CN109912600B - Imidazo pyrimidine derivative for preventing and treating pulmonary fibrosis and application thereof - Google Patents
Imidazo pyrimidine derivative for preventing and treating pulmonary fibrosis and application thereof Download PDFInfo
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Abstract
The invention provides an imidazopyrimidine derivative for preventing and treating pulmonary fibrosis, wherein the structural formula of the derivative is shown in the specification
Description
Technical Field
The invention belongs to the field of medicaments, and relates to an imidazopyrimidine derivative for preventing and treating pulmonary fibrosis and application of the derivative in preparation of medicaments for preventing and treating pulmonary fibrosis.
Background
Diffuse interstitial pulmonary fibrosis (abbreviated as "pulmonary fibrosis") is the result of repair of the body after progressive and irreversible damage to the lung function due to various chemical or physical causes. Pulmonary fibrosis is mainly divided into idiopathic pulmonary interstitial fibrosis and secondary pulmonary interstitial fibrosis. Usually, the main pathological features are fibroblast proliferation, extracellular matrix deposition, pulmonary interstitial inflammation, pulmonary alveolar epithelial persistent damage and pulmonary alveolar structural disorder, which are clinically manifested as dyspnea and hypoxemia, and with the development of diseases, the compliance of lung is reduced, lung capacity is reduced, lung function is gradually decreased, and finally, the patient can die due to exhaustion of respiratory function.
In recent years, the incidence of patients with pulmonary fibrosis in China tends to rise year by year, and as the pathogenesis of pulmonary fibrosis is not clear, an effective treatment method is lacked, and the prognosis is poor, the survival time of patients once diagnosed with pulmonary embolism is only 2-3 years. According to research reports, the incidence rate of pulmonary fibrosis in countries such as the United states and Canada also tends to rise year by year, 2016 year data show that about 4.8 ten thousand pulmonary fibrosis patients are newly added in the United states every year, wherein the incidence rate of male patients is higher than that of female patients, 60 percent of patients die due to respiratory failure, the use cost of the United states for treating the pulmonary fibrosis is about 20 hundred million each year, the prognosis of the patients is poor, and the social and economic pressures are high. In China, pulmonary fibrosis becomes a serious intractable disease threatening the health of people in China, and also causes great economic stress.
The pulmonary fibrosis is caused by various causes, including genetic susceptibility, environmental harmful factors, drug-induced lung diseases, EB virus infection, hepatitis C virus infection, herpes virus infection and the like, and pulmonary fibrosis can also be caused by tumor radiotherapy and chemotherapy and the like. Diagnosis of these diseases is difficult, generally requiring high resolution CT examination of the chest and bronchoalveolar lavage, and various methods for lung biopsy and pathological examination if necessary. Numerous studies have found that the pathogenesis of pulmonary fibrosis is mainly related to inflammatory reaction, oxidative stress and epithelial cell injury, fibroblast activation, and the like. At present, the traditional method for treating pulmonary fibrosis mainly comprises hormones, and clinically, glucocorticoid, immunomodulator, antioxidant and the like are mainly used, but the traditional method has poor clinical effect after long-term use, can generate some inevitable adverse reactions, and can increase risks such as respiratory failure and secondary infection. The clinical use of nintedanib is as follows: 1H-indole-6-carboxylic acid, 2, 3-dihydro-3- [ [ [4- [ methyl [ (4-methyl-1-piperazinyl) acetyl ] amino ] phenyl ] amino ] phenylmethylene ] -2-oxo-, methyl ester, (3Z) -treatment of idiopathic pulmonary fibrosis, but nintedanib is often associated with gastrointestinal and hepatobiliary adverse reactions and may affect fertility, is contraindicated in pregnant women, and requires further improvement in its pharmacokinetic profile. In many traditional Chinese medicines, the pathogenesis of pulmonary fibrosis is complex, the lung is often accompanied by multi-organ pathological changes taking the lung as a center, and the condition of mixed deficiency and excess appears, so that the pathogenesis of the pulmonary fibrosis needs to be examined in detail in clinical practice, the symptoms and root causes are considered through differentiating the points of symptoms and signs, the treatment is performed based on differentiating the symptoms and the symptoms, and the overall regulation is performed, so that the clinical symptoms of patients are improved, and the pulmonary fibrosis can be prevented and delayed to a certain extent. Therefore, although there are new therapeutic means such as cytokine and its specific inhibitor therapy, gene therapy, and traditional Chinese medicine, there is still an urgent need for new anti-pulmonary fibrosis drugs with good efficacy, less side effects, and improved patient prognosis and survival rate.
Disclosure of Invention
The invention aims to provide an imidazopyrimidine derivative for preventing and treating pulmonary fibrosis and application of the derivative in preparing a medicament for preventing and treating pulmonary fibrosis aiming at the defects and shortcomings of the conventional medicament for treating pulmonary fibrosis, so as to solve the problems of large toxic and side effects and to-be-improved pharmacokinetic performance of the conventional medicament for preventing and treating pulmonary fibrosis.
The structural formula of the imidazopyrimidine derivative for preventing and treating pulmonary fibrosis is shown as a formula (I), or the derivative is a pharmaceutically acceptable salt of a compound shown as the formula (I),
in the technical scheme of the imidazopyrimidine derivative for preventing and treating pulmonary fibrosis, the pharmaceutically acceptable salt of the compound shown in formula (i) is an addition salt formed by the compound shown in formula (i) and hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
The imidazopyrimidine derivative for preventing and treating pulmonary fibrosis provided by the invention can be combined with pharmaceutically acceptable carriers, such as targeting nano-carriers, and the like to jointly exert the activity of preventing and treating pulmonary embolism.
The imidazopyrimidine derivative for preventing and treating pulmonary fibrosis provided by the invention can be prepared into preparations such as oral preparations, sprays, buccal tablets, injections and the like by adopting a conventional pharmaceutical method.
The preparation method of the imidazopyrimidine derivative for preventing and treating pulmonary fibrosis, provided by the invention, comprises the following steps:
adding hypoxanthine, iodoisopropane and sodium hydride into dimethyl sulfoxide (DMSO), stirring at 80 deg.C for reaction for 3h, adding acid for quenching, and spin-drying under reduced pressure to obtain isopropyl-modified hypoxanthine; adding isopropyl-modified hypoxanthine and Lawesson reagent (Lawesson reagent) into toluene, heating and refluxing for 3h, then performing rotary drying under reduced pressure, and passing through a silica gel column to obtain the final product.
The invention also provides application of the imidazopyrimidine derivative for preventing and treating pulmonary fibrosis in preparation of a medicament for preventing and treating pulmonary fibrosis. Animal experiments prove that the imidazopyrimidine derivative for preventing and treating pulmonary fibrosis can obviously relieve the pathological degree of pulmonary fibrosis and delay the progress of pulmonary fibrosis. Compared with clinical first-line anti-pulmonary fibrosis drug nintedanib, the imidazopyrimidine derivative provided by the invention has better pharmacokinetics and lower toxic and side effects.
Compared with the prior art, the technical scheme of the invention has the following beneficial technical effects:
experiments prove that the imidazopyrimidine derivative for preventing and treating pulmonary fibrosis can obviously relieve the pathological degree of pulmonary fibrosis and delay the progress of pulmonary fibrosis, and has the effect of obviously preventing and treating pulmonary fibrosis. In addition, compared with clinical first-line anti-pulmonary fibrosis drug nintedanib, the imidazopyrimidine derivative provided by the invention has better pharmacokinetics and lower toxicity. The maximum plasma concentration is reached approximately 2-4 hours after oral administration of the nintedanib capsule, the absolute bioavailability is 4.69% at a 100mg dose, a steady state plasma concentration is reached for at least 1 week after administration, and the terminal half-life is 10 to 15 hours. Experiments prove that the maximum blood concentration can be reached within 0.5 hour after the imidazopyrimidine derivative is administrated, the absolute bioavailability of 50mg dose is 54.51%, the steady blood concentration is reached after two days when the imidazopyrimidine derivative is continuously administrated, the terminal half-life period is more than 72 hours, and toxicity tests show that the imidazopyrimidine derivative provided by the invention has no obvious adverse reaction. In addition, the imidazopyrimidine derivative for preventing and treating pulmonary fibrosis has the advantages of simple synthesis process, capability of reducing production cost and high economical efficiency.
Drawings
FIG. 1 shows HE staining results of lung tissue sections of mice in the white control group, model group, treatment group and prevention group in example 2.
Detailed Description
The imidazopyrimidine derivative for preventing and treating pulmonary fibrosis and the application thereof provided by the invention are further illustrated by the following examples. It should be noted that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention, and those skilled in the art can make certain insubstantial modifications and adaptations of the present invention based on the above disclosure and still fall within the scope of the present invention.
Example 1
In this embodiment, the preparation of the imidazopyrimidine derivative for preventing and treating pulmonary fibrosis includes the following steps:
taking 1.36g of hypoxanthine, 3mL (1.703g/mL) of iodoisopropane and 0.24g of sodium hydride, adding the mixture into a flask containing 300mL of DMSO, stirring and reacting at 80 ℃ for 3h, then adding acid for quenching, and carrying out rotary drying under reduced pressure to obtain the isopropyl modified hypoxanthine. Adding 1.5g of isopropyl modified hypoxanthine and 8.08g of Lawesson reagent into a flask containing 500mL of toluene, heating and refluxing for 3h, then performing reduced pressure spin drying, and passing through a silica gel column to obtain the imidazopyrimidine derivative CSA for preventing and treating pulmonary fibrosis.
And (3) detecting the CSA by nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum, wherein the results are as follows:1H NMR(500MHz,Chloroform-d)δ8.57(s,1H),7.76(s,1H),5.26(hept,J＝6.2Hz,1H),4.86(hept,J＝6.2Hz,1H),1.46(d,J＝6.1Hz,6H),1.23(d,J＝6.2Hz,6H)。13C NMR(125MHz,Common NMR Solvents)δ178.12,150.12,142.21,139.31,129.43,53.98,47.79,23.32,21.98,21.13。
example 2
In this example, the CSA prepared in example 1 was tested for anti-pulmonary embolism activity.
1. Test method
(1) Animals: SPF grade c57bl/6 mice, 25 g. + -. 2 g.
(2) Grouping
Animals were divided into blank control group, model control group, prevention group and treatment group, 10 animals per group.
The preventive group is subjected to drug intervention 14 days in advance, and the dosage is 50 mg/kg/d. The treatment group is administered after modeling for intervention, and the dosage is 50 mg/kg/d.
(3) The mice were intraperitoneally injected with 1% sodium pentobarbital at a dose of 50mg/kg, anesthetized, supine fixed on the operating table, the trachea was exposed with forceps (tongue pulled out), 5mg/kg bleomycin was injected slowly, then the mouse plates were quickly erected, rotated for 5min, and the drug was distributed uniformly in the lungs.
The blank control group is administered with isoosmotic saline with equal volume through gastric gavage, the treatment group starts to be administered with the gastric gavage with 50mg/kg/d after 10 days, the blank control group and the model control group are administered with isoosmotic saline with equal volume through gastric gavage, the prevention group is administered with the gastric gavage with 50mg/kg/d for up to 35 days continuously and 1 time per day.
(4) Material drawing and index determination
Mice were sacrificed 35 days after administration by bleeding, both lung tissues were collected, weighed, the same part of the upper right lung was taken, fixed with 4% paraformaldehyde for 48h, sectioned in paraffin, and HE stained for histopathological observation. And (3) taking the same part of the left lung middle lobe to detect the HYP content of the lung tissue. Collecting plasma, and detecting T-SOD, MDA and GSH-PX.
2. Results
(1) Analysis of HYP content in mouse lung tissue
The detection results of the lung tissue HYP content of each group of mice are shown in table 1, and compared with a blank control group, the lung tissue HYP content of each group of mice is increased (P is less than 0.01); compared with a model control group, the HYP content of the drug intervention group is obviously reduced (P is less than 0.01).
TABLE 1 HYP content (. + -. s) in mouse lung tissue
| Group of | HYP(μg/g) |
| Blank control group | 12.3±0.5 |
| Model control group | 92.3±6.2* |
| Prevention group | 24.1±2.2# |
| Treatment group | 31.4±4.1# |
Note: comparison with blank control: p < 0.01; comparison with model control group: # P < 0.01.
(2) Content analysis of mouse plasma T-SOD, MDA and GSH-PX
Compared with the blank control group, the plasma MDA content of each group of mice is increased (P is less than 0.01); compared with a blank control group, the plasma T-SOD and GSH-PX content of each group of mice is reduced (P < 0.01). Compared with a model control group, the content of MDA in the plasma of mice in each group is obviously reduced (P is less than 0.01); compared with the model control group, the plasma T-SOD and GSH-PX of each group of mice are increased (P < 0.01).
TABLE 2 mouse plasma T-SOD, MDA, GSH-PX content (. + -. s)
| Group of | T-SOD(U/mL) | MDA(nmol/mL) | GSH-PX(U/L) |
| Blank control group | 192.1±12.5 | 3.6±0.9 | 1121.5±122.5 |
| Model control group | 82.3±9.5 | 25.7±3.5 | 320.5±23.2 |
| Prevention group | 177.1±10.1 | 5.2±1.2 | 991.7±12.3 |
| Treatment group | 159.5±19.4 | 8.7±2.1 | 890.5±23.2 |
Note: comparison with blank control: p < 0.01; comparison with model control group: # P < 0.01.
(3) Pathological change analysis of lung tissue
The results of HE staining of lung tissue sections of mice in the blank control group, the model control group, the treatment group and the prevention group are shown in fig. 1, and it can be seen from fig. 1 that the lung structure of the blank control group is clear, the alveolar space of the model control group is remarkably widened, the alveolar structure is seriously damaged, collapse is seriously caused, collagen fibers are remarkably increased, a large amount of inflammatory cells are infiltrated, and the pulmonary fibrosis of the prevention group and the treatment group is remarkably reduced.
Example 3
Toxicity testing of CSA was performed in this example.
Compound CSA was gavaged to C57 mice at a dose of 50mg/kg/d for 180 consecutive days, and an equal volume of isotonic saline was gavaged to the blank control group. After the last administration for 1h, the mice were anesthetized by intraperitoneal injection of pentobarbital sodium (40mg/kg), placed on a constant temperature hot plate at 37 + -1 ℃, and blood was taken by cardiac puncture. The results of measurements of blood pathological indicators such as blood routine, liver and kidney function, electrolytes, etc. were as shown in Table 3, according to the instructions of the instrument. As shown in Table 3, CSA has no significant adverse effect on the liver and kidney functions of mice and has the characteristic of low toxicity.
TABLE 3 results of liver and kidney function tests (values are expressed as mean. + -. SED, n-9-10)
Example 4
This example analyzes the pharmacokinetic properties of CSA.
Nintedanib is used more clinically: 1H-indole-6-carboxylic acid, 2, 3-dihydro-3- [ [ [4- [ methyl [ (4-methyl-1-piperazinyl) acetyl ] amino ] phenyl ] amino ] phenylmethylene ] -2-oxo-, methyl ester, (3Z) -treatment idiopathic pulmonary fibrosis, the imidazopyrimidine derivative synthesized by the invention has the characteristics of better pharmacokinetics and low toxicity compared with the clinical first-line anti-pulmonary fibrosis medicament, namely nintedanib.
The C57 mouse compounds of nintedanib and CSA are intragastrically administered at a dose of 50mg/Kg/d, blood is collected intravenously before and after administration respectively at different time points, plasma is separated, a ZORBAXSB-C18 chromatographic column is used as a separation column, acetonitrile-0.1% trifluoroacetic acid-water (volume ratio 35:20:45) is used as a mobile phase, the flow rate is 1.0mL/min, the detection wavelength is 286nm, the column temperature is 35 ℃, and detection is carried out after extraction by ethyl acetate under alkaline conditions. Pharmacokinetic parameters were calculated with DAS 3.0.
The maximum plasma concentration is reached approximately 2-4 hours after oral administration of the nintedanib capsule, the absolute bioavailability is 4.69% at a 100mg dose, a steady state plasma concentration is reached for at least 1 week after administration, and the terminal half-life is 10 to 15 hours. The maximum blood concentration can be reached within 0.5 hour after the CSA is synthesized by the invention, the absolute bioavailability of 50mg dose is 54.51%, and the steady blood concentration is reached after two days when the CSA is continuously administrated, and the terminal half-life period is more than 72 hours. And nintedanib is commonly seen in adverse reactions of gastrointestinal tract, liver and gallbladder, and may affect fertility, and is forbidden for pregnant women. The imidazopyrimidine derivative synthesized by the invention has no obvious adverse reaction, can be used by pregnant women and has obvious advantages.
Claims (3)
1. An imidazopyrimidine derivative for preventing and treating pulmonary fibrosis is characterized in that the structural formula of the derivative is shown as a formula (I), or the derivative is a pharmaceutically acceptable salt of a compound shown as the formula (I),
2. the imidazopyrimidine derivative according to claim 1, wherein the pharmaceutically acceptable salt of the compound represented by formula (i) is an addition salt of the compound represented by formula (i) with hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or ferulic acid.
3. Use of the imidazopyrimidine derivative according to claim 1 or 2 for the preparation of a medicament for the prevention or treatment of pulmonary fibrosis.
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| CN114588161A (en) * | 2020-12-07 | 2022-06-07 | 四川大学华西医院 | Hypoxanthine derivative with effect of preventing and treating pneumonia |
| CN114588160A (en) * | 2020-12-07 | 2022-06-07 | 四川大学华西医院 | Hypoxanthine derivative with anti-pulmonary fibrosis effect |
| WO2023169557A1 (en) * | 2022-03-11 | 2023-09-14 | 四川易阿索医药科技有限公司 | Use of hypoxanthine compound in preparation of drug for treating pulmonary fibrosis |
| CN116763794A (en) * | 2022-03-11 | 2023-09-19 | 四川大学华西医院 | Application of 1, 7-dihydro-6H-purin-6-one compound in preparation of anti-pulmonary fibrosis drugs |
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| CN103788095A (en) * | 2014-01-20 | 2014-05-14 | 四川大学华西医院 | 2,4(1H, 3H)-ryrimidinedione derivatives and preparation method thereof |
| US20150315207A1 (en) * | 2014-05-05 | 2015-11-05 | Signalrx Pharmaceuticals, Inc. | Novel Heterocyclic Compound Classes for Signaling Modulation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103788095A (en) * | 2014-01-20 | 2014-05-14 | 四川大学华西医院 | 2,4(1H, 3H)-ryrimidinedione derivatives and preparation method thereof |
| US20150315207A1 (en) * | 2014-05-05 | 2015-11-05 | Signalrx Pharmaceuticals, Inc. | Novel Heterocyclic Compound Classes for Signaling Modulation |
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