CN1025029C - Preparation for camptothecin arginine salt - Google Patents
Preparation for camptothecin arginine salt Download PDFInfo
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- CN1025029C CN1025029C CN 88105147 CN88105147A CN1025029C CN 1025029 C CN1025029 C CN 1025029C CN 88105147 CN88105147 CN 88105147 CN 88105147 A CN88105147 A CN 88105147A CN 1025029 C CN1025029 C CN 1025029C
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- camptothecine
- arginine
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- camptothecin
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Abstract
The present invention relates to a preparing method of a new anticancer preparation, namely L-arginine salts of camptothecine. The present invention is characterized in that camptothecine is used to react with the aqueous solution of L-arginine in a proper solvent at a certain temperature and pH value to prepare the arginine salts of the camptothecine. In the reaction, arginine is excessive for increasing the stability of the salts in the aqueous solution and performing a function of liver protection. The cancer-inhibiting function of the salts is slightly stronger than that of the camptothecine, and the salts have obvious liver target directivity. The present invention not only overcomes the disadvantages of large toxicity, poor stability, etc. of camptothecine sodium salts, but also provides a liver-targeting type antitumor medicine with accurate curative effects.
Description
The invention belongs to a kind of preparation method of new preparation camptothecin arginine salt.
Camptothecine is from a kind of jade
The anti-tumor biological alkali that extracts in section's plant camptotheca acuminata, China's camptothecin plant aboundresources.Camptothecine is since clinical application at home in 1970, because of its solution degree in water is lower than 0.001%, and how is used for clinical with the sodium salt of camptothecine.According to example surplus Shanghai report camptothecine treatment cancer of the stomach, the rectum cancer, suede cancer, liver cancer, lung cancer, the esophagus cancer etc. 1000, proof has short term effect preferably to cancer of the stomach, the rectum cancer, suede cancer etc., cancer of the stomach is efficient to be reached about 60%, and lump is dwindled, and the pyloric obstruction symptom is eliminated than 5-fluorine arteries and veins pyrimidine, thiophene
Chemotherapeutics such as piperazine are good; Malignant mole, chorioepithelioma are also had higher curative effect, and behind the excision primary lesion, metastasis has the possibility of disappearing, than chemotherapeutics Ismipur, 5-fluorine arteries and veins pyrimidine, ammonia first
Purine is superior, (1 page of the 7th phase of medicine industry, 1972); Treat 23 routine late gastric canceres according to Wuhan report camptothecine, best to the gastric cardia cancer curative effect, up to 87.5%, camptothecine also has positive effect to suppressing relaxing tumor pain except that higher antitumor activity is arranged.The clinical toxicity of camptothecine mainly shows urinary system, cardiovascular systems and Digestive tract etc., and is the most outstanding with urinary system, comparatively serious as frequent micturition, odynuria and blood urine etc. take place, and generally appears at 200mg, the most obvious during semi-invariant.Next is a digestive tract reaction, as (20 pages of the 1st phases of Wuhan new pharmaceutical, 1972) such as diarrhoea, upper gastrointestinal hemorrhage, limitation abdominal distension.
The later stage seventies domesticly begins to lay stress on treatment primary hepatocarcinoma and the leukemia, and the targeting type suspension is made in the camptothecine crystallization, and medicine is concentrated in liver, spleen and marrow.According to Shanghai report, in 224 examples that the hepatic region that statistics is arranged or lump dwindle, 165 examples are dwindled greater than 2cm, make some be in margins of excision or unresectable at all patient through the meeting of camptothecine treatment back acquisition buster.A large amount of clinical datas prove: the antitumous effect of camptothecine is sure, and is particularly particularly remarkable to digestive tract cancer and Lymphocytic leukemia curative effect.Unfortunately because factors such as pharmaceutical preparation can not be eliminated camptothecine inherent toxic side effects, the for example easy oxidation of camptothecin sodium saline injection, and toxicity increases after the oxidation, and the requirement of injection for intravenous liver targeting type Camptothecine Suspension particle dia is very strict, generally below 2.0 μ m, but particle diameter increased during goods were stored, so fail so far to produce in enormous quantities.
The objective of the invention is to seek and prepare a kind of new organic salt of camptothecine, can be increased in the solubleness in the water, improve it at the intravital anti-tumor activity of people, can reduce its toxic side effect again, its chemical property is more stable again, camptothecine effect clinically is not fully exerted, for tumour patient provides that a kind of curative effect is reliable, drug safety, cheap medicine.
[Japan Kokai 76,44623(C.A.85:68297)] such as Kagitani Yoshio reported the industrialization method for making of acetylsalicylic acid arginic acid salt.Acetylsalicylic acid solubleness in water very low (0.3%) can't be made injection liquid, just acetylsalicylic acid is combined salify with alkaline total free aminoacids L-arginine, and this salt very easily is dissolved in the water, and solubleness can be for making powder injection greater than 40% in water.This salt instability, every 0.9g need add 0.1g arginine used as stabilizers.
But do not see report so far as yet about the camptothecine organic salt.
The object of the present invention is achieved like this: the microcrystal and the arginic aqueous solution of free L-of camptothecine status nascendi are reacted in solvent, under suitable temperature and pH value, make lactonic ring cracking in the camptothecin molecule, the amino that the hydroxyl that driffractive ring produces and the arginic alkalescence of L-the are stronger generation salt that combines must camptothecin arginine salt.
The key of this technology is the alkalescence and the arginic consumption of L-of reaction solution.Reaction must be to carry out under alkaline condition, otherwise lactonic ring can not ftracture, and also can not form organic salt with the L-arginine.
Because the arginic acid salt of camptothecine is similar to the arginic solubleness of L-, the L-arginine that is difficult to react excessive with general method separates Ex-all.Excessive L-is arginic to exist (alkalescence) and have only in preparation, and this salt could be stablized.Itself has hepatoprotective effect again the L-arginine, and L-arginine that therefore will be inexcessive separates to be removed.
The prepared camptothecin arginine salt of the present invention has following characteristics:
1. the toxicity of this salt obviously reduces than camptothecine sodium salt, its LD50 value is that (camptothecine sodium salt LD50 is 47.5mg/kg for 4.17 times of camptothecine sodium salt, camptothecin arginine salt LD50 is 198.5mg/kg), clinical value is high more than camptothecine sodium salt and Camptothecine Suspension.
2. distribution target in the tangible body is arranged after this salt administration, mainly concentrate in liver and digestive tube after individually dosed, and the time that continues is long, the abundance in other organ-tissue is less.The L-arginine is a hepatic, can protect normal liver cell to preserve from.This salt is made injection liquid or seal in the dried liposome, then can further improve target, experimental results show that to make the concentration of camptothecine in liver, lung improve 10 and 100 times than other tissue respectively liver, lung.Therefore, be applicable to treatment liver cancer and lung cancer.
3. experimental results show that: the antitumor activity of this salt is stronger.The S180 tumour inhibiting rate is respectively 52%(5mg/kg, uses separately) and 74%(5mg/kg, be encapsulated in the liposome); The liver-cancer solid tumor tumour inhibiting rate is respectively 53.1%(5mg/kg, uses separately) and 82%(5mg/kg, be encapsulated in the liposome), to the EAC(ehrlich carcinoma) significant inhibitory effect arranged, can make the mouse increase in life span reach 126%, the part mouse ascites disappears, can long-term surviving.The antitumor activity that this salt is described is stronger slightly than camptothecine sodium salt.The tumour concomitant immunity is measured and is confirmed that the restraining effect of this salt pair body immune system is slight more than the camptothecine sodium salt.
4. the physical and chemical stability of this salt is than camptothecine sodium salt and Camptothecine Suspension height, thermostability height not only, and be subjected to
-The effect of OH ionic catalysis weakens, and crystallization is not separated out in room temperature storage nondiscoloration in 2 years yet, can overcome the problem that camptothecine sodium salt oxidation toxicity increases.
5. this salt is very easily water-soluble, and dissolved degree of separating surpasses 10%, and water-soluble much higher than camptothecine sodium salt except that can preparing liver targeting type preparation such as liposome, still can prepare multiple high density camptothecine.
6. this salt adopts a ring-opening reaction preparation, and method is easy, and yield side reaction and residual organic solvent problem can not occur up to 100%.
Embodiment
One, gets camptothecine 5.0g(0.0143 mole), add chloroform-methanol (1: 1) mixed solution 50ml, put and heat in the water-bath to dissolving, under the stirring that refluxes, slowly drip the L-arginine aqueous solution [25g(0.143 mole) L-arginine be dissolved in the 30ml distilled water], continue to reflux 30 minutes to reaction solution clear and bright substantially after, filtered while hot, filtrate is reclaimed chloroform, methyl alcohol.Get the lyophilize of residuary water solution, get camptothecin arginine salt faller gill shape yellow crystal, 30g(contains excessive L-arginine altogether).
Chemical structural formula
Camptothecin arginine salt
Camptothecine
Infrared spectra cm
-11750cm
-1(carbonyl on the lactonic ring)
1650cm
-1(carbonyl on the heterocycle)
Camptothecin arginine salt
Infrared spectra cm
-11580cm
-1(carbonyl in the carboxyl)
1650cm
-1(carbonyl on the heterocycle)
Two, get camptothecine 0.5g(0.00143 mole), add dimethyl sulfoxide (DMSO) 10ml, put and heat in the water-bath to dissolving, under the stirring that refluxes, slowly dripping the 0.25g(0.00143 mole) the L-arginine is dissolved in the solution of distilled water, it is clear and bright to continue to be back to solution, after 10 minutes, and the reclaim under reduced pressure dimethyl sulfoxide (DMSO).With the dry thing and 2.5g(0.0143 mole that obtains) the L-arginine mixes, add less water and heat after the dissolving, filtered while hot, the filtrate lyophilize, camptothecin arginine salt faller gill shape yellow crystal 3.25g(contains excessive L-arginic acid salt).
Three, get camptothecine 3.0g(0.00862 mole), add chloroform-ethanol (1: 2) mixed solution 20ml, put the dissolving of heating in the water-bath, under the stirring that refluxes, once adding the L-arginine aqueous solution (with the 18g(0.1034 mole) L-arginine is dissolved in the 50ml distilled water), it is clear and bright to continue to be back to reaction solution.Reclaim chloroform, the remaining aqueous solution lyophilize.Get camptothecin arginine salt faller gill shape yellow crystal 21g(and contain excessive L-arginine).
Claims (1)
1, a kind of preparation method of camptothecin arginine salt preparation, it is characterized in that with camptothecine and L-arginine be raw material, can in chloroform-methanol, chloroform-ethanol, dimethyl sulfoxide (DMSO) and water, be carried out to reactant salt respectively, temperature of reaction is the reflux temperature of each solvent, and the arginic mole ratio of raw materials used camptothecine and L-can be in the reaction: camptothecine: L-arginine=1: 10,1: 11 and 1: 12.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 88105147 CN1025029C (en) | 1988-10-22 | 1988-10-22 | Preparation for camptothecin arginine salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 88105147 CN1025029C (en) | 1988-10-22 | 1988-10-22 | Preparation for camptothecin arginine salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1042151A CN1042151A (en) | 1990-05-16 |
| CN1025029C true CN1025029C (en) | 1994-06-15 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 88105147 Expired - Fee Related CN1025029C (en) | 1988-10-22 | 1988-10-22 | Preparation for camptothecin arginine salt |
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| Country | Link |
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| CN (1) | CN1025029C (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE318823T1 (en) * | 2001-09-25 | 2006-03-15 | Reddys Lab Ltd Dr | PHARMACEUTICALLY APPLICABLE SALTS OF 20(S)-CAMPTOTHECINES |
| CN1978448B (en) * | 2005-12-07 | 2010-08-25 | 成都三康药物研究所 | 10-hydroxy camptothecin arginine salt, and its preparing method and use |
| CN1978447A (en) * | 2005-12-07 | 2007-06-13 | 成都三康药物研究所 | 10-hydroxy camptothecin arginine salt, and its preparing method and use |
-
1988
- 1988-10-22 CN CN 88105147 patent/CN1025029C/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| CN1042151A (en) | 1990-05-16 |
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