CN112245440A - Use of tocotrienol derivatives - Google Patents
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Abstract
Use of tocotrienol derivatives. The present invention relates to the use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and/or treatment of cytopenia in a subject to be, being or having been treated with a chemotherapeutic drug:
wherein: r1, R2 and R3 may be the same or different and each independently represents H or C1‑C3An alkyl group. Compared with the clinically common drugs such as G-CSF which are used for increasing the number of blood cells in a subject receiving chemotherapy, the compound of the invention can remarkably increase the number of blood cells, particularly white blood cells, especially neutrophils and monocytes in the subject receiving chemotherapy. The compound of the invention has good clinical prospect.
Description
The present application is a divisional application of chinese patent application No. 201680063949.3 entitled "use of tocotrienol derivatives" filed 2016, 11, 4.
Technical Field
The present invention relates to the use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof as described and defined herein for the manufacture of a medicament for the prevention and/or treatment of cytopenia in a subject to be, being or having been treated with a chemotherapeutic drug.
Background
For the treatment of neoplastic diseases, a large number of chemotherapeutic drugs have been proposed. However, chemotherapeutic drugs are often non-specific and toxic to normal cells. Chemotherapeutic drugs often produce various side effects in patients receiving chemotherapy.
Myelosuppression is one of the major side effects of chemotherapeutic drugs. Clinically, patients receiving chemotherapy are highly vulnerable to damage in their bone marrow hematopoietic system, manifested by, for example, a reduction in peripheral blood leukocyte counts, a reduction in neutrophil counts and/or thrombocytopenia. At present, some chemotherapy protective agents are clinically used for relieving the side effects of chemotherapy drugs, particularly neutropenia and thrombocytopenia caused by chemotherapy. Chemoprotectants that are clinically common include agents such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and Thrombopoietin (TPO). However, G-CSF and GM-CSF can increase the later risk of secondary myeloid disorders such as leukemia and myelodysplasia (> 2 years after treatment). TPO can cause abnormal elevation of platelet counts in cancer patients, leading to increased thrombosis and death.
In view of these deficiencies of the above-described methods, there remains a need to develop new chemoprotectants, particularly chemoprotectants that increase the number of blood cells, such as white blood cells, platelets, and red blood cells, in a subject receiving chemotherapy.
Disclosure of Invention
The present invention provides a compound capable of increasing the number of blood cells in a subject receiving chemotherapy.
The present invention relates to the use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and/or treatment of cytopenia in a subject to be, being or having been treated with a chemotherapeutic drug:
wherein:
r1, R2 and R3 may be the same or different and each independently represents H or C1-C3An alkyl group.
In one embodiment, R1 and R3 each independently represent H or methyl; and R2 is H.
In one embodiment, the compound is selected from the group consisting of:
in one embodiment, the pharmaceutically acceptable salt is selected from the group consisting of sodium, potassium, magnesium, calcium and ammonium salts.
In one embodiment, the cytopenia is leukopenia or thrombocytopenia.
In one embodiment, the leukopenia is a granulocytopenia.
In one embodiment, the subject is selected from subjects having the following tumors: lung, gastrointestinal, nasopharyngeal, genitourinary, head and neck, thyroid, breast, sarcoma, leukemia, and lymphoid tumors.
In one embodiment, the subject is selected from subjects suffering from: myelodysplastic syndrome, myeloproliferative disorders, and autoimmune disorders.
In one embodiment, the chemotherapy uses a chemotherapeutic agent selected from the group consisting of: melphalan (melphalan), cyclophosphamide (cyclophosphamide), oxazaphospholene (oxazaphosphorine), cisplatin (cissplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), satraplatin (satraplatin), tetraplatin (tetraplatin), iproplatin (iproplatin), mitomycin (mitomycin), streptozocin (streptacin), carmustine (carmustine), lomustine (lomustine), busulfan (busufan), ifosfamide (ifosfamide), streptozocin (streptazocin), thiotepa (thiotepa), chlorambucil (chlomambucil), mechlorethamine, cytarabine (cyrabbine), 5-fluorouracil (5-FU), mellitrexed (mepiquat), gazepine (azathiouracil), chloropurine (fludarabine), thioguanidine (fludarabine), mecarbutine (fludarabine), 5-fluorouracil (5-FU), mecarbitracin (mepiquine), gazine (oxypurin), mecarbutin (oxypurine (oxyphenidine), mecarbutinine (thioguanine), mecarbutinine (xanthatinine (meperidine), mecarbine (fludarabine), mecarbine (xanthatin), mecarbine (xanthatin), mecarb (e), mecarbine), mecarbutin (xanthatine), mecarbine), mecarbutin (xanthatine (xanthatin, Paclitaxel (paclitaxel), docetaxel (docetaxel), taxotere (taxotere), navelbine (navelbine), vinblastine (vinblastatin), vincristine (vinchristin), vindesine (vindesine), vinorelbine (vinorelbine), colchicine (colchicine), sytansine (maytansine), ansamitocin (ansamitocin), rhizoxin (rhizoxin), phomopsin (phomopsin), dolastatin (dolastatin), etoposide (etoposide), teniposide (teniposide), cimycin (stanin), combretastatin (combretastatin), amphetamine (amphetamine), procarbazine (procarbazine), camptothecin (capicin), irinotecan (thevidin), irinotecan (interferon), interferon (tacrine), interferon (tacroline), tacroline (10331-166-D), interferon (EK-11248, EK-D-1122016), EK-29-D-11248, EK-D-1122016, EK-29-D-15, and interferon (interferon-D-3-5648, interferon-D-15, interferon (EK-D-6648, interferon (EK-D-15-D-15-D-S-D-E, a, and a, HKI-272, herceptin (herceptin) and apremizumab (apoluzumab).
In one embodiment, the medicament is administered by subcutaneous injection or intramuscular injection.
In one embodiment, the medicament is administered at intervals or continuously, once or more times per day, in a dose of 1 to 100mg/kg/d, preferably 5 to 40mg/kg/d, for example 10 mg/kg/d.
Drawings
FIG. 1 effect of rhG-CSF, delta-T3 HP and delta-THP on peripheral blood leukopoiesis on day 5 after chemotherapy in mice with cyclophosphamide chemotherapy.
FIG. 2 effect of rhG-CSF, delta-T3 HP and delta-THP on peripheral blood leukopoiesis on day 7 after chemotherapy in mice with cyclophosphamide chemotherapy.
FIG. 3 the effect of rhG-CSF, delta-T3 HP and delta-THP on peripheral thrombopoiesis on day 10 after chemotherapy in cyclophosphamide-chemotherapeutic mice.
FIG. 4 Effect of delta-T3 HP on the number of peripheral blood leukocytes in macaques treated with cyclophosphamide chemotherapy.
FIG. 5 Effect of delta-T3 HP on the number of neutrophils in peripheral blood of macaques treated with cyclophosphamide chemotherapy.
FIG. 6 Effect of delta-T3 HP on the number of peripheral blood mononuclear cells in cynomolgus monkeys after cyclophosphamide chemotherapy.
FIG. 7 Effect of delta-T3 HP on the number of platelets in macaques treated with cyclophosphamide chemotherapy.
Figure 8 effect of delta-T3 HP on the number of peripheral red blood cells in cynomolgus monkeys after cyclophosphamide chemotherapy.
FIG. 9 Effect of delta-T3 HP on the number of peripheral reticulocytes from macaques treated with cyclophosphamide chemotherapy.
Detailed Description
In a first aspect, the present invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof for use in the prevention and/or treatment of cytopenia in a subject to be, being or having been treated with a chemotherapeutic drug:
wherein:
r1, R2 and R3 may be the same or different and each independently represents H or C1-C3An alkyl group.
The terms mentioned herein preferably have the following meanings:
the term "C1-C3Alkyl "refers to a straight or branched chain, saturated, monovalent hydrocarbon group having 1, 2, or 3 carbon atoms, including methyl, ethyl, n-propyl, and isopropyl. In particular, C1-C3The alkyl group is selected from methyl and ethyl, preferably methyl.
In one embodiment, the invention includes compounds of general formula (I) as described above, wherein R1 and R3 each independently represent H or methyl, and R2 is H.
In one embodiment, the compound is selected from the group consisting of:
in one embodiment, the invention includes pharmaceutically acceptable salts of the compounds of general formula (I) as described above, wherein the pharmaceutically acceptable salts are selected from sodium, potassium, magnesium, calcium and ammonium salts. In one embodiment, the pharmaceutically acceptable salt is selected from sodium salts.
In one embodiment, the invention includes the following compounds:
the compound or the pharmaceutically acceptable salt thereof has good stability and water solubility.
In a second aspect, the present invention relates to the use of a compound of the first aspect or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and/or treatment of cytopenia in a subject who is to be, is being, or has been treated with a chemotherapeutic drug.
The term "subject" refers to mammals, including humans and non-humans, including, but not limited to, humans, pigs, dogs, rabbits, monkeys, cats, and the like. The subject of the invention is selected from subjects suffering from tumors, the definition and classification of which can be found, for example, in the histological classification of tumors as established by the World Health Organization (WHO), second edition (1989-2000). Subjects of the invention also include subjects suffering from: including, but not limited to, myelodysplastic syndromes (MDS), such as refractory cytopenia with unilineage pathopoiesis (RCUD), Refractory Anemia (RA), Refractory Neutropenia (RN), Refractory Thrombocytopenia (RT), refractory anemia with cricoid granulocytes (RARS), refractory cytopenia with multilineage pathopoiesis (RCMD), refractory anemia with primitive cytosis-1 (RAEB-1), refractory anemia with primitive cytosis-2 (RAEB-2), MDS-unclassified (MDS-U), MDS with simple 5 q-; myeloproliferative disorders (MPD) such as polycythemia vera, Chronic Myelogenous Leukemia (CML), essential thrombocythemia, essential myelofibrosis; and certain autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, ulcerative colitis. In one embodiment, the subject further comprises a subject having aplastic anemia.
The term "blood cells" refers to the collective term for red blood cells, white blood cells and platelets in the blood. Erythrocytes are derived from the hematopoietic multipotent stem cells of the bone marrow, reticulocytes are not yet fully mature erythrocytes whose value in the peripheral blood reflects the production function of bone marrow erythrocytes. The leukocytes mainly comprise neutrophils, lymphocytes, monocytes, eosinophils and basophils, wherein the neutrophils and monocytesThe proportion of cells is large. The number of the white blood cells in healthy people is usually 4.0-10.0 multiplied by 109a/L, wherein the number of neutrophils is usually 2.0-7.5 x 109The number of monocytes is usually 0.2 to 0.77X 109And L. The number of platelets in healthy people is usually 100-300 multiplied by 109/L。
FIGS. 1-3 show the effect of the compounds of the invention on the number of peripheral blood leukocytes and platelet counts, respectively, in mice receiving cyclophosphamide chemotherapy. FIGS. 4-9 show the effect of compounds of the invention on the number of cynomolgus peripheral blood leukocytes, neutrophils, monocytes, platelets, erythrocytes and reticulocytes, respectively, of macaques receiving cyclophosphamide chemotherapy. Cytopenia (hypocytosis) is a common adverse effect of chemotherapy drug administration, and is usually most pronounced as leukopenia and/or thrombocytopenia. The number of adult peripheral blood leukocytes is continuously less than 3.5 × 109/L, known as leukopenia; severe leukopenia may result in a significant reduction in the number of peripheral blood neutrophils in a subject, when the absolute value of peripheral blood neutrophils is below 2 x 10 in adults9at/L, granulocytopenia can be diagnosed; when the absolute value of the neutrophil in the peripheral blood is lower than 0.5 multiplied by 10 in adults9below/L, granulocytopenia can be diagnosed. The medicines widely used in clinic at present for increasing the number of blood cells, especially white blood cells, of a subject after chemotherapy are recombinant human granulocyte colony-stimulating factor (rhG-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The experimental result shows that compared with the recombinant human granulocyte colony stimulating factor, the compound of the invention can more obviously increase the number of leukocytes after chemotherapy, particularly neutrophils and monocytes. Meanwhile, the compound of the invention also has certain effect on increasing the number of platelets, red blood cells and reticulocytes after chemotherapy.
In one embodiment, the blood cells are selected from the group consisting of leukocytes, platelets, and erythrocytes. In one embodiment, the subject has chemotherapy-associated leukopenia or thrombocytopenia. In one embodiment, the subject has a chemotherapy-associated agranulocytosis.
The term "chemotherapy" refers to a treatment regimen that uses chemical drugs to prevent the proliferation, infiltration, and metastasis of cancer cells until the cancer cells are ultimately killed. Common chemotherapeutic agents include, but are not limited to: melphalan (melphalan), cyclophosphamide (cyclophosphamide), oxazaphospholene (oxazaphosphorine), cisplatin (cissplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), satraplatin (satraplatin), tetraplatin (tetraplatin), iproplatin (iproplatin), mitomycin (mitomycin), streptozocin (streptacin), carmustine (carmustine), lomustine (lomustine), busulfan (busufan), ifosfamide (ifosfamide), streptozocin (streptazocin), thiotepa (thiotepa), chlorambucil (chlomambucil), mechlorethamine, cytarabine (cyrabbine), 5-fluorouracil (5-FU), mellitrexed (mepiquat), gazepine (azathiouracil), chloropurine (fludarabine), thioguanidine (fludarabine), mecarbutine (fludarabine), 5-fluorouracil (5-FU), mecarbitracin (mepiquine), gazine (oxypurin), mecarbutin (oxypurine (oxyphenidine), mecarbutinine (thioguanine), mecarbutinine (xanthatinine (meperidine), mecarbine (fludarabine), mecarbine (xanthatin), mecarbine (xanthatin), mecarb (e), mecarbine), mecarbutin (xanthatine), mecarbine), mecarbutin (xanthatine (xanthatin, Paclitaxel (paclitaxel), docetaxel (docetaxel), taxotere (taxotere), navelbine (navelbine), vinblastine (vinblastatin), vincristine (vinchristin), vindesine (vindesine), vinorelbine (vinorelbine), colchicine (colchicine), sytansine (maytansine), ansamitocin (ansamitocin), rhizoxin (rhizoxin), phomopsin (phomopsin), dolastatin (dolastatin), etoposide (etoposide), teniposide (teniposide), cimycin (stanin), combretastatin (combretastatin), amphetamine (amphetamine), procarbazine (procarbazine), camptothecin (capicin), irinotecan (thevidin), irinotecan (interferon), interferon (tacrine), interferon (tacroline), tacroline (10331-166-D), interferon (EK-11248, EK-D-1122016), EK-29-D-11248, EK-D-1122016, EK-29-D-15, and interferon (interferon-D-3-5648, interferon-D-15, interferon (EK-D-6648, interferon (EK-D-15-D-15-D-S-D-E, a, and a, HKI-272, herceptin (herceptin) and apremizumab (apoluzumab).
Radiotherapy (abbreviated as radiotherapy) can also be used for treating tumors. Radiotherapy irradiates tumor tissues with high-energy ions, and can directly act on target spots such as cell DNA and the like or interact with intracellular water molecules and the like through ionization excitation to generate free radicals to indirectly act on the target spots such as the cell DNA and the like, so that tumor cells are killed. Radiation therapy also causes a reduction in the number of peripheral blood cells. However, radioprotectors do not act on the same mechanism as chemoprotectants. For example, the radioprotectant amifostine (WR-2721) for radiotherapy can eliminate active free radicals in the cell environment by prophylactic administration or early administration after radiation to inhibit side effects caused by radiation.
The term "treatment" is understood to include the alleviation, reduction, reversal and/or elimination of the decrease in the number of blood cells, in particular the decrease in the number of leukocytes and platelets, caused by the administration of a chemotherapeutic drug to a subject. Treatment is also understood to include prophylactic treatment.
The term "medicament of the invention" is understood to mean a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof and suitable pharmaceutical excipients and/or adjuvants. The pharmaceutical excipients and/or adjuvants include, but are not limited to, starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, calcium carbonate, kaolin, microcrystalline cellulose, glycerol, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, glucose solution, acacia slurry, gelatin, sodium carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, and the like.
In a third aspect, the present invention also relates to a method for the prevention and/or treatment of cytopenia in a subject about to, being treated with or having been treated with a chemotherapeutic drug, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof or a pharmaceutical composition.
The compound of the present invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered by subcutaneous injection or intramuscular injection. Accordingly, the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof may be prepared in the form of a solution, an injection, or a powder.
The compounds of the present invention, pharmaceutically acceptable salts or pharmaceutical compositions thereof may be administered by administration at intervals or continuously, once or more times per day, for example 2 to 5 times per day, preferably once per day. The compound, pharmaceutically acceptable salt or pharmaceutical composition thereof of the present invention can be administered at a dose of 1 to 100 mg/Kg/day, preferably 5 to 40mg/Kg/d, for example 10mg/Kg/d or 20mg/Kg/d, preferably 1 to 3 times/day, more preferably 1 time/day. The compounds of the invention, pharmaceutically acceptable salts or pharmaceutical compositions thereof may also be used in combination with other agents which help to increase the blood cell count, particularly the white blood cell count, of a subject following chemotherapy, such as G-CSF or GM-CSF.
In one embodiment, the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered by intramuscular injection or subcutaneous injection. In another embodiment, the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof are administered intermittently or continuously. In another embodiment, the compound, pharmaceutically acceptable salt or pharmaceutical composition of the invention is administered one or more times per day for a treatment period of not less than 3 days. In another embodiment, the compound, pharmaceutically acceptable salt or pharmaceutical composition of the present invention is administered in a daily dose of 1 to 100mg/Kg/d, preferably 5 to 40mg/Kg/d, such as 10mg/Kg/d or 20 mg/Kg/d.
Examples
The present invention will be described in more detail with reference to the following examples. However, the following examples are provided only for explaining the present invention and should not be construed as limiting the scope and spirit of the present invention.
Example 1: (2, 8-dimethyl-2R- ((3E, 7E) -4,8, 12-trimethyltridec-3, 7, 11-trienyl) benzene
Preparation of sodium salt of Diarapyran-6-yloxy) phosphate (i.e., sodium salt of delta-tocotrienol phosphate, abbreviated as delta-T3 HP)
And confirmation
Structural formula (xvi):
the reaction equation is as follows:
step a:
taking 15g of delta-tocotrienol, adding 45ml of toluene into a 250ml round-bottom flask for dissolving, then adding 6ml of pyridine, stirring and cooling to 0-5 ℃. 4.5ml of phosphorus oxychloride are slowly added dropwise. After the dropwise addition, the mixture was transferred to room temperature and stirred for 3 hours.
Step b:
then, the reaction system was cooled to 0 ℃ or lower, and 60ml of distilled water was slowly added. After the dropwise addition, the mixture is heated to reflux for 4 hours.
Step c:
100ml of each of toluene and distilled water was added to the reaction mixture, and the mixture was shaken and allowed to stand for separation. The organic layer was transferred to a rotary evaporator and the solvent was removed. The remaining material was redissolved in 15ml of isopropanol and heated with stirring. To the filtrate, 25ml of methanol in which 2.4g of sodium hydroxide was dissolved was slowly added, and stirred vigorously until a precipitate was generated. The supernatant was decanted and washed with a small amount of methanol. Filtration was carried out and the residue was redissolved in 400ml of methanol. Filtering, concentrating the filtrate to 100-150 ml, dripping 300ml of acetone until white flocculent precipitate is generated, fully stirring, and filtering to obtain 11.3g of white solid, wherein the yield is as follows: and 59.4 percent.
Of the resulting product1The H-NMR results were as follows:
1H-NMR(400MHz；CDCl3)δ＝1.24(s,3H，CH3-2a),1.49～1.81(m,16H,CH2-1`,CH2-2`,CH3-4`a,CH3-8`a,CH3-12`a,CH3-13),1.94～2.13(m,13H,CH2-3,CH2-5`,CH2-6`,CH2-9`,CH2-10`,CH3-8a),2.78(t,J＝6.6Hz,2H,CH2-4),6.61(d，J＝2.8Hz,1H，CH-7)，6.66(d，J＝2.8Hz,1H，CH-5)；MS(ESI，m/s)：C27H39O5P，[M-H+]475.26 (calculated 476.25).
Example 2: 2, 2-dimethyl- (2R- (4R,8R, 12-trimethyltridecyl) chroman-6-yloxy
Base) disodium phosphate (i.e. sodium salt of delta-tocopherol phosphate, abbreviated as delta-THP)Prepare and confirm
Structural formula (xvi):
the reaction equation is as follows:
step a:
taking 15g of delta-tocopherol, adding 45ml of toluene into a 250ml round-bottom flask for dissolving, then adding 6ml of pyridine, stirring and cooling to 0-5 ℃. 4.5ml of phosphorus oxychloride are slowly added dropwise. After the dropwise addition, the mixture was transferred to room temperature and stirred for 3 hours.
Step b:
then, the reaction system was cooled to 0 ℃ or lower, and 60ml of distilled water was slowly added. After the dropwise addition, the mixture is heated to reflux for 4 hours.
Step c:
100ml of each of toluene and distilled water was added to the reaction mixture, and the mixture was shaken and allowed to stand for separation. The organic layer was transferred to a rotary evaporator and the solvent was removed. The remaining material was redissolved in 15ml of isopropanol and heated with stirring. To the filtrate, 25ml of methanol in which 2.4g of sodium hydroxide was dissolved was slowly added, and stirred vigorously until a precipitate was generated. The supernatant was decanted and washed with a small amount of methanol. Filtration was carried out and the residue was redissolved in 400ml of methanol. Filtering, concentrating the filtrate to 100-150 ml, dripping 300ml of acetone until white flocculent precipitate is generated, fully stirring, and filtering to obtain white solid. Drying gave 8.8g, 44.2% yield.
Of the resulting product1The H-NMR results were as follows:
1H-NMR(400MHz；CDCl3)δ：0.85(m，12H，CH3-4`a,CH3-8`a,CH3-12`a,CH3-13a,),1.0-1.6(m，24H，CH1-4`,CH1-8`,CH2-1`,CH2-2`,CH2-3`,CH2-5`,CH2-6`,CH2-7`,CH2-9`,CH2-10`,CH2-11`,CH3-2a`)，1.74(m，2H，CH2-3)，2.13(s,3H,CH3-8a),2.71(t，2H，J＝7.2Hz，CH2-4),6.61(d，J＝2.8Hz，1H，CH-7)，6.66(d，J＝2.8Hz，1H，CH-5)；MS(ESI，m/s)：C27H45O5P[M-H+]481.61 (calculated 482.81).
Example 3: effect of delta-T3 HP and delta-THP on peripheral blood count in mice receiving cyclophosphamide chemotherapy
3.1 materials and methods
3.1.1 Primary reagents and instruments
Cyclophosphamide is available from henry pharmaceutical, inc. MEK-7222K full-automatic hemocytometer and peripheral blood measurement dilutions were purchased from Nippon Denshoku Kogyo Co.
3.1.2 Experimental animals and groups
The experiment adopts 6-8 week-old SPF grade C57BL/6J male mice with weight (22.6 +/-0.89) g purchased from Beijing Huafukang Biotechnology GmbH.
3.1.3 conditions of chemotherapy
Cyclophosphamide is used as a chemotherapeutic agent: before use, the solution is prepared into 11.25mg/ml solution by 0.9% physiological saline, and 100mg/Kg and 200 mul of the solution are administrated in the abdominal cavity of each mouse.
3.1.4 methods of grouping and administration
The experiments were carried out with rhG-CSF control and treatment, delta-T3 HP control and treatment, and delta-THP control and treatment, with 7 mice per group.
rhG-CSF 250. mu.g/bottle, 11. mu.g/ml with physiological saline, 100mg/Kg per mouse, 200. mu.l subcutaneous administration.
delta-T3 HP was dissolved in physiological saline at 11mg/ml and administered subcutaneously at 200. mu.l/100 mg/Kg per mouse.
Delta-THP was dissolved in PEG400 at 11mg/ml and administered subcutaneously at 200. mu.l/100 mg/Kg per mouse.
2 hours after intraperitoneal injection of cyclophosphamide, delta-T3 HP (100mg/Kg) and delta-THP (100mg/Kg) were subcutaneously administered to the experimental mice 1 time a day for 3 consecutive days.
The experimental mice were administered rhG-CSF (100. mu.g/Kg) subcutaneously starting 24 hours after intraperitoneal injection of cyclophosphamide, 1 time per day for 3 consecutive days.
Chemotherapy control mice were injected subcutaneously with 0.2 ml/mouse of the corresponding solvent.
3.1.5 peripheral blood picture detection
Each group of animals was bled 20. mu.l from the tails before (0d) and after (1, 3, 5, 7, 10, 14, 18, 22d) administration, and injected into 2ml of a dilution of a hemocytometer, and the peripheral blood leukocyte (WBC) and Platelet (PLT) counts were measured using a MEK-7222K fully automatic hemocytometer.
3.1.6 statistical treatment
The results are expressed as mean ± sd and statistically analyzed by GraphPad Prism 5 software. The results of the hemogram measurements were analyzed by Student's t-test, and P < 0.05 indicated a statistical difference.
3.2 results
As shown in Table 1 and FIG. 1, the WBC of peripheral blood of rhG-CSF, delta-T3 HP and delta-THP control mice were 4.3. + -. 1.2X 10, respectively, at day 5 after chemotherapy9/L、5.7±1.3×109L and 8.2. + -. 1.3X 109The values of the three groups are obviously lower than the normal values before chemotherapy (13.7 +/-2.1X 10)9L). After rhG-CSF, delta-T3 HP and delta-THP treatment after chemotherapy, the WBC values of peripheral blood of mice in each treatment group were significantly increased, 1.4, 2.8 and 1.2 times higher than those of the corresponding control group, respectively, and the statistical analysis showed p values of less than 0.01, 0.001 and 0.05, respectively, with the best treatment effect being delta-T3 HP.
On day 7 after chemotherapy, the WBC in the peripheral blood of each treated group of rhG-CSF, delta-T3 HP and delta-THP and the control group thereof are obviously increased, wherein the WBC in the peripheral blood of each treated group of rhG-CSF, delta-T3 HP and delta-THP is 0.7, 2.7 and 1.1 times of that of the corresponding control group thereof respectively. Compared with the control group, only the delta-T3 HP treatment group has statistical difference, the p value is less than 0.001, and the leucocyte of the rhG-CSF treatment group is obviously lower than that of the control group.
TABLE 1 Effect of rhG-CSF, delta-T3 HP and delta-THP on peripheral blood leukopoiesis in mice receiving cyclophosphamide chemotherapy
As shown in table 2 and figure 2, cyclophosphamide chemotherapeutic agents had no significant effect on mouse peripheral blood platelet count. On day 10 after chemotherapy, the peripheral blood platelet count of each treatment group, rhG-CSF, delta-T3 HP, and delta-THP, was 0.95, 1.4, and 1.1 times that of its corresponding control group, respectively. Compared with the control group, only the delta-T3 HP treatment group has statistical difference, and the p value is less than 0.001.
TABLE 2 Effect of rhG-CSF, delta-T3 HP and delta-THP on peripheral thrombopoiesis in cyclophosphamide chemotherapy mice
| Group of | Peripheral blood PLT number for 10 days |
| rhG-CSF control group | 896±38.7 |
| rhG-CSF | 847.1±66.4 |
| delta-T3 HP control group | 697.9±47.5 |
| δ-T3HP | 979±76.5 |
| Delta-THP control group | 786±102.4 |
| δ-THP | 832.1±87.3 |
Example 4: effect of four T3HP on the number of peripheral hemograms in mice treated with cyclophosphamide chemotherapy
4.1 preparation of the Compounds
α -T3HP, β -T3HP, and γ -T3HP were prepared by the method of the foregoing example 1, respectively, except that α -tocotrienol, β -tocotrienol, and γ -tocotrienol were used as raw materials, respectively. The product is processed by1H-NMR confirmed.
4.2 methods of grouping and administration
Experiments were carried out with treatment groups of α -T3HP, β -T3HP, γ -T3HP and δ -T3HP, with rhG-CSF as a control group, 7 mice per group.
The treatment groups of α -T3HP, β -T3HP, γ -T3HP and δ -T3HP were prepared as 11mg/ml solutions in physiological saline and administered subcutaneously at 200 μ l per mouse at 100 mg/Kg.
rhG-CSF 250. mu.g/bottle, 11. mu.g/ml with physiological saline, 100mg/Kg per mouse, 200. mu.l subcutaneous administration.
The method of the previous example 3 was used to administer α -T3HP, β -T3HP, γ -T3HP, δ -T3HP and rhG-CSF, respectively, after the experimental mice were injected with cyclophosphamide.
4.3 peripheral blood picture detection
The amounts of peripheral blood leukocytes (WBC) and Platelets (PLT) were determined before and after administration using the method described in example 3 above.
4.4 results
The results show that in the chemotherapy mice treated with α -T3HP, β -T3HP, γ -T3HP, δ -T3HP and rhG-CSF, respectively, the mouse peripheral blood WBC values were significantly increased on day 5. The magnitude of WBC elevation was best seen with δ -T3HP in the α -T3HP, β -T3HP, γ -T3HP, and δ -T3HP treatment groups.
On day 10 after chemotherapy, the magnitude of the increase in peripheral blood platelet count was best at delta-T3 HP in the treatment groups α -T3HP, β -T3HP, γ -T3HP, and delta-T3 HP.
Example 5: effect of delta-T3 HP on the number of peripheral hemograms in macaques treated with cyclophosphamide chemotherapy
5.1 materials and methods
5.1.1 Experimental animals
14 rhesus monkeys, male, 2 weeks old, body weight 5.0 + -1.0 kg. Purchased at the institute of biological resources, synelxin, beijing.
5.1.2 Experimental drugs
delta-T3 HP, dissolved in physiological saline, 100mg/mL, filter sterilized. rhG-CSF was purchased from Hangzhou Jiuyuan genetic engineering Co. Cyclophosphamide is available from henry pharmaceutical, inc.
5.1.3 Experimental groups
14 rhesus monkeys were randomly divided into a saline negative control group (5), a delta-T3 HP20mg/Kg group (4), a delta-T3 HP 10mg/Kg group (2), and an rhG-CSF positive control group (3).
5.1.4 macaque chemotherapy model
Cyclophosphamide is used as a chemotherapeutic agent, formulated with 0.9% normal saline, and administered by intravenous injection at a rate of 50mg/Kg per macaque, once daily for two consecutive days. Note that it is ready for use.
5.1.5 methods of administration
delta-T3 HP intramuscular injection of delta-T3 HP was started 2 hours after the last cyclophosphamide chemotherapy, 1 time daily for 8 consecutive days. rhG-CSF was administered subcutaneously 1 time a day for 8 consecutive days starting the first day after cyclophosphamide chemotherapy and at 10. mu.g/Kg. The control group was given physiological saline.
5.1.6 peripheral blood picture detection
Taking about 1ml of upper limb peripheral blood to be put in an EDTA anticoagulation test tube, reversing and mixing uniformly, and then carrying out peripheral blood picture detection by using a SYSMEX XE-2100 full-automatic hemocytometer, wherein the peripheral blood picture detection comprises the detection of White Blood Cells (WBC), Red Blood Cells (RBC), Hemoglobin (HGB), Platelets (PLT), Neutrophils (NE) and Reticulocytes (RET).
5.1.7 data processing
The results are expressed as mean ± sd and statistically analyzed by GraphPad Prism 5 software. The hemogram test results are analyzed by Student's t-test, and P < 0.05 shows that the difference is statistical.
5.2 results of the experiment
5.2.1 Effect of delta-T3 HP on the number of peripheral blood leukocytes in macaques treated with chemotherapy
As shown in figure 4, the peripheral blood leukocytes of the macaques in the negative control group are progressively reduced after chemotherapy, reduced to the minimum value 5-10 days after the chemotherapy, then slowly increased, and basically recovered to the level before the chemotherapy 15 days after the chemotherapy. After the macaque is subjected to chemotherapy, delta-T3 HP20mg/Kg is given, the leucocyte is obviously increased the next day and then rapidly decreased, and the lowest value is reached 5 days after the chemotherapy; WBCs began to rise rapidly on day 6 post-chemotherapy, remained at 2-fold the pre-chemotherapy level for 8-13 days, then declined slowly and declined to the pre-chemotherapy level 20 days post-chemotherapy. After the chemotherapy of the macaques, the delta-T3 HP 10mg/Kg is given, the leukocyte mobilization effect is not obvious in the early stage after the chemotherapy, but the WBC recovery is also remarkably promoted, but the recovery effect is weaker than that of the delta-T3 HP20mg/Kg group.
The rhG-CSF given after the chemotherapy of macaque also has obvious mobilization effect on leucocytes in the early stage after the administration, and also has obvious recovery promoting effect on leucocytes in the recovery stage after the chemotherapy. However, the recovery-promoting effect on leukocytes was rapidly decreased in the rhG-CSF negative control group after 10 days. Compared with the rhG-CSF negative control group, the delta-T3 HP20mg/Kg administration group has no obvious drug withdrawal reaction after 10 days.
5.2.2 Effect of delta-T3 HP on the number of neutrophils in peripheral blood of macaques undergoing chemotherapy
As shown in fig. 5, the neutrophil changes after macaque chemotherapy were very close to leukocytes. delta-T3 HP recovered more from neutrophil chemotherapy than the rhG-CSF positive control and was dose-effective.
5.2.3 Effect of delta-T3 HP on monocyte counts in peripheral blood of chemo-treated macaques
As shown in figure 6, after macaque chemotherapy, delta-T3 HP and rhG-CSF are respectively used for treatment, the peripheral blood mononuclear cells are increased 5-10 days after the chemotherapy, and the delta-T3 HP20mg/Kg treatment group is most remarkable.
5.2.4 Effect of Delta-T3 HP on the number of platelets in peripheral blood of chemo-treated macaques
As shown in FIG. 7, the peripheral blood platelets in the control macaque after chemotherapy were slowly decreased to the minimum level 7 days after chemotherapy, then slowly increased back to the minimum level, and substantially returned to the level before chemotherapy 10 days after chemotherapy. After the chemotherapy of macaques, the treatment of delta-T3 HP is performed, the platelet recovery speed is accelerated and maintained at a higher level, and the delta-T3 HP20mg/Kg group is slightly better than 10 mg/Kg. The positive drug rhG-CSF has no obvious influence on the platelet recovery of the chemotherapy macaques.
5.2.5 Effect of Delta-T3 HP on the number of peripheral red blood cells in macaques treated with chemotherapy
As shown in figure 8, peripheral red blood cells are not obviously reduced after the chemotherapy of the macaques, and peripheral red blood cells of the delta-T3 HP treatment group are obviously reduced and return to the level before the chemotherapy 20 days after the chemotherapy. At day 5, the number of cynomolgus peripheral red blood cells in the rhG-CSF positive control group was reduced more compared to the delta-T3 HP treated group.
5.2.6 Effect of Delta-T3 HP on the number of peripheral reticulocytes in macaques treated with chemotherapy
As shown in fig. 9, the negative control group showed a rapid decrease in peripheral blood reticulocytes after macaque chemotherapy and began to recover on day 6 after chemotherapy. After the chemotherapy macaques are treated by delta-T3 HP or rhG-CSF, peripheral blood reticulocytes are obviously higher than a control group 9-18 days after chemotherapy, wherein the delta-T3 HP20mg/Kg group is the most prominent.
Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.
Claims (8)
1. Use of a compound selected from the group consisting of:
2. the use of claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of sodium, potassium, magnesium, calcium and ammonium salts.
3. Use according to any one of claims 1-2, wherein the cytopenia is leukopenia or thrombocytopenia, preferably the leukopenia is agranulocytosis.
4. The use according to any one of claims 1 to 3, wherein the subject is selected from subjects having a tumor, for example subjects having a tumor selected from: lung, gastrointestinal, nasopharyngeal, genitourinary, head and neck, thyroid, breast, sarcoma, leukemia, and lymphoid tumors.
5. The use according to any one of claims 1 to 4, wherein the subject is selected from subjects suffering from: myelodysplastic syndrome, myeloproliferative disorders, and autoimmune disorders.
6. The use of any one of claims 1-5, wherein the chemotherapy uses a chemotherapeutic agent selected from the group consisting of: melphalan (melphalan), cyclophosphamide (cyclophosphamide), oxazaphospholene (oxazaphosphorine), cisplatin (cissplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), satraplatin (satraplatin), tetraplatin (tetraplatin), iproplatin (iproplatin), mitomycin (mitomycin), streptozocin (streptacin), carmustine (carmustine), lomustine (lomustine), busulfan (busufan), ifosfamide (ifosfamide), streptozocin (streptazocin), thiotepa (thiotepa), chlorambucil (chlomambucil), mechlorethamine, cytarabine (cyrabbine), 5-fluorouracil (5-FU), mellitrexed (mepiquat), gazepine (azathiouracil), chloropurine (fludarabine), thioguanidine (fludarabine), mecarbutine (fludarabine), 5-fluorouracil (5-FU), mecarbitracin (mepiquine), gazine (oxypurin), mecarbutin (oxypurine (oxyphenidine), mecarbutinine (thioguanine), mecarbutinine (xanthatinine (meperidine), mecarbine (fludarabine), mecarbine (xanthatin), mecarbine (xanthatin), mecarb (e), mecarbine), mecarbutin (xanthatine), mecarbine), mecarbutin (xanthatine (xanthatin, Paclitaxel (paclitaxel), docetaxel (docetaxel), taxotere (taxotere), navelbine (navelbine), vinblastine (vinblastatin), vincristine (vinchristin), vindesine (vindesine), vinorelbine (vinorelbine), colchicine (colchicine), sytansine (maytansine), ansamitocin (ansamitocin), rhizoxin (rhizoxin), phomopsin (phomopsin), dolastatin (dolastatin), etoposide (etoposide), teniposide (teniposide), cimycin (stanin), combretastatin (combretastatin), amphetamine (amphetamine), procarbazine (procarbazine), camptothecin (capicin), irinotecan (thevidin), irinotecan (interferon), interferon (tacrine), interferon (tacroline), tacroline (10331-166-D), interferon (EK-11248, EK-D-1122016), EK-29-D-11248, EK-D-1122016, EK-29-D-15, and interferon (interferon-D-3-5648, interferon-D-15, interferon (EK-D-6648, interferon (EK-D-15-D-15-D-S-D-E, a, and a, HKI-272, herceptin (herceptin) and apremizumab (apoluzumab).
7. The use of any one of claims 1-6, wherein the medicament is administered by subcutaneous or intramuscular injection.
8. The use according to any one of claims 1 to 7, wherein the medicament is administered at intervals or continuously, once or more times per day, at a dose of 1 to 100mg/kg/d, preferably 5 to 40mg/kg/d, such as 10mg/kg/d or 20 mg/kg/d.
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