Aminopyrazines and related compounds useful as mitochondrial uncouplers
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A technology of compound and alkyl, applied in the field of aminopyrazine and related compounds 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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Currently, there are no uncoupler drugs that are safe enough for use in humans
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example 1
[0202] Synthesis of Example 1.2-(Benzyloxy)-3-chloropyrazine (3-1)
[0203]
[0204] Compound 3-1 was synthesized by general procedure 3-A to give 3-1 as a clear oil which crystallized as a white solid. (87% yield). 1 H NMR (400MHz, chloroform-d) δ8.02 (d, J = 2.7Hz, 1H), 7.94 (d, J = 2.7Hz, 1H), 7.49 (m, 2H), 7.42–7.33 (m, 3H) ,5.48(s,2H). 13 C NMR (101 MHz, chloroform-d) δ 139.14, 138.16, 135.95, 135.68, 135.18, 128.69, 128.35, 127.98, 69.00.
example 2
[0205] Synthesis of Example 2.3-(Dodecylamino)pyrazin-2-ol (3-2)
[0206]
[0207] Compound 3-2 was synthesized by general procedure 3-B to afford 3-2 as a tan solid. (20% yield). HRMS (ESI + ): C 16 h 30 N 3 O+[M+H]+ calculated value: 280.2383, measured value: 280.2385
example 3
[0208] Synthesis of Example 3.3-((4-dodecylphenyl)amino)pyrazin-2-ol (3-3)
[0209]
[0210] Compound 3-3 was synthesized by general procedure 3-B to afford 3-3 as an off-white solid. (33% yield). 1 H NMR (400MHz, chloroform-d) δ12.16(s, 1H), 8.04(s, 1H), 7.68(d, J=8.1Hz, 2H), 7.17(d, J=8.1Hz, 2H), 7.09 (d, J=4.4Hz, 1H), 6.67(d, J=4.4Hz, 1H), 2.58(t, J=7.7Hz, 2H), 1.60(p, J=7.2Hz, 2H), 1.37–1.24 (m, 14H), 0.88 (t, J = 6.6Hz, 3H). 13 C NMR (101MHz, chloroform-d) δ153.11, 148.87, 138.02, 136.53, 129.03, 123.44, 119.37, 114.03, 35.53, 32.04, 31.73, 29.77, 29.76, 29.67, 29.48, 29.42, 242.83, 1 HRMS (ESI + ): C 20 h 30 N 3 O+[M+H]+ calculated: 328.2383, found: 328.2383.
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Abstract
The disclosure provides compounds of Formula I and the pharmaceutically acceptable salts thereof. The variables, R1, R2, R3, R4, R5, 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. The disclosure includes pharmaceutical composition comprising a compound or salt Formula I, and apharmaceutically acceptable carrier. Compounds and salts of Formula I are useful for treating or decreasing the risk of conditions responsive to mitochondrial uncoupling, such as obesity, cancer, 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 ...
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