KR20220067894A - Novel quinazolinone compound as therapeutics for treating metabolic disorder - Google Patents

Abstract

The inventors of the present application have confirmed that a novel quinazolinone derivative has efficacy in treating metabolic diseases, and thus achieved the present application. The quinazolinone derivative according to the present application has a structure similar to that of idelalisib, but shows very different properties from those of the idelalisib, and shows a different mechanism of action. In addition, derivative molecules of the present invention show excellent effects on metabolic diseases, particularly lipid metabolism diseases, through different functional mechanisms. The derivative molecules also show excellent efficacy against non-alcoholic steatohepatitis (NASH). There are no non-alcoholic steatohepatitis treatment drugs approved as of the time of application.

Description

Novel quinazolinone compound as therapeutics for treating metabolic disorder

The present application relates to a novel quinazolinone compound that can be used for the treatment of metabolic diseases, particularly fatty liver.

Quinazolinone derivatives have been studied in a variety of ways medically. Among them, Idelalisib (Formula 2) is a substance that has been developed as a treatment for blood cancer and is used as a second-line drug for blood cancer.

[Formula 2]

BACKGROUND ART Metabolic disorder is a disease that occurs in many modern people and poses a great risk to modern people's health. Various attempts have been made to treat metabolic diseases.

The inventors of the present application have arrived at the present application by confirming that the novel quinazolinone derivative exhibits therapeutic efficacy for metabolic diseases. The quinazolinone derivative according to the present application has a structure similar to that of ideralisib, but exhibits very different properties from ideralisib and a different mechanism of action. In addition, it was found that the present derivative molecule exhibits excellent efficacy in metabolic diseases, particularly lipid metabolic diseases, through different mechanisms of action. This derivative molecule also showed excellent efficacy against Non-Alcoholic Steatohepatitis (NASH). At the time of filing, there are no approved nonalcoholic steatohepatitis treatment drugs.

A novel quinazolinone derivative is provided by the present application.

A pharmaceutical use of the quinazolinone derivative is provided by the present application. Furthermore, the use of the quinazolinone derivative for treating metabolic diseases is provided.

The present application provides a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:

[Formula 1]

In this case, * is a stereocenter, and the compound is an S-form or R-form based on the stereocenter, or a racemate in which the S-form and the R-form are mixed, and R ₁ is C _{1~ 5} selected from alkyl, halogen, and —CF ₃ , and R ₂ is halogen. Furthermore, the structure of the compound may be different from Formula 5:

[Formula 5]

.

.

Furthermore, the present application provides the above compound or a pharmaceutically acceptable salt thereof, characterized in that it is in the S-form based on the stereogenic center. Alternatively, the present application provides the compound or a pharmaceutically acceptable salt thereof, characterized in that it is R-form based on the stereogenic center. Alternatively, according to the present application, R ₁ is 5-C, or 6-C of the quinazoline structure. The compound or a pharmaceutically acceptable salt thereof is characterized in that it is substituted. Furthermore, according to the present application, R ₁ is provided with the compound or a pharmaceutically acceptable salt thereof, characterized in that it is substituted with 5-C of the quinazoline structure. Alternatively, according to the present application, R ₂ is provided with the above compound or a pharmaceutically acceptable salt thereof, characterized in that it is substituted with 2-C of the phenyl structure. Or further, a compound represented by any one of Formulas 5 to 11 is provided:

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

[Formula 11]

.

.

According to the present application, there is provided a pharmaceutical composition for treating a lipid metabolic disease comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:

[Formula 1]

In this case, * is a stereocenter, and the compound is an S-form or R-form based on the stereocenter, or a racemate in which the S-form and the R-form are mixed, and R ₁ is C _{1~ 5} selected from alkyl, halogen, and —CF ₃ , and R ₂ is halogen. Furthermore, the structure of the compound may be different from Formula 5:

[Formula 5]

.

.

As a result of administering the novel compound according to the present application, therapeutic efficacy for metabolic diseases was confirmed as described below. Furthermore, it was confirmed that the present compound has therapeutic efficacy for metabolic diseases through phosphorylation of AMPK, activation of SIRT1, inhibition of inflammation, or multiple pharmacological mechanisms by two or more selected among them. Therefore, better treatment of metabolic diseases will be possible through the compound of the present application, and in particular, innovative treatment for non-alcoholic steatohepatitis without commercial drugs will be possible.

Justice

Unless defined otherwise, all technical and scientific terms used in this application have the meanings commonly understood by one of ordinary skill in the art of this application. The following references provide those skilled in the art with general definitions of many of the terms used in this application: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used in this application, the following terms have the meanings assigned to them below, unless otherwise specified.

In some embodiments, chemical structures are disclosed with corresponding chemical names. In case of a dispute, the meaning should be grasped by the chemical structure in preference to the chemical name.

"Alkyl" or "alkane" is a chain or branched non-aromatic hydrocarbon that is fully saturated. Typically, chain or branched alkyl groups have from 1 to about 20 carbon atoms, preferably from 1 to about 10 carbon atoms, unless otherwise defined. Chained and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl.

"Halogen" or "halo" means a group comprising fluorine, chlorine, bromine and iodine included in the halogen group elements in the periodic table.

The term "C _x-y ", when used in conjunction with a moiety such as, for example, alkyl, is intended to include moieties comprising from x to y carbons in the chain. For example, the term "C _x-y alkyl" includes substituted or unsubstituted, chain-like alkylene and branched alkyl groups comprising x-y carbons in the chain, illustratively difluoro is meant to include haloalkyl groups such as romethyl and 2,2,2-trifluoroethyl, and the like. C ₀ alkyl means hydrogen.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt that has the efficacy of a parent agent and is not biologically or undesirable (eg, non-toxic or not harmful to its receptor). say Suitable salts include, for example, a solution of the parent agent in an inorganic acid such as hydrochloric acid, phosphoric acid, sulfuric acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid. acid salts, which may be formed by mixing with a solution of a pharmaceutically acceptable acid such as an organic acid such as acid, glucuronic acid, trifluoroacetic acid or benzoic acid. When the drug carries an acidic moiety (such as -COOH or a phenolic group), pharmaceutically acceptable salts include alkali metal salts (such as sodium or potassium salts), alkaline earth metal salts (such as calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts.

Treatment of metabolic diseases: SIRT1 activator

In one embodiment, the present application provides a therapeutic agent for metabolic diseases comprising a SIRT1 activator. In addition, in one embodiment, the present application provides a method of treating a metabolic disease comprising prescribing a SIRT1 activator to a subject. Also provided by the present application in one embodiment is a molecule that functions as a SIRT1 activator.

The molecule according to the present application can function as an activator of SIRT1, as shown in the experimental examples below. The activator of SIRT1 can function as a therapeutic agent for metabolic diseases as described below.

Sirtuin 1 (hereinafter referred to as SIRT1) is a NAD-dependent deacetylase (NAD-dependent deacetylase) and gene regulatory proteins (genes such as ChREBP, SREBP-1, PPARα, PGC-1α, and NF-κB) as well as histones. -regulatory protein) is known to regulate deacetylation and activity.

SIRT1 is known to be involved in fatty acid oxidation and hepatic fat metabolism. Steatosis, an early stage of fatty liver disease, is characterized by the accumulation of excess triglycerides in the form of fat globules in the liver. One cause is that triglyceride-rich chylomicrons and free fatty acids enter the liver through transmembrane proteins. Another cause is that high levels of glucose and insulin promote new lipid production, and transcription factors such as the transcription factors ChREBP and SREBP1c are activated, which activate lipogenic enzymes such as FAS, ACC1, SCD1, and ELOVL6 in the liver. There are those from which triglycerides and free fatty acids are synthesized. One of the pathways to remove these triglycerides and fatty acids is fatty acid beta oxidation through the PPARα/PGC-1α signaling pathway in mitochondria, and the other is to convert triglycerides into blood in the form of very low-density lipoprotein (VLDL). There is something to emit. When SIRT1 is activated, it can deacetylate ChREBP and SREBP1c to block the expression of lipogenesis-related genes, thereby inhibiting new lipogenesis (lipogenesis), and deacetylating PPARα/PGC-1α to increase fatty acid beta oxidation (Ding). RB, Bao J, Deng CX. Int J Biol Sci. (2017) 13(7):852-867).

Purushotham A, et al. Cell Metab. (2009) 9(4):327-38, liver cell-specific SIRT1 deletion impairs PPARα signaling and reduces fatty acid beta-oxidation. In addition, when a high-fat diet was fed to a liver-specific SIRT1 knockout mouse, hepatic steatosis and hepatic inflammation were observed.

Choi SE, Kwon S, Seok S, et al. Mol Cell Biol. (2017) 37(15):e00006-17, when SIRT1 is phosphorylated by CK2 and the activity of SIRT1 is reduced, the symptoms of fatty liver and fatty liver-related diseases such as decreased fat metabolism in vivo, increased adipogenesis, increased inflammatory response, etc. gets worse

Considering the above study results, it is expected that the SIRT1 activating substance can be used for the prevention or treatment of fatty liver and fatty liver-related diseases.

SIRT1 activating substances are known to be effective in preventing or improving symptoms of obesity, NAFLD, and diabetes. Among the compounds known to activate SIRT1 is resveratrol. Resveratrol (3,4',5-trihydroxystilbene) is a polyphenol compound found in plants such as grapes and has a molecular formula of C ₁₄ H ₁₂ O ₃ . The effect of resveratrol on the prevention or treatment of heart disease, cancer, diabetes, and non-alcoholic fatty liver disease (NAFLD), etc. is being studied.

Treatment of metabolic diseases: AMPK activators

In one embodiment, the present application provides a therapeutic agent for metabolic diseases comprising an AMPK activator. In addition, in one embodiment, according to the present application, there is provided a method of treating a metabolic disease comprising prescribing an AMPK activator to a subject. Also provided by the present application in one embodiment is a molecule that functions as an AMPK activator.

The molecule according to the present application can function as an activator of AMPK, as shown in the experimental examples below. The activator of AMPK can function as a therapeutic agent for metabolic diseases as described below.

AMPK (AMP-activated protein kinase) functions to maintain intracellular energy homeostasis, and is known to promote glucose and fatty liver uptake and oxidation when intracellular energy is low. Specifically, AMPK is activated when energy in cells decreases due to metabolic stress or exercise, and inhibits the process of consuming ATP (fatty acid synthesis, cholesterol synthesis, etc.) and inhibits the process of ATP production (fatty acid oxidation, glycolysis, etc.) (Wing RR, Goldstein MG, Acton KJ, et al. Behavioral science research in diabetes: lifestyle changes related to obesity, eating behavior, and physical activity. Diabetes Care. 2001;24(1):117-123.) AMPK is known to inhibit lipid production by participating in the phosphorylation of lipid production-related factors, Acetyl-CoA carboxylase (ACC) and Sterol regulatory element-binding protein 1c (SREBP1c). (Jeon SM. Regulation and function of AMPK in physiology and diseases. Exp Mol Med. 2016;48(7):e245. Published 2016 Jul 15.) In addition, AMPK is hexokinase II (hexokinase II, a factor related to beta oxidation of fatty acids) II), Peroxisome proliferator-activated receptor alpha (hereinafter PPARα), peroxisome proliferator-activated receptor δ, peroxisome proliferator-activated receptor δ coactivator-1 (PPARγ coactivator) -1; hereinafter, it is known to promote beta oxidation by activating PGC-1), UCP-3, cytochrome C and TFAM. Focusing on the function of AMPK, there was an idea to treat metabolic diseases through AMPK activation (Winder WW, Hardie DG. AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol 1999;277(1):E1-E10.)

Treatment of metabolic diseases: inhibitors of inflammation

In one embodiment, the present application provides a therapeutic agent for metabolic diseases comprising an inflammatory inhibitor. In addition, in one embodiment, the present application provides a method of treating a metabolic disease comprising prescribing an inflammatory inhibitor to the subject. Also, in one embodiment, a molecule that functions as an anti-inflammatory agent is provided by the present application. In this case, the inflammation inhibitor is an inflammatory factor, for example, IκB kinase α (IκB kinase α; hereafter referred to as IKKα), nuclear factor-κB (nuclear factor kappa-light-chain-enhancer of activated B cells; hereinafter NF-κB), interleukin 6, or 8 (interleukin; hereinafter IL6 or IL8), monocyte chemoattractant protein 1 (MCP1 hereinafter), or tumor necrosis factor α (Tumor necrosis factor α; hereinafter TNFα) can be inhibited.

The molecule according to the present application may function as an anti-inflammatory agent as shown in the following experimental examples. This is also due to the activation of AMPK and SIRT1. Inflammatory inhibitors may function as therapeutic agents for metabolic diseases as described below.

It is known that metabolic diseases and inflammation are closely related. Inflammation is generally a beneficial phenomenon for returning tissues from an abnormal state to a normal state. However, in some patients with metabolic diseases, the tissue is not restored to a normal state, and thus chronic inflammation is a state of continuous inflammation. Prolonged inflammatory conditions, such as chronic inflammation, can be harmful to the human body. Changes in the composition of immune cells in tissues due to inflammation are being studied to cause major symptoms of metabolic diseases including diabetes. For example, in diabetes mellitus, it is said that the insulin secretion gland may be destroyed due to the cytokine secretion of inflammatory immune cells. In addition, when the liver is damaged in fatty liver, Kupffer cells are activated to induce immune cells and activate immune cells in the liver cells. Double hepatic stellate cells (hepatic stellate cells; hereafter referred to as HSC cells) are known to promote the secretion and degradation of extracellular matrix proteins including fibrous collagen. Sustained activation of Kupffer cells and HSC cells is known as one of the main causes of liver fibrosis (Bataller R, Brenner DA. Liver fibrosis [published correction appears in J Clin Invest. 2005 Apr;115(4):1100]. J Clin Invest) 2005;115(2):209-218.) In other words, anti-inflammatory drugs have the potential to improve the symptoms of fibrosis caused by metabolic diseases including liver fibrosis.

Treatment of metabolic diseases: multiple mode regulators

As used herein, the term “multiple mode regulator” refers to a drug or compound having two or more modes of action expected to treat a target disease. The molecule according to the present application can function as a multimodal modulator for treating metabolic diseases. In this case, the mechanism of action of the multimodal modulator may be selected from an activator of SIRT1, an activator of AMPK, and inhibition of inflammation, as described above.

In one embodiment, the present application provides a therapeutic agent for metabolic diseases comprising a multimodal modulator. In addition, in one embodiment, the present application provides a method of treating a metabolic disease comprising prescribing a multimodal modulator to the subject. Also provided by the present application in one embodiment is a molecule that functions as a multimodal modulator.

In one embodiment, the multimodal modulator may function as an activator of SIRT1 and an activator of AMPK. In one embodiment, the multimodal modulator may function as an activator of SIRT1 and an inhibitor of inflammation. In one embodiment, the multimodal modulator may function as an activator of AMPK and an inhibitor of inflammation. In one embodiment, the multimodal modulator may function as an activator of SIRT1, an activator of AMPK, and an inhibitor of inflammation.

Structure of the compound according to the present application

In one embodiment, the present application provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Formula 1]

In this case, * is a stereocenter, and the compound is an S-form or R-form based on the stereocenter, or a racemate in which the S-form and the R-form are mixed, and R ₁ is C _{1~ 5} selected from alkyl, halogen, and —CF ₃ , and R ₂ may be halogen.

In one example, R ₁ may be methyl, F, Cl, or —CF ₃ .

In one example, R ₂ may be F or Cl.

In the formula of the present application, the number of the quinazoline structure to which R ₁ is bonded and the phenyl structure to which R ₂ is bonded is the numbering of ring carbon. The numbering is indicated for convenience in order to specify the positions of the substituents R ₁ , and R ₂ . When R ₁ , and R ₂ are connected to the center of the ring, it means that they may be connected to any position of the ring. For example, that R ₁ is substituted with 5-C means that R ₁ is substituted with the carbon at which 5 is indicated.

The wavy bond structure bound to the stereocenter is intended to show that, depending on the isomer, it can be a bond entering the plane or a bond coming out of the plane.

In one example, the pharmaceutically acceptable salt may be an acid salt. In this case, the acid salt is an inorganic acid such as hydrochloric acid, phosphoric acid, sulfuric acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, glucuronic acid, tri Organic acids such as fluoroacetic acid or benzoic acid include all forms that can be used by those skilled in the art.

Differences from Edelaliship

The molecule according to the present application shares a structure similar to that of the previously developed drug Idelalisib. The structure of ideralisip is as shown in Chemical Formula 2 below.

[Formula 2]

Idelalisib has been studied as a treatment for blood cancer and as an inhibitor of phosphoinositide 3-kinase (PI3K).

However, the inventor of the present application confirmed that while changing the molecular structure of ideralisib, it has a different mechanism of action and has efficacy against different diseases. Hereinafter, structural differences between idealilisib and the molecules of the present application and their meanings will be described.

Substitution of the quinazoline structure

This table of contents describes the R ₁ substituent.

The inventor of the present application found that the combination of halogen or R ₁ having a size equivalent to that in Formula 1 and the 'isopropyl' group introduced to the stereocenter carbon shows a different aspect of pharmaceutical efficacy than the conventional ideralisib. confirmed that That is, while idelalisib is limited to the efficacy of hematologic cancer, the quinazolinone derivative of the present invention having the above-described characteristics showed more characteristic pharmaceutical efficacy in fatty liver-related diseases.

In one example, R ₁ may be substituted at one or more positions selected from 5-C, 6-C, 7-C, and 8-C of the quinazoline structure. Furthermore, R ₁ may be substituted with 5-C of the quinazoline structure. Or further, R ₁ may be substituted with 6-C of the quinazoline structure.

substitution of the phenyl structure

This table of contents describes the R ₂ substituent.

Substituents on the phenyl structure were found to exhibit sufficiently meaningful efficacy in the course of testing various pharmacological effects in vitro.

In one example, R ₂ may be substituted at one or more positions selected from 1-C, 2-C, and 3-C of the phenyl structure. Furthermore, R ₂ may be substituted with 2-C of the phenyl structure.

stereocenter

This table of contents describes the stereocenter of the compound. The stereocenter exhibits different properties depending on the type of the substituent substituted therefor (hereinafter, the stereocenter substituent) and the type of isomer.

In the present application, the stereocenter substituent is an isopropyl (isopropyl) moiety. This corresponds to a new structure compared to the prior art such as idealaliship. Looking at the prior art, the structure of the stereocenter substituent has a great influence on the properties of the compound. For example, Duvelisib is a quinazolinone derivative in which the stereocentric substituent is methyl. Despite these differences, duvelisib showed very poor selectivity for the isoform of PI3K than that of ideralisib. In another example, another patent registration No. 10-1932146 of the same applicant discloses a compound wherein the stereocentric substituent is cyclopropyl or cyclobutyl. The compound was found to have improved hematologic cancer therapeutic activity and selectivity for the PI3K isoform protein compared to ideelalisib.

The inventors of the present application confirmed that, when the stereocenter substituent is an isopropyl residue, the function of regulating SIRT1, AMPK, and inflammatory factors is excellent, unlike previously known. Taking this into consideration, the inventors of the present application have confirmed that the novel molecule has an excellent effect on metabolic diseases (Experimental Example).

In the present application, the stereogenic center may be of two isomeric types (S-type, R-type). The type of isomer has a great influence on the properties of the present compound. Typically, the type of isomer can affect the cytotoxicity and mode of action of a compound.

In the present application, the stereocenter may be S-type or R-type. In one example, the stereocenter may be S-shaped. In another example, the stereogenic center may be R-shaped. In another example, the compound may be a racemate in which S-form and R-form are mixed based on the stereogenic center.

specific example

In one embodiment, the present application provides a compound represented by the following formula (3) or a pharmaceutically acceptable salt thereof:

[Formula 3]

In this case, R ₁ may be selected from C _1-5 alkyl, halogen, and —CF ₃ , and R ₂ may be halogen.

In one embodiment, the present application provides a compound represented by the following formula (4) or a pharmaceutically acceptable salt thereof:

[Formula 4]

In this case, R ₁ may be selected from C _1-5 alkyl, halogen, and —CF ₃ , and R ₂ may be halogen.

The following relates to examples of Chemical Formulas 3 and 4. In one example, R ₁ may be methyl, F, Cl, or —CF ₃ .

In one example, R ₂ may be F or Cl.

R ₁ may be substituted at one or more positions selected from 5-C, 6-C, 7-C, and 8-C of the quinazoline structure. Furthermore, R ₁ may be substituted with 5-C of the quinazoline structure. Or further, R ₁ may be substituted with 6-C of the quinazoline structure.

In one example, R ₂ may be substituted at one or more positions selected from 1-C, 2-C, and 3-C of the phenyl structure. Furthermore, R ₂ may be substituted with 2-C of the phenyl structure.

In one embodiment, the present application provides a compound represented by one selected from Formulas 5 to 11, or a pharmaceutically acceptable salt thereof:

[Formula 5] 5-chloro-2-[(1R)-2-methyl-1-[(7H-purin-6-yl)amino]propyl]-3-phenyl-3,4-dihydroquinazoline-4 -On

[Formula 6] 5-chloro-2-[(1S)-2-methyl-1-[(7H-purin-6-yl)amino]propyl]-3-phenyl-3,4-dihydroquinazoline-4 -On

[Formula 7] 5-fluoro-2-[(1R)-2-methyl-1-[(7H-purin-6-yl)amino]propyl]-3-phenyl-3,4-dihydroquinazoline- 4-on

[Formula 8] 5-methyl-2-[(1R)-2-methyl-1-[(7H-purin-6-yl)amino]propyl]-3-phenyl-3,4-dihydroquinazoline-4 -On

[Formula 9] 5-trifluoromethyl-2-[(1R)-2-methyl-1-[(7H-purin-6-yl)amino]propyl]-3-phenyl-3,4-dihydroquina sleepin-4-one

[Formula 10] 6-chloro-2-[(1R)-2-methyl-1-[(7H-purin-6-yl)amino]propyl]-3-phenyl-3,4-dihydroquinazoline-4 -On

[Formula 11] 5-chloro-3-(3-fluorophenyl)-2-[(1R)-2-methyl-1-[(7H-purin-6-yl)amino]propyl]-3,4- Dihydroquinazolin-4-one

therapeutic use

In one embodiment, the present application provides use of at least one compound selected from Formulas 1 and 3 to 11 for treating metabolic diseases.

In one embodiment, the present application provides a pharmaceutical composition comprising at least one compound selected from Formulas 1 and 3 to 11. The pharmaceutical composition may include a pharmaceutically acceptable excipient. In the pharmaceutical composition according to the present application, the compound according to the present application, or a pharmaceutically acceptable salt thereof, may be administered in various formulations according to oral and/or parenteral methods during clinical administration. At this time, when formulating the compound or a pharmaceutically acceptable salt thereof, the compound or a pharmaceutically acceptable salt thereof is a filler, a weight agent, a binder, a wetting agent, a disintegrant, a diluent such as a surfactant, or at least one of excipients is used. and can be formulated.

For example, formulations for oral administration containing the compound according to the present application or a pharmaceutically acceptable salt thereof as an active ingredient include tablets, pills, hard/soft capsules, solutions, suspensions, emulsions, granules, granules, elixirs, There may be troches and the like. In addition to the active ingredient, the formulation for oral administration includes a diluent (eg, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycic), and a lubricant (eg, silica, talc, stearic acid). and magnesium or calcium salts thereof and/or polyethylene glycol). For example, the tablet may include at least one of a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine. In addition, the tablet may contain at least one of a disintegrant or a boiling mixture and/or an absorbent, a colorant, a flavoring agent, and a sweetening agent, such as starch, agar, alginic acid or sodium salt thereof, depending on the case.

For example, a pharmaceutical composition comprising the compound according to the present application or a pharmaceutically acceptable salt thereof as an active ingredient may be used as a parenteral administration method. The parenteral administration method may be any one of a method of injection by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

For example, a formulation for parenteral administration containing the compound according to the present application or a pharmaceutically acceptable salt thereof as an active ingredient may be prepared as a solution or suspension by mixing it with water together with a stabilizer or a buffer, which is an ampoule or vial unit. can be prepared in dosage form. In addition, the formulation for parenteral administration containing the compound according to the present application or a pharmaceutically acceptable salt thereof as an active ingredient is an adjuvant such as a preservative, a stabilizer, a wetting agent or emulsification accelerator, a salt and/or a buffer for regulating osmotic pressure, and others. It may contain therapeutically useful substances and may be formulated according to mixing, granulation or coating in a conventional manner. In addition, the pharmaceutical composition according to the present application may be prepared as a formulation for sustained release of a compound or a pharmaceutically acceptable salt thereof through a polymer excipient or the like.

In addition, the pharmaceutical composition of the present application may include at least one active ingredient capable of exhibiting the same or similar function in addition to the compound according to the present application or a pharmaceutically acceptable salt thereof.

In addition, a preferred dosage of the pharmaceutical composition of the present application may be appropriately selected according to the patient's condition and body weight, severity of symptoms, drug form, administration route, and period. In the pharmaceutical composition of the present application, it may be desirable for optimal efficacy to administer the active ingredient at 0.2 mg/kg to 200 mg/kg per day. In addition, the pharmaceutical composition of the present application may be administered once a day or may be administered in several divided doses, but is not limited thereto.

In one embodiment, the present application provides a method of treating a metabolic disease comprising administering to a subject one or more compounds selected from Formulas 1 and 3 to 11. In this case, the compound may be administered through an appropriate route, in the form of an appropriate composition, in an effective dose. Such routes, compositions, and doses can be determined by means known in the art.

In one embodiment, the present application provides a health functional food composition comprising one or more compounds selected from Chemical Formulas 1 and 3 to 11.

Target disease: metabolic disease

This table of contents describes the target diseases for the therapeutic uses described above. A compound of the present application or a pharmaceutically acceptable salt thereof, and a therapeutic use thereof are directed to a metabolic disease. In particular, it targets those related to lipid metabolism among metabolic diseases. The compound according to the present application can improve abnormal lipid metabolism because it has the effect of promoting lipid degradation and inhibiting lipid production.

In one embodiment, provided by the present application is a pharmaceutical composition for treating a lipid metabolic disease. In one embodiment, the present application provides a nutraceutical composition for treating a lipid metabolism disease. In one embodiment, provided by the present application is a method of treating a metabolic disease associated with fat metabolism.

Exemplary lipid metabolic diseases include steatosis, liver disease, obesity, diabetes, hypertension, hypercholesterolemia, insulin resistance, and the like. Exemplary liver diseases include fatty liver, such as alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD). Nonalcoholic fatty liver includes simple fatty liver and non-alcoholic steatohepatitis (NASH), and complications due to fatty liver, e.g. liver fibrosis, cirrhosis, liver cancer, and esophageal varices.

Experimental example

Experimental Example 1. Synthesis method of the compound of the present invention (NMR data)

Experimental Example 2. Fat accumulation inhibition verification experiment (FIG. 3)

Experimental Example 3. Confirmation of fat accumulation protein level (FIG. 4)

Experimental Example 4. Inhibition of fat accumulation in adipocytes (FIG. 5, FIG. 6)

3T3L1 cells

Experimental Example 5. Effect of inhibiting accumulation of triglycerides ( FIGS. 7 and 8 )

TG assay; Huh7 cells

Experimental Example 6. Confirmation of lipid production-related factor protein and gene expression level (FIG. 9)

Experimental Example 7. Confirmation of fatty acid beta oxidizing factor protein and gene expression level (FIG. 10)

Experimental Example 8. Confirmation of inflammatory factor protein and gene expression level (FIGS. 11, 12)

Experimental Example 9. Confirmation of multi-mode modulator activity (FIGS. 13-15)

Experimental Example 10. PK confirmation (FIG. 16)

Experimental Example 11. (FIG. 17)

Experimental Example 12. In-vivo efficacy (FIG. 18)

Experimental Example 13. Efficacy of improving liver fibrosis (FIG. 19)

Experimental Example 14. Plasma protein level confirmation (FIG. 20)

Experimental Example 15. (FIG. 21)

Experimental Example 16. Confirmation of changes in insulin resistance (FIG. 22)

Claims (8)

A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

In this case, * is a stereocenter, and the compound is an S-form or R-form based on the stereocenter, or a racemate in which the S-form and the R-form are mixed;
R ₁ is selected from C _1-5 alkyl, halogen, and —CF ₃ ,
R ₂ is halogen,
The structure of this compound is different from Formula 5:
[Formula 5]

. The method of claim 1,
A compound or a pharmaceutically acceptable salt thereof, characterized in that it is S-form based on the stereogenic center. The method of claim 1,
A compound or a pharmaceutically acceptable salt thereof, characterized in that R-form based on the stereogenic center. The method of claim 1,
R ₁ is 5-C or 6-C in the quinazoline structure, or a pharmaceutically acceptable salt thereof is substituted. 5. The method of claim 4,
R ₁ is substituted with 5-C of the quinazoline structure, or a pharmaceutically acceptable salt thereof. The method of claim 1,
R ₂ is substituted with 2-C of the phenyl structure, or a pharmaceutically acceptable salt thereof. According to claim 1, wherein the compound represented by any one of Formulas 6 to 11:
[Formula 6]

[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

[Formula 11]

. A pharmaceutical composition for treating a lipid metabolic disease comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

In this case, * is a stereocenter, and the compound is an S-form or R-form based on the stereocenter, or a racemate in which the S-form and the R-form are mixed;
R ₁ is selected from C _1-5 alkyl, halogen, and —CF ₃ ,
R ₂ is halogen,
The structure of this compound is different from Formula 5:
[Formula 5]

.

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