Application of flumatinib in preparation of medicine for treating pulmonary arterial hypertension

Abstract

The invention provides an application of flumatinib in preparation of a medicine for treating pulmonary arterial hypertension. The medicine comprises flumatinib as an active component. Through a mouse pulmonary hypertension model, flumatinib is given for intervention treatment, and the effect of flumatinib on pulmonary vessels is defined: flumatinib can improve the survival rate of animals with pulmonary hypertension, and flumatinib can significantly inhibit weight loss of mice with pulmonary hypertension after medication treatment, so that the effect of flumatinib on pulmonary vessels is obvious. The food intake and the water intake of the pulmonary arterial hypertension mice are increased, and flumatinib can reduce the right ventricular pressure of the pulmonary arterial hypertension mice.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to a new use of flumatinib (N-[6-methyl-5-[[4-(pyridin-3-yl)pyrimidin-2-yl]amino]pyridin-3-yl]-4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)benzamide), and in particular to the use of flumatinib in the preparation of drugs for treating pulmonary hypertension. Background Art

[0002] Pulmonary arterial hypertension (PAH) refers to a clinical and pathophysiological syndrome caused by changes in pulmonary vascular structure or function due to a variety of heterogeneous diseases (causes) and different pathogenesis, resulting in increased pulmonary vascular resistance and pulmonary artery pressure, which then develops into right heart failure or even death.

[0003] The pathogenesis of pulmonary hypertension is still unclear. It is currently believed that it may be related to the disruption of the normal balance between vasodilators and vasoconstrictors, growth inhibitors and mitogens, and anti-thrombotic and pro-thrombotic determinants due to pulmonary endothelial cell dysfunction and / or damage. These imbalances cause the pulmonary vascular lumen to narrow, which in turn leads to increased vascular resistance during vasoconstriction, promoting vascular wall remodeling and in situ thrombosis. In particular, the long-term production disorder of vasoactive mediators (such as nitric oxide and prostacyclin) and the long-term overexpression of vasoconstrictor factors (endothelin-1) affect vascular tone and lead to vascular remodeling.

[0004] Drugs for the treatment of pulmonary arterial hypertension include calcium ion antagonists, anticoagulants, diuretics and oxygen administration. There is currently no cure. In recent years, PAH-specific drugs that have been internationally registered and marketed mainly include: 1. Prostacyclin drugs (iloprost, treprostinil, epoprostenol); 2. Endothelin receptor antagonists (bosentan, ambrisentan, macitentan); 3. Phosphodiesterase type 5 inhibitors (sildenafil, tadalafil); 4. Prostacyclin receptor agonists (selexipag) and 5. Guanylate cyclase agonists, namely riociguat. Although the application of these targeted drugs has played an important role in the treatment of PAH, the side effects of the drugs have limited the clinical application of the drugs. For example, prostacyclin drugs can cause adverse reactions such as headache, facial flushing, diarrhea, hypotension, pain at the infusion site, and infection; endothelin receptor antagonists can cause elevated transaminases, peripheral edema, and anemia; prostacyclin receptor agonists can cause headache, diarrhea, nausea, vomiting, and jaw pain; phosphodiesterase type 5 inhibitors can cause headache, flushing, myalgia, and visual impairment; guanylate cyclase agonists can cause gastrointestinal symptoms, hypotension, and hemoptysis. Therefore, the prospects for these existing targeted drug treatments are not optimistic, and finding new therapeutic drugs is a problem that needs to be solved at present.

[0005] WO2006069525 (its Chinese equivalent patent is CN 200580020883.1) discloses flumatinib mesylate, whose chemical name is N-[6-methyl-5-[[4-(pyridin-3-yl)pyrimidin-2-yl]amino]pyridin-3-yl]-4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)benzamide methanesulfonate, and provides a use of the compound and its salt alone or in combination with other drugs in the treatment of cell proliferative diseases (such as cancer), the structure of which is shown in the following formula:

[0006]

[0007] Chinese patent CN201380031403.6 discloses a crystalline form of flumatinib mesylate and a preparation method thereof, as well as a pharmaceutical composition containing a therapeutically effective amount of the crystalline form and its use in the treatment of chronic myeloid leukemia.

[0008] However, there are no reports on the use of flumatinib for pulmonary arterial hypertension (PAH). Summary of the invention

[0009] In order to solve the above-mentioned technical problems existing in the prior art, the present invention provides the use of flumatinib in the preparation of a drug for treating pulmonary arterial hypertension.

[0010] To achieve the above purpose, the present invention adopts the following technical means:

[0011] The first object of the present invention is to provide the use of flumatinib and / or its pharmaceutically acceptable salt in the preparation of a drug for treating pulmonary arterial hypertension.

[0012] Furthermore, the drug includes flumatinib or a pharmaceutically acceptable salt thereof.

[0013] Further, the chemical name of flumatinib is N-[6-methyl-5-[[4-(pyridin-3-yl)pyrimidin-2-yl]amino]pyridin-3-yl]-4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)benzamide, and the chemical structure is shown in Formula 1:

[0014]

[0015] Furthermore, the pharmaceutically acceptable salt is methanesulfonate.

[0016] Furthermore, the drug also includes a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient.

[0017] Furthermore, the pharmaceutically acceptable auxiliary material is an excipient.

[0018] Furthermore, the dosage form of the drug is tablets, capsules, oral liquids, lozenges, granules, granules, pills, powders, ointments, pills, suspensions, powders or injections.

[0019] Furthermore, the drug is administered orally, transdermally, intramuscularly, subcutaneously or intravenously.

[0020] The second object of the present invention is to provide a drug for treating pulmonary arterial hypertension, wherein the active ingredient of the drug comprises flumatinib and / or a pharmaceutically acceptable salt thereof.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] The present invention provides a novel drug for preventing and treating pulmonary hypertension, namely, flumatinib, which can be used for pulmonary hypertension. In the prior art, flumatinib is used to treat cell proliferative diseases (such as cancer), and more specifically, this drug has been approved in China for the treatment of chronic myeloid leukemia.

[0023] The present invention constructs a mouse model of pulmonary hypertension. After flumatinib is administered by intraperitoneal injection, the fur, diet, activity, death and the like of the mouse model of pulmonary hypertension are observed. The results show that flumatinib can improve the survival rate of animals with pulmonary hypertension, and flumatinib can significantly inhibit the weight loss of mice with pulmonary hypertension after treatment, increase the food intake and water intake of mice with pulmonary hypertension, and flumatinib can reduce the right ventricular pressure of mice with pulmonary hypertension.

[0024] The invention provides a new technical means for the prevention and treatment of pulmonary hypertension, and will also give flumatinib a broad application prospect in the prevention and treatment of pulmonary hypertension. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The figure shows the changes in body weight of mice in the normoxia+solvent group, normoxia+flumatinib group, hypoxia+solvent group and hypoxia+flumatinib group at different days in Example 1. DETAILED DESCRIPTION

[0026] The present invention is further explained below with reference to the examples, but the examples do not limit the present invention in any form.

[0027] Example 1: Use of flumatinib mesylate in the preparation of a drug for treating pulmonary hypertension

[0028] (1) Animals and experimental reagents:

[0029] 24 mice (weight 20-25 g).

[0030] Flumatinib: 200 mg.

[0031] (2) Establishment of hypoxia-induced pulmonary hypertension model:

[0032] 2.1 Healthy male mice (weight 20-25 g).

[0033] 2.2 Trial Grouping and Drug Intervention

[0034] Twenty-four healthy male mice (weighing 20-25 g) were randomly divided into two groups, the experimental group and the control group, according to the principle of weight balance.

[0035] The mice in the control group were raised in a standard sterile breeding environment and randomly divided into two groups according to the principle of weight balance, namely, the normoxia + solvent group (the solvent volume was equal to that of the flumatinib group, the solvent was 0.9% saline, intraperitoneal injection method) and the normoxia + flumatinib group (flumatinib 600 mg / day / time, intraperitoneal injection method).

[0036] The mice in the experimental group were placed in a hypoxia box for adaptive hypoxia for one week (oxygen partial pressure 12%), and then randomly divided into 2 groups according to the principle of weight balance, namely, normoxia + solvent group (solvent with the same volume as the flumatinib group, the solvent was 0.9% saline, intraperitoneal injection method) and hypoxia + flumatinib group (flumatinib 600 mg / day / time, intraperitoneal injection method). After being placed in a hypoxia box for continuous hypoxia (oxygen partial pressure 10%) for 20 days, the fur, diet, activity, death, and the change of right ventricular pressure were observed.

[0037] (3) Results

[0038] 3.1 Flumatinib improves the survival rate of animals with pulmonary hypertension

[0039] Through research, it was found that animals with pulmonary hypertension induced by hypoxia began to die as the feeding time prolonged. 20 days after the injection of hypoxia, the mortality rate of the hypoxia + solvent group reached 83% (10 deaths, a total of 12 animals), while the mortality rate of hypoxia + flumatinib (flumatinib 600 mg / day / time, intraperitoneal injection) was only 50% (6 deaths, a total of 12 animals). This shows that flumatinib can improve the survival rate of animals with pulmonary hypertension. The results are shown in Table 1.

[0040] Table 1: Survival rates of the normoxia + solvent group, normoxia + flumatinib group, hypoxia + solvent group, and hypoxia + flumatinib group after 20 days, indicating that flumatinib can improve the survival rate of animals with pulmonary hypertension.

[0041]

[0042] Note: Hypoxia + Flumatinib group VS normoxia + Flumatinib group, P = 3.86*10^ -10 , that is, P < 0.05; hypoxia + flumatinib group VS hypoxia + solvent group, P = 9.91*10^-4 ,P<0.01. Among them, 0.01≤P<0.05 indicates a significant difference, and P<0.01 indicates an extremely significant difference. P value calculation formula: F(X)=TTEST(array1,array2,tails,type).

[0043] 3.2 Flumatinib improves the quality of life of animals with pulmonary hypertension

[0044] Through research, it was found that hypoxia induced pulmonary hypertension in mice. As the feeding time was prolonged, the mice not only began to die one after another, but also their weight gradually decreased during the feeding process, and their food and water intake gradually decreased, and their body hair became dull and lusterless. Flumatinib treatment can significantly inhibit weight loss and significantly increase the food and water intake of mice. The results are shown in Table 2 and Figure 1 shown.

[0045] Table 2: Changes in body weight of mice in the normoxia + solvent group, normoxia + flumatinib group, hypoxia + solvent group, and hypoxia + flumatinib group on different days. Figure 1 The results showed that hypoxia caused a gradual decrease in the amount of food and water intake of mice. Flumatinib treatment could significantly inhibit the weight loss of mice with pulmonary hypertension and increase the food and water intake of mice with pulmonary hypertension. After 20 days of hypoxia, the average weight of mice in the hypoxia + solvent group continued to decline, while the average weight of mice in the hypoxia + flumatinib group showed an upward trend since the 11th day. At the end of the experiment (the 20th day), the average weight of mice was higher than that at the beginning of the experiment (the 0th day). This showed that flumatinib could not only inhibit the weight loss of mice with pulmonary hypertension, but also effectively restore the survival status of mice.

[0046]

[0047]

[0048] Note: Hypoxia + Flumatinib group VS normoxia + Flumatinib group, P = 0.046, that is, P < 0.05; Hypoxia + Flumatinib group VS hypoxia + solvent group, P = 1.42*10^ -11 ,P<0.01. Among them, 0.01≤P<0.05 indicates a significant difference, and P<0.01 indicates an extremely significant difference. P value calculation formula: F(X)=TTEST(array1,array2,tails,type).

[0049] 3.3 Flumatinib can effectively reduce right ventricular pressure in mice with pulmonary hypertension

[0050] The study found that the right ventricular pressure increased significantly in the hypoxia-induced pulmonary hypertension model. The hypoxia+flumatinib group showed significantly reduced right ventricular pressure compared with the hypoxia+solvent group. The results are shown in Table 3.

[0051] Table 3: Right ventricular pressure values ​​of mice in the normoxia + solvent group, normoxia + flumatinib group, hypoxia + solvent group and hypoxia + flumatinib group on day 0 and day 20, indicating that flumatinib can reduce the right ventricular pressure of mice with pulmonary hypertension.

[0052]

[0053] Note: Hypoxia + Flumatinib group VS normoxia + Flumatinib group, P = 6.46*10^ -8 ,P<0.01; hypoxia+flumatinib group VS hypoxia+solvent group,P=6.38*10^ -5 ,P<0.01. Among them, 0.01≤P<0.05 indicates a significant difference, and P<0.01 indicates an extremely significant difference. P value calculation formula: F(X)=TTEST(array1,array2,tails,type).

[0054] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. Use of flumatinib and / or its pharmaceutically acceptable salt in the preparation of a drug for treating pulmonary arterial hypertension.

2. The use according to claim 1, characterized in that: The drug includes flumatinib or a pharmaceutically acceptable salt thereof.

3. The use according to claim 1, characterized in that: The chemical name of flumatinib is N-[6-methyl-5-[[4-(pyridin-3-yl)pyrimidin-2-yl]amino]pyridin-3-yl]-4-[(4-methylpiperazine-1-yl)methyl]-3-(trifluoromethyl)benzamide, and the chemical structure is shown in Formula 1:

4. The use according to claim 2, characterized in that: The pharmaceutically acceptable salt is methanesulfonate.

5. The use according to claim 1 or 2, characterized in that: The medicine further includes a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient.

6. The use according to claim 1 or 2, characterized in that: The pharmaceutically acceptable auxiliary material is an excipient.

7. The use according to claim 1, characterized in that: The dosage form of the medicine is tablet, capsule, oral liquid, lozenge, granule, granule, pill, powder, paste, pill, suspension, powder or injection.

8. The use according to claim 1, characterized in that: The administration route of the drug is oral, transdermal, intramuscular, subcutaneous or intravenous injection.

9. A drug for treating pulmonary hypertension, characterized in that: The active ingredient of the drug includes flumatinib and / or a pharmaceutically acceptable salt thereof.

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