Application of the compound in the preparation of drugs for treating anemia in patients with non-myeloid malignant tumors

Abstract

The use of the compound and its pharmaceutical composition in the preparation of a drug for treating anemia in patients with non-myeloid malignant tumors undergoing chemotherapy, wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazole[1,5-a]pyridine-8-carbonyl]glycine.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical application technology, and relates to the use of compounds and their pharmaceutical compositions in the preparation of drugs for treating anemia in patients with non-myeloid malignant tumors undergoing chemotherapy, wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazole[1,5-a]pyridine-8-carbonyl]glycine. Background Technology

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

[0003]

[0004] 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; those other than myeloid malignancies are considered non-myeloid malignancies. Summary of the Invention

[0005] In view of the problems existing in the prior art, the present invention first provides the use of the compound in the preparation of a drug for treating anemia in patients with non-myeloid malignancies who have undergone chemotherapy (also known as "chemotherapy-induced anemia in patients with non-myeloid malignancies"), wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazole[1,5-a]pyridine-8-carbonyl]glycine (compound A).

[0006] The N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazole[1,5-a]pyridine-8-carbonyl]glycine is a compound having the following structure:

[0007]

[0008] Further, the use of a pharmaceutical composition containing a compound in the preparation of a medicament for treating anemia in patients with non-myeloid malignancies who have undergone chemotherapy is provided, wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazole[1,5-a]pyridine-8-carbonyl]glycine, and the pharmaceutical composition contains one or more excipients.

[0009] As a preferred embodiment of the present invention, the daily dose is from about 1 mg to about 30 mg, comprising:

[0010] 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.

[0011] As a preferred embodiment of the present invention, the patient is receiving platinum-based myelosuppressive chemotherapy.

[0012] As a preferred embodiment of the present invention, the patient is receiving non-platinum-based myelosuppressive chemotherapy.

[0013] As a preferred embodiment of the present invention, the chemotherapy is myelosuppressive chemotherapy, and the myelosuppressive chemotherapy agent includes:

[0014] Atezolizumab, bevacizumab, relizumab, cetuximab, denosumab, durvalumab, envorimab, inetuximab, pembrolizumab, penprimab, tislelizumab, sintilimab, toripalimab;

[0015] Gefitinib, carquetinib, pyrotinib, apatinib;

[0016] Carboplatin, cisplatin, lobaplatin, nedaplatin, oxaliplatin;

[0017] Paclitaxel, docetaxel, capecitabine, gemcitabine, cyclophosphamide, epirubicin, eribulin, etoposide, fluorouracil, fulvestrant, irinotecan, doxorubicin, cantharidin, oteracil, pemetrexed, pyridoxine, tamoxifen, tegafur, and vinorelbine.

[0018] As a preferred embodiment 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.

[0019] As a preferred embodiment of the present invention, the lung cancer includes: small cell lung cancer and non-small cell lung cancer; gastrointestinal cancer includes gastric cancer, colon and rectal cancer; gynecological cancer includes: cervical cancer, endometrial cancer and ovarian cancer.

[0020] As a preferred embodiment of the present invention, the platinum-based chemotherapy includes the use of carboplatin, cisplatin, and other drugs for non-myeloid malignant tumors, wherein:

[0021] Cisplatin is primarily used to treat testicular tumors and osteosarcoma. It also shows some efficacy in treating ovarian cancer, breast cancer, lung cancer, head and neck cancer, bladder cancer, malignant lymphoma, esophageal cancer, gastric cancer, and cervical cancer.

[0022] The main indications for carboplatin 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.

[0023] As one embodiment of the present invention, the preparation of the compound is described in CN201780072928.2, which is incorporated herein by reference.

[0024] The crystal form and formulation used in the pharmaceutical composition are incorporated herein by reference to the technical solution described in US20200017492A1.

[0025] The advantages of this invention over the prior art include, but are not limited to:

[0026] (1) The application of the compound of the present invention in the preparation of a drug for treating anemia caused by chemotherapy in patients with non-myeloid malignant tumors shows that it is superior to roxadustat in terms of smaller dosage and fewer adverse reactions. However, no significant improvement was observed in the experimental results for myeloid animals. Attached Figure Description

[0027] Figure 1 Example 3: Clinical trial procedure for Ennadustat (Compound A) tablets.

[0028] Figure 2 Example 3: Clinical dosage adjustment protocol for ennadustat (compound A) tablets.

[0029] Figure 3 Hb test results from the central laboratory.

[0030] Figure 4 The results of Hct testing at the local laboratory.

[0031] Figure 5 Example 4: Schematic diagram of platelet count in rat peripheral blood.

[0032] Figure 6 Example 4: Schematic diagram of the number of peripheral blood red blood cells in rats. Detailed Implementation

[0033] The present invention will be further described in detail below with reference to the embodiments, but the implementation of the invention is not limited thereto. Experiment 1: Study on the therapeutic effect of compound A on a carboplatin-induced rat anemia model

[0034] Experimental methods: Male SD 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, roxadustat group (40mg / kg), and low, medium and high dose groups of compound A (1, 3 and 10mg / kg), with ten rats in each group.

[0035] On the first day of the experiment (D1), the normal control group was given a solvent intraperitoneally, while each group was given carboplatin (45 mg / kg) intravenously to establish the model. Two hours before modeling, roxadustat (40 mg / kg) or compound A (1, 3, 10 mg / kg) or the solvent was administered by gavage. The roxadustat treatment group continued to be administered by gavage on Days 3, 5, 8, 10, and 12, while the compound A group was administered once daily for 14 consecutive days.

[0036] The detection indicators included: whole blood was collected on day 14 (D14) after the first administration, 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 automated blood cell analyzer within 1 hour after blood collection. The results are shown in Table 1.

[0037] Table 1

[0038]

[0039] Results: Day 14 results showed that the RBC, Hct, and Hb indices of animals treated with compound A (1, 3, and 10 mg / kg) were significantly improved, and were superior to those of roxadustat.

[0040] Experiment 2: Therapeutic effect of compound A on cisplatin-induced rat anemia model

[0041] Experimental methods: 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, and low, medium and high dose groups of compound A (1, 3 and 10 mg / kg), with ten rats in each group.

[0042] On the first day of the experiment (D1), the normal control group was given a solvent intraperitoneally, while each group was given cisplatin (5 mg / kg) intravenously to induce modeling. Two hours before modeling, compound A (1, 3, or 10 mg / kg) or the solvent was administered by gavage. The compound A group was given once daily for 14 consecutive days.

[0043] The detection indicators include: whole blood was collected on day 14 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 automated blood cell analyzer within 1 hour after blood collection.

[0044] Results: Day 14 results showed that the RBC, Hct, and Hb levels in animals treated with compound A (1, 3, and 10 mg / kg) were significantly improved.

[0045] Example 3:

[0046] Experimental objective:

[0047] To evaluate the safety and efficacy of endostat (compound A) tablets in treating chemotherapy-induced anemia in patients with non-myeloid malignancies, including its effects on erythrocyte-related and iron metabolism-related values, and its pharmacokinetic characteristics.

[0048] Experimental drug:

[0049] Ennadustat, 1mg, 2mg, 4mg, 5mg, tablets

[0050] Test procedure:

[0051] The study includes a screening period (4 weeks), an open-label treatment period (up to 16 weeks), and a follow-up period (2 weeks), lasting a total of approximately 22 weeks.

[0052] Dosage regimen:

[0053] Subjects were divided into two groups based on their initial dose: a 4 mg initial dose group and a 5 mg initial dose group. Individualized dose adjustments were made every 4 weeks based on the subjects' hemoglobin (Hb) levels to ensure Hb levels were ≥100 and <120 g / L. The trial flowchart and dose adjustment rules are detailed below. Figure 1 and 2 As shown:

[0054] • Starting dose 4mg group: Adjustments should be made stepwise between 1mg, 2mg, 4mg, 6mg, 8mg and 10mg, without skipping levels;

[0055] • Starting dose 5mg group: Adjustments should be made stepwise between 2mg, 3mg, 5mg, 7mg, 9mg and 11mg, without skipping levels;

[0056] • Take once daily, before meals or at bedtime, for up to 16 consecutive weeks. If the subject completes the entire chemotherapy course, the study treatment must be terminated.

[0057] • Taking medication before meals is defined as taking it 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.

[0058] Selection criteria:

[0059] Subjects who meet all of the following criteria are eligible for this trial.

[0060] 1. For Chinese male and female participants aged 18 and older, the participant must be at least 18 years old (including the day they turned 18) when signing the ICF agreement.

[0061] 2. Weight ≥ 40kg during the screening period;

[0062] 3. Diagnosed by histology or cytology as a non-myeloid malignant tumor (non-curable), and scheduled to receive at least 8 weeks of anti-tumor therapy (myelosuppressive chemotherapy) after the first dose (day 1);

[0063] 4. Myelosuppressive chemotherapy-related anemia, defined as central laboratory Hb ≤ 100 g / L during the screening period, and as determined by the investigator, there is a record showing that the subject's Hb level decreased by ≥ 10 g / L after the start of chemotherapy;

[0064] 5. During the screening period, laboratory ferritin ≥50 ng / mL and TSAT ≥10%;

[0065] 6. During the screening period, the Eastern Cooperative Oncology Group (ECOG) performance status score was ≤1 point;

[0066] 7. During the screening period, the investigator determined that the life expectancy was ≥6 months;

[0067] 8. All male subjects and female subjects of childbearing potential agree to use medically acceptable contraception from the date of signing the ICF until 90 days after the last dose of the investigational drug;

[0068] 9. Voluntarily participate in the trial and sign an informed consent form. Understand the procedures and methods of this trial and be willing to strictly adhere to the clinical trial protocol to complete the trial.

[0069] The study found that after 5 weeks of medication, some patients showed an increase in Hb of more than 5 g / L. The Hb and Hct test results from the central laboratory and the local laboratory were as follows: Figure 3 and Figure 4 As shown, both Hb and Hct showed some improvement.

[0070] Example 4: The therapeutic effect of compound A on chemotherapy-induced anemia

[0071] This experiment used the human hepatocellular carcinoma cell line HUH-7. After cell expansion culture, tumor cells in the logarithmic growth phase were used for in vivo tumor inoculation in mice. After cell collection, the cells were washed twice with PBS and adjusted to a suitable cell suspension for later use. 100 μL of the cell suspension was injected subcutaneously into the left flank of BALB / c Nude mice, with a cell count of 2 × 10⁶ cells per mouse. 6 Cells / mouse. The tumor grows until its average volume reaches approximately 100-120 mm. 3 Animals were randomly assigned to groups based on tumor volume and body weight (Day 0 was the day of grouping), and administration began on the following day (Day 1). Grouping and administration are shown in Table 2.

[0072] Table 2 Grouping and Dosage Table

[0073]

[0074] Mice in the solvent control group received intraperitoneal injection and gavage with the solvent. Mice in the carboplatin monotherapy group received intraperitoneal injection of carboplatin (100 mg / kg) every two weeks, and simultaneously received the solvent via gavage once daily. Mice in the combination therapy group received intraperitoneal injection of carboplatin (100 mg / kg), and simultaneously received either compound A (60 mg / kg) or roxadustat (60 mg / kg) via gavage once daily. The entire experimental period lasted 20 days, with a total of two administrations of carboplatin and 20 administrations of either compound A or roxadustat.

[0075] Following drug administration, 50 μL of whole blood was collected from the orbital cavity on Day 8, Day 15, and Day 20, 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. The animals were euthanized at the end of the experiment. The results are shown in Table 3.

[0076] Table 3. Mouse cell parameter values ​​during drug administration

[0077]

[0078] The results showed that after carboplatin administration to tumor-bearing mice, red blood cell parameters decreased significantly over time, indicating that chemotherapy drugs caused anemia in mice with subcutaneous transplanted liver cancer. After administration of compound A or roxadustat, the values ​​of RBC, Hb, and Hct were significantly improved, and at the same dose, compound A showed better improvement than roxadustat.

[0079] Example 5: Effect of compound A on a rat model of myelodysplastic syndrome

[0080] 1. Method

[0081] Four- to five-week-old SD rats were randomly divided into a normal control group and model animals. Blood was collected from all experimental animals before model induction and initial hematological values ​​were measured.

[0082] Modeling: On Day 0, animals were induced for the first time by intravenous injection (iv) of 35 mg / kg of dimethylbenzanthracene (DMBA). On Day 11, a second induction was performed by intravenous injection (iv) of 35 mg / kg of dimethylbenzanthracene (DMBA). On Day 14, blood samples were collected from the induced animals to test hematological parameters. These parameters were used as baseline parameters before drug administration. The animals were then divided into three groups before drug administration: a model control group, a roxadustat group (10 mg / kg), and a compound A group (10 mg / kg). Drug administration was then initiated.

[0083] Administration and indicator monitoring: Starting from Day 15, the normal control group, model control group, roxadustat group (10 mg / kg), and compound A group (10 mg / kg) were administered the solvent or corresponding drug. Hematological tests were performed on Day 21 and Day 28, i.e., the first and second weeks after administration, and the differences in various hematological indicators were analyzed and compared.

[0084] 2. Experimental Results

[0085] Following two injections of DMBA for induction, peripheral blood erythrocyte and platelet counts in rats were significantly reduced, indicating successful simulation of rat myelodysplastic syndrome based on literature reports. Continuous administration for two weeks, starting on day 14 of the initial modeling period, showed no significant changes in hematological parameters between the roxadustat (10 MPk) and compound A (10 MPk) groups and the model group. Therefore, it was determined that neither drug demonstrated any effect in improving disease symptoms in this model. Specifically... Figure 5 and 6 As shown.

[0086] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. Use of a compound for the manufacture of a medicament for the treatment of anemia in a patient with a non-myeloid malignancy who is being treated with 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 manufacture of a medicament for the treatment of anemia in a patient with a non-myeloid malignancy who is being treated with chemotherapy, wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]glycine, the pharmaceutical composition containing one or more excipients.

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

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

5. The use according to claim 1 or 2, wherein the patient is being treated with a non-platinum-based myelosuppressive chemotherapy.

6. The use according to claim 1 or 2, wherein the chemotherapy is a myelosuppressive chemotherapy, the myelosuppressive chemotherapy agent being selected from the group consisting of: atezolizumab, bevacizumab, robenituximab, cetuximab, desulotamab, durvalumab, envafolimab, inotuzumab, pembrolizumab, pidilizumab, sasanlimab, tislelizumab, tremelimumab; gefitinib, karfilzomib, 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 malignancy is selected from the group consisting of breast cancer, lung cancer, gastrointestinal cancer, gynecological cancer, pancreatic cancer, and head and neck cancer. ​

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