Application of compound in preparation of anemia medicine for treating non-myeloid malignant tumor patients

Abstract

The invention relates to an application of a compound and a pharmaceutical composition thereof in preparation of a medicine for treating anemia of patients with non-myeloid malignant tumors subjected to chemotherapy, and the compound is N-[7-hydroxy-5-(2-phenethyl) [1, 2, 4] triazole [1, 5-a] pyridine-8-carbonyl] glycine.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical applications, 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]triazole[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]

[0004] Anemia is common in patients with non-myeloid malignancies who have undergone chemotherapy. Currently, there is a lack of effective oral drugs for this type of patients. Among them, myeloid malignancies can refer to the relevant classification of WHO, and these other than myeloid malignancies are 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 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]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 provided is the use of a pharmaceutical composition containing a compound 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]triazole[1,5-a]pyridine-8-carbonyl]glycine, and the pharmaceutical composition contains one or more excipients.

[0009] As a preferred technical solution of the present invention, the daily dose is about 1 mg to about 30 mg, including:

[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 technical solution of the present invention, the patient is receiving platinum-based myelosuppressive chemotherapy.

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

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

[0014] Atezolizumab, bevacizumab, reslizumab, cetuximab, denosumab, durvalumab, envolimab, initutumab, pembrolizumab, penampalimumab, tislelizumab, sintilimab, toripalimab;

[0015] Gefitinib, cabotinib, 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 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.

[0019] 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.

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

[0021] Cisplatin is mainly used to treat testicular tumors and osteosarcoma. It has certain effects on ovarian cancer, breast cancer, lung cancer, head and neck cancer, bladder cancer, malignant lymphoma, esophageal cancer, gastric cancer, and cervical cancer.

[0022] 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.

[0023] As an implementation technical scheme of the present invention, the preparation of the compound is introduced into the present invention by the technical scheme recorded in CN201780072928.2;

[0024] The crystal form and preparation used in the pharmaceutical composition are introduced into the present invention by the technical solution described in US20200017492A1.

[0025] The beneficial effects of the present invention compared with the prior art include but are not limited to:

[0026] (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 small dosage and lower adverse reactions. However, no significant improvement was observed in the experimental results for myeloid animals. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 , Example 3: Clinical trial process of Enadostat (Compound A) tablets.

[0028] Figure 2 , Example 3 Clinical dose adjustment plan of Enadostat (Compound A) Tablets.

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

[0030] Figure 4 , local laboratory Hct test results.

[0031] Figure 5 , Example 4 Schematic diagram of the number of platelets in rat peripheral blood.

[0032] Figure 6 , Example 4 Schematic diagram of the number of peripheral blood red blood cells in rats. DETAILED DESCRIPTION

[0033] 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 model in rats

[0034] Experimental method: Male SD rats (200-230g) were used. After the animal quarantine and adaptation period, they were randomly divided into groups according to the hematocrit. The groups were: normal control group, model control group, rosuvastatin group (40mg / kg), low-, medium- and high-dose groups of compound A (1, 3, 10mg / kg), with ten rats in each group.

[0035] 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 carboplatin (45 mg / kg) to establish the model. Rosuvastatin (40 mg / kg) or compound A (1, 3, 10 mg / kg) or the vehicle was gavaged 2 hours before modeling. After that, the rosuvastatin treatment group continued to be gavaged on Day 3, 5, 8, 10, and 12. The compound A group) was given the drug once a day for 14 consecutive days.

[0036] The detection indicators include: whole blood was collected on the 14th day (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 automatic 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 indicators of animals in the compound A (1, 3, and 10 mg / kg) treatment group were significantly improved and were superior to roxadustat.

[0040] Experiment 2: Study on the therapeutic effect of compound A on cisplatin-induced anemia in rats

[0041] Experimental method: Male Wistar rats (200-230g) were used. After the animal quarantine and adaptation period, they were randomly divided into groups according to the hematocrit: normal control group, model control group, low-, medium- and high-dose groups of compound A (1, 3, 10 mg / kg), with ten rats in each group.

[0042] 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 gavage 2 hours before model establishment. The compound A group was given the drug once a day for 14 consecutive days.

[0043] The detection indicators include: whole blood is collected on the 14th day (D 14) after the first administration, anticoagulated with EDTA-K2, and hematological indicators such as red blood cell count (RBC), hematocrit (HCT), and hemoglobin concentration (Hb) are measured using an automatic blood cell analyzer within 1 hour after blood collection.

[0044] 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 group were significantly improved.

[0045] Embodiment 3:

[0046] Purpose of the test:

[0047] 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-related test values, iron metabolism-related test values, and the pharmacokinetic characteristics

[0048] Trial Drugs:

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

[0050] Test process:

[0051] 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.

[0052] Dosage regimen:

[0053] According to the starting dose, the subjects were divided into 4 mg starting dose group and 5 mg starting dose group. The dose was adjusted according to the Hb level of the subjects every 4 weeks to make the Hb level reach ≥100 and <120g / L. The trial flow chart and dose adjustment rules are respectively Figure 1 and 2 As shown:

[0054] · Initial dose 4 mg group: stepwise adjustment in 1 mg, 2 mg, 4 mg, 6 mg, 8 mg and 10 mg, no skipping;

[0055] · Starting dose 5 mg group: stepwise adjustment in 2 mg, 3 mg, 5 mg, 7 mg, 9 mg and 11 mg, no skipping;

[0056] · Take orally once a day 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.

[0057] Taking the medicine before a meal is defined as taking the medicine at least 1 hour before the next meal and at least 2 hours after the previous meal. It is recommended to take the medicine before the same meal every day.

[0058] Inclusion criteria:

[0059] Subjects who meet all of the following criteria can be included in this trial

[0060] 1. For Chinese male and female subjects aged 18 or above, when signing the ICF, the subject must be at least 18 years old (including the day they turn 18)

[0061] 2. Body weight ≥40kg during screening period;

[0062] 3. Patients diagnosed with non-myeloid malignancies (non-curative) by histology or cytology, and planned to receive anti-tumor treatment (myelosuppressive chemotherapy) for at least 8 weeks after the first dose (Day 1);

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

[0064] 5. Laboratory ferritin ≥50ng / mL and TSAT ≥10% during the screening period;

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

[0066] 7. Life expectancy during the screening period is determined by the researchers to be ≥ 6 months;

[0067] 8. All male subjects and female subjects of fertile potential agree to take medically acceptable contraceptive measures for contraception from the date of signing the ICF until 90 days after the last dose of the trial drug;

[0068] 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.

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

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

[0071] This experiment used the human liver cancer cell line HUH-7. After cell proliferation and culture, the tumor cells in the logarithmic growth phase were used for tumor inoculation in mice. After collecting the cells, they were washed twice with PBS and adjusted to a cell suspension of appropriate density for use. The cell suspension was injected subcutaneously in the left flank of BALB / c nude mice at a rate of 100 μL / mouse. The number of injected cells was 2×10 6 cells / mouse. When the tumor grows to an average volume of about 100-120mm 3 At 14:00, animals were randomly divided into groups and administered according to tumor volume and animal weight (the day of grouping was recorded as Day 0), and administration began on the day after grouping (Day 1). Grouping and administration are shown in Table 2.

[0072] Table 2 Grouping and dosing schedule

[0073]

[0074] The vehicle control group was intraperitoneally injected and gavaged with the vehicle, the carboplatin alone group was intraperitoneally injected with carboplatin (100 mg / kg) once every two weeks, and the vehicle was gavaged once a day; the combination group was intraperitoneally injected with carboplatin (100 mg / kg), and compound A (60 mg / kg) or roxadustat (60 mg / kg) was gavaged once a day. The entire experimental period lasted for 20 days, with carboplatin administered twice and compound A or roxadustat administered 20 times.

[0075] After administration, 50 μL of whole blood was collected from the eye sockets on Day 8, Day 15, and Day 20, respectively, and placed in EDTA-K2 anticoagulation tubes. The 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 was given 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.

[0079] Example 5: Effect of Compound A on Myelodysplastic Syndrome Rat Model

[0080] 1. Methods

[0081] 4-5 week old SD rats were randomly divided into normal control group and modeling animals. Before modeling induction, blood was collected from all experimental animals and initial hematological values ​​were tested.

[0082] Modeling: On Day 0, animals were injected with 35 mg / kg of dimethylbenzanthracene (DMBA) modeling agent (iv) in the tail vein for the first induction; on Day 11, the second induction was performed with 35 mg / kg of dimethylbenzanthracene (DMBA) injected (iv) in the tail vein. On Day 14, blood was collected from the modeling induced animals and hematological indicators were tested. The indicators tested were used as the baseline before drug administration, and the animals were grouped before drug administration. The modeling induced animals were divided into the model control group, the rosuvastatin group (10 mg / kg), and the compound A group (10 mg / kg), and drug administration began.

[0083] Drug administration and index detection: 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 with solvent or corresponding drugs. 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] After two injections of DMBA, the peripheral blood red blood cells and platelets of rats decreased significantly, which, based on literature reports, showed that the rat myelodysplastic syndrome was successfully simulated. The drug was administered for two weeks starting from the 14th day of the first modeling. Compared with the model group, the hematological indicators of the drug-treated group of rosuvastatin (10 mpk) and compound A (10 mpk) did not change significantly. Therefore, it was judged that the two drugs did not improve the symptoms of the disease in this model. Figure 5 and 6 shown.

[0086] 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 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 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, and the pharmaceutical composition contains one or more excipients.

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