Crystalline forms of nicotinoyl ribosides, modified derivatives thereof, and phosphorylated analogs thereof, and methods of preparation thereof

Patent metadata

Field	Value
Publication number	US-9975915-B1
Application number	US-201715809731-A
Country	US
Kind code	B1
Filing date	Nov 10, 2017
Priority date	Nov 11, 2016
Publication date	May 22, 2018
Grant date	May 22, 2018

Abstract

The present disclosure provides novel crystalline forms of 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, modified derivatives thereof, and phosphorylated analogs thereof, or salts, solvates, or prodrugs thereof; and methods of preparation thereof.

First claim

We claim:

1. A crystalline Form I of nicotinic acid riboside (NAR) according to formula (VIII):

2. The crystalline Form I of claim 1 that is characterized by a powder X-ray diffraction pattern having peaks at 19.2, 21.6, and 26.4 degrees two theta±0.2 degrees two theta.

3. The crystalline Form I of claim 1 that is characterized by a powder X-ray diffraction pattern having peaks at 15.7, 19.2, 21.6, 26.4, and 28.9 degrees two theta±0.2 degrees two theta.

4. The crystalline Form I of claim 1 that is characterized by a powder X-ray diffraction pattern having peaks substantially as shown in FIG. 17 .

5. The crystalline Form I of claim 1 that is prepared by a method comprising the steps of:
(a) dissolving the compound or derivative having formula (VIII), or a salt or solvate thereof, in a volume of methanol;
(b) adding a volume of acetone, of an equal volume to the volume of methanol, to the compound or derivative having formula (VIII), or salt or solvate thereof, in the volume of methanol;
(c) precipitating the crystalline Form I; and
(d) isolating the crystalline Form I.

6. The crystalline Form I of claim 5 that is prepared by a method further comprising the steps of:
(a1) providing a compound or derivative having formula (1a), or a salt thereof:

wherein Z 2 is oxygen;
n is 0;
R 1 is hydrogen;
wherein the compound or derivative having formula (1a) may optionally take the form of the carboxylate anion conjugate base species of the compound or derivative having formula (1a), further optionally associated with a positively charged counterion selected from the group consisting of calcium, magnesium, potassium, sodium, zinc, and ammonium cations;
each of R 2 , R 3 , R 4 , and R 5 is hydrogen;
(a2) treating the compound or derivative having formula (1a), or salt thereof, with excess trimethylsilylating reagent(s) so as to produce a compound or derivative having formula (1a), or salt thereof, wherein R 1 is a TMS group;
(a3) removing the trimethylsilylating reagent(s);
(a4) treating the compound or derivative having formula (1a), or salt thereof, wherein R 1 is a TMS group, with a molar equivalent amount of a compound or derivative having formula (2), or a salt thereof, and a molar equivalent amount of TMSOTf, in an organic solvent co-reagent:

wherein X′ is selected from the group consisting of fluoro, chloro, bromo, iodo, HCO 2 , acetoxy, propionoxy, butyroxy, glutamyloxy, aspartyloxy, ascorbyloxy, benzoxy, HOCO 2 , citryloxy, carbamyloxy, gluconyloxy, lactyloxy, succinyloxy, sulfoxy, trifluoromethanesulfoxy, trichloromethanesulfoxy, tribromomethanesulfoxy, and trifluoroacetoxy;
each of R 6 , R 7 , and R 8 is —C(O)R′;
R′ is methyl;
(a5) processing the compound or derivative having formula (1a), or salt thereof, wherein R 1 is a TMS group, the compound or derivative having formula (2), or salt thereof, the TMSOTf, and the organic solvent co-reagent so as to produce a compound or derivative having formula (Ia), or salt or solvate thereof, wherein R 1 is a TMS group;
(a6) adding water to, optionally, the compound or derivative having formula (1a), or salt thereof, wherein R 1 is a TMS group, optionally, the compound or derivative having formula (2), or salt thereof, optionally the TMSOTf, the organic solvent co-reagent, and the compound or derivative having formula (Ia), or salt or solvate thereof, optionally wherein R 1 is a TMS group;
(a7) isolating the compound or derivative having formula (Ia), or salt or solvate thereof;
(a8) dissolving the compound or derivative having formula (Ia), or salt or solvate thereof, in methanol, in a gas pressure tube;
(a9) cooling the solution of the compound or derivative having formula (Ia), or salt or solvate thereof, in methanol, to −78° C.;
(a10) bubbling ammonia gas into the solution of the compound or derivative having formula (Ia), or salt or solvate thereof, in methanol;
(a11) sealing the pressure tube;
(a12) raising the temperature to −20° C.;
(a13) cooling the pressure tube at −20° C. for about 12 hours to about 4 days, so as to produce the compound or derivative having formula (VIII), or salt or solvate thereof;
(a14) unsealing the gas pressure tube; and
(a15) isolating the compound or derivative having formula (VIII), or salt or solvate thereof;
wherein the steps (a1) to (a15) are performed sequentially, before step (a).

7. The crystalline Form I of claim 6 , wherein the processing of step (a5) is selected from the group consisting of batch processing, liquid-assisted mixing, milling, grinding, and extruding.

8. A crystalline Form I of nicotinamide riboside triacetate (NRTA) chloride according to formula (IX):

9. The crystalline Form I of claim 8 that is characterized by a powder X-ray diffraction pattern having peaks at 19.6, 22.1, and 26.6 degrees two theta±0.2 degrees two theta.

10. The crystalline Form I of claim 8 that is characterized by a powder X-ray diffraction pattern having peaks at 9.8, 19.2, 19.6, 22.1, and 26.6 degrees two theta±0.2 degrees two theta.

11. The crystalline Form I of claim 8 that is characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 18 .

12. The crystalline Form I of claim 8 that is prepared by a method comprising the steps of:
(a) adding a volume of acetonitrile to the compound or derivative having formula (IX), or a salt or solvate thereof, at room temperature, so as to dissolve the compound or derivative having formula (IX), or salt or solvate thereof, in the volume of acetonitrile;
(b) adding a volume of acetone, which is at least equal in volume to the volume of acetonitrile, to the solution of the compound or derivative having formula (IX), or salt or solvate thereof, in the volume of acetonitrile so as to precipitate the crystalline Form I; and
(c) isolating the crystalline Form I.

13. The crystalline Form I of claim 12 that is prepared by a method further comprising the steps of:
(a1) providing a compound or derivative having formula (2), or a salt thereof:

wherein X′ is selected from the group consisting of fluoro, chloro, bromo, iodo, HCO 2 , acetoxy, propionoxy, butyroxy, glutamyloxy, aspartyloxy, ascorbyloxy, benzoxy, HOCO 2 , citryloxy, carbamyloxy, gluconyloxy, lactyloxy, succinyloxy, sulfoxy, trifluoromethanesulfoxy, trichloromethanesulfoxy, tribromomethanesulfoxy, and trifluoroacetoxy;
each of R 6 , R 7 , and R 8 is —C(O)R′;
R′ is methyl;
(a2) treating the compound or derivative having formula (2), or salt thereof, with a molar equivalent amount of a compound or derivative having formula (1a), or a salt thereof, and a molar equivalent amount of TMSOTf;

wherein Z 2 is NH;
n is 0;
R 1 is hydrogen;
each of R 2 , R 3 , R 4 , and R 5 is hydrogen;
(a3) processing the compound or derivative having formula (2), or salt th

Assignees

• Univ Belfast
• Chromadex Inc

Inventors

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

Classifications

• C07H19/048 Primary

  Pyridine radicals · CPC title

• C07H19/04

  Heterocyclic radicals containing only nitrogen atoms as ring hetero atom · CPC title

• C07H19/20

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

• C07D307/20

  Oxygen atoms · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title