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Nicotinamide riboside analogs and pharmaceutical compositions and uses thereof

A technology of nicotinamide riboside hydrogenated product and nicotinamide riboside, which is applied in the field of the composition of nicotinamide riboside analogues, and can solve the problems of bioavailability limitation, cell toxicity, side effects, etc.

Inactive Publication Date: 2017-05-24
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although nicotinamide riboside itself can be used as a potent NAD + precursor to boost NAD + levels and improve the health of cells and organisms, but bioavailability may be limited by the conditions of different modes of administration
Therefore, there is a need for nicotinamide riboside analogs with improved bioavailability and optimal tissue selectivity, but such compounds have also proven to be potentially toxic to cells
For example benzamide nucleosides are well known anticancer agents that are metabolized to the active NAD analog benzamide adenine dinucleotide, which inhibits certain NAD-dependent dehydrogenases such as malate dehydrogenase enzymes and glutamate dehydrogenase, which may cause side effects

Method used

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  • Nicotinamide riboside analogs and pharmaceutical compositions and uses thereof
  • Nicotinamide riboside analogs and pharmaceutical compositions and uses thereof
  • Nicotinamide riboside analogs and pharmaceutical compositions and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0327] Embodiment 1: the synthesis of NRH triacetate .

[0328]

[0329] Step 1. 3-carbamoyl-1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridine-1- Onium triflate (NR triacetate triflate). At room temperature, to 27.98g (229mmol) nicotinamide in 350mL CH 3To the suspension in CN was added 73 mL (403 mmol) trimethylsilyl triflate (TMSOTf) in one portion. The niacinamide is completely dissolved within 5 minutes. Separately prepare α / β-D-ribofuranose-1,2,3,5-tetra-O-acetate 24.31g (76.39mmol) in 30mL CH 3 The solution in CN was then added to the nicotinamide solution in one batch. Dissolve the last trace of ribose ester in 10 mL CH 3 CN and added it to the reaction mixture. The solution was stirred at room temperature for 30 min, then dissolved by adding 1 mL of 1.2M NaHCO 3(水溶液) to quench the excess TMSOTf, followed by the addition of 20 g solid NaHCO in small batches 3 to control CO 2 release. The suspension was stirred at room temperatur...

Embodiment 2

[0332] Embodiment 2: the synthesis of NRH tripropionate

[0333]

[0334] Step 1. α / β-D-ribofuranose-1,2,3,5-tetra-O-propionate. To 1.11 g (6.76 mmol) of 1-O-methyl-α / β-D-furan Add 20mL (150mmol) propionic anhydride and 1.0mL (13mmol) propionic acid to ribose. The mixture was stirred and heated at 100°C for 1.5 hours, then it was stored at -20°C overnight (18h). In the morning, the reaction mixture was warmed to 25 °C, then 0.2 mL of H 2 SO 4 , and the reaction mixture was stirred at room temperature for 2 hours. Pour this solution into 100 mL of cold 1.2M NaHCO 3 solution, and the mixture was washed with CH 2 Cl 2 (2x 100 mL) extraction. CH that will be merged 2 Cl 2 Layer with 1.2M NaHCO 3(水溶液) (1x 100 mL) and brine (1x 100 mL), filtering if necessary to break up any emulsion. The organic layer was washed with Na 2 SO 4 Dry, filter, and concentrate in vacuo. The residue was purified by silica gel chromatography (40 g column) with 40 mL of pentane, a gradie...

Embodiment 3

[0339] Embodiment 3: the synthesis of NRH tri-n-butyrate

[0340]

[0341] Step 1. α / β-D-ribofuranose-1,2,3,5-tetra-O-n-butyrate. Add 1.00 g (6.09 mmol) of 1-O-methyl-α / β-D- Add 20mL (120mmol) butyric anhydride and 1.0mL (11mmol) butyric acid to ribofuranose. The stirred reaction mixture was heated at 100 °C for 1.5 h, then cooled to room temperature. Then add 0.30 mL (5.6 mmol) of 98% H 2 SO 4 , and the reaction was stirred at room temperature for 1 h. LCMS (also known as LC-MS or liquid chromatography-mass spectrometry) showed that the reaction was complete after this time. Pour this solution into 100 mL of cold 1.2M NaHCO 3 solution, and the mixture was washed with CH 2 Cl 2 (2x 100 mL) extraction. CH that will be merged 2 Cl 2 layer with 1.2M NaHCO 3(水溶液) (1x 100 mL) and brine (1x 100 mL), filtering if necessary to break up any emulsion. The organic layer was washed with Na 2 SO 4 Dry, filter, and concentrate in vacuo. The residue was purified by silica...

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Abstract

Provided herein are stereoisomerically pure ester and carbonate analogues of nicotinamide riboside and nicotinamide riboside hydride, and pharmaceutical compositions and uses thereof. The stereoisomerically pure ester and carbonate analogues of nicotinamide riboside and nicotinamide riboside hydride may be used to treat a disease or disorder that would benefit from increased NAD levels including a mitochondrial disease or disorder, insulin resistance, a metabolic syndrome, diabetes, obesity, for increasing insulin sensitivity in a subject, or to treat or prevent a skin condition. The compounds have general formulas (I) or (II) wherein R1 is -C(=O)-X-(C2-C18 straight chain or branched) alkyl or -C(=O)-X-(C2-C18 straight chain or branched) alkenyl; each R2 is independently selected from hydrogen, and a -C(O)-X-(C2-C18 straight chain or branched) alkyl or a -C(O)-X-(C2-C18 straight chain or branched) alkenyl; and X is a covalent bond or O.

Description

technical field [0001] The present invention relates to compositions of nicotinamide riboside (nicotinamide riboside) analogs (including esters and carbonates) for increasing nicotinamide adenine dinucleotide (NAD) in cells and tissues of organisms + )s level. The new composition includes pharmaceutical composition and nutritional supplement, and the present invention also relates to + A method of treating or preventing a disease or condition in an organism. [0002] Background of the invention [0003] In the early 20th century, vitamin B3 was identified as a missing ingredient in the diet of patients with pellagra. By supplementing with niacin (or niacin), the symptoms of dermatitis were improved and the occurrence of the condition was prevented in areas where the condition was endemic. The biochemistry of niacin was elucidated in the 1930s and found to be critical for the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a compound essential for cellular respira...

Claims

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Application Information

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IPC IPC(8): C07H19/048A61K8/67A61K31/706A61K45/06A61Q19/00A61Q19/08
CPCA61K8/675A61K31/706A61K45/06A61K2800/522A61Q19/004A61Q19/08A61P3/00A61P3/10A61P9/10A61P17/00A61P17/02A61P17/06A61P21/00A61P25/00A61P25/08A61P27/02A61P29/00A61P35/00A61P37/08A61P43/00C07H19/048A61K2300/00
Inventor K.科派奇R.B.珀尼B.什切潘基威茨F.普罗格沙特
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