CN111514140B

CN111514140B - Application of MEK inhibitor and androgen receptor antagonist in preparation of tumor treatment drug

Info

Publication number: CN111514140B
Application number: CN202010078274.8A
Authority: CN
Inventors: 杨健; 张曼; 廖成
Original assignee: Jiangsu Hengrui Medicine Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd
Priority date: 2019-02-01
Filing date: 2020-02-03
Publication date: 2021-09-03
Anticipated expiration: 2040-02-03
Also published as: CN111514140A

Abstract

The invention relates to an application of a MEK inhibitor and an androgen receptor antagonist in preparing a medicament for treating tumors. Specifically, the MEK inhibitor is selected from a compound shown in a formula (I) or a pharmaceutically acceptable salt thereof, and the androgen receptor antagonist is selected from a compound shown in a formula (II) or a pharmaceutically acceptable salt thereof.

Description

Application of MEK inhibitor and androgen receptor antagonist in preparation of tumor treatment drug

Technical Field

The invention relates to an application of a MEK inhibitor and an Androgen Receptor (AR) antagonist in preparation of a medicine for treating or preventing androgen receptor mediated diseases, belonging to the field of medicines.

Background

Prostate cancer is a malignancy on the worldwide male morbidity line 2 and mortality line 6. The incidence rate of prostate cancer in China is lower than that in the western countries, but the prostate cancer incidence rate is on a rapid rising trend in recent years. According to the latest statistical data of the national cancer center, about 6.03 ten thousand cases of new prostate cancer and about 2.66 ten thousand cases of death in 2015 in China exist, and the morbidity and the mortality respectively reside in the 7 th and 10 th malignant tumors of males.

Most prostate cancer patients in our country have a characteristic androgen dependence on the growth of prostate cancer cells, so endocrine therapy to suppress the action of androgen is an important means for prostate cancer treatment (endocrine Relat cancer. 2003, 6 months; 10 (2): 209-16), and mainly by the following means: 1) androgen deprivation therapy (ADT, including surgical or drug castration), inhibition of testosterone synthesis; 2) blocking androgen binding to Androgen Receptor (AR), i.e., using an AR antagonist to competitively block androgen binding to AR in the cytoplasm of prostate cancer cells. Prostate Cancer treated with ADT often progresses to Castration Resistant Prostate Cancer (CRPC). At this time, the malignancy of the tumor increased and conventional ADT treatment was ineffective. Currently, FDA approved standard treatments at the CRPC stage include docetaxel chemotherapy, abiraterone (an inhibitor of the testosterone-synthesizing key enzyme CYP-17) and enzalutamide (a second generation AR antagonist), however, patients will develop resistance to the above treatment regimen and reappear disease progression after 5-14 months of treatment. However, there is currently a lack of effective treatment regimens for CRPC following the development of ADT combinations (docetaxel, abiraterone and enzalutamide).

Numerous studies have demonstrated that the occurrence and development of malignant tumors is closely associated with the abnormal sustained activation of intracellular signaling pathways. The signaling pathway consisting of Mitogen-Activated Protein kinases (MAPKs) regulates many important cellular physiological processes, sharing 4 MAPK pathways in vertebrates and in all multicellular organisms, of which the ERK pathway (RAS-RAF-MEK1/2-ERK1/2) is a classical MAPK signaling pathway in which dysregulation of cascade signaling is most frequently occurring in human tumors. Aberrant activation of the ERK pathway is usually caused by acquired mutations in members of the RAS and RAF gene families, such as mutations in RAS-encoding genes (mainly KRAS, NRAS and HRAS) in 33% of biliary cancers, 36% of large bowel cancers, 19% of lung cancers, 18% of bladder cancers, 63% of pancreatic cancers, and 15% of prostate cancers; BRAF gene mutations are present in 50% of melanomas, 45% of papillary thyroid tumors and 36% of low grade ovarian cancers. MEK (MEK1 and MEK2) is a dual-functional serine/threonine and tyrosine kinase in the ERK pathway, which can be phosphorylated by upstream RAS and RAF kinases, and after activation, it can transmit signals to downstream, and finally phosphorylate some core transcription factors, thus participating in regulation of cell proliferation and differentiation. Therefore, the further conduction of the signal can be prevented by inhibiting the phosphorylation of MEK, so that the effects of inhibiting the continuous activation of a signal path and inhibiting the growth of tumors are achieved.

Naderi et al (Naderi et al. Breast Cancer Research 2011,13: R36) found that the combination of AR antagonist Flutamide and MEK inhibitor CI-1040 or PD0325901 can be used for treating ER-negative breast Cancer, and other effects of the combination of AR antagonist and MEK inhibitor are rarely reported.

A series of MEK inhibitors are disclosed at present, wherein WO2015058589 discloses a structure and a preparation method thereof, in vitro studies show that the MEK inhibitors have better tumor inhibition activity, the specific structure is shown as formula I,

CN106795116A discloses p-toluenesulfonate and a crystal form of a compound shown in formula I.

Chinese patent application CN103958480A discloses a novel AR antagonist, the structure of which is shown below:

disclosure of Invention

The application provides an application of a MEK inhibitor and an androgen receptor antagonist in combination in preparing a medicament for treating tumors.

The tumor in the present application is selected from melanoma, brain tumor, esophageal cancer, gastric cancer, hepatocellular cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, pancreatic cancer, neuroblastoma, sarcoma, osteochondrosis, osteoma, osteosarcoma, seminoma, testicular tumor, endometrioid cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, chorioepithelial cancer or pediatric tumor, preferably cysts, endometrioid cancers, pancreatic cancer, prostate cancer, breast cancer, fallopian tube cancer, ovarian cancer, most preferably prostate cancer.

In some embodiments, the prostate cancer described herein is metastatic hormone sensitive prostate cancer (mHSPC), Castration Resistant Prostate Cancer (CRPC). Castration-resistant prostate cancer (CRPC) as used herein refers to prostate cancer in which the lesions recur and progress after initial continuous androgen ablation therapy, including androgen-independent prostate cancer (AIPC) and hormone-resistant prostate cancer (HRPC). Second line therapy remains effective and is called AIPC, and second line therapy is ineffective or the lesion continues to progress during second line therapy is called HRPC.

In a preferred embodiment of the present application, castration resistant prostate cancer refers to drug resistant metastatic castration resistant prostate cancer (mCRPC) after treatment. The chemotherapeutic agent may be selected from Docetaxel, Abiraterone, Enzalutamide, Cabazitaxel, etc.

The MEK inhibitor described in the application is selected from AZD-8330, GDC-0623, CI-1040, WX-554, TAK-733, SL-327, APS-2-79, BI-847325, HL-085, BI-847325, CEP-1347, U-0126, Binimetib, Pimasertib, Cobimetiib, PD-0325901, PD-318088, RO-5126766, BIX-02189, BIX-02188, PD-98059, Trametinib, Refametinib, AS-703988, E-6201, Selumetib, or a compound shown in formula (I) or a pharmaceutically acceptable salt thereof, preferably a compound shown in formula (I) or a pharmaceutically acceptable salt thereof,

the androgen receptor antagonist described herein is selected from Enzalutamide, Apalutamide, Ozarelix, Nilutamide, Quisinosinostat, HC-1119, Proxalutamide, Cortexolone 17alpha-propionate, Liproca Depot, IONIS-AR-2.5Rx, Bicalutamide, Darolutamide, Phenylothiocyanocanate, ASCJ-9, APC-100, TRC-253, Seviterone, Apatorsen sodium, ONC1-0013B, ONC1-13B, antiandrogens or a compound of formula (II) or a pharmaceutically acceptable salt thereof, preferably a compound of formula (II) or a complex thereof or a pharmaceutically acceptable salt thereof,

the MEK inhibitors provided herein in combination with androgen receptor antagonists may adjust the dosage regimen to provide the most desirable response, e.g., maximum therapeutic response and/or minimal adverse effects.

In some embodiments, the MEK inhibitor is in a dosage range selected from 0.01-500mg, preferably from 0.1mg, 0.25mg, 0.5mg, 0.75mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg, 30mg, 45mg, 50mg, 60mg, 70mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 400mg, 500mg, more preferably 0.25mg, 0.5mg, 1mg, 2mg, 3mg, 4mg, 10mg, 15mg, 20mg, 30mg, 45mg, 50mg, 60mg, 75mg, 100 mg; the frequency of administration is 2 times daily, 1 time every 2 days, once every 3 days, preferably 2 times daily or 1 time daily, most preferably 1 time daily.

The androgen receptor antagonist in this application is administered as a unitary dose, specifically selected from 1-1000mg, such as 10mg, 20mg, 40mg, 60mg, 80mg, 100mg, 120mg, 140mg, 160mg, 180mg, 200mg, 220mg, 240mg, 260mg, 280mg, 300mg, 320mg, 340mg, 360mg, 380mg, 400mg, 420mg, 440mg, 460mg, 480mg, 500mg, 520mg, 540mg, 560mg, 580mg, 600mg, 620mg, 640mg, 660mg, 680mg, 700mg, 720mg, 740mg, 760mg, 780mg, 800mg, 820mg, 840mg, 860mg, 880mg, 900mg, 920mg, 940mg, 960mg, 980mg, 1000mg, preferably 40mg, 80mg, 160mg, 240mg, 360mg or 480mg, most preferably 240 mg; the administration frequency is selected from 2 times per day, 1 time per day, preferably 1 time per day.

In some embodiments, the amount of MEK inhibitor in a unit dosage form of the MEK inhibitor described herein is 0.125mg or 0.5mg or 2 mg.

The MEK inhibitor described in a preferred embodiment of this application is administered in a dose of 0.25mg, 0.5mg, 1mg, 2mg, 3mg, 4mg, 10mg, 15mg, 20mg, 30mg, 45mg, 50mg, 60mg, 75mg, 100mg, 1 time per day; the androgen receptor antagonist is administered in a dose of 40mg, 80mg, 160mg, 240mg, 360mg or 480mg, most preferably 240mg, with a frequency of 1 administration per day.

In a preferred embodiment of the present application, the MEK inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof and the androgen receptor antagonist is a compound of formula (II) or a pharmaceutically acceptable salt thereof.

In a preferred embodiment of the present application, the MEK inhibitor is a compound of formula (I) or a complex thereof or a pharmaceutically acceptable salt thereof, administered in an amount of 0.25mg, 0.5mg, 1mg, 2mg, 3mg, 4mg, 10mg, 15mg, 20mg, 30mg, 45mg, 50mg, 60mg, 75mg, 100mg, 1 time per day; the androgen receptor antagonist is a compound shown in a formula (II) or a pharmaceutically acceptable salt thereof, and the administration dosage is 40mg, 80mg, 160mg, 240mg, 360mg or 480mg, most preferably 240mg, and the administration frequency is 1 time per day.

In a preferred embodiment of the present application said MEK inhibitor is a compound of formula (I) or a complex thereof or a pharmaceutically acceptable salt thereof, administered in an amount of 0.25mg, 0.5mg, 1mg, 2mg, 3mg, 4mg, 10mg, frequently 1 time per day; the androgen receptor antagonist is a compound shown in a formula (II) or a pharmaceutically acceptable salt thereof, and the administration dosage is 40mg, 80mg, 160mg, 240mg, 360mg or 480mg, most preferably 240mg, and the administration frequency is 1 time per day.

In a preferred embodiment of the present application the MEK inhibitor is a compound of formula (I) or a complex thereof or a pharmaceutically acceptable salt thereof, administered in a dose of 0.25mg, 0.5mg, 1mg, 2mg, 3mg, 4mg, 10mg, 1 time per day; the androgen receptor antagonist is a compound shown as a formula (II) or a pharmaceutically acceptable salt thereof, the administration dosage is 240mg, and the administration frequency is 1 time per day.

In a preferred embodiment of the present application the MEK inhibitor is a compound of formula (I) or a complex thereof or a pharmaceutically acceptable salt thereof, administered in an amount of 0.25mg at a frequency of 1 time per day; the androgen receptor antagonist is a compound shown as a formula (II) or a pharmaceutically acceptable salt thereof, the administration dosage is 240mg, and the administration frequency is 1 time per day.

In a preferred embodiment of the present application the MEK inhibitor is a compound of formula (I) or a complex thereof or a pharmaceutically acceptable salt thereof, administered in an amount of 0.5mg at a frequency of 1 time per day; the androgen receptor antagonist is a compound shown as a formula (II) or a pharmaceutically acceptable salt thereof, the administration dosage is 240mg, and the administration frequency is 1 time per day.

In a preferred embodiment of the present application the MEK inhibitor is a compound of formula (I) or a complex thereof or a pharmaceutically acceptable salt thereof, administered in a dose of 1mg, frequently 1 time per day; the androgen receptor antagonist is a compound shown as a formula (II) or a pharmaceutically acceptable salt thereof, the administration dosage is 240mg, and the administration frequency is 1 time per day.

In a preferred embodiment of the present application the MEK inhibitor is a compound of formula (I) or a complex thereof or a pharmaceutically acceptable salt thereof, administered in an amount of 2mg at a frequency of 1 time per day; the androgen receptor antagonist is a compound shown as a formula (II) or a pharmaceutically acceptable salt thereof, the administration dosage is 240mg, and the administration frequency is 1 time per day.

In a preferred embodiment of the present application the MEK inhibitor is a compound of formula (I) or a complex thereof or a pharmaceutically acceptable salt thereof, administered in a dose of 4mg, frequently 1 time per day; the androgen receptor antagonist is a compound shown as a formula (II) or a pharmaceutically acceptable salt thereof, the administration dosage is 240mg, and the administration frequency is 1 time per day.

In a preferred embodiment of the present application the MEK inhibitor is a compound of formula (I) or a complex thereof or a pharmaceutically acceptable salt thereof, administered in a dose of 10mg, frequently 1 time per day; the androgen receptor antagonist is a compound shown as a formula (II) or a pharmaceutically acceptable salt thereof, the administration dosage is 240mg, and the administration frequency is 1 time per day.

The pharmaceutically acceptable salt of the compound represented by formula (I) or the compound represented by formula (II) described in the present application may 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, vanilate, mandelate, succinate, gluconate, lactobionate, laurylsulfonate, or the like.

In some embodiments the pharmaceutically acceptable salt of the compound of formula (I) herein is a tosylate salt.

When the MEK inhibitor described herein is administered in combination with an androgen receptor antagonist, the route of administration is selected from oral, parenteral, including but not limited to intravenous, subcutaneous, intramuscular administration, transdermal administration.

The present application provides a pharmaceutical composition comprising a MEK inhibitor and an androgen receptor antagonist as described above, in addition to comprising as active ingredients the MEK inhibitor and androgen receptor antagonist, in combination with one or more pharmaceutically acceptable excipients, diluents or carriers. The composition can be prepared into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection, sterile powder for injection and concentrated solution for injection), suppositories, inhalants or sprays.

The pharmaceutical compositions provided herein, which contain a MEK inhibitor and an androgen receptor antagonist, can be used to treat tumors.

The present application provides a method of treating a tumor comprising administering to a patient a therapeutically effective amount of a MEK inhibitor as described above and a therapeutically effective amount of an androgen receptor antagonist.

The MEK inhibitor and the androgen receptor antagonist are optionally administered by the same or different routes selected from oral administration, parenteral administration, transdermal administration, and parenteral administration including but not limited to intravenous injection, subcutaneous injection, intramuscular injection, preferably by oral administration.

In certain embodiments, any combination treatment disclosed herein lasts for at least 3 weeks, or at least 1 month, or at least 3 months, or at least 6 months, or 9 months, or at least 1 year, or at least 18 months, or at least 24 months.

As used herein, "combination" is a mode of administration and refers to the administration of at least one dose of a MEK inhibitor, or a pharmaceutically acceptable salt thereof, and an androgen receptor antagonist, wherein both drugs exhibit pharmacological effects over a period of time. 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. The MEK inhibitor, or a pharmaceutically acceptable salt thereof, and the androgen receptor antagonist may be administered simultaneously or sequentially. Such term includes treatments wherein the MEK inhibitor, or a pharmaceutically acceptable salt thereof, and the androgen receptor antagonist are administered by the same route of administration or by different routes of administration.

Drawings

FIG. 1. tumor volumes in groups of mice after administration;

figure 2. body weight of mice in each group after administration.

Detailed Description

The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.

Example 1 study of the pharmacological effects of a Compound of formula (II) (drug A) alone or in combination with a Compound of formula (I) p-toluenesulfonate (drug B) in mouse model of castration prostate cancer the main observations in this experiment were:

tumor volume, and relative tumor inhibition, TGI (%), calculated as:

TGI% (1-T/C) × 100% (T and C are the Relative Tumor Volume (RTV) or Tumor Weight (TW) at a particular time point in the treated and control groups, respectively).

In the experiment, the medicine A is prepared according to the published method in CN 103958480A; drug B was prepared according to the method disclosed in patent CN 106795116A.

Cell culture: the tumor cell line VCaP was cultured at 37 ℃ in a 5% CO2 incubator using the medium DMEM (containing 10% fetal bovine serum). When the tumor cells grew to logarithmic growth phase, the tumor cells were collected and resuspended in PBS to an appropriate concentration for subcutaneous tumor inoculation in nude mice.

Tumor inoculation

Each experimental mouse was inoculated subcutaneously on the right dorsal side with 1 x 107VCaP tumor cells, resuspended in PBS (0.1 ml/mouse), and inoculated at a volume of 0.1ml per mouse. The growth of the tumor was observed periodically.

Random grouping

When the average size of the subcutaneously inoculated tumors reached 200mm3, the mice were subjected to castration surgery, followed by observation of the mice until the mice tumors stopped to atrophy and resumed growth to about 200mm³At the time, the samples were randomly assigned into 4 experimental groups of 6 per group using a random grouping method according to Table 1. The detailed administration method, administration dose and administration route are shown in Table 1

TABLE 1 route of administration, dose and group of administration for efficacy test of VCaP model in castrated mice

Experimental results and conclusions:

the mice were dosed after the grouping, and the tumor sizes of the mice were measured periodically, and the dosing was stopped by day 28 of dosing, and the tumor inhibition rates were calculated as follows:

TABLE 2 drug efficacy in combination in the VCaP model in castrated mice

Day 0: time of first administration;

the experimental results show that the single use of the drug A (10mg/kg) or the single use of the drug B (0.5mg/kg) does not show remarkable inhibition of the growth of the VCaP subcutaneous transplantation tumor of the castrated mice. The drug A (10mg/kg) and the drug B (0.5mg/kg) are respectively combined to be administrated to show the synergistic tumor inhibition effect, the tumor inhibition rate is close to 50 percent, and the good clinical application prospect of the combined scheme in castration prostate cancer is shown. No obvious weight loss condition appears in each group of tumor-bearing mice, which shows that the tumor-bearing mice have good tolerance to the drug combination under the dosage.

The tumor volume of each group after administration is shown in figure 1, and the body weight of the mice is shown in figure 2.

Claims

1. Use of a MEK inhibitor which is a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an androgen receptor antagonist which is a compound of formula (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of prostate cancer,

2. the use of claim 1, wherein the prostate cancer is metastatic hormone sensitive prostate cancer, or castration resistant prostate cancer.

3. The use of claim 1, wherein the prostate cancer is metastatic castration resistant prostate cancer after chemotherapy resistance.

4. The use of claim 1, wherein the MEK inhibitor is a p-toluenesulfonate salt of the compound of formula (I).

5. The use according to claim 1, characterized in that the MEK inhibitor is present in a dosage range selected from 0.01-500 mg; the frequency of administration is 2 times per day, 1 time per 2 days or 3 days.

6. Use according to claim 5, characterized in that the MEK inhibitor is administered in a dosage range selected from 0.01-500 mg; the administration frequency is 2 times per day or 1 time per day.

7. Use according to claim 6, characterized in that the MEK inhibitor is administered in a dosage range selected from 0.01-500 mg; the frequency of administration was 1 time per day.

8. Use according to claim 1, characterized in that the dose of the compound of formula (I) is selected from 0.25mg, 0.5mg, 0.75mg, 1mg, 2mg, 3mg, 4mg, 10mg, 15mg, 20mg, 30mg, 45mg, 50mg, 60mg, 75mg or 100 mg; the frequency of administration is 2 times per day, 1 time per 2 days or 3 days.

9. Use according to claim 8, characterized in that the dose of the compound of formula (I) is selected from 0.25mg, 0.5mg, 0.75mg, 1mg, 2mg, 3mg, 4mg, 10mg, 15mg, 20mg, 30mg, 45mg, 50mg, 60mg, 75mg or 100 mg; the administration frequency is 2 times per day or 1 time per day.

10. Use according to claim 9, characterized in that the dose of the compound of formula (I) is selected from 0.25mg, 0.5mg, 0.75mg, 1mg, 2mg, 3mg, 4mg, 10mg, 15mg, 20mg, 30mg, 45mg, 50mg, 60mg, 75mg or 100 mg; the frequency of administration was 1 time per day.

11. The use of claim 1, wherein the amount of MEK inhibitor in the unit dosage form of the MEK inhibitor is 0.125mg or 0.5mg or 2 mg.

12. The use according to claim 1, wherein the dose of androgen receptor antagonist is selected from the range of 1-1000 mg; the administration frequency is selected from 2 times per day or 1 time per day.

13. The use of claim 12, wherein the dose of androgen receptor antagonist is selected from the range of 1-1000 mg; the frequency of administration was 1 time per day.

14. The use of claim 13, wherein the dose of androgen receptor antagonist is selected from 40mg, 80mg, 160mg, 240mg, 360mg or 480 mg; the administration frequency is selected from 2 times per day or 1 time per day.

15. The use of claim 14, wherein the dose of androgen receptor antagonist is selected from 40mg, 80mg, 160mg, 240mg, 360mg or 480 mg; the frequency of administration was 1 time per day.

16. The use according to claim 15, wherein the dose of androgen receptor antagonist is 240 mg; the administration frequency is selected from 2 times per day or 1 time per day.

17. The use according to claim 16, wherein the dose of androgen receptor antagonist is 240 mg; the frequency of administration was 1 time per day.

18. A pharmaceutical composition comprising a MEK inhibitor and an androgen receptor antagonist according to any one of claims 1-17, further comprising one or more pharmaceutically acceptable excipients, diluents or carriers.