Imidazopyridines useful as mitochondrial uncouplers

An alkyl and compound technology, applied in the field of imidazopyridine that can be used as a mitochondrial uncoupling agent, can solve problems such as drugs without an 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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  • Imidazopyridines useful as mitochondrial uncouplers
  • Imidazopyridines useful as mitochondrial uncouplers
  • Imidazopyridines useful as mitochondrial uncouplers

Examples

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example

[0209] general method

[0210] The following starting materials and general procedures were used in the following synthetic examples.

[0211] In all synthetic examples, room temperature (rt) was about 21 °C.

[0212] NMR solvent reference: (CD 3 ) 2 CO (2.05 / 29.84ppm); (CD 3 ) 2 SO (2.50 / 39.52ppm).

[0213] NMR Abbreviations: aq. = aqueous, app = apparent, br = broad, s = singlet, d = doublet, t = triplet, q = quartet, p = quintet. * refers to rotamers.

[0214] Imidazole-pyrazine series

[0215] General Procedure A. For the Preparation of 5-Methoxy Compounds

[0216]

[0217] In a dram vial, the desired oxadiazole-pyrazine 1 (0.2 mmol), iron (1 mmol), ytterbium(III) triflate (0.02 mmol) were dissolved in glacial acetic acid (0.45 mL) and the desired fluorinated ester (ethyl trifluoroacetate or methyl pentafluoropropionate) (2 mL); the mixture was stirred vigorously at 95°C for 4 hours. After cooling to room temperature, 5 mL of H 2 0 and 5 mL of EtOAc were adde...

example 1

[0230] Example 1. 6-Methoxy-N-(4-(trifluoromethoxy)phenyl)-2-(trifluoromethyl)-1H-imidazo[4,5-B]pyrazine-5- Synthesis of Amine (2-1)

[0231]

[0232] 6-Methoxy-N-(4-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5- Amine (1-156) Synthesis of compound 2-1 afforded 2-1 (70% yield) as a pale yellow solid. 1 H NMR (500MHz, acetone-d 6 )δ13.06(brs, 1H), 8.65(brs, 1H), 8.11(d, 2H, J=9.1Hz), 7.33(d, 2H, J=8.6Hz), 4.11(s, 3H); 13 C NMR (125MHz, acetone-d 6 )δ148.1, 143.6, 140.8, 139.2, 135.2 (d, J = 40.7Hz), 121.5, 120.7 (q, J = 254.6Hz), 120.6, 119.3 (q, J = 268.4Hz), 53.9; 19 F NMR (376MHz, acetone-d 6 )δ-58.88(s,3F),-64.41(s,3F); HRMS(ESI):C 14 h 10 f 6 N 5 o 2 + [M+H] + Calculated: 394.0733, Observed: 394.0714.

example 2

[0233] Example 2. 6-Methoxy-N-(4-(N-butyl)phenyl)-2-(trifluoromethyl)-1H-imidazo[4,5-B]pyrazin-5-amine Synthesis of (2-2)

[0234]

[0235] Using N-(4-butylphenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-157 ) to synthesize compound 2-2 to obtain 2-2 (63% yield) as a pale yellow solid. 1 H NMR (500MHz, acetone-d 6 )δ8.35(brs,1H),7.86(d,2H,J=8.5Hz),7.20(d,2H,J=8.5Hz),4.10(s,3H),2.61(t,2H,J=7.7 Hz), 1.62(m, 2H), 1.38(h, 2H, J=7.4Hz), 0.94(t, 3H, J=7.4Hz); 13 C NMR (125MHz, acetone-d 6 )δ148.0, 141.3, 137.6, 137.0, 134.6 (d, J = 41.0Hz), 128.4, 119.3 (q, J = 268.2Hz), 119.6, 53.8, 34.7, 33.8, 22.1, 13.3; 19F NMR (376MHz, acetone-d 6 )δ-64.30(s,3F); HRMS(ESI): C 17 h 19 f 3 N 5 o + [M+H] + Calculated: 366.1536, Observed: 366.1531.

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Abstract

The disclosure provides compounds of Formula ( I-A ) and ( I-B) and the pharmaceutically acceptable salts thereof. The variables, R, R2, R3, X1, X2, X3, Y1, Y, and Z are defined herein. Certain compounds of Formula ( I-A) and (I-B) act as selective mitochondrial protonophore uncouplers that do not affect plasma membrane potential. These compounds 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, the compounds are useful for increasing lifespan. Compounds and salts of Formula( I-A ) and (I-B) are also useful for regulating glucose homeostasis or insulin actionin 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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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D471/04C07D498/04A61P3/04A61P3/00A61P25/16A61P25/28A61P35/00A61P37/00A61P3/10A61K31/4985A61K31/4745
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·桑托斯戴昱旻约瑟·A·圣地亚哥-里韦拉雅各布·H·默里
Owner 弗吉尼亚理工大学知识产权有限公司
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