CN110833551B - Use of pyrazolopyrimidine derivatives for the treatment of acute pancreatitis - Google Patents
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- CN110833551B CN110833551B CN201810927819.0A CN201810927819A CN110833551B CN 110833551 B CN110833551 B CN 110833551B CN 201810927819 A CN201810927819 A CN 201810927819A CN 110833551 B CN110833551 B CN 110833551B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
Abstract
The invention relates to the technical field of medicines, in particular to application of pyrazolopyrimidine derivative in treatment of acute pancreatitis. The pyrazolopyrimidine derivative has a good treatment effect on acute pancreatitis, can obviously improve the edema degree, inflammatory cell infiltration, cell necrosis and other symptoms of pancreatic tissues, and obviously reduce ET and TXA in the pancreatic tissues 2 The therapeutic effect of the recombinant human interleukin-10 is equal to or even better than that of the recombinant human interleukin-10.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of pyrazolopyrimidine derivative in treatment of acute pancreatitis.
Background
Acute Pancreatitis (AP) is one of the clinically common Acute abdominal symptoms, which is caused by excessive activation of pancreatin in pancreatic tissues due to various causes, thereby causing a series of inflammatory reactions such as self digestion, hemorrhage, edema, necrosis of the pancreatic tissues and the like, with or without function changes of multiple organs. The disease incidence rate is about 13-45/100000 in China, and if timely and effective treatment measures are not taken for 20% of patients, the disease condition can be further developed into Severe Acute Pancreatitis (SAP), the SAP is complex in disease condition, dangerous in disease course, large in treatment difficulty and high in death rate of 30%.
The AP Atlanta diagnostic standard in 2012 further standardizes the clinical classification of the AP on the original basis, and experts and scholars consistently classify the AP into three categories, namely: three major categories, namely m ild acueperatitis (MAP), moderate Severe Acute Pancreatitis (MSAP) and Severe Acute Pancreatitis (SAP), make the classification of AP more accurate, and have great guiding significance for clinical staging, treatment and prognosis improvement.
Pyrazolopyrimidine derivative (formula I) is a small molecule inhibitor targeting FLT3 kinase, is a novel compound independently developed by the applicant, and the compound patent is already granted in China, america, japan and other areas.
Only the pyrazolopyrimidine derivative is reported to treat acute myelogenous leukemia and psoriasis at present, and the application of the pyrazolopyrimidine derivative in treating acute pancreatitis is not seen.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides application of pyrazolopyrimidine derivative in treating acute pancreatitis.
The purpose of the invention can be realized by the following technical scheme:
application of pyrazolopyrimidine derivative shown as formula I or pharmaceutically acceptable salt and hydrate thereof in preparation of medicine for treating acute pancreatitis
Preferably, the acute pancreatitis is manifested by an elevated level of endothelin in pancreatic tissue.
Preferably, the acute pancreatitis is manifested by thromboxane A in pancreatic tissue 2 The level increased.
Preferably, the acute pancreatitis is manifested by edema of pancreatic tissue.
Preferably, the acute pancreatitis is manifested by infiltration of inflammatory cells by pancreatic tissue.
Preferably, said acute pancreatitis is manifested by the phenomenon of cellular necrosis of the pancreatic tissue.
Preferably, the acute pancreatitis comprises mild acute pancreatitis, moderate severe acute pancreatitis and severe acute pancreatitis.
Preferably, the pharmaceutically acceptable salts include hydrochloride, sulfate, mesylate, phosphate.
The invention also provides application of the pharmaceutical composition in preparing a medicine for treating acute pancreatitis, which is characterized in that the pharmaceutical composition comprises pyrazolopyrimidine derivative shown as formula I or pharmaceutically acceptable salt or hydrate thereof as an active ingredient and a pharmaceutically acceptable excipient.
Preferably, the pharmaceutical composition is an injection preparation, an oral preparation, an external preparation, a sustained release preparation, or a controlled release preparation.
Preferably, the oral preparation comprises tablets, granules and capsules.
Preferably, the pharmaceutical composition is a controlled release formulation, a sustained release formulation, an immediate release formulation.
Endothelin (ET) is one of the most potent vasoactive substances known at present, and its content in vascular smooth muscle cells is high, with a strong and long-lasting vasoconstrictive action after activation. The ET can participate in the whole process of generation and development of AP, the action mechanism of the ET can be that the ET acts on vascular smooth muscle, the permeability of pancreatic capillary vessels is increased, leakage is increased, blood flow is reduced, receptors are activated at the same time, calcium concentration overload occurs in cells through signal conduction, formed calcium salt can block microcirculation to a certain extent, pancreatic capillary blood vessels leak, blood concentration and viscosity increase in pancreas are caused to a certain extent, blood platelets aggregate to form tiny thrombus, the hemodynamics in pancreas is changed, microcirculation stasis is caused, pancreatic cell ischemia and hypoxia are caused, AP is induced or the original condition is aggravated, and AP is converted into SAP.
Thrombin A 2 (TXA 2 ) Is an endogenous inflammatory factorThe internal source is mainly platelets (AP is synthesized by pancreatic acinar cells). The body activates TXA after being stimulated by outside or inside 2 The combination of its activity and corresponding substances on the vascular endothelium exerts a strong vasoconstriction effect, and also has a platelet aggregation promoting effect, which can lead to pancreatic tissue ischemia, edema and even necrosis, and the AP disease progresses to SAP.
The pyrazolopyrimidine derivative is originally an FLT3 inhibitor, and researches show that the pyrazolopyrimidine derivative has a good treatment effect on acute pancreatitis, can remarkably improve the edema degree, inflammatory cell infiltration, cell necrosis and other symptoms of pancreatic tissues, and remarkably reduces ET and TXA in the pancreatic tissues 2 The therapeutic effect of the recombinant human interleukin-10 is equal to or even better than that of the recombinant human interleukin-10.
Compared with the prior art, the method has the following advantages:
the pyrazolopyrimidine derivative provided by the invention is a novel drug for treating acute pancreatitis, not only expands the selectivity of the existing drug for treating acute pancreatitis, provides more drug choices for the effective treatment of acute pancreatitis, but also further expands the application range of the pyrazolopyrimidine derivative as an FLT3 inhibitor.
Drawings
FIG. 1 is a graph of HE staining of rat pancreatic tissue at 12h in the blank control group.
FIG. 2 is a graph showing HE staining of rat pancreatic tissue at 12h in the model group.
FIG. 3 is a graph of HE staining of rat pancreatic tissue at 12h in the positive drug group.
FIG. 4 is a graph of HE staining of rat pancreatic tissue at 12h in the pyrazolopyrimidine derivative group.
Fig. 5 is the acute pancreatitis tissue injury scoring criteria.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Example 1 Effect on rats with severe acute pancreatitis
1. Experimental animals: clean SD rat, male, with a body mass of 200-250 g, purchased from Beijing Wintolite laboratory animals technologies, inc.
2. Experimental materials: pyrazolopyrimidine derivative was synthesized by the inventors. Pyrazolopyrimidine derivative was synthesized by the inventors. Mixing castor oil with ethanol 1:1, passing through a sterile filter membrane of 0.22 mu m to obtain an ELE solution, weighing a certain mass of pyrazolopyrimidine derivative powder, dissolving the powder by using the ELE solution, adding a certain volume of sterilized water after the powder is completely dissolved, and uniformly mixing for later use. The volume ratio of the ELE solution to the sterile water is 1:3. l-arginine (sigma), interleukin 10 (rhIL-10, protech).
3. Animal grouping: rats were randomly divided into a blank control group, a model group, a positive drug group, and a pyrazolopyrimidine derivative drug group (hereinafter referred to as a test drug group), and 30 rats were administered to each group. Each large group was then randomly divided into three subgroups by time limit, 3h,6h,12h groups, 10 each.
4. Preparing an animal model: except for the blank control group, rats (Li Yikui, methodology of pharmacological experiments of Chinese medicine, shanghai science Press, second edition) were fasted and freely drunk water for 12h before molding, and 6% L-arginine (L-arginine) solution was slowly injected intraperitoneally at a dose of 150mg/10g, with the injection frequency: 1 time per hour for a total of 3 times. The successful modeling inspection standard is that the pancreatic tissue is observed by naked eyes to show edema and hemorrhage, part of the tissue has necrosis, the calcification spots scattered in the pancreatic tissue can be seen, the abdominal cavity is dilated, a large amount of bloody ascites can be seen after the abdominal opening, the capillary vessels of the intestinal wall are obviously dilated, the pancreatic lobular edema can be seen under an optical microscope, a large amount of inflammatory cells are infiltrated, the range of the affected pancreatic cells is wide, and a plurality of necrotic pancreatic cells can be seen under the visual field.
5. The administration scheme is as follows: (1) normal control group, model group: 3 days before molding, 10mL/kg of mixed solution of the ELE solution and the distilled water 1:3 with volume ratio is administered for continuous 3 days by intragastric administration. The model group then injected the L-arginine (L-arginin) solution into the peritoneal cavity as per "step 4".
(2) A positive drug group: 1h before molding, the diluted human recombinant interleukin 10 is injected into the abdominal cavity according to the dose of 10000 IU/mouse. Then, according to "step 4", L-arginine (L-arginine) solution is injected into the abdominal cavity.
(3) Test drug groups: 3 days before molding, the rats were gavaged with 12mg/kg/d (10 mL/kg,1.2 mg/mL) for 3 consecutive days. Then, according to "step 4", L-arginine (L-arginine) solution is injected into the abdominal cavity.
6. Collecting a specimen: the time was counted by the last intraperitoneal injection of 6% L-arginine (L-arginine) solution into the rat's abdominal cavity. At three time points of 3h,6h and 12h, the rats are killed in batches, the abdominal cavity is fully opened, the visual field is exposed, the position of the pancreas is found, the pancreas tissues are quickly separated and cut under the aseptic condition, and part of the tissues are put into paraformaldehyde solution with the volume fraction of 4 percent for preparing pathological sections and observing under an optical microscope. The remaining part was put into an EP tube containing 1.5ml of physiological saline in advance, sufficiently crushed and ground, and then centrifuged at 3000 rpm for 10 minutes in a low-temperature centrifuge to obtain a supernatant. Subpackaging the supernatant, and freezing at-20 deg.C for detecting ET, NO and TXA 2 、PGI 2 And (4) content.
7. Detecting the index
(1) And (3) detecting the pathological histology: at the end of the experiment, rat pancreatic tissue was removed, routinely HE stained, 10 fields of view were observed per section, and histological scoring was performed with reference to the severity of tissue edema, inflammation, bleeding and cell necrosis according to Rongione et al (see figure 5 of the specification).
(2) Determination of ET and TXA in rat pancreatic tissue by enzyme-linked immunosorbent assay (ELISA) 2 The content of (b). The operation is referred to the reagent instructions.
8. The statistical method comprises the following steps: data were processed using SPSS17.0, the metrology data was expressed as (mean ± standard deviation), variance Ji Zeshi was analyzed using variance, variance was analyzed using rank-sum test if variance was irregular, and P <0.05 was statistically significant for the differences.
9. Results of the experiment
(1) Histopathological examination results
As shown in figure 1, the sections of the blank control group can be seen to have clear pancreatic lobule structures, complete acinar structures and no obvious pathological changes, and only individual sections can be seen to have small amount of inflammatory cell infiltration, mild edema among lobules and limited range.
As shown in FIG. 2, the lesions of the model group are obvious, and it can be seen that the pancreatic lobular space is widened, the edema of the pancreatic lobules and the lobular space is obvious, a large amount of neutrophil infiltration is carried out around the glandular duct and in the acinar cells, the focal vacuole degeneration of the acinar cells in the lobules, and the punctate necrosis of part of the acinar cells appears. The slice with the most obvious change is a 12h node slice, and neutrophils are distributed and infiltrated in a large area under a visible field; many scattered bleeding and cell necrosis, incomplete structure of lobule, and different degrees.
As shown in figure 3, under the light microscope, the enlargement of the pancreatic lobular space, edema of the pancreatic lobules and the lobular space, the wide infiltration of the neutrophil at the periphery of the glandular duct and in the acinar cells, the focal vacuolar degeneration of the acinar cells in the lobules, and the punctate necrosis of part of the acinar cells can be seen, but the pathological change of the acinar cells is lighter than that of the model group.
As shown in FIG. 4, the test drug group showed similar changes in pancreas section as the model group and the positive drug group, but in the lesion coverage, the degree of pancreas shrinkage She Shuizhong, inflammatory cell infiltration, and the number of cell necrosis were less than those of the two groups, and the lesion degree was relatively reduced.
(2) Comparison of pancreatic histopathological scoring results at different time points
TABLE 1 comparison of pancreatic histopathology score results at different time points
P <0.05 compared to placebo; compared with the model group, the Delta P is less than 0.05.
As can be seen from Table 1, compared with the model group, the tested drug group can significantly reduce pathological scores (P < 0.05) of rat pancreatic tissues for 3h,6h and 12h, and the effect is equivalent to or even superior to that of the positive drug group.
(3) Pancreatic tissue ET content level changes
TABLE 2 pancreatic tissue ET content variation at different time points
| Group of | 3h | 6h | 12h |
| Blank control group | 35.08±0.82 | 34.15±0.64 | 32.12±1.63 |
| Model set | 88.26±1.72* | 148.02±2.08* | 165.31±3.52* |
| Positive drug group | 80.15±1.24△ | 124.77±2.52△ | 142.25±2.12△ |
| Test drug group | 86.37±2.20 | 132.85±1.82△ | 140.73±2.36△ |
P <0.05 compared to placebo; compared with the model group, the Delta P is less than 0.05.
As shown in Table 2, compared with the model group, the tested drug group can obviously reduce the ET content in the pancreatic tissues of rats at 6h and 12h (P is less than 0.05), and the effect is equal to or even superior to that of the positive drug group. The test showed only a decreasing trend at 3h, and was not statistically significant.
(4) Pancreatic tissue TXA 2 Change in content level
TABLE 3 pancreatic tissue TXA at different time points 2 Content change
| Group of | 3h | 6h | 12h |
| Blank control group | 280.46±18.35 | 282.95±20.14 | 281.74±15.63 |
| Model set | 475.28±61.32* | 688.30±65.41* | 912.23±72.63* |
| Positive drug group | 314.76±29.36△ | 463.71±35.94△ | 662.45±58.31△ |
| Test drug group | 322.58±25.72△ | 428.59±42.15△ | 548.26±48.92△ |
P <0.05 compared to control blank; compared with the model group, the Delta P is less than 0.05.
As shown in Table 3, the tested drug groups significantly reduced TXA at 6h and 12h in rat pancreatic tissue compared with the model group 2 (P) content of<0.05 The effect is equal to or even superior to that of the positive medicine group.
Conclusion
The pyrazolopyrimidine derivative has a good treatment effect on acute pancreatitis, can obviously improve the edema degree, inflammatory cell infiltration, cell necrosis and other symptoms of pancreatic tissues, and obviously reduce ET and TXA in the pancreatic tissues 2 The therapeutic effect of the recombinant human interleukin-10 is equal to or even better than that of the recombinant human interleukin-10.
Although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that modifications and improvements can be made thereto without departing from the scope of the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (12)
1. Application of pyrazolopyrimidine derivative shown as formula I or pharmaceutically acceptable salt thereof in preparation of medicine for treating acute pancreatitis
Formula I.
2. The use according to claim 1, characterized in that said acute pancreatitis is manifested by an increase in the level of endothelin in the pancreatic tissues.
3. The use according to claim 1, characterized in that said acute pancreatitis is manifested by an increase in the level of thromboxane A2 in the pancreatic tissues.
4. The use according to claim 1, wherein the acute pancreatitis is manifested by edema in the pancreatic tissue.
5. The use according to claim 1, characterized in that said acute pancreatitis is manifested by infiltration of inflammatory cells in the pancreatic tissues.
6. Use according to claim 1, characterized in that said acute pancreatitis is manifested by the phenomenon of cellular necrosis of the pancreatic tissue.
7. The use according to claim 1, wherein the acute pancreatitis includes mild acute pancreatitis, moderate severe acute pancreatitis, severe acute pancreatitis.
8. Use according to claim 1, wherein the pharmaceutically acceptable salts comprise hydrochloride, sulfate, mesylate, phosphate.
9. Use of a pharmaceutical composition for the manufacture of a medicament for the treatment of acute pancreatitis, wherein the pharmaceutical composition comprises a pyrazolopyrimidine derivative represented by formula i, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, as an active ingredient, and a pharmaceutically acceptable excipient.
10. The use according to claim 9, wherein the pharmaceutical composition is an oral formulation.
11. The use according to claim 10, wherein the oral formulation comprises tablets, granules, capsules.
12. The use according to claim 9, wherein the pharmaceutical composition is a controlled release formulation, a sustained release formulation, an immediate release formulation.
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| WO2011106168A1 (en) * | 2010-02-24 | 2011-09-01 | Dcam Pharma Inc | Purine compounds for treating autoimmune and demyelinating diseases |
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| ZA200501536B (en) * | 2002-08-14 | 2006-10-25 | Vertex Pharma | Protein kinase inhibitors and uses thereof |
| JP4741948B2 (en) * | 2002-08-14 | 2011-08-10 | バーテックス ファーマシューティカルズ インコーポレイテッド | Protein kinase inhibitors and their use |
| IL161903A0 (en) * | 2003-07-17 | 2005-11-20 | Gamida Cell Ltd | Ex vivo progenitor and stem cell expansion for usein the treatment of disease of endodermally- deri ved organs |
| US20080234262A1 (en) * | 2007-03-21 | 2008-09-25 | Wyeth | Pyrazolopyrimidine analogs and their use as mtor kinase and pi3 kinase inhibitors |
| CN107001283B (en) * | 2014-07-31 | 2021-05-25 | 国家健康与医学研究院 | FLT3 receptor antagonists |
| CN105769851A (en) * | 2016-03-11 | 2016-07-20 | 张雪燕 | Medicinal composition for treating severe acute pancreatitis and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102018689A (en) * | 2009-09-16 | 2011-04-20 | 北京大学 | New application of curcumin |
| WO2011106168A1 (en) * | 2010-02-24 | 2011-09-01 | Dcam Pharma Inc | Purine compounds for treating autoimmune and demyelinating diseases |
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| Expression of Reg family proteins in embryonic stem cells and its modulation by Wnt/beta-catenin signaling;Jing D,et al;《Stem Cells Dev》;第19卷(第09期);第1307-期19页 * |
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