B-vitamin and amino acid conjugates of nicotinoyl ribosides and reduced nicotinoyl ribosides, derivatives thereof, and methods of preparation thereof

Patent metadata

Field	Value
Publication number	US-10934322-B2
Application number	US-201815977851-A
Country	US
Kind code	B2
Filing date	May 11, 2018
Priority date	Mar 16, 2016
Publication date	Mar 2, 2021
Grant date	Mar 2, 2021

Abstract

The present disclosure provides nicotinate/nicotinamide riboside compounds or derivatives of formula (I):

wherein X − , Z 1 , Z 2 , n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are described herein, reduced analogs thereof, and synthetic processes for the preparation thereof.

First claim

We claim:

1. A nicotinate/nicotinamide riboside compound or derivative of formula (I):

wherein X − as counterion is absent, or when X − is present, X − is selected from the group consisting of fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate, succinate, sulfate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluoroacetate;
Z 1 and Z 2 are independently NH or oxygen;
n is 0 or 1;
R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted (C 1 -C 8 )alkyl, substituted or unsubstituted (C 3 -C 8 ) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, thiamine ester, pterostilbenyl ester, choline ester, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, and —C**H(R A )—CO 2 R B ; wherein the substituted (C 1 -C 8 )alkyl, substituted (C 3 -C 8 ) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halogen, —CN, —NO 2 , —C(O)R C , —C(O)OR C , —C(O)NR C 2 , —C(═NR C )NR C 2 , —OR C , —OC(O)(C 1 -C 6 )alkyl, —OC(O)O(C 1 -C 6 )alkyl, —OC(O)NR C 2 , —(C 1 -C 6 )alkylene-NR C 2 , —NR C 2 , —NR C C(O)R C , —NR C C(O)O(C 1 -C 6 )alkyl, —NR C C(O)NR C 2 , —NR C SO 2 NR C , —SR C , —S(O)R C , —SO 2 R C , —OSO 2 (C 1 -C 6 )alkyl, —SO 2 NR C 2 , —(C 1 -C 6 )perfluoroalkyl, and —(C 1 -C 6 )alkylene-OR C ;
R A is selected from the group consisting of —H, —(C 1 -C 6 )alkyl, —(CH 2 ) 3 —NH—C(NH 2 )(═NH), —CH 2 C(═O)NH 2 , —CH 2 COOH, —CH 2 SH, —(CH 2 ) 2 C(═O)—NH 2 , —(CH 2 ) 2 COOH, —CH 2 -(2-imidazolyl), —CH(CH 3 )—CH 2 —CH 3 , —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 4 —NH 2 , —(CH 2 ) 2 —S—CH 3 , phenyl, —CH 2 -phenyl, —CH 2 —OH, —CH(OH)—CH 3 , —CH 2 -(3-indolyl), —CH 2 -(4-hydroxyphenyl), —CH(CH 3 ) 2 , and —CH 2 —CH 3 ;
R B is hydrogen or —(C 1 -C 8 )alkyl;
each R C is independently selected from the group consisting of hydrogen, —(C 1 -C 8 )alkyl, substituted or unsubstituted pyridyl, and substituted or unsubstituted 1,4-dihydropyridyl; wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted with one to five substituents independently selected from the group consisting of —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halogen, —CN, —NO 2 , —C(O)R B , —C(O)OR B , —C(O)NR B 2 , —C(═NR B )NR B 2 , —OR B , —OC(O)(C 1 -C 6 )alkyl, —OC(O)O(C 1 -C 6 )alkyl, —OC(O)NR B 2 , —(C 1 -C 6 )alkylene-NR B 2 , —NR B 2 , —NR B C(O)R B , —NR B C(O)O(C 1 -C 6 )alkyl, —NR B C(O)NR B 2 , —NR B SO 2 NR B , —SR B , —S(O)R B , —SO 2 R B , —OSO 2 (C 1 -C 6 )alkyl, —SO 2 NR B 2 , —(C 1 -C 6 )perfluoroalkyl, and —(C 1 -C 6 )alkylene-OR B ;
R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halogen, —CN, —NO 2 , —C(O)R C , —C(O)OR C , —C(O)NR C 2 , —C(═NR C )NR C 2 , —OR C , —OC(O)(C 1 -C 6 )alkyl, —OC(O)O(C 1 -C 6 )alkyl, —OC(O)NR C 2 , —(C 1 -C 6 )alkylene-NR C 2 , —NR C 2 , —NR C C(O)R C , —NR C C(O)O(C 1 -C 6 )alkyl, —NR C C(O)NR C 2 , —NR C SO 2 NR C , —SR C , —S(O)R C , —SO 2 R C , —OSO 2 (C 1 -C 6 )alkyl, —SO 2 NR C 2 , —(C 1 -C 6 )perfluoroalkyl, and —(C 1 -C 6 )alkylene-OR C ;
R 6 is selected from the group consisting of hydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, —P(O)(OY 1 )(OY 2 ), —P(O)(OY 1 )(NHR″), substituted or unsubstituted (C 1 -C 8 )alkyl, substituted or unsubstituted (C 3 -C 8 ) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, tryptophan ester, isoleucine ester, alanine ester, phenylalanine ester, valine ester, methionine ester, leucine ester, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, and —C**H—(R A )—CO 2 R B ; wherein the substituted (C 1 -C 8 )alkyl, substituted (C 3 -C 8 ) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halogen, —CN, —NO 2 , —C(O)R C , —C(O)OR C , —C(O)NR C 2 , —C(═NR C )NR C 2 , —OR C , —OC(O)(C 1 -C 6 )alkyl, —OC(O)O(C 1 -C 6 )alkyl, —OC(O)NR C 2 , —(C 1 -C 6 )alkylene-NR C 2 , —NR C 2 , —NR C C(O)R C , —NR C C(O)O(C 1 -C 6 )alkyl, —NR C C(O)NR C 2 , —NR C SO 2 NR C , —SR C , —S(O)R C , —SO 2 R C , —OSO 2 (C 1 -C 6 )alkyl, —SO 2 NR C 2 , —(C 1 -C 6 )perfluoroalkyl, and —(C 1 -C 6 )alkylene-OR C ;
R′ is selected from the group consisting of hydrogen, substituted or unsubstituted (C 1 -C 8 )alkyl, substituted or unsubstituted (C 3 -C 8 ) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl(C 1 -C 4 )alkyl, heterocycle(C 1 -C 4 )alkyl, and —C**H—(R A )—CO 2 R B ; wherein the substituted (C 1 -C 8 )alkyl, substituted (C 3 -C 8 ) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halogen, —CN, —NO 2 , —C(O)R C , —C(O)OR C , —C(O)NR C 2 , —C(═NR C )NR C 2 , —OR C , —OC(O)(C 1 -C 6 )alkyl, —OC(O)O(C 1 -C 6 )alkyl, —OC(O)NR C 2 , —(C 1 -C 6 )alkylene-NR C 2 , —NR C 2 , —NR C C(O)R C , —NR C C(O)O(C 1 -C 6 )alkyl, —NR C C(O)NR C 2 , —NR C SO 2 NR C , —SR C , —S(O)R C , —SO 2 R C , —OSO 2 (C 1 -C 6 )alkyl, —SO 2 NR C 2 , —(C 1 -C 6 )perfluoroalkyl, and —(C 1 -C 6 )alkylene-OR C ;
R″ is selected from the group consisting of hydrogen, substituted or unsubstituted (C 1 -C 8 )alkyl, substituted or unsubstituted (C 3 -C 8 ) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl(C 1 -C 4 )alkyl, heterocycle(C 1 -C 4 )alkyl, and —C**H—(R A )—CO 2 R B ; wherein the substituted (C 1 -C 8 )alkyl, substituted (C 3 -C 8 ) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halogen, —CN, —NO 2 , —C(O)R C , —C(O)OR C , —C(O)NR C 2 , —C(═NR C )NR C 2 , —OR C , —OC(O)(C 1 -C 6 )alkyl, —OC(O)O(C 1 -C 6 )alkyl, —OC(O)NR C 2 , —(C 1 -C 6 )alkylene-NR C 2 , —NR C 2 , —NR C C(O)R C , —NR C C(O)O(C 1 -C 6 )alkyl, —NR C C(O)NR C 2 , —NR C SO 2 NR C , —SR C , —S(O)R C , —SO 2 R C , —OSO 2 (C 1 -C 6 )alkyl, —SO 2 NR C 2 , —(C 1 -C 6 )perfluoroalkyl, and —(C 1 -C 6 )alkylene-OR C ;
R 7 and R 8 are independently selected from the group consisting of —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C 1 -C 8 )alkyl, substituted or unsubstituted (C 3 -C 8 ) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C 1 -C 4 )alkyl, and substituted or unsubstituted heterocycle(C 1 -C 4 )alkyl; wherein the substituted (C 1 -C 8 )alkyl, substituted (C 3 -C 8 ) cycloalkyl, substitute

Assignees

• Chromadex Inc
• Univ Belfast

Inventors

• Migaud Marie Eugenie
• Redpath Philip
• Crossey Kerri
• Cunningham Richard
• Dellinger Ryan
• Rhonemus Troy
• Venkataraman Sylesh
• Nettles Brian

Classifications

• C07H19/048 Primary

  Pyridine radicals · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• C07H19/04

  Heterocyclic radicals containing only nitrogen atoms as ring hetero atom · CPC title