New application of HIF compound and pharmaceutical composition thereof in preparation of medicine

Abstract

New application of the HIF compound and the pharmaceutical composition thereof in preparation of drugs for treating diseases comprises application in preparation of drugs for preventing or treating anemia induced by chemotherapy in non-myeloid malignant tumor subjects, altitude sickness and the like.

Description

Technical Field

[0001] The present invention belongs to the field of medical application technology, and relates to a new use of HIF compounds and pharmaceutical compositions thereof in the preparation of drugs for treating diseases, including their use in the preparation of drugs for preventing or treating chemotherapy-induced anemia in subjects with non-myeloid malignancies, as well as altitude sickness and the like. Background Art

[0002] Chemotherapy-induced anemia (CIA) is the result of a decrease in red blood cells (RBC) produced by the bone marrow due to myelosuppression by chemotherapy agents, which reduces the hemoglobin (Hb) level. The low-pressure and low-oxygen environment of plateaus above 3,000 meters above sea level has a great impact on human health, especially when people who have not adapted to the plateau quickly enter the plateau from the plains, they are very likely to develop acute mountain sickness. There is currently a lack of effective oral drugs for such patients.

[0003] CN118634223A discloses a method for treating anemia associated with cancer chemotherapy in a subject undergoing chemotherapy using a chemotherapeutic agent, comprising orally administering to the subject a therapeutically effective amount of roxadustat, wherein the anemia is treated.

[0004] Chin Heart J 2021, 33(5): 472-477 disclosed the effect of roxadustat on the adaptation of cardiac function to acute high-altitude hypoxia and its mechanism. Among them, roxadustat can upregulate the protein levels of HIF-1α and HIF-2α by inhibiting PHD2 activity, while reducing myocardial damage, thereby promoting the adaptation of mouse cardiac function in the high-altitude hypoxic environment.

[0005] Currently, there are no oral HIF compound drugs approved for marketing for related drug uses, so further research and exploration is needed. Summary of the invention

[0006] In view of the problems existing in the prior art, the present invention provides new uses of HIF compounds and pharmaceutical compositions thereof in the preparation of drugs for treating diseases, including use in the preparation of drugs for preventing or treating chemotherapy-induced anemia in subjects with non-myeloid malignancies, and altitude sickness.

[0007] Specifically, the present invention is achieved through the following technical solutions:

[0008] The present invention provides the use of a HIF compound in the preparation of a medicament for preventing or treating chemotherapy-induced anemia in a subject with a non-myeloid malignancy, wherein the compound has the following structure:

[0009]

[0010] The present invention also provides the use of a HIF compound in the preparation of a drug for preventing or treating altitude sickness, wherein the compound has the following structure:

[0011]

[0012] The present invention also provides the use of a pharmaceutical composition containing a HIF compound in the preparation of a medicament for preventing or treating chemotherapy-induced anemia in a subject with a non-myeloid malignancy, wherein the compound has the following structure:

[0013]

[0014] The present invention also provides the use of a pharmaceutical composition containing a HIF compound in the preparation of a drug for preventing or treating altitude sickness, wherein the compound has the following structure:

[0015]

[0016] The present invention also provides the use of a HIF compound in the preparation of a medicament for preventing or treating chemotherapy-induced anemia in a subject with a non-myeloid malignancy, wherein the compound has the following structure:

[0017]

[0018] The present invention also provides the use of a HIF compound in the preparation of a drug for preventing or treating altitude sickness, wherein the compound has the following structure:

[0019]

[0020] The present invention also provides the use of a pharmaceutical composition containing a HIF compound in the preparation of a medicament for preventing or treating chemotherapy-induced anemia in a subject with a non-myeloid malignancy, wherein the compound has the following structure:

[0021]

[0022] The present invention also provides the use of a pharmaceutical composition containing a HIF compound in the preparation of a drug for preventing or treating altitude sickness, wherein the compound has the following structure:

[0023]

[0024] The present invention also provides the use of a HIF compound in the preparation of a medicament for preventing or treating chemotherapy-induced anemia in a subject with a non-myeloid malignancy, wherein the compound has the following structure:

[0025]

[0026] The present invention also provides the use of a HIF compound in the preparation of a drug for preventing or treating altitude sickness, wherein the compound has the following structure:

[0027]

[0028] The present invention also provides the use of a pharmaceutical composition containing a HIF compound in the preparation of a medicament for preventing or treating chemotherapy-induced anemia in a subject with a non-myeloid malignancy, wherein the compound has the following structure:

[0029]

[0030] The present invention also provides the use of a pharmaceutical composition containing a HIF compound in the preparation of a drug for preventing or treating altitude sickness, wherein the compound has the following structure:

[0031]

[0032] The pharmaceutical composition contains more than one excipient.

[0033] As a preferred technical solution of the present invention, the chemotherapy subject is receiving multiple cycles of platinum-based myelosuppressive chemotherapy, and further, the platinum drug is selected from carboplatin, lobaplatin, cisplatin, nedaplatin, oxaliplatin and the like.

[0034] As a preferred technical solution of the present invention, the chemotherapy subject is receiving multiple cycles of basic chemotherapy, and further, the basic chemotherapy is selected from docetaxel, gemcitabine, paclitaxel, pemetrexed, tamoxifen and the like.

[0035] As a preferred technical solution of the present invention, the altitude sickness is acute altitude sickness.

[0036] As a preferred technical solution of the present invention, the angioedema is high altitude pulmonary edema and angioedema.

[0037] As a preferred technical solution of the present invention, the drug contains additional active ingredients for preventing or treating altitude sickness caused by hypobaric hypoxia, such as Rhodiola rosea, recombinant human erythropoietin EPO for injection, etc.

[0038] As a preferred technical solution of the present invention, the daily dose of compound 1 is about 1 mg to about 1000 mg, including: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 ,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73 ,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100mg.

[0039] As a preferred technical solution of the present invention, the usage can be once a day, or twice or three times a day as needed, wherein each drug can be given a starting dose as needed, and then the dose can be adjusted according to the change of Hb of the subject; for example, the starting dose of compound 1 is about 1 mg to about 1000 mg, including: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 mg and the like.

[0040] As a preferred technical solution of the present invention, the daily dose of compound 2 is about 1 mg to about 1000 mg, including: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 ,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73 ,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100mg.

[0041] As a preferred technical solution of the present invention, the usage can be once a day, or twice or three times a day as needed, wherein each drug can be given a starting dose as needed, and then the dose can be adjusted according to the change of Hb of the subject; for example, the starting dose of compound 2 is about 1 mg to about 1000 mg, including: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 mg and the like.

[0042] As a preferred technical solution of the present invention, the daily dose of compound 3 is about 1 mg to about 1000 mg, including: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 ,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73 ,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100mg.

[0043] As a preferred technical solution of the present invention, the usage can be once a day, or twice or three times a day as needed, wherein each drug can be given a starting dose as needed, and then the dose can be adjusted according to the change of Hb of the subject; for example, the starting dose of compound 3 is about 1 mg to about 1000 mg, including: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 mg and the like.

[0044] As an implementation scheme of the present invention, the compound can be obtained by a method reported in the literature, wherein:

[0045] The preparation of compound 1 can refer to the records of CN201380067856.4, the preparation of the crystalline form can refer to the records of CN202280022325.2, the preparation of the amorphous form can refer to the records of PCT / IB2022 / 057993, and the salt and its preparation method can refer to the records of PCT / IB2021 / 052090.

[0046] The preparation of compounds 2 and 3 can refer to the record in CN201380067856.4, and the preparation of the crystalline forms of compounds 2 and 3 can refer to CN115368303 and CN115010662.

[0047] The beneficial effects of the present invention compared with the prior art include but are not limited to:

[0048] The use of the compound of the present invention in the preparation of a drug for treating chemotherapy-induced anemia in non-myeloid malignancies and increasing the level of red blood cells in the hypoxic state of altitude sickness can inhibit the activity of PHD2 and upregulate the protein levels of HIF-1α and HIF-2α, and is expected to exhibit good preventive and therapeutic effects. DETAILED DESCRIPTION

[0049] The present invention is further described in detail below with reference to examples, but the embodiments of the present invention are not limited thereto.

[0050] Example 1 Evaluation of atmospheric pressure airtight hypoxia resistance test

[0051] Experimental method: 60 C57BL / 6J mice were divided into 6 groups, namely, vehicle + normoxia group, vehicle + hypoxia group, compound 1, 2 and 3 (10 mg / kg) + hypoxia group, rosuvastatin (10 mg / kg) + hypoxia group, with 10 mice in each group.

[0052] The hypoxic mice were placed in a simulated high altitude hypoxic environment for 1 week, and were given 10 mg / kg of compounds 1, 2 and 3, roxadustat, or an equal amount of normal saline by oral gavage every day starting from the first day.

[0053] Vehicle + normoxic group: The mice were kept in a normoxic environment and given an equal amount of normal saline by gavage.

[0054] Compared with the vehicle + hypoxia group, the experimental results are as follows:

[0055] (1) The survival time of mice in the groups treated with compounds 1, 2 and 3 was significantly prolonged, showing a significant improvement.

[0056] (2) Compounds 1, 2 and 3 can significantly increase the improvement of red blood cell count (RBC), increasing by 3%-5%.

[0057] (3) EPO test results showed that 24 hours after the last administration, EPO levels in the compound 1, 2 and 3 groups were still maintained at a relatively high level.

[0058] Example 2 Experimental evaluation of cisplatin-induced renal anemia in rats

[0059] Experimental method: 60 male SD rats were divided into 6 groups and randomly divided into normal control group, cisplatin group, and drug administration group: compounds 1, 2 and 3 (10 mg / kg), roxadustat (100 mg / kg), with 10 rats in each group.

[0060] The cisplatin group and the drug-treated group were injected with 8 mg / kg cisplatin by tail vein once. From the 15th day to the 29th day after the injection of cisplatin, the drug-treated group was given 10 mg / kg (dissolved or suspended in saline, by oral gavage) of compounds 1, 2 and 3 and rosuvastatin every day, and the cisplatin group and the normal control group were given an equal amount of saline by oral gavage every day.

[0061] Experimental results: The fetal liver cell 3H-TdR permeation method was used to detect the content of erythropoietin (EPO) in rat serum. The EPO levels in the compound 1, 2 and 3 groups remained at a relatively high level. Compared with the cisplatin group, the EPO levels in the compound 1, 2 and 3 groups increased by about 10% on the 10th day after administration.

[0062] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. Use of a HIF compound in the preparation of a medicament for preventing or treating chemotherapy-induced anemia in a subject with a non-myeloid malignancy, wherein the compound has the following structure:

2. Use of a HIF compound in the preparation of a drug for preventing or treating altitude sickness, wherein the compound has the following structure:

3. Use of a pharmaceutical composition containing a HIF compound in the preparation of a medicament for preventing or treating chemotherapy-induced anemia in a subject with a non-myeloid malignancy, wherein the compound has the following structure:

4. Use of a pharmaceutical composition containing a HIF compound in the preparation of a drug for preventing or treating altitude sickness, wherein the compound has the following structure:

5. Use of a HIF compound in the preparation of a medicament for preventing or treating chemotherapy-induced anemia in a subject with a non-myeloid malignancy, wherein the compound has the following structure:

6. Use of a HIF compound in the preparation of a drug for preventing or treating altitude sickness, wherein the compound has the following structure:

7. Use of a pharmaceutical composition containing a HIF compound in the preparation of a medicament for preventing or treating chemotherapy-induced anemia in a subject with a non-myeloid malignancy, wherein the compound has the following structure:

8. Use of a pharmaceutical composition containing a HIF compound in the preparation of a drug for preventing or treating altitude sickness, wherein the compound has the following structure:

9. Use of a HIF compound or a pharmaceutical composition containing a HIF compound in the preparation of a medicament for preventing or treating chemotherapy-induced anemia in a subject with a non-myeloid malignancy, wherein the compound has the following structure:

10. Use of a HIF compound or a pharmaceutical composition containing a HIF compound in the preparation of a drug for preventing or treating altitude sickness, wherein the compound has the following structure:

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