CN111821304A

CN111821304A - Application of tyrosine kinase inhibitor and vinblastine drug in preparation of drugs for preventing or treating tumor diseases

Info

Publication number: CN111821304A
Application number: CN202010293739.1A
Authority: CN
Inventors: 王路
Original assignee: Jiangsu Hengrui Medicine Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd
Priority date: 2019-04-16
Filing date: 2020-04-15
Publication date: 2020-10-27

Abstract

The invention relates to an application of a tyrosine kinase inhibitor and vinblastine combined medicine in preparing a medicine for preventing or treating tumor diseases. Specifically, the invention relates to an application of a tyrosine kinase inhibitor compound shown in formula (I) or a pharmaceutically acceptable salt thereof and a vinblastine medicament in preparation of a medicament for preventing or treating tumor diseases.

Description

Application of tyrosine kinase inhibitor and vinblastine drug in preparation of drugs for preventing or treating tumor diseases

Technical Field

The invention belongs to the field of medicines, and relates to an application of a tyrosine kinase inhibitor and a vinblastine drug combination in preparation of drugs for preventing or treating tumor diseases.

Background

Malignant tumor is a serious disease which endangers the life and health of people. In recent years, with the rapid development of tumor biology and related disciplines, specific anti-tumor drugs aiming at abnormal signal system targets in tumor cells are the focus of new drug development. Meanwhile, the combination of multiple antitumor drugs for treating tumor diseases is also a hot spot of scientific research.

Breast cancer is the most common malignancy in women, with about 200 million new breast cancer patients worldwide each year. Breast cancer is a type of tumor that is highly heterogeneous at the molecular level, with great differences in tissue morphology, immunophenotype, biological behavior, and therapeutic response. Based on three receptors: expression of Estrogen Receptor (ER), Progesterone Receptor (PR), and human epidermal growth factor receptor-2 (Her2), divides breast cancer into three subtypes. Estrogen receptor positive (ER +) breast cancer is the most common molecular subtype of breast cancer, and the incidence rate of the population is about 65% -70%. Among breast cancers, prognosis is best, and early stage patients are more. Compared with other molecular subtype breast cancers, ER + breast cancer has better prognosis, but still has a 5-year recurrence and metastasis rate of about 15-30%. The human epidermal growth factor receptor-2 (HER2) molecule is an independent factor with a poor prognosis of breast cancer, and the HER2 gene amplification/overexpression exists in about 20-30% of Chinese breast cancer patients. HER2 overexpression is typically associated with aggressive, metastatic forms of breast cancer that have high recurrence rates and/or are associated with poor patient prognosis.

Receptor tyrosine kinases are a class of transmembrane proteins involved in signal transduction and are expressed in a variety of cells to regulate cell growth, differentiation and neovascularization. Research shows that over 50% of proto-oncogenes and oncogene products have tyrosine kinase activity, and abnormal expression of the proto-oncogenes and oncogene products leads to tumorigenesis and is also closely related to tumor invasion and metastasis, tumor angiogenesis, and tumor chemotherapy resistance. Several tyrosine kinase inhibitors have been disclosed, such as Lapatinib (Lapatinib), Neratinib (Neratinib), and the like. WO2011029265 discloses an effective tyrosine kinase inhibitor pyrroltinib and a preparation method thereof, the structure of the pyrroltinib is shown as a formula I,

the compound has obvious drug effect advantage. CN102933574A describes the dimaleate form of this compound, which has improved physicochemical, pharmacokinetic and bioavailability properties.

In addition, a number of documents have disclosed that trastuzumab (trastuzumab), pertuzumab (pertuzumab), and T-DM1 can selectively act on human epidermal growth factor receptor-2 to inhibit the growth of tumor cells. Trastuzumab is currently used clinically mainly for Her-2 overexpressed metastatic breast cancer.

The cytotoxicity of vinblastine drugs is achieved by binding to tubulin, which has a common binding site on the tubulin dimer, and can inhibit microtubule polymerization, prevent the formation of pituitary microtubules, stop metaphase of mitosis, and prevent division and proliferation of cancer cells. Vinblastine drugs that are currently marketed and used clinically are mainly Vinblastine (Vinblastine, VLB), Vincristine (Vincristine, VCR), vindesine (Vindesin, VDS) and Vinorelbine (Vinorelbine, NVB). Vinorelbine was first developed in 1989 by Pierre Fabre, France, and was approved for the treatment of non-small cell lung cancer and breast cancer. The structure of the compound is shown in a formula II,

several studies of the combination therapy of the compounds of formula I with other drugs have been published. WO2018133838 discloses the use of a compound of formula I in combination with capecitabine in the preparation of a medicament for treating cancer, and shows a good anti-tumor effect. Research results show that the compound shown in the formula I is combined with capecitabine to treat breast cancer patients, and the patients have obvious treatment benefit. Treatment of a compound of formula I in combination with capecitabine increases the Objective Remission Rate (ORR) of the patient, extends the Progression Free Survival (PFS) and time to disease progression (TTP) of the patient, and improves the duration of remission (DoR). The tolerance of the patient is good while the curative effect of the patient is improved. The compound shown in the formula I and capecitabine have excellent clinical treatment effect, and are preferentially approved and listed by the national drug administration on the basis of phase 2 clinical data.

The invention provides the application of the combination of a novel tyrosine kinase inhibitor and a vinblastine medicament in the preparation of medicaments for preventing or treating tumor diseases, and shows good tumor inhibition effect.

Disclosure of Invention

The invention provides an application of a tyrosine kinase inhibitor and a vinblastine medicament in preparing a medicament for preventing or treating tumor diseases, wherein the tyrosine kinase inhibitor is selected from a compound (compound I) shown in a formula (I) or a medicinal salt thereof,

in another aspect, the invention provides the use of a tyrosine kinase inhibitor in combination with a monoclonal antibody and a vinblastine drug in the preparation of a medicament for the prevention or treatment of a neoplastic disease, wherein the tyrosine kinase inhibitor is selected from a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

in certain embodiments, the monoclonal antibody of the invention is selected from trastuzumab, pertuzumab, or T-DM 1.

In certain embodiments, the monoclonal antibodies of the invention are administered in a dosage range selected from 4mg/kg to 20 mg/kg.

In certain embodiments, the vinblastine drug of the present invention is selected from vinblastine, vincristine, vindesine or vinorelbine, preferably vinorelbine.

In certain embodiments, the dose range of the vinca alkaloid drug of the present invention is selected from 2-30mg/m²。

In certain embodiments, the vinblastine drug of the present invention is vinorelbine, preferably in a dosage range of 10-30mg/m²More preferably 25 to 30mg/m²。

In certain embodiments, the tumor disease according to the invention is selected from HER2 positive or HER2 mutant tumors, in particular HER2 positive or HER2 mutant breast tumors.

In certain embodiments, the breast tumor of the present invention is selected from the group consisting of a nipple tumor, a male breast tumor, a malignant lymphoma of the breast, a fibroepithelial tumor, an epithelial-myoepithelial tumor, an intraductal carcinoma, a lobular carcinoma in situ, a breast eczematoid carcinoma of the nipple, an early invasive ductal carcinoma, an early invasive lobular carcinoma, a papillary carcinoma, a medullary carcinoma, a tubular carcinoma, an adenoid cystic carcinoma, a mucinous adenocarcinoma, a apocrine adenoid carcinoma, a squamous cell carcinoma, an invasive lobular carcinoma, an invasive ductal carcinoma, a dura mater.

In certain embodiments, the tyrosine kinase inhibitor of the present invention is administered in a dosage range selected from 100-1000mg, and may be, for example, 100mg, 125mg, 150mg, 175mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 600mg, 700mg, 750mg, 800mg, 900mg, 1000 mg.

The pharmaceutically acceptable salt of the drug of the invention can be hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanilliate, mandelate, succinate, gluconate, lactobionate or laurylsulfonate, and the like.

In certain embodiments, the pharmaceutically acceptable salt of the compound of formula I is a maleate salt, preferably a dimaleate salt.

The administration route of the combination of the present invention is selected from oral administration, parenteral administration, transdermal administration, and the parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection.

The invention further relates to the use of a tyrosine kinase inhibitor in combination with a vinca alkaloid drug for the preparation of a medicament for the prevention or treatment of a HER2 positive breast tumor, wherein the tyrosine kinase inhibitor may be administered once a day, twice a day, three times a day, once a week, once a three week or once a month; the vinblastine drug can be administered once a day, once a week, once a three week, or once a month.

In certain embodiments, the tyrosine kinase inhibitor is administered once daily and the vinca alkaloid drug is administered once a week.

In certain embodiments, the use of a tyrosine kinase inhibitor in combination with a monoclonal antibody and a vinblastine drug in the manufacture of a medicament for the prevention or treatment of a HER2 positive breast tumor, wherein the tyrosine kinase inhibitor may be administered once daily, twice daily, three times daily, once a week, once weekly, once every three weeks, or once a month; the frequency of administration of the monoclonal antibody may be once a week, once three weeks, or once a month; the vinblastine drug can be administered once a day, once a week, once a three week, or once a month.

In certain embodiments, the tyrosine kinase inhibitor is administered once daily, the monoclonal antibody is administered once a week, once three weeks, and the vinblastine drug is administered once a week.

In the embodiment of the present invention, the combination optionally further comprises other components, including but not limited to other antitumor agents, etc.

The invention provides a method for treating tumor diseases, which comprises the step of administering the compound shown as the formula (I) or the pharmaceutically acceptable salt thereof and vinblastine medicaments to a patient.

The invention also provides a method for treating tumor diseases, which comprises the step of administering the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof, the monoclonal antibody and the vinblastine medicament to a patient.

In certain embodiments, the tumor disease is selected from HER2 positive or HER2 mutant tumors, in particular HER2 positive or HER2 mutant breast tumors.

The invention also provides a method for reducing the dosage of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof, which comprises the step of administering the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof and a vinblastine medicament to a patient.

The invention also provides a method for reducing the dosage of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof, which comprises the step of administering the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof, the monoclonal antibody and the vinblastine medicament to a patient.

The invention also relates to a pharmaceutical composition containing the compound shown in the formula I or the medicinal salt thereof, vinblastine medicaments and one or more medicinal carriers, excipients and diluents.

The invention also relates to a pharmaceutical composition containing the compound shown in the formula I or the pharmaceutically acceptable salt thereof, the monoclonal antibody, the vinblastine drug and one or more pharmaceutically acceptable carriers, excipients and diluents.

The pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form. For example, it can be formulated into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections and concentrated solutions for injections), suppositories, inhalants or sprays.

The pharmaceutical compositions of the present invention may be administered alone or in combination with one or more therapeutic agents.

The components to be combined (e.g., the compound of formula I or a pharmaceutically acceptable salt thereof, the monoclonal antibody, the vinca alkaloid drug, and optionally any other component drugs) may be administered simultaneously or separately in sequential order. Furthermore, the components to be combined may also be administered in combination in the same formulation or in separate and distinct formulations.

The invention also provides a medicine packaging box, wherein the tyrosine kinase inhibitor and the vinblastine medicine or the tyrosine kinase inhibitor, the monoclonal antibody and the vinblastine medicine are packaged, and the tyrosine kinase inhibitor is selected from a compound shown in the formula I or pharmaceutically acceptable salts thereof.

The "combination" of the present invention is an administration mode, and means that at least one dose of the compound represented by formula I or the pharmaceutically acceptable salt thereof and at least one dose of the vinblastine drug, or at least one dose of the compound represented by formula I or the pharmaceutically acceptable salt thereof, at least one dose of the monoclonal antibody and at least one dose of the vinblastine drug are administered within a certain period of time. Wherein the administered drugs all show pharmacological effects. The time period may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours. The compound shown in the formula I or the pharmaceutically acceptable salt thereof, the monoclonal antibody and the vinblastine medicament can be simultaneously or sequentially administered. Such terms include treatments wherein the compound of formula I or a pharmaceutically acceptable salt thereof, the monoclonal antibody, and the vinblastine drug are administered by the same route of administration or different routes of administration. The mode of administration of the combinations of the invention is selected from simultaneous administration, separate formulation and co-administration or separate formulation and sequential administration.

The invention combines the tyrosine kinase inhibitor compound shown in formula I or the medicinal salt thereof with the vinblastine medicine for administration, and the tyrosine kinase inhibitor compound shown in formula I or the medicinal salt thereof, the monoclonal antibody and the vinblastine medicine for administration for HER2+ breast tumor, thereby enhancing the antitumor activity and improving the treatment effect of tumor diseases.

Drawings

FIG. 1 shows the change in tumor volume of experimental mice in example 1;

FIG. 2 is a graph showing the change in body weight of the experimental mice in example 1.

Detailed Description

Example 1: the pharmacodynamic action of the compound I, trastuzumab and vinorelbine in combination with two or three drugs and independent drug administration on breast cancer (HER2+) BALB/c nude mice is studied.

1. Test drug

The name of the medicine is: dimaleate salt of compound I, prepared according to the method disclosed in CN 102933574A; trastuzumab

Purchased from genentech (roche) corporation; vinorelbine tartrate

Supplied by Jiangsu Haofen pharmaceuticals, Inc.

The preparation method comprises the following steps: the dimaleate salt of compound I was formulated with 0.1% Tween-80 (w/v); trastuzumab

Redissolving with solvent provided by original manufacturer, and diluting with normal saline; vinorelbine tartrate was diluted with physiological saline.

2. Laboratory animal

BALB/c nude mice, 5 weeks old, female, were purchased from Shanghai Ling Biotech, Inc. License number for experimental animals: SCXK (Shanghai) 2018 and 0003; animal certification number: 2013001838317, respectively; a breeding environment: SPF grade.

3. Experimental procedure

Nude mice were subcutaneously inoculated with human breast cancer BT-474 cells (human breast cancer BT-474 cells purchased from cell bank of chinese academy of sciences) cultured adherent to 10-cm dishes under conditions of DMEM medium supplemented with 10% fetal bovine serum and penicillin and streptomycin, cultured in an incubator containing 5% CO2 air at 37 ℃ for 2-3 passages a week, when cells were in exponential growth phase, trypsinized, collected, counted, inoculated), and after tumors grew to 150mm3, animals were grouped according to tumor volume (D0). Mice were administered Intravenously (IV), or gavage (i.g.), 1 time per day (QD), 7 days per day (Q7D), or 2 times per week (BIW); the administration volume is 10 mL/kg; solvent group given the same volume of "solvent"; specific dosages and schedules are shown in table 1. Pirtinib is calculated as salt and vinorelbine as free base. Tumor volumes were measured 2 times per week, mice were weighed and data recorded.

The use and welfare of the experimental animals were carried out in compliance with the provisions of the International Commission on evaluation and approval of Experimental animals (AAALAC). The health and death of the animals are monitored daily and routine examinations include observations of the effects of the test substances and drugs on the daily performance of the animals, such as behavioral activities, weight changes, physical signs of appearance, etc.

The experimental index is to examine the influence of the drug on the tumor growth, and the specific index is T/C% or tumor inhibition rate TGI (%).

Tumor diameter was measured 2 times per week with a vernier caliper and tumor volume (V) was calculated as:

tumor volume (V) was calculated as:

v is 1/2 × a × b2, where a and b represent length and width, respectively.

T/C(％)＝(T-T₀) V (C-C0). times.100%, where T, C is the tumor volume at the end of the experiment; t0, C0 are tumor volumes at the beginning of the experiment.

Tumor inhibition rate (TGI) (%) 100-T/C (%).

When tumors regress, tumor inhibition rate (TGI) (%) 100- (T-T0)/T0 × 100

Partial tumor regression (PR) is defined if the tumor shrinks from the starting volume, i.e., T < T0 or C < C0; if the tumor completely disappears, it is defined as complete tumor regression (CR).

The experiment is finished, the experimental end point is reached, or the tumor volume reaches 1500mm³The animals were sacrificed under CO2 anesthesia and then the tumors were dissected and photographed.

Table 1: experimental protocol

Note: doubling the initial dose of trastuzumab; BIW: 2 times per week; IV: intravenous injection; i.g., intragastric administration; QD: 1 time per day. The frequency of drug administration is shown in the darkened, underlined portions, and the frequency of solvent administration is shown in the other portions. BIW solvent: physiological saline; QD solvent: 0.1% Tween 80; Q7D solvent: physiological saline.

The results are shown in table 2, vinorelbine alone can inhibit the growth of subcutaneous transplantable tumor of HER2 positive human breast cancer BT-474 nude mice, while neither compound of formula I alone nor trastuzumab alone can significantly inhibit the growth of subcutaneous transplantable tumor of human breast cancer nude BT-474 mice. The compound of the formula I and the vinorelbine are combined to have very obvious anti-tumor effect, the combined administration has synergistic effect, the tumor inhibition rate is 96 percent, and 2/6 tumors are partially faded. The compound of the formula I, trastuzumab and vinorelbine are combined to have very obvious anti-tumor effect, the tumor inhibition rate is 141%, and 6/6 tumors are partially regressed. The combined antitumor effect of the compound shown in the formula I, the trastuzumab and the vinorelbine is obviously stronger than that of the combined compound shown in the formula I and the vinorelbine, or the combined compound shown in the formula I and the trastuzumab (P <0.05), and the toxicity is not obviously increased. No obvious weight loss condition appears in all tumor-bearing mice, which indicates that the tumor-bearing mice have good tolerance to the single or combined drug under the dosage.

Example 2: study of the pharmacodynamic effects of compound I administered in combination with capecitabine and each administered alone on breast cancer (HER2+) BALB/c nude mice.

1. Test drug

The name of the medicine is: dimaleate salt of compound I, prepared according to the method disclosed in CN 102933574A; capecitabine

Supplied by Henry pharmaceutical products of Jiangsu, Inc.

The preparation method comprises the following steps: the dimaleate of the compound I is prepared into the required concentration by distilled water; capecitabine is formulated with citrate buffer.

2. Laboratory animal

BALB/c A-nude mice, 6-7 weeks female, were purchased from Shanghai Spiker laboratory animals, Inc. Certificate number: SCXK (Shanghai) 2007 & 0005. A breeding environment: SPF grade.

3. Experimental procedure

Inoculating human breast cancer BT-474 cells to nude mice subcutaneously until the tumor grows to 100-200mm³Thereafter, the animals were randomly assigned (d 0). The dosage and schedule of administration are shown in table 3. Measuring tumor volume 2-3 times per weekWeigh the mouse and record the data. Tumor volume (V) was calculated as:

V＝1/2×a×b²wherein a and b represent length and width, respectively.

T/C(％)＝(T-T₀)/(C-C₀) X 100 where T, C is the tumor volume at the end of the experiment; t is₀、C₀Tumor volume at the beginning of the experiment.

TABLE 3 therapeutic Effect of Compound I in combination with Capecitabine on human Breast cancer BT-474 nude mouse transplantable tumors

D0: a first time of administration; p-values refer to comparison to controls. Control group n is 10 and treatment group n is 6.

The results are shown in Table 3, where the compound of formula (I) (5mg/kg) in combination with capecitabine (359mg/kg) had a significant antitumor effect with a tumor inhibition of 94% and 1/6 partial tumor regression.

Example 1 the antitumor effect of the combination of compound of formula (I) (1.5mg/kg) and vinorelbine (7mg/kg) is very similar to the antitumor effect of the combination of compound of formula (I) (5mg/kg) and capecitabine (359mg/kg), but the combination of compound of formula (I) (1.5mg/kg) and vinorelbine (7mg/kg) can significantly reduce the dosage of compound of formula (I) and reduce the risk of toxic and side effects.

Claims

1. The application of the compound shown in the formula (I) or the medicinal salt thereof in combination with vinblastine medicaments in preparing medicaments for preventing or treating tumor diseases,

2. the compound shown in the formula (I) or the medicinal salt thereof, the monoclonal antibody and the vinblastine medicine are combined to prepare the medicine for preventing or treating the tumor diseases,

3. use according to claim 1 or 2, characterized in that the tumor disease is selected from HER2 positive or HER2 mutant tumors.

4. Use according to claim 3, characterized in that the tumor disease is selected from breast tumors.

5. The use of claim 4, wherein said breast tumor is selected from the group consisting of a nipple tumor, a male breast tumor, a malignant lymphoma of the breast, a fibroepithelial tumor, an epithelial-myoepithelial tumor, an intraductal carcinoma, a lobular carcinoma in situ, a breast eczematoid carcinoma of the nipple, an early invasive ductal carcinoma, an early invasive lobular carcinoma, a papillary carcinoma, a medullary carcinoma, a tubular carcinoma, an adenoid cystic carcinoma, a mucinous adenocarcinoma, a hyperhidrotic adenoid carcinoma, a squamous cell carcinoma, an invasive lobular carcinoma, an invasive ductal carcinoma, a dura mater.

6. Use according to claim 1 or 2, characterized in that the pharmaceutically acceptable salt of the compound of formula (I) is a maleate salt, preferably a dimaleate salt.

7. The use as claimed in claim 1 or 2, wherein the dosage of the compound of formula (I) or the pharmaceutically acceptable salt thereof is in the range of 100-1000 mg.

8. Use according to claim 1 or 2, characterized in that the vinblastine drug is selected from vinblastine, vincristine, vindesine or vinorelbine, preferably vinorelbine.

9. Use according to claim 1 or 2, characterized in that the dose range of the vinca alkaloid drug is selected from 2-30mg/m²。

10. Use according to claim 2, wherein the monoclonal antibody is selected from trastuzumab, pertuzumab or T-DM 1.

11. The use according to claim 2, wherein the monoclonal antibody is administered in a dosage range selected from 4mg/kg to 20 mg/kg.

12. A pharmaceutical composition comprises a compound shown in formula (I) or a pharmaceutically acceptable salt thereof, a vinblastine medicament and one or more pharmaceutically acceptable excipients, diluents or carriers.

13. A pharmaceutical composition comprises a compound shown in formula (I) or a pharmaceutically acceptable salt thereof, a monoclonal antibody, a vinblastine medicament and one or more pharmaceutically acceptable excipients, diluents or carriers.