CN1563014A - New compound ramification of garcinia acid - Google Patents
New compound ramification of garcinia acid Download PDFInfo
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- CN1563014A CN1563014A CN 200410033298 CN200410033298A CN1563014A CN 1563014 A CN1563014 A CN 1563014A CN 200410033298 CN200410033298 CN 200410033298 CN 200410033298 A CN200410033298 A CN 200410033298A CN 1563014 A CN1563014 A CN 1563014A
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Abstract
This invention relates to modification of three isomers of total garcinolic acid, and shows their general formulas: (I), (II) and (III). This invention also describes the three noval compounds, and their pharmaceutically acceptable salts, and their prepn. methods, where: X1, X2, R1, R2, (R3), (R6), (R7), (R9), (R11), R4, R5, R8, R10, R12 are illustrated as specification of this invention.
Description
Technical field
The present invention relates to be used for the treatment of the new compound of cancer and broad-spectrum antimicrobial--morellic acid, neogambogic acid, allogambogic acid series derivates and preparation method thereof.
Background technology
Gamboge is guttiferae plant gamboge tree excretory dry resin, and is cold in nature, and it is sour, hot, puckery, poisonous to distinguish the flavor of, and the successive dynasties are that cream, ball, the powder of main component has multiple with the gamboge.Gamboge is recorded by American Pharmacopeia, and its activeconstituents is mainly morellic acid (comprising a spot of neogambogic acid and allogambogic acid).General chemotherapy anticarcinogen also influences normal hemopoietic system and white corpuscle in kill cancer cell.And morellic acid is when using as cancer therapy drug, and it is kill cancer cell optionally, can not influence normal hemopoietic system and white corpuscle.Therefore, total cambogic acid is used as anticancer chemicals, compares with anticancer chemicals commonly used in the market to have extraordinary advantage.
" Jiangxi Medical College's journal " 1980 (1), 17,1981 (1) 13 report morellic acids are to sarcoma (S
180) and ehrlich carcinoma restraining effect is arranged." Jiangxi Medical College's journal " 1983 (3), 5 be the morellic acid extraction using alcohol, and the total ethanol extract that obtains reclaims ethanol, uses the boric acid water dissolution, and add the tween 80 solubility promoter and make injection, and this injection is carried out relevant toxicity research.
" Tianjin medicine oncology supplement " 1981,8,230 reports are made injection liquid with morellic acid and are used for clinical treatment 50 routine malignant tumours.Present report mainly is that the general extractive with gamboge is dissolved in the physiological saline and uses.According to " Jiangxi medicine ": the clinical use of gamboge has local irritant effect to blood vessel, and is too fast when instiling, concentration is high slightly or administration time when longer, can cause superficial phlebitis; Soup leaks into outside the blood vessel during injection, can cause local swelling and pain.Though so total cambogic acid has the advantage of selectively killing cancer cells as anticancer chemicals, it is bigger yet to exist toxicity.Use inconvenience and bring the problem of side effect.
The patent of China Medicine University " mixture of gambogic acid compounds with anticancer activity and preparation method thereof ", and publication number: CN1309125A (application number: 01108049.3), 2001/01/17.It is with gambogic acid compounds and different base or ion formation mixtures, mainly make morellic acid and amino acid form water miscible mixture, and be that effective constituent has been made anticancer chemical drug respectively with this mixture, powder injection, complex tablet, complex capsule, emulsion etc. are arranged.Thereby improved drug effect, reduced pungency and toxicity.This patent is that morellic acid is laid a good foundation as a kind of good promoting the use of of PTS.Morellic acid is planted as pure natural and is carried cancer therapy drug, and it has obtained very big success.
Morellic acid is orange-yellow crystalline powder, solubleness is bigger in organic solvents such as alcohols, ketone, but in water, can not dissolve, though in highly basic (as sodium hydroxide solution), can dissolve, but the morellic acid in the alkaline solution is extremely unstable, is easy to hydrolysis, and patent CN1309125A selects compound L-arginine for use, solved water-soluble problem, but stability also not very high.Simultaneously, though patent CN1309125A has improved the anticancer drug effect of morellic acid, compare with cancer therapy drug such as camptothecine or slightly inferior.
Summary of the invention
The purpose of this patent is exactly under the prerequisite of the main framing that keeps total cambogic acid (comprising morellic acid, neogambogic acid, allogambogic acid) structure, its group is modified, so that when using, compare with total cambogic acid and to have as the effective constituent of new cancer therapy drug and broad-spectrum antimicrobial:
(1) higher stability.
(2) better solvability, better at the partition ratio of fat phase and aqueous phase.
(3) better drug effect.
(4) smaller toxic side effect.
Nineteen fifty-five Amorosa obtains highly purified morellic acid first through the pyridinium salt crystallization, and nineteen sixty-five has been determined the molecular structure of morellic acid by nucleus magnetic resonance, and the report document of morellic acid preparation is more.We select for use following method to prepare highly purified total cambogic acid (HPLC＞97%) at this:
(1) select a kind of organic solvent for use: acetone or methyl alcohol or pyridine etc. are molten to be got and crystallization obtains the crude product of morellic acid pyridinium salt.
(2) with behind the ether-sherwood oil recrystallization three times, obtain purified morellic acid pyridinium salt.
(3) thus this salt obtains highly purified morellic acid with hydrochloric acid flush away pyridine in organic solvents such as ether.
This morellic acid is obtained morellic acid, neogambogic acid, allogambogic acid through the high performance column separation.Structural formula is as follows respectively:
Morellic acid
Neogambogic acid
Allogambogic acid
One, total cambogic acid ketone carbonyl (
8C and
12C; Formula II is
12C and
16C) preparation of reduzate
A kind of (morellic acid or neogambogic acid or allogambogic acid) in the total cambogic acid is dissolved in the suitable organic solvent, for example methyl alcohol, ethanol etc., with selectivity ratios such as sodium borohydride or lithium aluminum hydride reductive agent (first-selected sodium borohydride) preferably, can accomplish the ketone carbonyl in the redox molecule, and it is reduced and be converted into hydroxyl, and the carboxylic acid group can not be reduced.Simultaneously, we find recently to obtain different total cambogic acid derivatives by the control reductive agent with the mole of morellic acid reaction: when (1) reductive agent was slightly excessive, what obtain was that two carbonyls all are reduced into hydroxyl, at this moment the X among general formula (I), (II), (III)
1, X
2Be CHOH.
(2) when reductive agent is not enough, the product that obtains separates through silicagel column can obtain three kinds of product: X
1, X
2Be CHOH; X
1Be CHOH, X
2Be C=O; X
1Be C=O, X
2Be CHOH.Work as X
1, X
2When having at least one to be CHOH, by obtaining working as X with acyl chloride reaction or the reaction of iodine alkane
1, X
2Have at least one to be CHOR
2Different products.
Two, total cambogic acid (
30C) preparation of the carboxylate of carboxyl, amidate
A kind of (morellic acid or neogambogic acid or allogambogic acid) in the total cambogic acid is dissolved in corresponding alcohol is among the ROH, adding a spot of anhydrous magnesium sulfate stirred 3 hours, remove by filter sal epsom, add mole number and be the DMAP of twice of morellic acid and EDC stirring reaction more than 2 hours at room temperature, in reactant impouring frozen water, with the target product in multiple extraction this decant thing of ether equal solvent, abandon water, merge organic phase, with removing organic solvent behind the anhydrous sodium sulfate drying, the crude product that obtains separates with silicagel column, obtains the higher gamboge acid esters of purity.Promptly obtain the R among general formula (I), (II), (III)
1Serial total cambogic acid compound (wherein R as defined above) for RO-.
A kind of (morellic acid or neogambogic acid or allogambogic acid) in the total cambogic acid is dissolved in the methyl alcohol, adding a spot of anhydrous magnesium sulfate stirred after 3 hours, remove by filter sal epsom, vacuum is removed methyl alcohol, adding mole number all is the DMAP of morellic acid twice, EDC and organic amine etc., at room temperature stirring reaction is more than 2 hours, then with in the reactant impouring frozen water, with the target product in ether or multiple extraction this decant thing of ethyl acetate equal solvent, abandon water, merge organic phase, and with removing organic solvent behind the anhydrous sodium sulfate drying, the crude product that obtains separates with silicagel column, obtains the higher morellic acid acid amides of purity.Promptly obtain the R among general formula (I), (II), (III)
1For RNH-or be the total cambogic acid series compound (R wherein of R
1, R as defined above).
Three, the total cambogic acid hydroxyl (
6C; Formula III is
4C and
6C) preparation of carboxylate
(1) a kind of (morellic acid or neogambogic acid or allogambogic acid) in the total cambogic acid is dissolved in the suitable organic solvent (as isopropyl ether, methylene dichloride etc.), adding a spot of anhydrous magnesium sulfate stirred 3 hours, remove by filter sal epsom, again after adding a small amount of triethylamine, at room temperature or to drip acyl chloride below 40 ℃ (be RCOCl, R is as defined above), insulation reaction 3-24 hour.In the impouring trash ice, up to neutrality, water is abandoned it with cold water washing isopropyl ether solution.The organic phase anhydrous sodium sulfate drying, obtain after vacuum removal isopropyl ether, product separate through silicagel column hydroxyl on the parent esterified series derivates.Be the R among general formula (I), (II), (III)
2Be RCO-.
(2) a kind of (morellic acid or neogambogic acid or allogambogic acid) in the total cambogic acid is dissolved in the suitable organic solvent (as isopropyl ether, methylene dichloride etc.), adding a spot of anhydrous magnesium sulfate stirred 3 hours, remove by filter sal epsom, add an amount of DMAP and DPC, add the R of 1.2 times of moles again
1COOH was 70 ℃ of reactions 100 hours, then with in the reactant impouring frozen water, with the target product in ether or multiple extraction this decant thing of ethyl acetate equal solvent, abandon water, merge organic phase, remove organic solvent after there is no dried over sodium sulfate, the crude product that obtains separates with silicagel column, obtains the higher gamboge acid esters of purity.Promptly obtain the R among general formula (I), (II), (III)
1Be RCO-total cambogic acid series compound (R wherein
1As defined above).
In a kind of (morellic acid or neogambogic acid or allogambogic acid) in total cambogic acid dissolving and methylene dichloride, add excessive iodine alkane, and add a spot of potassium hydroxide stirring reaction at room temperature, through separating the etherate that promptly can obtain total cambogic acid.I.e. R among (I), (II), (III)
2Total cambogic acid derivative (wherein R as defined above) for R-.Or total cambogic acid reacted at normal temperatures with methyl-sulfate in methylene dichloride, can obtain the etherate of total cambogic acid equally.I.e. R among (I), (II), (III)
2Total cambogic acid derivative (wherein R as defined above) for R-.
Four, the preparation of total cambogic acid and halogen affixture
A kind of (morellic acid or neogambogic acid or allogambogic acid) in the total cambogic acid is dissolved in the suitable organic solvent (as methyl alcohol etc.), add 3 hours after-filtration of a spot of anhydrous magnesium sulfate stirring and remove sal epsom, when the temperature of maintenance reaction mass is 0-5 ℃, (with the liquid bromine is good to import the exsiccant halogen under stirring preferably lentamente in the methanol solution of morellic acid, chlorine also can), the mole number that adds halogen is that 5 times of morellic acid mole number [add 4 times for general formula (II), and do not have (R in the product
9), R
10Substituting group].Continue to stir after fading to reactant after adding halogen, after vacuum is removed methyl alcohol, obtain thick morellic acid halogenide, the separation of this crude product being passed through silicagel column obtains purer target product, promptly obtains (R among general formula (I), (II), (III) respectively
3), (R
6), (R
7) (R
9), (R
11), R
4, R
5, R
8, R
10, R
12(neogambogic acid does not exist 9 and 10) all is two halogenide (being that each two key is by the addition of two halogen atom institutes) of the total cambogic acid of halogen atom: Cl, Br.
Will be two halid a kind of (purify through silicagel column or do not purify) be dissolved in the anhydrous methanol, adds after a spot of anhydrous magnesium sulfate stirs 3 hours after-filtration and remove sal epsom, adds dry that cross and the equimolar sodium hydrate methanol solution of morellic acid.At room temperature placing response is more than 12 hours, with the reactant of dark color in entry, extract several times with ether, wash ether with water, behind the anhydrous sodium sulfate drying, solvent removed in vacuo obtains the darker dope of color, separate through silicagel column, can obtain: removed a hydrogen halide molecule between 3 and 4,5 and 6,7 and 8,9 and 10 (neogambogic acid does not exist 9 and 10), 11 and 12 carbon carbon atoms and formed the Gamboges acid derivative of two keys.At this moment, parenthesized (R
3), (R
6), (R
7) (R
9), (R
11) just do not existed, and R
4, R
5, R
8, R
10, R
12(neogambogic acid does not exist 9 and 10) all is halogen atom (as Cl, Br etc.).
Five, the preparation of total cambogic acid and haloid acid affixture
A kind of (morellic acid or neogambogic acid or allogambogic acid) in the total cambogic acid is dissolved in the suitable organic solvent (as methyl alcohol etc.), add 3 hours after-filtration of a spot of anhydrous magnesium sulfate stirring and remove sal epsom, when the temperature of maintenance reaction mass is 0-5 ℃, (with Hydrogen bromide is good to import the exsiccant haloid acid under stirring preferably lentamente in the methanol solution of morellic acid, hydrogenchloride also can), the mole number that adds haloid acid is that [for general formula (II) add-on is 4 times, and does not have (R in the product for 5 times of morellic acid mole number
9), R
10Substituting group].Reaction stirred obtained thick morellic acid halogenide more than 3 hours, and the separation of this crude product being passed through silicagel column obtains purer target product, promptly obtains (R among general formula (I), (II), (III) respectively
3), (R
6), (R
7) (R
9), (R
11) all be H.R
4, R
5, R
8, R
10, R
12(neogambogic acid does not exist 9 and 10) all is single halogenide of the total cambogic acid of halogen atom: Cl, Br.
Above-mentioned bromide for preparing or muriate are dissolved in the anhydrous methanol, add fluorochemical (NH for example
4F, NaF) react under the room temperature, just can obtain corresponding morellic acid fluorine substituent.
Six, the preparation of the hydrogenation thing of total cambogic acid
A kind of (morellic acid or neogambogic acid or allogambogic acid) in the total cambogic acid is dissolved in the suitable organic solvent (as methyl alcohol etc.), add 3 hours after-filtration of a spot of anhydrous magnesium sulfate stirring and remove sal epsom, add a spot of hydrogenation catalyst (palladium carbon etc.), under room temperature normal pressure violent stirring, feed hydrogen.Just can obtain 3 and 4,5 and 6,7 and 8,9 and 10 (neogambogic acid does not exist 9 and 10) on the total cambogic acid, 11 and 12 carbon-carbon double bonds by the hydrogen addition compound, promptly obtain (R among general formula (I), (II), (III) respectively
3), (R
6), (R
7) (R
9), (R
11), R
4, R
5, R
8, R
10, R
12(there is not R in neogambogic acid
9With R
10) all be single halogenide (being only to contain a halogen atom after each two key addition) of the total cambogic acid of H.
Seven, the preparation of halogen atom substitution product in the total cambogic acid halogenide
A kind of (being mainly bromide) in the single halogenide of the above-mentioned total cambogic acid for preparing (morellic acid or neogambogic acid or allogambogic acid) is dissolved in the acetonitrile, adds 3 hours after-filtration of a spot of anhydrous magnesium sulfate stirring and remove sal epsom, add the dry RNH that crosses
2(R for as defined above) acetonitrile solution is at room temperature placed more than one day the room temperature solvent removed in vacuo.Separation obtains corresponding morellic acid aminated compounds to this compound through silicagel column, promptly obtains R among general formula (I), (II), (III) respectively
4, R
5, R
8, R
10, R
12All be that (wherein the qualification of R as defined above for the series derivates of RNH, or be heteroatomic ring group as defined above), this compound has better water solubility, and very easily be dissolved in acidic aqueous solution, also can be dissolved in alkaline aqueous solution, and stability is splendid in the subacidity or the neutral aqueous solution.
A kind of (being mainly bromide) in the single halogenide of the above-mentioned total cambogic acid for preparing (morellic acid or neogambogic acid or allogambogic acid) is dissolved in the methanol aqueous solution (50%-95%'s), add an amount of about 30% sodium hydroxide solution in batches, at room temperature react more than 24 hours, the PH of regulator solution is to neutral, the water that adds equivalent, multiple extraction with ether, after merging ether, solvent removed in vacuo, separation through silicagel column, obtain the polyhydric series derivates of total cambogic acid, promptly obtain R among general formula (I), (II), (III) respectively
4, R
5, R
8, R
10, R
12(there is not R in neogambogic acid
10) all be the series derivates of OH.
A kind of (being mainly bromide) in the single halogenide of the above-mentioned total cambogic acid for preparing (morellic acid or neogambogic acid or allogambogic acid) is dissolved in the methanol aqueous solution (50%-95%'s), in this solution, drip an amount of silver nitrate solution, just can prepare the nitrate derivatives of total cambogic acid, promptly obtain R among general formula (I), (II), (III) respectively
4, R
5, R
8, R
10, R
12(there is not R in neogambogic acid
10) all be NO
3Series derivates.
Should use the same method, the halogen atom with on the replacement of the sulfonate radical in the sodium bisulfite total cambogic acid obtains the sulfonic acid of total cambogic acid or the compound of sulfonate through separating, and promptly obtains R among general formula (I), (II), (III) respectively
4, R
5, R
8, R
10, R
12(there is not R in neogambogic acid
10) all be SO
3Na or SO
3The total cambogic acid series derivates of H.
What have basic groups such as amino in the derivative of total cambogic acid can prepare corresponding salt with the acceptable acid of pharmacology, and this acid has haloid acid, sulfuric acid, phosphoric acid, citric acid, tartrate etc.
What have the acid group of carboxyl or sulfonic group in the derivative of total cambogic acid can prepare corresponding salt with the acceptable alkali of pharmacology, this alkali has sodium hydroxide, amino acid, ammoniacal liquor etc., neutralize about PH7 with alkali as long as the acid derivant of morellic acid is dissolved in the suitable organic solvent, promptly can obtain corresponding salt.
Eight, the order of preparation feedback
(1) total cambogic acid ketone carbonyl (
8C and
12C; Formula II is
12C and
16C) reduction reaction
Be raw material with morellic acid or neogambogic acid or allogambogic acid directly, also the derivative that can obtain with other any reaction of at least one step above having finished is that raw material reduces.
(2), total cambogic acid (
30C) esterification of carboxyl, amidate action
Can be directly be raw material with morellic acid or neogambogic acid or allogambogic acid, also the derivative that can obtain with other any reaction of at least one step above having finished is that raw material carries out esterification, amidate action.But, can not with the total cambogic acid hydroxyl (
6C; Formula III is
4C and
6C) esterification products is that raw material reacts, promptly can only first esterification, amidation, and then carry out the esterification of hydroxyl.
(3), the total cambogic acid hydroxyl (
6C; Formula III is
4C and
6C) esterification
Be raw material with morellic acid or neogambogic acid or allogambogic acid directly, also the derivative that can obtain with other any reaction of at least one step above having finished is that raw material reduces.
(4), the addition reaction of total cambogic acid and halogen, hydrogen halide, hydrogen
With the addition reaction of halogen, hydrogen halide can be directly be raw material with morellic acid or neogambogic acid or allogambogic acid, also the derivative that can obtain with other any reaction of at least one step above having finished is that raw material carries out addition.But, finish before being preferably in esterification with the addition reaction of halogen, hydrogen halide.
(5), the replacement(metathesis)reaction of halogen atom in the total cambogic acid halogenide
Can be raw material with any in single halogenide, also the derivative that can obtain with other any reaction of at least one step above having finished be that raw material carries out replacement(metathesis)reaction.But replacement(metathesis)reaction is finished before being preferably in esterification.
Embodiment
When different total cambogic acid or derivatives thereof was reaction raw materials, the material rate of reaction should be adjusted as the case may be.
Following embodiment is just to further specifying the present invention, rather than restriction the present invention.
The preparation of embodiment one morellic acid ketone carbonyl reduction thing
In 250 milliliters of there-necked flasks that have stirring, 0-50 ℃ thermometer and 25 milliliters of constant pressure funnels, add (0.01 mole of morellic acid 6.47 gram, 97%), 60 milliliters of methyl alcohol, get (0.011 mole of lithium aluminum hydride 0.42 gram, 98%) be dissolved in the constant pressure funnel that is added with 10 milliliters of ether, open and stir, the temperature of control methanol solution drips solutions of lithium aluminium hydride lentamente in the time of 0-5 ℃.After being added dropwise to complete, continue stirring reaction more than 3 hours.Then the reactant limit is stirred in the limit impouring 60 gram mixture of ice and water with glass stick, extract (30,30,10 milliliters) three times, merge diethyl ether solution with 70 milliliters of branches of ether.Wash ether with water, until neutrality, abandon water, the organic phase anhydrous sodium sulfate drying removes by filter sodium sulfate, and room temperature vacuum removal ether obtains dark-brown solid 6.2 grams.With 1: 50-100 times of 200-300 purpose silica gel, with sherwood oil: ethyl acetate=80: 20 is an elutriant, all is reduced to hydroxy derivative through separating two carbonyls that obtain morellic acid, i.e. X in the general formula (I)
1, X
2Be the new compound of CHOH, about 4.12 grams (63.9%).MP:121-123 ℃, (C18 post 4.6*250 was with methyl alcohol-Virahol-water-formic acid=95: 100 for HPLC; Be moving phase at 75: 4, flow velocity 0.7 ml/min, (detecting wavelength 350 nanometers): 98.1%.
Ultimate analysis is found: C71.930%, H7.776%; Molecular formula (C
38H
48O
8) calculate: C72.126%, H7.640%.
Infrared analysis (Impact-410-nicolet) is found: wave number is 1737CM
-1And 1635CM
-1Two strong absorption peaks disappeared, and at 1685CM
-1The strong absorption peak at place still exists, simultaneously at 2972CM
-1, 3300CM
-1The broad peak at place is slightly strengthened.The absorption of other correspondence does not almost change.The molecular weight that Finnigan MAT8430 spectrometer analysis draws product is 632.With CDCl
3Be solvent, adopt BrukerACF-300 type nuclear magnetic resonance analyser to detect, collection of illustrative plates shows 38 carbon signals, 48 proton signals.
Two ketone carbonyls on this explanation morellic acid have been reduced into hydroxyl, and carboxyl still exists.The product that obtains is exactly our target compound.
Similarly, with neogambogic acid or allogambogic acid, perhaps having finished the derivative that other any reaction of at least one step obtains is that raw material reduces, and adopts the method for embodiment one can prepare the series derivates that corresponding carbonyl has been reduced.
Embodiment two morellic acids
20The preparation of C carboxylate
Have stirring at one, in 250 milliliters of there-necked flasks of 0-50 ℃ of thermometer, add (0.01 mole of morellic acid 6.47 gram, 97%), add 70 milliliters of ethanol, after DMAP2.5 gram (0.02 mole) stirs dissolving fully, adding a spot of anhydrous magnesium sulfate stirred 3 hours, remove by filter sal epsom, DMAP2.5 gram (0.02 mole) and EDC1.8 gram (0.02 mole), at room temperature stirring reaction in reactant impouring frozen water, divided three times (40 with 80 milliliters of ether more than 2 hours, 30,10) extract target product in this decant thing, abandon water, the combined ether phase, with removing organic solvent behind the anhydrous sodium sulfate drying, the crude product that obtains separates with silicagel column, obtain the higher gamboge acid esters of purity, promptly obtain the R in the general formula (I)
1Be CH
3CH
2The morellic acid ethyl ester compound 5.59 gram (yields: 85%) of O-.MP：93-94℃，HPLC：98.7％。
Ultimate analysis is found: C73.026%, H7.401%;
Molecular formula (C
40H
48O
8) calculate: C73.148%, H7.366%.
With CDCl
3Be solvent, adopt BrukerACF-300 type nuclear magnetic resonance analyser to detect, collection of illustrative plates shows 40 carbon signals, 48 proton signals.
The molecular weight that spectrometer analysis draws product is 656.
The reaction product that this explanation obtains is exactly the target compound that we need, i.e. morellic acid
30The ethanol ester of C.
Similarly, with neogambogic acid or allogambogic acid, perhaps having finished the derivative that other any reaction of at least one step obtains is raw material and various alcohol (ROH, the qualification of R as defined above) esterification, adopts the method for embodiment two can prepare accordingly
30The C esterification the respective series derivative.
Embodiment three morellic acids
30The preparation of C acid amides
In 250 milliliters of there-necked flasks that have stirring, a 0-50 ℃ thermometer, add 50 milliliters of acetonitriles, morellic acid 6.47 grams (0.01 mole, 97%).After stirring dissolving fully, add a spot of anhydrous magnesium sulfate and stirred 3 hours, remove by filter sal epsom.Add butylamine 1.45 grams (0.02 mole), DMAP2.5 gram (0.02 mole) and EDC1.8 gram (0.02 mole), at room temperature stirring reaction is more than 6 hours.In reactant impouring frozen water, divide three times (40,30,10) to extract target product in the decant thing with 80 milliliters of ether, abandon water, the combined ether phase, and, remove organic solvent with behind the anhydrous sodium sulfate drying, the crude product that obtains separates with silicagel column, obtains the higher morellic acid butyramide of purity.Promptly obtain the R in the general formula (I)
1Be CH
3(CH
2)
3NH
2-morellic acid amide compound 5.61 gram (yields: 82%).HPLC：98.7％。
Ultimate analysis is found: C73.445%, H8.002%, N2.138%.
Molecular formula (C
42H
53NO
7) calculate: C73.763%, H7.812%, N2.048%.
With CDCl
3Be solvent, adopt BrukerACF-300 type nuclear magnetic resonance analyser to detect, collection of illustrative plates shows 42 carbon signals, 53 proton signals.
The molecular weight that spectrometer analysis draws product is 683.
The reaction product that this explanation obtains is exactly the target compound that we need, i.e. morellic acid
30The butyramide of C.
Similarly, with neogambogic acid or allogambogic acid, perhaps having finished the derivative that other any reaction of at least one step obtains is raw material and various organic amine (RNH
2, the qualification of R is as defined above) and amidate action, adopt the method for embodiment three can prepare accordingly
30The C amidation the respective series derivative.
The preparation of the carboxylate of embodiment four morellic acid hydroxyls
(1) in 250 milliliters of there-necked flask that have stirring, 0-50 ℃ thermometer and 25 milliliters of constant pressure funnels, add (0.01 mole of morellic acid 6.47 gram, 97%), 60 milliliters of isopropyl ethers, 10 milliliters of chloroforms, after stirring dissolving fully, add a spot of anhydrous magnesium sulfate and stirred 3 hours, remove by filter sal epsom.Get 1.15 gram propionyl chlorides (0.012 mole, 98%) and be dissolved in the constant pressure funnel that is added with 10 milliliters of dry isopropyl ethers of crossing, open and stir, the control solution temperature drips propionyl chloride solution lentamente in the time of 40 ℃.After being added dropwise to complete, continue stirring reaction more than 12 hours.Then the reactant limit is stirred in the limit impouring 60 gram mixture of ice and water with glass stick, extract (30,30,10 milliliters) three times, merge diethyl ether solution with 70 milliliters of branches of ether.Wash ether with water, until neutrality, use the anhydrous sodium sulfate drying diethyl ether solution again, remove by filter sodium sulfate, room temperature vacuum removal ether obtains auburn solid, with 1: 50-100 times of 200-300 purpose silica gel, with sherwood oil: ethyl acetate=80: 20 is an elutriant, obtains content: 98.2% (HPLC's)
6Hydroxyl on the C by the propionic acid esterification Gamboges acid derivative (be R in the general formula I
2Be CH
3CH
2The derivative of CO-) 3.84 the gram (yield: 56%), MP:64-66 ℃.
Ultimate analysis is found: C71.973%, H7.200%.
Molecular formula (C
41H
48O
9) calculate: C71.908%, H7.065%.
With CDCl
3Be solvent, adopt BrukerACF-300 type nuclear magnetic resonance analyser to detect, collection of illustrative plates shows 41 carbon signals, 48 proton signals.
The molecular weight that spectrometer analysis draws product is 684.
The reaction product that this explanation obtains is exactly the target compound that we need, promptly
6The propionic ester morellic acid of C hydroxyl.
Similarly, with neogambogic acid or allogambogic acid, perhaps finished derivative that other any reaction of at least one step obtains and be raw material and various as defined above organic acid chloride adopts aforesaid method generation esterification, can prepare hydroxyl on the corresponding parent esterified series derivates.
(2) with acid anhydrides replace acyl chlorides adopt the method for embodiment four (1) also can prepare hydroxyl on the corresponding parent esterified the respective series derivative.
In 250 milliliters of there-necked flasks that have stirring, 0-150 ℃ thermometer and a condensing reflux pipe, add morellic acid 6.47 grams (0.01 mole, 97%), 70 milliliters of propionic acid, Sodium Propionate is a small amount of, after stirring is dissolved fully, add a spot of anhydrous magnesium sulfate and stirred 3 hours, remove by filter sal epsom.Add 120 ℃ of reactions of 6.5 gram propionic anhydride (0.05 mole, 98%) heated and stirred more than 6 hours.Then the reactant cooling vacuum is removed and desolvate, add 100 milliliters in water after cold, extract (30,30,10 milliliters) three times, merge diethyl ether solution with 70 milliliters of branches of ether.Wash ether with water, until neutrality, abandon water, organic phase is used anhydrous sodium sulfate drying again, remove by filter sodium sulfate, room temperature vacuum removal ether obtains the solid of light brown, with 1: 50-100 times of 200-300 purpose silica gel, with sherwood oil: ethyl acetate=80: 20 is an elutriant, obtains content: 98.6% (HPLC's)
8Hydroxyl on the C by the propionic acid esterification Gamboges acid derivative (be R in the general formula I
2Be CH
3CH
2The derivative of CO-) 6.32 gram (yields: 92.2%).
Ultimate analysis is found: C71.743%, H7.165%.
Molecular formula (C
41H
48O
9) calculate: C71.908%, H7.065%.
With CDCl
3Be solvent, adopt BrukerACF-300 type nuclear magnetic resonance analyser to detect, collection of illustrative plates shows 41 carbon signals, 48 proton signals.
The molecular weight that spectrometer analysis draws product is 684.
Illustrate that the reaction product that obtains is exactly the target compound that we need, promptly
6The propionic ester morellic acid of C hydroxyl.
Similarly, with neogambogic acid or allogambogic acid, perhaps finished derivative that other any reaction of at least one step obtains and be raw material and various as defined above organic acid acid anhydrides adopts aforesaid method generation esterification, can prepare hydroxyl on the corresponding parent esterified series derivates.
The preparation of embodiment five morellic acid alkoxy compounds
In 250 milliliters of there-necked flasks that have stirring, 0-50 ℃ thermometer and 25 milliliters of constant pressure funnels, add (0.01 mole of morellic acid 6.47 gram, 97%), 60 milliliters of isopropyl ethers, 5 milliliters of methylene dichloride, after stirring dissolving fully, add a spot of anhydrous magnesium sulfate and stirred 3 hours, remove by filter sal epsom.Get 1.55 gram methyl-sulfates (0.012 mole) and be dissolved in the constant pressure funnel that is added with 10 milliliters of dry isopropyl ethers of crossing, open and stir, the control solution temperature drips methyl-sulfate solution lentamente in the time of 35 ℃.After being added dropwise to complete, continue stirring reaction more than 2 hours.With in reactant impouring 60 grams, the water, extract (30,30,10 milliliters) three times then, merge diethyl ether solution with 70 milliliters of branches of ether.Wash ether with water, until neutrality, use the anhydrous sodium sulfate drying diethyl ether solution again, remove by filter sodium sulfate, room temperature vacuum removal ether obtains auburn solid, with 1: 50-100 times of 200-300 purpose silica gel, with sherwood oil: ethyl acetate=80: 20 is an elutriant, obtains content: 98.2% (HPLC's)
6Hydroxyl on the C by methoxylation Gamboges acid derivative (be R in the general formula I
2Be CH
3-derivative) 5.6 the gram (yield: 88%), MP:61-62 ℃.
Ultimate analysis is found: C72.908%, H7.065%.
Molecular formula (C
39H
48O
8) calculate: C72.874%, H7.213%.
With CDCl
3Be solvent, adopt BrukerACF-300 type nuclear magnetic resonance analyser to detect, collection of illustrative plates shows 39 carbon signals, 46 proton signals.
The molecular weight that spectrometer analysis draws product is 642.
The reaction product that this explanation obtains is exactly the target compound that we need, promptly
6C is converted into the Gamboges acid derivative of methoxyl group.
Similarly, with neogambogic acid or allogambogic acid, perhaps finish derivative that other any reaction of at least one step obtains and be raw material and various as defined above sulfuric acid diester or alkyl iodide adopts aforesaid method generation alkoxylation, can prepare the series derivates that hydroxyl on the corresponding parent is converted into methoxyl group.
The preparation of embodiment six morellic acids and liquid bromine affixture
With (0.01 mole of 6.47 gram in the morellic acid, 97%), be dissolved in 50 ml methanol, add 3 hours after-filtration of a spot of anhydrous magnesium sulfate stirring and remove sal epsom, when the temperature of maintenance material reaction is 0-5 ℃, under stirring preferably, in the methanol solution of morellic acid, drip 8 gram (0.05 mole) exsiccant liquid bromines lentamente, fade fully up to methanol solution.Vacuum is removed methyl alcohol, obtains thick morellic acid bromide, with this crude product through the separation of silicagel column obtain purer target product 12.42 grams (yield: 87.0%), HPLC:98.12%.Promptly obtain (R among general formula (I), (II), (III)
3), (R
6), (R
7) (R
9), (R
11), R
4, R
5, R
8, R
10, R
12(there is not R in neogambogic acid
9With R
10) all be bromine atoms.At this moment number 3 and 4,9 and 10,27 and 28,32 and 33,37 with 38 carbon atom between all combine the morellic acid halogenide that the key of dotted line representative has not existed with singly-bound
Ultimate analysis is found: C31.999%, H3.216%, Br56.025%;
Molecular formula (C
38H
44Br
10O
8) calculate: C31.966%, H3.106%, Br56.025%.
With CDCl
3Be solvent, nuclear magnetic resonance analyser detects, and collection of illustrative plates shows 38 carbon signals, 44 proton signals.
The molecular weight that spectrometer analysis draws product is 1427.
Illustrate that the reaction product that obtains is the bromide of ester morellic acid.
Similarly,, perhaps finished derivative that other any reaction of at least one step obtains and be raw material and various as defined above halogen adopts aforesaid method to carry out addition reaction, can prepare corresponding halogenide series derivates with neogambogic acid or allogambogic acid.
The preparation of embodiment seven morellic acids and hydrogen bromide affixture
With (0.01 mole of 6.47 gram in the morellic acid, 97%), be dissolved in 50 ml methanol, add 3 hours after-filtration of a spot of anhydrous magnesium sulfate stirring and remove sal epsom, when the temperature of maintenance reaction mass is 0-5 ℃, methanol solution to morellic acid imports about 4.1 (0.05 mole) exsiccant bromize hydrogen gas lentamente under stirring preferably, and stirring reaction is more than 3 hours.Vacuum is removed methyl alcohol, obtains thick morellic acid bromination composition compound, and the separation of this crude product being passed through silicagel column obtains purer target product, and 7.57 grams (yield: 73.2%), HPLC:98.4%.Promptly obtain (R among general formula (I), (II), (III)
3), (R
6), (R
7) (R
9), (R
11) be H, R
4, R
5, R
8, R
10, R
12(there is not R in neogambogic acid
9With R
10) all be bromine atoms, at this moment number 3 and 4,9 and 10,27 and 28,32 and 33,37 with 38 carbon atom between all combine the morellic acid halogenide that the key of dotted line representative has not existed with singly-bound
Ultimate analysis is found: C44.332%, H4.910%, Br38.338%.
Molecular formula (C
38H
49Br
5O
8) calculate: C44.170%, H4.780%, Br38.663%.
With CDCl
3Be solvent, nuclear magnetic resonance analyser detects, and collection of illustrative plates shows 38 carbon signals, 44 proton signals.
The molecular weight that spectrometer analysis draws product is 1033.
Illustrate that the reaction product that obtains is the bromide of ester morellic acid.
Similarly,, perhaps finished derivative that other any reaction of at least one step obtains and be raw material and various as defined above hydrogen halide adopts aforesaid method to carry out addition reaction, can prepare corresponding halogenide series derivates with neogambogic acid or allogambogic acid.
Embodiment eight morellic acid R
4, R
5, R
8, R
10, R
12The bromide that all is bromine atoms is by the preparation of amine substitution product
Morellic acid bromide 5.2 grams (0.005 mole) that last example is prepared are dissolved in 40 milliliters of acetonitriles, add 3 hours after-filtration of a spot of anhydrous magnesium sulfate stirring and remove sal epsom, add dry 3.72 gram (0.05 mole) butylamine of crossing, acetonitrile solution was at room temperature placed more than one day 40 ℃ of solvent removed in vacuo and excessive n-Butyl Amine 99.Obtain pink solid, add 35 milliliters in cold water, divide three extractions with 100 milliliters of ethyl acetate, combined ethyl acetate, with 10 milliliters of * 2 cold water washings, use anhydrous sodium sulfate drying, ethyl acetate is concentrated to about about 20 milliliters, obtain the morellic acid butylamine crystalloid of white, promptly obtain R in the general formula (I)
4, R
5, R
8, R
10, R
12All be CH
3CH
2CH
2CH
2The white crystal of NH-, MP:173-175 ℃, HPLC:98.5%.This compound has better water solubility, and both very easily is dissolved in acidic aqueous solution, also can be dissolved in alkaline aqueous solution, and stability is splendid in the subacidity or the neutral aqueous solution.
Ultimate analysis is found: C69.852%, H10.205%, N7.172%.
Molecular formula (C
58H
99N
5O
8) calculate: C70.052%, H10.035%, N7.042%.
With CDCl
3Be solvent, adopt BrukerACF-300 type nuclear magnetic resonance analyser to detect, collection of illustrative plates shows 58 carbon signals, 99 proton signals.
The molecular weight that spectrometer analysis draws product is 994,
Illustrate that the reaction product that obtains is exactly the target compound that we need.
Similarly, halogenide with neogambogic acid or allogambogic acid, perhaps having finished the derivative that other any reaction of at least one step obtains is that raw material and various various as defined above amine adopt aforesaid method to carry out replacement(metathesis)reaction, can prepare corresponding amine series derivates.
With the sodium bisulfite is that the displacement substituent replaces amine, uses the same method, and can obtain the sulfonic acid substituent of corresponding morellic acid.I.e. (R among (I), (II), (III)
3), (R
6), (R
7) (R
9), (R
11) be H, R
4, R
5, R
8, R
10, R
12(there is not R in neogambogic acid
9With R
10) all be-SO
3The derivative of H.
Embodiment nine morellic acid R
4, R
5, R
8, R
10, R
12The bromide that all is bromine atoms is by the preparation of nitration product
Morellic acid bromide 5.2 grams (0.005 mole) that prepare are dissolved in 40 ml methanol, while stir drip be dissolved with 4.25 the gram Silver Nitrates the aqueous solution in the morellic acid bromide solution, this solution just has flaxen Silver monobromide precipitation to produce at once, after being added dropwise to complete, about 40 ℃, continue to stir 20 minutes, after the cooling, remove by filter the Silver Nitrate precipitation.Behind the methanol solution evaporate to dryness, can obtain the nitric ether of 4.526 gram (96%) morellic acids.Promptly obtain R in the general formula (I)
4, R
5, R
8, R
10, R
12All be-NO
3Derivative.HPLC：98.4％。
Ultimate analysis is found: C48.674%, H5.203%, N7.220.
Molecular formula (C
38H
49N
5O
23) calculate: C48.358%, H5.233%, N7.420%.
With CDCl
3Be solvent, adopt BrukerACF-300 type nuclear magnetic resonance analyser to detect, collection of illustrative plates shows 38 carbon signals, 49 proton signals.
The molecular weight that spectrometer analysis draws product is 943.
Illustrate that the reaction product that obtains is exactly the target compound that we need.
Similarly, with the halogenide of neogambogic acid or allogambogic acid, perhaps having finished the derivative that other any reaction of at least one step obtains is that raw material and Silver Nitrate adopt aforesaid method to carry out replacement(metathesis)reaction, can prepare corresponding Silver Nitrate series derivates.
(R in general formula (I), (II), (III)
3), (R
6), (R
7) (R
9), (R
11), R
4, R
5, R
8, R
10, R
12(there is not R in neogambogic acid
9With R
10) all be that the morellic acid halogenide of halogen atom is raw material, make halogen atom generation replacement(metathesis)reaction wherein, then can obtain R among general formula (I), (II), (III)
4, R
5, R
8, R
10, R
12Be halogen atom, and (R
3), (R
6), (R
7) (R
9), (R
11) (there is not R in neogambogic acid
9With R
10) the morellic acid series derivates of having been replaced.
The preparation of embodiment ten morellic acid butylamine derivant hydrochloric acid salts
Get morellic acid n-Butyl Amine 99 derivative 5 grams of embodiment eight, be dissolved in 30 milliliters of acetone, normal temperature drips 36% hydrochloric acid down, making the pH value of solution is 7, and vacuum is removed partial solvent, and promptly the crystal of adularescent is separated out, filter, just can obtain the hydrochloride of morellic acid n-Butyl Amine 99 derivative, yield 97%.HPLC：98.5％。
Claims (5)
1, the series derivates of morellic acid promptly has acceptable salt on the compound of general formula I and the pharmacology thereof:
(1), X wherein
1Be C=O, CHOH, CHOR
2X
2Be C=O, CHOH, CHOR
2X
1, X
2For identical substituting group or be respectively different substituting groups, R
2Limited by following.
R
1Be RO-, R is the saturated or unsaturated straight-chain alkyl of H, a 1-10 carbon, the saturated or unsaturated branched alkyl of a 3-10 carbon, saturated or unsaturated cyclic hydrocarbon radical or aryl, and can have heteroatomic substituting group, as nitro, sulfonic group etc.For example:
The alkane CH that straight chain is saturated
3-, CH
3(CH
2)
N-, wherein N is 1-6,
The undersaturated alkane of straight chain has CH
2=CHCH
2CH
2-, CH
2=CHCH=CHCH
2-wait the alkene that contains two keys at least;
Have saturated, the undersaturated hydro carbons of side chain or ether etc. (CH is arranged
3)
2CH
2-, (CH
3)
3CH
2-, CH
2=CHCH (CH
3) CH
2-, CH
3CH
2YCH
2CH
2-etc.Y=S wherein, O, NH.
The cyclic hydro carbons has saturated undersaturated at least one ring more than three Yuans
Deng, P=S wherein, O, N; Z=H, a 1-6 carbon full and or the saturated or unsaturated branched alkyl of undersaturated straight-chain alkyl, a 3-10 carbon etc.ArCH
2CH
2-, CH
3ArCH
2CH
2-, Ar is phenyl or has substituent phenyl etc.
R
1Or be RNH-, the qualification of R as defined above, R
1Or be the heteroatomic ring group, as
Deng
R
2Be H or R or RCO-, the qualification of R as defined above.
R
2Also be-PO
3H ,-SO
2CH
3Deng.
(R
3), (R
6), (R
7) (R
9), (R
11) all be halogen atom: F, Cl, Br, or be H.
R
4, R
5, R
8, R
10, R
12All be halogen atom: F, Cl, Br, or be H, OH, HSO
3, NO
3, RNH, wherein the qualification of R or is the heteroatomic ring group as defined above, as
Deng.
(2), when all being pair key between numbering 3 and 4,9 and 10,27 and 28,32 and 33,37 and 38 the carbon atom, (R
3), (R
6), (R
7), (R
9), (R
11) just do not exist; R
4, R
5, R
8, R
10, R
12Qualification as defined above.When numbering between 3 and 4,9 and 10,27 and 28,32 and 33,37 and 38 carbon atoms all is pair key, and R
1, R
2Not all be H or X
1, X
2When not all being C=O, substituting group (R
3), (R
6), (R
7) (R
9), (R
11), R
4, R
5, R
8, R
10, R
12Do not exist.
2, the series derivates of allogambogic acid promptly has acceptable salt on the compound of general formula I I and the pharmacology thereof:
R wherein
1, R
2, R
3, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12And X
1, X
2Qualification as defined above.
3, the series derivates of neogambogic acid promptly has acceptable salt on the compound of general formula III and the pharmacology thereof:
R wherein
1, R
2, R
3, R
5, R
6, R
7, R
8, R
11, R
12And X
1, X
2Qualification as defined above.
4, the compound that is limited according to right 1 to 3 formula of (I), (II), (III) (or on the pharmacology acceptable salt), select for use wherein at least aly, adopt usual method to make paste, the soup of the liquor of tablet for oral administration, capsule, oral liquid etc. or injection, pulvis etc. or external application.Be used for the treatment of the antibiotic of cancer and wide spectrum, also be used for protozoacide and fungi.
5, the compound that is limited according to right 1 to 3 formula of (I), (II), (III) (or on the pharmacology acceptable salt) is selected for use wherein at least aly, is applied to pharmacy or synthetic dyestuff.
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Application publication date: 20050112 |