KR101711732B1 - 3-Aryl-1,2,4-triazole derivatives and use thereof - Google Patents

Abstract

The present invention relates to a 3-aryl-1,2,4-triazole derivative compound and a compound used as a prophylactic and therapeutic agent for diabetes mellitus or diabetic complication using the selective inhibitory activity of PDK (pyruvate dehydrogenase kinase) And the like. The 3-aryl-1,2,4-triazole derivative compounds of the present invention are useful for the treatment of diseases associated with the PDK4 (Pyruvate dehydrogenase Kinase 4) enzyme such as type 1 and type 2 diabetes, adult type latent autoimmune diabetes (LADA) Diabetic microvascular complications (retinopathy, neuropathy, nephropathy), diabetic macrovascular complications (cardiovascular disease, cerebrovascular disease, peripheral vascular disease), morbidity and mortality, Is useful as an agent for the prevention, control and treatment of vascular calcification and atherosclerosis.

Description

3-Aryl-1,2,4-triazole derivatives and their uses {3-Aryl-1,2,4-triazole derivatives and use thereof [

The present invention relates to 3-aryl-1,2,4-triazole derivatives and their use. More specifically, it relates to novel compounds which exhibit an inhibitory effect on selective activity against PDK (pyruvate dehydrogenase kinase) -1,2,4-triazole derivatives and pharmaceutically acceptable salts thereof, and to a pharmaceutical composition for preventing or treating diabetes and diabetic complications containing the same as an active ingredient.

The pyruvate dehydrogenase complex (PDC) present in the mitochondria is important for controlling blood glucose levels in fasting and feeding situations. The activity of PDC increases in the feeding state, resulting in the production of NADH and acetyl-CoA via the oxidative decarboxylation of pyruvic acid. The acetyl-CoA thus produced enters the Krebs cycle and is oxidized and used for the synthesis of fatty acids and cholesterol. On the other hand, in the fasting state, activity of PDC decreases, and lactate, alanine (alanine) and pyruvate, which are precursors of glucose, are preserved and your life is increased.

PDC activity is reduced by phosphorylation of pyruvate dehydrogenase kinase (PDK) mediated pyruvate dehydrogenase and increased by pyruvate dehydrogenase phosphatase (PDP). PDK4 has been shown to have four isoenzymes ranging from PDK1 to PDK4, and it is known that PDK4 is the most sensitive in the fasting state (Wu et al. Arch Biochem Biophys 2000 Sep 1; 381 (1) : 1-7).

PDK4 has been shown to increase not only in fasting but also in diabetic state, especially in PDK4-deficient mouse models (PDK4 knock-out mice). We also confirmed that lactate, alanine, and pyruvate, which are precursors of glucose, are reduced in the same animal model. In PDK4-deficient rats, the activity of PDC is increased and the oxidation of pyruvic acid to acetylcholine is increased, resulting in a decrease in blood glucose.

In PDK4 - deficient mouse model, PDK4 inhibition was proved to be effective in obesity by lowering body weight gain by low fat diet and decreasing body fat increase as compared with control group.

Unlike PDK4, which is mainly expressed in smooth muscle and cardiac muscle, PDK2 is expressed uniformly in various tissues of the body. In the fasting and diabetic state, expression is particularly increased in liver and kidney, and when PDK2 is deleted in mouse, it is similar to PDK4 deficient rat , Fasting blood glucose decreased, insulin sensitivity increased, and body weight and body fat gain decreased.

Accordingly, the present inventors have searched for a compound having selective inhibitory activity against PDK, particularly PDK4 enzyme, for the purpose of controlling or treating metabolic syndrome diseases such as obesity and diabetes. As a result, the novel 3-aryl- -Triazole derivatives, and confirmed that these novel compounds exhibit selective inhibitory activity of the PDK4 enzyme. Thus, the present invention has been completed.

It is an object of the present invention to provide 3-aryl-1,2,4-triazole derivative compounds and pharmaceutically acceptable salts thereof using organic synthesis techniques.

Another object of the present invention is to provide a composition for the prophylaxis or treatment of diabetes and diabetic complications using a 3-aryl-1,2,4-triazole derivative and a pharmaceutically acceptable salt thereof as an active ingredient, .

However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

In order to accomplish the above object, the present invention provides a 3-aryl-1,2,4-triazole derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

Wherein R ¹ is C ₁ -C ₁₀ linear or branched alkyl; C ₄ to C ₁₀ cycloalkyl; A 5- to 7-membered substituted or unsubstituted aromatic group to which carbon, oxygen, nitrogen, or sulfur is added, wherein the aromatic group is a furanyl group, a thiophenyl group, a phenyl group, a thiazole group, an indole group, an isoindole group, a pyridinyl group, , a pyridazine group, a naphthyl group, a represents a quinoline group, isoquinoline group, wherein the substituent is hydrogen, halogen, cyano, nitro, hydroxy, C ₁ ~ C ₁₀ straight or branched chain alkyl, C ₁ ~ C ₁₀ of Alkoxy, C ₁ to C ₁₀ haloalkyl, C ₁ to C ₁₀ haloalkoxy, C ₁ to C ₁₀ alkylthio, C ₁ to C ₁₀ alkylcarbonyl and C ₁ to C ₁₀ alkoxycarbonyl 1 > to R < 4 >, R < ² > A straight chain or branched or cyclic alkyl group of ₁ to ₁₀ carbon atoms; And - (CH ₂ ) _n -R ⁴ , wherein n is 0 or an integer from 1 to 6; A, B, C and D are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C ₁ -C ₁₀ linear or branched alkyl, C ₁ ~ C ₁₀ alkoxy, C ₁ ~ C ₁₀ of haloalkyl, C ₁ ~ C ₁₀ of haloalkoxy, C ₁ ~ C ₁₀ alkyl thio, C ₁ ~ C ₁₀ alkyl-carbonyl and C ₁ ~ of ≪ _RTI ID = 0.0 > C10 < / RTI > alkoxycarbonyl.

In one embodiment of the present invention, in Formula 1, R ¹ is an ethyl group, n- propyl group, an isopropyl group, a cyclopropyl group, a cyclopropyl group, n- butyl group, a t- butyl group, a cyclopentenyl group, a cycloalkyl A methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a butyl group, a butyl group, a butyl group, a propyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, a cyclopropylmethyl group, an n-butyl group, a t-butyl group, a cyclopentyl group, a cyclopropylethyl group, a cyclopentylmethyl group, a n-hexyl group, a cyclohexylmethyl group , A cyclohexylethyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a chloromethyl group, a chloroethyl group, a dichloroethyl group, a difluoromethyl group, An aromatic group having 1 to 3 substituents selected from the group consisting of a trifluoromethyl group, a methyl ester group and an ethyl ester group, wherein the aromatic group is a phenyl group, a furanyl group, a thiophenyl group, a pyridinyl group, an indole group, a naphthyl group, A, B, C, and D are each independently hydrogen, fluoro, chloro, bromo, methyl, or methyl, R ² represents hydrogen, a methyl group, or a benzyl group, X represents oxygen or sulfur, Ethyl, n-propyl, isopropyl, methoxy, trifluoromethoxy, trifluoromethyl, or hydroxy.

In another embodiment of the invention, in Formula 1, R ¹ is methyl, fluoro, chloro, methoxy, or hydroxy group is from 1 to 2 dogs represents a substituted phenyl group or indole, wherein R ² represents a hydrogen or a methyl group, Wherein X represents oxygen or sulfur, and A, B, C and D in the above A and C are hydroxy, B is hydrogen and D is hydrogen, chloro or isopropyl group.

And as yet another embodiment of the invention, in Formula 1, R ¹ is methyl, methoxy, or hydroxy group is from 1 to 2-substituted phenyl group, wherein R ² is a hydrogen group, wherein X is oxygen or sulfur, Wherein A and C are hydroxy, B is hydrogen, and D is hydrogen, chloro, or isopropyl group.

In another embodiment of the present invention, the 3- (2,4-dihydroxyphenyl) -4- (p-tolyl) -1H-1,2,4-triazole-5 (4H) (4H) -thione, 3- (2,4-dihydroxyphenyl) -4- (4-methoxyphenyl) 4- (2-methoxyphenyl) -1H-1,2,4-triazole-5 (4H) -thione, 3- (2,4-dihydroxyphenyl) -4- Yl) -1H-1,2,4-triazole-5 (4H) -thione, 4- (2,3- dihydrobenzo [b] [1,4] dioxin- Dihydroxyphenyl) -1H-1,2,4-triazole-5 (4H) -thione, 3- (5-chloro-2,4- (2,4-dihydroxy-5-isopropylphenyl) -4- (p-tolyl) -LH-1,2,4-triazol-5 (4H) -thione, 3- (2,4-dihydroxyphenyl) -4- (p- (4H) -one, 3- (2,4-dihydroxyphenyl) -4- (4-methoxyphenyl) -One, 3- (2,4-dihydroxyphenyl) -4- (4-hydroxyphenyl) -1H-1,2 (2,4-dihydroxyphenyl) -4- (4-methoxy-2-methylphenyl) -lH-l, 2,4- triazol- 5- (4H) -one, 3- (2,4-dihydroxyphenyl) -4- (2-methoxy-4-methylphenyl) (2,4-dihydroxyphenyl) -4- (2,4-dimethoxyphenyl) -1H-1,2,4-triazol-5 (4H) (2,4-dihydroxyphenyl) -4- (2,4-dimethylphenyl) -1H-1,2,4-triazole- 5- (4H) -one, 3- (5-chloro-2,4-dihydroxyphenyl) - (2,4-dihydroxy-5-isopropylphenyl) -4- (p-tolyl) -1H-1,2,4-triazole- ) -1H-1,2,4-triazol-5 (4H) -one.

The present invention relates to a pharmaceutical composition for preventing or treating diabetes and diabetic complications, which comprises the 3-aryl-1,2,4-triazole derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient Lt; / RTI >

In one embodiment of the invention, the diabetic and diabetic complications are selected from the group consisting of type 1 and type 2 diabetes, adult type latent autoimmune diabetes (LADA), pathological obesity, impaired glucose tolerance (IGT), fasting glucose deficiency (IFG) And is selected from the group consisting of microvascular complications (retinopathy, neuropathy, nephropathy), diabetic macrovascular complications (cardiovascular disease, cerebrovascular disease, peripheral vascular disease), vascular calcification and arteriosclerosis.

In another embodiment of the present invention, the composition is characterized by inhibiting the activity of the PDK4 enzyme.

The present invention provides a method of treating diabetes and diabetic complications comprising administering the pharmaceutical composition to a subject.

The present invention provides a method of using the pharmaceutical composition for preventing or treating diabetes mellitus and diabetic complications.

The present invention provides a 3-aryl-1,2,4-triazole derivative compound and a pharmaceutically acceptable salt thereof, and by identifying the selective inhibitory activity of the derivative against the PDK4 enzyme, the PDK4 enzyme activity It is expected to be useful for the prevention or treatment of diabetes and diabetic complications through the inhibitory effect.

(IGT), fasting glucose insufficiency (IFG), diabetic microvascular complications (such as retinopathy, neuropathy, diabetic retinopathy, diabetic retinopathy, diabetes mellitus, Nephropathy), diabetic macrovascular complications (cardiovascular diseases, cerebrovascular diseases, peripheral vascular diseases), vascular calcification, and arteriosclerosis.

Figure 1 shows the results of confirming the hypoglycemic effect of intraperitoneal administration of Compound 1-75 in an intraperitoneal glucose load test (IPGTT) mouse model.
FIG. 2 shows the results of confirming the hypoglycemic effect of intraperitoneal administration of Compound 1-79 in an intraperitoneal glucose load test (IPGTT) mouse model.

The present invention provides a 3-aryl-1,2,4-triazole derivative represented by the following formula (1) and a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

Wherein R ¹ is C ₁ -C ₁₀ linear or branched alkyl; C ₄ to C ₁₀ cycloalkyl; A 5- to 7-membered substituted or unsubstituted aromatic group to which carbon, oxygen, nitrogen, or sulfur is added, wherein the aromatic group is a furanyl group, a thiophenyl group, a phenyl group, a thiazole group, an indole group, an isoindole group, a pyridinyl group, , a pyridazine group, a naphthyl group, a represents a quinoline group, isoquinoline group, wherein the substituent is hydrogen, halogen, cyano, nitro, hydroxy, C ₁ ~ C ₁₀ straight or branched chain alkyl, C ₁ ~ C ₁₀ of Alkoxy, C ₁ to C ₁₀ haloalkyl, C ₁ to C ₁₀ haloalkoxy, C ₁ to C ₁₀ alkylthio, C ₁ to C ₁₀ alkylcarbonyl and C ₁ to C ₁₀ alkoxycarbonyl 1 > to R < 4 >, R < ² > A straight chain or branched or cyclic alkyl group of ₁ to ₁₀ carbon atoms; And - (CH ₂ ) _n -R ⁴ , wherein n is 0 or an integer from 1 to 6; A, B, C and D are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C ₁ -C ₁₀ linear or branched alkyl, C of ₁ ~ C ₁₀ alkoxy, C ₁ ~ C ₁₀ of haloalkyl, C ₁ ~ C ₁₀ haloalkoxy, C ₁ ~ C ₁₀ alkylthio, C ₁ ~ C ₁₀ alkyl-carbonyl and C ₁ ~ C ₁₀ of the ≪ / RTI > alkoxycarbonyl, and the like.

The 3-aryl-1,2,4-triazole derivative represented by the formula (1) according to the present invention is more preferably as follows.

Among the above-mentioned 3-aryl-1,2,4-triazole derivatives, R ¹ is preferably an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, a cyclopropylmethyl group, A cyclohexyl group, a cyclohexylmethyl group, or a cyclohexylethyl group, or may be a hydrogen atom, a chloro group, a fluoro group, a bromo group, a hydroxy group, a cyano group, a nitro group, Examples of the alkyl group include a methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, cyclopropylmethyl group, n-butyl group, t- butyl group, cyclopentyl group, cyclopropylethyl group, cyclopentylmethyl group, , A cyclohexylmethyl group, a cyclohexylethyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a chloromethyl group, a chloroethyl group, a dichloroethyl group, a difluoromethyl group, An aromatic group having 1 to 3 substituents selected from the group consisting of a fluorine atom, a trifluoromethyl group, a methyl ester group and an ethyl ester group, wherein the aromatic group is a phenyl group, a furanyl group, a thiophenyl group, a pyridinyl group, It represents a quinoline group, wherein R ² is hydrogen, methyl, or represents a benzyl, wherein X represents oxygen or sulfur, wherein a, B, hydrogen, fluoro, respectively C, D are, independently, chloro, bromo, methyl , Ethyl, n-propyl, isopropyl, methoxy, trifluoromethoxy, trifluoromethyl, or hydroxy.

Of the 3-aryl-1,2,4-triazole derivative, R ¹ is methyl, fluoro, chloro, methoxy, or hydroxy group is from 1 to 2 dogs represents a substituted phenyl group or indole, wherein R ² is hydrogen B, C, and D in which A and C are hydroxy, B is hydrogen, and D represents hydrogen, chloro, or isopropyl group.

Among the 3-aryl-1,2,4-triazole derivative compounds, R ¹ is a phenyl group substituted by 1 to 2 methyl, methoxy, or hydroxy groups, R ² is a hydrogen group, X is oxygen Or sulfur, A and C are hydroxy, B is hydrogen and D is hydrogen, chloro, or isopropyl.

Further, the 3-aryl-1,2,4-triazole derivative represented by the formula (1) according to the present invention is more preferably as follows.

Synthesis of 3- (2,4-dihydroxyphenyl) -4- (p-tolyl) -1H-1,2,4-triazole-5 (4H) 5- (4H) -thione, 3- (2,4-dihydroxyphenyl) -4- (2-methoxyphenyl) -1H-1,2,4-triazol-5 (4H) -thione, 3- (2,4-dihydroxyphenyl) -4- (naphthalen- Dihydrobenzo [b] [1,4] dioxin-6-yl) -3- (2,4-di Hydroxyphenyl) -1H-1,2,4-triazol-5 (4H) -thione, 3- (5-chloro-2,4- dihydroxyphenyl) -4- (p- (2,4-dihydroxy-5-isopropylphenyl) -4- (p-tolyl) -1H- (4H) -thiazole-5 (4H) -thione, 3- (2,4-dihydroxyphenyl) -4- (2,4-dihydroxyphenyl) -4- (4-methoxyphenyl) -lH-1,2,4-triazol-5 (4H) Dihydroxyphenyl) -4- (4-hydroxyphenyl) -1H-1,2,4-triazol-5 (4H) -one, 3- (4H) -one, 3- (2,4-dihydroxyphenyl) -4- (4-methoxy-2-methylphenyl) (2,4-dihydroxyphenyl) -4- (2,4-dimethoxyphenyl) -1H-1,2,4-triazole- -1H-1,2,4-triazol-5 (4H) -one, 3- (2,4-dihydroxyphenyl) -4- (2,4- (2,4-dihydroxyphenyl) -4- (l-methyl-lH-indol-5-yl) -Thiazol-5 (4H) -one, 3- (5-chloro-2,4-dihydroxyphenyl) -4- (p- ) -One, 3- (2,4-dihydroxy-5-isopropylphenyl) -4- (p-tolyl) -1H- 1,2,4-triazol-5 (4H) -one.

The term "pharmaceutically acceptable salt thereof" as used in the present invention means a salt which can be prepared by a method common in the art, for example, hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, Or an organic acid such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestic acid, fumaric acid, lactobionic acid, salicylic acid or acetylsalicylic acid (aspirin) Or by reacting with an alkali metal ion such as sodium, potassium or the like to form a metal salt thereof or reacting with an ammonium ion to form another form of a pharmaceutically acceptable salt thereof, .

According to one embodiment of the present invention, the PDK4 enzyme inhibitory activity of the compounds prepared was confirmed by PDC activity assay, and the effect of compound treatment on blood glucose lowering effect was confirmed by using intraperitoneal glucose tolerance test (IPGTT) mouse model (See Examples 4 to 5). Thus, the 3-aryl-1,2,4-triazole derivatives of the present invention and their pharmaceutically acceptable salts can be used for the prevention or treatment of diabetes and diabetic complications.

Accordingly, the present invention provides a pharmaceutical composition for preventing or treating diabetic and diabetic complications, which comprises a 3-aryl-1,2,4-triazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.

As used herein, the term "prevention" refers to all actions that inhibit or delay the onset of diabetes and diabetic complications by administration of the pharmaceutical composition according to the present invention.

The term "treatment" used in the present invention means all the actions for improving or alleviating symptoms of diabetes and diabetic complications by administration of the pharmaceutical composition according to the present invention

As used herein, the term "individual" means a subject in need of treatment for a disease and more specifically refers to a human or non-human primate, mouse, rat, dog, Of mammals.

In the present invention, the diabetic and diabetic complications are selected from the group consisting of type 1 and type 2 diabetes, adult type latent autoimmune diabetes (LADA), pathological obesity, impaired glucose tolerance (IGT), fasting glucose insufficiency (IFG), diabetic microvascular complications But are not limited to, those selected from the group consisting of diabetic macrovascular complications (cardiovascular disease, cerebrovascular disease, peripheral vascular disease), vascular calcification, and arteriosclerosis.

The pharmaceutical composition of the present invention comprises a 3-aryl-1,2,4-triazole derivative compound represented by the general formula (1), a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof, The pharmaceutical composition may be formulated into preparations for oral administration such as tablets, capsules, troches, solutions and suspensions, or parenteral preparations such as tablets, capsules, suspensions and the like by adding conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient The composition may be formulated for administration.

The excipient that can be used in the pharmaceutical composition of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, . For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, Water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, and the like.

The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dosage level is determined depending on the type of disease, severity, , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including co-administered drugs, and other factors well known in the medical arts. The pharmaceutical composition according to the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the pharmaceutical composition according to the present invention may vary depending on the age, sex, condition, body weight, absorbency, inactivation rate and excretion rate of the active ingredient in the body, the type of disease, May be administered in an amount of 0.1 mg / kg to 100 mg / kg per day, preferably 1 to 30 mg / kg per day, and may be administered once or several times a day.

The pharmaceutical composition of the present invention may be administered to a subject in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine dural or intracerebral injection. The pharmaceutical composition of the present invention is determined depending on the kind of the active ingredient, together with various related factors such as the disease to be treated, the route of administration, the age, sex, and weight and disease severity of the patient.

In addition, the pharmaceutical composition of the present invention can be used alone or in combination with methods for the prevention and treatment of diabetes and diabetic complications or using surgery, hormone therapy, drug therapy and biological response modifiers.

The present invention provides a process for preparing 3-aryl-1,2,4-triazole derivatives represented by the general formula (1).

The production method of the present invention is schematically shown in the following Reaction Scheme 1.

[Reaction Scheme 1]

R ¹ , R ² , A, B, C, and D are each as defined above. Here, the formula (1-A) represents the case where X is sulfur, and the formula (1-B) represents the case where X is oxygen.

The method for preparing the 3-aryl-1,2,4-triazole derivative according to the present invention will be described in more detail as follows.

A conventionally obtainable benzohydrazide compound represented by the above-mentioned formula (2) is reacted with isothiocyanate wherein R < ^{1 >} is substituted and converted into the hydrazine carbothioamide represented by the formula (4) A first step of synthesizing a 3-aryl-1,2,4-triazothion (when X is sulfur) represented by the formula 1-A by a cyclization reaction under a basic condition;

The compound represented by the formula (1-A) is reacted with iodomethane to convert it into the sulfide represented by the formula (5), the sulfide is converted into sulfone by an oxidation reaction, Aryl-1,2,4-triazolone (when X is hydrogen); And

The synthesis of 3-aryl-1,2,4-triazole derivative represented by Formula 1-B of Formula 1-C of the compound R ² is substituted alkyl halide in the reaction to introduce R ² is represented by And the third step.

The manufacturing method according to the present invention will be described in more detail with respect to each manufacturing step.

In the first step, the reaction for synthesizing the hydrazine carbothioamide represented by Formula 4 is carried out using ethanol, methanol, dichloromethane (CH ₂ Cl ₂ ), acetonitrile (MeCN), dichloroethane (ClCH ₂ CH ₂ Cl ), Dioxane, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO) And ethanol is preferably used. The isothiocyanate in which R ¹ is substituted in this reaction is preferably used in an amount of 1 to 5 equivalents based on the benzohydrazide compound represented by the formula 2, preferably 1 to 2 equivalents It is economical.

In the first step, in the cyclization reaction, the reduction reaction is carried out in the presence of water, ethanol, methanol, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), or dimethylsulfoxide It is used as a solvent, and preferably water is used. The base used in this reaction is preferably used in an amount of 1 to 10 equivalents, preferably 2 to 5 equivalents, based on the compound represented by the formula (4). At this time, as the base used, 1% to 10% of sodium hydroxide, sodium carbonate, potassium hydroxide, or potassium carbonate aqueous solution can be used, and it is most effective to use an aqueous solution of sodium hydroxide of 2% to 5% .

During the second step process, the reaction to convert to sulfide is carried out in the presence of a base such as ethanol, methanol, dichloromethane (CH ₂ Cl ₂ ), acetonitrile (MeCN), dichloroethane (ClCH ₂ CH ₂ Cl), dioxane, (THF), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO) or acetone as a solvent. Ethanol is preferably used. The base used in this reaction is preferably used in an amount of 1 to 5 equivalents, preferably 1.5 to 3.0 equivalents, based on the compound represented by the formula (1-A). At this time, the base used is potassium carbonate, sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, triethylamine (Et ₃ N), N, N- diisopropylethylamine, DB acids (DBU), pyridine, or Ruti And the like can be used, and it is most preferable to use potassium carbonate.

First of a two-step process, the reaction for oxidizing the sulfide to the sulfone are dichloromethane (CH ₂ Cl _2), acetonitrile (MeCN), dichloroethane (ClCH ₂ CH ₂ Cl), dioxane (dioxane), or tetrahydrofuran ( THF) is used as a solvent, and dichloromethane is preferably used. The oxidizing agent used in this reaction is preferably used in an amount of 2 to 5 equivalents, preferably 2 to 3 equivalents, based on the compound represented by the formula (5). At this time, meta-chloro and benzoic acid (mCPBA), hydrogen peroxide or oxone may be used as the oxidizing agent to be used, and it is most effective to use meta-chloro and benzoic acid.

During the second step, the reaction to hydrate the sulfone is carried out in a solvent such as ethanol, methanol, dichloromethane (CH ₂ Cl ₂ ), acetonitrile (MeCN), dichloroethane (ClCH ₂ CH ₂ Cl), dioxane, (THF), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO) do. As the base used in this reaction, 0.5-2.0 N sodium hydroxide, sodium carbonate, potassium hydroxide, or potassium carbonate aqueous solution can be used, and it is most preferable to use 1.0 N aqueous sodium hydroxide solution.

The third step reaction is carried out in a solvent such as ethanol, methanol, dichloromethane (CH ₂ Cl ₂ ), acetonitrile (MeCN), dichloroethane (ClCH ₂ CH ₂ Cl), dioxane, tetrahydrofuran (THF) Dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), or acetone is used as a solvent, preferably ethanol. The base used in this reaction is preferably used in an amount of 1 to 5 equivalents, preferably 1.5 to 3.0 equivalents, based on the compound represented by the formula (1-B). At this time, the base used is potassium carbonate, sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, triethylamine (Et ₃ N), N, N- diisopropylethylamine, DB acids (DBU), pyridine, or Ruti And the like can be used, and it is most preferable to use potassium carbonate.

In addition, in the course of the production of the 3-aryl-1,2,4-triazole derivative represented by Formula 1 according to the present invention, The derivative compound represented by 1-115 was isolated and purified, and its structure was analyzed and confirmed by NMR or Mass spectrum (see Examples 1 to 4).

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.

Example  1. 3- (2,4- Bis (methoxymethoxy) phenyl ) -4- (p-tolyl) -1H-1,2,4- Triazole -5 (4H) -thione < / RTI >

Step 1: Addition reaction of 2,4-bis (methoxymethoxy) benzohydrazide

[Reaction Scheme 2]

(3.84 g, 15.0 mmol) was dissolved in tetrahydrofuran (50 mL), and 1-isothiocyanato-4-methylbenzene (2.49 mL , 18.0 mmol), and the mixture was stirred at room temperature for 15 hours. The resulting solid was washed with a mixed solvent of diethyl ether / hexane (1/1, v / v) to give 2- (2,4-bis (methoxymethoxy) benzoyl) -N - p - tolyl hydrazine carbonyl thioamide compound (5.26 g, yield 86%) of the ^{(1 H NMR (500 MHz,} CDCl 3) δ 11.92 (br s, 1H), 10.66 (br s, 1H), 8.79 (br s, 1H), 7.98 (d , J = 8.8 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 2.1 Hz, 1H), 6.74 (dd, J = 8.8, 2.2 Hz, 1H), 5.47 (s, 2H), 5.20 (s, 2H), 3.59 (s, 3H), 3.48 (s, 3H), 2.34 (s, 3H ); LC-MS (ESI) m / z 406 ([M + 1] ⁺ )).

Step 2: The hydrazine carbothioamide and the cyclization reaction

[Reaction Scheme 3]

To a solution of 2- (2,4-bis (methoxymethoxy) benzoyl) -N - p -tolylhydrazine carbothioamide (5.26 g, 13.0 mmol) obtained in Step 1 in 2% aqueous sodium hydroxide solution (50 mL) , And the mixture was heated and stirred at 80 占 폚 for 15 hours. After the reaction, the reaction mixture was neutralized with a saturated aqueous solution of ammonium chloride at 0 ° C, dissolved in dichloromethane (200 mL) and washed with brine (200 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated mixture was separated and purified by column chromatography on silica gel in a mixed solvent of hexane / ethyl acetate (2/1, v / v) to give 3- (2,4-bis (methoxymethoxy) 4- (p - tolyl) -1 H -1,2,4- triazole -5 (4 H) - Cy on the compound; to give the (formula 1-1 3.21 g, yield ^{64%) (1 H NMR (} 500 _{MHz, CDCl 3) δ 11.70 (} br s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.18-7.14 (m, 4H), 6.76-6.70 (m, 2H), 5.14 (s, 2H) , 4.72 (s, 2H), 3.46 (s, 3H), 3.23 (s, 3H), 2.33 (s, 3H); LC-MS (ESI) m / z 388 ([M + 1] ⁺ ).

Synthesis of 3- (2,4-bis (methoxymethoxy) phenyl) -4- (p-tolyl) -1H-1,2,4-triazole-5 (4H)

Step 1: 3- (2,4-Bis (methoxymethoxy) phenyl) -4- ( p - tolyl) -1 H -1,2,4-triazole-5 (4 H ) - methylation of thion

[Reaction Scheme 4]

3- (2,4-bis (methoxymethoxy) phenyl) -4- (p - tolyl) -1 H -1,2,4- triazole -5 (4 H) - Cy-on (1.00 g, 2.58 mmol) was dissolved in ethanol (15 mL), potassium carbonate (433 mg, 3.10 mmol) and methyl iodide (0.195 mL, 3.10 mmol) were added and reacted at 80 ° C with stirring for 1 hour. After the reaction, the reaction mixture was neutralized with a saturated aqueous solution of ammonium chloride at 0 ° C, dissolved in dichloromethane, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated after filtration. Dichloromethane / methanol to the concentrated mixture (20/1, v / v), separated by column chromatography on silica gel under a mixed solvent to yield the title compound as an oil (987 mg, yield 95%) of ⁽¹ H NMR (500 _{MHz, CDCl 3) δ 7.42 (} d, J = 9.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2H), 6.76-6.71 (m, 2H) (S, 3H), 2.72 (s, 3H), 2.34 (s, 3H); LC-MS (ESI) m / z 402 ([M + 1] ⁺ )).

Step 2: Oxidation and hydration of sulfide compounds

[Reaction Scheme 5]

The sulphide compound (817 mg, 2.03 mmol) obtained in Step 1 was dissolved in dichloromethane (10 mL), m- CPBA (1.37 g, 6.10 mmol) was added at 0 ° C, and the mixture was reacted at room temperature for 1 hour with stirring. The reaction was terminated by adding an aqueous solution of sodium thiosulfate, rinsed with dichloromethane, and then washed with an aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated hexane mixture / ethyl acetate (1/2, v / v), separated by chromatography on a silica gel column under a mixed solvent to yield the sulfonamide intermediate compound (760 mg, yield 84%) as a foam in the form of a solid ⁽¹ _{H NMR (500 MHz, CDCl 3} ) δ 7.37 (d, J = 8.4 Hz, 1H), 7.21-7.14 (m, 4H), 6.78-6.73 (m, 2H), 5.15 (s, 2H), 4.76 (s , 2H), 3.53 (s, 3H), 3.46 (s, 3H), 3.23 (s, 3H), 2.34 (s, 3H); LC-MS (ESI) m / z 434 ([m + 1] +) ).

The obtained sulfone intermediate compound (609 mg, 1.40 mmol) was dissolved in dimethylsulfoxide (5 mL), and 1N sodium hydroxide (3.00 mL, 3.00 mmol) was added thereto at room temperature, followed by heating and stirring at 100 ° C for 2 hours. After completion of the reaction, the reaction mixture was neutralized with an aqueous solution of ammonium chloride, dissolved in ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated after filtration. The concentrated mixture was separated and purified by column chromatography on silica gel in a mixed solvent of dichloromethane / methanol (15/1, v / v) to give 3- (2,4-bis (methoxymethoxy) ( ¹ H NMR (400 MHz, CDCl ³ , yield: 89%) of 4- (p-tolyl) -1H-1,2,4- triazol- _{3) δ 9.67 (br s,} 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.14-7.05 (m, 4H), 6.78-6.74 (m, 2H), 5.16 (s, 2H), 4.63 ( s, 2H), 3.47 (s, 3H), 3.14 (s, 3H), 2.30 (s, 3H); LC-MS (ESI) m / z 372 ([M + 1] ⁺ ).

Example 3. Synthesis of 3- (2,4-dihydroxyphenyl) -4- (p-tolyl) -1H-1,2,4-triazole-5 (4H)

[Reaction Scheme 6]

The resulting 3- (2,4-bis (methoxymethoxy) phenyl) -1-methyl-4- ( p -tolyl) -1 H -1,2,4-triazol-5 ( 4H ) 116 mg, 0.301 mmol) was dissolved in methanol (5 mL), 5N hydrochloric acid (3.00 mL, 15.0 mmol) was added at room temperature, and the mixture was stirred under heating at room temperature for 15 hours. After completion of the reaction, the reaction mixture was neutralized by adding a saturated aqueous solution of sodium hydrogencarbonate, dissolved in ethyl acetate, washed with brine, and then the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated mixture was separated and purified by column chromatography on silica gel in a mixed solvent of dichloromethane / methanol (20/1, v / v) to give 3- (2,4-dihydroxyphenyl) 4- (p - tolyl) -1 H -1,2,4- triazole -5 (4 H) - one compound (formula 1-3; 83 mg, yield 93%) of the ⁽¹ H NMR (400 MHz _{, DMSO- d 6) δ 9.63 (} s, 1H), 9.56 (s, 1H), 7.15 (d, J = 8.1 Hz, 2H), 7.08-7.01 (m, 3H), 6.22 (dd, J = 8.3, 2.3 Hz, 1H), 6.17 ( d, J = 2.2 Hz, 1H), 3.42 (s, 3H), 2.27 (s, 3H) .; LC-MS (ESI) m / z 298 ([m + 1] + )).

Example  4. 3- (2,4- Bis (methoxymethoxy) phenyl )-One- methyl -4-( p - tolyl) -1 H -1,2,4- Triazole -5 (4 H ) - On  synthesis

[Reaction Scheme 7]

(4-methoxyphenyl) -4- (p-tolyl) -1H-1,2,4-triazole-5 (4H) -one (186 mg, 0.498 mmol) Potassium carbonate (279 mg, 2.00 mmol) and methyl iodide (0.940 mL, 1.50 mmol) were added at room temperature, and the mixture was reacted at room temperature for 12 hours with stirring . After completion of the reaction, the reaction mixture was dissolved in ethyl acetate and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated mixture was separated and purified by column chromatography on silica gel in a mixed solvent of hexane / ethyl acetate (1/2, v / v) to give 3- (2,4-bis (methoxymethoxy) 1-methyl -4- (p - tolyl) -1 H -1,2,4- triazole -5 (4 H) - one compound; to give the (formula 1-4 180 mg, yield 93%) ⁽¹ H _{NMR (400 MHz, CDCl 3)} δ 7.41-7.37 (m, 1H), 7.13-7.03 (m, 4H), 6.78-6.40 (m, 2H), 5.16 (s, 2H), 4.60 (s, 2H), 3H), 3.47 (s, 3H), 3.11 (s, 3H), 2.29 (s, 3H); LC-MS (ESI) m / z 386 ([M + 1] ⁺ ).

The structure and analytical results of the 3-aryl-1,2,4-triazole derivative compounds synthesized by the same method as those of Examples 1 to 4 are summarized in Table 1 below.

[Table 1]

Example  5. PDK4 Of the enzyme activity

In order to confirm the effect of the compound of the present invention on PDK4 enzyme activity, the following experiment was conducted.

100 mM Tris-HCl (Tris-HCl), 0.5 mM ethylene diamine tetraacetic acid (EDTA), 1 mM magnesium chloride (MgCl _2), 1mM thiamine pyrophosphate (thiamine pyrophosphate), 5 mM beta-mercaptoethanol (β-mercaptoethanol ), 1.5 mM nicotinamide adenine dinucleotide (NAD), and 0.3 mM coenzyme A (CoA). This was dispensed into 96 wells at 176 μL / well. In addition, 1 μL of PDC, 0.25 μL of PDK4, and 1 μL of the PDK inhibitor were added to 1 mM magnesium chloride (MgCl ₂ ), 20 mM potassium fluoride (KF), 50 mM potassium phosphate (KPi) Was prepared and maintained in a heating block at 30 ° C. After 10 minutes, 1 mM of ATP was added to solution 2, and after 0 minutes and 10 minutes, 20 占 퐇 of solution 2 was pipetted and added to solution 1. Then, 4 μL of 40 mM sodium pyruvate was added to each well using a multipipette to prepare 200 μL of solution per well. PDC activity mediated the catalysis of acetyl CoA and NADH in pyruvate and NAD ⁺ , respectively, and the absorbance was used to measure PDC activity using the difference that NADH had the maximum absorbance at the wavelength of 340 nm but not NAD ⁺ . The absorbance was measured using a VeraMax microplate reader for 30 min to confirm the rate of decrease of NAD +. The inhibition of PDK4 inhibitor by IC ₅₀ and 10 μM was measured by PDC activity assay. The results are shown in Table 2 and Table 3, respectively.

[Table 2]

[Table 3]

As shown in Table 2 and Table 3, the 3-aryl-1,2,4-triazole derivative of the present invention was found to have an excellent enzyme inhibitory activity against PDK4.

Example  6. abdominal cavity My party  Load test Intraperitoneal Glucose Tolerance Test ; IPGTT) mouse model of blood glucose lowering effect

In order to confirm the hypoglycemic effect in the IPGTT mouse model of the compound according to the present invention, the following experiment was conducted.

Diet-induced obesity (DIO) mouse model was constructed by administering 60% high fat diet (32% unsaturated fatty acid, 68% saturated fatty acid) for 10 weeks to 8 week old C57BI / 6J mice. 10% (2-hydroxypropyl) -β-cyclodextrin containing 17.5% (w / v) for the intraperitoneal administration of Compound 1-75, Compound 1-79, PDK inhibitor positive control PS- DMSO solvent to dissolve. Preparations were administered intraperitoneally to DIO mice daily at a dose of 70 mg / kg for 4 weeks. After 4 weeks of drug administration, 1.5 g / kg glucose was intraperitoneally administered and the changes of blood glucose were measured according to the passage of time (0, 15, 30, 60, 120 minutes) Are shown in Tables 4 and 5, respectively.

[Table 4]

[Table 5]

As shown in Table 4, Table 5, and Figures 1-2, the IPGTT mouse model treated with Compound 1-75 or 1-79 showed 22% and 20% lower blood glucose levels, respectively, as compared to the control . Particularly, Compound 1-75 specifically confirmed that the blood glucose lowering effect was superior to that of the positive control (PS-10). Based on the above experimental results, it has been confirmed that the 3-aryl-1,2,4-triazole derivatives can be used for the treatment of diabetes mellitus and diabetic complication diseases through blood glucose lowering.

[ Formulation example ]

   Preparation Example 1. Preparation of tablets (pressurized system)

As the active ingredient, 5.0 mg of the compound represented by the formula (1) of the present invention was sieved, and 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized to prepare tablets.

Formulation Example 2. Preparation of tablets (wet granulation)

As an active ingredient, 5.0 mg of the compound represented by the formula (1) of the present invention was sieved, and 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressurized to make tablets.

Formulation Example 3. Preparation of powders and capsules

As an active ingredient, 5.0 mg of the compound represented by the formula (1) of the present invention was sieved and then mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. 5 gelatin capsules.

Formulation Example 4. Preparation of injection

As an active ingredient, 100 mg of the compound represented by the formula (1) of the present invention was contained. In addition _, injections were prepared by adding 180 mg of mannitol _, 26 mg of Na ₂ HPO _{4 ,} 26 mg of 12H ₂ O and 2,974 mg of distilled water.

It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.

Claims (8)

delete delete A pharmaceutical composition for preventing or treating diabetic and diabetic complications, which comprises a 3-aryl-1,2,4-triazole derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient as,
[Chemical Formula 1]

Wherein R ¹ is an aromatic group having 1 to 2 substituents selected from the group consisting of methyl, methoxy, and hydroxy, wherein the aromatic group is phenyl, naphthyl, benzodioxolyl or indolyl;
R < ² > is hydrogen;
X is oxygen or sulfur;
Wherein A, B, C and D are each independently hydrogen, chloro, hydroxy or isopropyl.
4. The compound according to claim 3, wherein the 3-aryl-1,2,4-triazole derivative represented by the formula (1)
Synthesis of 3- (2,4-dihydroxyphenyl) -4- (p-tolyl) -1H-1,2,4-triazole-5 (4H) 5- (4H) -thione, 3- (2,4-dihydroxyphenyl) -4- (2-methoxyphenyl) -1H-1,2,4-triazol-5 (4H) -thione, 3- (2,4-dihydroxyphenyl) -4- (naphthalen- Dihydrobenzo [b] [1,4] dioxin-6-yl) -3- (2,4-di Hydroxyphenyl) -1H-1,2,4-triazol-5 (4H) -thione, 3- (5-chloro-2,4- dihydroxyphenyl) -4- (p- (2,4-dihydroxy-5-isopropylphenyl) -4- (p-tolyl) -1H- (4H) -thiazole-5 (4H) -thione, 3- (2,4-dihydroxyphenyl) -4- (2,4-dihydroxyphenyl) -4- (4-methoxyphenyl) -lH-1,2,4-triazol-5 (4H) Dihydroxyphenyl) -4- (4-hydroxyphenyl) -1H-1,2,4-triazol-5 (4H) -one, 3- (4H) -one, 3- (2,4-dihydroxyphenyl) -4- (4-methoxy-2-methylphenyl) (2,4-dihydroxyphenyl) -4- (2,4-dimethoxyphenyl) -1H-1,2,4-triazole- -1H-1,2,4-triazol-5 (4H) -one, 3- (2,4-dihydroxyphenyl) -4- (2,4- (2,4-dihydroxyphenyl) -4- (l-methyl-lH-indol-5-yl) -Thiazol-5 (4H) -one, 3- (5-chloro-2,4-dihydroxyphenyl) -4- (p- ) -One and 3- (2,4-dihydroxy-5-isopropylphenyl) -4- (p-tolyl) -lH-1,2,4- triazol- Lt; RTI ID = 0.0 > 1, < / RTI >
4. The method of claim 3, wherein the diabetic and diabetic complications are selected from the group consisting of type 1 and type 2 diabetes, adult type latent autoimmune diabetes (LADA), pathological obesity, impaired glucose tolerance (IGT), fasting glucose insufficiency (IFG), diabetic microvessels Complications, diabetic macrovascular complications, vascular calcification, and atherosclerosis.
The pharmaceutical composition according to claim 5, wherein the diabetic microvascular complication is retinopathy, neuropathy or nephropathy.
The pharmaceutical composition according to claim 5, wherein the diabetic macrovascular complication is cardiovascular disease, cerebrovascular disease or peripheral vascular disease.
4. The pharmaceutical composition according to claim 3, wherein the composition inhibits the activity of the PDK4 enzyme.

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