KR101864426B1 - 1,2-Naphthoquinone-based Derivatives and and Methods for Preparing them - Google Patents

1,2-Naphthoquinone-based Derivatives and and Methods for Preparing them Download PDF

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KR101864426B1
KR101864426B1 KR1020150043050A KR20150043050A KR101864426B1 KR 101864426 B1 KR101864426 B1 KR 101864426B1 KR 1020150043050 A KR1020150043050 A KR 1020150043050A KR 20150043050 A KR20150043050 A KR 20150043050A KR 101864426 B1 KR101864426 B1 KR 101864426B1
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KR20160116211A (en
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이휘성
이미정
김보정
이강우
노태철
서강식
김진환
민기남
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영진약품 주식회사
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

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Abstract

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

Figure 112015030158489-pat00047
(One)
In the above formula (1), R 1 to R 6 , Q, Q 2 , X 1 to X 6 , and n 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 .

Figure 112015030158489-pat00001
(One)

In this formula,

ROne And R2Are each independently selected from the group consisting of hydrogen, a halogen atom, a substituted or unsubstituted C1-C20 alkoxy, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C4-C10 aryl, a substituted or unsubstituted C4-C10 aryloxy, C2-C10heteroaryl, -NO2, -NR 'OneR '2, -NR 'One(CO (O) R '2), -NR 'One(C (O) NR 'OneR '2), -CO (O) R 'One, -C (O) NR 'OneR '2, -CN, -SO (O) R 'One, -SO (O) NR 'OneR '2, -NR 'One(SO (O) R '2), -CSNR 'OneR '2, Or ROne And R2May form a cyclic structure of substituted or unsubstituted C4-C10 aryl or a substituted or unsubstituted C2-C10 heteroaryl ring structure by mutual bonding,

Wherein R 'OneAnd R '2The Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C1- Heteroaryl, substituted or unsubstituted - (CR "OneR "2) m'-C4-C10 aryl or substituted or unsubstituted NR "OneR "2ego; Where R "One And R "2Are each independently hydrogen, C1-C3 alkyl, or R "One And R "2Lt; / RTI > may form a cyclic structure of substituted or unsubstituted C4-C10 aryl by mutual bonding;

R 3 , R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, a halogen atom, substituted or unsubstituted C 1 -C 9 alkyl, substituted or unsubstituted C 1 -C 20 alkoxy, substituted or unsubstituted C 3 -C 8 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 -C4-C10 heteroaryl, , substituted or unsubstituted - (CR '5 R' 6 ) m -C4-C10 heterocycloalkyl, substituted or unsubstituted - (CR '5 R' 6 ) m -NR '3 R' 4, substituted or unsubstituted - (CR '5 R' 6) m -OR '3, -CO (O) R' 3, -CONR '3 R' 4, -NR '3 R' 4, -NR '3 (C (O) R' 4), -SO (O) R '3, -SO (O) NR' 3 R '4, -NR' 3 (SO (O) R '4), -CSNR' 3 R '4, the general formula (1) when the compound is "a" -CH 2 a, or chemical (1) The compound is -A when the "A"of;

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 - (CH 2) m -C4-C10 aryl, substituted or unsubstituted - (CH 2) m -C4- C10 aryloxy, -CO (O) R '' 3, or R '3 and R' 4 are replaced by cross-coupled Or a cyclic structure of unsubstituted C4-C10 heterocycloalkyl, or a substituted or unsubstituted C4-C10 heteroaryl cyclic structure;

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

When Q 1 is COR 7 and Q 2 is COR 8 , Q 1 and Q 2 form a double bond

Wherein R 7 and R 8 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 20 alkoxy, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 4 -C 10 aryl, substituted or unsubstituted C 4 -C 10 aryloxy, substituted or unsubstituted C2-C10 heteroaryl, -CO (O) R '7 , -C (O) NR' 7 R '8, -SO (O) R' 7, -SO (O) NR '7 R' 8 , -SO 3 R ' 7 , -PO 3 R' 7 , -CSNR ' 7 R' 8 , or R 7 and R 8 are each a cyclic structure of a substituted or unsubstituted C3-C10 heterocycloalkyl, Or an unsubstituted C3-C10 heteroaryl ring structure,

Wherein R 7 and R 8 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 C 4 -C 10 aryloxy , Substituted or unsubstituted C 1 -C 8 heteroaryl, or substituted or unsubstituted - (CR " 7 R" 8 ) m'-C 4 -C 10 aryl; Where R " 7 and R" 8 are each independently hydrogen, C1-C3 alkyl;

When Q 1 is a cyclic structure of a substituted or unsubstituted C3-C5 heterocycloalkyl and Q 2 is CO or when Q 1 is CO and Q 2 is a cyclic structure of a substituted or unsubstituted C3-C5 heterocycloalkyl, Q 1 And Q < 2 > form a single bond

Wherein the substituent is selected from the group consisting of hydroxy, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocyclo Alkyl, C4-C10 aryl, and C2-C10 heteroaryl;

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

The heteroatom is at least one selected from N, O and S;

X 1 , X 2 , X 3 and X 4 are each independently C (H) or N;

X 5 is N or O, X 6 is N, O or S; And

n is 0 or 1, and when n is 0, adjacent carbon atoms thereof form a cyclic structure by direct bonding.

In the above formula

Figure 112015030158489-pat00002
Is a single bond or a double bond,
Figure 112015030158489-pat00003
May not be a single bond or a bond,
Figure 112015030158489-pat00004
Means that the cyclic structure containing it may be aromatic or may not be aromatic.

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 the formula (1) according to the present invention has a novel structure which is not known in the prior art. As can be seen from the following experimental examples, the compound of the formula (1) according to the present invention is excellent in the treatment and prevention of metabolic diseases .

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 above-mentioned "pharmaceutically acceptable salt" means an acid which forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion such as inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, Organic carboxylic acids such as acetic acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and salicinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- Sulfonic acids such as sulfonic acids and the like. 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 " alkene " means a group in which at least two carbon atoms are composed of at least one carbon-carbon double bond, and " alkyne " means that at least two carbon atoms are composed of at least one carbon- Group.

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,

The compound of formula (1) may be a compound of formula (2).

Figure 112015030158489-pat00005
(2)

Wherein R 1 , R 2 , R 4 , R 5 , Q 1 , Q 2 , X 1 , X 2 , X 3 and X 4 are as defined in claim 1.

The compound of formula (2) may be exemplified by the following formula (2-1), but the following compounds do not limit the invention.

Figure 112015030158489-pat00006
(2-1)

In another example according to the present invention,

The compound of formula (1) may be a compound of formula (3) and / or a compound of formula (4).

Figure 112015030158489-pat00007

In this formula,

The ROneTo R4, R6, QOne, Q2XOne, X2, X3, X4,X5And X6Is as defined in claim 1.

In the compound of the above formula (3) and the compound of the formula (4)

In detail, each of R 1 and R 2 is independently H, F, Cl, -N (CH 3 ) 2 , -NHCOCH 3 , or -NHCOC 3 H 5 , X 1 to X 4 are each C ) And X 5 and X 6 may each be N, more specifically, R 1 and R 2 are each H, X 1 to X 4 are each C (H), X 5 and X 6 Respectively.

More specifically, R 3 and R 6 are each independently selected from the group consisting of H, a halogen atom, substituted or unsubstituted C 1 -C 9 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, 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 -C4-C10 heteroaryl, substituted or unsubstituted - (CR '5 R' 6 ) m -C4-C10 heterocycloalkyl, substituted or unsubstituted - (CHR '5) m -NR ' 3 R '4, -CO (O) R '3, -CONR' 3 R ' 4, -NR' 3 R '4, -NR' 3 (C (O) R '4), or the compound of formula (1) "a" when one -CH 2 A;

R4Substituted or unsubstituted C2-C9 alkyl, substituted or unsubstituted C1-C10 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 '5R '6)m-C4-C10 aryl, substituted or unsubstituted - (CR '5R '6)m-C4-C10 aryloxy, substituted or unsubstituted - (CR '5R '6)m-C4-C10heteroaryl, substituted or unsubstituted - (CHR '5)m-NR '3-C4-C10 aryl, substituted or unsubstituted - (CR '5R '6)m-C4-C10heterocycloalkyl, substituted or unsubstituted - (CR '5R '6)m-NR '3R '4, Substituted or unsubstituted - (CR '5R '6)m-OR '3, -NR '3R '4, Or -A when the compound of formula (1) is " A ";

Wherein, R '3, R' 4 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted - (CH 2) m -C4- C10 aryl, Substituted or unsubstituted - (CH 2 ) m -C 4 -C 10 aryloxy, -CO (O) R " 3 , or R ' 3 and R' 4 are substituted or unsubstituted C4-C10 heterocycloalkyl Or a cyclic structure of substituted or unsubstituted C4-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 hydroxy, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocyclo Alkyl, C4-C10 aryl, and C2-C10 heteroaryl;

m is a natural number from 1 to 4; And

The heteroatom may be one or more selected from N, O, and S.

More specifically, R 3 and R 6 are each independently H, a halogen element, or a substituted or unsubstituted C 1 -C 9 alkyl;

R 4 may be a halogen atom, substituted or unsubstituted C 2 -C 9 alkyl.

More specifically, when Q 1 is COR 7 and Q 2 is COR 8 , Q 1 and Q 2 form a double bond

R 7 and R 8 are each independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 4 -C 10 aryl, substituted or unsubstituted C 4 -C 10 aryloxy, substituted or unsubstituted C 2 -C 10 heteroaryl, CO (O) R '7, -C (O) NR' 7 R '8, -SO (O) R' 7, -SO (O) NR '7 R' 8, -SO 3 R '7, -PO 3 R ' 7 , -CSNR' 7 R ' 8 , or R 7 and R 8 are each a cyclic structure of substituted or unsubstituted C3-C10 heterocycloalkyl or a substituted or unsubstituted C3-C10 heteroaryl cyclic structure Structure,

Wherein R 7 and R 8 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 C 4 -C 10 aryloxy , Substituted or unsubstituted C 1 -C 8 heteroaryl, or substituted or unsubstituted - (CR " 7 R" 8 ) m'-C 4 -C 10 aryl; Where R " 7 and R" 8 are each independently hydrogen, C1-C3 alkyl;

When Q 1 is a cyclic structure of substituted or unsubstituted C3 heterocycloalkyl and Q 2 is CO or when Q 1 is CO and Q 2 is a cyclic structure of substituted or unsubstituted C3 heterocycloalkyl, then Q 1 and Q 2 are A single bond

Wherein the substituent is C1-C5;

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

The heteroatom may be one or more selected from N, O, and S.

More specifically, when Q 1 is COR 7 and Q 2 is COR 8 , Q 1 and Q 2 form a double bond

R 7 and R 8 is 7 each independently represent hydrogen, substituted or unsubstituted C1-C6 alkyl, -CO (O) R '7 , -C (O) NR' 7 R 'R 8, -SO (O)', -SO (O) NR '7 R ' 8, -CSNR '7 R' 8, or R 7 and R 8 is a ring structure, or a substituted or unsubstituted, a substituted or unsubstituted C3-C5 heterocycloalkyl by the mutual coupling C3-C5 heteroaryl, < / RTI >

Wherein R '7 and R' 8 each independently represent hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted NR '' R 7 '' and 8; Where R " 7 and R" 8 are each independently hydrogen, C1-C3 alkyl;

When Q 1 is a cyclic structure of an unsubstituted C3 heterocycloalkyl and Q 2 is CO or when Q 1 is CO and Q 2 is a cyclic structure of an unsubstituted C3 heterocycloalkyl, Q 1 and Q 2 form a single bond

The heteroatom may be one or more selected from N, O, and S.

More specifically, the compound of formula (3) and the compound of formula (4) may be exemplified by one or more of the compounds represented below, but the following compounds are not intended to limit the invention.

Figure 112015030158489-pat00008

Figure 112015030158489-pat00009

Figure 112015030158489-pat00010

Figure 112015030158489-pat00011

Figure 112015030158489-pat00012

Figure 112015030158489-pat00013

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 the formula (5) and a compound of the formula (6) in the presence of a base to synthesize a compound of the formula (7);

B) reacting the compound produced in step A) with HNO 3 under acidic conditions to introduce -NO 2 to the compound of formula (7);

C) reduction of the compound produced in step B)2To -NH2;

D) subjecting the compound produced in step C) to a cyclization reaction under acidic conditions;

E) optionally reacting the compound produced in step D) in a basic condition, and then performing an oxidation reaction; And

F) subjecting the compound produced in step E) to a reduction reaction to produce an end product;

. ≪ / RTI >

Figure 112015030158489-pat00014

In this formula,

X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , and R 4 are as defined in claim 1;

Z 'is a halogen atom or R'COO-, in which R' is a ring substituted or unsubstituted, C1-C9 alkyl, substituted or unsubstituted - (CH 2) m -C4-C10 aryl, substituted or unsubstituted - (CH 2) m -C4-C10 aryloxy or substituted or unsubstituted C4-C10 aryl wherein the substituents are selected from the group consisting of hydroxy, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C10 alkoxycarbonyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C4-C10 aryl, and C5-C10 heteroaryl; And

Y is -NH2, -NH3Z Or -NO2, Wherein Z is a halogen element.

-NH 3 Z as defined above may be in a state in which -NH 2 and HZ are coordinated to each other.

In the present invention, the basic condition can be formed using triethylamine, diisopropylethylamine or pyridine, but is not limited thereto.

In the present invention, acid conditions can be formed using nitric acid, sulfuric acid, acetic acid, or acetic anhydride, but are not limited thereto.

In the present invention, the reduction reaction can proceed through, for example, a hydrogenation reaction, and the hydrogenation reaction is a process of reacting hydrogen with a metal catalyst such as Pd / C or Zn, Will be omitted below.

Alternatively, more particularly, the reduction reaction of step F) can be carried out using a reducing agent such as Na 2 S 2 O 4 .

In the present invention, a cyclization reaction means a reaction in which a ring is formed in a reactant.

In the present invention, " optional " means that the corresponding reaction may or may not be included depending on the case.

In the above manufacturing method,

G) The compound produced in step F) above is reacted with R7COOH, R7COCl, (R7)2O, R7COOH, R8COCl, or (R8)2O (provided that the R7And R8Lt; / RTI > are each independently as defined in claim 1) under basic conditions or under a metal catalyst to produce an end product; . ≪ / RTI >

The metal catalyst is not limited as long as it is known in the art and can be, for example, Pd / C, Zn, or the like.

In the above manufacturing method,

H) Compounds generated in step G) above in NR "7R "8C (O) Cl (provided that R "7And R "8Lt; / RTI > are each independently as defined in claim 1) to yield the final product.

NR "' 7 R" 8 C (O) Cl can be specifically dimethyl carbamoyl chloride.

The present invention, as another example,

A process for preparing a compound of formula (1)

A 1 ) synthesizing a compound of the following formula (7) by reacting a compound of the formula (5) and a compound of the formula (6) in a base condition;

B 1 ) introducing -NO 2 to a compound of formula (7) by reacting the compound produced in step A 1 ) with HNO 3 under acid conditions;

COne) Step BOne) Through reduction reaction of -NO2To -NH2;

D 1 ) subjecting the compound formed in step C 1 ) to a cyclization reaction under acidic conditions;

E 1 ) selectively reacting the compound formed in step D 1 ) in a basic condition, and then performing an oxidation reaction; And

F 1 ) subjecting the compound produced in step E 1 ) to a cyclization reaction to produce an end product;

The method comprising the steps of:

The compounds of formulas (5), (6) and (7) are as defined in claim 12.

The cyclization reaction may comprise reacting with CHR 9 R 10 NO 2 or camphorsulfonic acid wherein R 9 and R 10 are each independently selected from the group consisting of hydrogen, C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C10 heteroaryl. ≪ / RTI >

Specifically, in the above formula, R 9 and R 10 each independently may be hydrogen or C 1 -C 10 alkyl, and more specifically may be hydrogen, methyl, ethyl, or propyl.

The present invention, as another example,

A process for preparing a compound of formula (1)

A 2 ) synthesizing a compound of the following formula (7) by reacting a compound of the formula (5) and a compound of the formula (6) in the presence of a base;

B 2 ) introducing -NO 2 to the compound of formula (7) by reacting the compound produced in step A 2 ) with HNO 3 under acidic conditions;

C2) Step B2) Through reduction reaction of -NO2To -NH2;

D 2 ) subjecting the compound produced in step C 2 ) to a cyclization reaction under acidic conditions;

E 2 ) selectively reacting the compound produced in step D 2 ) in a basic condition and then performing an oxidation reaction; And

F 2) (R 3) of the compound produced in Step E 2) 2 O, (R 6) 2 O, R 3 Z '' , or R 6 Z '' (wherein, R 3 and R 6 are each a first And Z " is a halogen element) to produce an end product;

G2) Step F2) Was reacted with R7COOH, R7COCl, (R7)2O, R7COOH, R8COCl, and (R8)2O (provided that the R7And R8Lt; / RTI > are each independently as defined in claim 1) under a metal catalyst to produce an end product; ≪ / RTI >

The compounds of formulas (5), (6) and (7) are as defined in claim 12.

The present invention, as another example,

A process for preparing a compound of formula (1)

A 3 ) synthesizing a compound of the following formula (7) by reacting a compound of the formula (5) and a compound of the formula (6) in a base condition;

B 3 ) introducing -NO 2 to the compound of formula (7) by reacting the compound produced in step A 3 ) with HNO 3 under acidic conditions;

C3) Step B3) Through reduction reaction of -NO2To -NH2;

D 3 ) subjecting the compound produced in step C 3 ) to a cyclization reaction under acid conditions;

E 3 ) selectively reacting the compound formed in step D 3 ) in a basic condition, and then performing an oxidation reaction; And

F 3) (R 3) of the compound produced in Step E 3) 2 O, (R 6) 2 O, R 3 Z '' , or R 6 Z '' (wherein, R 3 and R 6 are each a first And Z " is a halogen element) to produce an end product;

G3) Step F3) Is NR "7R "8C (O) Cl (provided that R "7And R "8Lt; / RTI > are each independently as defined in claim 1) and optionally (R7)2O, (R8)2O (provided that the R7And R8Lt; / RTI > are each independently as defined in claim 1) to produce the final product.

In the above manufacturing method,

H 3 ) a step of subjecting the compound produced in the step G 3 ) to a hydrogenation reduction reaction to produce an end product.

The present invention, as another example,

A process for preparing a compound of formula (1)

A 4 ) reacting a compound of the formula (5) and a compound of the formula (6) in the presence of a base to synthesize a compound of the formula (7);

B 4 ) introducing -NO 2 to the compound of formula (7) by reacting the compound produced in step A 4 ) with HNO 3 under acidic conditions;

C4) Step B4) Through reduction reaction of -NO2To -NH2;

D 4 ) subjecting the compound formed in step C 4 ) to a cyclization reaction under acidic conditions;

E 4 ) selectively reacting the compound formed in step D 4 ) in a basic condition and then performing an oxidation reaction; And

F 4) (R 3) of the compound produced in Step E 4) 2 O, (R 6) 2 O, R 3 Z '' , or R 6 Z '' (wherein, R 3 and R 6 are each a first And Z " is a halogen element) to produce an end product;

G 4 ) reacting the compound produced in the above step F 4 ) with SO 3 and subjecting to a hydrogenation reduction reaction to produce an end product.

The present invention, as another example,

A process for preparing a compound of formula (1)

A 5 ) synthesizing a compound of the following formula (7) by reacting a compound of the formula (5) and a compound of the formula (6) in a base condition;

B 5 ) introducing -NO 2 to the compound of formula (7) by reacting the compound produced in step A 5 ) with HNO 3 under acidic conditions;

C5) Step B5) Through reduction reaction of -NO2To -NH2;

D 5 ) subjecting the compound produced in step C 5 ) to a cyclization reaction under acid conditions;

E 5 ) selectively reacting the compound formed in step D 5 ) in a basic condition, and then performing an oxidation reaction; And

F 5) (R 3) of the compound produced in Step E 5) 2 O, (R 6) 2 O, R 3 Z '' , or R 6 Z '' (wherein, R 3 and R 6 are each a first And Z " is a halogen element) to produce an end product;

G5) Step F5) Was reacted with R7NZ '' 'or R8NZ '" (provided that R7And R8Are each independently as defined in claim 1 and Z '' 'is a halogen element, followed by a hydrogenation-reduction reaction to produce an end product.

After completion of the reaction according to the present invention, separation of a typical mixture can be carried out by conventional post treatment methods such as tube chromatography, recrystallization, HPLC and the like.

The details are described in the following embodiments and experimental examples.

The present invention also provides a pharmaceutical composition comprising (a) a pharmacologically effective amount of a compound of formula (1) above, a 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. 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.

FIG. 1 is a graph showing weight gain, weight change, and intake of obesity rat (ob / ob) for the compound of Example 3 of Experimental Example 3-1 and Example 4 and the 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 3-2 and the compound according to Example 10 and the control;
3 is a graph showing weight gain, weight change, and intake of obesity rat (ob / ob) for the compound according to Example 12 of Experimental Example 3-3 and the compound according to Example 13 and the control;
4 is a graph showing weight gain, weight change, and intake of obesity rat (ob / ob) for the compound according to Example 16 of Experimental Example 3-4 and a control group;
5 is a graph showing the glucose level of the compound according to Example 12 of Experimental Example 4 and the compound according to Example 13 and the diabetic rat (db / db) relative to the control; And
FIG. 6 is a graph showing weight gain, weight change, and intake of diabetic rats (db / db) for the compound according to Example 12 of Experimental Example 5 and the compound according to Example 13 and a control group.

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

Example 1 [Synthesis of compound 1]

Figure 112015030158489-pat00015

1) 1Step

Pyridine (5 ml) is added to compound A (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 then dropwise added. The reaction is stirred at the same temperature for 2.5 hours. The reaction product is quenched with methanol and then concentrated under reduced pressure to remove pyridine. 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 B-1 (686 mg, 90%).

2) 2Step

Add acetic anhydride (3 ml) to the compound B-1 (300 mg, 1.00 mmol) and dropwise dropwise the fuming nitric acid (0.20 ml, 2.00 mmol) at 0 ° C. The reaction is stirred for 1 hour and then filtered. The filtered solids are obtained by washing several times with hexane as compound B-2. compound B-2 (217 mg, 63%).

1 H NMR (300 MHz, Acetone -d 6) δ 9.55 (s, 1H), 8.33 (d, J = 6.6 Hz, 1H), 8.06 (d, J = 6.2 Hz, 1H), 7.86 (s, 1H) J = 7.0 Hz, 6H), 1.25 (d, J = 7.0 Hz, 6H), 7.81-7.73 (m, 2H), 3.16-3.07 )

3) 3Step

After dissolving Compound B-2 (500 mg, 1.45 mmol) in ethanol (5 ml), add Pd / C (50 mg) and Hydrazine (0.29 ml, 5.81 mmol) in this order. The reactants react at 70 ° C for 1 hour. The reaction is cooled to room temperature and celite filtered to remove Pd / C. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B-3 (232 mg, 51%).

1 H NMR (300 MHz, CD 3 OD) δ 8.02 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.13 ( J = 8.1 Hz, 1H), 6.47 (s, 1H), 2.85-2.83 (m,

LC-MS m / z 245.1 (M + 1) <

4) 4Step

Acetic acid (15 ml) was added to Compound B-3 (700 mg, 2.86 mmol), and the mixture was stirred and refluxed for 3 hours. Acetic acid was removed by concentration under reduced pressure and purified by silica gel column chromatography to obtain compound B-4 (575 mg, 89%)

1 H NMR (300 MHz, CD 3 OD) δ 8.30 (d, J = 8.4 Hz, 2H), 7.60 (t, J = 8.0 Hz, 1H), 7.47 (t, J = 8.1 Hz, 1H), 6.99 ( s, 1 H), 3.35-3.28 (m, 1 H), 1.46 (d, J = 7.0 Hz,

LC-MS m / z 227.0 (M + 1) <

5) 5Step

To the compound B-4 (50 mg, 0.22 mmol) is dissolved DMF (2.5 ml) and then IBX (159 mg, 0.26 mmol) is added. The reaction is allowed to react at room temperature for 1 hour. EA is added, and the organic layer is washed with a saturated aqueous NaHCO 3 solution. The separated organic layer was dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain compound B-5 (47 mg, 89%).

1 H NMR (300 MHz, CDCl 3) δ 9.96 (NH, s, 1H), 8.06 (d, J = 7.7 Hz, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.65 (t, J = 7.7 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 3.26-3.17

Figure 112015030158489-pat00016

6) 6Step

Add 6 ml of EA and H 2 O at a ratio of 5: 1 to 300 mg of Compound B-5, add Na 2 S 2 O 4 and stir at room temperature for 3 hours. The reaction solution changes from red to light pink. When the reaction is complete, immediately filter to obtain a solid.

1H NMR (300 MHz, DMSO)? 8.25-8.19 (m, IH), 8.14-8.04 (m, IH), 7.39-7. 31 (m, 2H), 3.14-3.03 d, J = 6.9 Hz, 6H)

Example 2 [Synthesis of Compound 2]

Figure 112015030158489-pat00017

Compound B-5 (0.2 g, 0.832 mmol) was dissolved in ether (17 ml) and H 2 O (4 ml), followed by stirring for 10 minutes. The reaction solution was concentrated under reduced pressure, and then pyridine (8 ml) and Ac 2 O (8 ml) were added thereto and stirred for 24 hours. Add EA and NaHCO 3 saturated aqueous solution to the reaction solution and wash several times. The organic layer was dried over MgSO 4 , filtered, separated by column chromatography and purified by recrystallization

Ivory solid

1 H NMR (300 MHz, CDCl 3) δ 11.15 (br, 2H), 8.15 (d, 1H), 7.72 (d, 1H, J = 8.8 Hz), 7.34 (t, 1H), 7.17 (t, 1H) , 2.83 (s, 3H), 0.99 (d, 6H, J = 5.9 Hz)

Examples 3 and 4. [Synthesis of compounds 3 and 4]

Figure 112015030158489-pat00018

1) 1step (Compound 3):

To SM (500 mg, 2.08 mmol) was added AcOH (0.2 M, 10.4 ml) and the mixture was stirred at 60 占 폚. At this time, Zn (680 mg, 10.405 mmol) was added and the temperature was raised to 100 ° C. Add Ac 2 O at 100 ° C and react for 7 hours. After distillation under reduced pressure, the mixture is diluted with EA, and then washed with an aqueous solution of NaHCO 3 . The EA layer is separated, treated with MgSO 4 and filtered using celite. The filtrate is distilled under reduced pressure and recrystallized with Hex / EA.

White solid: 621 mg (92%)

Compound 3: 1H NMR (300 MHz, CDCl 3) δ 7.86-7.80 (m, 1H), 7.49-7.30 (m, 3H), 7.30-7.18 (m, 1H), 2.49 (s, 3H), 2.23 (s , 3H), 1.36 (d, J = 6.0 Hz, 6H)

2) 2 step (Compound 4):

ACN was added to compound 3 (439 mg, 1.345 mmol), K 2 CO 3 (372 mg, 2.69 mmol) and dimethylcarbamylchloride (320 mg, 2.96 mmol) were added and the mixture was refluxed for 21 hours. After neutralization with Aq.NaHCO 3 , it is extracted with EA. The separated organic layer was dried over MgSO 4 , filtered, distilled under reduced pressure, and subjected to silica gel column chromatography. Finally, the objective compound was obtained by recrystallization from Hex / EA.

Ivory solid: 290 mg (61%)

Compound 4: 1 H NMR: 1 H NMR (300 MHz, DMSO)? 8.42-8.35 (m, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.62 (S, 3H), 2.44 (s, 3H), 1.40 (d, J = 6.6 Hz, 6H)

Example 5. [Synthesis of compound 5]

Figure 112015030158489-pat00019

1) 1step

SM (500 mg, 2.081 mmol) was dissolved in THF (0.2 M, 10 ml), TEA (0.44 ml, 3.121 mmol), Di-tert-butyldicarbonate (0.52 ml, 2.289 mmol) and DMAP , And the mixture is stirred at room temperature for 15 hours. After distillation under reduced pressure, short column (Hex: EA = 5: 1) gave 594 mg (84%) of light orange solid.

Figure 112015030158489-pat00020

2) 2 step

AcOH (1.45 ml, 0.2 M) was added to the product of Step 1 (100 mg, 0.294 mmol) and the mixture was heated to 60 ° C. When the temperature reaches 60 캜, Zn powder (96 mg, 1.47 mmol) is added. After raising the temperature to 120 ° C, Ac 2 O (0.4 ml) was added and the mixture was refluxed with stirring for 7 hours. After neutralizing with Aq.NaHCO 3 , extract with EA. The separated organic layer was dried over MgSO 4 , silicagel filtered with EA, and then distilled under reduced pressure and recrystallized with Hex / EA to obtain the target compound.

White solid: 82 mg, 76%

1 H NMR:

1H NMR (300 MHz, CDCl 3 ) δ 8.17-8.13 (m, 1H), 7.81-7.77 (m, 1H), 7.41-7.36 (m, 2H), 3.26-3.16 (m, 1H), 2.49 (S, 3H), 2.28 (s, 3H), 1.32 (d, J = 5.1 Hz, 6H)

Example 6. [Synthesis of compound 6]

Figure 112015030158489-pat00021

1) 1step:

A SM (0.5 g, 2.08 mmol) dissolved in CH 3 CN (10 ml). K 2 CO 3 (0.9 g, 6.24 mmol) was added thereto, followed by stirring at room temperature for 10 minutes. Benzyl chloroformate (0.36 ml, 1.2 mmol) was added and refluxed for 21 hours. Add EA and distilled water, then wash several times. The separated organic layer is dried with MgSO 4 and filtered. The filtrate is concentrated under reduced pressure and purified by silica gel column chromatography.

Red solid 0.44 g (56%)

1 H NMR (300 MHz, CDCl 3) δ 8.04-8.01 (m, 2H), 7.61 (t, J = 7.7 Hz, 8.2 Hz, 1H), 7.41-7.15 (m, 6H), 5.59 (s, 2H) , 3.08-3.04 (m, 1H), 1.31 (d, J = 6.8 Hz, 6H)

Figure 112015030158489-pat00022

2) Step 2:

To the compound No. 1 (100 mg, 0.267 mmol) was added dry pyridine (1.3 ml, 0.2 M), Zn was added, and the mixture was warmed to 40 ° C. Add pyridine-sulfer trioxide (213 mg, 1.337 mmol) at 40 ° C and stir for 20 minutes. The reaction product is evaporated and subjected to silica gel column chromatography to obtain the target compound. White solid: 110 mg (77%)

3) Step 3:

MeOH (1.6 ml, 0.1 M) and Pd / C were added to the compound No. 2 (89 mg, 0.166 mmol), degassed, and then replaced with H 2 . After stirring at room temperature for 24 hours, celite is filtered. The filtrate is distilled under reduced pressure and then separated by prep TLC to obtain the target compound.

1H NMR (300 MHz, DMSO)? 9.82 (s, IH), 8.28-8.20 (m, IH), 8.03-7.96 (m, IH), 7.42-7.35 Hz, 6H)

Example 7. [Synthesis of Compound 7]

Figure 112015030158489-pat00023

1) 1step:

ACN (6.2 ml, 0.2 M) and K 2 CO 3 (518 mg, 3.747 mmol) were added to SM (300 mg, 1.249 mmol) and the mixture was stirred at room temperature for 15 minutes. Then, PMB-Cl is added, and the mixture is refluxed for 15 hours. The reaction product is extracted with EA after adding water. The separated organic layer was dried over MgSO 4 and the filtrate was concentrated under reduced pressure. Hex / EA to obtain 400 mg (89%) of orange solid.

Figure 112015030158489-pat00024

2) Step 2:

AcOH (0.1 M, 3 ml) and Zn (91 mg, 1.385 mmol) were added to the 1step product (100 mg, 0.277 mmol) and the mixture was stirred at room temperature for 20 minutes. Ac 2 O (1 ml) was added and reacted at 100 ° C for 2 hours. After distillation under reduced pressure, neutralize with EA and NaHCO 3 aqueous solution, and then extract the EA layer. The separated organic layer is treated with MgSO 4 , filtered, and then distilled under reduced pressure to be recrystallized with Hex / EA. 99 mg (80%)

1H NMR (300 MHz, CDCl 3 ) δ 8.69 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.64-7.58 (m, 1H), 7.53-7.47 (m, 1H ), 6.89-6.80 (m, 4H), 5.52 (s, 2H), 3.76 (s, 3H), 3.16-3.12 d, J = 6.9 Hz, 6H)

Example 8 [Synthesis of Compound 8]

Figure 112015030158489-pat00025

1) 1step:

(92 mg, 1.415 mmol), K 2 CO 3 (195 mg, 1.415 mmol) and N, N-dimethylcarbamyl chloride (65 mg, 0.215 mmol) were dissolved in DMF ul, 0.708 mmol), and the mixture was reacted at 80 ° C for 2 hours. The filtrate is neutralized with celite filter, ac.NaHCO3 and extracted with EA. The separated organic layer is dried over MgSO4 and filtered. The filtrate is concentrated under reduced pressure and then separated into a column to obtain a compound. 22 mg (15%)

2 step)

1step insert the product Ac 2 O (0.8 ml, 0.07 M) in (22 mg, 0.053 mmol), stirred and refluxed for 40 minutes. When the reaction is complete, distill off under reduced pressure and neutralize with EA and aq. NaHCO 3 . The separated organic layer was dried with MgSO 4 , filtered, concentrated under reduced pressure, and recrystallized with Hex / EA.

16 mg (67%)

1H NMR (300 MHz, CDCl 3 ) δ 8.67 (d, J = 7.5 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.49 (t, 3H), 3.17-3.12 (m, 1H), 3.05 (s, 2H), 3.75 , 3H), 1.96 (s, 3H), 1.41 (d, J = 6.6 Hz, 6H)

Examples 9 and 10. [Synthesis of compounds 9 and 10]

Figure 112015030158489-pat00026

Compound 9

To SM (100 mg, 0.277 mmol) CHCl 3 put (1.4 ml, 0.2 M), Pyridine (67 ul, 0.831 mmol), N, N-dimethylcarbamyl chloride (77 ul, 0.831 mmol), Zn (181 mg, 2.77 mmol) are added in this order, and the mixture is refluxed for 3 hours. After neutralization with EA and H 2 O, the separated organic layer is dried over MgSO 4 , filtered (silicagel filter), concentrated under reduced pressure, and recrystallized with Hex / EA. 65 mg (46%)

1H NMR (300 MHz, CDCl 3 ) δ 8.66 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.47 (t, (D, J = 9.0 Hz, 2H), 6.75 (s, 3H), 3.19-3.11 (s, 3H), 2.85 (s, 3H), 1.40 (s, J = 6.6 Hz, 6H)

Compound 10

Add MeOH (1 ml, 0.1 M) and MC (0.5 ml, 0.2 M) to compound 9 (50 mg, 0.1 mmol). Put the 20wt% Pd (OH) 2 21 mg (0.03 mmol) and the reaction then replaced with H 2, at room temperature for 2.5 days. After celite filtration, the filtrate is distilled under reduced pressure and short column is obtained. 29 mg (76%)

1H NMR (300 MHz, DMSO)? 8.40-8.28 (m, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.65-7.60 (S, 3H), 2.96 (s, 6H), 1.39 (d, J = 6.9 Hz, 6H)

Example 11 [Synthesis of Compound 11]

Figure 112015030158489-pat00027

1) step1:

Compound 1 (0.2 g, 0.83 mmol) is dissolved in CH 3 CN (8.5 ml). K 2 CO 3 (0.35 g, 2.5 mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes. Iodomethane (65 ul, 1.0 mmol) was added thereto, followed by stirring at 80 ° C for 2 hours. Add EA and distilled water, wash several times. The separated organic layer is dried with MgSO 4 and filtered. The filtrate is concentrated under reduced pressure and purified by silica gel column chromatography.

Red solid 0.13 g (62%)

1 H NMR (300 MHz, CDCl 3) δ 8.00-7.94 (m, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 3.94 (s, 3H) , 3.11-3.06 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H)

Figure 112015030158489-pat00028

2) step2:

AcOH (24 ml) was added to Step 2 product (0.6 g, 2.36 mmol) and Zn (0.8 g, 11.8 mmol) and the mixture was stirred at room temperature for 20 minutes. Add Ac 2 O (2.4 ml) and reflux for 1 hour. Concentrate the reaction solution, add EA and NaHCO 3 saturated aqueous solution and wash several times. The organic layer is dried over MgSO 4 , filtered and purified by recrystallization.

White solid (0.73 g, 92%)

1 H NMR (300 MHz, CDCl 3) δ 8.64 (d, 1H, J = 8.0 Hz), 7.79 (d, 1H, J = 8.4 Hz), 7.56 (t, 1H, J = 7.0 Hz), 7.49 (t , 1H, J = 6.9 Hz) , 3.88 (s, 3H), 3.26-3.21 (m, 1H), 2.47 (s, 3H), 2.44 (s, 3H), 1.47 (d, 6H, J = 7.0 Hz)

Example 12. [Synthesis of compound 12]

Figure 112015030158489-pat00029

SM (0.1 g, 0.42 mmol) was dissolved in Carbonate buffer [Na 2 CO 3 (0.35 g, 3.33 mmol / CH 3 CN: THF: H 2 O = 1: 1: 1, 8.4 ml)], . 2-Nitropropane (0.4 ml, 4.16 mmol) was slowly added thereto, followed by stirring at 55 ° C for 58 hours. Add EA and NaCl saturated aqueous solution and rinse several times. The separated organic layer is dried with MgSO 4 and filtered. The filtrate is concentrated under reduced pressure and purified by silica gel column chromatography.

Ivory solid 21 mg (18%)

1 H NMR (300 MHz, DMSO ) δ 12.86 (br, s, 1H), 8.28 (m, 1H), 7.74-7.71 (m, 1H), 7.41-7.37 (m, 2H), 3.26-3.17 (m, 1H), 1.76 (s, 6H), 1.38 (d, J = 7.0 Hz, 6H)

LC-MS m / z 283.0 (M + 1)

Example 13 [Synthesis of Compound 13]

Figure 112015030158489-pat00030

SM (0.1 g, 0.42 mmol) was dissolved in Carbonate buffer [Na 2 CO 3 (0.35 g, 3.33 mmol / CH 3 CN: THF: H 2 O = 1: 1: 1, 8.4 ml)], . 2-Nitroethane (0.3 ml, 4.16 mmol) was slowly added thereto, followed by stirring at 55 ° C for 15 hours. Add EA and NaCl saturated aqueous solution and rinse several times. The separated organic layer is dried with MgSO 4 and filtered. The filtrate is concentrated under reduced pressure and purified by silica gel column chromatography.

Ivory solid 28 mg (25%)

1 H NMR (300 MHz, DMSO ) δ 12.91 (br, s, 1H), 8.30 (m, 1H), 7.76-7.73 (m, 1H), 7.43-7.40 (m, 2H), 6.56-6.54 (m, J = 7.8 Hz, 3H), 1.38 (d, J = 7.0 Hz, 6H)

LC-MS m / z 269.0 (M + 1) <

Example 14 [Synthesis of Compound 14]

Figure 112015030158489-pat00031

1) 1step:

1.85 ml (0.3 M) of THF and 0.6 ml (1 M) of H 2 O were added to 200 mg (0.555 mmol) of SM, 45 mg (0.139 mmol) of 4 NBr and 511 mg (2.5 mmol) of 85% Na 2 S 2 O 4 , And the mixture is stirred at room temperature. Subsequently, 1.3 ml (0.38 M) of Me 2 SO 4 and 4.5 M NaOH are added in this order and the mixture is stirred at room temperature for 1 hour. After neutralization with EA and H 2 O, the separated organic layer is dried over MgSO 4 , filtered, concentrated under reduced pressure, and then columned. 212 mg (98%)

(M, 2H), 4.25 (s, 2H), 4.06 (s, 2H), 8.04 (d, 1H), 3.87 (s, 3H), 3.25-3.20 (m,

2) Step 2:

To the above material (220 mg, 0.563 mmol) is added MeOH (2.8 ml, 0.2 M). After adding 118 mg of 20 wt% Pd (OH) 2 and replacing with H 2 , react at room temperature for 2.5 days. After celite filtration, the filtrate is distilled under reduced pressure and columned to obtain a compound. 60 mg (39%)

Examples 15 and 16. [Synthesis of compounds 15 and 16]

Figure 112015030158489-pat00032

3.5 ml of Glycol: MeOH was added to SM (150 mg, 0.624 mmol) and camphorsulfonic acid (22 mg, 0.094 mmol) and the mixture was reacted at 120 ° C for 6 hours. The reaction product is distilled under reduced pressure and then columned.

Compound 15: 18 mg (11%)

7.58 (d, J = 7.5 Hz, 1H), 7.46-7.34 (m, 2H), 4.58 (m, 2H) 1H), 1.44 (d, J = 6.9 Hz, 6H), 4.40 (m, 2H), 4.43-4.40

Compound 16: 15 mg (8.5%)

1H NMR (300 MHz, CDCl3) [delta] 7.93 (d, J = 6.9 Hz, IH), 7.74 (brs, IH), 7.57-7.50 (m, IH), 7.28-7.19 2H), 4.28 (s, 2H), 3.18-3.13 (m, IH), 1.36 (d, J = 6.9 Hz,

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 enzymatic reaction is initiated by the addition of NADH and 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) 214.8 Example 2 (Compound 2) 142.5 Example 3 (Compound 3) 20.3 Example 4 (Compound 4) 27.3 Example 5 (Compound 5) 5.8 Example 6 (Compound 6) 111.5 Example 7 (Compound 7) 6.1 Example 8 (Compound 8) 4.5 Example 9 (Compound 9) 5.7 Example 10 (Compound 10) 6.5 Example 11 (Compound 11) 6.3 Example 12 (Compound 12) 7.8 Example 13 (Compound 13) 9.6 Example 14 (Compound 14) 4.5 Example 15 (Compound 15) 5.4 Example 16 (Compound 16) 40.9

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 using 400 μl 1 M KOH, and the final volume is adjusted to 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) 6.8 Example 2 (Compound 2) 6.8 Example 3 (Compound 3) 7.8 Example 4 (Compound 4) 7.8 Example 5 (Compound 5) 6.9 Example 6 (Compound 6) 10.1 Example 7 (Compound 7) 9.1 Example 8 (Compound 8) 11.1 Example 9 (Compound 9) 10.1 Example 10 (Compound 10) 9.5 Example 11 (Compound 11) 8.1 Example 12 (Compound 12) 9.2 Example 13 (Compound 13) 9.6 Example 14 (Compound 14) 10.1 Example 15 (Compound 15) 6.8 Example 16 (Compound 16) 7.1

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 3-1: Effect of the compound according to Example 3 and the compound according to Example 4 on weight loss in obese rats (ob / ob)

A 10-week-old C57BL / 6J Lep ob / ob mouse with ORIENTBIO genetic obesity characteristics was prepared and incubated at 20-24 ° C, 35-65% relative humidity, 150-300 lux, 12- 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, USA) 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 3 synthesized in the present invention and the compound according to Example 4 were administered to three C57BL / 6J Lep ob / ob mice at a dose of 100 mg / kg once a day for a total of 1 week for oral administration. Orally in the stomach using an attached disposable syringe. As a control, 0.1% SLS (Sodium Lauryl Sulfate) was administered to three C57BL / 6J Lep ob / ob mice at a dose of 10 mg / kg for 2 weeks using the same method. The body weight gain, weight change, and intake amount according to the administration time were measured and are shown in FIG.

The body weight of the test animals was measured at the time of group separation (immediately before administration of the test substance) and from the start of administration to the end of the test, and the total weight gain was calculated by subtracting body weight at the start of the experiment from the body weight measured before the end. 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, weight gain and body weight change of C57BL / 6J Lep ob / ob mice administered with the compound according to Example 3 and the compound according to Example 4, respectively, , And the intake of C57BL / 6J Lep ob / ob mice after 7 days of administration of the compound according to Example 3 was significantly decreased as compared with the control group.

EXPERIMENTAL EXAMPLE 3-2: Weight loss effect on the compound according to Example 7 and the compound according to Example 10 in obese rats (ob / ob)

6.5 weeks of C57BL / 6J Lep ob / ob mice having the genetic obesity characteristics of ORIENTBIO were prepared , and the compound according to Example 7 and the compound according to Example 10 were administered to three C57BL / 6J Lep ob / ob mice mg / kg, and the control group was administered with 10 mg / kg of 0.1% SLS to 3 C57BL / 6J Lep ob / ob mice for a total of 1 week, Weight change, body weight change and intake amount according to the administration time were measured, and the results are shown in FIG.

As shown in the graph of FIG. 2, weight gain and body weight change of the C57BL / 6J Lep ob / ob mice administered with the compound according to Example 7 and the compound according to Example 10, respectively, It can be seen that it is significantly reduced in comparison with the conventional method.

Experimental Example 3-3: Effect of the compound according to Example 12 and the compound according to Example 13 on weight loss in obese rats (ob / ob)

6.5 weeks of a C57BL / 6J Lep ob / ob mouse having the genetic obesity characteristic of ORIENTBIO were prepared , and the compound according to Example 12 and the compound according to Example 13 were administered to three C57BL / 6J Lep ob / ob mice mg / kg, and the control group was administered with 10 mg / kg of 0.1% SLS to 3 C57BL / 6J Lep ob / ob mice for 6 days in total. Weight change, body weight change, and intake amount according to the administration time were measured, and the results are shown in FIG.

As shown in the graph of FIG. 3, weight gain, body weight change, and intake after six days of C57BL / 6J Lep ob / ob mice administered with the compound according to Example 12 and the compound according to Example 13, Compared with the control group.

Experimental Example 3-4: Weight loss effect on obesity rat (ob / ob) on the compound according to Example 16

6.5 weeks of a C57BL / 6J Lep ob / ob mouse having the genetic obesity characteristic of ORIENTBIO was prepared and 100 mg / kg of the compound according to Example 16 was administered to each of three C57BL / 6J Lep ob / ob mice, As a control group, experiments were carried out under the same conditions as in Experimental Example 3-1 except that 10 mice / kg of 0.1% SLS was administered to 3 C57BL / 6J Lep ob / ob mice for a total of 14 days, Weight change, body weight change and intake amount were measured and are shown in Fig.

As shown in the graph of FIG. 4, weight gain, body weight change and ingestion of C57BL / 6J Lep ob / ob mice administered with the compound according to Example 16 were significantly decreased in some sections compared with the control group Able to know.

Experimental Example 4: Glucose level measurement in diabetic rat (db / db) for the compound according to Example 12 and the compound according to Example 13

C57BLKS / 6 db / db mouse with ORIENTBIO genetic obesity characteristics was prepared for 10 weeks. Temperature was 22 ~ 24 degree, relative humidity was 50 ~ 30%, illumination was 150 ~ 300 lux, Two races per breeding box were fed in a polycarbonate breeding box (200W × 260L × 130H (mm), Three-shine) kept in breeding environment per hour / hr. The feeds were ORIENTBIO's low fat diet (11.9 kcal% fat, 5053, Labdiet) was purchased and freely taken. The drinking water was filtered and sterilized using a filter sterilizer and water sterilized in a polycarbonate water bottle (250 mL) for free consumption.

The compound according to Example 12 synthesized in the present invention and the compound according to Example 13 were respectively administered to three C57BLKS / 6 db / db mice at a dose of 80 mg / kg using a sonde-attached disposable syringe for oral administration Orally in the stomach. As a control group, 0.1% SLS was administered to three C57BLKS / 6 db / db mice at a dose of 10 mg / kg using the same method. Glucose levels were measured for 14 days and are shown in FIG.

As shown in the graph of FIG. 5, it can be seen that the glucose level of C57BLKS / 6 db / db mice administered with the compound according to Example 12 and the compound according to Example 13, respectively, was significantly decreased as compared with the control group.

Experimental Example 5: Weight loss effect in the diabetic rat (db / db) on the compound according to Example 12 and the compound according to Example 13

C57BLKS / 6 db / db mice with ORIENTBIO genetic diabetes characteristics were prepared at a temperature of 22 to 24 ° C, relative humidity of 50 to 30%, illumination of 150 to 300 lux, light intensity of 12 hours, Two races per breeding box were fed in a polycarbonate breeding box (200W × 260L × 130H (mm), Three-shine) kept in breeding environment per hour / hr. The feeds were ORIENTBIO's low fat diet (11.9 kcal% fat, 5053, Labdiet) was purchased and freely taken. The drinking water was filtered and sterilized using a filter sterilizer and water sterilized in a polycarbonate water bottle (250 mL) for free consumption.

The compound according to Example 12 and the compound according to Example 13 synthesized in the present invention were administered to each of three C57BLKS / 6 db / db mice at a dose of 80 mg / kg for 14 days, and the control group was C57BLKS / 6 db / db mice were administered with 10 mg / kg of 0.1% SLS at a dose of 0.1 mg / kg. The experiment was conducted under the same conditions as in Experimental Example 3-1 except that the weight gain, weight change and intake And the results are shown in Fig.

The body weight of the test animals was measured at the time of group separation (immediately before administration of the test substance) and from the start of administration to the end of the test, and the total weight gain was calculated by subtracting body weight at the start of the experiment from the body weight measured before the end. Dietary intake was measured by feeding amount and residual amount from the beginning of the test substance to the end of the test.

As shown in the graph of FIG. 6, the weight gain, body weight change and ingestion of C57BLKS / 6 db / db mice to which the compound according to Example 12 and the compound according to Example 13, respectively, And a significant decrease in the interval.

Claims (26)

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
Figure 112018041754554-pat00033
(One)
In this formula,
R 1 and R 2 are each independently hydrogen;
R 3 is hydrogen or -C (O) -C1 to C3 alkyl;
R 4 is C1-C4 alkyl;
R < 6 > is hydrogen, C1-C3 alkyloxybenzyl or C1-C3 alkyl;
When Q 1 is COR 7 and Q 2 is COR 8 , Q 1 and Q 2 form a double bond
Wherein R 7 and R 8 are each independently hydrogen, -C (O) C1-C3-alkyl, -SO 3 H, -C (O ) N (C1-C3 alkyl) 2, or R 7 and R 8 are mutually coupled Substituted or unsubstituted dioxolane or dioxane by C1-C3 alkyl,
X 1 , X 2 , X 3 and X 4 are each independently C (H);
X 5 is N, X 6 is N; And
n is 0, and adjacent carbon atoms thereof form a cyclic structure by direct bonding; And
Figure 112018041754554-pat00054
Is a single bond or a double bond,
Figure 112018041754554-pat00055
May not be a single bond or a bond,
Figure 112018041754554-pat00056
Means that the cyclic structure containing it may be aromatic or may not be aromatic. The compound according to claim 1, wherein the compound of formula (1) is a compound of formula (2): wherein R 1 is hydrogen or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer, Acceptable diastereomers:
Figure 112018041754554-pat00037
(2)
Wherein R 1 , R 2 , R 4 , R 5 , Q 1 , Q 2 , X 1 , X 2 , X 3 and X 4 are as defined in claim 1. delete The compound of claim 1, wherein the compound of formula (1) is a compound of formula (3), a compound of formula (4), or a combination thereof, a pharmaceutically acceptable salt, Solvate, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof:
Figure 112018041754554-pat00039
In this formula,
Wherein R 1 to R 4 , R 6, Q 1 , Q 2, X 1 , X 2 , X 3, X 4, X 5 and X 6 are as defined in claim 1. delete delete delete delete delete delete 5. A compound according to claim 4, wherein the compound of formula (3) or the compound of formula (4) is one of the compounds represented by the following formulas, a pharmaceutically acceptable salt, hydrate, solvate, Tautomers, enantiomers or pharmaceutically acceptable diastereomers:
Figure 112018041754554-pat00040

Figure 112018041754554-pat00041

Figure 112018041754554-pat00042

Figure 112018041754554-pat00043

Figure 112018041754554-pat00044

Figure 112018041754554-pat00045
 A process for preparing a compound of formula (1) according to claim 1,
A) reacting a compound of the formula (5) and a compound of the formula (6) in the presence of a base to synthesize a compound of the formula (7);
B) reacting the compound produced in step A) with HNO 3 under acidic conditions to introduce -NO 2 to the compound of formula (7);
C) Step B) the step of reducing the -NO 2 through a reduction reaction of the resulting compound with -NH 2 at;
D) subjecting the compound produced in step C) to a cyclization reaction under acidic conditions;
E) optionally reacting the compound produced in step D) in a basic condition, and then performing an oxidation reaction; And
F) subjecting the compound produced in step E) to a reduction reaction to produce an end product;
Comprising the steps of:
Figure 112018041754554-pat00046

In this formula,
X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , and R 4 are as defined in claim 1;
Z 'is a halogen atom or R'COO-, in which R' is a ring substituted or unsubstituted, C1-C9 alkyl, substituted or unsubstituted - (CH 2) m -C4-C10 aryl, substituted or unsubstituted - (CH 2) m -C4-C10 aryloxy or substituted or unsubstituted C4-C10 aryl wherein the substituents are selected from the group consisting of hydroxy, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C10 alkoxycarbonyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C4-C10 aryl, and C5-C10 heteroaryl;
Y is -NH 2, -NH 3, or Z is -NO 2, where Z is a halogen atom;
and m is a natural number of 1 to 4. The method according to claim 12, wherein the reduction reaction in step F) comprises reacting at least one reducing agent selected from the group consisting of Na 2 S 2 O 4 , Zn and Fe. 13. The method of claim 12,
G) The compound produced in step F) above is reacted with R7COOH, R7COCl, (R7)2O, R8COOH, R8COCl, or (R8)2O (provided that the R7And R8Lt; / RTI > are each independently as defined in claim 1) under basic conditions or under a metal catalyst to produce an end product; ≪ / RTI > 15. The method of claim 14,
H) Compounds generated in step G) above in NR "7R "8C (O) Cl (provided that R "7And R "8Lt; / RTI > are each independently as defined in claim 1) to produce the final product. A process for preparing a compound of formula (1) according to claim 1,
AOneReacting a compound of the formula (5) with a compound of the formula (6) in the presence of a base to synthesize a compound of the formula (7);
BOne) Step AOne) And HNO < RTI ID = 0.0 >3Is reacted under acidic conditions to give the compound of formula (7)2;
COne) Step BOne) Through reduction reaction of -NO2To -NH2;
DOne) Step COneA) cyclizing the compound formed in step a) under acidic conditions;
EOne) Step DOneReacting the compound produced in the step (a) with a base in an optional base, and then performing an oxidation reaction; And
FOne) Step EOne) Cyclizing the resulting compound to produce an end product;
Comprising the steps of:
The compounds of formulas (5), (6) and (7) are as defined in claim 12. The method of claim 16, wherein the cyclization reaction comprises reacting with CHR 9 R 10 NO 2 or camphorsulfonic acid.
Wherein R 9 and R 10 are each independently selected from the group consisting of hydrogen, hydroxy, halogen element, 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, C 3 -C 10 alkoxycarbonyl C8 cycloalkyl, C2-C8 heterocycloalkyl, C4-C10 aryl, and C2-C10 heteroaryl. A process for preparing a compound of formula (1) according to claim 1,
A 2 ) synthesizing a compound of the following formula (7) by reacting a compound of the formula (5) and a compound of the formula (6) in the presence of a base;
B 2 ) introducing -NO 2 to the compound of formula (7) by reacting the compound produced in step A 2 ) with HNO 3 under acidic conditions;
C 2 ) reducing -NO 2 to -NH 2 through reduction reaction of the compound produced in step B 2 );
D 2 ) subjecting the compound produced in step C 2 ) to a cyclization reaction under acidic conditions;
E 2 ) selectively reacting the compound produced in step D 2 ) in a basic condition and then performing an oxidation reaction; And
F 2) (R 3) of the compound produced in Step E 2) 2 O, (R 6) 2 O, R 3 Z '' , or R 6 Z '' (wherein, R 3 and R 6 are each a first And Z " is a halogen element) to produce an end product;
G 2) The compound produced in Step F 2) R 7 COOH, R 7 COCl, (R 7) 2 O, R 8 COOH, R 8 COCl, and (R 8) 2 O (provided that said R 7, and And R < 8 > are each independently as defined in claim 1, under a metal catalyst to produce an end product; Comprising the steps of:
The compounds of formulas (5), (6) and (7) are as defined in claim 12. A process for preparing a compound of formula (1) according to claim 1,
A 3 ) synthesizing a compound of the following formula (7) by reacting a compound of the formula (5) and a compound of the formula (6) in a base condition;
B 3 ) introducing -NO 2 to the compound of formula (7) by reacting the compound produced in step A 3 ) with HNO 3 under acidic conditions;
C 3 ) reducing -NO 2 to -NH 2 through a reduction reaction of the compound produced in step B 3 );
D 3 ) subjecting the compound produced in step C 3 ) to a cyclization reaction under acid conditions;
E 3 ) selectively reacting the compound formed in step D 3 ) in a basic condition, and then performing an oxidation reaction; And
F 3) (R 3) of the compound produced in Step E 3) 2 O, (R 6) 2 O, R 3 Z '' , or R 6 Z '' (wherein, R 3 and R 6 are each a first And Z " is a halogen element) to produce an end product;
G 3 ) The compound produced in step F 3 ) above is reacted with NR " 7 R" 8 C (O) Cl, wherein R " 7 and R 8 " are each independently as defined in claim 1 ) And optionally reacting with (R 7 ) 2 O, or (R 8 ) 2 O, wherein R 7 and R 8 are each independently as defined in claim 1, ; ≪ / RTI >
The compounds of formulas (5), (6) and (7) are as defined in claim 12. 20. The method of claim 19,
H 3 ) a step of subjecting the compound formed in the step G 3 ) to a hydrogenation reduction reaction to produce an end product. A process for preparing a compound of formula (1) according to claim 1,
A 4 ) reacting a compound of the formula (5) and a compound of the formula (6) in the presence of a base to synthesize a compound of the formula (7);
B 4 ) introducing -NO 2 to the compound of formula (7) by reacting the compound produced in step A 4 ) with HNO 3 under acidic conditions;
C 4 ) reducing -NO 2 to -NH 2 through reduction of the compound produced in step B 4 );
D 4 ) subjecting the compound formed in step C 4 ) to a cyclization reaction under acidic conditions;
E 4 ) selectively reacting the compound formed in step D 4 ) in a basic condition and then performing an oxidation reaction; And
F 4) (R 3) of the compound produced in Step E 4) 2 O, (R 6) 2 O, R 3 Z '' , or R 6 Z '' (wherein, R 3 and R 6 are each a first And Z " is a halogen element) to produce an end product;
G 4 ) reacting the compound produced in the above step F 4 ) with SO 3 and subjecting to a hydrogenation reduction reaction to produce an end product; and
The compounds of formulas (5), (6) and (7) are as defined in claim 12. A process for preparing a compound of formula (1) according to claim 1,
A 5 ) synthesizing a compound of the following formula (7) by reacting a compound of the formula (5) and a compound of the formula (6) in a base condition;
B 5 ) introducing -NO 2 to the compound of formula (7) by reacting the compound produced in step A 5 ) with HNO 3 under acidic conditions;
C 5 ) reducing -NO 2 to -NH 2 through reduction of the compound formed in step B 5 );
D 5 ) subjecting the compound produced in step C 5 ) to a cyclization reaction under acid conditions;
E 5 ) selectively reacting the compound formed in step D 5 ) in a basic condition, and then performing an oxidation reaction; And
F 5) (R 3) of the compound produced in Step E 5) 2 O, (R 6) 2 O, R 3 Z '' , or R 6 Z '' (wherein, R 3 and R 6 are each a first And Z " is a halogen element) to produce an end product;
G 5) The compound produced in Step F 5) R 7 Z '' ', R 8 Z''', (R 7) 2 SO 4 or (R 8) 2 SO 4 (However, the R 7 and R 8 are each independently as defined in claim 1, and Z '''is a halogen element, followed by a hydrogenation reduction reaction to produce an end product.
The compounds of formulas (5), (6) and (7) are as defined in claim 12. (a) a pharmacologically effective amount of a compound of formula (1) according to claim 1, its pharmaceutically acceptable salts, hydrates, solvates, tautomers, enantiomers, pharmaceutically acceptable diastereoisomers, Combination; And (b) a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof. The pharmaceutical composition for treating or preventing a metabolic disease,
Wherein the metabolic disease is obesity, fatty liver or diabetes. delete delete delete
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