CN117797151A - Quinoline derivatives combined with chemotherapeutics for treating non-small cell lung cancer - Google Patents

Quinoline derivatives combined with chemotherapeutics for treating non-small cell lung cancer Download PDF

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CN117797151A
CN117797151A CN202410036103.7A CN202410036103A CN117797151A CN 117797151 A CN117797151 A CN 117797151A CN 202410036103 A CN202410036103 A CN 202410036103A CN 117797151 A CN117797151 A CN 117797151A
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lung cancer
cell lung
small cell
chemotherapeutic agent
compound
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耿文军
王善春
张喜全
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The application belongs to the field of medicines, provides a quinoline derivative combined chemotherapeutic medicine for treating non-small cell lung cancer, and particularly relates to application of a 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine combined chemotherapeutic medicine in treating non-small cell lung cancer.

Description

Quinoline derivatives combined with chemotherapeutics for treating non-small cell lung cancer
The invention relates to a Chinese application (the invention name is that quinoline derivatives are combined with chemotherapeutics to treat non-small cell lung cancer; the application date is 2019, 3, 4 and 201910159974.7).
Technical Field
The invention belongs to the field of medicines, and particularly relates to a quinoline derivative combined with a chemotherapeutic drug for treating non-small cell lung cancer.
Background
Cancer is a major public health problem in many parts of the world. Among them, lung cancer has high morbidity and mortality, and is a major cause of cancer death worldwide. In 2012, approximately 180 ten thousand people worldwide are new to develop lung cancer, and 160 ten thousand people die. Lung cancer is a common cause of cancer death in men, and is second only to breast cancer in women, second to the list. In recent years, the incidence and death of lung cancer in China are rapidly increasing. Currently, based on the biological properties and prognosis of lung cancer, the World Health Organization (WHO) classifies it into two major categories: non-small cell lung cancer (non-small cell lung cancer, NSCLC) and small cell lung cancer (small cell lung cancer, SCLC). Non-small cell lung cancer includes squamous cell carcinoma (squamous carcinoma), adenocarcinoma, large cell carcinoma, which has slower growth and division of cancer cells and relatively late diffusion metastasis compared to small cell carcinoma. Non-small cell lung cancer accounts for about 80% of all lung cancers, with about 75% of patients found to be in the middle and late stages with very low survival rates of 5 years.
Tyrosine kinases are a group of enzymes that catalyze the phosphorylation of protein tyrosine residues, play an important role in intracellular signal transduction, and are involved in the regulation, signaling and development of normal cells, and are also closely related to proliferation, differentiation, migration and apoptosis of tumor cells. Many receptor tyrosine kinases are involved in tumor formation and can be classified into Epidermal Growth Factor Receptor (EGFR), platelet Derived Growth Factor Receptor (PDGFR), vascular Endothelial Growth Factor Receptor (VEGFR), fibroblast Growth Factor Receptor (FGFR), etc. according to the structure of their extracellular regions.
Chemotherapy is one of the most effective means for treating cancer at present, and is also called as three major treatment means of cancer together with surgery and radiotherapy. The combination of chemotherapeutic agents has the following advantages: (1) The synergistic effect is generated in the aspect of killing tumor cells, thereby improving the curative effect; (2) Reducing the dosage and/or time of administration of the single agent, thereby reducing toxicity; (3) reduces the likelihood of cancer cells developing drug resistance; (4) The combination of a chemotherapeutic drug which enters the brain can prevent or treat brain metastasis.
Disclosure of Invention
In one aspect, the present application provides a pharmaceutical combination comprising: (i) Compound I, or a pharmaceutically acceptable salt, hydrate or prodrug thereof; and (ii) a chemotherapeutic agent.
In another aspect, the present application provides a pharmaceutical combination comprising: (i) Compound I, or a pharmaceutically acceptable salt, hydrate or prodrug thereof; and (ii) a chemotherapeutic agent, optionally in combination with radiation therapy, in the manufacture of a medicament for the treatment of non-small cell lung cancer.
In some embodiments, a pharmaceutical combination is provided, comprising: (i) Compound I, or a pharmaceutically acceptable salt, hydrate or prodrug thereof; and (ii) platinum and pemetrexed, optionally in combination with radiotherapy, in the manufacture of a medicament for the treatment of non-small cell lung cancer. In some embodiments, a pharmaceutical combination is provided, comprising: (i) Compound I, or a pharmaceutically acceptable salt, hydrate or prodrug thereof; and (ii) platinum and gemcitabine, optionally in combination with radiation therapy, in the manufacture of a medicament for the treatment of non-small cell lung cancer. In some embodiments, a combination is provided, comprising: (i) Compound I, or a pharmaceutically acceptable salt, hydrate or prodrug thereof; and (ii) carboplatin and pemetrexed, in the manufacture of a medicament for treating non-squamous non-small cell lung cancer. In some specific embodiments, a combination is provided comprising: (i) Compound I, or a pharmaceutically acceptable salt, hydrate or prodrug thereof; and (ii) carboplatin and pemetrexed, in the manufacture of a medicament for treating adenocarcinoma non-small cell lung cancer. In some specific embodiments, a combination is provided comprising: (i) Compound I, or a pharmaceutically acceptable salt, hydrate or prodrug thereof; and (ii) carboplatin and gemcitabine, in the manufacture of a medicament for the treatment of squamous cell lung carcinoma.
In yet another aspect, the present application provides a method of treating non-small cell lung cancer comprising: administering to a patient in need thereof an effective amount of (I) compound I, or a pharmaceutically acceptable salt, hydrate or prodrug thereof; and (ii) a chemotherapeutic agent, and optionally radiation therapy.
In some embodiments, the present application provides a treatmentA method of non-small cell lung cancer comprising: administering to a patient in need thereof an effective amount of (I) compound I, or a pharmaceutically acceptable salt, hydrate or prodrug thereof; and (ii) pemetrexed and carboplatin. Wherein the dosage of pemetrexed is 250-600mg/m 2 Preferably 300-500mg/m 2 The method comprises the steps of carrying out a first treatment on the surface of the Every 3 weeks (i.e., 21 days) is a cycle, and is administered on the first day of each cycle. Carboplatin was administered once every 3 weeks (i.e., 21 days); in some embodiments, carboplatin is administered on the first day of each cycle. Preferably, the non-small cell lung cancer is non-squamous. In some embodiments, the non-small cell lung cancer is adenocarcinoma.
In some embodiments, the present application provides a method of treating non-small cell lung cancer comprising: administering to a patient in need thereof an effective amount of (I) compound I, or a pharmaceutically acceptable salt, hydrate or prodrug thereof; and (ii) gemcitabine and carboplatin. Wherein the administration dose of gemcitabine is 0.7-1.0g/m 2 Preferably 0.8-1.0g/m 2 The method comprises the steps of carrying out a first treatment on the surface of the Every 3 weeks (i.e., 21 days) is a cycle, and is administered on the first and eighth days of each cycle. Carboplatin was administered once every 3 weeks (i.e., 21 days); in some embodiments, carboplatin is administered on the first day of each cycle. In some embodiments, the non-small cell lung cancer is squamous cancer.
In yet another aspect, the present application provides a kit for use in the treatment of a combination of non-small cell lung cancer comprising: (i) Compound I, or a pharmaceutically acceptable salt, hydrate or prodrug thereof; and (ii) a chemotherapeutic agent;
optionally in combination with radiation therapy,
the method is characterized in that: (i) Contained in a first compartment, and (ii) contained in a second compartment.
In this application, compound I has the chemical name 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, having the structural formula:
in this application, prodrugs of compound I are converted in vivo to the free base form of compound I. Pharmaceutically acceptable salts of compound I can be produced from various organic and inorganic acids according to methods well known in the art. "pharmaceutically acceptable salts" include, but are not limited to, acid addition salts with mineral acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like; or with an organic acid such as acetic acid, trifluoroacetic acid, propionic acid, caproic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and the like. In some embodiments, the pharmaceutically acceptable salt of compound I is the hydrochloride salt of compound I. In some embodiments, the pharmaceutically acceptable salt of compound I is a monohydrochloride salt of compound I. In some embodiments, the pharmaceutically acceptable salt of compound I is a dihydrochloride salt of compound I. In some embodiments, the hydrochloride salt of compound I is in crystalline form. In some embodiments, the pharmaceutically acceptable salt of compound I is a crystal of compound I dihydrochloride. In some embodiments, the pharmaceutically acceptable salt of compound I is the maleate salt of compound I.
Examples of such chemotherapeutic agents include, but are not limited to, one or more of alkylating agents, podophyllones, camptothecins, taxanes, antimetabolites, antibiotic antineoplastic agents, and examples that may be cited include, but are not limited to, platinum-based agents (e.g., oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin), fluoropyrimidine derivatives (e.g., gemcitabine, capecitabine, fluorouracil, bifluoride, doxifluridine, tegafur, carmofur), taxanes (e.g., paclitaxel, albumin-bound paclitaxel, and docetaxel), camptothecins (e.g., camptothecins, hydroxycamptothecins, irinotecan, topotecan), vinorelbine, vincristine, vindesine, vinflunine (vinflunine), pemetrexed, etoposide, mitomycin, ifosfamide, cyclophosphamide, azamide, azacitidine, ammonia, methotrexate, stand-62, and other than one of the two of the salts, the salts of fluzamide, the other than one of the two of the salts, the salts of fluzamide, the salts of the two of the salts of fluxaprop-IV, the salts of the two of the drugs.
In some embodiments, the chemotherapeutic agent is a platinum-based agent.
In some embodiments, the chemotherapeutic agent is a platinum agent and one or more of the chemotherapeutic agents described above.
In some embodiments, the chemotherapeutic agent is a platinum-based agent (e.g., one of oxaliplatin, cisplatin, carboplatin, nedaplatin, or dicycloplatin) and a taxane (e.g., one of paclitaxel, albumin-bound paclitaxel, or docetaxel); in some embodiments, the chemotherapeutic agent is carboplatin or paclitaxel; in some embodiments, the chemotherapeutic agent is carboplatin and albumin-bound paclitaxel. In some embodiments, the chemotherapeutic agent is carboplatin or docetaxel; in some embodiments, the chemotherapeutic agent is cisplatin or paclitaxel; in some embodiments, the chemotherapeutic agent is cisplatin-and albumin-bound paclitaxel. In some embodiments, the chemotherapeutic agent is cisplatin or docetaxel.
In some embodiments, the chemotherapeutic agent is a platinum-based agent (e.g., one of oxaliplatin, cisplatin, carboplatin, nedaplatin, or dicycloplatin) and a vinblastine (e.g., one of vinorelbine, vinblastine, vincristine, vindesine, or vinblastine); in some embodiments, the chemotherapeutic agent is carboplatin or vinorelbine. In some embodiments, the chemotherapeutic agent is cisplatin or vinorelbine.
In some embodiments, the chemotherapeutic agent is a platinum-based agent (e.g., one of oxaliplatin, cisplatin, carboplatin, nedaplatin, or dicycloplatin) and a fluoropyrimidine derivative (e.g., one of gemcitabine, capecitabine, fluorouracil, bififluridine, doxifluridine, tegafur, carmofur, trifluoretide); in some embodiments, the chemotherapeutic agent is a platinum-based agent (e.g., one of oxaliplatin, cisplatin, carboplatin, nedaplatin, or dicycloplatin) and gemcitabine; in some embodiments, the chemotherapeutic agent is cisplatin or gemcitabine.
In some embodiments, the chemotherapeutic agent is a platinum-based agent (e.g., one of oxaliplatin, cisplatin, carboplatin, nedaplatin, or dicycloplatin) and pemetrexed. In some embodiments, the chemotherapeutic agent is cisplatin or pemetrexed. In some embodiments, the chemotherapeutic agent is carboplatin or pemetrexed.
In some embodiments, the chemotherapeutic agent is a platinum-based agent (e.g., one of oxaliplatin, cisplatin, carboplatin, nedaplatin, or dicycloplatin) and etoposide. In some embodiments, the chemotherapeutic agent is cisplatin and etoposide, or carboplatin and etoposide.
In some embodiments, the chemotherapeutic agent is pemetrexed.
In some embodiments, the chemotherapeutic agent is pemetrexed and a taxane (e.g., one of paclitaxel, albumin-bound paclitaxel, or docetaxel); in some embodiments, the chemotherapeutic agent is pemetrexed and docetaxel.
In some embodiments, the chemotherapeutic agent is pemetrexed and a vinblastine (e.g., one of vinorelbine, vinblastine, vincristine, vindesine, or vinblastine); in some embodiments, the chemotherapeutic agent is pemetrexed and vinorelbine.
In some embodiments, the chemotherapeutic agent is a camptothecin (e.g., one of camptothecin, hydroxycamptothecin, irinotecan, or topotecan); in some embodiments, the chemotherapeutic agent is irinotecan.
In some embodiments, the chemotherapeutic agent is a fluoropyrimidine derivative (e.g., one of gemcitabine, capecitabine, fluorouracil, bififluridine, doxifluridine, tegafur, carmofur, trifluoracetam) and a taxane (e.g., one of paclitaxel, albumin-bound paclitaxel, or docetaxel); in some embodiments, the chemotherapeutic agent is gemcitabine and docetaxel.
In some embodiments, the chemotherapeutic agent is a fluoropyrimidine derivative (e.g., one of gemcitabine, capecitabine, fluorouracil, bififluridine, deoxyfluorouridine, tegafur, carmofur, trifluoracetin) and a vincristine (e.g., one of vinorelbine, vinblastine, vincristine, vindesine, or vinfuneraline); in some embodiments, the chemotherapeutic agent is gemcitabine and vinorelbine.
In some embodiments, the chemotherapeutic agent is trifluoracetam and dipivefrin hydrochloride. In some embodiments, the chemotherapeutic agent is encquidar mesylate and paclitaxel.
In some embodiments, the chemotherapeutic agent is tegafur.
In this application, the histological typing of non-small cell lung cancer includes, but is not limited to, adenocarcinoma, squamous cell carcinoma, large cell carcinoma or undefined non-small cell lung cancer; clinical stages include, but are not limited to, locally advanced, and/or advanced (e.g., stage IIIB/IV) and/or metastatic non-small cell lung cancer. Wherein metastatic non-small cell lung cancer includes, but is not limited to, focal single metastasis, disseminated metastasis, diffuse metastasis; the metastatic lesions include, but are not limited to, lymph nodes, pleura, bone, brain, pericardium, adrenal gland, liver; in some embodiments, the small cell lung cancer is brain-transferred non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is recurrent non-small cell lung cancer, including but not limited to intrabronchial obstructive non-small cell lung cancer, resectable recurrent non-small cell lung cancer, recurrent non-small cell lung cancer of the mediastinum lymph node, superior Vena Cava (SVC) obstructive non-small cell lung cancer, severe hemoptysis non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer that develops or recurs after having been previously subjected to at least one chemotherapy. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer that is intolerant to chemotherapy. In a preferred embodiment, the non-small cell lung cancer is non-small cell lung cancer that has not previously been treated systematically. In some embodiments, the non-small cell lung cancer is preferably squamous carcinoma; in some embodiments, the non-small cell lung cancer is a non-squamous carcinoma; in some specific embodiments, the non-small cell lung cancer is adenocarcinoma.
In the application, the non-small cell lung cancer is non-small cell lung cancer with negative gene mutation; the genetic mutations are EGFR genetic mutations (including but not limited to, exon 18, exon 19 (e.g., DEL 19), exon 21 (e.g., L858R), exon 20 insertion (e.g., T790M)), ALK rearrangements, and/or ROS1 mutations.
The components of the pharmaceutical combination of the present invention may optionally be combined with one or more pharmaceutically acceptable carriers, wherein the components may each independently, or some or all of them together comprise pharmaceutically acceptable carriers and/or excipients. The pharmaceutical combinations of the invention may be formulated separately from each other or some or all of them may be formulated together. Preferably, the components of the pharmaceutical combination are formulated separately or each as a suitable pharmaceutical composition. In some embodiments, the pharmaceutical combinations of the present application may be formulated into pharmaceutical compositions suitable for single or multiple administration. In some particular embodiments, the pharmaceutical composition containing compound I, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, may be selected from solid pharmaceutical compositions including, but not limited to, tablets or capsules.
The components of the pharmaceutical combinations of the present application may each be administered alone, or some or all of them may be co-administered. The components of the pharmaceutical combinations of the present application may be administered substantially simultaneously, or some or all of them may be administered substantially simultaneously.
The components of the pharmaceutical combinations of the present application may each be administered independently, or some or all of them together, by suitable routes, including, but not limited to, oral or parenteral (via intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the components of the pharmaceutical combinations of the present application may each be administered orally or by injection, e.g., intravenously or intraperitoneally, independently, or in combination with some or all of them.
The components of the pharmaceutical combinations of the present application may each independently, or some or all of them together, be in a suitable dosage form including, but not limited to, tablets, troches, pills, capsules (e.g., hard capsules, soft capsules, enteric capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions, and dosage forms of sustained release formulations for oral or non-oral administration.
In this application, the components of the pharmaceutical combination may be administered to a patient as separate entities (e.g., pharmaceutical compositions) simultaneously, alternately or sequentially, wherein the active ingredients administered to the patient reach therapeutically effective levels. In some embodiments, the individual active components may be packaged, marketed, or administered as a completely separate pharmaceutical composition.
The amount of each component administered in the pharmaceutical combinations of the present application may be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, is from 6 mg to 20 mg; preferably 8mg to 16 mg; more preferably 8mg to 14 mg; most preferably 8mg, 10mg or 12 mg. Compound I, or a pharmaceutically acceptable salt, hydrate or prodrug thereof, may be administered one or more times daily, preferably once daily; in some embodiments, compound I, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, is administered once daily in an oral solid formulation.
The dosage regimen may be determined in general terms of the activity, toxicity, tolerance of the drug, etc. Typically, the components of the pharmaceutical combinations of the present application may be administered according to dosing regimens known in the art. In some embodiments, compound I, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, is administered in a divided dosing regimen; the interval administration includes administration period and withdrawal period, and can be administered once or multiple times daily during administration period. In some embodiments, the ratio of dosing period to withdrawal period in days is from 2:0.5 to 5, preferably from 2:0.5 to 3, more preferably from 2:0.5 to 2, more preferably from 2:0.5 to 1. In some embodiments, administration is stopped for 1 week for 2 weeks. In certain particular embodiments, compound I, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, is administered orally at a dose of 8, 10, and/or 12mg once daily for 2 weeks, and for 1 week in a continuous dosing regimen.
In some embodiments, pemetrexed is administered intravenously at a dose of 500mg/m 2 The method comprises the steps of carrying out a first treatment on the surface of the Every 3 weeks (i.e., 21 days) is a cycle, and is administered on the first day of each cycle.
In some embodiments, gemcitabine is administered intravenously at a dose of 1.0g/m 2 Every 3 weeks (i.e., 21 days) is a cycle, and is administered on the first and eighth days of each cycle.
In some embodiments, the dose of carboplatin administered intravenously is calculated according to formulas well known to those skilled in the art at an AUC of 5mg/ml/min, and is administered once every 3 weeks (i.e., 21 days) for a period.
The pharmaceutical combinations of the invention are particularly effective in inhibiting tumor growth, survival and metastasis thereof, have a synergistic effect, or are capable of increasing the patient's tolerance to the relevant treatment. In some embodiments, sensitivity to chemotherapy and/or radiation therapy may be induced or rebuilt or enhanced in the patient. In the present invention, the amount of each therapeutic agent alone is not sufficient to achieve the effect achieved by administration of the pharmaceutical combination, and wherein the combined effect of the therapeutic agents is better than the total therapeutic effect achieved by each therapeutic agent at that dose.
The dosages and ranges provided herein are based on the molecular weight of the free base form of compound I, unless otherwise indicated.
For the purposes of this application, the following terms, as used in the specification and claims, shall have the following meanings, unless otherwise indicated.
"patient" means a mammal, preferably a human.
By "pharmaceutically acceptable" is meant that it is used to prepare a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes that it is acceptable for human pharmaceutical use.
By "therapeutically effective amount" is meant an amount of a compound that, when administered to a human being for treating a disease, is sufficient to effect treatment of the disease.
"treatment" means any administration of a therapeutically effective amount of a compound and includes:
(1) Inhibiting the disease in a human experiencing or exhibiting the pathology or symptomology of the disease (i.e., arresting further development of the pathology and/or symptomology), or
(2) Improving the disease in a human experiencing or exhibiting the pathology or symptomology of the disease (i.e., reversing the pathology and/or symptomology).
"treatment failure" refers to intolerance of toxic or side effects, disease progression during treatment, or recurrence after treatment has ended.
"optionally" means with or without.
"CR" means complete remission, i.e., disappearance of all target lesions, all pathological lymph nodes (including target nodules and non-target nodules) short diameter must be reduced to < 10mm.
By "PR" is meant partial remission, the sum of target lesion diameters is reduced by at least 30% from baseline levels.
"ORR" refers to the objective rate of remission, which is the sum of the ratio of complete remission and partial remission. That is, orr=cr+pr.
"PD" refers to disease progression, relative increase in diameter and diameter of at least 20% relative to the minimum sum of all measured diameters of target lesions throughout the course of the study (baseline value if the baseline measurement is minimal); and must meet the relative increase in diameter sum of at least 5mm, if a new lesion appears, it is also considered as disease progression.
"SD" means that the disease is stable, the target lesions are reduced to a degree that does not reach PR levels, nor are increased to a degree that does not reach PD levels, between the two.
"DCR" refers to disease control rate and includes the percentage of patients who are fully relieved, partially and stable for disease and who have sustained more than 4 weeks of disease in which efficacy can be assessed.
"PFS" refers to progression-free survival from random grouping until the time of objective progression of the tumor or death of the patient.
"OS" total lifetime refers to the time from the start of the group to death due to any source. Subjects who were not visited, in days, were generally counted as dead from the last follow-up time.
Detailed Description
The present application is further illustrated below in conjunction with specific embodiments. It should be understood that these examples are presented by way of illustration only and are not intended to limit the scope of the present application.
Example 1
Locally advanced (IIIb), metastatic or recurrent (stage IV) NSCLC, driving gene negative (EGFR/ALK/ROS 1), 19 patients who had not received systemic anti-tumor treatment against advanced disease and who were pathologically examined as adenocarcinoma, which were not surgically treated and did not receive radical simultaneous radiotherapy and chemotherapy, were histologically or cytologically confirmed. The dosing scheme is as follows: pemetrexed 500mg/m 2 Combined carboplatin (auc=5), administered intravenously 1 time every 3 weeks; in combination with An Luoti Ni hydrochloride capsule, an Luoti Ni is administered orally at a dose of 12mg, 1 time daily, and continuously administered for 2 weeks to stop for 1 week, i.e. 3 weeks (21 days) is a administration period. After 4-6 cycles of combination, maintenance therapy was performed with An Luoti n+pemetrexed. The dose administered may be adjusted down, for example 10% or 20% of the dose, and An Luoti Ni may be adjusted down to 10mg or 8mg during the course of treatment, depending on the patient's tolerance and adverse effects.
In this study, efficacy was evaluated and data analyzed every 2 cycles (C2, i.e., 6 weeks). The main curative effect index is the safety of observing the combined administration and the Objective Remission Rate (ORR); the secondary efficacy indicators are observed patient Progression Free Survival (PFS), disease Control Rate (DCR), total survival (OS).
The results of the patient efficacy evaluation are shown in table 1 below.
Table 1 results of evaluation of efficacy in patients
Example 2
Locally advanced (IIIb), metastatic or recurrent (stage IV) NSCLC, driving gene negative (EGFR/ALK/ROS 1) which were not treated surgically or by cytology, and which were not treated by systemic anti-tumor therapy against advanced disease, and 7 patients with squamous cell carcinoma by pathological examination. The dosing scheme is as follows: gemcitabine 1.0g/m 2 (d 1, d8 days of administration), in combination with carboplatin (auc=5), administered intravenously 1 time every 3 weeks; in combination with An Luoti Ni hydrochloride capsule, an Luoti Ni is administered orally at a dose of 12mg, 1 time daily, and continuously administered for 2 weeks to stop for 1 week, i.e. 3 weeks (21 days) is a administration period. After 4-6 cycles of combination administration, maintenance therapy was performed with An Luoti Ni. The dose administered may be adjusted down, for example 10% or 20% of the dose, and An Luoti Ni may be adjusted down to 10mg or 8mg during the course of treatment, depending on the patient's tolerance and adverse effects.
In this study, efficacy was evaluated every 2 courses (C2, i.e., 6 weeks) and data analysis was performed. The main curative effect index is the safety of observing the combined administration and the Objective Remission Rate (ORR); the secondary efficacy indicators are observed subject Disease Control Rate (DCR), progression Free Survival (PFS), total survival (OS).
The results of the patient efficacy evaluation are shown in table 2 below.
TABLE 2 evaluation results of efficacy in squamous carcinoma patients

Claims (10)

1. A pharmaceutical combination, comprising: (i) Compound I, or a pharmaceutically acceptable salt, hydrate or prodrug thereof; and (ii) a chemotherapeutic agent
2. The pharmaceutical combination of claim 1, characterized in that the chemotherapeutic drug is one or more of alkylating agents, podophyllons, camptothecins, taxanes, antimetabolites, antibiotic antitumor drugs.
3. The pharmaceutical combination according to claim 2, characterized in that the chemotherapeutic agent comprises, but is not limited to, a platinum-based agent: oxaliplatin, cisplatin, carboplatin, nedaplatin, and dicycloplatin; fluoropyrimidine derivatives: gemcitabine, capecitabine, fluorouracil, bifurouracil, doxifluridine, tegafur, carmofur, and trifluoretide; taxanes: paclitaxel, albumin-bound paclitaxel, and docetaxel; camptothecins: camptothecine, hydroxycamptothecine, irinotecan, topotecan; vinblastine: vinorelbine, vinblastine, vincristine, vindesine, and vinfuning; one or two or three of pemetrexed, etoposide, irinotecan, mitomycin, ifosfamide, cyclophosphamide, azacytidine, amrubicin, methotrexate, bendamustine, epirubicin, doxorubicin, temozolomide, LCL-161, KML-001, sapacitabine, plinabulin, troxifogline, dipivefrine hydrochloride, tigaone, and encequidar.
4. The pharmaceutical combination of claim 3, wherein the chemotherapeutic agent is carboplatin or pemetrexed.
5. The pharmaceutical combination of claim 4, wherein the chemotherapeutic agents carboplatin and gemcitabine.
6. Use of a pharmaceutical combination according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment of non-small cell lung cancer.
7. The use according to claim 6, characterized in that the non-small cell lung cancer is squamous or non-squamous cell lung cancer.
8. Use according to claim 6 or 7, characterized in that it is combined with radiotherapy.
9. A method of treating non-small cell lung cancer, comprising: administering to a patient in need thereof an effective amount of (I) compound I, or a pharmaceutically acceptable salt, hydrate or prodrug thereof; and (ii) a chemotherapeutic agent, and optionally radiation therapy.
10. A kit for use in a pharmaceutical combination for treating non-small cell lung cancer, comprising: (i) Compound I, or a pharmaceutically acceptable salt, hydrate or prodrug thereof; and (ii) a chemotherapeutic agent, and optionally radiation therapy.
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