Beta-nicotinate ester nucleotides and processes for preparing same

Patent metadata

Field	Value
Publication number	US-11530233-B2
Application number	US-202117216533-A
Country	US
Kind code	B2
Filing date	Mar 29, 2021
Priority date	Apr 5, 2017
Publication date	Dec 20, 2022
Grant date	Dec 20, 2022

Abstract

The invention provides a compound of formula (I):

wherein R is as described herein. The invention also provides a process for the preparation of the compound.

First claim

The invention claimed is:

1. A process for the preparation of a compound of formula (I):

wherein R is straight or branched chain C 3 -C 20 alkyl, straight or branched chain C 3 -C 20 alkenyl, C 3 -C 20 alkynyl, C 3 -C 20 cycloalkyl, C 6 -C 10 aryl, C 3 -C 20 heterocyclyl, or C 5 -C 10 heteroaryl, or a salt thereof, wherein R is substituted or unsubstituted, and wherein the process comprises the step of reacting a compound of formula (III):

with a mixture of POCl 3 and PO(OR 5 ) 3 , wherein R 5 is C 1 -C 6 alkyl, followed by isolation of the compound of formula (I).

2. The process of claim 1 , wherein R is n-propyl.

3. The process of claim 1 , wherein the compound of formula (III) is prepared by reacting a compound of formula (II):

wherein R′ is methyl or ethyl, with a compound of formula ROH in the presence of a base in a solvent to form the compound of formula (III).

4. The process of claim 3 , wherein the base is potassium t-butoxide, the solvent is ROH, or the base is potassium t-butoxide and the solvent is ROH.

5. The process of claim 1 , wherein the compound of formula (III) is prepared by reacting a nicotinate ester (IV):

with 1,2,3,4-tetra-O-acetyl-D-ribofuranose to provide a compound of formula (V):

and reacting the compound of formula (V) with a base to form the compound of formula (III).

6. A compound of formula (I):

wherein R is n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, 2,2-dimethylpropyl, 3-methylbutyl, isopropyl, 1,1-dimethylpropyl, t-butyl, substituted or unsubstituted morpholine, substituted or unsubstituted piperidine, substituted or unsubstituted tetrahydrofuryl, substituted or unsubstituted oxetanyl, substituted or unsubstituted pyrrolidinyl, or substituted or unsubstituted dihydrobenzofuran, or a salt thereof.

7. A pharmaceutical composition comprising the compound or salt of claim 6 and a pharmaceutically acceptable carrier.

8. A nutraceutical composition comprising a compound or salt of claim 6 .

9. A method for increasing cell NAD + production comprising administering to a cell a compound of claim 6 or a salt thereof.

10. The method of claim 9 , wherein the cell is in a mammal having a lipid disorder, a metabolic dysfunction, a cardiovascular disease, CNS or PNS trauma, a neurodegenerative disease or condition, or hearing loss, or is in a mammal that has been exposed to a toxic agent.

11. The method of claim 9 , wherein the cell is in a mammal, wherein the compound is administered in an amount effective for promoting the function of the metabolic system, promoting muscle function or recovery, promoting the function of the auditory system, or promoting cognitive function.

12. A method of improving mitochondrial densities in a cell, wherein the method comprises administering to the cell a compound of claim 6 or a salt thereof.

13. The method of claim 12 , wherein the cell is in a mammal having a lipid disorder, a metabolic dysfunction, a cardiovascular disease, CNS or PNS trauma, a neurodegenerative disease or condition, hearing loss, or is in a mammal that has been exposed to a toxic agent.

14. The method of claim 12 , wherein the cell is in a mammal at risk for hearing loss.

15. The method of claim 12 , wherein the cell is in a mammal, wherein the compound is administered in an amount effective for promoting the function of the metabolic system, promoting muscle function or recovery, promoting the function of the auditory system, or promoting cognitive function.

16. The process of claim 1 , wherein R is n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, 2,2-dimethylpropyl, 3-methylbutyl, isopropyl, 1,1-dimethylpropyl, or t-butyl.

17. The process of claim 3 , wherein R is n-propyl.

18. The process of claim 1 , wherein R is substituted or unsubstituted C 3 -C 20 heterocyclyl.

19. The process of claim 18 , wherein the substituted or unsubstituted C 3 -C 20 heterocyclyl is selected from substituted or unsubstituted morpholine, substituted or unsubstituted piperidine, substituted or unsubstituted tetrahydrofuryl, substituted or unsubstituted oxetanyl, substituted or unsubstituted pyrrolidinyl, and substituted or unsubstituted dihydrobenzofuran.

20. The process of claim 19 , wherein the substitution comprises 1, 2, 3, 4, or 5 substituents independently selected from alkyl, halo, or aryl.

21. The compound of claim 6 , wherein:
R is substituted or unsubstituted morpholine, substituted or unsubstituted piperidine, substituted or unsubstituted tetrahydrofuryl, substituted or unsubstituted oxetanyl, substituted or unsubstituted pyrrolidinyl, or substituted or unsubstituted dihydrobenzofuran, or a salt thereof; and
optionally, the substitution comprises 1, 2, 3, 4, or 5 substituents independently selected from alkyl, halo, or aryl.

22. The compound of claim 6 , wherein R is n-propyl.

23. The method of claim 9 , wherein R is n-propyl.

24. The method of claim 12 , wherein R is n-propyl.

Assignees

• Univ Cornell

Inventors

• Sauve Anthony A

Classifications

• A61P27/16

  Otologicals · CPC title

• A61P21/00 Primary

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• A23V2200/322

  having an effect on the health of the nervous system or on mental function · CPC title

• C07F9/65586

  at least one of the hetero rings does not contain nitrogen as ring hetero atom · CPC title

• C07H19/048 Primary

  Pyridine radicals · CPC title