IP Library › Granted Patent US 10,934,322
Granted Patent B2
US 10,934,322 · App. 15/977,851 · Granted Mar 2, 2021

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

Inventors: Marie Eugenie Migaud (Lurgan, GB); Philip Redpath (Portadown, GB); Kerri Crossey (Magherafelt, GB); Richard Cunningham (Portadown, GB); Ryan Dellinger (Azusa, CA); Troy Rhonemus (Mission Viejo, CA); Sylesh Venkataraman (Irvine, CA); Brian Nettles (Irvine, CA)
Assignees: ChromaDex Inc.; The Queen's University of Belfast
C07H19/048C07H1/00C07H19/04
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Quick Facts
Patent No.
US 10,934,322
App. No.
15/977,851
Granted
Mar 2, 2021
Kind
B2
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.

Claims (121)

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, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl(C 1 -C 4 )alkyl, and substituted heterocycle(C 1 -C 4 )alkyl 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 ;

Y 1 is selected from the group consisting of hydrogen, sodium, potassium, lithium, 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; 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 ;

Y 2 is selected from the group consisting of 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; wherein the substituted (C 1 -C 8 )alkyl, substituted (C 1 -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 ;

provided that when Z 2 is NH, the absolute configuration of C** is R or S, or a mixture of R and S;

further provided that when n is 0, Z 2 is NH, and R 1 , R 2 , R 3 , R 4 , and R 5 are each hydrogen, then R 6 is not —C(O)R′ or —C(O)OR′ where R′ is alkyl, and each of R 7 and R 8 are not independently —C(O)R′ or —C(O)OR′, where R′ is alkyl;

further provided that when n is 0, Z 2 is NH, R 1 is (C 1 -C 8 )alkyl or (C 3 -C 8 ) cycloalkyl, R 2 , R 3 , R 4 , and R 5 are each hydrogen, then each of R 6 , R 7 , and R 8 is not independently —C(O)R′;

further provided that when n is 0, Z 2 is oxygen, R 1 is (C 1 -C 8 )alkyl, (C 3 -C 8 ) cycloalkyl, aryl, or substituted aryl, and R 2 , R 3 , R 4 , and R 5 are each hydrogen, then R 6 , R 7 , and R 8 are not all simultaneously —C(O)R′; and

further provided that when R 6 is —P(O)(OY 1 )(NHR″), then Y 1 is not substituted or unsubstituted aryl and R″ is not —C**H—(R A )—CO 2 R B .

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

X − is selected from the group consisting of chloride, ascorbate, citrate, phosphate, sulfate, and trifluoromethanesulfonate;

Z 2 is oxygen;

n is 0;

R 1 is selected from the group consisting of thiamine ester, pterostilbenyl ester, choline ester, vitamin B1 ester, vitamin B2 ester, and vitamin B6 ester;

R 2 , R 3 , R 4 , and R 5 are each hydrogen;

R 6 is selected from the group consisting of hydrogen, —C(O)R′, tryptophan ester, isoleucine ester, alanine ester, phenylalanine ester, valine ester, methionine ester, leucine ester, vitamin B1 ester, vitamin B2 ester, and vitamin B6 ester;

R′ is selected from the group consisting of unsubstituted (C 1 -C 8 )alkyl, and substituted or unsubstituted heteroaryl; and

R 7 and R 8 are independently selected from the group consisting of hydrogen and —C(O)R′.

3. A nicotinate/nicotinamide riboside compound or derivative of formula (I) of claim 2 , wherein R′ is methyl or nicotinyl.

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

X − is selected from the group consisting of chloride, ascorbate, citrate, phosphate, sulfate, and trifluoromethanesulfonate;

Z 2 is NH;

n is 0;

R 1 is selected from the group consisting of hydrogen, thiamine ester, pterostilbene ester, choline ester, vitamin B1 ester, vitamin B2 ester, and vitamin B6 ester;

R 2 , R 3 , R 4 , and R 5 are each hydrogen;

R 6 is selected from the group consisting of hydrogen, —C(O)R′, tryptophan ester, isoleucine ester, alanine ester, phenylalanine ester, valine ester, methionine ester, leucine ester, vitamin B1 ester, vitamin B2 ester, and vitamin B6 ester;

R′ is selected from the group consisting of unsubstituted (C 1 -C 8 )alkyl and substituted or unsubstituted heteroaryl; and

R 7 and R 8 are independently selected from the group consisting of hydrogen and —C(O)R′.

5. A nicotinate/nicotinamide riboside compound or derivative of formula (I) of claim 4 , wherein R′ is methyl or nicotinyl.

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

X − is selected from the group consisting of chloride, ascorbate, citrate, phosphate, sulfate, and trifluoromethanesulfonate;

Z 2 is oxygen;

n is 0;

R 1 is selected from the group consisting of thiamine ester, pterostilbenyl ester, choline ester, vitamin B1 ester, vitamin B2 ester, and vitamin B6 ester;

R 2 , R 3 , R 4 , and R 5 are each hydrogen;

R 6 is —P(O)(OY 1 )(OY 2 );

Y 1 is selected from the group consisting of hydrogen, sodium, potassium, and lithium;

R 7 and R 8 are independently selected from the group consisting of hydrogen and —C(O)R′; and

R′ is selected from the group consisting of unsubstituted (C 1 -C 8 )alkyl and substituted or unsubstituted heteroaryl.

7. A nicotinate/nicotinamide riboside compound or derivative of formula (I) of claim 6 , wherein R′ is methyl or nicotinyl.

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

X − is selected from the group consisting of chloride, ascorbate, citrate, phosphate, sulfate, and trifluoromethanesulfonate;

Z 2 is NH;

n is 0;

R 1 is selected from the group consisting of thiamine ester, pterostilbenyl ester, choline ester, vitamin B1 ester, vitamin B2 ester, and vitamin B6 ester;

R 2 , R 3 , R 4 , and R 5 are each hydrogen;

R 6 is —P(O)(OY 1 )(OY 2 );

Y 1 is selected from the group consisting of hydrogen, sodium, potassium, and lithium;

R 7 and R 8 are independently selected from the group consisting of hydrogen and —C(O)R′; and

R′ is selected from the group consisting of unsubstituted (C 1 -C 8 )alkyl and substituted or unsubstituted heteroaryl.

9. A nicotinate/nicotinamide riboside compound or derivative of formula (I) of claim 8 , wherein R′ is methyl or nicotinyl.

10. A reduced nicotinate/nicotinamide riboside compound or derivative of formula (II):

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 B , —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 —(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 and R 3 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 4 is 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 ;

wherein C* has an absolute configuration of R or S, or a mixture of R and S;

R 5 is 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, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl(C 1 -C 4 )alkyl, and substituted heterocycle(C 1 -C 4 )alkyl 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 ;

Y 1 is selected from the group consisting of hydrogen, sodium, potassium, lithium, 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; 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 ;

Y 2 is selected from the group consisting of 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; 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 , —SO 2 (C 1 -C 6 )alkyl, —SO 2 NR C 2 , —(C 1 -C 6 )perfluoroalkyl, and —(C 1 -C 6 )alkylene-OR C ;

provided that when Z 2 is NH, the absolute configuration of C** is R or S, or a mixture of R and S;

further provided that when n is 0, Z 2 is NH, and R 2 , R 3 , R 4 , and R 5 are each hydrogen, then R 6 is not —C(O)R′ or —C(O)OR′, where R′ is alkyl, and each of R 7 and R 8 are not independently —C(O)R′ or —C(O)OR′;

further provided that when n is 0, Z 2 is oxygen, R 1 is hydrogen or (C 1 -C 4 )alkyl, and R 2 , R 3 , R 4 , and R 5 are each hydrogen, then each of R 6 , R 7 , and R 8 is not —C(O)R′, —C(O)OR′, or —C(O)NHR′, where R′ is hydrogen, unsubstituted (C 1 -C 8 )alkyl, unsubstituted (C 3 -C 8 ) cycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted heterocycle, unsubstituted aryl(C 1 -C 4 )alkyl, or unsubstituted heterocycle(C 1 -C 4 )alkyl; and

further provided that when R 6 is —P(O)(OY 1 )(NHR″), then Y 1 is not substituted or unsubstituted aryl and R″ is not —C**H—(R A )—CO 2 R B .

11. A nicotinate/nicotinamide riboside compound or derivative of formula (II) of claim 10 , wherein:

Z 2 is oxygen;

n is 0;

R 1 is selected from the group consisting of thiamine ester, pterostilbenyl ester, choline ester, vitamin B1 ester, vitamin B2 ester, and vitamin B6 ester;

R 2 , R 3 , R 4 , and R 5 are each hydrogen;

R 6 is selected from the group consisting of hydrogen, —C(O)R′, tryptophan ester, isoleucine ester, alanine ester, phenylalanine ester, valine ester, methionine ester, leucine ester, vitamin B1 ester, vitamin B2 ester, and vitamin B6 ester;

R′ is selected from the group consisting of unsubstituted (C 1 -C 8 )alkyl, and substituted or unsubstituted heteroaryl; and

R 7 and R 8 are independently selected from the group consisting of hydrogen and —C(O)R′.

12. A nicotinate/nicotinamide riboside compound or derivative of formula (II) of claim 11 , wherein R′ is methyl or nicotinyl.

13. A nicotinate/nicotinamide riboside compound or derivative of formula (II) of claim 10 , wherein:

Z 2 is NH;

n is 0;

R 1 is selected from the group consisting of hydrogen, thiamine ester, pterostilbene ester, choline ester, vitamin B1 ester, vitamin B2 ester, and vitamin B6 ester;

R 2 , R 3 , R 4 , and R 5 are each hydrogen;

R 6 is selected from the group consisting of hydrogen, —C(O)R′, tryptophan ester, isoleucine ester, alanine ester, phenylalanine ester, valine ester, methionine ester, leucine ester, vitamin B1 ester, vitamin B2 ester, and vitamin B6 ester;

R′ is selected from the group consisting of unsubstituted (C 1 -C 8 )alkyl and substituted or unsubstituted heteroaryl; and

R 7 and R 8 are independently selected from the group consisting of hydrogen and —C(O)R′.

14. A nicotinate/nicotinamide riboside compound or derivative of formula (II) of claim 13 , wherein R′ is methyl or nicotinyl.

15. A nicotinate/nicotinamide riboside compound or derivative of formula (II) of claim 10 , wherein:

Z 2 is oxygen;

n is 0;

R 1 is selected from the group consisting of thiamine ester, pterostilbenyl ester, choline ester, vitamin B1 ester, vitamin B2 ester, and vitamin B6 ester;

R 2 , R 3 , R 4 , and R 5 are each hydrogen;

R 6 is —P(O)(OY 1 )(OY 2 );

Y 1 is selected form the group consisting of hydrogen, sodium, potassium, and lithium;

R 7 and R 8 are independently selected from the group consisting of hydrogen and —C(O)R′; and

R′ is selected from the group consisting of unsubstituted (C 1 -C 8 )alkyl and substituted or unsubstituted heteroaryl.

16. A nicotinate/nicotinamide riboside compound or derivative of formula (II) of claim 15 , wherein R′ is methyl or nicotinyl.

17. A nicotinate/nicotinamide riboside compound or derivative of formula (II) of claim 10 , wherein:

Z 2 is nitrogen;

n is 0;

R 1 is selected from the group consisting of thiamine ester, pterostilbenyl ester, choline ester, vitamin B1 ester, vitamin B2 ester, and vitamin B6 ester;

R 2 , R 3 , R 4 , and R 5 are each hydrogen;

R 6 is —P(O)(OY 1 )(OY 2 );

Y 1 is selected from the group consisting of hydrogen, sodium, potassium, and lithium;

R 7 and R 8 are independently selected from the group consisting of hydrogen and —C(O)R′; and

R′ is selected from the group consisting of unsubstituted (C 1 -C 8 )alkyl and substituted or unsubstituted heteroaryl.

18. A nicotinate/nicotinamide riboside compound or derivative of formula (II) of claim 17 , wherein R′ is methyl or nicotinyl.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 17, 2026
From: QUEEN'S UNIVERSITY BELFAST
To: CHROMADEX INC.
Reel/Frame 075102/0433 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 24, 2020
From: CROSSEY, KERRI; CUNNINGHAM, RICHARD; DELLINGER, RYAN; MIGAUD, MARIE; NETTLES, BRIAN; REDPATH, PHILIP; RHONEMUS, TROY; VENKATARAMAN, SYLESH
To: CHROMADEX, INC.; THE QUEEN'S UNIVERSITY OF BELFAST
Reel/Frame 054456/0001 →