Use of compound in preparing medicament for treating anemia in non-myeloid malignant tumor patient

Abstract

Provided is use of a compound and a pharmaceutical composition thereof in preparing a medicament for treating anemia in a non-myeloid malignant tumor patient receiving chemotherapy, wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazole[1,5-a]pyridine-8-carbonyl]glycine.

Description

Application of compounds in the preparation of drugs for treating anemia in patients with non-myeloid malignancies Technical Field

[0001] The present invention belongs to the field of medical application technology and relates to the use of a compound and a pharmaceutical composition thereof in the preparation of a drug for treating anemia in patients with non-myeloid malignancies undergoing chemotherapy, wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]glycine. Background Art

[0002] CN102471337B discloses triazolopyridine compounds having prolyl hydroxylase inhibitory effects and erythropoietin production induction capabilities, specifically including compounds having the following structure:

[0003] Anemia is common in patients with non-myeloid malignancies undergoing chemotherapy. Currently, there are few effective oral medications for these patients. Myeloid malignancies can be classified according to the WHO classification; all other types of malignancies are considered non-myeloid. Summary of the Invention

[0004] In view of the problems existing in the prior art, the present invention first provides the use of a compound in the preparation of a drug for treating anemia in patients with non-myeloid malignancies undergoing chemotherapy (also known as "anemia induced by chemotherapy in patients with non-myeloid malignancies"), wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]glycine (Compound A).

[0005] The N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]glycine is a compound having the following structure:

[0006] Further provided is the use of a pharmaceutical composition containing a compound for the preparation of a medicament for treating anemia in patients with non-myeloid malignancies undergoing chemotherapy, wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]glycine, and the pharmaceutical composition contains one or more excipients.

[0007] As a preferred technical solution of the present invention, the daily dose is about 1 mg to about 30 mg, including:

[0008] 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9; 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9; 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9; 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9; 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9; 6, 6.1, 6.2, 6.3 9 , 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9; 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30mg.

[0009] As a preferred technical solution of the present invention, the patient is receiving platinum-based myelosuppressive chemotherapy.

[0010] As a preferred technical solution of the present invention, the patient is receiving non-platinum myelosuppressive chemotherapy.

[0011] As a preferred technical solution of the present invention, the chemotherapy is myelosuppressive chemotherapy, and the myelosuppressive chemotherapy agent includes:

[0012] Atezolizumab, bevacizumab, reslizumab, cetuximab, denosumab, durvalumab, envolimab, initutumab, pembrolizumab, penampalimumab, tislelizumab, sintilimab, toripalimab;

[0013] Gefitinib, cabotinib, pyrotinib, apatinib;

[0014] Carboplatin, cisplatin, lobaplatin, nedaplatin, oxaliplatin;

[0015] Paclitaxel, docetaxel, capecitabine, gemcitabine, cyclophosphamide, epirubicin, eribulin, etoposide, fluorouracil, fulvestrant, irinotecan, doxorubicin, cantharidin, oteracil, pemetrexed, pyridoxine, tamoxifen, tegafur, and vinorelbine.

[0016] As a preferred technical solution of the present invention, the non-myeloid malignant tumors include breast cancer, lung cancer, gastrointestinal cancer, gynecological cancer, pancreatic cancer and head and neck cancer.

[0017] As a preferred technical solution of the present invention, the lung cancer includes: small cell lung cancer, non-small cell lung cancer; gastrointestinal cancer includes gastric cancer, colon and rectal cancer; gynecological cancer includes: cervical cancer, endometrial cancer, ovarian cancer.

[0018] As a preferred technical solution of the present invention, the platinum chemotherapy includes the use of carboplatin, cisplatin and other drugs for non-myeloid malignancies, wherein:

[0019] Cisplatin is mainly used to treat testicular tumors and osteosarcoma. It also has certain therapeutic effects on ovarian cancer, breast cancer, lung cancer, head and neck cancer, bladder cancer, malignant lymphoma, esophageal cancer, gastric cancer, and cervical cancer.

[0020] The indications of carboplatin mainly include small cell lung cancer, ovarian cancer, testicular cancer, head and neck squamous cell carcinoma, bladder cancer, pleural mesothelioma, cervical cancer, and non-small cell lung cancer.

[0021] As an embodiment of the present invention, the preparation of the compound is introduced into the present invention by the technical solution described in CN201780072928.2;

[0022] The crystal form and preparation used in the pharmaceutical composition are introduced into the present invention by the technical solution described in US20200017492A1.

[0023] The beneficial effects of the present invention over the prior art include but are not limited to:

[0024] (1) The use of the compound of the present invention in the preparation of a drug for treating chemotherapy-induced anemia in patients with non-myeloid malignancies is superior to roxadustat in terms of lower dosage and fewer adverse reactions. However, no significant improvement was observed in myeloid animals. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the clinical trial process of Enadostat (Compound A) tablets in Example 3.

[0026] Figure 2 is the clinical dose adjustment plan for Enadostat (Compound A) tablets in Example 3.

[0027] Figure 3. Hb test results in the central laboratory.

[0028] Figure 4. Hct test results from the local laboratory.

[0029] Figure 5 is a schematic diagram of the platelet count in the peripheral blood of rats in Example 4.

[0030] Figure 6 is a schematic diagram of the number of peripheral blood red blood cells in rats in Example 4. DETAILED DESCRIPTION

[0031] The present invention is further described in detail below with reference to the examples, but the embodiments of the invention are not limited thereto. Experiment 1: Study on the therapeutic effect of compound A on carboplatin-induced anemia in rats

[0032] Experimental method: Male SD rats (200-230g) were used. After the animal quarantine and adaptation period, they were randomly divided into groups according to their hematocrit. The groups were: normal control group, model control group, rosuvastatin group (40mg / kg), and low-, medium-, and high-dose groups of compound A (1, 3, and 10mg / kg), with ten rats in each group.

[0033] On the first day of the experiment (D1), the normal control group was intraperitoneally administered with the solvent, and each group was intravenously injected with carboplatin (45 mg / kg) to establish the model. Rosuvastatin (40 mg / kg) or compound A (1, 3, 10 mg / kg) or the solvent was administered by gavage 2 hours before modeling. After that, the rosuvastatin treatment group continued to receive the drug by gavage on Day 3, 5, 8, 10, and 12. The compound A group) was given the drug once a day for 14 consecutive days.

[0034] The test indicators include: whole blood was collected on the 14th day after the first administration (D14), anticoagulated with EDTA-K2, and hematological indicators such as red blood cell count (RBC), hematocrit (HCT), and hemoglobin concentration (Hb) were measured using a fully automatic blood cell analyzer within 1 hour after blood collection. The results are shown in Table 1.

[0035] Table 1

[0036] Results: Day 14 results showed that the RBC, Hct, and Hb indicators of animals in the Compound A (1, 3, and 10 mg / kg) treatment groups were significantly improved and were superior to those of roxadustat.

[0037] Experiment 2: Study on the therapeutic effect of compound A on cisplatin-induced anemia in rats

[0038] Experimental method: Male Wistar rats (200-230g) were used. After the animal quarantine and adaptation period, they were randomly divided into groups according to hematocrit: normal control group, model control group, low-dose, medium-dose and high-dose groups of compound A (1, 3 and 10 mg / kg), with ten rats in each group.

[0039] On the first day of the experiment (D1), the normal control group was intraperitoneally administered with the vehicle, and each group was intravenously injected with cisplatin (5 mg / kg) to establish the model. Compound A (1, 3, 10 mg / kg) or the vehicle was administered by gavage 2 hours before modeling. The compound A group was given the drug once a day for 14 consecutive days.

[0040] The detection indicators include: whole blood was collected on the 14th day after the first administration (D 14), anticoagulated with EDTA-K2, and hematological indicators such as red blood cell count (RBC), hematocrit (HCT), and hemoglobin concentration (Hb) were measured using a fully automatic blood cell analyzer within 1 hour after blood collection.

[0041] Results: Day 14 results showed that the RBC, Hct, and Hb indicators of animals in the Compound A (1, 3, and 10 mg / kg) treatment groups were significantly improved.

[0042] Example 3:

[0043] Purpose of the test:

[0044] To evaluate the safety and efficacy of Enadostat (Compound A) tablets in the treatment of chemotherapy-induced anemia in patients with non-myeloid malignancies, the effects on red blood cell and iron metabolism test values, and the pharmacokinetic characteristics

[0045] Trial drug:

[0046] Enadostat, 1mg, 2mg, 4mg, 5mg tablets

[0047] Test process:

[0048] It includes a screening period (4 weeks), an open treatment period (up to 16 weeks), and a follow-up period (2 weeks), lasting a total of approximately 22 weeks.

[0049] Dosage regimen:

[0050] The patients were divided into 4mg and 5mg groups according to the starting dose. The dose was adjusted every 4 weeks based on the subjects' Hb levels to achieve an Hb level of ≥100 and <120 g / L. The trial flow chart and dose adjustment rules are shown in Figures 1 and 2, respectively:

[0051] · For the 4 mg starting dose group, the dose can be adjusted in steps of 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, and 10 mg, but not across levels;

[0052] 5 mg starting dose group: Adjust the dose in steps of 2 mg, 3 mg, 5 mg, 7 mg, 9 mg, and 11 mg, and do not skip the dose.

[0053] · Administer orally once daily before meals or before bedtime for up to 16 weeks. If the subject completes the entire chemotherapy course, the study treatment needs to be terminated.

[0054] Taking the medication before a meal is defined as taking the medication at least 1 hour before the next meal and at least 2 hours after the previous meal. It is recommended to take the medication before the same meal every day.

[0055] Inclusion criteria:

[0056] Subjects who meet all of the following criteria can be included in this trial

[0057] 1. For Chinese male and female subjects aged 18 and above, the subject must be at least 18 years old (including the day they turn 18) when signing the ICF.

[0058] 2. Weight ≥40kg during the screening period;

[0059] 3. Patients diagnosed with non-myeloid malignancies (non-curable) by histology or cytology, and planned to receive at least 8 weeks of anti-tumor treatment (myelosuppressive chemotherapy) after the first dose (Day 1);

[0060] 4. Myelosuppressive chemotherapy-related anemia, defined as Hb ≤ 100 g / L in the central laboratory during the screening period, and the investigator's judgment that there is a record showing that the subject's Hb level has decreased by ≥ 10 g / L after the start of chemotherapy;

[0061] 5. Ferritin ≥50 ng / mL and TSAT ≥10% in the screening laboratory;

[0062] 6. Eastern Cooperative Oncology Group (ECOG) performance status score ≤1 during the screening period;

[0063] 7. Life expectancy ≥ 6 months as determined by the investigator during the screening period;

[0064] 8. All male subjects and female subjects of childbearing potential agree to take medically acceptable contraceptive measures from the date of signing the ICF until 90 days after the last dose of the investigational drug;

[0065] 9. Volunteer to participate in the trial and sign the informed consent form. Be able to understand the procedures and methods of this trial and be willing to strictly abide by the clinical trial protocol to complete the trial.

[0066] The study found that after 5 weeks of dosing, some patients had elevated Hb levels by more than 5 g / L. The results of Hb testing by the central laboratory and Hct testing by the local laboratory are shown in Figures 3 and 4, respectively, showing some improvement in both Hb and Hct.

[0067] Example 4: Therapeutic effect of compound A on chemotherapy-induced anemia

[0068] This experiment used the human hepatocellular carcinoma cell line HUH-7. After cell expansion and culture, tumor cells in the logarithmic growth phase were used to inoculate tumors in mice. After harvesting, the cells were washed twice with PBS and adjusted to a cell suspension of appropriate density for later use. The cell suspension was injected subcutaneously into the left flank of BALB / c nude mice at a concentration of 100 μL per mouse, with a total number of 2 × 10 cells injected. 6cells / mouse. When the tumor grows to an average volume of approximately 100-120 mm 3 At 4 hr, animals were randomly divided into groups based on tumor volume and body weight for drug administration (the day of grouping was designated as Day 0). Drug administration began on the day following grouping (Day 1). Grouping and drug administration are shown in Table 2.

[0069] Table 2 Grouping and dosing table

[0070] Mice in the vehicle control group received vehicle by intraperitoneal injection and oral gavage. Mice in the carboplatin-alone group received carboplatin (100 mg / kg) by intraperitoneal injection every two weeks and vehicle by oral gavage daily. Animals in the combination group received carboplatin (100 mg / kg) by intraperitoneal injection and Compound A (60 mg / kg) or roxadustat (60 mg / kg) by oral gavage daily. The entire experimental period lasted 20 days, with carboplatin administered twice and Compound A or roxadustat administered 20 times.

[0071] On Days 8, 15, and 20 after administration, 50 μL of whole blood was collected from the eye sockets and placed in EDTA-K2 anticoagulant tubes. Red blood cell count (RBC), hemoglobin (Hb), and hematocrit (Hct) were measured using a complete blood cell analyzer. At the end of the experiment, the animals were euthanized. The results are shown in Table 3.

[0072] Table 3 Mouse cell parameter values ​​during drug administration

[0073] The results showed that after carboplatin was administered to tumor-bearing mice, red blood cell parameters decreased significantly over time, indicating that chemotherapy drugs caused anemia in mice with subcutaneous liver cancer transplantation. After the administration of compound A or roxadustat, the values ​​of RBC, Hb, and Hct were significantly improved, and at the same dose, the degree of improvement of compound A was better than that of roxadustat.

[0074] Example 5: Effect of Compound A on Myelodysplastic Syndrome Rat Model

[0075] 1. Methods

[0076] 4-5 week old SD rats were randomly divided into normal control group and modeling animals. Before model induction, blood was collected from all experimental animals and initial hematological values ​​were tested.

[0077] Modeling: On Day 0, animals were injected intravenously (iv) with 35 mg / kg of dimethylbenzanthracene (DMBA) as a modeling agent for the first induction. On Day 11, a second induction was performed with an intravenous injection of 35 mg / kg of dimethylbenzanthracene (DMBA). On Day 14, blood was collected from the animals undergoing modeling and hematological parameters were tested. These parameters were used as the pre-dose baseline, and the animals were divided into pre-dose groups: a model control group, a roxadustat group (10 mg / kg), and a compound A group (10 mg / kg), and drug administration was initiated.

[0078] Dosing and Index Assessment: Starting on Day 15, the normal control group, model control group, roxadustat group (10 mg / kg), and Compound A group (10 mg / kg) were administered with vehicle or the corresponding drug. Hematological tests were performed on Day 21 and Day 28, i.e., the first and second weeks after dosing, and the differences in hematological indicators were analyzed and compared.

[0079] 2. Experimental Results

[0080] After two injections of DMBA, the rats' peripheral blood red blood cells and platelets decreased significantly, indicating successful simulation of myelodysplastic syndrome in rats based on literature reports. Starting on day 14 of the initial modeling, and continuing for two weeks, the rosuvastatin (10 mpk) and compound A (10 mpk) treatment groups showed no significant changes in hematological parameters compared to the model group. Therefore, it is concluded that the two drugs did not improve disease symptoms in this model. This is shown in Figures 5 and 6.

[0081] 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 considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. Use of a compound in the preparation of a medicament for treating anemia in patients with non-myeloid malignancies undergoing chemotherapy, wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]glycine.

2. Use of a pharmaceutical composition containing a compound for the preparation of a medicament for treating anemia in patients with non-myeloid malignancies undergoing chemotherapy, wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]glycine, and the pharmaceutical composition contains one or more excipients.

3. The use according to claim 1 or 2, wherein the daily dose is from about 1 mg to about 30 mg.

4. The use according to claim 1 or 2, wherein the patient is receiving platinum-based myelosuppressive chemotherapy.

5. The use according to claim 1 or 2, wherein the patient is receiving non-platinum myelosuppressive chemotherapy.

6. The use according to claim 1 or 2, wherein the chemotherapy is myelosuppressive chemotherapy, and the myelosuppressive chemotherapy agent comprises: Atezolizumab, bevacizumab, reslizumab, cetuximab, denosumab, durvalumab, envolimab, initutumab, pembrolizumab, penampalimumab, tislelizumab, sintilimab, toripalimab; Gefitinib, cabotinib, pyrotinib, apatinib; Carboplatin, cisplatin, lobaplatin, nedaplatin, oxaliplatin; Paclitaxel, docetaxel, capecitabine, gemcitabine, cyclophosphamide, epirubicin, eribulin, etoposide, fluorouracil, fulvestrant, irinotecan, doxorubicin, cantharidin, oteracil, pemetrexed, pyridoxine, tamoxifen, tegafur, and vinorelbine.

7. The use according to claim 1 or 2, wherein the non-myeloid malignancies include breast cancer, lung cancer, gastrointestinal cancer, gynecological cancer, pancreatic cancer and head and neck cancer.

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