CN102210681B - Application of ectoine and derivatives thereof in preparing medicament for treating digestive tract diseases - Google Patents
Application of ectoine and derivatives thereof in preparing medicament for treating digestive tract diseases Download PDFInfo
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- CN102210681B CN102210681B CN 201110111310 CN201110111310A CN102210681B CN 102210681 B CN102210681 B CN 102210681B CN 201110111310 CN201110111310 CN 201110111310 CN 201110111310 A CN201110111310 A CN 201110111310A CN 102210681 B CN102210681 B CN 102210681B
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Abstract
The invention discloses novel application of 1,4,5,6-tetralin-2-methyl-4-pyrimidinyl carboxy in the medical field, and particularly relates to application in preparing a medicament for treating digestive tract diseases caused by chemotherapy medicaments. The inventor is surprised to find in researches that: the 1,4,5,6-tetralin-2-methyl-4-pyrimidinyl carboxy and derivatives thereof have unexpected treatment effect on gastritis, gastric ulcer and duodenal ulcer caused by chemotherapy medicaments, so that the 1,4,5,6-tetralin-2-methyl-4-pyrimidinyl carboxy and derivatives thereof can be used in preparing medicaments for treating gastritis, gastric ulcer and duodenal ulcer caused by chemotherapy medicaments. The invention also provides a medicament for treating digestive tract diseases, which consists of ectoine or derivatives thereof and medically acceptable pharmaceutic adjuvant. Experiments prove that: the ectoine and derivatives thereof have good treatment effect on the gastritis, the gastric ulcer, the duodenal ulcer and other digestive tract diseases, and is superior to ranitidine, Sanjiu Weitai, domperidone and other medicaments.
Description
Technical field
The present invention relates to the application in the medicine of preparation treatment digestive tract disease of tetrahydropyrimidine and derivant thereof, relate in particular to the common digestive tract disease such as gastritis, gastric ulcer and duodenal ulcer.
Background technology
Gastritis, gastric ulcer and duodenal ulcer are common digestive tract disease, have the advantages that the course of disease is long, complication is many, easily recur.The medicine for the treatment of gastric and duodenal ulcers has following a few class:
Antacid (aluminium hydroxide, magnesium oxide etc.): in mainly being and gastric acid, reduce stomach and ID acidity, be 60～90 minutes after the meal its best medicine time; Anticholinergic agent (Semen daturae etc.) can reduce gastric acid secretion, removes the gastrointestinal smooth muscle spasm, prolongs the gastric emptying time, because it acts on peak at oral rear 60～90 minutes, therefore be good at 15～30 minutes before the meal medicine time;
H2 receptor blocking agent (cimetidine, ranitidine etc.) reduces gastric acid secretion by blocking-up H2 receptor, in order not affect the digestion to food, should once take medicine just before going to bed, not only guarantees curative effect, and can reduce side effect.
1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic, be commonly called as tetrahydropyrimidine, English ectoine by name, CAS number is 96702-03-3, chemistry 2-Methyl-1 by name, 4,5,6-tetrahydropyrimidine-4-carboxylic acid or (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acid or Isosorbide-5-Nitrae, 5,6-tetrahydro-2-methyl-4-pyrimidine carbonicacid, be the amino acid derivativges of finding in 1985, discovered in recent years has certain mitigation to allergic disease, may be relevant with its moisture-keeping function.In addition Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic has been used to cosmetics, as moisturizing or suntan lotion.
Summary of the invention
For above-mentioned prior art, the purpose of this invention is to provide 1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and derivant thereof are at a kind of new purposes of field of medicaments, specifically Isosorbide-5-Nitrae, the application in the alimentary canal inflammation medicine that preparation treatment chemotherapeutics causes of 5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and derivant thereof.
For achieving the above object, the technical solution used in the present invention is:
Under study for action surprised discovery of the present inventor, (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acid and derivant thereof have unexpected therapeutical effect to gastritis, gastric ulcer and the duodenal ulcer that the treatment chemotherapeutics causes.Therefore, can be for the preparation of the digestive tract disease such as gastritis, gastric ulcer and duodenal ulcer for the treatment of by the chemotherapeutics initiation.
Described (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acid derivant is Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic.
The route of administration of described (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acid and derivant thereof is oral administration.
The dosage of described (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acid and derivant thereof is 0.04mg/kg-100mg/kg, and is preferred, is 4.0mg/kg-60mg/kg, further preferred, is 5mg/kg-10mg/kg.
The present invention also provides a kind of medicine for the treatment of digestive tract disease, is comprised of tetrahydropyrimidine or derivatives thereof and medically acceptable pharmaceutic adjuvant.
Preferably, described medically acceptable pharmaceutic adjuvant is: microcrystalline Cellulose, lactose, Sodium Hydroxymethyl Stalcs, magnesium stearate and polyvinylpyrrolidone, wherein, the weight ratio of tetrahydropyrimidine or derivatives thereof and microcrystalline Cellulose, lactose, Sodium Hydroxymethyl Stalcs, magnesium stearate and polyvinylpyrrolidone is 10: 50: 100: 37.5: 12: 30, make tablet.
Preferably, described medically acceptable pharmaceutic adjuvant is: microcrystalline Cellulose, Sodium Hydroxymethyl Stalcs, differential silica gel, polyvinylpyrrolidone and sodium lauryl sulphate, wherein, the weight ratio of tetrahydropyrimidine or derivatives thereof and microcrystalline Cellulose, Sodium Hydroxymethyl Stalcs, differential silica gel, polyvinylpyrrolidone and sodium lauryl sulphate is 10: 10: 12: 20: 30: 5, make tablet.
The experiment proved that, tetrahydropyrimidine and derivant thereof have preferably therapeutical effect to digestive tract disease such as gastritis, gastric ulcer, duodenal ulcers, are better than the Common drugs such as ranitidine, SANJIU WEITAI, motilium.
Isosorbide-5-Nitrae described in the technical scheme of the present invention, 5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic is commonly called as tetrahydropyrimidine, English ectoine by name, CAS number is 96702-03-3, chemistry 2-Methyl-1 by name, 4,5,6-tetrahydropyrimidine-4-carboxylic acid or (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acid or Isosorbide-5-Nitrae, 5,6-tetrahydro-2-methyl-4-pyrimidine carbonic acid; Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is commonly called as the hydroxy tetrahydro pyrimidine, and this is well-known to those skilled in the art.
The specific embodiment
Below in conjunction with embodiment the present invention is further explained.Should be understood that, following examples only are used for explaining the present invention, rather than restriction protection scope of the present invention.
Embodiment 1 (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acid and Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is to the therapeutical effect of gastritis
The Wistar rat, body weight 180-200g, male and female half and half.Rat oral gavage gives 80mM sodium taurocholate 1mL; get 30 of rats after the modeling success; be divided at random 6 groups; one group of gavage gives tap water, and one group of gavage gives Isosorbide-5-Nitrae; 5; 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic (Ect, 2mg/kg), one group of gavage gives 1; 4; 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic (Ect-OH, 2mg/kg); one group of gavage gives motilium (10mg/kg); one group of gavage gives SANJIU WEITAI (8.3g/kg), and one group of gavage gives ranitidine (150mg/kg) administration every day 2 times, successive administration 5 days.
Administration is cutd open inspection with sacrifice of animal after finishing, and draws the gastric juice determining pepsin activity, observes mucosal lesion point length, presses the damage index of every gastric mucosa of table 1 evaluation, and this evaluation criteria adopts Fringes B method.
Table 1
Each is organized experimental result and sees Table 2.
Table 2
The result shows, Ect and Ect-OH have significant therapeutical effect to the gastritis that sodium taurocholate causes, and are better than ranitidine, SANJIU WEITAI and motilium etc., the medicine for the treatment of gastritis commonly used.
Embodiment 2 (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acids and Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is to the therapeutical effect of gastritis
After the rat fasting 48 hours, operate under anesthesia, aseptic condition, the Banded Rats pylorus is closed the abdominal cavity.Get 30 of rats after the modeling success, be divided at random 6 groups, one group of gavage gives tap water, one group of gavage gives 1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic (Ect, 8mg/kg), one group of gavage gives Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic (Ect-OH, 8mg/kg), one group of gavage gives motilium (10mg/kg), and one group of gavage gives famotidine (20mg/kg), one group of gavage gives ranitidine (150mg/kg) administration every day 2 times, successive administration 5 days.
Administration is cutd open inspection with sacrifice of animal after finishing, and draws the gastric juice determining pepsin activity, observes mucosal lesion point length, presses the damage index of every gastric mucosa of table 1 evaluation, and this evaluation criteria adopts Fringes B method.
The result shows, Ect and Ect-OH cause rat gastritis model therapeutic effect to pylorus ligation and significantly be better than motilium, famotidine and ranitidine.
Embodiment 3 (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acids and Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is to the therapeutical effect of gastric ulcer
The rat fasting be can't help water 24 hours, and then gavage gives indomethacin (30mg/kg).After the modeling success, get 30 of rats, be divided at random 6 groups, one group of gavage gives tap water, and one group of gavage gives Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic (Ect, 2mg/kg), one group of gavage gives 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic (Ect-OH, 2mg/kg), one group of gavage gives bismuth aluminate (7mg/kg), one group of gavage gives omeprazole (0.8mg/kg), and one group of gavage gives ranitidine (150mg/kg) administration every day 2 times, successive administration 5 days.
After administration finishes, put to death rat.Open the abdominal cavity and cut off ventral aorta, take out fast gastric tissue, along greater gastric curvature stomach is cut off, with 4 ℃ normal saline rinsing.
The body of stomach of processing is launched gently, be covered on the body of stomach with cellophane, mark in ulcer spot with marking pen, then cellophane is covered and calculate ulcer area on the graph paper.The results are shown in Table 3.
Table 3
As known from Table 3, Ect and Ect-OH are to the medicine that is better than the treatment gastric ulcers commonly used such as bismuth aluminate, omeprazole and ranitidine evident in efficacy of gastric ulcer.
Embodiment 4 (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acids and Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is to the therapeutical effect of duodenal ulcer
The Wistar rat, male, weight 180-220g, fasting, freely drank water 24 hours after, subcutaneous 10% cysteamine, the 400mg/kg of giving.After the modeling success, get 40 of rats, be divided at random 4 groups, one group of gavage gives tap water, and one group of gavage gives Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic (Ect, 2mg/kg), one group of gavage gives Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic (Ect-OH, 2mg/kg), one group of gavage gives omeprazole (0.8mg/kg), administration every day 2 times, successive administration 5 days.
Administration is opened the abdominal cavity after finishing, and takes out the harmonization of the stomach duodenum, fixes 15 minutes in 1% formaldehyde, cuts off along greater gastric curvature and mesoduodenum offside, and the flushing content is tiled on the glass plate, observes the duodenal injury situation under the anatomic microscope.The index method evaluation of mucosa injury degree, adopt people's method and the slightly improvement such as Moraes: 0 to be divided into mucosa normal, and 1 is divided into mucosa hyperemia, edema, and 2 are divided into mucosal erosion, hemorrhage, and 3 are divided into fester, and 4 are divided into dark ulcer, and 5 are divided into perforated ulcer.The results are shown in Table 4.
Table 4
By as seen from Table 4, Ect and Ect-OH are better than the common drug omeprazole to the curative effect of duodenal ulcer.
The preparation of embodiment 5 (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acid tablets
Fill a prescription as follows:
The (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acid of prescription is crossed 150 μ m sieve, and it is for subsequent use that adjuvant is crossed 180 μ m sieve; Now (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acid is mixed with microcrystalline Cellulose, successively mix with lactose, carboxymethyl starch sodium, polyvinylpyrrolidone, magnesium stearate, tabletting gets final product behind the mix homogeneously.
Embodiment 6 Isosorbide-5-Nitraes, the preparation of 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic tablet
With the Isosorbide-5-Nitrae of prescription, it is for subsequent use that 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is crossed 180 μ m sieve; With the Isosorbide-5-Nitrae that sieves, 5, press large stretch of behind 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic and microcrystalline Cellulose, carboxymethyl starch sodium and the polyvinylpyrrolidone mixing, to obtain less granule behind large stretch of crushing and pelletizing, add sodium lauryl sulphate and differential silica gel, the mixing tabletting gets final product.
Claims (6)
1. tetrahydropyrimidine and derivant thereof the application in the medicine of preparation treatment gastritis, gastric ulcer, duodenal ulcer, it is characterized in that: described tetrahydropyrimidine is (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acid; The derivant of described tetrahydropyrimidine is Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic.
2. application according to claim 1 is characterized in that: during application, the tetrahydropyrimidine or derivatives thereof is prepared into oral formulations.
3. application according to claim 1 and 2 is characterized in that: the dosage of described tetrahydropyrimidine or derivatives thereof is 0.04mg/kg-100mg/kg.
4. application according to claim 1 and 2 is characterized in that: the dosage of described tetrahydropyrimidine or derivatives thereof is 4.0mg/kg-60mg/kg.
5. application according to claim 1 and 2 is characterized in that: the dosage of described tetrahydropyrimidine or derivatives thereof is 5mg/kg-10mg/kg.
6. medicine for the treatment of gastritis, gastric ulcer, duodenal ulcer is characterized in that: be comprised of tetrahydropyrimidine or derivatives thereof and medically acceptable pharmaceutic adjuvant, described tetrahydropyrimidine is (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acid; The derivant of described tetrahydropyrimidine is Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic;
Described medically acceptable pharmaceutic adjuvant is: microcrystalline Cellulose, lactose, Sodium Hydroxymethyl Stalcs, magnesium stearate and polyvinylpyrrolidone, wherein, the weight ratio of tetrahydropyrimidine or derivatives thereof and microcrystalline Cellulose, lactose, Sodium Hydroxymethyl Stalcs, magnesium stearate and polyvinylpyrrolidone is 10:50:100:37.5:12:30;
Or: described medically acceptable pharmaceutic adjuvant is: microcrystalline Cellulose, Sodium Hydroxymethyl Stalcs, differential silica gel, polyvinylpyrrolidone and sodium lauryl sulphate, wherein, the weight ratio of tetrahydropyrimidine or derivatives thereof and microcrystalline Cellulose, Sodium Hydroxymethyl Stalcs, differential silica gel, polyvinylpyrrolidone and sodium lauryl sulphate is 10:10:12:20:30:5.
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| WO2018002018A1 (en) * | 2016-06-29 | 2018-01-04 | Bitop Ag | Composition for controlling gastroesophageal reflux diseases |
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| CN112220790A (en) * | 2020-12-17 | 2021-01-15 | 清华大学 | Application of tetrahydropyrimidine and derivatives thereof in preventing and/or treating intestinal diseases |
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| CN102210685A (en) * | 2011-04-29 | 2011-10-12 | 济南环肽医药科技有限公司 | Application of ectoine and derivatives thereof in preparing medicament for preventing and treating digestive tract diseases caused by chemotherapy medicaments |
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| CN102210685A (en) * | 2011-04-29 | 2011-10-12 | 济南环肽医药科技有限公司 | Application of ectoine and derivatives thereof in preparing medicament for preventing and treating digestive tract diseases caused by chemotherapy medicaments |
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| 朱道辰等.相容性溶质四氢嘧啶及其羟基化衍生物的研究进展.《中国生物工程杂志》.2011,第31卷(第2期),95-102. * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018002018A1 (en) * | 2016-06-29 | 2018-01-04 | Bitop Ag | Composition for controlling gastroesophageal reflux diseases |
| CN109328063A (en) * | 2016-06-29 | 2019-02-12 | 比托普股份公司 | For controlling the composition of gastroesophageal reflux disease |
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