CN1699400A - Toosendanin derivatives and their preparation and use - Google Patents
Toosendanin derivatives and their preparation and use Download PDFInfo
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- CN1699400A CN1699400A CN 200510025888 CN200510025888A CN1699400A CN 1699400 A CN1699400 A CN 1699400A CN 200510025888 CN200510025888 CN 200510025888 CN 200510025888 A CN200510025888 A CN 200510025888A CN 1699400 A CN1699400 A CN 1699400A
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- toosendanin
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Abstract
本发明公开了一种式(II)所示的川楝素衍生物或其药学上可接受的盐，其中，R为CO(CH2) mCH3或CO(CH2) nCOOH；m为0－3，n为1－3。本发明还公开了川楝素衍生物或其药学上可接受的盐的制备方法和用途。本发明的川楝素衍生物或其药学上可接受的盐在对肉毒中毒动物保持良好的治疗效果的同时，比川楝素具有更小的毒性。
The invention discloses a toosendanin derivative represented by formula (II) or a pharmaceutically acceptable salt thereof, wherein, R is CO(CH 2 ) m CH 3 or CO(CH 2 ) n COOH; m is 0-3, n is 1-3. The invention also discloses the preparation method and application of the toosendanin derivative or its pharmaceutically acceptable salt. The toosendanin derivative or the pharmaceutically acceptable salt thereof of the present invention has less toxicity than toosendanin while maintaining a good therapeutic effect on botulism animals.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to a kind of Toosendanin derivatives and preparation method thereof and the purposes in preparation resisting botulinus toxin medicine.
Background technology
Botulinus toxin is the toxin that is produced by clostridium botulinum Clostridium Botulinum, and seven kinds of hypotypes of A-E are arranged.Wherein A type, Type B and E type are harmful, are the strongest toxin of present known toxicity.Though the non-clinically common frdquently encountered disease of sausage poisoning, the mortality ratio height all has the case report every year at home and abroad.Have the therapeutic action except the sausage poisoning of antibotulinicum serum at present, still do not have the medicine of effectively curing sausage poisoning at home and abroad corresponding type.
(toosendanin chuanliansu) is the bast separation from plant melia toosendan (Melia toosendan Sieb etZucc), the triterpenoid of purifying to Toosendanin.Chemistry journal paper (Shu Guoxin, Liang Xiaotian. about the correction .1980 of the chemical structure of Toosendanin, 38:196-198) chemical structure and the physico-chemical property to Toosendanin is described in detail.The molecular formula of Toosendanin is C
30H
38O
11, structural formula is suc as formula shown in (I).
Toosendanin has good result of treatment to the animal of sausage poisoning, can cure the mouse and the monkey of A type sausage poisoning, but this toxicity of compound is bigger, its mouse subcutaneous injection mld (LD
50) be 15.2mg/kg (Li Peizhong etc. Toosendanin is to the result of treatment of sausage poisoning animal. herbal medicine 1982,13 (6): 28-30).Therefore, press for the medicine of the little resisting botulinus toxin of the toxicity that makes new advances of exploitation.
Summary of the invention
The compound that the purpose of this invention is to provide the little resisting botulinus toxin of a kind of toxicity, this compound are Toosendanin derivatives or its pharmacy acceptable salt, and its structural formula is suc as formula shown in (II):
Wherein, R is CO (CH
2)
mCH
3Or CO (CH
2)
nCOOH; M is 0-3, and n is 1-3.
What m was preferable in the formula II compound of the present invention is 1, is the Toosendanin propionic ester; What n was preferable is 2, i.e. the Toosendanin succinate.
Described pharmacy acceptable salt can be various metal-salts and non-metal salt, and as an alkali metal salt: sodium salt or sylvite etc., alkaline earth salt: calcium salt etc., non-metal salt has ammonium salt etc.
Another object of the present invention provides the preparation method of above-mentioned Toosendanin derivatives or its pharmacy acceptable salt, comprising:
1) with Toosendanin and CH
3(CH
2)
mCOOH or HOOC (CH
2)
nCOOH carries out esterification, or and CH
3(CH
2)
mThe acid anhydrides of COOH or HOOC (CH
2)
nThe acid anhydrides of COOH carries out acylation reaction and makes this Toosendanin derivatives; Wherein, the definition of m, n as above;
2) selectively this Toosendanin derivatives is carried out to reactant salt and makes the Toosendanin derivatives pharmacy acceptable salt.
Above-mentioned formula I Toosendanin can be with chemical synthesis process synthetic Toosendanin, it also can be the Toosendanin that from the bast of plant melia toosendan, extracts, pass through chloroform extraction as bast with melia toosendan, the Toosendanin that obtains through ethyl alcohol recrystallization (institute of Chinese materia medica, Sichuan: Toosendanin production process safety technique data, 1971) again.
Step 1) among the Toosendanin derivatives preparation method of the present invention adopts conventional esterification or acylation reaction, such as preferably making condensing agent with anhydrous pyridine or anhydrous sodium acetate.
Above-mentioned preparation method can also be further purified the Toosendanin derivatives of the present invention that step 1) makes, and can adopt conventional method;
For example: (R is CO (CH to the product that makes with the above-mentioned preparation method of acetic acid ethyl dissolution
2)
nDuring COOH), the sodium hydrogen carbonate solution with 3% extracts three times, and respectively with ethyl acetate and ether washing extracting solution, water layer is used ether extraction, anhydrous sodium sulfate drying, crystallisation by cooling after using the dilute hydrochloric acid acidifying again; Or also can be that (R is CO (CH with above-mentioned product
2)
mCH
3The time) in dehydrated alcohol, carry out crystallization or recrystallization, preferably be 1-3 time.
Above-mentioned steps 2) salt-forming reaction in can be the salt-forming reaction of any routine, to make formula II compound pharmacy acceptable salt, as the inorganic salt of following formula III compound and sodium Metal 99.5, potassium, preferably its carbonate reaction is made the sodium salt of formula III compound and sylvite etc.
Another object of the present invention provides the derivative or the purposes of its pharmacy acceptable salt in preparation resisting botulinus toxin medicine of above-mentioned Toosendanin.
Positive progressive effect of the present invention is: Toosendanin derivatives has littler toxicity than Toosendanin when the sausage poisoning animal is kept good therapeutic action.
Embodiment
Further set forth technical scheme of the present invention with specific embodiment below, but the present invention is not limited to this.Wherein, the formula I compound Toosendanin among the embodiment is to extract preparation according to document described in the summary of the invention, and all the other reagent are conventional commercially available chemical pure.
Embodiment 1
Formula I compound Toosendanin 2.87g, succinyl oxide 0.5g, anhydrous sodium acetate 1.5g and anhydrous propanone 20mL place reaction flask, back flow reaction 10 hours.Filter solid, after removing acetone, evaporation adds acetic acid ethyl dissolution, sodium hydrogen carbonate solution with 3% extracts three times, and respectively with ethyl acetate and ether washing extracting solution, water layer is used ether extraction after using the dilute hydrochloric acid acidifying again, anhydrous sodium sulfate drying, ether is removed in evaporation, crystallisation by cooling, filter collection solid, drying obtains 1.25g Toosendanin succinate (productive rate: 37%).Its molecular formula is: C
34H
42O
14Fusing point: 169-171 ℃; Mass spectrum m/z:674[M]
+Nuclear magnetic resonance spectrum (solvent: (CD
3)
2CO, interior mark: TMS) δ: 0.81 (3H, unimodal), 1.16 (3H, unimodal), 1.38 (3H, unimodal, CH
3), 1.95 (3H, unimodal), 2.02 (3H, unimodal, COCH
3), 2.71 (4H, unimodal, COCH
2CH
2CO); Structural formula is suc as formula shown in (III):
Embodiment 2
Formula I compound Toosendanin 800mg, 8mL anhydrous pyridine and 8mL propionic anhydride, back flow reaction is 8 hours in reaction flask.Crude product makes 675mg Toosendanin propionic ester (productive rate: 76%) with the dehydrated alcohol crystallization for several times.Its molecular formula: C
33H
42O
12Fusing point 235-237 ℃; Mass spectrum m/z:630[M]
+Structural formula is suc as formula shown in (IV):
Embodiment 3
Formula III compound Toosendanin succinate 1g adds in the 5mL distilled water, adds 111mg yellow soda ash or 144mg salt of wormwood, is stirred to whole dissolvings, and lyophilize makes Toosendanin sodium succinate or Toosendanin potassium succinate.
Effect embodiment 1
Toosendanin succinate that embodiment 1 and 2 makes and Toosendanin propionic ester be with the distillation water as solvent of 10% ethanol, 10% tween-80,10% poly-ethanol and 70%, and be diluted to suitable concentration according to the experiment needs.Botulinum toxin type A is purchased institute of biological products, white orchid state.Available from Chinese Academy of Sciences's Shanghai Experimental Animal Center, body weight 18-22 restrains with Shanghai kind mouse in experiment, and male and female are suitably arranged in pairs or groups.
Toosendanin succinate and Toosendanin propionic ester acute toxicity LD
50Measure: the administration group of blank group, solvent control group and 5 dosage is set up in experiment, every group of each 10 mouse.Mouse was observed 96 hours with the subcutaneous injection administration, according to the number of dead mouse, calculated its LD by the Bliss method
50Value.The results are shown in Table 3.
Toosendanin succinate and Toosendanin propionic ester treatment A type sausage poisoning mouse median effective dose ED
50Measure: experiment setting solvent control group, botulinum toxin type A group, Toosendanin derivatives treatment group (4 dosage groups).Each 10 mouse of solvent control group and A type meat poison group wherein, Toosendanin derivatives treatment are organized each 20 mouse of each dosage (4 dosage group totally 80 mouse).The poison amount of attacking of botulinum toxin type A is 1.7 times of mouse medium lethal doses, and Toosendanin succinate and Toosendanin propionic ester dosage are by this compound L D
50The multiple of value calculates, and administering mode is subcutaneous injection, and total amount once gives.Toosendanin succinate and Toosendanin propionic ester see Table 1,2 for the mouse curative effect of A type sausage poisoning.
The Toosendanin succinate of table 1. various dose is to the curative effect of A type sausage poisoning mouse
| Dosage LD 50Multiple | Dosage (mg/kg) | Survival rate (%) |
| ??0.1 ??0.2 ??0.4 ??0.6 | ??29.4 ??58.8 ??117.6 ??176.4 | ??6 ??55 ??85 ??95 |
Annotate: solvent control group mouse does not have death, and botulinum toxin type A group mouse is all dead.
The Toosendanin propionic ester of table 2. various dose is to the curative effect of A type sausage poisoning mouse
| Dosage LD 50Multiple | Dosage (mg/kg) | Survival rate (%) |
| ??0.1 ??0.2 ??0.4 ??0.6 | ??11 ??22 ??44 ??66 | ??10 ??55 ??85 ??95 |
Annotate: solvent control group mouse does not have death, and botulinum toxin type A group mouse is all dead.
Toosendanin succinate and Toosendanin propionic ester treatment median effective dose ED
50Value calculates with the Bliss method, the results are shown in Table 3.
Table 3. Toosendanin derivatives is to the curative effect of botulinum toxin type A poisoning mice
| Compound | ??ED 50(mg/kg) | ??LD 50(mg/kg) |
| Toosendanin succinate Toosendanin propionic ester | ??56 ??22 | ??294 ??110 |
Claims (9)
1, the Toosendanin derivatives shown in the formula (II) or its pharmacy acceptable salt:
Wherein, R is CO (CH
2)
mCH
3Or CO (CH
2)
nCOOH; M is 0-3, and n is 1-3.
2, Toosendanin derivatives as claimed in claim 1 or its pharmacy acceptable salt is characterized in that m is 1; N is 2.
3, Toosendanin derivatives as claimed in claim 1 or its pharmacy acceptable salt is characterized in that it is sodium salt or sylvite at pharmacy acceptable salt.
4,, it is characterized in that it comprises as the preparation method of the described Toosendanin derivatives of claim 1～3 or its pharmacy acceptable salt:
1) with Toosendanin and CH
3(CH
2)
mCOOH or HOOC (CH
2)
nCOOH carries out esterification, or and CH
3(CH
2)
mThe acid anhydrides of COOH or HOOC (CH
2)
nThe acid anhydrides of COOH carries out acylation reaction and makes this Toosendanin derivatives; Wherein, the definition of m, n as above;
2) selectively this Toosendanin derivatives is carried out to reactant salt and makes the Toosendanin derivatives pharmacy acceptable salt.
5, preparation method as claimed in claim 4 is characterized in that step 1) reaction makes condensing agent with anhydrous pyridine or anhydrous sodium acetate.
6, preparation method as claimed in claim 4 is characterized in that also comprising the step that product that step 1) is made is further purified.
7, preparation method as claimed in claim 6, it is characterized in that described purification step is: the product that makes with the acetic acid ethyl dissolution step 1), sodium hydrogen carbonate solution with 3% extracts three times, again respectively with ethyl acetate and ether washing extracting solution, water layer is used ether extraction after using the dilute hydrochloric acid acidifying, anhydrous sodium sulfate drying, crystallisation by cooling.
8, preparation method as claimed in claim 6 is characterized in that described purification step is: the product that step 1) is made carries out crystallization or recrystallization in dehydrated alcohol.
9, the derivative of the described Toosendanin of claim 1～3 or its pharmacy acceptable salt purposes in preparation resisting botulinus toxin medicine.
Priority Applications (1)
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|---|---|---|---|
| CN 200510025888 CN1699400A (en) | 2005-05-18 | 2005-05-18 | Toosendanin derivatives and their preparation and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510025888 CN1699400A (en) | 2005-05-18 | 2005-05-18 | Toosendanin derivatives and their preparation and use |
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| Publication Number | Publication Date |
|---|---|
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ID=35475664
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101235066B (en) * | 2008-03-04 | 2010-04-14 | 江苏先声药物研究有限公司 | New Toosendan Bark Extract |
| CN102093342A (en) * | 2010-12-13 | 2011-06-15 | 西北农林科技大学 | C-28 toosendanin carboxylic ester derivatives and synthesis method thereof as well as application of C-28 toosendanin carboxylic ester derivative in preparing plant source pesticide |
| CN114940696A (en) * | 2022-05-25 | 2022-08-26 | 四川大学华西医院 | Toosendanin derivative and application thereof in breast cancer treatment |
-
2005
- 2005-05-18 CN CN 200510025888 patent/CN1699400A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101235066B (en) * | 2008-03-04 | 2010-04-14 | 江苏先声药物研究有限公司 | New Toosendan Bark Extract |
| CN102093342A (en) * | 2010-12-13 | 2011-06-15 | 西北农林科技大学 | C-28 toosendanin carboxylic ester derivatives and synthesis method thereof as well as application of C-28 toosendanin carboxylic ester derivative in preparing plant source pesticide |
| CN114940696A (en) * | 2022-05-25 | 2022-08-26 | 四川大学华西医院 | Toosendanin derivative and application thereof in breast cancer treatment |
| CN114940696B (en) * | 2022-05-25 | 2023-04-28 | 四川大学华西医院 | Toosendanin derivative and application thereof in breast cancer treatment |
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