KR101644778B1 - 1,2-Naphthoquinone-based Derivatives and and Methods for Preparing them - Google Patents

Abstract

(1)
상기 화학식 1에서, R₁ 내지 R₃, X₁ 내지 X₄는 제 1 항에서 정의된 바와 같다. The present invention relates to a compound represented by the following formula (1), a pharmaceutically acceptable salt, a hydrate, a solvate, a prodrug, a tautomer, an enantiomer or a pharmaceutically acceptable diastereomer thereof, And a pharmaceutical composition having a therapeutic or preventive effect for a metabolic disease containing the same.

(One)
Wherein R ₁ to R ₃ and X ₁ to X ₄ are as defined in claim 1.

Description

1,2-Naphthoquinone Derivatives and Methods for Their Preparation {1,2-Naphthoquinone-based Derivatives and Methods for Preparing Them,

The present invention relates to a 1,2-naphthoquinone derivative, a process for producing the same, and a composition having a therapeutic and preventive effect on a metabolic disease containing the same.

Metabolic Syndrome refers to a syndrome in which risk factors such as hypertriglyceridemia, hypertension, glucose metabolism abnormality, blood clotting abnormality, and obesity coexist, and includes heart failure, ischemic heart disease, type 2 diabetes, hypercholesterolemia, , Cholelithiasis, arthritis, arthralgia, respiratory diseases, sleep apnea, enlargement of the prostate gland, menstrual irregularities, and the like. According to the US National Cholesterol Education Program (NCEP) standard published in 2001, ① waist circumference is 40 inches (102 cm) for men and 35 inches (88 cm) for women. Abdominal obesity; ② triglycerides 150 mg / dL Of the risk factors for HDL cholesterol were 40 mg / dL for men, 50 mg / dL for women, ≥ 130/85 mmHg for blood pressure, and 110 mg / dL for fasting glucose. If three or more are shown, the disease is judged to be a metabolic disease. In Oriental medicine, when the waist circumference is 90 cm for men and 80 cm for women or more, it is somewhat adjusted to abdominal obesity. According to recent research report, about 25% of Koreans have metabolic disease have.

This metabolic disorder is considered to be a major risk factor for chronic long-term high caloric intake. Metabolic efficiency is decreased in the process of excess energy intake, lack of exercise, prolongation of life and aging, and it is known that it deepens the problem of energy overload and shifts to obesity, diabetes and metabolic diseases.

However, because the cause of the disease has not been clarified, the current effect is insignificant, only to alleviate the symptoms or delay the progress of the disease. Therapeutic targets for the development of therapeutic agents have also been presented in various ways.

On the other hand, when NAD ⁺ / NADH and NADP ⁺ / NADPH ratios are reduced in vivo or in vitro, and NADH and NADPH remain as surplus, they are used not only for the fat biosynthesis process, (ROS), it is also a cause of important diseases including inflammatory diseases caused by ROS. For this reason, if the in vivo or in vitro environment can be established to stably maintain the increased NAD ⁺ / NADH and NADP ⁺ / NADPH ratios, the fat content by NAD ⁺ and NADP ⁺ Oxidation and various energy expenditure metabolism can be activated. As a result, if it is possible to activate the action mechanism that keeps the concentration of NAD (P) H constantly low, it is considered that it will be possible to treat various diseases including obesity by inducing exhaustion of excess energy.

Such a method of increasing the concentration and the ratio of the known signal communicator of NAD (P) by a variety of features ⁺ is, first, NAD (P) ⁺ Biosynthesis processes the salvage method for controlling the synthesis process, and second, NAD (P) H (P) ⁺ or its analogs, derivatives, precursors and prodrugs from the outside to activate NAD (P) ^{+ in} vivo by activating the gene or protein of the enzyme using the enzyme as a substrate or coenzyme. A method of increasing the concentration of (P) ⁺ can be considered.

NAD (P) H: quinone oxidoreductase (EC1.6.99.2) is called DT-diaphorase, quinone reductase, menadione reductase, vitamin K reductase or azo-dye reductase. These NQOs are two isoforms: NQO1 And NQO2 (ROM. J. INTERN. MED. 2000-2001, vol. 38-39, 33-50). NQO is a flavoprotein that catalyzes two electron reduction and decontamination of quinone 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, quinone, and reduces the toxicity of chromium. The activity of NQO is present in all tissues, but the activity varies from tissue to tissue. In general, the expression level of NQO was found to be high in tissues such as cancer cell tissue, liver, stomach, and kidney. The gene expression of NQO is induced by xenobiotics, antioxidants, oxidants, heavy metals, ultraviolet rays, radiation and the like. NQO is part of a number of cellular defense mechanisms induced by oxidative stress. Associated expression of genes involved in these defense mechanisms, including NQO, plays a role in protecting cells against oxidative stress, free radicals and neoplasia. NQO has a very broad substrate specificity, and besides quinone, quinone-imines, nitro and azo compounds can be used as substrates.

Among them, NQO1 is mainly distributed in epithelial cells and endothelial cells. This means that it can act as a defense mechanism against compounds absorbed through air, esophagus or blood vessels. Recently, the gene expression of NQO1 has been shown to increase significantly in adipose tissues of people with metabolic diseases. Especially, the expression level of NQO1 was significantly higher in adipocytes with large fat cells. When weight loss was induced through diet, weight loss and proportion of NQO1 expression decreased proportionally. There was a correlation between the amount of mRNA of NQO1 and GOT and GPT, which are known to be related to the degree of fatty liver. Therefore, NQO1 may play a role in obesity-related metabolic diseases when the expression of NQO1 in adipose tissue is correlated with adiposity, glucose tolerance, and liver function index (The Journal of Clinical Endocrinology & Metabolism 92 (6): 2346 2352).

SUMMARY OF THE INVENTION The present invention has been made in view of the above problems, and it is an object of the present invention to solve the technical problems required from the past and the past.

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

It is another object of the present invention to provide a process for preparing such novel compounds.

It is a further object of the present invention to provide a composition for the treatment and prevention of metabolic diseases comprising as active ingredients such novel compounds in a pharmacologically effective amount.

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

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

(1)

(One)

In this formula,

R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, a halogen atom, hydroxy, substituted or unsubstituted C 1 -C 20 alkoxy, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 4 -C 10 aryl, C10 aryloxy, substituted or unsubstituted C2-C10 _{heteroaryl, -NO 2, -NR '1 R} ' 2, -NR '1 (CO (O) R' 2), -NR '1 (C (O) NR _{'1 R' 2), -CO} (O) R '1, -C (O) NR' 1 R '2, -CN, -SO (O) R' 1, -SO (O) NR '1 R' ₂ , -NR ' ₁ (SO (O) R' ₂ ), -CSNR ' ₁ R' ₂ or R ₁ and R ₂ are each a cyclic structure of substituted or unsubstituted C 4 -C 10 aryl, Lt; RTI ID = 0.0 > C2-C10heteroaryl < / RTI >

Wherein R _'1 and R' ₂ each is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryl (CR " ₁ R" ₂ ) m'-C4-C10 aryl, substituted or unsubstituted - (CR " ₁ R" ₂ ) m'-C4-C10heteroaryl or substituted or unsubstituted NR " ₁ R"₂; Wherein R " ₁ and R" ₂ are each independently hydrogen, C1-C3 alkyl, or R " ₁ and R" ₂ are taken together to form a cyclic structure of substituted or unsubstituted C4-C10 aryl Have;

R ₃ is selected from the group consisting of hydrogen, hydroxy, a halogen atom, a substituted or unsubstituted C 1 -C 10 alkyl, a substituted or unsubstituted C 2 -C 20 alkene, a substituted or unsubstituted C 1 -C 20 alkoxy, a substituted or unsubstituted C 3 -C 8 cycloalkyl, 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 -C1-C10 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 - ( _{4 5 R '6) m (} O) COR' 3, -CO (O) R '3, -CONR' 3 R '- CR' 5 R '6) m -OR' (CR 3, substituted or unsubstituted, _{when, -NR '3 R' 4,} -NR '3 (C (O) R' 4), the "a" compound of formula (1) -CH ₂ a, or formula Is -A when the compound of formula (1) is " A ";

Wherein R ' ₃ and R' ₄ each independently represent hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 4 -C 10 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 -C1 -C10 heteroaryl, -CO (O) R '''3, or R' ₃ and R _'4 is a substituted or unsubstituted C4-C10 cyclic structure of a heterocycloalkyl, or a substituted or unsubstituted C1- by the mutual coupling ≪ / RTI > 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 selected from the group consisting of a hydroxy, a nitro group, a halogen element, hydroxy, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 1 -C 10 alkoxycarbonyl, , C3-C8 heterocycloalkyl, C4-C10 aryl, and C5-C10 heteroaryl;

X ₁ , X ₂ , X ₃ and X ₄ are each independently CH or N;

m and m 'are each independently a natural number of 1 to 4; And

The hetero atom is at least one selected from N, O and S.

Unless otherwise specified hereinafter, the compound of formula (I) as the active ingredient of the therapeutic agent may be combined with a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or pharmacological , All of which are to be construed as being included within the scope of the present invention. For convenience of explanation, the compound of the formula (1) may be simply abbreviated herein.

The compound of formula (1) according to the present invention has a novel structure known in the art and, as seen in the following experimental examples, has excellent effects on the treatment and prevention of metabolic diseases through exercise-mimetic effect in vivo .

Specifically, the compound of formula (1) according to the present invention induces NAD (P) H: quinone oxidoreductase (NQO1) as an oxidoreductase to increase the ratio of NAD + / NADH in vivo to increase the ratio of AMP / ATP . The increase of AMP in these cells activates AMPK, which acts as an energy gauge, and promotes fat metabolism by PGC1a expression, which activates energy metabolism in mitochondria, to supplement deficient ATP energy. In addition, increased NAD ⁺ is used as a cofactor of glucose and lipid metabolism enzymes in the body to promote metabolism. CADPR produced by degradation of NAD ⁺ releases Ca ²⁺ from the endoplasmic reticulum (ER) Synergistic activation of the action of the in vivo motion mimetic effect can be obtained.

The terms used herein are briefly described.

The term " pharmaceutically acceptable salt " means a formulation of a compound that 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.

The terms "hydrate", "solvate", "prodrug", "tautomer", "enantiomer or pharmaceutically acceptable diastereomer" have the same meaning as above.

The pharmaceutical salts may be formed with acids which form non-toxic acid addition salts containing a pharmaceutically acceptable anion, for example inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like, tartaric acid, formic acid, Organic carboxylic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and salicinic acid, and organic carboxylic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- Sulfonic acid, sulfonic acid, sulfonic acid, sulfonic acid, sulfonic acid, For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed with lithium, sodium, potassium, calcium, magnesium and the like, amino acid salts such as lysine, arginine and guanidine, dicyclohexylamine, N Organic salts such as methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline and triethylamine, and the like. The compound of formula (1) according to the present invention may be converted into its salt by a conventional method.

The term " hydrate " refers to a compound of the present invention comprising a stoichiometric or non-stoichiometric amount of water combined by non-covalent intermolecular forces Or a salt thereof.

The term " solvate " means a compound of the present invention or a salt thereof, comprising a stoichiometric or non-stoichiometric amount of a solvent bound by noncovalent intermolecular forces. Preferred solvents therefor are volatile, non-toxic, and / or solvents suitable for administration to humans.

The term " prodrug " refers to a substance that is transformed into a parent drug in vivo. Prodrugs are often used in some cases because they are easier to administer than parent drugs. For example, they may achieve viability by oral administration, whereas parent drugs may not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. For example, a prodrug is an ester that facilitates the passage of a cell membrane, which is hydrolyzed to a carboxylic acid that is active by metabolism in a cell whose water solubility is once beneficial, Drug "). ≪ / RTI > Another example of a prodrug may be a short peptide (polyamino acid) that is attached to an acid group that is converted by metabolism so that the peptide reveals its active site.

The term " tautomer " is a type of structural isomer that has the same chemical or molecular formula but has a different configuration of constituent atoms, such as a keto-eno structure, Is changed.

The term " enantiomer or pharmaceutically acceptable diastereomer " refers to an isomer that has the same chemical or molecular formula but is formed as a result of a change in the spatial arrangement of atoms in a molecule. The term " enantiomer "Quot; and " diastereomer " are stereoisomers which are not in mirror image relationship, such as trans form and cis form, and are defined as pharmaceutically acceptable diastereomers in the present invention. All of these isomers and mixtures thereof are also included within the scope of the present invention.

The term " alkyl " means an aliphatic hydrocarbon group. In the present invention, the term "alkyl" refers to a "saturated alkyl" meaning that it does not contain any alkene or alkyne moieties and an "unsaturated alkyl" meaning that the alkyl includes at least one alkene or alkyne moiety. Quot; and " saturated alkyl ", which is used in the concept that includes no alkene or alkyne moiety in detail. The alkyl may include branched, straight, or cyclic, and may also include structural isomers, for example, in the case of C3 alkyl, may mean propyl, isopropyl.

The term " heterocycloalky " refers to a substituent wherein the ring carbon is replaced by oxygen, nitrogen, sulfur, or the like.

The term " aryl " means an aromatic substituent having at least one ring having a covalent pi electron system. The term includes monocyclic or fused ring polycyclic (i.e., rings that divide adjacent pairs of carbon atoms) groups. When substituted, the substituent may be suitably bonded to the ortho (o), meta (m), para (p) positions.

The term " heteroaryl " means 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, in particular fluorine, chlorine, bromine, iodine.

The term " aryloxy " means a group bonded to any one of carbon and oxygen constituting an aromatic substituent. For example, when oxygen is bonded to a phenyl group, -OC ₆ H ₅ , -C ₆ H ₄ -O- As shown in FIG.

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

In a preferred example according to the present invention,

Each of X ₁ and X _{2 is} independently CH, CO or N (R ₃ '); Here, R ₃ 'is hydrogen, or C1-C3 alkyl; And X ₃ and X ₄ may each be CH.

In another example according to the present invention,

Wherein R ₁ and R ₂ are each independently hydrogen, a halogen _{atom, -OCH 3, -OCH 2 CH 3} , -O (CH 2) 2 CH 3, -CH 3, -NO 2, -CN, -NR '1 R ' ₂ , or -OH wherein R' ₁ and R ' ₂ each independently represent hydrogen, C ₁ -C 3 alkyl, substituted or unsubstituted -CH ₂ -C ₄ -C 10 aryl, substituted or unsubstituted -C ₂ H ₄ -C4-C10 aryl, or substituted or unsubstituted C2-C10 heteroaryl, wherein the substituent is a halogen atom).

More specifically,

Wherein R ₁ and R ₂ are each independently hydrogen, Cl, -NO ₂ , -NH ₂ or -NR ' ₁ R' ₂ , wherein R ' ₁ and R' ₂ each independently represent hydrogen, -CH ₂ -C4-C6 and aryl may be the substituent is a halogen atom).

In another example according to the present invention,

R ₃ represents hydrogen, substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, substituted or unsubstituted C4- aryloxy, substituted or unsubstituted C1-C8 heteroaryl group, a 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 -C1-C10 heteroaryl, substituted or unsubstituted _{- (CR '5 R' 6} ) m -C4-C10 heterocycloalkyl, or a substituted or Unsubstituted - (CH ₂ ) _m -NR ' ₅ R'₆;

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

Wherein the substituent is selected from the group consisting of halogen atoms, hydroxy, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C3-C8 heterocyclo Alkyl, C4-C10 aryl, and C5-C10 heteroaryl; A heteroatom is N, O or S; and m may be a natural number of 1 to 4.

More specifically,

R ₃ represents hydrogen, substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, substituted or unsubstituted C4- 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

More specifically,

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

More specifically,

R ₃ can be methyl, isopropyl, t-butyl, phenyl, or neopentyl.

The compound of the above formula (1) may be exemplified as one of the compounds represented by the following, but the following compounds are not intended to limit the present invention.

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

Those of ordinary skill in the art ("those skilled in the art") will be able to prepare the compounds by various methods based on the structure of formula (1), and all of these methods are within the scope of the present invention . That is, within the scope of the present invention, it is possible to prepare the compound of the formula (1) by arbitrarily combining various synthetic methods described in the present specification or disclosed in the prior art. Therefore, the scope of the present invention is not limited thereto.

As an example, the compound of formula (1)

A) reacting a compound of formula (2) with R ₃ COCl or (R ₃ CO) ₂ O;

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

C) cyclizing the compound produced in step B), optionally reacting with an acid, and then carrying out an oxidation reaction; And the like.

(2)

(2)

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

In detail, the step A) may be a step A 'in which the compound of the formula (2) is subjected to halogenation and then R ₃ COCl or (R ₃ CO) ₂ O is reacted.

의 구조식을 가진다. The Lawesson ' s regent is a reagent for introducing sulfur into a compound and is generally known in the art. Specifically,

.

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

As another example, the present invention further provides a process comprising the further step D) of reacting the compound produced in step C) with HNO ₃ to introduce -NO ₂ into the compound produced in step C).

As another example, the present invention further provides a process comprising the further step (E) of introducing -NH ₂ to the compound produced in step D) via hydrogenation of the compound produced in step D) above.

As another example, the present invention relates to a process for the preparation of a compound of formula (I) wherein M is a leaving group, Further comprising the step of introducing -NO ₂ to the compound.

As another example, the present invention provides a process for the preparation of a compound of formula (I), which comprises the additional step G) of reacting the compound produced in step E) with R ₅ CHO wherein R ₅ is a substituted or unsubstituted C 4 -C 6 aryl and the substituent is a halogen element And a method of producing the same.

The details are described in the following embodiments and examples.

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

The term " pharmaceutical composition " means a mixture of compounds of the present invention and other chemical components such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound into the organism. Various techniques exist for administering the compounds, including, but not limited to, oral, injectable, 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-toluenesulfonic acid, salicylic acid and the like.

The term " therapeutically effective amount " means that the amount of the compound administered will alleviate or reduce to some extent one or more symptoms of the disorder being treated, delay the onset of clinical markers or symptoms of the disease in need of prevention, Quot; means the amount of active ingredient that is effective to effect. Thus, a pharmacologically effective amount can be any amount effective to (1) reverse the rate of progression of the disease, (2) to some extent inhibit further progression of the disease, and / or (3) (Preferably, eliminating) the degree of the effect. A pharmacologically effective amount can be determined empirically by testing 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, dimethylsulfoxide (DMSO) is a commonly used carrier that facilitates the introduction of many organic compounds into cells or tissues of an organism.

The term " diluent " is defined as a compound that not only stabilizes the biologically active form of the compound of interest, but also dilutes in water to which the compound is dissolved. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, since it mimics the salt state of the human solution. Since buffer salts can control the pH of the solution at low concentrations, buffer diluents rarely modify the biological activity of the compounds.

The compounds used herein can be administered to a human patient either as such, or as a pharmaceutical composition mixed with other active ingredients, such as in a combination therapy, or with suitable carriers or excipients. A description of the formulation and administration of the compounds in this application can be found in " Remington ' s Pharmaceutical Sciences, " Mack Publishing Co., Easton, PA, 18th edition,

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

The pharmaceutical compositions for use according to the invention thus comprise one or more pharmacologically acceptable excipients which comprise excipients or auxiliaries which facilitate the treatment of the active compounds with pharmaceutically usable formulations Or may be prepared by a conventional method using a carrier. Suitable formulations depend on the route of administration chosen. Any of the known techniques, carriers and excipients may be used as appropriate and as understood in the art, for example, Remingston's Pharmaceutical Sciences, supra. In the present invention, the compound of formula (1) may be formulated into injectable preparations and oral preparations according to the purpose.

For injection, the components of the present invention may be formulated as a liquid solution, preferably a pharmacologically compatible buffer such as a Hank solution, Ringer solution, or physiological saline solution. For mucosal permeation administration, a non-permeabilizing agent suitable for the barrier to be passed is used in the formulation. Such impermeabilizers are generally known in the art.

For oral administration, the compounds can be formulated readily by combining the pharmacologically acceptable carriers known in the art with the active compounds. Such carriers enable 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, capsules, tablets, pills, powders and granules are possible, and in particular, capsules and tablets are useful. Tablets and pills are preferably prepared as preservative. Pharmaceutical preparations for oral use can be prepared by mixing one or two or more compounds of the present invention with one or more excipients, optionally milling such mixture, and if necessary passing the appropriate adjuvant, then treating the mixture of granules Tablets or sugar cores can be obtained. Suitable excipients include fillers such as lactose, sucrose, mannitol, or sorbitol; Corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone PVP), and the like. If necessary, a carrier such as a crosslinking polyvinylpyrrolidone, a starch or a disintegrating agent such as alginic acid or sodium alginate and a lubricant such as magnesium stearate, a binder and the like may be added.

Pharmaceutical preparations which can be used orally may include soft seal capsules made of gelatin and a plasticizer such as glycol or sorbitol, as well as push-fix capsules made of gelatin. Capsules for push-fixing may also contain active ingredients, such as a filler such as lactose, a binder such as starch, and / or a mixture with talc or a lubricant such as magnesium stearate. In soft capsules, the active compounds may be dissolved or dispersed in suitable solvents such as fatty acids, liquid paraffin, or liquid polyethylene glycols. A stabilizer may also be included. All formulations 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. The injectable formulation may be presented in unit dosage form, for example, as an ampoule or a multi-dose container with an added preservative. The compositions may take such forms as suspensions, solutions, emulsions on oily or liquid vehicles, and may also contain components for the formulation, such as suspending, stabilizing and / or dispersing agents.

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

The compounds may also be formulated into rectal administration compositions such as suppositories or rectal enema containing, for example, conventional suppository bases such as cocoa butter or other glycerides.

Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount refers to an amount of a compound that is effective to prolong the survival of an object to be treated or to prevent, alleviate, or alleviate symptoms of the disease. The determination of a therapeutically effective amount is well within the ability of those skilled in the art, particularly in light of the detailed disclosure provided herein.

When formulated in unit dose form, the compound of formula (1) as an 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) will depend upon the physician'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 therapy is usually in the range of about 1 to 1000 mg per day depending on the frequency and intensity of administration. A total dosage of about 1 to 500 mg per day, separated by a single dose when administered intramuscularly or intravenously to an adult, may be sufficient, but in some patients a higher daily dose may be desirable.

In the present invention, the objective disease may be obesity, fatty liver, arteriosclerosis, stroke, myocardial infarction, cardiovascular disease, ischemic disease, diabetes, hyperlipidemia, hypertension, retinopathy or renal failure, Huntington's disease or inflammation, Or a Huntington's disease, but is not limited thereto.

The present invention also relates to a pharmaceutical composition comprising a compound of formula (1) according to claim 1, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof in a pharmacologically effective amount As an effective amount, to treat or prevent a metabolic disease. The term " treatment " as used herein refers to stopping or delaying the progression of a disease when used in an object having an onset symptom. The term " prevention " Delay.

As described above, the novel 1,2-naphthoquinone derivative according to the present invention can enhance the NAD (P) + / NAD (P) H ratio through in vivo NQO1 activity, (AMPK activation of energy consumption, activation of mitochondrial energy metabolism, PGC1a expression, etc.) and long-term calorie restriction and induction of genetic changes during exercise, resulting in mitochondrial biosynthesis due to mitochondrial activation, Since the improvement of the system brings about the exercise mimetic treatment effect which increases the physical activity of the body, the medicines using it as an active ingredient can be usefully used for treating or preventing metabolic diseases.

1 is a graph showing weight gain, weight change, and intake of an obesity mouse (ob / ob) against a compound according to Example 2 of Experimental Example 3 and a control group;
2 is a graph showing weight gain, weight change, and intake of obesity rat (ob / ob) for the compound according to Example 7 of Experimental Example 3-1 and a control group; And
FIG. 3 is a graph showing weight gain, body weight change, and intake of obesity rat (ob / ob) relative to the compound of Example 9 of Experimental Example 3-2 and a control group.

The present invention will be described in detail with reference to the following examples and embodiments, but the scope of the present invention is not limited thereto. In the following, the examples describe methods for synthesizing intermediates for making final compounds, and examples describe methods for synthesizing final compounds using the compounds of the examples.

Example 1 [Synthesis of compound 1]

1-> 2

Pyridine (10 ml) is added to compound 1 (4-amino-1-naphthol hydrochloride, 2.0 g, 10.20 mmol) and then cooled with an ice bath. Tert-Butylacetyl chloride (4.0 ml, 30.60 mmol) is dropwise added. The reaction is stirred at the same temperature for 2.5 hours. The reaction product is quenched with distilled water, and pyridine is removed under reduced pressure. After adding EA and distilled water, adjust the pH to about 6.5 with 1 N HCl solution, and wash the organic layer several times to remove the remaining pyridine. The organic layer is 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%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.88 - 7.84 (m, 1H), 7.80 - 7.75 (m, 2H), 7.49 - 7.46 (m, 3H), 7.19 (d, J = 8.0 Hz, 1H), 2H), 2.34 (s, 2H), 1.21 (s, 9H), 1.15

2-> 3

Compound 2 (500 mg, 1.41 mmol) was dissolved in THF (5 ml) and Lawesson reagent (853 mg, 2.12 mmol) was added. Reactant reacts at 70 degrees for 15 hours. The reaction product is cooled and concentrated under reduced pressure. The concentrated reaction product was purified by silica gel column chromatography to obtain compound 3 ( 428 mg, 82%).

¹ H NMR (300 MHz, CDCl ₃ )? 8.79 (s, NH, 1H), 7.88-7.84 (m, 1H), 7.74-7.71 2H, J = 7.3 Hz, 1H), 2.90 (s, 2H), 2.63

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 and purged with N ₂ . pyridine (2.32 mmol) and DMSO (4 ml), and the mixture is stirred 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 ( 385 mg, yield 90%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.83 (d, J = 8.1 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.67 - 7.57 (m, 3H), 3.07 (s, 2H) , 2.64 (s, 2H), 1.21 (s, 9H), 1.10 (s, 9H)

4-> 5

Compound 4 (100 mg, 0.27 mmol) was dissolved in MeOH (3 ml), hydrazine (0.05 ml, 20% mmol) was added thereto, and the mixture was 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 ( 65 mg, 88%).

^{1 H NMR (300 MHz, CDCl} 3) δ = 8.78 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 7.9 Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.58 ( (t, J = 8.4 Hz, 1H), 7.21 (s, 1H), 3.05 (s, 2H), 1.12

5-> 6

Compound 5 (65 mg, 0.24 mmol) was dissolved in DMF (1.5 ml) and then IBX (157 mg, 0.26 mmol) was added. After reacting at room temperature for 1 hour, add distilled water and EA and extract. The organic layer was treated with MgSO 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, CDCl} 3) δ = 8.21 (d, J = 7.7 Hz, 1H), 8.13 (d, J = 7.7 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H), 7.53 ( t, J = 7.7 Hz, 1H), 3.00 (s, 2H), 1.10 (s, 9H)

LC-MS m / z 286.0 (M + 1)

Example 2 [Synthesis of Compound 2]

1-> 2

Pyridine (5 ml) is added to compound 1 (4-amino-1-naphthol hydrochloride, 500 mg, 2.55 mmol) and then cooled with an ice bath. isobutyric anhydride (1.7 ml, 10.2 mmol) is dropwise added. The reaction is stirred at the same temperature for 2.5 hours. The reaction product is quenched with methanol, and then pyridine is removed under reduced pressure. After adding EA and distilled water, adjust the pH to about 6.5 with 1 N HCl solution, and wash the organic layer several times to remove the remaining pyridine. The organic layer is 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 (686 mg, 90%).

.

2-> 3

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

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

3-> 4

To the dried flask was added 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) and purge with N 2. pyridine (2.32 mmol) and DMSO (4 ml), and the mixture is stirred 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 ( 398 mg, yield 90%).

^{1 H NMR (300 MHz, Acetone} -d 6) δ 8.79 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.64 ( t, J = 8.0 Hz, 1H), 3.50 (heptet, J = 7.0 Hz, 1H), 3.07 (heptet, J = 7.0 Hz, 1H), 1.51 (d, J = 7.0 Hz , 6H), 1.42 (d, J = 7.0 Hz, 6H);

4-> 5

Compound 4 (355 mg, 1.13 mmol) was dissolved in MeOH (5 ml), hydrazine (0.11 ml, 10% mmol) was added thereto, and the mixture was 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%).

^{1 H NMR (300 MHz, Acetone} -d 6) 8.55 (d, J = 8.1 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.44 ( (t, J = 8.4 Hz, 1H), 7.27 (s, 1H), 3.32 (heptet, J = 7.0 Hz, 1H), 1.36 (d, J = 7.0 Hz, 6H);

5-> 6

Compound 5 (100 mg, 0.41 mmol) was dissolved in DMF (2 ml) and then IBX (294 mg, 0.49 mmol) was added. After reacting at room temperature for 2 hours, add distilled water and EA and extract. The organic layer was treated with MgSO 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, CDCl} 3) 8.19 (d, J = 7.5 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 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-1, 2-naphthoquinones

1-> 2

Pyridine (10 ml) is added to compound 1 (4-amino-1-naphthol hydrochloride, 2.0 g, 10.20 mmol) and then cooled with an ice bath. Pivalogy chloride (3.8 ml, 30.60 mmol) is dropwise added. The reaction is stirred at the same temperature for 3 hours. The reaction product is quenched with distilled water, and pyridine is removed under reduced pressure. After adding EA and distilled water, adjust the pH to about 6.5 with 1 N HCl solution, and wash the organic layer several times to remove the remaining pyridine. The organic layer is 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-> 3

Compound 2 (500 mg, 1.53 mmol) was dissolved in THF (5 ml) and Lawesson reagent (927 mg, 2.29 mmol) was added. Reactant reacts at 70 degrees for 15 hours. The reaction product is cooled and concentrated under reduced pressure. The concentrated reaction product is purified by silica gel column chromatography to obtain compound 3 ( 451 mg, 86%).

¹ H NMR (300 MHz, CDCl ₃ )? 8.87 (s, NH, IH), 7.90-7.86 (m, IH), 7.70-7.66 , J = 8.1 Hz, 1 H), 1.56 (s, 9 H), 1.47 (s, 9 H)

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) are placed in a dried flask and purged with N ₂ . pyridine (2.76 mmol) and DMSO (4 ml), and the mixture is stirred 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%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.84 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.66 (t, J = 8.4 Hz, 1H), 7.63 (s , 7.56 (t, J = 8.4 Hz, 1H), 1.56 (s, 9H), 1.50 (s, 9H)

4-> 5

Compound 4 (320 mg, 0.94 mmol) was dissolved in MeOH (5 ml), hydrazine (0.10 ml, 10% mmol) was added thereto, and the mixture was 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 ( 217 mg, 90%)

^{1 H NMR (300 MHz, CD} 3 OD) δ 8.64 (d, J = 8.1 Hz, 1H), 8.28 (d, J = 8.1 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.47 ( t, J = 8.0Hz, 1H), 7.21 (s, 1H), 1.47 (s, 9H)

5)

Compound 5 (170 mg, 0.66 mmol) was dissolved in DMF (3 ml) and then IBX (472 mg, 0.79 mmol) was added. After reacting at room temperature for 2 hours, add distilled water and EA and extract. 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%).

^{1 H NMR (300 MHz, CD3OD} ) δ 8.21 (d, J = 7.5 Hz, 1H), 8.08 (d, J = 7.5 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1 H), 1.53 (s, 9 H)

LC-MS m / z 272.0 (M + 1)

Example 4. [Synthesis of compound 4]

1step:

660 mg of 8- (benzyloxy) -6-bromoquinolin-5-amine is dissolved in 4 ml (0.5 M) of pyridine and then 0.23 ml (1.1 eq.) Of isobutyryl chloride is dropwise added in an ice bath. The reaction is stirred at room temperature for 1 hour. When finished, add EA and wash with H ₂ O 3 times. The EA layer is immediately concentrated under reduced pressure and then filtered with Ether: Hex.

Ivory solid: 676 mg (85%)

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

N- (8- (benzyloxy) -6-bromoquinolin-5-yl) isobutyramide 676 mg dry. After dissolving in toluene, 411 mg (0.6 eq.) Of Lawesson's reagent was added, and the mixture was stirred and refluxed for 1.5 hours. Thioamide and thiazole occur in 7: 3 ratio. When the reaction is complete, concentrate under reduced pressure, and then filter with silicagel.

Crude solid: 690 mg (98%)

Step 3: Preparation of 5- (benzyloxy) -2-isopropylthiazolo [4,5-f] quinoline

A mixture of 890 mg (1.5 eq.) Of Cs ₂ CO ₃ , 30 mg (0.1 eq.) Of 1,10-phenanthroline, 611 mg of CuI Add 17 ml (0.1 M) of DME to the flask containing 16 mg (0.05 eq.) And react at 90 ° for 3 hours. After the reaction is completed, extract with MC, wash with MgSO ₄ , silicagel filter and MC, and finally wash with Hex: EA = 1: 1. The filtrate is concentrated under reduced pressure and recrystallized from ether: hexane to be filtered.

Ivory solid: 540 mg (97%)

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

100 mg of 5- (benzyloxy) -2-isopropylthiazolo [4,5-f] quinoline was dried. Dichloromethane was dissolved in 3 ml (0.1 M), then 1.5 ml (0.2 M) of methanesulfonic acid was dropwise added in an ice bath, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, MC and aq.NaHCO ₃ are added, and the MC layer is separated, and the mixture is treated with MgSO ₄ , filtered, and concentrated under reduced pressure. Filter by recrystallization with Ether: Hex.

solid: 34 mg (45%)

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 9.02 (d, J = 8.4 Hz, 1H), 8.84 (d, J = 4.5 Hz, 1H), 7.61 (dd, J = 8.4 Hz, 4.5 Hz, 1H), 7.55 (s, 1H), 3.53-3.44 (m, 1H), 1.52 (d, J = 6.6 Hz, 6H)

5step:

1.4 ml (0.1 M) of DMF is added to 34 mg of 2-isopropylthiazolo [4,5-f] quinolin-5-ol and 91 mg (1.1 eq.) Of IBX is portionwise weighed. The reaction is stirred at room temperature for 30 minutes. When the reaction is complete, rinse the EA layer several times with aq.NaHCO ₃ in excess of EA. The EA layer is treated with MgSO ₄ , filtered, concentrated under reduced pressure, and recrystallized with ether: Hex.

Yellow solid: 12 mg (33%)

J = 8.1 Hz, 1H), 7.63 (dd, J = 7.8 Hz, 4.5 Hz, 1H), 3.47 (d, J = 3.38 (m, 1 H), 1.51 (d, J = 6.9 Hz, 6 H)

Example 5. [Synthesis of compound 5]

1-> 2

Pyridine (10 ml) is added to compound 1 (4-amino-1-naphthol hydrochloride, 2.0 g, 10.20 mmol) and then cooled with an ice bath. benzoyl chloride (3.6 ml, 30.60 mmol) is dropwise added. The reaction is stirred at the same temperature for 2.5 hours. The reaction product is quenched with distilled water, and pyridine is removed under reduced pressure. After adding EA and distilled water, adjust the pH to about 6.5 with 1 N HCl solution, and wash the organic layer several times to remove the remaining pyridine. The organic layer is 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 (3372 mg, 90%).

2-> 3

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

3-> 4

To the dried flask was added compound 3 (365 mg, 0.95 mmol), FeCl ₃ (15 mg, 0.10 mmol) and Na ₂ S ₂ O ₈ (271 mg, 1.14 mmol) and purge with N 2. pyridine (1.9 mmol) and DMSO (4 ml), and the mixture is stirred 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 ( 368 mg, yield 90%).

4-> 5

Compound 4 (100 mg, 0.23 mmol) was dissolved in MeOH (3 ml), hydrazine (0.05 ml, 20% mmol) was added thereto, and the mixture was 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 ( 54 mg, 85%).

5-> 6

Compound 5 (54 mg, 0.19 mmol) was dissolved in DMF (1.5 ml) and then IBX (145 mg, 0.23 mmol) was added. After reacting at room temperature for 1 hour, add distilled water and EA and extract. 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 to 8]

[Synthesis of Compound 6]

2-isopropylnaphtho [1,2-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, 15.29 mmol) and stir at room temperature for a further 30 min. Pour the reaction solution into ice and wash the solid several times with distilled water. After dissolving the solid with MC, it is dried with MgSO ₄ , filtered and concentrated under reduced pressure. Crude is purified by recrystallization to obtain 2-isopropyl-7-nitronaphtho [1,2-d] thiazole-4,5-dione.

3.14 g (82%)

^{1 H 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 (3.14 g, 10.39 mmol) in methanol (100 ml) and MC (50 ml), add 5% Pd / C (2.2 g, 1.039 mmol) and connect the hydrogen balloon. Stir at room temperature for 1 hour. The reaction solution is filtered through celite, and the filtrate is purified by recrystallization under reduced pressure to obtain 7-amino-2-isopropylnaphtho [1,2-d] thiazole-4,5-dione.

1.75g (62%)

_{1H NMR (300 MHz, CDCl 3} + DMSO small amount) δ 7.92 (d, J = 7.7 Hz, 1H), 7.38 (s, 1H), 6.89 (d, J = 7.3 Hz, 1H), 4.45 (s, 2H) , 3.40-3.30 (m, 1H), 1.47 (d, J = 6.6 Hz, 6H)

[Synthesis of Compound 8]

Compound 7 (76 mg, 0.279 mmol) was added to 1 N HCl (3 ml), and the mixture was stirred in an ice bath for 10 minutes at room temperature. Slowly dropwise a solution of NaNO ₂ (27 mg, 0.391 mmol) in water (0.4 ml). After stirring for an additional 20 minutes, a solution of CuCl ₂ 2H ₂ O (0.24 g, 1.395 mmol) in water (0.7 ml) was added and stirred at 60 ° C for an additional hour. After adding MC and distilled water, extract several times with MC. The separated organic layer is dried with MgSO ₄ , filtered and concentrated under reduced pressure. Crude is purified by silicagel column chromatography and recrystallization to obtain 7-chloro-2-isopropylnaphtho [1,2-d] thiazole-4,5-dione.

34.5 mg (42%)

^{1 H NMR (300 MHz, CDCl} 3) 8.15 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.67 (dd, J = 8.5 Hz,, 2.2 Hz, 1H), 3.45 - 3.36 (m, 1H), 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)을 DMF (100 ml)에 녹인 뒤, K₂CO₃ (11 g, 79.3 mmol)를 넣고 섭씨 80 도로 가열한다. BnBr (6.3 ml, 52.9 mmol)를 넣어 준 후, 같은 온도에서 30 분 더 교반 시킨다. 반응 용액에 NaCl 포화 수용액과 EA를 넣고 추출한다. 분리한 유기층을 MgSO4로 건조시킨 뒤 여과한다. 여과 액은 감압 농축한 뒤, Silica gel filter (MC) 후 재결정 (HX:EA)한다.

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 the mixture is heated to 80 ° C. BnBr (6.3 ml, 52.9 mmol) was added thereto, followed by stirring at the same temperature for 30 minutes. Add NaCl saturated aqueous solution and EA to the reaction solution and extract. The separated organic layer is dried over MgSO4 and filtered. The filtrate is concentrated under reduced pressure and recrystallized (HX: EA) after silica gel filter (MC).

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 Cl (5.9 g, 109.6 mmol) and Fe (9.9 g, 182.6 mmol) were added thereto and refluxed for 2 hours. Add NaCl saturated aqueous solution and EA to the reaction solution and extract. The separated organic layer is dried over MgSO4 and filtered. The filtrate is concentrated under reduced pressure and purified by silica gel column chromatography (HX: EA = 3: 1).

Brown oil 3.9 g (86%)

In the ice bath, dissolve Compound 3 (0.59 g, 2.35 mmol) in MC (47 ml) and slowly add Br ₂ solution (Br ₂ 0.13 ml, 2.45 mmol / MC 9.5 ml). After stirring for 10 minutes, excess Na ₂ S ₂ O ₃ is added and stirring is continued for 10 minutes. Distilled water and MC are added to the reaction solution and extracted. The separated organic layer is dried with MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure, purified by silica gel column chromatography (HX: EA = 7: 1) and recrystallized (HX: Ether).

Brown solid 0.36 g (46%)

Compound 4 (0.26 g, 0.79 mmol) is dissolved in pyridine (1.6 ml, 0.5 M) in an ice bath and then Ac ₂ O (0.1 ml, 0.95 mmol) and Et ₃ N (0.35 ml, 2.38 mmol) are added. After stirring for 20 hours, NaCl saturated aqueous solution and EA are added to the reaction solution and extracted. The separated organic layer is dried with MgSO 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 min. After cooling, the reaction solution is concentrated under reduced pressure. The concentrated solution is purified by silica gel column chromatography and then purified by recrystallization.

Sky-blue solid 0.18 g (77%)

To a flask charged with Compound 6 (0.18 g, 0.45 mmol), Cs ₂ CO ₃ (0.22 g, 0.68 mmol), 1,10-phenanthroline (8.2 mg, 0.045 mmol) and CuI (4.5 mg, 0.023 mmol) ml, 0.1 M), and the mixture is stirred at 90 ° C for 10 minutes. Distilled water and EA are added to the reaction solution and extracted. The separated organic layer is dried with MgSO 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.

conc. HCl (0.5 ml) was slowly added thereto, followed by stirring at 100 ° C for 20 hours. Distilled water and EA are added to the reaction solution and extracted. The separated organic layer is dried with MgSO ₄ and filtered. The concentrated solution was dissolved in DMF (2 ml), and IBX (70 mg, 0.12 mmol) was added thereto. After stirring for 15 minutes, saturated aqueous NaHCO ₃ solution and EA are added and extracted. The separated organic layer is dried over MgSO4 and filtered. The filtrate is concentrated under reduced pressure and purified by recrystallization.

Orange solid 9 mg (41%)

^{1 H NMR (300 MHz, CDCl} 3) δ 8.17-8.11 (m, 2H), 7.71 (t, J = 7.5Hz, 7.7 Hz, 1H) 7.51 (t, J = 6.8 Hz, 8.2 Hz, 1H), 2.86 (s, 3 H)

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 the mixture was stirred at room temperature for 30 minutes. NaBH₃CN (55 mg, 0.881 mmol) were added thereto and stirred for 5 minutes. AcOH (1 ml, 0.65 M) was added thereto. The reaction solution is stirred at the same temperature for 1 hour. Pour the reaction solution into ice. NaHCO₃ Extract with saturated aqueous solution and EA. The separated organic layer was washed with MgSO4₄And dried. The filtrate is concentrated under reduced pressure and purified by recrystallization.

Indigo solid 0.2 g (72%)

^{1 H NMR (300 MHz, DMSO} ) δ 7.74 (d, J = 8.4 Hz, 1H), 7.41-7.36 (m, 2H), 7.25-7.13 (m, 4H), 6.84 (d, J = 8.4 Hz, 1H ), 4.37 (d, J = 5.9 Hz, 2H), 3.40-3.33 (m, 1H), 1.37 (d, J = 6.8 Hz, 6H)

Experimental Example 1: Measurement of NQO1 activity

The enzyme reaction solution contained 25 mM Tris / HCl (pH 7.4), 0.14% bovine serum albumin, 200 uM NADH, 77 uM Cytochrome C and 5 ng of NQO1 protein. The enzyme reaction is initiated with NADH addition and is performed at 37 ° C. At this time, the reaction rate was observed at 550 nm for 10 min that the absorbance was increased by reducing Cytochrome C, and the NQO1 activity was expressed as the amount of reduced cytochrome C [nmol cytochrome C reduced / min / ug protein].

Extinction coefficient for cytochrome C: 21.1 mmol / L / cm = 21.1 [mu] mol / ml / cm

The results are shown in Table 1 below.

compound NQO1 activity (5 uM, [nmol cytochrome C reduced / min / ug protein]). Example 1 (Compound 1) 249.4 Example 2 (Compound 2) 236.2 Example 3 (Compound 3) 222.5 Example 4 (Compound 4) 618.6 Example 5 (Compound 5) 146.4 Example 6 (Compound 6) 351.9 Example 7 (Compound 7) 189.9 Example 8 (Compound 8) 220.9 Example 9 (Compound 9) 201.1 Example 10 (Compound 10) 40.7

As shown in Table 1, the compounds according to the present invention show NQO1 activity.

Experimental Example 2: Measurement of Lactate Change in Cells

Cells are treated with 400 μl 6% PCA and recovered and extracted. Centrifuge (13,000 rpm, 10 min). The precipitate is dried by speed-vac, dried and the cell dry weight is measured. The supernatant is neutralized with 400 μl 1 M KOH and adjusted to a final volume of 1 ml using 0.33 M KH 2 PO 4 / K 2 HPO 4, pH 7.5. Centrifuge (13,000 rpm, 10 min) and measure the amount of lactate (Megazyme, K-LATE) in the supernatant.

The results are shown in Table 2 below.

compound Lactate change in cell
(nmol / mg cell) Example 1 (Compound 1) 5.2 Example 2 (Compound 2) 4.8 Example 3 (Compound 3) 6.0 Example 4 (Compound 4) 8.4 Example 5 (Compound 5) 8.6 Example 6 (Compound 6) 5.3 Example 7 (Compound 7) 5.8 Example 8 (Compound 8) 6.8 Example 9 (Compound 9) 4.6 Example 10 (Compound 10) 6.6

As shown in Table 2, it can be seen that Lactate activity in cells according to the embodiment of the present invention is shown. Since the ratio of NAD / NADH in Cytosol is similar to that of pyruvate / lactate, the ratio of NAD / NADH in the cytosol can be measured with pyruvate / lactate ratio. Therefore, when the amount of lactate decreases, the ratio of NAD / NADH in the cell increases.

Experimental Example 3: Effect of the compound according to Example 2 on weight loss in obese rats (ob / ob)

A 10-week-old C57BL / 6J Lep ob / ob mouse having the characteristics of genetic obesity of ORIENTBIO was prepared and incubated at a temperature of 22-24 ° C, a relative humidity of 50-30%, a light intensity of 150-300 lux, a dark cycle of 12 hours, Two races per breeding box were fed in a polycarbonate breeding box (200 W × 260 L × 130 H (mm), Three-shine) maintained at 15 times / hr. The feed was ORIENTBIO's low fat diet (11.9 kcal% fat, 5053 , Labdiet) were purchased and freely taken. The drinking water was filtered and sterilized by using a water sterilizer, and the purified water was freely taken in a polycarbonate-negative bottle (250 mL).

The compound according to Example 2 synthesized in the present invention was administered once daily for 1 week at a dosage of 150 mg / kg for each of three C57BL / 6J Lep ob / ob mice, using a disposable syringe with a sonde for oral administration ml / kg was administered orally in the stomach. As a control, 0.1% SLS was administered to three C57BL / 6J Lep ob / ob mice at a dose of 150 mg / kg using the same method. The body weight gain was measured according to the administration time and is shown in FIG.

The body weight of the test animals was measured six times a week from the start of administration (immediately before administration of the test substance) 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 at the end of the experiment. Dietary intake was measured twice a week from the beginning of the test substance administration to the end of the test.

As shown in the graph of FIG. 1, the weight gain of the C57BL / 6J Lep ob / ob mice administered with the compound according to Example 2 was significantly decreased as compared with the control.

Experimental Example 3-1: Effect of the compound according to Example 7 on weight loss in obese rats (ob / ob)

C57BL / 6J Lep ob / ob mice with ORIENTBIO genetic obesity characteristics were prepared at a temperature of 22-24 ° C, a relative humidity of 50-30%, a light intensity of 150-300 lux, a dark cycle of 12 hours, Two races per breeding box were fed in a polycarbonate breeding box (200 W × 260 L × 130 H (mm), Three-shine) maintained at 15 times / hr. The feed was ORIENTBIO's low fat diet (11.9 kcal% fat, 5053 , Labdiet) were purchased and freely taken. The drinking water was filtered and sterilized by using a water sterilizer, and the purified water was freely taken in a polycarbonate-negative bottle (250 mL).

The compound according to Example 7 synthesized in the present invention was administered once daily 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 a sonde for oral administration, ml / kg was administered orally in the stomach. As a control, 0.1% SLS was administered to three C57BL / 6J Lep ob / ob mice at a dose of 150 mg / kg using the same method. The body weight gain rate according to the administration time was measured and is shown in FIG.

The body weight of the test animals was measured six times a week from the start of administration (immediately before administration of the test substance) 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 at the end of the experiment. Dietary intake was measured twice a week from the beginning of the test substance administration to the end of the test.

As shown in the graph of FIG. 2, the weight gain of the C57BL / 6J Lep ob / ob mice administered with the compound according to Example 7 was significantly decreased as compared with the control.

Experimental Example 3-2: Effect of the compound according to Example 9 on weight loss in obese rats (ob / ob)

A 10-week-old C57BL / 6J Lep ob / ob mouse having the characteristics of genetic obesity of ORIENTBIO was prepared and incubated at a temperature of 22-24 ° C, a relative humidity of 50-30%, a light intensity of 150-300 lux, a dark cycle of 12 hours, Two races per breeding box were fed in a polycarbonate breeding box (200 W × 260 L × 130 H (mm), Three-shine) maintained at 15 times / hr. The feed was ORIENTBIO's low fat diet (11.9 kcal% fat, 5053 , Labdiet) were purchased and freely taken. The drinking water was filtered and sterilized by using a water sterilizer, and the purified water was freely taken in a polycarbonate-negative bottle (250 mL).

The compound according to Example 9 synthesized in the present invention was administered once daily for 1 day at a dosage of 150 mg / kg for 3 C57BL / 6J Lep ob / ob mice each for 10 days using a disposable syringe with a sonde for oral administration for 10 days. ml / kg was administered orally in the stomach. As a control, 0.1% SLS was administered to three C57BL / 6J Lep ob / ob mice at a dose of 150 mg / kg using the same method. The body weight gain rate according to the administration time was measured and is shown in FIG.

The body weight of the test animals was measured six times a week from the start of administration (immediately before administration of the test substance) 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 at the end of the experiment. Dietary intake was measured twice a week from the beginning of the test substance administration to the end of the test.

As shown in the graph of FIG. 3, the weight gain of the C57BL / 6J Lep ob / ob mice administered with the compound according to Example 9 was significantly decreased as compared with the control.

Claims (19)

A compound represented by the following formula (1), a pharmaceutically acceptable salt, a hydrate, a solvate, a tautomer, an enantiomer or a pharmaceutically acceptable diastereomer thereof:

(One)
In this formula,
R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, a halogen atom, hydroxy, substituted or unsubstituted C 1 -C 20 alkoxy, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 4 -C 10 aryl, C10 aryloxy, substituted or unsubstituted C2-C10 heteroaryl, -NO _2, Lt; ₁ > R < ₂ >
Wherein R _'1 and R' ₂ each is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryl (CR " ₁ R" ₂ ) m'-C4-C10 aryl, substituted or unsubstituted - (CR " ₁ R" ₂ ) m'-C4-C10heteroaryl or substituted or unsubstituted NR " ₁ R"₂; Wherein R " ₁ and R" ₂ each independently represent hydrogen, C1-C3 alkyl, or R " ₁ and R" ₂ may be substituted or unsubstituted C4-C10 aryl structures by mutual bonding;
R ₃ represents hydrogen, substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, substituted or unsubstituted C4- aryloxy, substituted or unsubstituted C1-C8 heteroaryl group, a 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 -C1-C10 heteroaryl, substituted or unsubstituted _{- (CR '5 R' 6} ) m -C4-C10 heterocycloalkyl, or a substituted or Unsubstituted - (CH ₂ ) _m -NR ' ₅ R'₆;
R ' ₅ , and R ' ₆ are each independently hydrogen or C1-C3 alkyl;
Here, the substituent is a halogen element;
X ₁ is CH or N, X ₂ , X ₃ and X ₄ are each independently CH or N;
m and m 'are each independently a natural number of 1 to 4; And
Hetero atoms are selected from N, O and S. delete delete delete delete The method according to claim 1,
R ₃ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, neopentyl, phenyl or phenyl substituted with halogen; A pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof. The method according to claim 1,
R ₃ is methyl, isopropyl, t-butyl, phenyl, or neopentyl; A pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof. The compound according to claim 1, wherein the compound of formula (1) is one of the compounds represented below, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer or pharmacological agent Enantiomerically acceptable diastereomers:

A process for preparing a compound of formula (1) according to claim 1,
A) reacting a compound of formula (2) with R ₃ COCl or (R ₃ CO) ₂ O;
B) reacting the compound produced in step A) with Lawesson's regent; And
C) cyclizing the compound produced in step B), optionally reacting with an acid, and then carrying out an oxidation reaction;
Comprising the steps of:

(2)
Wherein X ₁ to X ₄ and R ₁ to R ₃ are as defined in formula (1) and R ₄ is hydrogen, C 1 -C 4 alkyl, phenyl, benzyl. 10. The method of claim 9, wherein the cyclization reaction comprises reacting with MX.
Here, M is Al, B, Cu, Fe or CN, and X is a halogen element. The method according to claim 9, wherein the step A) is a step A ') in which R ₃ COCl or (R ₃ CO) ₂ O is reacted after halogenating the compound represented by the formula (2) Lt; / RTI > The process according to claim 9, further comprising a step D) of reacting the compound produced in step C) with HNO ₃ to introduce -NO ₂ into the compound produced in step C). 13. The method of claim 12 wherein the method comprises the further step E) to introduce -NH ₂ in the resulting compound from step D) through the hydrogenation of the compound produced in Step D): The process according to claim 13, further comprising a step F) of reacting the compound produced in step E) with M'X 'to introduce -NO ₂ to the compound produced in step E).
Here, M 'is Al, B, Cu, Fe or CN, and X' is a halogen element. 14. A process according to claim 13, further comprising a step G) of reacting the compound produced in step E) with R < ₅ > CHO.
Here, R ₅ is substituted or unsubstituted C 4 -C 6 aryl, and the substituent is a halogen atom. (a) 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; Atherosclerosis, stroke, myocardial infarction, cardiovascular disease, ischemic disease, diabetes, hyperlipidemia, hypertension, hyperlipidemia, hyperlipidemia, hyperlipidemia, hypertension, Retinopathy or renal failure, Huntington ' s disease or an inflammatory disease. delete 17. The pharmaceutical composition according to claim 16, wherein the metabolic disease is fatty liver, diabetes or Huntington's disease. delete

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