WO2015102370A1

WO2015102370A1 - 1,2-naphthoquinone derivative and method for preparing same

Info

Publication number: WO2015102370A1
Application number: PCT/KR2014/013039
Authority: WO
Inventors: 이휘성; 이미정; 김보정; 노태철; 이승훈; 이규대; 이유희; 곽태환
Original assignee: 주식회사 케이티앤지생명과학
Priority date: 2013-12-30
Filing date: 2014-12-30
Publication date: 2015-07-09
Also published as: KR101644778B1; KR20150080426A

Abstract

The present invention relates to: a compound represented by chemical formula (1), a pharmaceutically acceptable salt thereof, a hydrate, a solvate, a prodrug, a tautomer, an enantiomer, or a pharmaceutically acceptable diastereomer, a method for preparing same, and a pharmaceutical composition containing same and having effects of treating or preventing metabolic diseases. In chemical formula (1), R1 to R3 and X1 to X4 are the same as defined in claim 1.

Description

Specification

[Name of invention]

1,2 naphthoquinone derivatives and preparation methods thereof

Technical Field

The present invention relates to 1,2 naphthoquinone derivatives, methods for their preparation and compositions having the therapeutic and prophylactic effect of metabolic diseases containing the same.

Background Art

Metabolic disease (Metabolic Syndrome) refers to a syndrome in which risk factors such as hypertriglyceridemia, hypertension, abnormal glucose metabolism, abnormal blood glucose levels, and obesity are present. Heart attacks, ischemic heart disease, type 2 diabetes, hypercholesterolemia It is one of the most threatening diseases in the modern world because it can be accompanied by diseases such as cancer, gallstones, arthritis, joint pain, respiratory diseases, sleep apnea, enlarged prostate, and menstrual irregularities. According to the US National Cholesterol Education Program (NCEP), which was published for 20 years, ① Abdominal obesity with waist circumference of 40 inches (102 cm) for men and 35 inches (88 cm) for women, ② Triglycerides 150 5 mg / dL or higher, ③ HDL cholesterol, male 40 mg / dL, female 50 mg / dL or lower, ④ blood pressure 130/85 mmHg or higher, ⑤ fasting glucose (110 mg / dL or higher) If one of the risk factors is more than three, it is considered a metabolic disease. For Asians, the abdominal obesity is slightly adjusted when the waist circumference is more than 90 cm for males and 80 cm for females. According to this rule, Koreans have about 25% of the population with metabolic disease. There are also reports.

These metabolic diseases are considered to be a major risk factor for chronic long-term high calorie intake. It is known that metabolic efficiency decreases during excessive energy intake, lack of exercise, life extension, and aging, and this causes the problem of excess energy, which leads to obesity, diabetes and metabolic diseases. As a treatment method, diet therapy, exercise therapy, behavioral therapy therapy, drug therapy, etc. are being performed. However, since the cause is not known precisely, the present effect is insignificant and only to relieve symptoms or slow the progression of the disease. Therapeutic targets for the development of therapeutics have also been proposed in various ways, but the groundbreaking therapeutic targets have not been reported.

On the other hand, when the NAD ⁺ / NADH and NADP ⁺ / NADPH ratios are reduced in vivo or in vitro, and the NADH and NADPH remain in excess, they are not only used in the fat biosynthesis process, but also in excess. In the case of the semi-ungseong oxygen species (ROS) is also used as a major substrate, and thus may be a cause of important diseases including ROS-induced inflammatory diseases. For this reason, fatty acidization by NAD ⁺ and NADP ⁺ if the environment can be created in vivo or in vitro so that the NAD ⁺ NADH and NADP ⁺ / NADPH ratios remain stable. And various energy metabolism can be activated. As a result, if it is possible to activate the mechanism of action to keep the concentration of NAD (P) H continuously low, it is believed that it is possible to treat a variety of diseases including obesity by inducing excess energy to be consumed.

The method of increasing the concentration and ratio of NAD (P) ⁺ , a signal transmitter known to perform such various functions, firstly, adjusts the salvage synthesis process of NAD (P) ⁺ biosynthesis process, and secondly, NAD (P) H. To increase the concentration of NAD (P) ^{+ in} vivo by activating the gene or protein of an enzyme using as a substrate or coenzyme. Third, NAD (P) ⁺ or its analogs, derivatives, precursors and prodrugs are supplied from outside. For example, a method of increasing the concentration of NAD (P) ⁺ may be considered.

N AD (P) H: quinone oxidoreductase (EC1.6.99.2) is called DT-diaphorase, quinone reductase, menadione reductase, vitamin K reductase, or azo-dye reductase, and these NQOs have two isoforms, Present as NQ01 and NQ02 (ROM. J. INTERN. MED. 2000-2001, vol. 38-39, 33-50). NQO is a flavoprotein and acts to catalyze two electron reduction and detoxification of quinones or quinone derivatives. NQO uses both NADH and NADPH as electron donors. The activity of NQO prevents the formation of highly reactive quinone metabolites, detoxifies benzo (d) pyrene and quinone, and reduces the toxicity of crems. The activity of NQO is present in all tissues, but the activity is tissue dependent. In general, NQO expression was found to be high in tissues such as cancer cell tissue, liver, stomach and kidney. NQO gene expression is induced by xenobiotics, antioxidants, oxidants, heavy metals, ultraviolet radiation, and radiation. NQO is part of numerous cell defense mechanisms induced by oxidative stress. The associated expression of genes involved in these defense mechanisms, including NQO, serves to protect cells against oxidative stress, free radicals and neoplasia. NQO has a very broad substrate specificity. In addition to quinones, quinone-imines, nitro and azo compounds can be used as substrates.

Among them, NQ01 is mainly distributed in epithelial cells and endothelial cells. This means that it can act as a defense against compounds absorbed through air, esophagus or blood vessels. Recently, gene expression of NQ01 was found to be significantly increased in adipose tissue of humans with metabolic disease, and especially in the fat cells with large fat cells, the expression level of NQ01 was significantly higher. When weight loss was induced by diet, NQ01 expression was proportionally decreased along with weight loss. MRNA levels of NQ01 correlated proportionally with GOT and GPT, which are known as indicators of fatty liver. Therefore, the role of NQ01 in obesity-related metabolic disorders may be considered when NQ01 expression in adipose tissue is associated with adiposity, glucose tolerance, and liver function indices (The Journal of Clinical Endocrinology & Metabolism 92 (6): 2346. 2352).

[Detailed Description of the Invention]

[Technical problem]

On the other hand, an object of the present invention is to solve the problems of the prior art as described above and the technical problem that has been requested from the past.

Specifically, the present invention provides a 1,2-naphthoquinone derivative having a novel structure.

Another object of the present invention is to provide a method for preparing such novel compounds.

It is another object of the present invention to provide a composition for the treatment and prevention of metabolic diseases comprising a pharmacologically effective amount of such a novel compound as an active ingredient.

Another object of the present invention is to provide a method for the treatment and prevention of metabolic diseases by using such a novel compound as an active ingredient.

Technical Solution

The present invention provides a compound represented by the following formula (1), a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof. .

CD

Where

Ri and R ₂ are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4- C10 aryloxy, substituted or unsubstituted C2-C10 heteroaryl, -N0 ₂ , -NR ', R' ₂ , -NR '

CO (0) R'i, -C (0) NR'iR ' ₂ , -CN, -SO (0) R' ,, -SO (0) NR ' _! R ' ₂ , -NR'i (SO (0) R' ₂ ),-CSNR ', R' ₂ or ¾ and R ₂ are substituted or unsubstituted by cyclic structure of cyclic structure of C4-C10 aryl, or substituted Or a cyclic structure of unsubstituted C2-C10 heteroaryl.

Where R '! And R ' ₂ are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or Unsubstituted C1-C8 heteroaryl, substituted or unsubstituted-(CR ^ R '^ m'-dCH) aryl, substituted S is unsubstituted-(CR ^ R' ^ m'-C ^ Cl O heteroaryl or substituted or Unsubstituted NR ^ R ^ where and R " ₂ are each independently hydrogen, C1-C3 alkyl, or R" i and R " ₂ are mutually bonded to form a substituted or unsubstituted cyclic structure of C4-C10 aryl. Can; R ₃ is hydrogen, hydroxy, halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C20 alkene, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or Unsubstituted C2-C8 heterocycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C1-C10 heteroaryl, substituted or unsubstituted-(CR ' ₅ R' ₆ ) _m -C 4 -C 10 aryl, substituted or unsubstituted-(CR ' ₅ R' ₆ ) _m -C 4 -C 10 aryloxy, substituted or unsubstituted-(CR ' ₅ R' ₆ ) _m -Cl-C 10 heteroaryl , Substituted or unsubstituted-(CR ' ₅ R' ₆ ) _m -NR ' ₃ R'4, substituted or unsubstituted-(CR' ₅ R ' ₆ ) _m -C2-C10 heterocycloalkyl, substituted or unsubstituted -(CR ' ₅ R' ₆ ) _m -OR ' ₃ , substituted or unsubstituted-(CR' ₅ R'6) _m (0) COR ' ₃₎ -CO (0) R' ₃ ,-CONR ' ₃ _{_{R '4, -NR' 3 R}} '4, -NR' 3 (C (0) R '4), the "a" compound of formula (I) when one -CH ₂ a, or chemical (1) the compound is "Α ', when one of a -Α;

Wherein R'3, R ' ₄ are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted _{_{- (CR '5 R' 6}} ) m -C4-C10 aryl, substituted or unsubstituted _{_{- (CR '5 R' 6}} ) m -C4- C10 aryloxy, substituted or unsubstituted _{_{- (CR '5 R' 6}} ) _m- Cl-C10 heteroaryl,-CO (0) R '" ₃ , or R'3 and R'4 are cyclic structures of substituted or unsubstituted C4-C10 heterocycloalkyl, or substituted or unsubstituted by mutual bonding Cyclic structure of C1-C10 heteroaryl;

R'5, and R'6 are each independently hydrogen or C1-C3 alkyl; R '" ₃ is C1-C6 alkyl;

Wherein the substituent is hydroxy, halogenated nitro group, hydroxy, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, At least one selected from the group consisting of C3-C8 heterocycloalkyl, C4-C10 aryl, and C5-C10 heteroaryl;

X, X ₂ , X ₃ and ¾ are each independently CH or N; m and m, each independently represent a natural number of 1 to 4; And

The hetero atom is at least one selected from Ν, Ο and S.

Unless stated otherwise, the compound of formula (1) as an active ingredient of a therapeutic agent includes a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or pharmaceutical agent thereof. All acceptable diastereomers are included, and they should all be construed as being included in the scope of the present invention. For convenience of description, it is also simply abbreviated herein as a compound of formula (1).

The compound of formula (1) according to the present invention has a novel structure known in the prior art, and as can be seen in the following experimental examples, excellent effect on the treatment and prevention of metabolic diseases through exercise mimicking effect in vivo Exert. Specifically, the compound of the formula (1) according to the present invention induces NAD (P) H: quinone oxidoreductase (NQ01) as a redox enzyme to increase the ratio of NAD + / NADH in vivo, thereby increasing the ratio of AMP / ATP. You can. The increase in AMP in the cell activates AMPK, which acts as an energy gauge, promotes fat metabolism with PGCla expression that activates energy metabolism in the mitochondria, thereby compensating for insufficient ATP energy. In addition, increased NAD ⁺ is used as a cofactor for glucose and fat metabolism-related enzymes in the body to promote metabolism, and cADPR, produced by the breakdown of NAD ⁺ , releases Ca ²⁺ from the endoplasmic reticulum (ER) to mitochondrial metabolism. Synergistic activation acts to mimic the effects of exercise in vivo.

The terms used herein are briefly described.

The term "pharmaceutically acceptable salts" does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound. Means a formulation of a compound.

The terms "hydrate", "solvate", "fred force", "tautomer", "enantiomer or pharmaceutically acceptable diastereomer" also have the same meaning. ^'

The pharmaceutical salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, Organic carbon acids such as citric acid, acetic acid, trichloroacetic acid, trichloroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, P-luluenesulfonic acid, etc. Acid addition salts formed by the same sulfonic acid and the like. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, amino acid salts such as lysine, arginine, guanidine, dicyclonucleoamine, N Organic salts such as ᅳ methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline and triethylamine, and the like. The compounds of formula (1) according to the invention can also be converted to their salts by conventional methods.

The term " hydrate " is a compound of the present invention comprising a stoichiometric or non-stoichiometric amount of water bound by a non-covalent intermolecular force. Or salts thereof. The term "solvate" refers to a compound of the present invention or a salt thereof comprising a stoichiometric or non stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents therein are volatile, non-toxic, and / or solvents suitable for administration to humans.

The term "prodrug" is used to modify the parent drug in vivo. Mean material. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may be bioavailable by oral administration, while the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions than the parent drug. For example, prodrugs are esters that facilitate the passage of cell membranes, which are hydrolyzed to carboxylic acids, which are active by metabolism, once the water solubility is detrimental to mobility, but once the water solubility is beneficial. Drug "). Another example of a prodrug may be a short peptide (polyamino acid) that is bound to an acid group which is converted by metabolism to reveal the active site.

The term "tautomer" is a type of structural isomer that has the same chemical formula or molecular formula but differs in the way in which its members are linked, such as, for example, a keto-eno structure, reciprocating between both isomers Means change.

The term "enantiomer or pharmaceutically acceptable diastereomer" is an isomer which has the same chemical formula or molecular formula but is caused by a change in the spatial arrangement of atoms in a molecule, and the term "enantiomer" is an enantiomer, such as the relationship between right and left hand. And isomers that do not overlap with each other, and "diastereomers" are stereoisomers that are not enantiomeric such as trans and cis forms, and are limited to pharmaceutically acceptable diastereomers in the present invention. All of these isomers and combinations thereof are also within the scope of the present invention.

The term "alkyl" refers to an aliphatic hydrocarbon group. Alkyl in the present invention includes "saturated alkyl" meaning that it does not contain any alkenes or alkyne moieties, and at least one alkene or alkyne moiety. The term "unsaturated alkyl" is used to include all of the term "unsaturated alkyl", and in detail, may be "saturated alkyl" meaning that it does not contain any alkene or alkyne moiety. The alkyl may include branched, straight chain or cyclic, and also includes structural isomers, for example, in the case of C3 alkyl, may mean propyl, isopropyl.

The term "heterocycloalky" is a substituent in which the ring carbon is substituted with oxygen, nitrogen, sulfur or the like.

The term "aryl" refers to an aromatic substituent having at least one ring having a covalent pi-electron field. The term monocyclic or fused ring polycyclic (ie, rings that divide adjacent pairs of carbon atoms). ) Groups. When substituted, the substituents may be appropriately bonded at ortho (0), meta (m), para (p) positions.

The term "heteroaryl" refers to an aromatic group containing at least one heterocyclic ring.

Examples of the aryl or heteroaryl include, but are not limited to, phenyl, furan, pyran, pyridyl, pyrimidyl, triazyl, and the like.

The term "halogen" refers to elements belonging to group 17 of the periodic table, specifically fluorine, chlorine, bromine and iodine.

The term "aryloxy ,， means a group bonded to any one carbon and oxygen constituting an aromatic substituent, for example, when oxygen is bonded to a phenyl group-0-C ₆ ¾, -C ₆ H _4- Can be marked 0-.

Other terms may be interpreted as meanings commonly understood in the field to which the present invention belongs.

In a preferred example according to the invention,

And, X ₂ are each independently CH, CO or N (R ₃ ′); Where " Hydrogen or C 1 -C 3 alkyl; And X ₃ and X ₄ may each be CH. In another example according to the invention,

The ¾ and R ₂ are each independently hydrogen, a halogen _{_{_{atom, -OCH 3, -OCH 2 CH 3}}} , - 0 (CH 2) 2 CH 3, -CH 3, -N0 2, -CN, -NR 'iR' ₂ , or -OH (wherein R ', and R' ₂ are each independently hydrogen, C1-C3 alkyl, substituted or unsubstituted -C¾-C4-C10 aryl, substituted or unsubstituted -C ₂ H ₄ -C4- C10 aryl, or substituted or unsubstituted C2-C10 heteroaryl, and the substituent is a halogen element.

More specifically,

R, and R ₂ are each independently hydrogen, CI, —N0 ₂ , —NH ₂ or —ΝΙΊΙ ^, (wherein, and R ′ ₂ are each independently hydrogen, substituted or unsubstituted —CH ₂ -C 4- C6 aryl and the substituent is a halogen element.

In another example according to the invention,

¾ is hydrogen, substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, substituted or unsubstituted C4-C8 aryl, substituted or unsubstituted C4-C8 aryl Oxy, substituted or unsubstituted C 1 -C8 heteroaryl, substituted or unsubstituted-(CR'5R'6) m-C4-C K) aryl, substituted or unsubstituted-(CR ' ₅ R' ₆ ) _m -C4 -C 10 aryloxy, substituted or unsubstituted-(CR ' ₅ R' ₆ ) _m -Cl -C 10 heteroaryl, substituted or unsubstituted-(CR ' ₅ R' ₆ ) _m -C4-C10 heterocycloalkyl, or Substituted or unsubstituted-(CH ₂ ) _m -NR ' ₅ R'₆;

R'5, and R _'6 each independently is hydrogen or C 1 -C3 alkyl

Wherein the substituent is halogen, hydroxy, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C3-C8 At least one selected from the group consisting of heterocycloalkyl, C 4 -C 10 aryl, and C 5 -C 10 heteroaryl; Hetero atom is N, 0 or S; m may be a natural number of 1 to 4. In more detail,

R ₃ is hydrogen, substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, substituted or unsubstituted C4-C8 aryl, substituted or unsubstituted C4-C8 Aryloxy, substituted or unsubstituted-(CH ₂ ) _m -C 4 -C 10 heterocycloalkyl, or substituted or unsubstituted-(CH ₂ ) _m -NR ' ₅ R'₆;

R ' ₅ , and R' ₆ are each independently hydrogen or C1-C3 alkyl;

In more detail,

R ₃ may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, neopentyl, phenyl, phenyl substituted with halogen element,

More specifically,

¾ may be methyl, isopropyl, t-butyl, phenyl, or neopentyl.

The compound of Formula (1) may be exemplified as one of the compounds represented below, but the following compounds do not limit the present invention.

The present invention also provides a process for preparing the compound of formula (1).

Those skilled in the art to which the present invention pertains (“an authorized person”),

Based on the structure of (1), the compound may be prepared by various methods, and all of these methods should be interpreted to include the scope of the present invention. That is, within the scope of the present invention, it is possible to prepare the compounds of the formula (1) by arbitrarily combining various synthesis methods described herein or disclosed in the prior art. Therefore, the scope of the present invention is not limited only to this doll.

As one example, the compound of formula (1) according to the structure,

A) reacting a compound of formula (2) with R ₃ C0C1 or (R ₃ CO) ₂ 0;

B) reacting the compound produced in step A) with Lawesson's regaent; And

C) cyclization of the compound produced in step B) and optionally reaction with acid followed by oxidation reaction; It may be prepared through a process comprising a.

Wherein X, to X ₄ and Ri to R ₃ are as defined in formula (1) and ¾ is hydrogen, C 1 -C 4 alkyl, phenyl, benzyl.

Specifically, step A) may be a step A ′) of reacting R ₃ C0C1 or (R ₃ CO) ₂ 0 after halogenating the compound of Formula (2).

Lawesson's regaent is a reagent for introducing sulfur into a compound in the art

Generally known, in detail

Have

The cyclization reaction may include reacting with MX (wherein M is Al, B, Cu, Fe, or CN, and X is a halogen element).

As another example, the present invention provides a method further comprising the step D) for introducing a -N0 ₂ to the compound produced in step C) by banung and the compounds produced in the above step C) HN0 _3.

As another example, the present invention provides a preparation method further comprising the step E) of introducing -NH ₂ to the compound produced in step D) through the hydrogenation reaction of the compound produced in step D).

In another example, the present invention reacts the compound produced in step E) with M'X '(wherein M is Al, B, Cu, Fe or CN, and X is a halogen element). There is provided a preparation method further comprising the step F) of introducing -N0 ₂ into the compound. In another embodiment, the present invention further comprises the step G) of reacting the compound produced in step E) with R ₅ CHO (wherein R ₅ is substituted or unsubstituted C4-C6 aryl and the substituent is a halogen element) It provides a manufacturing method comprising the.

Further details are described in a number of embodiments and embodiments described hereinafter.

The invention also provides (a) a pharmacologically effective amount of a compound of formula (1) according to claim 1, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer and / or pharmaceutically acceptable salt thereof Possible diastereomers; And (b) a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof; provides a pharmaceutical composition for treating and preventing metabolic diseases.

The term "pharmaceutical composition" means a mixture of a compound of the invention with other chemical components, such as a diluent or carrier. The pharmaceutical composition facilitates administration of the compound into the organism. There are a variety of techniques for administering compounds, including but not limited to oral, injection, aerosol, parenteral, and topical administration. The pharmaceutical composition may be obtained by reacting acid compounds such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, P-luenesulfonic acid, salicylic acid and the like.

The term "therapeutically effective amount" refers to the amount of the compound administered reduces or reduces to some extent one or more symptoms of the disorder being treated, or delays the onset of a clinical marker or symptom of a disease that requires prevention. It means the amount of active ingredient effective to. Thus, the pharmacologically effective amount is (1) the effect of reversing the rate of progression of the disease, (2) more The amount has the effect of inhibiting progression to some extent and / or (3) alleviating (preferably eliminating) one or more symptoms associated with the disease. A pharmacologically effective amount can be determined empirically by experimenting with compounds in known in vivo and in vitro model systems for diseases in need of treatment.

The term "carrier" is defined as a compound that facilitates the addition of a compound into a cell or tissue. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the incorporation of many organic compounds into a cell or tissue of an organism.

The term "diluent" is defined as a compound that is not only to stabilize the biologically active form of a compound of interest, but also to be soluble in water that will dissolve the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, because it mimics the salt state of human solutions. Buffer salts rarely modify the compound's biological activity because buffer salts can take the pH of the solution at low concentrations.

The compounds used herein may be administered to a human patient as such or in combination with other active ingredients as in combination therapy or as a pharmaceutical composition combined with a suitable carrier or excipient. Formulations and Administration of Compounds in this Application] may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.

The pharmaceutical compositions of the present invention may be prepared in a known manner, for example, by means of conventional mixing, dissolving, granulating, sugar-making, powdering, emulsifying, encapsulating, trapping or lyophilizing processes. .

Thus, pharmaceutical compositions for use according to the invention, can be used pharmaceutically It may also be prepared by conventional methods using one or more pharmaceutically acceptable carriers which comprise excipients or auxiliaries which facilitate the treatment of the active compounds in the formulations which can be employed. Proper formulation is dependent upon the route of administration chosen. Any of the known techniques, carriers and excipients can be used as precisely and as understood in the art, for example in Remingston's Pharmaceutical Sciences described above. In the present invention, the compound of formula (1) may be formulated as an injection preparation, oral preparation, and the like as desired.

For injection, the components of the invention may be formulated in liquid solutions, preferably in pharmacologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline solution. For mucosal permeation administration, noninvasive agents suitable for the barrier to pass through are used in the formulation. Such non-invasive agents are generally known in the art.

For oral administration, the compounds can be formulated readily by combining the active compounds with pharmacologically acceptable carriers known in the art. Such carriers allow the compounds of the present invention to be formulated into tablets, pills, powders, granules, sugars, capsules, liquids, gels, syrups, slurries, suspensions and the like. Preferably, the tablets, tablets, pills, powders and granules are possible, and especially the tablets and tablets are useful. Tablets and pills are preferably prepared with enteric agents. Pharmaceutical preparations for oral use include mixing one or more compounds of the invention with one or more excipients, optionally grinding such mixtures and, if necessary, the mixture of granules after permeation of appropriate adjuvants. Treatment can yield a tablet or sugar core. Suitable excipients include fillers such as lactose, sucrose, manny, or sorbide; Corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragakens, methyl celrose, Hydroxypropylmethyl-celrose, sodium carboxymethyl celrose, and / or cellulose based materials such as polyvinylpyrrolidone (PVP). If necessary, a disintergrinding agent such as cross-linked polyvinyl pyridone, butadiene, or a salt thereof such as alginic acid or sodium alginate and a lubricant such as magnesium stearate, a carrier such as a binder, or the like may be added. Pharmaceutical preparations that can be used orally may include soft sealing capsules made of gelatin and plasticizers such as glycols or sorbates, as well as pushable capsules made of gelatin. The push-fix capsule may contain the active ingredients as a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate. In soft capsulation, the active compounds may be dissolved or dispersed in fatty acids, liquid paraffin, or a suitable solution ground with liquid polyethylene glycol. In addition, stabilizers may be included. All preparations for oral administration should be in amounts suitable for such administration.

The compounds may be formulated for parenteral administration by injection, for example by large pill injection or continuous infusion. Injectable formulations may also be presented in unit dose form, eg, as a 3/4 or multi-dos container with preservatives added. The compositions may take the form of suspensions, solutions, emulsions on oily or liquid vehicles, and may include formulation components such as suspending, stabilizing and / or dispersing agents.

The active ingredient may also be in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

The compounds may also be formulated in rectal dosage compositions, such as suppositories or retention enemas, including, for example, conventional suppository bases such as cocoa butter or other glycerides. Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an amount effective to achieve their intended purpose. More specifically, a therapeutically effective amount means an amount of a compound effective to prolong the survival of the subject to be treated or to prevent, alleviate or alleviate the symptoms of a disease. Determination of a therapeutically effective amount is within the capabilities of those skilled in the art, in particular in terms of the detailed disclosure provided herein.

When formulated in unit dose form, the compound of formula (1) as the active ingredient is preferably contained in a unit dose of about 0.1 to 1,000 mg. The dosage of the compound of formula (1) depends on the doctor's prescription depending on factors such as the patient's weight, age and the particular nature and severity of the disease. However, the dosage required for adult treatment typically ranges from about 1 to 1000 mg per day, depending on the frequency and intensity of administration. Intramuscular or intravenous administration to adults will be divided into single doses, usually at a total dosage of about 1 to 500 mg per day, but for some patients a higher daily dose may be desirable.

In the present invention, the target disease may be obesity, fatty liver, arteriosclerosis, stroke, myocardial infarction, cardiovascular disease, ischemic disease, diabetes mellitus, hyperlipidemia, hypertension, retinopathy or kidney failure, Huntington's disease or inflammation, specifically fatty liver, diabetes Or Huntington's disease, but is not limited to that.

The invention also provides a pharmacologically effective amount of a compound of formula (1) according to claim 1, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof Using in an effective amount, a method of treating or preventing metabolic diseases is provided. "Therapeutic" means stopping or delaying the progression of the disease when used in a subject exhibiting symptoms of the disease, and "preventing" means stopping or manifesting the disease when used in a subject who does not exhibit symptoms but has a high risk of developing the disease. Delayed Means that.

[Brief Description of Drawings]

1 is a graph showing the weight gain rate, weight change, and intake of obese rats (ob / ob) for the compound according to Example 2 of Experimental Example 3 and the control group;

Figure 2 is a rat obese to the compound and the control according to Example 7 of Experimental Example 3-1

(ob / ob) is a graph showing weight loss ratio, weight change, and intake; And FIG. 3 shows obese rats for the compound and the control group according to Example 9 of Experimental Example 3-2

It is a graph showing the weight gain rate, weight change, and intake amount of (ob / ob).

[Form for implementation of invention]

The present invention will be described in detail with reference to the following Examples and Examples, but the scope of the present invention is not limited thereto. In the following, Examples are described for the synthesis method of the intermediate to make the final compound, Examples are described for the synthesis method of the final compound using the compound of the Example. Example 1. [Synthesis of Compound 1]

1) 1-> 2 Pyridine (10 ml) is added to Compound 1 (4-amino-1 -naphthol hydrochloride, 2.0 g, 10.20 mmol) and the ice bath is dehydrated and cooled. Drop down Tert-Butylacetyl chloride (4.0 ml, 30.60 mmol). The reaction product is stirred at the same temperature for 2.5 hours. Banungmul is quenched with distilled water and concentrated under reduced pressure to remove pyridine. After adding EA and distilled water, adjust pH to about 6.5 with 1 N HC1 aqueous solution, and then remove the remaining Pyridine by washing the organic layer several times. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The concentrated reaction product was purified by silica gel column chromatography to obtain compound 2 (3233 mg, 90%).

NMR (300 MHz, CDC1 ₃ ) δ 7.88-7.84 (m, IH), 7.80-7.75 (m, 2H), 7.49-7.46 (m, 3H), 7.19 (d, J = 8.0 Hz, IH), 2.62 (s, 2H), 2.34 (s, 2H), 1.21 (s, 9H), 1.15 (s, 9H)

2) 2-> 3

Dissolve Compound 2 (500mg, 1.41 mmol) in THF (5ml) and add Lawesson reagent (853 mg, 2.12 mmol). The reaction is repeated for 15 hours at 70 degrees. The semi-cold water is concentrated after distillation under reduced pressure. The concentrated reaction product is purified by silica gel column chromatography to obtain compound 3 ( ⁴²⁸ mg, ⁸² %).

1 H NMR (300 MHz, CDC1 ₃ ) δ 8.79 (s, NH, IH), 7.88-7.84 (m, IH), 7.74-7.71 (m, IH), 7.50-7.44 (m, 3H), 7.19 (d, J = 7.3 Hz, IH), 2.90 (s, 2H), 2.63 (s, 2H), 1.21 (s, 9H), 1.19 (s, 9H)

3) 3-> 4

Compound 3 (430 mg, 1.16 mmol), FeCl ₃ (20 mg, 0.12 mmol) and Na ₂ S ₂ O ₈ (282 mg, 1.38 mmol) were added to the dried flask, followed by purge with N 2. Pyridine (2.32 mmol) and DMSO (4ml) were added thereto, followed by stirring at 40 ° C for 6 hours. The reaction water is quenched with water and extracted with EA. The organic layer was separated and treated with Na ₂ S0 ₄ , filtered, After distillation under reduced pressure, the compound was purified by silica gel column chromatography to obtain compound 4 (385 mg, yield 90%).

NMR (300 MHz, CDC1 ₃ ) δ 8.83 (d, J = 8.1 Hz, IH), 7.97 (d, J = 8.4 Hz, IH), 7.67-7.57 (m, 3H), 3.07 (s, 2H), 2.64 (s, 2H), 1.21 (s, 9H), 1.10 (s, 9H)

4) 4-> 5

Compound 4 (100 mg, 0.27 mmol) was dissolved in MeOH (3 ml), and then Hydrazine (0.05 ml, 20% mmol) was added and reacted at 40 ° C. for 4 hours. After the extraction, the product was purified by concentration under reduced pressure and silica gel column chromatography to obtain compound 5 (65 mg, 88%).

MR NMR (300 MHz, CDC1 ₃ ) δ = 8.78 (d, J = 8.4 Hz, IH), 8.29 (d, J = 7.9 Hz, IH), 7.66 (t, J = 8.1 Hz, IH), 7.58 (t , J = 8.4 Hz, IH), 7.21 (s, IH), 3.05 (s, 2H), 1.12 (s, 9H)

5) 5-> 6

Dissolve Compound 5 (65 mg, 0.24 mmol) in DMF (1.5 ml) and add IBX (157 mg, 0.26 mmol). In fact, after reacting for 1 hour at distilled water, distilled water and EA were added and extracted. The organic layer was treated with MgS0 ₄ , filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 6 (57 mg, 85%).

1 H NMR (300 MHz, CDC1 ₃ ) δ-8.21 (d, J = 7.7 Hz, IH), 8.13 (d, J = 7.7 Hz, IH), 7.71

(t, J = 7.7 Hz, IH), 7.53 (t, J = 7.7 Hz, IH), 3.00 (s, 2H), 1.10 (s, 9H)

LC-MS m / z 286.0 (M + 1) Example 2. Synthesis of Compound 2

5 6

1) l-> 2

Pyridine (5 ml) is added to Compound 1 (4-amino-1 -naphthol hydrochloride, 500 mg, 2.55 mmol), and the ice bath is dehydrated and cooled. Dropwise isobutyric anhydride (1.7 ml, 10.2 mmol). The reaction product is stirred at the same temperature for 2.5 hours. The reaction is quenched with methane and concentrated under reduced pressure to remove pyridine. After adding EA and distilled water, adjust pH to about 6.5 with 1 N HC1 aqueous solution, and then wash the organic layer several times to remove the remaining pyridine. The organic layer is dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The concentrated reaction product was purified by silica gel column chromatography to give compound 2 (686mg, 90%).

Got.

2) 2-> 3

Dissolve Compound 2 (500 mg, 1.67 mmol) in THF (5 ml) and add Lawesson reagent (1012 mg, 2.51 mmol). The reaction reacts at 70 degrees for 15 hours. The reaction is concentrated under reduced pressure after cooling. The concentrated reaction product was purified by silica gel column chromatography to obtain compound 3 (462 mg, 88%).

1 H NMR (300 MHz, CDC1 ₃ ) δ 8.91 (s, IH), 7.81 (d, J = 7.3 Hz, IH), 7.98 (d, J = 7.0 Hz, IH), 7.47-7.40 (m, 2H), 7.28 (d, J = 8.0 Hz, IH), 7.10 (d, J = 8.0 Hz, IH), 3.01 (m, 2H), 1.44 (d, J = 7.0 Hz, 6H), 1.35 (d, J = 7.0 Hz, 6H);

3) 3-> 4

Compound 3 (447 mg, 1.42 mmol), FeCl ₃ (24 mg, 0.14 mmol) and Na ₂ S ₂ O ₈ (345 mg, 1.42 mmol) were added to the dried flask, and then purged with N 2. Pyridine (2.32 mmol) and DMSO (4 ml) are added, followed by stirring at 40 ° C. for 6 hours. The reaction water is quenched with water and extracted with EA. The organic layer was separated, treated with Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 4 (398 mg, yield 90%).

NMR (300 MHz, Acetone-d ₆ ) δ 8.79 (d, J = 8.0 Hz, IH), 7.98 (d, J = 8.0 Hz, IH), 7.85 (s, IH), 7.70 (t, J = 8.0 Hz, IH), 7.64 (t, J = 8.0 Hz, IH), 3.50 (heptet, J = 7.0 Hz, IH), 3.07 (heptet, J = 7.0 Hz, IH), 1.51 (d, J = 7.0 Hz, 6H), 1.42 (d, J = 7.0 Hz, 6H);

4) 4-> 5

Compound 4 (355 mg, 1.13 mmol) was dissolved in MeOH (5 ml), Hydrazine (0.1 1 ml, 10% mmol) was added and reacted at 40 ° C. for 4 hours. After cooling, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 5 (226 mg, 80%). 'H NMR (300 MHz, Acetone-d ₆ ) 8.55 (d, J = 8.1 Hz, IH), 8.21 (d, J = 8.4 Hz, IH), 7.54 (t, J = 8.1 Hz, IH), 7.44 ( t, J = 8.4 Hz, IH), 7.27 (s, IH), 3.32 (heptet, J = 7.0 Hz, IH), 1.36 (d, J = 7.0 Hz, 6H);

5) 5-> 6

Dissolve Compound 5 (100 mg, 0.41 mmol) in DMF (2 ml) and add IBX (294 mg, 0.49 mmol). After reacting for 2 hours at room temperature, distilled water and EA were added thereto. Ship. The organic layer was treated with MgS0 ₄ , filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 6 (92 mg, 88%).

1 H NMR (300 MHz, CDC1 ₃ ) 8.19 (d, J = 7.5 Hz, IH), 8.10 (d, J = 7.8 Hz, IH), 7.70 (t, J = 7.5 Hz, IH), 7.50 (t, J = 7.5 Hz, IH), 3.42-3.38 (m, 1H) '1.49 (d, J-6.9 Hz, 6H); LC-MS m / z 258.0 (M + 1) Example 3. Synthesis of Compound 3

3, 4-Thiazole-l, 2 -naphthoquinones

1) 1-> 2

Pyridine (10 ml) is added to Compound 1 (4-amino-1 -naphthol hydrochloride, 2.0 g, 10.20 mmol) and the ice bath is dehydrated and cooled. Dropwise pivalogy chloride (3.8 ml, 30.60 mmol). The reaction product is stirred for 3 hours at the same temperature. The reaction water is quenched with distilled water and concentrated under reduced pressure to remove pyridine. After adding EA and distilled water, adjust pH to about 6.5 with 1 N HC1 aqueous solution, and then wash the organic layer several times to remove the remaining pyridine. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The concentrated reaction product was purified by silica gel column chromatography to obtain compound 2 (3035 mg, 91%). 2) 2-> 3

Dissolve Compound 2 (500 mg, 1.53 mmol) in THF (5ml) and add Lawesson reagent (927 mg, 2.29 mmol). The reaction is allowed to react for 15 hours at 70 degrees. After reacting, the reaction is concentrated under reduced pressure. The concentrated reaction product was purified by silica gel column chromatography to obtain compound 3 (451 mg, 86%).

'H NMR (300 MHz, CDC1 ₃ ) δ 8.87 (s, NH, IH), 7.90-7.86 (m, IH), 7.70-7.66 (m, IH), 7.53-7.45 (m, 3H), 7.20 (d , J = 8.1 Hz, IH), 1.56 (s, 9H), 1.47 (s, 9H)

3) 3-> 4

Compound 3 (472 mg, 1.38 mmol), FeCl ₃ (23 mg, 0.14 mmol) and Na ₂ S ₂ O ₈ (335 mg, 1.38 mmol) were added to the dried flask, and then purged with N 2. Pyridine (2.76 mmol) and DMSO (4ml) were added, followed by stirring at 40 ° C for 6 hours. The reaction is quenched with water and extracted with EA. The organic layer was separated, treated with Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 4 (420 mg, yield 88%).

MR NMR (300 MHz, CDC1 ₃ ) δ 8.84 (d, J = 8.4 Hz, IH), 7.91 (d, J = 8.4 Hz, IH), 7.66 (t, J = 8.4 Hz, IH), 7.63 (s, IH), 7.56 (t, J = 8.4 Hz, IH), 1.56 (s, 9H), 1.50 (s, 9H)

4) 4-> 5

Dissolve Compound 4 (320 mg, 0.94 mmol) in MeOH (5 ml), add Hydrazine (0.10 ml, 10% mmol) and react at 40 ° C. for 4 hours. After cooling, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 5 (217 mg, 90%). 'H NMR (300 MHz, CD ₃ OD) δ 8.64 (d, J = 8.1 Hz, IH), 8.28 (d, J = 8.1 Hz, IH), 7.57 (t, J = 8.0 Hz, IH), 7.47 ( t, J = 8.0 Hz, IH), 7.21 (s, IH), 1.47 (s, 9H)

5)

Compound 5 (170 mg, 0.66 mmol) was dissolved in DMF (3ml), and IBX (472 mg, 0.79 mmol) was added thereto. After reaction at room temperature for 2 hours, distilled water and EA were added and extracted. The organic layer was treated with MgSO ₄ , filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 6 (162 mg, 89%).

NMR (300 MHz, CD30D) δ 8.21 (d, J = 7.5 Hz, IH), 8.08 (d, J = 7.5 Hz, IH), 7.69

(t, J = 7.5 Hz, IH), 7.48 (t, J = 7.5 Hz, IH), 1.53 (s, 9H)

LC-MS m / z 272.0 (M + 1) Example 4. [Synthesis of Compound 4]

4 & {ep 5step

Istep:

After dissolving 660 mg of 8- (benzyloxy) -6-bromoquinolin-5-amine in 4 ml (0.5 M) of Pyridine, 0.23 ml (l.leq.) Of isobutyryl chloride is dropped in an ice bath. The reaction is stirred at room temperature for 1 hour. When done, add EA and wash 3 times with H ₂ 0 All. The EA layer is concentrated under reduced pressure immediately and then filtered through EthenHex.

Ivory solid: 676 mg (85%)

2step ： N- (8- (benzyloxy) -6-bromoquinolin-5-yl) -2-methylpropanethioamide

Dry 676 mg of N- (8- (benzyloxy) -6-bromoquinolin-5-yl) isobutyr amide. After dissolving in toluene, add 411 mg (0.6eq.) Of Lawesson's reagent, stir and reflux for 1.5 hours. Thioamide and thiazole are produced in a 7: 3 ratio. When reaction was completed, concentrated under reduced pressure, and silicagel filter.

Crude solid: 690 mg (98%)

3 step: 5- (benzyloxy) -2-isopropylthiazolo [4,5-f) quinoline

N- (8- (benzyloxy) -6-bromoquinolin-5-yl) -2-methylpropanethioamide 690 mg, Cs ₂ C0 ₃ 811 mg (1.5 eq.), 1, 10-phenanthroline 30 mg (0.1eq.), Cul 17 ml (0.1 M) of DME was added to a flask containing 16 mg (0.05 eq.) And reacted at 90 ° for 3 hours. When reaction was completed, extract with MC, MgS0 ₄ treatment, silicagel filter and wash with MC and finally with Hex: EA = l: l. The filtrate is concentrated under reduced pressure, and then filtered by recrystallization with Ether: He, x.

Ivory solid: 540 mg (97%)

4step: 2-isopropylthiazolo [4,5-f] quinolin-5-ol

Dry 100 mg of 5- (benzyloxy) -2-isopropylthiazolo [4,5-f] quinoline. After dissolving in 3 ml (0.1M) of dichloromethane, 1.5 ml (0.2 M) of methanesulfonic acid is dropped in an ice bath, followed by stirring at room temperature for 2 hours. When the reaction was completed, MC and aq.NaHC0 ₃ were added, and then the MC layer was separated, treated with MgS0 ₄ , filtered, and concentrated under reduced pressure. Recrystallize with EthenHex and filter. solid: 34 mg (45%)

MR NMR (300 MHz, CDC1 ₃ ) δ 9.02 (d, J = 8.4 Hz, IH), 8.84 (d, J-4.5 Hz, IH), 7.61 (dd, J = 8.4 Hz, 4.5 Hz, IH), 7.55 ( s, IH), 3.53-3.44 (m, IH), 1.52 (d, J = 6.6 Hz, 6H)

5 step:

To 34 mg of 2-isopropylthiazolo [ ⁴ , 5-flquinolin-5-ol, add 1.4 ml (0.1 M) of DMF and portionwise IBX 91 mg (l.leq.). The reaction is stirred for 30 minutes at room temperature. When the reaction is complete, wash the EA layer several times with aq.NaHC0 ₃ in excess of EA. EA layer is filtered by MgS0 ₄ treatment, filter, concentrated under reduced pressure and recrystallized by Ether: Hex.

Yellow solid: 12 mg (33%)

IH NMR (300 MHz, CDC13) δ 8.83 (d, J = 4.5 Hz, IH), 8.56 (d, J = 8.1 Hz, IH), 7.63 (dd, J = 7.8 Hz, 4.5 Hz, IH), 3.47- 3.38 (m, IH), 1.51 (d, J = 6.9 Hz, 6H)

1) 1-> 2

Pyridine (10 ml) is added to Compound 1 (4-amino-1 -naphthol hydrochloride, 2.0 g, 10.20 mn l) and the ice bath is dehydrated and cooled. benzoyl chloride (3.6 ml, 30.60 mmol) dropwise. The reaction product is stirred at the same temperature for 2.5 hours. The reaction is quenched with distilled water and concentrated under reduced pressure to remove pyridine. After adding EA and distilled water, adjust pH to about 6.5 with 1 N HC1 aqueous solution, and then wash the organic layer several times to remove the remaining pyridine. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The concentrated reaction product was purified by silica gel column chromatography to obtain compound 2 ( ³ 372 mg, ⁹ 0%).

2) 2-> 3

Dissolve Compound 2 (500 mg, 1.36 mmol) in THF (5 ml) and add Lawesson reagent (825 mg, 2.04 mmol). The reaction reacts at 70 degrees for 15 hours. The reaction product is concentrated under reduced pressure after cooling. The concentrated reaction product was purified by silica gel column chromatography to obtain compound 3 (365 mg, 70%).

3) 3-> 4

Compound 3 (365 mg, 0.95 mmol), FeCl ₃ (15 mg, 0.10 mmol) and Na ₂ S ₂ 0 ₈ (271 mg, 1.14 mmol) were added to the dried flask, followed by purge with N 2. Pyridine (1.9 mmol) and DMSO (4ml) were added, followed by stirring at 40 ° C. for 6 hours. The reaction is quenched with water and extracted with EA. The organic layer was separated, treated with Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 4 (368 mg, yield 90%).

4) 4-> 5

Compound 4 (100 mg, 0.23 mmol) was dissolved in MeOH (3 ml), and then Hydrazine (0.05 ml, 20% mmol) was added and reacted at 40 ° C. for 4 hours. After engraving, concentrated under reduced pressure, silica Purification by gel column chromatography yields compound 5 (54 mg, 85%). 5) 5-> 6

Compound 5 (54 mg, 0.19 mmol) is dissolved in DMF (1.5 ml), and IBX (145 mg, 0.23 mmol) is added. After reacting at room temperature for 1 hour, distilled water and EA were added and extracted. The organic layer was treated with MgSO ₄ , filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 6 (47 mg, 85%). Examples 6, 7 and 8. [Synthesis of Compounds 6-8]

com.7 ∞ ™ 8

[Synthesis of Compound 6]

2-isopropylnaphtho [l, 2-d] thiazole-4,5-dione (3.1 g, 12.74 mmol) was added to H ₂ SO ₄ (25 ml) and stirred in an ice bath. Add HNO ₃ (90%) (0.8 ml, 15. ² 9 mmol) and stir at room temperature for 30 minutes. Pour the semi-aqueous solution into the ice and wash with distilled water several times to filter the solids. The solid was dissolved in MC, dried over MgS0 ₄ , filtered and concentrated under reduced pressure. Crude is purified by recrystallization to give 2-isopropyl- ^7- nitronaphtho [l, ² -d] thiazole-4,5-dk e.

3.14g (82%)

NMR (300 MHz, CDCl ₃ ) 8.91 (d, J = 2.2 Hz, 1H), 8.56 (dd, J = 8.4 Hz,, 2.6 Hz, 1H), 8.45 (d, J = 8.4 Hz, 1H), 3.50 -3.41 (m, 1H), 1.53 (d, J = 7.0 Hz, 6H) [Synthesis of Compound 7]

Dissolve compound 6 (3.14g, 10.39mmol) in methanol (100ml) and MC (50ml), add 5% Pd / C (2.2g, i.039mmol) and connect the hydrogen balloon. Stir at room temperature for 1 hour. After filtering the semi-aqueous solution through Celite, the filtrate was purified by recrystallization concentrated under reduced pressure to obtain 7-amino- ² -isopropylnaphtho [l, ² -d] thiazole-4,5-dione.

1.75 g (62%)

IH NMR (300 MHz, CDC1 ₃ + DMSO Small) δ 7.92 (d, J = 7.7 Hz, IH), 7.38 (s, IH), 6.89 (d, J-7.3 Hz, IH), 4.45 (s, 2H) , 3.40-3.30 (m, IH), 1.47 (d, J = 6.6 Hz, 6H)

[Synthesis of Compound 8]

Compound 7 (76 mg, 0.279 mmol) was added to 1N HCl (3 ml) and stirred in ice bath at room temperature for 10 minutes. Slowly dropwise a solution of NaN0 ₂ (27 mg, 0.391 mmol) dissolved in water (0. ⁴ ml). ^After further stirring for ² 0 minutes, add a solution of CuCl ₂ ^• 2H ₂ 0 (0.24 g, 1.395 mmol) dissolved in water (0.7 ml), and further stir at 60 ° C. for 1 hour. Extract it several times. The separated organic layer was dried over MgS0 ₄ , filtered and concentrated under reduced pressure. Crude is purified by silicagel column chromatography and recrystallization to obtain 7-chloro-2-isopiOpylnaphtho [l, 2-d] thiazole-4,5-dione.

34.5 mg (42%)

1 H NMR (300 MHz, CDCl ₃ ) 8.15 (d, J = 8.1 Hz, IH), 8.07 (d, J = 2.2 Hz, IH), 7.67 (dd, J = 8.5 Hz, 2.2 Hz, IH), 3.45 -3.36 (m, IH), 1.49 (d, J = 7.0 Hz, 6H) Example 9 [Synthesis of Compound 9]

Compound 1 (4-amino-1 -naphthol hydrochloride, 5 g, 26.4 mmol) is dissolved in DMF (100 ml), K ₂ CO ₃ (11 g, 79.3 mmol) is added and heated to 80 degrees Celsius. BnBr (6.3 ml, 52.9 mmol) was added and stirred at the same temperature for 30 minutes. In a reaction solution, saturated NaCl aqueous solution and EA were added and extracted. The separated organic layer was dried over MgS04 and filtered. The filtrate is concentrated under reduced pressure, and then recrystallized from Silica gel filter (MC) (HX: EA).

Yellow solid 5.2 g (70%)

Compound 2 (5.1 g, 18.3 mmol) is dissolved in Acetone (145 ml) and distilled water (36.5 ml) and heated to 45 ^° C. NH ₄ C1 (5.9 g, 109.6 mmol) and Fe (9.9 g, 182.6 mmol) were added and refluxed for 2 hours. In a reaction solution, saturated NaCl aqueous solution and EA were added and extracted. The separated organic layer was dried over MgS04 and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (HX: EA = 3: 1).

Brown oil 3.9 g (86%) Dissolve Compound 3 (0.59 g, 2.35 mmol) in MC (47 ml) in an ice bath and slowly add Br ₂ solution (Br ₂ 0.13 ml, 2.45 mmol / MC 9.5ml). After stirring for 10 minutes, Na ₂ S ₂ 0 ₃ is added in excess and stirred for 10 minutes. Add distilled water and MC to the reaction solution. The separated organic layer was dried over MgS0 ₄ and filtered. The filtrate is concentrated under reduced pressure, purified by silica gel column chromatography (HX: EA = 7: 1), and then recrystallized (HX: Ether).

Brown solid 0.36 g (46%)

Dissolve Compound 4 (0.26 g, 0.79 mmol) in Pyridine (1.6 ml, 0.5 M) in an ice bath and add Ac ₂ 0 (0.1 ml, 0.95 mmol) and Et ₃ N (0.35 ml, 2.38 mmol). After stirring for 20 hours, saturated aqueous NaCl solution and EA were added to the reaction solution. The separated organic layer was dried over MgS0 ₄ and filtered. The filtrate is concentrated under reduced pressure and purified by recrystallization.

Ivory solid 0.23 g (80%)

Compound 5 (0.23 g, 0.61 mmol) is dissolved in THF (6 ml, 0.1 M). Add Lawesson reagent (0.15 g, 0.37 mmol) and reflux for 10 minutes. The reaction solution is concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography and then recrystallized.

Sky-blue solid 0.18 g (77%)

Compound 6 (0.18 g, 0.45 mmol), Cs ₂ C0 ₃ (0.22 g, 0.68 mmol), 1,10-phenanthroline (8.2 mg, 0.045 mmol) and Cul (4.5 mg, 0.023 mmol) were added to the flask with DME (4.5 ml, 0.1 M) and stirred at 90 ° C for 10 minutes. Add distilled water and EA to the reaction solution. The separated organic layer was dried over MgS0 ₄ and filtered. The filtrate is concentrated under reduced pressure and crystallized.

Ivory solid: 0.14 g (98%)

Compound 7 (30 mg, 0.098 mmol) is dissolved in EtOH (1 ml, 0.1 M) in an ice bath. Add cone, HC1 (0.5 ml) slowly and stir at 100 ^° C for 20 hours. Distilled water and EA were added to the reaction solution, followed by extraction. The separated organic layer was dried over MgS0 ₄ and filtered. The concentrated solution under reduced pressure was dissolved in DMF (2 ml) again and IBX (70 mg, 0.12 mmol) was added thereto. After stirring for 15 minutes, NaHC0 ₃ saturated aqueous solution and EA were added and extracted. The separated organic layer was dried over MgS04 and filtered. The filtrate is concentrated under reduced pressure and purified by recrystallization.

Orange solid 9 mg (41%)

"H NMR (300 MHz, CDC1 ₃ ) 5 8.17-8.11 (m, 2H), 7.71 (t, J = 7.5 Hz, 7.7 Hz, 1H) 7.51 (t, J = 6.8 Hz, 8.2 Hz, 1H), 2.86 (s, 3H) Example 10 Synthesis of Compound 10

Compound 1 (0.2 g, 0.734 mmol) and 4-fluorobenzaldehyde (79 ul, 0.734 mmol) were dissolved in MeOH (7.3 ml) and stirred at room temperature for 30 minutes. Add NaBH ₃ CN (55 mg, 0.881 mmol), stir for another 5 minutes, and add AcOH (1 ml, 0.65 M). The reaction solution is stirred for another hour at the same temperature. Pour the reaction solution into ice. Add NaHC0 ₃ saturated aqueous solution and EA. The separated organic filler is dried over MgS0 ₄ and filtered. The filtrate is concentrated under reduced pressure, and then purified by recrystallization.

Indigo solid 0.2 g (72%)

NMR (300 MHz, DMSO) δ 7.74 (d, J = 8.4 Hz, IH), 7.41-7.36 (m, 2H), 7.25-7.13 (m, 4H), 6.84 (d, J = 8.4 Hz, IH) , 4.37 (d, J = 5.9 Hz, 2H), 3.40-3.33 (m, IH), 1.37 (d, J = 6.8 Hz, 6H) Experimental Example 1: Determination of N001 activity

Enzyme reactions included 25 mM Tris / HCl (pH 7.4), 0.14% bovine serum albumin, 200 uM NADH, 77 uM Cytochrome C and 5 ng of NQOl protein. Enzyme reactions are initiated by addition of NADH and are performed at 37 degrees. In this case, the reaction rate is increased by absorbing Cytochrome C for 10 minutes at 550 nm. Observed, NQ01 activity is represented by the amount of reduced cytochrome C [nmol cytochrome C reduced I min Iug protein].

Extinction coefficient for cytochrome C: 21.1 mmol / L / cm = 21.1 umol / ml / cm The results are shown in Table 1 below.

TABLE 1

As shown in Table 1, it can be seen that the compound according to the present invention exhibits NQ01 activity.

Experimental Example 2: Measurement of Lactate Change in Cells

400 ul 6% PCA treatment on the cells to recover and extract. Centrifuge (13,000 rpm, 10 min). The precipitate is dried by speed-vac and dried to measure the dry weight of the cells. The supernatant is neutralized with 400 ul 1 M KOH and the final amount is adjusted to 1 ml using 0.33 M KH 2 P04 / K2HP04, pH 7.5. Centrifuge (13,000 rpm, 10 min) and measure the amount of lactate (Megazyme, K-LATE) as supernatant. The results are shown in Table 2 below. TABLE 2

As shown in Table 2, it can be seen that the Lactate activity in the cell according to the embodiment of the present invention. Since the NAD / NADH ratio in the cytosol changes similarly to the pyruvate / lactate ratio, the pyruvate / lactate ratio can be used to measure the NAD / NADH ratio in the cytosol. Therefore, decreasing lactate amount increases the intracellular NAD / NADH ratio. Experimental Example 3: Obese rats (weight loss effect in ob / ob to the compound according to Example 2

10 weeks old C57BL / 6J Lep ob / ob mice with ORIENTBI's genetic obesity, temperature 22-24 degrees, relative humidity 50-30%, light intensity 150-300 lux, contrast cycle 12 hours, exhaust 10 In the polycarbonate breeding box (200WX 260L X 130H (mm), Three-shine) maintained -15 times / hr of breeding environment, two dogs were raised per breeding box and the feed was low fat diet (11.9 kcal% fat, 5053) from ORIENTBIO. , Labdiet) was purchased and placed in the feeder for free consumption. Filtered and sterilized purified water was added to a polycarbonate drinking bottle (250 mL) using a flowing water sterilizer for free intake.

The compound according to Example 2 synthesized in the present invention was administered once every day for 1 week at a dose of 150 mg / kg for each of three C57BL / 6J Lep ob / ob mice, using a disposable syringe with oral administration sonde for 10 days. A ml / kg dose was forced orally in the stomach. As a control group, 0.1% SLS was administered to three C57BL / 6J Lep ob / ob mice using the same method at a dose of 150 mg / kg. Body weight gain with time of administration was measured and shown in Figure 1 below.

The body weight of the test animals was measured six times a week from the time of group separation (just before administration of the test substance) and from the start of the administration to the end of the test, and the total weight gain was calculated by subtracting the weight at the start of the experiment from the weight measured on the day before the end of the experiment. The dietary intake was measured twice a week from the start of the administration of the test substance to the end of the test.

As shown in the graph of Figure 1 it can be seen that the weight gain of the C57BL / 6J Lep ob / ob mice administered the compound according to Example 2 significantly decreased compared to the control. Experimental Example 3-1: Weight loss effect in obese rats (ob / ob) on the compound according to Example 7

ORIENTBIO's genetic obesity, C57BL / 6J Lep ob / ob mouse 6.5 weeks of age at 22-24 degrees, relative humidity 50-30%, illuminance 150-300 lux, contrast cycle 12 hours, exhaust 10- In the polycarbonate breeding box (200 \ ^><2601<13011 (mm), Three-shine) maintained 15 times / hr of feeding environment, two animals per breeding box were fed and low fat diet (11.9 kcal%) by ORIENTBIO. fat, 5053, Labdiet) was purchased and fed into the feeder and freely ingested. Drinking water was filtered and filtered using a filter and an oil sterilizer, and then freely ingested into a polycarbonate drinking bottle (250 mL).

The compound according to Example 7 synthesized in the present invention was administered using a disposable syringe attached to a sonde for oral administration once a day for a total of 1 week at a dose of 150 mg / kg for 3 mice each of C57BL / 6J Lep ob / ob mice. A ml / kg dose was forced orally in the stomach. As a control group, 0.1% SLS was administered to three C57BL / 6J Lep ob / ob mice using the same method at a dose of 150 mg / kg. The weight gain rate according to the administration time is shown in Figure 2 below.

The body weight of the test animals was measured six times a week from the time of group separation (just before administration of the test substance) and from the start of the administration to the end of the test, and the total weight increase was calculated by subtracting the weight at the start of the experiment from the weight measured on the day before the end of the experiment. The dietary intake was measured twice a week from the start of the administration of the test substance to the end of the test.

As shown in the graph of Figure 2 it can be seen that the weight gain rate of the C57BL / 6J Lep ob / ob mice administered the compound according to Example 7 significantly reduced compared to the control. Experimental Example 3-2: Weight loss effect in obese rats (ob / ob) on the compound according to Example 9

10 weeks old C57BL / 6J Lep ob / ob mice with ORIENTBIO's genetic obesity, prepared for temperature 22-24 degrees, relative humidity 50-30%, light intensity 150-300 lux, contrast cycle 12 hours, exhaust 10- Two birds per breeding box in a polycarbonate breeding box (200 \\ 0 <2601 <13 (^ (mm), Three-shine) maintained a 15 / hr breeding environment The feed was fed ORIENTBIO's Low fat diet (11.9 kcal% fat, 5053, Labdiet) and fed into the feeder for free intake. 250 mL) was freely ingested.

The compound according to Example 9 synthesized in the present invention was administered once every day for 5 days at a dose of 150 mg / kg for 3 mice each of C57BL / 6J Lep ob / ob mice, using a disposable syringe attached with a sonde for oral administration for 5 days. A ml / kg dose was forced orally in the stomach. As a control group, 0.1% SLS was administered to three C57BL / 6J Lep ob / ob mice using the same method at a dose of 150 mg / kg. The weight gain rate with time of administration was measured and shown in FIG. 3.

The body weight of the test animals was measured at the time of group separation (just before administration of the test substance) and six times a week from the start date to the end date of the test, and the total weight gain was calculated by subtracting the weight at the start of the experiment from the weight measured on the day before the end of the test. The dietary intake was measured twice a week from the start of the administration of the test substance to the end of the test.

As shown in the graph of Figure 3 it can be seen that the weight gain rate of the C57BL / 6J Lep ob / ob mice administered the compound according to Example 9 is significantly reduced compared to the control.

Industrial Applicability

As described above, the novel 1,2-naphthoquinone derivatives according to the present invention increase the ratio of NAD (P) + / NAD (P) H through NQ01 activity in vivo, thereby increasing the cellular energy environment. Mitochondrial activity by inducing long-term calorie restriction and genetic changes during exercise, such as AMPK activation, an energy consumption mechanism, and PGCla expression that activates mitochondrial energy metabolism Improvements in the system, such as mitochondrial biosynthesis and changes in endurance motility muscle fibers due to ignition, have the effect of treating exercise mimics that increase the physical activity of the body. It can be useful for prevention.

Claims

scope of claim

【Claim 1】

Compound represented by the following formula (1), its pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or pharmaceutically acceptable diastereomer:

In the above equation,

R, and R ₂ are each independently hydrogen, a halogen atom, hydroxy, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4 -C10 aryloxy, substituted or unsubstituted C2- C10 heteroaryl, -N0 ₂ , -NR',R' ₂ , -NR' X0)1， 2), -NR'^C^NR'^^), - CO(0)R' i, -C(0)NR',R' ₂ , -CN, -SO(0)R' _{l 5} -SO(0)NR',R' ₂ , -NR',(SO (0) ' ₂ ), - CSNR^R^ or ¾ and R ₂ are bonded to each other to form a cyclic structure of substituted or unsubstituted C4-C10 aryl, or a cyclic structure of substituted or unsubstituted C2-C10 heteroaryl. You can,

Here and R'2 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or ^ᅵ-substituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy. , substituted or unsubstituted C1-C8 Heteroaryl, substituted or unsubstituted -(CR^R'^m'-C^ClO Aryl, substituted or unsubstituted -(CR^R/'^m'-C ClO heteroaryl, or substituted or unsubstituted NR^R^ where Ι 'Ί and R" ₂ are each independently hydrogen, C1-C3 alkyl, or R", and R" ₂ may form a cyclic structure of substituted or unsubstituted C4-C10 aryl by mutual bonding;

R ₃ is hydrogen, hydroxy, halogen element, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C20 alkene, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or Unsubstituted C2-C8 heterocycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C1-C10 heteroaryl, substituted or unsubstituted -(CR' ₅ R' ₆ ) _m -C4- C10 Aryl, substituted or unsubstituted -(CR' ₅ R' ₆ ) _m -C4-C10 Aryloxy, substituted or unsubstituted -(CR' ₅ R' ₆ ) _m -Cl-C10 heteroaryl ， Substituted or unsubstituted -(CR' ₅ R' ₆ ) _m -NR' ₃ R'4, substituted or unsubstituted -(CR' ₅ R' ₆ ) _ni -C2-C10 heterocycloalkyl, substituted or unsubstituted of

Substituted or unsubstituted -(CR' ₅ R' ₆ ) _m (0)COR' ₃ , -CO(0)R' ₃ , -CONR' ₃ R', -NR' ₃ R' ₄ , -NR' ₃ ( C(0)R' ₄ ), -CH ₂ A when the compound of formula (1) is "A", or -A when the compound of formula (1) is "A";

Here, R' ₃ and R'4 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted -(CR ' ₅ R' ₆ ) _m -C4-C10 Aryl, substituted or unsubstituted - (CR' ₅ R' ₆ ) _m -C4-C10 Aryloxy, substituted or unsubstituted - (CR' ₅ R' ₆ ) _m -Cl -C10 heteroaryl, -CO(0)R'" ₃ , or R'3 and R'4 are a cyclic structure of substituted or unsubstituted C4-C10 heterocycloalkyl, or substituted or unsubstituted C1-C10 by mutual bonding. It can be a cyclic structure of hateroaryl;

R' ₅ , and R'6 are each independently hydrogen or C1-C3 alkyl; R'" ₃ is C1-C6alkyl; Here, the substituent is hydroxy, nitro group, halogen atom, hydroxy, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl. , C3-C8 heterocycloalkyl, C4-C10 aryl, and C5-C10 heteroaryl;

X,, X ₂ , X ₃ and ¾ are each alternatively CH or N;

m and m are each independently natural numbers from 1 to 4; and

The heteroatom is one or more selected from Ν, Ο and S.

【Claim 2】

According to claim 1,

Wherein , and Χ ₂ are each independently CH, CO or N(R ₃ '); Here, ¾ is hydrogen or C1-C3 alkyl; and

and ¾ each being CH; A compound characterized by a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof.

[Claim 3]

According to claim 1,

The R, and are each independently hydrogen, halogen elements, -OC¾, -OCH ₂ CH ₃ , -0(CH ₂ ) ₂ CH ₃ , -CH ₃ , -N0 ₂ , -CN, -NR',R' ₂ , or -OH (in the above formula, R' and R' ₂ are each independently hydrogen, C1-C3 alkyl, substituted or unsubstituted -CH ₂ -C4-C10 aryl, substituted or unsubstituted -C ₂ H ₄ -C4- C10 aryl, or substituted or unsubstituted C2-C10 heteroaryl, and the substituent is a halogen atom); A compound characterized in that, its pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or pharmaceutically acceptable diastereomer.

【Claim 4】

According to claim 1, and R ₂ are each independently hydrogen, CI, -N0 ₂ , -NH ₂ or -NR'tR'z, (in the above formula, and R' ₂ are each independently hydrogen, substituted or unsubstituted -CH ₂ -C4- C6 aryl and the substituent is a halogen atom); A compound characterized by a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, macroisomer or pharmaceutically acceptable diastereomer thereof.

【Claim 5】

According to claim 1,

¾ is hydrogen, substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, substituted or unsubstituted C4-C8 aryl, substituted or unsubstituted C4-C8 aryl Oxy, substituted or unsubstituted C1-C8 heteroaryl, substituted or unsubstituted -(CR' ₅ R' ₆ ) _m -C4-C10 aryl, substituted or unsubstituted -(CR' ₅ R' ₆ ) _m -C4-C10 Aryloxy, substituted or unsubstituted -(CR' ₅ R' ₆ ) _m -Cl-C10 heteroaryl, substituted or unsubstituted -(CR' ₅ R' ₆ ) _m -C4-C10 heterocycloalkyl, or substituted or unsubstituted The ring is - (C¾) _m -NR' ₅ R'₆;

R' ₅ , and R'6 are each independently hydrogen or C1-C3 alkyl.

Here, the substituent is a halogen atom, hydroxy, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C3-C8 heterocyclo. It may be one or more selected from the group consisting of alkyl, C4-C10 aryl, and C5-C10 heteroaryl; heteroatoms are N, 0, or S; m is a natural number from 1 to 4; A compound characterized in that, its pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or pharmaceutically acceptable diastereomer.

[Claim 6]

According to claim 5, R ₃ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, neopentyl, phenyl, or phenyl substituted with a halogen element; A compound characterized by a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof.

【Claim 7】

According to claim 5,

R ₃ is methyl, isopropyl, t-butyl, phenyl, or neopentyl; A compound characterized by a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof.

【Claim 8】

The compound according to claim 1, wherein the compound of formula (1) is one of the compounds expressed below, its pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or mirror image. Isomers or pharmaceutically acceptable diastereomers:

【Claim 9】

As a method for producing a compound of formula (1) according to claim 1,

A) reacting a compound of the following formula (2) with R ₃ C0C1 or (R ₃ CO) ₂ 0;

B) reacting the compound produced in step A) with Lawesson's regaent; and

C) cyclization reaction of the compound produced in step B), optionally reaction with acid, and then oxidation reaction;

A manufacturing method comprising:

In the above formula, Xi to X4 and Ri to R ₃ are as defined in formula (1) and ¾ is hydrogen, C1-C4alkyl, phenyl, and benzyl.

【Claim 10】

The method of claim 9, wherein the cyclization reaction includes a process of reacting with MX (wherein, M is Al, B, Cu, Fe or CN, and X is a halogen element).

【Claim 11】

The method of claim 9, wherein step A) is performed by subjecting the compound of formula 2 (the compound of formula 2 is as defined in clause 9) to a halogenation reaction, and then reacting R ₃ C0C1 or (R ₃ CO) ₂ 0. A manufacturing method characterized in that step A'):

【Claim 12】

The method of claim 9, further comprising a step D) of introducing -Ν0 ₂ into the compound produced in step C) by reacting the compound produced in step C) with HN0 ₃ :

[Claim 13]

The method of claim 12, further comprising the step Ε) of introducing -ΝΗ ₂ into the compound produced in step D) through hydrogenation reaction of the compound produced in step D):

[Claim 14]

The method of claim 13, wherein the compound produced in step Ε) is reacted with Μ'Χ'(Μ' is Al, Β, Cu, Fe or CN, and X' is a halogen element) to obtain the compound produced in step E). A manufacturing method characterized in that it further comprises step F) of introducing -N0 ₂ into:

[Claim 15]

The method of claim 13, wherein the compound produced in step E) is R ₅ CHO (in the formula R ₅ is substituted or unsubstituted C4-C6 aryl, and the substituent is a halogen element) and step G) of reaction.

[Claim 16]

(a) a pharmacologically effective amount of the compound of formula (1) according to paragraph 1, its pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer and/or pharmaceutically acceptable diastereomer; and (b) a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof. A pharmaceutical composition for treating and preventing metabolic diseases.

【Claim 17】

The pharmaceutical composition according to claim 16, wherein the metabolic disease is obesity, fatty liver, arteriosclerosis, stroke, myocardial infarction, cardiovascular disease, ischemic disease, diabetes, hyperlipidemia, hypertension, retinopathy or renal failure, Huntington's disease, or inflammation.

【Claim 18】

The pharmaceutical composition according to claim 16, wherein the metabolic disease is fatty liver, diabetes, or Huntington's disease.

【Claim 19】

Using a pharmacologically effective amount of the compound of formula (1) according to paragraph 1, its pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer or pharmaceutically acceptable diastereomer, How to treat or prevent metabolic disease.