CN1850797A - Tiopronin amino salt, and its preparing method - Google Patents
Tiopronin amino salt, and its preparing method Download PDFInfo
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- CN1850797A CN1850797A CN 200610019090 CN200610019090A CN1850797A CN 1850797 A CN1850797 A CN 1850797A CN 200610019090 CN200610019090 CN 200610019090 CN 200610019090 A CN200610019090 A CN 200610019090A CN 1850797 A CN1850797 A CN 1850797A
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Abstract
This invention relates tiopronin amino acid salt used to cure chronic hepatitis and its preparation method. Its constitutional formula is shown as follow; R is 1-20 carbon atoms straight chain or branched chain alkyl radical. This invention solves the problem of tiopronin oxidation degradation in water, and volatilization decomposition in heat. The tiopronin in this invention is prepared into amino acid salt, it prevent the tiopronin combining with oxygen, and its oxidation. Medical using substance melting point is improved, so its thermal stability is greatly improved, so its medical effect as effective constituent is greatly improved.
Description
Technical field
The present invention relates to a kind of amino acid salts of preparing medicine and preparation method thereof, specifically a kind of tiopronin amidate that is used for the treatment of the acute and chronic hepatitis medicine and preparation method thereof of being used to.
Background technology
Tiopronin (English name Tiopronin, chemical name: N-(2-mercapto radical propionyl group) glycine) is a kind of metabolism improving toxinicide, its molecular formula: C
5H
9NO
3S, molecular weight: 163.20, structural formula is as follows:
It can activate metabolic enzyme, improves protein metabolism, promotes the liver function reparation, and it is mainly used in the treatment acute and chronic hepatitis.From the nineties in 20th century, China successfully develops the tiopronin bulk drug, and the several formulations listing of tiopronin is arranged afterwards successively: comprise tablet, capsule, liquid drugs injection and freeze-dried powder etc., now be widely used in clinically, become the important drugs of treatment hepatopathy.
But tiopronin has its great defective, and is promptly very unstable, and in the presence of water, easily oxidative degradation has influenced the curative effect and the security of its clinical treatment.And the fusing point of tiopronin is also relatively low is 96-99 ℃, and is therefore also unstable to heat.The physico-chemical property of tiopronin has directly limited it and has been directly used in the purposes of the various medicinal preparationss of preparation.Therefore in order to improve the result of use of tiopronin, many investigators are prepared into composition with the material of itself and other component, and its result of use is still bad.As open day being that the application for a patent for invention that February 23, publication number in 2005 are CN1582911A discloses a kind of new tiopronin freeze-dried powder injection, it is that tiopronin is formed pharmaceutical composition as activeconstituents and drug excipient amino acid, it has certain improvement to the stability of tiopronin in the aqueous solution, oxidative degradation to tiopronin has certain restraining effect, but quite a few tiopronin still can oxidative degradation.Especially not its thermostability is not almost improved to tiopronin.So the problem of easy oxidative degradation of tiopronin and poor heat stability that how to solve for a long time, is the problem that those skilled in the art studies always.
Summary of the invention
Purpose of the present invention is exactly the defective at easy oxidative degradation of tiopronin and poor heat stability, and a kind of tiopronin amidate is provided, and it can overcome the above-mentioned defective of tiopronin, and has the identical drug effect of tiopronin.
Another object of the present invention has provided a kind of synthetic method for preparing tiopronin amidate.
The present invention is through research, after finding tiopronin and amino acid whose reaction generated tiopronin amidate, can improve the stability of tiopronin, both prevented that tiopronin from meeting the easy oxidative degradation of the water capacity, prevent again its meet the volatile and decomposition of thermal capacitance problem.Its reason is that amino acid is the oxidation inhibitor that uses in the medicine, tiopronin is prepared into amino acid salts stoped combining of tiopronin and oxygen, can prevent its oxidation.Improved the fusing point of medicinal substance simultaneously, its thermostability is obviously improved.And amino acid itself also is effective ingredient, and the drug action of tiopronin amidate is also higher than the drug action of single tiopronin.
Structural formula of the present invention is as follows:
Wherein R is the straight or branched alkyl of 1 to 20 carbon atom.
Tiopronin amidate described in the present invention is arginic acid salt, lysine salt, leucine salt, Isoleucine salt, glycinate, cystine salt, cysteine salt, tyrosine salt, L-Ala salt, phenylalanine salt, Histidine salt, Serine salt, Threonine salt, methionine salt, tryptophane salt, glutaminate, aspartate or Xie Ansuan salt.The arginic acid salt that the preferred structure formula is following,
Or the following lysine salt of structural formula
Tiopronin amidate of the present invention prepares by the following method:
Starting raw material is a tiopronin
And amino acid
H
2N—R—COOH
Reaction formula:
Tiopronin of the present invention and the amino acid whose mole ratio that feeds intake are 1: 0.8～1: 1.2, preferred 1: 1.05.
The solvent that uses in the reaction process among the present invention is an ethanol as methyl alcohol, ethanol, propyl alcohol, acetone, acetonitrile or ethyl acetate, preferred solvent.
Embodiment
Below in conjunction with embodiment the present invention is further described:
Embodiment 1: the preparation of tiopronin arginic acid salt
Feed ratio:
| Material name | Charging capacity | Mole ratio |
| Tiopronin L-arginine methyl alcohol (95%) | 100g 112g 600ml | 1 1.05 |
Operation:
Tiopronin, L-arginine, ethanol are dropped in three mouthfuls of reaction flasks of 1000ml, stir, be heated to 50 ℃ of backflows, back flow reaction is after 3 hours, filtered while hot, and filtrate is put 5-10 ℃ of crystallisation by cooling in the refrigerator.After 5 hours, filter, the white crystals body, xln was put in the baking oven 80 ℃ of dryings 6 hours, white crystalline solid 196g, yield 94.8%, mp197-200 ℃.
The infrared absorption spectrum data of sample:
Absorption peak (cm
-1): 2957.92,1647.58,1604.88,1525.77,1457.23,1407.90,1386.21,1357.38,1335.77,1313.99,1246.37,1159.37,1012.96,670.43,555.97.
Embodiment 2: the preparation of tiopronin lysine salt
Feed ratio:
| Material name | Charging capacity | Mole ratio |
| Tiopronin L-Methionin ethanol (95%) | 100g 94g 600ml | 1 1.0 |
Working method is with embodiment 1: the 177g white crystalline solid, yield 93.4%, mp172-175 ℃.
The infrared absorption spectrum data of sample:
Absorption peak (cm
-1): 3328.57,2939.20,1646.85,1593.90,1521.17,1405.00,1357.70,1316.94,1023.31,904.87,701.58,550.03,420.12.
Embodiment 3:
Tiopronin, the phenylalanine salt ratio in 1: 0.8 is dropped in three mouthfuls of reaction flasks of 1000ml, add the 650ml ethyl acetate then and stir, be heated to 100 ℃ of backflows, back flow reaction is after 3 hours, filtered while hot, and filtrate is put 5-10 ℃ of crystallisation by cooling in the refrigerator.After 5 hours, filter, the white crystals body, xln was put in the baking oven 80 ℃ of dryings 6 hours, white crystalline solid 196g, yield 94.2%, mp195-200 ℃.
Embodiment 4:
Tiopronin, the Xie Ansuan salt ratio in 1: 1 is dropped in three mouthfuls of reaction flasks of 1000ml, add the 650ml acetonitrile then and stir, be heated to 80 ℃ of backflows, back flow reaction is after 3 hours, filtered while hot, and filtrate is put 5-10 ℃ of crystallisation by cooling in the refrigerator.After 5 hours, filter, the white crystals body, xln was put in the baking oven 80 ℃ of dryings 6 hours, white crystalline solid 196g, yield 93.2%, mp185-190 ℃.
Embodiment 5:
Tiopronin, the cystine salt ratio in 1: 1 is dropped in three mouthfuls of reaction flasks of 1000ml, add 650ml acetone then and stir, be heated to 90 ℃ of backflows, back flow reaction is after 3 hours, filtered while hot, and filtrate is put 5-10 ℃ of crystallisation by cooling in the refrigerator.After 5 hours, filter, the white crystals body, xln was put in the baking oven 80 ℃ of dryings 6 hours, white crystalline solid 206g, yield 95.0%, mp185-190 ℃.
Embodiment 6:
Compare A: tiopronin, B: tiopronin arginic acid salt, C: the stability of tiopronin lysine salt in water.
A, B, C are dissolved in respectively in the distilled water, are mixed with the aqueous solution of content 5%, pour in the 2ml ampoule, sealing by fusing is put in the constant temperature oven, 40 ℃, investigates 10 days under 60 ℃ of conditions.In 0,5, sampling respectively in 10 days, check related substance and content as follows:
Related substance is measured according to high performance liquid chromatography (HPLC method).
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is weighting agent, is moving phase with the 0.07mol/L potassium dihydrogen phosphate, and flow velocity is about per minute 1.0ml, and the detection wavelength is 210nm.Number of theoretical plate calculates by tiopronin should be not less than 2000.
Assay method: it is an amount of that precision takes by weighing this product, add moving phase make contain 0.5mg among every 1ml solution as need testing solution; It is an amount of to measure need testing solution, add moving phase make contain 5 μ g among every 1ml solution as prerun solution.Get prerun solution 20 μ l and inject liquid chromatograph, regulate detection sensitivity, the peak height that makes the principal constituent chromatographic peak is the 5%-10% of full range; Get need testing solution 20 μ l again, inject liquid chromatograph, the record color atlas is to 3.5 times of principal constituent peak retention time.
Assay is according to high effective liquid chromatography for measuring.
Chromatographic condition and system suitability test are with under the determination of related substances item.
Assay method: precision takes by weighing this product 1ml and puts in the 100ml measuring bottle, is diluted to scale with moving phase, shakes up, as need testing solution.Other gets the tiopronin reference substance, and accurate the title decides, and makes the solution that contains 0.5mg among every 1ml, solution in contrast with moving phase.Get each 20 μ l of need testing solution and reference substance solution and inject liquid chromatograph, the record color atlas is pressed external standard method with calculated by peak area, promptly.
Measurement result sees Table 1:
| Time (my god) | 0 | 5 | 10 | |||||||
| Test sample | A | B | C | A | B | C | A | B | C | |
| Content (%) | 40□ | 99.2 | 99.6 | 99.5 | 92.3 | 96.7 | 95.5 | 89.4 | 93.4 | 92.2 |
| 60□ | 99.2 | 99.6 | 99.5 | 89.8 | 94.5 | 93.2 | 81.5 | 90.8 | 88.6 | |
| Related substance (%) | 40□ | 0.78 | 0.47 | 0.48 | 7.72 | 3.32 | 4.48 | 10.63 | 6.57 | 7.98 |
| 60□ | 0.78 | 0.47 | 0.48 | 11.01 | 5.51 | 6.72 | 18.42 | 9.23 | 11.20 | |
As can be seen, at 40 ℃, under 60 ℃ of influence factor conditions, tiopronin arginic acid salt, tiopronin lysine salt are all stable than tiopronin in water.Wherein the tiopronin arginic acid salt is better than tiopronin lysine salt-stable.
Embodiment 7:
Compare A: tiopronin, B: tiopronin arginic acid salt, C: the stability of tiopronin lysine salt under the strong illumination condition.
Get A, B respectively, C is an amount of, puts into moisture eliminator, places under the injection clarity determinator, with 3000Lx illuminance irradiation 10 days, in 0,5, related substance and content were measured in sampling respectively in 10 days.
Detection method is with embodiment 3.
Measurement result sees Table 2:
| Time (my god) | 0 | 5 | 10 | ||||||
| Test sample | A | B | C | A | B | C | A | B | C |
| Content (%) | 99.4 | 99.5 | 99.5 | 97.1 | 98.8 | 98.2 | 94.0 | 97.9 | 96.3 |
| Related substance (%) | 0.61 | 0.51 | 0.52 | 3.01 | 2.19 | 2.69 | 6.02 | 2.11 | 3.70 |
As can be seen, the ordering of the stability of A, B, C is under 10 days strong illuminations: tiopronin arginic acid salt＞tiopronin lysine salt＞tiopronin.
From example 6,7 as can be seen, the amino acid salts of tiopronin is more stable than tiopronin.This provides a kind of good approach for the stability of improving tiopronin.
Claims (7)
1. tiopronin amidate, its structural formula is as follows:
Wherein R is the straight or branched alkyl of 1 to 20 carbon atom.
2. according to a kind of tiopronin amidate of claim 1, wherein said tiopronin amidate is arginic acid salt, lysine salt, leucine salt, Isoleucine salt, glycinate, cystine salt, cysteine salt, tyrosine salt, L-Ala salt, phenylalanine salt, Histidine salt, Serine salt, Threonine salt, methionine salt, tryptophane salt, glutaminate, aspartate or Xie Ansuan salt.
3. according to a kind of tiopronin amidate of claim 1, wherein said tiopronin amidate is the following arginic acid salt of structural formula
4. according to a kind of tiopronin amidate of claim 1, wherein said tiopronin amidate is the following lysine salt of structural formula
5. the preparation method of a kind of tiopronin amidate of claim 1, it be by
With H
2N-R-COOH is carried out to reactant salt and is prepared from the presence of organic solvent, its mole ratio is 1: 0.8～1: 1.2.
6. according to the preparation method of a kind of tiopronin amidate of claim 5, wherein said solvent organic solvent is methyl alcohol, ethanol, propyl alcohol, acetone, acetonitrile or ethyl acetate.
7. according to the preparation method of a kind of tiopronin amidate of claim 5, the temperature of reaction of wherein said salt-forming reaction is 50-100 ℃.
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|---|---|---|---|
| CNB2006100190904A CN100436411C (en) | 2006-05-18 | 2006-05-18 | Tiopronin amino salt, and its preparing method |
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|---|---|---|---|
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| CN100436411C CN100436411C (en) | 2008-11-26 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107501390A (en) * | 2016-06-14 | 2017-12-22 | 首都医科大学 | Tiopronin acyl-Met-AA, it is synthesized, activity and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100393310C (en) * | 2003-08-20 | 2008-06-11 | 江西欧氏药业有限责任公司 | Frozen powder injection of tiopronin |
| CN1880301B (en) * | 2006-05-11 | 2012-11-07 | 沈阳药科大学 | Tiopronin lysine and its preparing process and use |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107501390A (en) * | 2016-06-14 | 2017-12-22 | 首都医科大学 | Tiopronin acyl-Met-AA, it is synthesized, activity and application |
| CN107501390B (en) * | 2016-06-14 | 2021-07-06 | 首都医科大学 | Tiopronin acyl-Met-AA, and synthesis, activity and application thereof |
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| CN100436411C (en) | 2008-11-26 |
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Owner name: WUHAN WUYAO PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: WUHAN YUANDA PHARMACEUTICAL GROUP CO.,LTD. Effective date: 20090807 |
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Effective date of registration: 20090807 Address after: Gutian road in Hubei province Wuhan City Qiaokou District No. 5 Patentee after: Wuhan Wuyao Pharmaceutical Co., Ltd. Address before: Gutian road in Hubei province Wuhan City Qiaokou District No. 5 Patentee before: Wuhan Yuanda Pharmaceutical Group Co., Ltd. |