CN112891357A - New use of pyrimidine heterocycles for treating fibrotic diseases - Google Patents
New use of pyrimidine heterocycles for treating fibrotic diseases Download PDFInfo
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- CN112891357A CN112891357A CN201911221649.5A CN201911221649A CN112891357A CN 112891357 A CN112891357 A CN 112891357A CN 201911221649 A CN201911221649 A CN 201911221649A CN 112891357 A CN112891357 A CN 112891357A
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Abstract
The invention relates to a novel application of a pyrimidine heterocyclic compound in treating fibrotic diseases, wherein the pyrimidine heterocyclic compound is specifically a compound shown in a general formula (I), and each substituent of the general formula (I) is defined in the specification. Experiments prove that the compound shown in the general formula (I) has good activity of resisting non-alcoholic steatohepatitis, hepatic fibrosis and idiopathic pulmonary fibrosis.
Description
Technical Field
The invention relates to a new application of a pyrimidine heterocyclic compound in treating a fibrotic disease, in particular to a new application of the pyrimidine heterocyclic compound or a composition containing the pyrimidine heterocyclic compound in preparing a medicine for treating and/or preventing the fibrotic disease, and belongs to the technical field of medicines.
Background
Non-alcoholic fatty liver disease (NAFLD) refers to a type of syndrome mainly including fat accumulation in liver cells, including simple fatty liver, Non-alcoholic steatohepatitis (NASH), liver fibrosis, liver cirrhosis and liver cancer, except that alcohol and other definite factors cause damage to the liver. The incidence of NAFLD accounts for 25.249% of the population all over the world, and the incidence of NAFLD in China is gradually increased year by year, and the NAFLD has gradually replaced chronic viral liver diseases and becomes the first of chronic liver diseases. At present, an effective treatment means aiming at the NAFLD is lacked, the NAFLD is mainly treated clinically by using an insulin sensitizer, an antioxidant, a lipid regulating drug and a liver protecting drug, but the treatment effect is unsatisfactory, and clinical and experimental findings show that part of the drugs can generate obvious toxic and side effects to greatly hurt the patients.
Liver fibrosis (Hepatic fibrosis) is the result of excessive deposition of Extracellular matrix (ECM) in the liver following damage to the liver by factors such as hepatitis virus, alcohol or chemical poisons. Nonalcoholic steatohepatitis (NASH), a disease associated with severe hepatic steatosis, lobular complex inflammation and pericellular fibrosis, is generally considered benign by simple NAFLD (hepatic steatosis), and is a potentially serious disease, accounting for about 5% of NAFLD. Patients with NASH are most likely to develop cirrhosis and liver failure or liver cancer. Recent studies have shown that liver fibrosis is particularly important for NASH. The persistent liver injury can lead the liver fibrosis to develop into cirrhosis which takes serious disorder of liver blood vessel and liver lobule structure as main pathological manifestations, and finally to develop into liver failure and liver cancer, which is one of the main causes of death of patients with liver diseases.
NASH and liver fibrosis are complex in etiology and diverse in expression, and no effective therapy is known at present, while liver transplantation is the only choice for advanced NASH cirrhosis, and the prognosis survival rate is low. Therefore, there is an urgent need to develop drugs for the treatment of NASH and liver fibrosis.
Pulmonary fibrosis is a disease of lung inflammation, pulmonary alveolus persistent injury, repeated destruction, repair, reconstruction and excessive deposition of extracellular matrix caused by various causes, and finally, lung tissue structure is changed and function is lost. The exact pathogenesis of the pulmonary fibrosis is not fully elucidated, and specific and effective therapeutic means for preventing or reversing pulmonary fibrosis are still lacking. Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease with lesions confined to the lungs, well-developed in the elderly population, characterized by common interstitial pneumonia (UIP) with unclear etiology in lung histology and/or high-resolution ct (hrct) of the chest. Statistically, the prevalence rate in the entire population is about (2-29)/10 ten thousand per year, and increases at a rate of 11% per year. As a country with serious aging, the number of IPF sick people is increased year by year, and the conservative estimation is at least about 50 ten thousand. As a chronic interstitial lung disease, IPF is hidden and gradually worsened, or is manifested as acute exacerbation. The mean survival after IPF diagnosis is only 2.8 years, with mortality higher than most tumors, and is therefore referred to as a "neoplastic-like disease". Because of the irreversibility of IPF, the existing drugs are far from meeting the requirements of clinical treatment, and therefore, the development of more efficient anti-pulmonary fibrosis drugs is still urgent.
In view of the urgent need for the treatment and/or prevention of fibrotic diseases, there is a need in the art to develop anti-fibrotic drugs with novel structures and remarkable effects on unique mechanisms of action.
Disclosure of Invention
The invention aims to provide a pyrimidine heterocyclic compound, and the compound has new application in treating nonalcoholic steatohepatitis, hepatic fibrosis and pulmonary fibrosis (preferably idiopathic pulmonary fibrosis).
The invention provides application of a compound shown in a general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof in preparing a medicament for treating and/or preventing a fibrotic disease, wherein the compound shown in the general formula (I) has the following structure:
wherein the content of the first and second substances,
x is selected from NH or O;
R1selected from hydrogen, chloro, methyl, fluoro or methoxy;
r is selected from
In some embodiments, the compounds of formula (I) have the structures shown in I-1 to I-9:
in some embodiments, the compound of formula (I) is I-3.
In some embodiments, the pharmaceutically acceptable salt is selected from one or more of the group consisting of sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, hydrochloride, hydrobromide, hydroiodide, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propionate, oxalate, malonate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, mandelate, and sulfonate.
In some embodiments, the fibrotic disease is selected from non-alcoholic steatohepatitis, liver fibrosis, or pulmonary fibrosis.
In some embodiments, the fibrotic disease is non-alcoholic steatohepatitis.
In some embodiments, the fibrotic disease is liver fibrosis.
In some embodiments, the fibrotic disease is pulmonary fibrosis.
In some embodiments, the fibrotic disease is idiopathic pulmonary fibrosis.
In some embodiments, the pharmaceutical composition comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier; optionally, it may also include another or more active agents for therapeutic use.
Experiments prove that the compound shown in the general formula (I) has good activity of resisting non-alcoholic steatohepatitis, hepatic fibrosis and idiopathic pulmonary fibrosis.
Drawings
FIG. 1 shows the test results of the compound I-3 for the anti-inflammatory factor in serum of non-alcoholic steatohepatitis and hepatic fibrosis.
FIG. 2 shows the results of the test of AST and ALT enzyme activities of compound I-3 against nonalcoholic steatohepatitis and liver fibrosis.
FIG. 3 shows the results of determination of total cholesterol and triglycerides in serum against non-alcoholic steatohepatitis and liver fibrosis by Compound I-3.
FIG. 4 shows the results of biochemical index measurements of compound I-3 against non-alcoholic steatohepatitis and liver fibrosis.
FIG. 5 shows the results of HE staining of liver tissue against nonalcoholic steatohepatitis and liver fibrosis with Compound I-3.
FIG. 6 shows the Masson staining results of compound I-3 against nonalcoholic steatohepatitis and liver fibrosis.
FIG. 7 shows the hydroxyproline assay results of Compound I-3 against nonalcoholic steatohepatitis and liver fibrosis.
FIG. 8 shows the effect of compound I-3 on IL-17A, IL-6, TNF-. alpha.and hydroxyproline content in pulmonary fibrosis tissues.
FIG. 9 is a graph of Masson staining of Compound I-3 pulmonary fibrosis tissues.
Fig. 10 is a morphological observation picture of compound I-3 pulmonary fibrosis tissue.
Detailed Description
The present invention is further described and explained below in conjunction with specific examples, which are not intended to limit the scope of the present invention.
The experimental method of the present invention, in which the specific conditions are not specified, is generally carried out under the conventional conditions or the conditions recommended by the manufacturers of the raw materials or the commercial products. Reagents of specific sources are not indicated, and conventional reagents are purchased in the market.
Example 1 establishment of NASH animal model and NASH-resistant and hepatic fibrosis experiment
1. The experimental animal source is as follows: male C57BL/6J mice (18-22g), provided by the institute of important disease genetic engineering model animals of university of Dalian medicine, were raised with free food intake and water intake, alternating between daylight at room temperature of 25. + -. 2 ℃. The SPF grade of the mouse growth and reproduction feed and the mouse padding is purchased from the SPF animal experiment center of the university of Dalian medical science.
2. Mouse injection and oral drug preparation: preparing 25% carbon tetrachloride: mixing 25ml carbon tetrachloride and 75ml olive oil; prescription for gastric lavage: 5% DMSO, 5% Tween 20, 40% polyethylene glycol 400, and 50% normal saline, adding gradually and mixing, and making oral gavage prescription solvent for blank control group.
3. Animal grouping and NASH model establishment and dosing test:
(1) male C57BL/6J mice (18-22g) at 6-8 weeks were divided approximately evenly by weight into a blank group (negative control group), a model group, a 10mg/ml obeticholic acid group (positive control), a 10mg/kg I-3 group, and a 30mg/kg I-3 group, which were labeled separately. Blank group 4 had a normal diet free of feed. The remaining groups had 10 mice per group and were fed free on high fat diet.
(2) After the mice are fed with the high-fat feed for 8 weeks, the weight of the mice exceeds 35g, and 25 percent of carbon tetrachloride (CCl) begins4) Intraperitoneal injection, the dose of carbon tetrachloride is 0.5mL/kg each time, and the injection lasts for four weeks twice a week.
(3) The carbon tetrachloride is injected into the abdominal cavity for 3 weeks and then is administered by gastric lavage. Mice body weight changes were recorded daily.
(4) Animal treatment: before the experiment is finished, fasting is not forbidden at night, blood is taken from the venous plexus behind the eyes, and the blood is kept stand and then centrifuged to obtain serum, and the serum is stored at the temperature of minus 80 ℃. Taking out the liver, fixing part of liver tissue in 4% paraformaldehyde after photographing for histopathological study, and storing the rest tissue at-80 deg.C for subsequent experiment.
Collecting serum: after the mouse is anesthetized, the left thumb and the index finger grasp the skin of the two ears and the back of the neck of the mouse, the tail of the little finger is fixed, the middle finger lightly presses the front limb on the left side of the mouse on the heart part of the sternum, and the ring finger is pressed on the abdomen. Twisting the thumb to the right side, and pressing the skin of the left eye part to make the left eyeball congestion and protrusion; if the right eyeball is picked up, the index finger is twisted to the left side to make the right eyeball congestion and protrusion. The frosted capillary tube is inserted into the posterior canthus of the mouse, the thumb and the index finger are twisted according to the needs, the blood vertically flows into the 1.5mL centrifuge tube from the orbit at different speeds, and the heart of the mouse is not kneaded, so that the heart and lung tissues are not damaged. Standing the blood at 4 deg.C for 2 hr, centrifuging at 3500rpm for 15min, collecting supernatant (serum), packaging, and storing at-80 deg.C.
Detection experiment and results:
the kit is prepared from the following sources: glutamic-oxaloacetic transaminase (AST/GOT), glutamic-pyruvic transaminase (ALT/GPT), total cholesterol (T-CHO), Triglyceride (TG), superoxide dismutase (SOD), Malondialdehyde (MDA), Lactate Dehydrogenase (LDH) and Hydroxyproline (HYP) detection kits are purchased from Nanjing Biotech company.
1. Inflammatory factors in serum
Measuring IL-2, IL-4, IL-6, IL-10, TNF-alpha, IL-17A and the like by a flow microsphere joint detection method, and analyzing the content change by a flow cytometer. The results are shown (in FIG. 1).
2. Detection of activity of glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase in serum
Glutamate-oxaloacetate transaminase (AST/GOT) and glutamate-pyruvate transaminase (ALT/GPT) were measured according to the kit instructions to evaluate mouse liver function. The results are shown in FIG. 2.
3. Determination of total cholesterol and triglycerides in serum
Serum total cholesterol and triglyceride levels were determined according to kit protocol. The results are shown in FIG. 3.
4. Determination of biochemical index
Measuring the content change of LDH in serum and MDA and SOD in liver tissue according to the kit operation instruction. The results are shown in FIG. 4.
5. HE staining of liver tissue specimens
(1) Tissues were fixed routinely, rinsed overnight in running water, embedded routinely dehydrated, and sections were deparaffinized to water.
(2) Dyeing the core: the hematoxylin staining solution is used for staining for 12-15 minutes and washed by tap water.
(3) Color separation: under the mirror, if the cell nucleus is stained too deeply, it is washed with tap water after color separation for several seconds by using 1% hydrochloric acid alcohol solution.
(4) Staining cytoplasm: the fabric was immersed in eosin dye for 5 minutes and washed with tap water. The image was photographed after air-drying (observation under a 200-fold microscope), and the result is shown in FIG. 5.
6. Masson staining of liver tissue specimens
(1) Tissues were fixed routinely, rinsed overnight in running water, embedded routinely dehydrated, and sections were deparaffinized to water.
(2) The Weigart iron hematoxylin A, B liquid is mixed in equal proportion (the two liquids are mixed in equal parts before use, which is not suitable for pre-mixing, otherwise, the oxidation precipitation is easy to lose the dyeing power gradually), and the mixture is used after being mixed, dyed for 2 minutes and slightly washed by running water.
(3) Differentiation with 1% hydrochloric acid alcohol for 3 seconds, rinsing with running water, staining with ponceau acid fuchsin staining solution for 1 minute, and slightly rinsing with running water.
(4) The phosphomolybdic acid solution is treated for 1 minute (controlled under a mirror, the myofibers are red, and the collagen fibers are light red), and the 95 percent alcohol is dehydrated for multiple times.
(5) Dehydrated by absolute alcohol, transparent xylene and sealed by neutral gum.
(6) Collagen fibers, mucus, and cartilage were blue, muscle fibers, cellulose, and red blood cells were stained red, and nuclei were stained blue-black, and the results are shown in fig. 6.
7. Detection of hydroxyproline HYP
Hydroxyproline HYP (frozen liver tissue) was measured according to the kit instructions and the results are shown in fig. 7.
The test results show that: compared with the model group, after the treatment of 10mg/ml obeticholic acid, 10mg/kgI-3 and 30mg/kgI-3, the contents of inflammatory factors IL-2, IL-4, IL-6, IL-10, TNF-alpha, IL-17A and the like in the serum of the mice are obviously reduced, and the inflammatory factors in the serum of the model group are obviously increased compared with the serum of the mice of a blank control group. Compared with a model group, after treatment of 10mg/ml obeticholic acid group, 10mg/kgI-3 and 30mg/kgI-3, the levels of glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, total cholesterol, triglyceride, malondialdehyde and lactate dehydrogenase are obviously reduced, the level of superoxide dismutase is increased, the level of hydroxyproline in liver fibrosis mice is obviously reduced, the anti-inflammatory and anti-fibrosis effects of the compound I-3 are obviously better than those of a reference medicament obeticholic acid, and the larger the dose of the compound I-3 is, the better the effect is.
Example 2 establishment of pulmonary fibrosis animal model and anti-pulmonary fibrosis experiment
1. Establishment of pulmonary fibrosis animal model
(1) Animals: clean grade C57BL/6J mice (female) were purchased from the university of Dalian medical laboratory animal institute and weighed 18-20 g. Is suitable for one week. The mice were randomly divided into eight groups, normal group, model group, Nintedanib 30mg/kg, Nintedanib 60mg/kg, pirfenidone 120mg/kg, gefitinib 60mg/kg, I-330 mg/kg and I-360 mg/kg.
(2) Administration: PEG400 was gavaged in the normal and model groups; the Nintedanib 30mg/kg group is administered with Nintedanib 30mg/kg by intragastric administration, the Nintedanib 60mg/kg group is administered with Nintedanib 60mg/kg by intragastric administration, the pirfenidone 120mg/kg group is administered with pirfenidone 120mg/kg by intragastric administration, the Gefitinib 60mg/kg group is administered with Gefitinib 60mg/kg by intragastric administration, the I-330 mg/kg group is administered with I-330 mg/kg by intragastric administration, the I-360 mg/kg group is administered with I-360 mg/kg by intragastric administration, and the liquid volume of each group is 0.1ml/10g of body weight.
(3) Establishing a model: an intratracheal injection method is adopted. After the mice were anesthetized, they were fixed on a mouse plate with cotton thread to secure the extremities and upper incisors. According to the weight of the mouse, a micro-syringe is used for sucking the bleomycin liquid medicine (3mg/kg weight) with the corresponding volume and dripping the bleomycin liquid medicine into an air pipe, the breathing of the mouse is noticed at any time in the injection process, and the asphyxia is avoided. The mouse plate is quickly erected after bleomycin liquid medicine or normal saline is injected, the mouse plate is rotated, the breathing condition of the mouse is concerned at any time, and if the breathing is weakened and the frequency is unstable, auxiliary breathing needs to be given in time until the breathing of the mouse tends to be stable. The rotation of the mouse is beneficial to the uniform distribution of the bleomycin liquid medicine or the physiological saline in the lung, the neck wound is disinfected by 75% alcohol cotton after the rotation, the vertical mouse plate is leaned against the wall surface, the mouse is kept stand for 5min, and the breath of the mouse is observed at any time. And (3) after standing for 5min, taking the mouse down from the mouse plate if the respiratory frequency of the mouse is stable, putting the mouse back to a dry and clean mouse cage for rest, and waiting for awakening. Fresh rat food and water are given for normal breeding.
(4) Model animal treatment: after 15 days of the experiment, the animals were sacrificed. The lung tissue was removed by opening the chest, rinsed with PBS, blotted dry with absorbent paper, and weighed. All mice in each group take the left lung lobe, fix the left lung lobe with 4% paraformaldehyde, perform histopathological section, freeze-store other lung lobes in liquid nitrogen for preservation, and detect related indexes.
2. Lung tissue collection and serum preparation
(1) After the mouse is anesthetized, the left thumb and the index finger grasp the skin of the two ears and the back of the neck of the mouse, the tail of the little finger is fixed, the middle finger lightly presses the front limb on the left side of the mouse on the heart part of the sternum, and the ring finger is pressed on the abdomen. Twisting the thumb to the right side, and pressing the skin of the left eye part to make the left eyeball congestion and protrusion; if the right eyeball is picked up, the index finger is twisted to the left side to make the right eyeball congestion and protrusion.
(2) The eyeball is taken by an elbow forceps clip, the direction of the thumb and the forefinger is twisted according to the needs, blood vertically flows into a 1.5mL centrifuge tube from the orbit at different speeds, and the heart of the mouse is not kneaded, so as to avoid damaging the heart lung tissue.
(3) Standing at 4 deg.C for 2 hr, centrifuging at 3000rpm for 20min, collecting supernatant (serum), packaging, and storing at-80 deg.C.
(4) The mice from which blood had been taken were fixed on a mouse plate, and four limbs and upper incisors were fixed with cotton thread. Opening abdominal cavity under xiphoid process, passing through diaphragm, opening thoracic cavity, cutting off rib left and right respectively, turning over sternum and rib, fixing hemostatic forceps, exposing heart and lung, taking out heart and lung, rinsing gently in PBS buffer solution once to remove blood stain, blotting surface of lung with absorbent paper, removing trachea and heart, and peeling off lung.
1. Determination of inflammatory factor and tissue HYP in serum
Measuring IL-6, TNF-alpha, IL-17A and the like by a flow microsphere joint detection method, and analyzing the content change by a flow cytometer; hydroxyproline HYP was determined according to kit instructions. The results are shown in FIG. 8.
2. Masson trichrome staining of lung tissue specimens
(1) Tissues were fixed routinely, rinsed overnight in running water, embedded routinely dehydrated, and sections were deparaffinized to water.
(2) The Weigart iron hematoxylin A, B liquid is mixed in equal proportion (the two liquids are mixed in equal parts before use, which is not suitable for pre-mixing, otherwise, the oxidation precipitation is easy to lose the dyeing power gradually), and the mixture is used after being mixed, dyed for 2 minutes and slightly washed by running water.
(3) Differentiation with 1% hydrochloric acid alcohol for 3 seconds, rinsing with running water, staining with ponceau acid fuchsin staining solution for 1 minute, and slightly rinsing with running water.
(4) The phosphomolybdic acid solution is treated for 1 minute (controlled under a mirror, the myofibers are red, and the collagen fibers are light red), and the 95 percent alcohol is dehydrated for multiple times.
(5) Dehydrated by absolute alcohol, transparent xylene and sealed by neutral gum.
(6) Collagen fibers, mucus, and cartilage were blue, muscle fibers, cellulose, and red blood cells were stained red, and nuclei were stained blue-black, and the results are shown in fig. 9.
3. Morphological observation of pulmonary fibrosis tissue
After the experiment, the fresh lung was peeled off, the surface was blotted with absorbent paper, the trachea and the heart were removed, and a photograph was taken. The results are shown in FIG. 10.
The above test results show that: the compound I-3 in the invention can obviously reduce the content of IL-6, TNF-alpha and IL-17A in serum and the content of collagen fiber in lung tissue, compared with a model group, the main index of pulmonary fibrosis is obviously reduced, and the treatment effect is superior to that of a control drug pirfenidone and is similar to that of nintedanib. The research indicates that the molecules have the potential of developing novel efficient anti-pulmonary fibrosis drugs.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the technical principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. The application of a compound shown in a general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof in preparing a medicament for treating and/or preventing fibrosis diseases, wherein the compound shown in the general formula (I) has the following structure:
wherein the content of the first and second substances,
x is selected from NH or O;
R1selected from hydrogen, chloro, methyl, fluoro or methoxy;
r is selected from
2. The use according to claim 1, wherein the compound of formula (I) has a structure represented by I-1 to I-9:
3. the use according to claim 2, wherein the compound of formula (I) is I-3.
4. The use according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt is selected from one or more of the group consisting of sulphate, pyrosulphate, bisulphate, sulphite, bisulphate, phosphate, hydrochloride, hydrobromide, hydroiodide, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propionate, oxalate, malonate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, mandelate and sulphonate.
5. The use according to any one of claims 1 to 4, wherein the fibrotic disease is selected from non-alcoholic steatohepatitis, liver fibrosis or pulmonary fibrosis.
6. The use of claim 5, wherein the fibrotic disease is non-alcoholic steatohepatitis.
7. Use according to claim 5, wherein the fibrotic disease is liver fibrosis.
8. The use according to claim 5, wherein the fibrotic disease is pulmonary fibrosis.
9. The use according to claim 8, wherein the fibrotic disease is idiopathic pulmonary fibrosis.
10. The use according to any one of claims 1 to 9, wherein the pharmaceutical composition comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier; optionally, it may also include another or more agents for the treatment of non-alcoholic steatohepatitis, liver fibrosis and idiopathic pulmonary fibrosis.
Priority Applications (1)
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| CN106565612A (en) * | 2016-10-25 | 2017-04-19 | 大连医科大学 | Diphenyl vinyl pyridine compound, composition and application thereof |
| CN106565614A (en) * | 2016-11-16 | 2017-04-19 | 大连医科大学 | Diphenylaminopyrimidine compound, composition and application |
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| CN106565612A (en) * | 2016-10-25 | 2017-04-19 | 大连医科大学 | Diphenyl vinyl pyridine compound, composition and application thereof |
| CN106565614A (en) * | 2016-11-16 | 2017-04-19 | 大连医科大学 | Diphenylaminopyrimidine compound, composition and application |
| CN109265469A (en) * | 2018-11-12 | 2019-01-25 | 大连医科大学附属第医院 | Pyrimido thiazole heterocyclic compounds, composition and its purposes for treating lymphocytic leukemia |
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