CN-122011067-A - Crystalline solids of nicotinic acid mononucleotide and esters thereof and methods of making and using the same

Abstract

The present disclosure relates to crystalline solids of nicotinic acid mononucleotides and esters thereof, and methods of making and using the same. The present disclosure further relates to crystalline solids comprising a compound of formula (I), (I) Wherein R is n-propyl, and methods of making compounds of formula (I) wherein R is C1-C4 alkyl or C2-C4 alkenyl. The present disclosure also relates to crystalline solids comprising a compound of formula (II), (II) the present disclosure further relates to methods of preparing crystalline solids, pharmaceutical formulations of crystalline solids, and the use of such pharmaceutical formulations in the treatment of diseases and conditions.

Inventors

• J. N. Kremia
• B. Spencken Weiss
• K. Kopech
• J. HARRIS
• M. Pitak
• M. Bates

Assignees

• 麦德龙国际生物科技有限责任公司

Dates

Publication Date

20260512

Application Date

20220526

Priority Date

20210527

Claims (10)

1. 1. A crystalline solid comprising compound 1: 。
2. 2. The crystalline solid of claim 1, having 2Θ values of 16.1, 20.1, and 24.5.
3. 3. The crystalline solid of any one of claims 1 to 2, wherein the solid is anhydrous.
4. 4. A crystalline solid according to any one of claims 1 to 3, wherein the solid is selected from methanol solvate, ethanol solvate, 1-propanol solvate, 2-propanol solvate, C-4 alcohol solvate, C-5 alcohol solvate and C-6 alcohol solvate, preferably the methanol solvate.
5. 5. The crystalline solid of any one of claims 1-4, wherein the crystalline solid contains residual non-solvating solvent or residual non-hydration water.
6. 6. The crystalline solid of any one of claims 1 to 5, comprising less than about 5 wt% propyl nicotinate, preferably less than about 1 wt% propyl nicotinate.
7. 7. The crystalline solid of any one of claims 1-4, comprising less than about 5 wt% of compound 2: 。
8. 8. the crystalline solid of claim 7, comprising less than about 1% by weight of compound 2.
9. 9. The crystalline solid of any one of claims 1 to 8, comprising at least about 90 wt% compound 1.
10. 10. The crystalline solid of claim 9, comprising at least about 95% by weight of compound 1.

Description

Crystalline solids of nicotinic acid mononucleotide and esters thereof and methods of making and using the same The application relates to a PCT International application PCT/US2022/031124 submitted at 26 months of 2022, 11/27 days of 2023, which enters the national stage of China and has the patent application number of 202280037999.X, and the application is a divisional application of 'crystalline solid of nicotinic acid mononucleotide and ester thereof, and a manufacturing and using method thereof'. Cross Reference to Related Applications The present application claims priority from U.S. provisional application No. 63/193,905 filed on day 2021, 5, 27, which is incorporated herein by reference in its entirety for all purposes. Technical Field The present application relates to crystalline solids of nicotinic acid mononucleotides and esters thereof, and methods of making and using the same. Background Nicotinamide Adenine Dinucleotide (NAD) and related compounds are known to be essential coenzymes in cellular redox reactions in all living organisms. Various lines of evidence have also shown that NAD is involved in many important signaling pathways in mammalian cells, including poly (ADP-ribosyl) ation in DNA repair, mono ADP-ribosyl in immune response and G protein coupled signaling, and cyclic ADP-ribose and Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) synthesis in intracellular calcium signaling. NAD and its metabolites have also been shown to play an important role in transcriptional regulation. In particular, the discovery of Sir2 NAD-dependent deacetylase activity has raised concerns over such effects of NAD. Despite advances in understanding NAD biology, there remains a need for improved compositions and methods of using such compositions for pharmacological intervention and/or manipulation of NAD pathways in living cells and tissues. Nicotinic acid mononucleotide (also known as nicotinic acid ribonucleotide) and certain nicotinic acid mononucleotide derivatives are believed to increase cellular NAD production (Sauve, U.S. patent 10,961,268 B2). However, these compounds are difficult to synthesize on a pharmaceutically suitable scale with sufficient purity. In view of the therapeutic benefits associated with nicotinic acid mononucleotides and derivatives thereof, there is a need for improved compositions and methods for preparing such compositions. Disclosure of Invention The present disclosure relates to compounds, crystalline solids, and compositions of compounds and/or crystalline solids for modulating nicotinamide adenine dinucleotide (NAD, also referred to as nad+ in its oxidized form and NADH in its reduced form). One aspect of the present disclosure relates to crystalline solids comprising a compound of formula (I), (I) Wherein R is n-propyl (Compound 1). A further aspect of the present disclosure relates to crystalline solids comprising a compound of formula (II), (II)。 A further aspect of the disclosure relates to a crystalline solid comprising compound 1: 。 in some embodiments, the crystalline solid has 2θ values of 16.1, 20.1, and 24.5. In some embodiments, the solid is anhydrous. In some embodiments, the solid is selected from the group consisting of methanol solvates, ethanol solvates, 1-propanol solvates, 2-propanol solvates, C-4 alcohol solvates, C-5 alcohol solvates, and C-6 alcohol solvates, preferably methanol solvates. In some embodiments, the crystalline solid contains residual non-solvating solvent or residual non-hydration water. In some embodiments, the crystalline solid comprises less than about 5% by weight propyl nicotinate, preferably less than about 1% by weight propyl nicotinate. In some embodiments, the crystalline solid comprises less than about 5% by weight of compound 2: 。 in some embodiments, the crystalline solid comprises less than about 1% by weight of compound 2. In some embodiments, the crystalline solid comprises at least about 90% by weight of compound 1. In some embodiments, the crystalline solid comprises at least about 95% by weight of compound 1. In some embodiments, the crystalline solid comprises at least about 99% by weight of compound 1. In some embodiments, the crystalline solid is non-hygroscopic. In some embodiments, the crystalline solid remains stable at a relative humidity of less than about 70%. A further aspect of the present disclosure relates to a pharmaceutical composition comprising the crystalline solid described herein and one or more pharmaceutically acceptable excipients. A further aspect of the present disclosure relates to a process for preparing the crystalline solid of the present application, comprising: a) Dissolving compound 1 in a solvent to form a solution, and B) Compound 1 was crystallized from the solution to form a crystalline solid. In some embodiments, the solvent is methanol. In some embodiments, the solution is anhydrous. In some embodiments, the temperature of the solvent during the dissolving step is about 30