阅读说明：本技术 包括烟酰胺核苷的磷衍生物的组合物以及用于调节烟酰胺腺嘌呤二核苷酸的方法 (Compositions comprising phosphorus derivatives of nicotinamide riboside and methods for modulating nicotinamide adenine dinucleotide ) 是由 B·斯潘肯维斯 J·M·麦克瑞 于 2020-03-18 设计创作，主要内容包括：本发明涉及用于调节烟酰胺腺嘌呤二核苷酸(NAD+)的化合物和组合物。本发明还涉及制造这样的化合物和组合物的方法。本发明涉及含有与一种或更多种活性药物成分组合的作为第一成分的一种或更多种NAD+调节化合物的药物组合物。此外,本发明涉及使用这样的化合物或组合物促进细胞和组织中烟酰胺腺嘌呤二核苷酸(NAD+)的细胞内水平的增加以治疗疾病和/或改善细胞和组织存活的方法。(The present invention relates to compounds and compositions for modulating nicotinamide adenine dinucleotide (NAD +). The invention also relates to methods of making such compounds and compositions. The present invention relates to pharmaceutical compositions containing one or more NAD + modulatory compounds as a first ingredient in combination with one or more active pharmaceutical ingredients. Furthermore, the invention relates to methods of using such compounds 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.)

1. A compound having the structure:

or a salt of said compound.

2. The compound of claim 1, wherein the compound is selected from H⁺、Li⁺、Na⁺、K⁺、Mg²⁺And Ca²⁺The cation of (a) forms the salt.

3. The compound of claim 1, wherein the compound is selected from the group consisting of acetate, triflate, halide, trifluoroacetate, formate, H₂PO₄ ^-、HPO₄ ^2-、OH^-、HSO₄ ^-、SO₄ ^2-、NO₃ ^-、HCO₃ ^-And CO₃ ^2-The anion of (a) forms the salt.

4. A composition comprising one or more pharmaceutically acceptable solid excipients and one or more compounds having a structure represented by formula I:

and/or one or more salts of said compounds, wherein n is 1.

5. The composition of claim 4, wherein the pharmaceutically acceptable solid excipient is selected from the group consisting of anti-adherents, binders, coatings, dyes, disintegrants, flavoring agents, glidants, lubricants, preservatives, adsorbents, sweeteners, dispersants, diluents, fillers, granulating agents, coating agents, waxes, suspending agents, wetting agents, vehicles, and combinations thereof.

6. The composition of claim 4, wherein the composition is in a solid form selected from the group consisting of tablets, pills, capsules, caplets, dragees, granules, powders, sachets, dry powder inhaler forms, chewables, pastilles, and lozenges.

7. The composition of claim 4, wherein the composition is in the form of a tablet.

8. The composition of claim 4, wherein the compound of formula I is present in the composition in an amount from about 0.001% to about 10% by weight.

9. The composition of claim 4, wherein the amount of the compound of formula I in the composition is about 0.25% by weight of the composition.

10. The composition of claim 4, wherein the pharmaceutically acceptable excipient is present in an amount of at least about 5% by weight.

11. The composition of claim 4, wherein the pharmaceutically acceptable excipient is present in an amount of about 30% by weight.

12. A solid composition comprising one or more active pharmaceutical ingredients and a compound having a structure represented by formula I:

and/or one or more salts of said compounds, wherein n is 1.

13. The composition of claim 12, wherein the amount of the compound of formula I ranges from about 0.001% to less than about 50% by weight relative to the amount of the one or more active pharmaceutical ingredients.

14. The composition of claim 12, wherein the amount of the compound of formula I is from about 0.1% to about 1.5% by weight relative to the amount of the one or more active pharmaceutical ingredients.

15. The composition of claim 12, wherein the one or more active pharmaceutical ingredients are selected from Niacin (NA), nicotinamide (Nam), Nicotinamide Mononucleotide (NMN), Nicotinamide Riboside (NR), nicotinic acid mononucleotide (NaMN), Nicotinic Acid Riboside (NAR), Nicotinamide Adenine Dinucleotide (NAD)⁺NADH), Nicotinamide Adenine Dinucleotide Phosphate (NADP), nicotinic acid adenine dinucleotide (NaAD), one or more compounds of formula II:

and salts of the compounds of formula II, and combinations thereof, wherein m is 2 or 3.

16. The composition of claim 15, wherein m is 2.

17. A compound according to claims 1-3 or a composition according to claims 4-16 for use in increasing NAD + levels.

18. A method of increasing NAD + levels in a subject in need thereof, the method comprising administering a composition of any one of claims 4-17.

Background

Nicotinamide Adenine Dinucleotide (NAD) and related compounds are considered to be an essential coenzyme for cellular redox reactions in all organisms. Several lines of evidence have also shown that NAD is involved in a number of important signalling pathways in mammalian cells, including poly ADP-ribosylation in DNA repair (menisier de Murcia et al, EMBO j., (2003)22, 2255-. NAD and its metabolites have also been shown to play an important role in transcriptional regulation (Lin and Guarente, curr. Opin. cell. biol., (2003)15, 241-. In particular, the discovery of Sir2 NAD-dependent deacetylase activity (e.g., Imai et al, Nature, (2000)403, 795-; Landry et al, biochem. Biophys. Res. Commun., (2000)278, 685-.

Despite advances in the understanding of the biology of NAD, there remains a need for improved compositions and methods of using such compositions for pharmacological intervention and/or manipulation of the NAD pathway in living cells and tissues.

SUMMARY

The present invention relates to compounds and compositions for modulating nicotinamide adenine dinucleotide (NAD +). In some embodiments, the present invention relates to methods of making such compounds and compositions. In some embodiments, the present invention relates to pharmaceutical compositions containing one or more NAD + modulatory compounds as a first ingredient in combination with one or more active pharmaceutical ingredients. In a further embodiment, the invention relates to methods of using such compounds 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

Figure 1 depicts nad (h) normalized to total protein in treated AML12 cells at concentrations of 2mM, 1mM and 500 micromolar compound a and compound B compared to untreated cells (first data column normalized to 1.0), indicating that both compounds have nad (h) enhancing activity in AML12 cells. Compound a is of formula I, n ═ 2. Compound B is of formula I, n ═ 1.

Detailed Description

Definition of

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the following terms have the meanings given below, unless otherwise specified.

In the present disclosure, "include", "contain", "have", and the like may have meanings ascribed to them in the us patent law, and may mean "include", "including", and the like; "consisting essentially of" or "consisting essentially of" has the meaning ascribed to U.S. patent law and is open-ended (thereby permitting the existence of more than its stated meaning, provided that the essential or novel characteristics of its stated meaning do not change by the existence of more than its stated meaning), but excludes prior art embodiments.

Ranges provided herein are to be understood as a shorthand way of expressing all values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or subrange from 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.

As used herein, the phrase "a" or "an" entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. As such, the terms "a" (or "an)", "one or more", and "at least one" may be used interchangeably herein.

As used herein, the term "about" is understood to be within the normal tolerance of the art (e.g., within 2 standard deviations of the mean), unless explicitly stated or otherwise evident from the context. About may 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 stated value. Unless otherwise clear from the context, all numbers provided herein are modified by the term about.

As used herein, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may occur, but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optional bond" means that a bond may or may not be present, and the description contains a single bond, a double bond, or a triple bond.

As described herein, the term "purified" refers to the purity of a given compound. For example, a compound is "purified" when the given compound is the major component of a composition (i.e., at least about 50% w/w pure). Thus, "purified" includes at least about 50% w/w purity, at least about 60% w/w purity, at least about 70% w/w purity, at least about 80% w/w purity, at least about 85% w/w purity, at least about 90% w/w purity, at least about 92% w/w purity, at least about 94% w/w purity, at least about 96% w/w purity, at least about 97% w/w purity, at least about 98% w/w purity, at least about 99% w/w purity, at least about 99.5% w/w purity, and at least about 99.9% w/w purity, wherein "substantially pure" includes at least about 97% w/w purity, at least about 98% w/w purity, at least about 99% w/w purity, at least about 99.5% w/w purity, and, And a purity of at least about 99.9% w/w.

As described herein, the term "metabolite" refers to a compound that is produced in vivo following administration to a subject.

As described herein, the term "salt" refers to a compound comprising a cation and an anion, which compound can be produced by protonation of a proton-accepting moiety and/or deprotonation of a proton-donating moiety. It should be noted that protonation of the proton accepting moiety results in the formation of cationic species (where charge is balanced by the presence of physiological anions), whereas deprotonation of the proton donating moiety results in the formation of anionic species (where charge is balanced by the presence of physiological cations).

The phrase "pharmaceutically acceptable salt" means a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include (but are not limited to): (1) with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like); or an acid addition salt with an organic acid (e.g., 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-hydroxyethylsulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, salicylic acid, hexadiene diacid, etc.) or a base formed (2) with a conjugate base of any of the above-listed inorganic acidsAddition salts wherein the conjugate base comprises a base selected from Na⁺、K⁺、Mg²⁺、Ca²⁺、NH_gR_4-g ⁺Wherein R is C_1-3Alkyl, and g is a number selected from 0, 1,2, 3, or 4. It will be understood that all references to pharmaceutically acceptable salts comprise the same acid addition salt in the form of a solvate addition (solvate) or crystalline form (polymorph) as defined herein.

The invention also encompasses useful forms (e.g., metabolites, hydrates, solvates, prodrugs, salts (especially pharmaceutically acceptable salts), and/or co-precipitates) of the compounds of the invention.

The compounds of the invention may exist as hydrates or as solvates, wherein the compounds of the invention form crystals containing molecules of polar solvents (in particular water, methanol or ethanol), for example, as structural elements of the crystal lattice of the compounds. Molecules of the polar solvent (particularly water) may be present in stoichiometric or non-stoichiometric proportions with molecules of the compound. In the case of stoichiometric solvates (e.g. hydrates), hemi-, (hemi-), mono-, one-and-half-, di-, tri-, tetra-, penta-, etc. solvates or hydrates, respectively, are possible. The present invention encompasses all such hydrates or solvates.

Furthermore, it is possible that the compounds of the invention are present in free form (e.g. as a free base, or as a free acid, or as a zwitterion) or in the form of a salt. The salts may be any salt (organic or inorganic, in particular any pharmaceutically acceptable organic or inorganic), which is usually used in pharmacy, or which is used, for example, for the isolation or purification of the compounds of the invention.

The term "subject" (administration is intended for "subject") includes, but is not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle aged adults, or elderly adults)) and/or other primates (e.g., cynomolgus monkey, rhesus monkey); mammals (including commercially relevant mammals such as cows, pigs, horses, sheep, goats, cats, and/or dogs); and/or birds (including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys).

The terms "treatment", "treating", "alleviating" and "improving" are used interchangeably herein. These terms refer to a method for obtaining a beneficial or desired result, including, but not limited to, a therapeutic benefit and/or a prophylactic benefit. Therapeutic benefit means eradication or amelioration of the underlying disorder being treated. In addition, therapeutic benefit is achieved with eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such that, while the patient may still be suffering from the underlying disorder, an improvement is observed in the patient. For prophylactic benefit, a pharmaceutical compound and/or composition may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though diagnosis of the disease may not have been completed.

The terms "dosage form" or "dosage form" are intended to encompass both solid and liquid dosage forms of the active compound, and one skilled in the art will appreciate that the active ingredient may be present in different dosage forms depending on the desired dosage and pharmacokinetic parameters.

As used herein, the term "excipient" refers to the following compounds: are used in the preparation of pharmaceutical compositions and are generally safe, non-toxic and not biologically or otherwise undesirable, and contain excipients acceptable for veterinary and human pharmaceutical use.

Compounds, compositions and methods of treatment

Provided herein are compounds having the following structure:

and salts of the compounds.

Also provided herein are compositions comprising one or more pharmaceutically acceptable excipients and one or more compounds, and/or salts of compounds, wherein the compounds have a structure represented by formula I:

wherein n is an integer from 1 to 3.

Provided herein are compositions comprising one or more additional active pharmaceutical ingredients and one or more compounds, and/or salts of one or more compounds, wherein the compounds have a structure represented by formula I:

wherein n is an integer from 1 to 3.

In some embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3.

In some embodiments, the composition is in a solid form selected from the group consisting of tablets, pills, capsules, caplets, dragees, granules, powders, sachets, dry powder inhaler forms, chewables, pastilles, and lozenges. In certain embodiments, the composition is in the form of a tablet. In other embodiments, the composition is in the form of a hard gelatin capsule or a soft gelatin capsule.

In some embodiments, the compound is in an amorphous solid form. In other embodiments, the compound is in a crystalline solid form.

In some embodiments, the amount of the compound of formula I in the composition is from about 0.001% to about 10%, from about 0.01% to about 10%, from about 0.1% to about 8%, from about 0.25% to about 8%, from about 0.5% to about 5%, from about 0.5% to about 3%, or from about 0.1% to about 1% (preferably about 0.5%) by weight of the composition. In certain embodiments, the amount of the compound of formula I in the composition is about 0.25% by weight of the composition.

In some embodiments, the pharmaceutically acceptable excipient is selected from the group consisting of anti-adherents, binders, coatings, dyes, disintegrants, flavoring agents, glidants, lubricants, preservatives, adsorbents, sweeteners, syrups, elixirs, dispersants, diluents, fillers, granulating agents, coating agents, waxes, suspending agents, wetting agents, thickening agents and vehicles, and combinations thereof. In some embodiments, the excipient is a solid excipient.

In some embodiments, the pharmaceutically acceptable excipient is present in an amount of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% by weight of the composition. In some embodiments, the pharmaceutically acceptable excipient is present in an amount of at least about 20%, at least about 25%, at least about 30%, at least about 35%, or at least about 40% (preferably at least about 30%) by weight of the composition. In other embodiments, the pharmaceutically acceptable excipient is present in an amount of at least about 50% by weight of the composition.

In some embodiments, the amount of the compound of formula I relative to the amount of the one or more additional active pharmaceutical ingredients in the composition is within the following ranges of the composition: from about 0.001 wt% to less than about 50 wt%, from about 0.01 wt% to about 45 wt%, from about 0.05 wt% to about 40 wt%, from about 0.1 wt% to about 30 wt%, from about 0.5 wt% to about 30 wt%, from about 1 wt% to about 30 wt%, from about 1.5 wt% to about 20 wt%, from about 2 wt% to about 20 wt%, from about 2.5 wt% to about 20 wt%, from about 3 wt% to about 20 wt%, or from about 0.5 wt% to about 5 wt% (preferably from about 0.5 wt% to about 1.5 wt%). In certain embodiments, the amount of the compound of formula I is 0.5% by weight of the composition relative to the amount of the one or more additional active pharmaceutical ingredients in the composition. In other embodiments, the amount of the compound of formula I is 1.5% by weight of the composition relative to the amount of the one or more additional active pharmaceutical ingredients in the composition.

In some embodiments, the amount of the compound of formula I relative to the amount of the one or more additional active pharmaceutical ingredients is greater than zero. The term "greater than zero" refers to an amount that is at the lower limit of detection by any quantitative means known in the art. Non-limiting examples of methods for quantifying chemical substances include chromatography (liquid chromatography LC, high performance liquid chromatography HPLC, gas chromatography G), electrospray ionization (ESI), Atmospheric Pressure Chemical Ionization (APCI), and Atmospheric Pressure Photoionization (APPI). These separation methods are combined with mass spectrometers for identifying the compounds to be tested. Mass spectrometry techniques include triple quadrupole (QQQ), Ion Trap (IT), triple quadrupole-linear ion trap (QTrap), time of flight (TOF), triple quadrupole-time of flight (Q-TOF), orbital trap, and fourier transform ion cyclotron resonance (FT-ICR). See Roskar, R.et al, analytical Methods for Quantification of Drug metabolism in Biological Samples 2012, pg.87-91.

In some embodiments, the active pharmaceutical ingredient is selected from compounds in the NAD + pathway, such as Nicotinic Acid (NA), nicotinamide (Nam), Nicotinamide Mononucleotide (NMN), Nicotinamide Riboside (NR), nicotinic acid mononucleotide (NaMN), Nicotinic Acid Riboside (NAR), Nicotinamide Adenine Dinucleotide (NAD)⁺NADH), Nicotinamide Adenine Dinucleotide Phosphate (NADP), and nicotinic acid adenine dinucleotide (NaAD). In some embodiments, the active pharmaceutical ingredient is an amorphous solid. In some embodiments, the active pharmaceutical ingredient is a crystalline solid. In some embodiments, the active pharmaceutical ingredient is amorphous NMN.

In some embodiments, the active pharmaceutical ingredient is selected from anti-aging compounds (such as antioxidants (e.g., CoQ10, vitamin C, vitamin E), peptides (such as basal peptides (Matrixyl) (palmitoyl pentapeptide-3), Argireline (Argireline) (acetyl hexapeptide-3)), vitamin a, related retinoids, and anti-aging sunscreens (such as Helioplex and Mexoryl SX) (ecamsule)).

In some embodiments, the active pharmaceutical ingredient is selected from analgesics and anti-inflammatory agents (e.g., acetaminophen, duloxetine, aspirin, ibuprofen, naproxen, diclofenac, and diclofenac-misoprostol). Other NSAID active pharmaceutical ingredients include celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac, diflunisal, nabumetone, oxaprozin, tolmetin, salsalate, etodolac (etodolac), fenoprofen, flurbiprofen, ketorolac, meclofenamic acid, and mefenamic acid.

In some embodiments, the active pharmaceutical ingredient is selected from compounds used to treat dermatitis (e.g., triamcinolone, clobetasol, betamethasone, hydrocortisone, fluocinolone, and prednisolone). In other embodiments, the active pharmaceutical ingredient is selected from compounds used for treating wounds (such as silver sulfadiazine, santyl collagenase, chlorhexidine, urea, venelex, and levicin).

In some embodiments, the active pharmaceutical ingredient is selected from anti-aging drugs (senolytics) (such as dasatinib, quercetin, cortisol, corticosterone, metformin, resveratrol, apigenin, wogonin, kaempferol, rapamycin, ruxotinib, tofacitinib, simvastatin, and navigators).

In some embodiments, the active pharmaceutical ingredient is selected from compounds used for the treatment of cardiovascular diseases and disorders (such as amiloride, bumetanide, chlorothiazide, chlorthalidone, furosemide, hydrochlorothiazide, indapamide, and spironolactone).

In some embodiments, the active pharmaceutical ingredient is selected from the group consisting of Serotonin Reuptake Inhibitors (SRI), 5HT2 receptor antagonists, anticonvulsants, norepinephrine reuptake inhibitors, alpha-adrenoceptor antagonists, NK-3 antagonists, NK-1 receptor antagonists, PDE4 inhibitors, neuropeptide Y5 receptor antagonists, D4 receptor antagonists, 5HT1A receptor antagonists, 5HT1D receptor antagonists, CRF antagonists, monoamine oxidase inhibitors, and sedative-hypnotics.

In some embodiments, the SRI is selected from fluoxetine, norfluoxetine (norfluoxetine), nefazodone (nefazodo)ne), hydroxynefazodone (hydroxyynefazodone), oxafazodone (oxonefazodone), duloxetine (duloxetine), venlafaxine (venlafaxine), milnacipran (milnacipran), citalopram (citalopram), fluvoxamine (fluvoxamine), paroxetine (parooxetine), and selective SRI of sertraline. In some embodiments, the sedative hypnotic agent is selected from alprazolam, methotrexateClonazepam, chlordiazepoxideClobazam, diazepam, halazepam (halazepam), lorazepam, oxazepam, pramipeam, zolpidem, and barbiturates. In some embodiments, the 5HT1A receptor antagonist is selected from buspirone, fluocinolone (flesinoxan), gepirone, and ixabepilone (ipsapirone).

In certain embodiments, the norepinephrine reuptake inhibitor is selected from the group consisting of tertiary tricyclics (e.g., amitriptyline, clomipramine, doxepin, imipramine, and trimipramine). In other embodiments, the norepinephrine reuptake inhibitor is selected from the group consisting of secondary amine tricycles (e.g., amoxapine, desipramine, maprotiline, nortriptyline, and protriptyline).

In some embodiments, the monoamine oxidase inhibitor is selected from the group consisting of isocarboxazid, phenelzine, tranylcypromine, selegiline, and moclobemide.

In other embodiments, the active pharmaceutical ingredient is a chemotherapeutic agent selected from the group consisting of: 1-amino-4-phenylamino-9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonate (acid blue 25), 1-amino-4- [ 4-hydroxyphenyl-amino ] -9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonate, 1-amino-4- [ 4-aminophenylamino ] -9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonate, 1-amino-4- [ 1-naphthylamino ] -9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonate, 1-amino-4- [ 4-fluoro-2-carboxyphenylamino ] -9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonate, 1-amino-4- [ 2-anthracylamino ] -9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonate, ABT-263, afatinib maleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, BCG (bcg), bicalutamide, bleomycin, bortezomib, beta-methylene-ADP (AOP), buserelin (buserelin), buserelin, cabazitaxel (cabazitaxel), cabozinib (cabozantinib), camptothecin (camptothecin), capecitabine (capecitabine), carboplatin (carzozomib), carmustine (monoclinic butyrate), chlorambucil (chlorazidine), chloracil (chloracil, chloracil (cloquindoxamide), anc (benclamide), ampelin (benclami), benclami (benclami), benclami (benclami), benclami (benclami), benclami (benclami), benclami (benclami), benclami (benclami), benfurila), benclami (benfurbenclami (benclami), benclami (benfuril), benclami (benclami), benclami (benclami), benclami (ben), benclami (benclami), benfuril (benil), benclami (benfurbenclami (benclami), benil), benfuril), benfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenfuril), benfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenclami (benfurben, Clodronate, cobimetinib (cobimetinib), colchicine, crizotinib (crizotinib), cyclophosphamide, cyproterone, cytarabine, dacarbazine, actinomycin D, daunorubicin, desmoxylucamycin (demethoxyviridin), dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin (eribulin), erlotinib (erlotinib), estradiol, estramustine, etoposide, everolimus (everolimus), exemestane (exemestane), filgrastim (filgrastim), fludarabine (fludarabine), fludrocortisone, fluorouracil, flumetsterone, flutamide, gefitinib (gefitinib), gemcitabine, genistein (genistein), sertraline, GSK, 0212, hydroxyurea, isoxatinib (irinotecan), irinotecan (irinotecan), irinotecan, an, irinotecan, and a, Lenalidomide, letrozole (letrozole), folinic acid, leuprolide (leuprolide), levamisole, lomustine, lonidamine (lonidamine), mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine (luteosine), mitomycin, mitotane, mitoxantrone, MK-2206, mutamycin (mutamycin), N- (4-sulfamoylphenylcarbamoylthio) palmitamide, NF279, NF449, nilutamide (nilutamide), nocodazole (nocodazole), octreotide, olaparib (olaparib), oxaliplatin, paclitaxel, pamoate (pamidronate), pazopanib (pazopanib), pemetrexed (meperidine), pentraxin (loperamide), pteridine (04691502), quercetin (paporophyrin), quercetin (PF), quercetin (paporophyrin(s), quercetin (paporophyrin), quercetin(s), quercetin (paporophyrin), quercetin (e), quercetin (paporophycin), quercetin (e), quercetin (p-p), and p-e (e), e (e), p-p (e, p-p, Raltitrexed, ramucirumab, active blue 2, rituximab, rolifylline (rolifylline), romidepsin (romidepsin), rucapanib (rucaparib), semetinib (selumetinib), sirolimus, 2, 4-dinitrobenzenesulfonate, sorafenib (sorafenib), streptozocin, sunitinib (sunitinib), suramin (suramin), talazoliparib (talazoparib), tamoxifen, temozolomide (temozolomide), temsirolimus (temirinimus), teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, tolnaftifine (tonapoyline), topotecan, trametanide, trastuzumab, tretinomycin, vellicanib (vinorelbine), vinorelbine (vinorelbine), vinorelbine (vinorelbine, vinorelbine (HA).

In other embodiments, suitable chemotherapeutic agents comprise: ABT-263, dexamethasone, 5-fluorouracil, PF-04691502, romidepsin, and vorinostat (SAHA). In other embodiments, the chemotherapeutic agent comprises: 1-amino-4-phenylamino-9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonate (acid blue 25), 1-amino-4- [ 4-hydroxyphenyl-amino ] -9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonate, 1-amino-4- [ 4-aminophenylamino ] -9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonate, 1-amino-4- [ 1-naphthylamino ] -9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonate, 1-amino-4- [ 4-fluoro-2-carboxyphenylamino ] -9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonate, 1-amino-4- [ 2-anthracenylamino ] -9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonate, APCP, β -methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N- (4-sulfamoylphenylcarbamoylthio) palmitamide, NF279, NF449, PPADS, quercetin, reactive blue 2, rolipramine, sodium 2, 4-dinitrobenzenesulfonate, suramin, and tolnaftifine.

Other types of chemotherapeutic agents include immunotumoral agents (e.g., abamectin (abagomab), adalimumab (adezelimumab), atolizumab (afutuzumab), alemtuzumab (alemtuzumab), maanalimumab (anatumab mafenadox), aprezumab (apolizumab), belinostumab (blinatumomab), BMS-936559, rituximab (cataxomab), dewalimumab (durvalib), idazolpidotat (epacadiostat), epratuzumab (epratuzumab), indole (indoximod), imipramoxine (inolizumab), rituzumab (indozogamycin), rituximab (indolizumab), rituximab (indouzumab), rituximab (indozogamumab), rituximab (inteluzumab), ipilimumab (ipilimumab), isozelimumab (isavulizumab), wurtuzumab (3280A), rituximab (beautymab dl), rituximab (beautymab (e), rituximab (mexillizumab), rituximab (e), macluravizumab), rituximab (e), rituximab (e), maculob (e), maculob (e), rituximab (e), maculob), maclekul (e), maclekul (e), macluravizumab), maclekul (e), maclekul (e), maclurolizumab), maclekul (e), maclekul), maclurolizumab), maclekul (e), maclekul (e), maclekub), maclekul (e), macluruab), maclurolizumab), maclekub (e), maclekub (e kub (e d-wurtuzumab), maclurolib), maclekub (e), maclekub) and maclekub), maclekub (e d-32, maclekub), maclekub (e), maclekub), maclurolib), maclurotuzumab), maclekub (e kub), maclekub), maclurotuzumab), maclekub), maclurotuzumab), maclekub), maclurotuzumab), maclurotuz, Tiximumab (ticilimumab), samarazumab (samalizumab), and tremelimumab (tremelimumab)).

In some embodiments, the active pharmaceutical ingredient is selected from PARP inhibitors known to repair DNA damage (e.g., olaparib, veliparib, nilapanib (niraparib), NMS-P118, talapanib, and lucapanib (rucapanib)).

In some embodiments, the active pharmaceutical ingredient is selected from agents for treating neurodegenerative diseases (such as amantadine, apomorphine, baclofen, carbidopa, dantrolene, donepezil, entacapone, galantamine, levodopa, memantine, pramipexole, rasagiline, riluzole, rivastigmine, ropinirole, selegiline, tacrine, tetrabenazine, tizanidine, and tolcapone).

In some embodiments, the active pharmaceutical ingredient is selected from agents used to treat neuropathy (e.g., gabapentin, levocarnitine, duloxetine, carbamazepine, capsaicin (capsaicine), pregabalin, and capsaicin (qutenza)).

In some embodiments, the active pharmaceutical ingredient is selected from agents used to treat thrombotic disorders (e.g., heparin, activating enzyme, alteplase, argatroban, Acova, urokinase, and jacobinase).

In some embodiments, the active pharmaceutical ingredient is selected from agents for the treatment of obesity and weight gain (such as phentermine, Adipex-P, topiramate, lorcaserin (Belviq), naltrexone (Contrave), methamphetamine (Desoxyn), alei (Alli), phendimetrazine, senecanol (xenicate), orlistat, and amfepramone hydrochloride (Tenuate)).

In some embodiments, the active pharmaceutical ingredient is selected from agents used in the treatment of diabetes and regulation of blood glucose levels (such as chlorpropamide, tolbutamide, tolazamide, glimepiride, glyburide, glipizide, gliclazide, metformin, miglitol, acarbose, pioglitazone, rosiglitazone, repaglinide, nateglinide, exenatide, liraglutide, dulaglutide, lixatide, somatide, semaglutide, saxagliptin, sitagliptin, linagliptin, alogliptin, canagliflozin, dapagliflozin, engagliflozin, and eggliflozin).

In some embodiments, the active pharmaceutical ingredient is selected from agents for treating circadian rhythm disorders (e.g., melatonin, ramelteon (rozerem), benzodiazepinesClass, ampien (Ambien), Sonata (Sonata), Ranita (Lunesta), Suvorexant (Bellomra) and modafinil (Provigil).

Also disclosed herein are compounds of formula II:

or a salt of a compound of formula II wherein m is 2 or 3. In some embodiments, m is 2, while in other embodiments, m is 3.

In some embodiments, the one or more active pharmaceutical ingredients are selected from Niacin (NA), nicotinamide (Nam), Nicotinamide Mononucleotide (NMN), Nicotinamide Riboside (NR), nicotinic acid mononucleotide (NaMN), Nicotinic Acid Riboside (NAR), nicotinamide adenine dinucleotide (NAD +/NADH), Nicotinamide Adenine Dinucleotide Phosphate (NADP), nicotinic acid adenine dinucleotide (NaAD), and one or more compounds of formula II:

and salts of one or more compounds of formula II, and combinations thereof, wherein m is 2 or 3.

The invention encompasses the use of pharmaceutically acceptable salts of the compounds of the invention in the compositions and methods of the invention. In certain embodiments, contemplated salts of the present invention include, but are not limited to, alkylammonium, dialkylammonium, trialkylammonium or tetraalkylammonium salts. In certain embodiments, contemplated salts of the present invention include (but are not limited to) the following salts: l-arginine, benzphetamine (benenthamine), benzathine, betaine, calcium hydroxide, choline, dimethylaminoethanol, diethanolamine, diethylamine, 2- (diethylamino) ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydroxylamine, 1H-imidazole, lithium, L-lysine, magnesium, 4- (2-hydroxyethyl) morpholine, piperazine, potassium, 1- (2-hydroxyethyl) pyrrolidine, sodium, triethanolamine, tromethamine and zinc.

In certain embodiments, the compound is a salt having an anion selected from acetate, trifluoromethanesulfonate, halide, trifluoroacetate, or formate. In other embodiments, if the disclosed compounds are contacted with a medium (e.g., an aqueous medium), the anion can be selected from, for example, OH^-、H₂PO₄ ^-、HPO₄ ^2-、HSO₄ ^-、SO₄ ^2-、NO₃ ^-HCO₃ ^-And CO₃ ^2-。

In some embodiments, the disclosed compounds are in the form of a negatively charged phosphate salt that can form a salt with any suitable cation. The cation may change as the compound is separated or transferred into a medium with a different anionic species. For example, the disclosed compounds can be in the form of a phosphate salt, which is a pharmaceutically acceptable salt as described herein. In certain embodiments, the cation may be selected from Li⁺、Na⁺、K⁺、Mg²⁺And Ca²⁺。

Provided herein are methods of increasing NAD + levels in a subject in need thereof, the methods comprising administering a compound or a salt of a compound, wherein the compound is a compound disclosed herein.

Provided herein are methods of treating a disease or disorder associated with NAD + biosynthesis, the method comprising administering a compound or a salt of a compound, wherein the compound is a compound disclosed herein.

Provided herein are any of the compositions described herein for increasing NAD + levels. In one embodiment, the composition comprises a compound of formula I.

Diseases, disorders and conditions

Provided herein are methods for using the disclosed compounds and pharmaceutical compositions thereof. The disclosed compounds and pharmaceutical compositions thereof can be useful for a variety of therapeutic applications, including, for example, treating and/or ameliorating a variety of diseases and disorders, including, for example, diseases or disorders associated with aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing, among others. The methods comprise administering to a subject in need thereof a disclosed compound and/or a pharmaceutical composition thereof.

In other embodiments, the disclosed compounds and/or pharmaceutical compositions thereof may be used to treat a skin condition. Exemplary skin conditions that can be treated according to the methods described herein include disorders or diseases associated with or caused by inflammation, sun damage, or natural aging. For example, the compositions find utility in the treatment of contact dermatitis (including irritant contact dermatitis and allergic contact dermatitis), atopic dermatitis (also known as allergic eczema), actinic keratosis, keratinization disorders (including eczema), epidermolysis bullosa diseases (including pemphigus), 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 and/or pharmaceutical compositions thereof may be used to treat wounds and/or burns (including, for example, first, second or third degree burns and/or thermal, chemical and electrical burns) to promote healing.

The disclosed compounds and pharmaceutical compositions thereof can also be administered to subjects having an acute disease (e.g., organ or tissue injury) (e.g., subjects having stroke or myocardial infarction or subjects having spinal cord injury). The disclosed compounds and pharmaceutical compositions thereof may also be used to repair alcoholic liver.

In certain embodiments, the compounds or pharmaceutical compositions disclosed herein may be used to treat or prevent a disease or condition 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 extending the lifespan of a subject; methods for treating or preventing a life-related disease or condition; methods for treating or preventing a disease or condition associated with the proliferative capacity of a cell; and methods for treating or preventing a disease or condition caused by cell damage or cell death. In certain embodiments, the method does not function by reducing the incidence of disease that shortens the lifespan of the subject. In certain embodiments, the method does not work by reducing the mortality rate caused by a disease (e.g., cancer).

In certain embodiments, a compound or pharmaceutical composition disclosed herein may be administered to a subject in order to generally increase the lifespan of its cells and protect its cells from stress and/or from apoptosis. Treating a subject with a compound described herein can be similar to subjecting the subject to a stimulus (i.e., a mild stress that is beneficial to the organism and can extend its life).

In other embodiments, provided herein are methods for treating cardiovascular disease by administering to a subject in need thereof a disclosed compound and/or a pharmaceutical composition thereof. Cardiovascular diseases that can be treated using the disclosed compounds and pharmaceutical compositions thereof include cardiomyopathy or myocarditis (e.g., idiopathic cardiomyopathy, metabolic cardiomyopathy, alcoholic cardiomyopathy, pharmaceutical cardiomyopathy, ischemic cardiomyopathy, and hypertensive cardiomyopathy). Atherosclerotic diseases (macrovascular disease) of the major blood vessels (e.g., aorta, coronary, carotid, cerebrovascular, renal, iliac, femoral, and popliteal) also can be treated using the compounds and methods described herein. Other vascular diseases that may be treated include vascular diseases associated with platelet aggregation, retinal arterioles, glomerular arterioles, neurotrophic vessels, cardiac arterioles, and associated capillary beds of the eye, kidney, heart, and central and peripheral nervous systems. The disclosed compounds and pharmaceutical compositions thereof may also be used to increase HDL levels in the plasma of an individual.

The disclosed compounds and pharmaceutical compositions thereof can be administered to a subject who has recently received or is likely to receive a dose of radiation or toxin. In one embodiment, the dose of radiation or toxin is received as part of a work-related or medical procedure (e.g., work in nuclear power plants, piloting airplanes, X-rays, CAT scans, or administration of radioactive dyes for medical imaging); in such embodiments, the compound is administered as a prophylactic measure. In other embodiments, radiation or toxin exposure is received unintentionally (e.g., due to an industrial accident, living at a natural radiation site, terrorist activity, or war acts involving radioactive or toxic materials). In such cases, it is preferred to administer the disclosed compounds and pharmaceutical compositions thereof as soon as possible after exposure to inhibit apoptosis and the subsequent development of acute radiation syndrome.

In other embodiments, the disclosed compounds and pharmaceutical compositions thereof may be useful for treating age-related disorders (such as, for example, cancer). Exemplary cancers that can be treated using the disclosed compounds and pharmaceutical compositions thereof include brain and kidney cancers; hormone-dependent cancers (including breast, prostate, testicular, and ovarian cancers); lymphomas and leukemias. Other diseases that may be treated include autoimmune diseases (e.g., systemic lupus erythematosus, scleroderma, and arthritis) where autoimmune cells should be removed. Viral infections (such as herpes, HIV, adenovirus, and HTLV-1 associated malignant and benign disorders) can also be treated by administration of the disclosed compounds and pharmaceutical compositions thereof.

In some embodiments, the disclosed compounds and pharmaceutical compositions thereof may be used to treat patients suffering from neurodegenerative diseases, as well as traumatic or mechanical injury 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), Parkinson's Disease (PD), Huntington's Disease (HD), amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), diffuse Lewy body disease (difusse Lewy body disease), chorea-like motor echinocytosis, primary lateral sclerosis, ocular diseases (ocular neuritis), chemotherapy-induced neuropathy (e.g., due to vincristine, paclitaxel, bortezomib), diabetes-induced neuropathy, and Friedreich's ataxia.

In other embodiments, the disclosed compounds and pharmaceutical compositions thereof may be used to reduce appetite and/or increase satiety, thereby causing weight loss or avoiding weight gain. A subject in need of such treatment may be an overweight, obese subject or a subject that may become overweight or obese.

In other embodiments, the disclosed compounds and pharmaceutical compositions thereof may be used to treat subjects having cachexia or who may develop cachexia. The method may further comprise monitoring a disease state in the subject. Methods for promoting appetite and/or weight gain may comprise, for example, pre-identifying a subject in need of reduced fat or lipid metabolism (e.g., by weighing the subject, determining the subject's BMI). The methods can further comprise monitoring the subject, e.g., during and/or after administration of the disclosed compounds or pharmaceutical compositions thereof. Administration may comprise one or more doses (e.g., delivered in a bolus or continuous manner). Monitoring may comprise assessing hormones or metabolites. Exemplary hormones include leptin, adiponectin, resistin, and insulin. Exemplary metabolites include triglycerides, cholesterol and fatty acids.

In some embodiments, the disclosed compounds and pharmaceutical compositions thereof may be used to treat metabolic disorders (e.g., insulin resistance, pre-diabetic conditions, type II diabetes, and/or complications thereof).

Administration of the disclosed compounds and pharmaceutical compositions thereof can increase insulin sensitivity and/or decrease insulin levels in a subject. A subject in need of such treatment may be a subject having insulin resistance or other precursor symptoms of type II diabetes, a subject suffering from type II diabetes, or a subject who may develop any of these conditions. For example, the subject may be a subject with insulin resistance (e.g., having high levels of circulating insulin and/or having an associated condition such as hyperlipidemia, lipogenic disorders (dysadipogenesis), hypercholesterolemia, impaired glucose tolerance, hyperglycemia levels, other manifestations of syndrome X, hypertension, atherosclerosis, and lipodystrophy)).

Provided herein are methods for modulating blood glucose concentration in a mammal. As used herein, modulating blood glucose concentration refers to any increase, decrease, and/or maintenance in blood glucose concentration or any increase, decrease, and/or maintenance in blood glucose concentration as compared to a previously determined level.

The therapeutic methods disclosed herein are also directed to methods of modulating a circadian clock, thereby modulating or affecting a biological function modulated by (sometimes also considered to be affected by, attached to, or mediated by) circadian clock activity. Typically, these biological functions exhibit a pattern of activity and inactivity, which typically repeats about every 24 hours, oscillating between an "active" state and an "inactive" state during a 24 hour period.

Accordingly, the present invention provides methods of modulating circadian clock activity by administering a compound or pharmaceutical composition disclosed herein to a mammal in need thereof. In general, modulation of the activity of the circadian CLOCK is a result of modulation of CLOCK: BMAL1, which is achieved by modulating the activity of SIRT1 according to the methods of the invention. Generally the method according to the invention is as disclosed hereinAdministration of the disclosed compounds or pharmaceutical compositions and, in certain embodiments, by affecting NAD⁺Administration of a compound of the pathway modulates the activity of SIRT 1. The regulation of the circadian clock thus allows for the regulation of activities mediated by the circadian clock.

According to the present invention, the activity of the circadian clock may be increased, decreased, or maintained by administration of a compound or pharmaceutical composition disclosed herein. Accordingly, the biological function (sometimes also referred to as biological activity) regulated by the activity of the circadian clock may also be increased, decreased, or maintained. Furthermore, these biological functions may also be time-shifted; that is, activities that typically occur during certain periods of time, such as, for example, during daytime or daylight hours (sometimes also referred to as photoperiods) or during night or nighttime (sometimes also referred to as dark cycles), may be switched such that activities instead occur during dark cycles or photoperiods, respectively.

Pharmaceutical preparation

The compounds of the present invention are formulated with conventional carriers and excipients which may be conventionally selected. Tablets may contain excipients, glidants, fillers, binders and the like. All formulations will optionally contain Excipients such as those shown in the Handbook of Pharmaceutical Excipients (1986). Suitable excipients are also listed in the U.S. food and drug administration inactive ingredients database. Excipients include ascorbic acid and other antioxidants, chelating agents (such as EDTA), carbohydrates (such as dextran, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, and the like). The pH of the formulation may range from about 3 to about 11, but is typically about 7 to about 10.

While it is possible to administer the active ingredients separately, it may be preferred to present them in a pharmaceutical formulation. Both the veterinary and human formulations of the invention comprise at least one active ingredient as defined above, together with one or more of its acceptable carriers, and optionally other therapeutic ingredients. One or more carriers must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not physiologically deleterious to the recipient thereof.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissue of a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle (such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material). Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars (such as lactose, glucose and sucrose); (2) starches (e.g., corn starch and potato starch); (3) cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate); (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients (such as cocoa butter and suppository waxes); (9) oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil); (10) glycols (e.g., propylene glycol); (11) polyols (such as glycerol, sorbitol, mannitol, and polyethylene glycol); (12) esters (e.g., ethyl oleate and ethyl dodecanoate); (13) agar; (14) buffering agents (such as magnesium hydroxide and aluminum hydroxide); (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) a ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible materials employed in pharmaceutical formulations.

Formulations of the present invention suitable for oral administration may be presented as discrete units, such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient as a powder or granules. The active ingredient may also be administered as a bolus, electuary or paste.

Tablets are manufactured by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally formulated so as to provide slow or controlled release of the active ingredient therefrom.

Pharmaceutical formulations according to the invention comprise a compound according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. The pharmaceutical preparation containing the active ingredient may be in any form suitable for the intended method of administration. For example, when intended for oral use, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide palatable dosage forms. Tablets containing the active ingredient incorporated with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture are acceptable. For example, these excipients may be inert diluents (such as calcium or sodium carbonate, lactose, calcium or sodium phosphate); granulating and disintegrating agents (e.g., corn starch or alginic acid); binding agents (e.g., starch, gelatin, or acacia); and lubricating agents (such as magnesium stearate, stearic acid or talc). The tablets may be uncoated or they may be coated by known techniques (including microencapsulation) to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material (such as glyceryl monostearate or glyceryl distearate) may be employed alone or with a wax.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, dibasic calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with an aqueous or oily medium, for example peanut oil, liquid paraffin, or olive oil.

The aqueous suspensions of the present invention contain one or more active materials incorporated with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents (such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia), and dispersing or wetting agents (such as naturally-occurring phosphatides (e.g., lecithin), condensation products of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate)). The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Dispersible powders or granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients (e.g., sweetening, flavoring, and coloring agents) may also be present.

The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration. For example, an extended release formulation intended for oral administration to humans may contain from about 1mg to about 1000mg of the active material admixed with a suitable and convenient amount of carrier material which may vary from about 5% to about 95% (weight: weight) of the total composition. Pharmaceutical compositions can be prepared to provide an amount for administration that is readily measured.

Formulations suitable for intrapulmonary or nasal administration having a particle size, for example, in the range of about 0.1 micron to about 500 microns (e.g., about 0.5 micron, about 1 micron, about 30 microns, or about 35 microns, etc.), are administered by rapid inhalation through the nasal passages or by inhalation through the oral cavity to reach the alveolar sacs. Suitable formulations comprise aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration or dry powder administration can be prepared according to conventional methods and can be delivered with other therapeutic agents.

The formulations are presented in unit-dose or multi-dose containers (e.g., sealed ampoules and vials), and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier (e.g., water for injections) immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose of the active ingredient, or an appropriate fraction thereof, as hereinbefore recited.

It will be understood that, in addition to the ingredients explicitly mentioned above, the formulations of the invention may contain other agents conventional in the art having regard to the type of formulation in question (e.g., those suitable for oral administration may contain flavoring agents).

While the foregoing written description of the invention enables one of ordinary skill to make and use what is presently considered to be the best mode thereof, those of ordinary skill will understand and appreciate the existence of variations, combinations, and equivalents of the specific embodiments, methods, and examples herein. Accordingly, the present invention should not be limited by the above-described embodiments, methods and examples, but by all embodiments and methods within the scope and spirit of the invention.

It is to be understood that wherever values and ranges are provided herein, all values and ranges subsumed therein are intended to be encompassed within the scope of the present invention. Moreover, all values falling within these ranges, as well as upper or lower limits of the ranges of values, are also contemplated by this application.

Is incorporated by reference

All U.S. patent and PCT published patent applications and non-patent documents referred to in this specification are incorporated by reference herein to the same extent as if each individual patent and publication was specifically and individually indicated to be incorporated by reference.

Examples

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific processes, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of the present invention and are covered by the claims appended hereto. For example, it is understood that modifications to reaction conditions (including but not limited to reaction times, reaction sizes/volumes) and experimental reagents (such as solvents, catalysts, pressures, atmospheric conditions (e.g., nitrogen atmospheres), and reducing/oxidizing agents) with art-recognized alternatives and using only routine experimentation are also within the scope of the present application.

The recitation of a list of elements in any definition of a variable herein includes the definition of that variable as any single element or combination (or sub-combination) of the listed elements. Recitation of embodiments herein includes such embodiments as any single embodiment or in combination with any other embodiments or portions thereof. Unless otherwise indicated, the starting materials for the syntheses described herein are obtained from commercial sources or known synthetic processes and are used without further purification.

General synthetic schemes

Preparation of bis (((2R,3S,4R,5R) -5- (3-carbamoylpyridin-1-ylium-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methyl) phosphate acetate

NR triflate (5.00g, 12.38mmol) was placed in a 100mL single neck 24/40 round bottom flask and placed under argon. Placing the flask in a cooling bath at-15 deg.C to-10 deg.C, and adding trimethyl phosphate(18ml) and the reaction mixture was stirred. Phosphorus oxychloride (0.865mL, 1.42g, 9.28mmol, 0.75 equiv) was added dropwise from the syringe over a 2 minute period. The reaction was stirred in the cold bath for 30 minutes and then placed in a refrigerator at 5 ℃ for 1-2 days. Then, the reaction was cooled to-15 ℃ to-10 ℃, and 1 equivalent to 6 equivalents of water was added dropwise over 20 min. The reaction mixture was then placed on an aminopropyl silica gel column and eluted with a gradient of ethyl acetate: 0.1M acetic acid in methanol: 0.1M acetic acid in water to yield the desired product as its monoacetate salt.¹H NMR(500MHz,D₂O)9.43(d,2H J＝0.6Hz),9.21(dd,2H,J＝6.3,1.1Hz),8.95(ddd,2H,J＝8.1,1.7,1.2Hz),8.25(td,2H,J＝7.2,1.7Hz),6.18(d,2H,J＝5.2Hz),4.57(m,2H),4.48(td,2H,J＝5.1,2.1Hz),4.37(m,2H),4.29(ddd,2H,J＝12.0,4.8,2.4Hz),4.12(ddd,2H,J＝12.0,5.7,2.7Hz),1.87(s,3H)；¹³C NMR(125MHz,D₂O)181.40,165.66,145.97,142.45,139.80,134.00,128.51,99.72,86.92,77.57,70.65,64.64,23.23；³¹P NMR(200MHz,D₂O),0.74。(MS(ESI⁺)m/z＝571.1(M⁺)。

Preparation of formula I, n ═ 2

4.00g (9.89mmol) nicotinamide riboside trifluoromethanesulfonate and a stir bar were charged into a 50mL recovery flask. The flask was purged with argon and covered with a septum. The flask was cooled with an ice bath and 24mL trimethyl phosphate was then added via syringe. The mixture was stirred under ice-cooling for 5-10min, then 1.45mL (15.56mmol) of phosphorus oxychloride was added via syringe. After 3h, 400 μ l pyridine was added to the reaction. After 5.25h 534 microliter of water was added dropwise over 1 min. Next, 3.2mL of pyridine was added. The suspension was stirred under ice-cooling for 1.5h, then stored at 4 ℃ for 15.5 h.

The reaction was diluted with ethyl acetate until cloudy, then a small amount of methanol (about 1mL) was added to give a clear solution. Half of the mixture was loaded onto 90g aminopropyl functionalized silicon which had been pre-equilibrated with ethyl acetateGel column (acetate form). The column was then eluted with a series of the following mobile phases: mobile phase a-ethyl acetate, mobile phase B: 0.1M acetic acid in methanol, mobile phase C: 0.1M acetic acid in water. The elution sequence is as follows (all ratios are v: v): 1000mL A, 50:50A: B, 40:60A: B, 100% B, 80:20B: C, 60:40B: C, 40:60B: C, and 100% C. By HPLC MS (ESI)⁺Scan pattern) identified the fraction containing the product, where m/z-651 amu is the product mass. The product was predominantly in the 60:40B: C and 40:60B: C fractions. The fractions containing the product were combined and concentrated in vacuo to a foam, then taken up in 0.5mL of water and reconcentrated to a foam. The foam was dissolved in 3mL of water, frozen, and lyophilized to yield an impure product. The foam was repurified via the same chromatography and lyophilization sequence to yield the desired product as a white solid.

Then, the latter half of the crude product solution was purified via the same sequence as that of the first half. This produced a second crop of product as a white solid. The total yield of the combined batches was 50-500 mg.