CN116172994A - Application of anthraquinone derivative in preparation of anti-pancreatitis medicine - Google Patents
Application of anthraquinone derivative in preparation of anti-pancreatitis medicine Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to application of anthraquinone derivatives in preparation of anti-pancreatitis medicines. In order to develop new drugs targeting pancreatic and lung tissues, acute severe pancreatitis and its lung injury were treated. The invention provides application of 2,4, 5-triiodo-1, 3, 8-trihydroxy-6-methyl-9, 10-anthraquinone or salt thereof in preparing medicines for treating or preventing pancreatitis, and compared with parent nucleus emodin, the compound disclosed by the invention can obviously increase the activity of the compound in treating acute and heavy pancreatitis and related lung injury, is hopeful to become an innovative medicine for treating pancreatitis with high efficiency and low toxicity, and has wide industrialization prospect.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of anthraquinone derivatives in preparation of anti-pancreatitis medicines.
Background
Severe Acute Pancreatitis (SAP) belongs to a special type of acute pancreatitis, and is a clinically common acute abdomen with rapid onset, rapid development, complex and changeable disease conditions, more complications and high death rate. Besides the characteristics of clinical manifestation and biochemical change of acute pancreatitis, SAP is accompanied with continuous organ failure for more than 48 hours, and respiratory dysfunction can not recover by itself, and can involve one or more viscera to cause the characteristics of multi-organ dysfunction syndrome, the death rate is as high as 20% -30%, and the life and health are seriously threatened. Because of the complex pathogenesis of multiple factors, the treatment methods are relatively more, but the curative effect is not satisfactory. Therefore, the development of medicines capable of curing severe acute pancreatitis and related lung injuries is important for preventing and treating severe acute pancreatitis.
The emodin is one of the effective components of radix et rhizoma Rhei, and has chemical name of 1,3, 8-trihydroxy-6-methylanthraquinone (1, 3, 8-trihydroxy-6-methylanthraquinone) and molecular formula of C 15 H 10 O 5 . The existing evidence proves that the emodin can remarkably reduce the pancreatic and lung tissue injury of mice with severe pancreatitis, reduce the level of serum amylase and lipase, and is an effective natural lead compound for treating severe acute pancreatitis. However, due to their limited therapeutic effect, lack of pancreatic and lung tissue targeting has greatly limited their clinical development potential. Therefore, research and development of emodin derivatives with remarkable anti-severe acute pancreatitis effects and with remarkable pancreatic and lung tissue targeting are necessary.
Disclosure of Invention
The invention aims to provide application of a 2,4, 5-triiodo-1, 3, 8-trihydroxy-6-methyl-9, 10-anthraquinone derivative (a compound shown as a formula I and defined as a compound 1) in preparing medicines for preventing and/or treating pancreatitis, and particularly, the compound 1 is found to have good treatment or prevention effects on severe acute pancreatitis.
The invention provides application of a compound shown in a formula I or a salt thereof in preparing a medicine for preventing and/or treating pancreatitis:
The invention also provides application of the compound shown in the formula I or the salt thereof in preparing a medicament for preventing and/or treating lung injury caused by pancreatitis;
Further, the pancreatitis is severe acute pancreatitis.
Further, the drug is targeted to pancreatic and/or lung tissue.
Further, the medicament reduces necrosis of acinar cells in pancreatitis.
Further, the medicament reduces pancreatic tissue damage in acute severe pancreatitis.
Further, the medicament reduces mortality from acute severe pancreatitis.
Further, the medicament reduces pathological damage to pancreatic tissue.
Further, the medicament reduces pancreatic enzyme, pancreatic amylase secretion.
Further, the medicament reduces at least one of lung tissue injury, lung tissue edema or necrosis, and inflammatory infiltration caused by acute severe pancreatitis.
Further, the medicine is a preparation prepared by taking a compound shown in a formula I or salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
Further, the preparation is a slow release agent or a controlled release agent.
Further, the auxiliary material is at least one of glyceryl behenate, hypromellose and magnesium stearate.
Further, the preparation is an oral preparation, a nasal mucosa administration preparation, an oral mucosa administration preparation or an injection preparation.
Further, the preparation is tablets, granules, capsules, oral liquid, nasal spray or injection.
Further, the preparation is effervescent tablets or sublingual tablets.
Preferably, the preparation is a sustained release agent, and the oral administration dosage is 0.4-4.1mg/kg (weight of human body) per time, 1-3 times daily.
More preferably, the formulation is a sustained release formulation, and the oral administration dose is 0.8mg/kg (weight of human body) per time, 1 time a day.
In a preferred embodiment of the present invention, the effective dose of the compound of formula I or a salt thereof may vary depending on the mode of administration, age and weight of the patient, severity of the illness and other relevant factors, and the recommended dose for oral administration is 100-1000 mg/time, 1-3 times daily; the recommended dosage for injection administration is 15-45 mg/time, 1 time a day; the spray is administered by inhalation at a recommended dose of 500-1000 mg per time, 1-3 times daily.
In the preferred technical scheme of the invention, the dosage of the compound 1 taken as the bulk drug by the mice in the embodiment is 50-100 mg/kg (weight of the mice), and the dosage converted into the adult dosage is 4.1-8.1mg/kg (weight of human body)/time, 1-2 times a day. The effect is preferably 50 mg/kg (weight of mice) of the drug substance administered to mice, and the dose converted into an adult dose is 4.1mg/kg (weight of human body) per time, 2 times a day.
In the preferred technical scheme of the invention, the slow release agent for the mice is 5-50 mg/kg (weight of the mice) and converted into the dosage for adults, namely 0.4-4.1mg/kg (weight of human body) for 1 time per day. The effect is preferably that the sustained release agent is administered to the mice at a dose of 10 mg/kg (weight of the mice), and the dose is converted into an adult dose of 0.8mg/kg (weight of the human body) 1 time a day.
In a preferred embodiment of the invention, the medicament contains one or more inert, non-toxic, pharmacologically suitable excipients.
Preferably, the excipient is selected from at least one of a carrier (e.g. microcrystalline cellulose, lactose, mannitol, starch), a solvent (e.g. liquid polyethylene glycol), an emulsifier, a dispersant, a humectant (e.g. sodium lauryl sulfate, polyoxysorbitan oleate, propylene glycol), a binder (e.g. polyvinylpyrrolidone), a stabilizer (e.g. an antioxidant such as ascorbic acid), a colorant (e.g. an inorganic pigment such as iron oxide), a perfume.
The beneficial effects are that: the invention provides application of anthraquinone derivative 2,4, 5-triiodo-1, 3, 8-trihydroxy-6-methyl-9, 10-anthraquinone or salt thereof in preparing medicines for preventing and/or treating lung injury caused by pancreatitis. Animal experiments show that the compound 1 shown in the formula I has excellent activity of resisting severe acute pancreatitis in vitro and in vivo, can obviously reduce death rate, reduce acinar cell necrosis and lung injury causing death main cause, reduce amylase and trypsin level, has activity obviously higher than that of parent nucleus emodin, and has safety higher than that of emodin. The application of the invention can provide a new medicine source for treating pancreatitis, and has potential significant economic and social benefits. The preparation prepared by the compound 1 has the application prospect of being used as a medicine for treating pancreatitis, is hopeful to become an innovative medicine for treating pancreatitis with high efficiency and low toxicity, and has wide industrialization prospect.
Drawings
FIG. 1 shows the maximum tolerating dose (A) of the compound of test example 2 to acinar cells and the lethal dose (B) of mice;
FIG. 2 shows the effect of Compound 1 of test example 3 on Sodium Taurocholate (STC) induced severe acute pancreatitis model pancreas (A), lung injury (B), and serum amylase (C), trypsin (D). L: low dose (25 mg/kg) of compound 1; m: medium dose (50 mg/kg) of compound 1; h: high dose (150 mg/kg) of Compound 1.
Detailed Description
After halogenation of the compound, because of the variation of the electronic domain, the property of difference is often expressed, and in combination with the previous research foundation and the latest drug design concept of the applicant, the applicant designs a series of halogenated emodin derivatives, and as shown below, the applicant discovers that the synthesized triiodo-substituted emodin derivative (2, 4, 5-triiodo-1, 3, 8-trihydroxy-6-methyl-9, 10-anthraquinone, compound 1) shows remarkable anti-severe acute pancreatitis and pancreatic and lung tissue targeting, has more efficient in vivo and in vitro anti-severe acute pancreatitis activity compared with the parent emodin, has pancreatic and lung tissue targeting which the parent nucleus does not have, and is a emodin derivative with high safety.
The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1 preparation of Compounds 1, 2, 3
1) Preparation of Compound 1 (2, 4, 5-triiodo-1, 3, 8-trihydroxy-6-methyl-9, 10-anthraquinone)
Taking 1.0 g (3.60 mmol) of emodin, 34.0 g iodine simple substance and 2.24 g N-iodosuccinimide (NIS), using tetrahydrofuran as a solution, gradually adding sodium bicarbonate for catalytic reaction after ice bath for 5-10 minutes, then reacting at room temperature for about 6-18 hours, extracting the reaction solution by using dichloromethane, collecting an organic phase, washing for 3-4 times by using purified water, concentrating under reduced pressure, and adding absolute ethyl alcohol to obtain a red precipitate product. R is R f 0.2 (dichloromethane: methanol: glacial acetic acid=9:1:0.025).
The nuclear magnetic resonance detection data are as follows: 1 H NMR (400 MHz, DMSO) δ 13.70 (s, 1H), 12.77 (s, 1H), 7.55 (s, 1H), 2.51 (s, 3H).
13 C NMR (100 MHz, DMSO) δ 178.62 (s), 163.84 (s), 163.89 (s), 159.41 (s), 150.43 (s), 133.49 (s), 132.13 (s), 120.24 (s), 112.03 (s), 106.90 (s), 105.75 (s), 101.02 (s), 64.53 (s), 29.00 (s), 23.32 (s). HRMS (ESI−) Calc. for C 15 H 6 I 3 O 5 : 646.7428 [M−H] − ; Found 646.7357 [M−H] − 。
2) Preparation of Compound 2 (2, 4-diiodo-1, 3, 8-trihydroxy-6-methyl-9, 10-anthraquinone)
Taking 4.0 g emodin, taking tetrahydrofuran and water as solvents, adding 58.2 g iodine simple substance under ice bath condition, then slowly adding sodium bicarbonate for catalysis, reacting for 1.5-6 hours, extracting twice with dichloromethane, collecting an organic phase, washing with water, concentrating, adding ethanol, precipitating red precipitate to obtain a crude product, and using petroleum ether: dichloromethane = 2: the eluent of 1 is passed through a silica gel column to obtain a red solid product (5.2 g,68 percent) R f 0.3 (dichloromethane: methanol: glacial acetic acid=9:1:0.025).
The nuclear magnetic resonance detection data are as follows: 1 H NMR (400 MHz, DMSO)：δ13.86 (d,J=9.0 Hz, 1H), 12.38(s, 1H), 11.58(s, 1H),7.42 (s, 1H),7.07 (s, 1H), 2.39 (s, 3H).
13 C NMR (100 MHz, DMSO) δ 187.54 (s), 181.03 (s), 164.99 (s), 163.76 (s), 160.63 (s), 148.45 (s), 133.77 (s), 133.21 (s), 123.30 (s), 120.64 (s), 112.75 (s), 110.12 (s), 83.81 (s), 66.99 (s), 21.62 (s), HRMS (ESI+) Calc. for C 15 H 8 I 2 O 5 : 522.8539 [M+H] + ; Found 522.8532 [M+H] + 。
3) Preparation of Compound 3 (2-iodo-1, 3, 8-trihydroxy-6-methyl-9, 10-anthraquinone)
Taking 0.56 g emodin, taking NIS as an iodinating agent and tetrahydrofuran as a solvent, stirring and reacting at normal temperature for 1-12 h, adding water for quenching, concentrating, and using petroleum ether: dichloromethane = 3: separating and extracting the eluent of 1 by a silica gel column to obtain a yellow solid product, R f 0.8 (dichloromethane: methanol: glacial acetic acid=9:1:0.025).
The nuclear magnetic resonance detection data are as follows: 1 H NMR (400 MHz, DMSO) δ: 13.10 (s, 1H), 12.27 (s, 1H), 11.87 (s, 1H), 7.50 (s, 1H), 7.23 (s, 1H), 7.19 (s, 1H), 2.42 (s, 3H).
13 C NMR (100 MHz, DMSO) δ: 189.41 (s), 181.27 (s), 165.23（s），163.45 (s), 161.38 (s), 148.53 (s), 134.18 (s), 132.78 (s), 124.25 (s), 120.54 (s), 113.15 (s), 108.46 (s), 106.83 (s)，83.12（s），21.53（s）. HRMS (ESI+) Calc. for C 15 H 9 IO 5 : 396.9573 [M+H] + ; Found 396.9576 [M+H] + 。
test example 1 in vitro anti-severe acute pancreatitis Activity of Compound 1 prepared in example 1 was examined
Taking pancreatic tissues of 8-week-old C57BL/6 mice, flushing the pancreatic whole tissues with HEPES buffer solution, injecting IV type collagenase, incubating in 37 ℃ water bath for 19 minutes, repeatedly blowing and beating dispersed acinar cells by a 1 mL pipette gun tip, and then filtering by a 100 mu M cell filter to obtain primary acinar cells.
Primary acinar cell group dosing: primary acinar cells are divided into blank groups, model groups and model administration groups; blank dosing model dosing groups were treated with equal volumes of PBS buffer for 50 min; model group was incubated with sodium taurocholate (NaT) 5 mM for 50 min; model dosing groups were incubated for 50 min with addition of 5 mM sodium taurocholate, 10. Mu.M, 50. Mu.M, 100. Mu.M of compounds 1, 2, 3 and emodin, respectively. After the incubation, each group was centrifuged at 700 rpm for 2 min, the supernatant was discarded, the cells were resuspended with HEPES buffer, and then PI (blue, staining all cells) and Hoechst (red, necrotic cells) were added to stain the acinar cells, and the cell death of each group was examined using a fluorescence microscope. The results are shown in Table 1.
Wherein, the blank control group is to implement the molding operation but not to administer the molding agent (sham operation) and to administer the same volume of physiological saline at the time of administration; the model control group is used for carrying out modeling operation and giving modeling agent, and physiological saline with the same volume as the administration group is given in the administration process; the medicine groups are respectively used for carrying out the modeling operation and giving physiological saline solution with different medicine concentrations to the modeling agent in the process of administration; the volume of the administration physiological saline or physiological saline is calculated as 5 mL/kg.
Experimental results show that 10, 50 and 100 mu M of compound 1 has remarkable improvement effect on in vitro model of severe acute pancreatitis (NaT induced acinar cell necrosis), and the effect is remarkably superior to that of parent nucleus emodin and analogues of compounds 2 and 3 #P< 0.001), and the concentration of 50. Mu.M is most effective. Thus, the compound 1 according to the present invention has an excellent effect of resisting severe acute pancreatitis at the cellular level.
Test example 2 toxicity of Compound 1 prepared in example 1 against acinar cells and mice
Taking pancreatic tissues of a C57BL/6 mouse, flushing the pancreatic whole tissues with HEPES buffer solution, injecting IV type collagenase, incubating in a 37 ℃ water bath for 19 minutes, repeatedly blowing and dispersing acinar cells by a gun tip of a 1 mL pipette, and then filtering by a 100 mu M cell filter to obtain primary acinar cells.
The administration group is added with 5 mM sodium taurocholate, and simultaneously added with different doses of the compounds 1, 2, 3 and emodin respectively, and incubated for 50 min. The maximum tolerated dose of drug to acinar cells was tested. The results are shown in FIG. 1A. The results of monitoring the Lethal Dose (LD) of compounds 1, 2, 3 and emodin in C57BL/6 mice with a single gastric lavage by observing the death of mice in 24 h are shown in FIG. 1B.
Experimental results show that the maximum tolerance dose of the compound 1 to acinar cells is far greater than that of the analogues, namely the compound 2, the compound 3 and the parent nucleus emodin, and the experimental results show that compared with other iodinated analogues and the parent nucleus thereof, the experimental results show thatP< 0.001), compound 1 has better cell safety. Similarly, the lethal dose result of the compound shows that the lethal dose of the compound 1 is far greater than that of the analogues of diiodo compound 2, triiodo compound 3 and the parent nucleus emodin thereof, and the experimental result shows that the compound 1 has better in vivo safety compared with other iodo analogues and the parent nucleus thereofP＜0.001）。
Test example 3 detection of Activity of Compound 1 obtained in example 1 against severe acute pancreatitis and related Lung injury
To test compound 1 for anti-severe pancreatitis activity, applicant constructed a mouse severe pancreatitis model. C57BL/6 male mice (25-30 g) were fasted one night before surgery and were not water-inhibited. Sodium pentobarbital anesthetized mice, sterilized with iodophor, the abdominal cavity opened with precision scissors along the xiphoid process of the mice, gently turned over the duodenum with forceps, turned over onto sterile gauze, after finding the pancreas, the bile duct near the hepatic portal was gripped with micro forceps, the pancreatic bile duct was penetrated from the duodenal intestinal wall with a 25G needle, and 3.5% sodium taurocholate (STC, sodium taurocholate) was slowly pumped with a microinjection pump at a rate of 0.1 mL/min. Compound 1 was administered to the abdominal cavity at 25, 50, or 150 mg/kg after surgery at 1, h, or 12, h, and samples were collected from pancreatic tissue, lung tissue, and blood after surgery model 24, h, and HE pathological damage detection and serum amylase and trypsin detection were performed, and the data are shown in fig. 2.
Wherein, the blank control group is to implement the molding operation but not to administer the molding agent (sham operation) and to administer the same volume of physiological saline at the time of administration; the model control group is used for carrying out modeling operation and giving modeling agent, and physiological saline with the same volume as the administration group is given in the administration process; the medicine groups are respectively used for carrying out the modeling operation and giving physiological saline solution with different medicine concentrations to the modeling agent in the process of administration; the volume of the administration physiological saline or physiological saline is calculated as 5 mL/kg.
As shown in the experimental results in FIG. 2, the compound 1 can obviously reduce the mortality rate (Table 2), pancreas injury (FIG. 2A) and lung injury (FIG. 2B) of a severe pancreatitis model, reduce the amylase (FIG. 2C) and trypsin (FIG. 2D) levels in serum, reduce the mortality rate (Table 2) of mice of the severe pancreatitis model, and has a treatment effect which is obviously higher than that of the parent nucleus emodin (both of whichP< 0.0001), and the optimal effect dose is 50 mg/kg.
In conclusion, the compound 1 has excellent anti-severe acute pancreatitis activity in vitro and in vivo, can obviously reduce death rate, reduce acinar cell necrosis and lung injury causing death main cause, reduce amylase and trypsin level, has activity obviously higher than that of parent nucleus emodin, and has safety higher than that of emodin.
Test example 4 preparation of Compound 1 sustained release preparation
If the medicine can be prepared into a slow-release preparation, the medicine taking times of patients are reduced, the fluctuation of the blood concentration of the organism is small, the compliance of the patients can be well increased, the medicine effect is improved, and the toxic and side effects are reduced. The half-life of the emodin derivative is only 0.25-1. 1 h, so that the preparation of the compound 1 sustained release preparation is necessary, and thus the compound 1 sustained release tablet is prepared according to the implementation of the following method. Wherein HPMC K100M is pharmaceutical grade hydroxypropyl methylcellulose K100M. ATO is glyceryl behenate Compritol 888.
1) Prescription information
Note that: N/A indicates that the stock does not need equipment, is not applicable or does not relate to equipment; the manual tablet pressing method is that a tablet pressing machine is used for manually pressing tablets and then crushing the tablets for granulating.
2) Analysis results
3) Summary
The compound 1 sustained release tablet is successfully prepared, and the sustained release effect reaches more than 72 h.
Test example 5 detection of Compound 1 sustained Release tablet for severe acute pancreatitis and related pulmonary injury Activity
C57BL/6 male mice (25-30 g) were fasted one night before surgery and were not water-inhibited. Sodium pentobarbital anesthetized mice, sterilized with iodophor, the abdominal cavity opened with precision scissors along the xiphoid process of the mice, gently turned over the duodenum with forceps, turned over onto sterile gauze, after finding the pancreas, the bile duct near the hepatic portal was gripped with micro forceps, the pancreatic bile duct was penetrated from the duodenal intestinal wall with a 25G needle, and 3.5% sodium taurocholate (STC, sodium taurocholate) was slowly pumped with a microinjection pump at a rate of 0.1 mL/min. Compound 1 was administered by gavage at 1 h and 12 h to 50 mg/kg after the API pharmaceutical group operation, compound 1 sustained release preparation group was administered by gavage at 1 h to 5, 10 and 50 mg/kg after the operation, pancreatic tissue, lung tissue and blood were collected after the operation model 24 h, HE pathological damage detection and serum amylase and trypsin detection were performed, and the data are shown in table 7.
Note that: the data are the mean ± SEM, x-rayP＜0.05，**P＜0.001。
The results in Table 7 show that the sustained release preparation 10 mg/kg has a remarkable effect on treating severe pancreatitis compared with the effect on once administration of 50 mg/kg of API (drug substance) and twice administration (total 100 mg/kg/d)P< 0.05), including pancreatic injury, lung tissue injury, and serum amylase, trypsin, and is most effective when the slow release formulation dose is 10 mg/kg.
In summary, the compound 1 is taken as an API (raw material medicine) (1), and the gland acinar cell necrosis inhibition effect is remarkable, namely the diiodide compound 2, the monoiodo compound 3 and the compound mother nucleus emodin; (2) the anti-severe pancreatitis effect in the body is remarkable, the pancreatic injury is obviously reduced, the lung injury which is the main cause of death is caused, the death rate of severe acute pancreatitis mice is reduced, the serum amylase and trypsin levels are reduced, and the effect is remarkably better than that of a mother nucleus; (3) the optimal API dose was confirmed to be 100 mg/kg/d (twice per 50 mg/kg by gavage).
In order to reduce the administration frequency and dosage and increase the administration compliance of patients, we prepared a slow release preparation of the compound 1 and prove that (1) the slow release effect can reach more than 72 hours; (2) even after the administration times and dosage are reduced, the pancreatic injury, the maximum complication lung injury and the serum amylase and trypsin level of the severe acute pancreatitis model mice can be obviously reduced; (3) better than the effect of the optimum administration dosage of the API; (4) the optimal dosage of the sustained release preparation of compound 1 was found to be 10 mg/kg/d.
The applicant can know according to the equivalent dose conversion formula of mice and human bodies, which is given by the industry guide 'Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers' 7 and page table 1 given by the FDA, that the recommended dose of the prepared sustained release preparation of the compound 1 to the human body is as follows: the compound 1 is 50-100 mg/kg (weight of mice) and converted into a dosage of 4.1-8.1mg/kg (weight of human body) for adults, which is administered by stomach administration, 1-2 times daily. The effect is preferably 50 mg/kg (weight of mice) of the drug substance administered to mice, and the dose converted into an adult dose is 4.1mg/kg (weight of human body) per time, 2 times a day.
The slow release agent is 5-50 mg/kg (weight of mice) and converted into 0.4-4.1mg/kg (weight of human body) for adults, and the slow release agent is administered to the mice by stomach irrigation for 1 time a day. Wherein, the effect is that the slow release agent is preferably given to the mice at a rate of 10 mg/kg (weight of the mice), the dosage of the medicine is converted into 0.8mg/kg (weight of human body) for adults, and the medicine is taken 1 time a day.
It is to be noted that the particular features, structures, materials, or characteristics described in this specification may be combined in any suitable manner in any one or more embodiments. Furthermore, the various embodiments described in this specification, as well as the features of the various embodiments, can be combined and combined by one skilled in the art without contradiction.
Claims (10)
1. Use of a compound represented by formula i or a salt thereof for the preparation of a medicament for the prophylaxis and/or treatment of pancreatitis:
2. Use of a compound represented by formula i or a salt thereof for the preparation of a medicament for preventing and/or treating lung injury caused by pancreatitis;
3. Use according to claim 1 or 2, characterized in that: the pancreatitis is severe acute pancreatitis.
4. Use according to claim 1 or 2, characterized in that: the medicament satisfies at least one of the following:
targeting pancreatic and/or lung tissue;
reduce acinar cell necrosis in pancreatitis;
reducing pancreatic tissue damage in acute severe pancreatitis;
reducing mortality of acute severe pancreatitis;
reducing pathological damage to pancreatic tissue;
reducing secretion of pancreatic enzyme and pancreatic amylase;
reducing at least one of lung tissue injury, lung tissue edema or necrosis, and inflammatory infiltration caused by acute severe pancreatitis.
5. Use according to claim 1 or 2, characterized in that: the medicine is a preparation prepared by taking a compound shown in a formula I or salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
6. Use according to claim 5, characterized in that: the preparation is a slow release agent or a controlled release agent.
7. Use according to claim 5, characterized in that: the auxiliary material is at least one of glyceryl behenate, hypromellose and magnesium stearate.
8. Use according to claim 5, characterized in that: the preparation is an oral preparation, a nasal mucosa administration preparation, an oral mucosa administration preparation or an injection preparation.
9. Use according to claim 5, characterized in that: the preparation is a sustained release agent, and the oral administration dosage is 0.4-4.1mg/kg (weight of human body)/time, 1 time a day.
10. Use according to claim 1, characterized in that: an effective dose of the compound shown in the formula I or the salt thereof is 100-1000 mg/time recommended for oral administration, and 1-3 times daily; the recommended dosage for injection administration is 15-45 mg/time, 1 time a day; the spray is administered by inhalation at a recommended dose of 500-1000 mg per time, 1-3 times daily.
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