Compound for preparing tumor treatment medicine and pharmaceutical composition thereof

Abstract

The invention belongs to the technical field of discovery of anti-cancer drugs and pharmaceutical compositions, and particularly relates to a compound for preparing a tumor treatment drug and a pharmaceutical composition thereof, the compound is a compound as shown in a formula I, and the pharmaceutical composition comprises a taxane drug and a structural compound as shown in the formula I; the IUPAC of the compound is named as N1-(2-((4-fluorobenzyl) oxy) benzyl)-N3-methylpropane-1, 3-diamine, and the compound is prepared in the form of pharmaceutically acceptable salt and crystal types, optical isomers and acceptable pharmaceutical dosage forms when being used for preparing tumor treatment drugs. The invention verifies that the compound has the medicinal value of treating tumors, the clinical application of the compound is further expanded by the synergistic effect of the compound and the taxane medicines, the compound is combined with the taxane medicines, and the compound and the taxane medicines have a synergistic effect and also have a good effect of inhibiting tumor growth.

Description

Technical Field

[0001] The present invention relates to the technical field of discovery of anticancer drugs and pharmaceutical compositions, and in particular to a compound for preparing tumor therapeutic drugs and a pharmaceutical composition thereof. Background Art

[0002] Taxanes (paclitaxel, PTX) are diterpenoid compounds extracted from the bark of Taxus plants in the Taxaceae family. They have broad-spectrum anticancer activity and a molecular formula of C47H51NO14. Taxanes have become one of the first choice drugs for the treatment of breast cancer, ovarian cancer, lung cancer and other cancers. However, with the deepening of clinical application, the drug resistance of taxanes has gradually emerged, becoming an important factor restricting their application;

[0003] Triple-negative breast cancer is a special type of breast cancer, referring specifically to breast cancer patients whose estrogen receptor (ERR), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) are all negative. Its cancer cells are highly malignant and prone to recurrence, progression, or metastasis, and the prognosis is relatively poor. Triple-negative breast cancer is more common in young premenopausal women. Its 5-year survival rate is low, usually between 30% and 50%, which is much lower than other types of breast cancer. Patients who are discovered early and undergo radical resection have a higher survival rate, but the prognosis of advanced patients is relatively poor.

[0004] It should be noted that the above contents belong to the technical knowledge of the inventor and do not necessarily constitute prior art. Summary of the invention

[0005] In view of the deficiencies of the prior art, the present invention provides a compound for preparing a tumor therapeutic drug and a pharmaceutical composition thereof, which solves the existing problems.

[0006] To achieve the above-mentioned object, the present invention provides the following technical solutions: a compound for preparing a tumor treatment drug and a pharmaceutical composition thereof, comprising a compound and a pharmaceutical composition, wherein the compound is a compound represented by Formula I, and the pharmaceutical composition comprises a taxane drug and a compound represented by Formula I;

[0007] The compound has an IUPAC name of N1-(2-((4-fluorobenzyl)oxy)benzyl)-N3-methylpropane-1,3-diamine, and is prepared in the preparation of tumor therapeutic drugs using pharmaceutically acceptable salts and crystal types as well as optical isomers and acceptable pharmaceutical dosage forms. Its structure is shown below:

[0008]

[0009] The taxane drugs include taxane drugs, docetaxel, and derivatives having a taxane skeleton structure.

[0010] In some embodiments, the concentration of the taxane drug is in the range of 5-800 mg / kg, and the concentration of the composition is in the range of 2-1000 mg / kg.

[0011] In some embodiments, the compound of formula I is used for preparing tumor treatment drugs, which can be combined with taxane drugs or alkane drugs to prepare a pharmaceutical composition.

[0012] In some embodiments, the tumor treatment types include solid tumors and hematological tumors.

[0013] In some embodiments, the solid tumor is non-small cell lung cancer, renal cell carcinoma, head and neck cancer, melanoma, hepatocellular carcinoma, breast cancer, endometrial cancer, ovarian cancer, gastric cancer, colorectal cancer, bladder cancer, pancreatic cancer, glioblastoma, biliary tract cancer, glioma, cervical cancer, advanced and refractory solid tumors, small cell lung cancer, squamous cell carcinoma of the lung, desmoplastic melanoma, mesothelin-positive pleural mesothelioma, esophageal cancer, anal cancer, prostate cancer and thyroid cancer.

[0014] In some of these embodiments, the hematological tumor is acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's disease lymphoma, mantle cell lymphoma, multiple myeloma, myeloid leukemia-1 protein, myelodysplastic syndrome, non-Hodgkin's lymphoma or small lymphocytic lymphoma.

[0015] In some embodiments, the compound inhibits the proliferation of tumor cells by inhibiting the activity of protein arginine methyltransferase (PRMT);

[0016] The use implementation form is to treat tumors by administering the compound of formula I alone, or in combination with a taxane compound for combined treatment;

[0017] The scheme of the use embodiment is that the single dosage of the compound represented by formula I is 2 mg / kg to 1000 mg / kg, and when combined with taxane drugs for treatment, the single dosage of the taxane drugs is 5 mg / kg to 800 mg / kg.

[0018] In some of the embodiments, the method for constructing the compound and pharmaceutical composition comprises the following steps:

[0019] Step 1: Virtual drug screening: Establish a small-scale drug library to test the anti-cancer effects of different compounds under a certain concentration gradient, and comprehensively consider the IC50 value, efficacy and toxicity to determine the compound and compound dose for the next experiment;

[0020] Step 2: In vitro experiments are conducted to further verify at the cell level that the combination of the selected drug and taxane drugs can significantly improve the efficacy compared with single use, and the anti-cancer effect of the selected drug combination is confirmed by judging the indicators of cell proliferation and apoptosis;

[0021] Step 3: In vivo experiments in mice verify the effects of taxanes alone and the combination of taxanes and PRMT1 inhibitors on tumor volume.

[0022] Compared with the prior art, the present invention provides a compound for preparing a tumor treatment drug and a pharmaceutical composition thereof, which has the following beneficial effects:

[0023] The compound and its pharmaceutical composition for preparing a tumor treatment drug, a taxane drug, a taxane drug and a compound for combined use, a compound (molecular formula: C18H23FN2O, molecular weight 302.3934), when used in combination with a taxane drug, the two have a synergistic effect and also have a good tumor growth inhibition effect;

[0024] Current studies have shown that PRMT1 is the first mammalian protein arginine methyltransferase discovered, and in mammalian cells, more than 90% of methylated arginine is catalyzed by PRMT1. Studies have found that PRMT1 is highly expressed in triple-negative breast cancer cells, enhancing the growth, survival, metastasis and invasion of tumor cells, so PRMT1 is expected to become a new target for the treatment of triple-negative breast cancer. The present invention found a compound that has the effect of targeting PRMT1 through computer virtual drug screening. Its chemical formula is C18H23FN2O, its molecular weight is 302.3934, and its IUPAC name is N1-(2-((4-fluorobenzyl)oxy)benzyl)-N3-methylpropane-1,3-diamine, named YH-4. After research, YH-4 has an inhibitory effect on a variety of cancer cells, and its effect of using it in combination with taxanes and taxane drugs is significantly better than that of using each drug alone. Therefore, the YH-4 compound not only has excellent anti-tumor activity itself, but also has clinical benefit advantages in the application of preparing tumor treatment drug compositions in combination with taxane drugs.

[0025] Animal experiments have verified the safety and effectiveness of taxane drugs and compound combinations in treating tumors, fully exploring their potential anti-tumor potential and clinical application value;

[0026] The present invention verifies that the compound has medicinal value for treating tumors, and the synergistic effect with taxane drugs further expands the clinical use of the compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 is a schematic diagram of the chemical structure of the compound of the present invention;

[0028] Figure 2 This is a schematic diagram for evaluating the inhibitory activity of the compounds of the present invention on PRMT1;

[0029] Figure 3 Schematic diagram of the anti-tumor cell proliferation activity of the compound of the present invention;

[0030] Figure 4 It is a schematic diagram of a tumor volume curve of an in vivo experiment of a combined administration of the compound of the present invention and a taxane drug, and a nude mouse body weight curve of an in vivo experiment of a combined administration of the compound and a taxane drug;

[0031] Figure 5 This is a live imaging picture of the triple-negative breast cancer model of the present invention 21 days after administration;

[0032] Figure 6 This is a schematic diagram of the original experimental data of the compounds of the present invention inhibiting PRMT1. DETAILED DESCRIPTION

[0033] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] It should be understood that the step numbers used in this article are only for the convenience of description and are not intended to limit the order in which the steps are executed.

[0035] It should be understood that the terms used in the present specification are only for the purpose of describing specific embodiments and are not intended to limit the present invention. As used in the present specification and the appended claims, unless the context clearly indicates otherwise, the singular forms "a", "an" and "the" are intended to include plural forms.

[0036] The terms “include” and “comprising” indicate the presence of described features, integers, steps, operations, elements and / or components, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components and / or combinations thereof.

[0037] The term "and / or" means and includes any and all possible combinations of one or more of the associated listed items.

[0038] See also Figure 1-6 In this embodiment: a compound for preparing a tumor treatment drug and a pharmaceutical composition thereof, comprising a compound and a pharmaceutical composition, wherein the compound is a compound shown in Formula I, and the pharmaceutical composition comprises a taxane drug and a compound of the structure shown in Formula I;

[0039] The compound has an IUPAC name of N1-(2-((4-fluorobenzyl)oxy)benzyl)-N3-methylpropane-1,3-diamine. When preparing tumor therapeutic drugs, it is prepared with pharmaceutically acceptable salts and crystal types and optical isomers and acceptable pharmaceutical dosage forms. Its structure is shown below:

[0040]

[0041] Taxane drugs include taxanes, docetaxel, and derivatives with a taxane skeleton structure;

[0042] It should be noted in this example that: the concentration range of the taxane drug is 5-800 mg / kg, and the concentration range of the composition is 2-1000 mg / kg;

[0043] The compound represented by formula I is used for preparing tumor treatment drugs, and can be combined with taxane drugs or alkane drugs to prepare a pharmaceutical composition.

[0044] Tumor treatment types include solid tumors and hematological tumors;

[0045] Solid tumors are non-small cell lung cancer, renal cell carcinoma, head and neck cancer, melanoma, hepatocellular carcinoma, breast cancer, endometrial cancer, ovarian cancer, gastric cancer, colorectal cancer, bladder cancer, pancreatic cancer, glioblastoma, biliary tract cancer, glioma, cervical cancer, advanced and refractory solid tumors, small cell lung cancer, squamous cell carcinoma of the lung, desmoplastic melanoma, mesothelin-positive pleural mesothelioma, esophageal cancer, anal cancer, prostate cancer, and thyroid cancer;

[0046] Preferably breast cancer;

[0047] The hematological neoplasm is acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's disease lymphoma, mantle cell lymphoma, multiple myeloma, myeloid leukemia-1 protein, myelodysplastic syndrome, non-Hodgkin's lymphoma, or small lymphocytic lymphoma;

[0048] Acute lymphoblastic leukemia and multiple myeloma are preferred

[0049] The compound inhibits the proliferation of tumor cells by inhibiting the activity of protein arginine methyltransferase (PRMT);

[0050] The use implementation form is to treat tumors by administering the compound represented by formula I alone, or in combination with a taxane compound for combined treatment;

[0051] The scheme of the use embodiment is that the single dosage of the compound represented by formula I is 2 mg / kg to 1000 mg / kg, and when combined with taxane drugs for treatment, the single dosage of the taxane drugs is 5 mg / kg to 800 mg / kg.

[0052] The above content construction method, its specific steps are as follows:

[0053] Step 1: Complete drug screening. First, the staff will establish a small-scale drug library through virtual screening.

[0054] The inhibition rate of different drugs on PRMT1 was tested under a certain concentration gradient, and the inhibitor was selected as compound (YH-4);

[0055] Step 2: Complete in vitro experiments to further verify at the cell level that the selected drug combined with taxane drugs can significantly improve the efficacy compared with single use, including the effects on cell proliferation, apoptosis and other indicators;

[0056] The following points should be noted about the above experimental scheme:

[0057] The above cell lines were treated with the compound, taxane drugs alone, or the compound and taxane drugs were combined to detect the cell survival rate by CCK-8 method, as follows:

[0058] Survival rate = (OD of experimental group - OD of blank group) / (OD of solvent control group - OD of blank group) × 100%;

[0059] The interaction coefficient between the two drugs is Q = E(A+B) / (EA+EB-EA×EB), where E(A+B) refers to the inhibition rate of the combination of drugs A and B on cells, and EA and EB refer to the inhibition rates of drugs A and B on cells respectively. When Q>1.15, the two drugs have a synergistic effect; when Q=0.85-1.15, the two drugs have an additive effect; when Q<0.85, the two drugs show an antagonistic effect;

[0060] Step 3: Complete the in vivo experiment of triple-negative breast cancer model, and the dosing regimen of Kelun albumin-bound taxane is: 25 mg / kg dose injected into the tail vein on the 1st and 14th day;

[0061] YH-4 compound administration regimen: 30 mg / kg per day from day 1 to day 7, and 30 mg / kg per day from day 11 to day 17;

[0062] Preliminary experiments determined that the maximum tolerated dose (MTD) of the taxane drug PTX in mice was 300 mg / kg, and the MTD of YH-4 in mice was 100 mg / kg;

[0063] Subcutaneous transplanted tumor: 6-week-old Balb / c Nu male mice. Triple negative breast cancer cells were diluted to 1×107 cells / ml, and 0.2 ml was injected into the axilla of each nude mouse, that is, 2×106 triple negative breast cancer cells were inoculated into the axilla of each nude mouse, and the growth of the transplanted tumor was observed every other day. When the volume of the subcutaneous transplanted tumor grew to 100 mm3, the drug was administered;

[0064] Taxane drug administration regimen: 25 mg / kg dose injected into the tail vein on day 1 and day 14;

[0065] Compound YH-4 administration regimen: 30 mg / kg per day from day 1 to day 7, and 30 mg / kg per day from day 11 to day 17;

[0066] Data collection was performed every three days to measure the tumor volume and body weight of mice;

[0067] The first administration was recorded as day 0, and the body weight of nude mice was recorded every 3 days thereafter. The body weight of nude mice was compared among blank control, taxane drugs, YH-4, and combination of YH-4 and taxane drugs;

[0068] The first administration was recorded as day 0, and the tumor volume was recorded every 3 days thereafter to compare the tumor volumes of nude mice in blank control, taxane drugs, YH-4, and combination of YH-4 and taxane drugs.

[0069] Each embodiment in this specification is described in a progressive manner, and the same or similar parts between the embodiments can be referred to each other, and each embodiment focuses on the differences from other embodiments. In particular, for the system embodiment, since it is basically similar to the method embodiment, the description is relatively simple, and the relevant parts can be referred to the partial description of the method embodiment.

[0070] Finally, it should be noted that the above are only preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A compound for preparing a tumor therapeutic drug and a pharmaceutical composition thereof, characterized in that: It includes a compound and a pharmaceutical composition, wherein the compound is a compound shown in Formula I, and the pharmaceutical composition contains a taxane drug and a compound of the structure shown in Formula I; The compound has an IUPAC name of N1-(2-((4-fluorobenzyl)oxy)benzyl)-N3-methylpropane-1,3-diamine, and is prepared in the preparation of tumor therapeutic drugs using pharmaceutically acceptable salts and crystal types as well as optical isomers and acceptable pharmaceutical dosage forms. Its structure is shown below: The taxane drugs include taxane drugs, docetaxel, and derivatives having a taxane skeleton structure.

2. A compound for preparing a tumor therapeutic drug and a pharmaceutical composition thereof according to claim 1, characterized in that: The concentration range of the taxane drug is 5-800 mg / kg, and the concentration range of the composition is 2-1000 mg / kg.

3. A compound for preparing a tumor therapeutic drug and a pharmaceutical composition thereof according to claim 1, characterized in that: The compound represented by formula I is used for preparing tumor treatment drugs, and can be combined with taxane drugs and alkane drugs to prepare a pharmaceutical composition.

4. A compound for preparing a tumor therapeutic drug and a pharmaceutical composition thereof according to claim 1, characterized in that: The tumor treatment types include solid tumors and hematological tumors.

5. A compound for preparing a tumor therapeutic drug and a pharmaceutical composition thereof according to claim 4, characterized in that: The solid tumors are non-small cell lung cancer, renal cell carcinoma, head and neck cancer, melanoma, hepatocellular carcinoma, breast cancer, endometrial cancer, ovarian cancer, gastric cancer, colorectal cancer, bladder cancer, pancreatic cancer, glioblastoma, biliary tract cancer, glioma, cervical cancer, advanced and refractory solid tumors, small cell lung cancer, squamous cell carcinoma of the lung, desmoplastic melanoma, mesothelin-positive pleural mesothelioma, esophageal cancer, anal cancer, prostate cancer and thyroid cancer.

6. A compound for preparing a tumor therapeutic drug and a pharmaceutical composition thereof according to claim 4, characterized in that: The hematological tumor is acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's disease lymphoma, mantle cell lymphoma, multiple myeloma, myeloid leukemia-1 protein, myelodysplastic syndrome, non-Hodgkin's lymphoma or small lymphocytic lymphoma.

7. A compound for preparing a tumor therapeutic drug and a pharmaceutical composition thereof according to claim 3, characterized in that: The compound inhibits the proliferation of tumor cells by inhibiting the activity of protein arginine methyltransferase (PRMT); The use implementation form is to treat tumors by administering the compound of formula I alone, or in combination with a taxane compound for combined treatment; The scheme of the use embodiment is that the single dosage of the compound represented by formula I is 2 mg / kg to 1000 mg / kg, and when combined with taxane drugs for treatment, the single dosage of the taxane drugs is 5 mg / kg to 800 mg / kg.

8. A compound for preparing a tumor therapeutic drug and a pharmaceutical composition thereof according to claims 1-7, characterized in that: The method for constructing the compound and pharmaceutical composition comprises the following steps: Step 1: Virtual drug screening: Establish a small-scale drug library to test the anti-cancer effects of different compounds under a certain concentration gradient, and comprehensively consider the IC50 value, efficacy and toxicity to determine the compound and compound dose for the next experiment; Step 2: In vitro experiments are conducted to further verify at the cell level that the combination of the selected drug and taxane drugs can significantly improve the efficacy compared with single use, and the anti-cancer effect of the selected drug combination is confirmed by judging the indicators of cell proliferation and apoptosis; Step 3: In vivo experiments in mice verify the effects of taxanes alone and the combination of taxanes and PRMT1 inhibitors on tumor volume.

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