CN1052472C - Acetyl-salicylic derivate combined with niacinamide and zinc - Google Patents
Acetyl-salicylic derivate combined with niacinamide and zinc Download PDFInfo
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- CN1052472C CN1052472C CN94111976A CN94111976A CN1052472C CN 1052472 C CN1052472 C CN 1052472C CN 94111976 A CN94111976 A CN 94111976A CN 94111976 A CN94111976 A CN 94111976A CN 1052472 C CN1052472 C CN 1052472C
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- zinc
- asprin
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Abstract
The present invention relates to an acetyl-salicylic derivative combined with niacinamide and zinc. The structure is shown in the formula above.
Description
But what the present invention relates to is a kind of acetyl-salicylic derivate of hyoscine, specifically is a kind of acetyl-salicylic derivate that is combined with nicotinic acid derivates and metal ingredient.
Acetylsalicylic acid (Asprin) is as classical and unspent so far antipyretic-antalgic anti-inflammatory agent thing was used more than 100 year, and finds constantly again that in the recent period it also has treatment cardiovascular disorder and some anticancer therapeutic, has more enlarged its range of application.But because it is acid strong, the gastrorrhagia that GI irritation is easily caused, even side effect such as ulcerate disease also is the puzzlement people and the problem of managing to solve always.For reducing its acidity, except that making prodrugs such as ester class and acid amides, form double salt also is approach that report is arranged more at present.As J55141438, documents such as DT2909829 have all been reported the Asprin aluminum compound; What DT2925718 introduced is the compound that Asprin is become with zinc; What US4294819 introduced is the salt that Asprin is become with calcium, magnesium; US3284489 has introduced the salt of calcium and amino acid and Asprin combining form; J56022748 has introduced the salt that Asprin is become with basic aminoacids; US3318892 has introduced the form that Asprin combines with nicotinic acid and aluminium; EP200628A, EP233459A, documents such as FR2492368 and FR2638742A have introduced the form that Asprin combines with urea, calcium and/or magnesium respectively.Can understand from the content that these documents are introduced, the derivative of above-mentioned Asprin all can reduce acidity, and increase water-soluble, but on pharmacology the more or new valuable active effect of generation.
At the problems referred to above, the present invention's purpose at first provides a kind of acetyl-salicylic derivate that is combined with the new texture of zinc and niacinamide.A further object of the present invention provides a kind of acidity that not only can reduce in the clinical use, increases water-solublely, and can produce the acetyl-salicylic derivate that is combined with zinc and niacinamide of valuable active effect to acetylsalicylic acid on pharmacology.
Acetyl-salicylic derivate of the present invention by two acetylsalicylic acid respectively with carboxyl, and the forms that combine with a zinc simultaneously with pyridine ring N respectively of two niacinamide, its structure is
This derivative of the present invention (I) synthetic general and uncomplicated can be with reference to as US3318892, EP233459A, and the similar document of EP200628A or other institute reported method is carried out, and also can carry out with reference to following method.Wherein used solvent can be methyl alcohol, ethanol, Virahol, or the small molecular alcohol of C1-C5 such as acetone, butanone or ketone.Zinc can use mineral acid zinc salts such as zinc chloride zinc sulfate, zinc nitrate, or organic acid zinc salt such as zinc lactate, zinc acetate, Zinc Undecylenate.The consumption of each material composition can be by acetylsalicylic acid during preparation: niacinamide: zinc salt=(1.8～2.4): (1.8～2.4): (0.9～1.2) [mol ratio].For example: acetylsalicylic acid 36 grams under agitation are dissolved in 200 milliliters of acetone.In addition niacinamide 22 grams and zinc sulfate 30 grams are dissolved in 40 ml waters.Under agitation the above-mentioned aqueous solution is splashed in the acetone soln, stirred 5 hours under the room temperature.Filtration gained precipitation is washed with anhydrous propanone.After 60 ℃ of oven dry, must this derivative products (I) 40 grams (yield 60%), mp142～145 ℃, purity detecting content is not less than 98%.Acetylsalicylic acid content ratio in the product (I) is about 54%.This product is easily molten in water, and solubleness is 5～8%, and is molten at ethanol, acetone part omitted, almost insoluble in ether, chloroform, ethyl acetate.Product is made and recorded pH in 5% aqueous solution is 6.4.Except that this method, also can adopt method of fractional steps preparation, for example, be prepared into niacinamide zinc earlier after, again with acetylsalicylic acid synthetic product (I), or be prepared into earlier behind the Zinc acelylsalicylate again and niacinamide synthetic product (I).
The chemical formula of this derived products (I) is C30H26N4O10Zn, and the ultimate analysis theoretical value should be: C:53.95%, H:3.92%, N:8.39%, Zn:9.79%.The ultimate analysis measured value of above-mentioned product (I) is: C:54.19%, H:4.01%, N:8.07%, Zn:9.95%.
The infrared absorpting light spectra of above-mentioned product (I) as shown in drawings.Wherein the ownership of charateristic avsorption band is: 3340 (wave numbers, as follows) (NH), 1750 (C=O), 1625 (C=N), 1600 (C=C), 1370 (C-H), 1220 (C-N).
It is an amount of to get above-mentioned product (I) sample, puts respectively in 50 ℃ of baking ovens 5 days and room temperature was placed after 18 months, and free-water poplar acid content shows that all less than 0.2% the above-mentioned product of the present invention (I) has good stability in the sample for reference.
The above-mentioned product of the present invention (I) is made the acute toxicity animal experiment: get 60 of the mouse of body weight 19～23 gram male and female half and half, be divided into two batches totally six groups at random, test group and control group respectively are a collection of three groups.The Asprin of product (I) and contrast usefulness all is made into oral administration behind the suspensoid with tragakanta, according to animal dead situation gained medium lethal dose (LD50) result in 72 hours: Asprin is 972.7 (literature values 1050), and product (I) is 1456 (milligram/kilograms).
The result of relevant pharmacological experiment is as follows:
Irritation test to stomach: get body weight and be 70 of the SD rats that 210～230 gram male and female have concurrently, random packet.After the fasting 24 hours, above-mentioned product (I) and Asprin reference substance are made into the suspensoid of various dose respectively with tragakanta, make blank with equivalent tragakanta liquid in addition, all put to death after 6 hours, do the inspection of stomach ulcer index with filling stomach form administration.Median ulcerated dose (UD50) result that the result is done after the linear regression processing is: Asprin 215.7, product (I) 631.1 (wherein being equivalent to Asprin 340.8) (milligram/kilogram).
Analgesic activities test: 70 random packet of mouse of heavy 18～22 gram male and female half and half of taking a sample.Water is prohibited in fasting before the experiment.Product (I) is made into the aqueous solution, and contrast is made into suspensoid with Asprin with tragakanta, and blank is an equivalent physiological saline.Behind the oral administration 30 minutes,, begin counting animal writhing response number of times in 15 minutes after 5 minutes by amount abdominal injection 0.6% acetate solution of 10 milliliters/kg body weight.Cause pain significant quantity (ED50) result according to causing the half that reacts the linear regression gained of inhibiting rate bitterly: Asprin is 368.2, and product (I) is 216.5 (wherein being equivalent to Asprin 116.9) (milliliter/kilograms).The analgesic activity that shows product (I) is equivalent to 3.2 times of Asprin.
Anti-inflammatory activity test: get 70 random packet of above-mentioned mouse equally.Water is prohibited in fasting before the experiment.Trial drug preparation and blank product are identical with the analgesic activities test.Behind the oral administration 30 minutes, drip 0.03 milliliter of dimethylbenzene with micro sample adding appliance at animal left side ear and cause inflammation after 30 minutes, put to death animal, get auricle with punch tool and weigh, calculate the swelling degree shown in the two auricle weight differences.Reach 15% o'clock anti-inflammatory effective amount (ED15) result according to causing the inhibiting rate that scorching reaction inhibiting rate makes the linear regression gained: Asprin 682.8, product (I) are 138.2 (wherein being equivalent to Asprin 74.6) (milligram/kilograms).The anti-inflammatory action that shows product (I) is equivalent to 9.2 times of Asprin.
These experimental results fully show, the aqueous solution of the above-mentioned product of the present invention (I) is neutral, oral back is little to gastric stimulation, and there have been obviously analgesic activity and anti-inflammatory action the while and increase substantially, and has significantly reduced the actual amount of Asprin under identical curative effect.
In addition, niacinamide is the main component of nadide as water-soluble vitamins, is playing an important role aspect the metabolism of participation body.Zinc element is the trace element of needed by human, and is relevant with the activity of tens of kinds of enzymes in the body, particularly keep the cell integrity and reactive aspect play an important role.Recently entered the clinical experiment stage with zinc as the novel method for the treatment of stomach ulcer, having demonstrated due to antagonism Asprin has remarkable superiority aspect the gastrointestinal irritation side effect.Above-mentioned acetyl-salicylic derivate of the present invention (I) combines with Asprin by niacinamide and zinc element, replenishing human body beneficial's element and composition and when can obviously resist the side effect of Asprin, also significantly improving the pharmacology performance of traditional Asprin medicine.Along with the continuous discovery and the expansion of new purposes of Asprin and suitable application area scope, the shown positive effect that goes out of said derivative of the present invention (I) and be worth also will be day by day obviously and important.
Claims (1)
1, a kind of acetyl-salicylic derivate that is combined with nicotinic acid derivates and metal ingredient is characterized in that nicotinic acid derivates wherein is a niacinamide, and metal ingredient is a zinc, and has following structure
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94111976A CN1052472C (en) | 1994-11-16 | 1994-11-16 | Acetyl-salicylic derivate combined with niacinamide and zinc |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94111976A CN1052472C (en) | 1994-11-16 | 1994-11-16 | Acetyl-salicylic derivate combined with niacinamide and zinc |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1107140A CN1107140A (en) | 1995-08-23 |
| CN1052472C true CN1052472C (en) | 2000-05-17 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94111976A Expired - Fee Related CN1052472C (en) | 1994-11-16 | 1994-11-16 | Acetyl-salicylic derivate combined with niacinamide and zinc |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP6033041B2 (en) * | 2012-10-31 | 2016-11-30 | 株式会社オハラ | Automatic quality inspection device for optical glass base material and automatic quality inspection method for optical glass base material |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0200628A1 (en) * | 1985-04-19 | 1986-11-05 | Rhone-Poulenc Sante | Derivative of acetylsalicylic acid, its preparation and pharmaceutical compositions containing it |
| EP2333459A2 (en) * | 2009-11-30 | 2011-06-15 | Sanyo Electric Co., Ltd. | Refrigerating apparatus |
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1994
- 1994-11-16 CN CN94111976A patent/CN1052472C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0200628A1 (en) * | 1985-04-19 | 1986-11-05 | Rhone-Poulenc Sante | Derivative of acetylsalicylic acid, its preparation and pharmaceutical compositions containing it |
| EP2333459A2 (en) * | 2009-11-30 | 2011-06-15 | Sanyo Electric Co., Ltd. | Refrigerating apparatus |
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| Publication number | Publication date |
|---|---|
| CN1107140A (en) | 1995-08-23 |
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