Efficient and scalable syntheses of nicotinoyl ribosides and reduced nicotinoyl ribosides, modified derivatives thereof, phosphorylated analogs thereof, adenylyl dinucleotide conjugates thereof, and novel crystalline forms thereof

Patent metadata

Field	Value
Publication number	US-12195494-B2
Application number	US-202318237503-A
Country	US
Kind code	B2
Filing date	Aug 24, 2023
Priority date	Nov 11, 2016
Publication date	Jan 14, 2025
Grant date	Jan 14, 2025

Abstract

The present disclosure provides methods of making nicotinoyl 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, modified derivatives thereof, phosphorylated analogs thereof, and adenylyl dinucleotide conjugates thereof, or salts, solvates, or prodrugs thereof, and novel crystalline forms thereof.

First claim

We claim:

1. A method of making a compound or derivative having formula (I-H), or salt, solvate, or prodrug thereof, wherein R 6 , R 7 and R 8 are each hydrogen:

wherein X − as counterion is absent, or when X − is present, X − is selected from the group consisting of a fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, succinate, sulfate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, malate, tartrate, glycolate, glucuronate, maleate, fumarate, pyruvate, anthranilate, 4-hydroxyl benzoate, phenylacetate, mandelate, palmoate, methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, trifluoroacetate, trichloroacetate, tribromoacetate, 2-hydroxyethananesulfonyl, p-toluenesulfonyl, sulfanilate, cyclohexylaminosulfonate, stearate, alginate, beta-hydroxybutyrate, salicylate, galactarate, galacturonate, nitrate, and phosphate,
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, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl (C 1 -C 4 )alkyl, heterocycle (C 1 -C 4 )alkyl, —N(R A )—CO 2 R C , —N(R A )—CO 2 R B , —C**H—(R A )—NH 2 , 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)NR2 C , -C(═NR C )NR 2 C , —OR C , —OC(O)(C 1 -C 6 )alkyl, —OC(O)O(C 1 -C 6 )alkyl, —OC(O)NR 2 C , —(C 1 -C 6 )alkylene-NR 2 C , —NR 2 C , —NR C C(O)R C , —NR C C(O)O(C 1 -C 6 )alkyl, —NR C C(O)NR 2 C , —NR C SO 2 NR2 C , —SR C , —S(O)R C , —SO 2 R C , —OSO 2 (C 1 -C 6 )alkyl, —SO 2 NR 2 C , —(C 1 -C 6 )perfluoroalkyl, and —(C 1 -C 6 )alkylene-OR C ;
wherein when R 1 is hydrogen, Z 2 is oxygen, and n is 0, the compound or derivative having formula (I-H) may optionally take the form of the carboxylate anion conjugate base species of the compound or derivative having formula (I-H), further optionally associated with a positively charged counterion selected from the group consisting of calcium, magnesium, potassium, sodium, zinc, and ammonium cations;
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 , —NH 2 , and —CH 2 —CH 3 ;
each R B is independently 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 2 B , -C(═NR B )NR 2 B , —OR B , —OC(O)(C 1 -C 6 )alkyl, —OC(O)O(C 1 -C 6 )alkyl, —OC(O)NR 2 B , —(C 1 -C 6 )alkylene-NR 2 B , —NR 2 B , —NRBC(O)R B , —NRBC(O)O(C 1 -C 6 )alkyl, —NRBC(O)NR 2 B , —NR B SO 2 NR 2 B , —SR B , —S(O)R B , —SO 2 R B , —OSO 2 (C 1 -C 6 )alkyl, —SO 2 NR 2 B , —(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 2 C , -C(═NR C )NR 2 C , —OR C , —OC(O)(C 1 -C 6 )alkyl, —OC(O)O(C 1 -C 6 )alkyl, —OC(O)NR 2 C , —(C 1 -C 6 )alkylene-NR 2 C , —NR 2 C , —NR C C(O)R C , —NR C C(O)O(C 1 -C 6 )alkyl, —NR C C(O)NR 2 C , —NR C SO 2 NR 2 C , —SR C , —S(O)R C , —SO 2 R C , —OSO 2 (C 1 -C 6 )alkyl, —SO 2 NR 2 C , (C 1 -C 6 ) perfluoroalkyl, and —(C 1 -C 6 )alkylene-OR C ;
provided that the absolute configuration of C** is R or S, or a mixture of R and S; comprising the steps of:
(a) providing a compound or derivative having formula (I), or a salt, solvate, or prodrug thereof:

wherein X − as counterion is absent, or when X − is present, X − is selected from the group consisting of a fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, succinate, sulfate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, malate, tartrate, glycolate, glucuronate, maleate, fumarate, pyruvate, anthranilate, 4-hydroxyl benzoate, phenylacetate, mandelate, palmoate, methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, trifluoroacetate, trichloroacetate, tribromoacetate, 2-hydroxyethananesulfonyl, p-toluenesulfonyl, sulfanilate, cyclohexylaminosulfonate, stearate, alginate, beta-hydroxybutyrate, salicylate, galactarate, galacturonate, nitrate, and phosphate;
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, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl (C 1 -C 4 )alkyl, TMS, heterocycle (C 1 -C 4 )alkyl, —N(R A )—CO 2 R C , -N(R A )—CO 2 R B , —C**H—(R A )—NH 2 , 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 2 C , -C(═NR C )NR 2 C , —OR C , —OC(O)(C 1 -C 6 )alkyl, —OC(O)O(C 1 -C 6 )alkyl, —OC(O)NR 2 C , —(C 1 -C 6 )alkylene-NR 2 C , —NR 2 C , —NR C C(O)R C , —NR C C(O)O(C 1 -C 6 )alkyl, —NR C C(O)NR2 C , —NR C SO 2 NR 2 C , —SR C , —S(O)R C , —SO 2 R C , —OSO 2 (C 1 -C 6 )alkyl, —SO 2 NR 2 C , —(C 1 -C 6 ) perfluoroalkyl, and —(C 1 -C 6 )alkylene-OR C ;
wherein when R 1 is hydrogen, Z 2 is oxygen, and n is 0, the compound or derivate having formula (I) may optionally take the form of the carboxylate anion conjugate base species of the compound or derivative having formula (I), further optionally associated with a positively charged counterion selected from the group consisting of calcium, magnesium, potassium, sodium, zinc, and ammonium cations;
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

Assignees

• Univ Belfast
• Chromadex Inc

Inventors

• Migaud Marie Eugenie
• Redpath Philip
• Crossey Kerri
• Cunningham Richard
• Erickson Aron
• Nygaard Richard
• Storjohann Amanda

Classifications

• C07B2200/07

  Optical isomers · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• C07H19/048 Primary

  Pyridine radicals · CPC title

• C07H19/20

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title

• C07D307/20

  Oxygen atoms · CPC title