WO2022199656A1 - Combinaison pharmaceutique, kit la contenant et son utilisation - Google Patents

Combinaison pharmaceutique, kit la contenant et son utilisation Download PDF

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WO2022199656A1
WO2022199656A1 PCT/CN2022/082747 CN2022082747W WO2022199656A1 WO 2022199656 A1 WO2022199656 A1 WO 2022199656A1 CN 2022082747 W CN2022082747 W CN 2022082747W WO 2022199656 A1 WO2022199656 A1 WO 2022199656A1
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active ingredient
compound
pharmaceutical combination
heterocyclyl
dosage
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PCT/CN2022/082747
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English (en)
Chinese (zh)
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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
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贝达药业股份有限公司
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Priority to CN202280023140.3A priority Critical patent/CN117222411A/zh
Publication of WO2022199656A1 publication Critical patent/WO2022199656A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • 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.
  • CDKs 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.
  • the marketed breast cancer drugs include Palbociclib (PD-0332991), Ribociclib (LEE011) and Abemaciclib (LY2835219).
  • Palbociclib PD-0332991
  • Ribociclib LE011
  • Abemaciclib LY2835219
  • the single drugs that have been listed are still difficult to meet the clinical needs.
  • 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.
  • 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.
  • a pharmaceutical combination 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;
  • 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
  • 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,
  • 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,
  • 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,
  • 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.
  • the above-mentioned tartrate compound has crystal form A
  • the X-ray powder diffraction pattern of crystal form A has characteristic peaks with diffraction angles 2 ⁇ 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 2 ⁇ 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 2 ⁇ 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°.
  • 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.
  • first active ingredient and second active ingredient are administered simultaneously, separately or sequentially.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • ER+ estrogen receptor positive
  • HER2- human epidermal growth factor receptor 2 negative
  • kits 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.
  • 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.
  • ER+ estrogen receptor positive
  • HER2- human epidermal growth factor receptor 2 negative
  • 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).
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • treatment includes treatment that alleviates, alleviates or reduces at least one symptom of an individual or affects a delay in disease progression.
  • treatment may be to eliminate one or several symptoms of the disorder or to completely eradicate the disorder (eg, cancer).
  • 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.
  • 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.
  • 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.
  • 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.).
  • “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.
  • 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.
  • 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.
  • 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.
  • 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;
  • 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
  • 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 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.
  • 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.
  • 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:
  • 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.
  • ER+ estrogen receptor positive
  • HER2- human epidermal growth factor receptor 2-negative
  • the comprehensive effect is more stable.
  • 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.
  • 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.
  • the above-mentioned tartrate compound has crystal form A, and the X-ray powder diffraction pattern of crystal form A has a diffraction angle 2 ⁇ of 4.4 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of crystal form A has diffraction angles 2 ⁇ 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 2 ⁇ 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • diluents such as water, various organic solvents, excipients, etc.
  • fillers such as starch, sucrose, etc.
  • Binders such as cellulose derivatives, alginates, gelatin, and polyvinylpyr
  • compositions suitable for the desired dosage form and desired mode of administration are preferably used.
  • 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. .
  • 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.
  • ER+ estrogen receptor positive
  • HER2- human epidermal growth factor receptor 2 negative
  • kits 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).
  • 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.
  • a method for treating breast cancer using a drug combination is provided.
  • 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.
  • 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.
  • 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 ⁇ -estradiol to the medium to maximize the effect of the combination.
  • T-47D cells were cultured in DMEM medium without phenol red, and 10 ⁇ g/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 ⁇ -estradiol medium, counted, and prepared into a cell suspension of appropriate density. The cell suspension was added to a 96-well plate, 100 ⁇ L 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.
  • test compound fulvestrant concentration 150 nM.
  • Combination concentration 150nM fulvestrant+60nM first active ingredient.
  • CDI coefficient of drug in interaction
  • 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.
  • mice were subcutaneously inoculated with 17 ⁇ -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%).
  • 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 ⁇ T/ ⁇ C(%) (Ti-T0)/(Vi-V0) ⁇ 100.
  • 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.
  • 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 ⁇ T/ ⁇ C (%) 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.
  • c.p value is a comparative analysis of tumor volume between the treatment group and the solvent control group.
  • 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).
  • T47D cells were cultured in phenol red-free RPMI-1640 medium, and 10 ⁇ g/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.
  • 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.
  • 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.
  • Structural formula I-8 is a compound
  • MCF-7 cells were cultured in phenol red-free RPMI-1640 medium, and 10 ⁇ g/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.
  • 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.
  • 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 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.
  • 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;
  • 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.
  • 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.
  • 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;
  • 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.
  • drug A capsules were administered in a single dose, and after 7 days of elution, continuous administration was performed once a day.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Une combinaison pharmaceutique, un kit la contenant et son utilisation dans la préparation d'un médicament pour traiter le cancer du sein sont divulgués. La combinaison pharmaceutique comprend un premier principe actif et un second principe actif, le premier principe actif étant l'un quelconque parmi un composé ayant une structure représentée par la formule développée I, un stéréoisomère associé, un tautomère associé, un polymorphe associé, un solvate associé et un sel pharmaceutiquement acceptable associé ; et le second principe ingrédient actif est un antagoniste du récepteur des œstrogènes ou un inhibiteur de l'aromatase. Le premier principe actif et le second principe actif susmentionnés sont co-administrés en combinaison, l'activité de co-traitement obtenue présente un effet d'amélioration important par rapport à l'administration séparée de chaque principe actif, et l'effet synergique est obtenu.
PCT/CN2022/082747 2021-03-24 2022-03-24 Combinaison pharmaceutique, kit la contenant et son utilisation WO2022199656A1 (fr)

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