WO2023274316A1 - Application de plinabuline deutérée dans la préparation d'un médicament pour le traitement de la neutropénie - Google Patents

Application de plinabuline deutérée dans la préparation d'un médicament pour le traitement de la neutropénie Download PDF

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WO2023274316A1
WO2023274316A1 PCT/CN2022/102466 CN2022102466W WO2023274316A1 WO 2023274316 A1 WO2023274316 A1 WO 2023274316A1 CN 2022102466 W CN2022102466 W CN 2022102466W WO 2023274316 A1 WO2023274316 A1 WO 2023274316A1
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plinabulin
deuterated
cyclophosphamide
administration
pharmaceutically acceptable
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PCT/CN2022/102466
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Chinese (zh)
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李文保
丁忠鹏
李飞飞
彭超
古敏晴
徐赟
王新文
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深圳华泓海洋生物医药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the invention relates to the fields of chemistry and medicine, in particular to the application of deuterated plinabulin in the preparation of medicines for treating neutropenia.
  • Plinabulin (plInabulIn) is derived from the natural product Phenylahistin isolated from the marine fungus Aspergillus pylorus, and is a new type of 2,5-diketopiperazine (DKP) heterocyclic compound. It is a colchicine-like tubulin inhibitor that prevents microtubule assembly by affecting the dynamic cycle of microtubule depolymerization-polymerization, thereby interfering with cell division. At the same time, Plinabulin is also a novel vascular disruptor that selectively destroys the tumor vascular endothelial structure to achieve its anti-tumor activity. Due to the good effect of Plinabulin in the treatment of neutropenia, Plinabulin has obtained the breakthrough therapy certification in China and the United States at this stage, and has applied for a new drug NDA.
  • DKP 2,5-diketopiperazine
  • Neutropenia is a common hematological toxicity during chemotherapy. Accurate assessment, prevention and treatment are critical to the prognosis of cancer patients. Chemotherapy is one of the main treatments for malignant tumors. Myelosuppression is the most common dose-limiting toxicity of chemotherapy, among which neutropenia is very common. Neutropenia is a common and potentially life-threatening complication of cytotoxic myelosuppressive chemotherapy. Studies have shown that individuals with neutropenia are more susceptible to infection, and complications are likely to be life-threatening.
  • G-CSF granulocyte colony-stimulating factor
  • the technical problem to be solved by the present invention is to provide a kind of application of deuterated plinabulin in the preparation of medicine for the treatment of neutropenia in order to overcome the deficiency of the lack of drugs for effectively treating neutropenia in the prior art .
  • the present invention provides an application of deuterated plinabulin represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of medicines for treating and/or preventing neutropenia;
  • the present invention also provides a method for treating and/or preventing neutropenia, which comprises administering a therapeutically effective amount of deuterated plinabulin represented by formula (I) or its pharmaceutical preparation to an individual in need. acceptable salt;
  • the pharmaceutically acceptable salt of deuterated plinabulin represented by formula (I) is:
  • the neutropenia is induced by administering chemotherapy or by administering radiation therapy.
  • the chemotherapy comprises administering a chemotherapeutic composition of one or more chemotherapeutic agents.
  • the chemotherapeutic composition is docetaxel, paclitaxel, cyclophosphamide, "combination of docetaxel, doxorubicin and cyclophosphamide", “docetaxel, paclitaxel, vinca combination of doxorubicin, doxorubicin, and cyclophosphamide” or “a combination of docetaxel and cyclophosphamide”.
  • docetaxel, paclitaxel, cyclophosphamide and other drugs alone, “docetaxel, doxorubicin and cyclophosphamide (TAC)", “docetaxel, paclitaxel, vinblastine, doxorubicin and cyclophosphamide Phosphamide” or “docetaxel and cyclophosphamide (TC)” and other combinations.
  • TAC docetaxel, doxorubicin and cyclophosphamide
  • TC cyclophosphamide
  • the chemotherapeutic composition is cyclophosphamide.
  • the neutropenia is induced by chemotherapy or radiation therapy treating an individual with liver, pancreatic, lung, breast, colon, or prostate cancer.
  • the individual in need thereof has liver cancer, pancreatic cancer, lung cancer, breast cancer, colon cancer, or prostate cancer.
  • the method comprises administering a single dose of deuterated plinabulin represented by formula (I) or its pharmaceutically acceptable salt.
  • the method comprises administering deuterated plinabulin as represented by formula (I) after administering the chemotherapeutic composition or a pharmaceutically acceptable salt thereof.
  • the deuterated plinabulin represented by formula (I) or its pharmaceutically acceptable is less than 60mg/kg.
  • the method comprises administration of deuterated prunab as represented by formula (I) within 24 hours after administration of cyclophosphamide Lin or a pharmaceutically acceptable salt thereof.
  • the method comprises administration of deutepurina represented by formula (I) within about 12 hours after administration of cyclophosphamide Bollin or a pharmaceutically acceptable salt thereof is administered, for example, 0.5 hours later.
  • the administration dose of deuterated plinabulin or its pharmaceutically acceptable salt shown in formula (I) is less than 60mg/ kg.
  • the method includes administration of "docetaxel, doxorubicin and cyclophosphamide", “docetaxel, paclitaxel, vinblastine, doxorubicin and cyclophosphamide” or “docetaxel and cyclophosphamide” within 24 hours after administration of deuterated plinabulin or a pharmaceutically acceptable salt thereof as represented by formula (I).
  • the deuterated plinabulin represented by formula (I) or a pharmaceutically acceptable salt thereof can be administered by any suitable route in the art, including oral administration, injection (such as intravenous, intramuscular , subcutaneous), etc., for example, by intravenous infusion.
  • the deuterated plinabulin represented by formula (I) or a pharmaceutically acceptable salt thereof can be administered according to the body weight of the individual, and the non-limiting example range can be 0.5-60 mg/kg (single dose), such as 0.5-20 mg/kg (single dose), specifically, the administration dose may be 1.875 mg/kg, 3.75 mg/kg, 7.5 mg/kg or 10 mg/kg.
  • the above dosage of deuterated plinabulin represented by formula (I) or a pharmaceutically acceptable salt thereof can be administered at least once a week, for example, every 7 days 1 time.
  • the method comprises simultaneously administering deuterated plinabulin represented by formula (I) or a pharmaceutically acceptable salt thereof and one or more G-CSF drugs.
  • the method when the individual in need has liver cancer, pancreatic cancer, lung cancer, breast cancer, colon cancer, or prostate cancer, the method includes identifying a patient with said liver cancer, pancreatic cancer, lung cancer, breast cancer, A patient with colon cancer or prostate cancer; and administering deuterated plinabulin represented by formula (I) or a pharmaceutically acceptable salt thereof at a dose of about 0.5 mg/kg to about 60 mg/kg.
  • the present invention also provides a pharmaceutical composition, which comprises about 0.5 mg to about 60 mg of deuterated plinabulin represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises about 0.5 mg to about 10 mg of deuterated plinabulin represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
  • “Individual” as used herein refers to a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate or bird, such as a chicken, and any other vertebrate or invertebrate.
  • an “effective amount” or “therapeutically effective amount” refers to an amount of a therapeutic agent effective to the extent that it relieves one or more symptoms of a disease or condition or reduces the likelihood of its onset, and includes curing the disease or condition.
  • prevention refers to treating an individual who has not yet exhibited symptoms of a disease or condition, but is susceptible to or at risk for a particular disease or condition, whereby the treatment reduces the likelihood of the patient developing the disease or condition.
  • treatment refers to the treatment of an individual already suffering from a disease or condition.
  • pharmaceutically acceptable salt refers to a salt that retains the biological effectiveness and properties of the compound and which is not biologically or otherwise undesirable for use in medicine.
  • the compounds disclosed herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like.
  • Organic acids from which salts can be derived include, for example, acetic, propionic, glycolic, pyruvic, oxalic, maleic, malonic, succinic, fumaric, tartaric, citric, benzoic, cinnamic, mandelic , Methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.
  • Inorganic and organic bases can also be used to form pharmaceutically acceptable salts.
  • Inorganic bases from which salts can be derived include, for example, bases containing sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc.; particularly preferred are the ammonium, potassium, sodium, calcium, salt and magnesium salt.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, in particular isopropylamine, trimethylamine, di Ethylamine, Triethylamine, Tripropylamine, and Ethanolamine.
  • deuterated plinabulin or its pharmaceutically acceptable salt as shown in formula (I) can be used for the treatment and/or prevention of neutropenia, especially for the treatment of doxene Neutropenia caused by chemotherapeutic drugs such as taxel, doxorubicin and cyclophosphamide (TAC) or docetaxel and cyclophosphamide (TC), improve the toxic and side effects of clinical tumor treatment.
  • chemotherapeutic drugs such as taxel, doxorubicin and cyclophosphamide (TAC) or docetaxel and cyclophosphamide (TC)
  • TAC doxorubicin and cyclophosphamide
  • TC docetaxel and cyclophosphamide
  • Fig. 1 is the body weight change curve of male SD rats
  • Fig. 2 is the body weight change curve of female SD rats
  • Fig. 3 is the change curve of the white blood cell quantity of male SD rat
  • Fig. 4 is the change curve of the number of white blood cells in female SD rats
  • Fig. 5 is the change curve of the number of neutrophils in male SD rats
  • Fig. 6 is the change curve of the number of neutrophils in female SD rats
  • Fig. 7 is the thymus coefficient of male SD rat
  • Fig. 8 is female SD rat thymus coefficient
  • Fig. 9 is the body weight change curve of SD rats.
  • Figure 10 is the change curve of the number of white blood cells in SD rats.
  • Fig. 11 is the change curve of the number of neutrophils in SD rats.
  • Fig. 12 is SD rat thymus coefficient
  • Fig. 13 is the body weight change curve of SD rats
  • Fig. 14 is the body weight change curve of SD rats
  • Figure 15 is the change curve of the number of white blood cells in SD rats.
  • Figure 16 is the change curve of the number of white blood cells in SD rats.
  • Fig. 17 is the change curve of the number of neutrophils in SD rats.
  • Fig. 18 is the change curve of the number of neutrophils in SD rats.
  • Fig. 19 is SD rat thymus coefficient
  • Fig. 20 is SD rat thymus coefficient
  • Fig. 21 is the body weight change curve of SD rats
  • Figure 22 is the change curve of the number of white blood cells in SD rats.
  • Figure 23 is the change curve of the number of neutrophils in SD rats.
  • Figure 24 is SD rat thymus coefficient
  • Fig. 25 is the body weight change curve of SD rats
  • Figure 26 is the change curve of the number of white blood cells in SD rats.
  • Figure 27 is the change curve of the number of neutrophils in SD rats.
  • Figure 28 is SD rat thymus coefficient
  • Fig. 29 is the body weight change curve of SD rats
  • Figure 30 is the change curve of the number of white blood cells in SD rats.
  • Figure 31 is the change curve of the number of neutrophils in SD rats.
  • Figure 32 is the SD rat thymus coefficient.
  • Deuterated plinabulin represented by formula (I) can be prepared and purified according to the methods and procedures detailed in Chinese invention patents ZL201510293269.8, ZL201610224082.7 and ZL201610664088.6, which are incorporated herein by reference in their entirety.
  • the synthesis steps are as follows: the first step is to close the ring to form an oxazole ring; the second step is to heat treatment in formamide to form an imidazole ring; and then reduce and oxidize to obtain an imidazole aldehyde compound.
  • the specific preparation process includes the following steps: Weigh 5-tert-butyl-1H-imidazole-4-carbaldehyde (304mg, 2mmol) into a 50mL dry single-necked bottle, and replace the nitrogen protection. Add 5 mL of dry ethanol and sodium borodeuteride (420 mg, 10 mmol) to the reaction bottle, replace the nitrogen protection, react overnight at room temperature, add 10 mL of water to quench the reaction, extract the organic phase with 30 mL of ethyl acetate, spin dry and put it directly into the next reaction , add 10mL of dry acetone and manganese dioxide (1.7g, 20mmol), react overnight at room temperature, filter with sand core funnel, and spin the filtrate to dry column chromatography to obtain 5-tert-butyl-1H-imidazole-4-deuterium Formaldehyde (199 mg, 1.3 mmol), a white solid, yield 65%.
  • reaction solution was added to cold water, a yellow solid was precipitated, filtered, the filter cake was dissolved in a mixed solvent of absolute ethanol and ethyl acetate, the insoluble matter was filtered off, concentrated to dryness under reduced pressure, and 63 mg of a yellow solid was obtained, which was the compound 1, yield 36.65%.
  • mice per cage rearing temperature is room temperature 16-26 °C (diurnal temperature difference ⁇ 4 °C), 12/12 hours day and night alternating light and dark (turn off the light at 07:30, turn off the light at 19:30).
  • Rats and mice were fed maintenance feed, which was purchased from Beijing Keao Xieli Feed Co., Ltd. Animals were free to ingest feed and drinking water for experimental animals.
  • Preparation method Add an appropriate amount of sterile 0.9% sodium chloride injection into the drug bottle containing the drug powder, shake it slightly to make it fully dissolve and mix to form a solution of the corresponding concentration. If the dry powder cannot be completely dissolved immediately, the solution can be statically Leave it for a few minutes until it is completely clear (the whole process needs to be operated in a sterile environment).
  • the white blood cell count in the 12.5mg/kg cyclophosphamide group was significantly higher on the 1st, 2nd, 3rd, and 4th days. decreased (P ⁇ 0.05), and the white blood cell count increased significantly on the 13th day (P ⁇ 0.05).
  • the white blood cell count in the 25mg/kg cyclophosphamide group decreased significantly (P ⁇ 0.05) on the 1st to 7th day, and in the 50mg/kg cyclophosphamide group, the white blood cell count decreased significantly on the 1st to 7th, 10th, and 14th day (P ⁇ 0.05).
  • the experimental data are shown in Table 9.
  • the thymus was taken from each animal, weighed and the organ coefficient was calculated.
  • the results show that, as shown in Figure 7 and Figure 8, compared with the normal control group, after the male SD rats were modeled with cyclophosphamide, there was no significant difference in the thymus coefficient of each dose group; after the female SD rats were modeled with cyclophosphamide, The thymus coefficient in the 25mg/kg cyclophosphamide group decreased significantly (P ⁇ 0.001), and there was no significant difference in the thymus coefficient in the other dosage groups.
  • Preparation method Each preparation is prepared according to the actual use requirement and the proportion of the prescription.
  • the specific preparation process is as follows:
  • Preparation frequency single preparation, injection diluent needs to be prepared on the day of administration (precipitation will occur when the concentration is slightly higher, please pay attention to observation, if precipitation occurs, it needs to be re-prepared), concentrated solution can be prepared once a week;
  • Temporary storage conditions and expiry date after preparation store in a dry place in the dark at room temperature, transport it to the animal room in the dark, and use it immediately;
  • Temporary storage conditions and expiry date after preparation of subpackages Complete administration in the dark within 6 hours after preparation of the injection diluent;
  • the experiment consisted of 4 groups, each with 8 male SD rats, which were the normal control group, the deuterated plinabulin single administration group, the model control group, and the deuterated plinabulin treatment group. Rats with uniform levels of neutrophils were randomly divided into groups, and the specific group information is shown in Table 10.
  • the animals in the other groups were given intraperitoneal injection of cyclophosphamide for modeling, the modeling dose was 100 mg/kg, and the administration volume 10mL/kg; after the non-modeling group animals were given normal saline for 30min, the normal control group was given 5% glucose solution, and the deuterated plinabulin single administration group was given the test product deuterated plinabulin at 7.5mg/kg , intravenous infusion for 15 minutes; the rest of the model-making groups were given modeling drugs for 30 minutes, the model control group was given 5% glucose solution by tail vein injection, and the deuterated plinabulin treatment group was given the test product deuterated at 7.5 mg/kg. Plinabulin, intravenous infusion 15min.
  • the normal control group was injected with normal saline for 30 minutes and then injected with 5% glucose solution through the tail vein; the deuterium plinabulin alone group was given normal saline for 30 minutes after intraperitoneal injection with 7.5 mg/kg of deuterium Daprenabuline, intravenous infusion 15min.
  • the model control group and the deuterated plinabulin treatment group were given intraperitoneal injection of cyclophosphamide for the second modeling, the modeling dose was 100 mg/kg, and the administration volume was 10 mL/kg; after 30 minutes of administration of the modeling drug, the model control The group was given 5% glucose solution by tail vein injection, and the deuterated plinabulin treatment group was given the test product deuterated plinabulin at 7.5 mg/kg, intravenously infused for 15 minutes.
  • the general state was observed once a day, the body weight was measured twice a week after the administration, and the blood test was performed once a day before and after the administration.
  • the blood test was performed once a day before and after the administration.
  • all rats were dissected, and the thymus of each animal was taken, weighed and its organ coefficient (the weight of the organ per 10 g body weight (mg)) was calculated.
  • the model control group and the deuterated plinabulin treatment group all had symptoms such as hypoactivity, sparse back hair, shapeless feces, perianal filth, etc. symptom.
  • the body weight of the deuterated plinabulin treatment group was significantly lower than that of the model control group on the 16th day after administration of the model (P ⁇ 0.05).
  • the white blood cell count of the model control group was significantly lower than that of the normal control group on the 1st to 10th day and the 15th to 28th day after administration (P ⁇ 0.05). After one modeling, it decreased and then increased, and after another modeling, it decreased and rose to close to the normal level.
  • the white blood cell counts in the deuterated plinabulin alone administration group were significantly lower than those in the normal control group on the 2nd, 3rd, 15th, and 16th days after administration (P ⁇ 0.05), and the other test days were comparable to the normal control group.
  • the white blood cell counts in the deuterated plinabulin treatment group increased significantly on the 1st, 2nd, 14th, and 15th days after administration (P ⁇ 0.05).
  • the number of neutrophils in the model control group decreased significantly (P ⁇ 0.05) after administration to the 2nd to 8th day and the 15th to 22nd day; On the 10th to 14th day and the 24th to 28th day after the administration, the neutrophil count in the model control group increased significantly (P ⁇ 0.05), and the overall trend was to decrease after the first modeling and then increase and return to normal level.
  • the neutrophil count of the deuterated plinabulin alone administration group was significantly higher than that of the normal control group on the first day, and the other test days were comparable to the normal control group.
  • the neutrophil counts in the deuterated plinabulin treatment group were significantly increased on days 1, 2, 14, and 15 (P ⁇ 0.05).
  • the thymus coefficient of the model control group was significantly lower than that of the normal control group (P ⁇ 0.05); the thymus coefficient of the deuterated plinabulin treatment group was significantly higher than that of the model control group (P ⁇ 0.05), and the remaining groups No statistical difference.
  • the animals in the other groups were given intraperitoneal injection of cyclophosphamide for modeling, the modeling dose was 100mg/kg, and the administration volume was 10mL/kg;
  • Model control group 1 and group 2 were given 5% glucose solution by tail vein injection, Plinabulin group 1 and group 2 were given Plinabulin at 7.5 mg/kg, deuterated plinabulin group 1 and group 2 were given at 7.5 mg/kg.
  • the test product deuterated plinabulin was administered intravenously for 15 minutes, with a single administration volume of 20mL/kg.
  • the normal control group was given normal saline, and the model control group 2, Plinabulin 2 group and deuterated plinabulin 2 group were given intraperitoneal injection of cyclophosphamide for the second modeling, the modeling dose was 100mg/kg, The administration volume was 10mL/kg; 30 minutes after administration of the modeling drug, the model control group 2 was given 5% glucose solution by tail vein injection, the Plinabulin 2 group was given Plinabulin at 7.5 mg/kg, and the deuterated Plinabulin 2 group was given 7.5 mg/kg.
  • Deuterated plinabulin was given per kg, intravenously infused for 15 minutes, single dose, and the dose volume was 20 mL/kg.
  • the general state was observed once a day, the weight was weighed once a day after the administration, the blood test was performed once a day before and after the administration, and the rats were dissected on the 14th and 24th days after the administration. Take the thymus from each animal, weigh it and calculate its organ coefficient (the weight of the organ per 10g body weight (mg)).
  • Model control groups 1 and 2 Plinabulin 1 and 2 groups, and deuterated plinabulin 1 and 2 groups all had symptoms such as deformed stool, perianal secretions, and sparse back hair.
  • the body weight of the animals in the normal control group showed a steady upward trend throughout the test.
  • the body weight of the model control group 1 and 2 was significantly lower than the normal control group (P ⁇ 0.05);
  • the body weight of the Plinabulin 2 group decreased significantly (P ⁇ 0.05);
  • the model control group 2 the deuterated Plinabulin The body weight of the two groups decreased significantly (P ⁇ 0.05).
  • the white blood cell count in the deuterated plinabulin 1 group tended to be higher than that in the Plinabulin 1 group, and on the 7th and 8th days after administration, the white blood cell count in the deuterated plinabulin 1 group was significantly higher than that in the Plinabulin 1 group. Higher than Plinabulin 1 group.
  • the deuterated plinabulin group 2 was significantly higher than the model control group 2 on the 8th to 9th day and the 18th to 20th day after administration (P ⁇ 0.05).
  • the white blood cell count of the deuterated plinabulin 2 group showed a rising trend compared with that of the Plinabulin 2 group.
  • the deuterium plinabulin 2 group was significantly higher than that of the Plinabulin 2 group (P ⁇ 0.05).
  • the intraperitoneal injection of cyclophosphamide was carried out on the first day for modeling and administration once, and the neutrophil count in the model control group 1 was significantly lower than that in the normal control group on days 1 to 8 (P ⁇ 0.05), then increased and then decreased to the normal level. On the 10th to 11th day, the neutrophil count in the model control group 1 was significantly higher than that in the normal control group (P ⁇ 0.05).
  • the neutrophil count in the deuterated plinabulin 1 group was significantly increased (P ⁇ 0.05); compared with the model control group 1, the deuterated plinabulin In the Bollinger 1 group, neutrophils showed an increasing trend on the 8th to 11th days after administration, but there was no statistical significance.
  • the neutrophil count in the deuterated plinabulin 1 group was significantly increased (P ⁇ 0.05); compared with the Plinabulin 1 group, the deuterated plinabulin In group 1, neutrophils showed an increasing trend on the 9th to 11th day after administration, but there was no statistical significance.
  • the intraperitoneal injection of cyclophosphamide was carried out on the 1st and 8th day for modeling and administration, and the neutrophil count in the model control group 2 was significantly lower than that of the normal control group on the 2nd to 14th day (P ⁇ 0.05), then increased and then decreased to normal levels, and was significantly higher than the normal control group (P ⁇ 0.05) on the 16th to 22nd day.
  • the neutrophil count in the Plinabulin 2 group was significantly increased on the 2nd and 9th day (P ⁇ 0.05), and was significantly decreased on the 15th to 17th day (P ⁇ 0.05);
  • the neutrophil counts in Nabulin 2 group increased significantly on the 2nd to 3rd day, the 8th to 10th day, and the 18th to 20th day (P ⁇ 0.05).
  • the neutrophil count in the deuterated Plinabulin 2 group was significantly increased on the 2nd to 3rd day, the 8th to 10th day, and the 18th to 20th day (P ⁇ 0.05).
  • the thymus coefficient of the model control group 1 was significantly lower than that of the normal control group (P ⁇ 0.05).
  • the thymus coefficient of the model control group 2 was significantly lower than that of the normal control group (P ⁇ 0.05).
  • neutrophils and leukocytes in the model control group decreased significantly about one week after cyclophosphamide modeling, and general clinical observations showed symptoms such as hypoactivity, diarrhea, and significant weight loss. Cyclophosphamide induced neutrophils Reduced model build succeeded.
  • the neutrophils in the Plinabulin group were significantly higher than those in the model control group at multiple time points; the neutrophils and The white blood cells were significantly higher than those in the model control group and Plinabulin group.
  • the animals in the other groups were intraperitoneally injected with cyclophosphamide for modeling, the modeling dose was 50 mg/kg, and the administration volume was 10 mL/kg;
  • the normal control group and the model control group were given 5% glucose solution through tail vein injection, and the deuterated plinabulin treatment group was given 10 mg/kg deuterated plinabulin by intravenous infusion for 15 minutes, single administration.
  • the design is shown in Table 29.
  • the white blood cell count in the model control group decreased significantly on the 2nd to 7th day and the 14th day (P ⁇ 0.05), and the overall trend was to decrease after modeling and then rise to the normal level .
  • the white blood cell count in the deuterated plinabulin treatment group was significantly increased on the second day (P ⁇ 0.05), and the white blood cell count was significantly decreased on the ninth day (P ⁇ 0.05).
  • the neutrophil count in the model control group decreased significantly (P ⁇ 0.05) on days 2 to 7, and increased significantly on day 9 (P ⁇ 0.05) , the overall trend was modeled and then decreased and then increased, and then dropped to the normal level.
  • the neutrophil count in the deuterated plinabulin treatment group was significantly higher on the second day (P ⁇ 0.05), and the neutrophil count on the ninth day was significantly lower than that in the model control group (P ⁇ 0.05), but comparable to the normal control group.
  • the animals in the other groups were given cyclophosphamide by tail vein injection for modeling, the modeling dose was 50mg/kg, and the administration volume was 5mL/kg; , the normal control group and the model control group were given 5% glucose solution by tail vein injection, and the deuterated plinabulin treatment group was given the test product deuterated plinabulin at 7.5mg/kg, intravenous infusion for 15min, single administration , the administration volume is 20mL/kg.
  • the design is shown in Table 35.
  • the rats in the other groups showed symptoms such as hypoactivity, sparse back hair, shapeless feces, and perianal filth.
  • the normal control group showed a steady upward trend after administration to the end of the test. Compared with the normal control group, there was no significant decrease in the model control group; compared with the model control group, there was a downward trend in the deuterated plinabulin treatment group, but there was no significant difference.
  • the intravenous injection of cyclophosphamide was used for modeling and administration on the first day, and the white blood cell count in the model control group was significantly lower than that in the normal control group on the 2nd to 9th day after administration (P ⁇ 0.05 ), then increased and then decreased to normal levels.
  • the white blood cell count in the deuterated plinabulin treatment group was significantly higher (P ⁇ 0.05).
  • neutrophils and leukocytes in the model control group decreased significantly about one week after intravenous injection of cyclophosphamide, and general clinical observations showed symptoms such as hypoactivity, diarrhea, and weight loss to a certain extent, indicating that intravenous injection Cyclophosphamide-induced neutropenia model was established successfully.
  • Intravenous injection of cyclophosphamide was administered once 30 minutes after modeling on the first day.
  • the neutrophils in the deuterated plinabulin treatment group were significantly increased on the second day, and the white blood cells and neutrophils were significantly increased on the 12th day. raised.
  • the model control group was given intraperitoneal injection of cyclophosphamide for modeling, the modeling dose was 50 mg/kg, and the administration volume was 10 mL/kg. 1.875, 3.75, and 7.5 mg/kg deuterated plinabulin were given to the low, medium, and high doses of deuterated plinabulin alone, intravenous infusion for 15 minutes, single administration, normal control group and model control group A 5% glucose solution was injected into the tail vein. The design is shown in Table 41.
  • the body weight of the rats in the low-dose deuterated plinabulin group was not different from that in the normal control group.
  • the body weight of the model control group was significantly lower than that of the normal control group on the second day after administration (P ⁇ 0.05).
  • the body weight of the rats in the middle and high dose groups of deuterated plinabulin decreased significantly from day 1 to day 7 (P ⁇ 0.05).
  • the white blood cell count in the model control group decreased significantly (P ⁇ 0.05) on days 2 to 9 and 18, and the overall trend was to increase after the model was established. to normal levels. There was no significant difference in white blood cell count between the low and middle dose groups of deuterated plinabulin compared with the normal control group. The white blood cell count in the high-dose deuterated plinabulin group was significantly lower than that in the normal control group on the second day after administration (P ⁇ 0.05), and then rose to the normal level.
  • the neutrophil count in the model control group decreased significantly (P ⁇ 0.05) on the 2nd to 5th day, and was higher than that of the normal control group on the 9th to 11th day, but No significant difference. Overall, it decreased after modeling and then increased, and then dropped to normal levels.
  • the model control group had no abnormalities in the general clinical observation after intraperitoneal modeling with 50 mg/kg cyclophosphamide, and the body weight dropped first and then recovered after administration.
  • the neutrophils and leukocytes decreased significantly about one week after modeling, indicating that the cyclophosphamide-induced neutropenia model was successfully established at this dose.
  • the body weight of the rats in the middle and high doses of deuterated plinabulin group was significantly lower than that of the normal control group in the first week after administration, and the body weight of the rats in the high doses of deuterated plinabulin group was significantly lower than that of the normal control group in the first week after administration.
  • the white blood cell count decreased significantly on the first day, the neutrophils in the middle-dose deuterated plinabulin group decreased significantly on the 2nd and 3rd day after administration (P ⁇ 0.05), and the high-dose deuterated plinabulin group decreased significantly on the 2nd and 3rd day after administration.

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Abstract

L'invention concerne une application de plinabuline deutérée dans la préparation d'un médicament pour le traitement de la neutropénie. Est divulguée une méthode de traitement et/ou de prévention de la neutropénie, comprenant l'administration à un sujet qui en a besoin d'une quantité thérapeutiquement efficace de plinabuline deutérée telle que représentée dans la formule (I), ou d'un sel pharmaceutiquement acceptable de celle-ci. La plinabuline deutérée telle que représentée dans la formule (I) ou un sel pharmaceutiquement acceptable de celle-ci peuvent être utilisés pour traiter et/ou prévenir la neutropénie, et améliorer les effets secondaires toxiques du traitement clinique des tumeurs.
PCT/CN2022/102466 2021-06-29 2022-06-29 Application de plinabuline deutérée dans la préparation d'un médicament pour le traitement de la neutropénie WO2023274316A1 (fr)

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