CN100422168C - Hesperetin derivant and preparation process thereof - Google Patents
Hesperetin derivant and preparation process thereof Download PDFInfo
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- CN100422168C CN100422168C CNB2006100880153A CN200610088015A CN100422168C CN 100422168 C CN100422168 C CN 100422168C CN B2006100880153 A CNB2006100880153 A CN B2006100880153A CN 200610088015 A CN200610088015 A CN 200610088015A CN 100422168 C CN100422168 C CN 100422168C
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Abstract
The present invention relates to a hesperetin derivative which is a compound represented by a (1) formula. In the formula, R1 is OH, OR'1 or OOCR'2; R2 is H, halogen or OR'1; R3 is H, NO2 or NR'3R'4; R1 on the three positions of 5, 7 and a' can be identical, and can also be different; R2 on the three positions of 6, 8 and the hesperetin derivative ' can be identical, and can also be different, wherein the R'1 is a straight chain or branched alkyl of C1 to C10, and the R2 is a straight chain or branched alkyl of C1 to C6; R'3 and R'4 are saturated alkyl of C1 toC6 (the R'3 and the R'4 can be identical, and can also be different) or 3 to 7 member saturated not replaced or replaced N-hetero-single ring comprises the R'3, the R'4 and a nitrogen atom connected with the R'3 and the R'4. The activity experiment of peritoneal macrophage (PM phi) in vitro inhibiting adjuvant-induced arthritis rat (AA rat) of the hesperetin derivative synthesizing PGE2 and LTB4 indicates that the anti-inflammatory activity of the hesperetin derivative is apparently higher than that of parent body hesperetin.
Description
One, technical field
The invention belongs to flavonoid compound, be specifically related to derivative of a class Hesperitin and preparation method thereof.
Two, background technology
Hesperitin is the non-saccharide compound of Hesperidin after glycosyl is sloughed in hydrolysis, belongs to flavonoid compound, its chemical structure as the formula (3):
Has wide biological activity, as anti-oxidant (Park, people J.Agric.Food Chem.51 such as B-S., 7203,2003.), antitumor (Dauzonne, people such as D., J.Med.Chem.46,3900-3913,2003; Brueggemeier, people such as R.W., J.Med.Chem.47,4032-4040,2004), anti-inflammatory (Kang, people such as Y.-H., J.Agric.FoodChem.53,5150-5157,2005), prevention and the treatment disease (Chinese patent: CN 1278170, the 2000.12.27 that raise and cause by cholesterol; CN 97198803.X, 1999.10.27), prevention and the treatment disease (Chinese patent: CN1317938A that raises and cause by blood fat or glucose level, 2001.10.17) and with 5-hydroxyl look ammonia diseases associated (Chinese patent: CN02153313.X, 2003.5.14).
But the above-mentioned biological activity of Hesperitin only just plays produce effects in heavy dose of (〉=100mg/kg body weight/day), and Hesperitin difficulty be absorbed in the body, therefore also seldom directly be used as curative, as seen, exploitation drug effect novel derivative stronger than Hesperitin itself, that bioavailability is higher is necessary.
Three, summary of the invention
The purpose of this invention is to provide hesperetin derivant of a class formation novelty and preparation method thereof.
Hesperetin derivant of the present invention; it is characterized in that: three hydroxyl acylations of Hesperitin 5-position, 7-position and 3 '-position or 7-position, 3 '-two hydroxy alkylateds in position and/or 6-position, 8-position and 2 '-position are introduced 1-3 halogen atom and replaced, and nitro or amino replacement are introduced in 5 '-position.Be expressed as follows with chemical structure of general formula:
In the formula: R
1Be OH, OR '
1Or OOCR '
2
R
2Be H or halogen;
R
3Be H, NO
2Or NR '
3R '
4
R
4Be OH or OOCR '
2
7, the R on 3 '-position
1Can be identical, also can be different;
R on 6,8,2 '-three
2Can be identical, also can be different;
Wherein: R '
1Be C
1-C
10The straight or branched alkyl;
R '
2Be C
1-C
6The straight or branched alkyl;
R '
3, R '
4Be H
OrC
1-C
6Saturated alkyl, they can be identical, also can be different; Or R '
3, R '
4Form the assorted monocycle of the saturated N-that does not replace or replace of 3-7 person with the nitrogen-atoms that links to each other with them.
In the preferred formula:
R
1Be OH, OCH
3Or OOCCH
3
R
2Be H, F, Cl, Br;
R
3Be H, NO
2Or NH
2
R
4Be OH or OOCR '
2
7, the R on 3 '-position
1Can be identical, also can be different;
R on 6,8,2 '-three
2Can be identical, also can be different.
Most preferably in the formula:
R
1Be OH, OCH
3Or OOCCH
3
R
2Be H or Br
R
3Be H, NO
2Or NH
2
R
4Be OH or OOCH
3
R on 7,3 '-three
1Can be identical, also can be different;
R on 6,8,2 '-three
2Can be identical, also can be different.
Preferred following compound:
5,7,3 '-triacetyl Hesperitin (4) or 5 '-nitro-5,7,3 '-triacetyl Hesperitin (5) or 5 '-nitro Hesperitin (6) or 5 '-amino-5,7,3 '-triacetyl Hesperitin (7) or 7,3 '-dimethoxy Hesperitin (8) or 6,8,2 '-tribromo Hesperitin (9) or 8-bromo-7,3 '-dimethoxy Hesperitin (10).
Hesperetin derivant of the present invention is to be raw material with Hesperitin, makes through the following steps:
A Hesperidin (2) solves Hesperitin (3) through sour water;
B Hesperitin (3) carries out acylations with aceticanhydride/pyridine and gets 5,7,3 '-triacetyl Hesperitin (4);
Hesperitin and excessive aceticanhydride and pyridine react at ambient temperature, and the consumption of aceticanhydride (double as solvent) is the 10-3 equivalent, preferred 15-20 equivalent; The consumption of pyridine is the 1.2-3 equivalent, preferred 1.5-2 equivalent; Temperature of reaction is 15-35 ℃, preferred 20-25 ℃, stir 4-7h under these conditions, and reaction promptly reaches terminal point.Reaction mixture gets 5,7,3 '-triacetyl Hesperitin straight product, productive rate 87-95% through separating and column chromatography purification.
C 5,7,3 '-triacetyl Hesperitin (4) (CF
3CO)
2O/NH
4NO
3Carry out nitrated 5 '-nitro-5,7, the 3 '-triacetyl Hesperitin (5) of getting;
With 5,7,3 '-triacetyl Hesperitin is a raw material, with (CF
3CO)
2O/NH
4NO
3Be nitrating agent, under the room temperature be dissolved in CHCl
3In 5,7,3 '-triacetyl Hesperitin stirs 3h together, productive rate 75-78%.
D 5 '-nitro-5,7,3 '-triacetyl Hesperitin (5) solves 5 '-nitro Hesperitin (6) through alkaline water;
5 '-nitro-5,7, hydrolysis under 3 '-triacetyl Hesperitin alkaline condition, described alkali is various mineral alkalis, as NaOH, KOH, K
2CO
3, Na
2CO
3Deng, preferably use K
2CO
3Mixed solvent (CH at methyl alcohol and water
3OH: H
2O=4-5: reaction 1-3h 1), product dehydrated alcohol recrystallization gets pure 5 '-nitro Hesperitin yellow solid, productive rate 70-82%.
E 5 '-nitro-5,7,3 '-triacetyl Hesperitin (5) gets 5 '-amino-5,7,3 '-triacetyl Hesperitin (7) through palladium/carbon shortening;
With 5 '-nitro-5,7,3 '-triacetyl Hesperitin is dissolved in ethyl acetate, and elimination catalyzer after normal temperature and pressure is reached home with the 10%Pd/C catalytic hydrogenation reaction down gets final product high yield (90-95%) and obtains target product 5 '-amino Hesperitin.
Under f Hesperitin (3) alkaline condition with methyl-sulfate methylate 7,3 '-dimethoxy Hesperitin (8);
Hesperitin is dissolved in acetone and NaH and (CH
3)
2SO
4React 5-7h down in 60-75 ℃.After reaction is reached home, remove excessive methyl-sulfate with proper ammonia, product is directly used column chromatography purification, productive rate 50-55% after precipitation, separation.
Bromo gets 6,8 under g Hesperitin (3) normal temperature, 2 '-tribromo Hesperitin (9);
Hesperitin is dissolved in ethyl acetate, drips Br down in normal temperature
2/ AcOEt stirs 4-6h, and product is through column chromatography purification, and 6,8, the productive rate 90-92% of 2 '-tribromo Hesperitin.
H 7,3 '-dimethoxy Hesperitin (8) at low temperatures on the 8-position selectivity bromo get 8-bromo-7,3 '-dimethoxy Hesperitin (10).
With 7,3 '-dimethoxy Hesperitin is dissolved in THF (tetrahydrofuran (THF)), and (0-5 ℃) drips Br under-5-10 ℃ condition
2In THF solution, stirring reaction 6-9h, product be through column chromatography purification, 8-bromo-7, the productive rate 50-52% of 3 '-dimethoxy Hesperitin.
Above-mentioned preparation process can be expressed as follows with the reaction sketch:
A. dense H
2SO
4/ CH
3OH, backflow b. (CH
3CO)
2O/ pyridine c. (CF
3CO)
2O/NH
4NO
3
d.H
2O，CH
3OH/K
2CO
3 e.H
2，Pd/C f.NaH/(CH
3)
2SO
4，CH
3COCH
3
g.Br
2/AcOEt，rt h.Br
2/THF，＜10℃
Hesperetin derivant vitro inhibition adjuvant arthritis rats of the present invention (AA rat) peritoneal macrophage (PM φ) synthesizes PGE
2And LTB
4Activity experiment show that its anti-inflammatory activity is apparently higher than its parent Hesperitin.For example, hesperetin derivant 8 provided by the invention and 10 is 10
-4Mol.L
-1, 10
-5Mol.L
-1, 10
-6Mol.L
-1With 10
-7Mol.L
-1All significantly reduce AA P of Rats M φ secretion PGE under four kinds of concentration
2Amount, it suppresses PGE
2The activity that generates is apparently higher than Hesperitin itself (seeing Table the data on 1 the 8th, 10 hurdle vs the 11st hurdle); And the synthetic LTB of hesperetin derivant vitro inhibition AA P of Rats M φ provided by the invention
4Half-inhibition concentration IC
50All than the low (IC of Hesperitin
50Low more, show that compound suppresses LTB
4The synthetic ability is strong more).The IC of compound (8), (4) and (9) wherein
50Be respectively 5.56 * 10
-8, 1.41 * 10
-7With 2.06 * 10
-7MolL
-1, all well below the IC of Hesperitin itself
50(1.41 * 10
-4), the IC of compound (7) and (5)
50(2.41 * 10
-6With 8.03 * 10
-6) also be starkly lower than Hesperitin.
In addition, all have antitumor, anti-oxidant, antibiotic and antiviral in various degree and multiple biological activitys such as prevention and treatment cardiovascular disorder according to known flavonoid compound, hesperetin derivant of the present invention can also be developed their application in above-mentioned each biological activity field, is the new compound that important use is arranged.
Hesperidin of having reported or hesperetin derivant are never seen the product of selective alkylation on 7-position and 3 '-position; also never see in 6,8,2 '-position bromo simultaneously; or the independent selectivity bromo in 8-position; or in nitrated, the amino replacement of 5 '-position selection; also or earlier in alkylation of 5,7,3 '-position or acylations; bromo, nitrated or amino replacement on above-mentioned specified location then; therefore hesperetin derivant provided by the invention is different with known hesperetin derivant on structure, composition, and they are brand-new compounds.
Because hesperetin derivant of the present invention is the new compound that does not appear in the newspapers, its preparation method also is what not appear in the newspapers, though similarly reactions steps is known, but the present invention has done important improvement when implementing these steps, as: the nitration reaction traditional method on the aromatic nucleus is that the nitration mixture of forming with the vitriol oil and concentrated nitric acid is a nitrating agent, or uses CH
3COO
-+NO
2Be nitrating agent, but in the nitration reaction of embodiments of the invention 4,, then cause the reaction solution blackening, almost can not get product if use nitration mixture; Promptly use CH
3COO
-+NO
2Be nitrating agent, productive rate is also very low.And with provided by the invention
(CF 3 CO) 2 O/NH 4 NO 3 Be nitrating agent, then reflection is carried out steadily, and productive rate reaches more than 75%.And for example, introduce the bromo-reaction of three bromine atoms simultaneously in Hesperitin 6-position, 8-position and 2-position, by the Br that adopts usually
2/ CCl
4Or Br
2/ THF is a brominated reagent, can not get target compound or productive rate very low (＜50%), and the ethyl acetate that adopts by the present invention is a solvent, can high yield obtain target compound (90%).
Four, embodiment
Advance-go on foot explanation the present invention below by embodiment, but it does not limit the present invention.
Embodiment 1: the preparation of Hesperitin (3)
2g Hesperidin 80mL methyl alcohol is added in the 150mL there-necked flask successively, stir and slowly to drip the 2mL vitriol oil down, reflux 7.5h then, solution becomes clarification by muddiness, reaction solution is poured in the 300mL ethyl acetate, leave standstill a moment, produce precipitation, filter, solid washs with a small amount of cold ethyl acetate, merging filtrate is with saturated common salt washing, anhydrous Na
2SO
4Dry.The pressure reducing and steaming solvent, gained yellow solid crude product gets pure Hesperitin (3) product 0.75g, productive rate 75.7%, m.p.227.5-228.5 ℃ with ethanol/water mixed solvent (7: 3) recrystallization.
1HNMR(DMSO-d
6)，δ(ppm)：2.67-3.25(m，2H)；3.77(s，3H)；5.43(dd，1H，J＝3.0Hz，12.4Hz)；5.89(s，2H)；6.86(m，3H).
IR (KBr) cm
-1: 3304 (V
0-H); 1637 (V
C=0); 1587,1514,1465 (phenyl ring)
Embodiment 2:5,7, the preparation of 3 '-triacetyl Hesperitin (4)
(16.2g, 158.6mmol) (3.03g 31.2mmol), stirs 3h under the room temperature, and reaction solution is become pale yellow by yellow with pyridine 3.2mL to add Hesperitin 3.13g (10.4mmol), aceticanhydride 15mL in the 50mL there-necked flask successively.Aceticanhydride that pressure reducing and steaming is excessive and pyridine, residue CH
2Cl
2Saturated NaHCO is used in dissolving then successively
3, rare HCL and saturated common salt water washing, anhydrous Na
2SO
4Dry.Boil off solvent and get light yellow solid, through column chromatography purification (eluent: ethyl acetate: sherwood oil=1: 3 or acetone: normal hexane=1: 4), pure 5,7,3 '-triacetyl Hesperitin (4) white solid 4.16g, productive rate 90%, m.p.140.5-142 ℃.
1H?NMR(CDCl
3)，δ(ppm)：2.30(s，3H)；2.33(s，3H)；2.38(s，3H)；2.76(dd，1H，J＝2.61Hz，16.68Hz)；3.02(dd，1H，J＝13.5Hz，16.65Hz)；3.85(s，3H)；5.42(dd，1H，J＝2.45Hz，13.44Hz)；6.53(d，1H，J＝2.01Hz)；6.76(d，1H，J＝2.01Hz)；7.01(d，1H，J＝8.46Hz)；7.16(d，1H，J＝1.74Hz)；7.26(t，1H，J＝7.8Hz).
IR (KBr) cm
-1: 1773 (V
C=0, ester); 1691 (V
C=0, ketone); 1618,1516,1434 (phenyl ring).
Embodiment 3:
(5.4g, 5.27mmol) (1.52g 15.6mmol), stirs 6h under the room temperature, and reaction solution is become pale yellow by yellow with chloroform 10mL, pyridine 1.6mL to add Hesperitin 3.13g (10.4mmol), aceticanhydride 5mL in the 50mL there-necked flask successively.Aceticanhydride that pressure reducing and steaming is excessive and pyridine, residue CH
2Cl
2Saturated NaHCO is used in dissolving then successively
3, rare HCL and saturated common salt water washing, anhydrous Na
2SO
4Dry.Boil off solvent and get light yellow solid, through column chromatography purification (eluent: ethyl acetate: sherwood oil=1: 3), pure 5,7,3 '-triacetyl Hesperitin (4) white solid 4.07g, productive rate 88%.
Embodiment 4:5 '-nitro-5,7, the preparation of 3 '-triacetyl Hesperitin (5)
In the 100mL round-bottomed bottle, add 5,7,3 '-triacetyl Hesperitin 4.8g (11.2mmol), NH
4NO
30.9g (11.2mmol), (CF
3CO)
2O 6mL and CHCl
320mL is stirred to NH under the room temperature
4NO
3Dissolving (about 2h) is poured reaction mixture in the 40mL water into fully, uses CHCl
3(3x40mL) extraction, combining extraction liquid, drying boils off most of solvent, residuum through column chromatography for separation (eluent: ethyl acetate: sherwood oil=1: 3), pure products (5) white solid 3.7g, productive rate 75-78%, m.p.58-58.5 ℃.
1H?NMR(CDCl
3)，δ(ppm)：2.31(s，3H)；2.38(s，3H)；2.40(s，3H)；2.79-3.03(m，2H)；3.96(s，3H)；5.50(dd，1H，J＝3.1Hz，13.3Hz)；6.60(d，1H，J＝2.2Hz)；6.82(d，1H，J＝2.2Hz)；7.43(d，1H，J＝2.2Hz)；7.83(d，1H，J＝2.2Hz).
IR (KBr) cm
-11776 (V
C=0, ester); 1693 (V
C=0, ketone); 1618,1540,1435 (phenyl ring).
MS：m/z＝473(M
+).
Embodiment 5:
Above-mentioned nitration reaction is added drop-wise to 5,7 with nitration mixture if make nitrating agent with the nitration mixture that adopts usually under the room temperature, and 3 '-three second Hesperitins are at CH
2Cl
2In the solution, reaction solution is blackening gradually, and has jelly to generate, and can not separate desired product at last from this reaction mixture.
Embodiment 6:
Gentle nitrating agent CH is used in above-mentioned reaction instead
3COONO
2At CHCl
3With 5,7, the reaction of 3 '-triacetyl Hesperitin is stirred 24h under the room temperature in the solution, and TLC shows that reactant does not change fully; Using oil of mirbane instead is solvent, the reaction 24h down that refluxes, and reactant has acted on fully, but the product more complicated directly uses column chromatography, and can get target product 5 '-nitro-5,7,3 '-triacetyl Hesperitin, but productive rate 35-47% only.
The preparation of embodiment 7:5 '-nitro Hesperitin (6)
In the 50mL round-bottomed bottle, add 5 '-nitro-5,7,3 '-triacetyl Hesperitin 2g (4.23mmol), methyl alcohol 20mL, water 5mL and K
2CO
3620mg (4.5mmol), stir about 1h boils off solvent under the room temperature, and residue is with dehydrated alcohol extraction and carry out recrystallization, gets pure products yellow solid 1.08g, yield 75%, m.p.225-226 ℃.
1HNMR(CD
3COCD
3)，δ(ppm)：2.82-3.20(m，2H)；3.95(s，3H)；5.55(dd，1H，J＝3.1Hz，12.6Hz)；6.00(dd，2H，J＝2.1Hz，13.7Hz)；7.45(dd，2H，J＝2.0Hz，16.7Hz).
IR (KBr) cm
-13394 (V
0-H); 1648 (V
C=0); 1618,1524,1357 (phenyl ring).
MS：m/z＝347(M
+).
Embodiment 8:5 '-amino-5,7, the preparation of 3 '-triacetyl Hesperitin (7)
With 5 '-nitro-5,7,3 '-triacetyl Hesperitin 4g (8.5mmol) is dissolved in the 60mL ethyl acetate, adds 10%Pd/C catalyzer 0.6g, and normal temperature stirs down and feeds H
2, react about 20h, elimination Pd/C, filtrate decompression boils off solvent, the residuum column chromatography purification (eluent: ethyl acetate: sherwood oil=1: 3), get glassy yellow solid 3.8g, productive rate 95%, m.p.77-78 ℃.
1H?NMR(CDCl
3)，δ(ppm)：2.14(s，2H)；2.30(s，3H)；2.34(s，3H)；2.38(s，3H)；2.72-3.03(m，2H)；3.78(s，3H)；5.34(dd，1H，J＝2.7Hz，13.4Hz)；6.53(d，1H，J＝2.2Hz)；6.62(d，1H，J＝1.54Hz)；6.80(d，1H，J＝1.4Hz)；6.78(d，1H，J＝2.2Hz).
IR (KBr) cm
-1: 3377 (V
N-H); 1771 (V
C=0, ester); 1692 (V
C=0, ketone); 1618,1434 (phenyl ring).
MS：m/z＝443(M
+).
Embodiment 9:7, the preparation of 3 '-dimethoxy Hesperitin (8)
The 1.2g Hesperitin is dissolved in the 20mL acetone, adds 650mg NaH, produce a large amount of gases immediately, generate yellow solid simultaneously.Be stirred to no gas and produce, add 20mL water and make the solid dissolving.Add the 3mL methyl-sulfate then, add under the room temperature of back and stir 8h, reactant is most of not to be changed; Be warming up to 60 ℃, react about 3h, TLC shows that reactant transforms fully.In reaction mixture, drip less ammonia to remove unnecessary methyl-sulfate.With reaction solution pressure reducing and steaming solvent, residuum extracts with ethyl acetate (3x20mL), combining extraction liquid, dry (Na
2SO
4) the pressure reducing and steaming solvent, the residue column chromatography purification (eluent: ethyl acetate: sherwood oil=1: 5), get white solid product 0.7g, productive rate 53%, m.p.138-139 ℃.
1H?NMR(CDCl
3)，δ(ppm)：2.80(dd，1H，J＝3.03Hz，17.16Hz)；3.11(dd，1H，J＝12.99Hz，17.16Hz)；3.81(s，3H)；3.90(s，3H)；3..92(s，3H)；5.40(dd，1H，J＝3.1Hz，12.3Hz)；6.06(dd，2H，J＝2.31Hz，5.22Hz)；6.90(d，1H，J＝8.76Hz)；6.98(dd，2H，J＝1.95Hz，5.58Hz)；12.03(s，1H).
IR (KBr) cm
-1: 3434 (V
0-H); 1637 (V
C=0); 1573,1517,1427 (phenyl ring); 1303,1156 (V
C-0).
Embodiment 10:
Above-mentioned methylation reaction behind the stirring 3h, mainly generates the product 5,7 of exhaustive methylation, 3 '-trimethoxy Hesperitin if carry out under higher temperature (＞75 ℃).
Embodiment 11:6,8, the preparation of 2 '-tribromo Hesperitin (9)
The 4.4g Hesperitin is dissolved in the 300mL ethyl acetate, to the solution of the slow Dropwise 5 mL of this solution bromine in the 30mL ethyl acetate, TLC follows the tracks of until the raw material complete reaction, the reaction solution steaming is directly used column chromatography (eluent: ethyl acetate: sherwood oil=1: 1) except that behind the partial solvent, get light yellow powdery solid 5.5g, productive rate 90%, m.p.204.5-205.5 ℃.
1H?NMR(CD
3COCD
3)，δ(ppm)：2.93-3.30(m，2H)；3..91(s，3H)；5.64(dd，1H，J＝3.2Hz，12.0Hz)；7.00(d，1H，J＝3.3Hz)；7.09(s，1H).
IR (KBr) cm
-13517,3386 (V
0-H); 1636 (V
C=0); 1561,1440 (phenyl ring); 1356,1106 (V
C-0).
Embodiment 12:
Above-mentioned bromo-reaction is if use CCl
4Be solvent, Br
2/ CCl
4Be brominated reagent, reaction does not take place basically.
Embodiment 13:
Above-mentioned bromo-reaction, if be solvent with THF, Br
2/ THF is a brominated reagent, stirs 4h under the room temperature, and TLC shows that reactant has acted on fully, but the product complexity that generates, through column chromatography for separation, and productive rate only 23%.
Embodiment 14:8-bromo-7, the preparation of 3 '-dimethoxy Hesperitin (10)
With 3g 7,3 '-dimethoxy Hesperitin is dissolved among the 100mL THF, and ice bath (0-5 ℃) cooling slowly drips the solution of 1mL bromine in 10mL THF to this solution down, follows the tracks of reaction with TLC, and is complete until the raw material effect.The reaction solution steaming is directly used column chromatography except that behind the partial solvent (eluent: ethyl acetate: sherwood oil=1: 4), get white solid 2.01g, productive rate 52%, m.p.201-202 ℃.
1H?NMR(CDCl
3)，δ(ppm)：2.82-3.21(m，2H)；3..91(s，3H)；3..92(s，3H)；3..93(s，3H)；5.39(dd，1H，J＝2.9Hz，13.1Hz)；6.18(s，1H)7.00(m，3H).
IR (KBr) cm
-1: 3432 (V
0-H); 1633 (V
C=0); 1554,1523 (phenyl ring).
MS：m/z＝408(M
+).
The anti-inflammatory activity of hesperetin derivant of the present invention is measured:
Experimental principle:
Prostaglandin PGE
2With leukotriene LTB4 be two kinds of important inflammatory mediators of inflammatory reaction.The present invention adopts the treated in vitro mode, and research Hesperitin and derivative thereof suppress the synthetic PGE of adjuvant arthritis rats peritoneal macrophage
2With the activity of LTB4, filter out the high hesperetin derivant of anti-inflammatory activity.
1, the Hesperitin novel derivative suppresses the synthetic PGE of adjuvant arthritis (AA) rat macrophage (PM φ)
2Experiment peritoneal macrophage preparation:
Sacrificed by decapitation adjuvant arthritis rat (AA rat) is injected D-Hank ' s liquid 5mL in intraperitoneal, gently rubs belly, extracts irrigating solution out; Repeat twice, merge irrigating solution, centrifuge washing promptly gets the suspension that is rich in scavenger cell (PM φ).Be adjusted to required cell concn (1x10 with 10% calf serum RPMI-1640 suspension cell
6/ mL).
Above-mentioned rat abdominal cavity scavenger cell suspension is divided into 39 groups.Remove normal group, AA group and positive drug A
771726Outside 3 groups, the Hesperitin of all the other 8 kinds Hesperitin novel derivatives to be measured and contrast is totally 9 kinds of compounds, every kind of branch 10
-4Mol.L
-1, 10
-5Mol.L
-1, 10
-6Mol.L
-1With 10
-7Mol.L
-1Four kinds of concentration.Establish two pipes for every group, (the scavenger cell final concentration is 5x10 to the medicine of every pipe adding 0.5mL PM φ suspension and 0.5mL different concns
5/ mL), 20min. vibrates in 37 ℃ of water-baths.Except that the AA group, all the other each groups all add stimulant A
231871uL, vibration 5min. adds 1M HCl again and is acidified to Ph=3.Take out 400uL, be sub-packed in 2 pipes, preserve to be measured down for-20 ℃.Measure PGE with putting the method for exempting from
2Content (n=4), gained the results are shown in Table 1:
Table 1 Hesperitin and derivative thereof suppress the synthetic PGE of AA P of Rats M φ
2Experimental result (x ± s, n=4)
(3)-(10) be the Hesperitin novel derivative;
△ △P＜0.01, the contrast normal group; * P＜0.05, * * P＜0.01, contrast model group
Experimental data from table 1 as can be seen, hesperetin derivant provided by the invention (8) and (10) are 10
-4Mol.L
-1, 10
-5Mol.L
-1, 10
-6Mol.L
-1With 10
-7All significantly reduce AA P of Rats M φ secretion PGE under four kinds of concentration of mol.L-1
2Amount, it suppresses PGE
2The activity that generates is apparently higher than Hesperitin itself (data on the 8th, 10 hurdle vs the 11st hurdle).
2, the synthetic LTB of Hesperitin novel derivative vitro inhibition AA P of Rats M φ
4Experiment
Prepare AA rat macrophage (PM φ) suspension with experiment 1 identical method, PM φ suspension is divided into 38 groups, except that AA group and positive drug FC, the Hesperitin of all the other 8 kinds Hesperitin novel derivatives to be measured and contrast is totally 9 kinds of compounds, every kind of branch 10
-4Mol.L
-1, 10
-5Mol.L
-1, 10
-6Mol.L
-1With 10
-7Four kinds of concentration of mol.L-1.Each concentration is established 3 multiple pipes, every pipe adds 0.9mL PM φ suspension, add testing sample and solvent (10uL then respectively, DMSO concentration＜0.5%), place 37 ℃ of constant temperature shaking bath temperature to incubate 10min., add arachidonic acid 5uL (final concentration 50umol/L), Calcium ionophore A then successively
231875uL (final concentration 3umol/L), CaCl
2And MgCl
2Mixed solution 0.1mL (final concentration 5mmol/L), 37 ℃ are continued down temperature and incubate 5min., and every pipe adds 2mL dehydrated alcohol termination reaction, and adding 10.5mL distilled water again, to make the alcohol concn dilution be 15%; It is centrifugal under 4 ℃ that (5000g 10min.), gets supernatant liquor and transfers to Ph=3 with 1M HCl.By anti-phase pretreatment column (SEP-PAK C
18Cartridge Waters Associates Milford MA), and with 15% ethanol 20mL, distilled water 20mL, sherwood oil 20mL and ethyl acetate 10mL wash-out successively, collect eluent ethyl acetate liquid, decompression nitrogen down dries up, residue adds 200uL methyl alcohol and redissolves, get the 100uL sample introduction, reversed-phase HPLC detects LTB4 (5-lipoxygenase product) (Waters HPLC, 6x150mm ODS C
18Post) eluent: methyl alcohol: water: acetic acid (70: 30: 0.01), flow velocity 0.8mL/min. detects wavelength 280nm.Measurement result sees Table 2.
As can be seen from Table 2, the synthetic LTB of Hesperitin novel derivative vitro inhibition AA P of Rats M φ provided by the invention
4, half-inhibition concentration IC
50All than the low (IC of Hesperitin
50Low more, show that compound suppresses LTB
4The synthetic ability is strong more).The IC of compound (8), (4) and (9) wherein
50Be respectively 5.56 * 10
-8, 1.41 * 10
-7With 2.06 * 10
-7MolL
-1, all well below the IC of Hesperitin itself
50(1.49 * 10
-4), the IC of compound (7) and (5)
50(2.41 * 10
-6With 8.03 * 10
-6) also be starkly lower than Hesperitin.
According to the physical properties of derivative compound, can utilize existing medicine processing technology with Hesperitin novel derivative provided by the invention be processed into injection or freeze-dried or powder injection or oral tablet, capsule, electuary, sustained release preparation is used for clinical.
Claims (10)
1. hesperetin derivant is characterized in that: by the compound of following general formula (1) expression:
In the formula: R
1Be OH, OR '
1Or OOCR '
2
R
2Be H, halogen;
R
3Be H, NO
2Or NR '
3R '
4
R
4Be OH or OOCR '
2
7, the R on 3 '-position
1Can be identical, also can be different;
R on 6,8,2 '-three
2Can be identical, also can be different;
Wherein: R '
1Be C
1-C
10The straight or branched alkyl;
R '
2Be C
1-C
6The straight or branched alkyl;
R '
3, R '
4Be H or C
1-C
6Saturated alkyl, they can be identical, also can be different; Or R '
3, R '
4Form the assorted monocycle of the saturated unsubstituted N-of 3-7 person with the nitrogen-atoms that links to each other with them.
2. hesperetin derivant according to claim 1 is characterised in that:
In the formula: R
1Be OH, OCH
3Or OOCCH
3
R
2Be H, F, Cl or Br;
R
3Be H, NO
2Or NH
2
R
4Be OH or OOCR '
2
7, the R on 3 '-position
1Can be identical, also can be different;
R on 6,8,2 '-three
2Can be identical, also can be different.
3. hesperetin derivant according to claim 1 and 2 is characterised in that:
In the formula: R
1Be OH, OCH
3Or OOCCH
3
R
2Be H or Br
R
3Be H, NO
2Or NH
2
R
4Be OH or OOCR '
2
7, the R on 3 '-position
1Can be identical, also can be different;
R on 6,8,2 '-three
2Can be identical, also can be different.
4. hesperetin derivant according to claim 3 is characterised in that they are following compounds:
5,7,3 '-triacetyl Hesperitin (4) or
5 '-nitro-5,7,3 '-triacetyl Hesperitin (5) or
5 '-nitro Hesperitin (6) or
5 '-amino-5,7,3 '-triacetyl Hesperitin (7) or
7,3 '-dimethoxy Hesperitin (8) or
6,8,2 '-tribromo Hesperitin (9) or
8-bromo-7,3 '-dimethoxy Hesperitin (10).
5. hesperetin derivant 5,7 as claimed in claim 4, the preparation method of 3 '-triacetyl Hesperitin (4), it is characterized in that: with Hesperitin is raw material, reacts with excessive aceticanhydride and pyridine, and the consumption of aceticanhydride is the 10-30 equivalent, the consumption of pyridine is the 1.2-3 equivalent, temperature of reaction is 15-35 ℃, stirs 4-7h, and reaction promptly reaches terminal point, reaction mixture is through separation and use column chromatography purification, get final product 5,7,3 '-triacetyl Hesperitin white solid.
6. preparation method according to claim 5 is characterized in that: the consumption of aceticanhydride is the 15-20 equivalent, and the consumption of pyridine is the 1.5-2 equivalent, and temperature of reaction is 20-25 ℃.
7. hesperetin derivant 5 ' as claimed in claim 4-nitro-5,7, the preparation method of 3 '-triacetyl Hesperitin (5) is characterized in that: with 5,7,3 '-triacetyl Hesperitin is a raw material, with (CF
3CO)
2O/NH
4NO
3Be nitrating agent, under the room temperature be dissolved in CHCl
3In 5,7,3 '-triacetyl Hesperitin stirs together, the reaction 3h.
8. hesperetin derivant 7 as claimed in claim 4, the preparation method of 3 '-dimethoxy Hesperitin (8) is characterized in that: with Hesperitin is raw material, is dissolved in acetone and reaches (CH with NaH again
3)
2SO
4Reaction, temperature of reaction is controlled at 60-75 ℃, after reaction is reached home, removes excessive methyl-sulfate with proper ammonia, and product is directly used column chromatography purification after precipitation separates.
9. hesperetin derivant 6,8 as claimed in claim 4, the preparation method of 2 '-tribromo Hesperitin (9) is characterized in that: with Hesperitin is raw material, is solvent with ethyl acetate, normal temperature drips Br down
2/ AcOEt brominated reagent, stirring reaction 4-6h.
10. hesperetin derivant 8-bromo-7 as claimed in claim 4, the preparation method of 3 '-dimethoxy Hesperitin (10), it is characterized in that: with 7,3 '-dimethoxy Hesperitin is a raw material, tetrahydrofuran (THF) is a solvent, dripping bromine is in tetrahydrofuran solution under-5-10 ℃ condition, stirring reaction 6-9h.
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| CN103910703B (en) * | 2014-04-29 | 2016-02-03 | 安徽医科大学 | The preparation and application of hesperetin derivant and salt thereof |
| CN106565657A (en) * | 2016-11-23 | 2017-04-19 | 陕西科技大学 | Hesperetin cinnamate compound with anti-tumor activity and synthetic method thereof |
| CN114605273B (en) * | 2022-03-29 | 2023-06-02 | 南昌航空大学 | Method for synthesizing arylaminophenol compound by palladium-catalyzed CO-participated 1, 4-eneyne aromatization reaction |
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|---|---|---|---|---|
| US6184246B1 (en) * | 1999-07-30 | 2001-02-06 | The United States Of America As Represented By The Secretary Of Agriculture | Inhibition of cytokine production by polymethoxylated flavones |
| WO2001021137A1 (en) * | 1999-09-21 | 2001-03-29 | Rutgers, The State University | Extracts of orange peel for prevention and treatment of cancer |
| CN1318366A (en) * | 2000-04-19 | 2001-10-24 | 日本油脂株式会社 | Cosmetics composition |
| US20060003947A1 (en) * | 2005-06-03 | 2006-01-05 | Udell Ronald G | Soft gel capsules containing polymethoxylated flavones and palm oil tocotrienols |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6184246B1 (en) * | 1999-07-30 | 2001-02-06 | The United States Of America As Represented By The Secretary Of Agriculture | Inhibition of cytokine production by polymethoxylated flavones |
| WO2001021137A1 (en) * | 1999-09-21 | 2001-03-29 | Rutgers, The State University | Extracts of orange peel for prevention and treatment of cancer |
| CN1318366A (en) * | 2000-04-19 | 2001-10-24 | 日本油脂株式会社 | Cosmetics composition |
| US20060003947A1 (en) * | 2005-06-03 | 2006-01-05 | Udell Ronald G | Soft gel capsules containing polymethoxylated flavones and palm oil tocotrienols |
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