Pharmaceutical combination product and combination therapy

Abstract

Relates to a pharmaceutical combination product and a combination therapy thereof. In particular, a pharmaceutical combination comprising a first pharmaceutically active ingredient and a second pharmaceutically active ingredient is provided. Also provided are combination therapies for treating abnormal cell growth, such as cancer, comprising administering a pharmaceutical combination to a subject in need thereof.

Description

Drug combination products and combination therapies

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese patent application number CN202210872332.3 filed on July 20, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to a pharmaceutical combination product comprising a first pharmaceutically active ingredient and a second pharmaceutically active ingredient. The present invention also relates to a combination therapy for treating abnormal cell growth (e.g., cancer) comprising administering to a subject, either separately or simultaneously, the first pharmaceutically active ingredient and the second pharmaceutically active ingredient. Background Art

[0004] Cancer is one of the most serious threats to human life and health today, accounting for seven million cancer deaths worldwide each year. Currently, four main approaches are used to treat cancer: surgery, medication, radiotherapy, and immunotherapy; adjuvant therapies are also available. Among these various treatments, targeted drug therapy is the most promising and promising cancer treatment, and researchers are constantly searching for effective targeted drug therapies.

[0005] CN112585129 discloses a novel heterocyclic compound that can be used to inhibit KRASG12C mutant proteins in cells. The patent application also discloses the use of the heterocyclic compound in combination with a platinum-based drug (e.g., cisplatin or carboplatin), a SHP2 inhibitor (e.g., RMC-4550, RMC-4630, TNO155), and / or a MEK inhibitor (e.g., trametinib) to reduce tumor volume.

[0006] WO2010058032 discloses a pyrimidine compound that can be used as a FAK inhibitor to prevent and / or treat diseases characterized by excessive or abnormal cell proliferation. The pyrimidine compound includes the BI853520 / IN10018 compound used in clinical trials.

[0007] WO2021155764 discloses the combination of BI853520 compound and chemotherapy drugs, which include pegylated liposomal doxorubicin (PLD), taxane or cisplatin.

[0008] WO2021154929 discloses a combination therapy for treating abnormal cell growth. The results of this patent application show that a triple combination of a RAF / MEK inhibitor (such as VS-6766), a FAK inhibitor (such as defatinib), and a KRASG12C inhibitor (such as AMG-510) produces tumor regression in mice.

[0009] Although cancer patients have many treatment options, there is still a need for effective and safe therapeutic agents, and a need for new combination therapies that can be used for effective long-term cancer treatment. Combinations of effective cancer therapeutics can more effectively prevent and / or treat diseases associated with abnormal cell growth (e.g., cancer).

[0010] Summary of the Invention

[0011] In one aspect, the present invention provides a pharmaceutical combination product comprising a first pharmaceutical active ingredient and a second pharmaceutical active ingredient, wherein the first pharmaceutical active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0012] and wherein the second pharmaceutically active ingredient is a compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0013] In some embodiments, the first pharmaceutically active ingredient is a compound of formula (I). In some embodiments, the second pharmaceutically active ingredient is a pharmaceutically acceptable salt of a compound of formula (II).

[0014] In some embodiments, the first pharmaceutically active ingredient is the free base of a compound of formula (I). In some embodiments, the second pharmaceutically active ingredient is a pharmaceutically acceptable salt (e.g., maleate, malate, or tartrate) of a compound of formula (II).

[0015] In some embodiments, the weight ratio of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient is from about 50:1 to about 1:50, preferably from about 25:1 to about 1:25, and more preferably from about 15:1 to about 1:15.

[0016] In some embodiments, the first pharmaceutically active ingredient and the second pharmaceutically active ingredient can be administered separately, in no particular order. In some embodiments, the first pharmaceutically active ingredient and the second pharmaceutically active ingredient can be administered simultaneously.

[0017] In some embodiments, the pharmaceutical combination product is in the form of a pharmaceutical composition. In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0018] In another aspect, the present invention provides a use of a pharmaceutical combination according to the present invention in the preparation of a medicament for treating abnormal cell growth (eg cancer).

[0019] In some embodiments, the abnormal cell growth comprises a solid tumor, a soft tissue tumor, a metastasis, or a non-solid cancer. In some embodiments, the abnormal cell growth is a KRASG12C mutation-positive locally advanced or metastatic solid tumor, such as non-small cell lung cancer, colorectal cancer, or bile duct cancer.

[0020] In yet another aspect, the present invention provides a method for treating a disease associated with abnormal cell growth, comprising administering the pharmaceutical combination according to the present invention to a subject in need thereof.

[0021] In some embodiments, the first pharmaceutical active ingredient is administered orally. In some embodiments, the first pharmaceutical active ingredient is administered at least once a day, for example, the first pharmaceutical active ingredient is administered once a day, or the first pharmaceutical active ingredient is administered two or more times a day. In some embodiments, the first pharmaceutical active ingredient is administered in a single dose of about 1 mg to about 5000 mg.

[0022] In some embodiments, the second pharmaceutical active ingredient is administered orally. In some embodiments, the second pharmaceutical active ingredient is administered at least once a day, for example, the second pharmaceutical active ingredient is administered once a day, or the second pharmaceutical active ingredient is administered two or more times a day. In some embodiments, the second pharmaceutical active ingredient is administered in a single dose of about 1 mg to about 5000 mg.

[0023] In some embodiments, the abnormal cell growth-related disease comprises a solid tumor, a soft tissue tumor, a metastasis, or a non-solid cancer. In some embodiments, the administering comprises administering the first pharmaceutically active ingredient and the second pharmaceutically active ingredient separately or simultaneously.

[0024] Surprisingly, it was found that the first pharmaceutically active ingredient and the second pharmaceutically active ingredient according to the present invention can synergistically achieve overall tumor remission and increase the median survival percentage in preclinical models.

[0025] In patient-derived tumor xenografts, a drug combination product comprising a first active ingredient and a second active ingredient can produce synergistic anti-tumor activity compared to a single active ingredient. Experimental data show that for locally advanced or metastatic solid tumors (such as non-small cell lung cancer, colorectal cancer, bile duct cancer, etc.) that are positive for KRASG12C mutations, the combination of the first active ingredient and the second active ingredient can achieve a greater and more sustained response. Importantly, the first active ingredient and the second active ingredient can only reduce the tumor growth rate when used as a single active ingredient, while the same dose can achieve a reduction in tumor volume when the two active ingredients are combined, thereby alleviating tumor growth overall. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 shows the changes in body weight of mice in each drug-dosing group in the human non-small cell lung cancer cell NCI-H358 xenograft model;

[0027] Figure 2 shows the weight change rate of mice in each drug-dosing group in the human non-small cell lung cancer cell NCI-H358 xenograft model;

[0028] Figure 3 shows the changes in tumor volume of each drug-dosing group in the human non-small cell lung cancer cell NCI-H358 xenograft model;

[0029] FIG4 shows the tumor volume change rate of each drug-dosing group in the human non-small cell lung cancer cell NCI-H358 xenograft model. DETAILED DESCRIPTION

[0030] First active pharmaceutical ingredient

[0031] The present invention provides a pharmaceutical combination product comprising a first pharmaceutical active ingredient. In some embodiments, the first pharmaceutical active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0032] In some embodiments, the first active pharmaceutical ingredient is a compound of formula (I). The compound of formula (I) described herein is a known compound, all of which, in their known forms and compositions, can be used in the pharmaceutical combination products provided by the present invention. For example, the preparation and confirmation of the compound of formula (I) have been described in PCT International Applications WO2020233592, WO2021121330, and WO2021120045.

[0033] In some embodiments, the first pharmaceutically active ingredient is a pharmaceutically acceptable salt of a compound of formula (I), including but not limited to hydrochloride, phosphate, hydrogen phosphate, sulfate, bisulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or laurylsulfonate, etc.

[0034] In some embodiments, the first pharmaceutically active ingredient may be in amorphous form, crystalline form, and combinations thereof.

[0035] In other embodiments, the first pharmaceutically active ingredient may also be other pharmaceutically active ingredients with the same or similar pharmacological effects as the compound of formula (I), such as ARS-853, ARS-1620, ARS-3248, LY3499446 and MRTX849 known in the prior art, or pharmaceutically acceptable salts thereof.

[0036] Second active pharmaceutical ingredient

[0037] The present invention provides a pharmaceutical combination product comprising a second pharmaceutically active ingredient. In some embodiments, the second pharmaceutically active ingredient is a compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0038] In some embodiments, the second pharmaceutically active ingredient is a compound of formula (II). The compound of formula (II) described herein is a known compound, and all known forms and compositions thereof can be used in the pharmaceutical combination products provided by the present invention. For example, the preparation and confirmation of the compound of formula (II) have been described in WO2010058032.

[0039] In some embodiments, the second pharmaceutically active ingredient is a pharmaceutically acceptable salt of a compound of formula (I), including but not limited to hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or laurylsulfonate, etc. In some embodiments, the pharmaceutically acceptable salt is maleate, malate or tartrate, and further, preferably tartrate.

[0040] The pharmaceutically acceptable salts can be prepared by dissolving the free base in a suitable solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art can determine various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable acid addition salts without undue experimentation.

[0041] In some embodiments, the second pharmaceutically active ingredient may be in amorphous form, crystalline form, and combinations thereof.

[0042] In other embodiments, the second pharmaceutically active ingredient may also be other pharmaceutically active ingredients with the same or similar pharmacological effects as the compound of formula (II), such as defactinib, TAE226, GSK2256098, PF-03814735, BI-4464, VS-4718 and APG-2449 known in the prior art, or pharmaceutically acceptable salts thereof.

[0043] Drug combination products

[0044] The pharmaceutical combination according to the present invention comprises a first pharmaceutically active ingredient and a second pharmaceutically active ingredient.

[0045] The pharmaceutical combination products according to the present invention may include all suitable isotopic variants of the first and / or second pharmaceutically active ingredients. An isotopic variant of a compound of the present invention is defined as a compound of the present invention in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example, 2 H (deuterium), 3 H (tritium), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 P. 33 P. 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 129 I and 131 I. Certain isotopic variations of the compounds of the present invention, for example, wherein one or more radioactive isotopes (e.g., 3 H or 14 C) can be used for drug and / or substrate tissue distribution studies. Tritium and carbon-14 (i.e., 14C) isotopes, due to their ease of preparation and detectability. Further, substitution with isotopes such as deuterium can provide definite therapeutic advantages resulting from better metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some cases. Isotopic variants of the compounds of the invention can generally be prepared using conventional methods known to those skilled in the art, for example, using the illustrative methods or the preparation methods described in the Examples below, using suitable isotopic variants of suitable reagents.

[0046] The pharmaceutical combination according to the present invention may comprise all possible stereoisomers of the first and / or second pharmaceutically active ingredient as single stereoisomers or any mixture of said stereoisomers in any ratio. The separation of single stereoisomers, such as single enantiomers or single diastereomers, of the compounds of the present invention may be achieved by any suitable prior art method, such as chromatography, in particular, for example, chiral chromatography.

[0047] The pharmaceutical combination according to the present invention may comprise all possible tautomers of the first and / or second pharmaceutically active ingredient in the form of single tautomers or in any mixture of said tautomers in any ratio.

[0048] Furthermore, the pharmaceutical combination according to the present invention may comprise all possible crystalline forms or polymorphs of the first and / or second pharmaceutically active ingredient, either as a single polymorph or as a mixture of more than one polymorph in any ratio.

[0049] In some embodiments, the pharmaceutical combination product according to the present invention further comprises an optional third active pharmaceutical ingredient selected from HDAC inhibitors, CDK4 / 6 inhibitors, ALK inhibitors, JAK2 inhibitors, Bcl-2 inhibitors, Hsp90 inhibitors, glucocorticoids, vinca alkaloids, antimetabolites, DNA damaging agents, lenalidomide, rituximab, PKC interferon, Lyn / Fyn inhibitors, Syk inhibitors, PI3K inhibitors, PKCβ inhibitors, IKK inhibitors, 20s proteasome, IRF-4, IRAK4 antibodies, CXCR4 antibodies, CXCR5 antibodies, GLS antibodies, PLK antibodies, CD20 antibodies, TopoII inhibitors, DNA methyltransferase inhibitors, Ras / MAPK inhibitors or FGFR1 inhibitors; the HDAC inhibitor is preferably panobinostat lactate, belinostat, cedamide, romidepsin, vorinostat, besanostat or entinostat, and the CDK4 / 6 inhibitor is preferably palbociclib, blinatumomab, tiagabine Hydrochloride or Itolizumab, the Bcl-2 inhibitor is preferably Venetoclax, Amplisen sodium, ABT-737 or HA14-1, the Hsp90 inhibitor is preferably Sebelipase alfa or Retaspimycin Hydrochloride, the JAK2 inhibitor is preferably Tofacitinib Citrate, Ruxolitinib Phosphate, Lestaurtinib, Momelotinib Dihydrochloride, Peficitinib or Filgotinib, the PKC interferon is preferably teprenone, Truheal, HO / 03 / 03, Sotrastaurin, Enzastaurin or GF109203X, the ALK inhibitor is preferably AlectinibHdrochloride, Ceritinib, Crizotinib, Bendamustine, Carmustine, Lomustine, Nitrogen Mustard Hydrochloride or NVP-TAE684, the PI3K inhibitor is preferably GS-1101, IPI-145, BKM120, BEZ235, GDC-0941, AMG319, CAL-101 or A66, the IKK inhibitor is preferably auranofin, BAY86-9766 or RDEA-119.

[0050] In some embodiments, the pharmaceutical combination products according to the present invention further comprise one or more pharmaceutically acceptable excipients, diluents or carriers.

[0051] In some embodiments, the pharmaceutical composition product according to the present invention can include the first independent pharmaceutical active ingredient and the second independent pharmaceutical active ingredient.For example, the pharmaceutical combination product according to the present invention can include the first pharmaceutical active ingredient and the second pharmaceutical active ingredient that are formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection and concentrated solutions for injection), suppositories, inhalants or sprays respectively.Alternatively, The pharmaceutical composition product according to the present invention can be a pharmaceutical composition comprising the first pharmaceutical active ingredient and the second pharmaceutical active ingredient.For example, the first pharmaceutical active ingredient and the second pharmaceutical active ingredient are formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection and concentrated solutions for injection), suppositories, inhalants or sprays together.

[0052] The first and / or second pharmaceutically active ingredient according to the present invention can be tableted using a combination of conventional tablet bases such as lactose, sucrose, and corn starch with the following components: a binder such as gum arabic, corn starch, or gelatin; a disintegrant such as potato starch, alginic acid, corn starch, and guar gum, tragacanth gum, or gum arabic to help the tablet disintegrate and dissolve after application; a lubricant such as talc, stearic acid or magnesium stearate, calcium stearate, or zinc stearate to improve tablet granule flow and prevent adhesion of tablet material to tablet molds and punch surfaces; and dyes, colorants, and flavorings such as peppermint, wintergreen oil, or cherry flavor to enhance the aesthetic quality of the tablet and make it more acceptable to patients. Suitable excipients for oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols (e.g., ethanol, benzyl alcohol, and polyvinyl alcohols), with or without the addition of pharmaceutically acceptable surfactants, suspending agents, or emulsifiers. Various other materials may be present as coatings or otherwise modify the physical form of the dosage unit. For example, tablets, pills, or capsules can be coated with shellac, sugar, or both. Dispersible powders and granules are suitable for preparing aqueous suspensions. They provide the active ingredient in admixture with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those mentioned above. Additional excipients, such as those sweeteners, flavorings, and coloring agents mentioned above, may also be present.

[0053] The pharmaceutical combination product according to the present invention also includes a commercial package comprising instructions for the simultaneous, separate or sequential administration of the pharmaceutically active ingredients according to the present invention to a patient in need thereof.

[0054] Combination therapy

[0055] In some embodiments, the dosage regimen of the first pharmaceutically active ingredient and the second pharmaceutically active ingredient in a pharmaceutical combination according to the present invention can be adjusted to provide the optimal desired response, eg, maximum therapeutic response and / or minimum adverse effects.

[0056] In some embodiments, the single dose of the first pharmaceutical active ingredient can range from 1 to 5000 mg. In some embodiments, the administration frequency of the first pharmaceutical active ingredient can be 5 times a day, 4 times a day, 3 times a day, 2 times a day, once a day, once every 2 days, etc.

[0057] In some embodiments, the single dose of the second pharmaceutical active ingredient can range from 1 to 5000 mg. In some embodiments, the second pharmaceutical active ingredient can be administered 5 times a day, 4 times a day, 3 times a day, 2 times a day, once a day, once every 2 days, etc.

[0058] In some embodiments, the weight ratio of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient in the pharmaceutical combination according to the present invention may be from about 50:1 to about 1:50, preferably from about 25:1 to about 1:25, and more preferably from about 15:1 to about 1:15. In some embodiments, the weight ratio can be about 14:1 to about 1:14, about 13:1 to about 1:13, about 12:1 to about 1:12, about 11:1 to about 1:11, about 10:1 to about 1:10, about 9:1 to about 1:9, about 8:1 to about 1:8, about 7:1 to about 1:7, about 6:1 to about 1:6, about 5:1 to about 1:5, about 4:1 to about 1:4, about 3:1 to about 1:3, about 2:1 to about 1:2, or about 1:1, for example, the weight ratio is about 14:1, about 12:1, about 10:1, about 8:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:4, or about 1:5.

[0059] The dosage is within the level of ordinary technicians in this field, and the single dose or daily dose of the drug can vary depending on various factors such as the degree of disease onset, onset time, age, health status and complications of the subject to be administered.

[0060] The pharmaceutical combination products according to the present invention may be administered orally, alone or in combination. Alternatively, the pharmaceutical combination products according to the present invention may be administered parenterally, i.e., subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly or intraperitoneally, as injectable doses of the compounds, preferably in a physiologically acceptable diluent and a pharmaceutical carrier, which may be a sterile liquid or a mixture of liquids, such as water, saline, aqueous dextrose and related sugar solutions, alcohols such as ethanol, isopropanol or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, oils, fatty acids, fatty acid esters or fatty acid glycerides or acetylated fatty acid glycerides, with or without the addition of pharmaceutically acceptable surfactants such as soaps or detergents, suspending agents such as pectin, carbomer, methylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose, or emulsifiers and other pharmaceutical adjuvants.

[0061] In the case of once daily administration of a compound of formula (I) and a compound of formula (II), this can be achieved by administering a fixed dose combination containing a combination of a compound of formula (I) and a compound of formula (II).

[0062] If desired, oral dosage forms can be presented in a package or dispenser device, such as an FDA-approved kit, which can contain one or more unit dosage forms of the active ingredient. For example, the package can comprise metal or plastic foil, such as a blister pack. The package or dispenser device can be accompanied by instructions for administration.

[0063] Therapeutic uses

[0064] The present invention provides combination therapies for treating abnormal cell growth comprising administering to a subject in need thereof a pharmaceutical combination according to the present invention.

[0065] In some embodiments, the pharmaceutical composition product of the present invention comprises a therapeutically effective amount of a first pharmaceutically active ingredient and a therapeutically effective amount of a second pharmaceutically active ingredient; in some embodiments, the pharmaceutical composition product of the present invention may comprise a therapeutically effective amount of a separate first pharmaceutically active ingredient and a therapeutically effective amount of a separate second pharmaceutically active ingredient.

[0066] In some embodiments, the abnormal cell growth, such as cancer, includes, but is not limited to, solid tumors, soft tissue tumors, metastases or non-solid cancers. In some embodiments, cancer is a solid tumor. In some embodiments, solid tumors are malignant tumors (e.g., sarcomas, adenocarcinomas and carcinomas) of organs (e.g., lung, breast, lymph, gastrointestinal tract (e.g., colon) and urogenital (e.g., kidney, urothelial or testicular tumors), pharynx, prostate and ovary). In some embodiments, the cancer is mesothelioma; neurofibromatosis; for example, neurofibromatosis type 2, neurofibromatosis type 1; renal cancer; lung cancer, non-small cell lung cancer; liver cancer; thyroid cancer; ovarian cancer; breast cancer; nervous system tumors; schwannomas; meningiomas; schwannomatosis (schwannomatosis); acoustic neuroma; adenoid cystic carcinoma; ependymomas; or ependymal tumors. In some embodiments, the cancer is mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma), breast cancer (e.g., triple-negative breast cancer), ovarian cancer (e.g., advanced ovarian cancer), lung cancer (e.g., non-small cell lung cancer (NSCLC), e.g., KRAS mutated NSCLC)) or a non-hematological malignancy. In some embodiments, the cancer is non-small cell lung cancer (NSCLC), e.g., KRAS mutated NSCLC). In some embodiments, the cancer is melanoma (e.g., locally advanced or metastatic malignant cutaneous melanoma with N-Ras mutation), colorectal cancer (e.g., metastatic colorectal cancer), leukemia (e.g., acute myeloid leukemia), adenocarcinoma (e.g., pancreatic adenocarcinoma) or a solid tumor (e.g., locally advanced solid tumor, metastatic solid tumor, hepatocellular carcinoma).

[0067] The cancer may include a cancer characterized as comprising cancer stem cells, cancer-associated mesenchymal cells, or tumor-initiating cancer cells. The cancer may include a cancer that has been characterized as being rich in cancer stem cells, cancer-associated mesenchymal cells, or tumor-initiating cancer cells (e.g., a tumor rich in cells undergoing epithelial-mesenchymal transition or a metastatic tumor).

[0068] A tumor can be a primary tumor, i.e., located at the anatomical site where the tumor initially grew. The cancer can also be metastatic, i.e., appear at at least a second anatomical site other than the anatomical site where the tumor initially grew. The cancer can be a recurrent cancer, i.e., a cancer that returns after treatment and after a period of time when the cancer cannot be detected. Recurrent cancer can be anatomically localized to the primary tumor, e.g., anatomically near the primary tumor; in the region of the primary tumor, e.g., a lymph node located near the primary tumor; or distal to the primary tumor, e.g., in an area anatomically distant from the primary tumor.

[0069] Cancers may also include lung adenocarcinoma, colorectal cancer (CRC), endometrioid carcinoma, bladder urothelial carcinoma, invasive lobular carcinoma of the breast, cervical squamous cell carcinoma, skin melanoma, cervical adenocarcinoma, hepatocellular carcinoma, pancreatic cancer, biphasic pleural mesothelioma, renal clear cell carcinoma, renal clear cell carcinoma, gastric adenocarcinoma, tubular gastric adenocarcinoma, uterine carcinosarcoma or uterine malignant mixed Müllerian tumor, or other cancers.

[0070] Other cancers include, but are not limited to, uveal melanoma, brain, abdomen, esophagus, gastrointestinal tract, glioma, liver, tongue, neuroblastoma, osteosarcoma, ovary, retinoblastoma, Wilms tumor, multiple myeloma, skin, lymphoma, blood and bone marrow cancer (such as advanced hematologic malignancies, leukemias, such as acute myeloid leukemia (such as primary or secondary)), acute lymphoblastic leukemia, acute lymphoblastic leukemia, T-cell leukemia, hematologic malignancies, advanced myeloproliferative diseases, myelodysplastic syndrome, relapsed or refractory multiple myeloma, advanced myeloproliferative diseases), retina, bladder, cervix, kidney, endometrium, meningioma, lymphoma, skin, uterus, lung, non-small cell lung, nasopharyngeal carcinoma, neuroblastoma, solid tumors, hematologic malignancies, squamous cell carcinoma, testis, thyroid, mesothelioma, vulva, sarcoma, Intestinal, oral, endocrine, salivary, spermatocytic seminoma, sporadic medullary thyroid carcinoma, non-proliferative testicular cells, cancers associated with malignant mast cells, non-Hodgkin lymphoma, and diffuse large B-cell lymphoma.

[0071] definition

[0072] As used herein, the term "about" to modify the amount related to the present invention refers to the numerical quantity changes that may occur, for example, through routine testing and processing; through unintentional errors in such testing and processing; through differences in the manufacture, source or purity of the components used in the present invention, etc. As used herein, "about" a particular value also includes that particular value, for example, about 10% includes 10%. Whether or not modified by the term "about", the claims include equivalents of the listed quantities. In one embodiment, the term "about" means within 20%, within 10% or within 5% of the reported value.

[0073] As used herein, the term "treatment" refers to eliminating, alleviating or alleviating a disease or condition and / or the symptoms associated therewith. Although not excluded, treating a disease or condition does not require completely eliminating the disease, condition or the symptoms associated therewith. As used herein, the term "treatment" may include "preventative treatment," which refers to reducing the likelihood of further development of a disease or condition or a previously controlled recurrence for a subject who is not ill but who is at risk or prone to developing the disease or condition again or who has a recurring disease or condition. The term "treatment" and synonyms are understood to be pharmaceutical compositions according to the present invention administered to a subject in need of such treatment in an amount effective for treatment.

[0074] As used herein, the term "therapeutically effective amount" refers to that amount of an active compound or agent that elicits the biological or medicinal response in a tissue system, animal, or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician, including alleviation or reversal of the symptoms of the disease or condition being treated. As used herein, the term "therapeutically effective amount" may be based on a single active pharmaceutical ingredient or a combination of two active pharmaceutical ingredients.

[0075] Example

[0076] Source and storage of compound raw materials

[0077] The experimental methods in the following examples without specifying specific conditions can be carried out according to conventional conditions of such reactions or according to conditions recommended by the manufacturers.

[0078] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0079] The first active pharmaceutical ingredient (API) is a compound of formula (I), which is prepared according to the method disclosed in patent application WO2020233592, WO2021121330 or WO2021120045, has a purity greater than 99%, and is stored at room temperature in the dark.

[0080] The second active pharmaceutical ingredient (API) is a tartrate salt of a compound of formula (II), which is prepared according to the method disclosed in patent application WO2010058032. The tartrate salt of the compound of formula (II) is prepared according to the conventional operation of preparing acid addition salts from basic compounds. The purity of the tartrate salt of the compound of formula (II) is greater than 97% and is stored at 4°C in the dark.

[0081] experimental animals

[0082] Example 1

[0083] 1. Animal husbandry

[0084] Upon arrival, the animals were housed in the experimental environment for 3-7 days before the experiment began. The animals were housed in an SPF-grade animal room in cages with an independent ventilation system (IVC) (5 animals per cage). The animal information card for each cage indicated the number of animals in the cage, sex, strain, date of receipt, dosing regimen, experiment number, group, and start date of the experiment. All cages, bedding, and drinking water were sterilized before use. Cages, feed, and drinking water were changed twice a week. The housing environment and lighting conditions were as follows:

[0085] Temperature: 20-26 degrees Celsius.

[0086] Humidity: 32-70%.

[0087] Cages: Made of polycarbonate, 300mm x 180mm x 150mm. Bedding is corn cobs, changed twice a week.

[0088] Food: The experimental animals had free access to food (irradiation sterilized, dry pelleted food) throughout the experimental period.

[0089] Drinking water: Experimental animals can drink sterile water freely.

[0090] 2. Animal Grouping and Dosing

[0091] The mice were divided into 4 groups, 8 in each group, and medicated according to the administration method in Table a.

[0092] Table a: Animal groups and dosing regimens for in vivo efficacy studies

[0093] 3. Preparation of blank solution and compound solution

[0094] A blank control group was prepared according to the method and formula described in Table 1, and the first API and the second API were prepared into solutions according to the following methods and formulas, respectively.

[0095] Table 1: Blank solution and compound solution preparation and storage conditions

[0096] 4. Cell culture

[0097] Human non-small cell lung cancer cells NCI-H358 ( CRL-5807™ cells were cultured in a monolayer in RPMI-1640 basal medium supplemented with 10% fetal bovine serum, 100 units / mL penicillin, and 100 μg / mL streptomycin at 37°C in a 5% CO2 incubator. Twice weekly, cells were routinely digested with trypsin and passaged. When cell saturation reached 80%-90% and the desired number of cells was reached, cells were harvested, counted, and plated.

[0098] 5. Tumor Cell Inoculation

[0099] Containing 1×10 7 100 μL PBS of NCI-H358 cells was subcutaneously inoculated under the right forelimb scapula of each mouse. On the 28th day after cell inoculation, the mice were divided into groups for drug administration. The average tumor volume in each group was 246.38 mm 3 .

[0100] 6. Daily observation of experimental animals

[0101] Animal health and mortality were monitored daily. Routine examinations included observation of tumor growth and the effects of drug treatment on the animals' daily behaviors, such as activity, food and water intake (visual observation only), weight change (measured twice weekly), physical signs, or other abnormalities. Group deaths and adverse reactions were recorded based on the number of animals in each group.

[0102] 7. Tumor Measurement and Experimental Indicators

[0103] The experimental indicator is to examine whether tumor growth is inhibited, delayed or cured.

[0104] Tumor diameters were measured twice a week using a vernier caliper.

[0105] The formula for calculating tumor volume is: V = 0.5a × b 2 , a and b represent the long diameter and short diameter of the tumor, respectively.

[0106] The anti-tumor efficacy of the compound was evaluated by TGI (%), which reflects the tumor growth inhibition rate.

[0107] Calculation of TGI (%): TGI (%) = [1-(average tumor volume of a treatment group at the end of drug administration - average tumor volume of the treatment group at the beginning of drug administration) / (average tumor volume of the solvent control group at the end of treatment - average tumor volume of the solvent control group at the beginning of treatment)] × 100%.

[0108] The TGI values ​​have the following meanings:

[0109] a) TGI>100%, indicating overall tumor remission;

[0110] b) TGI = 100%, indicating tumor growth arrest;

[0111] c) 100%>TGI, indicating that the tumor growth rate is reduced.

[0112] 8. Experimental Results

[0113] 8.1 Weight

[0114] Figures 1 and 2 show the body weight changes and rates of change in tumor-bearing mice from different groups. In these figures, relative body weight changes are calculated based on the animals' weight at the start of dosing. Data points represent the mean percentage change in body weight within each group. Error bars represent the standard error of the mean (SEM).

[0115] 8.2 Tumor Growth Volume

[0116] The tumor growth volumes of animals in different groups at different time periods are shown in Table 2 .

[0117] Table 2. Tumor volume of each group at different time periods

[0118] 8.3 Tumor Growth Inhibition Rate

[0119] During the administration period, the animals could tolerate the test drugs, so the tumor growth inhibition rate (TGI%) and p value were calculated based on the data on the last day (day 28), see Table 3.

[0120] Table 3: Evaluation of tumor size inhibition

[0121] Remark:

[0122] a. Mean ± standard deviation

[0123] The bp value was calculated based on the relative tumor volume of each mouse in different groups. The P value was obtained by comparing the control group and each drug-treated group using the one-way ANOVA method. P < 0.01 statistically indicated that there was a significant difference between each group and the control group, and P > 0.05 statistically indicated that there was no significant difference between each group and the control group.

[0124] The cP value was calculated using a one-way ANOVA method by comparing the first and second API combined dose groups with the single-dose groups. P < 0.01 indicated a significant difference between each group and the control group.

[0125] QD means once a day.

[0126] 8.4 Tumor Weight

[0127] The tumor weights of animals in different groups are shown in Table 4.

[0128] Table 4: Evaluation of tumor weight inhibition

[0129] Remark:

[0130] a. Mean ± standard deviation

[0131] The bP value was obtained by comparing the control group and each drug-treated group using the T-test method. P<0.01 in statistical analysis indicated that there was a significant difference between each group and the control group.

[0132] The cP value was obtained by comparing the (first API + second API) combination group and the two single-drug groups using the T-test method. P<0.01 in statistical analysis indicated that there was a significant difference between each single-drug group and the combination group.

[0133] QD means once a day.

[0134] In this example, the efficacy of the first and second APIs as single agents and in combination was evaluated in subcutaneous xenografts of human non-small cell lung cancer cells (NCI-H358). The changes in animal body weight at different time points after administration are shown in Figures 1 and 2.

[0135] After administration, the changes in tumor volume and weight of each group at different time points are shown in Table 2, Table 3, Table 4 and Figures 3 and 4. On the 27th day after administration, the tumor volume of the blank group reached 1255.3 cubic millimeters. In the monotherapy group, the tumor growth inhibition rates TGI (%) of the first API and the second API were 84.95% and 60.05%, respectively. In contrast, the tumor growth inhibition rate TGI (%) of the combination group of the first API compound and the second API compound reached 118.85%. The TGI value shows that the efficacy of the combination group of the first API compound and the second API compound is significantly better than that of each single-dose group (p<0.01), achieving an overall tumor remission effect.

[0136] It should be understood that the above description may describe one or more, but not all, exemplary embodiments of the present invention, and the scope of the present invention should not be limited by any of the above exemplary embodiments.

[0137] Where aspects of the invention are described as "comprising" or "including" features, "consisting of" or "consisting essentially of" embodiments are also contemplated.

[0138] All of the various aspects, embodiments, options, and numerical ranges described herein can be combined in any and all variations.

[0139] The foregoing description of specific embodiments will fully reveal the general nature of the invention so that others can readily modify and / or adapt various applications such as these specific embodiments by applying the knowledge of the art without undue experimentation without departing from the general concept of the invention. Therefore, based on the teachings and guidance set forth herein, such adaptations and modifications are also included in the meaning and range of equivalents of the disclosed embodiments. It should be understood that the wording or terminology herein is for the purpose of description and not limitation, and thus the terms or wording of this specification will be interpreted by the skilled person based on the teachings and guidance.

Claims

1. A pharmaceutical combination product comprising a first pharmaceutical active ingredient and a second pharmaceutical active ingredient, wherein the first pharmaceutical active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt thereof, and wherein the second pharmaceutically active ingredient is a compound of formula (II) or a pharmaceutically acceptable salt thereof, 2. The pharmaceutical combination product according to claim 1, wherein the first pharmaceutically active ingredient is a compound of formula (I), and wherein the second pharmaceutically active ingredient is a pharmaceutically acceptable salt of a compound of formula (II).

3. The pharmaceutical combination product according to any one of the preceding claims, wherein the weight ratio of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient is from about 50:1 to about 1:50, preferably from about 25:1 to about 1:25, and more preferably from about 15:1 to about 1:

15.

4. The pharmaceutical combination product according to any one of the preceding claims, wherein the first pharmaceutically active ingredient and the second pharmaceutically active ingredient are administered separately or simultaneously.

5. The pharmaceutical combination product according to any one of the preceding claims, wherein the pharmaceutical combination product is in the form of a pharmaceutical composition, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

6. Use of a pharmaceutical combination according to any one of the preceding claims in the preparation of a medicament for the treatment of abnormal cell growth, such as cancer.

7. Use according to the preceding claim, wherein the abnormal cell growth comprises a solid tumor, a soft tissue tumor, a metastasis or a non-solid cancer.

8. A method for treating a disease associated with abnormal cell growth, comprising administering a therapeutically effective amount of the pharmaceutical combination according to any one of claims 1 to 5 to a subject in need thereof.

9. The method of claim 8, wherein the first pharmaceutically active ingredient is administered orally; preferably, the first pharmaceutically active ingredient is administered at least once a day, for example, the first pharmaceutically active ingredient is administered once a day, or the first pharmaceutically active ingredient is administered two or more times a day; preferably, the first pharmaceutically active ingredient is administered in a single dose of about 1 mg to about 5000 mg; and / or wherein the second pharmaceutically active ingredient is administered orally; preferably, wherein the second pharmaceutically active ingredient is administered at least once a day, for example, the second pharmaceutically active ingredient is administered once a day, or, the second pharmaceutically active ingredient is administered two or more times a day; preferably, wherein the second pharmaceutically active ingredient is administered in a single dose of about 1 mg to about 5000 mg.

10. The method of claim 8, wherein the abnormal cell growth-related disease comprises a solid tumor, a soft tissue tumor, a metastasis, or a non-solid cancer, wherein the administering comprises administering the first pharmaceutically active ingredient and the second pharmaceutically active ingredient separately or simultaneously.

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