CN112638385B

CN112638385B - Quinoline derivatives for the treatment of brain tumors

Info

Publication number: CN112638385B
Application number: CN201980052519.5A
Authority: CN
Inventors: 王善春; 钱文娟; 卢琴; 徐宏江; 于鼎; 王训强; 彭邦安; 刘璐; 代洁
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2018-09-18
Filing date: 2019-09-18
Publication date: 2023-03-31
Anticipated expiration: 2039-09-18
Also published as: CN112638385A; WO2020057536A1

Abstract

A quinoline derivative for treating brain tumors, wherein the compound I or a pharmaceutically acceptable salt thereof can be used for treating brain metastatic tumors, and particularly has a remarkable curative effect on patients with lung metastatic brain tumors.

Description

Quinoline derivatives for the treatment of brain tumors

Technical Field

The invention belongs to the field of medicines, and particularly relates to application of a quinoline derivative in treating brain tumors.

Background

The adult brain is a site that is easily metastasized by tumor cells. The brain tumors are divided into two types, namely primary brain tumors and brain metastatic tumors, and the primary brain tumors are primary lesions of the brain tumors and appear in the brain. Brain metastatic tumors are 10 times more abundant than primary brain tumors, and it is estimated that 20% to 40% of cancer patients have intracranial metastases. Metastatic brain tumors include brain parenchymal metastasis (BM) and meningeal metastasis (LM). The most common site of occurrence of brain parenchymal metastases is the cerebral hemisphere, followed by the cerebellum and brainstem. Meningeal metastases are less common than brain parenchyma metastases, but the prognosis is worse. The brain metastatic tumor has different sources, different degrees and different metastatic parts, so the symptoms and the treatment are also greatly different. The therapeutic principle is determined according to specific conditions, slow-developing and limited metastatic focus treatment is mainly carried out locally, surgery or radiotherapy is adopted, systemic chemotherapy is adopted, and the opposite is true for extensive metastasis.

In recent years, with the increase of incidence rate of lung cancer, diagnosis and treatment technologies are continuously developed, so that the life cycle of a patient is prolonged, and the incidence and diagnosis rate of lung cancer brain metastasis are also increased year by year. The incidence of lung cancer brain metastasis is significantly higher than that of melanoma, breast cancer, kidney cancer and colorectal cancer. 20% -65% of lung cancer patients develop brain metastases during the course of the disease, the most common type of brain metastatic tumor. The prognosis of the patient with lung cancer brain metastasis is poor, and the natural average survival time is only 1-2 months.

One long-term follow-up in the U.S. medical insurance supervision, epidemiology and End Results (SEER) database shows 11%, 6% and 12% risk of brain metastasis for lung adenocarcinoma, squamous carcinoma and large cell carcinoma, respectively, in non-metastatic non-small cell lung cancer (NSCLC). The incidence rate of brain metastasis of Small Cell Lung Cancer (SCLC) in the first visit is 10%, the incidence rate of brain metastasis in the diagnosis and treatment process is 40% -50%, and the brain metastasis of patients who survive for more than 2 years reaches 60% -80%, which is one of important factors influencing the survival and life quality of SCLC patients.

The treatment of brain metastatic tumor often becomes worse because the medicine can not effectively penetrate the blood brain barrier, and the patient can progress quickly once the brain metastasis occurs. At present, the treatment means aiming at the brain metastatic tumor is limited. Rapid diagnosis and proper treatment are important for patients with brain metastases, since nerve damage has a profound impact on their quality of life, and any delayed or incorrect treatment will cause serious sequelae to the patient. About 53% of patients with brain metastases have multiple lesions, and are suitable for radiotherapy and chemotherapy. There is therefore a great need to find new chemotherapeutic approaches to the treatment of brain metastatic tumors in an attempt to control the progression of multiple lesions in patients.

Disclosure of Invention

In a first aspect, the present invention provides a method for the treatment of brain tumors, said method comprising administering to a patient in need thereof a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof.

Compound I has the chemical name 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, which has the following structural formula:

in some embodiments, the brain tumor is a primary brain tumor. In some embodiments, the brain tumor is a brain metastatic tumor. In some embodiments, brain metastatic tumors include, but are not limited to, brain parenchymal metastases and meningeal metastases. In some embodiments, the brain metastatic tumor includes, but is not limited to, a brain metastatic tumor in a patient caused by failure of treatment with a chemotherapeutic drug and/or a targeted drug. In some embodiments, the primary cancer of a metastatic tumor of the brain includes, but is not limited to, lung cancer, melanoma, breast cancer, kidney cancer, stomach cancer, adrenal cancer, cervical chorioepithelial cancer, nasopharyngeal cancer, thyroid cancer, pelvic cancer, and colorectal cancer. In some embodiments, the brain metastatic tumor is a lung metastatic brain tumor. In some embodiments, the brain metastatic tumor is a non-small cell lung cancer metastatic brain tumor. In some embodiments, the brain metastatic tumor is a small cell lung cancer metastatic brain tumor.

The present invention also provides a method of treating metastatic tumors of the brain comprising administering to a patient in need thereof a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof. The present invention also provides a method of treating metastatic brain tumor of the lung, comprising administering to a patient in need thereof a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof.

In some exemplary embodiments, the chemotherapeutic agent comprises a first-line chemotherapeutic agent and a second-line chemotherapeutic agent. Some typical embodiments include, but are not limited to, one or more of podophyllum, alkylating agents, camptothecins, taxoids, antimetabolites, antibiotic antineoplastic agents; examples that may be enumerated include, but are not limited to, one or more of temozolomide, pemetrexed, cisplatin, etoposide, carboplatin, nedaplatin, oxaliplatin, miriplatin, lobaplatin, irinotecan, topotecan, paclitaxel, docetaxel, temozolomide, vinorelbine, gemcitabine, cyclophosphamide, doxorubicin, vincristine, bendamustine, epirubicin, methotrexate, and amrubicin. It will be appreciated by those skilled in the art that the patient may also receive radiation therapy either simultaneously with or subsequent to the described chemotherapy.

Compound I can be administered in its free base form, as well as in the form of its salts, hydrates, and prodrugs, which convert in vivo to the free base form of compound I. For example, pharmaceutically acceptable salts of compound I are within the scope of the invention, which salts can be produced from various organic and inorganic acids according to methods well known in the art.

In some embodiments, compound I is administered as the hydrochloride salt of compound I. In some embodiments, compound I is administered as the monohydrochloride salt of compound I. In some embodiments, compound I is administered as the dihydrochloride salt. In some embodiments, the compound I is administered as a crystalline form of the hydrochloride salt of compound I. In a particular embodiment, compound I dihydrochloride is administered as a crystalline form.

Compound I or a pharmaceutically acceptable salt thereof may be administered by a variety of routes including, but not limited to, a route selected from: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical administration, subcutaneous, intraadipose, intraarticular, intraperitoneal and intrathecal. In some particular embodiments, administration is by oral administration.

The amount of compound I or a pharmaceutically acceptable salt thereof administered may be determined according to the severity of the disease, the response to the disease, any treatment-related toxicities, the age and health of the patient. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 2mg to 30 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 6 mg to 20 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof administered is from 8mg to 20 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof administered is from 10mg to 16 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 10mg to 14 mg. In some particular embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is 8 mg. In some particular embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof administered is 10 mg. In some particular embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is 12 mg. In some particular embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is 14 mg.

Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times per day. In some embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, the oral solid formulation is administered once daily.

The method of administration can be determined comprehensively on the basis of the activity, toxicity of the drug, tolerance of the patient, and the like. Preferably, compound I or a pharmaceutically acceptable salt thereof is administered in a manner that results in intermittent administration. The intermittent administration includes a dosing period during which compound I or a pharmaceutically acceptable salt thereof may be administered one or more times per day and a rest period. For example, compound I or a pharmaceutically acceptable salt thereof is administered daily during a dosing period, then the administration is stopped for a period of time during a rest period, followed by a dosing period, then a rest period, and so on, which may be repeated multiple times. Wherein the ratio of the administration period to the withdrawal period in days is 2: 0.5-5, preferably 2: 0.5-3, more preferably 2: 0.5-2, and most preferably 2: 0.5-1.

In some embodiments, the administration is discontinued for 2 weeks. In some embodiments, the administration is 1 time per day for 14 days followed by 14 days off; the administration is then 1 time per day for 14 days and then 14 days off, so that the administration may be repeated a plurality of times at 2-week intervals with 2 weeks off for 2 consecutive administrations.

In some embodiments, the administration is discontinued for 1 week for 2 weeks. In some embodiments, the administration is 1 time per day for 14 days followed by 7 days of rest; the administration is then 1 time per day for 14 days and then 7 days off, so that the administration may be repeated a number of times at 1 week intervals with 2 weeks off for continuous administration.

In some embodiments, the administration is continued for 5 days and discontinued for 2 days. In some embodiments, administration is 1 time per day for 5 days, followed by 2 days off; the administration is followed 1 time per day for 5 days and then discontinued for 2 days, and the administration may be repeated multiple times at intervals of 5 consecutive days and 2 discontinued days.

In certain particular embodiments, the administration is oral at a dose of 12mg once daily for 2 weeks with 1 week rest.

In certain particular embodiments, the 10mg is administered orally once daily for 2 weeks with 1 week rest.

In certain particular embodiments, the 8mg is administered orally once daily for 2 weeks with 1 week rest.

In some embodiments, compound I or a pharmaceutically acceptable salt thereof is administered alone as the sole active ingredient to a patient with brain metastatic tumor. In some embodiments, compound I or a pharmaceutically acceptable salt thereof is administered to a patient with a brain metastatic tumor simultaneously or sequentially with other anti-tumor drugs. In some embodiments, the additional anti-neoplastic agent includes, but is not limited to, one or more of an anti-folate anti-neoplastic agent, a podophyllum anti-neoplastic agent, a hormonal anti-neoplastic agent, an alkylating agent anti-neoplastic agent, a camptothecin anti-neoplastic agent, a fluoropyrimidine derivative, an anthracycline, a taxane, an EGFR inhibitor, a VEGFR inhibitor, a mitomycin, and trastuzumab.

In a second aspect, the present invention provides the use of compound I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of brain tumours.

The invention also provides application of the compound I or pharmaceutically acceptable salts thereof in preparing medicines for treating brain metastatic tumors. The invention also provides application of the compound I or pharmaceutically acceptable salts thereof in preparing medicines for treating lung metastatic brain tumors.

In some exemplary embodiments, the chemotherapeutic agent comprises a first-line chemotherapeutic agent and a second-line chemotherapeutic agent. Some typical embodiments include, but are not limited to, one or more of podophyllum, alkylating agents, camptothecins, taxoids, antimetabolites, antibiotic antineoplastic agents; examples that may be enumerated include, but are not limited to, one or more of temozolomide, pemetrexed, cisplatin, etoposide, carboplatin, nedaplatin, oxaliplatin, miriplatin, lobaplatin, irinotecan, topotecan, paclitaxel, docetaxel, temozolomide, vinorelbine, gemcitabine, cyclophosphamide, doxorubicin, vincristine, bendamustine, epirubicin, methotrexate, and amrubicin. It will be appreciated by those skilled in the art that the patient may also receive radiation therapy either simultaneously with or subsequent to the chemotherapy.

Compound I may be in its free base form, or in the form of its salts, hydrates and prodrugs, which convert in vivo to the free base form of compound I. For example, pharmaceutically acceptable salts of compound I are within the scope of the invention and may be generated from various organic and inorganic acids according to methods well known in the art.

In some embodiments, compound I or a pharmaceutically acceptable salt thereof is the hydrochloride salt form of compound I. In some embodiments, in the form of compound I monohydrochloride. In some embodiments, is the form of compound I dihydrochloride. In some embodiments, is a crystalline form of the hydrochloride salt of compound I. In a particular embodiment, is a crystalline form of compound I dihydrochloride.

The amount of compound I or a pharmaceutically acceptable salt thereof may be determined according to the severity of the disease, the response to the disease, any treatment-related toxicities, the age and health of the patient. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 2mg to 30 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 6 mg to 20 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is from 8mg to 20 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is from 10mg to 16 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is from 10mg to 14 mg. In some particular embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is 8 mg. In some particular embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is 10 mg. In some particular embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is 12 mg. In some particular embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is 14 mg.

Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times daily. In some embodiments, compound I or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, the oral solid formulation is administered once daily.

In some embodiments, the administration is discontinued for 2 weeks. In some embodiments, administration is 1 time per day for 14 days followed by 14 days off; the administration is then 1 time per day for 14 days and then 14 days off, so that the administration may be repeated a plurality of times at 2-week intervals with 2 weeks off for 2 consecutive administrations.

In some embodiments, the administration is discontinued for 1 week for 2 weeks. In some embodiments, administration is 1 time per day for 14 days followed by 7 days of discontinuation; the administration is then 1 time per day for 14 days and then 7 days off, so that the administration may be repeated a number of times at 1 week intervals with 2 weeks off for continuous administration.

In a third aspect, the present invention provides a pharmaceutical composition for treating brain tumor, which comprises compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments, the brain tumor is a primary brain tumor. In some embodiments, the brain tumor is a brain metastatic tumor. In some embodiments, brain metastatic tumors include, but are not limited to, brain parenchymal metastases and meningeal metastases. In some embodiments, the brain metastatic tumor includes, but is not limited to, a brain metastatic tumor in a patient caused by a failure of treatment with a chemotherapeutic drug and/or a targeted drug. In some embodiments, the primary cancer of a metastatic tumor of the brain includes, but is not limited to, lung cancer, melanoma, breast cancer, kidney cancer, stomach cancer, adrenal cancer, cervical chorioepithelial cancer, nasopharyngeal cancer, thyroid cancer, pelvic cancer, and colorectal cancer. In some embodiments, the brain metastatic tumor is a lung metastatic brain tumor. In some embodiments, the brain metastatic tumor is a non-small cell lung cancer metastatic brain tumor. In some embodiments, the brain metastatic tumor is a small cell lung cancer metastatic brain tumor.

The invention also provides a pharmaceutical composition for treating brain metastatic tumors, which comprises the compound I or the pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. The invention also provides a pharmaceutical composition for treating lung metastasis brain tumor, which comprises the compound I or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

Compound I may be in its free base form, or in the form of a salt, hydrate, or prodrug that is converted in vivo to the free base form of compound I. For example, pharmaceutically acceptable salts of compound I are within the scope of the invention and may be generated from various organic and inorganic acids according to methods well known in the art.

In some embodiments, the pharmaceutical composition may be a formulation suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intralipid, intraarticular, intraperitoneal, and intrathecal administration.

In some embodiments, the amount of the pharmaceutical composition administered may be determined based on the severity of the disease, the response to the disease, any treatment-related toxicities, the age and health of the patient. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 2mg to 30 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 6 mg to 20 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is from 8mg to 20 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is from 10mg to 16 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is from 10mg to 14 mg. In some particular embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is 8 mg. In some particular embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is 10 mg. In some particular embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is 12 mg. In some particular embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is 14 mg.

In some embodiments of the present invention, the pharmaceutical composition is a formulation suitable for oral administration, including tablets, capsules, powders, granules, dripping pills, pastes, powders, and the like, preferably tablets and capsules. Wherein the tablet can be common tablet, dispersible tablet, effervescent tablet, sustained release tablet, controlled release tablet or enteric coated tablet, and the capsule can be common capsule, sustained release capsule, controlled release capsule or enteric coated capsule. The oral preparation can be prepared by a conventional method using a pharmaceutically acceptable carrier well known in the art. Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like. Fillers include starch, lactose, mannitol, microcrystalline cellulose, and the like; the absorbent comprises calcium sulfate, calcium hydrophosphate, calcium carbonate and the like; wetting agents include water, ethanol, and the like; the adhesive comprises hydroxypropyl methylcellulose, polyvidone, microcrystalline cellulose, etc.; the disintegrating agent comprises croscarmellose sodium, crospovidone, surfactant, low-substituted hydroxypropyl cellulose, etc.; the lubricant comprises magnesium stearate, pulvis Talci, polyethylene glycol, sodium laurylsulfate, silica gel micropowder, pulvis Talci, etc. The medicinal adjuvants also include colorant, sweetener, etc.

In some embodiments, the pharmaceutical composition is a solid formulation suitable for oral administration. The composition may be in the form of a tablet or capsule, for example. In some particular embodiments, the pharmaceutical composition is a capsule. In some particular embodiments of the invention, the pharmaceutically acceptable carrier of the oral solid formulation comprises mannitol, microcrystalline cellulose, hydroxypropylcellulose, magnesium stearate.

The method of administration can be determined comprehensively depending on the activity, toxicity of the drug, tolerance of the patient, and the like. Preferably, compound I or a pharmaceutically acceptable salt thereof is administered at intervals. The intermittent administration includes a dosing period during which compound I or a pharmaceutically acceptable salt thereof may be administered one or more times per day and a rest period. For example, compound I or a pharmaceutically acceptable salt thereof is administered daily for a dosing period, followed by a rest period for a period of time, followed by a dosing period, followed by a rest period, which may be repeated multiple times. Wherein the ratio of the administration period to the withdrawal period in days is 2: 0.5-5, preferably 2: 0.5-3, more preferably 2: 0.5-2, and still more preferably 2: 0.5-1.

In some embodiments, the administration is discontinued for 2 weeks. In some embodiments, administration is 1 time per day for 14 days followed by 14 days off; followed by 1 administration per day for 14 days and then 14 days, so that the administration may be repeated several times at 2-week intervals.

In some embodiments, the administration is continued for 5 days and discontinued for 2 days. In some embodiments, administration is 1 time per day for 5 days, followed by 2 days off; the administration is then 1 time per day for 5 days and then 2 days off, so that the administration may be repeated a plurality of times at intervals of 5 consecutive days off for 2 days.

In some embodiments, a pharmaceutical composition formulated in a unit dosage form for the treatment of brain tumors is provided. In some embodiments, the pharmaceutical composition in unit dosage form contains 2mg to 30 mg of compound I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains 6 mg to 20mg of compound I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains 8mg to 20mg of compound I or a pharmaceutically acceptable salt thereof, preferably 10mg to 16 mg of compound I or a pharmaceutically acceptable salt thereof, more preferably 10mg to 14 mg of compound I or a pharmaceutically acceptable salt thereof. In some particular embodiments, the pharmaceutical composition in unit dosage form contains 8mg of compound I or a pharmaceutically acceptable salt thereof. In some particular embodiments, the pharmaceutical composition in unit dosage form contains 10mg of compound I or a pharmaceutically acceptable salt thereof. In some particular embodiments, the pharmaceutical composition in unit dosage form contains 12mg of compound I or a pharmaceutically acceptable salt thereof. In some particular embodiments, the pharmaceutical composition in unit dosage form contains 14 mg of compound I or a pharmaceutically acceptable salt thereof.

The invention also provides a pharmaceutical composition of brain metastatic tumor formulated in unit dosage form, which comprises compound I or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier. The invention also provides a pharmaceutical composition of lung metastatic brain tumor formulated in unit dosage form, which comprises compound I or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier.

In some exemplary embodiments, the chemotherapeutic agent comprises a first-line chemotherapeutic agent and a second-line chemotherapeutic agent. Some typical embodiments include, but are not limited to, one or more of podophyllotoxins, alkylating agents, camptothecins, taxanes, antimetabolites, antibiotic antineoplastic agents; examples that may be enumerated include, but are not limited to, one or more of temozolomide, pemetrexed, cisplatin, etoposide, carboplatin, nedaplatin, oxaliplatin, miriplatin, lobaplatin, irinotecan, topotecan, paclitaxel, docetaxel, temozolomide, vinorelbine, gemcitabine, cyclophosphamide, doxorubicin, vincristine, bendamustine, epirubicin, methotrexate, and amrubicin. It will be appreciated by those skilled in the art that the patient may also receive radiation therapy either simultaneously with or subsequent to the described chemotherapy.

Preferably, the pharmaceutical composition is administered in a manner of intermittent administration. The interval administration comprises an administration period and a drug stopping period, and the pharmaceutical composition can be administered once or more times per day in the administration period. For example, the administration of the pharmaceutical composition may be repeated several times, with the administration being given daily, followed by a rest period, followed by an administration period, followed by a rest period. Wherein the ratio of the administration period to the withdrawal period in days is 2: 0.5-5, preferably 2: 0.5-3, more preferably 2: 0.5-2, even more preferably 2: 0.5-1.

In certain particular embodiments, the 12mg dose is administered orally once daily for 2 weeks with 1 week rest.

In certain particular embodiments, the 8mg is administered orally once daily for 2 weeks, and then 1 week off.

In some embodiments, compound I or a pharmaceutically acceptable salt thereof is administered alone as the sole active ingredient to a patient with a brain metastatic tumor. In some embodiments, compound I or a pharmaceutically acceptable salt thereof is administered to a brain metastatic tumor patient simultaneously or sequentially with other anti-tumor drugs. In some embodiments, the other anti-tumor drugs include, but are not limited to, one or more of anti-folic acid anti-tumor drugs, podophyllum anti-tumor drugs, hormone anti-tumor drugs, alkylating agent anti-tumor drugs, camptothecin anti-tumor drugs, fluoropyrimidine derivatives, anthracyclines, taxanes, EGFR inhibitors, VEGFR inhibitors, mitomycin, trastuzumab.

In a fourth aspect, the invention provides a kit comprising (a) at least one unit dose of a pharmaceutical composition of compound I or a pharmaceutically acceptable salt thereof and (b) instructions for the treatment of a brain tumor.

The invention also provides a kit comprising (a) at least one unit dose of a formulation suitable for oral administration of compound I or a pharmaceutically acceptable salt thereof and (b) instructions for use in the treatment of a brain tumor by intermittent administration. In some particular embodiments, a kit is provided comprising (a) at least one unit dose of a tablet or capsule of compound I or a pharmaceutically acceptable salt thereof and (b) instructions for the treatment of a brain tumor by intermittent administration. In some more typical embodiments, the brain tumor is a brain tumor that has failed treatment with a chemotherapeutic and/or targeted drug.

The invention also provides a kit comprising (a) at least one unit dose of a pharmaceutical composition of compound I or a pharmaceutically acceptable salt thereof and (b) instructions for the treatment of a brain metastatic tumor. The invention also provides a kit comprising (a) at least one unit dose of a pharmaceutical composition of compound I or a pharmaceutically acceptable salt thereof and (b) instructions for the treatment of a lung metastatic brain tumor.

Herein, it will be understood by those skilled in the art that radiation therapy and chemotherapy may also be received in an alternating, sequential or simultaneous manner during the administration of a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof to a patient in need thereof.

Herein, the "unit dose" refers to a pharmaceutical composition packaged in a single package for convenience of administration, such as each tablet or capsule. For example, with respect to tablets or capsules, a "pharmaceutical composition in unit dose form" means each tablet or each capsule.

Herein, unless otherwise indicated, the dosages and ranges provided herein are based on the molecular weight of compound I in its free base form.

Crystalline forms of the hydrochloride salt of compound I described herein include, but are not limited to, forms a, B and C disclosed in chinese patent application CN102344438A, wherein forms a and B are crystals substantially free of water of crystallization and other solvents and form C is a crystal containing two water of crystallization. In some embodiments, the crystalline form of the dihydrochloride salt of compound I is form a crystalline.

Unless otherwise indicated, the following terms used in the specification and claims shall have the following meanings for the purposes of this application.

By "patient" is meant a mammal, preferably a human.

By "pharmaceutically acceptable" is meant that it is used to prepare pharmaceutical compositions that are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and include that they are acceptable for human pharmaceutical use.

"pharmaceutically acceptable salts" include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic, trifluoroacetic, propionic, hexanoic, heptanoic, cyclopentanepropionic, glycolic, pyruvic, lactic, malonic, succinic, malic, maleic, fumaric, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, 1, 2-ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-chlorobenzenesulfonic, p-toluenesulfonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, dodecylsulfuric, gluconic, glutamic, hydroxynaphthoic, salicylic, stearic acid and the like.

By "therapeutically effective amount" is meant an amount of a compound that, when administered to a human for the treatment of a disease, is sufficient to effect treatment for the disease.

By "treatment" is meant any administration of a therapeutically effective amount of a compound and includes:

(1) Inhibiting the disease (i.e., arresting the further development of the pathology and/or symptomatology) in a human experiencing or exhibiting the pathology or symptomatology of the disease, or

(2) Ameliorating the disease (i.e., reversing the pathology and/or symptomatology) in a human experiencing or exhibiting the pathology or symptomatology of the disease.

"treatment failure" refers to intolerance of toxic side effects, disease progression during treatment, or relapse after treatment is complete.

"limited-term" was defined according to the staging criteria of the U.S. refuge military hospital lung cancer research group VALG in 1973 as: lesion is in one thoracic cavity and can be taken into the radiotherapy field.

"Wide-term" was defined according to the staging criteria of the U.S. Return military Hospital Lung cancer research team VALG in 1973 as: lesions extend beyond one side of the thorax and include malignancy and cardiac fluid or blood metastases.

"EGFR inhibitor" refers to an epidermal growth factor receptor inhibitor.

"VEGFR inhibitors" refers to inhibitors of vascular endothelial growth factor receptors.

"CR" refers to complete remission, specifically to disappearance of the target lesion of the tumor.

"PR" means partial remission with the sum of target lesion diameters reduced at least 30% from baseline levels.

"PD" refers to disease progression with at least a 20% increase in diameter and relative to the minimum of the sum of all measured target lesion diameters over the course of the study (baseline values are referenced if the baseline measurement is minimal); and it must be satisfied that the relative value of the sum of the diameters increases by at least 5mm, and that disease progression is also considered if one or more new lesions appear.

"SD" refers to stable disease, specifically to a decrease in the extent of a tumor target lesion that does not reach PR levels and an increase that does not reach PD levels, which is in between.

"PFS" refers to progression-free survival, defined as the time from random grouping until objective progression or death of a tumor.

"DCR" refers to the rate of disease control, including complete remission, partial remission, and the percentage of cases stable and sustained for more than 4 weeks among patients with evaluable efficacy.

The "OS" overall survival, refers to the time from the start of the group to death due to any cause. Subjects who were missed in the visit, on a day basis, typically had the last follow-up time counted as dead.

"FAS" refers to a complete analysis data set, and efficacy analysis was performed on all cases with at least one drug, according to the principle of intent to analyze (ITT).

"RECIST1.1" refers to the evaluation criterion 1.1 for the curative effect of solid tumor.

Detailed Description

The present application is further illustrated with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present application.

Example 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine dihydrochloride (dihydrochloride of Compound I)

1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine prepared by the method of example 24 in WO2008112407 and then the title compound was prepared by the method of preparation of "example as salt" in the specification of WO2O 08112407. Or by referring to the method disclosed in Chinese patent application CN 102344438A.

EXAMPLE 2 Capsule containing 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine dihydrochloride (dihydrochloride of Compound I)

Crushing dihydrochloride of the compound I, and sieving the crushed dihydrochloride with a 80-mesh sieve; then evenly mixing with mannitol and hydroxypropyl cellulose; then adding the microcrystalline cellulose with the prescription amount, uniformly mixing, and sieving by a 0.8mm sieve; and finally, adding magnesium stearate with the prescription amount, mixing uniformly, and filling capsules.

Capsules with other contents of dihydrochloride salt of compound I can be prepared in the corresponding proportions and formula in the manner described above.

Example 3 Lung cancer brain metastasis permeability study biological sample analysis

100 μ L of cerebrospinal fluid from a patient with brain metastasis from lung cancer was taken, 50 μ L of internal standard ([ D5] -deuterated compound of formula I, structure shown below) (10 ng/mL) was mixed, 400 μ L of methanol was added, vortexed at 3min, centrifuged at 4 ℃ at 4000rpm for 10min, 150 μ L of supernatant was taken to be placed in a new plate, 100 μ L of mobile phase A was added, vortexed at 3min, and analyzed by LC-MS/MS system injection.

Detection method-LC-MS/MS method

Liquid phase conditions:

phase A: 0.1% aqueous formic acid solution

Phase B: 0.1% methanoic acid solution in methanol

Flow rate: 0.3mL/min

Column temperature: 40 deg.C

A chromatographic column: waters BEH C18.7. Mu.50 x 2.1mm

Mass spectrum conditions:

an ionization mode: (+) ESI

Scanning mode: (MRM) parent ion, fragment ion and Collision Energy (CE):

and (3) measuring results:

TABLE 1 drug concentration in cerebrospinal fluid of patients with lung cancer brain metastases

Serial number	Determination of concentration (ng/mL)
		1	0.358
2	0.353
		3	0.350
4	0.365
		5	0.327
6	0.350
		7	0.352
8	0.353

It is illustrated by table 1 above that the compounds of formula I are capable of penetrating the blood brain barrier in a certain proportion and are present in a certain concentration in the cerebrospinal fluid.

Example 4

A multicenter, randomized, double-blind, placebo-controlled phase II clinical study was conducted in patients with small cell lung cancer with measurable lesions that had previously received standard treatment and recurrence. In this study, 120 patients were enrolled and randomized to receive treatment once a day, 1 capsule of compound I dihydrochloride at a dose of 12mg/0 mg. The oral administration is continued for 2 weeks and stopped for 1 week, i.e. 3 weeks (21 days) for 1 treatment cycle. The age of these patients was between 18-75 years, with the dihydrochloride capsules of compound I and placebo controls excluded from patients who had previously used other, immune-targeted drugs (such as sunitin, bevacizumab, engdu) and the like. And (4) stopping taking the medicine in the subject when the curative effect evaluation standard is determined as the disease Progress (PD) or is clinically considered as the disease progress, and other anti-tumor medicine treatment (such as chemotherapy, targeted therapy or biological agent treatment) influencing the curative effect judgment is used, accidental pregnancy, death and the like. Patients with disease control (CR + PR + SD) and tolerated adverse reactions, continued medication. When the investigator considers the patient to be unsuitable for further medication or to be evaluated as PD according to RECIST1.1 criteria, the medication is terminated. During the medication process, according to the drug-related toxicity reaction degree of the patients and the possible curative effect benefit situation, the researchers decide whether to adjust the dosage, and the adjustable dosage is 8mg/0mg or 10mg/0mg.

In this study, data analysis was performed for the evaluation of the efficacy of patients (30 total cases) in which brain metastases had occurred. The primary efficacy evaluation index is progression-free survival (PFS), and the secondary efficacy index is Overall Survival (OS), objective Remission Rate (ORR) (CR + PR), disease Control Rate (DCR) (CR + PR + SD), quality of life score, and safety. The objective efficacy index was evaluated according to the efficacy evaluation criteria for solid tumors (RECIST 1.1).

All statistical analyses were calculated using the SAS 9.2 statistical analysis software programming. All statistical tests adopt bilateral test, the P value is less than or equal to 0.05, the tested difference is considered to have statistical significance, and the credibility interval adopts 95% credibility.

For the main efficacy index PFS, a product limit method is adopted, 50 percent (median) PFS and PFS at different time after the treatment is started are respectively calculated according to the actual situation of data, and a Log-Rank test is adopted to compare the two groups. The product limit method is adopted for OS, 50% (median) OS is calculated according to the actual situation of the data, and the two groups are compared by adopting Log-Rank test. The statistical data set employs a full analysis data set (FAS). The results of the study are summarized in tables 2 and 3 below.

TABLE 2 analysis of progression free survival (PFS, month) of patients

TABLE 3 analysis of overall survival (OS, month) of patients

Example 5

49 years old female, in 2013 for 10 months, the postoperative pathological diagnosis is left lung inferior lobe small cell lung cancer. MRI 24 days after 12 months in 2016 showed multiple metastases in bilateral cerebral hemisphere, cerebellar hemisphere and brain stem, multiple abnormal signal nodules in liver, and the metastases were considered, which indicated the progress of the disease. The patients were admitted to the hospital for 1 cycle of liposomal paclitaxel + carboplatin + temozolomide chemotherapy and discharged on 28 days 12 months. The TC regimen (paclitaxel + carboplatin) chemotherapy 1 cycle was started on day 17 of 2017, 1 month, and the efficacy evaluation PD was performed on day 10 of 2017, 2 months. IP regimen (irinotecan 120mg d1, 80mg d8; cisplatin 100mg d 1) chemotherapy for 1 cycle on day 16, 2 months, 2017. After 24 days after 4 months, CT indicates that the lesion in the lung and the craniocerebral is stable, the intrahepatic metastatic tumor is enlarged compared with the former, and the curative effect is evaluated as PD; target lesion (64 mm): left lobe nodule and right lobe nodule of liver; non-target lesions: multiple metastases in the brain.

On 12 days 5/2017, a capsule of compound I dihydrochloride, 12mg treatment, was started once daily for 2 weeks and stopped for 1 week, with one dosing cycle every 3 weeks until the disease progressed or was intolerant. The patient has good tolerance during taking the medicine and can continue to take the medicine.

The CT results are as follows:

after cycle 1 dosing: target lesion: 63mm; non-target lesions: non-CR/non-PD.

After cycle 2 dosing: target lesion: 65mm; non-target lesions: non-CR/non-PD.

After cycle 4 dosing: target lesion: 66mm; non-target lesions: non-CR/non-PD.

After cycle 6 dosing: target lesion: 72mm; non-target lesions: non-CR/non-PD.

Claims

1. The application of the compound I or the pharmaceutically acceptable salt thereof in preparing the medicine for treating the small cell lung cancer metastatic brain tumor,

2. the use according to claim 1, wherein the brain tumor is a brain metastatic tumor in the patient caused by the failure of chemotherapy and/or targeted drug therapy.

3. The use according to claim 2, wherein the chemotherapeutic agent is one or more of temozolomide, pemetrexed, cisplatin, etoposide, carboplatin, nedaplatin, oxaliplatin, miriplatin, lobaplatin, irinotecan, topotecan, paclitaxel, docetaxel, temozolomide, vinorelbine, gemcitabine, cyclophosphamide, doxorubicin, vincristine, bendamustine, epirubicin, methotrexate, and amrubicin.

4. The use according to claim 1, wherein the pharmaceutically acceptable salt is a salt of compound I with any of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, hexanoic 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, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid.

5. The use of claim 4, wherein the pharmaceutically acceptable salt is a hydrochloride or maleate salt.

6. The use of claim 4, wherein the pharmaceutically acceptable salt is dihydrochloride.

7. The use according to claim 1, wherein the compound I or the pharmaceutically acceptable salt thereof is administered in a daily dose of 3 mg to 30 mg.

8. The use according to claim 7, wherein the daily dose of compound I or a pharmaceutically acceptable salt thereof administered is from 5 mg to 20 mg.

9. The use according to claim 7, wherein the daily dose of compound I or a pharmaceutically acceptable salt thereof administered is from 8mg to 16 mg.

10. The use according to claim 7, wherein the daily dose of compound I or a pharmaceutically acceptable salt thereof administered is from 8mg to 14 mg.

11. The use according to claim 7, wherein the daily dose of compound I or the pharmaceutically acceptable salt thereof administered is 8mg, 10mg or 12 mg.

12. The use according to any one of claims 1 to 11, wherein compound I or the pharmaceutically acceptable salt thereof is administered at intervals between an administration period and a withdrawal period.

13. Use according to claim 12, wherein the ratio of the administration period to the withdrawal period in days is 2.

14. The use according to claim 12, wherein the ratio of the administration period to the withdrawal period in days is 2.

15. Use according to claim 12, wherein the ratio of the administration period to the withdrawal period in days is 2.

16. The use according to claim 12, wherein the ratio of the administration period to the withdrawal period in days is 2.

17. Use according to claim 12, wherein the interval administration is selected from one of the following: the drug is stopped for 2 weeks, 1 week for 2 weeks, or 2 days for 5 days.

18. The use according to claim 17, wherein the intermittent administration is 2 weeks continuous with 1 week off.