Crystalline solids of nicotinic acid mononucleotide and esters thereof and methods of making and use

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) wherein R is a n-propyl group, and to a process for making a compound of formula (I) wherein R is a C1-C4 alkyl group or a C2-C4 alkenyl group. The present disclosure also relates to crystalline solids comprising a compound of formula (II), (II) The disclosure further relates to processes for preparing crystalline solids, pharmaceutical formulations of crystalline solids, and the use of such pharmaceutical formulations in the treatment of diseases and conditions.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202512023379.9 (22) Application Date 2022.05.26 (30) Priority Data 63 / 193,905 2021.05.27 US (62) Divisional Application Data 202280037999.X 2022.05.26 (71) Applicant Metro International Biotechnology Co., Ltd. Address USA (72) Inventors J.N. Klimsky B. Spunkenvis K. Kopesch J. Harris M. Pitak M. Bates (74) Patent Agency Beijing Jiahe Tiangong Intellectual Property Agency (General Partnership) 11269 Patent Attorney Wang Yuejiao Gan Ling (51) Int.Cl. C07H 19 / 048 (2006.01) C07H 1 / 06(2006.01) (54) Invention Title: Crystalline Solid of Nicotinic Acid Mononucleotide and its Ester and Methods of Preparation and Use Thereof (57) Abstract: This disclosure relates to crystalline solid of nicotinic acid mononucleotide and its ester and methods of preparation and use thereof. This disclosure further relates to crystalline solids comprising compounds of formula (I), wherein R is n-propyl, and methods of preparing compounds of formula (I), wherein R is C1-C4 alkyl or C2-C4 alkenyl. This disclosure also relates to crystalline solids comprising compounds of formula (II), wherein R is n-propyl. This disclosure further relates to methods of preparing crystalline solids, pharmaceutical preparations of crystalline solids, and use of such pharmaceutical preparations in the treatment of diseases and conditions. Claims: 1 page Description: 34 pages Drawings: 7 pages CN 122011067 A 2026.05.12 CN 1 22 01 10 67 A 1. A crystalline solid comprising compound 1: . 2. The crystalline solid according to claim 1, having a 2θ value of 16.1, 20.1, and 24.5. 3. The crystalline solid according to any one of claims 1 to 2, wherein the solid is anhydrous. 4. The crystalline solid according to any one of claims 1 to 3, wherein the solid is selected from methanol solvates, ethanol solvates, 1-propanol solvates, 2-propanol solvates, C-4 alcohol solvates, C-5 alcohol solvates, and C-6 alcohol solvates, preferably the methanol solvate. 5. The crystalline solid according to any one of claims 1 to 4, wherein the crystalline solid contains residual unsolvated solvent or residual dehydrated water. 6. The crystalline solid according to any one of claims 1 to 5, comprising less than about 5% by weight of propyl nicotinate, preferably less than about 1% by weight of propyl nicotinate. 7. The crystalline solid according to any one of claims 1 to 4, comprising less than about 5% by weight of compound 2.8. The crystalline solid according to claim 7, comprising less than about 1% by weight of compound 2. 9. The crystalline solid according to any one of claims 1 to 8, comprising at least about 90% by weight of compound 1. 10. The crystalline solid according to claim 9, comprising at least about 95% by weight of compound 1. Claims 1 / 1 page 2 CN 122011067 A Crystalline solid of nicotinic acid mononucleotide and its ester, and methods for its preparation and use

[0001] This application is a divisional application of Chinese patent application No. 202280037999.X, entitled "Crystalline solid of nicotinic acid mononucleotide and its ester, and methods for its preparation and use," filed on May 26, 2022, under PCT international application PCT / US2022 / 031124, which entered the Chinese national phase on November 27, 2023.

[0002] Cross-Reference to Related Applications This application claims priority to U.S. Provisional Application No. 63 / 193,905, filed May 27, 2021, which is incorporated herein by reference in its entirety for all purposes. Technical Field

[0003] This application relates to crystalline solids of nicotinic acid mononucleotide and its esters, and methods of their preparation and use. Background Art

[0004] Nicotinamide adenine dinucleotide (NAD) and related compounds are known to be essential coenzymes in cellular redox reactions in all living organisms. Extensive evidence has also shown that NAD participates in many important signaling pathways in mammalian cells, including poly(ADP-ribosylation) in DNA repair, mono(ADP-ribosylation) in immune responses and G protein-coupled signaling, and the synthesis of cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate (NAADP) in intracellular calcium signaling. NAD and its metabolites have also been shown to play important roles in transcriptional regulation. In particular, the discovery of Sir2 NAD-dependent deacetylase activity has drawn attention to this role of NAD. Despite advances in understanding the biology of NAD, there remains a need for improved compositions and methods for using such compositions for pharmacological intervention and / or manipulation of the NAD pathway in living cells and tissues.

[0005] Nicotinic acid mononucleotides (also known as nicotinic acid ribonucleotides) and certain nicotinic acid mononucleotide derivatives are thought to increase cellular NAD production (Sauve, U.S. Patent 10,961,268 B2). However, these compounds are difficult to synthesize on a pharmaceutically appropriate scale with sufficient purity. Given the therapeutic benefits associated with nicotinic acid mononucleotides and their derivatives, there is a need for improved compositions and methods for preparing such compositions.

[0006] This disclosure relates to compounds, crystalline solids, and compositions of compounds and / or crystalline solids for regulating nicotinamide adenine dinucleotide (NAD, also known as its oxidized form NAD+ and its reduced form NADH).

[0007] One aspect of this disclosure relates to a crystalline solid comprising a compound of formula (I), wherein R is n-propyl (compound 1).

[0008] A further aspect of this disclosure relates to a crystalline solid comprising a compound of formula (II), see specification 1 / 34 page 3 CN 122011067 A (II).

[0009] A further aspect of this disclosure relates to a crystalline solid comprising compound 1: .

[0010] In some embodiments, the crystalline solid has 2θ values ​​of 16.1, 20.1, and 24.5.

[0011] In some embodiments, the solid is anhydrous.

[0012] In some embodiments, the solid is selected from 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.

[0013] In some embodiments, the crystalline solid contains residual unsolvated solvent or residual non-hydrated water.

[0014] In some embodiments, the crystalline solid contains less than about 5% by weight of propyl nicotinate, preferably less than about 1% by weight of propyl nicotinate.

[0015] In some embodiments, the crystalline solid contains less than about 5% by weight of compound 2.

[0016] In some embodiments, the crystalline solid contains less than about 1% by weight of compound 2.

[0017] In some embodiments, the crystalline solid contains at least about 90% by weight of compound 1.

[0018] In some embodiments, the crystalline solid contains at least about 95% by weight of compound 1.

[0019] In some embodiments, the crystalline solid contains at least about 99% by weight of compound 1.

[0020] In some embodiments, the crystalline solid is non-hygroscopic.

[0021] In some embodiments, the crystalline solid remains stable at a relative humidity of less than about 70%.

[0022] A further aspect of this disclosure relates to a pharmaceutical composition comprising the crystalline solid described in this application and one or more pharmaceutically acceptable excipients.

[0023] A further aspect of this disclosure relates to a method for preparing the crystalline solid described in this application, comprising: a) dissolving compound 1 in a solvent to form a solution; and b) crystallizing compound 1 from the solution to form a crystalline solid.

[0024] In some embodiments, the solvent is methanol.

[0025] In some embodiments, the solution is anhydrous.

[0026] In some embodiments, the temperature of the solvent during the dissolution step is about 30 to about 40°C.

[0027] In some embodiments, prior to the crystallization step, compound 1 is completely dissolved in the solvent.

[0028] In some embodiments, crystallization includes forming a supersaturated solution from the solution, wherein the supersaturated solution is supersaturated relative to compound 1.

[0029] In some embodiments, forming a supersaturated solution includes adding an antisolvent to the solution, lowering the temperature of the solution, reducing the volume of the solution, or any combination thereof.

[0030] In some embodiments, forming a supersaturated solution includes lowering the temperature of the solution.

[0031] In some embodiments, forming a supersaturated solution includes lowering the temperature of the solution from about 0°C to about 25°C.

[0032] In some embodiments, forming a supersaturated solution includes adding an antisolvent to the solution.

[0033] In some embodiments, the antisolvent is selected from EtOAc, iPrOAc, TBME, MIBK, THF, 1-propanol, 2-propanol, and EtOH, preferably denatured EtOH.

[0034] In some embodiments, the antisolvent is TBME.

[0035] In some embodiments, the solvent to antisolvent ratio is about 1:1 to about 8:1 by volume.

[0036] In some embodiments, the solvent to antisolvent ratio is about 5:1 by volume.

[0037] In some embodiments, the supersaturated solution has a supersaturation ratio of about 1 to 4.

[0038] In some embodiments, the supersaturated solution has a supersaturation ratio of about 2.

[0039] In some embodiments, crystallization includes adding seed crystals to the solution, wherein the seed crystals contain compound 1.

[0040] In some embodiments, the method further includes separating the crystalline solid.

[0041] In some embodiments, the method further includes drying the crystalline solid under reduced pressure.

[0042] In some embodiments, the method does not include performing chromatographic analysis to purify compound 1.

[0043] In some embodiments, the method does not include lyophilization during the purification of compound 1.

[0044] In some embodiments, the weight of the crystalline solid is at least about 100 mg.

[0045] In some embodiments, the amount of the crystalline solid is at least about 1 g.

[0046] In some embodiments, the crystalline solid contains less than about 1% propyl nicotinate.

[0047] In some embodiments, the crystalline solid comprises at least about 90% of compound 1.

[0048] In some embodiments, the crystalline solid comprises at least about 95% of compound 1.

[0049] In some embodiments, the crystalline solid comprises at least about 99% of compound 1.

[0050] In some embodiments, the crystalline solid is formed according to the method described above.

[0051] A further aspect of this disclosure relates to a crystalline solid comprising a compound of formula (II), (II).

[0052] In some embodiments, the crystalline solid has 2θ values ​​of 21.5, 24.2, 26.7, and 19.6.

[0053] In some embodiments, the compound of formula (II) is a hydrate.

[0054] In some embodiments, the crystalline solid has greater than 90% stability after being stored at elevated temperatures for 14 days, as measured by the percentage of area under the curve at 254 nm.

[0055] In some embodiments, the solid is selected from methanol solvates, ethanol solvates, 1-propanol solvates, 2-propanol solvates, C-4 alcohol solvates, C-5 alcohol solvates, and C-6 alcohol solvates.

[0056] In some embodiments, the crystalline solid contains residual unsolvated solvent or residual unhydrated water.

[0057] In some embodiments, the crystalline solid contains less than about 5% by weight of nicotinic acid, preferably less than about 1% by weight of nicotinic acid.

[0058] In some embodiments, the crystalline solid contains less than about 1% nicotinic acid riboside.

[0059] In some embodiments, the crystalline solid comprises at least about 90% of the compound of formula (II), preferably at least about 95% of the compound of formula (II).

[0060] In some embodiments, the crystalline solid comprises at least about 99% of the compound of formula (II).

[0061] In some embodiments, the average size of the single crystals of the crystalline solid is 20 to 500 micrometers.

[0062] A further aspect of this disclosure relates to a pharmaceutical composition comprising the crystalline solid described herein and one or more pharmaceutically acceptable excipients.

[0063] A further aspect of this disclosure relates to a method for preparing the crystalline solid described herein, comprising: a) dissolving the compound of formula (II) in a solvent to form a solution; and b) crystallizing the compound of formula (II) from the solution to form a crystalline solid.

[0064] In some embodiments, the solvent comprises water.

[0065] In some embodiments, the solvent comprises an alcohol.

[0066] In some embodiments, the alcohol is 1-propanol.

[0067] In some embodiments, the temperature of the solvent during the dissolution step is ambient temperature.

[0068] In some embodiments, the compound of formula (II) is completely dissolved in the solvent prior to the crystallization step.

[0069] In some embodiments, crystallization includes forming a supersaturated solution from the solution, wherein the supersaturated solution is supersaturated relative to the compound of formula (II).

[0070] In some embodiments, forming a supersaturated solution includes adding an antisolvent to the solution, lowering the temperature of the solution, reducing the volume of the solution, or any combination thereof.

[0071] In some embodiments, forming a supersaturated solution includes lowering the temperature of the solution.

[0072] In some embodiments, forming a supersaturated solution includes adding an antisolvent to the solution.

[0073] In some embodiments, the antisolvent is an alcohol.

[0074] In some embodiments, the antisolvent is 1-propanol.

[0075] In some embodiments, the solvent to antisolvent ratio is about 1:0 to about 1:2 by volume.

[0076] In some embodiments, the solvent to antisolvent ratio is about 6:7.

[0077] In some embodiments, the supersaturated solution has a supersaturation ratio of about 1 to 4.

[0078] In some embodiments, the supersaturated solution has a supersaturation ratio of about 2.

[0079] In some embodiments, forming a supersaturated solution does not involve adding an antisolvent to the solution.

[0080] In some embodiments, the compound of formula (II) to the solvent is about 1:3 by weight.

[0081] In some embodiments, crystallization includes adding seed crystals to the solution, wherein the seed crystals comprise the compound of formula (II).

[0082] In some embodiments, the method further includes separating the crystalline solid.

[0083] In some embodiments, the method further includes drying the crystalline solid under reduced pressure.

[0084] In some embodiments, the method does not include performing chromatographic analysis to purify the compound of formula (II).

[0085] In some embodiments, the method does not include lyophilization to purify the compound of formula (II).

[0086] In some embodiments, the weight of the crystalline solid is at least about 100 mg.

[0087] In some embodiments, the amount of the crystalline solid is at least about 1 g.

[0088] In some embodiments, the crystalline solid contains less than about 1% nicotinic acid riboside.

[0089] In some embodiments, the crystalline solid contains at least about 90% of the compound of formula (II).

[0090] In some embodiments, the crystalline solid contains at least about 95% of the compound of formula (II).

[0091] In some embodiments, the crystalline solid contains at least about 99% of the compound of formula (II). Specification 4 / 34 pages 6 CN 122011067 A

[0092] In some embodiments, the crystalline solid is formed according to the method described above.

[0093] A further aspect of this disclosure relates to a method for preparing a compound of formula (I), wherein R is a C1-C6 alkyl or C2-C6 alkenyl; the method comprising: contacting a compound of formula (II), in the presence of an acid, with an alcohol R-OH.

[0094] In some embodiments, R is a C1-C6 alkyl.

[0095] In some embodiments, R is a C3 alkyl.

[0096] In some embodiments, R is n-propyl.

[0097] In some embodiments, the acid is HCl.

[0098] In some embodiments, the compound of formula (II) is provided as a crystalline solid as described in this application.

[0099] In some embodiments, the method further includes preparing a crystalline solid comprising a compound of formula (II) according to any method described in this application.

[0100] In some embodiments, the compound of formula (I) is provided as a crystalline solid described in this application.

[0101] In some embodiments, the method further includes preparing a crystalline solid comprising a compound of formula (I) according to any method described in this application.

[0102] A further aspect of this disclosure relates to a method for increasing NAD levels in a subject, the method comprising administering the crystalline solid described in this application to the subject.

[0103] A further aspect of this disclosure relates to a method for treating or preventing a disease or disorder in a subject, the method comprising administering the crystalline solid described in this application to the subject.

[0104] In some embodiments, the disease or disorder is associated with NAD biosynthesis.

[0105] In some embodiments, the disease or disorder is a neurological or neurodegenerative disorder.

[0106] In some embodiments, the neurodegenerative disorder is selected from Alzheimer's disease (AD), dementia other than Alzheimer's disease, Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), diffuse Lewy body disease, chorea-acanthocytosis, primary lateral sclerosis, multiple sclerosis (MS), eye disease, spinal muscular atrophy, chemotherapy-induced neuropathy, diabetes-induced neuropathy, and Friedrich's ataxia.

[0107] In some embodiments, the disease or disorder is a symptom caused by COVID-19 infection.

[0108] In some embodiments, the disease or disorder is acute kidney injury (AKI) or chronic kidney disease, such as nephropathy.

[0109] In some embodiments, the disease or disorder is caused by or associated with a cytokine storm.

[0110] In some embodiments, the disease or disorder is inflammation.

[0111] In some embodiments, inflammation is selected from multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, arthropathy, spondyloarthritis, gouty arthritis, systemic lupus erythematosus, juvenile arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, diabetes, menstrual pain, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucinous colitis, ulcerative colitis, gastritis, esophagitis, pancreatitis, peritonitis, Alzheimer's disease, shock, ankylosing spondylitis, gastritis, conjunctivitis, pancreatitis, multiple organ injury syndrome, myocardial infarction, atherosclerosis, stroke, reperfusion injury, acute glomerulonephritis, vasculitis, thermal injury, necrotizing enterocolitis, granulocyte transfusion-related syndrome, and Sjögren's syndrome.

[0112] In some embodiments, the disease or ailment is cancer.

[0113] In some embodiments, the cancer is selected from brain cancer, kidney cancer, breast cancer, prostate cancer, testicular cancer, ovarian cancer, lung cancer, colorectal cancer, cervical cancer, skin cancer, gastric cancer, lymphoma, and leukemia.

[0114] In some embodiments, the disease or ailment is a muscle disorder or ailment, such as sarcopenia.

[0115] In some embodiments, the disease or ailment is a solid organ disease or ailment, preferably selected from liver diseases or ailments caused by alcohol-induced cirrhosis.

[0116] In some embodiments, the disease or ailment is treated by transplantation of a solid organ, wherein the solid organ is treated with a crystalline solid prior to transplantation.

[0117] In some embodiments, the crystalline solid is administered at a unit dose of about 1 to 3000 mg.

[0118] In some embodiments, the crystalline solid is administered at a unit dose of about 100 to 1000 mg.

[0119] In some embodiments, the crystalline solid is administered in an amount of about 250 to 750 mg.

[0120] In some embodiments, the crystalline solid is administered twice daily.

[0121] In some embodiments, the subject is a human.

[0122] A further aspect of this disclosure relates to a method for purifying a compound, the method comprising: a) dissolving a compound selected from compound 1 or compound 2 in a solvent to form a solution; and b) crystallizing the compound from the solution to form a solid with a purity greater than that of the compound dissolved in step (a).

[0123] In some embodiments, the compound is compound 1.

[0124] In some embodiments, the compound is compound 2.

[0125] In some embodiments, step (a) is performed with an amorphous compound.

[0126] In some embodiments, the solid with higher purity in step (b) is greater than about 95% pure.

[0127] In some embodiments, this disclosure relates to methods for preparing such compounds, crystalline solids, and compositions, and compounds and compositions of formula (I) wherein R is a C1-C4 alkyl or C2-C4 alkenyl. In some embodiments, this disclosure relates to pharmaceutical compositions comprising one or more NAD-regulating compounds and / or crystalline solids as a first component in combination with one or more active pharmaceutical ingredients. In further embodiments, this disclosure relates to methods of using such compounds, crystalline solids, and / or compositions to promote an increase in intracellular levels of nicotinamide adenine dinucleotide (NAD) in cells and tissues to treat diseases and / or improve cell and tissue survival. Brief Description of the Drawings

[0128] Figure 1A shows an experimentally obtained XRD pattern of compound 1 as a crystalline solid. Figure 1B shows an overlay diagram, where the top pattern is the experimental diffraction pattern of compound 1 at room temperature; and the bottom pattern is the calculated diffraction pattern of compound 1 simulated at 100 K. The subtle differences between the simulated and experimental diffraction patterns can be attributed to variations in the lattice with temperature and preferred orientation. Figure 1C is a representation of the lattice cells of compound 1.

[0129] Figure 2A shows the experimentally obtained XRD pattern of compound 2 as a crystalline solid. Figure 2B shows the simulated XRD pattern of compound 2 as a crystalline solid, as described on page 6 / 34 of the specification, 8 CN 122011067 A. Figure 2C shows an overlay diagram, where the top pattern is the experimental diffraction pattern of compound 2; and the bottom pattern is the diffraction pattern calculated from the single-crystal X-ray structure. The subtle differences between the simulated and experimental diffraction patterns can be attributed to variations in the lattice with temperature and preferred orientation.

[0130] Figure 3 shows the proton NMR spectrum of compound 1 obtained experimentally in DMSO-d6. The x-axis shows the chemical shift (ppm).

[0131] Figure 4 shows the proton NMR spectrum of compound 2 obtained experimentally in D2O. The x-axis shows the chemical shift (ppm). Detailed Description

[0132] Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Unless otherwise stated, the following terms as used herein have the meanings assigned to them as follows.

[0133] In this disclosure, “comprises,” “comprising,” “containing,” and “having” may have the meanings assigned to them under U.S. Patent Law and may mean “includes,” “including,” etc.; “consisting essentially of” or “consists essentially” also have the meanings given under U.S. Patent Law and the term is open-ended, allowing for more than those listed, provided that the essential or novel features of the listed ones are not altered by the presence of more than those listed, but excluding prior art embodiments.

[0134] The scope provided herein should be understood as shorthand for all values ​​within that scope. For example, the range 1 to 50 should be understood to include any number, combination of numbers, or subrange of numbers of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0135] The phrase “a” or “an” as used herein refers to one or more of the entities; for example, a compound refers to one or more compounds or at least one compound.Thus, the terms “a / an,” “one or more,” and “at least one” are used interchangeably herein.

[0136] Unless specifically stated or obvious from the context, as used herein, the term “about” is understood to be within the normal tolerance range in the art, for example, within 2 standard deviations of the mean. “About” can be understood to be within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the specified value. Unless the context otherwise requires, all numerical values ​​provided herein are modified by the term “about.”

[0137] As used herein, the term “alkyl” is a branched or unbranched saturated hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms. Examples of straight-chain and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl. Alkyl groups can be cyclic or acyclic. Alkyl groups can be branched or unbranched (i.e., linear). "Lower alkyl" refers to an alkyl group containing one to six (e.g., one to four) carbon atoms.

[0138] As used herein, the term "alkenyl" refers to an aliphatic group containing at least one double bond.

[0139] As used herein, the terms "optional" or "optionally" mean that an event or condition subsequently described may but not necessarily occur, and the description includes examples in which the event or condition occurs as well as examples in which the event or condition does not occur. For example, "optional bond" means that the bond may or may not be present, and the description includes single, double, or triple bonds.

[0140] As described herein, the term "purified" refers to the purity of a given compound. For example, a compound is "purified" when it is the major component of the composition specification page 7 / 34 9 CN 122011067 A, i.e., at least about 50% w / w pure. Therefore, “purified” includes at least about 50% w / w purity, at least about 60% w / w purity, at least about 70% purity, at least about 80% purity, at least about 85% purity, at least about 90% purity, at least about 92% purity, at least about 94% purity, at least about 96% purity, at least about 97% purity, at least about 98% purity, at least about 99% purity, at least about 99.5% purity, and at least about 99.9% purity, wherein “substantially pure” includes at least about 97% purity, at least about 98% purity, at least about 99% purity, at least about 99.5% purity, and at least about 99.9% purity.

[0141] As described herein, the term “metabolite” refers to a compound produced in the body after administration to a subject.

[0142] The term “salt” as used herein refers to a compound containing cations and anions, which can be produced by protonation of the proton acceptor portion and / or deprotonation of the proton donor portion.It should be noted that protonation of the proton acceptor leads to the formation of a cation, in which the charge is balanced by the presence of a physiological anion, while deprotonation of the proton donor leads to the formation of an anion, in which the charge is balanced by the presence of a physiological cation.

[0143] The phrase “pharmaceutically acceptable salt” refers to a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or formed from organic acids such as acetic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, dodecyl sulfate, gluconic acid, glutamic acid, salicylic acid, mucoconic acid, etc.; or (2) base addition salts formed from the conjugate base of any of the inorganic acids listed above, wherein the conjugate base comprises a subset selected from Na+, K+, Mg2+, Ca2+, NH4gR4-g+. The cationic component, wherein R is a C1-3 alkyl group, and g is a number selected from 0, 1, 2, 3, or 4. It should be understood that all references to pharmaceutically acceptable salts include solvation forms (solvents) or crystalline solids of the same acid addition salts as defined herein.

[0144] This disclosure also includes useful forms of the compounds of this disclosure, such as metabolites, solvates, prodrugs, salts, particularly pharmaceutically acceptable salts, and / or coprecipitates.

[0145] The compounds of this disclosure can exist as solvates, wherein the compounds of this disclosure form crystals containing molecules of a polar solvent such as water, methanol, or ethanol as structural elements of the compound's lattice. Molecules of the polar solvent may be present with molecules of the compound in stoichiometric or non-stoichiometric proportions. In the case of stoichiometric solvates, for example, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc., solvates are possible. This disclosure includes all such solvates.

[0146] Furthermore, the compounds of this disclosure may exist in free form, for example, as a free base, or as a free acid, or as a zwitterion, or as a salt. The salt may be any salt, organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt that is commonly used in pharmaceutical manufacturing or for, for example, the isolation or purification of the compounds of this disclosure.

[0147] The term “subject” as intended for application includes, but is not limited to, humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quails, and / or turkeys.

[0148] The terms “treatment,” “treating,” “relief,” and “improvement” are used interchangeably herein. These terms refer to a method of obtaining a beneficial or desired outcome, including but not limited to therapeutic benefits and / or preventive benefits. A therapeutic benefit means the eradication or relief of an underlying condition that is being treated. Furthermore, improvements have been observed in patients by achieving therapeutic benefits through eradication or reduction of one or more physiological symptoms associated with the underlying disease, but the patient may still suffer from the underlying disease. For preventive benefits, pharmaceutical compounds and / or compositions may also be administered to patients at risk of developing a specific disease or to patients reporting one or more physiological symptoms of a disease, even if the disease has not yet been diagnosed.

[0149] As used herein, “prevention” of a disease or condition means a compound and / or its crystalline solid that reduces the occurrence of a disease or condition in a treated sample relative to an untreated control sample, or that delays the onset of one or more symptoms of a disease or condition relative to an untreated control sample and reduces its severity.

[0150] The term “treatment” includes preventive and / or therapeutic treatment. The term “preventive or therapeutic” treatment is recognized in the art and includes administration of one or more of the disclosed compositions to a subject. If administered before the clinical manifestation of an unwanted condition (e.g., a subject’s disease or other unwanted state), the treatment is preventative (i.e., it protects the subject from developing the unwanted condition), and if administered after the manifestation of the unwanted condition, the treatment is therapeutic (i.e., it aims to reduce, improve, or stabilize the existing unwanted condition or its side effects).

[0151] The terms “formulation” or “dosage form” are intended to include solid and liquid formulations comprising an active compound and / or its crystalline solid, and those skilled in the art will understand that the active ingredient may be present in different formulations depending on the desired dosage and pharmacokinetic parameters.

[0152] As used herein, the term “excipient” refers to a compound used to prepare a pharmaceutical composition and is generally safe, non-toxic, neither biologically nor otherwise required, and includes excipients acceptable for veterinary use as well as for human pharmaceutical use.

[0153] As used herein, the phrase “pharmaceutically acceptable” means compounds, materials, compositions, and / or dosage forms that are suitable for contact with a subject’s tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of reasonable medical judgment, and that are commensurate with a reasonable benefit / risk ratio.

[0154] As used herein, the phrase “pharmaceutically acceptable carrier” means pharmaceutically acceptable materials, compositions, or mediators, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and harmless to the subject.

[0155] As used herein, the phrase “combined administration” means any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., both agents are effective simultaneously in the patient, which may include the synergistic effect of the two agents). For example, different therapeutic compounds may be administered simultaneously or sequentially in the same formulation or in separate formulations. Thus, an individual receiving such treatment may benefit from the combined effect of the different therapeutic agents.

[0156] The description of a list of elements in any definition of a variable herein includes any single element or combination (or sub-combination) that defines the variable as the listed elements. The description of embodiments herein includes embodiments as any single embodiment, or embodiments combined with any other embodiment or part thereof.

[0157] It should be understood that whatever values ​​and ranges are provided herein, all values ​​and ranges encompassed by such values ​​and ranges are meant to be encompassed within the scope of this disclosure. Furthermore, all values ​​falling within these ranges, as well as the upper or lower limits of the value ranges, are also contemplated by this application.

[0158] Compounds and Crystalline Solids In one aspect, this disclosure provides crystalline solids comprising compounds of formula (I), 9 / 34 pages, 11 CN 122011067 A (I) where R is n-propyl. Compounds of formula (I) where R is n-propyl are alternatively referred to herein as “Compound 1”.

[0159] In some embodiments, the crystalline solids described herein are characterized by X-ray diffraction (XRD). In some embodiments, XRD is X-ray powder diffraction (XRPD). θ represents the diffraction angle, measured in degrees. In some embodiments, the diffraction angle measured by the diffractometer used in XRD is twice the diffraction angle θ. Therefore, in some embodiments, the diffraction pattern described herein refers to the X-ray intensity measured against the angle 2θ.

[0160] In some embodiments, the crystalline solid comprising the compound of formula (I) has 2θ values ​​of 16.1, 20.1, and 24.5.In some embodiments, the crystalline solid comprising the compound of formula (I) has 2θ values ​​of 16.1, 20.1, 24.5, 23.7, 18.8, 21.5, 17.7, 8.1, 9.9, 13.0, 26.3, and 30.4. In some embodiments, the crystalline solid comprising the compound of formula (I) has 2θ values ​​of 16.1, 20.1, 24.5, 23.7, 18.8, 21.5, 17.7, 8.1, 9.9, 13.0, 26.3, 30.4, 23.0, 26.6, 25.3, 25.5, and 19.7. In some embodiments, the crystalline solid comprising the compound of formula (I) has an XRD pattern substantially as shown in FIG1 (A or B). In some embodiments, the XRD pattern is a methanol solvate of the compound of formula (I). In some embodiments, the XRD pattern is a non-solventized form of the compound of formula (I). In some embodiments, the XRD pattern corresponds to a three-dimensional shape corresponding to FIG. 1C.

[0161] In some embodiments, the compound of formula (I) is not solvated or hydrated in a crystalline solid (e.g., the lattice does not contain molecules of solvent or water). In some embodiments, the crystalline solid containing the compound of formula (I) contains unhydrated water and / or unsolvated solvent. In some embodiments, such unhydrated water and / or unsolvated solvent are present in residual amounts (e.g., less than 10% by weight, or less than 5% by weight), or in amounts greater than zero but less than 1% by weight.

[0162] In some embodiments, the compound of formula (I) is solvated by one or more solvents. In some embodiments, the compound of formula (I) is solvated by an alcohol to form an alcohol solvate, preferably by methanol to form a methanol solvate. In some embodiments, the crystalline methanol solvate of the compound of formula (I) contains about 1.0, about 1.1, or about 1.2 molecules of methanol relative to one molecule of the compound of formula (I). In some embodiments, the compound of formula (I) is solvated with ethanol. In some embodiments, the compound of formula (I) is solvated with water. In some embodiments, the compound of formula (I) is solvated / hydrated with ethanol and water. In various embodiments, the crystalline solid is a solvate selected from 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.

[0163] In various embodiments, the compound of formula (I) having the XRD pattern disclosed herein is prepared from an amorphous material with a purity greater than 90%, comprising the steps of dissolving the amorphous material in an alcohol and precipitating the product over time, preferably at ambient temperature. In various embodiments, the compound of formula (I) is prepared from an amorphous material by a method comprising the steps of: dissolving the amorphous material in water or an aqueous solution, then diluting the resulting solution with an antisolvent, and precipitating the compound of formula (I) over time.In various embodiments, the antisolvent is an alcohol, such as ethanol, methanol, propanol, or another alcohol having eight or fewer carbon atoms. In various embodiments, the antisolvent is ethanol. In various embodiments, the antisolvent is denatured ethanol.

[0164] In one aspect, this disclosure provides crystalline solids comprising compounds of formula (II), specification 10 / 34 pages 12 CN 122011067 A (II).

[0165] The compounds of formula (II) are alternatively referred to herein as "compound 2".

[0166] In some embodiments, the crystalline solids comprising the compounds of formula (II) have 2θ values ​​of 21.5, 24.2, 26.7, and 19.6. In some embodiments, the crystalline solids comprising the compounds of formula (II) have 2θ values ​​of 21.5, 24.2, 26.7, 19.6, 15.6, and 29.3. In some embodiments, the crystalline solid comprising the compound of formula (II) has 2θ values ​​of 21.5, 24.2, 26.7, 19.6, 15.6, 29.3, 22.9, 23.1, 22.5, 13.3, 22.2, 30.0, 30.6, 13.1, 27.2, and 17.5. In some embodiments, the crystalline solid comprising the compound of formula (II) has an XRD pattern substantially as shown in FIG2. In some embodiments, the XRD pattern is a hydrate of the compound of formula (II).

[0167] In some embodiments, the compound of formula (II) is not solvated or hydrated in the crystalline solid (e.g., the lattice does not contain molecules of solvent or water). In some embodiments, the compound of formula (II) is solvated by one or more solvents. In some embodiments, the crystalline solid comprising the compound of formula (II) contains non-hydrated water and / or non-solventizing solvent. In some embodiments, such non-hydrated water and / or non-solventized solvent are present in residual amounts (such as less than 10% by weight, or less than 5% by weight), or in amounts greater than zero but less than 1% by weight.

[0168] In some embodiments, the compound of formula (II) is solvated with water to form a hydrate. In other embodiments, the compound of formula (II) is solvated with alcohol to form an alcohol solvate. In some embodiments, the crystalline hydrate of the compound of formula (II) contains about 1.0, about 1.1, or about 1.2 molecules of methanol relative to one molecule of the compound of formula (II). In some embodiments, the compound of formula (II) is solvated with ethanol. In some embodiments, the compound of formula (II) is solvated / hydrated with water and ethanol. In various embodiments, the crystalline solid comprising the compound of formula (II) is a solvate selected from 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.

[0169] In various embodiments, compounds of formula (II) having the XRD patterns disclosed herein are prepared from amorphous materials with a purity greater than 90% by a method comprising the steps of: dissolving the amorphous material in an alcohol, and precipitating the compound of formula (II) over time, preferably at ambient temperature. In various embodiments, compounds of formula (II) are prepared from amorphous materials by a method comprising the steps of: dissolving the amorphous material in water or an aqueous solution, then diluting the resulting solution with an antisolvent, and precipitating the compound of formula (II) over time. In various embodiments, the antisolvent is an alcohol, such as ethanol, methanol, propanol, or another alcohol having eight or fewer carbon atoms. In various embodiments, the antisolvent is ethanol. In various embodiments, the antisolvent is denatured ethanol.

[0170] It is apparent that compounds of formula (I) and (II) can exist in a variety of protonated states, which depends particularly on the pH of their environment. In various pH environments, compounds of formula (I) and (II) exist as zwitterions or internal salts, as shown herein.

[0171] In various embodiments, the compounds of formulas (I) and (II) are one or more salts, wherein the salt is formed from a cation selected from H+, Li+, Na+, K+, Mg2+ and Ca2+, and / or the salt is formed from an anion selected from acetate, trifluoromethansulfonate, halides, trifluoroacetate, formate, H2PO4-, HPO42-, OH-, HSO4-, SO42-, NO3-, HCO3- and CO32-, and mixtures thereof. In the description of various embodiments, page 11 / 34 of 13 CN 122011067 A, the compounds are zwitterions.

[0172] This disclosure includes the use of pharmaceutically acceptable salts and / or crystalline solids of the compounds of this disclosure. In some embodiments, the contemplated salts of this disclosure include, but are not limited to, alkyl, dialkyl, trialkyl or tetraalkylammonium salts. In some embodiments, the intended salts of the present invention include, but are not limited to, L-arginine, phenethylbenzylamine, benzathine penicillin, betaine, calcium hydroxide, choline, dimethylethanolamine, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucosamine, hepaticillin, 1H-imidazolium, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts.

[0173] In some embodiments, the compound is a salt having anion selected from acetate, trifluoromethanesulfonate, halide, trifluoroacetate, or formate.In other embodiments, if the disclosed compound is in contact with a medium (e.g., an aqueous medium), the anion may be selected from, for example, OH−, H2PO4−, HPO42−, HSO4−, SO42−, NO3−, HCO3−, and CO32−.

[0174] In some embodiments, the disclosed compound is in the form of a negatively charged phosphate, which may form a salt with any suitable cation. The cation may be changed when the compound is isolated or transferred to a medium with different anionic substances. For example, the disclosed compound may be in the form of a phosphate that is a pharmaceutically acceptable salt as described herein. In some embodiments, the cation may be selected from Li+, Na+, K+, Mg2+, and Ca2+.

[0175] In some embodiments, the crystalline solid described herein is not part of a solution, suspension, mixture, slurry, reaction mixture, or the like.

[0176] In some embodiments, the average size of a single crystal of a crystalline solid comprising a compound of formula (I) or (II) is greater than about 1 micrometer, greater than about 5 micrometers, greater than about 10 micrometers, or greater than about 20 micrometers. In further embodiments, the average size of a single crystal of a crystalline solid comprising a compound of formula (I) or (II) is about 1 to about 100 micrometers, about 20 to about 100 micrometers, about 1 to about 500 micrometers, about 1 to about 250 micrometers, about 20 to about 250 micrometers, or about 20 to about 500 micrometers.

[0177] In some embodiments, the crystalline solids described herein have lower solubility in water compared to the amorphous solids of the compounds of formulas (I) and (II). In a preferred embodiment, the solubility ratio of the crystalline solid to water, by weight, is about 1:5 to about 1:75. In a more preferred embodiment, the solubility ratio of the crystalline solid to water, by weight, is about 1:10 to about 1:60. This lower solubility in water can impart desirable therapeutic properties.

[0178] In various embodiments, the crystalline solid is anhydrous. In various embodiments, the crystalline solid contains less than about 5% water, less than about 2% water, less than about 1% water, less than about 0.5% water, or less than about 0.1% water. In some embodiments, the percentages are by weight.

[0179] In preferred embodiments, the compound of formula (I) or its crystalline solid contains less than about 5% impurities, less than about 2% impurities, less than about 1% impurities, or less than about 0.5% impurities. For example, in preferred embodiments, the compound of formula (I) or its crystalline solid contains less than about 5% propyl nicotinate, less than about 2% propyl nicotinate, less than about 1% propyl nicotinate, less than about 0.5% propyl nicotinate, or less than about 0.1% propyl nicotinate. In some embodiments, the percentages are by weight.

[0180] In a preferred embodiment, the compound of formula (II) or its crystalline solid contains less than about 5% impurities, less than about 2% impurities, less than about 1% impurities, or less than about 0.5% impurities. For example, in a preferred embodiment, the compound of formula (II) or its crystalline solid contains less than about 5% nicotinic acid riboside, less than about 2% nicotinic acid riboside, less than about 1% nicotinic acid riboside, less than about 0.5% nicotinic acid riboside, less than about 0.1% nicotinic acid riboside, or less than about 0.01% nicotinic acid riboside. In some embodiments, the percentages are by weight.

[0181] In some preferred embodiments, the crystalline solid containing the compound of formula (I) or formula (II) is pure or substantially pure. In some preferred embodiments, the crystalline solid is greater than about 90% pure. More preferably, the crystalline solid is greater than about 95% pure, or even more preferably greater than about 98% pure, for example, greater than about 99% pure. In some embodiments, the percentages are by weight. In preferred embodiments, the crystalline solid comprises at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, or at least about 99.9% of a compound of formula (I) or formula (II). In some embodiments, the percentages are by weight.

[0182] The crystalline solids described herein may have advantageous properties compared to the amorphous forms of the compounds of formulas (I) and (II). In some embodiments, for example at elevated temperatures, the crystalline solids exhibit improved chemical and / or physical stability. In some embodiments, compositions comprising the crystalline solids exhibit improved chemical and / or physical stability. In some embodiments, the crystalline solids have improved storage stability. In some embodiments, the crystalline solids exhibit better handling properties during manufacturing than the amorphous forms, which may result in higher purity, stability, and / or consistency of the compounds, crystalline solids, and compositions. In some embodiments, the crystalline solids may be easier to process under typical pharmaceutical processing conditions. In some embodiments, improved processability properties include improved viscosity and flowability. In some embodiments, the crystalline solids described herein have lower hygroscopicity compared to their amorphous forms. For example, when exposed to a humid environment (e.g., at least 50% humidity), the crystalline solids may absorb less water than their corresponding amorphous forms under the same conditions. In some embodiments, the crystalline solids maintain structural integrity when exposed to humidity; for example, they may be less prone to swelling or transforming into less stable forms. In some embodiments, the crystalline solids described herein have lower solubility and / or dissolution rate compared to their amorphous forms. In some embodiments, to prolong the effect of the crystalline solids as a drug, it is desirable to slow down the absorption of the crystalline solids.For example, in some embodiments, the crystalline solids described herein are efficiently delivered to the intestine and do not dissolve significantly in the stomach. In some embodiments, for example, a prolonged release effect is achieved by using an aqueous suspension of the crystalline solid. In other embodiments, delayed release is achieved by dissolving or suspending the solid material in an oil-based medium. In some embodiments, the crystalline solids described herein have higher purity than the amorphous form and / or are advantageous for the large-scale preparation of pure materials, for example, at a lower cost or using less material or space-intensive purification methods. In some such embodiments, the crystalline solids and methods described herein are advantageous for large-scale purification, for example, greater than about 1 gram, greater than about 10 grams, or greater than about 100 grams.

[0183] Methods for Preparing Crystalline Solids Methods for preparing crystalline solids of compounds of formula (I) are also provided herein. In some embodiments, this disclosure relates to methods for preparing crystalline solids of compounds of formula (I), comprising a) dissolving the compound of formula (I) in a solvent to form a mixture; and b) crystallizing the compound of formula (I) from the mixture to form a crystalline solid.

[0184] In a preferred embodiment, the mixture comprising the compound of formula (I) is a solution. In other embodiments, the mixture is a slurry or suspension. In some embodiments, the solvent is selected from alcohols, ketones, carboxylic acids, esters, ethers, alkanes, water, amines, other liquids with similar polarity and properties, and combinations thereof. In some embodiments, the solvent includes acetonitrile, N,N-dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methanol, ethanol, ethyl acetate, isopropyl acetate, methanol, methyl ethyl ketone, N-methyl-2-pyrrolidone (NMP), tetrahydrofuran, propanol, butanol, water, or any combination thereof. In some embodiments, the solvent is a straight-chain or branched alcohol, such as methanol, ethanol, propanol, or butanol, including its branched and unbranched isomers. In a preferred embodiment, the solvent is methanol. In some embodiments, the solvent includes two or more of the solvents described herein. In some embodiments, the solution is anhydrous.

[0185] In some embodiments, the temperature of the solvent is above ambient temperature during the dissolution step. In such embodiments, the method includes heating the solvent. For example, the temperature of the solvent may be about 30 to about 50°C or about 30 to about 40°C, for example about 35°C. In other embodiments, the solvent temperature is approximately ambient temperature during the dissolution step. In still other embodiments, the solvent temperature is below ambient temperature during the dissolution step. In such embodiments, the method includes cooling the solvent. In some embodiments, the solvent temperature is approximately 20 to approximately 30°C, for example, approximately 25°C. In a preferred embodiment, the compound of formula (I) is completely dissolved in the solvent prior to the crystallization step. Complete dissolution means that the compound is present in a homogeneous solution, rather than in a slurry or suspension.In other embodiments, prior to the crystallization step, the compound of formula (I) is partially dissolved in a solvent.

[0186] In some embodiments, the method includes forming a supersaturated solution from a mixture (e.g., a solution) of the compound of formula (I), wherein the supersaturated solution is supersaturated relative to the compound of formula (I). In some embodiments, the supersaturated solution has a supersaturation ratio of about 1 to about 4, for example, about 2. In some such embodiments, the compound of formula (I) is precipitated (e.g., crystallized) from the supersaturated solution. In some embodiments, the resulting precipitate (e.g., crystals) is a crystalline solid as described herein.

[0187] The supersaturated solution can be formed according to various methods. In some embodiments, forming a supersaturated solution may include adding an antisolvent to the mixture (e.g., a solution), lowering the temperature of the mixture (e.g., a solution), reducing the volume of the mixture (e.g., a solution), or any combination thereof. For example, the method may include adding an antisolvent, subsequently cooling the resulting mixture, and subsequently adding additional antisolvent.

[0188] In some embodiments, forming a supersaturated solution includes lowering the temperature of a mixture containing the compound of formula (I). In some such embodiments, the temperature of the solution is lowered to about 0 to about 25°C, about 0 to about 10°C, or about -5 to about 5°C, for example, about 0°C. In some embodiments, cooling the solution can be passive (e.g., allowing the solution to stand at ambient temperature) or active (e.g., cooling the solution in an ice bath or refrigerator).

[0189] In some embodiments, forming a supersaturated solution includes adding an antisolvent to a mixture containing compounds of formula (I). As used herein, "antisolvent" means a liquid in which compounds of formulas (I) and (II) are insoluble, minimally soluble, or partially soluble. In practice, adding an antisolvent to a solution containing compounds of formulas (I) and (II) reduces the solubility of compounds of formulas (I) and (II) in the solvent, thereby promoting precipitation.

[0190] In some embodiments, the antisolvent may be added slowly to prevent uncontrolled crystallization. In some embodiments, the antisolvent is selected from alcohols, ketones, carboxylic acids, esters, ethers, alkanes, water, amines, other liquids miscible with the solvent of similar polarity and properties, and combinations thereof. In some embodiments, the antisolvent is an alkane solvent, such as hexane or pentane, or an aromatic hydrocarbon solvent, such as benzene, toluene, or xylene. In some embodiments, the antisolvent is selected from ethyl acetate, isopropyl acetate, methyl tert-butyl ether, methyl isobutyl ketone, tetrahydrofuran, 1-propanol, 2-propanol, ethanol, denatured ethanol, and combinations thereof. In a preferred embodiment, the antisolvent is TBME. In some embodiments, the antisolvent comprises two or more of the solvents described herein. In some embodiments, the solvent to antisolvent ratio is from about 1:1 to about 8:1 by volume, or from about 4:1 to about 6:1 by volume, for example, about 5:1 by volume.

[0191] In some embodiments, the method further includes evaporating the solvent from the mixture. In some embodiments, the solvent may be removed under reduced pressure and / or by heating the solvent to cause it to evaporate.

[0192] In some embodiments, crystallization includes inducing secondary nucleation. In some embodiments, crystallization includes adding a seed crystal to the solution, wherein the seed crystal comprises a compound of formula (I). In some embodiments, the seed crystal is formed during a previous crystallization. In some such embodiments, the previous crystallization is carried out on a smaller scale than the crystallization with the addition of the seed crystal.

[0193] In other embodiments, secondary nucleation may be caused by other changes in the environment of the mixture. For example, crystallization may be facilitated by environmental changes, including but not limited to crystallizer walls, stirring impellers, and ultrasonic treatment.

[0194] In a preferred embodiment, the method includes separating the crystalline solid, for example by filtering the crystal, by decanting fluid from the crystal, or by any other suitable separation technique.

[0195] In some embodiments, the method includes washing the crystalline solid containing a compound of formula (II), for example, by washing the crystalline solid with one or more of the solvents described herein or a mixture of these solvents and / or antisolvents. In some embodiments, washing the crystalline solids includes washing with a liquid selected from antisolvents, solvents, alcohols, ketones, carboxylic acids, esters, ethers, alkanes, water, amines, other liquids with similar polarity and properties, and combinations thereof. In some embodiments, the liquid is selected from acetonitrile; N,N-dimethyl ethyl ether (DMA); dimethylformamide (DMF); dimethyl sulfoxide (DMSO); ethyl acetate; isopropyl acetate; methyl ethyl ketone; methyl isobutyl ketone; N-methyl-2-pyrrolidone (NMP); tetrahydrofuran; alcohols such as methanol, ethanol, propanol, or butanol; water; alkane solvents such as pentane, hexane, or heptane; aromatic hydrocarbon solvents such as benzene, toluene, or xylene; methyl tert-butyl ether; and combinations thereof. In some embodiments, the solvent and / or antisolvent is cooled prior to washing. In some embodiments, the method includes drying the crystalline solid, for example under reduced pressure and / or by heating the crystalline solid, and / or under a drying gas such as nitrogen, argon, or air.

[0196] In some embodiments, the method for preparing the crystalline solid removes one or more impurities from the compound of formula (I). In some embodiments, the method does not include chromatographic analysis or lyophilization to purify the compound of formula (I). In some such embodiments, the methods described herein are used to purify the compound of formula (I), for example, as a final purification step in the manufacture of the compound of formula (I).

[0197] The methods described herein can provide benefits such as removing impurities from the compound of formula (I).In preferred embodiments, the crystalline solid contains less than about 5% impurities, less than about 2% impurities, less than about 1% impurities, or less than about 0.5% impurities. In some preferred embodiments, the crystalline solid contains less than about 5% propyl nicotinic acid, less than about 2% propyl nicotinic acid, less than about 1% propyl nicotinic acid, less than about 0.5% propyl nicotinic acid, or less than about 0.1% propyl nicotinic acid. In some embodiments, the percentages are by weight.

[0198] In some preferred embodiments, the crystalline solid containing the compound of formula (II) is pure or substantially pure. In some preferred embodiments, the crystalline solid is greater than about 90% pure. More preferably, the crystalline solid is greater than about 95% pure, or even more preferably greater than about 98% pure. In some embodiments, the percentages are by weight.

[0199] In a preferred embodiment, the crystalline solid comprises at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, or at least about 99.9% of the compound of formula (I). In some embodiments, the percentages are by weight.

[0200] Another aspect of this disclosure provides a method for preparing a crystalline solid of a compound of formula (II). In some embodiments, this disclosure relates to a method for preparing a crystalline solid of a compound of formula (II), comprising a) dissolving a compound of formula (II) in a solvent to form a mixture; and b) crystallizing the compound of formula (II) from the mixture to form a crystalline solid. In some embodiments, the method comprises reacting nicotinic riboside with a phosphorus-containing group such as phosphoryl chloride prior to the dissolution and crystallization steps to provide a compound of formula (II).

[0201] In a preferred embodiment, the mixture comprising the compound of formula (II) is a solution. In other embodiments, the mixture is a slurry or suspension. In some embodiments, the solvent is selected from alcohols, ketones, carboxylic acids, esters, ethers, alkanes, water, amines, other liquids with similar polarity and properties, and combinations thereof. In some embodiments, the solvent includes acetonitrile, N,N-dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methanol, ethanol, ethyl acetate, isopropyl acetate, methanol, methyl ethyl ketone, N-methyl-2-pyrrolidone (NMP), tetrahydrofuran, propanol, butanol, water, or any combination thereof. In some embodiments, the solvent is a straight-chain or branched alcohol, such as methanol, ethanol, propanol, or butanol, including its branched and unbranched isomers. In a preferred embodiment, the solvent is water. In some embodiments, the solvent includes an alcohol, such as 1-propanol. In some embodiments, the solvent includes two or more of the solvents described herein. In some embodiments, the ratio of the compound of formula (II) to the solvent is from about 1:2 to about 1:4 by weight, for example, about 1:3 by weight.

[0202] In some embodiments, the temperature of the solvent is higher than ambient temperature during the dissolution step.In such embodiments, the method includes heating the solvent. For example, the temperature of the solvent may be about 30 to about 50°C or about 30 to about 40°C, such as about 35°C. In other embodiments, the temperature of the solvent is about ambient temperature during the dissolution step. In still other embodiments, the temperature of the solvent is below ambient temperature during the dissolution step. In such embodiments, the method includes cooling the solvent. In some embodiments, the temperature of the solvent is about 20 to about 30°C, such as about 25°C. In a preferred embodiment, the compound of formula (II) is completely dissolved in the solvent prior to the crystallization step. Complete dissolution means that the compound is present in a homogeneous solution, rather than in a slurry or suspension. In other embodiments, the compound of formula (II) is partially dissolved in the solvent prior to the crystallization step.

[0203] In some embodiments, the method includes forming a supersaturated solution from a mixture (e.g., a solution) of the compound of formula (II), wherein the supersaturated solution is supersaturated relative to the compound of formula (II). In some embodiments, the supersaturated solution has a supersaturation ratio of 1 to about 4, for example, about 2. In some such embodiments, the compound of formula (I) is precipitated (e.g., crystallized) from the supersaturated solution. In some embodiments, the resulting precipitate (e.g., crystals) is a crystalline solid as described herein.

[0204] Supersaturated solutions can be formed according to various methods. In some embodiments, forming a supersaturated solution may include adding an antisolvent to a mixture (e.g., a solution), lowering the temperature of the mixture (e.g., a solution), reducing the volume of the mixture (e.g., a solution), or any combination thereof. For example, the method may include adding an antisolvent, subsequently cooling the resulting mixture, and subsequently adding additional antisolvent.

[0205] In some embodiments, forming a supersaturated solution includes lowering the temperature of a mixture containing a compound of formula (II). In some such embodiments, the temperature of the solution is lowered to about 0 to about 25°C, about 0 to about 10°C, or about -5 to about 5°C, for example, about 0°C. In some embodiments, cooling the solution may be passive (e.g., allowing the solution to stand at ambient temperature) or active (e.g., cooling the solution in an ice bath or refrigerator).

[0206] In some embodiments, forming a supersaturated solution includes adding an antisolvent to a mixture comprising a compound of formula (II). In some embodiments, the antisolvent may be added slowly to prevent uncontrolled crystallization. In some embodiments, the antisolvent is selected from alcohols, ketones, carboxylic acids, esters, ethers, alkanes, water, amines, other liquids miscible with the solvent of similar polarity and properties, and combinations thereof. In some embodiments, the antisolvent is an alkane solvent, such as hexane or pentane, or an aromatic hydrocarbon solvent, such as benzene, toluene, or xylene. In some embodiments, the antisolvent is selected from ethyl acetate, isopropyl acetate, methyl tert-butyl ether, methyl isobutyl ketone, tetrahydrofuran, and combinations thereof.In other embodiments, the solvent is a straight-chain or branched alcohol, such as methanol, ethanol, propanol, or butanol, including its branched and unbranched isomers. In a preferred embodiment, the antisolvent is 1-propanol. In some embodiments, the antisolvent includes two or more of the solvents described herein. In some embodiments, the solvent to antisolvent ratio is from about 1:0 to about 1:2 by volume, or from about 1:0 to about 6:7 by volume, for example, about 6:7 by volume. In some embodiments, a supersaturated solution is formed without the addition of an antisolvent.

[0207] In some embodiments, the method further includes evaporating the solvent from the mixture. In some embodiments, the solvent may be removed under reduced pressure and / or by heating the solvent to evaporate it.

[0208] In some embodiments, the method further includes adding an acid or base to adjust the pH of the mixture (e.g., a solution) to change the protonated state of the compound of formula (II). In some embodiments, the base is an amine, such as triethylamine. In some embodiments, the method further includes adding a base to the solution. In some embodiments, the pH of the solution is adjusted to from about 2 to about 4, for example, about 3.

[0209] In some embodiments, crystallization includes causing secondary nucleation to occur. In some embodiments, crystallization includes adding a seed crystal to the solution, wherein the seed crystal comprises a compound of formula (II). In some embodiments, the seed crystal is formed during a previous crystallization. In some such embodiments, the previous crystallization is carried out on a smaller scale than the crystallization with the addition of the seed crystal.

[0210] In other embodiments, secondary nucleation may be caused by other changes in the environment of the mixture. For example, crystallization can be facilitated by environmental changes, including but not limited to crystallizer walls, stirring impellers, and ultrasonic treatment.

[0211] In a preferred embodiment, the method includes separating the crystalline solid, for example by filtering the crystal, by decanting fluid from the crystal, or by any other suitable separation technique. Specification 16 / 34 pages 18 CN 122011067 A

[0212] In some embodiments, the method includes washing the crystalline solid containing a compound of formula (II), for example, washing the crystalline solid with one or more of the solvents described herein or a mixture of these solvents and / or antisolvents. In some embodiments, washing the crystalline solids includes washing with a liquid selected from antisolvents, solvents, alcohols, ketones, carboxylic acids, esters, ethers, alkanes, water, amines, other liquids with similar polarity and properties, and combinations thereof.In some embodiments, the liquid is selected from acetonitrile; N,N-dimethylacetamide (DMA); dimethylformamide (DMF); dimethyl sulfoxide (DMSO); ethyl acetate; isopropyl acetate; methyl ethyl ketone; methyl isobutyl ketone; N-methyl-2-pyrrolidone (NMP); tetrahydrofuran; alcohols such as methanol, ethanol, propanol, or butanol; water; alkane solvents such as pentane, hexane, or heptane; aromatic hydrocarbon solvents such as benzene, toluene, or xylene; methyl tert-butyl ether; and combinations thereof. In a preferred embodiment, the method includes washing the crystalline solid with a 2:1 volumetric mixture of 1-propanol and water, optionally followed by washing the crystalline solid with MTBE. In some embodiments, the solvent and / or antisolvent is cooled prior to washing. In some embodiments, the method includes drying the crystalline solid, for example under reduced pressure and / or by heating the crystalline solid.

[0213] In some embodiments, the method for preparing the crystalline solid removes one or more impurities from the compound of formula (II). In some embodiments, the method does not include chromatographic analysis or lyophilization to purify the compound of formula (II). In some such embodiments, the methods described herein are used to purify compounds of formula (II), for example, as a final purification step in the manufacture of compounds of formula (II).

[0214] The methods described herein can provide benefits such as removing impurities from compounds of formula (II). In preferred embodiments, the crystalline solid contains less than about 5% impurities, less than about 2% impurities, less than about 1% impurities, or less than about 0.5% impurities. In some embodiments, the crystalline solid contains less than about 5% nicotinic acid riboside, less than about 2% nicotinic acid riboside, less than about 1% nicotinic acid riboside, less than about 0.5% nicotinic acid riboside, or less than about 0.1% nicotinic acid riboside. In some embodiments, the percentages are by weight.

[0215] In some preferred embodiments, the crystalline solid containing the compound of formula (II) is pure or substantially pure. In some preferred embodiments, the crystalline solid is greater than about 90% pure. More preferably, the crystalline solid is greater than about 95% pure, or even more preferably greater than about 98% pure. In some embodiments, the percentages are by weight.

[0216] In a preferred embodiment, the crystalline solid comprises at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, or at least about 99.9% of a compound of formula (II). In some embodiments, the percentages are by weight.

[0217] Synthesis In various embodiments, this disclosure provides a method (I) for forming a compound of formula (I) wherein R is a C1-C6 alkyl or C2-C6 alkenyl; the method comprises contacting a compound of formula (II) with an alcohol R-OH in the presence of an acid. See, for example, Scheme 1.Specification 17 / 34 pages 19 CN 122011067 A Scheme 1 In some embodiments, R is a C1-C6 alkyl. In some embodiments, R is a C1-C4 alkyl or C2-C4 alkenyl. In some embodiments, R is a C3 alkyl. In some embodiments, R is n-propyl.

[0218] In some embodiments, the acid is a strong acid. In some embodiments, the acid is an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. In other embodiments, the acid is an organic acid, such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, lauryl sulfate, gluconic acid, glutamic acid, salicylic acid, mucoconic acid, etc. In a preferred embodiment, the acid is HCl.

[0219] In some embodiments, the method includes purifying the compound of formula (II). In some embodiments, the method includes removing an ammonium salt, such as triethylammonium salt, from the compound of formula (II). In some embodiments, the compound of formula (II) is provided as a crystalline solid. In some embodiments, the method includes crystallizing the compound of formula (II) according to the method described herein.

[0220] In some embodiments, the method includes adding a solvent to the compound of formula (II) to form a mixture, such as a solution. In some embodiments, the solvent is a polar solvent. Polar solvents include polar groups, which may be selected from, for example, hydroxyl, carbonyl, ether, ester, amine, amide, and carboxyl groups. In some embodiments, the solvent comprises water. In a preferred embodiment, the alcohol R-OH is the reaction solvent. In a preferred embodiment, the solvent is a straight-chain or branched alcohol, such as methanol, ethanol, propanol, or butanol, including its branched and unbranched isomers. In a more preferred embodiment, the solvent is propanol, such as 1-propanol or 2-propanol. In some embodiments, the temperature of the mixture comprising the compounds of formula (II) is about -5 to about 10°C, about -5 to about 5°C, or about 0°C.

[0221] In some embodiments, the method comprises mixing the compound of formula (II) with an alcohol. In some embodiments, the mixing step is carried out for about 12 to about 72 hours, about 12 to about 48 hours, or about 12 to about 24 hours. In some embodiments, throughout the mixing step, the mixture comprising the compounds of formula (II) is about -5 to about 10°C, about -5 to about 5°C, or about 0°C.

[0222] In some embodiments, the method includes adding a base. In various embodiments, the base is added after about 12 to about 72 hours, about 12 to about 48 hours, or about 12 to about 24 hours. In some embodiments, the base is added until the pH of the reaction mixture is about 4 to about 5. In some embodiments, the base is an amine base.In some such embodiments, the base is a trialkylamine base. In a preferred embodiment, the base is triethylamine. In a further embodiment, the method includes adding a seed crystal of a compound of formula (I) to the reaction mixture.

[0223] In various embodiments, the method includes purifying the resulting product (i.e., the compound of formula (I)). In some embodiments, the purified product includes chromatographic analysis. In other embodiments, the purified product does not include chromatographic analysis. In a preferred embodiment, the purified product includes a crystalline compound of formula (I) according to the method described herein. In a preferred embodiment, the compound of formula (I) is provided as a crystalline solid as described herein.

[0224] Methods for Treating Diseases, Disorders, and Conditions This document provides methods for regulating NAD levels in a subject in need, including administering compounds, crystalline solids, and / or compositions described herein. Any compound, crystalline solid, or composition described herein may be used to manufacture a medicament for treating any disease or condition disclosed herein.

[0225] This document provides methods for treating diseases or disorders associated with NAD biosynthesis, including administering compounds, crystalline solids, and / or compositions described herein.

[0226] This document provides methods for using the disclosed compounds, crystalline solids, and pharmaceutical compositions thereof. The disclosed compounds, crystalline solids, and pharmaceutical compositions thereof can be used for a variety of therapeutic applications, including, for example, treating and / or alleviating a variety of diseases and disorders, including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, ataxia and related muscle disorders, acute organ failure, viral symptoms such as cytokine storms, cardiovascular diseases, coagulation disorders, inflammation, cancer, and / or flushing, etc. The method includes administering the disclosed compounds, crystalline solids, and / or pharmaceutical compositions thereof to a subject in need. The disclosed compounds, crystalline solids, and pharmaceutical compositions thereof can be used to increase or maintain NAD levels in certain tissues or cells while decreasing NAD levels in other tissues or cells. In various embodiments, the disclosed compounds, crystalline solids, and pharmaceutical compositions thereof can be used to selectively decrease NAD levels in some tissues or cells while decreasing NAD levels in other tissues or cells to a lesser extent.

[0227] The disclosed compounds, crystalline solids, and pharmaceutical compositions thereof may also be used to treat diseases or conditions associated with inflammation.Exemplary inflammatory conditions include, for example, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, degenerative joint disease, spondyloarthritis, gouty arthritis, systemic lupus erythematosus, juvenile arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, diabetes (e.g., insulin-dependent diabetes mellitus or juvenile-onset diabetes), dysmenorrhea, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucinous colitis, ulcerative colitis, gastritis, esophagitis, pancreatitis, peritonitis, Alzheimer's disease, shock, ankylosing spondylitis, gastritis, conjunctivitis, pancreatitis (acute or chronic), multiple organ injury syndrome (e.g., secondary to sepsis or trauma), myocardial infarction, atherosclerosis, stroke, reperfusion injury (e.g., due to cardiopulmonary bypass or kidney dialysis), acute glomerulonephritis, vasculitis, heat injury (i.e., sunburn), necrotizing enterocolitis, granulocyte transfusion-related syndrome, and / or Sjögren's syndrome. Exemplary inflammatory skin conditions include, for example, eczema, atopic dermatitis, contact dermatitis, urticaria, scleroderma, psoriasis, and skin diseases with acute inflammatory components.

[0228] In other embodiments, the disclosed compounds, crystalline solids, and / or pharmaceutical compositions thereof may be used to treat skin conditions. Exemplary skin conditions treatable according to the methods described herein include disorders or diseases associated with or caused by inflammation, sunburn, or natural aging. For example, the composition has been found to treat contact dermatitis (including irritant contact dermatitis and allergic contact dermatitis), atopic dermatitis (also known as allergic eczema), actinic keratosis, keratinization disorders (including eczema), bullous epidermolysis, exfoliative dermatitis, seborrheic dermatitis, erythema (including erythema multiforme and erythema nodosum), damage caused by the sun or other light sources, discoid lupus erythematosus, dermatomyositis, psoriasis, skin cancer, and the effects of natural aging. In other embodiments, the disclosed compounds, crystalline solids, and pharmaceutical compositions thereof may be used to treat wounds and / or burns to promote healing, including, for example, first-, second-, or third-degree burns and / or thermal, chemical, or electrical burns.

[0229] The disclosed compounds, crystalline solids, and pharmaceutical compositions thereof may also be administered to subjects with acute illnesses (e.g., organ or tissue damage), such as subjects with stroke or myocardial infarction or spinal cord injury, or subjects who have received solid organ transplants (e.g., liver or kidney). In some embodiments, the compounds, their crystalline solids, and pharmaceutical compositions may be administered to subjects with acute kidney injury (AKI), also known as acute kidney failure (ARF). Kidney function screening may be performed on subjects with AKI or at risk of AKI, for example by testing for abnormal levels of serum creatinine. Subjects may be given prophylactic treatment or treatment in response to acute kidney injury (e.g., stage 1 AKI).As a form of organ preservation, subjects receiving solid organ transplants may receive prophylactic or post-transplant treatment, or individual organs may be treated in vitro prior to transplantation. Subjects undergoing surgeries other than organ transplantation (such as biopsies or resections or wound repair) may receive prophylactic or post-operative treatment.

[0230] The disclosed compounds, crystalline solids, and pharmaceutical compositions thereof may also be used in subjects who have or may have chronic damage or chronic disease of solid organs such as the kidneys or liver. In some embodiments, the crystalline solids and pharmaceutical compositions thereof may be administered to subjects with chronic kidney disease (such as end-stage renal failure, or nephropathy, or diabetic nephropathy). In some embodiments, the crystalline solids and pharmaceutical compositions thereof may be administered to subjects with chronic liver disease such as chronic infection, cirrhosis, or liver cancer to repair or limit further damage to the liver. In some embodiments, the crystalline solids and pharmaceutical compositions thereof may be administered to repair alcoholic liver disease, or to stabilize or repair damage from non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD).

[0231] In some embodiments, the compounds, crystalline solids, or pharmaceutical compositions disclosed herein may be used to treat or prevent diseases or conditions induced or exacerbated by cellular senescence in a subject; methods for reducing the rate of aging in a subject, e.g., after the onset of aging; methods for prolonging the lifespan of a subject; methods for treating or preventing lifespan-related diseases or conditions; methods for treating or preventing diseases or conditions related to cell proliferation capacity; and methods for treating or preventing diseases or conditions caused by cell damage or death. In some embodiments, the method does not work by reducing the incidence of diseases that shorten the lifespan of a subject. In some embodiments, the method does not work by reducing mortality from diseases such as cancer.

[0232] In some embodiments, the compounds, crystalline solids, or pharmaceutical compositions disclosed herein may be administered to a subject to generally prolong the lifespan of their cells and protect their cells against stress and / or against apoptosis. Treating a subject with the compounds or crystalline solids described herein may be similar to subjecting the subject to the stimulant effect of a toxic substance, i.e., a mild stress that is beneficial to the organism and can prolong its lifespan.

[0233] In other embodiments, this document provides a method for treating cardiovascular diseases by administering the disclosed compounds, crystalline solids, and / or pharmaceutical compositions thereof to a subject in need. Cardiovascular diseases that can be treated with the disclosed compounds, crystalline solids, and pharmaceutical compositions thereof include cardiomyopathy or myocarditis; such as idiopathic cardiomyopathy, metabolic cardiomyopathy, alcoholic cardiomyopathy, drug-induced cardiomyopathy, ischemic cardiomyopathy, and hypertensive cardiomyopathy.The compositions and methods described herein can also be used to treat atherosclerotic disorders (large vessel diseases) of major blood vessels, such as the aorta, coronary arteries, carotid arteries, cerebral arteries, renal arteries, iliac arteries, femoral arteries, and popliteal arteries. Other vascular diseases that can be treated include those related to platelet aggregation, retinal arterioles, glomerular arterioles, nerve-feeding vessels, cardiac arterioles, and associated capillary beds of the eyes, kidneys, heart, and central and peripheral nervous systems. The disclosed compounds, crystalline solids, and pharmaceutical compositions thereof can also be used to increase HDL levels in an individual's plasma.

[0234] The disclosed compounds, crystalline solids, and pharmaceutical compositions thereof can be administered to subjects who have recently received or may receive a dose of radiation or toxins. In one embodiment, the dose of radiation or toxins is received as part of a work-related or medical procedure, such as working in a nuclear power plant, flying an aircraft, X-ray, CAT scan, or administration of radioactive dyes for medical imaging; in this embodiment, the compound or crystalline solid is administered as a precautionary measure. In other embodiments, the radiation or toxin exposure is unintentional, for example, due to industrial accidents, residence in locations with natural radiation, acts of terrorism, or acts of war involving radioactive or toxic materials. In such cases, it is preferable to apply the disclosed compounds, crystalline solids, and pharmaceutical compositions thereof as soon as possible after exposure to inhibit apoptosis and the subsequent development of acute radiation syndrome.

[0235] In other embodiments, the disclosed compounds, crystalline solids, and pharmaceutical compositions thereof can be used to treat age-related conditions such as cancer. Exemplary cancers that can be treated with the disclosed compounds, crystalline solids, and pharmaceutical compositions thereof include those of the brain and kidneys; hormone-dependent cancers, including breast cancer, prostate cancer, testicular cancer, and ovarian cancer; lymphoma and leukemia. Other conditions that can be treated include autoimmune diseases such as systemic lupus erythematosus, scleroderma, and arthritis, in which autoimmune cells should be removed.

[0236] Viral infections, such as herpes, HIV, adenovirus, and HTLV-1-associated malignant and benign diseases, can also be treated by applying the disclosed compounds, crystalline solids, and pharmaceutical compositions thereof.

[0237] In some embodiments, the disclosed compounds, crystalline solids, and pharmaceutical compositions thereof can be used to treat patients with infectious diseases such as COVID-19 and other viral infections, including those experiencing symptoms such as cytokine release syndrome (cytokine storm). In some embodiments, the compounds, crystalline solids, and pharmaceutical compositions thereof alleviate or prevent cytokine storms without treating the underlying viral infection (e.g., COVID-19). Cytokine release syndrome is an acute systemic inflammatory syndrome that can be caused by a variety of factors.In particular, cytokine storms have been described in COVID-19 and other severe viral syndromes (SARS, MERS). A subset of patients exhibit significantly elevated cytokines, and severely ill patients also show much higher levels of IL-6, CRP, ferritin, D-dimer, and other markers, as well as lymphopenia (decreased CD4+ and CD8+ T cell counts). For example, in one report, D-dimer levels > 2.0 ug / ml at admission identified a subgroup of patients likely to die (12 / 67 >= 2.0 vs 1 / 267 < 2.0, sensitivity 92.3%, specificity 83.3%) (“D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19” Zhang L, Yan X, Fan Q, et al., *Journal of Thrombosis and Haemost*, April 19, 2020). NAD regulates the release of the NLRP3 inflammasome from IL-1β, thereby regulating the cytokine storm. NAD levels are known to decline with age, which may also contribute to a worse prognosis in older COVID-19 patients. One aspect of this disclosure provides a method of treating COVID-19 in a human patient, comprising administering to the patient the disclosed compound, crystalline solid, and pharmaceutical composition thereof without the administration of zinc sulfate, betaine, or mixtures thereof.

[0238] In some embodiments, the disclosed compound, crystalline solid, and pharmaceutical composition thereof may be used to treat patients suffering from neurodegenerative diseases and traumatic or mechanical injuries to the central nervous system (CNS) or peripheral nervous system (PNS). Examples of neurodegenerative diseases include, but are not limited to, ataxia, Alzheimer's disease (AD), dementia other than Alzheimer's disease, Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), diffuse Lewy body disease, chorea-acanthocytosis, primary lateral sclerosis, multiple sclerosis (MS), eye diseases (ocular neuritis), spinal muscular atrophy, chemotherapy-induced neuropathy (e.g., from vincristine, paclitaxel, bortezomib), diabetes-induced neuropathy, and Friedrich's ataxia.

[0239] In some embodiments, the disclosed compounds, crystalline solids, and pharmaceutical compositions thereof may be used to treat skeletal muscle disorders, muscle disorders, and conditions including muscle loss, atrophy, and sarcopenia.

[0240] In other embodiments, the disclosed compounds, crystalline solids, and pharmaceutical compositions thereof may be used to reduce appetite and / or increase satiety, thereby resulting in weight loss or preventing weight gain. Subjects requiring such treatment may be overweight, obese, or likely to become overweight or obese.

[0241] In other embodiments, the disclosed compounds, crystalline solids, and pharmaceutical compositions thereof may be used to treat subjects with cachexia or likely to develop cachexia. One method may further include monitoring the subject's disease status. Methods for promoting appetite and / or weight gain may include, for example, pre-identifying subjects who require reduced fat or lipid metabolism, for example, by weighing the subject and determining the subject's BMI. The method may also include monitoring the subject, for example, during and / or after administration of the disclosed compounds, crystalline solids, or pharmaceutical compositions thereof. Administration may include one or more doses, for example, in pellet form or continuous delivery. Monitoring may include assessing hormones or metabolites. Exemplary hormones include leptin, adiponectin, resistin, and insulin. Exemplary metabolites include triglycerides, cholesterol, and fatty acids.

[0242] In some embodiments, the disclosed compounds, crystalline solids, and pharmaceutical compositions thereof may be used to treat metabolic disorders, such as insulin resistance, prediabetes, type 2 diabetes, and / or its complications. Administration of the disclosed compounds, crystalline solids, and pharmaceutical compositions thereof may increase insulin sensitivity and / or decrease insulin levels in a subject. Subjects requiring such treatment may be subjects with insulin resistance or other prodromal symptoms of type 2 diabetes, subjects with type 2 diabetes, or subjects who may develop any of these conditions. For example, a subject may be a subject with insulin resistance, such as a subject with high circulating insulin levels and / or associated conditions, such as hyperlipidemia, lipogenic disorders, hypercholesterolemia, impaired glucose tolerance, high blood sugar levels, other manifestations of syndrome X, hypertension, atherosclerosis, and lipodystrophy.

[0243] This document provides a method for regulating blood glucose concentration in mammals. As used herein, regulating blood glucose concentration refers to any increase, decrease, and / or maintenance of blood glucose concentration compared to a previously determined level.

[0244] The treatment methods disclosed herein also relate to methods for modulating circadian clocks, thereby modulating or influencing biological functions regulated (sometimes referred to as their influence, by, or mediated by) the activity of circadian clocks. Typically, these biological functions exhibit patterns of activity and inactivity that usually repeat approximately every 24 hours, oscillating between “active” and “inactive” states during the 24-hour period.

[0245] Therefore, the present invention provides a method for modulating the activity of a circadian rhythm clock by administering the compounds, crystalline solids, or pharmaceutical compositions disclosed herein to a mammal in need. Typically, the regulation of circadian rhythm clock activity is a result of biological clock:BMAL1 regulation, which is achieved according to the method of the present invention by modulating the activity of SIRT1. SIRT1 activity is typically modulated according to the method of the present invention by administering the compounds, crystalline solids, or pharmaceutical compositions disclosed herein, and in some embodiments, by administering compounds or crystalline solids that affect the NAD pathway. Regulation of the circadian rhythm clock thus allows for the modulation of activities mediated by the circadian rhythm clock.

[0246] According to the present invention, the activity of the circadian rhythm clock can be increased, decreased, or maintained by administering the compounds, crystalline solids, or pharmaceutical compositions disclosed herein. Therefore, biological functions (sometimes referred to as biological activities) regulated by the activity of the circadian rhythm clock can also be increased, decreased, or maintained. Furthermore, these biological functions may also be time-shifted; that is, activities that typically occur during specific time periods, such as, for example, during daytime or diurnal (sometimes also called photoperiods) or nighttime or nocturnal (sometimes also called darkperiods), can be shifted so that the activity instead occurs during the darkperiod or photoperiod, respectively.

[0247] In various embodiments, methods for differentially modulating nicotinamide adenine dinucleotide (NAD) levels in two or more tissue or cell types are disclosed herein. Such methods may include administering compounds, crystalline solids, or compositions disclosed herein, wherein said administration induces a differential response in NAD levels in a first tissue or cell type compared to a second tissue or cell type. In various implementation schemes, the differential response to NAD levels is selected from at least 10% NAD level difference, at least 20% NAD level difference, at least 30% NAD level difference, at least 40% NAD level difference, at least 50% NAD level difference, at least 60% NAD level difference, at least 70% NAD level difference, at least 80% NAD level difference, at least 90% NAD level difference, at least 100% NAD level difference, at least 200% NAD level difference, at least 300% NAD level difference, at least 400% NAD level difference, at least 500% NAD level difference, at least 600% NAD level difference, at least 700% NAD level difference, at least 800% NAD level difference, at least 900% NAD level difference, and at least 1000% NAD level difference.In various embodiments, the differential response of NAD levels compared to untreated NAD levels or pre-treatment NAD levels is an increase of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% in NAD levels in a first tissue or cell type, and a simultaneous decrease of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% in NAD levels in a second tissue or cell type compared to untreated NAD levels or pre-treatment NAD levels. In various embodiments, the differential response of NAD levels, as described on pages 22 / 34 of the specification (CN 122011067 A), is that the NAD level in the first tissue or cell type is maintained within 10% compared to the untreated NAD level, and the NAD level in the second tissue or cell type is simultaneously reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% compared to the untreated NAD level. In various embodiments, the differential response of NAD levels is a reduction of at least 10% in NAD levels in a first tissue or cell type compared to untreated NAD levels, and a simultaneous reduction in NAD levels in a second tissue or cell type compared to untreated NAD levels, wherein the reduction in the second tissue or cell type is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% greater than the reduction in the first tissue or cell type. In various embodiments, the first tissue or cell type is normal tissue or cells, and the second tissue or cell type is neoplastic or cancerous.

[0248] The cancer treatment methods disclosed herein include treatment for individuals in need. Exemplary cancers that can be treated using the disclosed compounds, crystalline solids, and pharmaceutical compositions thereof include those of the brain and kidneys; hormone-dependent cancers, including breast cancer, prostate cancer, testicular cancer, and ovarian cancer; lymphoma and leukemia. In various embodiments, the cancer can be a type of cancer common in men, such as lung cancer, prostate cancer, colorectal cancer, and stomach cancer. In various embodiments, the cancer can be a type of cancer common in women, such as breast cancer, colorectal cancer, lung cancer, and cervical cancer.In various embodiments, the cancer may be skin cancer, such as melanoma, squamous cell carcinoma, or basal cell carcinoma. In various embodiments, the cancer may be a type of cancer common in children, such as acute lymphoblastic leukemia, brain tumor, or non-Hodgkin's lymphoma. In various embodiments, the method exhibits selective cell inhibition or cytotoxicity, wherein this effect is demonstrated by a reduction in the viability of the neoplastic or cancerous tissue or cells compared to untreated neoplastic or cancerous tissue or cells.

[0249] The method includes cases where the first tissue or cell type is normal tissue or cells, and the method is a treatment for promoting health or increasing the bioactivity of the first tissue or cell type in an individual in need. In various embodiments, the treatment does not result in an increased risk of cancer diagnosis in the treated individual. Preferably, the treatment reduces the risk of cancer diagnosis in the treated individual.

[0250] Various methods include treating or inhibiting cancer in an individual in need, wherein the method includes administering the compounds, crystalline solids, or compositions described herein. In various embodiments, methods are disclosed herein for increasing or maintaining healthy tissue or cells in an individual without increasing the risk of growth of neoplastic or cancerous tissue or cells, such methods comprising administering the compounds, crystalline solids, or compositions described herein.

[0251] In various embodiments, methods are described herein for increasing or maintaining healthy tissue or cells in an individual while inhibiting the growth of neoplastic or cancerous tissue or cells, such methods comprising administering the compounds, crystalline solids, or compositions described herein. In various embodiments, the disclosed methods comprise methods for increasing or maintaining nicotinamide adenine dinucleotide (NAD) levels in at least one healthy tissue or cell type, such methods comprising administering the compounds, crystalline solids, or compositions described herein to the healthy tissue or cell type. In various embodiments, methods are described herein for reducing the viability of at least one cancerous tissue or cell type, such methods comprising administering the compounds, crystalline solids, or compositions described herein to the cancerous tissue or cell type.

[0252] Furthermore, the methods described herein comprise methods for modulating NAD levels in at least one tissue or cell type in a mixture of tissue or cell types, such methods comprising targeted delivery of the compounds, crystalline solids, or compositions described herein to the desired tissue or cell type. In various embodiments, the targeted delivery is non-systemic.

[0253] Compositions and Pharmaceutical Compositions Compositions of the disclosed compounds and crystalline solids are also provided herein. In some embodiments, the composition comprises 1) a crystalline solid comprising a compound of formula (I) or formula (II) or a salt thereof, and 2) one or more pharmaceutically acceptable excipients. In other embodiments, the composition comprises 1) a compound of formula (I) or formula (II) or a salt thereof, and 2) one or more pharmaceutically acceptable excipients.

[0254] In some embodiments, the composition is a solution. For example, in some embodiments, a crystalline solid comprising a compound of formula (I) or formula (II) is dissolved in a solvent or carrier to form a solution of the compound of formula (I) or formula (II). In preferred embodiments, the purity of the crystalline solid is such that the resulting solution is pure or substantially pure and / or free from or substantially free from one or more impurities.

[0255] In some preferred embodiments, this disclosure provides a composition comprising a compound of formula (I) or formula (II) or a crystalline solid comprising a compound of formula (I) or formula (II), wherein the composition is pure or substantially pure. In some preferred embodiments, the composition is greater than about 90% pure. More preferably, the composition is greater than about 95% pure, or even more preferably greater than about 98% pure, for example, greater than about 98% pure. In some embodiments, the percentages are by weight.

[0256] In preferred embodiments, the composition contains less than about 5% impurities, less than about 2% impurities, less than about 1% impurities, or less than about 0.5% impurities. For example, in a preferred embodiment of a composition comprising a compound of formula (I), the composition comprises less than about 5% propyl nicotinic acid, less than about 2% propyl nicotinic acid, less than about 1% propyl nicotinic acid, less than about 0.5% propyl nicotinic acid, less than about 0.1% propyl nicotinic acid, or less than about 0.01% propyl nicotinic acid. In a preferred embodiment of a composition comprising a compound of formula (II), the composition comprises less than about 5% nicotinic acid riboside, less than about 2% nicotinic acid riboside, less than about 1% nicotinic acid riboside, less than about 0.5% nicotinic acid riboside, less than about 0.1% nicotinic acid riboside, or less than about 0.01% nicotinic acid riboside. In some embodiments, the percentages are by weight.

[0257] In some embodiments, the pharmaceutically acceptable excipient is selected from anti-adhesives, adhesives, coatings, dyes, disintegrants, flavorings, flow aids, lubricants, preservatives, adsorbents, sweeteners, syrups, elixirs, dispersants, diluents, fillers, granulators, coating agents, waxes, suspending agents, wetting agents, thickeners, and mediators, and combinations thereof. In some embodiments, the excipient is a solid excipient.

[0258] In some embodiments, the pharmaceutically acceptable excipient is present in an amount of at least about 5% by weight, at least about 10% by weight, at least about 15% by weight, at least about 20% by weight, at least about 25% by weight, at least about 30% by weight, at least about 35% by weight, at least about 40% by weight, at least about 45% by weight, at least about 50% by weight, at least about 55% by weight, or at least about 60% by weight of the composition. In some embodiments, a pharmaceutically acceptable excipient is present in an amount of at least about 20% by weight, at least about 25% by weight, at least about 30% by weight, at least about 35% by weight, or at least about 40% by weight, preferably at least about 30% by weight, of the composition.In other embodiments, pharmaceutically acceptable excipients are present in an amount of at least about 50% by weight of the composition. The pH of the formulation may be in the range of about 3 to about 11, but is typically about 7 to about 10.

[0259] In some embodiments, the composition is in a solid form selected from tablets, pills, capsules, pouches, lozenges, granules, powders, sachets, dry powder inhalation forms, chewable tablets, soft lozenges, and sugar lozenges. In some embodiments, the composition is in the form of tablets. In other embodiments, the composition is in the form of hard or soft capsules.

[0260] The compounds and crystalline solids of this disclosure are formulated with conventional carriers and excipients, which may be selected according to conventional practice. Tablets may contain excipients, flow aids, fillers, binders, etc. All formulations will optionally contain excipients, such as those described in the Handbook of Pharmaceutical Excipients (1986). Suitable excipients are also listed in the FDA Inactive Ingredient Database. Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc.

[0261] Although the active pharmaceutical ingredient can be administered alone, it is preferred to be in the form of a pharmaceutical formulation. The veterinary and human formulations of the present invention contain at least one active ingredient as defined above, as well as one or more acceptable carriers and optional therapeutic ingredients as described on pages 24 / 34 of the specification, 26 CN 122011067 A. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, (1) Glucose and sucrose; (2) Starch, such as corn starch and potato starch; (3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) Powdered tragacanth gum; (5) Malt; (6) Gelatin; (7) Talc; (8) Excipients, such as cocoa butter and suppository wax; (9) Oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) Glycols, such as propylene glycol; (11) Polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) Esters, such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) Alginate; (16) Pyrogen-free water; (17) Isotonic saline; (18) Ringer's solution; (19) Ethanol; (20) Phosphate buffer solution; (21) Other non-toxic and compatible substances used in drug formulations.

[0262] The pharmaceutical composition (formulation) may be administered to a subject via any of a variety of routes of administration, including, for example, oral (e.g., infusions in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including dispersed capsules and gelatin capsules), granules, powders, pellets, or pastes applied to the tongue); absorption via the oral mucosa (e.g., sublingual); anal, rectal, or vaginal (e.g., as vaginal suppositories, creams, or foams); parenteral (including intramuscular, intravenous, subcutaneous, or intrathecal, e.g., as sterile solutions or suspensions); nasal; intraperitoneal; subcutaneous; percutaneous (e.g., as patches applied to the skin); and topical (e.g., as creams, ointments, or sprays applied to the skin, or as eye drops). The compound or crystalline solid may also be formulated for inhalation. In some embodiments, the crystalline solid of the compound may simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions applicable thereto can be found, for example, in U.S. Patents 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896, and the patents referenced therein.

[0263] Formulations of this disclosure suitable for oral administration may be in the form of discrete units, such as capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient in powder or granule form. The active ingredient may also be administered as a pellet, syrup, or paste.

[0264] Tablets are made by compression or molding, optionally together with one or more excipients. Compressed tablets can be prepared by pressing the active ingredient in a free-flowing form (such as powder or granules) optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant in a suitable machine. Molded tablets can be manufactured by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored, and may optionally be formulated to provide a slow or controlled release of the active ingredient from it.

[0265] Pharmaceutical formulations according to this disclosure comprise compounds or crystalline solids according to this disclosure, as well as one or more pharmaceutically acceptable carriers or excipients and optional other therapeutic agents. Pharmaceutical formulations containing active ingredients can be in any form suitable for the intended method of administration. When intended for oral administration, for example, tablets, lozenges, sugar lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared. Compositions intended for oral administration can be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more pharmaceutical agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable formulation.Tablets containing an active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for tablet manufacturing are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated, or they may be coated using known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer duration of action. For example, a delaying material (such as glyceryl monostearate or glyceryl distearate) may be used alone or in combination with wax.

[0266] Formulations for oral use may also be presented as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium phosphate or kaolin), or as soft gelatin capsules, wherein the active ingredient is mixed with an aqueous or oil medium (such as peanut oil, liquid paraffin, or olive oil).

[0267] The aqueous suspensions of this disclosure may contain active substances mixed with excipients suitable for preparing aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum arabic, and gum arabic; and dispersants or wetting agents such as natural phospholipids (e.g., lecithin), condensation products of alkyl esters and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecanethoxyethanol), and condensation products of ethylene oxide and esters derived from fatty acids and hexadiol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives (such as ethylparaben or n-propylparaben), one or more colorants, one or more flavoring agents, and one or more sweeteners (such as sucrose or saccharin). Liquid formulations may also include eye drops or other forms delivered to the surface of the eye or adjacent sites such as the lacrimal gland. Liquid formulations may include intravenous formulations, excipients, and carriers such as saline solutions or buffer solutions, and packaging or containers for such formulations for injection or infusion.

[0268] By adding water, dispersible powders and granules suitable for preparing aqueous suspensions of this disclosure provide an active ingredient that can be mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Other excipients may also be present, such as sweeteners, flavoring agents, and coloring agents.

[0269] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated and the specific administration method.For example, a sustained-release formulation for human oral administration may contain about 1 to about 1000 mg of active material combined with a suitable and appropriate amount of carrier material, the amount of which may vary from about 5% to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide an easily measurable dosage.

[0270] Although the dosage will vary depending on the patient's symptoms, age and weight, the nature and severity of the disease to be treated or prevented, the route of administration and the form of the drug, generally, for adult human patients, a daily dose of the compound or crystalline solid is recommended to be from 0.01 to 3000 mg, and this may be administered in a single dose or in divided doses. Generally, the compositions of this disclosure may be provided in an aqueous solution containing about 0.1-30% w / v of the compound or crystalline solid disclosed herein, as well as other substances, for parenteral administration. Typical dosage ranges are from about 0.01 to about 50 mg / kg body weight per day, administered in a single dose or in 2-4 divided doses. In some embodiments, the compounds and / or crystalline solids described herein are administered in amounts of about 1 to about 3000 mg daily, about 100 to about 1000 mg daily, or about 250 to about 750 mg daily. If desired, the effective daily dose of the active compound or crystalline solid may be divided into one, two, three, four, five, six, or more sub-dose administrations at appropriate time intervals throughout the day, optionally administered in a single dosage form. In some embodiments, the compounds and / or crystalline solids described herein are administered once, twice, three, four, five, six, or more times daily. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will typically be the amount by which the compound and / or crystalline solid produces a therapeutic effect.

[0271] Formulations suitable for intrapulmonary or intranasal administration have particle sizes, such as about 0.5, about 1, about 30, or about 35 micrometers, in the range of about 0.1 to about 500 micrometers, administered by rapid inhalation through the nasal passages or by oral inhalation to reach the alveolar sacs. Suitable formulations comprise aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered together with other therapeutic agents.

[0272] The formulation is present in single-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under freeze-dried (lyophilized) conditions where a sterile liquid carrier (e.g., water for injection) is added immediately before use. Temporary injectable solutions and suspensions are prepared from the aforementioned types of sterile powders, granules, and tablets. Preferred single-dose formulations are those containing a daily dose or a sub-daily dose or an appropriate fraction of the active ingredient as described above.

[0273] It should be understood that, in addition to the ingredients specifically mentioned above, formulations of this disclosure may include other pharmaceutical agents conventional in the art related to the type of formulation discussed, such as flavoring agents suitable for oral administration.

[0274] In some embodiments, the amount of the compound and / or crystalline solid in the composition is from about 0.001% by weight to up to 100% by weight.

[0275] In some embodiments, the compound and / or crystalline solid is the only active pharmaceutical ingredient in the composition. Alternatively, the compound and / or crystalline solid is formulated into a composition with one or more additional active pharmaceutical ingredients. When formulated as the only active pharmaceutical ingredient, the compound and / or crystalline solid may be administered alone or as part of a regimen having one or more separately formulated active pharmaceutical ingredients.

[0276] When administered in combination in the same formulation or as part of a regimen having one or more separately formulated active pharmaceutical ingredients, the additional active pharmaceutical ingredient may be selected from compounds in the NAD pathway, such as nicotinic acid (NA), nicotinamide (Nam), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinic acid riboside (NAR), nicotinamide adenine dinucleotide (NAD / NADH), nicotinamide adenine dinucleotide phosphate (NADP), and nicotinamide adenine dinucleotide (NaAD). In some embodiments, compounds of formulas I and II are administered in combination. In some embodiments, the additional active pharmaceutical ingredient is an amorphous solid. In some embodiments, the additional active pharmaceutical ingredient is a crystalline solid. In some embodiments, the additional active pharmaceutical ingredient is amorphous NMN. In some embodiments, the additional active pharmaceutical ingredient is crystalline NMN.

[0277] The invention described herein in general will be more readily understood by reference to the following examples, which are included only for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0278] Example 1.1: Preparation of Compound 2 1.00 g (3.92 mmol) of nicotinic acid riboside was packed into a 50 mL recovery flask and purged with argon. 6 mL of trimethyl phosphate was added, and stirring was initiated, with the reaction cooled in an ice bath. Next, 0.73 mL (7.84 mmol) of phosphoryl chloride was added. After 30 minutes, the reaction was confirmed to be complete by LC / MS. The reaction mixture was added dropwise to 10 mL of ice-cold water. After the addition was complete, the mixture was concentrated under vacuum to remove approximately 9 g of solvent. The concentrated mixture was then added dropwise to 3.2 mL (23.0 mmol) of triethylamine in 50 mL of 1-propanol in a stirred, ice-cold solution to give a mixture with pH = 3 (determined by pH paper).The suspension was stirred for 1 h, then the solid precipitate was filtered and washed with 1-propanol to obtain the first batch of crude compound 2. After filtration, a solid formed in the supernatant. The filtrate was stirred for 72 h, then the suspension was filtered, and the precipitate was washed with 1-propanol to obtain the second batch of crude compound 2. The second batch was vacuum dried to a weight of 1.00 g, but still moist. ¹H and 31P NMR analysis showed that the purity of the second batch was better than that of the first batch. The second batch was used as seed material for subsequent experiments. See Figure 4.

[0279] 1H-NMR (500 MHz; D2O): δ9.42 (s, 1H), 9.25 (d, J=6.3 Hz, 1H), 9.00 (d, J=8.0 Hz, 1H), 8.22 (dd, J=7.8, 6.5 Hz, 1H), 6.16 (d, J = 5.3 Hz, 1H), 4.58-4.56 (m, 1H), 4.49 (t, J = 5.1 Hz, 1H), 4.37 (dd, J = 5.0, 2.8 Hz, 1H), 4.26-4.22 (m, 1H) , 4.12–4.08 (d,d,d 1H, J = 12.0, 5.1, 2.2 Hz) Example 1.2A: Crystallization of Compound 2 300 μL of water was added to 100 mg of amorphous compound 2 (prepared alone). 350 μL of 1-propanol was added to it, and a turbid solution was obtained. The mixture was seeded using a second batch of compound 2 from the above experiment. After several hours, crystals formed in a vial. The mixture was not filtered and remained as a slurry.

[0280] Example 1.2B: Crystallization of Compound 2 2.00 g of amorphous compound 2 (prepared alone) was dissolved in 6 mL of water, and then 7 mL of 1-propanol was added to obtain a turbid solution. 2 mL of water was then added to obtain a clear solution. The mixture was seeded using a second batch of compound 2 from the above experiment, but no crystals formed. Add 0.2 mL of n-propanol to obtain a turbid mixture. Stir it for one day, without obtaining crystals. Then, seed the mixture with a drop of slurry from the second experiment to prepare compound 2 crystals, resulting in rapid crystallization. Stir it at ambient temperature for two days. Filter the solid and wash with 15 mL of (2:1 v:v) 1-propanol:water, 15 mL of 1-propanol, and then 2 x 15 mL of methyl tert-butyl ether. Dry the sample under high vacuum at ambient temperature for 1 hour to obtain 1.92 g (96% mass recovery) of white solid.The water solubility of the isolated product was approximately 20 mg / mL (50:1 w:w water:compound 2), compared to the free solubility of the starting compound 2 in water (3:1 water:compound 2).

[0281] Example 1.2C: Crystallization of Compound 2 500 mg of amorphous compound 2 was dissolved in 1.5 mL of water. The sample was completely dissolved, and crystals began to form. The crystals were allowed to grow without stirring. The water was gently poured off, and the solid was dried under high vacuum. Single-crystal X-ray diffraction quality crystals of compound 2 were prepared. These crystals were used to generate the XRPD signature of the crystals of compound 2 (Figure 2) and also to obtain the single-crystal X-ray structure of compound 2 (Figure 2C).

[0282] Example 2.1: Preparation of Compound 1 Compound 2 was filtered from 1-propanol before use and packed into a 500 mL recovery bottle and purged with argon. The solid was suspended in 1-propanol and cooled in an ice bath. HCl gas was bubbled into the reaction mixture. The solid dissolves when gas is bubbled into the suspension. The reactants are removed from the ice bath and stirred at room temperature for more than three days. When LC / MS confirms no starting material residue, the reaction mixture is concentrated on a rotary evaporator until an oil is obtained. An aliquot is placed under high vacuum for 30 minutes. No foaming occurs in the aliquot. This sample is used for LC / MS. The oil is diluted with 10 mL of 1-propanol and cooled in an ice bath. A total of 1.5 mL of triethylamine is added to bring the pH to 4 to 5. The addition of triethylamine results in the formation of a large amount of precipitate. 40 mL of 1-propanol is added to dissolve all the precipitate. Seed crystals of compound 1 are added to the solution. Over time, the solution becomes cloudy and precipitate formation is observed. The suspension is stirred overnight at room temperature. After 4 hours under high vacuum, a sample of the aliquot is used for LC / MS. The contents of the flask appear more crystalline and filterable compared to the “emulsion” suspension. The solid is filtered. The filter cake was washed twice with 10 mL of 1-propanol, and then twice with 10 mL of MTBE after each wash. A sample of the 1-propanol filtrate was used for LC / MS. The solid was transferred to a vial. The wet weight was approximately 1.2 g. It was placed under high vacuum for 1 hour. 1.23 g (55% yield) of white solid was obtained. The sample was used for LC / MS, 1H and 31P NMR. See Figure 3.

[0283] Example 2.2A: Polymorph Screening The polymorphs of amorphous compound 1 were screened according to the conditions provided in Table 1. Treatment was performed between observation 1 and observation 2, including a 4-day aging cycle between 0°C (1 hr) and -20°C (7 hrs). The results are shown in the figure.

[0284] Table 1: Specification 28 / 34 pages 30 CN 122011067 A x = Suspension Example 2.2B: Salt Screening Specification 29 / 34 pages 31 CN 122011067 A The polymorph of amorphous compound 1 was screened according to Table 2. Compound 1 (15 mg) was weighed into an HPLC vial and a magnetic stir bar was added. The compound was dissolved in about 15 vol (200 µl) of EtOH at 5°C while stirring at 500 rpm. After dissolution, a one molar equivalent of counterion was added and stirred at 5°C (45 µl of 1M stock solution or 90 µl of 0.5M stock solution). The sample was cooled to -20°C at 1°C / min, but still in solution. The solution was slowly evaporated at 5°C through a needle in the cap.

[0285] Table 2: Note: P = solution, N / P = not performed Example 2.2C: Co-crystal screening Polymorphs of amorphous compound 1 were screened according to Table 3. Compound 1 (25 mg) was weighed into an HPLC vial and two grinding balls were added. 1 mol equivalent of the co-formed product (as a solid) was added. The mixture was initially milled at 500 rpm for 2 hours on a Fritsch planetary mill, and the recovered solid was analyzed by XRPD. No crystals were obtained, and the resulting solid was moistened with a drop of THF (7.5 µl) and milled at 500 rpm for 2 hours on a Fritsch planetary mill. The milling was observed, and the recovered solid was subjected to XRPD.

[0286] Table 3: Specification 30 / 34 pages 32 CN 122011067 A Note: P = solution, N / P = not performed Example 2.2D: Crystal form of compound 1 At room temperature, compound 1 (150 mg) was dissolved in 10 vol (1.5 ml) of pure EtOH with stirring. After 3 minutes, precipitate began to form. The sample was stirred for another 15 minutes, then filtered and dried under positive pressure. The sample was then placed in a vacuum oven under vacuum and kept at room temperature for 30 minutes. Then, before characterization, the sample was placed in a fume hood in a vial capped with perforated aluminum foil overnight. XPD chromatograms were obtained according to Figure 1A. See also Figure 1B. Percentage yield = approximately 63% and purity 98.7% obtained by HPLC. After storage at 40°C / 75%RH for seven days, the material was a viscous solid and the purity was obtained by HPLC as 96.4%. The sample is a fine white powder stable at room temperature. A small amount of solvent is retained, but analysis indicates that the sample is an anhydrous, non-solventized solid. The sample is stable at a humidity level of up to 70% RH.

[0287] Figure 1C is a representation of the crystal cell of compound 1 having the following properties: Specification 31 / 34 pages 33 CN 122011067 A The data for compound 1 were obtained by single-crystal X-ray diffraction, and the structure was solved by a direct method and corrected using least squares correction. The atomic distribution and positions in the crystal structure were specified based on the electron density observed in the Fourier difference plot, which converged to a model that fits the experimental data well. Non-hydrogen atoms were anisotropically corrected, giving anisotropic displacement parameters (thermal ellipsoids), which can be seen in the ORTEP image (Figure 1C).

[0288] Example 2.2E: Magnification of the crystal form of compound 1 Amorphous compound 1 (1.23 g) was weighed and placed in a 20 ml vial and treated with 7 vol (8.60 ml) methanol to obtain a clear solution. The solution was stirred at 400 rpm at 35°C on a 'Polar Bear' device. The solution was supersaturated by adding 0.5 vol (615 µl) TBME, and then seeded with the previously crystallized material (approximately 60 mg) held in solution. The sample was then cooled to 25 °C at 0.1 °C / min before adding the antisolvent. 2.6 vol (3.2 ml) TBME was added over 50 minutes (1 µl / sec) using a syringe pump. The suspension was then cooled to 5 °C at 0.1 °C / min. The sample was held at 5 °C for one hour before separation under vacuum using a Buchner funnel. The sample was dried under vacuum for 20 mins and then further dried overnight in a vacuum oven. XPD chromatograms were obtained according to Figure 1A. See also Figure 1B. Percentage yield = approximately 45% obtained by HPLC and purity 97.9%.

[0289] Example 3: Stability Study of Compound 2 Amorphous and crystalline forms of Compound 2 were prepared and stored under stress conditions to compare the stability of their respective forms, as shown in Table 4. At T=0, the AUC for amorphous compound 2 was 97.3%, and the AUC for crystalline compound 2 was 99%. Samples were sealed in wide-mouth bottles containing saturated salt solutions to generate the required relative humidity: ammonium nitrate for RH = 60%; sodium chloride for RH = 75%; and saturated potassium nitrate for RH = 97%. Solid phosphorus pentoxide was used for RH = 0%. HPLC data were collected using an Agilent 1290 system equipped with a Waters Atlantis T3 C18 column (3 μm, 100 x 4.6 mm) and an online guard column. Mobile phase A: 200 mM ammonium carbonate (pH 3.8); Mobile phase B: 95:5 MeOH: Mobile phase A. The pump rate was 1 mL / min.The gradient was 0% B for 5 minutes, then 20 minutes to 100% B, and finally held for 3 minutes. Relevant data were collected at 254 nm via DAD. [Specification 32 / 34, page 34, CN 122011067 A] Legend: AUC = Area under the curve at 254 nm; RH = Relative humidity; OS = Exceeding the scale. The results in Table 4 show that the crystalline form of compound 2 has improved stability compared to the amorphous form.

[0290] All publications and patents mentioned herein are hereby incorporated in their entirety by reference, as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. In the event of conflict, the definitions contained herein shall prevail.

[0291] While specific embodiments of the invention have been discussed, the foregoing description is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon reading this specification and the following claims. The full scope of this invention should be determined by reference to the full scope of the claims and their equivalents, the description, and these variations.Instruction manual, page 34 / 34, page 36, CN 122011067 A, Figure 1A, Figure 1B, Instruction manual figure 1 / 7, page 37, CN 122011067 A, Figure 1C, Instruction manual figure 2 / 7, page 38, CN 122011067 A, Figure 2A, Instruction manual figure 3 / 7, page 39, CN 122011067 A, Figure 2B, Instruction manual figure 4 / 7, page 40, CN 122011067 A, Figure 2C, Instruction manual figure 5 / 7, page 41, CN 122011067 A, Figure 3, Instruction manual figure 6 / 7, page 42, CN 122011067 A, Figure 4, Instruction manual figure 7 / 7, page 43, CN 122011067 A. Abstract: The present disclosure relates to crystalline solids of nicotinic acid mononucleotide and esters thereof and methods of making and use. 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 further relates to methods of preparing the crystalline solids, and pharmaceutical preparations of the crystalline solids, and use of such pharmaceutical preparations in treatment of diseases and conditions.

Claims

1. A crystalline solid comprising compound 1: 。 2. The crystalline solid according to claim 1, having 2θ values ​​of 16.1, 20.1, and 24.

5.

3. The crystalline solid according to any one of claims 1 to 2, wherein the solid is anhydrous.

4. The crystalline solid according to any one of claims 1 to 3, wherein the solid is selected from methanol solvates, ethanol solvates, 1-propanol solvates, 2-propanol solvates, C-4 alcohol solvates, C-5 alcohol solvates and C-6 alcohol solvates, preferably the methanol solvates.

5. The crystalline solid according to any one of claims 1 to 4, wherein the crystalline solid contains residual non-solventized solvent or residual non-hydrated water.

6. The crystalline solid according to any one of claims 1 to 5, comprising less than about 5% by weight of propyl nicotinic acid, preferably less than about 1% by weight of propyl nicotinic acid.

7. The crystalline solid according to any one of claims 1 to 4, comprising less than about 5% by weight of compound 2: 。 8. The crystalline solid according to claim 7, comprising less than about 1% by weight of compound 2.

9. The crystalline solid according to any one of claims 1 to 8, comprising at least about 90% by weight of compound 1.

10. The crystalline solid according to claim 9, comprising at least about 95% by weight of compound 1.

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