CN1260347A - Chlorophyll alpha degraded product metal complex, its preparation method and medicament for anti-gastric ulcer - Google Patents
Chlorophyll alpha degraded product metal complex, its preparation method and medicament for anti-gastric ulcer Download PDFInfo
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- CN1260347A CN1260347A CN 99119878 CN99119878A CN1260347A CN 1260347 A CN1260347 A CN 1260347A CN 99119878 CN99119878 CN 99119878 CN 99119878 A CN99119878 A CN 99119878A CN 1260347 A CN1260347 A CN 1260347A
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- chlorin
- acid
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- pheophorbide acid
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Abstract
The present invention provides five metal complex compounds obtained by stable degradation of chlorophyll a and preparation method thereof. The preparation method includes the following steps: using primary extract of silkworm excrement chlorphyll as raw material; adopting acid degradation and separation, anaerobic alkaline degradation to obtain dihydroporphine, aerobic degradation, heating dihydroporphine in pyridine, ring-opening reaction in alkaline liquor, making the above-mentioned products react with metal ions of zinc, cobalt, copper, magnesium and iron ,etc. in polar organic solvent of methyl alcohol or tetrahydrofuran, etc. to form the invented metal complex compounds, which can be used as effective components for making medicine for curing gastric ulcer. Its action is obvious, and toxicity is low.
Description
The present invention relates to the pharmaceutical chemistry field, be specifically related to chlorophyll alpha degraded product metal complex, its preparation method and medicament for anti-gastric ulcer.
The main effect of clinical application medicament for anti-gastric ulcer at present is directly or indirectly to control hydrochloric acid in gastric juice release and protection stomach mucous membrane; Direct chemical antacid is as sodium bicarbonate, aluminum hydroxide gel etc., control indirectly that hydrochloric acid in gastric juice discharges as H2 receptor blocking agent and so-called proton pump Luo Saike etc.; Bismuth subcarbonate etc. form one deck protectiveness film and mechanically reduce or alleviate stimulation and the damage of hydrochloric acid in gastric juice to mucous membrane on mucous membrane.In a sense, these all belong to (the Xie Changhe: pharmacy progress 1998,22 (2): 101 that takes stopgap measures; Peter A et al:J Med Chem 1990,33:543; MarshallBJ:Am J Gastroenterol 1991,86:16).
Some metal complex of known chlorophyll degradation product has certain preventive and therapeutic effect to the stomach ulcer that various different reasons cause, different with existing medicament for anti-gastric ulcer, the mechanism of the anti-gastric-ulcer effect that it is main is the inflammation that alleviates and eliminate the focus face, finally eliminate the ulcer focus and reach healing (Xu Deyu, Deng: external pharmacy-synthetic drug-biochemical medicine---preparation fascicle 1987,8 (3): 146; Japanese medicine thing research association: monthly magazine medicine thing 1988,30 (3): 69; Tao Haipeng: change university of doctor trained in Western medicine section journal 1990,21 (3): 31).
The object of the present invention is to provide chlorophyll a to stablize the metal complex of degraded product.
The present invention also aims to provide chlorophyll a to stablize the preparation method of the metal complex of degraded product.
Purpose of the present invention is again to provide and contains the medicament for anti-gastric ulcer that chlorophyll a is stablized degraded product metal complex.
Chlorophyll a provided by the invention is stablized degraded product metal complex: zinc, copper and cobalt pheophorbide acid a (I
*), burnt pheophorbide acid a (II
*), chlorin e
4(III
*), C.I. Natural Red 8 18 (IV
*) and chlorin p
6(V
*), they have the following chemical structure respectively:
M=Zn in the formula
2+Cu
2+Co
2+
The preparation method that chlorophyll a provided by the invention is stablized degraded product metal complex is to serve as base beginning raw material with tame silkworm faeces chlorophyll primary extract, obtains chlorophyll a and stablizes degraded product pheophorbide, burnt pheophorbide acid a, chlorin e through acid, alkaline degradation
4, C.I. Natural Red 8 18 and open loop isomer chlorin p thereof
6, these degraded products form their complex compound respectively with zinc, cobalt or mantoquita reaction.
Medicament for anti-gastric ulcer provided by the invention contains chlorophyll a and stablizes degraded product metal complex and pharmaceutically acceptable carrier.
Below the present invention is described in detail.
Chlorophyll a provided by the invention is stablized degraded product pheophorbide acid a, burnt pheophorbide acid a, chlorin e
4, C.I. Natural Red 8 18 and chlorin p
6Metal complex have following stable chemical structure:
M=Zn in the formula
2+Cu
2+Co
2+
Above-mentioned chlorophyll a is stablized degraded product and is blackish green or the class black solid, and is water insoluble, is dissolved in methyl alcohol, tetrahydrofuran (THF) isopolarity organic solvent; Be soluble in non-polar organic solvents such as ether, chloroform.
Their precursor pheophorbide acid a, burnt pheophorbide acid a, chlorin e
4, C.I. Natural Red 8 18 and chlorin p
6Have following structure:
Pheophorbide acid a (I)
Burnt pheophorbide acid a (II)
Chlorin e
4(III)
C.I. Natural Red 8 18 (IV)
Chlorin P
6(V)
The present invention serves as a base beginning raw material with the low-cost resource man silkworm faeces chlorophyll primary extract of China's abundant, obtains chlorophyll a and stablizes degraded product pheophorbide acid a, burnt pheophorbide acid a, chlorin e through acid, alkaline degradation
4, C.I. Natural Red 8 18 and open loop isomer chlorin p thereof
6And make their metal complex, concrete preparation method is as follows:
1, the preparation of pheophorbide acid a and burnt pheophorbide acid a:
With tame silkworm faeces chlorophyll primary extract by 1: 3-1: 10 weight ratios (are preferably 1: 4-1: 5) be dissolved in non-polar organic solvent and (be preferably ether, sherwood oil or gasoline), add equal-volume or excessive concentrated hydrochloric acid, under the room temperature stirring reaction 0.5-5 hour (being preferably 1-2 hour), divide and take off a layer acid solution, regulate pH to 5-6 with sodium hydroxide behind the thin up, the precipitation that the filter collection is separated out, add washing and promptly get the pheophorbide acid a crude product only, the latter separates the pure product that obtain pheophorbide acid a and burnt pheophorbide acid a respectively through silica gel column chromatography, and (chromatographic separation is launched system: chloroform-methanol-formic acid=10: 1: 0.3).
2, C.I. Natural Red 8 18 and chlorin p
6Preparation:
By 1: 30-1: 50 weight ratios are dissolved in non-polar organic solvent (being preferably ether or sherwood oil) with crude product pheophorbide acid a and burnt pheophorbide acid a mixture, add alkali metal alcohol solution (being preferably the 25%KOH n-propyl alcohol solution of 1/10 volume), the even blowing air 3-5 of reaction solution hour, then behind the thin up, regulate pH to 2-3, add the chloroform extraction, after the chloroform extraction liquid drying, evaporated under reduced pressure, gained C.I. Natural Red 8 18 crude products obtain pure C.I. Natural Red 8 18 (HPLC analyzes C.I. Natural Red 8 18 content 〉=95%) through the silica gel column chromatography separation.
3, chlorin e
4Preparation:
Crude product pheophorbide acid a and burnt pheophorbide acid a mixture are by 1: 5-1: 8 (W/V) and alkali metal alcohol solution (being preferably the 30%KOH ethanolic soln) reflux 0.5-2 hour (being preferably 0.5-1 hour), pH to 4 is regulated with dilute hydrochloric acid in the cooling back, thin up, the precipitation that the filter collection is separated out, drying obtains chlorin e after silica gel column chromatography separates
6(HPLC analyzes pure product: retention time 8.02min; Relative peak area 〉=95%).With chlorin e
6Be dissolved in pyridine by 1: 20 (W/V), back flow reaction 0.5-3 hour.After the reaction solution cooling, add 2 times of water gagings, regulate pH to 5-6 with dilute hydrochloric acid.The throw out that the filter collection is separated out, drying obtains chlorin e after silica gel column chromatography separates
4Pure product.
4, pheophorbide acid a, burnt pheophorbide acid a, chlorin e
4, C.I. Natural Red 8 18 and open loop isomer chlorin p thereof
6The preparation of metal complex:
Pheophorbide acid a, burnt pheophorbide acid a, chlorin e
4, C.I. Natural Red 8 18/ chlorin p
6Polar organic solvent solution at room temperature respectively with the saturated solution stirring reaction 0.5-3h (being preferably 1-2h) of the same solvent of zinc salt, mantoquita or cobalt salt, thin up, the precipitation that the filter collection is separated out, the abundant flush away unreacted metal of water salt, drying under reduced pressure, through silica gel chromatography separate the pure product of corresponding metal complex compound.
Described polar organic solvent is methyl alcohol, tetrahydrofuran (THF), morpholine etc.
Described zinc salt, mantoquita or cobalt salt are selected from Zn
2+, Co
2+, Cu
2+Deng muriate, acetate, vitriol or nitrate etc., be preferably Zn
2+, Co
2+, Cu
2+Deng muriate or acetate.
Above-mentioned preparation method's reaction process can letter show as follows:
Chlorophyll a is stablized the preparation feedback of degraded product
M=Cu
2+Co
2+Zn
2+Chlorophyll a is stablized the preparation feedback of degraded product metal complex
Medicament for anti-gastric ulcer provided by the invention comprises the chlorophyll a for the treatment of significant quantity and stablizes DeR product pheophorbide acid a, burnt pheophorbide acid a, chlorin e
4, C.I. Natural Red 8 18 or chlorin p
6Metal complex and pharmaceutically acceptable carrier.
" treatment significant quantity " of the present invention refers to the 5-50mg/kg body weight, is preferably the 7-30mg/kg body weight, is more preferred from the 10-20mg/kg body weight, and the best is the 15mg/kg body weight.
Pharmaceutically acceptable carrier of the present invention is selected from lactose, sucrose, fructose, starch, polyoxyethylene glycol (PEG), chitin, Magnesium Silicate q-agent, essential amino acid such as Methionin etc. and medicinal solubility promoter tween series etc.
Below with embodiment the present invention is illustrated, these embodiment are intended to set forth optimum implementation of the present invention.Those skilled in the art are according to enlightenment of the present invention, and the various changes in conjunction with the general knowledge of this area is done all drop in the scope of the application's claim.
The preparation of embodiment 1 pheophorbide acid a and burnt pheophorbide acid a
Get silkworm excrement chlorophyll primary extract 100g and be dissolved in the 300mL ether, add 36% hydrochloric acid 600mL, stirring reaction 2 hours.Standing demix, divide and take off a layer acid solution, add water 500mL dilution, regulate pH to 5-6 with 10mol/L NaOH, the precipitation that the filter collection is separated out, washing back drying under reduced pressure gets crude product pheophorbide acid a and burnt pheophorbide acid a mixture 20g, separates (developping agent: chloroform-methanol-formic acid 10: 1: 0.3) obtain pure pheophorbide acid a 6g and burnt pheophorbide acid a 4g through silica gel column chromatography.The spectroscopic measurement result of the two chemical structure is as follows:
Pheophorbide acid a:
FABMS(m/z)：594(M+2)，593M+1)，592(M)，533(M-COOCH
3)；
1H-NMR(δppm)：1.60(3H，s，4b-CH
3)，1.80(3H，d，8a-CH
3)，2.25-2.60(4H，m，7a-，7b-CH
2)，3.10(3H，s，3a-CH
3)，3.40(3H，s，1a-CH
3)，3.59(2H，q，4a-CH
2)，3.60(3H，，s，5a-CH
3)，3.84(3H，s，10b-CH
3)，4.19(1H，q，7-CH)，4.46(1H，q，8-CH)，6.25(2H，s，10-CH
2)，6.10-6.30(2H，dd，2b-CH
2)，7.90(1H，dd，2a-H)，8.51(1H，s.δ-H)，9.21(1H，s，α-H)，9.40(1H，s，β-H)；
IR (ν cm
-1): 3450,2900-2800,1750 (C=O), 1710 (C=O), 1625 (C=C), 1510 (chlorin skeletons), 1225 (C-N);
UV/VIS(λ
maxnm)：411，509，538，611，669。
Above-mentioned spectroscopic measurement result conforms to structural formula (I).
Burnt pheophorbide acid a:
FABMS(m/z)：536(M+2)，535(M+1)，534(M)，461(M-CH
2CH
2COOH)；
1H-NMR(δppm)：1.66(3H，t，4b-CH
3)，1.82(3H，d，8a-CH
3)，2.35-2.66(4H，m，7a-，7b-CH
2)，3.18(3H，s，3a-CH
3)，3.38(3H，s，1a-CH
3)，3.60(2H，q，4a-CH
2)，3.62(3H，s，5a-CH
3)，4.28(1H，m，7-CH)，4.46(1H，m，8-CH)，5.12-5.27(2H，q，10-CH
2)，6.15(1H，dd，2b-Ha)，6.24(1H，dd，2b-Hb)，7.90(1H，dd，2a-H)，8.52(1H，s，δ-H)，9.24(1H，s，α-H)，9.34(1H，s，β-H)；
IR (ν cm
-1): 3430,2990-2980,1710 (C=O), 1635 (C=C), 1510 (chlorin skeletons), 1230,1040 (C-N);
UV/VIS(λ
maxnm)：412，509，540.5，611，666。
The said determination result is consistent with structural formula (II).
Embodiment 2 chlorin e
4Preparation
Get pheophorbide acid a and burnt pheophorbide acid a crude mixture 20g that embodiment 1 described method makes, add 150mL 39%KOH ethanolic soln, back flow reaction 1 hour, pH to 4 is regulated with dilute hydrochloric acid in the cooling back, thin up, the precipitation that the filter collection is separated out is after the washing, drying under reduced pressure, gained are crude product chlorin e
6, through silica gel column chromatography separate the pure chlorin e of black powder shape
67g.Get above-mentioned chlorin e
6Pure product 5g is dissolved in the 100mL pyridine, reflux 1 hour, the cooling back adds 2 times of water gagings, regulate pH to 5-6 with dilute hydrochloric acid, the precipitation that the filter collection is separated out, after the washing, drying under reduced pressure, the gained crude product separates (developping agent: chloroform-methanol-formic acid/100: 5: 1v/v/v) obtain pure chlorin e through silica gel column chromatography
4Black powder shape solid 3.8g.Its results of structural analysis is as follows:
FABMS(m/z)：509(M)；
1HNMR(δppm)：1.61(3H，t，4b-CH
3)，2.27-2.68(4H，m，7a-，7b-CH
2)，3.20(3H，s，3a-CH
3)，3.43(3H，s，1a-CH
3)，3.56(3H，s，5a-CH
3)，3.39(3H，s，10-CH
3)，4.52-4.63(2H，m，7，8-CH)，6.05-6.09(1H，dd，2b-Ha)，6.30-6.36(1H，dd，2b-Hb)，8.10-8.20(2H，m，2a-H)，9.041h，s，δ-H)，9.521H，s，α-H)，9.65(1H，s，β-H)；
IR (ν cm
-1): 3350 (NH), 2960-2870 (CH), 1715 (C=O), 1620 (C=C), 1450 (chlorin skeletons), 1230 (C-N);
UV/VIS(λ
maxnm)：402，498，534，559，608，664。
Above-mentioned spectroscopic measurement result is consistent with structural formula (III).
Embodiment 3 C.I. Natural Red 8s 18/ chlorin p
6Preparation
Get pheophorbide acid a and burnt pheophorbide acid a crude mixture 10g that embodiment 1 described method makes, be dissolved in the 250mL ether, add 20mL 25%KOH n-propyl alcohol solution, room temperature blowing air reaction 5 hours.After reaction finishes, add water 250mL dilution, regulate pH to 2-3 with dilute hydrochloric acid.Acid solution extracts with chloroform (150mL * 3), extraction liquid adds anhydrous sodium sulfate drying and spends the night, remove solvent under reduced pressure, the gained remnant separates (developping agent: chloroform-ether-formic acid/100: 2: 1v/v/v) obtain pure C.I. Natural Red 8 18 red-purple pulverulent solids 2.3g through silica gel column chromatography.Its structural analysis data are as follows:
FABMS(m/z)：566(M+2)，565(M+1)，564(M)，491(M-CH
2CH
2COOH)；
1HNMR(δppm)：1.65(3H，t，4b-CH
3)，1.76(3H，d，8-CH
3)，2.10-2.51(4H，m，7-CH
2CH
2)，3.17(3H，s，3-CH
3)，3.34(3H，s，1-CH
3)，3.62(2H，q，4a-CH
2)，3.77(3H，s，5-CH
3)，4.42(1H，q，8-CH)，5.24(1H，m，7-CH)，6.20(1H，d，2b’-CH)，6.29(1H，d，2b-CH)，7.87(1H，dd，2a-H)，8.63(1H，s，δ-H)，9.40(1H，s，α-H)，9.63(1H，s，β-H)；
IR(νcm
-1)：3360(NH)，30002800(CH)，1740，1710(C＝O)，1600(C＝C)，1530
(chlorin skeleton), 1300 (CN), 990 (CH=);
UV/VIS(λ
maxnm)：412，478，510，547，645，701。
Above-mentioned spectroscopic measurement data and structural formula (IV) are in full accord.
1g C.I. Natural Red 8 18 is dissolved among the 50mL 0.1mol/L NaOH, and that obtain is chlorin p
6Sodium-salt aqueous solution (pH＞9).
The chlorin p that C.I. Natural Red 8 18 open loops generate
6Only being present in the alkaline aqueous solution, is that cyclization becomes C.I. Natural Red 8 18 after the dehydration.So can't obtain its structural parameter.
Synthesizing of embodiment 4 zinc pheophorbide acid as
Get the pheophorbide acid a 1g that makes by embodiment 1, be dissolved in 50mL methyl alcohol, add 50mL ZnCl
2The methyl alcohol saturated solution, stirring reaction is 2 hours under the room temperature, reaction mixture is inclined in the 500mL frozen water, the precipitation that the filter collection is separated out, washing, drying obtains green flour powder zinc pheophorbide acid a solid 0.7g after silica gel column chromatography separates.Its results of structural analysis is as follows:
FABMS(m/z)：657(M+2)，656(M+1)，655(M)，596(M-COOCH
3)；
1HNMR(δppm)：1.62(3H，s，4b-CH
3)，1.76(3H，d，8a-CH
3)2.25-2.58(4H，m，7a-，7b-CH
2)，3.10(3H，s，3a-CH
3)，3.37(3H，s，1a-CH
3)，3.60(3H，s，5a-CH
3)，3.82(3H，s，10-b-CH
3)，4.15(1H，q，7-CH)，4.43(1H，q，8-CH)，6.15(2H，s，10-CH
2)，7.93(1H，dd，2a-H)，8.52(1H，s，δ-H)，9.28(1H，s，α-H)，9.44(1H，s，β-H)；
IR (ν cm
-1): 2920-2780,1750 (C=O), 1625 (C=C), 1525 (chlorin skeletons),
UV/VIS(λ
maxnm)：431，515，556，605，670。
Said determination result and structural formula (I
*) unanimity.
Synthesizing of the burnt pheophorbide acid a of embodiment 5 zinc
Get the burnt pheophorbide acid a 1g that makes by embodiment 1, press the operation of embodiment 4 methods, obtain the burnt pheophorbide acid a pulverulent solids of deep green zinc 0.8g.Its structural analysis data are as follows:
FABMS(m/z)：598(M+2)，597(M+1)，596(M)，524(M-CH
2CH
2COOH)；
1HNMR(δppm)：1.20(3H，t，4b-CH
3)，1.40(3H，d，8a-CH
3)，1.73(2H，m，7a-CH
2)，
96(2H，m，7b-CH
2)，2.27(3H，s，3a-CH
3)，2.73(3H，s，1a-CH
3)，3.02(2H，q，4a-CH
2)，3.12(3H，s，5a-CH
3)，3.86(1H，m，7-CH)，4.19(1H，m，8-CH)，5.01(2H，q，10-CH
2)，5.82(1H，dd，2a-Ha)，5.92(1H，dd，2b-Hb)，7.63(1H，m，2a-CH)，8.17(1H，s，δ-H)，8.59(1H，s，α-H)，8.67(1?H，s，β-H)；
IR (ν cm
-1): 3000-2800 (CH), 1720 (C=O), 1620 (C=), 1560 (chlorin skeletons),
1355(C-N)，1235(C-O)；
UV/VIS(λ
maxnm)：427，524，566，611，656。
Said structure determination data and structural formula (II
*) unanimity.
Embodiment 6 zinc chlorin e
4Synthetic
Get the chlorin e that embodiment 2 makes
41g makes zinc chlorin e by embodiment 3 described methods
40.65g.Its structure determination data are as follows:
FABMS(m/z)：617M+2)，615(M+1)，614(M)；
IR (ν cm
-1): 3000-2800 (CH), 1740,1715 (C=O), 1620 (C=C), 1445 (chlorin skeletons), 1385 (CN), 990 (C=H);
UV/VIS(λ
maxnm)：416，514，550，591，632。
Said structure determination data and structural formula (III
*) unanimity.
Synthesizing of embodiment 7 zinc C.I. Natural Red 8s 18
Get C.I. Natural Red 8 18 1g that embodiment 3 makes, make black zinc C.I. Natural Red 8 18 pulverulent solids 0.67g by embodiment 3 described methods.Its structural analysis data are as follows:
FABMS(m/z)：628(M+2)，626(M)；
1HNMR(δppm)：1.51(3H，t，4b-CH
3)，1.62(3H，d，8a-CH
3)，2.03-2.38(4H，m，7a，7b-CH
3)，2.87(3H，s，3a-CH
3)，3.21(3H，s，1a-CH
3)，3.46(2H，q，4a-CH
2)，3.53(3H，s，5a-CH
3)，4.05(1H，m，8-CH)，4.85(1H，m，7_CH)，5.99(1H，dd，2b-Ha)，6.07(1H，dd，2b-hb)，7.76(1H，q，(2a-CH)，8.22(1H，s，δ-H)，9.08(1H，s，α-H)，9.301H，s，β-H)；
IR (ν cm
-1): 3000-2800 (CH), 1750,1715 (C=O), 1615 (C=C), 1565 (chlorin skeletons), 1305 (CN), 1210 (C-O), 980 (CH=);
UV/VIS(λ
maxnm)：423，521，561，673。
Said determination data and structural formula (IV
*) unanimity.
Synthesizing of the burnt pheophorbide acid a of embodiment 8 bronze medals
With burnt pheophorbide acid a of 1g and 1g Cu (AcO)
2.2H
2O is dissolved in 100mL tetrahydrofuran (THF), stirring and refluxing 2xs.After the reaction solution cooling, add the dilution of 500mL water, the precipitation that the filter collection is separated out, washing, drying under reduced pressure is after silica gel column chromatography separates (developping agent: chloroform-methanol-formic acid/100: 10: 2) obtain the blackish green pulverulent solids 0.76g of the burnt pheophorbide acid a of copper.Its structural analysis data are as follows:
FABMS(m/z)：597(M+2)，596(M+1)，595(M)；
IR (ν cm
-1): 3000-2800 (CH), 1740,1700 (C=O), 1640 (C=C), 1560 (chlorin skeletons), 1350 (CN), 1220 (C-O), 970 (CH=);
UV/VIS(λ
maxnm)：422，560，607，657。
Said structure determination data and structural formula (II
*) unanimity.
Embodiment 9-11 copper pheophorbide acid a, copper chlorin e
4, copper C.I. Natural Red 8 18 synthetic
Get pheophorbide acid a, chlorin e that embodiment 1,2,3 makes
4, C.I. Natural Red 8 18 is respectively by synthetic copper pheophorbide acid a, the copper chlorin e of obtaining of embodiment 7 described methods
4With copper C.I. Natural Red 8 18.Its structural analysis data are respectively:
The copper pheophorbide acid a:
FABMS(m/z)：538(M+2)，537(M+1)，536(M)；
IR (ν cm
-1): 3000-2800 (CH), 1735 (C=O), 1645 (C=C), 1545 (chlorin skeletons), 1325 (CN), 980 (CH=);
UV/VIS(λ
maxnm)：416，550，615，660。
Copper chlorin e
4:
FABMS(m/z)：614(M+1)，613(M)；
IR (ν cm
-1): 3000-2800 (CH), 1740,1700 (C=O), 1610 (C=C), 1460 (chlorin skeletons), 1385 (CN), 1220C-O), 990 (CH=);
UV/VIS(λ
maxnm)：422，555，603，650。
Copper C.I. Natural Red 8 18:
FABMS(m/z)：626(M+1)；
IR (ν cm
-1): 3000-2800 (CH), 1760,1725 (C=O), 1615 (C=C), 1565 (chlorin skeletons), 1300 (CN), 1220 (C=-O), 990 (CH=) '
UV/VIS(λ
maxnm)：418，507，549，669。
Above-mentioned respectively organize determination data respectively with structural formula (I
*), (III
*) and (IV
*) consistent.
Synthesizing of the burnt pheophorbide acid a of embodiment 12 cobalts
Get burnt pheophorbide acid a 1g and Cobaltous diacetate 1g that embodiment 1 makes, be dissolved in the 100mL tetrahydrofuran (THF), stirring and refluxing 0.5 hour adds water 500mL dilution after the cooling, the precipitation that the filter collection is separated out, washing, drying.The gained crude product obtains the burnt pheophorbide acid a 0.3g of black powder shape cobalt through the silica gel column chromatography separation.
Embodiment 13-15 cobalt pheophorbide acid a, cobalt chlorin e
4And cobalt violet red pigment 18 is synthetic
Get pheophorbide acid a, chlorin e that embodiment 1,2,3 makes
4And C.I. Natural Red 8 18 each 1g, press embodiment 12 methods synthesize cobalt pheophorbide acid a, cobalt chlorin e
4And cobalt violet red pigment 18.
Embodiment 12-15 synthetic four kinds of cobalt complexs as follows through the fast atom bombardment mass spectroscopy(FABMS) analytical results:
Cobalt pheophorbide acid a: 534 (M+2), 533 (M+1), 532 (M);
Cobalt chlorin e
4: 609 (M+2), 608 (M+1), 607 (M);
Cobalt violet red pigment 18:623 (M+2), 622 (M+1), 621 (M);
Burnt pheophorbide acid a: 593 (M+2) of cobalt, 592 (M+1), 591 (M).
Illustrate: because of copper and cobalt atom have diamagnetism, their complex compound does not have the nuclear magnetic resonance spectrum signal.So each title compound of embodiment 8-15 does not all have the nuclear magnetic resonance spectrum determination data.
Embodiment 16 chlorophyll alpha degraded product zinc, copper, cobalt complex tablet
Prescription (every)
Chlorophyll alpha degraded product zinc, copper and/or cobalt complex 100mg
Radix Glycyrrhizae extractum 100mg
Glycine 20mg
Starch 100mg
Talcum powder is an amount of
Technology is made coated tablet routinely
Chlorophyll degradation product zinc, copper and/or cobalt complex 100mg with other pharmaceutically common carrier replace Radix Glycyrrhizae extractum and glycine, by make chlorophyll degradation product zinc, copper and/or cobalt complex coated tablet with quadrat method.
Above-mentioned pharmaceutically common carrier can be selected from lactose, sucrose, fructose, starch, polyoxyethylene glycol (PEG), chitin, Magnesium Silicate q-agent, essential amino acid: as Methionin etc. and medicinal solubility promoter tween series etc.
Embodiment 17 chlorophyll degradation product zinc, copper and/or cobalt complex capsule
Prescription (every)
Chlorophyll degradation product zinc, copper and/or cobalt complex 100mg
Radix Glycyrrhizae extractum 100mg
Glycine 20mg
The pharmacy common carrier is an amount of
Technology fills in No. 1 capsule for medicine routinely.
As described in embodiment 16, replace Radix Glycyrrhizae extractum and glycine with common carrier pharmaceutically, by make chlorophyll alpha degraded product zinc, copper and/or cobalt complex capsule with quadrat method.
Above-mentioned pharmaceutically common carrier can be selected from lactose, sucrose, fructose, starch, polyoxyethylene glycol (PEG), chitin, Magnesium Silicate q-agent, essential amino acid such as Methionin etc. and medicinal solubility promoter tween series etc.
The anti-gastric-ulcer effect of experimental example 1 chlorophyll alpha degraded product metal cobalt complex
According to the method for " pharmacy and pharmacological toxicology were learned research governing principle compilation before new drug (Western medicine) was clinical " regulation of Ministry of Health promulgation, pheophorbide acid a, burnt pheophorbide acid a, chlorin e have been measured
4, C.I. Natural Red 8 18 and chlorin p
6Zinc, copper, cobalt complex to the curative effect (seeing the following form) of experimental stomach ulcer.Pheophorbide acid a, burnt pheophorbide acid a, chlorin e
4, C.I. Natural Red 8 18
Zinc, copper, cobalt complex to the effect test-compound of experimental stomach ulcer
※Dosage (mg/kg) number of animals ulcer number ulcer index (mm) I
*-Zn
2+80 6 2.27 ± 1.53
*21.11 ± 11.40
*I
*-Co
2+80 6 4.54 ± 2.66
*6.85 ± 4.46
*I
*-Cu
2+80 6 3.21 ± 2.05
*3.05 ± 1.78
*II
*-Zn
2+80 6 3.79 ± 2.08
*5.27 ± 4.32
*II
*-Cu
2+80 6 6.58 ± 4.39
*3.78 ± 1.43
*II
*-Co
2+80 6 3.95 ± 2.29
*5.63 ± 2.64
*III
*-Zn
2+80 6 3.25 ± 1.73
*4.18 ± 4.01
*III
*-Cu
2+80 6 7.26 ± 5.48
*4.33 ± 3.90
*III
*-Co
2+80 6 2.25 ± 1.49
*3.24 ± 3.05
*IV
*-Zn
2+80 6 3.56 ± 1.44
*4.23 ± 4.15
*IV
*-Cu
2+80 6 6.68 ± 6.13
*4.05 ± 4.29
*IV
*-Co
2+80 6 4.67 ± 4.54
*4.21 ± 3.94
*Famotidine 30 10 8.00 ± 5.19
*5.10 ± 3.10
*Blank-10 42.00 ± 22.43 41.59 ± 24.07
*P＜0.05;
*P＜0.01 (comparing) with blank.
The acute toxicity test of experimental example 2 chlorophyll alpha degraded product metal complexes
Chlorophyll alpha degraded product metal complex of the present invention is ground to form soup compound with CMC in mortar, gavage for 20 mouse (18-22g) with the capacity that maximum can tolerate, dosage is 5g/kg, observes 7 days, and none dead mouse is not seen tangible toxic agent reaction yet.
Above result shows, chlorophyll alpha degraded product pheophorbide acid a, burnt pheophorbide acid a, chlorin e
4, the zinc of C.I. Natural Red 8 18, copper, cobalt complex all has significant therapeutic effect to the rat experiment gastric ulcer, its acute toxicity is then all far below the medicament for anti-gastric ulcer of clinical application at present such as famotidine, thereby is a class high-efficiency low-toxicity and the desirable anti-gastric-ulcer new drug for the treatment of both principal and secondary aspect of disease.
Reference and citing document 1.Vernon LP and Seely GR: chlorophyll (The Chlorophylls) .Academic Press, 1966, New York and Lodon.2.Hynninen PH: the former reason chlorophyll of application choice hydrolysis mixture preparation symbol guest's derivative (Preparation of porbin derivatives from chlorophyll mixture ultilizing the priciple of selective hydrolysis.) Synthesis 1980,46 (7): 539.3.Wasielewski et al: chlorophyll a, burnt chlorophyll a, chlorophyll b and bacteriochlorophyll a covalency link synthetic (the Synthesis of covalently linked dimeric derivatives of chlorophyll a of dimer derivate, pyrochlorophyll a, chlorophyll b and bacteriochlorophyll a.) J Org Chem 1980,45:1969.4. square beautiful jade, Xu Deyu: chlorin ether derivant synthetic.Organic chemical reactions 995,15:493.5. Hu Longqin, Xu Deyu: phyllins are in pharmaceutically application.Foreign medical science-synthetic drug, biochemical medicine preparation fascicle 1987,8 (3): 146.6. it is surplus to be permitted moral: tumor photodynamic therapy: principle, medicine, clinical introduction.Chinese Medicine science and technology press, in June, 1996 first version, Beijing.7. it is surplus to be permitted moral: the progress of photodynamic tumor diagnosis and treatment medicine.Medicine industry 1987,18:31.8. Hu Longqin, Xu Deyu: the research of novel tumor photochemistry diagnosis and treatment agent pheophorbide acid a.The 2nd Army Medical College journal 1986,7:405.9.Ravindra KD et al: as the chlorin and derivatives of porphyrin (Chlorin and porphyrin derivatives as potential photosensitizer in photodynamic thrapy.) the Photochem Photobil 1991.53:65 of the potential photosensitizer of photodynamic therapy.
Claims (10)
1. CHLOROPHYLLINE a degraded product pheophorbide acid a, burnt pheophorbide acid a, chlorin e
4, C.I. Natural Red 8 18/ chlorin p
6Metal complex (I
*)-(V
*), it is characterized in that: have following chemical structure respectively:
In the formula, M=Cu
2+Co
2+Zn
2+
2. the preparation method of chlorophyll alpha degraded product metal complex according to claim 1 is characterized in that:
(1) is starting raw material with tame silkworm faeces chlorophyll primary extract, obtains pheophorbide acid a (I), burnt pheophorbide acid a (II), chlorin e through acid, alkaline degradation
4(III), C.I. Natural Red 8 18 (IV) and chlorin p
6(V);
Chlorophyll alpha degraded product: pheophorbide acid a, burnt pheophorbide acid a, chlorin e
4, C.I. Natural Red 8 18 (chlorin p
6) preparation feedback
(2) above-mentioned chlorophyll alpha degraded product generates corresponding metal complex compound (I with reactions such as zinc, copper and cobalt salts respectively
*)-(V
*).
M＝Cu
2+；Co
2+；Zn
2+
3, as method as described in the claim 2, wherein pheophorbide acid a and burnt pheophorbide acid a prepare as follows:
Silkworm faeces chlorophyll primary extract is dissolved in the non-polar solvent, add equal-volume or excessive concentrated hydrochloric acid, under the room temperature stirring reaction 0.5-5 hour, divide and get the acid layer, regulate pH to 4-6, the precipitation that the filter collection is separated out, washing, drying gets crude product pheophorbide acid a and burnt pheophorbide acid a mixture, separates pheophorbide acid a and the pure product of burnt pheophorbide acid a of obtaining through silica gel column chromatography.
4, as method, wherein C.I. Natural Red 8 18/ chlorin p as described in the claim 2
6Preparation as follows:
The crude product pheophorbide acid a is dissolved in the non-polar solvent, adds alkali metal alcohol solution, blowing air reaction 3-5 hour, behind the thin up, regulate pH to 2-3, chloroform extraction, after the extraction liquid drying, evaporate to dryness gets C.I. Natural Red 8 18 crude products, separates obtaining pure C.I. Natural Red 8 18 through silica gel column chromatography;
C.I. Natural Red 8 18 open loop in alkaline aqueous solution generates chlorin p
6
5, as method as described in claim 3 or 4, wherein said non-polar solvent is selected from ether, sherwood oil and gasoline etc.
6, as method, wherein chlorin e as described in the claim 2
4Preparation as follows:
Crude product pheophorbide acid a under oxygen free condition in alkali metal alcohol solution reflux 0.5-2 hour after the cooling, is regulated pH to 3-4, and the precipitation that the filter collection is separated out after the drying, separates to obtain chlorin e through silica gel column chromatography
6, the latter in pyridine reflux 0.5-3 hour, cooling back thin up is transferred pH to 5-6, and the precipitation that the filter collection is separated out after the drying, separates to obtain pure chlorin e through silica gel column chromatography
4
7, method as claimed in claim 2, wherein the preparation method of chlorophyll alpha degraded product metal complex is as follows:
Described various chlorophyll a is stablized the inert solvent solution of degraded product I-V, respectively with the same solvent saturated solution stirring reaction of zinc salt, mantoquita or cobalt salt 0.5-3 hour, thin up, the precipitation that the filter collection is separated out, the water thorough washing, drying under reduced pressure, the gained crude product obtains the pure product of respective metal complex compound through chromatographic separation.
8, method as claimed in claim 7, wherein said inert organic solvents are methyl alcohol, tetrahydrofuran (THF), morpholine etc.
9, method as claimed in claim 7, wherein said zinc salt, mantoquita or cobalt salt are selected from Zn
2+, Cu
2+, Co
2+Muriate, vitriol, acetate, nitrate.
10, medicament for anti-gastric ulcer comprises the metal complex (I of the described chlorophyll alpha degraded product of claim 1 of significant quantity
*)-(V
*) and pharmaceutically acceptable carrier.
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