WO2022199656A1

WO2022199656A1 - Pharmaceutical combination, kit containing same, and use thereof

Info

Publication number: WO2022199656A1
Application number: PCT/CN2022/082747
Authority: WO
Inventors: 王义乾; 郭晶; 欧阳昌赞; 张春辉; 王世华; 王钰; 张慧娟; 刘湘永; 兰宏; 陈将华; 罗成昆; 丁列明; 王家炳
Original assignee: 贝达药业股份有限公司
Priority date: 2021-03-24
Filing date: 2022-03-24
Publication date: 2022-09-29
Also published as: CN117222411A; TW202300145A

Abstract

Disclosed are a pharmaceutical combination, a kit containing same, and the use thereof in the preparation of a drug for treating breast cancer. The pharmaceutical combination comprises a first active ingredient and a second active ingredient, wherein the first active ingredient is any one of or more of a compound having a structure represented by structural formula I, a stereoisomer thereof, a tautomer thereof, a polymorph thereof, a solvate thereof and a pharmaceutically acceptable salt thereof; and the second active ingredient is an estrogen receptor antagonist or an aromatase inhibitor. The above-mentioned first active ingredient and second active ingredient are co-administered in combination, the achieved co-treatment activity has a prominent improvement effect with respect to the separate administration of each active ingredient, and the synergistic effect is achieved.

Description

Pharmaceutical combinations, kits containing the same and uses thereof

technical field

The present invention relates to the field of breast cancer drugs, in particular, to a drug combination, a kit containing the same, and uses thereof.

Background technique

Breast cancer has become the most threatening disease for women's health. There are at least 156 breast cancer drugs currently under development and on the market, of which 68% are targeted therapy drugs. A large number of studies have found that tumors are associated with cell cycle abnormalities, and a large number of mutations in mitotic signaling proteins and defects in anti-mitotic signaling proteins in tumor cells lead to proliferation disorders; at the same time, most tumors have genomic instability (GIN) and chromosome instability (CIN). ), all three fundamental cell cycle defects are caused directly or indirectly by the loss of control of CDKs. Cyclin-dependent protein kinase (CDK, Cyclin Dependent Kinase) inhibitors are increasingly becoming popular targets.

The function of CDKs is to phosphorylate and thus activate or deactivate certain proteins. The catalytic step mediated by CDKs involves the transfer of phosphate from ATP to a macromolecular enzyme substrate. Several groups of compounds (see eg Fischer, P.M. Curr. Opin. Drug Discovery Dev. 2001, 4, 623-634) have been found to have antiproliferative properties due to CDK-specific ATP antagonism.

Currently, the marketed breast cancer drugs include Palbociclib (PD-0332991), Ribociclib (LEE011) and Abemaciclib (LY2835219). However, the single drugs that have been listed are still difficult to meet the clinical needs. In view of this, the present invention provides a combination of a CDK inhibitor and other pharmaceutical preparations, and it is expected that an ideal synergistic effect can be achieved through the combination of the drugs.

SUMMARY OF THE INVENTION

The main purpose of the present invention is to provide a pharmaceutical combination, a kit containing the same and its use in preparing a medicine for treating breast cancer, so as to improve the effect of single medicine.

In order to achieve the above object, according to one aspect of the present invention, a pharmaceutical combination is provided, comprising: a first active ingredient, wherein the first active ingredient is a compound having the structure shown in structural formula I, its stereoisomer, its tautomerism any one or more of the structure, its polymorphs, its solvates and its pharmaceutically acceptable salts;

Wherein, ring A is aryl or heteroaryl; Z is selected from CH ₂ , NH, O or S; R ₁ is independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, C _1-8 alkane base, C _1-8 alkoxy, C _3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclyl-(CH ₂ ) _m -, aryl-C _1-6 alkyl- , heteroaryl-C _1-6 alkyl-, NR ₁₂ R ₁₃ , NR ₁₂ -C _1-6 alkylene-NR ₁₂ R ₁₃ , or heterocyclyl-C(O)-, wherein C _1-8 Alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclyl-(CH ₂ ) _m -, aryl-C _1-6 alkyl , heteroaryl-C _1-6 alkyl or heterocyclyl-C(O)- are each unsubstituted or by at least one selected from halogen, C _1-8 alkyl, C _3-8 cycloalkyl, heterocycle R ₂ and _{R 3} _are each independently selected from _hydrogen , hydroxyl, _cyano , nitro, amino, halogen, C _1-8 _alkyl , C _1-8 alkoxy, C _3-8 cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl , aryl, heteroaryl or heterocyclyl are each unsubstituted or substituted by at least one substituent selected from halogen, hydroxy, C _1-8 alkyl, C _3-8 cycloalkyl or heterocyclyl; R ₁₂ and R ₁₃ are each independently selected from hydrogen, C _1-8 alkyl, aryl, heteroaryl, heterocyclyl or C _3-8 cycloalkyl; wherein C _1-8 alkyl, aryl, heteroaryl , heterocyclyl or C _3-8 cycloalkyl are each unsubstituted or substituted by at least one substituent selected from halogen, hydroxy, C _1-8 alkyl, C _3-8 cycloalkyl or heterocyclyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; t is 0, 1, 2, 3 or 4, and aryl is a 6- to 10-membered monocyclic or bicyclic aromatic ring group; Heteroaryl is a 5- or 6-membered monocyclic aromatic ring system, which consists of carbon atoms and 1-4 heteroatoms selected from N, O or S; Heterocyclic groups are composed of carbon atoms and 1- A 3-8-membered stable saturated monocyclic system composed of 3 heteroatoms selected from N, O or S; the second active ingredient, the second active ingredient is an estrogen receptor antagonist or an aromatase inhibitor.

Further, the first active ingredient is a compound having a structure represented by any of structural formulas I-A to I-D or I-4 and I-6, its stereoisomers, its tautomers, its polymorphs, and its solvents any one or more of the compounds and their pharmaceutically acceptable salts,

Further, the first active ingredient is a compound having any of the structures represented by structural formulas I-1 to I-3, I-5, and I-7, its stereoisomers, its tautomers, and its polymorphs any one or more of the compounds, their solvates and their pharmaceutically acceptable salts,

Further, the above-mentioned first active ingredient is any one or more of a compound having the structure shown in structural formula I-1 and a pharmaceutically acceptable salt thereof,

Further, the above-mentioned pharmaceutically acceptable salts are the tartrate compound of the compound and the mesylate compound of the compound, preferably the first active ingredient is the compound or the tartrate compound of the compound.

Further, the above-mentioned tartrate compound has crystal form A, and the X-ray powder diffraction pattern of crystal form A has characteristic peaks with diffraction angles 2θ of 4.4±0.2°, 23.6±0.2° and 26.9±0.2°, preferably crystal form A The X-ray powder diffraction pattern has characteristic peaks with diffraction angles 2θ of 4.4±0.2°, 8.7±0.2°, 10.8±0.2°, 18.4±0.2°, 23.6±0.2° and 26.9±0.2°. The X-ray powder diffraction pattern has characteristic peaks with diffraction angles 2θ of 4.4±0.2°, 8.7±0.2°, 10.8±0.2°, 15.9±0.2°, 18.4±0.2°, 23.6±0.2° and 26.9±0.2°.

Further, the above-mentioned estrogen receptor antagonist is selected from any one of fulvestrant and tamoxifen, and the aromatase inhibitor is selected from any one of letrozole and anastrozole.

Further, the above-mentioned first active ingredient and second active ingredient are administered simultaneously, separately or sequentially.

Further, the first active ingredient is the compound represented by the structural formula I-1 or a pharmaceutically acceptable salt thereof; preferably, the daily dosage of the compound represented by the structural formula I-1 or a pharmaceutically acceptable salt thereof (with The compound represented by the structural formula I-1) ranges from 50 to 500 mg; more preferably, the daily dosage of the compound represented by the structural formula I-1 or a pharmaceutically acceptable salt thereof (based on the compound represented by the structural formula I-1) The range of the compound represented by the structural formula I-1 or the pharmaceutically acceptable salt thereof is 200-500 mg; further preferably, the daily dosage of the compound represented by the structural formula I-1 (calculated by the compound represented by the structural formula I-1) ranges from 300 to 400 mg.

Further, the second active ingredient is fulvestrant; preferably, the dosage of fulvestrant is 1-2000 mg each time, and the dosing frequency is 1-2 times a day; more preferably, the dosage of fulvestrant is 1-2 times a day; The dosage is 100-800 mg each time, and the administration frequency is 1-2 times a day; more preferably, the dosage of fulvestrant is 200-600 mg each time, and the administration frequency is 1-2 times a day.

Further, the second active ingredient is letrozole; preferably, the dosage of letrozole is 1-200 mg each time, and the dosing frequency is 1-2 times a day; more preferably, the dosage of letrozole is 1-2 times a day. 1-20 mg, the administration frequency is 1-2 times a day; more preferably, the dosage of letrozole is 1-5 mg each time, and the administration frequency is 1-2 times a day.

Further, the second active ingredient is anastrozole; preferably, the dosage of anastrozole per time is 0.1-50 mg, and the dosage frequency is 1-2 times a day; more preferably, the dosage of anastrozole per time is 1-25 mg, the administration frequency is 1-2 times a day; more preferably, the dosage of anastrozole is 1-10 mg each time, and the administration frequency is 1-2 times a day.

Further, the above-mentioned drug combination is used in the preparation of a medicine for the treatment of breast cancer, preferably breast cancer is estrogen receptor positive (ER+) breast cancer or/and is human epidermal growth factor receptor 2 negative (HER2-) breast cancer Or locally advanced or metastatic breast cancer.

According to another aspect of the present invention there is provided a kit comprising a pharmaceutical combination of any one of the above packaged in a container device, the first active ingredient and the second active ingredient in the pharmaceutical combination being administered simultaneously, separately administration or sequential administration.

According to another aspect of the present invention, there is provided the use of any one of the above-mentioned pharmaceutical combinations in the preparation of a medicament for treating breast cancer.

Further, the above-mentioned breast cancer is estrogen receptor positive (ER+) breast cancer, or/and human epidermal growth factor receptor 2 negative (HER2-) breast cancer, or locally advanced or metastatic breast cancer.

Applying the technical solution of the present invention, the application of the above-mentioned combination of the first active ingredient and the second active ingredient for co-administration, the achieved co-therapeutic activity has a prominent improvement effect compared to when each active ingredient is administered alone. Therefore, it is explained that two achieve a synergistic effect.

Description of drawings

The accompanying drawings forming a part of the present application are used to provide further understanding of the present invention, and the exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the attached image:

Fig. 1 shows the XRD pattern of the first active ingredient according to Example 1 of the present invention;

Figure 2 shows the synergistic effect of the first active ingredient and fulvestrant in combination according to Example 1 of the present invention on T-47D cell proliferation inhibition;

Figure 3 shows the tumor growth curve of the MCF-7 cell xenograft tumor Balb/c nude mice of Example 2 after the first active ingredient or in combination with Fulvestrant (Fulvestrant), the data points represent the average within the group Volume, error bars represent standard error (SEM); and

Figure 4 shows the body weight change of the MCF-7 cell xenograft tumor Balb/c nude mice of Example 2 after administration of the first active ingredient or in combination with Fulvestrant, and the data points represent the average body weight within the group , the error bars represent the standard error (SEM).

Detailed ways

It should be noted that the embodiments in the present application and the features of the embodiments may be combined with each other in the case of no conflict. The present invention will be described in detail below with reference to the accompanying drawings and in conjunction with the embodiments.

Unless otherwise specified, basic terms used in this application are defined by the following meanings:

Unless stated otherwise, the terms "comprising" and "including" are used in this application as open-ended and non-limiting concepts.

Unless otherwise indicated in this application or clearly contradicted by context, the terms "a" and "the" and similar recitations in the context of describing the invention, particularly in the context of the claims, are to be understood to encompass both singular and plural forms .

When the plural form of a compound, salt, etc. is used, this is considered to mean a single compound, salt, etc. simultaneously.

The first active ingredient and the second active ingredient in the term "pharmaceutical combination" can be administered independently in separate formulations for synergy or by using different fixed combinations (i.e. simultaneously or at different time points) containing different amounts of the combination partners. ) is administered to synergize. For ease of administration, it may take the form of a "kit" or "kit of kits" or "combination preparations", in the case of a kit, the parts of which may be administered, for example, simultaneously or sequentially staggered (ie any part of the kit is administered at the same or different time intervals at different time points). Combinations administered in a combined formulation, the ratio of the total amount of the first active ingredient and the second active ingredient may be varied, for example, to suit the needs of a subgroup of patients in need of treatment or the needs of an individual patient, particularly specific such as age or weight. sexual needs.

The term "pharmaceutical composition" is defined herein as a mixture or solution containing at least one therapeutic agent for administration to an individual (eg, a mammal or a human) for the prevention or treatment of a particular disease or condition affecting the mammal.

The term "pharmaceutically acceptable" is defined in this application as those that are suitable, within the scope of sound medical judgment, to contact the tissues of an individual (eg, a mammal or a human) without causing excessive toxicity, irritation of allergic reactions and other complications, and Compounds, materials, compositions and/or dosage forms with a reasonable benefit/risk ratio commensurate with it.

The terms "co-administration" or "combination administration" as used in this application are defined to encompass the administration of selected therapeutic agents to a single patient, and are meant to encompass therapeutic regimens in which the agents are not necessarily administered by the same route or at the same time.

As used in this application, the term "treatment" includes treatment that alleviates, alleviates or reduces at least one symptom of an individual or affects a delay in disease progression. For example, treatment may be to eliminate one or several symptoms of the disorder or to completely eradicate the disorder (eg, cancer). In the meaning of the present invention, the term "treating" also means preventing, delaying the onset (ie the time before the clinical manifestations of the disease appear) and/or reducing the risk of developing or worsening the disease. The term "protect" herein refers to preventing, delaying or treating (or, as appropriate, all) the development or persistence or exacerbation of a disease in an individual.

The term "co-therapeutic activity" or "co-therapeutic effect" means that the therapeutic agents can be treated individually (in a chronologically staggered manner, especially in a specific sequential manner) and according to the preference of the warm-blooded animal (especially a human) being treated but still Administration is timed to produce a (preferably synergistic) interaction (co-therapeutic effect). Whether this is the case can be determined by tracking blood levels that show that both compounds are present in the blood of the person to be treated at least during certain time intervals.

The term "pharmaceutically effective amount" or "clinically effective amount" or "therapeutically effective amount" of a combination of therapeutic agents refers to treatment with the combination sufficient to provide an observable improvement in the signs and symptoms observed at the clinical baseline of the disorder amount.

Unless otherwise specified, "pharmaceutically acceptable salts" in this application include salts of both acidic and basic groups that may be present in the compounds of the present invention. The compounds of the present invention are basic APIs and can form a variety of different salts with a variety of inorganic and organic acids. The acids that can be used to prepare the pharmaceutically acceptable acid addition salts of the basic compounds of the present invention are those that form non-toxic acid addition salts (i.e., salts containing a pharmaceutically acceptable anion, such as acetate, benzyl, etc.). acid salt, bromide, chloride, citrate, fumarate, hydrobromide, hydrochloride, iodate, lactate, maleate, mandelate, nitrate, oxalate , salicylates, succinates, and tartrates). "Pharmaceutically acceptable salts" of the present application can also locate amorphous or crystalline materials in which the free base API and the acid are ionized, or in which the two components, the free base API and the acid, utilize mutual intermolecular interactions, Such as hydrogen bonding to produce homogeneous crystalline material, or co-crystals formed by co-precipitation of free base and acid radicals. It should be understood that the salts of the present application may also be mixtures of partially ionized materials and partially eutectic materials.

As analyzed in the background art of the application, the application expects that the CDK inhibitor can achieve an ideal synergistic effect when used in combination with other pharmaceutical preparations. Based on this, the application provides a pharmaceutical combination, a kit comprising the same, and Its use in the preparation of a medicament for treating breast cancer.

It should be noted that although CDK4/6 inhibitors include more structural types of compounds, the inventors of the present application have found that not all CDK4/6 inhibitors can interact with the second active ingredient - estrogen receptor. Antagonists or aromatase inhibitors produce synergistic effects and even some degree of antagonism. In particular, the inventors found that CDK4/6 inhibitors, which have considerable inhibitory activity against breast cancer when administered alone, tend to have very different effects when used in combination with the above-mentioned second active ingredient.

Based on the above background, the present application provides a pharmaceutical combination comprising a first active ingredient and a second active ingredient, wherein the first active ingredient is a compound having the structure shown in structural formula I, its stereoisomer, its mutual Any one or more of the isomers, their polymorphs, their solvates and their pharmaceutically acceptable salts;

Wherein, ring A is aryl or heteroaryl; Z is selected from CH ₂ , NH, O or S; R ₁ is independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, C _1-8 alkane base, C _1-8 alkoxy, C _3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclyl-(CH ₂ ) _m -, aryl-C _1-6 alkyl- , heteroaryl-C _1-6 alkyl-, NR ₁₂ R ₁₃ , NR ₁₂ -C _1-6 alkylene-NR ₁₂ R ₁₃ , or heterocyclyl-C(O)-, wherein C _1-8 Alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclyl-(CH ₂ ) _m -, aryl-C _1-6 alkyl , heteroaryl-C _1-6 alkyl or heterocyclyl-C(O)- are each unsubstituted or by at least one selected from halogen, C _1-8 alkyl, C _3-8 cycloalkyl, heterocycle R ₂ and _{R 3} _are each independently selected from _hydrogen , hydroxyl, _cyano , nitro, amino, halogen, C _1-8 _alkyl , C _1-8 alkoxy, C _3-8 cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl , aryl, heteroaryl or heterocyclyl are each unsubstituted or substituted by at least one substituent selected from halogen, hydroxy, C _1-8 alkyl, C _3-8 cycloalkyl or heterocyclyl; R ₁₂ and R ₁₃ are each independently selected from hydrogen, C _1-8 alkyl, aryl, heteroaryl, heterocyclyl or C _3-8 cycloalkyl; wherein C _1-8 alkyl, aryl, heteroaryl , heterocyclyl or C _3-8 cycloalkyl are each unsubstituted or substituted by at least one substituent selected from halogen, hydroxy, C _1-8 alkyl, C _3-8 cycloalkyl or heterocyclyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; t is 0, 1, 2, 3 or 4, and aryl is a 6- to 10-membered monocyclic or bicyclic aromatic ring group; Heteroaryl is a 5- or 6-membered monocyclic aromatic ring system, which consists of carbon atoms and 1-4 heteroatoms selected from N, O or S; Heterocyclic groups are composed of carbon atoms and 1- A 3-8-membered stable saturated monocyclic system composed of 3 heteroatoms selected from N, O or S; the second active ingredient is an estrogen receptor antagonist or an aromatase inhibitor.

The first active ingredient of the present application is a CDK4/6 inhibitor, and the co-administration of the above-mentioned first active ingredient and the second active ingredient in combination can achieve a remarkable improvement in the co-therapeutic activity compared to when each active ingredient is administered alone Therefore, it shows that the two achieve a synergistic effect. And the test process shows that the combination of the first active ingredient and the second active ingredient of the present invention has better drug sensitivity to breast cancer cells, and can play a better inhibitory effect in low-dose administration, which is also conducive to avoiding. Side effects when large doses of drugs are administered.

The above-mentioned first active ingredient of the present application is that when the second active ingredient is co-administered, there are some differences in its synergistic effect. In some embodiments, the first active ingredient has structural formulas I-A to I-D or any of I-4 and I-6. Any one or more of the compounds of the shown structure, their stereoisomers, their tautomers, their polymorphs, their solvates and their pharmaceutically acceptable salts, with the expectation of further improvement Synergistic effect.

More preferably, the first active ingredient is a compound having any of the structures represented by structural formulas I-1 to I-3, I-5, and I-7, its stereoisomers, its tautomers, its polymorphs Any one or more of the form, its solvate and its pharmaceutically acceptable salts:

The above-mentioned pharmaceutical combination of the present application, especially when the above-mentioned pharmaceutical composition is used in the preparation of a medicine for the treatment of breast cancer, the test shows that its synergistic effect is more prominent, for example, breast cancer is estrogen receptor positive (ER+) breast cancer , or human epidermal growth factor receptor 2-negative (HER2-) breast cancer or locally advanced or metastatic breast cancer.

Especially when the first active ingredient is any one or more of the compound having the structure represented by structural formula I-1 and its pharmaceutically acceptable salts, the comprehensive effect is more stable.

In some embodiments of the present application, preferably the above-mentioned pharmaceutically acceptable salts are the tartrate compounds of the compounds and the mesylate compounds of the compounds, preferably the first active ingredient is the above-mentioned compounds or the tartrate compounds of the above-mentioned compounds.

A kind of structural formula of the tartrate compound of above-mentioned compound is:

A kind of structural formula of the mesylate compound of above-mentioned compound A is:

The first active ingredients used in this application are all existing compounds in the prior art, for example, PCT patent application documents with publication numbers WO2018/113771A1 and WO2019242719A1 may be referred to, and more specific preparation methods will not be repeated here.

Further, in order to improve the stability when the first active ingredient is combined with the second active ingredient, it is preferable that the above-mentioned tartrate compound has crystal form A, and the X-ray powder diffraction pattern of crystal form A has a diffraction angle 2θ of 4.4±0.2°. , 23.6±0.2° and 26.9±0.2° characteristic peaks, preferably the X-ray powder diffraction pattern of crystal form A has diffraction angles 2θ of 4.4±0.2°, 8.7±0.2°, 10.8±0.2°, 18.4±0.2°, Characteristic peaks at 23.6±0.2° and 26.9±0.2°, further preferably the X-ray powder diffraction pattern of crystal form A has diffraction angles 2θ of 4.4±0.2°, 8.7±0.2°, 10.8±0.2°, 15.9±0.2°, Characteristic peaks at 18.4±0.2°, 23.6±0.2° and 26.9±0.2°. The tartrate compound having the above-mentioned crystal form A has better solubility and more prominent stability, so its medicinal effect is more prominent.

In some embodiments of the present application, the above-mentioned estrogen receptor antagonist is selected from any one of fulvestrant and tamoxifen. The aromatase inhibitor is selected from any one of letrozole and anastrozole. The above drugs are the active ingredients of the current first- or second-line clinical commonly used drugs, so their safety is higher.

Although the optional ingredients of the above-mentioned second active ingredients are not the active ingredients in the existing commonly used medicines, the modes of administration and the amount of application are different during administration. In order to better realize the For the purpose of synergism of an active ingredient, a corresponding clinical application range can be given according to the individual needs of patients.

In clinical administration, the patient can select the first active ingredient and the second active ingredient to be administered simultaneously, separately or sequentially according to the specific form of the drug combination. The specific dosage relationship of the above-mentioned two types of active ingredients can be adjusted. Of course, in order to better exert the synergistic effect, it is preferred that the first active ingredient is the compound represented by structural formula I-1 or a pharmaceutically acceptable salt thereof; preferably , the daily dosage of the compound represented by structural formula I-1 or a pharmaceutically acceptable salt thereof (calculated by the compound represented by structural formula I-1) ranges from 50 to 500 mg, more preferably 200 to 500 mg, and further preferably 300 mg ~400mg. In some embodiments, the second active ingredient is fulvestrant; preferably, the dosage of fulvestrant is 1-2000 mg each time, and the dosage frequency is 1-2 times a day; more preferably, fulvestrant The dosage of the group is 100-800 mg each time, and the dosing frequency is 1-2 times a day; more preferably, the dosage of fulvestrant is 200-600 mg each time, and the dosing frequency is 1-2 times a day. Or, the second active ingredient is letrozole; preferably, the dosage of letrozole is 1-200 mg each time, and the administration frequency is 1-2 times a day; more preferably, the dosage of letrozole is 1-2 times a day ~20 mg, and the dosing frequency is 1-2 times a day; further preferably, the dosage of each letrozole is 1-5 mg, and the dosing frequency is 1-2 times a day. Or, the second active ingredient is anastrozole; preferably, the dosage of anastrozole is 0.1-50 mg each time, and the administration frequency is 1-2 times a day; more preferably, the dosage of anastrozole is 1 ~25 mg, the administration frequency is 1-2 times a day; more preferably, the dosage of anastrozole is 1-10 mg each time, and the administration frequency is 1-2 times a day.

Wherein, the above-mentioned pharmaceutical combination of the present application can be administered after forming a corresponding formulation with each of the current active ingredients and a pharmaceutically acceptable carrier. The aforementioned estrogen receptor antagonists, such as fulvestrant, are administered in the form of injections. Unless otherwise stated, they are prepared in a manner known per se, for example by various conventional mixing, comminution, direct compression, granulation, sugar coating, dissolution, lyophilization processes, melt granulation or processing well known to those skilled in the art technology. It should be noted that the unit content of a combination partner contained in an individual dose of each dosage form does not necessarily constitute an effective amount by itself, as the desired effective amount may be achieved by administering multiple dosage units.

The above-mentioned "pharmaceutically acceptable carrier" refers to a conventional pharmaceutical carrier suitable for the desired pharmaceutical preparation, for example: diluents such as water, various organic solvents, excipients, etc.; fillers such as starch, sucrose, etc.; Binders such as cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone (PVP); humectants such as glycerin; disintegrants such as agar, calcium carbonate, and sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds ; surfactants such as cetyl alcohol; absorbent carriers such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate and polyethylene glycols. In addition, other pharmaceutically acceptable adjuvants such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, fragrances, sweeteners and dyes can also be added therein. Excipients suitable for the desired dosage form and desired mode of administration are preferably used.

In another typical embodiment of the present application, there is provided the use of any one of the above-mentioned pharmaceutical combinations in the preparation of a medicament for treating breast cancer.

In the present application, the combined co-administration of the above-mentioned first active ingredient and the second active ingredient achieves a remarkable improvement in the co-therapeutic activity compared to the individual application of each active ingredient, thus indicating that the two achieve a synergistic effect. .

In some embodiments, the breast cancer described above is estrogen receptor positive (ER+) breast cancer, or human epidermal growth factor receptor 2 negative (HER2-) breast cancer, or locally advanced or metastatic breast cancer.

In another typical embodiment of the present application, there is provided a kit comprising any one of the above-mentioned pharmaceutical combinations packaged in a container device, a first active ingredient and a second active ingredient in the pharmaceutical combination The ingredients are administered simultaneously, separately or sequentially. The above kit is a convenient way of administering the pharmaceutical combination of the present application, but it is indicated that the pharmaceutical combination of the present application can only exist in the form of a kit.

The first active ingredient and the second active ingredient can be administered independently or by using different fixed combinations (ie simultaneously or at different time points) containing different amounts of the combination partners. The parts of the kit can then be administered, for example, simultaneously or sequentially staggered (ie, at different time points with the same or different time intervals of any part of the kit). When administered in a kit-formed combination formulation, the ratio of the total amount of the first active ingredient and the second active ingredient can be varied, for example, to suit the needs of a subgroup of patients in need of treatment or the needs of an individual patient, particularly such as age or Weight specific needs.

In yet another typical embodiment of the present application, a method for treating breast cancer using a drug combination is provided. In therapy, the respective clinically administered dosage ranges of the first active ingredient and the second active ingredient can be administered according to the individual needs of the patient.

The beneficial effects of the present application will be further described below in conjunction with the examples and comparative examples.

Example 1 Inhibitory effect of the first active ingredient in combination with fulvestrant on tumor cell proliferation

The chemical formula of the first active ingredient is

The crystal form is crystal form A, and the spectrum is shown in Figure 1. The first active ingredient is prepared with reference to the method of WO2019242719A1, and fulvestrant is commercially available.

Methods: This experiment used PerkinElmer's

Cell proliferation kit method was used to detect whether the combination of the first active ingredient and Fulvestrant had a synergistic effect on the inhibitory activity of T-47D cell proliferation to support the clinical combination strategy. This method utilizes the addition of BrdU (5-bromo-2'-deoxyuridine) to cells as a DNA analog to incorporate into the cell proliferation process, and then uses an anti-BrdU antibody to detect the amount of BrdU incorporated into DNA to respond to cells level of proliferation. The culture conditions of the cells in this experiment simulate the estrogen stimulation under the pathological conditions of breast cancer, and at the same time, the hormonal factors that may exist in the serum are removed by activated carbon treatment to ensure the controllability of the system. Therefore, the combination of the first active ingredient and fulvestrant was selected under the condition of adding activated carbon-treated serum and β-estradiol to the medium to maximize the effect of the combination.

The specific experimental steps were as follows: T-47D cells were cultured in DMEM medium without phenol red, and 10 μg/mL Human Insulin, 10% FBS and 1% double antibody were added. Incubate at 37°C and 5% CO ₂ . The cells are routinely cultured until the cell saturation is 80% to 90%, and the cells are harvested when the number reaches the requirement. Cells were resuspended with activated carbon-treated serum plus β-estradiol medium, counted, and prepared into a cell suspension of appropriate density. The cell suspension was added to a 96-well plate, 100 μL per well, at 3000 cells/well. Cell culture incubator overnight. The first active ingredient and fulvestrant were diluted in DMSO and diluted in medium for use. Twenty-four hours after the cells were plated, each well was supplemented with 90 [mu]L of medium, and then 10 [mu]L of the prepared compound was added to the wells. The final concentration of the test compound is: the concentration of the first active ingredient of the test: 60 nM. Test compound fulvestrant concentration: 150 nM. Combination concentration: 150nM fulvestrant+60nM first active ingredient. Place the cell culture plate in the incubator for 96 hours. Dilute the BrdU Labeling Reagent 10-fold with medium and add 2 μL per well. Place the cell culture plate in the incubator overnight. Aspirate the medium gently, add 100 μL of fixative to each well, and incubate at room temperature for 30 minutes. Discard the fixative, add 100 μL of 0.5 μg/mL Anti-BrdU-Eu antibody to each well, and incubate at room temperature for 60 minutes. Discard the antibody solution and wash 4 times with washing solution. Add 200 μL of DELFIA Inducer to each well and incubate at room temperature for 30 minutes. Fluorescence signal values were read with Envision.

Data analysis: The effect of compound combination was evaluated by the coefficient of drug in interaction (CDI). CDI was calculated according to the formula: CDI=AB/A×B, where AB was the ratio of cell well readings between the two-drug combination group and the DMSO control group, and A or B was the cell well reading ratio of each drug alone group and the control group. If CDI<1, it proves that the action properties of the two drugs are synergistic, and when CDI<0.7, the two drugs have very significant synergy; if CDI=1, the action properties of the two drugs are additive; if CDI>1, the action properties of the two drugs are antagonism.

Results: The experimental results of the inhibition of T-47D cell proliferation by the combination of the first active ingredient and fulvestrant showed that the CDI of the combination of 60nM of the first active ingredient and 150nM of fulvestrant was 0.59, according to the judgment standard of the combination index , indicating that the synergistic effect of the two drugs is very significant. The results are shown in Table 1 and Figure 2.

Conclusion: On T-47D cells, under estrogen stimulation conditions that simulate the pathological conditions of breast cancer patients, the combination index CDI of 60nM first active ingredient combined with 150nM fulvestrant is 0.59, indicating that the two drugs have a very synergistic effect. Significantly.

Table 1

组别group	荧光读数Fluorescence reading	％Ctrl%Ctrl	CDICDI
DMSODMSO	20160±705.920160±705.9	100.0±3.5100.0±3.5	//
第一活性成分first active ingredient	10783±425.610783±425.6	53.5±2.153.5±2.1	//
氟维司群Fulvestrant	11053±248.011053±248.0	54.8±1.254.8±1.2	//
第一活性成分+氟维司群First Active Ingredient + Fulvestrant	3466±130.13466±130.1	17.2±0.617.2±0.6	0.590.59

NOTE: Readings and %Ctrl are mean ± SEM characterization.

Example 2

In vivo pharmacodynamic study of the tartrate salt of the first active ingredient with structural formula (II) or combined with fulvestrant on human breast cancer MCF-7 cell subcutaneous xenograft tumor BALB/c nude mice model

Methods: Balb/c nude mice were subcutaneously inoculated with 17β-estradiol tablets (0.18 mg, 90 days sustained release) 3 days before inoculation of cells. MCF-7 cells were subcutaneously inoculated on the back to establish the MCF-7 xenograft tumor animal model. The experiment was divided into solvent blank control group, first active ingredient 25mg/kg group, first active ingredient 50mg/kg group, fulvestrant 200mg/kg group, first active ingredient 25mg/kg + fulvestrant 200mg/kg group , and the first active ingredient 50 mg/kg + fulvestrant 200 mg/kg group. There were 8 experimental animals in each group. The first active ingredient of the test was administered by gavage from the day of grouping, once a day, for a total of 29 days (QD×29 days). Fulvestrant was administered by subcutaneous injection from the day of grouping, once a week, for a total of 5 doses (QW x 5 times). The safety evaluation was carried out according to the changes of animal body weight and death, and the efficacy evaluation was carried out according to the relative tumor inhibition rate (TGI%).

The calculation formula of tumor volume is: V=0.5a×b ² , a and b represent the long and short diameters of the tumor, respectively. The antitumor efficacy of the compounds was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). TGI (%) reflects tumor growth inhibition rate. Calculation of TGI (%): TGI (%)=[(1-(average tumor volume at the end of administration of a certain treatment group - average tumor volume at the beginning of administration of this treatment group))/(average tumor volume at the end of treatment in the solvent control group Volume - the average tumor volume of the solvent control group at the beginning of treatment)] × 100%.

Relative tumor proliferation rate ΔT/ΔC(%): The calculation formula is as follows: ΔT/ΔC(%)=(Ti-T0)/(Vi-V0)×100. Where V0 is the average tumor volume measured in the solvent control group during group administration (i.e. D0), Vi is the average tumor volume in the solvent control group at a certain measurement; T0 is the average tumor volume measured in the administration group during group administration (i.e. D0) Tumor volume, Ti is the mean tumor volume of the administration group at one measurement.

result:

1. Efficacy evaluation of compounds on MCF-7 cell xenograft tumor model:

On the 28th day after administration in mice, the first active ingredient (25mg/kg) group did not show significant antitumor effect compared with the average tumor volume of the solvent control group, p value was 0.1706, relative tumor proliferation rate △T/△C (%) was 62.02%, and the tumor growth inhibition rate TGI (%) was 37.98%. The first active ingredient (50 mg/kg) group showed a significant anti-tumor effect compared with the average tumor volume of the solvent control group, with a p value of 0.0020; the relative tumor proliferation rate ΔT/ΔC (%) was 28.97%; tumor growth The inhibition rate TGI (%) was 71.03%. The fulvestrant (200 mg/kg) group also showed a significant anti-tumor effect compared with the average tumor volume of the solvent control group, with a p value of 0.0001; the relative tumor proliferation rate △T/△C (%) was 11.13%; tumor growth The inhibition rate TGI (%) was 88.87%. The mean tumor volume of the first active ingredient (25 mg/kg) + fulvestrant (200 mg/kg) group and the first active ingredient (50 mg/kg) + fulvestrant (200 mg/kg) group was also higher than that of the solvent control group. All showed significant anti-tumor effects, p values were <0.0001 and <0.0001; the relative tumor proliferation rates ΔT/ΔC (%) were -12.05% and -12.80%, respectively; tumor growth inhibition rates TGI (%) were were 112.05% and 112.80%. The evaluation of antitumor efficacy is shown in Table 2; the tumor growth curve is shown in Figure 3.

Table 2. Evaluation of the antitumor efficacy of the first active ingredient or combined use of fulvestrant on the MCF-7 xenograft tumor model (calculated based on the tumor volume on the 28th day after administration)

Note:

a. Mean±SEM, n=8.

b. Tumor growth inhibition was calculated from ΔT/ΔC and TGI (TGI(%)=[1-(T ₂₈ -T ₀ )/(V ₂₈ -V ₀ )]×100).

c.p value is a comparative analysis of tumor volume between the treatment group and the solvent control group.

2. Safety evaluation of compounds in MCF-7 cell xenograft tumor model

In this model, as shown in Figure 4, all animals showed no significant weight loss during the dosing period.

in conclusion:

In terms of drug safety, tumor-bearing mice showed good tolerance to the first active ingredient at two doses of 25 mg/kg and 50 mg/kg or in combination with Fulvestrant (200 mg/kg).

In terms of tumor volume and tumor weight, significant antitumor effects were also exhibited when the first active ingredient was used in combination with fulvestrant (200 mg/kg) at both doses of 25 mg/kg and 50 mg/kg.

From the aspect of drug sensitivity, it can be seen from the data in the above table that the p-value of the first active ingredient at both doses of 25mg/kg and 50mg/kg can reach <0.0001, which is much lower than other CDK4/6 in the prior art. Inhibitor administration p-value. This is enough to show that the combination of the first active ingredient and the second active ingredient provided by the present invention has more significant drug sensitivity to breast cancer cell proliferation, and has a better promotion effect on reducing drug dosage and reducing toxic and side effects.

Embodiment 3 to embodiment 7, comparative example 1

In Examples 3 to 8, different first active ingredients and fulvestrant were used in combination with the dosage in the table for T47D tumor cell proliferation inhibition, and the specific experimental process was as follows:

In this experiment, Abcam's Brdu ELISA kit method was used to detect whether the combination of each first active ingredient and Fulvestrant had a synergistic effect on the inhibitory activity of T47D cell proliferation to support the clinical combination strategy. The method utilizes the addition of BrdU (5-bromo-2'-deoxyuridine) to cells as a DNA analog to incorporate into the cell proliferation process, and then uses an anti-BrdU antibody to detect the amount of BrdU incorporated into DNA to respond to cells level of proliferation. The culture conditions of the cells in this experiment simulate the estrogen stimulation under the pathological conditions of postmenopausal breast cancer, and at the same time, the hormonal factors that may exist in the serum are removed by activated carbon treatment to ensure the controllability of the system. Therefore, the combination of the first active ingredient and fulvestrant was selected under the condition of adding activated carbon-treated serum and estradiol to the culture medium to maximize the effect of the combination.

The specific experimental steps were as follows: T47D cells were cultured in phenol red-free RPMI-1640 medium, and 10 μg/mL Human Insulin, 10% FBS and 1% double antibody were added. Incubate at 37°C and 5% CO ₂ . The cells are routinely cultured until the cell saturation is 80%-90%, and the cells are harvested when the number reaches the requirement. Cells were resuspended in activated carbon-treated serum plus estradiol medium, counted, and prepared into a cell suspension of appropriate density. The cell suspension was added to a 96-well plate and incubated overnight in a cell incubator. The first active ingredient and fulvestrant were diluted in DMSO and diluted in medium for use. Twenty-four hours after the cells were plated, the prepared compounds were added to the wells. Place the cell culture plate in the incubator for 96 hours. Twenty hours before the end of the experiment, 10ul of 1X Brdu was added to each well, and 10ul of phenol red-free 1640 medium containing 10% activated carbon adsorbed fetal bovine serum was added to the Background wells. Continue to incubate. Aspirate the medium gently, add fixative to each well, and incubate at room temperature for 30 minutes. Discard the fixative, add 100ul anti-BrdU monoclonal Detector Antibody to each well, and incubate at room temperature for 60 minutes. Discard the antibody solution and wash 4 times with washing solution. Add 100ul of 1X Peroxidase Goat Anti-Mouse IgG Conjugate to each well and incubate at room temperature for 30 minutes. Add 100ul TMB to each well, incubate at room temperature for 30 minutes and read the OD450.

Effect evaluation method: The effect of compound combination was evaluated by Bliss independence model. The synergy score was calculated using the Bliss independent model and the Loewe additive model. Above 5 indicates synergy, below -5 indicates antagonism.

The results are shown in Table 3:

table 3

Note: Structural formula I-8 is a compound

Examples 9 to 11

In Examples 9 to 11, different first active ingredients and letrozole were combined for the inhibition of MCF-7 tumor cell proliferation according to the dosage in the table, and the specific experimental process was as follows:

In this experiment, Abcam's Brdu ELISA kit was used to detect whether the combination of different first active ingredients and Letrozole had a synergistic effect on the inhibitory activity of MCF-7 cell proliferation to support the clinical combination strategy. The method utilizes the addition of BrdU (5-bromo-2'-deoxyuridine) to cells as a DNA analog to incorporate into the cell proliferation process, and then uses an anti-BrdU antibody to detect the amount of BrdU incorporated into DNA to respond to cells level of proliferation. The culture conditions of the cells in this experiment simulate the estrogen stimulation under the pathological conditions of postmenopausal breast cancer, and at the same time, the hormonal factors that may exist in the serum are removed by activated carbon treatment to ensure the controllability of the system. Therefore, the combination of different first active ingredients and letrozole was selected under the condition of adding activated carbon-treated serum plus androstenedione to the medium to maximize the effect of the combination.

The specific experimental steps were as follows: MCF-7 cells were cultured in phenol red-free RPMI-1640 medium, and 10 μg/mL Human Insulin, 10% FBS and 1% double antibody were added. Incubate at 37°C and 5% CO ₂ . The cells are routinely cultured until the cell saturation is 80%-90%, and the cells are harvested when the number reaches the requirement. Cells were resuspended in activated carbon-treated serum plus androstenedione medium, counted, and prepared into a cell suspension of appropriate density. The cell suspension was added to a 96-well plate and incubated overnight in a cell incubator. The first active ingredient and letrozole were diluted with DMSO and diluted in medium for use. Twenty-four hours after the cells were plated, the prepared compounds were added to the wells. Place the cell culture plate in the incubator for 96 hours. Twenty hours before the end of the experiment, 10ul of 1X Brdu was added to each well, and 10ul of phenol red-free 1640 medium containing 10% activated carbon adsorbed fetal bovine serum was added to the Background wells. Continue the incubation, gently aspirate the medium, add fixative to each well, and incubate at room temperature for 30 minutes. Discard the fixative, add 100ul anti-BrdU monoclonal Detector Antibody to each well, and incubate at room temperature for 60 minutes. Discard the antibody solution and wash 4 times with washing solution. Add 100ul of 1X Peroxidase Goat Anti-Mouse IgG Conjugate to each well and incubate at room temperature for 30 minutes. Add 100ul TMB to each well, incubate at room temperature for 30 minutes and read the OD450.

The results are shown in Table 4:

Table 4

Example 12

The tartrate salt of the first active ingredient (the compound represented by the structural formula II above) or the clinical trial of combined use of fulvestrant.

Inclusion criteria:

1. Single medication (dose escalation stage): patients with advanced breast cancer diagnosed by histology or cytology, the existing standard treatment regimens cannot benefit, and are not suitable for curative surgical resection or radiation therapy;

2. (Expanded enrollment stage) Combination medication: the following conditions must be met at the same time

Histology or cytology confirmed by the research center as HR-positive, HER-2-negative (if there is a needle biopsy for metastatic lesions, the results of the metastatic lesions shall prevail), locally advanced or recurrent/metastatic female breast cancer, and not suitable for Surgical resection or radiation therapy for curative purposes;

Natural state postmenopausal women; or premenopausal women who have previously undergone bilateral oophorectomy or medical castration to achieve postmenopausal state.

3. (Expansion enrollment stage) Combination medication:

① For patients with recurrent and metastatic disease, no more than 1 line of chemotherapy is allowed.

②The following standards must be met at the same time:

Patients who have received first-line endocrine therapy in the stage of recurrence/metastasis must meet the progression-free time of continuous first-line endocrine therapy for ≥6 months, and have disease progression confirmed by imaging;

For patients who have received adjuvant endocrine therapy, the disease recurrence confirmed by imaging must occur from the start of adjuvant endocrine therapy (continuous use for at least 2 years) to 12 months or less after the completion of adjuvant endocrine therapy.

There are measurable lesions defined by RECIST V.1.1, and tumor lesions that have received radiotherapy or other local treatments in the past are only regarded as measurable lesions if there is a clear record of disease progression at the treatment site after completion of treatment;

Dosing regimen:

(Dose escalation stage) Single medication: 6 doses are designed in this stage, which are Drug A (tartrate capsule of the compound represented by structural formula I-1) 50mg/d, 100mg/d, 200mg/d, 300mg/d, 400mg/d d and 500 mg/d. For oral administration, drug A capsules were administered in a single dose, and after 7 days of elution, continuous administration was performed once a day.

(Expansion phase) Combination medication: Drug A (tartrate capsule of the compound represented by structural formula I-1) 300mg/d combined with fulvestrant 500mg/28d or drug A 400mg/d combined with fulvestrant 500mg/28d. The first active ingredient capsule is orally administered, once a day, continuously. Fulvestrant 500mg: used once on D1 and D15 in the first cycle, once on D1 in the second cycle and thereafter, by continuous slow intramuscular injection (1-2min/5mL) in the buttocks, one injection on each side of the buttocks. Every 28 days is a cycle.

in conclusion:

As of February 25, 2022, (dose escalation phase) of the 13 efficacy-evaluable populations in the 300 mg/d, 400 mg/d, and 500 mg/d dose groups of monotherapy (dose escalation phase), 1 subject exhibited a partial response (PR) , the objective response rate (ORR) was 7.7%. (Expanded enrollment stage) Among the 30 patients in the efficacy evaluable population in the combination group (the first active ingredient capsules 300mg/d and 400mg/d combined with fulvestrant), 17 subjects showed partial remission (PR), The objective response rate (ORR) was 56.7%; among the 21 patients in the efficacy-evaluable population of drug A capsules 400 mg/d combined with fulvestrant group, 14 subjects showed partial response (PR), and the objective response rate (ORR) as high as 66.7%.

The efficacy of drug A combined with fulvestrant (≥300mg/d) group is better than that of single drug A; at the same time, the historical data of fulvestrant in the treatment of advanced breast cancer that has recurred or progressed after previous endocrine therapy (ORR: 9-21.3%) ), the combination therapy also showed superior efficacy.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

A drug combination, characterized in that, comprising:

The first active ingredient, the first active ingredient is the compound having the structure shown in structural formula I, its stereoisomer, its tautomer, its polymorph, its solvate and its pharmaceutically acceptable any one or more of the salts;

in,

Ring A is aryl or heteroaryl;

Z is selected from CH 2 , NH, O or S;

R 1 are each independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, aryl, heteroaryl , heterocyclyl, heterocyclyl-(CH 2 ) m -, aryl-C 1-6 alkyl-, heteroaryl-C 1-6 alkyl-, NR 12 R 13 , NR 12 -C 1- 6 alkylene-NR 12 R 13 , or heterocyclyl-C(O)-, wherein C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, aryl, heteroaryl radical, heterocyclyl, heterocyclyl-(CH 2 ) m -, aryl-C 1-6 alkyl, heteroaryl-C 1-6 alkyl or heterocyclyl-C(O)- are each not substituted or substituted by at least one substituent selected from halogen, C 1-8 alkyl, C 3-8 cycloalkyl, heterocyclyl, NR 12 R 13 , (CH 2 ) t -OH;

R 2 and R 3 are each independently selected from hydrogen, hydroxyl, cyano, nitro, amino, halogen, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, aryl, Heteroaryl or heterocyclyl; wherein C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, aryl, heteroaryl or heterocyclyl are each unsubstituted or replaced by at least one Substituents selected from halogen, hydroxy, C 1-8 alkyl, C 3-8 cycloalkyl or heterocyclyl;

R 12 and R 13 are each independently selected from hydrogen, C 1-8 alkyl, aryl, heteroaryl, heterocyclyl or C 3-8 cycloalkyl; wherein C 1-8 alkyl, aryl, hetero Aryl, heterocyclyl or C3-8cycloalkyl are each unsubstituted or substituted with at least one substituent selected from halogen, hydroxy, C1-8alkyl , C3-8cycloalkyl or heterocyclyl ;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2, 3 or 4;

t is 0, 1, 2, 3 or 4,

The aryl group is a 6- to 10-membered monocyclic or bicyclic aromatic ring group;

The heteroaryl group is a 5- or 6-membered monocyclic aromatic ring system consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S;

The heterocyclic group is a 3-8 membered stable saturated monocyclic ring system consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S;

The second active ingredient is an estrogen receptor antagonist or an aromatase inhibitor.
The pharmaceutical combination according to claim 1, wherein the first active ingredient is a compound having any of the structures represented by structural formulas I-A to I-D or I-4 and I-6, its stereoisomers, its mutual any one or more of the isomers, their polymorphs, their solvates and their pharmaceutically acceptable salts,
The pharmaceutical combination according to claim 1, wherein the first active ingredient is a compound having any of the structures represented by structural formulas I-1 to I-3, I-5, and I-7, and its stereoisomers any one or more of its isomers, its tautomers, its polymorphs, its solvates and pharmaceutically acceptable salts thereof,
The pharmaceutical combination according to claim 1, wherein the first active ingredient is any one or more of a compound having a structure represented by structural formula I-1 and a pharmaceutically acceptable salt thereof,
The pharmaceutical combination according to any one of claims 1 to 4, wherein the pharmaceutically acceptable salt is a tartrate compound of the compound and a mesylate compound of the compound, preferably the compound The first active ingredient is the compound or a tartrate compound of the compound.
The pharmaceutical combination according to claim 5, wherein the tartrate compound has a crystal form A, and the X-ray powder diffraction pattern of the crystal form A has diffraction angles 2θ of 4.4±0.2°, 23.6±0.2° and characteristic peaks of 26.9±0.2°, preferably the X-ray powder diffraction pattern of the crystal form A has diffraction angles 2θ of 4.4±0.2°, 8.7±0.2°, 10.8±0.2°, 18.4±0.2°, 23.6±0.2 ° and 26.9±0.2° characteristic peaks, further preferably, the X-ray powder diffraction pattern of the crystal form A has diffraction angles 2θ of 4.4±0.2°, 8.7±0.2°, 10.8±0.2°, 15.9±0.2°, 18.4° Characteristic peaks at ±0.2°, 23.6±0.2° and 26.9±0.2°.
The pharmaceutical combination according to any one of claims 1 to 6, wherein the estrogen receptor antagonist is selected from any one of fulvestrant and tamoxifen, and the aromatase The inhibitor is selected from any one of letrozole and anastrozole.
The pharmaceutical combination according to any one of claims 1 to 7, wherein the first active ingredient and the second active ingredient are administered simultaneously, separately or sequentially.
The pharmaceutical combination according to claim 8, wherein the first active ingredient is a compound represented by structural formula I-1 or a pharmaceutically acceptable salt thereof; preferably, the compound represented by structural formula I-1 The daily dosage of the compound or a pharmaceutically acceptable salt thereof ranges from 50 to 500 mg; more preferably, the daily dosage of the compound represented by the structural formula I-1 or a pharmaceutically acceptable salt thereof ranges from 200 to 500 mg. ; Further preferably, the daily dosage of the compound represented by the structural formula I-1 or a pharmaceutically acceptable salt thereof ranges from 300 to 400 mg.
The pharmaceutical combination according to claim 8, wherein the second active ingredient is fulvestrant; preferably, the dosage of the fulvestrant per time is 1-2000 mg, and the administration frequency is one day 1-2 times; more preferably, the dosage of fulvestrant is 100-800 mg each time, and the dosage frequency is 1-2 times a day; further preferably, the dosage of fulvestrant is 1-2 times a day. 200 to 600 mg, the frequency of administration is 1 to 2 times a day.
The pharmaceutical combination according to claim 8, wherein the second active ingredient is letrozole; preferably, the dosage of the letrozole is 1-200 mg each time, and the dosing frequency is 1-200 mg per day. 2 times; more preferably, the dosage of the letrozole is 1-20 mg each time, and the dosing frequency is 1-2 times a day; further preferably, the dosage of the letrozole is 1-5 mg each time, The frequency of administration is 1 to 2 times a day.
The pharmaceutical combination according to claim 8, wherein the second active ingredient is anastrozole; preferably, the dosage of the anastrozole per time is 0.1-50 mg, and the dosing frequency is 1-1 mg per day. 2 times; more preferably, the dosage of anastrozole per time is 1-25 mg, and the administration frequency is 1-2 times a day; further preferably, the dosage of anastrozole per time is 1-10 mg, The frequency of administration is 1 to 2 times a day.
The pharmaceutical combination according to claim 1, wherein the pharmaceutical combination is used in the preparation of a medicine for treating breast cancer, preferably the breast cancer is estrogen receptor positive (ER+) breast cancer, or/and human Epidermal growth factor receptor 2-negative (HER2-) breast cancer may be locally advanced or metastatic breast cancer.
A kit comprising the pharmaceutical combination of any one of claims 1 to 13 packaged in a container device, the first active ingredient and the second active ingredient in the pharmaceutical combination The ingredients are administered simultaneously, separately or sequentially.
A use of the pharmaceutical combination according to any one of claims 1 to 13 in the preparation of a medicament for treating breast cancer.
The use according to claim 15, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer, or/and human epidermal growth factor receptor 2 negative (HER2-) breast cancer or is Locally advanced or metastatic breast cancer.