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WO2015167211A1 - Dérivé de 3-aryl-1,2,4-triazole et utilisation correspondante - Google Patents

Dérivé de 3-aryl-1,2,4-triazole et utilisation correspondante Download PDF

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Publication number
WO2015167211A1
WO2015167211A1 PCT/KR2015/004234 KR2015004234W WO2015167211A1 WO 2015167211 A1 WO2015167211 A1 WO 2015167211A1 KR 2015004234 W KR2015004234 W KR 2015004234W WO 2015167211 A1 WO2015167211 A1 WO 2015167211A1
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WO
WIPO (PCT)
Prior art keywords
group
triazole
dihydroxyphenyl
hydrogen
diabetes
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2015/004234
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English (en)
Korean (ko)
Inventor
이태호
이인규
류광현
김남두
이두현
유은경
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kyungpook National University Hospital
Industry Academic Cooperation Foundation of KNU
Original Assignee
Kyungpook National University Hospital
Industry Academic Cooperation Foundation of KNU
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020150059040A external-priority patent/KR101711732B1/ko
Application filed by Kyungpook National University Hospital, Industry Academic Cooperation Foundation of KNU filed Critical Kyungpook National University Hospital
Publication of WO2015167211A1 publication Critical patent/WO2015167211A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/4196—1,2,4-Triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention relates to 3-aryl-1,2,4-triazole derivatives and the use thereof. More specifically, 3-aryl-1,2,4-triazole derivative is a novel compound exhibiting an inhibitory effect of selective activity on Pyruvate dehydrogenase Kinase (PDK) enzyme.
  • PDK Pyruvate dehydrogenase Kinase
  • the present invention relates to a pharmaceutical composition for preventing or treating diabetes mellitus and diabetic complications, which provides -1,2,4-triazole derivative and a pharmaceutically acceptable salt thereof, and contains the same as an active ingredient.
  • the pyruvate dehydrogenase complex (PDC) present in the mitochondria is important for glycemic control during fasting and feeding.
  • PDC pyruvate dehydrogenase complex
  • the activity of PDC is increased to produce NADH and acetyl-CoA through the oxidative decarboxylation of pyruvic acid.
  • Acetyl-CoA thus produced enters the Krebs cycle and is oxidized and used for fatty acid and cholesterol synthesis.
  • PDC activity decreases, preserving glucose precursors lactate, alanine and pyruvate, which increases your lifespan.
  • PDC pyruvate dehydrogenase kinase
  • PDP pyruvate dehydrogenase phosphatase
  • PDK4 has been identified in PDKs from PDK1 to PDK4 to date, and PDK4 is most sensitively expressed in fasting feeding (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 conditions, and has been shown to reduce blood sugar levels, particularly in PDK4 knock-out mice.
  • the precursors of glucose, lactate, alanine, and pyruvate were all reduced. That is, in PDK4-deficient mice, PDC activity is increased, and oxidation of pyruvate to acetylcoei is increased, thereby reducing blood glucose.
  • the PDK4-deficient rat model showed a decrease in body weight gain and a decrease in body fat gain by high-fat diet compared to the control group, demonstrating the efficacy in obesity of PDK4 inhibition.
  • Another object of the present invention is to provide a composition for preventing or treating diabetes and diabetic complications using a PDK4 enzyme activity inhibitory effect containing 3-aryl-1,2,4-triazole derivative and a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a 3-aryl-1,2,4-triazole derivative represented by the following formula (1) and a pharmaceutically acceptable salt thereof.
  • R 1 is C 1 ⁇ C 10 linear or branched alkyl; Cycloalkyl of C 4 to C 10 ; 5- to 7-membered substituted or unsubstituted aromatic group to which carbon, oxygen, nitrogen, or sulfur is added, wherein the aromatic group is furanyl group, thiophenyl group, phenyl group, thiazole group, indole group, isoindole group, pyridinyl group, piperazinyl group , Pyridazinyl group, naphthyl group, quinolinyl group, isoquinolinyl group, wherein the substituent is hydrogen, halogen, cyano, nitro, hydroxy, C 1 -C 10 straight or branched chain alkyl, C 1 -C 10 With alkoxy, C 1 to C 10 haloalkyl, C 1 to C 10 haloalkoxy, C 1 to C 10 alkylthio, C 1 to C 10 alkyl carbonyl and C
  • R 1 is an ethyl group, n-propyl group, isopropyl group, cyclopropyl group, cyclopropylmethyl group, n-butyl group, t-butyl group, cyclopentyl group, cyclo Propylethyl group, cyclopentylmethyl group, normal hexyl group, cyclohexyl group, cyclohexylmethyl group, or cyclohexylethyl group, or hydrogen, chloro, fluoro, bromo, hydroxy group, cyano group, nitro group, 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, normal hexyl group, cyclohex
  • R 1 is methyl, methoxy, or a phenyl group substituted with 1 to 2 hydroxyl groups
  • R 2 is a hydrogen group
  • X is oxygen or sulfur
  • a and C are hydroxy
  • B is hydrogen
  • D is hydrogen, chloro, or isopropyl group.
  • the present invention is a pharmaceutical for preventing or treating diabetes and diabetic complications, comprising 3-aryl-1,2,4-triazole derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. To provide a composition.
  • the diabetes and diabetes complications are type 1 and type 2 diabetes, adult type latent autoimmune diabetes (LADA), pathological obesity, impaired glucose tolerance (IGT), fasting glucose disorder (IFG), diabetic Microvascular complications (retinopathy, neuropathy, nephropathy), diabetic macrovascular complications (cardiovascular disease, cerebrovascular disease, peripheral vascular disease), vascular calcification and atherosclerosis.
  • LADA adult type latent autoimmune diabetes
  • IIG impaired glucose tolerance
  • IGF fasting glucose disorder
  • diabetic Microvascular complications retinopathy, neuropathy, nephropathy
  • diabetic macrovascular complications cardiacovascular disease, cerebrovascular disease, peripheral vascular disease
  • vascular calcification and atherosclerosis are type 1 and type 2 diabetes, adult type latent autoimmune diabetes (LADA), pathological obesity, impaired glucose tolerance (IGT), fasting glucose disorder (IFG), diabetic Microvascular complications (retinopathy, neuropathy, nephropathy), diabetic macrovascular complications (cardiovascular disease, cerebrovascular disease, peripheral vascular disease), vascular
  • the composition is characterized by inhibiting the activity of the PDK4 enzyme.
  • the present invention provides a method for treating diabetes mellitus and diabetic complications comprising administering the pharmaceutical composition to a subject.
  • type 1 and type 2 diabetes For example, type 1 and type 2 diabetes, adult latent autoimmune diabetes (LADA), pathological obesity, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), diabetic microvascular complications (retinopathy, neuropathy, Nephropathy), diabetic macrovascular complications (cardiovascular disease, cerebrovascular disease, peripheral vascular disease), vascular calcification and atherosclerosis have an effective effect as an agent.
  • LADA adult latent autoimmune diabetes
  • IIGT impaired glucose tolerance
  • IGF impaired fasting glucose
  • diabetic microvascular complications retinopathy, neuropathy, Nephropathy
  • diabetic macrovascular complications cardiacovascular disease, cerebrovascular disease, peripheral vascular disease
  • vascular calcification and atherosclerosis have an effective effect as an agent.
  • treatment means any action that improves or advantageously changes the symptoms for diabetes and diabetic complications by administration of the pharmaceutical composition according to the present invention.
  • composition of the present invention may be used alone or in combination with methods using surgery, hormone therapy, drug treatment and biological response modifiers for the prevention and treatment of diabetes and diabetic complications.
  • the reaction for synthesizing the hydrazine carbothioamide represented by Formula 4 is 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), dimethyl sulfoxide (DMSO), or acetone as solvent Use, preferably ethanol.
  • the isothiocyanate substituted with R 1 used in this reaction is preferably used in an amount of 1 to 5 equivalents, preferably in the range of 1 to 2 equivalents, relative to the benzohydrazide compound represented by Formula 2 above. Excellent economy
  • the reaction to hydrate the sulfone is 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), dimethyl sulfoxide (DMSO), or acetone are used as a solvent, preferably dimethyl sulfoxide is used. do.
  • 0.5-2.0N sodium hydroxide, sodium carbonate, potassium hydroxide, or potassium carbonate aqueous solution or the like may be used.
  • 1.0N aqueous sodium hydroxide solution is most effective.
  • Step 1 3- (2,4-bis (methoxymethoxy) phenyl) -4- ( p -Tolyl) -1 H -1,2,4-triazole-5 (4 H Methylation of Thion
  • the sulfide 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 reaction was stirred at room temperature for 1 hour. The reaction was terminated by adding an aqueous sodium thiosulfate solution, dissolved in dichloromethane and washed with an aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated after filtration.
  • Tris-HCl 100 mM Tris-HCl, 0.5 mM ethylenediaminetetraacetic acid (EDTA), 1 mM magnesium chloride (MgCl 2 ), 1 mM thiamine pyrophosphate, 5 mM beta mercaptoethanol ( ⁇ -mercaptoethanol ), 1.5 mM nicotinamide adenine dinucleotide (NAD), and 0.3 mM coenzyme A (CoA) were mixed to prepare Solution I. These were dispensed at 176 ⁇ L / well in 96 wells each.
  • EDTA ethylenediaminetetraacetic acid
  • MgCl 2 magnesium chloride
  • ⁇ -mercaptoethanol 5 mM beta mercaptoethanol
  • NAD nicotinamide adenine dinucleotide
  • CoA coenzyme A
  • PDC mediated the catalysis of pyruvate and NAD + to acetylcoei and NADH, respectively.
  • the PDC activity was measured using the absorbance using the difference that NADH had the maximum absorbance at the wavelength of 340nm but NAD + could not absorb it. .
  • the rate of reduction of NAD + was confirmed by measuring absorbance for 30 minutes using the VeraMax microplate reader.
  • Than PDC activity assay was to measure the degree of inhibition in% of PDK4 inhibitor IC 50 with 10 ⁇ M through the results are shown in Table 2 and Table 3, respectively.
  • a diet-induced obesity (DIO) mouse model was constructed in which 8-week-old C57BI / 6J mice received 60% high fat diet (32% unsaturated fatty acid and 68% saturated fatty acid) for 10 weeks. 10% including 17.5% (w / v) (2-hydroxypropyl) - ⁇ -cyclodextrin for intraperitoneal administration of compound 1-75, compound 1-79, PD-10 inhibitor positive control, PS-10, and vehicle Treated with DMSO solvent to dissolve.
  • Prepared drugs were intraperitoneal injection in DIO mice daily for 4 weeks at a dose of 70 mg / kg. After 4 weeks of drug administration, 1.5 g / kg of glucose was administered intraperitoneally to measure changes in blood glucose over time (0 minutes, 15 minutes, 30 minutes, 60 minutes, 120 minutes). Table 4 and Table 5, respectively.
  • the IPGTT mouse model treated with Compound 1-75 or Compound 1-79 lowered blood glucose levels by 22% and 20%, respectively, compared to the control. It was confirmed that there is an effect.
  • Compound 1-75 specifically confirmed that the blood sugar lowering effect than the positive control group (PS-10).
  • PS-10 positive control group
  • 100 mg of the compound represented by the formula (1) of the present invention was contained, and in addition, 180 mg of mannitol, Na 2 HPO 4 , 12H 2 O and 2,974 mg of distilled water were added to prepare an injection.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne : un composé dérivé de 3-aryl-1,2,4-triazole ; et une utilisation médicale correspondante en tant qu'agent préventif et thérapeutique pour le diabète ou des complications diabétiques à l'aide de l'activité inhibitrice sélective du composé contre l'enzyme de pyruvate déshydrogénase kinase (PDK). Le composé dérivé de 3-aryl-1,2,4-triazole de la présente invention est utile en tant qu'agent préventif, de régulation et thérapeutique pour des maladies associées à l'enzyme pyruvate déshydrogénase kinase 4 (PDK4), telles que le diabète de type 1 et le diabète de type 2, le diabète auto-immun latent chez l'adulte (LADA), l'obésité morbide, l'intolérance au glucose (IGT), les troubles de la glycémie à jeun (IFG), les complications microvasculaires diabétiques (la rétinopathie, la neuropathie, la néphropathie), les complications macrovasculaires diabétiques (maladies cardio-vasculaires, maladies cérébrovasculaires, maladies vasculaires périphériques), la calcification vasculaire et l'artériosclérose.
PCT/KR2015/004234 2014-04-30 2015-04-28 Dérivé de 3-aryl-1,2,4-triazole et utilisation correspondante Ceased WO2015167211A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR20140052930 2014-04-30
KR10-2014-0052930 2014-04-30
KR1020150059040A KR101711732B1 (ko) 2014-04-30 2015-04-27 3-아릴-1,2,4-트라이아졸 유도체 및 이의 용도
KR10-2015-0059040 2015-04-27

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WO2015167211A1 true WO2015167211A1 (fr) 2015-11-05

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113121505A (zh) * 2021-03-02 2021-07-16 中国人民解放军海军军医大学 一种具有抗真菌与抗肿瘤双重作用的三唑酮类化合物及应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006055760A1 (fr) * 2004-11-18 2006-05-26 Synta Pharmaceuticals Corp. Composes triazole modulant l'activite de hsp90
WO2006087077A2 (fr) * 2005-02-17 2006-08-24 Merck Patent Gmbh Derives triazole
US20090239782A1 (en) * 2006-10-03 2009-09-24 Masaharu Nakamura High-molecular weight conjugate of resorcinol derivatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006055760A1 (fr) * 2004-11-18 2006-05-26 Synta Pharmaceuticals Corp. Composes triazole modulant l'activite de hsp90
WO2006087077A2 (fr) * 2005-02-17 2006-08-24 Merck Patent Gmbh Derives triazole
US20090239782A1 (en) * 2006-10-03 2009-09-24 Masaharu Nakamura High-molecular weight conjugate of resorcinol derivatives

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113121505A (zh) * 2021-03-02 2021-07-16 中国人民解放军海军军医大学 一种具有抗真菌与抗肿瘤双重作用的三唑酮类化合物及应用
CN113121505B (zh) * 2021-03-02 2023-03-07 中国人民解放军海军军医大学 一种具有抗真菌与抗肿瘤双重作用的三唑酮类化合物及应用

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