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-11345720-B2
Application number	US-202117551592-A
Country	US
Kind code	B2
Filing date	Dec 15, 2021
Priority date	Nov 11, 2016
Publication date	May 31, 2022
Grant date	May 31, 2022

Abstract

The present disclosure provides methods of making nicotinoyl riboside compounds or derivatives of formula (I):wherein X−, Z1, Z2, n, R1, R2, R3, R4, R5, R6, R7, and R8 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 crystalline NR methanolate Form II of nicotinamide riboside chloride according to formula (VII):

2. The crystalline NR methanolate Form II of claim 1 that is characterized by a powder X-ray diffraction pattern having peaks at 23.7, 24.5, and 25.4 degrees two theta±0.2 degrees two theta.

3. The crystalline NR methanolate Form II of claim 1 that is characterized by a powder X-ray diffraction pattern having peaks at 12.9, 23.7, 24.5, and 25.4 degrees two theta±0.2 degrees two theta.

4. The crystalline NR methanolate Form II of claim 1 that is characterized by a powder X-ray diffraction pattern having peaks at 12.9, 13.9, 14.8, 23.7, 24.5, and 25.4 degrees two theta±0.2 degrees two theta.

5. The crystalline NR methanolate Form II of claim 1 that is characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 16 .

6. The crystalline NR methanolate Form II of claim 1 that is characterized by a powder X-ray diffraction pattern having peaks substantially as provided in Table 7±0.2 degrees two theta.

7. The crystalline NR methanolate Form II of claim 1 that is characterized by an IR spectrum having peaks at 565.1, 611.3, 638.3, and 680.8 cm −1 ±0.2 cm −1 .

8. The crystalline NR methanolate Form II of claim 1 that is characterized by an IR spectrum having peaks at 565.1, 611.3, 638.3, 680.8, 981.6, 1004.8, 1026.0, 1060.7, 1078.0, and 1097.3 cm −1 ±0.2 cm −1 .

9. The crystalline NR methanolate Form II of claim 1 that is characterized by an IR spectrum having peaks at 565.1, 611.3, 638.3, 680.8, 981.6, 1004.8, 1026.0, 1060.7, 1078.0, 1097.3, 1400.1, 1621.9, 1648.9, and 1700.9 cm −1 ±0.2 cm −1 .

10. The crystalline NR methanolate Form II of claim 1 that is characterized by an IR spectrum substantially as shown in FIG. 22 .

11. The crystalline NR methanolate Form II of claim 1 that is characterized by an IR spectrum having peaks substantially as provided in Table 8±0.2 cm −1 .

12. The crystalline NR methanolate Form II of claim 1 that is characterized by a DSC thermogram substantially as shown in FIG. 30 .

13. The crystalline NR methanolate Form II of claim 1 that is characterized by a DSC thermogram obtained using a heating rate of 10 K/min comprising an endothermic event with an onset temperature of 125° C.±2° C.

14. The crystalline NR methanolate Form II of claim 1 that is characterized by a DSC thermogram obtained using a heating rate of 10 K/min comprising an endothermic event with a peak temperature of 132° C.±2° C.

15. The crystalline NR methanolate Form II of claim 1 that is characterized by a DSC thermogram obtained using a heating rate of 10 K/min comprising an endothermic event with an onset temperature of 125° C.±2° C. and a peak temperature of 132° C.±2° C.

16. The crystalline NR methanolate Form II of claim 1 that is prepared by a method comprising the steps of:
(a) adding a volume of methanol and water in a 95:5 weight:weight ratio to the compound or derivative having formula (VII), or salt or solvate thereof, at room temperature, so as to dissolve approximately 15% of the compound or derivative having formula (VII), or salt or solvate thereof, in the volume of methanol and water;
(b) stirring the compound or derivative having formula (VII), or salt or solvate thereof, at 50° C. until all of the compound or derivative having formula (VII), or salt or solvate thereof, apparently dissolves in the volume of methanol and water;
(c) cooling the solution of the compound or derivative having formula (VII), or salt or solvate thereof, in the volume of methanol and water, to −10° C. with stirring so as to precipitate the crystalline NR methanolate Form II;
(d) isolating the crystalline NR methanolate Form II; and
(e) drying the crystalline NR methanolate Form II.

17. The crystalline NR methanolate Form II of claim 16 that is prepared by a method further comprising the steps of:
(a1) providing a compound or derivative having formula (Ia), or salt or solvate thereof:

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, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluoroacetate;
Z 2 is NH;
n is 0;
R 1 is hydrogen;
each of R 2 , R 3 , R 4 , and R 5 is hydrogen;
each of R 6 , R 7 , and R 8 is —C(O)R′;
R′ is methyl;
optionally in a particular anomeric ratio (alpha/beta);
(a2) treating the compound or derivative having formula (Ia), or salt or solvate thereof, with a molar equivalent amount of an alcohol and at least a sub-molar equivalent amount of a Brønsted inorganic base;
(a3) processing the compound or derivative having formula (Ia), or salt or solvate thereof, the alcohol, and the Brønsted inorganic base so as to produce the compound or derivative having formula (VII), or salt or solvate thereof;
(a4) neutralizing the Brønsted inorganic base using a concentrated acid solution; and
(a5) isolating the compound or derivative having formula (VII), or salt or solvate thereof;
wherein the steps (a1) to (a5) are performed sequentially, before step (a).

18. The crystalline NR methanolate Form II of claim 17 , wherein the processing of step (a3) is selected from the group consisting of batch processing, liquid-assisted-mixing, milling, and extruding.

19. The crystalline NR methanolate Form II of claim 16 that is prepared by a method further comprising the steps of:
(a1) providing a compound or derivative having formula (Ia), or salt or solvate thereof:

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, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluoroacetate;
Z 2 is NH;
n is 0;
R 1 is hydrogen;
each of R 2 , R 3 , R 4 , and R 5 is hydrogen;
each of R 6 , R 7 , and R 8 is —C(O)R′;
R′ is methyl;
optionally in a particular anomeric ratio (alpha/beta);
(a2) treating the compound or derivative having formula (Ia), or salt or solvate thereof, with a (3<x<100) molar equivalent amount of an alcohol and a (x≤20) molar equivalent amount of a Brønsted inorganic acid;
(a3) processing, under sealed conditions, the compound or derivative having formula (Ia), or salt or solvate thereof, the alcohol, and the Brønsted inorganic acid so as to produce the compound or derivative having formula (VII), or salt or solvate thereof; and
(a4) isolating the precipitated compound or derivative having formula (VII), or salt or solvate thereof;
wherein the steps (a1) to (a4) are perfor

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

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07D307/20

  Oxygen atoms · CPC title