WO2020078445A1 - Pharmaceutical combination or pharmaceutical composition for treatment of fibrotic diseases - Google Patents

Abstract

A pharmaceutical combination or a pharmaceutical composition for the treatment of fibrotic diseases, and a use for said pharmaceutical combination or pharmaceutical composition in the preparation of drugs for preventing and/or treating fibrotic diseases.

Description

Medicine combination or medicine composition for treating fibrosis disease Technical field

The present invention belongs to the field of medicine, and relates to a medicinal combination or medicinal composition for treating fibrotic diseases, and the use of the medicinal combination or medicinal composition for preparing a medicament for preventing and / or treating fibrotic diseases.

Background technique

Organ tissue fibrosis is called fibrosis, and severe cases cause tissue structure destruction and organ sclerosis. Tissue fibrosis not only occurs in the lungs, liver and other organs, but can affect almost all organs and systems of the human body. It is caused by substantial cell damage due to various reasons (such as inflammation, immunity, poison, ischemia and hemodynamic changes, etc.) , And then cause inflammation and deformation of the parenchymal cells, necrosis, and activate the corresponding macrophages to release a variety of cytokines and growth factors, these factors activate the resting extracellular matrix (ECM) to produce cells, making it into Myofibroblasts; Myofibroblasts proliferate and secrete cytokines, which then act on macrophages by paracrine. Myofibroblasts can synthesize large amounts of collagen and other ECM components, while ECM degradation is reduced, resulting in fibrosis of organs or tissues. Therefore, the occurrence and development of organ or tissue fibrosis is the result of the interaction of cells, cytokines and ECM, and the participation of multiple factors. In view of the important role of ECM-producing cells in the formation of organ or tissue fibrosis, one of the current important targets for the treatment of organ or tissue fibrosis is to inhibit the proliferation, activation and induction of apoptosis of ECM-producing cells.

Due to the different functions and morphologies of various organs or tissues, as well as the differences in the main constituent cells of each organ or tissue, the fibrosis of different organs or tissues has both commonness and personality in its pathogenesis; taking ECM-producing cells as an example: liver Hepatic stellate cells in the middle, mesangial cells in the glomeruli, renal interstitial fibroblasts in the renal interstitium, lung fibroblasts in the lungs, cardiac fibroblasts in the heart, and Peritoneal mesothelial cells. Therefore, there are certain differences in the pathogenesis and treatment targets of fibrosis in different organs or tissues.

Patent applications CN 103965199 and WO 2014130375 disclose the compound N- (5- (3-cyanopyrazolo [1,5-a] pyridin-5-yl) -2-methoxypyridin-3-yl) -2 , 4-Difluorobenzenesulfonamide (Compound A), which can effectively inhibit the activity of protein kinases such as phosphoinositide 3-kinase (PI ₃ K), can be used as a medicine for preventing or treating proliferative diseases.

Patent application WO2014012360 discloses the compound 3- (4- (dihexylamino) -3-fluorophenyl) -2,6-dimethylpyrimidine-4 (3H) -one (Compound B), which can be used as a drug For the treatment and / or prevention of tissue fibrosis diseases.

Summary of the invention

The present invention provides a pharmaceutical combination or pharmaceutical composition or kit for preventing and / or treating fibrotic diseases. The pharmaceutical combination or pharmaceutical composition or kit includes Compound A or a pharmaceutically acceptable salt thereof and Compound B or a pharmaceutically acceptable salt thereof.

In one aspect, the present invention provides a pharmaceutical combination comprising the following two parts:

Part One: Contains Component 1, which is Compound A or a pharmaceutically acceptable salt thereof as shown below; and

Part 2: Containing component 2, which is Compound B or its pharmaceutically acceptable salt as shown below;

In some embodiments, component 1 and component 2 of the present invention are administered separately, simultaneously, or in a single formulation.

In some embodiments, Component 1 described herein is a pharmaceutically acceptable salt of Compound A.

In some embodiments, component 1 described herein is the sodium salt of compound A.

In some embodiments, Component 2 described herein is a pharmaceutically acceptable salt of Compound B.

In some embodiments, component 2 of the present invention is the hydrochloride salt of compound B.

In some embodiments, the pharmaceutical combination of the present invention comprises component 1 and component 2, wherein component 1 is the sodium salt of compound A and component 2 is the hydrochloride salt of compound B.

In some embodiments, in the pharmaceutical combination of the present invention, the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 1600.

In some embodiments, in the pharmaceutical combination of the present invention, the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 800, or 1: 0.625 to 1: 640.

In some embodiments, in the pharmaceutical combination of the present invention, the amount ratio of the substances of component 1 and component 2 is 1: 5 to 1: 800, 1: 5 to 1: 320, 1:20 to 1: 320, 1:20 to 1: 160, 1:80 to 1: 160, 1:80 to 1: 800, 1: 160 to 1: 800, or 1: 200 to 1: 800.

In some embodiments, in the pharmaceutical combination of the present invention, the amount ratio of the substances of component 1 and component 2 is 1: 0.625, 1: 1.25, 1: 2.5, 1: 5, 1:10, 1: 12.5, 1:20, 1:40, 1:50, 1:80, 1: 100, 1: 150, 1: 160, 1: 200, 1: 250, 1: 300, 1: 320, 1: 400, 1: 500, 1: 640, 1: 800, 1: 1000 or 1: 1600.

In some embodiments, the pharmaceutical combination of the present invention, wherein the first part and the second part each independently optionally further comprise one or more pharmaceutically acceptable carriers. In other embodiments, the pharmaceutical combination of the present invention, wherein the carrier is an excipient, diluent, adjuvant, vehicle, or a combination thereof.

In some embodiments, the pharmaceutical combination of the invention optionally further comprises one or more pharmaceutically acceptable carriers. In other embodiments, the pharmaceutical combination of the present invention, wherein the carrier is an excipient, diluent, adjuvant, vehicle or a combination thereof.

In another aspect, the invention provides a pharmaceutical composition comprising a first part and a second part, wherein the first part comprises component 1 and the second part comprises component 2; wherein, the component 1 is as follows Compound A or a pharmaceutically acceptable salt thereof shown, the component 2 is Compound B or a pharmaceutically acceptable salt thereof as shown below,

In some embodiments, in the pharmaceutical composition of the present invention, the component 1 is a pharmaceutically acceptable salt of Compound A.

In some embodiments, in the pharmaceutical composition of the present invention, the component 1 is the sodium salt of compound A.

In some embodiments, in the pharmaceutical composition of the present invention, the component 2 is a pharmaceutically acceptable salt of Compound B.

In some embodiments, in the pharmaceutical composition of the present invention, the component 2 is the hydrochloride salt of Compound B.

In some embodiments, the pharmaceutical composition of the present invention comprises component 1 and component 2, wherein component 1 is the sodium salt of compound A, and component 2 is the hydrochloride salt of compound B.

In some embodiments, in the pharmaceutical composition of the present invention, the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 1600.

In some embodiments, in the pharmaceutical composition of the present invention, the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 800, or 1: 0.625 to 1: 640.

In some embodiments, in the pharmaceutical composition of the present invention, the amount ratio of the substances of component 1 and component 2 is 1: 5 to 1: 800, 1: 5 to 1: 320, 1:20 To 1: 320, 1:20 to 1: 160, 1:80 to 1: 160, 1:80 to 1: 800, 1: 160 to 1: 800, or 1: 200 to 1: 800.

In some embodiments, in the pharmaceutical composition of the present invention, the amount ratio of the substances of component 1 and component 2 is 1: 0.625, 1: 1.25, 1: 2.5, 1: 5, 1:10 , 1: 12.5, 1:20, 1:40, 1:50, 1:80, 1: 100, 1: 150, 1: 160, 1: 200, 1: 250, 1: 300, 1: 320, 1 : 400, 1: 500, 1: 640, 1: 800, 1: 1000 or 1: 1600.

In some embodiments, the pharmaceutical composition described herein further comprises one or more pharmaceutically acceptable carriers.

In some embodiments, the carrier of the present invention is an excipient, diluent, adjuvant, vehicle, or a combination thereof.

In one aspect, the invention provides a kit comprising a first part and a second part; wherein the first part comprises component 1, which is Compound A or a pharmaceutically acceptable salt thereof; the second part comprises Component 2, which is Compound B or a pharmaceutically acceptable salt thereof;

In some embodiments, in the kit of the present invention, the component 1 is Compound A sodium salt.

In some embodiments, in the kit of the present invention, the component 2 is the hydrochloride salt of Compound B.

In some embodiments, in the kit of the present invention, the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 1600.

In some embodiments, in the kit of the present invention, the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 800, or 1: 0.625 to 1: 640.

In some embodiments, in the kit of the present invention, the amount ratio of the substances of component 1 and component 2 is 1: 5 to 1: 800, 1: 5 to 1: 320, 1:20 to 1: 320, 1:20 to 1: 160, 1:80 to 1: 160, 1:80 to 1: 800, 1: 160 to 1: 800, or 1: 200 to 1: 800.

In some embodiments, in the kit of the present invention, the ratio of the amounts of the substances of component 1 and component 2 is 1: 0.625, 1: 1.25, 1: 2.5, 1: 5, 1:10, 1: 12.5, 1:20, 1:40, 1:50, 1:80, 1: 100, 1: 150, 1: 160, 1: 200, 1: 250, 1: 300, 1: 320, 1: 400, 1: 500, 1: 640 or 1: 800.

In some embodiments, in the kit of the present invention, the first part and the second part each independently comprise one or more pharmaceutically acceptable carriers.

In other embodiments, in the kit of the present invention, the carrier is an excipient, diluent, adjuvant, vehicle, or a combination thereof.

In some embodiments, in the pharmaceutical combination or pharmaceutical composition or kit of the present invention, the component 1 and the component 2 are respectively present in a therapeutically effective amount. In some embodiments, in the pharmaceutical combination, pharmaceutical composition, or kit of the present invention, the amounts of component 1 and component 2 are clinically therapeutically effective amounts, respectively.

In one aspect, the present invention also provides the use of the pharmaceutical combination or the pharmaceutical composition or the kit in the preparation of a medicament, wherein the medicament is used to prevent, treat or alleviate fibrotic diseases in patients.

In some embodiments, the fibrotic diseases of the present invention are renal interstitial fibrosis, glomerulosclerosis, liver fibrosis, lung fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, skeletal muscle fibrosis, hard Dermatosis, multiple sclerosis, pancreatic fibrosis, liver cirrhosis, myoma, neurofibromatosis, pulmonary interstitial fibrosis or vascular fibrosis disease.

In some embodiments, the pulmonary fibrosis of the present invention is idiopathic pulmonary fibrosis.

In another aspect, the present invention relates to the use of the pharmaceutical combination or the pharmaceutical composition or the kit in the prevention, treatment or alleviation of fibrotic diseases in patients.

In some embodiments, the use according to the present invention, wherein the fibrotic disease is renal interstitial fibrosis, glomerulosclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibers Disease, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myoma, neurofibromatosis, pulmonary interstitial fibrosis or vascular fibrosis.

In some embodiments, the use of the present invention, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

In one aspect, the present invention provides a method of using the pharmaceutical combination or the pharmaceutical composition or the kit to prevent, treat or reduce fibrotic diseases in a patient.

In some embodiments, the methods described herein include contacting the patient with an effective therapeutic amount of the active ingredient in the pharmaceutical combination or pharmaceutical composition or kit.

In some embodiments, the methods described herein include contacting the patient with a pharmaceutical combination or pharmaceutical composition containing an effective therapeutic amount.

In some embodiments, the method of the present invention, wherein the fibrotic disease is renal interstitial fibrosis, glomerulosclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibers Disease, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myoma, neurofibromatosis, pulmonary interstitial fibrosis or vascular fibrosis.

In some embodiments, the method of the present invention, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

In another aspect, the invention relates to the use of a composition for the preparation of a medicament for the prevention or treatment of fibrotic diseases, wherein the composition comprises a first part and a second part, wherein the first part comprises component 1, The second part contains component 2; wherein, component 1 is Compound A or a pharmaceutically acceptable salt thereof as shown below, and Component 2 is Compound B or a pharmaceutically acceptable salt thereof as shown below salt,

In some embodiments, the use according to the invention, wherein component 1 is the sodium salt of compound A.

In some embodiments, the use according to the invention wherein the component 2 is the hydrochloride salt of compound B.

In some embodiments, the use according to the present invention, wherein the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 1600.

In some embodiments, the use according to the present invention, wherein the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 800, or 1: 0.625 to 1: 640.

In some embodiments, the use according to the present invention, wherein the amount ratio of the substances of component 1 and component 2 is 1: 5 to 1: 800, 1: 5 to 1: 320, 1:20 to 1: 320, 1:20 to 1: 160, 1:80 to 1: 160, 1:80 to 1: 800, 1: 160 to 1: 800, or 1: 200 to 1: 800.

In some embodiments, the use according to the present invention, wherein the amount ratio of the substances of component 1 and component 2 is 1: 0.625, 1: 1.25, 1: 2.5, 1: 5, 1:10, 1: 12.5, 1:20, 1:40, 1:50, 1:80, 1: 100, 1: 150, 1: 160, 1: 200, 1: 250, 1: 300, 1: 320, 1: 400, 1: 500, 1: 640 or 1: 800.

In some embodiments, the use according to the present invention, wherein the medicament for preventing or treating fibrotic disease or the composition respectively further comprises one or more pharmaceutically acceptable carriers.

In some embodiments, the use according to the present invention, wherein the carrier is an excipient, diluent, adjuvant, vehicle or a combination thereof.

In some embodiments, the use according to the present invention, wherein the fibrotic disease is renal interstitial fibrosis, glomerulosclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibers Disease, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myoma, neurofibromatosis, pulmonary interstitial fibrosis or vascular fibrosis.

In some embodiments, the use according to the present invention, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

In one aspect, the present invention provides the use of a pharmaceutical combination or kit in the preparation of a medicament for the prevention, treatment or alleviation of fibrotic diseases in patients; wherein the pharmaceutical combination or kit contains the following two parts:

Part 1: It contains component 1, wherein component 1 is Compound A or a pharmaceutically acceptable salt thereof as shown below; and

Part 2: It contains component 2, wherein component 2 is Compound B or its pharmaceutically acceptable salt as shown below;

In some embodiments, the use according to the invention, wherein component 1 and component 2 can be administered separately, simultaneously or in a single formulation.

In some such solutions, the use of the invention wherein each of the first and second parts independently optionally includes one or more pharmaceutically acceptable carriers. In other embodiments, the use according to the present invention, wherein the carrier is an excipient, diluent, adjuvant, vehicle or a combination thereof.

In some embodiments, the use according to the invention, wherein component 1 is the sodium salt of compound A.

In some embodiments, the use according to the invention wherein the component 2 is the hydrochloride salt of compound B.

In some embodiments, the use according to the present invention, wherein the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 1600.

In some embodiments, the use according to the present invention, wherein the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 800, or 1: 0.625 to 1: 640.

In some embodiments, the use according to the present invention, wherein the amount ratio of the substances of component 1 and component 2 is 1: 5 to 1: 800, 1: 5 to 1: 320, 1:20 to 1: 320, 1:20 to 1: 160, 1:80 to 1: 160, 1:80 to 1: 800, 1: 160 to 1: 800, or 1: 200 to 1: 800.

In some embodiments, the use according to the present invention, wherein the amount ratio of the substances of component 1 and component 2 is 1: 0.625, 1: 1.25, 1: 2.5, 1: 5, 1:10, 1: 12.5, 1:20, 1:40, 1:50, 1:80, 1: 100, 1: 150, 1: 160, 1: 200, 1: 250, 1: 300, 1: 320, 1: 400, 1: 500, 1: 640 or 1: 800.

In some embodiments, the use of the present invention, wherein the drug or drug combination further comprises one or more pharmaceutically acceptable carriers.

In some embodiments, the use according to the present invention, wherein the carrier is an excipient, diluent, adjuvant, vehicle or a combination thereof.

In some embodiments, the use according to the present invention, wherein the fibrotic disease is renal interstitial fibrosis, glomerulosclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibers Disease, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myoma, neurofibromatosis, pulmonary interstitial fibrosis or vascular fibrosis.

In some embodiments, the use according to the present invention, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

Definition of Terms

Unless otherwise indicated, the following terms and phrases used herein have the meanings described below.

The term "about" or "approximately" has its simple and ordinary meaning of "about" or "approximately" and generally refers to the amounts shown ± 20%, ± 15%, ± 10%, ± 5%, or ± 1%. For example, "about 10: 378" means (9-11): (340.2-415.8) according to the ± 10% range.

The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergies or similarly inappropriate reactions, such as gastrointestinal discomfort, dizziness, and the like. Preferably, the term "pharmaceutically acceptable" as used herein refers to the use in animals, especially in humans, approved by the drug regulatory agency or national government or listed in the Chinese Pharmacopoeia or the United States Pharmacopoeia or other generally recognized pharmacopoeia. Carrier etc.

The term "carrier" refers to a glidant, diluent, adjuvant, adjuvant or excipient, etc., to be administered with the compound without limitation. Such carriers include, but are not limited to: diluents, buffers, suspensions, emulsions, granules, encapsulates, excipients, fillers, binders, sprays, transdermal absorbers, wetting agents, disintegrating agents Dissolving agent, absorption promoter, surfactant, colorant, flavoring agent or adsorption carrier. More examples of carriers are described in E.W. Martin's "Remington's Complete Book of Pharmacy".

The "excipient" described in the present invention refers to a compound used to prepare a pharmaceutical composition, which is generally a safe, non-toxic and biologically or otherwise undesirable compound, including veterinary and human drugs. Accepted excipients.

"Patient" as used in the present invention refers to mammals, including, but not limited to, dogs, humans, monkeys, mice, pigs, and sheep. Preferably, the patient is a human.

The term "effective amount" refers to an amount sufficient for effective treatment when administered to a mammal in need of treatment (including but not limited to, a human). The therapeutically effective amount varies depending on the patient to be treated, the patient's weight and age, the severity of the disease, the pharmaceutical dosage form, the administration method, etc., and those skilled in the art can easily determine the therapeutically effective amount.

As used herein, "treatment" refers to improving a disease or disorder (ie, slowing or preventing or alleviating the development of the disease or at least one of its clinical symptoms). In some embodiments, "treatment" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating a disease or condition physically (eg, stabilizing perceptible symptoms) or physiologically (eg, stabilizing the parameters of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

Pharmaceutical combination and pharmaceutical composition

The "pharmaceutical combination" described in the present invention means that two or more drugs used for the purpose of treatment are administered simultaneously or separately, or administered in a single dosage form. In some embodiments, the drugs in the drug combination are combined in an optimal ratio to maximize the therapeutic effect or minimize the side effects; the combined use of the two compounds may reveal an unexpected synergy and / or trigger a non-single compound Induced effect.

The pharmaceutical combination according to the present invention comprises component 1 and component 2, wherein component 1 is compound A or a pharmaceutically acceptable salt thereof, and component 2 is compound B or a pharmaceutically acceptable salt thereof salt. In some embodiments, the pharmaceutical combination comprises component 1 and component 2, wherein component 1 is the sodium salt of compound A and component 2 is the hydrochloride salt of compound B.

In the pharmaceutical combination of the present invention, component 1 and component 2 can be administered simultaneously or separately, or they can be administered in a single preparation.

The pharmaceutical composition of the present invention comprises component 1 and component 2, wherein component 1 is compound A or a pharmaceutically acceptable salt thereof, and component 2 is compound B or a pharmaceutically acceptable salt thereof Salt. In some embodiments, the pharmaceutical composition comprises component 1 and component 2, wherein component 1 is the sodium salt of compound A and component 2 is the hydrochloride salt of compound B. In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers; wherein the carrier is an excipient, diluent, adjuvant, vehicle, or a combination thereof.

In the pharmaceutical combination or pharmaceutical composition or kit of the present invention, component 1 and component 2 are used in combination at a reasonable ratio (simultaneous administration, separate administration or administration in a single formulation). In some embodiments, the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 1600, 1: 0.625 to 1: 800, or 1: 0.625 to 1: 640. In other embodiments, the amount ratio of the substances of component 1 and component 2 is 1: 5 to 1: 800, 1: 5 to 1: 320, 1:20 to 1: 320, 1:20 to 1: 160, 1:80 to 1: 160, 1:80 to 1: 800, 1: 160 to 1: 800, or 1: 200 to 1: 800. In some embodiments, the amount ratio of the substances of component 1 and component 2 is 1: 0.625, 1: 1.25, 1: 2.5, 1: 5, 1:10, 1: 12.5, 1:20, 1 : 40, 1:50, 1:80, 1: 100, 1: 150, 1: 160, 1: 200, 1: 250, 1: 300, 1: 320, 1: 400, 1: 500, 1: 640 , 1: 800, or 1: 1000. It can be understood in the art that the components 1 and 2 of the present invention are used in combination with the ratio described in the present invention, wherein the dosage of the components 1 and 2 will be adjusted according to the actual situation, and the safe and reasonable The dosage is used in combination to achieve the purpose of effective prevention or treatment of diseases. For example, the component 1 and component 2 can be based on a safe and effective dose or dose range for clinical administration. According to the compounding range described in the present invention, an appropriate dose and ratio are selected for combined use (simultaneous administration, simultaneous administration, Administered separately or in a single formulation).

When the component 1 and the component 2 of the present invention are used in combination (used alone, or simultaneously, or in a single dosage form), they have a more beneficial effect than when used separately. For example, when component 1 and component 2 are used in combination, they can significantly inhibit the expression of a-SMA protein in HFL1 cells, which has a stronger effect than when used separately. In another example, when component 1 and component 2 are used in combination, the inhibitory effect on cell proliferation is stronger than that of component 1 and component 2 administered separately. In addition, the combination of component 1 and component 2 also has a significantly better anti-fibrosis effect in vivo. That is, the pharmaceutical combination or pharmaceutical composition or kit described in the present invention has an excellent anti-fibrotic effect.

In some embodiments, the pharmaceutical composition of the present invention is used in one or more medically acceptable ways of injection, oral administration, and surgical placement.

In some embodiments, the dosage form of the pharmaceutical composition of the present invention is one or more medically acceptable dosage forms among powders, injection preparations, capsules, tablets, sustained-release preparations, or oral preparations. The drugs of the above various dosage forms can be prepared according to conventional methods in the pharmaceutical field.

The dosage of the pharmaceutical combination or pharmaceutical composition or kit of the present invention can be appropriately changed according to the administration object, administration route or the formulation form of the drug, but to ensure that the pharmaceutical combination or pharmaceutical composition or kit The premise is that the active ingredients (component 1 and component 2 according to the present invention) can achieve an effective blood drug concentration in the body of the subject. During clinical administration, component 1 and component 2 of the present invention are administered in a therapeutically effective amount, respectively. Wherein, the therapeutically effective amount or dose refers to the amount of an agent or compound or a salt of the compound that causes improvement of symptoms or prolonged survival of the individual.

In some embodiments, in the pharmaceutical combination or pharmaceutical composition or kit described in the present invention, the amount of component 1 may be 0.1-10 mg. In some embodiments, in the pharmaceutical combination or pharmaceutical composition or kit described in the present invention, the amount of component 2 may be 50-500 mg. In some embodiments, in the pharmaceutical combination or pharmaceutical composition or kit described in the present invention, the dosage of component 1 may be 0.1-10 mg, and the dosage of component 2 may be 50-500 mg. Wherein, the component 1 and component 2 in the pharmaceutical combination or pharmaceutical composition or kit are jointly administered according to the ratio of the amounts of the substances described in the present invention; wherein the amount refers to the therapeutically effective amount of each component, ie , The amount of active ingredient (compound A or its salt as described in the present invention) effective for preventing or treating disease in clinical application.

In the pharmaceutical combination or pharmaceutical composition or kit described in the present invention, Compound A or a pharmaceutically acceptable salt thereof, Compound B or a pharmaceutically acceptable salt thereof may be in an amorphous form, or may be a specific Crystalline form or a combination of multiple crystalline forms. Specifically, in the aforementioned pharmaceutical combination or pharmaceutical composition or kit, Compound A or its sodium salt may be in an amorphous form, or may be a specific crystal form or a combination of multiple crystal forms; the same, Compound B or its hydrochloride can also be applied to the pharmaceutical combination or pharmaceutical composition or kit in an amorphous form or in a certain crystalline form or in a combination of multiple crystalline forms.

Pharmaceutically acceptable salts

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the field, as described in the literature: S.M. Berge, et al., Describe, acceptable, salts, details, J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts, such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts, such as Acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, etc., or other methods described in the book literature such as ion exchange to obtain these salts. Pharmaceutically acceptable base addition salts include, but are not limited to, inorganic base salts, such as ammonium salts and metal salts of Groups I to XII of the periodic table, and organic base salts, such as those formed with primary, secondary, and tertiary amines salt.

For example, the pharmaceutically acceptable salts of Compound A of the present invention include, but are not limited to, inorganic base salts, such as sodium, potassium, or calcium salts. The pharmaceutically acceptable salts of Compound B of the present invention include but are not limited to inorganic acid salts or organic acid salts, such as hydrochloride, hydrobromide or p-benzenesulfonate.

Compound A and its sodium salt

Compound A (N- (5- (3-cyanopyrazolo [1,5-a] pyridin-5-yl) -2-methoxypyridin-3-yl) -2,4-difluorobenzenesulfonate Amide) can be prepared according to the method described in patent application WO2014130375. The sodium salt of Compound A can be prepared according to the method described in Example 1 of the present invention.

Compound B and its hydrochloride

Compound B (3- (4- (dihexylamino) -3-fluorophenyl) -2,6-dimethylpyrimidin-4 (3H) -one) can be prepared according to the method described in patent application WO2014012360 . The hydrochloride salt of Compound B can be prepared according to the method described in Example 2 of the present invention.

Use of pharmaceutical combination or pharmaceutical composition of the present invention

The pharmaceutical combination or pharmaceutical composition according to the present invention can be used to prepare a medicament for preventing, treating or alleviating fibrotic diseases in patients. The fibrotic diseases of the present invention include, but are not limited to, renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, skeletal muscle fibrosis, pancreatic fibrosis Cirrhosis, cirrhosis, myoma, neurofibroma, pulmonary interstitial fibrosis or vascular fibrosis disease.

The pharmaceutical combination or pharmaceutical composition of the present invention can also be used to treat post-operative adhesions, benign prostatic hypertrophy, scleroderma, multiple sclerosis, diabetic nephropathy or Alzheimer's disease.

The pulmonary fibrosis of the present invention includes, but is not limited to, idiopathic pulmonary fibrosis.

BRIEF DESCRIPTION

FIG. 1 shows the Western Blot results of α-SMA protein expression in human lung fibroblasts (HFL1 cells) stimulated by TGF-β1 by the drug or drug combination described in Example 4 of the present invention. Wherein, the pharmaceutical combination refers to a pharmaceutical combination of Compound A sodium salt and Compound B hydrochloride formulated according to the method described in Example 4, wherein the concentration ratio of Compound A sodium salt and Compound B hydrochloride is 200 nM : 2μM.

Figure 2 shows the results of quantitative analysis of α-SMA protein expression in TFL-β1 stimulated HFL1 cells as described in Example 4 of the present invention. Wherein, the pharmaceutical combination refers to a pharmaceutical combination of Compound A sodium salt and Compound B hydrochloride formulated according to the method described in Example 4, wherein the concentration ratio of Compound A sodium salt and Compound B hydrochloride is 200 nM : 2μM.

detailed description

The following examples are used to illustrate the present invention, but are not used to limit the scope of the present invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art, and the reagents used are commercially available.

The experimental methods without specific conditions in the examples are generally conventional methods in the art.

The main reagents and instruments used in the present invention:

HFL1 cells were purchased from the American Type Culture Collection, namely ATCC (Cat. No. CCL-153); F-12K medium, fetal bovine serum, and pancreatin were all purchased from Gibco (Cat. No. 21127-022, 10099-141, respectively) And 25200-072); penicillin and streptomycin double antibodies were purchased from Hyclone Corporation (Cat. No. SV30010); dimethyl sulfoxide (DMSO) was purchased from Sigma Corporation (Cat. No. D2650); Cell Counting Kit-8 (CCK-8 Kit) was purchased from Japan Dojindo Company (Catalog No. CK04-10000T). Smooth muscle actin α-SMA antibody was purchased from German Merk Millipore Company (Cat. No. CBL171); human recombinant transforming growth factor TGF-β1 was purchased from American Peprotech Company (Cat. No. AF-100-21C); BCA protein quantification kit was purchased from American Thermofisher Company (Cat. No. 23225); 800cw goat anti-mouse antibody was purchased from American LI-COR Company (Cat. No. 925-32210); Tubulin antibody, phenylmethylsulfonyl fluoride (PMSF), cell lysate were all purchased from China Biyuntian Biotechnology Company (item numbers AT819, ST506, P0013); phosphate buffer PBS was purchased from China Dingguo Changsheng Company (item number BF-0011).

The ultra-clean workbench was purchased from Sujing Group Antai (model SW-CJ-2FD); the cell incubator was purchased from Thermo Scientific (model HERA cell 150i); the Leica inverted microscope was purchased from Olympus (model CXX31); microplate reader Purchased from BMG LABTECH company (model PHERA starFS). The two-color infrared laser imager was purchased from Gene Co., Ltd. (model is ODYSSEY CLx).

Examples

Example 1 Sodium salt of compound A

Anhydrous ethanol (8 mL) and N- (5- (3-cyanopyrazole [1,5-a] pyridin-5-yl) -2-methoxypyridin-3-yl)- 2,4-Difluorobenzenesulfonamide (500mg, 1.13mmol), stirred at room temperature, added a solution of sodium hydroxide (50mg, 1.25mmol) in ethanol (2mL), heated to 80 ± 5 ° C and stirred for 30 minutes, cooled to 25 ± It was suction filtered at 5 ° C, and the solid was vacuum-dried at 60 ° C for 24 hours to obtain a pale yellow solid (446 mg, 84.97%).

Example 2 Hydrochloride of Compound B

Dissolve 3- (4- (dihexylamino) -3-fluorophenyl) -2,6-dimethylpyrimidin-4 (3H) -one (5.00 g, 12.3 mmol) in isopropanol (25 mL) Under stirring at room temperature, hydrochloric acid (1.50g, 13.0mmol) was added dropwise. After stirring at room temperature for 4 hours, it was heated to reflux overnight, cooled to room temperature and stirred for 3 hours, filtered with suction, and the filter cake was dried in a vacuum oven at 60 ° C. White solid (5.02g, 93.3%).

Example 3 Inhibition experiment of the drug combination / pharmaceutical composition of the present invention on cell proliferation

Suppression experiment one

1. Preparation of working fluid

1) Preparation of compound A sodium salt working solution

Dissolve the sodium salt of Compound A with DMSO to prepare a mother liquor with a concentration of 10 mM, then dilute the mother liquor with DMSO to a solution of 0.4 mM, and then dilute with DMSO twice to a solution of 7 concentration gradients (0.4 mM, 0.2 mM, 0.1 mM, 0.05mM, 0.025mM, 0.0125mM, 0.00625mM). Finally, the solution with a 7-gradient gradient was diluted 200 times with the medium to a working solution of a certain concentration (2 μM, 1 μM, 0.5 μM, 0.25 μM, 0.125 μM, 0.0625 μM, 0.03125 μM; DMSO content was 0.5%).

2) Preparation of compound B hydrochloride working solution

Dissolve the hydrochloride salt of Compound B with DMSO to prepare a mother liquor with a compound concentration of 20 mM, then dilute the mother liquor with DMSO to a solution of 8 mM, and then dilute with DMSO twice to a solution with 7 concentration gradients (8 mM, 4 mM, 2 mM, 1mM, 0.5mM, 0.25mM, 0.125mM). Finally, the 7-concentration gradient solution was diluted 200-fold with the culture medium to a certain concentration of working solution (40 μM, 20 μM, 10 μM, 5 μM, 2.5 μM, 1.25 μM, 0.625 μM; DMSO content was 0.5%).

3) Preparation of drug combination working fluid

According to the ratio shown in Table 1 below, the same volume of working solution of Compound A sodium salt and working solution of Compound B hydrochloride of different concentrations are mixed to obtain working solutions of drug combinations of different concentrations. Wherein, in the pharmaceutical combination, the ratio of the amount of the substance of Compound A sodium salt and Compound B hydrochloride is in the range of 1: 0.625 to 1: 640. For example, as shown in Table 1, the compound A sodium salt at a concentration of 0.125 μM is used in combination with the compound B hydrochloride at a concentration of 20 μM in the working solution of the drug combination, and the ratio of the amount of the substance is 1: 160.

Table 1 Preparation of working fluid of drug combination

Note: The concentration of the drug combination is μM. For example, 20 + 1 means that 20 μM Compound B hydrochloride and 1 μM Compound A hydrochloride are administered together.

2. Cell proliferation experiment

1) HFL1 cell culture: human embryo lung fibroblast cell line, cultured with F-12K medium (complete medium) containing 10% fetal bovine serum and 1% double antibody, placed at 37 ° C, 5% CO ₂ and It grows adherently in a saturated humidity incubator and is replaced with complete medium every 2 days to serve as the source of cells for the experiment.

2) Cell inoculation: collect the logarithmic growth phase cells, when the cells grow and fuse 85% to 95%, discard the old culture solution, rinse twice with phosphate buffer, add pancreatin digestion solution to digest, observe under an inverted microscope, Cells are retracted and rounded, complete medium is added to stop the digestion, repeated gentle pipetting, and then transferred to a 15mL sterile centrifuge tube, centrifuged at 800r / min for 5 minutes, discard the supernatant, and then collect the cells with complete medium, Cell count, adjust the cell concentration to 5 × 10 ⁴ cells / mL, inoculate in 96-well plates (50 wells per plate), add 5000 cells / 100 μL of cell suspension to each well, inoculate 3 96-well plates, at 37 ° C, Incubate overnight under 5% CO ₂ conditions.

3) Cell starvation treatment: Aspirate the supernatant the next day, add serum-free F-12K medium, and place in a 37 ° C, 5% CO ₂ incubator for 2 hours.

4) Cell administration: Add 100 μL of working solution of different concentrations (different groups) in sequence, 3 replicate wells of each concentration. Incubate at 37 ° C in a 5% CO ₂ incubator for 48 hours; at the same time, set up blank wells and control wells without drugs or drug combinations, which are 0.5% DMSO, cell-free complete medium and 0.5% DMSO, Complete medium with cells.

The various experimental groups and their related drugs or drug combinations and their corresponding concentrations are shown in Table 2 below. Among them, the different experimental groups are labeled in Table 2, such as G0-0, G0-1, G1-0 , G1-1, etc.

Table 2 Experimental Group One

5) Determination of CCK-8: 48 hours after administration, 100 μL of complete medium containing 10% CCK-8 was added to each well. After incubation in the incubator for about 1 to 2 hours, the absorbance of each well was detected at 450 nm at a microplate reader ( Absorbance, A) value.

3. Data processing

Calculate the inhibition rate (IR) according to the measured A value, the formula is as follows:

IR% = [A _C –A _D ] / [A _C –A _B ] × 100%

A _B : blank group, absorbance of wells containing 0.5% DMSO, CCK-8 and cell-free medium;

A _D : drug group, containing 0.5% DMSO, CCK-8, drugs (compound A sodium salt, compound B hydrochloride or a combination of both) and the absorbance of the pores of the culture medium with cells;

A _C : Absorbance of the control group, wells containing 0.5% DMSO, CCK-8 and culture medium with cells;

Graph Pad Prism5 software was used to analyze the data and graph, and calculate the IC ₅₀ value of each compound at 48 hours.

4. Experimental results

The experimental results of the inhibition of cell proliferation of Compound A sodium salt, Compound B hydrochloride and any combination thereof at different concentrations are shown in Table 3 below. The experimental results show that the combination of Compound A sodium salt and Compound B hydrochloride has a stronger cell proliferation inhibitory effect than the corresponding concentration of Compound A sodium salt or Compound B hydrochloride administered alone.

Table 3 The inhibitory effect of the drug combination of the present invention on cell proliferation

Group	G0-1	G0-2	G0-3
Proliferation inhibition rate IR%	41.41	30.89	20.22
Group	G1-0	G2-0	G3-0
Proliferation inhibition rate IR%	62.86	49.97	40.41
Group	G4-0	G5-0	G 6-0
Proliferation inhibition rate IR%	30.20	25.15	20.33
Group	G 1-1	G1-2	G 1-3
Proliferation inhibition rate IR%	66.98	65.23	65.78
Group	G2-1	G2-2	G2-3
Proliferation inhibition rate IR%	64.23	63.94	60.22
Group	G3-1	G3-2	G3-3
Proliferation inhibition rate IR%	58.00	59.28	55.46
Group	G4-1	G4-2	G4-3
Proliferation inhibition rate IR%	57.25	56.16	45.69
Group	G5-1	G5-2	G5-3
Proliferation inhibition rate IR%	55.09	53.52	41.37
Group	G6-1	G6-2	G6-3
Proliferation inhibition rate IR%	55.11	53.84	39.32
Group	G2-4	G2-5	G3-5
Proliferation inhibition rate IR%	59.28	53.47	50.21

Suppression Experiment 2

1. Preparation of working fluid

1) Preparation of compound A sodium salt working solution

Dissolve the sodium salt of Compound A with DMSO, prepare a mother liquor with a compound concentration of 6.4 mM, then dilute with DMSO to 0.16 mM, then dilute with DMSO twice to a solution with 7 concentration gradients; finally, use the 2nd to 7th concentration gradients The culture medium was diluted 200-fold into a certain concentration of working solution (0.4 μM, 0.2 μM, 0.10 μM, 0.05 μM, 0.025 μM, 0.0125 μM; DMSO content was 0.5%).

2) Preparation of compound B hydrochloride working solution

Dissolve the hydrochloride salt of Compound B with DMSO to prepare a mother liquor with a compound concentration of 8 mM, then dilute it with DMSO twice to a solution with 7 concentration gradients; then, the 2nd to 7th concentration gradients are diluted 200 times with the medium to a certain concentration Working solution (20μM, 10μM, 5μM, 2.5μM, 1.25μM, 0.625μM; DMSO content is 0.5%).

3) Preparation of drug combination working fluid

Take the same volume of different concentrations of Compound A sodium salt working solution and Compound B hydrochloride working solution for orthogonal mixing, and then add medium 400 times to dilute to a certain concentration of drug combination working solution (DMSO content is 0.5% ); Wherein, the concentration of each component in the working solution of the drug combination is shown in Table 4 below.

Table 4 Preparation 2 of the working fluid of the drug combination

Note: The concentration of the drug combination is μM. For example, 20 + 0.4 means that 20 μM Compound B hydrochloride and 0.4 μM Compound A hydrochloride are administered together.

2. Cell proliferation experiment

The method of suppressing an experiment, cell proliferation experiments working solution for the above-described pharmaceutical composition of the working fluid with different concentrations of the drug. Each experimental group and its related drugs or drug combinations and their corresponding concentrations are shown in Table 5 below. Among them, different experimental groups are labeled in Table 5, such as S0-0, S0-1, S1-0 , S1-1, etc.

Table 5 Experimental Group 2

3. Data processing

Processing data according to a method described in the inhibition assay.

4. Experimental results

The experimental results of cell proliferation inhibition for the drug combinations of different concentrations and ratios in Table 4 are shown in Table 6 below. Similarly, the experimental results show that the combination of Compound A sodium salt and Compound B hydrochloride has a stronger cell proliferation inhibitory effect than the corresponding concentrations of Compound A sodium salt or Compound B hydrochloride administered alone.

Table 6 Inhibitory effect of the drug combination of the invention on cell proliferation

Group	S0-1	S0-2	S0-3
Proliferation inhibition rate IR%	41.13	22.17	-0.88
Group	S1-0	S2-0	S3-0
Proliferation inhibition rate IR%	65.03	47.89	33.70
Group	S4-0	S5-0	S6-0
Proliferation inhibition rate IR%	22.77	18.03	19.74
Group	S1-1	S1-2	S1-3
Proliferation inhibition rate IR%	75.33	73.48	71.39
Group	S2-1	S2-2	S2-3
Proliferation inhibition rate IR%	59.05	50.64	60.57
Group	S3-1	S3-2	S3-3
Proliferation inhibition rate IR%	48.21	42.01	46.41
Group	S4-1	S4-2	S4-3
Proliferation inhibition rate IR%	48.33	35.35	34.29
Group	S5-1	S5-2	S5-3
Proliferation inhibition rate IR%	46.02	36.21	31.98
Group	S6-1	S6-2	S6-3
Proliferation inhibition rate IR%	45.76	36.79	26.83

Example 4 Western blot (Western Bolt) experiment

1. Working fluid preparation

1) Preparation of working fluid

Take 50 μg / mL of TGF-β1 (Peprotech, AF-100-21C-500), dilute to 10 ng / mL with serum-free F-12K medium, that is, F12K medium solution containing 10 ng / mL TGF-β1.

Pirfenidone (PFD), Compound A sodium salt and Compound B hydrochloride were weighed in appropriate amounts, and DMSO was used to prepare a drug mother liquor: pirfenidone (600 mM), Compound A sodium salt (0.02 mM), compound B hydrochloride (0.4 mM). Take 25 μL of the above drug mother liquor into 4975 μL F-12K medium solution containing 10 ng / mL TGF-β1 and dilute it 200 times to the following concentration of drug working solution: pirfenidone (3 mM), compound A sodium salt (200 nM), Compound B hydrochloride (2 μM) with DMSO content of 0.5%.

The working solution of the normal control group was prepared by using 4975μL of F12K medium solution without TGF-β1 and 25μL of DMSO, in which the DMSO content was 0.5%.

The model control working solution was prepared with 4975μL of F12K medium solution containing 10ng / mL TGF-β1 and 25μL of DMSO, in which the DMSO content was 0.5%.

2) Preparation of drug combination working fluid

The mother liquid of Compound A sodium salt and the mother liquid of Compound B hydrochloride were prepared into a pharmaceutical combination working solution according to the above method, wherein the final concentrations of Compound A sodium salt and Compound B hydrochloride were 200 nM and 2 μM (molar ratio 1:10, The mass ratio is 1: 9.45).

2. Experimental method

1) Plating: take HFL1 cells in the exponential growth phase, and when the cells grow and fuse 85% -95%, discard the old culture solution, rinse twice with phosphate buffer, add digestion with trypsin digestion solution, and observe under an inverted microscope. Cells are retracted and rounded, complete medium is added to stop the digestion, repeated gentle pipetting, and then transferred to a 15mL sterile centrifuge tube, centrifuged at 800r / min for 5 minutes, discard the supernatant, and then collect the cells with complete medium Cell count, adjust cell density to 2.5 × 10 ⁵ cells / mL, inoculate in 6-well plate, 2 mL / well, 5 × 10 ⁵ cells / well, divided into normal control group, model control group, pirfenidone group , Compound A sodium salt group, Compound B hydrochloride group and drug combination group, each group has three complexes. Incubate overnight at 37 ° C, 5% CO ₂ .

2) Cell starvation treatment: The next day after plating, when the cells adhere to and grow well, aspirate the supernatant, add 2mL of serum-free F-12K culture solution to each well, and incubate at 37 ° C in a 5% CO ₂ incubator 2 hours.

3) Cell dosing: Aspirate the cell supernatant and add each drug working solution (containing 10ng / mL TGF-β1) in sequence, 2mL / well. Place in a 37 ° C, 5% CO ₂ incubator for 48 hours; the groups are: normal control group (F12K medium with 0.5% DMSO), model control group, pirfenidone group, compound A sodium salt group , Compound B hydrochloride group and drug combination group; among them, the model control group and each drug-containing or drug combination group contain 0.5% DMSO and 10ng / mL TGF-β1.

4) Collect each group of proteins and determine the protein concentration, perform Western Blot detection, and develop using a two-color infrared laser imager (Gene Company Limited, Odyssey CLx).

3. Experimental results

The expression and quantitative analysis results of α-SMA protein in HFL-1 cells stimulated by TGF-β1 after drug treatment are shown in Figure 1 and Figure 2. The experimental results showed that the expression of α-SMA was significantly increased when TGF-β1 was used to stimulate HFL1 cells. The positive compound pirfenidone can significantly inhibit the expression of α-SMA, which can be reduced to 71.69%. Both Compound B hydrochloride and Compound A sodium salt can reduce the high expression of α-SMA caused by TGF-β1 stimulation, which can be reduced to 52.81% and 53.80%, respectively; that is, at the above experimental concentration, Compound B hydrochloride and The sodium salt of Compound A has similar efficacy and is superior to pirfenidone at higher concentrations. The combined use of Compound A sodium salt and Compound B hydrochloride is more effective than single use. The combination of drugs can reduce the high expression of α-SMA caused by TGF-β1 stimulation to 32.99%.

The above content is only the basic description under the concept of the present invention, and any equivalent transformation made according to the technical solution of the present invention shall fall within the protection scope of the present invention.

In the description of this specification, reference to the descriptions of the terms "one example", "some examples", "some embodiments", "examples", "specific examples", or "some examples" is meant to be combined with the examples The specific features, structures, materials, or characteristics described in the examples are included in at least one embodiment or example of the present invention. In this specification, the schematic expression of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. In addition, without contradicting each other, those skilled in the art may combine and combine different embodiments or examples and features of the different embodiments or examples described in this specification.

Although the embodiments of the present invention have been shown and described above, it should be understood that the above-mentioned embodiments are exemplary and cannot be construed as limitations to the present invention, and those of ordinary skill in the art may understand the above within the scope of the present invention. The embodiments are changed, modified, replaced, and modified.

Claims (58)

1. A drug combination, which contains the following two parts:

   Part One: Contains Component 1, which is Compound A or a pharmaceutically acceptable salt thereof as shown below; and

   Part 2: Containing component 2, which is Compound B or its pharmaceutically acceptable salt as shown below;

   
2. The pharmaceutical combination according to claim 1, wherein the component 1 is a sodium salt of compound A.
3. The pharmaceutical combination according to any one of claims 1-2, wherein the component 2 is the hydrochloride salt of Compound B.
4. The pharmaceutical combination according to any one of claims 1 to 3, wherein the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 1600.
5. The pharmaceutical combination according to any one of claims 1 to 4, wherein the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 800, or 1: 0.625 to 1: 640.
6. The pharmaceutical combination according to any one of claims 1 to 5, wherein the amount ratio of the substances of component 1 and component 2 is 1: 5 to 1: 800, 1: 5 to 1: 320, 1: 20 to 1: 320, 1:20 to 1: 160, 1:80 to 1: 160, 1:80 to 1: 800, 1: 160 to 1: 800, or 1: 200 to 1: 800.
7. The pharmaceutical combination according to any one of claims 1-6, wherein the ratio of the amounts of the substances of component 1 and component 2 is 1: 0.625, 1: 1.25, 1: 2.5, 1: 5, 1: 10, 1: 12.5, 1:20, 1:40, 1:50, 1:80, 1: 100, 1: 150, 1: 160, 1: 200, 1: 250, 1: 300, 1: 320, 1: 400, 1: 500, 1: 640 or 1: 800.
8. The pharmaceutical combination according to any one of claims 1-7, wherein the component 1 and the component 2 are administered separately, simultaneously or in a single formulation.
9. A pharmaceutical composition comprising a first part and a second part, wherein the first part comprises component 1, and the second part comprises component 2; wherein, the component 1 is Compound A or its pharmacy as shown below Acceptable salt, the component 2 is Compound B or a pharmaceutically acceptable salt thereof as shown below,

   
10. The pharmaceutical composition according to claim 9, wherein the component 1 is a sodium salt of compound A.
11. The pharmaceutical composition according to any one of claims 9-10, wherein the component 2 is the hydrochloride salt of Compound B.
12. The pharmaceutical composition according to any one of claims 9 to 11, wherein the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 1600.
13. The pharmaceutical composition according to any one of claims 9-12, wherein the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 800, or 1: 0.625 to 1: 640.
14. The pharmaceutical composition according to any one of claims 9-13, wherein the amount ratio of the substances of component 1 and component 2 is 1: 5 to 1: 800, 1: 5 to 1: 320, 1 : 20 to 1: 320, 1:20 to 1: 160, 1:80 to 1: 160, 1:80 to 1: 800, 1: 160 to 1: 800, or 1: 200 to 1: 800.
15. The pharmaceutical composition according to any one of claims 9 to 14, wherein the amount ratio of the substances of component 1 and component 2 is 1: 0.625, 1: 1.25, 1: 2.5, 1: 5, 1 : 10, 1: 12.5, 1:20, 1:40, 1:50, 1:80, 1: 100, 1: 150, 1: 160, 1: 200, 1: 250, 1: 300, 1: 320 , 1: 400, 1: 500, 1: 640, or 1: 800.
16. The pharmaceutical composition according to any one of claims 9-15, further comprising one or more pharmaceutically acceptable carriers.
17. The pharmaceutical composition according to claim 16, wherein the carrier is an excipient, diluent, adjuvant, vehicle or a combination thereof.
18. A kit comprising a first part and a second part; wherein the first part comprises component 1, which is Compound A or a pharmaceutically acceptable salt thereof; the second part comprises component 2, which is a compound B or its pharmaceutically acceptable salt;

    
19. The kit according to claim 18, wherein the component 1 is Compound A sodium salt.
20. The kit according to any one of claims 18-19, wherein the component 2 is the hydrochloride salt of Compound B.
21. The kit according to any one of claims 18 to 20, wherein the ratio of the amounts of the substances of component 1 and component 2 is 1: 0.625 to 1: 1600.
22. The kit according to any one of claims 18-21, wherein the ratio of the amounts of the substances of component 1 and component 2 is 1: 0.625 to 1: 800, or 1: 0.625 to 1: 640.
23. The kit according to any one of claims 18-22, wherein the amount ratio of the substances of component 1 and component 2 is 1: 5 to 1: 800, 1: 5 to 1: 320, 1: 20 to 1: 320, 1:20 to 1: 160, 1:80 to 1: 160, 1:80 to 1: 800, 1: 160 to 1: 800, or 1: 200 to 1: 800.
24. The kit according to any one of claims 18 to 23, wherein the ratio of the amounts of the substances of component 1 and component 2 is 1: 0.625, 1: 1.25, 1: 2.5, 1: 5, 1: 10, 1: 12.5, 1:20, 1:40, 1:50, 1:80, 1: 100, 1: 150, 1: 160, 1: 200, 1: 250, 1: 300, 1: 320, 1: 400, 1: 500, 1: 640 or 1: 800.
25. A kit according to any of claims 18-24, wherein the first part and the second part each independently comprise one or more pharmaceutically acceptable carriers.
26. The kit of claim 25, wherein the carrier is an excipient, diluent, adjuvant, vehicle, or a combination thereof.
27. Use of the pharmaceutical combination according to any one of claims 1-8 or the pharmaceutical composition according to any one of claims 9-17 or the kit according to any one of claims 18-26 in the preparation of a medicament, wherein The medicine is used for preventing, treating or alleviating fibrotic diseases.
28. The use according to claim 27, wherein the fibrotic disease is renal interstitial fibrosis, glomerulosclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, skeletal muscle fiber Disease, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myoma, neurofibroma, pulmonary interstitial fibrosis or vascular fibrosis.
29. The use according to claim 28, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.
30. The pharmaceutical combination according to any one of claims 1-8 or the pharmaceutical composition according to any one of claims 9-17 or the kit according to any one of claims 18-26 is used to prevent, treat or alleviate fibrosis Disease application.
31. The use according to claim 30, wherein the fibrotic disease is renal interstitial fibrosis, glomerulosclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, skeletal muscle fiber Disease, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myoma, neurofibroma, pulmonary interstitial fibrosis or vascular fibrosis.
32. The use according to claim 31, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.
33. Use of the pharmaceutical combination according to any one of claims 1-8 or the pharmaceutical composition according to any one of claims 9-17 or the kit according to any one of claims 18-26 to prevent, treat or alleviate Methods of fibrotic diseases.
34. The method according to claim 33, wherein the fibrotic disease is renal interstitial fibrosis, glomerulosclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, skeletal muscle fiber Disease, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myoma, neurofibroma, pulmonary interstitial fibrosis or vascular fibrosis.
35. The method of claim 34, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.
36. Use of a pharmaceutical combination in the preparation of a medicament for preventing, treating or alleviating fibrotic diseases; wherein the pharmaceutical combination comprises the following two parts:

    Part 1: It contains component 1, wherein component 1 is Compound A or a pharmaceutically acceptable salt thereof as shown below; and

    Part 2: It contains component 2, wherein component 2 is Compound B or its pharmaceutically acceptable salt as shown below;

    
37. The use according to claim 36, wherein the component 1 is the sodium salt of compound A.
38. The use according to claim 36 or 37, wherein the component 2 is the hydrochloride salt of compound B.
39. The use according to any one of claims 36-38, wherein the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 1600.
40. The use according to any one of claims 36-39, wherein the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 800, or 1: 0.625 to 1: 640.
41. The use according to any one of claims 36-40, wherein the amount ratio of the substances of component 1 and component 2 is 1: 5 to 1: 800, 1: 5 to 1: 320, 1:20 To 1: 320, 1:20 to 1: 160, 1:80 to 1: 160, 1:80 to 1: 800, 1: 160 to 1: 800, or 1: 200 to 1: 800.
42. The use according to any one of claims 36-41, wherein the amount ratio of the substances of component 1 and component 2 is 1: 0.625, 1: 1.25, 1: 2.5, 1: 5, 1:10 , 1: 12.5, 1:20, 1:40, 1:50, 1:80, 1: 100, 1: 150, 1: 160, 1: 200, 1: 250, 1: 300, 1: 320, 1 : 400, 1: 500, 1: 640 or 1: 800.
43. The use according to any one of claims 36-42, wherein the component 1 and the component 2 can be administered separately, simultaneously or in a single formulation.
44. The use according to any one of claims 36-43, wherein the medicament further comprises one or more pharmaceutically acceptable carriers.
45. The use according to claim 44, wherein the carrier is an excipient, diluent, adjuvant, vehicle or a combination thereof.
46. The use according to any one of claims 36-45, wherein the fibrotic disease is renal interstitial fibrosis, glomerulosclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, skin Fibrosis, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myoma, neurofibromatosis, pulmonary interstitial fibrosis or vascular fibrosis disease.
47. The use according to claim 46, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.
48. Use of a composition in the preparation of a medicament for preventing, treating or alleviating fibrotic diseases; wherein the composition comprises a first part and a second part, wherein the first part comprises component 1, and the second part comprises component 2; wherein, the component 1 is Compound A or a pharmaceutically acceptable salt thereof as shown below, and the component 2 is Compound B or a pharmaceutically acceptable salt thereof as shown below,

    
49. The use according to claim 48, wherein the component 1 is the sodium salt of compound A.
50. The use according to claim 48 or 49, wherein the component 2 is the hydrochloride salt of compound B.
51. The use according to any one of claims 48-50, wherein the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 1600.
52. The use according to any one of claims 48-51, wherein the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 800, or 1: 0.625 to 1: 640.
53. The use according to any one of claims 48-52, wherein the amount ratio of the substances of component 1 and component 2 is 1: 5 to 1: 800, 1: 5 to 1: 320, 1:20 To 1: 320, 1:20 to 1: 160, 1:80 to 1: 160, 1:80 to 1: 800, 1: 160 to 1: 800, or 1: 200 to 1: 800.
54. The use according to any one of claims 48-53, wherein the amount ratio of the substances of component 1 and component 2 is 1: 0.625, 1: 1.25, 1: 2.5, 1: 5, 1:10 , 1: 12.5, 1:20, 1:40, 1:50, 1:80, 1: 100, 1: 150, 1: 160, 1: 200, 1: 250, 1: 300, 1: 320, 1 : 400, 1: 500, 1: 640 or 1: 800.
55. The use according to any one of claims 48-54, wherein the composition comprises one or more pharmaceutically acceptable carriers.
56. The use according to claims 48-55, wherein the carrier is an excipient, diluent, adjuvant, vehicle or a combination thereof.
57. The use according to any one of claims 48-56, wherein the fibrotic disease is renal interstitial fibrosis, glomerulosclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, skin Fibrosis, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myoma, neurofibromatosis, pulmonary interstitial fibrosis or vascular fibrosis disease.
58. The use according to any one of claims 48-57, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

Images