WO2020175817A1 - Composition for preventing, ameliorating, or treating fibrosis - Google Patents
Composition for preventing, ameliorating, or treating fibrosis Download PDFInfo
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- WO2020175817A1 WO2020175817A1 PCT/KR2020/001857 KR2020001857W WO2020175817A1 WO 2020175817 A1 WO2020175817 A1 WO 2020175817A1 KR 2020001857 W KR2020001857 W KR 2020001857W WO 2020175817 A1 WO2020175817 A1 WO 2020175817A1
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- fibrosis
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Classifications
-
- 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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/314—Foods, ingredients or supplements having a functional effect on health having an effect on lung or respiratory system
Definitions
- the present invention relates to a composition for preventing, improving or treating fibrosis.
- Tissues contain well-ordered populations of cells that are bound to an extracellular matrix and are surrounded by a network of blood vessels. Fibrosis or fibrosis is responsible for injury or inflammation that alters the structure and function of various tissues. In the case of fibrosis, irrespective of where it occurs, excessive accumulation of fibrous connective tissue, such as the collagen matrix that replaces normal tissue, is responsible for most etiological factors: kidney, liver, fat, and Progressive fibrosis in the lungs, heart, bone or bone marrow, and skin is a major cause of death or pain.
- fibrosis refers to a disease in which inflammatory cells infiltrate only the alveolar wall of the lung tissue and induce tissue fibrosis, causing serious structural mutations in the lung tissue.
- the amount of oxygen supplied by the oxygen supply decreases, which leads to difficulty breathing.
- Treatment methods using growth factors such as steroid contracts and antioxidants have been continuously researched and reported since 2000, but there has not been any evidence of clear drug efficacy until long-term administration. It has been reported to cause systemic side effects or side effects that lead to resistance.
- Treatment through growth factor administration is a treatment method that has received a lot of attention in recent years, and is known as an important factor in pulmonary fibrosis.
- -(3) It is a comparatively fundamental treatment method using'interferon' that inhibits the production of the disease.
- the therapeutic efficacy of a single component such as interferon may be temporary, and this may be effective only in some patients, so continuous research and clinical trials are required.
- An object of the present invention is to provide a pharmaceutical composition for preventing, improving or treating fibrosis; or a food composition.
- Another object of the present invention is to provide a method for preventing, improving or treating fibrosis.
- composition for preventing, improving or treating fibrosis is a composition for preventing, improving or treating fibrosis
- composition of the present invention can be used as a pharmaceutical composition; or a food composition.
- composition of the present invention contains a compound represented by the following formula (1) as an active ingredient.
- Formula 1 may be a component separated from the root water of Nelumbagorosea 0?/3 ⁇ 4» (3 ⁇ 40 ⁇ 05 ⁇ 61). It can have a function of very effectively inhibiting the expression or activity of acetyltransferase (Histone acetyltrasferase), especially p300 (ElA binding protein p300).
- the fibrosis of the present invention is a disease in which abnormal production, accumulation and deposition of extracellular matrix by fibroblasts occurs, and collagen matrix due to damage or inflammation that may change the structure and function of various tissues may be abnormally accumulated.
- any organ it may include fibrosis of all organs, and preferably, but is not limited to, fibrosis of at least one organ selected from the group consisting of kidney, liver, lung, heart, bone or bone marrow and skin.
- the fibrosis is expressed with a high level of expression through the acetylase p300.
- TGF-(3 Transfomimg growth factor-(3)
- collagen a phenomenon that promotes the expression of genes related to fibrosis by TGF-(3 (Transfomimg growth factor-(3)), such as collagen, or it can recover cells from damage that may be induced by fibrosis. It may be induced due to the absence of enzymes, but is not limited to this.
- Myelofibrosis Liver fibrosis, Heart fibrosis, Multiple sclerosis, Kidney fibrosis, Cystic fibrosis, Neutropenia, Skeletal muscle fibrosis, Skin sclerosis, Dermatitis, It may be at least one selected from the group consisting of mediastinal fibrosis and splenic fibrosis due to sickle cell anemia, and preferably pulmonary fibrosis, but is not limited thereto.
- the "pulmonary fibrosis” of the present invention refers to the development of scarred (fibrous) tissue due to excessive fibrous connective tissue formation or development in the lung (fibrosis). Specifically, pulmonary fibrosis is Chronic causing swelling and scarring of the alveoli and interstitial tissues of the lungs
- pulmonary fibrosis is idiopathic pulmonary fibrosis
- Nonspecific Interstitial Pneumonia Acute Interstitial Pneumonia, Cryptogenic Organizing Pneumonia, Respiratory Bronchiolitis Associated with
- Interstitial Lung Desquamative Interstitial Pneumonia, Lymphoid Interstitial Pneumonia, Interstitial Pulmonary Fibrosis, and Diffuse Pulmonary Fibrosis may be at least one selected from the group consisting of, and preferably idiopathic. It may be, but is not limited to, pulmonary fibrosis.
- pulmonary fibrosis of the present invention is caused by various causes, such as microscopic damage to the lungs induced by inhalation of fine particles (asbestos, stone dust, metal dust, particles present in cigarette smoke, silica dust, etc.).
- pulmonary fibrosis is a side effect of other diseases (such as autoimmune diseases, viral or bacterial infections).
- cytotoxic agents such as bleomycin, busulfan and methotrexate
- Anti-inflammatory drugs such as nitrofurantoin and sulfasalazine
- anti-arrhythmic drugs such as amiodarone and tocainide
- anti-inflammatory drugs such as gold and penicylamine
- certain drugs such as illegal drugs (such as drugs, cocaine and heroin). May be caused by the above idiopathic
- the above “prevention” of the present invention may include, without limitation, any action that can block symptoms caused by fibrosis or suppress or delay the symptoms by using the above composition of the present invention.
- the "treatment" of the present invention may include, without limitation, any action that allows symptoms caused by fibrosis to be ameliorated or to benefit from the use of the composition of the present invention.
- the above "improvement" of the present invention may include, without limitation, any act in which symptoms caused by fibrosis are improved or changed to benefit using the above composition of the present invention.
- composition of the present invention can be used as a pharmaceutical composition.
- the above pharmaceutical composition of the present invention is not limited to these, but is formulated in the form of oral formulations such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories and sterile injectable solutions according to the usual methods.
- the pharmaceutical composition may be formulated to be used for intratracheal administration or inhalation administration; or as an injection, but is not limited thereto.
- fibrosis occurs in the respiratory tract such as the lungs. If so, it is desirable that the active ingredient be formulated for inhalation administration so that it can reach the target organ in a yield suitable for prevention or treatment.
- the pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier.
- the above pharmaceutically acceptable carriers are binding agents, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, and suspensions when administered orally.
- a buffer, preservative, painless agent, solubilizing agent, stabilizing agent, etc. can be mixed and used.
- a base agent, excipient, lubricant, Preservatives, etc. may be used.
- the formulation of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
- tablets, troches, capsules, elixirs (for oral administration) Elixir), suspension, syrup, wafers, etc. can be prepared in the form of unit dosage ampoules or multiple dosages for injections.
- Formulated with other solutions, suspensions, tablets, capsules, sustained-release preparations, etc. can do.
- examples of carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, Calcium silicate, cellulose, methyl 2020/175817 1»(:1/10 ⁇ 020/001857
- Cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used.
- heavy agents, anti-coagulants, lubricants, and It may additionally contain humectants, flavors, emulsifiers, and preservatives.
- the route of administration of the pharmaceutical composition of the present invention is not limited to these, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, Sublingual or rectal is included. Oral or parenteral delivery is preferred.
- the parenteral of the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or injection techniques.
- the pharmaceutical composition of the present invention It can also be administered in the form of a suppository for rectal administration.
- the pharmaceutical composition of the present invention depends on a number of factors including the activity of the specific compound used, age, weight, general health, sex, formula, administration time, route of administration, discharge rate, drug formulation, and the severity of the specific disease to be prevented or treated.
- the dosage of the pharmaceutical composition may vary widely, and the dosage of the pharmaceutical composition depends on the patient's condition, weight, degree of disease, drug type, route and duration of administration, but can be appropriately selected by the person skilled in the art, and 0.0001 to 5 () 113 ⁇ 4/day It can be administered at 13 ⁇ 4 or 0.001 to 50 13 ⁇ 4/13 ⁇ 4. Administration may be administered once a day, or may be administered in multiple doses.
- the above dosage does not limit the scope of the present invention in any way.
- the pharmaceutical composition according to the present invention may be formulated as a pill, sugar tablet, capsule, liquid, gel, syrup, slurry, and suspension.
- composition of the present invention can be used as a food composition.
- natural carbohydrates monosaccharides such as glucose, disaccharides such as fructose, and conventional sugars such as sucrose and polysaccharides, dextrins, cyclodextrins, and sugar alcohols such as xylitol, sorbitol, and erythritol are included.
- natural flavoring agents Trigger, Stevia
- It can be an extract (for example, rebaudioside, glycyrrhizin, etc.) and a synthetic flavoring agent (saccharin, aspartame, etc.).
- extract for example, rebaudioside, glycyrrhizin, etc.
- synthetic flavoring agent sacharin, aspartame, etc.
- the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavors, coloring agents, fectic acids and salts thereof, alginic acid and salts thereof, organic acids, ,Stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, etc. may be further included.
- the ingredients included in the food composition of the present invention can be used independently or in combination.
- the ratio of the additives does not correspond to the core element of the present invention, but 0.1 to 0.1 per 0 parts by weight of the food composition of the present invention About 50 parts by weight 2020/175817 1»(:1 ⁇ 1 ⁇ 2020/001857
- Another embodiment of the present invention provides a method for preventing, improving or treating fibrosis.
- the term "individual” in the present invention is an object in need of prevention, improvement or treatment of fibrosis, such as primates, such as humans, as well as cattle, horses, sheep, pigs, goats, camels, nutrition, dogs, cats, etc. May include, but is not limited to, all mammals.
- composition containing the above active ingredients including the type and extent of the reaction to be performed, whether or not other formulations are used in some cases, the patient's age, weight, general health status, sex and diet, administration time, administration route, and the above efficacy It is desirable to apply differently depending on the secretion rate of the composition containing the ingredients, the treatment period, various factors including drugs used with or concurrently with the specific composition and similar factors well known in the medical field.
- histone acetyltransferase Histone acetyltransferase
- histones in the tissue of a patient with idiopathic pulmonary fibrosis according to an embodiment of the present invention.
- Figures 3 and 4 show the results of confirming the degree of inhibition of histone acetylated protein in various candidate materials according to an embodiment of the present invention.
- 6A and 6B show wear in the fibrosis animal model according to an embodiment of the present invention.
- FIG. 7 shows the results of analysis through a soluble collagen assay in lung tissue of a fibrosis animal model according to an embodiment of the present invention.
- a pharmaceutical composition for the prevention, improvement or treatment of fibrosis comprising the following Formula 1 as an active ingredient; or a food composition is provided:
- Another embodiment of the present invention is to provide a method for preventing, improving, or treating fibrosis comprising administering to an individual a compound represented by Formula 1 in a pharmaceutically effective amount.
- a solution containing bleomycin (BLM) was administered by injecting it into the bronchi through surgery (40 to 5 mg/kg, body weight). After raising the mouse for 4 weeks, the following examples were carried out.
- TGF-(3-overexpressing mouse is a model in which fibrosis is induced specifically in the lungs by doxycycline, and a solution containing doxycycline ( 0.5 mg/ml of doxycycline containing 2% sucrose) was administered to the mice by water supply. Then, the mice were reared for 4 weeks, and the following examples were carried out.
- p300 ElA binding protein p300
- GCN5 histone acetyl ansferase GCN5
- PC AF P300/CB P- as sociated factor
- HDAC3 Histone Deacetylase 3
- p300 was increased in the tissues of patients with idiopathic pulmonary fibrosis compared to tissues obtained from normal individuals.
- HDAC3 Histone Deacetyltransferase
- Example 1 100 ⁇ concentration of Example 1 and Comparative Examples 1 to 4 as a kit for measuring histone acetyltransferase activity 1 (011, 110. 332, USA), to the method provided by the manufacturer Accordingly, the degree of inhibition of histone acetyltransferase activity (inhibitory activity) for GCN5 including ?300 and each was confirmed, and the results are shown in FIG. 3.
- Example 1 As shown in Table 2 and FIGS. 3 and 4, in the case of Example 1, it has a specific inhibitory effect on ?300, and because of the other histone acetyltransferase (30 and : ⁇ ), the inhibitory ability is In addition, in Example 1, 1050 was a4968 l ⁇ iM, compared to Comparative Examples 1 to 4, the activity inhibiting ability of p300 It was confirmed that it was remarkably excellent.
- Example 1 In the case of injecting Example 1 into the model, the ratio of collagen in the entire tissue was injected at a high dose (High + BLM), as well as at a low dose.
- Example 1 according to the present invention very effectively inhibits the expression or activity of p300, so that fibrosis of various organs, especially lungs, can be reduced.
- Example 1 was injected daily for 4 weeks at a high dose (High) or low dose (Low) in the pulmonary fibrosis animal model prepared in the phase reference comparative example 1, and then the lung tissue was removed from the animal model. Then, using a collagen assay kit (Biocolor, cat no.S1000, UK), the total amount of soluble collagen present in the extracted lung tissue was measured according to the method provided by the manufacturer, The results are shown in FIG. 7.
- Example 1 Based on the above results, Example 1 according to the present invention showed the expression or activity of p300.
- Example 12 After injecting Example 1 at a high dose or low dose for 4 weeks every day for 4 weeks, the body weight of the experimental animals was measured on days 0 and 17, and the results are shown in FIG.
- the compound corresponding to Example 1 of the present invention is not only non-toxic when administered to a subject as it is, and very effectively inhibits weight loss due to a substance that induces fibrosis such as bleomycin. You can see that you can.
- the present invention relates to a pharmaceutical composition for the prevention or treatment of fibrosis, and the composition comprising the compound represented by Formula 1 of the present invention as an active ingredient prevents fibrosis by inhibiting the expression or activity of histone acetyltransferase or
- the compound represented by the above formula 1 of the present invention specifically inhibits ⁇ 3 million among various histone acetyltransferases, so other acetylase enzymes that play an important role in maintaining life. It has no effect on the disease, so it can reduce side effects that may occur when preventing or treating fibrosis.
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Abstract
The present invention relates to a pharmaceutical composition for preventing or treating fibrosis. A composition comprising a compound represented by chemical formula 1 of the present invention as an active ingredient can be used very effectively for the prevention or treatment of fibrosis by inhibiting the expression or activity of histone acetyltransferases. Furthermore, since the compound represented by chemical formula 1 of the present invention specifically inhibits only p300 among various histone acetyltransferases, the compound does not affect other acetylating enzymes that play an important role in the maintenance of life, and thus can reduce side effects that may occur when preventing or treating fibrosis.
Description
2020/175817 1»（：1/10公020/001857 명세서 2020/175817 1»（：1/10公020/001857 Specification
발명의 명칭:섬유증의 예방，개선또는치료용조성물 기술분야 Title of the invention: Composition for prevention, improvement or treatment of fibrosis
[1] 본발명은섬유증의예방,개선또는치료용조성물에관한것이다. [1] The present invention relates to a composition for preventing, improving or treating fibrosis.
배경기술 Background
[2] 조직은세포외매트릭스에결합되어있고,혈관네트워크에의해둘러싸여 있는잘정돈된세포군집을포함한다.섬유화또는섬유증 (Fibrosis)은다양한 조직의구조및기능을변화시키는손상 (Injury)또는염증에따른콜라겐 매트릭스의비정상적인축적이다.섬유증의경우,그발생위치와는무관하게 , 정상조직을대체하는콜라겐매트릭스와같은섬유질결합조직의과도한 축적이대부분의병인학적요인에해당한다.신장,간,지방,폐,심장,뼈또는 골수,및피부등에서의진행성섬유증은사망또는고통의주요한요인이다. [2] Tissues contain well-ordered populations of cells that are bound to an extracellular matrix and are surrounded by a network of blood vessels. Fibrosis or fibrosis is responsible for injury or inflammation that alters the structure and function of various tissues. In the case of fibrosis, irrespective of where it occurs, excessive accumulation of fibrous connective tissue, such as the collagen matrix that replaces normal tissue, is responsible for most etiological factors: kidney, liver, fat, and Progressive fibrosis in the lungs, heart, bone or bone marrow, and skin is a major cause of death or pain.
[3] 상기섬유증중에서특히 ,폐에발생되는섬유증인폐섬유증 (Pulmonary [3] Among the above fibrosis, especially, pulmonary fibrosis, which is fibrosis occurring in the lungs (Pulmonary
fibrosis)은폐조직의폐포벽에만성염증세포들이침투하면서조직섬유화를 유도하여폐조직의심각한구조적변이를일으키는질환을말한다.어떠한 원인에의해일단섬유화가진행되면폐조직이단단하게굳고폐포벽이 두꺼워져혈액에의한산소공급량이줄어들게되고,이에따라호흡이 어려워지게된다.현재의학으로는이미섬유화가진행된폐조직을완전히 복구할수있는치료방법이없어,섬유화진행초기에발견하거나또는폐 이식을제외하면대개증상이발병되고 3 ~ 5년이후환자가결국사망에이르게 된다. fibrosis) refers to a disease in which inflammatory cells infiltrate only the alveolar wall of the lung tissue and induce tissue fibrosis, causing serious structural mutations in the lung tissue. The amount of oxygen supplied by the oxygen supply decreases, which leads to difficulty breathing. Currently, there is no treatment method that can completely repair the lung tissue that has already undergone fibrosis, so it is usually found in the early stages of fibrosis or if lung transplantation is excluded, symptoms usually develop. After 3 to 5 years, the patient eventually dies.
[4] 진행초기에발견된폐섬유증의치료방법으로는스테로이드 (Steroid), [4] As a treatment method for pulmonary fibrosis found in the early stages of progression, steroids,
아자티오프린 (Azathioprine),사이클로포스파마이드 (Cyclophosphamide)와같은 스테로이드계약물을이용한치료방법 ,아세틸시스테인 (Acetylcysteine)과같은 항산화제를이용한치료방법및사이토카인 (Cytokine) IFN-Y(Interferon-Y)와 같은성장인자투여를통한치료방법등이 있다.스테로이드계약물및 항산화제를이용한치료방법들은 2000년도부터지속적으로연구및보고된 것은많으나아직까지뚜렷한약물효능으로입증된것이없는상태이며,장기간 투여시전신부작용을초래하거나,내성이생기는부작용들을초래하는것으로 보고된바있다.성장인자투여를통한치료법은최근들어많은이목을받고 있는치료법으로서폐섬유증에중요한인자로알려진 TGF-(3(Transforming growth factor-(3)의생산을억제하는 '인터페론'을이용한비교적근본적인접근 방식의치료법이다.이러한발병의원인을분석하여치료하는접근방식때문에 스테로이드계약물및항산화제를이용한치료법에비해부작용이적고,효능이 우수하여주사제또는에어로졸방식과같은다양한형태의치료법들이 보고되어 있다.하지만아직까지폐섬유증의정확한발병원인이알려져있지
2020/175817 1»（：1^1{2020/001857 Treatment with steroid contracts such as azathioprine and cyclophosphamide, treatment with antioxidants such as acetylcysteine, and cytokines IFN-Y (Interferon-Y) Treatment methods using growth factors such as steroid contracts and antioxidants have been continuously researched and reported since 2000, but there has not been any evidence of clear drug efficacy until long-term administration. It has been reported to cause systemic side effects or side effects that lead to resistance. Treatment through growth factor administration is a treatment method that has received a lot of attention in recent years, and is known as an important factor in pulmonary fibrosis. -(3) It is a comparatively fundamental treatment method using'interferon' that inhibits the production of the disease. Because of this approach to treatment by analyzing the cause of the outbreak, it has less anatomical effect and efficacy compared to the treatment method using steroid contracts and antioxidants. It is excellent and various types of treatments such as injection or aerosol methods have been reported, but the exact cause of pulmonary fibrosis is still known. 2020/175817 1»（：1^1{2020/001857
2 않기 때문에 인터페론과같은단일성분에 의한치료효능은일시적일수있고, 이는일부환자들에 대해서만효능이 나타날수있으므로지속적인연구및 임상시험이 필요한실정이다. 2 Because it is not, the therapeutic efficacy of a single component such as interferon may be temporary, and this may be effective only in some patients, so continuous research and clinical trials are required.
이러한필요성에 따라전사작용에 직접적인역할을하는전사인자를비롯한 수많은단백질의기능을조절하는기작으로,단백질을구성하는기본단위인 아세트산중의 라이신 (1今 11句잔기를조절하여단백질의 발현등과같은현상에 영향을미치게되는히스톤단백질의 아세틸화와같은단백질의번역후변형과 관련된성분에 대한연구가진행되고있으나아직까지섬유증에 적합한 치료제는존재하지 않는실정이다. According to this need, it is a mechanism that regulates the functions of numerous proteins, including transcription factors that play a direct role in transcription, and lysine in acetic acid, the basic unit constituting the protein, is regulated to regulate the expression of proteins. Research on components related to post-translational modifications of proteins, such as acetylation of histone proteins, which affects the phenomenon, is being conducted, but there is still no suitable treatment for fibrosis.
발명의상세한설명 Detailed description of the invention
기술적과제 Technical task
[6] 본발명의 일목적은섬유증의 예방,개선또는치료용약학조성물;또는식품 조성물을제공하는것이다. [6] An object of the present invention is to provide a pharmaceutical composition for preventing, improving or treating fibrosis; or a food composition.
[7] 본발명의다른목적은섬유증의 예방,개선또는치료방법을제공하는것이다. [7] Another object of the present invention is to provide a method for preventing, improving or treating fibrosis.
[8] 그러나본발명이 이루고자하는기술적과제는이상에서 언급한과제에 [8] However, the technical task to be achieved by this invention is
제한되지 않으며,언급되지 않은또다른과제들은아래의 기재로부터 당 업계에서통상의지식을가진자에게 명확하게 이해될수있을것이다. Other tasks that are not limited and are not mentioned will be clearly understood by those of ordinary skill in the industry from the following description.
과제해결수단 Problem solving means
[9] 본발명의 일구현예에서는섬유증의 예방,개선또는치료용조성물을 [9] In one embodiment of the present invention, a composition for preventing, improving or treating fibrosis
제공한다. to provide.
[1이 본발명의상기조성물은약학조성물;또는식품조성물로사용될수있다. [1] The composition of the present invention can be used as a pharmaceutical composition; or a food composition.
[11] 본발명의상기조성물은아래화학식 1로표시되는화합물을유효성분으로 포함한다. [11] The above composition of the present invention contains a compound represented by the following formula (1) as an active ingredient.
[12] ［화학식 1］ [12] [Formula 1]
일반식 general meal
5 -히드록시 -2 -메틸- 1,4 -나프토퀴논 (5-11) '(«)/-2-11161;11)4-1,4 - 1 ］3111;110<¾1 10116)으로 서,상기 화학식 1은늘룸바고로세아 0?/¾» (¾0厂05^61)의뿌리주줄물로부터 분리된성분일수있다.이와같은상기화학식 1은히스톤
아세틸트렌스퍼라제 (Histone acetyltrasferase),특히 p300(ElA binding protein p300)의발현또는활성을매우효과적으로억제하는기능을가질수있다. As 5 -hydroxy -2 -methyl-1,4 -naphthoquinone (5-11 ) '(« )/ -2-11161;11 ) 4-1,4-1 ]3111;110<¾1 10116) , Formula 1 may be a component separated from the root water of Nelumbagorosea 0?/¾» (¾0厂05^61). It can have a function of very effectively inhibiting the expression or activity of acetyltransferase (Histone acetyltrasferase), especially p300 (ElA binding protein p300).
[15] 본발명의상기섬유증은섬유아세포에의한세포외기질의비정상적인생성, 축적및침착이일어나는질환으로,다양한조직의구조및기능을변화시킬수 있는손상또는염증에의한콜라겐매트릭스가비정상적으로축적될수있는 기관이라면모든기관의섬유증이포함될수있고,바람직하게는신장,간,폐, 심장,뼈또는골수및피부로구성된군으로부터선택되는적어도하나의 기관에발생된섬유증일수있으나,이에제한되는것은아니다.본발명의 목적상상기섬유증은아세틸화효소인 p300에통해발현수준이높아진 [15] The fibrosis of the present invention is a disease in which abnormal production, accumulation and deposition of extracellular matrix by fibroblasts occurs, and collagen matrix due to damage or inflammation that may change the structure and function of various tissues may be abnormally accumulated. If any organ, it may include fibrosis of all organs, and preferably, but is not limited to, fibrosis of at least one organ selected from the group consisting of kidney, liver, lung, heart, bone or bone marrow and skin. For the purposes of the present invention, the fibrosis is expressed with a high level of expression through the acetylase p300.
TGF-(3(Transfomimg growth factor-(3)에의하여섬유화와관련된유전자,예를 들면콜라겐등과같은유전자의발현이촉진되는현상에의해유도된것이거나, 섬유화가유도될수있는손상으로부터세포를회복시킬수있는효소의부재로 인해유도된것일수있으나,이에제한되는것은아니다. It is induced by a phenomenon that promotes the expression of genes related to fibrosis by TGF-(3 (Transfomimg growth factor-(3)), such as collagen, or it can recover cells from damage that may be induced by fibrosis. It may be induced due to the absence of enzymes, but is not limited to this.
[16] 본발명의상기섬유증은폐섬유증 (Pulmonary fibrosis),자궁근종, [16] Pulmonary fibrosis of the present invention, uterine myoma,
골수섬유증 (Myelofibrosis),간섬유증 (Liver fibrosis),심장섬유증 (Heart fibrosis), 다발성경화증,신장섬유증 (Kidney fibrosis),낭포성섬유증 (Cystic fibrosis), 호중구감소증,골격근섬유증,피부경화증,피부근염,종격동섬유증 (Mediastinal fibrosis)및겸상적혈구빈혈증에의한비장섬유증으로구성된군으로부터 선택되는적어도하나인것일수있고,바람직하게는폐섬유증일수있으나, 이에제한되는것은아니다. Myelofibrosis, Liver fibrosis, Heart fibrosis, Multiple sclerosis, Kidney fibrosis, Cystic fibrosis, Neutropenia, Skeletal muscle fibrosis, Skin sclerosis, Dermatitis, It may be at least one selected from the group consisting of mediastinal fibrosis and splenic fibrosis due to sickle cell anemia, and preferably pulmonary fibrosis, but is not limited thereto.
[17] 본발명의상기 "폐섬유증”은,폐에서의과도한섬유성연결조직의형성또는 발달 (섬유증)로인해 ,흉터가생긴 (섬유성 )조직의발달을의미한다.구체적으로, 폐섬유증은폐포및폐의간질성조직의팽윤및흉터를유발하는만성 [17] The "pulmonary fibrosis" of the present invention refers to the development of scarred (fibrous) tissue due to excessive fibrous connective tissue formation or development in the lung (fibrosis). Specifically, pulmonary fibrosis is Chronic causing swelling and scarring of the alveoli and interstitial tissues of the lungs
질환이다.이와같은흉터조직이건강한조직을대체하여염증을유발하며, 만성염증은섬유증의전조로파악될수있다.이와같은폐조직의손상으로 인하여폐가뻣뻣하게될수있고,개체가자가호흡이어려워지게될수있다. Such scar tissue replaces healthy tissue, causing inflammation, and chronic inflammation can be identified as a precursor to fibrosis. Such damage to the lung tissue can lead to stiff lungs, which makes it difficult for the individual to breathe. Can be
[18] 본발명에서폐섬유증은특발성폐섬유증 (Idiopa比 lie Pulmonary Fibrosis), [18] In the present invention, pulmonary fibrosis is idiopathic pulmonary fibrosis,
비특이성간질성폐렴 (Nonspecific Interstitial Pneumonia),급성간질성폐렴 (Acute Interstitial Pneumonia),특발성기질화폐렴 (Cryptogenic Organizing Pneumonia), 호톱계기관지염관련성간질설폐질환 (Respiratory Bronchiolitisassociated Nonspecific Interstitial Pneumonia, Acute Interstitial Pneumonia, Cryptogenic Organizing Pneumonia, Respiratory Bronchiolitis Associated with
Interstitial Lung),박리성간질성폐렴 (Desquamative Interstitial Pneumonia), 임파구성간질성폐렴 (Lymphoid Interstitial Pneumonia),간질성폐섬유증및 미만성폐섬유증으로구성된군으로부터선택되는적어도하나인것일수있고, 바람직하게는특발성폐섬유증일수있으나,이에제한되는것은아니다. Interstitial Lung), Desquamative Interstitial Pneumonia, Lymphoid Interstitial Pneumonia, Interstitial Pulmonary Fibrosis, and Diffuse Pulmonary Fibrosis may be at least one selected from the group consisting of, and preferably idiopathic. It may be, but is not limited to, pulmonary fibrosis.
[19] 본발명의상기폐섬유증은다양한원인,예를들면미세입자 (석면,돌가루, 금속분진,담배연기에존재하는입자들,실리카분진등)의흡입에의해 유도되는폐의미세손상에의해발병할수있다.또한,폐섬유증은다른 질병 (자가면역질환,바이러스또는박테리아감염등)의부차적인영향으로
발생할수있고,세포독성제제（블레오마이신,부설판및메토트렉세이트등）; 항생제（니트로푸란토인및술파살라진등）;부정맥치료제（아미오다론및 토카이니드등）;항염증약물（금및페니실아민등）;불법약물（마약,코카인및 헤로인등）과같은특정약물들에의해유발될수있으며,상기특발성 [19] The above pulmonary fibrosis of the present invention is caused by various causes, such as microscopic damage to the lungs induced by inhalation of fine particles (asbestos, stone dust, metal dust, particles present in cigarette smoke, silica dust, etc.). In addition, pulmonary fibrosis is a side effect of other diseases (such as autoimmune diseases, viral or bacterial infections). May occur, and cytotoxic agents (such as bleomycin, busulfan and methotrexate); Anti-inflammatory drugs (such as nitrofurantoin and sulfasalazine); anti-arrhythmic drugs (such as amiodarone and tocainide); anti-inflammatory drugs (such as gold and penicylamine); and certain drugs such as illegal drugs (such as drugs, cocaine and heroin). May be caused by the above idiopathic
폐섬유증의경우에는이와같은원인이외의다른알수없는원인에의해 나타나는것일수있다. In the case of pulmonary fibrosis, it may be caused by an unknown cause other than this.
[2이 본발명의상기”예방”은본발명의상기조성물을이용하여섬유증에의해 기인된증상을차단하거나,그증상을억제또는지연시킬수있는모든 행위라면제한없이포함될수있다. [2] The above “prevention” of the present invention may include, without limitation, any action that can block symptoms caused by fibrosis or suppress or delay the symptoms by using the above composition of the present invention.
[21] 본발명의상기 "치료”는본발명의상기조성물을이용하여섬유증에의해 기인된증상이호전될수있도록하거나,이롭게될수있도록하는모든 행위라면제한없이포함될수있다. [21] The "treatment" of the present invention may include, without limitation, any action that allows symptoms caused by fibrosis to be ameliorated or to benefit from the use of the composition of the present invention.
[22] 본발명의상기 "개선”은본발명의상기조성물을이용하여섬유증에의해 기인된증상이호전또는이롭게변경되는모든행위라면제한없이포함될수 있다. [22] The above "improvement" of the present invention may include, without limitation, any act in which symptoms caused by fibrosis are improved or changed to benefit using the above composition of the present invention.
[23] [23]
[24] 본발명의상기조성물은약학조성물로사용될수있다. [24] The above composition of the present invention can be used as a pharmaceutical composition.
[25] 본발명의상기약학조성물은이들로한정되는것은아니지만,각각통상의 방법에따라산제,과립제,캡슐,정제,수성현탁액등의경구형제형,외용제, 좌제및멸균주사용액의형태로제형화되어사용될수있다.바람직하게상기 약학조성물은기관내투여또는흡입투여용;또는주사제로사용될수있도록 제형화될수있으나,이에제한되는것은아니다.본발명의목적상섬유증이 폐와같은호흡기에발생된경우에는유효성분이타겟기관에예방또는치료에 적합한수율로도달될수있도록흡입투여용으로제형화되는것이바람직하다. [25] The above pharmaceutical composition of the present invention is not limited to these, but is formulated in the form of oral formulations such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories and sterile injectable solutions according to the usual methods. Preferably, the pharmaceutical composition may be formulated to be used for intratracheal administration or inhalation administration; or as an injection, but is not limited thereto. For the purposes of the present invention, fibrosis occurs in the respiratory tract such as the lungs. If so, it is desirable that the active ingredient be formulated for inhalation administration so that it can reach the target organ in a yield suitable for prevention or treatment.
[26] 본발명의약학조성물은약학적으로허용가능한담체를포함할수있다.상기 약학적으로허용되는담체는경구투여시에는결합제 ,활탁제 ,붕해제,부형제 , 가용화제,분산제,안정화제,현탁화제,색소,향료등이사용될수있으며, 주사제의경우에는완충제 ,보존제 ,무통화제 ,가용화제 ,등장제 ,안정화제등이 혼합되어사용될수있으며,국소투여용의경우에는기제,부형제,윤활제, 보존제등이사용될수있다.본발명의약학조성물의제형은상술한바와같은 약학적으로허용되는담체와혼합하여다양하게제조될수있다.예를들어 , 경구투여시에는정제，트로키，캡슐,엘릭서（Elixir）,서스펜션,시럽，웨이퍼등의 형태로제조할수있으며,주사제의경우에는단위투약엠플또는다수회투약 형태로제조할수있다.기타,용액,현탁액,정제,캡슐,서방형제제등으로 제형화할수있다. [26] The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier. The above pharmaceutically acceptable carriers are binding agents, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, and suspensions when administered orally. In the case of injection, a buffer, preservative, painless agent, solubilizing agent, stabilizing agent, etc. can be mixed and used. In the case of topical administration, a base agent, excipient, lubricant, Preservatives, etc. may be used. The formulation of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above. For example, tablets, troches, capsules, elixirs (for oral administration) Elixir), suspension, syrup, wafers, etc., can be prepared in the form of unit dosage ampoules or multiple dosages for injections. Formulated with other solutions, suspensions, tablets, capsules, sustained-release preparations, etc. can do.
[27] 한편,제제화에적합한담체，부형제및희석제의예로는,락토즈,덱스트로즈, 수크로즈,솔비톨,만니톨,자일리톨,에리스리톨,말티톨,전분,아카시아고무, 알지네이트,젤라틴,칼슘포스페이트,칼슘실리케이트,셀룰로즈,메틸
2020/175817 1»（：1/10公020/001857 [27] On the other hand, examples of carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, Calcium silicate, cellulose, methyl 2020/175817 1»（：1/10公020/001857
5 셀룰로즈,미정질셀룰로즈,폴리비닐피롤리돈,물,메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트,탈크,마그네슘스테아레이트또는광물유등이 사용될수있다.또한,중진제,항응집제,윤활제,습윤제,향료,유화제,방부제 등을추가로포함할수있다. 5 Cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used. In addition, heavy agents, anti-coagulants, lubricants, and It may additionally contain humectants, flavors, emulsifiers, and preservatives.
본발명의상기 약학조성물의투여 경로는이들로한정되는것은아니지만 구강,정맥내,근육내,동맥내,골수내,경막내,심장내,경피,피하,복강내, 비강내,장관,국소,설하또는직장이포함된다.경구또는비경구투하가 바람직하다. The route of administration of the pharmaceutical composition of the present invention is not limited to these, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, Sublingual or rectal is included. Oral or parenteral delivery is preferred.
[29] 본발명의상기비경구는피하,피내,정맥내,근육내,관절내,활액낭내,흉골내, 경막내,병소내 및두개골내주사또는주입기술을포함한다.본발명의 약학 조성물은또한직장투여를위한좌제의 형태로투여될수있다. [29] The parenteral of the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or injection techniques. The pharmaceutical composition of the present invention It can also be administered in the form of a suppository for rectal administration.
본발명의상기 약학조성물은사용된특정화합물의 활성,연령,체중, 일반적인건강,성별,정식,투여시간,투여 경로,배출율,약물배합및 예방또는 치료될특정질환의중증을포함한여러요인에 따라다양하게 변할수있고, 상기 약학조성물의투여량은환자의상태,체중,질병의정도,약무형태,투여 경로및기간에 따라다르지만당업자에의해 적절하게선택될수있고, 1일 0.0001내지 5（）11¾/1¾또는 0.001내지 50 1¾/1¾으로투여할수있다.투여는 하루에 한번투여할수도있고,수회 나누어투여할수도있다.상기투여량은 어떠한면으로든본발명의범위를한정하는것은아니다.본발명에 따른의약 조성물은환제，당의정,캡슐,액제,겔,시럽,슬러리,현탁제로제형화될수있다. The pharmaceutical composition of the present invention depends on a number of factors including the activity of the specific compound used, age, weight, general health, sex, formula, administration time, route of administration, discharge rate, drug formulation, and the severity of the specific disease to be prevented or treated. The dosage of the pharmaceutical composition may vary widely, and the dosage of the pharmaceutical composition depends on the patient's condition, weight, degree of disease, drug type, route and duration of administration, but can be appropriately selected by the person skilled in the art, and 0.0001 to 5 () 11¾/day It can be administered at 1¾ or 0.001 to 50 1¾/1¾. Administration may be administered once a day, or may be administered in multiple doses. The above dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as a pill, sugar tablet, capsule, liquid, gel, syrup, slurry, and suspension.
[31] [31]
[32] 본발명의상기조성물은식품조성물로사용될수있다. [32] The above composition of the present invention can be used as a food composition.
[33] 본발명의상기식품조성물이음료형태로제조되는경우지시된비율로상기 식품조성물을포함하는것외에특별한제한점은없으며,통상의음료와같이 [33] When the food composition of the present invention is manufactured in the form of a drink, there are no special restrictions other than including the food composition in a specified ratio, and like a normal drink
28 다양한향미제또는천연탄수화물등을추가성분으로서함유할수있다. 28 Various flavoring agents or natural carbohydrates may be included as additional ingredients.
구체적으로,천연탄수화물로서포도당등의모노사카라이드,과당등의 디사카라이드,슈크로스등의 및폴리사카라이드,덱스트린,시클로덱스트린 등과같은통상적인당및자일리톨,소르비톨,에리트리톨등의 당알콜등을 포함할수있다.상기 향미제로서는천연향미제（타우마틴,스테비아 Specifically, as natural carbohydrates, monosaccharides such as glucose, disaccharides such as fructose, and conventional sugars such as sucrose and polysaccharides, dextrins, cyclodextrins, and sugar alcohols such as xylitol, sorbitol, and erythritol are included. As the above flavoring agents, natural flavoring agents (Taumatine, Stevia
추출물（예를들어,레바우디오시드人글리시르히진등）및합성 향미제（사카린, 아스파르탐등）등일수있다. It can be an extract (for example, rebaudioside, glycyrrhizin, etc.) and a synthetic flavoring agent (saccharin, aspartame, etc.).
본발명의상기식품조성물은여러 가지 영양제 ,비타민,광물（전해질）,합성 풍미제 및천연풍미제등의풍미제,착색제,펙트산및그의 염,알긴산및그의 염，유기산,
，안정화제，방부제，글리세린, 알콜,탄산음료에사용되는탄산화제등이 더포함될수있다. The food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavors, coloring agents, fectic acids and salts thereof, alginic acid and salts thereof, organic acids, ，Stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, etc. may be further included.
[35] 본발명의상기식품조성물에포함되는성분들은독립적으로또는조합하여 사용될수있다.상기 첨가제의비율은본발명의 핵심적인요소에 해당하지 아니하지만,본발명의식품조성물 0중량부당 0.1내지 약 50중량부의
2020/175817 1»（：1^1{2020/001857 [35] The ingredients included in the food composition of the present invention can be used independently or in combination. The ratio of the additives does not correspond to the core element of the present invention, but 0.1 to 0.1 per 0 parts by weight of the food composition of the present invention About 50 parts by weight 2020/175817 1»（：1^1{2020/001857
6 범위에서선택될수있으나,이에제한되는것은아니다. It can be selected from a range of 6, but is not limited thereto.
[36] [36]
[37] 본발명의다른구현예에서는섬유증의 예방,개선또는치료방법을제공한다. [37] Another embodiment of the present invention provides a method for preventing, improving or treating fibrosis.
[38] 본발명의상기방법은하기화학식 1로표시되는화합물을약학적유효량으로 개체에투여하는단계를포함한다: [38] The method of the present invention includes the step of administering to the subject a compound represented by the following formula (1) in a pharmaceutically effective amount:
[39] [화학식 1] [39] [Formula 1]
[4이 [4 this
[41] 본발명의상기 "개체”란,섬유증의 예방,개선또는치료가필요한개체로서, 영장류예를들면인간뿐만아니라,소,말,양,돼지,염소,낙타,영양,개,고양이 등의포유동물을모두포함할수있으나,이에제한되는것은아니다. [41] The term "individual" in the present invention is an object in need of prevention, improvement or treatment of fibrosis, such as primates, such as humans, as well as cattle, horses, sheep, pigs, goats, camels, nutrition, dogs, cats, etc. May include, but is not limited to, all mammals.
[42] 본발명의상기“투여”란，임의의 적절한방법으로개체에게본발명의 [42] The above "administration" of the present invention means that the present invention is administered to an individual by any appropriate method.
유효성분을도입하는과정을의미하는것으로서，본발명의상기치료방법에서 투여 방법은경구또는비경구등의다양한경로를통해투여될수있다. It means the process of introducing the active ingredient, and the administration method in the above treatment method of the present invention can be administered through various routes such as oral or parenteral.
[43] 본발명의목적상,특정환자에 대한구체적인약학적유효량은달성하고자 [43] For the purpose of the present invention, to achieve a specific pharmaceutical effective amount for a specific patient
하는반응의종류와정도,경우에따라다른제제가사용되는지의 여부를비롯한 구체적상기유효성분을포함하는조성물,환자의 연령,체중,일반건강상태, 성별및식이,투여시간,투여경로및상기유효성분을포함하는조성물의 분비율,치료기간,구체적조성물과함께사용되거나동시사용되는약물을 비롯한다양한인자와의약분야에 잘알려진유사인자에 따라다르게 적용하는 것이 바람직하다. The composition containing the above active ingredients, including the type and extent of the reaction to be performed, whether or not other formulations are used in some cases, the patient's age, weight, general health status, sex and diet, administration time, administration route, and the above efficacy It is desirable to apply differently depending on the secretion rate of the composition containing the ingredients, the treatment period, various factors including drugs used with or concurrently with the specific composition and similar factors well known in the medical field.
[44] 본발명의상기섬유증의 예방,개선또는치료방법은하나이상의 질환에 대한 치료적 활성을가지는화합물또는물질을투여하는것을더포함하는병용 요법일수있으나,이에 제한되는것은아니다. [44] The method of preventing, improving or treating fibrosis of the present invention may be a combination therapy further comprising administering a compound or substance having therapeutic activity against one or more diseases, but is not limited thereto.
[45] 본발명에서상기 "병용”은동시,개별또는순차투여를나타내는것으로 [45] In the present invention, the above "combination" refers to simultaneous, individual or sequential administration.
이해되어야한다.상기투여가순차또는개별적인경우, 2차성분투여의 간격은 상기 병용의 이로운효과를잃지 않도록하는것이어야한다. It should be understood. If the administrations are sequential or individual, the interval between administrations of the secondary components should be such that the beneficial effects of the combination are not lost.
[46] 본발명의상기치료방법에서,화학식 1,섬유증,예방,개선,치료등과관련된 내용은앞서기재한바와중복되어 명세서의과도한복잡성을피하기 위하여 이하의 기재를생략한다. [46] In the above treatment method of the present invention, the contents related to formula 1, fibrosis, prevention, improvement, treatment, etc. are duplicated with those described above, and the following description is omitted to avoid excessive complexity of the specification.
발명의 효과
[47] 본발명의화학식 1로표시되는화합물을유효성분으로포함하는조성물은 히스톤아세틸트렌스퍼라제의발현또는활성을억제함으로써섬유증의 예방 또는치료에매우효과적으로사용될수있다.나아가,본발명의상기화학식 1로표시되는화합물은다양한히스톤아세틸트렌스퍼라제중에서특히 p300만을특이적으로억제하기때문에,생명유지에중요한역할을하는다른 아세틸화효소에는영향을미치지아니하므로섬유증을예방또는치료할때 발생될수있는부작용을줄일수있다. Effects of the Invention [47] The composition containing the compound represented by the formula 1 of the present invention as an active ingredient can be very effectively used in the prevention or treatment of fibrosis by inhibiting the expression or activity of histone acetyltransferase. Furthermore, the above formula of the present invention Since the compound represented by 1 specifically inhibits only p300 among various histone acetyltransferases, it does not affect other acetylases that play an important role in maintaining life.Therefore, a side effect that may occur when preventing or treating fibrosis Can be reduced.
도면의 간단한설명 Brief description of the drawing
[48] 도 1은본발명의일실시예에따른특발성폐섬유증환자조직에서히스톤 아세틸트렌스퍼라제 (Histone acetyltransferase)및히스톤 1 is a histone acetyltransferase (Histone acetyltransferase) and histones in the tissue of a patient with idiopathic pulmonary fibrosis according to an embodiment of the present invention.
탈아세틸트렌스퍼라제 (Histone deacetyltransferase)단백질의발현수준을면역 조직화학염색을통해확인한결과를나타낸것이다. This is the result of confirming the expression level of the protein histone deacetyltransferase through immunohistochemical staining.
[49] 도 2는본발명의일실시예에따른섬유증동물모델에서면역조직화학염색을 통해히스톤아세틸화단백질의발현수준의확인및마손트리크롬 (Masson’s Trichrome; MTS)염색을통해섬유화정도를확인한결과를나타낸것이다. 2 is a result of confirming the level of expression of histone acetylated protein through immunohistochemical staining and the degree of fibrosis through Masson's Trichrome (MTS) staining in a fibrosis animal model according to an embodiment of the present invention It represents
[5이 도 3및도 4는본발명의일실시예에따른다양한후보물질들에서히스톤 아세틸화단백질의억제정도를확인한결과를나타낸것이다. [5] Figures 3 and 4 show the results of confirming the degree of inhibition of histone acetylated protein in various candidate materials according to an embodiment of the present invention.
[51] 도 5는본발명의일실시예에따른섬유증동물모델에화학식 1의화합물투여 주기를모식도로나타낸것이다. 5 is a schematic diagram showing the administration cycle of the compound of Formula 1 to a fibrosis animal model according to an embodiment of the present invention.
[52] 도 6의 a및 b는본발명의일실시예에따른섬유증동물모델에서마손 6A and 6B show wear in the fibrosis animal model according to an embodiment of the present invention.
트리크롬염색을통해섬유화정도를확인한결과를나타낸것이다. It shows the result of checking the degree of fibrosis through trichrome dyeing.
[53] 도 7은본발명의일실시예에따른섬유증동물모델의폐조직에서가용성 콜라겐어세이 (Soluble collagen assay)를통해분석한결과를나타낸것이다. 7 shows the results of analysis through a soluble collagen assay in lung tissue of a fibrosis animal model according to an embodiment of the present invention.
[54] 도 8은본발명의일실시예에따른섬유증동물모델의실험전후에따른 8 is before and after the experiment of the animal model of fibrosis according to an embodiment of the present invention.
몸무게변화를그래프로나타낸것이다. It is a graph showing the weight change.
발명의 실시를위한최선의 형태 Best form for carrying out the invention
[55] 본발명의일구현예에서는하기화학식 1을유효성분으로포함하는섬유증의 예방,개선또는치료용약학조성물;또는식품조성물을제공하는것이다: [55] In one embodiment of the present invention, a pharmaceutical composition for the prevention, improvement or treatment of fibrosis comprising the following Formula 1 as an active ingredient; or a food composition is provided:
[56] [화학식 1] [56] [Formula 1]
[57] [57]
발명의실시를위한형태 Modes for the implementation of the invention
[59] 이하,실시예를통하여본발명을더욱상세히설명하고자한다.이들실시예는 오로지본발명을보다구체적으로설명하기위한것으로서，본발명의요지에 따라본발명의범위가이들실시예에의해제한되지않는다는것은당업계에서 통상의지식을가진자에게있어서자명할것이다. [59] Hereinafter, the present invention will be described in more detail through examples. These examples are only for describing the present invention more specifically, and the scope of the present invention according to the gist of the present invention is That it is not limited will be apparent to those of ordinary skill in the art.
[6이 [6 this
[61] 실시예 [61] Examples
[62] [62]
[63] [준비예 1]성유증동물모델제작 [63] [Preparation Example 1] Production of sexually transmitted animal models
[64] 7주령의 20 ~ 25은의무균수컷 C57BL/6마우스 (Orient Bio,한국)에 [64] Seven-week-old 20 to 25 silver sterile male C57BL/6 mice (Orient Bio, Korea)
블레오마이신 (Bleomycin; BLM)이포함된용액을수술을통하여기관지내로 주입시키는방식으로투여하였다 (40 에 5mg/kg·체중). 4주동안상기마우스를 사육한뒤아래의실시예를수행하였다. A solution containing bleomycin (BLM) was administered by injecting it into the bronchi through surgery (40 to 5 mg/kg, body weight). After raising the mouse for 4 weeks, the following examples were carried out.
[65] 다른섬유증동물모델인 TGF-(3과발현마우스 (CC10-rtTA-tTS-TGF-betal)는 독시사이클린 (Doxycycline)에의해폐에특이적으로섬유화가유도되는 모델로서,독시사이클린이포함된용액 (2% sucrose가포함된 0.5mg/ml의 독시사이클린)을마우스에급수하는방식으로투여하였다.그런다음, 4주동안 상기마우스를사육한뒤아래의실시예를수행하였다. [65] Another fibrosis animal model, TGF-(3-overexpressing mouse (CC10-rtTA-tTS-TGF-betal), is a model in which fibrosis is induced specifically in the lungs by doxycycline, and a solution containing doxycycline ( 0.5 mg/ml of doxycycline containing 2% sucrose) was administered to the mice by water supply. Then, the mice were reared for 4 weeks, and the following examples were carried out.
[66] [66]
[67] 『심험예 11성유증환자조직에서다백짐밤혀수주확이 [67] 『Experimental Example 11 Investigation of orders in a sexually transmitted patient tissue
[68] 특발성폐섬유증환자또는정상인으로부터얻은조직을 10%포르말린으로 고정시키고,파라핀에포매하여 7■두께의절편을슬라이드에부착하였다. 그런다음,자일렌을이용하여상기절편을탈파라핀화한뒤에고농도에서 저농도순으로에탄올을처리하고, p300(ElA binding protein p300), GCN5(histone acetyl仕 ansferase GCN5), PC AF (P300/CB P- as sociated factor)및 HDAC3(Histone Deacetylase 3)에특이적인항체를이용하여면역염색을수행한이후에 [68] a tissue obtained from idiopathic pulmonary fibrosis patients or normal subjects and fixed with 10% formalin, and embedded in paraffin and attached to a slide of the fragments 7 ■ thickness. Then, after deparaffinizing the fragment with xylene, ethanol was treated in the order of low concentration at high concentration, and p300 (ElA binding protein p300), GCN5 (histone acetyl ansferase GCN5), PC AF (P300/CB P- as sociated factor) and HDAC3 (Histone Deacetylase 3)-specific antibodies were used to perform immunostaining.
광학현미경을이용하여각단백질들의발현수준을측정하여,그결과를도 1에 나타내었다. The expression level of each protein was measured using an optical microscope, and the results are shown in FIG. 1.
[69] 도 1에서보는바와같이,히스톤아세틸트렌스퍼라제 (Histone acetyltransferase; [69] As shown in FIG. 1, histone acetyltransferase;
HAT)인 p300, GCN5및 PCAF중에서 p300이정상인으로부터얻은조직에 비하여,특발성폐섬유증환자의조직에서증가되어 있었으며,히스톤 Among the HAT) p300, GCN5 and PCAF, p300 was increased in the tissues of patients with idiopathic pulmonary fibrosis compared to tissues obtained from normal individuals.
탈아세틸트렌스퍼라제 (Histone Deacetyltransferase; HDAC)인 HDAC3의 경우에는정상과폐섬유증조직간의발현수준차이가없는것을확인하였다. In the case of HDAC3, a Histone Deacetyltransferase (HDAC), it was confirmed that there was no difference in the level of expression between normal and pulmonary fibrosis tissues.
P이 상기결과를통해 ,특발성폐섬유증의경우히스톤아세틸트렌스퍼라제중에서
2020/175817 1»（：1^1{2020/001857 Through the above results, P was found in the histone acetyltransferase in the case of idiopathic pulmonary fibrosis. 2020/175817 1»（：1^1{2020/001857
9 특히 ?300이정상조직에비하여높은수준으로존재하기 때문에, p300의 발현 또는그기능을특이적으로억제하는경우에는섬유증을효과적으로치료할수 있음을알수있다. 9 In particular, since ?300 exists at a higher level than normal tissues, it can be seen that fibrosis can be effectively treated when the expression of p300 or its function is specifically inhibited.
[기] [group]
[72] ［실험예 2］성유증동물모델에서다백짐밤혀수주확이 [72] [Experimental Example 2] Water injection by multi-packing in a sexually transmitted animal model
상기준비예 1에서독시사이클린을주입하여 가과발현되도록함으로써 섬유증을유도한폐섬유증동물모델의 폐조직을적출하여,상기실험예 丄에서와동일한방법으로 의발현수준을확인하였다.또한,상기조직이 부착된슬라이드를마손트리크롬 &88011’8 1¾ 01 ; MTS)으로염색하여 섬유화를확인하고,그결과를도 2에 나타내었다.여기서,대조군 ((¾加· 01)은 독시사이클린을대신하여 를주입하였다. In Preparation Example 1, the lung tissue of the animal model of pulmonary fibrosis induced fibrosis was excised by injecting doxycycline to allow overexpression, and the level of expression was confirmed by the same method as in Experimental Example 1. In addition, the tissue adhered The slides are made with trichrome &88011'8 1¾ 01; MTS) to confirm fibrosis, and the results are shown in Fig. 2. Here, the control group ((¾加· 01) was injected instead of doxycycline.
[74] 발현으로인해섬유증이 유
조직의섬유화가일어난 것을확인하였다.나아가,대조군에비하여
과발현으로인해섬유증이 유도된폐섬유증동물모델의
발현이높은것을 확인하였다. [74] The cause of fibrosis due to manifestation It was confirmed that the fibrosis of the tissue occurred. Further, compared to the control group Of an animal model of pulmonary fibrosis induced fibrosis due to overexpression It was confirmed that the expression was high.
상기결과를통해,정상동물에 비하여, 101나3의과발현으로인해유도된 폐섬유증의 경우에서도 p300의 발현이특이적으로높은수준으로존재하는 것을알수있다. From the above results, compared to normal animals, it can be seen that in the case of pulmonary fibrosis induced by overexpression of 101 or 3, the expression of p300 is present at a specific high level.
[76] [76]
[77] ［실시예 1］ [77] [Example 1]
[78] 하기화학식 1로표시되는 [78] represented by the following formula (1)
5 -히드록시 -2 -메틸- 1,4 -나프토퀴논 (5-11) («)/-2-11161;11)4-1,4 - 1 ］3111;110<¾1 10116)을 준비하였다. 5 -hydroxy -2 -methyl-1,4 -naphthoquinone (5-11 ) (« )/ -2-11161;11 ) 4-1,4-1 ]3111;110<¾1 10116) was prepared .
90 90
78 7 735 ［화학식 1］ 78 7 735 [Formula 1]
81] 81]
82] ［비교예 1내지 4］ 82] [Comparative Examples 1 to 4]
831 하기표 1에표시되는화합물을이용하여 비교예 1내지 4를준비하였다.
2020/175817 1»（：1^1{2020/001857 831 Comparative Examples 1 to 4 were prepared using the compounds shown in Table 1 below. 2020/175817 1»（：1^1{2020/001857
10 10
[84] [표 1] [84] [Table 1]
[85]
.또한, 실시예 1과동일한희석농도로비교예 1내지 4를희석하였다. [85] In addition, Comparative Examples 1 to 4 were diluted with the same dilution concentration as Example 1.
[88] 상기 100^농도의실시예 1과,비교예 1내지 4를히스톤아세틸트렌스퍼라제 활성을측정하는키트여1（ 011, 110. 332,미국）를이용하여 ,제조사가 제공하는방법에따라 ?300을포함한 GCN5및 각각에 대한히스톤 아세틸트렌스퍼라제활성 억제정도（저해능）를확인하고,그결과를도 3에 나타내었다. [88] Using the 100^ concentration of Example 1 and Comparative Examples 1 to 4 as a kit for measuring histone acetyltransferase activity 1 (011, 110. 332, USA), to the method provided by the manufacturer Accordingly, the degree of inhibition of histone acetyltransferase activity (inhibitory activity) for GCN5 including ?300 and each was confirmed, and the results are shown in FIG. 3.
[89] 또한,히스톤아세틸트렌스퍼라제 저해능이 있는것으로확인된실시예들의각 농도에 따른히스톤아세틸트렌스퍼라제활성 억제정도를확인하고, 1050값을 예측하여그결과를도 4및하기표 2에 나타내었다. [89] In addition, the degree of inhibition of histone acetyltransferase activity according to each concentration of the examples confirmed to have a histone acetyltransferase inhibitory ability was confirmed, and a value of 1050 was predicted, and the results are shown in Fig. 4 and Table 2 below. Indicated.
[9이 [표 ¾
[9] [Table ¾
[91] 상기표 2와도 3및 4에서보는바와같이,실시예 1의경우 ?300에특이적으로 저해효과를가지며,상기 ?300이아닌다른히스톤아세틸트렌스퍼라제인 （30 및 :的 므에는저해능이 없는것을확인하였다.뿐만아니라,상기실시예 1 은 1050이 a4968l·iM로비교예 1내지 4에비하여 p300의활성 저해능이
현저하게뛰어난것을확인하였다. [91] As shown in Table 2 and FIGS. 3 and 4, in the case of Example 1, it has a specific inhibitory effect on ?300, and because of the other histone acetyltransferase (30 and :的), the inhibitory ability is In addition, in Example 1, 1050 was a4968 l · iM, compared to Comparative Examples 1 to 4, the activity inhibiting ability of p300 It was confirmed that it was remarkably excellent.
[92] 상기결과를통해본발명에따른화학식 1로표시되는화합물은히스톤 [92] Based on the above results, the compound represented by Formula 1 according to the present invention is a histone
아세틸트렌스퍼라제중에서특히 p300의활성을매우효과적으로저해할수 있음을알수있다. Among the acetyltransferases, it can be seen that it can very effectively inhibit the activity of p300 in particular.
[93] [93]
[94] [실험예 4]성유증동물모델에서 P300저해름통한성유화억제효과확이 [94] [Experimental Example 4] Confirmation of the effect of inhibiting sexual emulsification through P300 inhibition in sexually transmitted animals
[95] 상기준비예 1에서,블레오마이신 (Bleomycin)이포함된용액을기관지내에 주입시키는방식으로투여하여제작한폐섬유증동물모델에실시예 1을 고용량 (5mg/kg; High)또는저용량 (2mg/kg; Low)으로 2주간매일주입한뒤 (도 5),상기실험예 2에서와같이마손트리크롬으로염색하여폐조직의섬유화를 확인하고,전체조직중에서콜라겐이차지하는부분에대한비율을나타내어, 그결과를도 6의 a및 b에나타내었다. [95] In Preparation Example 1, Example 1 was administered to a pulmonary fibrosis animal model prepared by administering a solution containing bleomycin into the bronchi, with a high dose (5 mg/kg; High) or a low dose (2 mg /kg; Low) after daily injection for 2 weeks (FIG. 5), as in Experimental Example 2, stained with marson trichrome to confirm fibrosis of the lung tissue, and the ratio of the collagen-charged portion of the entire tissue was shown. , The results are shown in a and b of FIG. 6.
[96] 도 6의 a및 b에서보는바와같이 ,블레오마이신을이용한폐섬유증동물 [96] As shown in Fig. 6 a and b, pulmonary fibrosis animals using bleomycin
모델에실시예 1을주입한경우,전체조직에서콜라겐이차지하는비율이 고용량으로주입한경우 (High+BLM)뿐만아니라저용량으로주입한 In the case of injecting Example 1 into the model, the ratio of collagen in the entire tissue was injected at a high dose (High + BLM), as well as at a low dose.
경우 (Low+BLM)에서도섬유화가유도된폐조직이정상조직 (Control)과거의 유사한정도로회복되는것을확인하였다. In the case (Low + BLM), it was confirmed that the lung tissue induced by fibrosis recovered to a similar degree to that of the normal tissue (Control).
[97] 상기결과를통해 ,본발명에따른실시예 1은 p300의발현또는활성을매우 효과적으로억제함으로써 ,다양한기관,특히폐의섬유화가감소될수있도록 하는것을알수있다. [97] From the above results, it can be seen that Example 1 according to the present invention very effectively inhibits the expression or activity of p300, so that fibrosis of various organs, especially lungs, can be reduced.
[98] [98]
[99] [실험예 5]성유증동물모델에서가용성콤라게분석 [99] [Experimental Example 5] Analysis of soluble comb crab in a sexually transmitted animal model
[10이 상기실험예 4에서와같이,상기준비예 1에서제조된폐섬유증동물모델에 실시예 1을고용량 (High)또는저용량 (Low)으로 4주간매일주입한뒤,동물 모델로부터폐조직을적출하였다.그런다음,콜라겐어세이키트 (Collagen assay kit; Biocolor, cat no. S1000,영국)를사용하여제조사가제공하는방법에따라 상기적출된폐조직에존재하는가용성콜라겐의총양을측정하여,그결과를 도 7에나타내었다. [10] As in Experimental Example 4, Example 1 was injected daily for 4 weeks at a high dose (High) or low dose (Low) in the pulmonary fibrosis animal model prepared in the phase reference comparative example 1, and then the lung tissue was removed from the animal model. Then, using a collagen assay kit (Biocolor, cat no.S1000, UK), the total amount of soluble collagen present in the extracted lung tissue was measured according to the method provided by the manufacturer, The results are shown in FIG. 7.
[101] 도 7에서보는바와같이 ,대조군 (PBS)에비하여저용량 (Low+BLM)또는 [101] As shown in FIG. 7, a low dose (Low+BLM) compared to the control (PBS) or
고용량 (High+BLM)으로실시예 1의화합물을투여하였을때, When the compound of Example 1 was administered at a high dose (High + BLM),
블레오마이신 (BLM)의흡입으로인해증가된가용성콜라겐의양이현저히 감소되는것을확인할수있었다. It was confirmed that the amount of soluble collagen increased by inhalation of bleomycin (BLM) was significantly reduced.
[102] 상기결과를통해,본발명에따른실시예 1은 p300의발현또는활성을 [102] Based on the above results, Example 1 according to the present invention showed the expression or activity of p300.
효과적으로억제함으로써 ,기관의섬유화가유도될때증가되는가용성 콜라겐의양이감소되는현상을유도할수있음을알수있다. By effectively inhibiting it, it can be seen that it can induce a phenomenon in which the amount of soluble collagen that is increased when fibrosis of the organ is induced is reduced.
[103] [103]
[104] [실험예 6]성유증동물모텔에서 p30n저해제주입으로 ?1하목무게며화확이 [104] [Experimental Example 6] Injected p30n inhibitor in a sexually transmitted animal motel with ?1 weight and chemical efficiency
[105] 상기실험예 4에서와같이,상기준비예 1에서제조된폐섬유증동물모델에
2020/175817 1»（：1^1{2020/001857 [105] As in Experimental Example 4, in the pulmonary fibrosis animal model prepared in the phase reference comparative example 1 2020/175817 1»（：1^1{2020/001857
12 실시예 1을고용량（ 沙）또는저용량山이 으로 4주간매일주입한뒤, 0일및 17일째에상기실험동물의몸무게를측정하고,그결과를도 8에나타내었다. 12 After injecting Example 1 at a high dose or low dose for 4 weeks every day for 4 weeks, the body weight of the experimental animals was measured on days 0 and 17, and the results are shown in FIG.
[106] 도 8에서보는바와같이,블레오마이신이주입된경우여1 [） 0일에약 [106] As shown in Fig. 8, when bleomycin is injected, 1 [) about 0 days
25은이었던체중이 17일에약 15은으로,약 1 감소된것을확인하였다.반면, 블레오마이신과본발명의상기실시예 1을고용량（ 沙+61 1）또는 It was confirmed that the weight, which was 25 silver, decreased by about 15 silver on the 17th. On the other hand, bleomycin and the above Example 1 of the present invention were used at a high dose (沙+61 1) or
저용량山 + 으로주입한경우에서몸무게의변화가일어나지않은것을 확인하였다.뿐만아니라,블레오마이신없이실시예 1만을주입한경우에서도 몸무게의변화가일어나지않는것을확인하였다. It was confirmed that no change in body weight occurred in the case of injecting with a low-dose 山+. In addition, it was confirmed that no change in body weight occurred even when only Example 1 was injected without bleomycin.
[107] 상기결과를통해본발명의실시예 1에해당하는화합물은그자체로서개체에 투여되었을때,독성이없을뿐만아니라,블레오마이신과같이섬유증을 유도하는물질에의한체중감소를매우효과적으로억제할수있음을알수 있다. [107] Based on the above results, the compound corresponding to Example 1 of the present invention is not only non-toxic when administered to a subject as it is, and very effectively inhibits weight loss due to a substance that induces fibrosis such as bleomycin. You can see that you can.
[108] [108]
[109] 이상으로본발명의특정한부분을상세히기술하였는바,당업계의통상의 지식을가진자에게있어서이러한구체적인기술은단지바람직한구현예일 뿐이며,이에본발명의범위가제한되는것이아닌점은명백하다.따라서,본 발명의실질적인범위는첨부된청구항과그의등가물에의하여정의된다고할 것이다. [109] As the specific parts of the present invention have been described in detail above, it is obvious that these specific technologies are only desirable implementation examples for those with ordinary knowledge in the industry, and the scope of the present invention is not limited thereto. Therefore, it will be said that the substantial scope of the present invention is defined by the appended claims and their equivalents.
산업상이용가능성 Industrial availability
[110] 본발명은섬유증의예방또는치료용약학조성물에관한것으로서,본발명의 화학식 1로표시되는화합물을유효성분으로포함하는조성물은히스톤 아세틸트렌스퍼라제의발현또는활성을억제함으로써섬유증의예방또는 치료에매우효과적으로사용될수있다.나아가,본발명의상기화학식 1로 표시되는화합물은다양한히스톤아세틸트렌스퍼라제중에서특히 ?300만을 특이적으로억제하기때문에,생명유지에중요한역할을하는다른아세틸화 효소에는영향을미치지아니하므로섬유증을예방또는치료할때발생될수 있는부작용을줄일수있다.
[110] The present invention relates to a pharmaceutical composition for the prevention or treatment of fibrosis, and the composition comprising the compound represented by Formula 1 of the present invention as an active ingredient prevents fibrosis by inhibiting the expression or activity of histone acetyltransferase or In addition, the compound represented by the above formula 1 of the present invention specifically inhibits ∼3 million among various histone acetyltransferases, so other acetylase enzymes that play an important role in maintaining life. It has no effect on the disease, so it can reduce side effects that may occur when preventing or treating fibrosis.
Claims
[화학식 1] [Formula 1]
[청구항 2] 제 1항에있어서, [Claim 2] In paragraph 1,
상기섬유증은폐섬유증 (Pulmonary fibrosis),자궁근종, Pulmonary fibrosis, uterine myoma,
골수섬유증 (Myelofibrosis),간섬유증 (Liver fibrosis),심장섬유증 (Heart fibrosis),다발성경화증,신장섬유증 (Kidney fibrosis),낭포성섬유증 (Cystic 加 rosis),호중구감소증,골격근섬유증,피부경화증,피부근염,종격동 섬유증 (Mediastinal fibrosis)및겸상적혈구빈혈증에의한비장 Myelofibrosis, Liver fibrosis, Heart fibrosis, Multiple sclerosis, Kidney fibrosis, Cystic fibrosis, Neutropenia, Skeletal muscle fibrosis, Skin sclerosis, Dermatitis , Mediastinal fibrosis and spleen due to sickle cell anemia
섬유증으로구성된군으로부터선택되는적어도하나인것인,약학 조성물. At least one selected from the group consisting of fibrosis, a pharmaceutical composition.
[청구항 3] 제 2항에있어서, [Claim 3] In paragraph 2,
상기섬유증은폐섬유증인것인,약학조성물. The fibrosis is that of pulmonary fibrosis, a pharmaceutical composition.
[청구항 4] 제 1항에있어서, [Claim 4] In paragraph 1,
상기약학조성물은기관내또는흡입투여용인것인,약학조성물. The pharmaceutical composition is intended for intratracheal or inhalation administration.
[청구항 5] 제 1항에있어서, [Claim 5] In paragraph 1,
상기약학조성물은주사제인것인,약학조성물. The pharmaceutical composition is an injection, a pharmaceutical composition.
[청구항 6] 하기화학식 1로표시되는화합물을유효성분으로포함하는섬유증의 예방또는개선용식품조성물: [Claim 6] A food composition for preventing or improving fibrosis comprising a compound represented by the following Chemical Formula 1 as an active ingredient:
[화학식 1] [Formula 1]
14 14
[청구항 7] 제 6항에 있어서, [Claim 7] The method of claim 6,
상기섬유증은폐섬유증,자궁근종,골수섬유증,간섬유증,심장섬유증, 다발성 경화증,신장섬유증,낭포성섬유증,호중구감소증,골격근섬유증, 피부경화증,피부근염,종격동섬유증및겸상적혈구빈혈증에 의한 비장섬유증으로구성된군으로부터선택되는적어도하나인것인,식품 조성물. The fibrosis is pulmonary fibrosis, uterine fibrosis, myelofibrosis, liver fibrosis, cardiac fibrosis, multiple sclerosis, renal fibrosis, cystic fibrosis, neutropenia, skeletal muscle fibrosis, scleroderma, dermatitis, mediastinal fibrosis, and splenic fibrosis caused by sickle cell anemia. At least one selected from the group consisting of, food composition.
[청구항 8] 제 7항에 있어서, [Claim 8] The method of claim 7,
상기섬유증은폐섬유증인것인,식품조성물. The fibrosis is that of pulmonary fibrosis, a food composition.
[청구항 9] 상기 화학식 1로표시되는화합물을약학적유효량으로개체에투여하는 단계를포함하는섬유증의 예방,개선또는치료방법 : [Claim 9] A method for preventing, improving, or treating fibrosis comprising administering to an individual the compound represented by Formula 1 in a pharmaceutically effective amount:
[화학식 1] [Formula 1]
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| KR20230051091A (en) * | 2021-10-08 | 2023-04-17 | 연세대학교 산학협력단 | Pharmaceutical composition for preventing, improving, alleviating or treating pulmonary fibrosis comprising ezetimibe as an active ingredient |
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