CN1397541A - Trijuganone and its derivative, and its preparing process and application - Google Patents
Trijuganone and its derivative, and its preparing process and application Download PDFInfo
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- CN1397541A CN1397541A CN 01120320 CN01120320A CN1397541A CN 1397541 A CN1397541 A CN 1397541A CN 01120320 CN01120320 CN 01120320 CN 01120320 A CN01120320 A CN 01120320A CN 1397541 A CN1397541 A CN 1397541A
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Abstract
A Trijuganone and its derivative, which are extracted from small red ginseng, its preparing process, and its application in preparing the medicines for treating myocardial ischemia are disclosed.
Description
Technical field
The present invention relates to Radix Rubiae Yunnanensis quinone and derivative thereof, its preparation method and application.
Background technology
The Chinese medicine Radix Rubiae Yunnanensis is the dry root and rhizome of madder wort Radix Rubiae Yunnanensis (Rabia ynananensis (Fraach.) Diels), another name Radix Rubiae Yunnanensis, Herba Rubiae Yunnanensis, little red medicine, little Shujin etc.Radix Rubiae Yunnanensis is warm in nature, and it is sweet to distinguish the flavor of, and little hardship has promoting blood circulation to restore menstrual flow, the broken long-pending function of sedation-analgesia and soft heavily fortified point.Cure mainly wind-cold-dampness pain, stomachache, dysphoria and insomnia, menoxenia, wound, lipoma etc.
Myocardial ischemia disease is still one of principal disease that threatens human health at present, though more existing clinical treatment medicines occur, effect is far undesirable.Radix Rubiae Yunnanensis is as traditional Chinese medicine simply, existing secular use experience among the people, and clinical and pharmacological evaluation confirms effective in cure to some myocardial ischemia disease really.
(herbal medicine such as the refined celestial being of king in 1986,7 (18): 19 (1986)) measured the influence of Radix Rubiae Yunnanensis, madder and Radix Salviae Miltiorrhizae extract to ATP content in mouse cardiac muscle and the cerebral tissue with biloluminescence method (Biolnmisescemt melnod), experimental observation to healthy mice abdominal injection Radix Rubiae Yunnanensis IIA5-9mg/ only, can make A77 content increase in the heart and brain tissues in 15-30 minute, mouse mainline Radix Rubiae Yunnanensis IIA-6mg/ only also can make that ATP content obviously increases in cardiac muscle and the cerebral tissue in 10 minutes.
Though it is effective in cure to myocardial ischemia disease that Radix Rubiae Yunnanensis extract proves through preliminary clinical and pharmacology, and do not know that what composition is effective, can't guarantee active constituent content, clinical medicine dose and result of treatment have limited its application and development.
Summary of the invention
The purpose of this invention is to provide a kind of compound with pharmaceutical use-Radix Rubiae Yunnanensis quinone that in the Chinese medicine Radix Rubiae Yunnanensis, extracts.
Radix Rubiae Yunnanensis quinone of the present invention is the compound of formula I and the derivative that methylates thereof
(formula I) wherein, R is the group of H, formula II or the group of formula III
Formula II
Formula III
Formula I compound when R is H is the 2-methyl isophthalic acid, 3, and 6-trihydroxy--9,10 anthraquinone; Formula I compound when R is formula II group is the 2-methyl isophthalic acid, 3, and 6-trihydroxy--9,10-anthraquinone-3-0-β-glycoside; Formula I compound when R is the formula III group is the 2-methyl isophthalic acid, 3, and 6-trihydroxy--9,10-anthraquinone-3-0-α-rhamanopyranosyl (1 → 2) β-glycoside.
Another object of the present invention provides a kind of preparation method who extracts the group up-to-date style I compound of group that R is H, formula II or formula III from the Chinese medicine Radix Rubiae Yunnanensis.
To achieve these goals, the present invention takes following technical scheme: a kind of method of extracting the Radix Rubiae Yunnanensis quinone in the Chinese medicine Radix Rubiae Yunnanensis may further comprise the steps:
1) be 1 by weight with Radix Rubiae Yunnanensis (Rubia ynananensis (Franch.) Diels): the ratio of 8-12 is dissolved in the distilled water, with acid, and preferred concentrated hydrochloric acid and Glacial acetic acid, the pH to 2.5-3.5 of regulator solution, 3 ℃ of-12 ℃ of placements are spent the night;
2) filter, get filter residue and filtrate;
3) use low-molecular-weight alcohol successively, particular methanol, ethanol or propyl carbinol and acetone refluxing extraction gained filter residue, the volume of methyl alcohol and acetone is respectively the above-mentioned 1/3-1/5 that is used to dissolve Radix Rubiae Yunnanensis distilled water volume;
4) methyl alcohol and the acetone extract of the above-mentioned gained of merging partly carry out silica gel column chromatography with methyl alcohol-acetone solution;
5) use hexanaphthene, 18-22 successively: chloroform-acetone of 1, methylene dichloride and acetone eluting silica gel post, circulation 12-14 time merges elutriant;
6) crystallization that obtains separating out, that is: the formula I compound when substituent R is H are spent the night in 3 ℃ of-12 ℃ of placements;
7) collect merging the above-mentioned the 5th) in the step, use hexanaphthene, 18-22 successively: chloroform-acetone of 1, methylene dichloride and the 13-16 time round-robin elutriant of acetone eluting silica gel post;
8) 3 ℃-12 ℃ are placed to crystallization and separate out, and suction filtration obtains filter cake;
9) with methyl alcohol-dehydrated alcohol-tetrahydrofuran (THF) of 1: 1: 1 filter cake is dissolved, 3 ℃-12 ℃ are placed to crystallization and separate out;
10) suction filtration, drying is separated the mixture of gained with centrifugal thin-layer chromatography, use the methylene chloride-methanol wash-out of 10: 1,8: 1,6: 1 and 4: 1 successively;
11) the II peak of the centrifugal thin-layer chromatography of collection;
12) drying, the formula I compound when promptly getting substituent R and being formula II;
13) collect the III peak of above-mentioned centrifugal thin-layer chromatography, drying, the formula I compound when promptly getting substituent R and being formula III.
In aforesaid method, described step 3) is used the pure and mild acetone refluxing extraction of lower molecular weight gained filter residue successively, and the pure and mild acetone of described lower molecular weight is isopyknic, is extracted into the extracting solution visual inspection less than color; Described step 5) is rotated evaporation after merging elutriant; After the crystallization that described step 6) obtains separating out, carry out suction filtration, filter cake dehydrated alcohol recrystallization, with the crystallization acetone solution, decolorizing with activated carbon, 3 ℃ of-12 ℃ of placements are spent the night, the crystallization that obtains separating out, also with 3 ℃-12 ℃ cold acetone washing leaching cake, drying obtains crystallization to suction filtration, that is: the formula I compound when substituent R is H.The filter cake that described step 8) obtains, with filter cake with the washing of 3 ℃-12 ℃ cold acetone after, enter the described the 9th again) step, with methyl alcohol-dehydrated alcohol of 1: 1: 1-tetrahydrofuran (THF) with after the filter cake dissolving, with decolorizing with activated carbon twice, rotary evaporation, be placed to crystallization in 3 ℃-12 ℃ again and separate out; Behind the described step 10) suction filtration, separate with carrying out described drying and centrifugal thin-layer chromatography behind 3 ℃-12 ℃ the cold acetone washing leaching cake again.Described step 13) is collected the III peak of above-mentioned centrifugal thin-layer chromatography, dry back recrystallizing methanol, drying again, the formula I compound when promptly getting substituent R and being formula III.
Substituent R is the formula I compound of H, can adopt the method for chemosynthesis to obtain, and may further comprise the steps:
1) 3, the 5-resorcylic acid is selected bromo, gets 2,5-two bromo-3,5-resorcylic acid;
2), get 2,5-two bromo-3,5-dihydroxyl-4-aminomethyl phenyl formic acid through Mannich reaction;
3) in alkali lye, add the Al-Ni alloy and carry out reduction reaction, obtain 3,5-dihydroxyl-4-tolyl acid;
4) at AlCl
3Exist down, make 3,5-dihydroxyl-4-tolyl acid and 4-hydroxy-benzoic acid react, and obtaining substituent R is the formula I compound of H.
In the process of above-mentioned chemosynthesis formula I compound: the selection bromo-reaction of described step 1) is at Br
2/ CHCl
3, carry out under 25 ℃ the condition; Described step 2) Mannich reaction is at 33% dimethyl amine (HNMe
2), 37%HCHO, (ethanol) E
tOH, HAc carries out under 25 ℃ the condition; Described step 3) is carried out in NaOH solution; In the described step 4) 3, the reaction of 5-dihydroxyl-4-tolyl acid and 4-hydroxy-benzoic acid is to stir, and is heated to carry out under 180-200 ℃.
It is the medicaments for resisting myocardial ischemia of activeconstituents that a further object of the present invention provides with compound of the present invention.
Another purpose of the present invention provides the purposes of compound of the present invention aspect the preparation medicaments for resisting myocardial ischemia.
Medicine of the present invention contains the compound of the present invention for the treatment of significant quantity, particularly contain the 2-methyl isophthalic acid, 3,6-trihydroxy--9,10 anthraquinone, 2-methyl isophthalic acid, 3,6-trihydroxy--9,10-anthraquinone-3-0-β-glycoside or 2-methyl isophthalic acid, 3,6-trihydroxy--9,10-anthraquinone-3-0-α-rhamanopyranosyl (1 → 2) β-glycoside be preferred.This medicine is used to resist myocardial ischemia.
In needs, in said medicine, can also contain one or more pharmaceutically acceptable carriers.Described carrier comprises thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant of pharmaceutical field routine etc., can also add flavouring agent, sweeting agent etc. in case of necessity.
Medicine of the present invention can be made various ways such as tablet, pulvis, granula, capsule, oral liquid and injection liquid.The medicine of above-mentioned various formulations all can be according to the ordinary method preparation of pharmaceutical field.
The survival dose of The compounds of this invention can be adjusted according to the severity of patient's age, body weight, disease, and per daily dose is generally the 5-10mg/kg body weight.
Experimental result shows; medicine of the present invention not only can improve mouse normal pressure hypoxia-bearing capability; and when low concentration (35 μ M), can increase coronary flow significantly; in addition; heart also there is certain restraining effect; this is to reducing energy metabolism of myocardial and oxygen metabolism, and the protection cardiac muscle all is useful.
Posterior Pituitary can make, and coronary artery shrinks, thereby the twin coronary flow that makes of convulsion descends, and causes acute myocardial ischemia, and Peripheral resistance increases in addition, causes cardiac load to increase the weight of, and presents ischemia and change on electrocardiogram(ECG.Medicine of the present invention not only can resist dirty coronary flow minimizing of guinea-pig heart and the decreased heart rate that Posterior Pituitary brings out external, and also almost can resist the acute myocardial ischemia EGC change that pituitrin brings out fully in vivo, show that medicine of the present invention resists myocardial ischemia, the anoxybiotic effect.
The major causes of death of acute myocardial infarction (AMI) is seriousness heart disorder and pump failure, and its incidence and myocardial infarct size are closely related, and pump failure increases the incidence of ventricular arrhythmia.Thereby the searching active drug, when dwindling heart stalk scope (IS), improve the early stage cardiac pump function of AMI, be the key of AMI treatment in the hope of reducing the AMI mortality ratio, improving its prognosis.Compound of the present invention can not only significantly dwindle the heart stalk scope of rats with acute myocardial infarction, and heart function is also had some improvement.
The present invention has done comprehensively traditional Chinese medicine Radix Rubiae Yunnanensis, systematic research, fundamentally checked on the essential place of Radix Rubiae Yunnanensis aspect the treatment myocardial ischemia disease, the clear and definite chemical structure of effective constituent, the method of extracting the Radix Rubiae Yunnanensis quinone and synthesizing the Radix Rubiae Yunnanensis quinone with the mode of chemosynthesis is provided in the Chinese medicine Radix Rubiae Yunnanensis, and to being that the medicine of activeconstituents has carried out comparatively deep research with the Radix Rubiae Yunnanensis quinone.The present invention extracts, the method for production Radix Rubiae Yunnanensis quinone is simple and convenient, practical, especially in the method for chemosynthesis, having adopted aluminum chloride dexterously is catalyzer, simple to operate quick, the productive rate height, need not chromatographic separation, making from now on, scale operation Radix Rubiae Yunnanensis quinone becomes possibility.
Below in conjunction with accompanying drawing embodiments of the invention are described further.
Description of drawings
Fig. 1 is the centrifugal thin-layer chromatogram of Radix Rubiae Yunnanensis quinone
Fig. 2 is the spectrogram of Remote Selection proton-decoupled
Fig. 3 is 2K-NMRl
1H-
1The spectrogram of H COSY
Embodiment
Embodiment 1: substituent R is the separation and the evaluation of the formula I Radix Rubiae Yunnanensis quinone of H
1) substituent R is the separation of the formula I Radix Rubiae Yunnanensis quinone of H
Take by weighing Radix Rubiae Yunnanensis 200g, be dissolved in the 2000ml distilled water, the pH to 3 of enriching hydrochloric acid conditioning solution, 5 ℃ of refrigerators are placed and are spent the night, filter precipitation PA 52g and mother liquor WL, use successively methyl alcohol 500ml and acetone 500ml in round-bottomed flask mid-score time refluxing extraction PA to the extracting solution visual inspection less than color, merge methyl alcohol and acetone extract and get methyl alcohol-insoluble part WAI of acetone solution part WAS 14g with methyl alcohol-acetone, WAS is partly carried out silica gel column chromatography (silica gel granularity 150-250 order, cylinder is 2.5X80cm), composition according to product in the elutant changes, use hexanaphthene successively, chloroform-acetone (20: 1), methylene dichloride and acetone eluting silica gel post, every 200ml collects a, merge 12-13 part, rotary evaporation is to a small amount of, 5 ℃ of refrigerators are placed to spend the night promptly has orange-yellow crystallization to separate out, suction filtration, filter cake is used the dehydrated alcohol recrystallization once, and crystallization acetone solution, decolorizing with activated carbon are once, acetone solution is concentrated on a small quantity, 5 ℃ of refrigerators are placed to crystallization and separate out, and suction filtration is also used cold acetone (3X5ml) washing leaching cake, gets orange-yellow needle crystal 1g after the vacuum-drying, this is the formula I Radix Rubiae Yunnanensis quinone that substituent R is H, and yield is 0.5%.
2) identify
Rf:0.75, system (1) launches.
mp：＞300℃
Ultimate analysis: C
15H
10O
5.
Theoretical value: c%, 66.67; H%, 3.70
Measured value: c%, 66.62; H%, 3.74
MeOH
UVλ nm：217，276，312(sh)，322，422
max
KBr
IRv cm
-13420,3411: (free-OH), 3020,3075 (association-OH
Max and/or virtue-H), 2840,2921 (Me), 1662 (free＞C=O),
1621 (associate＞C=O), 1600,1590 (aromatic rings).
1H-NMR(CD
3COCD
3)δ(ppm)：8.09(1H，d，J＝3.5Hz)，7.50(1H，d，J＝2.4Hz)，
725(1H，s)，7.21(1H，dd，J＝0.5，2.4Hz(，0.91(3H，s).
1H-NMR (DMSO) δ (ppm): 13.34 (1H, s, association hydroxyl protons), 11.12 (1H, s, no ortho position substituted hydroxy proton), 11.07 (1H, s, ortho position substituted hydroxy proton is arranged), 8.11 (1H, d, J=8.5Hz), 7.45 (1H, d, J=2.4Hz), 7.23 (1Hs), 7.22 (1H, dd, J=8.5,2.4Hz), 2.07 (3H, s).
13C-NMRδ(ppm)：185.41(S)，181.66(S)，162.90(S)，162.16(S)，
161.91(S)，134.95(S)，131.54(S)，129.07(d)，142.62(S)，
120.94(d)，117.29(S)，112.35(d)，108.41(S)，106.97(S)，
7.96(S)。
13C (｀ H)-NWR LRSD (Remote Selection proton-decoupled); See accompanying drawing 2
LR-MS(EI)m/z(％)：270(｀100，M
+)，252(3.1，M-H
2O)，242(11.4，M-CO)，
213(6.1，M-2XCO+H)，160(3.0)，(139(7.2)，121(6.9).
HR-MS(EI)M/Z(％)：270.0519(100，C
15H
10O
5)，242.0570(10.20，C
14H
10C
4)，
213.0560(4.93，C
13H
9O
3)，185.0625(0.61，C
12H
9O
2).
From the data of above-mentioned Analysis and Identification as can be seen, the 1st) resulting compound really is the formula I Radix Rubiae Yunnanensis quinone of H for substituent R in the step, i.e. 2-methyl isophthalic acid, 3,6-trihydroxy--9,10 anthraquinone.
The separation and the evaluation of embodiment 2, the formula I Radix Rubiae Yunnanensis quinone when substituent R is formula II
The separation of the formula I Radix Rubiae Yunnanensis quinone when 1) substituent R is formula II
MAS part silica gel column chromatography is the 15th part among the collection embodiment 1, rotary evaporation is concentrated on a small quantity, 5 ℃ of refrigerators are placed to crystallization and separate out, suction filtration is also used cold acetone (3 * 5ml) washing leaching cakes, with methyl alcohol-dehydrated alcohol one tetrahydrofuran (THF) (1: 1: 1) filter cake is dissolved, twice of decolorizing with activated carbon, the rotary evaporation concentrated solution is to a small amount of, 5 ℃ of refrigerators are placed to crystallization and separate out, suction filtration is also used cold acetone (3 * 5ml) washing leaching cakes, infrared drying gets an orange-yellow mixture, this mixture is separated with centrifugal thin-layer chromatography (CLC), use methylene chloride-methanol 10: 1 successively, 8: 1,6: 1 and 4: 1 each 500ml wash-outs are collected CLC-II peak (as shown in Figure 1), rotary evaporation is concentrated into dried, yellow residue, residue with recrystallizing methanol once, the formula I Radix Rubiae Yunnanensis quinone 300mg when crystallization vacuum-drying promptly gets substituent R and is formula II, this compound is yellow needle crystal, and yield is 0.15%.
2) identify
Rf:0.42, system (1) launches.
Mp:282-283 ℃ (decomposition)
[α]
25 D(DMSO)3-68.92℃(c＝0.74)
[M]
25 D-297.7℃
Ultimate analysis: C
21H
28O
101/2H
2O
Theoretical value: c%, 57.14% H%, 4.76%
Measured value: c%, 57.18% H%, 5.05%
NeOH
UVλ nm：220，267，300，323，410
max
KBr
IRv cm
-1: 3420 (OH), 2920 (Me) 1662 (free＞C=O), 1630 (form
Max closes＞C=O), and 1,600 1575 (aromatic rings), 1055 (glucoside keys).
1H-NMR(CD
3COCD
3)δ(ppm)：8.12(1H，d，J＝8.5Hz)，7.54(1H，d，J＝2.4Hz)，
7.48(1H，s)，7.25(1H，dd，J＝8.5，2.4Hz，5.20(1H，d，
J＝5.2Hz?3.47-3.85(mH，m)，2.18(3H，s).
1H-NMR (DMSO) δ (ppm): 13.18 (1H, s add D
2O disappears, and associates-OH), and 11.13 (1H, s add D
2O disappears, no ortho position substituted hydroxy proton), 8.03 (1H, d, J=8.5Hz), 7.43 (1H, d, J=2.4Hz), 7.38 (1Hs), 7.19 (1H, dd, J=8.5,2.4Hz), 5.09 (1H, d J=7.3Hz) .3.16-3.72 (mH, m), 2.10 (3H, s).
13C-NMR?δ(ppm)：186.37(S)，181.60(S)，163.48(S)，161.32(S)，160.76(S)，135.28(S)，131.97(S)，129.65(d)，124.53(S)，121.42(s)，120.82(d)，112.62(d)，110.56(S)，105.64(d)，190.34(d)，77.33(d)，76.31(d)，73.24(d)，69.38(d)，，60.47(t)，8.47(q)，
2Dz-NMR1
1H-
1H COSY: see accompanying drawing 3
LR-MS (EI) m/z (%): 270 (100, base peak), 252 (3,85, B-H
2O), 242 (10.43, B-CO) .213 (4.39, B-2XCO+H), 168 (2.16), (139 (3.86), 121 (5.62).
HR-MS(EI)m/z(％)：270.0532(100，C
15H
10O
5)，242.0597(10.43，C
14H
10O
4)，
213.0555(5.59，C
13H
9O
3)，185.0609(1.72，C
12H
9O)，128.0630(1.31，C
10H
8)
FD-MS?m/z(％)：866(3.51，2M+2)，434(100，M+2)，(271(6.32，M-161)。
Formula I Radix Rubiae Yunnanensis quinone when from the data of above-mentioned Analysis and Identification as can be seen, the 1st) resulting compound really is formula II for substituent R in the step, i.e. 2-methyl isophthalic acid, 3,6-trihydroxy--9,10-anthraquinone-3-0-β-glycoside.
The separation and the evaluation of embodiment 3, the formula I Radix Rubiae Yunnanensis quinone when substituent R is formula III
The separation of the formula I Radix Rubiae Yunnanensis quinone when 1) substituent R is formula III
Collect the isolating CLC-III of centrifugal thin-layer chromatography peak (as shown in Figure 1) among the embodiment 2, the rotary evaporation concentrate eluant is to doing, residue with the recrystallizing methanol final vacuum dry yellow powder shape compound 2mg, be the formula I Radix Rubiae Yunnanensis quinone of substituent R when being formula III, yield is 0.001%.
Formula I Radix Rubiae Yunnanensis quinone when being formula III in order to obtain more substituent R also can directly separate from the Radix Rubiae Yunnanensis crude extract.
Take by weighing Radix Rubiae Yunnanensis 1kg, be dissolved in the 10L distilled water, be acidified to pH3 with concentrated hydrochloric acid, room temperature is placed and is spent the night, suction filtration, precipitation is admixed proper silica gel, extremely light with acetone extraction after the infrared drying to the extracting solution color in the Sha Shi extractor, reclaim acetone to a small amount of and admix Silon, carry out polyamide column chromatography (polymeric amide 13-40 order after the drying, cylinder, 17 * 30cm), water successively, 53% ethanol, 84% ethanol and acetone wash-out, 84% ethanol elution part, reclaim ethanol to a small amount of, natural filtration, filtrate concentrate the back frost drying, and the sample behind the frost drying carries out silica gel column chromatography (silica gel granularity: 150-250 order, cylinder: 0.5 * 30cm), use ethyl acetate successively, ethyl acetate-acetone (2: 1) and ethyl acetate-methyl alcohol (2: 1) wash-out, the identical component of formula I Radix Rubiae Yunnanensis quinone when TLC control collection is formula III with substituent R, the rotary evaporation concentrate eluant is to a small amount of, 5 ℃ of refrigerators are placed to precipitation and separate out, suction filtration and with cold acetone (the formula I Radix Rubiae Yunnanensis quinone 2g when 3 * 5ml) wash-out filter cakes, vacuum-drying get substituent R and are formula III.
In addition, also obtain the formula I Radix Rubiae Yunnanensis quinone 32g that substituent R is H, the formula I Radix Rubiae Yunnanensis quinone 1.5g when silica gel column chromatography ethyl acetate-acetone wash-out partly obtains substituent R and is formula II from polymeric amide column chromatography acetone wash-out part.
2) identify
Rf:0.20, system (1) launches.
Mp:262-264 ℃ (decomposition)
[α])
25 D(DMSO)-57.27℃(C＝1.1)
[M]
25 D-331.0℃
Ultimate analysis: C
27H
30O
142H
2O
Theoretical value: c%, 52.76% H%, 5.54%
Measured value: c%, 52.72% H%, 5.24%
MeOH
UVλ nm：219，273，288，320，410
max
KBr
IRv cm
-13390,3250: (OH), 1680 (free＞C=O), 1625 (associate
Max＞C=O), 1,610 1585 (aromatic rings), 1056,1049 (glucoside keys).
1H-NMR (DMSO) δ (ppm): 13.26 (1H, s, association OH), 11.51 (1H, s, no ortho position substituted hydroxy proton), 8.09 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2.4Hz), 7.40 (1H, s), 7.3 1 (1H, dd, J=8.5,2.4Hz, 5.41 (1H, d, J=7.38Hz5.26 (1H, 6s), 3.17-5.60 (mH, m), 2.15 (3H, s), δ 1.15 (3H, s).
13C-NMR?δ(ppm)：186.31(S)，181.61(S)，183.51(S)，161.30(S)，160.21(S)，135.26(S)，131.92(d)，129.52(d)，124.52(S)，121.44(s)，120.64(s)，112.60(d)，110.59(S)，105.04(d)，100.22(d，J＝1716Hz)，97.50(d)，77.40(d)，77.40(d)，77.11(d)，76.42(d)，72.00(d)，70.50(d)，70,39(d)，69,55(d)，68.51(d)，60,33(t)，18,08(q)，8.74(q).
LR-MS(EI)m/z(％)：270(100，B)，252(4.45，B-H
2O)，242(15.65，B-CO，214(3.47，B-2XCO).FD-MS?m/s(％)：601(100，M123)，270(42.1，M-300)，23(100，Na
+).
Formula I Radix Rubiae Yunnanensis quinone when from the data of above-mentioned Analysis and Identification as can be seen, the 1st) resulting compound really is formula II for substituent R in the step, i.e. 2-methyl isophthalic acid, 3,6-trihydroxy--9,10-anthraquinone-3-0-α-rhamanopyranosyl (1 → 2) β-glycoside.
Embodiment 4, substituent R are the methylate preparation of derivative of the formula I Radix Rubiae Yunnanensis quinone of H
Substituent R is that the formula I Radix Rubiae Yunnanensis quinone 165mg of H is dissolved in MeI34ml, adds Ag
2O powder 6.5mg and methyl alcohol are a small amount of, magnetic agitation reflux 40 minutes, filtering Ag behind the reaction terminating
2O, the MeI rotary evaporation is concentrated into dried, residue re-crystallizing in ethyl acetate, suction filtration and dry yellow needle crystal 55mg.This compound is carried out following analysis, confirm that this compound is 2, the 5-methyl isophthalic acid, 3,6-trihydroxy--9, the 10-anthraquinone, promptly substituent R is the formula I Radix Rubiae Yunnanensis quinone methyl compound of H.
mp：212-214℃
KBr
IRv cm
-13080,3020: (association-OH and/or virtue-H), 1670 (free＞C=O),
Max 1630 (associate＞C=O), 1,600 1570 (aromatic rings).
1H-NMR?δ(ppm)：13.06(1H，s，)，8.16(1H，d，J＝8.6Hz)，7.56(1H，d，J＝2.4Hz)7.44
(1H，dd，J＝8.5，2.4Hz，7.30(1H，s，)，3.97(3H，s)，3.35(3H，s)，2.09(3H，s).LR-MS(EI)m/z(％)：298(109，M
+)，280(43.3，M-H
2O)，269(21.9，M-CO+H)，252(10.1M-H
2O-CO)。
The preparation of embodiment 5, the permethylated thing methyl alcohol of the formula I Radix Rubiae Yunnanensis quinone hydrolysis products when substituent R is formula II
Formula I Radix Rubiae Yunnanensis quinone 200mg when substituent R is formula II is dissolved in dimethyl formamide 5ml, adds Ag
2O0.5g and MeI10ml, mixed solution magnetic agitation reflux 4 hours, suction filtration, filtrate adds H
2O is an amount of, and precipitation is separated out, and suction filtration gets compound 100mg.
Above-mentioned methide is dissolved in MeOH 10ml, and enriching H
2SO
42ml, reflux 4 hours adds water precipitation is separated out after the question response liquid cooling but, suction filtration and water 3 * 1ml washing leaching cake, filtrate discards, and filter cake is again with 1NNaOH and H
2O washes molten repeatedly, and washings adds the dilute hydrochloric acid acidifying separates out precipitation, and suction filtration gets the yellow powder thing with filtration cakes torrefaction after the washing, is the formula I Radix Rubiae Yunnanensis quinone permethylated thing methyl alcohol hydrolysis products of substituent R when being formula II.Through following identification and analysis, conclude that its molecular formula is C
17H
14O
5
1H-NMR δ (ppm): 18.99 (1H, s, the hydroxyl protons that have the ortho position to replace), 8.07 (1H, d, J=8.7H), 7.40 (1H, d, and J=2.9Hz) 7.47 (1H, s), 7.36 (1H, dd, J=8.7,2.8Hz), 3.92 (3H, s), 3.77 (3H, s), 2.14 (3H, s).
LR-MS(EI)m/z(％)：293(109，M
+)，281(43.0，M-H
2O)，269(29.4，M-CO+H)，252(17.6M-H
2O-CO)。
Embodiment 6, chemosynthesis substituent R are the formula I Radix Rubiae Yunnanensis quinone of H
(1) synthesizes 3,5-dihydroxyl-4-tolyl acid
With 3, the 5-resorcylic acid is that raw material is through selecting bromo (Br
2/ CHCl
3, 25 ℃, 0.5h) get 2,6-two bromo-3, the 5-resorcylic acid, 2,6-two bromo-3, the 5-resorcylic acid is through Mannich reaction (33%HNNe
237%HCHO, EtOH, HAc, 25 ℃, 25h) get 2,6-two bromo-3,5-dihydroxyl-4-aminomethyl phenyl formic acid is in 2,6-two bromo-3, add the Al-Ni alloy in the benzoic NaOH solution of 5-dihydroxyl-4-aminomethyl and carry out reduction reaction (25-34 ℃ 16h) is sloughed bromine and amino obtains 3,5-dihydroxyl-4-tolyl acid.Analyze through spectrum (MS, NMR), consistent with document.
(2) synthetic substituent R is the formula I Radix Rubiae Yunnanensis quinone of H
With 3, the mixture porphyrize of 5-dihydroxyl-4-tolyl acid 1g and 4-hydroxy-benzoic acid 3g and dry back add fused AlCl
3(20g)-NaCl (4g)-P
2O
5(2g) in the mixed solution, holding temperature 180-200 ℃ (oil bath temperature), reaction 5min, reaction solution is put cold back and is added frozen water 80ml and concentrated hydrochloric acid 15ml, 120-140 ℃ is boiled 10min, promptly has after cold precipitation to generate, with supernatant liquor impouring separating funnel and with ethyl acetate (2 * 50ml) extractions, extraction liquid and above-mentioned precipitation merge, and use 5%NaHCO successively
3, each the 4 * 50ml washing of the saturated NaCl aqueous solution and water, the acetic acid ethyl acetate extract anhydrous Na after the washing
2SO
4Drying reclaims ethyl acetate to doing, and residue is with ethyl acetate recrystallization repeatedly, substituent R be the formula I Radix Rubiae Yunnanensis naphtoquinone compounds 110mg (productive rate is 7%) of H.
(3) the gained compound is identified that its result is as follows:
mp：＞300℃
Ultimate analysis: C
15H
10O
5H
2O
Theoretical value C% 62.50% H% 4.17%
Measured value C% 62.30% H% 4.14%
The folded spectrum of UV and 1R: I is in full accord with natural compounds.
Embodiment 7, The compounds of this invention are to the influence of normobaric hypoxia mouse Survival Time
1) medicine: respectively with the 2-methyl isophthalic acid, 3,6-trihydroxy--9,10 anthraquinones, 2-methyl isophthalic acid, 3,6-trihydroxy--9,10-anthraquinone-3-0-β-glycoside, 2-methyl isophthalic acid, 3,6-trihydroxy--9,10-anthraquinone-3-0-α-rhamanopyranosyl (1 → 2) β-glycoside such as are dissolved at the NaOH solution of mole number, physiological saline is diluted to the concentration that needs behind the frost drying, obtain medicine I respectively, medicine II, medicine III; With 2,5 dimethyl-1,3,6-trihydroxy--9,10 anthraquinone is dissolved in the NaOH solution of two mole numbers, and physiological saline is diluted to the concentration that needs behind the frost drying, obtains medicine Ia.
2) experimental technique
Get 98 of healthy mices, be divided into 10 groups at random, low dose of and heavy dose of each 5 groups (comprising control group), low dose of administration 1mg/0.2ml/ mouse; Heavy dose of administration 2mg/0.2ml/ mouse; Control group is given equal-volume physiological saline, is intraperitoneal administration, mouse is enclosed within the hypoxia tolerance experimental installation in 20 minutes after the administration, and the record animal breath termination time, the per-cent that increases than control group Survival Time with the administration group is the drug effect of each compound relatively.
3) result
As shown in table 1, medicine I and medicine II and heavy dose of medicine Ia all have the anti-hypoxia activity, intraperitoneal injection of drugs I 1mg/ mouse, 2mg/ mouse, and the mouse Survival Time prolongs 39.5% (P＜0.01), 26.3% (P＜0.01) respectively; Intraperitoneal injection of drugs II 1mg/ mouse, 2mg/ mouse, mouse Survival Time prolong 20.6% (P＜0.01), 39.4% (P＜0.001) respectively, intraperitoneal injection of drugs Ia 2mg/ mouse, and the mouse Survival Time prolongs 20.0% (P＜0.05).
Medicine III and small dose drug Ia compare difference with control group not remarkable.
Table 1:
2 milligrams/mouse of 1 milligram/mouse of group
Survival time (branch) increases (%) survival time (branch) increase (%) contrast 13.5 ± 0.9 8.0 17.5 ± 0.8 0.9
(10) (9) Compound I 25.5 ± 1.3 39.5
*22.1 ± 1.1 26.3
*
(10) (8) Compound I a 21.2 ± 1.2 14.6 21.4 ± 0.5 20.0
*
(10) (10) Compound I I 23.4 ± 1.7 20.6
*24.4 ± 1.5 39.4
* *
(10) (10) compound III 21.1 ± 1.2 14.1 20.3 ± 1.0 16.0
(10) (11)
*P＜0.05
*P＜0.01
* *P＜0.001 numerical value=mean ± standard error
Embodiment 8, the The compounds of this invention influence dirty to guinea-pig heart
1) reagent:
Medicine I, medicine II, medicine III, medicine Ia is with embodiment 7; Posterior Pituitary is Changsha biochemical-pharmaceutical factory production, lot number 861101.
2) experimental technique
Get 50 of cavys, be divided into 6 groups at random; Medicine I, Ia, II and III group, Posterior Pituitary and Posterior Pituitary add medicine I group.
During experiment, with the wooden mallet cavy hindbrain of fiercelying attack, take advantage of its stupor and cut off the thoracic cavity, expose heart and the entad dirty immediately interior anticoagulant heparin that injects, take off heart then and be hung on perfusion system, the apex of the heart is connected in little pulling force sensor and passes through polygraph recorded heart rate and heartbeat amplitude by frog heart clip, perfusate is oxygen-saturated Rockwell liquid, temperature 35-37 ℃, perfusion pressure 70mmH
2O, with two cover perfusion devices difference perfusion Rockwell liquid and soups, soup is diluted in the Rockwell liquid, and each liquor strength is 85 μ M (pH7.5).
Treat that heartbeat is stable on the oscilloscope, after coronary flow is constant, the heartbeat and the flow of per minute in continuous two minutes of the opening entry, with this normal control value before as administration, perfusion soup then, write down the heartbeat and the flow of per minute in continuous 5 minutes, the per-cent that on average increased than preceding 2 minutes per minute kind coronary flows of administration in 5 minutes when calculating administration, relatively drug effect.
3) result
As shown in table 2, when drug level in the perfusate is 85 μ M, medicine I and medicine Ia all can increase the dirty coronary flow of guinea-pig heart significantly, increase per-cent and be respectively 94.6% (P＜0.001) and 53.7% (P＜0.01), coronary flow is not had influence with the medicine II and the medicine III of concentration.
Each medicine is not obvious to the heart rate influence, and removing medicine I has outside certain restraining effect (35.5%, P＜0.05) the heartbeat amplitude, and all the other each medicines all do not have obvious influence to the heartbeat amplitude.
Posterior Pituitary (2 * 10
-3U/ml) can significantly reduce the dirty coronary flow of guinea-pig heart (36.9%, P＜0.05).Medicine I (85 μ M) can resist the coronary flow minimizing effect that pituitrin brings out fully.
Table 2: the group coronary flow X ± SE increase and decrease heart rate X ± easypro performance X that contracts of SE increase and decrease ± SE increase and decrease
Contrast administration (%) contrast administration (%) contrast administration (%) medicine I (9) 5.6 ± 0.5 10.9 ± 0.5 94.6
* *241 ± 16 248 ± 10 2.9 7.6 ± 0.7 4.9 ± 0.7-35.5
*Medicine Ia (9) 8.2 ± 0.7 12.6 ± 1.2 53.7
*226 ± 16 222 ± 11-1.8 6.7 ± 0.7 6.4 ± 0.9-4.5 medicine II (8) 5.8 ± 0.7 6.0 ± 0.6 3.4 252 ± 5 250 ± 7-0.8 12.2 ± 1.3 12.4 ± 1.1 1.6 medicine III (6) 7.0 ± 1.1 6.9 ± 1.2-1.4 220 ± 8 206 ± 11-5.4 5.8 ± 0.5 5.8 ± 0.6 0.0 pituitrins (6) 11.1 ± 0.9 7.0 ± 0.8-36.9
*251 ± 10 210 ± 9-16.3 13.0 ± 1.8 11.0 ± 2.0-15.4 pituitrins+I (6) 8.3 ± 0.7 9.9 ± 0.7 19.3 247 ± 4 239 ± 4-3.2 10.0 ± 1.3 6.0 ± 0.9-40.0
*P＜0.05
*P＜0.01
* *P＜0.001 numerical value=mean ± standard error
Perfusate: locke solution drug level: 85 μ M Pituitrin concentration 2 * 10
-3U/ml
Embodiment 9: the Electrocardiographic influence of rat heart muscle ischemic that medicine I brings out Posterior Pituitary
1) medicine I, Posterior Pituitary are with embodiment 7
2) experimental technique
Get 22 of rats, male and female half and half are divided into two groups at random, and Posterior Pituitary group and Posterior Pituitary add medicine I group.
It is fixing to lie on the back after rats by intraperitoneal injection 25% urethane (4ml/kg) anesthesia, at the subcutaneous insertion needle electrode of four limbs, regulate electrocardiograph calibration sensitivity 1mv=10mm, chart speed 50mm/s, after writing down normal II and leading electrocardiogram(ECG, control group is by vena femoralis injection physiological saline 0.2ml/ mouse, the administration group is by vena femoralis injection medicine 150mg/0.2ml/kg, inject pituitrin 0.75U/kg (injection finishes in 15 seconds) after 1 minute respectively, respectively at once, 15 ", 30 ", 1 ', 2 ', 3 ', 4 ' and 5 ' duplicate record II leads electrocardiogram(ECG.
Towering and S point is raised above 0.1mv with I phase (0-30 ') ECG T wave behind the injection pituitrin, the II phase (30 "-5 ') ECG T wave is forced down and the decline of S point is judged as positive ischemia electrocardiogram(ECG above 0.1mv person; on the contrary negative, compare two groups of negative rate differences, X
2The inspection statistics significance.
3) result
As shown in table 3: the quiet notes Pituitrin of rat 0.75U/kg, I, II phase ischemia electrocardiogram(ECG all appear, and have two examples pathologic Q liquid to occur, the quiet injection thing of rat I50mg/kg can resist above-mentioned I, II phase ischemia ECG change very effectively, does not also have pathologic Q liquid and occurs.
Table 3: the Electrocardiographic influence of rat heart muscle ischemic that medicine I brings out Posterior Pituitary
Negative number Q liquid of negative number I-phase of group number of animals I-phase
Contrast 11 012
Administration 11 9 10 9
P ＜0.001 ＜0.001
Route of administration: femoral vein
Dosage: control group, Pituitrin 0.75U/kg
The administration group, Compound I 50mg/kg
Embodiment 10, medicine I are to the influence of acute experiment myocardial infarction (AMI) rat left ventricle shrinkage and infarction size.
1) medicine I is with embodiment 7
2) experimental technique
Get 40 of healthy rats, be divided into four groups at random: small dose group, heavy dose of group, sham operated rats and psychological salt solution group.
Be administered once half an hour before the operation, then under etherization with all animals, be about the otch of 2cm in the most obvious place of left side 3-4 intercostal apex beat work one, cut off subcutaneous fascia and muscle, strut rib with a curved hemostat, apply a lateral pressure and under chest sidewall and xiphoid-process, extrude heart, with the heart surface vein is sign, between left auricle of heart root and pulmonary conus, be equivalent to the downward 2-3mm of arteria coroaria sinistra section start place, with No. 3 silk thread ligation left coronary artery main stems, only threading and not ligation of sham-operation, return heart immediately, gas in the extrusion thoracic cavity clamps skin incision pedestrian worker and breathes, after treating that autonomous respiration recovers, sew up the wall of the chest, immediate record animal electrocardiogram(ECG, no ischemia electrocardiogram(ECG variation person discards.
The administration group begins in the hand second day after operation, and every day is intraperitoneal injection of drugs I 25mg/kg (low dose), 50mg/kg (heavy dose) respectively; Control group is given with volume physiological saline; What does not give sham operated rats, together with once administration 8 times (8 days) altogether before the operation.
After the last administration 30 minutes, abdominal injection 25% urethane (4ml/kg) anesthetized rat, rat lain on the back be fixed on the experiment table, after isolating right common carotid artery, from tail vein injection heparin 300U anti-freezing, heart catheter is imported arteria carotis communis 0.5cm, continue again conduit is extended 2.5-3cm after measuring arterial pressure, when treating to demonstrate the left indoor pressure graphic representation on the oscilloscope, the expression conduit has entered left ventricle, conduit is fixed together with the arterial wall ligation, measured left chamber each index of shrinkage after 5 minutes, simultaneously recording ecg.
Survey index and condition determination is as follows:
Left indoor pressure (LVP) and left indoor pressure peak value (LVSP) curve; Calibration sensitivity 50mmHg/10mm, chart speed 50mm/s.
Left indoor pressure rate of change (dp/dt) curve, calibration sensitivity 2000mmHg/s/5mm, chart speed 100mm/s, derivative time constant 1ms, High frequency filter 50Hz.
After treating that These parameters is measured end, immediately rat is opened chest, take out heart, remove the atrium, the heart crosscut is become four, N-BT dyeing 15 minutes, 10% formaldehyde fixed, normal myocardium is dyed blueness, infarcted myocardium not painted (being canescence), and dyeing back heart section stalk tangent plane is taken a picture with colour film, flushing is amplified 3.3 times, describe left ventricle infarcted region and non-infarcted region boundary line on the photo with transparent plastic film, cut paper weighing method is calculated the per-cent that infarcted region square section scope accounts for whole left ventricle square section scope, and the P value is asked in the t check.
3) result
As shown in table 4: rats by intraperitoneal injection medicine I 50mg/kg/ days, continuous 8 days, heart function is significantly better than physiological saline control group (P＜0.05), not remarkable with sham operated rats difference, rats by intraperitoneal injection medicine I25mg/kg/ days, continuous 8 days, heart function also had the trend of improvement, but not remarkable with physiological saline control group difference
As shown in table 5, rats by intraperitoneal injection medicine I 50mg/kg/ days and 25mg/kg/ days, continuous 8 days, all can dwindle heart stalk scope very significantly, when control group heart stalk scope was 38.5%, heavy dose of and low dose of administration group heart stalk scope only was respectively 15.9% (P＜0.001) and 11.8% (P＜0.001).Inhibition strength is respectively 58.7% and 69.4%.
Table 4: medicine I influences group number of animals HR LVSP+dp/dtmax-dp/dtmax to chamber, rats with acute myocardial infarction left side myocardial contractility
(beals/min) (mmHg) (mmHg/sec) (mmHg/sec)
X ± SE X ± SE X ± SE X ± SE contrasts 7 429 ± 24 104.6 ± 5.3 9900 ± 585 7800 ± 526 sham-operation 7 450 ± 12 119.6 ± 6.4 11917 ± 306
*9714 ± 529
*Medicine I 7 394 ± 29 114.3 ± 5.7 19886 ± 622 8743 ± 614 (25mg/kg) medicine I 9 400 ± 11 111.8 ± 2.6 11570 ± 388
*8533 ± 666 (50mg/kg)
Route of administration: intraperitoneal administration number of times: once a day, P＜0.05 for three days on end
Minute: after the last administration 30 minutes
Table 5: medicine I contrasts 7 38.5 ± 2.5 0.0 Compound I (25mg/kg), 10 11.2 ± 1.8 69.4＜0.001 Compound I (50mg/kg) 9 15.9 ± 2.5 58.7＜0.001 to group number of animals heart stalk scope (%LV) inhibition strength (%) P that influences of the awake scope of the rats with acute myocardial infarction heart
Route of administration: abdominal cavity numerical value=mean ± standard error
Administration number of times: once a day, continuous 8 days.
As can be seen from the above-described embodiment, medicine I truly has function of resisting myocardial ischemia preferably.
Claims (11)
1, the compound of general formula I and the derivative that methylates thereof
Wherein, R is the group of H, formula II or the group of formula III
2, compound according to claim 1 is characterized in that: this compound is the compound of general formula I, and wherein, R is the group of H, formula II or the group of formula III.
3, compound according to claim 2 is characterized in that: this compound is the formula I compound of R when being H.
4, the production method of claim 2 compound may further comprise the steps:
1) be 1 by weight with Radix Rubiae Yunnanensis (Rubia ynananensis (Franch.) Diels): the ratio of 8-12 is dissolved in the distilled water, with acid, and preferred concentrated hydrochloric acid and Glacial acetic acid, the pH to 2.5-3.5 of regulator solution, 3 ℃ of-12 ℃ of placements are spent the night;
2) filter, get filter residue and filtrate;
3) use low-molecular-weight alcohol successively, particular methanol, ethanol or propyl carbinol and acetone refluxing extraction gained filter residue, the volume of methyl alcohol and acetone is respectively the above-mentioned 1/3-1/5 that is used to dissolve Radix Rubiae Yunnanensis distilled water volume;
4) methyl alcohol and the acetone extract of the above-mentioned gained of merging partly carry out silica gel column chromatography with methyl alcohol-acetone solution;
5) use hexanaphthene, 18-22 successively: chloroform-acetone of 1, methylene dichloride and acetone eluting silica gel post, circulation 12-14 time merges elutriant;
6) crystallization that obtains separating out, that is: the formula I compound when substituent R is H are spent the night in 3 ℃ of-12 ℃ of placements;
7) collect merging the above-mentioned the 5th) in the step, use hexanaphthene, 18-22 successively: chloroform-acetone of 1, methylene dichloride and the 13-16 time round-robin elutriant of acetone eluting silica gel post;
8) 3 ℃-12 ℃ are placed to crystallization and separate out, and suction filtration obtains filter cake;
9) with methyl alcohol-dehydrated alcohol-tetrahydrofuran (THF) of 1: 1: 1 filter cake is dissolved, 3 ℃-12 ℃ are placed to crystallization and separate out;
10) suction filtration, drying is separated the mixture of gained with centrifugal thin-layer chromatography, use the methylene chloride-methanol wash-out of 10: 1,8: 1,6: 1 and 4: 1 successively;
11) the II peak of the centrifugal thin-layer chromatography of collection;
12) drying, the formula I compound when promptly getting substituent R and being formula II;
13) collect the III peak of above-mentioned centrifugal thin-layer chromatography, drying, the formula I compound when promptly getting substituent R and being formula III.
5, method according to claim 4 is characterized in that: described step 3) is used the pure and mild acetone refluxing extraction of lower molecular weight gained filter residue successively, and the pure and mild acetone of described lower molecular weight is isopyknic, is extracted into the extracting solution visual inspection less than color; Described step 5) is rotated evaporation after merging elutriant; After the crystallization that described step 6) obtains separating out, carry out suction filtration, filter cake dehydrated alcohol recrystallization, with the crystallization acetone solution, decolorizing with activated carbon, 3 ℃ of-12 ℃ of placements are spent the night, the crystallization that obtains separating out, also with 3 ℃-12 ℃ cold acetone washing leaching cake, drying obtains crystallization to suction filtration, that is: the formula I compound when substituent R is H.
6, method according to claim 4, it is characterized in that: the filter cake that described step 8) obtains, with filter cake with the washing of 3 ℃-12 ℃ cold acetone after, enter the described the 9th again) step, with methyl alcohol-dehydrated alcohol of 1: 1: 1-tetrahydrofuran (THF) with after the filter cake dissolving, with decolorizing with activated carbon twice, rotary evaporation, be placed to crystallization in 3 ℃-12 ℃ again and separate out; Behind the described step 10) suction filtration, separate with carrying out described drying and centrifugal thin-layer chromatography behind 3 ℃-12 ℃ the cold acetone washing leaching cake again.
7, method according to claim 4 is characterized in that: described step 13) is collected the III peak of above-mentioned centrifugal thin-layer chromatography, dry back recrystallizing methanol, drying again, the formula I compound when promptly getting substituent R and being formula III.
8, the method for the described compound of chemosynthesis claim 3 may further comprise the steps:
1) 3, the 5-resorcylic acid is selected bromo, gets 2,5-two bromo-3,5-resorcylic acid;
2), get 2,5-two bromo-3,5-dihydroxyl-4-aminomethyl phenyl formic acid through Mannich reaction;
3) in alkali lye, add the Al-Ni alloy and carry out reduction reaction, obtain 3,5-dihydroxyl-4-tolyl acid;
4) at AlCl
3Exist down, make 3,5-dihydroxyl-4-tolyl acid and 4-hydroxy-benzoic acid react, and obtaining substituent R is the formula I compound of H.
9, method according to claim 8 is characterized in that: the selection bromo-reaction of described step 1) is at Br
2/ CHCl
3, carry out under 25 ℃ the condition; Described step 2) Mannich reaction is at 33%HNMe
2, 37%HCHO, (ethanol) E
tOH, HAc carries out under 25 ℃ the condition; Described step 3) is carried out in NaOH solution; In the described step 4) 3, the reaction of 5-dihydroxyl-4-tolyl acid and 4-hydroxy-benzoic acid is to stir, and is heated to carry out under the 180-200C.
10, the medicaments for resisting myocardial ischemia that is activeconstituents with the described Radix Rubiae Yunnanensis quinone of claim 1.
11, any one compound application in the preparation medicaments for resisting myocardial ischemia among the claim 1-3.
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| CN107722081A (en) * | 2017-11-07 | 2018-02-23 | 全椒先奇医药科技有限公司 | One kind treats myocardial ischemia drug composition and its application |
| CN112194690A (en) * | 2020-10-10 | 2021-01-08 | 贵州医科大学 | 3 new compounds in madder and extraction and separation method |
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| CN107722081A (en) * | 2017-11-07 | 2018-02-23 | 全椒先奇医药科技有限公司 | One kind treats myocardial ischemia drug composition and its application |
| CN112194690A (en) * | 2020-10-10 | 2021-01-08 | 贵州医科大学 | 3 new compounds in madder and extraction and separation method |
| CN112194690B (en) * | 2020-10-10 | 2023-10-20 | 贵州医科大学 | 3 compounds in radix Rubiae and extraction and separation method |
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