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Oxadiazolopyrazines and oxadiazolopyridines useful as mitochondrial uncouplers

An alkyl, C2-C8 technology, applied in the field of oxadiazolopyrazine and oxadiazolopyridine that can be used as mitochondrial uncoupling agent, can solve the problem of drugs without uncoupling agent

Pending Publication Date: 2021-01-22
弗吉尼亚理工大学知识产权有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, there are no uncoupler drugs that are safe enough for use in humans

Method used

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  • Oxadiazolopyrazines and oxadiazolopyridines useful as mitochondrial uncouplers
  • Oxadiazolopyrazines and oxadiazolopyridines useful as mitochondrial uncouplers
  • Oxadiazolopyrazines and oxadiazolopyridines useful as mitochondrial uncouplers

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Experimental program
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example

[0211] general method

[0212] The following starting materials and general procedures were used in the following synthetic examples.

[0213] In all synthetic examples, room temperature (rt) was about 21 °C.

[0214] NMR solvent reference: i (CD 3 ) 2 CO (2.05 / 29.84ppm); (CD 3 ) 2 SO (2.50 / 39.52ppm).

[0215] NMR Abbreviations: aq. = aqueous, app = apparent, br = broad, s = singlet, d = doublet, t = triplet, q = quartet, p = quintet. * refers to rotamers.

[0216] Synthesis of starting materials

example 1

[0217] Example 1. Synthesis of [1,2,5]oxadiazolo[3,4-B]pyrazine-5,6-diol (1-1)

[0218]

[0219] In a 500 mL round bottom flask equipped with a condenser, 1,2,5-oxadiazole-3,4-diamine (50.0 g, 500 mmol) and oxalic acid (49.6 g, 551 mmol) were dissolved in aqueous HCl (250 mL, 10 The mixture in % v / v) was heated to reflux in a sand bath for 4 hours. The resulting mixture was cooled in an ice bath, and the precipitate was filtered, rinsed with water (20 mL) followed by diethyl ether (2 x 150 mL), and collected to give 1-1 (55.2 g, 72%) as a colorless solid : 1 H NMR ((CD 3 ) 2 CO,400MHz)δ11.65(brs,2H); 13 C NMR ((CD 3 ) 2 CO, 100MHz) δ153.9, 144.8.

example 2

[0220] Synthesis of Example 2.5,6-dichloro-[1,2,5]oxadiazolo[3,4-B]pyrazine (1-2)

[0221]

[0222] With a glass stopper and with aqueous Na 2 CO 3 Diol 1-1 (37.0 g, 240 mmol) and PCl 5 (120g, 576mmol) in POCl 3 (45 mL) was heated to 95 °C for 2 hours. The mixture was allowed to cool to room temperature, and then to 5-10 °C in an ice bath. The reaction mixture was slowly poured into ice-cold water (3 × 250 mL beakers, each with 100 mL H 2 O) so that the temperature of the water does not rise above 25°C (monitored by a thermometer in the water bath). The colorless precipitate was filtered, rinsed with water, and dissolved in acetone (about 200 mL). Water (3 times the volume of acetone) was added to the organic solution to facilitate precipitation, and the colorless solid was collected by filtration under vacuum with P 2 o 5 Drying as a desiccant afforded 1-2 (35.1 g, 77%) as a colorless solid: 13 C NMR ((CD 3 ) 2 CO, 100MHz) δ155.9, 151.9.

[0223] The large-scal...

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Abstract

The disclosure provide compounds of Formula I and the pharmaceutically acceptable salts thereof. The variables, R1, R2, R3, X1, X2, and Z are defined herein. Certain compounds of Formula I act as selective mitochondrial protonophore uncouplers that do not affect the plasma membrane potential. Compounds and salts of Formula I are useful for treating or decreasing the risk of conditions responsive to mitochondrial uncoupling, such as cancer, obesity, type II diabetes, fatty liver disease, insulin resistance, Parkinson's disease, ischemia reperfusion injury, heart failure, non-alcoholic fatty liver disease (NALFD), and non-alcoholic steatohepatitis (NASH). Because mitochondrial uncouplers decrease the production of reactive oxygen species (ROS), which are known to contribute to age-related cell damage, compounds of Formula I are useful for increasing lifespan. Compounds and salts of Formula I are also useful for regulating glucose homeostasis or insulin action in a patient.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application No. 62 / 660,880, filed April 20, 2018, which is hereby incorporated by reference in its entirety. Background technique [0003] Cellular respiration is a physiological process whose primary goal is to generate energy in the form of ATP. During cellular respiration, chemical energy derived from nutrients is converted into ATP. Specifically, the oxidation of nutrients in the mitochondrial matrix generates the energetic electron carriers nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH 2 ), which are oxidized by the mitochondrial electron transport chain (ETC) located in the mitochondrial inner membrane (MIM). Electron flow through the ETC is an energy-releasing process that drives a series of proton pumps to efflux protons from the matrix to the intermembrane space (IMS) against their concentration gradient. The resulting proton ...

Claims

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Application Information

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IPC IPC(8): C07D498/04A61P3/04A61P3/00A61P25/16A61P25/28A61P35/00A61P37/00A61P3/10A61K31/4985A61K31/437
CPCA61P3/00A61P3/04A61P3/10A61P25/16A61P25/28A61P35/00A61P37/00C07D241/20A61P3/08A61P3/06C07D471/04C07D498/04C07D487/04C07D241/18A61K31/4965A61K31/44C07D241/16C07D213/73C07F5/025A61K45/06
Inventor 韦伯斯特·L·桑托斯约瑟夫·迈克尔·萨拉蒙克里斯托弗·J·加西亚雅各布·H·默里
Owner 弗吉尼亚理工大学知识产权有限公司
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