CN116509865B - Application of nitrone compounds in preparation of medicines for preventing or treating bone marrow suppression - Google Patents

Abstract

The invention provides application of nitrones in preparing medicaments for preventing or treating bone marrow suppression. The nitrone compound has the following general formula: Wherein: r ₁ is hydrogen, methyl or R ₂,R₃, which are the same or different, are each independently selected from hydrogen or C ₁-C₆ alkyl; r ₄ is sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl, and R ₅ is sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl.

Description

Application of nitrone compounds in the preparation of drugs for preventing or treating bone marrow suppression

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to Chinese patent application 2022100796928 filed on January 24, 2022, and the disclosed contents of said application are incorporated herein by reference.

Technical Field

The present invention belongs to the field of pharmaceutical technology, and relates to the prevention or treatment of bone marrow suppression, and specifically to the use of nitrone compounds in the preparation of drugs for the prevention or treatment of bone marrow suppression.

Background Art

Chemotherapy is the abbreviation of chemical drug therapy, which refers to the use of cytotoxic agents to eliminate cancer cells to treat tumors. Chemotherapy, surgery, and radiotherapy are collectively known as the three major treatments for cancer. Surgery and radiotherapy are local treatments, which are only effective for tumors at the treatment site. They are difficult to effectively treat potential metastatic lesions and cancers that have already undergone clinical metastasis. Chemotherapy is a means of systemic treatment. Whether it is oral, intravenous, or intracavitary administration, chemotherapy drugs will spread throughout the body with blood circulation and be distributed in most tissues and organs. Therefore, chemotherapy is the main treatment for tumors with a tendency to metastasize and tumors that have already metastasized. Chemotherapy drugs include but are not limited to cisplatin, carboplatin, cyclophosphamide, doxorubicin, daunorubicin, bleomycin, etoposide, vinblastine, vincristine, irinotecan, taxotere, paclitaxel, topotecan, gemcitabine, 5-fluorouracil, and chlorambucil. In fact, these drugs are non-specific, so when used in high doses, they will have toxic side effects on normal cells. In addition, the ionizing radiation of radiotherapy is also toxic to normal cells.

The essence of using chemotherapy drugs to treat cancer is to selectively combine cytotoxic mechanisms with highly proliferating tumor cells. In fact, this selectivity of chemotherapy drugs is generally poor. Due to the cytotoxic effects of chemotherapy drugs, the dosage of cancer patients cannot be too high, which affects the treatment cycle of cancer patients and seriously endangers the quality of life of patients. During chemotherapy or radiotherapy, the bone marrow may be adversely affected. Myelotoxicity is a common side effect of cancer treatment, which can lead to decreased blood cell counts, decreased hematocrit, decreased hemoglobin levels, and decreased neutrophils. The reason is that the killing effect of radiotherapy or chemotherapy drugs on these cells and the feedback mechanism induced by the emptying of the mature medullary chamber affect the differentiation of stem cells, resulting in a decrease in the number of replicated blood cells such as pluripotent stem cells and other progenitor cells. Over time, the patient's red blood cells and neutrophils may be greatly reduced. Red blood cell reduction can cause anemia, which can cause fatigue, dizziness, shortness of breath, and decreased concentration. Neutropenia increases the risk of infection in patients.

Summary of the invention

In order to solve the problems in the prior art, the present invention provides the use of nitrone compounds or pharmaceutically acceptable salts thereof in the preparation of a medicament for increasing the number of red and/or white blood cells in a patient in need of treatment.

To achieve the above object, the technical solution of the present invention is:

The use of a nitrone compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for increasing the number of red and/or white blood cells in a patient in need of treatment, wherein the nitrone compound has the following structure:

The nitrone compound of the present invention has a structure shown in the following general formula (I):

in:

R ₁ is hydrogen, methyl or;

R ₂ and R ₃ are the same or different and are independently selected from hydrogen or C ₁ -C ₆ alkyl; R ₄ is sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl; R ₅ is sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl.

Further, the nitrone compound of the present invention is selected from TBN or TN2:

The C ₁ -C ₆ alkyl group of the present invention is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, preferably methyl, ethyl or propyl.

Use of a nitrone compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for increasing the number of red and/or white blood cells in a patient in need of treatment; the use comprises administering a pharmaceutically effective amount of a composition comprising a nitrone compound or a pharmaceutically acceptable salt thereof as an active ingredient to the patient.

According to one embodiment of the present invention, the "pharmaceutically acceptable salt" of the nitrone compound of the present invention can be a salt formed with an inorganic acid, such as a salt formed with the following inorganic acids: hydrochloric acid (HCl), hydrobromic acid (HBr), hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid; or a salt formed with an organic acid, such as a salt formed with the following organic acids: methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, hexanoic acid, benzoic acid, salicylic acid, cinnamic acid, cyclopentanepropionic acid, dodecyl sulfuric acid, 2-naphthalenesulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, D-gluconic acid, aspartic acid.

According to one embodiment of the present invention, the use of the nitrone compound of the present invention or its pharmaceutically acceptable salt in the preparation of a medicament for increasing the number of red and/or white blood cells in a patient in need of treatment is for preventing or treating bone marrow suppression caused by chemotherapy or radiotherapy in the patient. The present invention uses the nitrone compound as a hematopoietic stimulating factor or chemoprotectant to treat bone marrow suppression caused by chemotherapy and/or radiotherapy.

According to one embodiment of the present invention, the use of the nitrone compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for increasing the number of red and/or white blood cells in a patient in need of treatment is for preventing or treating neutropenia in the patient.

According to one embodiment of the present invention, the use of the nitrone compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for increasing the number of red and/or white blood cells in a patient in need of treatment is for preventing or treating anemia caused by chemotherapy or radiotherapy in the patient.

The invention discloses an application of the nitrone compound in combination with a cytotoxic agent in preparing a drug for preventing or treating tumors.

The term "chemotherapy" as used in the present invention refers to the process of using cytotoxic agents to kill proliferating cells. The term "after chemotherapy" as used in the present invention refers to all situations in which a patient is administered a cytotoxic agent after administration. The term "cytotoxic agent" as used in the present invention refers to a chemical agent that kills highly proliferative cells, such as tumor cells, virus-infected cells or hematopoietic cells, including but not limited to: cisplatin, vinblastine, vincristine, vinorelbine, doxorubicin, bleomycin, irinotecan, cyclophosphamide, ifosfamide, pemetrexed, clofarabine, fludarabine, 6-mercaptopurine, nelarabine, pentostatin, docetaxel, cabazitaxel, paclitaxel, albumin-bound paclitaxel, capecitabine, cytarabine, 5-fluorouracil, gemcitabine, hydroxyurea, daunorubicin, topotecan, carboplatin, oxaliplatin, chlorambucil, nitrogen mustard, bischloroethyl methylamine, One or more of the following: busulfan, methotrexate, carmofur, tegafur, tamoxifen, aclarubicin, zidovudine, azidothymidine, lamivudine, stavudine, lenalidomide, pomalidomide, melphalan, dacarbazine, temozolomide, procarbazine, mitomycin, bortezomib, nitrosourea, carmustine, lomustine, bendamustine, aminoglutethimide, epirubicin, etoposide, teniposide, mitoxantrone, icotinib, dasatinib, telatinib, crizotinib, tofacitinib, erlotinib, gefitinib, imatinib, lapatinib, sunitinib, ibrutinib, osimertinib, anlotinib, alectinib, palbociclib, pazopanib, and sorafenib.

According to one embodiment of the present invention, the use of the nitrone compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for increasing the number of red and/or white blood cells in a patient in need of treatment is for preventing or treating drug-induced neutropenia in the patient.

In the treatment of cancer, chemotherapy and radiotherapy can destroy hematopoietic cells in the bone marrow. Therefore, bone marrow suppression is a dose-limiting factor in cancer treatment. The nitrone compounds of the present invention can increase the number of red blood cells and white blood cells of patients, restore the function of the patient's hematopoietic system, and thus reduce or offset the side effects caused by drug-induced red blood cell or white blood cell reduction. The nitrone compounds provided by the present invention can be used for the prevention and/or treatment of anemia and/or neutropenia associated with chemotherapy or radiotherapy, and can reduce the toxicity of chemotherapy or radiotherapy drugs.

The nitrone compound (such as TBN) or its pharmaceutically acceptable salt of the present invention is used as a pharmaceutical active ingredient and is formulated into a pharmaceutical composition together with a pharmaceutically acceptable carrier. The pharmaceutical composition is in the form of any composition suitable for oral, sublingual, topical inhalation (nasal spray), rectal, intramuscular, intradermal, subcutaneous or intravenous administration. The term "pharmaceutically acceptable carrier" used in the present invention refers to a substance that does not interfere with the physiological effects of the nitrone compound (such as TBN) and is non-toxic to mammals including humans. The pharmaceutical composition of the nitrone compound (such as TBN) of the present invention is prepared using a nitrone compound (such as TBN) and a pharmaceutically acceptable carrier by a method known to those skilled in the art. These compositions include but are not limited to solids, capsules, pills, suppositories, liquids, oils, emulsions, sprays, gels, aerosols, inhalants and patches.

The term "chemoprotection" as used herein refers to providing protection to mammals, including humans, against toxic effects caused by treatment with chemotherapeutic agents. For example, chemotherapeutic agents are cytotoxic agents, and their therapeutic effects are due to interference or inhibition of DNA replication, RNA transcription, or subsequent protein translation processes. Therefore, chemoprotectants refer to substances that protect against toxic effects caused by treatment with chemotherapeutic agents and are beneficial to the recovery of the body.

The term "neutropenia" in the present invention refers to a situation where the number of neutrophils is lower than the normal value. The term "anemia" in the present invention refers to a situation where the number of red blood cells, the amount of hemoglobin or the hematocrit is lower than the normal value.

Beneficial Effects

The nitrone compound of the present invention or its pharmaceutically acceptable salt can significantly increase the hemoglobin level, hematocrit, red blood cell count and neutrophil count of mice in the cisplatin-induced C57BL/6J mouse immunosuppression model, and can be used to reduce or offset the side effects of bone marrow suppression caused by chemotherapy or radiotherapy. The nitrone compound of the present invention or its pharmaceutically acceptable salt is used for the prevention and/or treatment of anemia and/or neutropenia associated with chemotherapy or radiotherapy, so as to reduce or offset the side effects caused by the decrease in red blood cells or neutrophils caused by chemotherapy drugs.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is the effect of TBN on the hemoglobin concentration of mice, where **P<0.01, ***P<0.001 and

****P<0.0001vs.Model mice; ^#### P<0.0001vs.Control mice. Among them, control group: 19 mice; model group: 19 mice; TBN 10mg/kg group: 20 mice; TBN 30mg/kg group: 20 mice; TBN 60mg/kg group: 21 mice; Roxadustat 10 mg/kg group: 20 mice.

Figure 2 is the effect of TBN on mouse hematocrit, where **P<0.01, ***P<0.001and****P<0.0001vs.Model mice; ^#### P<0.0001vs.Control mice. Among them, control group: 19 mice; model group: 19 mice; TBN 10 mg/kg group: 20 mice; TBN 30 mg/kg group: 20 mice; TBN 60 mg/kg group: 21 mice; Roxadustat 10 mg/kg group: 20 mice.

Figure 3 is the effect of TBN on the number of red blood cells in mice, where **P<0.01, ***P<0.001and****P<0.0001vs.Model mice; ^#### P<0.0001vs.Control mice. Among them, control group: 19 mice; model group: 19 mice; TBN 10 mg/kg group: 20 mice; TBN 30 mg/kg group: 20 mice; TBN 60 mg/kg group: 21 mice; Roxadustat 10 mg/kg group: 20 mice.

Figure 4 is the effect of TBN on the number of neutrophils in mice, where **P<0.01, ***P<0.001and****P<0.0001vs.Model mice; ^#### P<0.0001vs.Control mice. Among them, control group: 19 mice; model group: 19 mice; TBN 10 mg/kg group: 20 mice; TBN 30 mg/kg group: 20 mice; TBN 60 mg/kg group: 21 mice; Roxadustat 10 mg/kg group: 20 mice.

Example

The present invention is described in detail below through specific examples. It is pointed out that the following examples are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. The reagents used in the present invention are all commercially available products.

As is well known in the art, "cytotoxic agents" include vinblastine, vincristine, vinorelbine, doxorubicin, bleomycin, irinotecan, cyclophosphamide, ifosfamide, cisplatin, pemetrexed, clofarabine, fludarabine, 6-mercaptopurine, nelarabine, pentostatin, docetaxel, cabazitaxel, paclitaxel, albumin-bound paclitaxel, capecitabine, cytarabine, 5-fluorouracil, gemcitabine, hydroxyurea, daunorubicin, topotecan, carboplatin, oxaliplatin, chlorambucil, mechlorethamine, busulfan, methotrexate, carmofur, tegafur, tamoxifen, aclarubicin, zidovudine, Azidothymidine, lamivudine, stavudine, lenalidomide, pomalidomide, melphalan, dacarbazine, temozolomide, procarbazine, mitomycin, bortezomib, nitrosoureas, carmustine, lomustine, bendamustine, aminoglutethimide, epirubicin, etoposide, teniposide, mitoxantrone, icotinib, dasatinib, telatinib, crizotinib, tofacitinib, erlotinib, gefitinib, imatinib, lapatinib, sunitinib, ibrutinib, osimertinib, anlotinib, alectinib, palbociclib, pazopanib, and sorafenib can all induce a decrease in red blood cells and/or neutrophils.

The embodiment of the present invention takes the typical chemotherapy drug cisplatin as an example, and explains in detail the combined use of the nitrone compound (TBN) of the present invention and cisplatin to reduce or offset the side effects caused by the decrease of red blood cells or neutrophils caused by the chemotherapy drugs.

Example 1

TBN regulates immune cell proliferation

Establishment of cisplatin-induced C57BL/6J immunosuppressive mouse model: The animals were randomly divided into 6 groups (n=10), namely, normal control group, model group, and 4 treatment groups. The normal control group was injected with an equal volume of normal saline, and the model group and the 4 treatment groups were intraperitoneally injected with cisplatin (CDDP) 5 mg/kg once a week for a total of 4 weeks. The grouping and dosing of the animals are shown in Table 1 below.

Table 1 Animal grouping and drug administration

Grouping dose Dosage Dosing frequency Normal control group (Ctrl) / i.g. twice/day Model Group (model) / i.g. twice/day TBN 10mg/kg i.g. twice/day TBN 30mg/kg i.g. twice/day TBN 60mg/kg i.g. twice/day Roxadustat 10mg/kg i.g. once/two day

The administration route was oral administration, TBN was administered twice a day (fixed at 9:00-10:00 a.m. and 3:00-4:00 p.m. every day), and Roxadustat was administered once every two days (fixed at 9:00-10:00 a.m. every day), for 4 consecutive weeks.

Effect of blood routine indexes on mice

At the end of modeling, blood was collected from the tail vein and from the abdominal aorta after the experiment. The blood samples were added with anticoagulants to preserve as whole blood samples, and tested using a blood cell analyzer within four hours. The main observation indicators were hemoglobin concentration, hematocrit, red blood cell count and neutrophils (Figures 1-3). As shown in Figures 1-3, TBN can significantly increase hemoglobin levels, hematocrit and red blood cell counts, and is dose-dependent. High-dose TBN has the same effect as positive drugs.

By comparing the number of neutrophils at the time of successful modeling (week 4) and at the time of sampling after the end of the experiment (week 8), the results showed that different doses of TBN could increase the content of neutrophils, and the difference was statistically significant compared with the model group. The specific results are shown in Figure 4.

Referring to the above experiments, it was found that TN-2 compound can also increase the hemoglobin level, hematocrit and red blood cell count in the mouse model, and increase the number of neutrophils.

The nitrone compound of the present invention or its pharmaceutically acceptable salt can significantly increase the hemoglobin level, hematocrit, red blood cell count and neutrophil count of mice in the cisplatin-induced C57BL/6J mouse immunosuppression model, and can be used to reduce or offset the side effects of bone marrow suppression caused by chemotherapy or radiotherapy. The nitrone compound of the present invention or its pharmaceutically acceptable salt is used for the prevention and/or treatment of anemia and/or neutropenia associated with chemotherapy or radiotherapy, so as to reduce or offset the side effects caused by the decrease in red blood cells or neutrophils caused by chemotherapy drugs.

Claims (5)

1. Use of a nitrone compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating chemotherapy-induced bone marrow suppression in a patient, wherein the nitrone compound is . 2. The use according to claim 1, characterized in that the drug is used to prevent or treat anemia or neutropenia caused by chemotherapy in patients, and a pharmaceutically effective amount of a composition comprising a nitrone compound or a pharmaceutically acceptable salt thereof as an active ingredient is administered to the patient. 3. The use according to claim 1, characterized in that the pharmaceutically acceptable salt is a salt of a nitrone compound and an acid, and the acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, hexanoic acid, benzoic acid, salicylic acid, cinnamic acid, cyclopentanepropionic acid, dodecyl sulfuric acid, 2-naphthalenesulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, D-gluconic acid or aspartic acid. 4. The use as claimed in claim 3, characterized in that: the chemotherapy refers to the process of using a cytotoxic agent to kill proliferating cells; the cytotoxic agent is selected from cisplatin, vinblastine, vincristine, vinorelbine, doxorubicin, bleomycin, irinotecan, pemetrexed, clofarabine, fludarabine, 6-mercaptopurine, nelarabine, pentostatin, docetaxel, cabazitaxel, paclitaxel, albumin-bound paclitaxel, capecitabine, cytarabine, 5-fluorouracil, gemcitabine, hydroxyurea, daunorubicin, topotecan, carboplatin, oxaliplatin, bendamustine, chlorambucil, nitrogen mustard, busulfan, methotrexate, carmofur, tegafur, tamoxifen, a One or a combination of rubicin, zidovudine, azidothymidine, lamivudine, stavudine, lenalidomide, pomalidomide, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, dacarbazine, temozolomide, procarbazine, mitomycin, bortezomib, nitrosourea, carmustine, lomustine, bendamustine, aminoglutethimide, epirubicin, etoposide, teniposide, mitoxantrone, icotinib, dasatinib, telatinib, crizotinib, tofacitinib, erlotinib, gefitinib, imatinib, lapatinib, sunitinib, ibrutinib, osimertinib, anlotinib, alectinib, palbociclib, pazopanib, and sorafenib. 5. Use of a combination of a nitrone compound and cisplatin in the preparation of a drug for preventing or treating tumors; the nitrone compound is .