WO2024017316A1 - Produit pharmaceutique de polythérapie et polythérapie - Google Patents
Produit pharmaceutique de polythérapie et polythérapie Download PDFInfo
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- WO2024017316A1 WO2024017316A1 PCT/CN2023/108288 CN2023108288W WO2024017316A1 WO 2024017316 A1 WO2024017316 A1 WO 2024017316A1 CN 2023108288 W CN2023108288 W CN 2023108288W WO 2024017316 A1 WO2024017316 A1 WO 2024017316A1
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Classifications
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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
- A61K31/495—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
- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Definitions
- the present invention relates to a pharmaceutical combination product comprising a first pharmaceutically active ingredient and a second pharmaceutically active ingredient.
- the invention also relates to combination therapy for the treatment of abnormal cell growth, such as cancer, comprising administering to a subject a first pharmaceutically active ingredient and a second pharmaceutically active ingredient, either alone or simultaneously.
- Cancer is one of the most serious diseases threatening human life and health in contemporary times, with seven million cancer deaths worldwide every year.
- targeted drug therapy is the most promising and promising treatment for cancer, and people have been exploring effective targeted drug therapies.
- CN112585129 discloses a novel heterocyclic compound that can be used to inhibit KRASG12C mutant protein in cells.
- the patent application also discloses the combination of the heterocyclic compound with platinum-based drugs (such as cisplatin or carboplatin), SHP2 inhibitors (such as RMC-4550, RMC-4630, TNO155) and/or MEK inhibitors (such as trametidin Ni) used in combination to reduce tumor volume.
- platinum-based drugs such as cisplatin or carboplatin
- SHP2 inhibitors such as RMC-4550, RMC-4630, TNO155
- MEK inhibitors such as trametidin Ni
- 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 compounds include the BI853520/IN10018 compound used in clinical trials.
- WO2021155764 discloses the combination of BI853520 compounds and chemotherapy drugs, including pegylated liposomal doxorubicin (PLD), taxanes or cisplatin.
- WO2021154929 discloses combination therapies for the treatment of abnormal cell growth.
- the patent application concluded that a triple combination of a RAF/MEK inhibitor (e.g., VS-6766), a FAK inhibitor (e.g., defatinib), and a KRASG12C inhibitor (e.g., AMG-510) produced tumor regression in mice.
- a RAF/MEK inhibitor e.g., VS-6766
- FAK inhibitor e.g., defatinib
- KRASG12C inhibitor e.g., AMG-5
- Combinations of effective cancer therapeutic agents may more effectively prevent and/or treat diseases associated with abnormal cell growth (eg, cancer).
- the invention provides a pharmaceutical combination product comprising a first pharmaceutically active ingredient and a second pharmaceutically active ingredient, wherein the first pharmaceutically active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt thereof,
- said second pharmaceutically active ingredient is a compound of formula (II) or a pharmaceutically acceptable salt thereof
- the first pharmaceutically active ingredient is a compound of Formula (I).
- the second pharmaceutically active ingredient is a pharmaceutically acceptable salt of a compound of formula (II).
- the first pharmaceutically active ingredient is the free base of a compound of Formula (I).
- the second pharmaceutically active ingredient is a pharmaceutically acceptable salt (eg, maleate, malate, or tartrate) of a compound of formula (II).
- the weight ratio of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient is about 50:1 to about 1:50, preferably about 25:1 to about 1:25, and more preferably about 15:1 to approximately 1:15.
- first pharmaceutically active ingredient and the second pharmaceutically active ingredient may be administered separately, in no particular order. In some embodiments, the first pharmaceutically active ingredient and the second pharmaceutically active ingredient may be administered simultaneously.
- the pharmaceutical combination product is in the form of a pharmaceutical composition.
- the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
- the invention provides use of a pharmaceutical combination according to the invention for the preparation of a medicament for the treatment of abnormal cell growth, such as cancer.
- the abnormal cell growth includes solid tumors, soft tissue tumors, metastases, or non-solid cancers.
- the abnormal cell growth is a KRASG12C mutation-positive locally advanced or metastatic solid tumor, such as non-small cell lung cancer, colorectal cancer, cholangiocarcinoma.
- the present invention provides a method of treating a disease associated with abnormal cell growth, comprising administering a pharmaceutical combination according to the present invention to a subject in need thereof.
- the first pharmaceutically active ingredient is administered orally. In some embodiments, the first pharmaceutically active ingredient is administered at least once per day, for example, the first pharmaceutically active ingredient is administered once per day, or the first pharmaceutically active ingredient is administered two or more times per day. In some embodiments, the first pharmaceutically active ingredient is administered in a single dose of about 1 mg to about 5000 mg.
- the second pharmaceutically active ingredient is administered orally. In some embodiments, the second pharmaceutically active ingredient is administered at least once per day, for example, the second pharmaceutically active ingredient is administered once per day, or the second pharmaceutically active ingredient is administered two or more times per day. In some embodiments, the second pharmaceutically active ingredient is administered in a single dose of about 1 mg to about 5000 mg.
- the abnormal cell growth-associated disease includes solid tumors, soft tissue Tumor, metastasis or non-solid cancer.
- the administering includes administering the first pharmaceutically active ingredient and the second pharmaceutically active ingredient separately or simultaneously.
- the first pharmaceutically active ingredient and the second pharmaceutically active ingredient according to the present invention can synergistically achieve overall tumor response and increase the median survival percentage in preclinical models.
- pharmaceutical combination products containing a first pharmaceutically active ingredient and a second pharmaceutically active ingredient can produce synergistic antitumor activity compared to a single pharmaceutically active ingredient.
- Trial data show that for KRASG12C mutation-positive locally advanced or metastatic solid tumors (such as non-small cell lung cancer, colorectal cancer, cholangiocarcinoma, etc.), the combination of the first drug active ingredient and the second drug active ingredient can achieve larger and more precise tumors. Long lasting response.
- the first and second pharmaceutically active ingredients only reduce tumor growth rate when used as single pharmaceutically active ingredients, whereas the same dose when both pharmaceutically active ingredients are combined can achieve tumor volume reduction and thus overall response Tumor growth.
- Figure 1 shows the body weight changes of mice in each administration group of the human non-small cell lung cancer cell NCI-H358 xenograft model
- Figure 2 shows the body weight change rate of mice in each administration group of the human non-small cell lung cancer cell NCI-H358 xenograft model
- Figure 3 shows the changes in tumor volume in each administration group of the human non-small cell lung cancer cell NCI-H358 xenograft model
- Figure 4 shows the tumor volume change rate in each administration group of the human non-small cell lung cancer cell NCI-H358 xenograft model.
- the present invention provides a pharmaceutical combination product containing a first pharmaceutical active ingredient.
- the first pharmaceutically active ingredient is a compound of Formula (I) or a pharmaceutically acceptable salt thereof,
- the first pharmaceutically active ingredient is a compound of Formula (I).
- the compound of formula (I) described herein is a known compound, and all its known forms and components can be used in the pharmaceutical combination products provided by the present invention.
- the preparation and identification of compounds of formula (I) have been described in PCT International Applications WO2020233592, WO2021121330 and WO2021120045.
- 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, hydrogen sulfate, Sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate Acid salt, mesylate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate , succinate, gluconate, lactobiate or lauryl sulfonate, etc.
- 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, vale
- the first pharmaceutically active ingredient can be in amorphous, crystalline forms, and combinations thereof.
- the first pharmaceutical active ingredient can also be other pharmaceutical active ingredients that have the same or similar efficacy as the compound of formula (I), such as ARS-853, ARS-1620, ARS-3248, LY3499446 and MRTX849, or pharmaceutically acceptable salts thereof.
- the present invention provides a pharmaceutical combination product containing a second pharmaceutically active ingredient.
- the second pharmaceutically active ingredient is a compound of formula (II) or a pharmaceutically acceptable salt thereof,
- the second pharmaceutically active ingredient is a compound of formula (II).
- the compound of formula (II) described herein is a known compound, and all its known forms and components can be used in the pharmaceutical combination products provided by the present invention. For example, the preparation and identification of compounds of formula (II) have been described in WO2010058032.
- the second pharmaceutically active ingredient is a pharmaceutically acceptable salt of the 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 Acid salt, mesylate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate , succinate, gluconate, lactobiate or lauryl sulfonate, etc.
- the pharmaceutically acceptable salt is a maleate, a malate or a tartrate, further preferably a tartrate.
- the pharmaceutically acceptable salts may be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid following conventional procedures for the preparation of acid addition salts from basic compounds.
- One skilled in the art will be able to identify, without undue experimentation, various synthetic methods that can be used to prepare nontoxic pharmaceutically acceptable acid addition salts.
- the second pharmaceutically active ingredient can be in amorphous, crystalline forms, and combinations thereof.
- the second pharmaceutically active ingredient can also be other pharmaceutically active ingredients that have the same or similar efficacy as the compound of formula (II), such as defactinib, TAE226, GSK2256098, PF- 03814735, BI-4464, VS-4718 and APG-2449, or pharmaceutically acceptable salts thereof.
- the pharmaceutical combination product according to the present invention contains a first pharmaceutically active ingredient and a second pharmaceutically active ingredient.
- compositions according to the invention may comprise all suitable isotopic variants of said first and/or second pharmaceutically active ingredient.
- Isotopic variants of the compounds of the invention are defined as compounds of the invention in which at least one atom is replaced by an atom of the same atomic number but with an atomic weight different from that usually or predominantly found in nature.
- isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), respectively.
- isotopic variants of the compounds of the present invention eg, those in which one or more radioactive isotopes (eg, 3 H or 14 C) are incorporated, may be used in drug and/or substrate tissue distribution studies. Tritium and carbon-14 (ie, 14 C) isotopes are particularly preferred due to their ease of preparation and detectability.
- Isotopic variants of the compounds of the invention can generally be prepared using suitable isotopic variants of suitable reagents 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.
- compositions according to the invention may comprise all possible stereoisomers of the first and/or second pharmaceutically active ingredient as a single stereoisomer or as 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 invention can be achieved by any suitable state-of-the-art method, such as chromatography, in particular, for example, chiral chromatography.
- compositions according to the invention may comprise all possible tautomers of said first and/or second pharmaceutically active ingredients, either as single tautomers or in any ratio of said tautomers in the form of any mixture.
- pharmaceutical combinations according to the invention may comprise all possible crystalline forms or polymorphs of said first and/or second pharmaceutically active ingredient, either as a single polymorph or as more than one polymorph. A mixture of polymorphs in any proportion.
- the pharmaceutical combination product according to the present invention also contains an optional third pharmaceutical active ingredient selected from the group consisting of HDAC inhibitors, CDK4/6 inhibitors, ALK inhibitors, JAK2 inhibitors, Bcl-2 inhibitors , Hsp90 inhibitors, glucocorticoids, vinca alkaloids, antimetabolites, DNA damaging agents, lenalidomide, rituximab, PKC interferogens, Lyn/Fyn inhibitors, Syk inhibitors, PI3K inhibitors , PKC ⁇ inhibitor, IKK inhibitor, 20s proteasome, IRF-4, IRAK4 antibody, CXCR4 antibody, CXCR5 antibody, GLS antibody, PLK antibody, CD20 antibody, TopoII inhibitor, DNA methyltransferase inhibitor, Ras/MAPK inhibitor or FGFR1 inhibitor;
- the HDAC inhibitor is preferably panobinostat lactate, belinostat, chidamide, romidepsin, vorinostat, bexenostat or entino
- pharmaceutical combinations according to the invention further comprise one or more pharmaceutically acceptable excipients, diluents or carriers.
- a pharmaceutical composition product according to the present invention may comprise a first pharmaceutically active ingredient alone and a second pharmaceutically active ingredient alone.
- pharmaceutical combination products according to the present invention may include tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection liquids, sterile powders for injection and concentrates for injection), respectively. solution), suppository, inhaler or spray first pharmaceutically active ingredient and second pharmaceutically active ingredient.
- the pharmaceutical composition product according to the present invention may be a pharmaceutical composition comprising a first pharmaceutically active ingredient and a second pharmaceutically active ingredient.
- the first pharmaceutically active ingredient and the second pharmaceutically active ingredient are formulated together into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection and Concentrated solution for injection), suppository, inhalation or spray.
- the first and/or second pharmaceutically active ingredient according to the invention may be tabletted using conventional tablet bases such as lactose, sucrose and cornstarch in combination with a binder such as gum arabic, cornstarch or gelatin, after administration
- Disintegrants that aid tablet disintegration and dissolution such as potato starch, alginic acid, corn starch and guar gum, tragacanth, and acacia gum are used to improve tablet particle flow and prevent tablet materials from interacting with tablet molds and punches.
- Lubricants adhered to the head surface such as talc, stearic acid or magnesium stearate, calcium stearate or zinc stearate, dyes, colorants used to enhance the aesthetic qualities of the tablets and make them more acceptable to patients and flavorings such as peppermint, oil of wintergreen, or cherry essence.
- Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols (such as ethanol, benzyl alcohol and polyvinyl alcohols), with or without the addition of a pharmaceutically acceptable surfactant. , suspending agent or emulsifier.
- Various other materials may be present as coatings or otherwise modify the physical form of the dosage unit.
- tablets, pills, or capsules may be coated with shellac, sugar, or both.
- Dispersible powders and granules are suitable for the preparation of aqueous suspensions. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as those mentioned above for sweetening, flavoring and coloring agents, may also be present.
- the pharmaceutical combination product according to the invention also includes a commercial package comprising instructions for simultaneous, separate or sequential administration of the pharmaceutically active ingredients according to the invention to a patient in need thereof.
- the dosage regimen of the first pharmaceutically active ingredient and the second pharmaceutically active ingredient in the pharmaceutical combination product according to the present invention can be adjusted to provide an optimal desired response, e.g., maximum therapeutic response and/or minimum adverse effects. effect.
- the single dosage of the first pharmaceutically active ingredient may range from 1 to 5000mg.
- the administration frequency of the first pharmaceutically active ingredient may 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.
- the single dose of the second pharmaceutically active ingredient may range from 1 to 5000 mg.
- the administration frequency of the second pharmaceutically active ingredient may 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.
- the weight ratio of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient in the pharmaceutical combination product 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 about 15:1 to about 1:15. In some embodiments, the weight ratio may be from about 14:1 to about 1:14, from about 13:1 to about 1:13, from about 12:1 to about 1:12, from about 11:1 to about 1:1. 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.
- 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.
- the dosage is within the level of one of ordinary skill in the art, and the single dose or daily dose of the drug can be determined according to various factors such as the degree of disease, time of disease, age, health status and complications of the subject to be administered. And change.
- the pharmaceutical combination products according to the invention may be administered, alone or in combination, by oral administration.
- the pharmaceutical combination products according to the invention may be administered, alone or in combination, parenterally, i.e. subcutaneously, intravenously, intraocularly, Intrasynovial, intramuscular, or interperitoneal administration, as an injectable dose of the compound, preferably in a physiologically acceptable diluent and a pharmaceutical carrier, which may be a sterile liquid or mixture of liquids, such as water, saline , aqueous dextrose solutions and related sugar solutions, alcohols such as ethanol, isopropyl alcohol or cetyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1,1- Dioxolane-4-carbinol, ethers such as poly(ethylene glycol) 400, oils, fatty acids, fatty acid esters or fatty acid glycerides or acetylated
- an oral dosage form may be presented in a package or dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms of the active ingredient.
- a package or dispenser device such as an FDA-approved kit, which may contain one or more unit dosage forms of the active ingredient.
- the packaging may include metal or plastic foil, such as a blister pack.
- Packaging or dispenser devices may accompany administration instructions.
- the present invention provides a combination therapy for the treatment of abnormal cell growth, comprising administering to a subject in need thereof a pharmaceutical combination according to the present invention.
- the pharmaceutical composition product of the present invention includes 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 include a therapeutically effective amount of a second pharmaceutically active ingredient.
- the abnormal cell growth such as cancer
- the cancer includes, but is not limited to, solid tumors, soft tissue tumors, metastases, or non-solid cancers.
- the cancer is a solid tumor.
- the solid tumor is a malignant tumor of an organ (e.g., lung, breast, lymphatic, gastrointestinal tract (e.g., colon), and genitourinary (e.g., kidney, urothelial or testicular tumors), pharynx, prostate, and ovary) (eg sarcomas, adenocarcinomas and carcinomas).
- the cancer is mesothelioma; neurofibromatosis; e.g., neurofibromatosis type 2, neurofibromatosis type 1; kidney cancer; lung cancer, non-small cell lung cancer; liver cancer; thyroid cancer; Ovarian cancer; breast cancer; nervous system tumors; schwannoma; meningioma; schwannomatosis; acoustic neuroma; adenoid cystic carcinoma; ependymoma; or ependymoma.
- neurofibromatosis e.g., neurofibromatosis type 2, neurofibromatosis type 1
- kidney cancer lung cancer, non-small cell lung cancer
- liver cancer thyroid cancer
- Ovarian cancer breast cancer
- breast cancer nervous system tumors
- schwannoma meningioma
- schwannomatosis acoustic neuroma
- adenoid cystic carcinoma ependymoma
- 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 (eg, non-small cell lung cancer (NSCLC), eg, KRAS-mutated NSCLC)), or non-hematologic malignancies.
- the cancer is non-small cell lung cancer (NSCLC), e.g., KRAS-mutated NSCLC).
- the cancer is melanoma (e.g., N-Ras mutated locally advanced or metastatic malignant cutaneous melanoma), colorectal cancer (e.g., metastatic colorectal cancer), leukemia (e.g., acute myeloid leukemia), adenocarcinoma (eg, pancreatic adenocarcinoma), or solid tumor (eg, locally advanced solid tumor, metastatic solid tumor, hepatocellular carcinoma).
- melanoma e.g., N-Ras mutated locally advanced or metastatic malignant cutaneous melanoma
- colorectal cancer e.g., metastatic colorectal cancer
- leukemia e.g., acute myeloid leukemia
- adenocarcinoma eg, pancreatic adenocarcinoma
- solid tumor eg, locally advanced solid tumor, metastatic solid tumor, hepatocellular carcinoma
- the cancer may include cancer characterized by comprising cancer stem cells, cancer-associated mesenchymal cells, or tumor-initiating cancer cells.
- Cancers may include cancers that have been characterized as enriched in cancer stem cells, cancer-associated mesenchymal cells, or tumor-initiating cancer cells (eg, tumors or metastatic tumors enriched in cells undergoing epithelial-mesenchymal transition).
- the tumor can be a primary tumor, which is located at the anatomic site where the tumor growth begins.
- the cancer can also be metastatic, meaning it appears in at least a second anatomical location other than the one where the tumor grew.
- This cancer may be a relapsing cancer, which is a cancer that comes back after treatment and after a period of time when the cancer is undetectable.
- Recurrent cancer can be anatomically localized to the primary tumor, e.g., anatomically close to the primary tumor; in an area of the primary tumor, such as a lymph node located near the primary tumor; or distant from the original tumor, e.g., anatomically close to the primary tumor An area that is scientifically distant from the original tumor.
- Cancers may also include lung adenocarcinoma, colorectal cancer (CRC), endometrioid carcinoma, bladder urothelial carcinoma, breast invasive lobular carcinoma, cervical squamous cell carcinoma, cutaneous 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 Mullerian tumor, or other cancers.
- lung adenocarcinoma colorectal cancer (CRC), endometrioid carcinoma, bladder urothelial carcinoma, breast invasive lobular carcinoma, cervical squamous cell carcinoma, cutaneous melanoma, cervical adenocarcinoma, hepatocellular carcinoma , pancreatic cancer, biphasic ple
- cancers include, but are not limited to, uveal melanoma, brain, abdomen, esophagus, gastrointestinal tract, glioma, liver, tongue, neuroblastoma, osteosarcoma, ovary, retinoblastoma, Wilms tumor, multiple myeloid neoplasms, skin, lymphomas, blood and bone marrow cancers (e.g., advanced hematologic malignancies, leukemias, such as acute myeloid leukemia (e.g., primary or secondary)), acute lymphoblastic leukemia, acute lymphoblastic leukemia, T-cell Leukemia, hematologic malignancies, advanced myeloproliferative disorders, myelodysplastic syndromes, relapsed or refractory multiple myeloma, advanced myeloproliferative disorders), retina, bladder, cervix, kidney, endometrium, meningioma , lymphoma, skin, uterus,
- the term "about” modifying a quantity relevant to the present invention refers to variations in numerical quantities that may occur, such as through routine testing and handling; through inadvertent errors in such testing and handling; through the manufacture of the ingredients used in the present invention. , differences in origin or purity, etc.
- "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 recited quantities. In one embodiment, the term “about” means within 20%, within 10%, or within 5% of the reported value.
- treating refers to the elimination, reduction, or alleviation of a disease or disorder and/or symptoms associated therewith.
- treatment may include “preventive treatment,” which refers to the reduction of disease or disease in a subject who is not affected by the disease but is at risk or susceptible to developing the disease or condition or relapsing the disease or condition. Possibility of redevelopment of the condition or recurrence of previously controlled disease.
- treatment and synonyms are understood to mean the administration of a therapeutically effective amount of a pharmaceutical composition according to the invention to a subject in need of such treatment.
- the term “therapeutically effective amount” refers to an amount of an active compound or agent that elicits a biological or pharmaceutical response in a tissue system, animal, or human being sought by a researcher, veterinarian, MD, or other clinician, including Reduction or reversal of symptoms of the disease or condition being treated.
- the term “therapeutically effective amount” may be based on a single pharmaceutically active ingredient or a combination of two pharmaceutically active ingredients.
- the first active pharmaceutical ingredient (API) is a compound of formula (I), which is prepared according to the method disclosed in patent applications WO2020233592, WO2021121330 or WO2021120045, with a purity of greater than 99%, and is stored at room temperature in the dark.
- the second active pharmaceutical ingredient (API) is a tartrate salt of a compound of formula (II) prepared according to the method disclosed in patent application WO2010058032.
- the tartrate salt of a compound of formula (II) is prepared according to acid addition from a basic compound.
- the salt is prepared by conventional operations.
- the tartrate of the compound of formula (II) has a purity of greater than 97% and is stored in the dark at 4°C.
- the animal information card for each cage indicates the number of animals in the cage, gender, strain, date of receipt, dosage regimen, experiment number, group and experiment start date. All cages, bedding and drinking water are sterilized before use. Cages, feed and drinking water were changed twice a week.
- the feeding environment and lighting conditions are as follows:
- Cage Made of polycarbonate, volume 300mmx180mmx150mm.
- the bedding material is corn cobs and is changed twice a week.
- Experimental animals can eat freely during the entire experimental period (irradiation sterilization, dry granular form food).
- Drinking water Experimental animals can drink sterilized water freely.
- mice were divided into 4 groups, with 8 mice in each group, and were administered according to the administration method in Table A.
- Table a Animal groupings and dosing regimens for in vivo drug efficacy tests
- Human non-small cell lung cancer cell NCI-H358 ( CRL-5807TM) in vitro monolayer culture, the culture conditions are basal medium RPMI-1640 added with 10% fetal bovine serum, 100 units per ml of penicillin and 100 ⁇ g per ml of streptomycin, in a 5% CO 2 cell culture incubator at 37 degrees Celsius nourish. Passage was performed twice a week with routine digestion treatment with trypsin digestion. When cells are full When the concentration is 80%-90% and the number reaches the required number, cells are collected, counted, and inoculated.
- Routine examinations include observing tumor growth and the effects of drug treatment on the daily behavioral performance of the animals, such as behavioral activities, food and water intake (visual inspection only), and weight changes (measure body weight twice a week). Appearance signs or other abnormalities. The number of animal deaths and side effects within the group were recorded based on the number of animals in each group.
- the experimental indicator is to examine whether tumor growth is inhibited, delayed or cured.
- Tumor diameter was measured twice weekly using vernier calipers.
- TGI The antitumor efficacy of the compounds was evaluated by TGI (%).
- TGI (%) reflects the tumor growth inhibition rate.
- TGI (%) [1-(Average tumor volume at the end of administration in a certain treatment group-Average tumor volume at the beginning of administration in this treatment group)/(Average tumor volume at the end of treatment in the solvent control group- Average tumor volume in the solvent control group at the beginning of treatment)] ⁇ 100%.
- TGI values have the following meanings:
- the body weight changes and change rates of tumor-bearing mice in different groups are shown in Figures 1 and 2.
- the relative body weight change is calculated based on the animal body weight at the beginning of dosing. Data points represent the mean weight percent change within the group. Error bars represent standard error (SEM).
- the tumor growth volumes of animals in different groups at various time periods are shown in Table 2.
- TGI% tumor growth inhibition rate
- the p value is calculated based on the relative tumor volume of each mouse in different groups.
- the One-way ANOVA method is used to obtain the P value by comparing the control group and each administration group.
- P ⁇ 0.01 statistical analysis represents a significant difference between each group and the control group.
- P>0.05 statistical analysis means there is no significant difference between each group and the control group.
- c.P value is the P value obtained by comparing the first API and second API combined dose group with the single drug group using the One-wayANOVA method. P ⁇ 0.01 statistical analysis represents significant differences between each group and the control group.
- QD is once a day.
- the tumor weights of animals in different groups are shown in Table 4.
- the P value is obtained by comparing the control group and each administration group using the T-test method. P ⁇ 0.01 statistical analysis represents a significant difference between each group and the control group.
- the P value is obtained by comparing the (first API + second API) combination group and the two single-drug groups using the T-test method. P ⁇ 0.01 statistical analysis represents a significant difference between each single-drug group and the combination group.
- QD is once a day.
- the first API and the second API of the test drug were evaluated individually and in combination. Efficacy of the combination in subcutaneous xenografts of human non-small cell lung cancer cells NCI-H358. After administration, the body weight changes of the animals in each group at different time points are shown in Figures 1 and 2.
- the changes in tumor volume and weight in each group at different time points are shown in Table 2, Table 3, Table 4 and Figure 3 and Figure 4.
- the tumor volume in the white group reached 1255.3 cubic millimeters.
- the tumor growth inhibition rates TGI (%) of the first API and the second API were 84.95% and 60.05%, respectively.
- the tumor growth inhibition rate TGI (%) of the combined treatment group of the first API compound and the second API compound reached 118.85%.
- the TGI value showed that the efficacy of the combination of the first API compound and the second API compound was significantly better than that of each single dose group (p ⁇ 0.01), achieving overall tumor remission.
Abstract
L'invention concerne un produit pharmaceutique de polythérapie et une polythérapie correspondante. En particulier, l'invention concerne un produit pharmaceutique de polythérapie comprenant un premier ingrédient pharmaceutique actif et un second ingrédient pharmaceutique actif. L'invention concerne en outre une polythérapie pour le traitement d'une croissance cellulaire anormale (par exemple le cancer) qui comprend l'administration du produit pharmaceutique de polythérapie à un sujet en ayant besoin.
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---|---|---|---|---|
CN102292322A (zh) * | 2008-11-24 | 2011-12-21 | 贝林格尔.英格海姆国际有限公司 | 用于治疗例如癌症的疾病的取代的嘧啶 |
AR101982A1 (es) * | 2014-09-18 | 2017-01-25 | Araxes Pharma Llc | Terapias combinadas para el tratamiento del cáncer y composiciones |
CN112585129A (zh) * | 2019-05-21 | 2021-03-30 | 益方生物科技(上海)股份有限公司 | 杂环化合物,其制备方法和用途 |
WO2021120045A1 (fr) * | 2019-12-18 | 2021-06-24 | InventisBio Co., Ltd. | Composés hétérocycliques, leurs procédés de préparation et utilisations associées |
-
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- 2022-07-20 CN CN202210872332.3A patent/CN117462553A/zh active Pending
-
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102292322A (zh) * | 2008-11-24 | 2011-12-21 | 贝林格尔.英格海姆国际有限公司 | 用于治疗例如癌症的疾病的取代的嘧啶 |
AR101982A1 (es) * | 2014-09-18 | 2017-01-25 | Araxes Pharma Llc | Terapias combinadas para el tratamiento del cáncer y composiciones |
CN112585129A (zh) * | 2019-05-21 | 2021-03-30 | 益方生物科技(上海)股份有限公司 | 杂环化合物,其制备方法和用途 |
WO2021120045A1 (fr) * | 2019-12-18 | 2021-06-24 | InventisBio Co., Ltd. | Composés hétérocycliques, leurs procédés de préparation et utilisations associées |
WO2021121330A1 (fr) * | 2019-12-18 | 2021-06-24 | InventisBio Co., Ltd. | Composés hétérocycliques, leurs procédés de préparation et leurs utilisations |
Non-Patent Citations (1)
Title |
---|
GANDARA D, MARRONE K; GOVINDAN R; SKOULIDIS F; DURM G; CLARKE J; FRANK R; KRAUSS J; SNYDER W; DAI T; MATHER O; CIFUENTES P; HINDOY: "Abstract P05-02: A phase 1b study evaluating the combination of sotorasib, a KRASG12C inhibitor, and afatinib, a pan-ErbB tyrosine kinase inhibitor, in advanced KRAS p.G12C mutated non-small cell lung cancer (NSCLC) | Molecular Cancer Therapeutics | American Association for Cancer Research", MOL CANCER THER (2021) 20 (12_SUPPLEMENT), 31 December 2021 (2021-12-31), XP093004836, Retrieved from the Internet <URL:https://aacrjournals.org/mct/article/20/12_Supplement/P05-02/675859/Abstract-P05-02-A-phase-1b-study-evaluating-the> [retrieved on 20221205], DOI: 10.1158/1535-7163.TARG-21-P05-02 * |
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