Nicotinoyl riboside compositions and methods of use

• US 20070117765A1
• Filed: 11/17/2006
• Published: 05/24/2007
• Est. Priority Date: 11/18/2005
• Status: Active Grant

• Current Assignee: Cornell Research Foundation Incorporated (Cornell University)
• Original Assignee: Cornell Research Foundation Incorporated (Cornell University)
• Inventors: Sauve, Anthony, Yang, Tianle
• Granted Patent: US 8,106,184 B2
• Time in Patent Office: Days
• US Class Current: 514/43
• CPC Class Codes: A61K 31/351 not condensed with another ring
• CPC Class Codes: A61K 31/706 containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07H 1/00 Processes for the preparation of sugar derivatives
• CPC Class Codes: C07H 19/048 Pyridine radicals

Abstract

The invention relates to compositions of nicotinoyl ribosides and nicotinamide riboside derivatives and their methods of use. In some embodiments, the invention relates to methods of making nicotinoyl ribosides. In some embodiments, the invention relates to pharmaceutical compositions and nutritional supplements containing a nicotinoyl riboside. In further embodiments, the invention relates to methods of using nicotinoyl ribosides and nicotinamide riboside derivatives that promote the increase of intracellular levels of nicotinamide adenine dinucleotide (NAD+) in cells and tissues for improving cell and tissue survival.

Claims

1. A compound having the formula:

and salt complexes thereof wherein R is selected from the group consisting of alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkyloxy, substituted alkyloxy, aryloxy, substituted aryloxy, hydroxylamino, substituted hydroxylamino, O-alkyloxyamino, substituted O-alkyloxyamino, aminooxy, substituted aminoxy, N-alkylaminooxy, substituted N-alkylaminoxy, hydrazino, substituted hydrazino, alkylhydrazino, and substituted alkylhydrazino.

2. The compound of claim 1 wherein said alkoxy is —

OMe, —

OEt, or —

OCH₂CH₂OH.

3. The compound of claim 1 wherein said aryloxy is —

OPh.

4. The compound of claim 1 wherein said alkylamino is —

NHMe, —

NHEt, —

NHCH₂CH₂OH, —

NHCH₂CH═

CH₂, —

NHCH(CH₃)₂, —

NHCH₂CH₂NH₂, or NHcyclopropyl.

5. The compound of claim 1 wherein said dialkylamino is —

N(CH₃)₂ or N substituted pyrrolidinyl.

7. The compound of claim 1 wherein said alkoxy is —

OMe, —

OEt, or —

OCH₂CH₂OH.

8. The compound of claim 1 wherein said aryloxy is —

OPh.

9. The compound of claim 1 wherein said acyl is acetyl.

6. A compound having the following formula:

and salt complexes thereof wherein,

R¹ is alkyloxy, substituted alkyloxy, aryloxy, substituted aryloxy, arylthio, substituted arylthio, alkylthio, substituted alkylthio, aminooxy, substituted aminoxy, N-alkylaminooxy, and substituted N-alkylaminooxy; and

R², R³, and R⁴ are the same or different and, at each occurrence, independently acyl or substituted acyl.

10. A compound having the following formula:

and salt complexes thereof wherein,

R¹ is alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, hydrazine, substituted hydrazino, N-alkylaminohydrazino, hydroxylamino, substituted hydroxylamino, O-alkyloxyamino, or substituted O-alkyloxyamino;

R², R³, and R⁴ are the same or different and, at each occurrence, independently acyl or substituted acyl.

11. The compound of claim 10 wherein said acyl is acetyl.

12. The compound of claim 10 wherein said alkylamino is —

NHMe, —

NHEt, —

NHCH₂CH₂OH, —

NHCH₂CH═

CH₂, —

NHCH(CH₃)₂, —

NHCH₂CH₂NH₂, or NHcyclopropyl.

13. The compound of claim 10 wherein said dialkylamino is —

N(CH₃)₂ or N substituted pyrrolidinyl.

14. A method of making a compound having Formula I:

wherein, R¹ is amino, alkylamin, substituted alkylamino, dialkylamino, substituted dialkylamino, alkyloxy, substituted alkyloxy, aryloxy, substituted aryloxy, hydroxylamino, substituted hydroxylamino, O-alkyloxyamino, substituted O-alkyloxyamino, aminooxy, substituted aminoxy, N-alkylaminooxy, substituted N-alkylaminoxy, hydrazino, substituted hydrazino, alkylhydrazino, and substituted alkylhydrazino;

comprising;

i) mixing

a) tetra-acyl or substituted acyl ribofuranose and

b) a compound having formula II;

wherein, R² is alkyloxy, substituted alkyloxy, aryloxy, substituted aryloxy, alkylthiol, substituted alkylthiol, arylthiol, substituted arylthiol, aminooxy, substituted aminooxy, N-alkylaminooxy or substituted N-alkylaminooxy;

under conditions such that a compound of formula III;

wherein,

R² is alkyloxy, substituted alkyloxy, aryloxy, substituted aryloxy, alkylthiol, substituted alkylthiol, arylthiol, substituted arylthiol, aminooxy, substituted aminooxy, N-alkylaminooxy or substituted N-alkyl aminooxy, and R³, R⁴ and R⁵ are the same or different and, at each occurrence, independently acyl or substituted acyl

is formed; and

ii) mixing the compound of formula III with ammonia, hydrazine, substituted hydrazine, alkylhydrazine, substituted alkylhydrazine, hydroxylamine, substituted hydroxylamine, O-alkyloxyamine, substituted O-alkyloxylamine, N-alkylaminohydroxide, substituted N-alkylaminohydroxide, alkylamine, substituted alkylamine, dialkylamine, substituted dialkylamine, alkoxide, or substituted alkoxide under conditions such that a compound of formula I is formed.

15. The compound of claim 14 wherein said alkoxy is —

OMe, —

OEt, or —

OCH₂CH₂OH.

16. The compound of claim 14 wherein said aryloxy is —

OPh.

17. The compound of claim 14 wherein said acyl is acetyl.

18. The compound of claim 14 wherein said alkylamino is —

NHMe, —

NHEt, —

NHCH₂CH₂OH, —

NHCH₂CH═

CH₂, —

NHCH(CH₃)₂, —

NHCH₂CH₂NH₂, or NHcyclopropyl.

19. The compound of claim 14 wherein said dialkylamine is —

N(CH₃)₂ or N substituted pyrrolidinyl.

20. The method of claim 14 wherein the conditions of making compound I from compound III are in a halogenated alkyl alcohol solvent at a temperature below room temperature.

21. The method of claim 20 wherein said solvent is trifluoromethanol.

22. A method of making a compound comprising:

i) mixing

a) tetra-acyl or substituted acyl ribofuranose and

b) a compound having formula II;

wherein, R² is alkyloxy, substituted alkyloxy, aryloxy, substituted aryloxy, alkylthiol, substituted alkylthiol, arylthiol, substituted arylthiol, aminooxy, substituted aminooxy, N-alkylaminooxy or substituted N-alkyl aminooxy,

under conditions such that a compound of formula III;

wherein,

R² wherein, R² is alkyloxy, substituted alkyloxy, aryloxy, substituted aryloxy, alkylthiol, substituted alkylthiol, arylthiol, substituted arylthiol, aminooxy, substituted aminooxy, N-alkylaminooxy or substituted N-alkyl aminooxy, and

R³, R⁴ and R⁵ are the same or different and, at each occurrence, independently acyl or substituted acyl

is formed.

23. The compound of claim 22 wherein said alkoxy is —

OMe, —

OEt, or —

OCH₂CH₂OH.

24. The compound of claim 22 wherein said aryloxy is —

OPh.

25. The compound of claim 22 wherein said acyl is acetyl.

26. A method of making a compound comprising:

i) providing a compound of formula III;

wherein,

wherein, R² is alkyloxy, substituted alkyloxy, aryloxy, substituted aryloxy, alkylthiol, substituted alkylthiol, arylthiol, substituted arylthiol, aminooxy, substituted aminooxy, N-alkylaminooxy or substituted N-alkyl aminooxy, and

R³, R⁴ and R⁵ are the same or different and, at each occurrence, independently acyl or substituted acyl

is formed; and

ii) mixing the compound of formula III with ammonia, hydrazine, substituted hydrazine, alkylhydrazine, substituted alkylhydrazine, hydroxylamine, substituted hydroxylamine, O-alkyloxyamine, substituted O-alkyloxylamine, N-alkylaminohydroxide, substituted N-alkylaminohydroxide, alkylamine, substituted alkylamine, dialkylamine, substituted dialkylamine, alkoxide, or substituted alkoxide under conditions such that a compound of formula I;

wherein, R¹ is amino, substituted amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkyloxy, substituted alkyloxy, aryloxy, substituted aryloxy, hydroxylamino, substituted hydroxylamino, O-alkyloxyamino, substituted O-alkyloxyamino, aminooxy, substituted aminoxy, N-alkylaminooxy, substituted N-alkylaminoxy, hydrazino, substituted hydrazino, alkylhydrazino, and substituted alkylhydrazino;

is formed.

27. The compound of claim 26 wherein said alkoxy is —

OMe, —

OEt, or —

OCH₂CH₂OH.

28. The compound of claim 26 wherein said aryloxy is —

OPh.

29. The compound of claim 26 wherein said acyl is acetyl.

30. The compound of claim 26 wherein said alkylamino is —

NHMe, —

NHEt, —

NHCH₂CH₂OH, —

NHCH₂CH═

CH₂, —

NHCH(CH₃)₂, —

NHCH₂CH₂NH₂, or NHcyclopropyl.

31. The compound of claim 26 wherein said dialkylamino is —

N(CH₃)₂ or N substituted pyrrolidinyl.

32. The method of claim 26 wherein the conditions of making compound I from compound III are in a halogenated alkyl alcohol solvent at a temperature below room temperature.

33. The method of claim 26 wherein said solvent is trifluoromethanol.