WO2020078445A1 - Combinaison pharmaceutique ou composition pharmaceutique pour le traitement des maladies fibreuses - Google Patents

Combinaison pharmaceutique ou composition pharmaceutique pour le traitement des maladies fibreuses Download PDF

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WO2020078445A1
WO2020078445A1 PCT/CN2019/111838 CN2019111838W WO2020078445A1 WO 2020078445 A1 WO2020078445 A1 WO 2020078445A1 CN 2019111838 W CN2019111838 W CN 2019111838W WO 2020078445 A1 WO2020078445 A1 WO 2020078445A1
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component
fibrosis
compound
substances
use according
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PCT/CN2019/111838
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English (en)
Chinese (zh)
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曹生田
杨雯
徐愉林
吕爱贞
吴方园
郑晓敏
王慧
李晓青
詹志柱
李静
习宁
王晓军
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广东东阳光药业有限公司
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Priority to CN201980051380.2A priority Critical patent/CN112770757B/zh
Publication of WO2020078445A1 publication Critical patent/WO2020078445A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • 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.
  • 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.
  • ECM resting extracellular matrix
  • 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.
  • 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.
  • the fibrosis of different organs or tissues 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.
  • Compound A 4-Difluorobenzenesulfonamide
  • 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.
  • 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.
  • 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;
  • Part 2 Containing component 2, which is Compound B or its pharmaceutically acceptable salt as shown below;
  • component 1 and component 2 of the present invention are administered separately, simultaneously, or in a single formulation.
  • Component 1 described herein is a pharmaceutically acceptable salt of Compound A.
  • component 1 described herein is the sodium salt of compound A.
  • Component 2 described herein is a pharmaceutically acceptable salt of Compound B.
  • component 2 of the present invention is the hydrochloride salt of compound B.
  • 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.
  • the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 1600.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical combination of the present invention wherein the carrier is an excipient, diluent, adjuvant, vehicle, or a combination thereof.
  • the pharmaceutical combination of the invention optionally further comprises one or more pharmaceutically acceptable carriers.
  • the pharmaceutical combination of the present invention wherein the carrier is an excipient, diluent, adjuvant, vehicle or a combination thereof.
  • the invention provides a pharmaceutical composition
  • 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,
  • the component 1 is a pharmaceutically acceptable salt of Compound A.
  • the component 1 is the sodium salt of compound A.
  • the component 2 is a pharmaceutically acceptable salt of Compound B.
  • the component 2 is the hydrochloride salt of Compound B.
  • 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.
  • the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 1600.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical composition described herein further comprises one or more pharmaceutically acceptable carriers.
  • the carrier of the present invention is an excipient, diluent, adjuvant, vehicle, or a combination thereof.
  • 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;
  • the component 1 is Compound A sodium salt.
  • the component 2 is the hydrochloride salt of Compound B.
  • the amount ratio of the substances of component 1 and component 2 is 1: 0.625 to 1: 1600.
  • 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.
  • 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.
  • 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.
  • the first part and the second part each independently comprise one or more pharmaceutically acceptable carriers.
  • the carrier is an excipient, diluent, adjuvant, vehicle, or a combination thereof.
  • 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.
  • 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.
  • 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.
  • the pulmonary fibrosis of the present invention is idiopathic pulmonary fibrosis.
  • 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.
  • 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.
  • 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.
  • the use of the present invention wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.
  • 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.
  • 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.
  • the methods described herein include contacting the patient with a pharmaceutical combination or pharmaceutical composition containing an effective therapeutic amount.
  • 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.
  • 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.
  • the method of the present invention wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.
  • 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,
  • component 1 is the sodium salt of compound A.
  • the use according to the invention wherein the component 2 is the hydrochloride salt of compound B.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the use according to the present invention wherein the carrier is an excipient, diluent, adjuvant, vehicle or a combination thereof.
  • 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.
  • 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.
  • the use according to the present invention wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.
  • 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;
  • component 1 and component 2 can be administered separately, simultaneously or in a single formulation.
  • each of the first and second parts independently optionally includes one or more pharmaceutically acceptable carriers.
  • the carrier is an excipient, diluent, adjuvant, vehicle or a combination thereof.
  • component 1 is the sodium salt of compound A.
  • the use according to the invention wherein the component 2 is the hydrochloride salt of compound B.
  • 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.
  • 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.
  • 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.
  • 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.
  • the use of the present invention, wherein the drug or drug combination further comprises one or more pharmaceutically acceptable carriers.
  • the use according to the present invention wherein the carrier is an excipient, diluent, adjuvant, vehicle or a combination thereof.
  • 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.
  • 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.
  • the use according to the present invention wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.
  • 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.
  • pharmaceutically acceptable 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.
  • 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".
  • excipient 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers; wherein the carrier is an excipient, diluent, adjuvant, vehicle, or a combination thereof.
  • component 1 and component 2 are used in combination at a reasonable ratio (simultaneous administration, separate administration or administration in a single formulation).
  • 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.
  • 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.
  • 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.
  • 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.
  • the component 1 and component 2 can be based on a safe and effective dose or dose range for clinical administration.
  • an appropriate dose and ratio are selected for combined use (simultaneous administration, simultaneous administration, Administered separately or in a single formulation).
  • component 1 and the component 2 of the present invention 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.
  • component 1 and component 2 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.
  • the inhibitory effect on cell proliferation is stronger than that of component 1 and component 2 administered separately.
  • 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.
  • the pharmaceutical composition of the present invention is used in one or more medically acceptable ways of injection, oral administration, and surgical placement.
  • 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.
  • component 1 and component 2 of the present invention are administered in a therapeutically effective amount, respectively.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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 (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 (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.
  • 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.
  • FIG. 1 shows the Western Blot results of ⁇ -SMA protein expression in human lung fibroblasts (HFL1 cells) stimulated by TGF- ⁇ 1 by the drug or drug combination described in Example 4 of the present invention.
  • 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 : 2 ⁇ M.
  • Figure 2 shows the results of quantitative analysis of ⁇ -SMA protein expression in TFL- ⁇ 1 stimulated HFL1 cells as described in Example 4 of the present invention.
  • 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 : 2 ⁇ M.
  • 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 ⁇ -SMA antibody was purchased from German Merk Millipore Company (Cat. No.
  • TGF- ⁇ 1 human recombinant transforming growth factor TGF- ⁇ 1 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).
  • PMSF phenylmethylsulfonyl fluoride
  • 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).
  • Example 3 Inhibition experiment of the drug combination / pharmaceutical composition of the present invention on cell proliferation
  • 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.
  • 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.
  • the compound A sodium salt at a concentration of 0.125 ⁇ M is used in combination with the compound B hydrochloride at a concentration of 20 ⁇ M in the working solution of the drug combination, and the ratio of the amount of the substance is 1: 160.
  • the concentration of the drug combination is ⁇ M.
  • 20 + 1 means that 20 ⁇ M Compound B hydrochloride and 1 ⁇ M Compound A hydrochloride are administered together.
  • 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.
  • 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 ⁇ L of cell suspension to each well, inoculate 3 96-well plates, at 37 ° C, Incubate overnight under 5% CO 2 conditions.
  • Cell administration Add 100 ⁇ L 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.
  • CCK-8 48 hours after administration, 100 ⁇ L 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.
  • 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.
  • 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 ⁇ M, 0.2 ⁇ M, 0.10 ⁇ M, 0.05 ⁇ M, 0.025 ⁇ M, 0.0125 ⁇ M; DMSO content was 0.5%).
  • the concentration of the drug combination is ⁇ M.
  • 20 + 0.4 means that 20 ⁇ M Compound B hydrochloride and 0.4 ⁇ M Compound A hydrochloride are administered together.
  • TGF- ⁇ 1 (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- ⁇ 1.
  • 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).
  • pirfenidone (600 mM) pirfenidone (600 mM)
  • Compound A sodium salt 0.02 mM
  • compound B hydrochloride (0.4 mM) Take 25 ⁇ L of the above drug mother liquor into 4975 ⁇ L F-12K medium solution containing 10 ng / mL TGF- ⁇ 1 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 ⁇ M) with DMSO content of 0.5%.
  • the working solution of the normal control group was prepared by using 4975 ⁇ L of F12K medium solution without TGF- ⁇ 1 and 25 ⁇ L of DMSO, in which the DMSO content was 0.5%.
  • the model control working solution was prepared with 4975 ⁇ L of F12K medium solution containing 10ng / mL TGF- ⁇ 1 and 25 ⁇ L of DMSO, in which the DMSO content was 0.5%.
  • 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 ⁇ M (molar ratio 1:10, The mass ratio is 1: 9.45).
  • 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 .
  • Cell dosing Aspirate the cell supernatant and add each drug working solution (containing 10ng / mL TGF- ⁇ 1) 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- ⁇ 1.
  • 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- ⁇ 1.
  • Both Compound B hydrochloride and Compound A sodium salt can reduce the high expression of ⁇ -SMA caused by TGF- ⁇ 1 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 ⁇ -SMA caused by TGF- ⁇ 1 stimulation to 32.99%.

Abstract

L'invention concerne une combinaison pharmaceutique ou une composition pharmaceutique destinée au traitement des maladies fibreuses, ainsi que l'utilisation de ladite combinaison ou composition pharmaceutique dans la préparation de médicaments destinés à prévenir et/ou traiter les maladies fibreuses.
PCT/CN2019/111838 2018-10-19 2019-10-18 Combinaison pharmaceutique ou composition pharmaceutique pour le traitement des maladies fibreuses WO2020078445A1 (fr)

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