KR20230138472A - Novel compound for inhibiting histone acetyltransferase p300 and antifibrotic composition containing the same - Google Patents

Abstract

The present invention relates to a novel compound that enables additional hydrogen bonding with a specific amino acid position of HAT p300 through structural analysis of histone acetyltransferase (HAT) p300. The novel compound of the present invention It has a significantly excellent inhibitory effect on the activity of HAT p300 and can be used very effectively in the prevention, improvement or treatment of fibrosis, a disease related to the activation of HAT p300.

Description

Novel compound for inhibiting histone acetyltransferase P300 and antifibrotic composition containing the same

The present invention provides a novel compound for inhibiting histone acetyltransferase p300; An anti-fibrotic composition comprising the novel compound; and its various uses.

Tissues contain well-organized clusters of cells bound to an extracellular matrix and surrounded by a vascular network. Fibrosis or fibrosis is an abnormal accumulation of collagen matrix due to injury or inflammation that changes the structure and function of various tissues. In the case of fibrosis, regardless of its location, the most etiological factor is excessive accumulation of fibrous connective tissue, such as collagen matrix, replacing normal tissue. Progressive fibrosis in the kidneys, liver, fat, lungs, heart, bone or bone marrow, and skin is a major cause of death or suffering.

Among the above-mentioned fibrosis, pulmonary fibrosis, which is particularly fibrosis occurring in the lungs, refers to a disease in which chronic inflammatory cells infiltrate the alveolar walls of lung tissue, thereby inducing tissue fibrosis and causing serious structural changes in lung tissue. Once fibrosis progresses due to some cause, the lung tissue hardens and the alveolar walls thicken, reducing the amount of oxygen supplied by blood, making breathing difficult. Currently, there is no treatment method in medicine that can completely restore lung tissue that has already developed fibrosis, so unless the fibrosis is discovered early in the process or a lung transplant is performed, patients usually die 3 to 5 years after the onset of symptoms. .

Treatment methods for pulmonary fibrosis discovered in the early stages of progression include treatment using steroid drugs such as steroids, Azathioprine, and Cyclophosphamide, and antioxidants such as Acetylcysteine. There are treatment methods using and treatment methods using growth factors such as cytokines and interferon-γ (IFN-γ). Treatment methods using steroid drugs and antioxidants have been continuously studied and reported since 2000, but no clear drug efficacy has been proven yet, and long-term administration causes systemic side effects or side effects that develop resistance. It has been reported to do so. Treatment through growth factor administration is a treatment that has been receiving a lot of attention recently. It is a relatively fundamental treatment approach that uses 'interferon', which inhibits the production of TGF-β (Transforming growth factor-β), known as an important factor in pulmonary fibrosis. . Because of this approach to treatment by analyzing the cause of the disease, various forms of treatment, such as injection or aerosol methods, have been reported with fewer side effects and superior efficacy compared to treatments using steroid drugs and antioxidants. However, because the exact cause of pulmonary fibrosis is not yet known, the treatment efficacy of a single ingredient such as interferon may be temporary and may only be effective for some patients, so continuous research and clinical trials are necessary.

According to this need, it is a mechanism that regulates the function of numerous proteins, including transcription factors that play a direct role in transcription, and affects phenomena such as protein expression by regulating lysine residues in amino acids, which are the basic units that make up proteins. Research is being conducted on components related to post-translational modification of proteins, such as acetylation of histone proteins, but research on substances with excellent effects is still insufficient.

One object of the present invention is to provide a novel compound capable of inhibiting histone acetyltransferase (HAT) p300.

Another object of the present invention is to provide a composition for preventing, improving or treating diseases related to HAT p300, including a novel compound that inhibits HAT p300.

Another object of the present invention is to provide a method for preventing, improving or treating diseases related to HAT p300 using the composition.

However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the description below.

One embodiment of the present invention provides a compound selected from compounds represented by the following formula (1), pharmaceutically acceptable salts, optical isomers, hydrates, and solvates thereof:

[Formula 1]

In Formula 1,

p is an integer from 1 to 5;

q is an integer from 0 to 5;

r is an integer from 0 to 4;

m and n are each independently an integer from 0 to 3, but m + n is an integer from 0 to 4;

R ₁ is -N(R ₅ )(R ₆ ) or a hydroxy group (-OH), and when there are more than one R ₁ , they are the same or different from each other;

R ₂ and R ₃ are each independently a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkoxy group, or a halogen, and when there are multiple R ₂ and R ₃ , they are the same or different from each other, and R ₂ and R The alkyl group and alkoxy group of ₃ may be substituted or unsubstituted by a C ₁ to C ₆ alkyl group or a C ₁ to C ₆ alkoxy group, and when substituted by a plurality of substituents, they are the same or different from each other;

R ₄ is C ₁ ~C ₆ alkyl group, C ₁ ~C ₆ alkoxy group, -N(R ₇ )(R ₈ ), -C(=O)N(R ₇ )(R ₈ ) and hydroxy group (-OH) is any one selected from the group consisting of, and when there is a plurality of R ₄ , they are the same or different from each other, and the alkyl group and alkoxy group of R ₄ are substituted or provided by a C ₁ to C ₆ alkyl group or a C ₁ to C ₆ alkoxy group. may be substituted, and when substituted by a plurality of substituents, they may be the same or different from each other;

R ₅ to R ₈ are each independently hydrogen or a C ₁ to C ₆ alkyl group, and the alkyl group of R ₅ to R ₈ may be substituted or unsubstituted by a C ₁ to C ₆ alkyl group.

The term “halogen” in the present invention means fluorine, chlorine, bromine or iodine, unless otherwise specified.

The “alkoxy group” of the present invention is an alkyl group bonded to oxygen and, unless otherwise specified, may be, for example, a methoxy group or an ethoxy group, but is not limited thereto.

The “alkyl group” of the present invention refers to a straight-chain or branched-chain saturated monovalent hydrocarbon radical, and the alkyl group may be optionally substituted with one or more substituents described in the present invention. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, t -butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms) may be included.

The “pharmaceutically acceptable salt” of the present invention must have low toxicity to the human body and not adversely affect the biological activity and physicochemical properties of the parent compound. Pharmaceutically acceptable salts include, but are not limited to, acid addition salts of a pharmaceutically acceptable free acid and the base compound of Formula 1.

Preferred salt forms of the compounds of the present invention include salts with inorganic acids or organic acids. At this time, the inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, etc. In addition, organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, Oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid, etc. can be used. Organic bases that can be used to prepare organic base addition salts include tris(hydroxymethyl)methylamine and dicyclohexylamine. Amino acids that can be used to produce amino acid addition salts are natural amino acids such as alanine and glycine. It will be apparent to those skilled in the art that other acids or bases may be used in addition to the inorganic acids, organic acids, organic bases, and amino acids exemplified above.

The salt of the present invention can be prepared by conventional methods. For example, the compound of Formula 1 can be prepared by dissolving it in a water-miscible solvent such as methanol, ethanol, acetone, or 1,4-dioxane, then adding a free acid or base, and then crystallizing it.

The “optical isomer” of the present invention may have an asymmetric carbon center, so it is an R or S isomer or a racemic compound, and all optical isomers and mixtures that the compound of the present invention can form are included in the scope of the present invention.

In the present invention, the compound may be represented by the following formula (2):

[Formula 2]

In Formula 2,

Each of R ₁ , R ₂ , R ₃ , R ₄ and q is the same as defined in Formula 1 above.

In a preferred embodiment of the present invention, p and q may each independently be an integer of 1 to 3, preferably, p may be an integer of 1 or 2, and q may be an integer of 2 to 4.

In a preferred embodiment of the present invention, r may be an integer of 1 to 3, and preferably may be an integer of 1 or 2.

In a preferred embodiment of the present invention, m and n may each independently be integers of 1 or 2, and preferably both m and n may be integers of 1.

In a preferred embodiment of the present invention, R ₁ may be an amine group (-NH ₂ ) or a hydroxy group (-OH).

In a preferred embodiment of the present invention, R ₂ and R ₃ may each independently be a C ₁ to C ₆ alkoxy group or a halogen.

In a preferred embodiment of the present invention, R ₄ may be a C ₁ to C ₆ alkoxy group, an amine group (-NH ₂ ), a carbamoyl group (-C(=O)NH ₂ ), or a hydroxy group (-OH). .

The compound of the present invention may be at least one selected from the group consisting of the following compounds, but is not limited thereto:

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Compared to existing histone acetyltransferase inhibitors, the compounds of the present invention include R1410, T1411 and W1466 of histone acetyltransferase p300; Alternatively, it is improved to allow additional hydrogen bonds to occur with R1410 and T1411, thereby having a more significant effect in inhibiting histone acetyltransferase.

In another embodiment of the present invention, a compound for inhibiting histone acetyltransferase p300 is provided, represented by Formula 1 above.

In the inhibitory compound of the present invention, the compound, histone acetyltransferase p300, etc. are the same as described in the previous compound and are omitted to avoid excessive complexity of the specification.

Another embodiment of the present invention provides a composition for preventing, improving, or treating diseases related to histone acetyltransferase p300.

The composition of the present invention may be a pharmaceutical composition; food composition; Alternatively, it can be used as a cosmetic composition.

The composition of the present invention contains as an active ingredient a compound selected from the novel compound represented by Formula 1 of the present invention, pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof. Accordingly, since the composition of the present invention contains a novel compound that inhibits HAT p300 very effectively as an active ingredient, it can exert a preventive, improvement, or treatment effect in fibrosis patients with increased HAT p300.

In the composition of the present invention, the compounds corresponding to the active ingredients are the same as previously described for the compounds and are therefore omitted to avoid excessive complexity of the specification.

The histone acetyltransferase p300-related disease of the present invention refers to any disease caused by an excessively increased expression level or excessively increased activity of histone acetyltransferase compared to a normal control group that does not develop the disease. It may include, but is preferably fibrosis.

The “fibrosis” of the present invention is a disease in which abnormal production, accumulation and deposition of extracellular matrix occurs by fibroblasts, and the collagen matrix is abnormally accumulated due to damage or inflammation that can change the structure and function of various tissues. Fibrosis of any organ may be included, preferably in at least one organ selected from the group consisting of kidney, liver, lung, heart, bone or bone marrow, and skin, but is limited thereto. That is not the case. For the purpose of the present invention, the fibrosis is a phenomenon in which the expression of genes related to fibrosis, such as collagen, is promoted by TGF-β (Transforming growth factor-β) whose expression level is increased through the acetylating enzyme p300. It may be induced by or due to the absence of an enzyme capable of recovering cells from damage that may lead to fibrosis, but is not limited thereto.

The fibrosis of the present invention includes pulmonary fibrosis, uterine fibroids, myelofibrosis, liver fibrosis, heart fibrosis, multiple sclerosis, kidney fibrosis, and cystic fibrosis ( Cystic fibrosis), neutropenia, skeletal muscle fibrosis, scleroderma, dermatomyositis, mediastinal fibrosis, and splenic fibrosis due to sickle cell anemia, preferably pulmonary fibrosis. However, it is not limited to this.

The “pulmonary fibrosis” of the present invention refers to the development of scarred (fibrotic) tissue due to the formation or development of excessive fibrous connective tissue (fibrosis) in the lung. Specifically, pulmonary fibrosis is a chronic disease that causes swelling and scarring of the alveoli and interstitial tissue of the lung. Such scar tissue replaces healthy tissue and causes inflammation, and chronic inflammation can be identified as a precursor to fibrosis. This damage to lung tissue can cause the lungs to become stiff and make it difficult for the individual to breathe on their own.

In the present invention, pulmonary fibrosis refers to idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, acute interstitial pneumonia, idiopathic organizing pneumonia, and respiratory bronchitis-related epilepsy. It may be Respiratory Bronchiolitis associated Interstitial Lung, Desquamative Interstitial Pneumonia, Lymphoid Interstitial Pneumonia, Interstitial Pulmonary Fibrosis and Diffuse Pulmonary Fibrosis, preferably Idiopathic Pulmonary Fibrosis. It may be, but is not limited to this.

The pulmonary fibrosis of the present invention is caused by various causes, for example, microscopic damage to the lungs induced by inhalation of fine particles (asbestos, stone dust, metal dust, particles present in cigarette smoke, silica dust, etc.). can do. Additionally, pulmonary fibrosis may occur as a secondary effect of other diseases (such as autoimmune diseases, viral or bacterial infections) and cytotoxic agents (such as bleomycin, busulfan and methotrexate). Antibiotics (such as nitrofurantoin and sulfasalazine); Arrhythmia medications (such as amiodarone and tocainide); Anti-inflammatory drugs (such as gold and penicillamine); It may be caused by certain drugs such as illegal drugs (narcotics, cocaine, heroin, etc.), and in the case of idiopathic pulmonary fibrosis, it may be caused by other unknown causes.

The "prevention" of the present invention may include without limitation any action that can block, suppress or delay symptoms caused by fibrosis using the composition of the present invention.

The “treatment” of the present invention may include, without limitation, any action that allows the symptoms caused by fibrosis to improve or become beneficial by using the composition of the present invention.

The "improvement" of the present invention may include without limitation any action in which symptoms caused by fibrosis are improved or beneficially changed by using the composition of the present invention.

The pharmaceutical composition of the present invention is not limited to these, but can be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, and aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods. You can. Preferably, the pharmaceutical composition is for intratracheal administration or inhalation administration; Alternatively, it may be formulated to be used as an injection, but is not limited thereto. For the purpose of the present invention, when fibrosis occurs in the respiratory tract such as the lungs, it is preferable that the active ingredient is 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 include a pharmaceutically acceptable carrier. For oral administration, the pharmaceutically acceptable carrier may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, colorants, flavorings, etc., and for injections, buffers, preservatives, Analgesics, solubilizers, isotonic agents, stabilizers, etc. may be mixed and used, and for topical administration, bases, excipients, lubricants, preservatives, etc. may be used. The dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing it with a pharmaceutically acceptable carrier as described above. For example, for oral administration, it can be manufactured in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be manufactured in the form of unit dose ampoules or multiple doses. there is. In addition, it can be formulated as a solution, suspension, tablet, capsule, sustained-release preparation, etc.

Meanwhile, examples of carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil may be used. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, etc. may be additionally included.

The route of administration of the pharmaceutical composition of the present invention is not limited to these, but is oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, Includes sublingual or rectal areas. Oral or parenteral administration is preferred.

The parenteral of the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention can also be administered in the form of a suppository for rectal administration.

The pharmaceutical composition of the present invention may vary depending on several factors, including the activity of the specific compound used, age, body weight, general health, gender, diet, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated. It may vary, and the dosage of the pharmaceutical composition may vary depending on the patient's condition, body weight, degree of disease, drug form, route and period of administration, but may be appropriately selected by a person skilled in the art, and may range from 0.0001 to 50 mg/kg per day. Alternatively, it can be administered at 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered several times. The above dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention can be formulated into pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.

When the food composition of the present invention is manufactured in the form of a beverage, there are no particular limitations other than including the food composition in the indicated ratio, and various flavoring agents or natural carbohydrates can be contained as additional ingredients like ordinary beverages. . Specifically, natural carbohydrates include monosaccharides such as glucose, disaccharides such as fructose, common sugars such as polysaccharides such as sucrose, dextrin, and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. It can be included. The flavoring agent may be a natural flavoring agent (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and a synthetic flavoring agent (saccharin, aspartame, etc.).

The food composition of the present invention contains various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, It may further include pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated drinks, etc.

The ingredients included in the food composition of the present invention can be used independently or in combination. The ratio of the additive does not correspond to a key element of the present invention, but may be selected in the range of 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.

The cosmetic composition of the present invention includes lotion, nutritional lotion, nutritional essence, massage cream, beauty bath water additive, body lotion, body milk, bath oil, baby oil, baby powder, shower gel, shower cream, sunscreen lotion, and sunscreen cream. , suntan cream, skin lotion, skin cream, sunscreen cosmetics, cleansing milk, hair loss cosmetics, face and body lotion, face and body cream, skin whitening cream, hand lotion, hair lotion, cosmetic cream, jasmine oil, bath. Manufactured in the form of soap, liquid soap, beauty soap, shampoo, hand sanitizer (hand cleaner), non-medical medicated soap, cream soap, facial wash, body cleanser, scalp cleanser, hair rinse, cosmetic soap, teeth whitening gel, toothpaste, etc. It can be. The composition of the present invention may further include solvents commonly used in the production of cosmetic compositions, appropriate carriers, excipients, or diluents.

The type of solvent that can be added to the cosmetic composition of the present invention is not particularly limited, but for example, water, saline solution, DMSO, or a combination thereof can be used. In addition, carriers, excipients, or diluents include purified water, oil, wax, fatty acids, fatty alcohols, fatty acid esters, surfactants, humectants, thickeners, antioxidants, viscosity stabilizers, chelating agents, buffers, lower alcohols, etc. Included, but not limited to this. Additionally, if necessary, it may contain whitening agents, moisturizers, vitamins, sunscreen, perfume, dyes, antibiotics, antibacterial agents, and antifungal agents.

Hydrogenated vegetable oil, castor oil, cottonseed oil, olive oil, palm oil, jojoba oil, and avocado oil can be used as the oil of the present invention, and waxes include beeswax, spermaceti, carnauba, candelilla, montan, ceresin, and liquid paraffin. , lanolin can be used.

The fatty acids of the present invention include stearic acid, linoleic acid, linolenic acid, and oleic acid, and the fatty alcohols include cetyl alcohol, octyl dodecanol, oleyl alcohol, panthenol, lanolin alcohol, stearyl alcohol, and hexadecanol. Fatty acid esters include isopropyl myristate, isopropyl palmitate, and butyl stearate. As surfactants, cationic surfactants, anionic surfactants, and non-ionic surfactants known in the art can be used, and surfactants derived from natural products are preferred whenever possible. In addition, it may contain moisture absorbents, thickeners, antioxidants, etc., which are widely known in the cosmetics field, and their types and amounts are known in the art.

Another embodiment of the present invention provides a method for preventing, improving, or treating diseases related to histone acetyltransferase p300, comprising administering the composition of the present invention to a subject of interest.

In the present invention, general descriptions regarding histone acetyltransferase p300-related diseases, prevention, improvement, treatment, compounds, and compositions are the same as previously described in this specification, and are omitted to avoid excessive complexity of the specification.

In the present invention, the “individual” is an individual suspected of developing a histone acetyltransferase p300-related disease, and the subject suspected of developing a histone acetyltransferase p300-related disease is a mouse, including a human, that has or may develop the disease. , refers to mammals including livestock, etc., but includes without limitation individuals that can be treated with the fusion protein of the present invention or the composition containing the same.

The method of the present invention may include administering the active ingredient in a pharmaceutically effective amount. The appropriate total daily usage amount can be determined by the treating physician within the scope of sound medical judgment, and can be administered once or in several divided doses. However, for the purposes of the present invention, the specific therapeutically effective amount for a specific patient depends on the type and degree of response to be achieved, the specific composition, including whether other agents are used as the case may be, the patient's age, weight, and general health status, It is desirable to apply it differently depending on various factors including gender and diet, administration time, administration route and secretion rate of the composition, treatment period, drugs used together or simultaneously with the specific composition, and similar factors well known in the medical field.

The above “combined use” of the present invention should be understood to indicate simultaneous, separate or sequential administration. If the administration is sequential or separate, the interval between the administrations of the second components should be such that the beneficial effects of the combination are not lost.

The administered dose of the fusion protein of the present invention may be about 0.0001 μg to 500 mg per kg of patient body weight, but is not limited thereto.

The present invention relates to a novel compound that enables additional hydrogen bonding with a specific amino acid position of HAT p300 through structural analysis of histone acetyltransferase (HAT) p300. The novel compound of the present invention It has a significantly excellent inhibitory effect on the activity of HAT p300 and can be used very effectively in the prevention, improvement or treatment of fibrosis, a disease related to the activation of HAT p300.

Figures 1 to 3 show the histone acetyltransferase (HAT) protein p300 (histone acetyltransferase p300; Figure 1) and GCN5 (histone acetyltransferase GCN5; Figure 2) in the tissue of a patient with idiopathic pulmonary fibrosis according to an embodiment of the present invention. ) and PCAF (P300/CBP-associated factor; Figure 3) expression levels were confirmed through immunohistochemical staining.
Figure 4 is a diagram showing the results of observing changes in p300 HAT activity by treatment with each compound of the present invention.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

Example

Synthesis Example 1: P300-107

Chalcone methylether derivative (1.0 equiv.) was dissolved in dried DCM under nitrogen substitution, stirred at 0°C, and 1.0 M (2.0 equiv.) of BCl ₃ dissolved in methylene chloride was slowly added dropwise. After 1 hour, dichloromethane and water were added, stirred, and extracted with saturated NaHCO ₃ and dichloromethane. The organic layer was collected, the moisture in the organic layer was removed with anhydrous MgSO ₄ , and the mixture was distilled under reduced pressure. The remaining residue was separated and purified by silica gel chromatography.

[P300-107]

[P300-107]

(E)-3-(3-chloro-4-((3-(dimethylamino)benzyl)oxy)-5-methoxyphenyl)-1-(3-hydroxyphenyl)prop-2-phen-1- On (P300-107)

(E)-1-(3-(benzyloxy)phenyl)-3-(3-chloro-4-((3-(dimethylamino)benzyl)oxy)-5-methoxy phenyl)prop-2-phen- After reacting for 1 hour at 0°C using 1-one (50 mg, 0.09 mmol), dried DCM (12 mL), and 1.0 M (2.0 equiv.) of BCl ₃ dissolved in methylene chloride (0.28 mL, 0.28 mmol) It was separated and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:2) to obtain a yellow liquid (20 mg, 50.74%). Rf 0.79 (ethyl acetate: n-hexane = 1:1); HPLC: RT 6.69 min (purity: 99.3%); 1H-NMR (DMSO-d6, 400MHz) δ 2.90 (s, 6H), 3.95 (s, 3H), 5.03 (2, 2H), 6.68 (dd, J = 8.4, 2.4 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.85 (dd, J = 2.4, 1.2 Hz, 1H), 7.07 (ddd, J = 8.0, 1.2, 0.8 Hz, 1H), 7.17 (dd, J = 8.4, 8.0 Hz, 1H) ), 7.38 (dd, J = 8.0, 7.6 Hz, 1H), 7.48 (dd, J = 2.4, 1.6 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 15.6 Hz) , 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.66 (dd, J = 8.0, 2.0 Hz, 1H), 7.88 (d, J = 15.6 Hz, 1H), 9.80 (s, 1H) 13C- (NMR DMSO-d6, 100 MHz) 40.1, 56.5, 74.9, 111.0, 112.1, 114.7, 116.0, 119.7, 120.3, 122.3, 122.6, 127.6, 128.7, 129.8, 131.4, 137. 3, 138.9, 142.4, 145.2, 150.3, 153.7, 157.7, 188.9 ppm.

Synthesis Example 2: P300-108

[P300-108]

[P300-108]

(E)-3-(3-bromo-4-((3-(dimethylamino)benzyl)oxy)-5-methoxyphenyl)-1-(3-hydroxyphenyl)prop-2-phen-1 -On (P300-108)

(E)-1-(3-(benzyloxy)menyl)-3-(3-bromo-4-((3-(dimethylamino)benzyl)oxy)-5-methoxyphenyl)prop-2-phene Silica gel column chromatography using -1-one (163 mg, 0.28 mmol), dried DCM (11 mL), and 1.0 M BCl ₃ dissolved in methylene chloride (0.56 mL, 0.56 mmol) at 0°C for 1 hour. It was separated and purified by ethyl acetate: n-hexane = 1:2 to obtain an orange liquid (67 mg, 49.61%). Rf 0.79 (ethyl acetate: n-hexane = 1:1); HPLC: RT 7.57 min (purity: 95.6%); 1H-NMR (DMSO-d6, 400MHz) δ 2.91 (s, 6H), 3.95 (s, 3H), 5.02 (s, 2H), 6.70 (d, J = 6.4 Hz, 1H), 6.78 (d, J = 7.2 Hz, 1H), 6.89 (brs, 1H), 7.07 (ddd, J = 8.4, 2.4, 0.8 Hz, 1H), 7.18 (dd, J = 8.4, 8.0 Hz, 1H), 7.40 (dd, J = 8.0 , 8.0 Hz, 1H), 7.48 (dd, J = 2.4, 1.6 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 15.6 Hz, 1H), 7.66 (ddd, J = 7.6, 1.6, 1.2 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 15.6 Hz, 1H), 9.80 (s, 1H) 13C-NMR DMSO-d6, 100 MHz ) 40.2, 56.5, 74.7, 111.0, 112.3, 112.6, 114.7, 116.2, 117.4, 119.7, 120.3, 122.6, 125.2, 128.7, 129.8, 132.1, 137.3, 139. 0, 142.3, 146.2, 150.3, 153.5, 157.7, 188.9 ppm.

Synthesis Example 3: P300-109

[P300-109]

[P300-109]

(E)-3-(4-((3-(dimethylamino)benzyl)oxy)-3-iodo-5-methoxyphenyl)-1-(3-hydroxyphenyl)prop-2-phen-1 -On (P300-109)

(E)-1-(3-(benzyloxy)phenyl)-3-(3-iodo-5-methoxy-4-((3-(methylamino)benzyl)oxy)phenyl)prop-2-phene -1-one (203 mg, 0.34 mmol), dried DCM (12 mL), and 1.0 M BCl ₃ dissolved in methylene chloride (0.67 mL, 0.67 mmol) were used to react at 0°C for 1 hour, followed by silica gel column chromatography. It was separated and purified by ethyl acetate: n-hexane = 1:2 to obtain a light yellow liquid (25 mg, 14.3%). Rf 0.50 (ethyl acetate: n-hexane = 1:1); HPLC: RT 7.57 min (purity: 97.4%); 1H-NMR (DMSO-d6, 400 MHz) δ 2.92 (s, 6H), 3.94 (s, 3H), 4.98 (2, 2H), 6.70 (dd, J = 8.0, 2.4 Hz, 1H), 6.80 (d, J = 7.2 Hz, 1H), 6.94 (brs, 1H), 7.07 (ddd, J = 8.0, 1.6, 0.8 Hz, 1H), 7.18 (dd, J = 8.0, 7.6 Hz, 1H), 7.38 (dd, J = 8.0, 7.6 Hz, 1H), 7.48 (dd, J = 2.4, 2.0 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 15.6 Hz, 1H), 7.67 (ddd , J = 8.0, 1.2, 1.2 Hz, 1H), 7.86 (d, J = 15.6 Hz, 1H), 7.92 (d, J = 1.6 Hz, 1H), 9.79 (s, 1H) 13C-NMR DMSO-d6, 100 MHz) 40.2, 56.3, 74.4, 93.7, 112.2, 112.4, 113.3, 114.7, 116.2, 119.7, 120.3, 122.4, 129.8, 131.1, 132.9, 137.3, 139.0, 142.2, 148.8, 150.3, 152.4, 157.7, 188.9 ppm.

[Experimental Example 1] Determination of protein expression levels in fibrosis patient tissues

Tissues obtained from idiopathic pulmonary fibrosis patients or normal subjects were fixed in 10% formalin, embedded in paraffin, and 7-μm-thick sections were attached to slides. Then, the section was deparaffinized using xylene, then treated with ethanol in the order of concentration from high to low concentration, and treated with p300 (histone acetyltransferase p300), GCN5 (histone acetyltransferase GCN5), and PCAF (P300/CBP-associated factor). After performing immunostaining using a specific antibody, the expression level of each protein was measured using an optical microscope, and the results are shown in Figures 1 to 3.

As shown in Figures 1 to 3, among histone acetyltransferase (hereinafter referred to as 'HAT') p300, GCN5, and PCAF, p300 is increased in tissues from patients with idiopathic pulmonary fibrosis compared to tissues obtained from normal people. It was confirmed that it was done.

From the above results, in the case of fibrosis such as idiopathic pulmonary fibrosis, p300 is present at a higher level among histone acetyltransferases than in normal tissues, so specifically inhibiting the expression or function of p300 can effectively prevent fibrosis. You can see that it can be treated.

[Experimental Example 2] Measurement of HAT p300 inhibitory activity

Candidate p300-107, p300-108 and p300-109, which are HAT inhibitors produced based on the PCAF structure, and A25 compound (　(E)-3-(3-(4-((3-carbamoylbenzyl)oxy )-3-Ido-5-methoxyphenyl)acryloyl)　benzamide　) and diluted to 100 μM using C646, and then used a kit to measure the activity of HAT (Biovision K346-100, Cat no. K332, USA) ), the manufacturer confirmed the degree of inhibition (inhibitory ability) of HAT activity on p300 according to the manual, and the results are shown in Figure 4. Here, C646 (HAT inhibitor) was used as a positive control.

As shown in Figure 4, the candidate substances p300-107, p300-108, and p300-109 significantly inhibited the activity of HAT.

As the specific parts of the present invention have been described in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred implementation examples and do not limit the scope of the present invention. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (9)

A compound selected from compounds represented by the following formula (1), pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof:
[Formula 1]

In Formula 1,
p is an integer from 1 to 5;
q is an integer from 0 to 5;
r is an integer from 0 to 4;
m and n are each independently an integer from 0 to 3, but m + n is an integer from 0 to 4;
R ₁ is -N(R ₅ )(R ₆ ) or a hydroxy group (-OH), and when there are more than one R ₁ , they are the same or different from each other;
R ₂ and R ₃ are each independently a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkoxy group, or a halogen, and when there are multiple R ₂ and R ₃ , they are the same or different from each other, and R ₂ and R The alkyl group and alkoxy group of ₃ may be substituted or unsubstituted by a C ₁ to C ₆ alkyl group or a C ₁ to C ₆ alkoxy group, and when substituted by a plurality of substituents, they are the same or different from each other;
R ₄ is C ₁ ~C ₆ alkyl group, C ₁ ~C ₆ alkoxy group, -N(R ₇ )(R ₈ ), -C(=O)N(R ₇ )(R ₈ ) and hydroxy group (-OH) is any one selected from the group consisting of, and when there is a plurality of R ₄ , they are the same or different from each other, and the alkyl group and alkoxy group of R ₄ are substituted or provided by a C ₁ to C ₆ alkyl group or a C ₁ to C ₆ alkoxy group. may be substituted, and when substituted by a plurality of substituents, they may be the same or different from each other;
R ₅ to R ₈ are each independently hydrogen or a C ₁ to C ₆ alkyl group, and the alkyl group of R ₅ to R ₈ may be substituted or unsubstituted by a C ₁ to C ₆ alkyl group. According to clause 1,
where p and q are each independently an integer of 1 to 3;
where r is an integer of 1 or 2;
A compound wherein m and n are integers of 1 or 2. According to clause 1,
The compound is any one selected from the group consisting of the following compounds:

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. Compounds for inhibiting histone acetyltransferase p300 selected from compounds represented by the following formula (1), pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof:
[Formula 1]

In Formula 1,
p is an integer from 1 to 5;
q is an integer from 0 to 5;
r is an integer from 0 to 4;
m and n are each independently an integer from 0 to 3, but m + n is an integer from 0 to 4;
R ₁ is -N(R ₅ )(R ₆ ) or a hydroxy group (-OH), and when there are more than one R ₁ , they are the same or different from each other;
R ₂ and R ₃ are each independently a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkoxy group, or a halogen, and when there are multiple R ₂ and R ₃ , they are the same or different from each other, and R ₂ and R The alkyl group and alkoxy group of ₃ may be substituted or unsubstituted by a C ₁ to C ₆ alkyl group or a C ₁ to C ₆ alkoxy group, and when substituted by a plurality of substituents, they are the same or different from each other;
R ₄ is C ₁ ~C ₆ alkyl group, C ₁ ~C ₆ alkoxy group, -N(R ₇ )(R ₈ ), -C(=O)N(R ₇ )(R ₈ ) and hydroxy group (-OH) is any one selected from the group consisting of, and when there is a plurality of R ₄ , they are the same or different from each other, and the alkyl group and alkoxy group of R ₄ are substituted or provided by a C ₁ to C ₆ alkyl group or a C ₁ to C ₆ alkoxy group. may be substituted, and when substituted by a plurality of substituents, they may be the same or different from each other;
R ₅ to R ₈ are each independently hydrogen or a C ₁ to C ₆ alkyl group, and the alkyl group of R ₅ to R ₈ may be substituted or unsubstituted by a C ₁ to C ₆ alkyl group. A pharmaceutical composition for the prevention or treatment of diseases related to histone acetyltransferase p300, comprising as an active ingredient a compound selected from the group represented by the following formula (1), pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof:
[Formula 1]

In Formula 1,
p is an integer from 1 to 5;
q is an integer from 0 to 5;
r is an integer from 0 to 4;
m and n are each independently an integer from 0 to 3, but m + n is an integer from 0 to 4;
R ₁ is -N(R ₅ )(R ₆ ) or a hydroxy group (-OH), and when there are more than one R ₁ , they are the same or different from each other;
R ₂ and R ₃ are each independently a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkoxy group, or a halogen, and when there are multiple R ₂ and R ₃ , they are the same or different from each other, and R ₂ and R The alkyl group and alkoxy group of ₃ may be substituted or unsubstituted by a C ₁ to C ₆ alkyl group or a C ₁ to C ₆ alkoxy group, and when substituted by a plurality of substituents, they are the same or different from each other;
R ₄ is C ₁ ~C ₆ alkyl group, C ₁ ~C ₆ alkoxy group, -N(R ₇ )(R ₈ ), -C(=O)N(R ₇ )(R ₈ ) and hydroxy group (-OH) is any one selected from the group consisting of, and when there is a plurality of R ₄ , they are the same or different from each other, and the alkyl group and alkoxy group of R ₄ are substituted or provided by a C ₁ to C ₆ alkyl group or a C ₁ to C ₆ alkoxy group. may be substituted, and when substituted by a plurality of substituents, they may be the same or different from each other;
R ₅ to R ₈ are each independently hydrogen or a C ₁ to C ₆ alkyl group, and the alkyl group of R ₅ to R ₈ may be substituted or unsubstituted by a C ₁ to C ₆ alkyl group. According to clause 5,
A pharmaceutical composition, wherein the histone acetyltransferase p300-related disease is fibrosis. According to clause 6,
The fibrosis includes pulmonary fibrosis, uterine fibroids, myelofibrosis, liver fibrosis, heart fibrosis, multiple sclerosis, kidney fibrosis, and cystic fibrosis. , a pharmaceutical composition that is at least one selected from the group consisting of neutropenia, skeletal muscle fibrosis, scleroderma, dermatomyositis, mediastinal fibrosis, and splenic fibrosis due to sickle cell anemia. A food composition for preventing or improving diseases related to histone acetyltransferase p300, comprising as an active ingredient a compound selected from the group represented by the following formula (1), pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof:
[Formula 1]

In Formula 1,
p is an integer from 1 to 5;
q is an integer from 0 to 5;
r is an integer from 0 to 4;
m and n are each independently an integer from 0 to 3, but m + n is an integer from 0 to 4;
R ₁ is -N(R ₅ )(R ₆ ) or a hydroxy group (-OH), and when there are more than one R ₁ , they are the same or different from each other;
R ₂ and R ₃ are each independently a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkoxy group, or a halogen, and when there are multiple R ₂ and R ₃ , they are the same or different from each other, and R ₂ and R The alkyl group and alkoxy group of ₃ may be substituted or unsubstituted by a C ₁ to C ₆ alkyl group or a C ₁ to C ₆ alkoxy group, and when substituted by a plurality of substituents, they are the same or different from each other;
R ₄ is C ₁ ~C ₆ alkyl group, C ₁ ~C ₆ alkoxy group, -N(R ₇ )(R ₈ ), -C(=O)N(R ₇ )(R ₈ ) and hydroxy group (-OH) is any one selected from the group consisting of, and when there is a plurality of R ₄ , they are the same or different from each other, and the alkyl group and alkoxy group of R ₄ are substituted or provided by a C ₁ to C ₆ alkyl group or a C ₁ to C ₆ alkoxy group. may be substituted, and when substituted by a plurality of substituents, they may be the same or different from each other;
R ₅ to R ₈ are each independently hydrogen or a C ₁ to C ₆ alkyl group, and the alkyl group of R ₅ to R ₈ may be substituted or unsubstituted by a C ₁ to C ₆ alkyl group. A cosmetic composition for preventing or improving diseases related to histone acetyltransferase p300, comprising as an active ingredient a compound selected from the group represented by the following formula (1), pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof:
[Formula 1]

In Formula 1,
p is an integer from 1 to 5;
q is an integer from 0 to 5;
r is an integer from 0 to 4;
m and n are each independently an integer from 0 to 3, but m + n is an integer from 0 to 4;
R ₁ is -N(R ₅ )(R ₆ ) or a hydroxy group (-OH), and when there are more than one R ₁ , they are the same or different from each other;
R ₂ and R ₃ are each independently a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkoxy group, or a halogen, and when there are multiple R ₂ and R ₃ , they are the same or different from each other, and R ₂ and R The alkyl group and alkoxy group of ₃ may be substituted or unsubstituted by a C ₁ to C ₆ alkyl group or a C ₁ to C ₆ alkoxy group, and when substituted by a plurality of substituents, they are the same or different from each other;
R ₄ is C ₁ ~C ₆ alkyl group, C ₁ ~C ₆ alkoxy group, -N(R ₇ )(R ₈ ), -C(=O)N(R ₇ )(R ₈ ) and hydroxy group (-OH) is any one selected from the group consisting of, and when there is a plurality of R ₄ , they are the same or different from each other, and the alkyl group and alkoxy group of R ₄ are substituted or provided by a C ₁ to C ₆ alkyl group or a C ₁ to C ₆ alkoxy group. may be substituted, and when substituted by a plurality of substituents, they may be the same or different from each other;
R ₅ to R ₈ are each independently hydrogen or a C ₁ to C ₆ alkyl group, and the alkyl group of R ₅ to R ₈ may be substituted or unsubstituted by a C ₁ to C ₆ alkyl group.

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