduced pressure, and ethyl alcohol recrystallization obtains compound (II).
Step (2)：Compound (II) is added in reaction dissolvent, is slowly added to sodium hydrate aqueous solution, 40 DEG C of stirrings 2~
3 hours；TLC is monitored, and after reaction completely, watery hydrochloric acid is added dropwise and adjusts pH value to 4~5, twice, organic phase is successively for chloroform extraction
Washed with water and saturated sodium-chloride, anhydrous sodium sulfate drying, filtering is concentrated under reduced pressure, and obtains compound (III).
Step (3)：Compound (III) is added in reaction dissolvent, sequentially adds EDCHCl, HOBt and corresponding amine,
After stirring and dissolving, triethylamine is added；It is stirred overnight at room temperature, TLC monitorings, after compound (III) reaction completely, stops reaction, will
Reaction mixture is poured into frozen water, and ice-out is treated in stirring, is layered, and extraction, organic phase is washed twice with water, and anhydrous sodium sulfate is done
It is dry；Filtering is concentrated under reduced pressure, ethyl alcohol recrystallization, obtains radix glycyrrhizae gadoleic acid derivative.
Step (4)：Compound (III) is added in reaction dissolvent, adds corresponding alcohols or thio-alcohol, after stirring and dissolving, is added
Enter thionyl chloride or boron trifluoride ether solution；It is stirred overnight at room temperature, is stirred overnight at room temperature, TLC monitorings, treats that compound (III) is anti-
After answering completely, stop reaction, reaction mixture is poured into frozen water, ice-out is treated in stirring, layering, extraction, and organic phase is washed with water
Wash twice, anhydrous sodium sulfate drying；Filtering is concentrated under reduced pressure, ethyl alcohol recrystallization, obtains radix glycyrrhizae gadoleic acid derivative.
The invention also discloses application of the radix glycyrrhizae gadoleic acid derivative in anti-inflammatory drug or pharmaceutical composition is prepared；
Specifically preparing the medicine or medicine group of the relevant diseases such as treatment and prevention ALI, chronic obstructive pulmonary disease, septicopyemia
Application in compound.
The present invention has advantages below compared with prior art：
Radix glycyrrhizae gadoleic acid derivative provided by the present invention has reversible, selective anti-inflammatory activity, has good suppression
Inflammatory signals molecule NO generation；The preferable radix glycyrrhizae gadoleic acid derivative of which part is under 40 μM of concentration to suppression caused by NO
Rate shows very strong inhibitory activity more than 70%.
Brief description of the drawings
Fig. 1 is the synthetic route chart of radix glycyrrhizae gadoleic acid derivative.
Fig. 2 is the structural formula of radix glycyrrhizae gadoleic acid derivative.
Fig. 3 is that the suppression for the NO releases that lipopolysaccharides (LPS) induces in 2~18 pairs of RAW264.7 cells of compound derivatives is made
With.
Embodiment
Embodiments of the invention are elaborated below, the present embodiment is carried out lower premised on technical solution of the present invention
Implement, give detailed embodiment and specific operating process, but protection scope of the present invention is not limited to following implementation
Example.
The radix glycyrrhizae gadoleic acid derivative being related in the specific embodiment of the invention is as shown in table 1：
The different groups of the radix glycyrrhizae gadoleic acid derivative of table 1
1~embodiment of embodiment 16
The preparation of 1~derivative of derivative 16 (synthetic route is as shown in Figure 1)
Bibliography (Beseda I etc., Bioorg.Med.Chem., 2010,18 (1), 433-54), synthesize radix glycyrrhizae aldehyde.
80% sodium hydride (6.0mmol) is added in anhydrous tetrahydro furan (100mL), stirred under the conditions of 0 DEG C~5 DEG C, nitrogen
Gas shielded, phosphonoacetate (6.0mmol) was slowly added dropwise through 30 minutes, after adding, is stirred 1 hour under the same terms；
Gained radix glycyrrhizae aldehyde (5.0mmol) is dissolved in anhydrous tetrahydro furan (30mL), was added drop-wise under condition of ice bath through 30 minutes above-mentioned
In mixed reaction solution, it is stirred at room temperature 2~3 hours, TLC monitorings, treats that radix glycyrrhizae aldehyde reaction is complete, stop reaction；By reacting liquid filtering,
Ethyl acetate washes twice, merging filtrate, and extraction, organic phase is washed twice with water, anhydrous sodium sulfate drying, and filtering decompression is dense
Contracting, ethyl alcohol recrystallization obtain radix glycyrrhizae gadoleic acid derivative 1；
Gained radix glycyrrhizae alkene ester (3.2mmol) is dissolved in ethanol/chloroform (5/1) in the mixed solvent, is slowly added to hydrogen
Sodium hydroxide solution (50mL, 5%), is stirred at room temperature 2~3 hours；TLC is monitored, and after the reaction completely of radix glycyrrhizae alkene ester, stops reaction,
Watery hydrochloric acid is added dropwise and adjusts pH value to 4~5, chloroform extraction twice, respectively wash twice by organic phase washed with water and saturated sodium-chloride,
Anhydrous sodium sulfate drying, filtering are concentrated under reduced pressure, and obtain radix glycyrrhizae gadoleic acid derivative 2；
Radix glycyrrhizae olefin(e) acid (0.50mmol) is added in dichloromethane (20mL), stirring and dissolving, sequentially adds 1- ethyls-(3-
Dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (1.2mmol), I-hydroxybenzotriazole (1.2mmol) and corresponding amine
(1.0mmol, 2 equivalents), after stirring and dissolving, add triethylamine (2.0mmol)；It is stirred overnight at room temperature, TLC monitorings, treats radix glycyrrhizae alkene
After acid reaction is complete, reaction mixture is poured into frozen water (50mL), ice-out is treated in stirring, is layered, and extraction, organic phase is washed with water
Twice, anhydrous sodium sulfate drying；Filtering is concentrated under reduced pressure, ethyl alcohol recrystallization, obtains radix glycyrrhizae gadoleic acid derivative 3~16.
The Spectrum Analysis of the radix glycyrrhizae gadoleic acid derivative 1~16 is as follows：
Embodiment 1
Derivative 1：White powder, yield 64%, m.p.254-257 DEG C；1H-NMR(300MHz,CDCl3),δ(ppm):
6.89 (d, 1H, J=16.2Hz, H-30), 5.79 (d, 1H, J=16.2Hz, H-31), 5.63 (s, 1H, H-12), 4.52 (dd,
1H, J=11.4,5.0Hz, H-1), 4.20 (q, 2H, J=7.1Hz, OCH2CH3), 2.80 (dt, 1H, J=13.5,3.3Hz, H-
5),2.36(s,1H,H-9),2.05(s,3H,OAc),1.38(s,3H,H-27),1.13(s,3H,H-25),1.12(s,3H,H-
26),1.00(s,3H,H-23),1.01(s,3H,H-29),0.81(s,3H,H-24),0.80(s,3H,H-28).
Embodiment 2
Derivative 2：White powder, yield 91%；m.p.259-262℃；1H-NMR(300MHz,CDCl3),δ(ppm):
7.00 (d, 1H, J=16.2Hz, H-30), 5.82 (d, 1H, J=16.2Hz, H-31), 5.66 (s, 1H, H-12), 3.73 (q,
2H, J=7.0Hz), 3.24 (dd, 1H, J=9.8,6.5Hz, H-3), 2.79 (d, 1H, J=13.5, H-18), 2.36 (s, 1H,
H-9),1.38(s,3H,H-27),2.34(s,1H,H-9),1.13(s,3H,H-25),1.12(s,3H,H-26),1.00(s,
3H,H-23),1.01(s,3H,H-29),0.81(s,3H,H-24),0.80(s,3H,H-28)；13C-NMR(75MHz,CDCl3),
δ(ppm):200.3(C-11),170.43(C-13),169.5(C-32),157.9(C-30),128.3(C-12),119.4(C-
31),78.8(C-3),61.8(C-9),58.4(C-22),54.9(C-5),47.4(C-18),45.4(C-8),43.3(C-14),
42.8(C-20),39.1(C-4),39.1(C-1),38.0(C-10),37.1(C-19),36.7(C-21),32.7(C-2),
32.2(C-7),30.7(C-17),28.4(C-28),28.0(C-23),26.4(C-16),26.3(C-15),23.5(C-20),
18.6(C-26),18.4(C-27),17.4(C-6),16.3(C-25),15.5(C-24).
Embodiment 3
Derivative 3：White powder, yield 67%；m.p.269-271℃；1H-NMR(300MHz,CDCl3),δ(ppm):
6.78 (d, 1H, J=15.8Hz, H-30), 5.68 (d, 1H, J=15.8Hz, H-31), 5.55 (s, 1H, H-12), 3.23 (dd,
1H, J=10.0,60Hz, H-3), 2.90 (d, 3H, J=4.9Hz, NCH3),2.79(m,1H,H-18),2.34(s,1H,H-9),
1.38(s,3H,H-27),1.13(s,3H,H-25),1.12(s,3H,H-26),1.00(s,3H,H-23),1.01(s,3H,H-
29),0.81(s,3H,H-24),0.80(s,3H,H-28).TOF-HRMS:m/z[M+H]+calcd for C33H52NO3:
512.7910；found:512.7908.
Embodiment 4
Derivative 4：White powder, yield 70%；m.p.265-268℃；1H-NMR(300MHz,CDCl3),δ(ppm):
6.78 (d, 1H, J=15.8Hz, H-30), 5.68 (d, 1H, J=15.8Hz, H-31), 5.55 (s, 1H, H-12), 3.23 (dd,
1H, J=10.0,6.0Hz, H-3), 2.90 (s, 2 × 3H, NCH3),2.79(m,1H,H-18),2.34(s,1H,H-9),1.38
(s,3H,H-27),1.13(s,3H,H-25),1.12(s,3H,H-26),1.00(s,3H,H-23),1.01(s,3H,H-29),
0.81(s,3H,H-24),0.80(s,3H,H-28).TOF-HRMS:m/z[M+H]+calcd for C34H52NO3:524.8180；
found:524.8181.
Embodiment 5
Derivative 5：White powder, yield 60%；m.p.265-269℃；1H-NMR(300MHz,CDCl3),δ(ppm):
6.92 (d, 1H, J=15.6Hz, H-30), 6.07 (d, 1H, J=15.6Hz, H-31), 5.55 (s, 1H, H-12), 4.62 (d,
2H, J=24.9Hz), 3.14 (m, 2H, CH2CH3),2.77(d,1H,H-18),2.34(s,1H,H-9),1.38(s,3H,H-
27),1.13(s,3H,H-25),1.12(s,3H,H-26),1.00(s,3H,H-23),1.01(s,3H,H-29),0.81(s,
3H,H-24),0.80(s,3H,H-28).TOF-HRMS:m/z[M+H]+calcd for C34H54NO3:524.8049；found:
524.8050.
Embodiment 6
Derivative 6：White powder, yield 50%；m.p.278-281℃；1H-NMR(300MHz,CDCl3),δ(ppm):
6.82 (d, 1H, J=15.7Hz, H-30), 5.77 (d, 1H, J=15.5Hz, H-31), 5.59 (s, 1H, H-12), 3.78 (m,
2H,CH2O),3.52(m,2H,NCH2), 3.23 (m, 1H, H-3), 2.79 (d, 1H, J=13.0Hz, H-18), 2.34 (s, 1H, H-
9),1.38(s,3H,H-27),1.13(s,3H,H-25),1.12(s,3H,H-26),1.00(s,3H,H-23),1.01(s,3H,
H-29),0.81(s,3H,H-24),0.80(s,3H,H-28).TOF-HRMS:m/z[M+H]+calcd for C34H54NO4:
539.8048；found:539.8045.
Embodiment 7
Derivative 7：White powder, yield 60%；m.p.280-284℃；1H-NMR(300MHz,CDCl3),δ(ppm):
6.78 (d, 1H, J=15.8Hz, H-30), 6.57 (d, 1H, NH), 5.80 (d, 1H, J=15.8Hz, H-31), 5.62 (s, 1H,
H-17),1.13(s,3H,H-25),1.12(s,3H,H-26),1.00(s,3H,H-23),1.01(s,3H,H-29),0.81(s,
3H,H-24),0.80(s,3H,H-28).TOF-HRMS:m/z[M+H]+calcd for C35H56NO4:553.8311；found:
553.8315.
Embodiment 8
Derivative 8：White powder, yield 86%；m.p.254-257℃；1H-NMR(300MHz,CDCl3),δ(ppm):
6.78 (d, 1H, J=15.8Hz, H-30), 5.68 (d, 1H, J=15.8Hz, H-31), 5.61 (s, 1H, H-12), 5.58 (d,
1H, NH), 3.23 (dd, 1H, J=10.0,6.0Hz, H-3), 2.90 (d, 6H, J=4.9Hz, i-Pr-CH), 2.79 (m, 1H, H-
18),2.34(s,1H,H-9),1.13(s,3H,H-25),1.12(s,3H,H-26),1.00(s,3H,H-23),1.01(s,3H,
H-29),0.81(s,3H,H-24),0.80(s,3H,H-28).TOF-HRMS:m/z[M+H]+calcd for C35H56NO3:
537.8321；found:537.8320.
Embodiment 9
Derivative 9：White powder, yield 76%；m.p.264-268℃；1H-NMR(300MHz,CDCl3),δ(ppm):
6.78 (d, 1H, J=15.8Hz, H-30), 5.68 (d, 1H, J=15.8Hz, H-31), 5.55 (s, 1H, H-12), 3.94 (s,
1H, NH), 3.23 (dd, 1H, J=10.0,6.0Hz, H-3), 2.90 (d, 6H, J=4.9Hz, H-33), 2.9 (d, 3H, J=
4.9Hz,H-34),2.79(m,1H,H-18),2.34(s,1H,H-9),1.38(s,3H,H-27),1.13(s,3H,H-25),
1.12(s,3H,H-26),1.00(s,3H,H-23),1.01(s,3H,H-29),0.81(s,3H,H-24),0.80(s,3H,H-
28).TOF-HRMS:m/z[M+H]+calcd for C35H56NO3:537.8321；found:537.8325.
Embodiment 10
Derivative 10：White powder, yield 67%；m.p.243-246℃；1H-NMR(300MHz,CDCl3),δ
(ppm):6.78 (d, 1H, J=15.8Hz, H-30), 5.68 (d, 1H, J=15.8Hz, H-31), 5.55 (s, 1H, H-12),
3.62(t,2H,CH2Cl),3.50(m,2H,NCH2), 3.23 (dd, 1H, J=10.0,6.0Hz, H-3), 2.79 (m, 1H, H-
18),2.34(s,1H,H-9),1.38(s,3H,H-27),1.13(s,3H,H-25),1.12(s,3H,H-26),1.00(s,3H,
H-23),1.01(s,3H,H-29),0.81(s,3H,H-24),0.80(s,3H,H-28).TOF-HRMS:m/z[M+H]+calcd
for C35H55ClNO3:573.2770；found:573.2773.
Embodiment 11
Derivative 11：White powder, yield 50%；m.p.287-291℃；1H-NMR(300MHz,CDCl3),δ
(ppm):7.33 (m, 2H, H-Ar), 7.23 (m, 3H, H-Ar), 6.80 (d, 1H, J=15.8Hz, H-30), 5.65 (d, 1H, J=
15.8Hz, H-31), 5.57 (s, 1H, H-12), 3.61 (m, 2H, H-N), 3.23 (dd, 1H, J=10.0,6.0Hz, H-3),
2.88 (t, 2H, J=7.1Hz, NCH2),2.80(d,1H,H-18),2.34(s,1H,H-9),1.38(s,3H,H-27),1.13
(s,3H,H-25),1.12(s,3H,H-26),1.00(s,3H,H-23),1.01(s,3H,H-29),0.81(s,3H,H-24),
0.80(s,3H,H-28).TOF-HRMS:m/z[M+H]+calcd for C40H58NO3:600.4490；found:600.4495.
Embodiment 12
Derivative 12：White powder, yield 70%；m.p.281-285℃；1H-NMR(300MHz,CDCl3),δ
(ppm):8.26 (s, 1H, H-N), 7.21-6,87 (m, 6H, H-Ar, NH), 6.78 (d, 1H, J=15.8Hz, H-30), 5.80
(d, 1H, J=15.8Hz, H-31), 5.67 (s, 1H, H-12), 4.13 (dt, 1H, J=14.4,5.6Hz, H-N), 3.23 (dd,
1H, J=10.0,6.0Hz, H-3), 2.77 (d, 1H, H-18), 2.34 (s, 1H, H-9), 1.38 (s, 3H, H-27), 1.13 (s,
3H,H-25),1.12(s,3H,H-26),1.00(s,3H,H-23),1.01(s,3H,H-29),0.81(s,3H,H-24),0.80
(s,3H,H-28).TOF-HRMS:m/z[M+H]+calcd for C38H55N2O3:587.8624；found:587.8620.
Embodiment 13
Derivative 13：White powder, yield 78%；m.p.254-258℃；1H-NMR(300MHz,CDCl3),δ
(ppm):6.84 (d, 1H, J=15.7Hz, H-30), 6.19 (d, 1H, J=15.7Hz, H-31), 5.55 (s, 1H, H-12),
3.64(m,4H,NCH2), 3.23 (dd, 1H, J=10.0,6.0Hz, H-3), 2.77 (d, 1H, H-18), 2.43 (m, 4H, NCH2),
2.33(s,1H,H-9),2.33(s,3H,NCH3),1.38(s,3H,H-27),1.13(s,3H,H-25),1.12(s,3H,H-
26),1.00(s,3H,H-23),1.01(s,3H,H-29),0.81(s,3H,H-24),0.80(s,3H,H-28)；13C-NMR
(75MHz,CDCl3),δ(ppm):200.2(C-11),169.8(C-13),165.5(C-32),152.9(C-30),128.3(C-
12),118.3(C-31),78.7(C-3),61.8(C-9),54.9(C-5),47.4(C-18),45.9(2×NCH2),45.4
(C-8),43.3(C-14),43.0(C-20),39.1(C-4),39.1(C-1),37.7(C-10),37.1(C-19),36.7(C-
21),33.8(C-22),33.5(NCH3),32.7(C-7),32.3(2×NCH2),31.1(C-17),28.5(C-28),28.1
(C-23),27.3(C-2),26.4(C-16),26.3(C-15),26.3(C-29),23.5(C-27),18.7(C-26),17.4
(C-6),16.3(C-25),15.5(C-24).TOF-HRMS:m/z[M+H]+calcd for C37H59N2O3:579.8839；
found:579.8836.
Embodiment 14
Derivative 14：White powder, yield 74%；m.p.257-262℃；1H-NMR(300MHz,CDCl3),δ
(ppm):6.84 (d, 1H, J=15.7Hz, H-30), 6.19 (d, 1H, J=15.7Hz, H-31), 5.55 (s, 1H, H-12),
3.64(m,4H,NCH2), 3.23 (dd, 1H, J=10.0,6.0Hz, H-3), 2.77 (d, 1H, H-18), 2.45 (m, 6H,
CH2CH3,NCH2),2.34(s,1H,H-9),1.38(s,3H,H-27),1.13(s,3H,H-25),1.12(s,3H,H-26),
1.00(s,3H,H-23),1.01(s,3H,H-29),0.81(s,3H,H-24),0.80(s,3H,H-28)；13C-NMR(75MHz,
CDCl3),δ(ppm):200.2(C-11),169.8(C-13),165.5(C-32),152.9(C-30),128.3(C-12),
118.3(C-31),78.7(C-3),61.8(C-9),54.9(C-5),47.4(C-18),45.9(2×NCH2),45.4(C-8),
43.3(C-14),43.0(C-20),39.1(C-4),39.1(C-1),37.7(C-10),37.1(C-19),36.7(C-21),
33.8(C-22),33.5(CH2CH3),32.7(C-7),32.3(2×NCH2),31.1(C-17),28.5(C-28),28.1(C-
23),27.3(C-2),26.4(C-16),26.3(C-15),26.3(C-29),23.5(C-27),18.7(C-26),17.4(C-
6),16.3(C-25),15.5(C-24),11.8(CH2CH3).TOF-HRMS:m/z[M+H]+calcd for C38H61N2O3:
593.9105；found:593.9103.
Embodiment 15
Derivative 15：White powder, yield 76%；m.p.265-268℃；1H-NMR(300MHz,CDCl3),δ
(ppm):6.78 (d, 1H, J=15.8Hz, H-30), 6.57 (d, 1H, J=7.4Hz), 5.80 (d, 1H, J=15.8Hz, H-
31),5.62(s,1H,H-12),4.13-3.57(m,4H,2×CH2), O 3.23 (dd, 1H, J=10.0,6.0Hz, H-3),
2.77(d,1H,H-18),2.34(s,1H,H-9),2.34(s,3H),1.38(s,3H,H-27),1.13(s,3H,H-25),
1.12(s,3H,H-26),1.00(s,3H,H-23),1.01(s,3H,H-29),0.81(s,3H,H-24),0.80(s,3H,H-
28).TOF-HRMS:m/z[M+H]+calcd for C36H56NO4:566.8421；found:566.8423.
Embodiment 16
Derivative 16：White powder, yield 56%；m.p.272-276℃；1H-NMR(300MHz,CDCl3),δ
(ppm):6.89 (d, 1H, J=4.9Hz, NH), 6.78 (d, 1H, J=15.8Hz, H-30), 5.68 (d, 1H, J=15.8Hz, H-
31),5.55(s,1H,H-12),3.73(m,4H,OCH2),3.43(m,4H,NCH2), 3.23 (dd, 1H, J=10.0,6.0Hz,
H-3),2.78(d,1H,H-18),2.49(m,6H,NCH2),2.34(s,1H,H-9),1.38(s,3H,H-27),1.13(s,
3H,H-25),1.12(s,3H,H-26),1.00(s,3H,H-23),1.01(s,3H,H-29),0.81(s,3H,H-24),0.80
(s,3H,H-28)TOF-HRMS:m/z[M+H]+calcd for C39H63N2O4:623.9220；found:623.9223.
Embodiment 17~18
The preparation of derivative 17 (synthetic route is as shown in Figure 1)
Radix glycyrrhizae olefin(e) acid (1.0mmol) is added in dichloromethane (20mL), adds corresponding alcohols (10 equivalent), stirring ten
Minute, boron trifluoride ether solution (2.0mmol) is added, is reacted at room temperature 24 hours；Point plate detection, to the end of radix glycyrrhizae olefine acid reaction
Afterwards, reaction is stopped；Reaction solution is poured into frozen water (50mL), treats ice-out, is layered, extraction, organic phase is washed twice with water, nothing
Aqueous sodium persulfate is dried；Filtering is concentrated under reduced pressure, ethyl alcohol recrystallization, obtains radix glycyrrhizae gadoleic acid derivative 17~18.
The Spectrum Analysis of the derivative 17~18 of the radix glycyrrhizae olefin(e) acid is as follows：
Embodiment 17
Derivative 17：White powder, yield 50%；m.p.273-275℃；1H-NMR(300MHz,CDCl3),δ
(ppm):7.00 (d, 1H, J=16.2Hz, H-30), 5.82 (d, 1H, J=16.2Hz, H-31), 5.66 (s, 1H, H-12),
4.25(m,2H,OCH2CH3), 3.73 (q, 2H, J=7.0Hz), 3.24 (dd, 1H, J=9.8,6.5Hz, H-3), 2.80 (d, 1H,
J=13.5, H-18), 2.36 (s, 1H, H-9), 1.38 (s, 3H, H-27), 2.38 (s, 1H, H-9), 1.13 (s, 3H, H-25),
1.11(s,3H,H-26),1.00(s,3H,H-23),1.01(s,3H,H-29),0.80(s,3H,H-24),0.79(s,3H,H-
28).
Embodiment 17
Derivative 18：White powder, yield 48%；m.p.279-281℃；1H-NMR(300MHz,CDCl3),δ
(ppm):7.32-7.25 (m, 5H, Ar), 6.98 (d, 1H, J=16.2Hz, H-30), 5.80 (d, 1H, J=16.2Hz, H-31),
5.64 (s, 1H, H-12), 4.76 (s, 2H, OCH2Ph), 3.73 (q, 2H, J=7.0Hz), 3.24 (dd, 1H, J=9.8,
6.5Hz, H-3), 2.80 (d, 1H, J=13.5, H-18), 2.36 (s, 1H, H-9), 1.38 (s, 3H, H-27), 2.38 (s, 1H,
H-9),1.13(s,3H,H-25),1.11(s,3H,H-26),1.00(s,3H,H-23),1.01(s,3H,H-29),0.80(s,
3H,H-24),0.79(s,3H,H-28).
Test example 1
2~18 couples of NO of derivative of radix glycyrrhizae olefin(e) acid produce inhibitory activity detection：
NO is a kind of important pro-inflammatory mediator.It is relevant with inflammation related disease that excessive NO is produced in vivo.Make everybody widely
Receive, NO inhibitor has the method that new treatment inflammation related disease may be potentially looked for chance.In order to evaluate
The antiinflammatory action of radix glycyrrhizae gadoleic acid derivative, the NO that lipopolysaccharides (LPS) induces in RAW264.7 cells is detected using Griess reagents
Emission levels.RAW264.7 cells are seeded in 24 orifice plates and cultivated 20 hours with 1 × 105 cells/well；Then with 50 μM
The compound pretreatment cell of concentration, it is prepared 2 hours before being stimulated with LPS (1 μ g/mL) in serum free medium；Through
After LPS is stimulated 24 hours, nitrite level is detected using Griess reagents (Beyotime, China) by specification and come really
Determine to measure caused by NO；Then extinction of the measurement sample at 540nm in microplate reader (MQX200, Bio-Tek, USA)
Spend (OD540)；NO inhibiting rates=[control (OD540)-compound (OD540)]/[control (OD540)-blank (OD540)] × 100%；
The result of the MAO bioactivity detection of the derivative 1~18 of radix glycyrrhizae olefin(e) acid of the present invention is as shown in Figure 3.
Marginal data is as follows：
(1)aEach numerical value is from three empirical averages ± SEM (n=3)；
(2) compared with blank group, #p<0.05, ##p<0.01, ###p<0.001；
(3) the * p compared with LPS stimulation groups<0.05, * * p<0.01, * * * p<0.001.
The result of the test example 1 of the present invention shows：
The derivative of radix glycyrrhizae olefin(e) acid provided by the invention has good anti-inflammatory activity；
Radix glycyrrhizae gadoleic acid derivative can suppress the NO emission levels that lipopolysaccharides (LPS) induces in RAW264.7 cells；
The NO releases that radix glycyrrhizae gadoleic acid derivative 2,3~7,13,14 and 16 of the present invention significantly suppress LPS inductions increase
Add；Especially there is piperazine substituted compound 13 and 14 to show most strong inhibitory activity, and under 40 μM of concentration
Its inhibiting rate to NO releases is more than 70%.
Application examples 1
The preparation of following composition is prepared in a usual manner：
The radix glycyrrhizae gadoleic acid derivative prepared in embodiment 1~18 is crossed into 120 mesh sieves, amylum pregelatinisatum crosses 100 mesh sieves；Weigh
The amylum pregelatinisatum of recipe quantity is mixed with raw material by equal increments method；Hydroxypropyl methyl cellulose and polyvinylpyrrolidone dissolving
The wiring solution-forming in 75% ethanol, above-mentioned mixed powder is taken, with hydroxypropyl methyl cellulose and the ethanol solution of polyvinylpyrrolidone
As wetting agent softwood, the granulation of 30 mesh sieves, 60 DEG C of dryings 2~3 hours, 26 mesh sieve whole grains；
Above particle is taken, adds the magnesium stearate of recipe quantity, is mixed, determines intermediates content, tabletting or filling in capsule,
.
Sustained release tablets, dripping pill, electuary, injection etc. can also be made in radix glycyrrhizae gadoleic acid derivative.Its clinical recommended dose：30~
100mg/ days, orally, twice a day.
The above embodiments merely illustrate the technical concept and features of the present invention, and its object is to allow be familiar with this art
Personage can understand present invention and be carried out, and it is not intended to limit the scope of the present invention.It is all according to the present invention
The equivalent change or modification that Spirit Essence is made, it should all cover within the scope of the present invention.
Claims (3)
1. a kind of radix glycyrrhizae gadoleic acid derivative, it is characterised in that it has below formula：
2. application of the radix glycyrrhizae gadoleic acid derivative as claimed in claim 1 in anti-inflammatory drug is prepared.
3. radix glycyrrhizae gadoleic acid derivative as claimed in claim 1 is preparing treatment and prevention ALI, chronic obstructive pulmonary disease, septicopyemia blood
Application in the medicine of disease.
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| Discovery of a Potential Anti-Inflammatory Agent:3-Oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile;Ran You，et al.;《J.Med.Chem.》;20130201;第56卷;第1984−1995页 * |
| Synthesis and Pro-Apoptotic Activity of Novel Glycyrrhetinic Acid Derivatives;Evgeniya B.Logashenko，et al.;《ChemBioChem》;20110215;第12卷;第784-794页 * |
| SYNTHESIS AND REACTIONS OF 18β-GLYCYRRHETALDEHYDE;S. Rozen, et al.;《Tetrahedron》;19731231;第29卷;第2327-2331页 * |
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