CN111956649A - Quinoline derivatives or pharmaceutically acceptable salts thereof for use in the combined treatment of interstitial lung disease - Google Patents

Abstract

The invention discloses a quinoline derivative or a pharmaceutically acceptable salt thereof for combined treatment of interstitial lung diseases, and provides application of a therapeutically effective amount of quinoline compound I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a second therapeutic medicament in preparation of medicaments for treating interstitial lung diseases, wherein the chemical name of the quinoline compound I is 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine.

Description

Quinoline derivatives or pharmaceutically acceptable salts thereof for use in the combined treatment of interstitial lung disease

Technical Field

The present application is in the field of pharmaceutical technology and relates to the use of quinoline derivatives or a pharmaceutically acceptable salt thereof for the combined treatment of interstitial lung disease.

Background

Lung cancer is one of the most common malignant tumors in the world at present, the treatment means of lung cancer mainly includes surgery, chemotherapy, radiotherapy, targeted therapy, etc., however, various related side reactions are inevitably generated while the treatment is performed, and Interstitial Lung Disease (ILD) is one of the main side reactions of radiotherapy, chemotherapy and targeted therapy. ILD is a general term for clinical pathological entities consisting of heterogeneous disease groups with diffuse lung parenchyma, alveolitis and interstitial fibrosis as basic pathological changes, active dyspnea, X-ray chest radiographs as diffuse shadows, restrictive ventilatory dysfunction, diffuse dysfunction and hypoxemia as clinical manifestations, ranging from benign infiltration to fatal acute respiratory distress syndrome. Since ILD associated with chemotherapy, radiation therapy and targeted therapies is an unpredictable, rapidly developing, difficult to diagnose disease, it severely impacts the prognosis and even endangers the life of the patient. How to systematically assess factors associated with ILD is essential to prevent, diagnose, and treat ILD.

The term ILD was used as early as the 18 th Association of the Aspen pulmonary family in 1975. ILD was again investigated at the 28 th Aspen pulmonal discussion in 10 years (1985). Research into ILDs has progressed greatly over decades of development. Interstitial lung diseases are a group of diffuse diseases of the lung that mainly involve the pulmonary interstitium, alveoli and bronchioles, and are also commonly referred to as diffuse Parenchymal Lung Diseases (PLD). ILD is not an independent disease, it includes more than 200 disease species. Although clinical manifestations, laboratory and pathological changes of each disease are individually characterized, they share some common clinical, respiratory pathophysiology and chest X-ray features, manifested as progressive exertional breathlessness, restricted ventilation dysfunction with diffuse functional decline, hypoxemia and radiographic diffuse double lung lesions. The disease course progresses slowly, the alveolar-capillary functional unit is gradually lost, and finally diffuse pulmonary fibrosis and honeycomb lung are developed, so that the respiratory function is exhausted and died. Approximately 20% -30% of non-small cell lung cancer patients and 4.5% of small cell lung cancer patients are diagnosed with lung cancer and are found to have interstitial lung disease at the same time. In recent years, with the continuous progress of medical technology level, the research and development of chemotherapy drugs, the improvement of radiotherapy technology and the emergence of targeted drugs gradually diversify the treatment means of lung cancer, and the life cycle of lung cancer patients is obviously prolonged compared with the prior art. However, while the hope is seen, the side effects caused by radiotherapy, chemotherapy and targeted therapy, especially the occurrence of interstitial lung disease, seriously affect the prognosis of patients, and become a problem which cannot be ignored in the future treatment process. Pulmonary fibrosis occurs at the end of most interstitial lung diseases.

Pulmonary fibrosis is the terminal change of a large group of lung diseases characterized by fibroblast proliferation and massive extracellular matrix aggregation with inflammatory injury and tissue structure destruction, namely structural abnormality (scar formation) caused by abnormal repair after normal alveolar tissues are damaged. The majority of patients with pulmonary fibrosis have unknown etiology (idiopathic), and this group of diseases is called Idiopathic Interstitial Pneumonia (IIP), which is a large group of interstitial lung diseases. The most common disease type with pulmonary fibrosis as the main manifestation is Idiopathic Pulmonary Fibrosis (IPF), which is a serious interstitial lung disease that can lead to progressive loss of lung function. Pulmonary fibrosis seriously affects the respiratory function of the human body, manifested as dry cough and progressive dyspnea (insufficient subjective qi), and the respiratory function of the patient is continuously worsened with the aggravation of the disease condition and the lung injury. The incidence and mortality of idiopathic pulmonary fibrosis increases year by year, with an average survival period of only 2.8 years after diagnosis, with mortality rates higher than that of most tumors, known as a "neoplastic-like disease".

Disclosure of Invention

The invention aims to provide a new application of quinoline compound I or pharmaceutically acceptable salt thereof aiming at the defects in the prior art.

The purpose of the invention is realized by the following technical scheme:

the present invention provides the use of a therapeutically effective amount of a quinoline compound I, having the chemical name 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a second therapeutic agent, in the manufacture of a medicament for the treatment of interstitial lung disease, having the structural formula:

for interstitial lung disease

In some embodiments of the present application, the Interstitial Lung Disease (ILD) includes known causes of interstitial lung disease and interstitial lung disease of unknown etiology.

In some embodiments of the present application, the interstitial lung disease is manifested as pulmonary fibrosis formed during inflammation and repair; in some embodiments, the interstitial lung disease is a disease with pulmonary fibrosis as a pathological manifestation; pulmonary fibrosis, which can be caused by any etiology in the present application, is initially manifested by alveolar inflammation and/or alveolar cell injury, and then inflammation and abnormal repair lead to lung interstitial cell proliferation, which produces a large amount of collagen and extracellular matrix, and with the progress of inflammatory immune response, lung interstitial fibrosis and collagen deposition lead to the change of alveolar structure, resulting in pulmonary fibrosis.

In some embodiments, interstitial lung diseases of unknown etiology include, but are not limited to, Idiopathic Interstitial Pneumonia (IIP), granuloma, interstitial lung diseases associated with vasculitis, interstitial lung diseases associated with liver diseases, interstitial lung diseases associated with intestinal diseases, and the like.

In some embodiments, the interstitial lung disease is an interstitial lung disease of unknown etiology. In some embodiments, the interstitial lung disease is a disease of unknown etiology with pulmonary fibrosis as a pathological manifestation. In one embodiment, the pulmonary fibrosis described herein is Idiopathic Interstitial Pneumonia (IIP).

In one embodiment, the idiopathic interstitial pneumonia described herein includes, but is not limited to, major idiopathic interstitial pneumonia, rare idiopathic interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia.

In one embodiment, the primary idiopathic interstitial pneumonia described herein includes, but is not limited to, Idiopathic Pulmonary Fibrosis (IPF), idiopathic nonspecific interstitial pneumonia (iNSIP), bronchiolitis respiratory with interstitial lung disease (RB-ILD), Desquamating Interstitial Pneumonia (DIP), cryptogenic interstitial pneumonia (COP), Acute Interstitial Pneumonia (AIP).

In one embodiment, the rare idiopathic interstitial pneumonia described herein includes, but is not limited to, Idiopathic Lymphocytic Interstitial Pneumonia (iLIP), idiopathic pleuropneumoniae parenchymal fibroplasia (ipfe).

In one embodiment, the pulmonary fibrosis described herein is Idiopathic Pulmonary Fibrosis (IPF).

In some embodiments, interstitial lung diseases of known cause include, but are not limited to: (1) occupational, environmental factor-related interstitial lung diseases, such as: sucking inorganic dust: silicosis, asbestosis, pneumoconiosis and pneumoconiosis; sucking organic dust: exogenous allergic alveolitis; animal protein: lung of pigeon or bird; thermophilic actinomycetes: farmer's lungs, bagasse lungs, mushroom lungs, etc.; gas/smoke: nitrogen oxides, sulfur dioxide, metal oxides, and the like; (2) interstitial lung diseases associated with lung infections, such as: viral and bacterial interstitial lung diseases: disseminated tuberculosis, pneumocystis carinii, and various bacteria and viruses (CMV, SARS, HIV, etc.); (3) drug/therapy-related interstitial lung diseases, such as: anti-tumor drugs include targeted drug-induced interstitial lung disease: wherein the anti-tumor drugs include but are not limited to bleomycin, mitomycin, methotrexate and the like; and interstitial lung diseases caused by antibiotics and chemicals: including but not limited to furans, sulfonamides, amiodarone, hypoglycemic agents, contraceptive agents, non-steroidal anti-inflammatory agents, anti-spasmodics (phenytoin sodium, carbamazepine), penicillamine, colchicine, tricyclic antidepressants, methadone, radiation exposure, high concentration oxygen uptake, misuse of paraquat, etc.; (4) interstitial lung disease associated with collagen vasculature disease: for example: interstitial lung diseases related to Rheumatoid Arthritis (RA), Progressive Systemic Sclerosis (PSS), Systemic Lupus Erythematosus (SLE), polymyositis and dermatomyositis (PM/DM), sjogren's syndrome, Mixed Connective Tissue Disease (MCTD), and the like; (5) other diseases such as ARDS convalescent period, chronic left heart insufficiency, chronic renal insufficiency, cancerous lymphangitis, and interstitial lung disease caused by graft rejection.

In some embodiments, the interstitial lung disease is an interstitial lung disease of known etiology. In some embodiments, the interstitial lung disease is a disease of known etiology with pulmonary fibrosis as a pathological manifestation. In some embodiments, the etiology includes, but is not limited to, drug, environmental, connective tissue disease, allergic etiology, genetic etiology, and radioactive predispositions. In some embodiments, the interstitial lung disease is drug-induced pulmonary fibrosis. In some embodiments, the interstitial lung disease is radiation pulmonary fibrosis.

In some embodiments, the causative agent is a cytotoxic drug or a non-cytotoxic drug.

In some embodiments, the cytotoxic drug includes, but is not limited to, one or more of an anti-tumor antibiotic, an alkylating agent, an anti-metabolite. Wherein, the antitumor antibiotics include but are not limited to one or more of bleomycin, mitomycin, pingyangmycin, doxorubicin and aprepitant; the alkylating agent comprises one or more nitrosoureas such as busulfan, cyclophosphamide, ifosfamide, chlorambucil, migfarl, carmustine (carmustine), lomustine and the like; the antimetabolite includes but is not limited to one or more of methotrexate, edatrexate, azathioprine, cytarabine, fludarabine, gemcitabine, hydroxyurea, bortezomib, procarbazine and fluorouracil.

In some embodiments, the non-cytotoxic drug includes, but is not limited to, one or more of alkaloids, molecularly targeted drugs, immunosuppressants, cardiovascular drugs, anti-hormonal drugs, organic solvents, other drugs. Wherein, the alkaloids include but are not limited to one or more of paclitaxel, docetaxel, etoposide, irinotecan and vincristine; the molecular targeting drug comprises but is not limited to one or more of adalimumab, alemtuzumab, bevacizumab, rituximab, trastuzumab, infliximab, erlotinib, etanercept, imatinib, gefitinib and granulocyte colony stimulating factor; the immunosuppressant includes but is not limited to lenalidomide, thalidomide, sirolimus; the antibiotic includes but is not limited to one or more of nitrofurantoin, sulfasalazine, amphotericin B and isoniazid; the cardiovascular drugs include but are not limited to one or more of amiodarone, mexiletine, procaine, coumarin derivatives, hydrochlorothiazide, statins and B receptor blockers; the anti-hormone drugs include but are not limited to one or more of tamoxifen, bicalutamide and nilutamide; the organic solvent includes but is not limited to one or more of trichloroethylene, carbon tetrachloride, dichlorodifluoroethane and gasoline; the other drugs include, but are not limited to, one or more of leflunomide, penicillamine, gold preparations, interferon, measles vaccine, paraquat, carbamazepine, sodium valproate, levodopa, ergonovine, phenytoin sodium, bromocriptine, mesalamine, serrate peptidase, cabergoline, and propylthiouracil.

In some embodiments, the agent causing the etiology is an antacid, an anti-fibrotic drug (e.g., colchicine, D-penicillamine, pirfenidone, etc.), a glucocorticoid drug (e.g., prednisone, methylprednisolone, betamethasone, beclomethasone propionate, dipalmitosone, prednisolone, hydrocortisone, dexamethasone, etc.), a small molecule targeted drug (as described below), or an immunosuppressive drug (e.g., azathioprine or cyclophosphamide or cyclosporine).

For the second therapeutic agent

In some embodiments, the second therapeutic agent is an antacid, an anti-fibrotic drug (e.g., colchicine, D-penicillamine, pirfenidone, etc.), a glucocorticoid drug (e.g., prednisone, methylprednisolone, betamethasone, beclomethasone propionate, dipalmitosone, prednisolone, hydrocortisone, dexamethasone, etc.), or an immunosuppressive drug (e.g., azathioprine or cyclophosphamide or cyclosporine).

In some embodiments, the second therapeutic agent is a small molecule targeted agent, including but not limited to a protein kinase inhibitor. Wherein, the protein kinase inhibitor includes but is not limited to tyrosine kinase inhibitor, serine and/or threonine kinase inhibitor, the target of the inhibitor includes but is not limited to EGFR (epidermal growth factor receptor), Anaplastic Lymphoma (ALK), MET gene, ROS1 gene, HER2 gene, RET gene, BRAF gene, PI3K signal path, DDR2 (discoid death receptor 2) gene, FGFR1 (fibroblast growth factor receptor 1), NTRK1 (neurotrophic tyrosine kinase type 1 receptor) gene, KRAS gene; the target of the small molecule targeted drug also comprises COX-2 (cyclooxygenase-2), APE1 (apurinic apyrimidinic endonuclease), VEGFR-2 (vascular endothelial growth factor receptor-2), CXCR-4 (chemokine receptor-4), MMP (matrix metalloproteinase), IGF-1R (insulin-like growth factor receptor), Ezrin, PEDF (pigment epithelium derived factor), AS, ES, OPG (bone protection factor), Src and IFN, ALCAM (leukocyte activated adhesion factor), HSP, jis 1, GSK-3 β (glycogen synthesis kinase 3 β), CyclinD1 (cell cycle regulatory protein), CDK4 (cyclin dependent kinase), TIMP1 (tissue metalloproteinase inhibitor), THBS3, PTHR1 (parathyroid hormone-related protein receptor 1), TEM7 (human tumor vascular endothelial marker 7), COPS3, cathepsin K. Examples of small molecule targeted drugs include, but are not limited to, Sunitinib (Sunitinib), Nilotinib (Nilotinib), bosutinib (bosutinib), ceratinib (saratanib), Pazopanib (Pazopanib), Trabectedin (Trabectedin), Regorafenib (Regorafenib), Cediranib (Cediranib), Bortezomib (Bortezomib), Panobinostat (panosostat), Carfilzomib (carfilmib), ixazoib (ixazob), apatinib (apatinib), Afatinib (Afatinib), Crizotinib (critinib), Ceritinib (Ceritinib), Vemurafenib (darafenib), darafenib (dabrytinib), Nilotinib (Nilotinib), Nilotinib (bletinib), Nilotinib (Nilotinib), lanitinib (bletinib), Nilotinib (bletinib), lanitinib (bletinib), Nilotinib (bletinib), lantinib (lantinib), or (lantinib), or, Sorafenib (Sorafenib), tematinib (Olmutinib), Wolininib (Savoltinib), Fuquintinib (Fruquintinib), Entretinib (Entretinib), Dasatinib (Dasatinib), Ensatinib (Ensartinib), Levatinib (Lenvatinib), itacetinib, Pyrolinib (Pyratinib), Bimetinib (Binimitinib), Ervatinib (Erzatitinib), Axitinib (Axitinib), lenatinib (Neratinib), Coblitinib (Coblitinib), Alcalitinib (Acalantinib), Famitatinib (Famitininib 931), Masitinib (Masitinib), Iibritinib (Icinininib), Icinib (Icinicib), erlotinib (Lmitrinib), Lloyb (ALibrib-803, L-1205, L-101-L-101, L-101-01-101, L-3, L-a, tomivosertib, AST-2818, SKLB-1028, D-0316, LY-3023414, allitinib, MRTX-849, AP-32788, AZD-4205, lifirafenib, vactor-tib, mivebresib, napubucasin, sitravatinib, TAS-114, molibresib, CC-223, rivoceranib, CK-101, LXH-254, simotinib, GSK-3368715, TAS-0728, malitinib, tepotinib, HS-10296, AZD-4547, merestib, olaptedpipegol, galuninsertralib, ASN-003, gedatolisib, defatinib, lazerinib, lazeii-27, BPS-90076, BPI-4916, Skib-1028-7, ASN-377, SANZ-3780, SANZ-379, SANTC-3780, SANZ-3611, SANTB-369, SANTILOB-369, SAC-379, SAC-3780, SANTB, SANTICK-369, SANTB, SANTILOB-369, SAC-3780, SAC-7, SANTC-7, SANTB, SANTICK-7, SANTICTIB, SAID, SANTICK-7, SANTICS-7, SAID, SANTICTIB, SAID, Siremaddin, Telaglenastat, MP-0250, GLG-801, ABTL-0812, bortezomib, panobinostat (panobinostat), tucidinostat, vorinostat, remininostat, epacadostat, tazemetostat, entinostat, mocetinostat, quisinostat, LCL-161, KML-001. In some embodiments, the small molecule targeted drug is sorafenib, afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozantinib, dacomitinib, oxitinib, ibrutinib, brigatinib, loratinib, trametinib, larotinib, erlotinib, lapatinib, vandetanib, sematinib, tematinib, voritinib, furaquitinib, emtricitinib, dasatinib, emsatinib, lesatinib, lucatinib, itatinib, itacintinib, piriminib, bimatinib, ertinib, acetinib, lenatinib, cobitinib, acartitinib, famitinib, imatinib, nilotinib, perrolizumab, nilolizumab, perlitinib, Nivolumab, temab, temozolizumab, temab, trevallizumab, trevalinomumab, trolizumab, nilvalizumab, nilutab, nilutamab, nilutab, nilutamab, nilutab, and a, One or more of regorafenib, sunitinib, Endostatin (Endostatin), Cetuximab (Cetuximab), MK2206, BYL719, pazopanib, eribulin, cediranib, palbociclib, Trabectedin (trabectedentidine; trade name Yondelis), sorafenib, ridaforolimus, everolimus, temsirolimus, olaratumab, bevacizumab, olaratumab, cixutumumab, conatumumab, eribulin mesylate, AMG479, figltummab, and IMC-a 12.

In some embodiments, the second therapeutic agent is FG-3019, Aviptadil, BG00011, CC-90001, GLPG1690, INOpusle, KD025, Lebrikizumab, MK-7264, MN-001, Pamrevlumab, PBI-4050, PRM-151, DS-102, CKD-942, SAR-156597, TD139, ZSP-1603, Yinfenidone Hydrochloride, Neumomir, ZL-2102, Compound21, GSK3008348, HEC585, IW001, MMI-0100, Omipalisib, PX-1251, or S-5338, and the like.

In some embodiments, the second therapeutic agent is pirfenidone.

In some embodiments, the second therapeutic agent is nintedanib.

In some embodiments, the second therapeutic agent is FG-3019.

Quinoline compounds I

Quinoline 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 quinoline compound I. For example, pharmaceutically acceptable salts of quinoline compounds 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.

Further, the pharmaceutically acceptable salt thereof is a salt formed by the quinoline compound I and 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; preferably in the form of the hydrochloride or maleate salt, more preferably the dihydrochloride salt.

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

Further, the amount of quinoline compound I or a pharmaceutically acceptable salt thereof to be administered in the combination may be determined according to the severity of the disease, the response to 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 thereof, administered is from 3 mg to 30 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 5 mg to 20 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 8 mg to 16 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof administered is from 8 mg to 14 mg. In a particular embodiment, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is 8 mg. In a particular embodiment, compound I or a pharmaceutically acceptable salt thereof is administered in a daily dose of 10 mg. In a particular embodiment, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is 12 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.

The method of administration of compound I 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 spaced-apart manner. 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 still more preferably 2: 0.5-1.

Further preferably, compound I or a pharmaceutically acceptable salt thereof is administered at intervals of one of the following: stopping the drug for 2 weeks after 2 weeks of continuous administration, for 1 week after 2 weeks of continuous administration, or for 2 days after 5 days of continuous administration; the intermittent administration mode may be repeated a plurality of times.

In some embodiments, compound I is administered simultaneously or sequentially with one or more second therapeutic agents. In certain embodiments, the one or more second therapeutic agents have been administered to the subject prior to administration of compound I or prior to combination with compound I. In certain embodiments, the one or more second therapeutic agents are administered to the subject again after administration of compound I or after combination with compound I. In certain embodiments, compound I has been administered to the subject prior to or in combination with the one or more second therapeutic agents. In certain embodiments, compound I is administered to the subject again after administration of the one or more second therapeutic agents or after combination with the one or more second therapeutic agents. In certain embodiments, the one or more second therapeutic agents are not effective in treating cancer. In some embodiments, the second therapeutic agent is any anti-cancer agent described herein or known in the art.

Further, the combination is a formulation suitable for any administration form, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intralipid, intraarticular, intraperitoneal or intrathecal.

Wherein, the quinoline compound I or the pharmaceutically acceptable salt thereof with the effective treatment amount is preferably suitable for oral preparations, 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 hydrogen phosphate, calcium carbonate, etc.; wetting agents include water, ethanol, and the like; the binder comprises hypromellose, 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 one embodiment, 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 a particular embodiment, the pharmaceutical composition is a capsule. In a particular embodiment of the invention, the pharmaceutically acceptable carrier of the oral solid formulation comprises mannitol, microcrystalline cellulose, hydroxypropylcellulose, magnesium stearate.

In another aspect, the invention provides a method of treating interstitial lung disease, comprising administering to a patient in need thereof a therapeutically effective amount of quinoline compound I, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a second therapeutic agent, simultaneously, intermittently or sequentially.

In a further aspect, the invention provides a combination for the treatment of an interstitial lung disease comprising a therapeutically effective amount of quinoline compound I, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a second therapeutic agent.

Compared with the prior art, the invention has the beneficial effects that: the compound I or the pharmaceutically acceptable salt thereof and the second treatment medicament are combined for application, and the compound I or the pharmaceutically acceptable salt thereof can obviously enhance the killing effect of medicaments, particularly chemotherapeutic medicaments, on interstitial lung diseases, enhance the curative effect and reduce the dosage of the chemotherapeutic medicaments, thereby reducing the side effect. The invention provides a new idea for the treatment of interstitial lung diseases, in particular to the second-line treatment of interstitial lung diseases which fail to be treated by radiotherapy and chemotherapy medicaments.

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, t-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 control of 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 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.

Detailed Description

The present application is further described below with reference to specific examples, which, however, are only for illustration and do not limit the scope of the present application. Likewise, the present application is not limited to any particular preferred embodiment described herein. It will be understood by those skilled in the art that equivalents may be made to the features of the present application or modifications may be made thereto without departing from the scope of the invention. The reagents used in the following examples are commercially available products, and the solutions can be prepared by techniques conventional in the art, except where otherwise specified.

While the compositions and methods of this application have been described in terms of preferred embodiments in light of the present disclosure, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the application.

The disclosures of all documents cited herein are incorporated by reference herein, to the extent that they provide exemplary, procedural and other details supplementary to those set forth herein.

Claims (10)

1. The use of a therapeutically effective amount of quinoline compound I or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of a second therapeutic agent in the manufacture of a medicament for the treatment of interstitial lung disease,

2. the use of claim 1, wherein the interstitial lung disease comprises an interstitial lung disease of known cause and an interstitial lung disease of unknown etiology; preferably, the interstitial lung diseases of unknown etiology include idiopathic interstitial pneumonia, granuloma, vasculitis-associated interstitial lung diseases, liver disease-associated interstitial lung diseases, intestinal disease-associated interstitial lung diseases; in the known causes of interstitial lung disease, the causes include drug, environmental, connective tissue disease, allergic causes, genetic causes, and radiation predisposing causes; or preferably, the interstitial lung disease is manifested as pulmonary fibrosis formed during inflammation and repair; or preferably, the interstitial lung disease is a disease with pulmonary fibrosis as a pathological expression.

3. The use of claim 1 or 2, wherein the idiopathic interstitial pneumonia comprises major idiopathic interstitial pneumonia, rare idiopathic interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia; preferably, the main idiopathic interstitial pneumonia comprises idiopathic pulmonary fibrosis, idiopathic nonspecific interstitial pneumonia, respiratory bronchiolitis with interstitial lung disease, desquamation interstitial pneumonia, cryptogenic interstitial pneumonia, acute interstitial pneumonia; the rare idiopathic interstitial pneumonia comprises idiopathic lymphocytic interstitial pneumonia and idiopathic pleuropneumoniae parenchymal elastic fiber hyperplasia.

4. The use according to any one of claims 1 to 3, wherein the second therapeutic agent is an antacid, an antifibrotic, a glucocorticoid or an immunosuppressive agent; preferably, the second therapeutic agent comprises colchicine, D-penicillamine, pirfenidone, prednisone, methylprednisolone, betamethasone, beclomethasone dipropionate, debaosone, prednisolone, hydrocortisone, dexamethasone, azathioprine, cyclophosphamide or cyclosporine.

5. The use according to any one of claims 1 to 3, wherein the second therapeutic agent is a small molecule targeted drug, preferably a tyrosine kinase inhibitor, a serine and/or threonine kinase inhibitor; further preferably small molecule targeted drugs of EGFR, anaplastic lymphoma, MET gene, ROS1 gene, HER2 gene, RET gene, BRAF gene, PI3K signaling pathway, DDR2 gene, FGFR1, NTRK1 gene, KRAS gene, COX-2, APE1, VEGFR-2, CXCR-4, MMP, IGF-1R, Ezrin, PEDF, AS, ES, OPG, Src, IFN, ALCAM, HSP, JIP1, glycogen synthesis kinase 3 beta, CyclinD1, CDK4, TIMP1, THBS3, PTHR1, TEM7, COPS3, cathepsin K; further preferably selected from sunitinib, nilotinib, bosutinib, secatinib, pazopanib, trabectedin, regorafenib, cediranib, bortezomib, panobistat, carfilzomib, ixazomi, apatinib afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozertinib, dacomitinib, oxitinib, erlotinib, brigatinib, luratinib, tremerinib, erlotinib, lapatinib, vandetanib, semetinib, sorafenib, temotinib, voritinib, furatinib, emtricitinib, dasatinib, emtinib, getinib, rivatinib, itatinib, pyrroltinib, bimatinib, erlotinib, axitinib, lecitinib, lenitinib, lotinib, lenitinib, loxatinib, erlotinib, irinotectinib, gefitinib, erlotinib, gefitinib, erlotinib, vorolanib, bemcentinib, caplatinib, entretinib, TAK-931, ALT-803, palbociclib, famitinib L-malate, LTT-462, BLU-667, ningetinib, tipifarnib, poziotiib, DS-1205c, capivatilib, SH-1028, metformin, selicinib, OSE-2101, APL-101, berzosertib, idelalisib, lericiclib, ceralastib, PLB-1003, tomivotiib, AST-2818, SKLB-1028, D-0316, LY-3023414, alitininib, MRTX-849, AP-32788, AZD-4205, liptefenib, vacitinib, ASN-4996, AST-908, SANb-085, SANbS-078, SANbz-078, SAK-076, SAK-072, SAK-078, SANgrain-50, SANbS-366347, SANgrain-366347, SANb, SANbS-369, SANb, SANgutilissib, SANbz-072, SANbz-3, SANbz, SA, One or more of RMC-4630, AZD-3759, antirestenol, SAF-189s, AT-101, TTI-101, naputinib, LNP-3794, HH-SCC-244, ASK-120067, CT-707, epitinib succinate, tesevatinib, SPH-1188-11, BPI-15000, copanlisib, miraparib, olaparib, veliparib, talazoparatosylate, DV-281, Siremadlin, Telalgenastat, MP-0250, GLG-801, ABTL-0812, bortezomib, panobile, tucidinostat, vorinostat, reminiostat, epacadiostat, tazemetostat, motinostat, mocetinostat, quichinostat, LCL-161, KML-161; more preferably, the small molecule targeted drug is sorafenib, afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozantinib, dacomitinib, oxitinib, oletinib, brigatinib, loratinib, trametinib, larotinib, erlotinib, lapatinib, vandetanib, sematinib, tematinib, voritinib, furaquitinib, emtricitinib, dasatinib, emtinib, lenvatinib, itatinib, itacintinib, pyrroltinib, bimatinib, ertinib, axitinib, lenatinib, lenacitinib, cocatinib, alcalitinib, famitinib, isertinib, ibrutinib, pevollizumab, nivolumimab, atemab, attalizumab, temab, temozolizumab, temab, treumumab, trevallizumab, beauvelizumab, trelizumab, nilutab, nilutamab, and nilutamab Sunitinib, endostatin, cetuximab, MK2206, BYL719, pazopanib, eribulin, cediranib, palbociclib, trabectedin, sorafenib, ridaforolimus, everolimus, temsirolimus, Olarmab, bevacizumab, olaratumab, cixutumumab, conatumumab, eribulin mesylate, AMG479, Figlutumamab, IMC-A12.

6. The use according to any one of claims 1 to 3, wherein the second therapeutic agent is FG-3019, Aviptadil, BG00011, CC-90001, GLPG1690, INOpusle, KD025, Lebrikizumab, MK-7264, MN-001, Pamrevlumab, PBI-4050, PRM-151, DS-102, CKD-942, SAR-156597, TD139, ZSP-P, Yinfenidone Hydrochorride, Neumomir, ZL-2102, Compound21, GSK3008348, HEC585, IW001, MMI-0100, Omiplalisib, PAT-1251 or PXS-5338.

7. The use of any one of claims 1-3, wherein the second therapeutic agent is pirfenidone, FG-3019, or nintedanib.

8. The use according to any one of claims 1 to 7, wherein the daily dose for the administration of quinoline compound I or a pharmaceutically acceptable salt thereof is from 3 mg to 30 mg, preferably from 5 mg to 20 mg, more preferably from 8 mg to 16 mg, even more preferably from 8 mg to 14 mg, most preferably 8 mg, 10 mg, 12 mg.

9. The use according to any one of claims 1 to 7, wherein the therapeutically effective amount of quinoline compound I or a pharmaceutically acceptable salt thereof and the therapeutically effective amount of the second therapeutic agent are administered simultaneously or separately and not sequentially.

10. The use of any one of claims 1-7, wherein the medicament for the treatment of interstitial lung disease is a formulation suitable for any mode of administration, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intralipid, intra-articular, intraperitoneal, or intrathecal.