Compositions for Treating Inflammation

Abstract

Novel compositions and methods for treating inflammation are disclosed herein. Methods for identifying agents useful in the aforementioned methods are also described herein. The present invention relates to methods for treating and preventing disorders associated with inflammation by administering agents that can also increase NAD+ levels, such as NAD+ precursors or agents involved in NAD+ biosynthesis.

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 292,672, filed December 22, 2021, which is incorporated by reference in its entirety for all purposes. [Background technology]

[0002] Nicotinamide adenine dinucleotide (NAD) is an essential metabolic cofactor. Recent studies have shown that NAD levels decline with age and in certain mammalian disease states, and that therapeutically increasing NAD levels has health benefits. However, NAD is an intracellular metabolite and is not easily amenable to external supplementation. It has been suggested that utilizing precursors for the natural synthesis of NAD may be an effective way to increase NAD.

[0003] Two exemplary precursors that can be administered to increase NAD are nicotinamide mononucleotide (NMN), which is directly synthesized into NAD, and nicotinamide riboside (NR), which recycles NAD to NMN. There are no known dietary or environmental sources of NMN or NR. Therefore, in order to use these precursors as drugs or nutritional supplements, they must be produced.

[0004] Nicotinamide adenine dinucleotide (NAD) boosting compounds, such as β-nicotinamide mononucleotide (NMN), have recently attracted attention for their use in treating, ameliorating, mitigating, slowing, halting, preventing, and / or reversing a wide variety of diseases and conditions, including, but not limited to, age-related obesity, age-related increases in blood lipid levels, age-related decreased insulin sensitivity, age-related memory function decline, and age-related changes in ocular function, such as macular degeneration. Summary of the Invention

[0005] Disclosed herein are compounds that include a xanthine moiety, or an analog of a xanthine moiety, and an additional moiety that provide for administration for the treatment of inflammation, among other indications.

[0006] In some embodiments, the present disclosure provides a compound having a structure according to formula (I): [ka] During the ceremony, Q is H or a phosphate group (-PO(OH)2 or -PO(OH)(O - )) and Y is -NH- or -O-; L 2 is (C1-6) alkylene or [ka] (In the formula, L 2a is alkylene, and R 1 are each independently OH, O - , O-alkyl, NH-alkyl, or alkyl, Z is O or NH, n is 0 or 1, * is the point of attachment to the oxygen atom, ** is the point of attachment to D, or Y and L 2 is absent, D is an optionally substituted xanthine, or a pharma- ceutically acceptable salt thereof.

[0007] In various embodiments, the chemical variables are as further defined herein.

[0008] In various embodiments, the present disclosure provides a pharma- ceutically acceptable salt of a compound according to any one of the preceding clauses, the salt being represented by H + , Li + , Na + , K + , Mg 2+ , and Ca 2+In various embodiments, the present disclosure relates to a pharma- ceutically acceptable salt of a compound according to any one of the preceding clauses, the salt being selected from acetate, triflate, halide, trifluoroacetate, formate, H2PO4 - , HPO4 2- , O.H. - , HSO4 - , SO4 2- , NO3 - , HCO3 - , and CO3 2- The present invention relates to a pharma- ceutically acceptable salt comprising an anion selected from:

[0009] Also disclosed herein is a pharmaceutical composition comprising a compound or a pharma- ceutically acceptable salt according to any one of the preceding clauses and one or more pharma- ceutically acceptable excipients. In various embodiments, the pharma- ceutical acceptable excipients are selected from anti-adherents, binders, coatings, dyes, disintegrants, flavorings, glidants, lubricants, preservatives, adsorbents, sweeteners, dispersants, diluents, fillers, granulating agents, coatings, waxes, suspending agents, wetting agents, vehicles, liquid carriers, and combinations thereof.

[0010] In various embodiments, the composition is in a solid form selected from tablets, pills, capsules, caplets, troches, granules, powders, sachets, dry powder inhalation forms, chewables, pastilles, and lozenges.Further described herein is a pharmaceutical composition according to any one of the preceding clauses, wherein one or more of the compound and the pharma-ceutically acceptable salts are present in the composition in an amount of about 0.001% to about 90% by weight.

[0011] Also disclosed herein are various methods of treatment, including a method of treating inflammation in a subject in need of such treatment, comprising administering to the subject a compound or a pharma- ceutically acceptable salt as described in any one of the above clauses, or a pharmaceutical composition as described in any one of the above clauses. In various embodiments, the inflammation is mediated by phosphodiesterase. In various embodiments, the inflammation is associated with asthma, chronic obstructive pulmonary disease (COPD), psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), lupus, acute kidney injury (AKI), chronic kidney disease, or neuroinflammation. Also disclosed herein are methods of treating acute kidney injury in a subject, comprising administering to the subject a compound or a pharma- ceutically acceptable salt as described in any one of the above clauses, or a pharmaceutical composition as described in any one of the above clauses. Also disclosed herein is a therapeutic method for increasing NAD+ in a subject, comprising administering to the subject a compound or a pharma- ceutically acceptable salt as described in any one of the above clauses, or a pharmaceutical composition as described in any one of the above clauses. In various therapeutic methods, the compound, the pharma- ceutically acceptable salt, and / or the pharmaceutical composition are orally administered. In various embodiments, the oral administration occurs in an outpatient setting. In various embodiments, the subject administers the oral administration.

[0012] In some embodiments, the compound is administered at a dose of about 100 mg to about 4 grams per day. In some embodiments, the compound is administered at a dose of about 500 mg to about 2 grams per day. In some embodiments, the compound is administered at a daily dosage regimen selected from once per day, twice per day, three times per day, and four times per day. In some embodiments, the compound is administered for a period of up to five days (inclusive). In some embodiments, the compound is administered for a period of more than five days. [Brief description of the drawings]

[0013] [Figure 1]Provided are results from a study conducted to evaluate the specificity of PDE4 inhibition by compounds, as fully described in Example B1. The Y-axis provides the relative PDE4 activity compared to no treatment (no inhibitor=1.0 on a relative scale). IBMX is 3-isobutyl-1,7-bismethyl-xanthine. RLPM is rolipram. NRCl is nicotinamide riboside chloride. Controls in columns 1-4: 1) no inhibitor, 2) water, 3) RLPM 60 micromolar, 4) IBMX 60 micromolar. Columns 5-11 at 0.6 mM: 5) theophylline, 6) caffeine, 7) comparison compound, 8) NRCl, 9) compound 3, 10) compound 1, 11) compound 6. Columns 12-18 at 6 mM: 12) theophylline, 13) caffeine, 14) comparison compound, 15) NRCl, 16) compound 3, 17) compound 1, 18) compound 6. [Diagram 2] Provided are results from a cisplatin-induced model of acute kidney injury (AKI), as fully described in Example B2. Readouts from this study were (a) biliary urinary nitrogen (BUN), (b) serum creatinine (Cr), (c) histopathology of kidney sections assessed and graded for tubular necrosis, and (d) NAD concentration in the kidney. In each of (a)-(d), column 1 was cisplatin alone, column 2 was niacinamide (Nam), column 3 was nicotinamide mononucleotide (NMN), and column 4 was compound 4. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] definition Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art of this disclosure. As used herein, the following terms have the meanings ascribed to them below, unless otherwise specified.

[0015] In this disclosure, "comprises," "comprising," "containing," "having," and the like can have the meaning ascribed to them in U.S. Patent Law, and can mean "includes," "including," and similarly, "consisting essentially of" or "consists essentially" and the like can have the meaning ascribed to them in U.S. Patent Law, and the terms are open-ended, permitting the presence of more than what is recited so long as the basic or novel characteristics of what is recited are not altered by the presence of more than what is recited, but excluding prior art embodiments.

[0016] Ranges provided herein are understood to be shorthand for all values ​​within that range, for example, a range of 1 to 50 is understood to include any number, combination of numbers, or subranges from the group consisting 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.

[0017] Whenever values ​​and ranges are provided herein, it is to be understood that all values ​​and ranges encompassed by those values ​​and ranges are meant to be encompassed within the scope of the invention. Moreover, all values ​​that fall within these ranges, as well as the upper or lower limits of a range value, are also contemplated by the application.

[0018] The phrase "a" or "an" entity, as used herein, refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. Thus, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein.

[0019] Unless specifically stated or clear from the context, the term "about" as used herein is understood to mean within normal tolerances 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 stated value. Unless otherwise clear from the context, all numerical values ​​provided herein are modified by the term about.

[0020] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may occur, but need not occur, and that the description includes instances in which the event or circumstance occurs and instances in which it does not occur. For example, "optional bond" means that the bond may or may not be present, and that the description includes single bonds, double bonds, or triple bonds.

[0021] The term "purified" as described herein refers to the purity of a given compound. For example, a given compound is "purified" when it 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% 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, and "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.

[0022] The term "metabolite," as used herein, refers to a compound produced in vivo following administration to a subject.

[0023] The term "salt" as used herein refers to a compound comprising a cation and an anion that may be generated by protonation of a proton-accepting moiety and / or deprotonation of a proton-donating moiety. It should be noted that protonation of a proton-accepting moiety results in the formation of a cationic species whose charge is balanced by the presence of physiological anions, while deprotonation of a proton-donating moiety results in the formation of an anionic species whose charge is balanced by the presence of physiological cations.

[0024] The phrase "pharmaceutically acceptable salt" refers to a salt that is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or acid addition salts formed with organic acids 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, laurylsulfuric acid, gluconic acid, glutamic acid, salicylic acid, muconic acid, and the like; or (2) base addition salts formed with the conjugate base of any of the inorganic acids listed above, where the conjugate base is Na + , Mg 2+ , Ca 2+ , N.H. g R 4-g + (Wherein, R is C 1-3 and g is a number selected from 0, 1, 2, 3, or 4. It should be understood that all references to pharma- ceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs), as defined herein, of the same acid addition salt.

[0025] The present invention also includes useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, particularly pharma- ceutically acceptable salts, and / or co-precipitates.

[0026] The compounds of the present invention can exist as hydrates or solvates, in which case the compounds of the present invention form crystals that contain, for example, polar solvent molecules, particularly water, methanol, or ethanol, as structural elements of the crystal lattice of the compounds. The polar solvent molecules, particularly water, can be present in stoichiometric or non-stoichiometric ratios with the molecules of the compounds. In the case of stoichiometric solvates, for example hydrates, hemi-, (hemi), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates are possible, respectively. The present invention includes all such hydrates or solvates.

[0027] It is further possible for the compounds of the invention to exist in free form, e.g., as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt, which may be any salt, either an organic or inorganic addition salt, in particular any pharma- ceutically acceptable organic or inorganic addition salt customarily used in pharmacology or used, for example, to isolate or purify the compounds of the invention.

[0028] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult or elderly adult)) and / or mammals, including commercially relevant mammals such as other primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, cats, and / or dogs, and / or commercially relevant birds, such as chickens, ducks, geese, quail, and / or turkeys.

[0029] The terms "treatment," "treating," "alleviating," and "ameliorating" are used interchangeably herein. These terms refer to an approach to obtain a beneficial or desired result, including, but not limited to, therapeutic benefit and / or prophylactic benefit. Therapeutic benefit refers to the eradication or amelioration of the underlying disorder being treated. Therapeutic benefit is also achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, although the patient may still be afflicted with the underlying disorder. In the case of prophylactic benefit, the pharmaceutical compounds and / or compositions can be administered to patients at risk of developing a particular disease or who report one or more of the physiological symptoms of the disease, even if a diagnosis of the disease has not been made.

[0030] The term "preparation" or "dosage form" is intended to include both solid and liquid formulations of an active compound, and one of skill in the art will appreciate that the active ingredient may be present in different formulations depending on the desired dosage and pharmacokinetic parameters.

[0031] The term "excipient" as used herein refers to compounds that are used to prepare pharmaceutical compositions and that are generally safe, non-toxic, and not biologically or otherwise undesirable, and includes excipients that are acceptable for both veterinary and human pharmaceutical use.

[0032] The term "minimum effective dose" (MED), as used herein, refers to the lowest dose level of a pharmaceutical agent that provides a clinically significant response in mean efficacy and that is statistically significantly superior to the response provided by a placebo.

[0033] The term "institutional review board" or "IRB," as used herein, refers to a type of committee that applies research ethics by reviewing proposed methods for research to ensure that they are ethical.

[0034] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio.

[0035] The phrase "pharmacologically acceptable carrier" as used herein means a pharma- ceutically 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 harmful to the subject. Some examples of materials that can function as pharma-ceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (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 the like. oils, and soybean oil, (10) glycols, such as propylene glycol, (11) polyols, such as glycerin, 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) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer solutions, and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0036] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0037] The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0038] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0039] The term "alkoxy" refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0040] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0041] The term "alkenyl," as used herein, refers to an aliphatic group containing at least one double bond, and is intended to include both "unsubstituted alkenyl" and "substituted alkenyl," the latter of which refers to an alkenyl moiety having a substituent replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Furthermore, such substituents include all of the substituents contemplated for alkyl groups, as discussed below, except where stability would be prohibitive. For example, substitution of alkenyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0042] An "alkyl" group or "alkane" is a fully saturated, straight-chain or branched, non-aromatic hydrocarbon. Typically, a straight-chain or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 carbon atoms, unless otherwise defined. Examples of straight-chain and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl. C1-C6 straight-chain or branched alkyl groups are also referred to as "lower alkyl" groups.

[0043] Furthermore, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter of which refers to an alkyl moiety having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, unless otherwise specified, can include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, where appropriate. For example, the substituents of substituted alkyls can include amino, azido, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamides, sulfamoyl, and sulfonates), and silyl groups, as well as substituted and unsubstituted forms of ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, and the like. Exemplary substituted alkyls are described below. Cycloalkyls may be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.

[0044] "C x-y The term "C" when used in combination with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups containing x to y carbons in the chain. For example, "C x-yThe term "alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups including straight chain alkyl and branched chain alkyl groups containing x to y carbons in the chain, including, for example, haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. C0 alkyl indicates a hydrogen if the group is in a terminal position, or a bond if internal. 2-y alkenyl" and "C 2-y The term "alkynyl" refers to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0045] The term "alkylamino," as used herein, refers to an amino group substituted with at least one alkyl group.

[0046] The term "alkylthio," as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0047] The term "alkynyl," as used herein, refers to an aliphatic group containing at least one triple bond, and is intended to include both "unsubstituted alkynyl" and "substituted alkynyl," the latter of which refers to an alkynyl moiety having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Furthermore, such substituents include all of the substituents contemplated for alkyl groups, as discussed above, except where stability would be prohibitive. For example, substitution of alkynyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0048] The term "amide," as used herein, refers to the group: [ka] In the formula, R 30 each independently represents a hydrogen or a hydrocarbyl group, or two R30 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0049] The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines, and salts thereof, such as, a moiety that may be represented as: [ka] or in the formula, R 31 each independently represents a hydrogen or a hydrocarbyl group, or two R 31 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure. The term "aminoalkyl," as used herein, refers to an alkyl group substituted with an amino group.

[0050] The term "aralkyl," as used herein, refers to an alkyl group substituted with an aryl group.

[0051] The term "aryl" as used herein includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of the rings being aromatic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0052] The term "carbamate" is art-recognized and refers to the group: [ka] In the formula, R 32 and R 33independently represent hydrogen or a hydrocarbyl group such as an alkyl group, or R 32 and R 33 together with the intervening atom(s) complete a heterocycle having 4 to 8 atoms in the ring structure.

[0053] The terms "carbocycle" and "carbocyclic" as used herein refer to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings in which all carbon atoms are saturated, and cycloalkene rings that contain at least one double bond.

[0054] The term "carbocycle" includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Carbocycles include bicyclic molecules in which one, two, or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle, as long as valence permits. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A "carbocycle" may be substituted at any one or more positions that may have a hydrogen atom.

[0055] A "cycloalkyl" group is a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms, unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from a saturated ring, an unsaturated ring, and an aromatic ring. Cycloalkyl includes bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl may be selected from a saturated ring, an unsaturated ring, and an aromatic ring. A "cycloalkenyl" group is a cyclic hydrocarbon containing one or more double bonds.

[0056] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocycle group.

[0057] The term “carbonate” is art-recognized and refers to the group —OCO—R 34 In the formula, R 34 represents a hydrocarbyl group.

[0058] The term "carboxy," as used herein, refers to a group represented by the formula -CO2H.

[0059] The term "ester" as used herein refers to the group -C(O)OR 35 In the formula, R 35 represents a hydrocarbyl group.

[0060] The term "ether" as used herein refers to a hydrocarbyl group linked to another hydrocarbyl group via oxygen. Thus, the ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers can be either symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which can be represented by the general formula alkyl-O-alkyl.

[0061] The terms "halo" and "halogen" as used herein mean halogen and include chloro, fluoro, bromo, and iodo.

[0062] The terms "hetaralkyl" and "heteroaralkyl," as used herein, refer to an alkyl group substituted with a hetaryl group.

[0063] The term "heteroalkyl," as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.

[0064] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic ring structures, preferably 5-7 membered rings, more preferably 5-6 membered rings, in which the ring structure contains at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of the rings is heteroaromatic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.

[0065] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0066] The terms "heterocyclyl", "heterocycle", and "heterocyclic" refer to a substituted or unsubstituted non-aromatic ring structure, preferably a 3- to 10-membered ring, more preferably a 3- to 7-membered ring, in which the ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, where at least one of the rings is heterocyclic, e.g., the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0067] The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with a heterocycle group.

[0068] The term "hydrocarbyl" as used herein refers to a group that does not have =O or =S substituents and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but is bonded through carbon atoms that may optionally contain heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl for purposes of this application, while substituents such as acetyl (having =O substituents on the connecting carbon) and ethoxy (connected through oxygen rather than carbon) are not hydrocarbyl. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

[0069] The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with a hydroxy group.

[0070] The term "lower" when used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups in which there are 10 or fewer non-hydrogen atoms in the substituent, preferably 6 or fewer. "Lower alkyl" refers, for example, to alkyl groups containing 10 or fewer, preferably 6 or fewer carbon atoms. In certain embodiments, an acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituent as defined herein, whether appearing alone or in combination with other substituents such as hydroxyalkyl and aralkyl, is a lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively (where, for example, atoms in an aryl group are not counted when counting the carbon atoms in an alkyl substituent).

[0071] The terms "polycyclyl," "polycycle," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings." Each of the rings of a polycycle can be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains from 3 to 10 atoms, preferably from 5 to 7 atoms, in the ring.

[0072] The term "silyl" refers to a silicon moiety having three hydrocarbyl moieties attached thereto.

[0073] The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbons of the backbone. It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is subject to the allowed valences of the substituted atom and substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like. The term "substituted" as used herein is intended to include all permissible substituents of organic compounds. In a broad sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. The substituents may include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. Those skilled in the art will appreciate that the substituents themselves may be substituted, where appropriate. Unless specifically described as "unsubstituted," references to chemical moieties herein are understood to include substituted variants. For example, references to an "aryl" group or moiety implicitly include both substituted and unsubstituted variants.

[0074] The term "sulfate" is art-recognized and refers to the group -OSO3H, or a pharma- ceutically acceptable salt thereof.

[0075] The term "sulfonamide" is art-recognized and refers to a group that may be represented by the general formula: [ka] In the formula, R 36 and R 37 independently represents hydrogen or a hydrocarbyl such as alkyl, or R 36 and R 37 together with the intervening atom(s) complete a heterocycle having 4 to 8 atoms in the ring structure.

[0076] The term "sulfoxide" is art-recognized and refers to the group -S(O)-R 38 In the formula, R 38 represents hydrocarbyl.

[0077] The term "sulfonate" is art-recognized and refers to the group SO3H, or a pharma- ceutically acceptable salt thereof.

[0078] The term “sulfone” is art-recognized and refers to the group —S(O)—R 39 In the formula, R 39 represents hydrocarbyl.

[0079] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

[0080] The term "thioester" as used herein refers to the group -C(O)SR 40 Or -SC(O)R 40 In the formula, R 10 represents hydrocarbyl.

[0081] The term "thioether," as used herein, is equivalent to an ether where the oxygen is replaced with a sulfur.

[0082] "Xanthine" means R 1 , R 2 , and R 3"Substituted xanthine" refers to a moiety corresponding to the ring structure below, where R is a cyclic ring, R is a cyclic ring, and R is a cyclic ring, R is a cyclic ring, and R is a cyclic ring. 1 rank, R 2 rank, and R 3 Compounds having the following xanthine bicyclic core and various substituents at any or all of the positions: [ka]

[0083] A compound having a structure represented by formula (I): [ka] During the ceremony, Q is H or a phosphate group (-PO(OH)2 or -PO(OH)(O - )) and Y is -NH- or -O-; L 2 is (C1-6) alkylene or [ka] (In the formula, L 2a is alkylene, and R 1 are each independently OH, O - , O-alkyl, NH-alkyl, or alkyl, Z is O or NH, n is 0 or 1, * is the point of attachment to the oxygen atom, ** is the point of attachment to D, or Y and L 2 is absent, Disclosed herein are compounds, or pharma- ceutically acceptable salts thereof, where D is an optionally substituted xanthine.

[0084] In certain embodiments, Y is -O-. In other embodiments, Y is -HN-. In certain embodiments, L 2a is (C1-3)alkylene. In other embodiments, L 2a is a C alkylene. In some embodiments, R 1are each OH or O - In certain embodiments, each Z is O. In some embodiments, n is 1. In other embodiments, n is 0. In certain embodiments, Y and L are 2 In other embodiments, L 2 is a (C1-6)alkylene or a (C1-3)alkylene.

[0085] A compound having a structure represented by formula (II): [ka] During the ceremony, X is NH2, OH or O - and L 1 but [ka] (In the formula, R 1 are each independently OH, O - , O-alkyl, NH-alkyl, or alkyl, Z is O or NH, n is 0 or 1, * is the point of attachment to the oxygen atom, ** is the point of attachment to D; Disclosed herein are compounds, or pharma- ceutically acceptable salts thereof, where D is an optionally substituted xanthine.

[0086] In certain embodiments, X is OH or O - In other embodiments, X is NH2. In some embodiments, R 1 are each OH or O - In certain embodiments, each Z is O. In some embodiments, n is 1. In other embodiments, n is 0. In certain embodiments, D is an anti-inflammatory drug. In other embodiments, D is a substituted xanthine. In some embodiments, D is a methylxanthine. In certain embodiments, the methylxanthine is caffeine, theobromine, or theophylline, e.g., theobromine.

[0087] In some embodiments, D is L at the 1-position of the xanthine ring. 1 Or L 2 In another embodiment, D is linked to L at the 3-position of the xanthine ring. 1 Or L 2 In some embodiments, D is linked to L at the 7-position of the xanthine ring. 1 Or L 2 is bound to.

[0088] In certain embodiments, D is represented by formula (III): [ka] During the ceremony, R 1 , R 2 , R 3 , and R 4 are each independently H, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C3-7)cycloalkyl, aryl, heteroaryl, -C(=O)(C1-6)alkyl, C(=O)(O)(C1-6)alkyl, absent, or a point of attachment to L, with the proviso that R 1 , R 2 , R 3 , and R 4 is a point of attachment, and R 4 with the further proviso that if is not absent or is the point of attachment to L, the nitrogen to which it is attached is positively charged; R 5 is H, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C3-7)cycloalkyl, aryl, heteroaryl, or NR 6 R 7 and R 6 and R 7 are each independently H, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, or aryl.

[0089] In certain embodiments, R 1 and R 3are each independently (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C3-7)cycloalkyl, aryl, heteroaryl, -C(=O)(C1-6)alkyl, C(=O)(O)(C1-6)alkyl, or a point of attachment to L. In other embodiments, R 1 , R 2 , and R 3 are each independently (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C3-7)cycloalkyl, aryl, heteroaryl, -C(=O)(C1-6)alkyl, C(=O)(O)(C1-6)alkyl, or a point of attachment.

[0090] In one embodiment, R 1 , R 2 , R 3 , and R 4 are each independently H, (C1-6)alkyl, or absent. 1 , R 2 , R 3 , and R 4 At least one of R is (C)alkyl. 1 , R 2 , R 3 , and R 4 At least one of R is (C1-6)alkyl substituted with -C(O)CH3. 1 , R 2 , R 3 , and R 4 At least one of is methyl.

[0091] In some embodiments, R 4 is H or absent. In certain embodiments, R 5 is H or (C1-6)alkyl. In certain embodiments, R 5 is H. In some embodiments, R 1 is the point of attachment to L. In other embodiments, R 1 L 2 Or L 1 is the attachment point to R 2is CH3, R 3 is CH3, R 4 is absent, R 5 is H.

[0092] below: [ka] A compound having one of the structures of TIFF2025500336000014.tif255130TIFF2025500336000015.tif241130TIFF2025500336000016.tif92130, or a pharma- ceutically acceptable salt thereof is disclosed herein.

[0093] The compounds disclosed herein can be synthesized according to general methods known in the art using the various specific examples provided in the Examples herein. Modifications of the methods provided herein can be used to reach the full scope of general formula I.

[0094] A pharma- ceutically acceptable salt of the compound disclosed herein, the salt being represented by the formula: H + , Li + , Na + , K + , Mg 2+ , and Ca 2+ Provided herein are pharma- ceutically acceptable salts comprising a cation selected from the group consisting of acetate, triflate, halide, trifluoroacetate, formate, H2PO4 - , HPO4 2- , O.H. - , HSO4 - , SO4 2- , NO3 - , HCO3 - , and CO3 2- The anion is selected from the group consisting of

[0095] Disclosed herein is a pharmaceutical composition comprising a compound or a pharma- ceutically acceptable salt and one or more pharma- ceutically acceptable excipients. In some embodiments, the pharma- ceutical acceptable excipients are selected from anti-adherents, binders, coatings, dyes, disintegrants, flavorings, glidants, lubricants, preservatives, adsorbents, sweeteners, dispersants, diluents, fillers, granulating agents, coatings, waxes, suspending agents, wetting agents, vehicles, liquid carriers, and combinations thereof. In certain embodiments, the composition is in a solid form selected from tablets, pills, capsules, caplets, troches, granules, powders, sachets, dry powder inhalation forms, chewables, pastilles, and lozenges. In some embodiments, the composition is in the form of a tablet. In some embodiments, one or more of the compound and the pharma- ceutical acceptable salts are present in the composition in an amount of about 0.001% to about 90% by weight.

[0096] Disclosed herein is a method of treating inflammation in a subject, comprising administering to the subject a disclosed compound or a pharma- ceutically acceptable salt, or a pharmaceutical composition. In certain embodiments, the inflammation is mediated by phosphodiesterase. In other embodiments, the inflammation is associated with asthma, chronic obstructive pulmonary disease (COPD), psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), lupus, acute kidney injury (AKI), chronic kidney disease, or neuroinflammation. The phrase "associated with" encompasses cases where inflammation is a cause of the indication, a symptom of the indication, or both. In various embodiments, disclosed herein are methods of treating inflammation asthma, chronic obstructive pulmonary disease (COPD), psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), lupus, acute kidney injury (AKI), chronic kidney disease, or neuroinflammation.

[0097] Also disclosed herein is a method of treating acute kidney injury in a subject, comprising administering to the subject a compound or a pharma- ceutically acceptable salt as described in any one of the above clauses, or a pharmaceutical composition as described in any one of the above clauses. Also disclosed herein is a treatment method for increasing NAD+ in a subject, comprising administering to the subject a compound or a pharma- ceutically acceptable salt as described in any one of the above clauses, or a pharmaceutical composition as described in any one of the above clauses.

[0098] In certain embodiments, the compound, pharma- ceutically acceptable salt, and / or pharmaceutical composition is orally administered. In some embodiments, oral administration occurs in an outpatient setting. In some embodiments, the subject administers the oral dose.

[0099] Compositions and Pharmaceutical Formulations Although it is possible for the active ingredients to be administered alone, it may be preferable to present them as pharmaceutical formulations. The formulations of the present invention, both for veterinary and human use, comprise at least one active ingredient as defined above, together with one or more acceptable carriers therefor, and optionally other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically harmless to the recipient thereof.

[0100] In some embodiments, the composition is in a solid form selected from tablets, pills, capsules, caplets, troches, granules, powders, sachets, dry powder inhalation 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.The formulation of the present invention suitable for oral administration may be presented as a discrete unit, such as a capsule, cachet, or tablet, each of which contains 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.

[0101] In some embodiments, the pharma- ceutically acceptable excipient is selected from antiadherents, binders, coatings, dyes, disintegrants, flavorings, glidants, lubricants, preservatives, adsorbents, sweeteners, syrups, elixirs, dispersants, diluents, fillers, granulating agents, coatings, waxes, suspending agents, wetting agents, thickening agents, and vehicles, and combinations thereof. In some embodiments, the excipient is a solid excipient.

[0102] In some embodiments, the pharma- ceutically 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 pharma-ceutically 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 pharma-ceutically acceptable excipient is present in an amount of at least about 50% by weight of the composition.

[0103] The compounds of the invention are formulated with conventional carriers and excipients, which can be selected according to ordinary practice. Tablets can contain excipients, glidants, fillers, binders, and the like. All formulations optionally contain excipients, such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Suitable excipients are also listed in the U.S. Food and Drug Administration's Inactive Ingredients Database. Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like. The pH of the formulation can range from about 3 to about 11, but is usually about 7 to about 10.

[0104] Tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent, or dispersing agent, in a suitable machine. Molded tablets can be made by molding a mixture of the powdered active ingredient moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored, and are optionally formulated to provide sustained or controlled release of the active ingredient from the tablet.

[0105] A pharmaceutical formulation according to the invention comprises a compound according to the invention together with one or more pharma- ceutically acceptable carriers or excipients, and optionally other therapeutic agents. A pharmaceutical formulation containing the active ingredient may be in any form suitable for the intended method of administration. When intended for oral use, for example, 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 in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic pharma- ceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binders such as starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or 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.

[0106] Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0107] Aqueous suspensions of the present invention contain the active substance(s) in admixture 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, as well as dispersing or wetting agents such as naturally occurring phosphatides (e.g. lecithin), condensation products of alkylene oxides with fatty acids (e.g. polyoxyethylene stearates), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g. heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g. polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0108] Dispersible powders and granules of the present invention suitable for preparation of an aqueous suspension by adding water provide the active ingredient in a mixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above.Additional excipients, such as sweetening agents, flavoring agents, and coloring agents, may also be present.

[0109] The amount of active ingredient that may be combined with a carrier material to produce a single dosage form varies depending on the subject being treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain from about 1 to about 1000 mg of active ingredient mixed with an appropriate and convenient amount of carrier material, which may vary from about 5% to about 95% (weight:weight) of the total composition. Pharmaceutical compositions may be prepared to provide easily measurable amounts for administration.

[0110] Formulations suitable for pulmonary or nasal administration have particle sizes ranging from about 0.1 to about 500 microns, such as about 0.5, about 1, about 30, or about 35 microns, and are administered by rapid inhalation through the nasal passages or by inhalation through the mouth to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.

[0111] The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and stored in a frozen and dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, for example water, for injection 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 daily sub-dose (as herein above enumerated) of the active ingredient, or an appropriate fraction thereof.

[0112] Methods of Treatment and Administration of Compounds Methods for using the disclosed compounds and pharmaceutical compositions thereof are provided herein.The disclosed compounds and pharmaceutical compositions thereof can be useful for various therapeutic applications, including, for example, treating and / or alleviating a wide variety of diseases and disorders, including diseases or disorders associated with inflammation.The methods include administering the disclosed compounds and / or pharmaceutical compositions thereof to a subject in need thereof.

[0113] Without being bound by theory, phosphodiesterase is believed to be involved in some inflammatory pathways. For example, it has been reported that phosphodiesterase (PDE) degrades cyclic nucleotides, including cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP). cAMP and cGMP are important second messengers in many signal transduction pathways. Therefore, targeting PDE4 may be an effective treatment strategy for inflammatory conditions, including asthma, COPD, psoriasis, atopic dermatitis, IBD, rheumatoid arthritis, lupus, acute kidney injury (AKI), chronic kidney disease, and neuroinflammation. In various embodiments, provided herein is a method for treating acute kidney injury (AKI) by administering the compounds or compositions disclosed herein.

[0114] Also disclosed herein is a method of treating acute kidney injury in a subject, comprising administering to the subject a compound or a pharma- ceutically acceptable salt as described in any one of the above clauses, or a pharmaceutical composition as described in any one of the above clauses. Also disclosed herein is a treatment method for increasing NAD+ in a subject, comprising administering to the subject a compound or a pharma- ceutically acceptable salt as described in any one of the above clauses, or a pharmaceutical composition as described in any one of the above clauses.

[0115] It will be understood that in addition to the ingredients particularly mentioned above, the formulations of the present invention may include other agents conventional in the art having regard to the type of formulation in question. EXAMPLES

[0116] Example 1 [ka]

[0117] compound 1 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((3-(2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetoxy)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate. [ka]

[0118] 2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)tert-butyl acetate. Theobromine (8.00 g, 44.0 mmol), tert-butyl bromoacetate (10.64 g, 54.5 mmol), potassium carbonate (12.16 g, 88.0 mmol), potassium iodide (7.30 g, 44.0 mmol), and benzyltrimethylammonium bromide (1.57 g, 4.4 mmol) were charged to a 100 mL single neck round bottom flask. A magnetic stir bar was added, followed by anhydrous DMF (50 mL), stirring was started, and the mixture was heated at 100° C. for 2 hours. Additional tert-butyl bromoacetate (1.06 g, 5.43 mmol) was added, and the reaction was then heated at 100° C. for 1 hour. Heating was discontinued and the reaction was allowed to stir at ambient temperature overnight. The mixture was concentrated in vacuo to give a pasty solid. Dichloromethane (90 mL) was added, then the solution was filtered and the solid was washed with additional dichloromethane. The filtrate was extracted with water (2×60 mL) and then the organic phase was dried over sodium sulfate. The solution was decanted from the solid and concentrated in vacuo to give a thick oil. The oil was triturated twice with heptane and then placed under high vacuum to give a tan solid. The solid was treated with boiling water (60 mL) to give an oily layer and a solution. The solution was decanted from the oil. On cooling a white solid precipitated out of solution. After standing at 4° C. for 18 hours the cold solution was filtered and washed with cold water. The solid was then dissolved in dichloromethane and the layers were separated. The organic phase was dried over sodium sulfate, decanted and concentrated in vacuo to give 5.80 gm of an off-white solid (45% yield).

[0119] LRMS(ESI) + m / z: 295[M+H] + . 1 H NMR(CDCl3)δ7.54(1H,s),4.68(2H,s),3.99(3H,s),3.60(3H,s),1.51(9H,s).

[0120] [ka] 2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetic acid. A mixture of tert-butyl 2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetate (3.00 g, 10.2 mmol) and 97% formic acid (10.98 g, 239 mmol) was placed in a 100 mL single neck round bottom flask equipped with a magnetic stir bar. The reaction was heated at 55° C. for 18 hours after which it was cooled and concentrated in vacuo. The resulting white solid was washed with dichloromethane, filtered and dried in vacuo to give 2.35 g of product (97% yield).

[0121] LRMS(ESI) + m / z: 239[M+H] + .

[0122] [ka] 3-Bromopropyl 2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetate. 2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetic acid (2.35 g, 9.84 mmol) was placed in a 100 mL single neck round bottom flask equipped with a 24 / 40 septum and a magnetic stir bar and placed under argon. Acetonitrile (anhydrous, 12 mL) was added via syringe and thionyl chloride (2.34 g, 19.7 mmol) was added dropwise over 5 minutes. The reaction was kept under an argon balloon and heated in a 40° C. oil bath for 1 hour. The solvent was evaporated in vacuo, then dry acetonitrile (10 mL) was added and evaporated again to remove remaining traces of acid. An additional portion of dry acetonitrile (20 mL) was added. 3-Bromo-1-propanol (1.43 g, 10.3 mmol) and triethylamine (1.09 g, 10.8 mmol) were added dropwise successively via syringe at room temperature. After stirring for 20 minutes, the reaction was heated in a 50° C. oil bath for 2 hours. The reaction was concentrated in vacuo and the residue was dissolved in dichloromethane (20 mL). The organic phase was washed with saturated sodium bicarbonate solution (30 mL) and dried over sodium sulfate. The solution was decanted and then concentrated in vacuo to give a solid which was dissolved in a minimum amount of ethyl acetate. Hexane was then added to give 2.21 g of a tan solid (63% yield).

[0123] LRMS(ESI) + m / z: 360 [M+H] + .

[0124] [ka] 3-(2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetoxy)propyl nicotinate. 2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)3-bromopropyl acetate (2.43 g, 6.77 mmol), sodium nicotinate (1.00 g, 6.91 mmol), benzyltrimethylammonium bromide (0.48 g, 1.35 mmol), and potassium iodide (0.224 g, 1.35 mmol) were placed in a 100 mL single neck round bottom flask equipped with a magnetic stir bar and a 14 / 40 rubber septum under an argon balloon. DMF (anhydrous, 15 mL) was added and the reaction was stirred and heated in a 95° C. oil bath for 2 h. The reaction was concentrated in vacuo and co-evaporated with acetonitrile (2 x 20 mL). The resulting foam was triturated with MTBE (3 x 20 mL), placed under high vacuum, then dissolved in DCM. The resulting solution was filtered and the filtrate was concentrated in vacuo. The residue was redissolved in DCM, washed with saturated sodium bicarbonate (2 x 20 mL), dried over sodium sulfate, decanted, and concentrated in vacuo to give 2.53 gm of crude product. This was purified by silica gel chromatography (20 g column) eluting with a gradient of 100% dichloromethane-5% methanol / dichloromethane. The product eluted with 1% MeOH / DCM and the appropriate fractions were collected and concentrated to give 1.93 g (71%) of product.

[0125] LRMS(ESI) + m / z: 402[M+H] + .

[0126] [ka] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((3-(2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetoxy)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate.

[0127] 3-(2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetoxy)propyl nicotinate (1.80 g, 4.48 mmol) and β-D-ribofuranose-1,2,3,5-tetraacetate (1.43 g, 4.48 mmol) were placed in a 100 mL single neck 24 / 40 round bottom flask equipped with a magnetic stir bar and capped with a 24 / 40 rubber septum. The headspace was evacuated and placed under argon, then dichloromethane (18 mL) was added via syringe. The mixture was stirred at room temperature while trimethylsilyl trifluoromethanesulfonate (2.11 g, 9.50 mmol) was added via syringe over 5 minutes. The reaction was stirred for 1 hour, then the solution was extracted with saturated aqueous sodium bicarbonate (1×20 mL). The layers were separated and the organic phase was dried over sodium sulfate, decanted and concentrated in vacuo to give a yellow foam (3.62 g, 100% yield). LRMS (ESI) + m / z:660[M] + .

[0128] [ka] 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((3-(2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetoxy)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate.

[0129] Acetyl chloride (2.11 g, 26.9 mmol) was added dropwise to cold dry anhydrous methanol (20 mL) with stirring, and this cold acidic solution was added to 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((3-(2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetoxy)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate (3.62 g, 4.48 mmol) all while keeping the reagents cold and under argon. After stirring overnight at 4° C., the product was precipitated using MTBE. This process of dissolving the crude product in methanol and precipitating with MTBE was repeated until 2.30 g of foam or glass was obtained. Purification by silica gel chromatography using a gradient of 100% dichloromethane-30% methanol / 70% dichloromethane solvent system afforded the desired product (0.665 g, 21.7% yield).

[0130] LRMS(ESI) + m / z: 534.2[M] + . 1 H NMR(D2O)δ9.70(s,1H),9.30(d,1H),9.07(d,1H),8.29(m,1H),7.80(s,1H),6.23(d,1H),5.19(s,2H),4.47(m, 2H),4.39(m,4H),4.33(t,1H),4.01(double line of double line,1H),3.90(double line of double line,1H),3.51(s,3H),3.21(s,3H),2.16(m,2H).

[0131] Example 2 [ka]

[0132] compound 2 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate. [ka]

[0133] 2-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethyl nicotinate. A 100 mL single neck round bottom flask equipped with a magnetic stir bar and rubber septum was charged with 7-(2-hydroxyethyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (5.00 g, 22.3 mmol), nicotinic acid (2.75 g, 22.3 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.28 g, 22.3 mmol), then the headspace was purged with argon. Dichloromethane (40 mL) was added and stirring was commenced to give a suspension. 4-N,N-dimethylaminopyridine (0.55 g, 4.50 mmol) was then added and the reaction was stirred at ambient temperature for 2 hours. Saturated sodium bicarbonate (30 mL) was added and then the mixture was transferred to a separatory funnel. The organic phase was separated, dried over sodium sulfate, decanted, and concentrated in vacuo to give 6.70 g of crude product, which was purified using silica gel (65 g) and elution with a gradient of 100% dichloromethane-97:3 (v:v) dichloromethane:methanol to give 5.50 g of a white solid (74.9% yield).

[0134] LRMS(ESI) + m / z: 330 [M+H] + .

[0135] [ka] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate.

[0136] 2-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethyl nicotinate (5.50 g, 16.70 mmol) and β-D-ribofuranose-1,2,3,5-tetraacetate (5.31 g, 16.70 mmol) were combined in a 500 mL single neck round bottom flask equipped with a magnetic stir bar and a 24 / 40 septum and placed under argon. Dry dioxane (50 mL) was added via syringe and trimethylsilyl trifluoromethylsulfonate (7.42 g, 33.4 mmol) was added dropwise over 10 minutes. The reaction was heated in a 40° C. oil bath for 15 hours and then allowed to cool to room temperature. MTBE was added to precipitate the product. The solvent was decanted from the solid, which was dissolved in ACN (minimal amount) and reprecipitated by addition of MTBE. After decanting the solvent from the solid, the process was repeated using ACN and MTBE. The resulting solid was placed under high vacuum to give 19.3 g (157%, still containing some solvent).

[0137] LRMS(ESI) + m / z:588[M] + .

[0138] [ka] 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate.

[0139] Prepared using a procedure similar to that used for 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((3-(2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetoxy)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate. Yield: 8.66g, 85%.

[0140] LRMS(ESI) + m / z: 462[M] + . 1 HNMR(DO) δ 9.62(s,1H), 9.25(d,1H), 8.98(d,1H), 8.25(doublet of doublet,1H), 8.07(s,1H), 6.20(d,1H), 4.86(m,1H), 4.75(m,1H), 4.42(t,1H), 4.28(t,1H), 3.90(doublet of doublet,1H), 3.81(doublet of doublet,1H), 3.46(s,3H), 3.14(s,3H).

[0141] Example 2P [ka]

[0142] Compound 2P ((2R,3S,4R,5R)-5-(3-((2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethoxy)carbonyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate

[0143] Compound 2 (5.00 g, 8.18 mmol) was added to a 200 mL single neck round bottom flask with a magnetic stir bar and rubber septum in an ice water bath. The flask was evacuated and placed under argon. Dry TMP (25 mL) was added via syringe and stirred. The mixture became a semi-solid mass. Phosphorus oxychloride was added dropwise via syringe but did not break up the mass. The solid was carefully broken up using a spatula until it could be stirred. After 6.5 hours, 8% of the starting material remained. 7 hours after the start of the reaction, water (4.42 g, 245 mmol) was slowly added dropwise to the cold reaction over 10 minutes. The reaction was stirred for 5 minutes and then placed in a -25°C freezer overnight. The reaction was placed in an ice water bath and became a gelatinous mass. IPA (25 mL) was added and the gel was broken up using a spatula. Triethylamine (4.98 g, 49.2 mmol) was added to IPA (15 mL). This solution was carefully added to the cold reaction mixture until the pH was 3.0. Once that pH was reached, the reaction was stirred in an ice-water bath for 30 min, then filtered and the isolated solid was washed with IPA followed by MTBE. The pale yellow solid was dried in vacuo to give 4.03 g of crude product. A portion of this was purified using a 40 g C-18 column with a gradient of 5-30% methanol / water as eluent.

[0144] LRMS(ESI)+ m / z:542.2

[0145] Example 3 [ka]

[0146] compound 3 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate [ka]

[0147] 1-(2-hydroxyethyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione

[0148] A 500 mL single neck round bottom flask was charged with theobromine (10.0 g, 55.5 mmol) and potassium carbonate (8.50 g, 61.5 mmol, ground). A magnetic stir bar was added and then the headspace was purged with argon. DMF (100 mL) was then added via syringe and stirring was started. The flask was heated in a 140° C. oil bath for 40 minutes during which time the mixture thickened. During this time another aliquot of DMF (40 mL) was added to facilitate stirring. After heating for 40 minutes, 2-iodoethanol (9.53 g, 55.5 mmol) was added dropwise over 10 minutes. 50 minutes after the first aliquot was added, a second aliquot of 2-iodoethanol (1.47 g, 8.54 mmol) was added over 5 minutes. After stirring for an additional 30 minutes, a third aliquot of 2-iodoethanol (2.47 g, 14.4 mmol) was added. The reaction was stirred for an additional 30 minutes before a fourth aliquot of 2-iodoethanol (1.88 g, 10.9 mmol) was added. The mixture was stirred at 140° C. for 18 hours before being cooled to ambient temperature. The reaction was filtered, concentrated in vacuo, and the residue was then placed under high vacuum overnight. This gave an off-white solid, which was swirled with acetone (50 mL). The resulting solid was filtered, washed with acetone, and then placed under high vacuum. The resulting solid (29.59 g) was dissolved in boiling EtOH (500 mL), and the solution was then allowed to cool. The resulting solid was filtered, washed with additional ethanol, and dried under high vacuum to give 14.63 g of product (110% yield).

[0149] LRMS(ESI) + m / z: 225[M+H] + . 1 H NMR(D2O)δ7.85(1H,s),4.1(2H,t),3.9(3H,s),3.7(2H,t),3.5(3H,s).

[0150] [ka] 2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl nicotinate

[0151] 2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl nicotinate was prepared using a method similar to that used to prepare 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethyl nicotinate. A solution of 12.6 g (52.9 mmol) of 1-(2-hydroxyethyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione, 6.59 g (53.5 mmol) of nicotinic acid, 11.35 g (59.20 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 1.31 g of DMAP (10.7 mmol) in DCM (75 mL) was utilized to give 82% yield of 2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl nicotinate (13.58 g).

[0152] LRMS(ESI) + m / z:330.

[0153] [ka] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate

[0154] Prepared using a similar procedure as 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate, except that the reaction took only 1 h at 40° C. to complete.

[0155] 2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl nicotinate (13.00 g, 39.5 mmol) and β-D-ribofuranose-1,2,3,5-tetraacetate (12.94 g, 40.7 mmol) were combined and dry dioxane (100 mL) was added. Stirring was started and trimethylsilyl trifluoromethanesulfonate (9.66 g, 43.45 mmol) was added dropwise over 10 min. An alternative workup was used. The reaction was removed from the hot oil bath and allowed to cool to room temperature. DCM (50 mL) was added followed by saturated sodium bicarbonate solution (50 mL). The biphasic solution was stirred for 10 min, then separated and the organic solution was dried over sodium sulfate. The organic solution was concentrated in vacuo to give a yellow foam (29.17 g, 97.2%).

[0156] LRMS(ESI) + m / z:588

[0157] [ka] 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate

[0158] Prepared using a procedure similar to that used to prepare 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((3-(2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetoxy)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate.

[0159] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate (29.17 g, 39.5 mmol) was deprotected by treatment with a cold methanolic HCl solution generated from a solution of acetyl chloride (18.63 g, 237 mmol) in cold methanol (120 mL). Precipitation using MTBE (approximately 400 mL) and redissolution in a minimum amount of methanol after decanting the solvent gave a glass which was reprecipitated a total of four times using MTBE to give an off-white solid (15.20 g, 62.9%) after 18 hours under high vacuum.

[0160] LRMS(ESI) + m / z:462

[0161] Example 4 [ka]

[0162] compound 4 ((2R,3S,4R,5R)-5-(3-((2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate

[0163] 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate (3.00 g, 4.91 mmol) was placed in a 100 mL single neck 24 / 40 round bottom flask equipped with a magnetic stir bar and a 24 / 40 septum and placed in an ice / water bath under argon. TMP (20 mL, over sieves and under argon) was added to the flask via syringe. The reaction was kept in the ice / water bath for the entire reaction period. This resulted in a heterogeneous solution upon stirring. After 10 min, 2 was added dropwise via syringe over 5 min. After 1 h, 3 was added dropwise via syringe over 2 min. After 3 hours, HPLC indicated the reaction was nearly complete. After 3 hours and 10 minutes, 4 was added dropwise over 5 minutes, at which point the reaction went from heterogeneous to homogeneous. 5 was added to IPA (200 mL) in a 500 mL Erlenmeyer flask and the solution was placed in a cold bath, under an argon blanket, and sealed with parafilm. The reaction mixture was added dropwise over 8 minutes to the IPA solution, then stirred for 30 minutes. The pH reached 2 (pH 0-14 paper). The resulting suspension was stirred in the cold for 30 minutes, then filtered, washed with cold IPA, and then placed under high vacuum. This gave 3.39 gm of crude product (131% yield). 2.50 gm of crude product was purified on an Interchim chromatography system using a solvent system of 95% ACN:H2O (100 mM formic acid)-95:5 H2O:ACN (100 mM formic acid). The appropriate fractions were combined and concentrated under high vacuum at 20-23° C. to give 1.62 g of product.

[0164] 1 H NMR(D2O)δ9.41(s,1H),9.32(d,1H),8.99(d,1H),8.28(m,1H),7.85(s,1H),6.17(d,1H),4 .72(m,1H),4.62(m,1H),4.50(m,1H),4.37(m,3H),4.06(m,2H),3.83(s,3H),3.42(s,3H); 31 P(DO)δ-0.1; LRMS(ESI)+ m / z:462

[0165] Example 5 [ka]

[0166] compound 5 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((3-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate [ka]

[0167] 1-(3-hydroxypropyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione

[0168] Theobromine (6.00 g, 33.3 mmol), potassium iodide (11.06 g, 66.7 mmol), and ground potassium carbonate (5.08 g, 36.8 mmol) were placed in a 100 mL 24 / 40 single neck round bottom flask with a magnetic stir bar and a 24.40 rubber septum. The flask was evacuated and placed under argon. Dry DMF (70 mL) was added via syringe and the reaction was heated in a 140° C. oil bath. After 15 minutes, the first aliquot of 3-chloro-1-propanol (3.14 g, 33.3 mmol) was added dropwise via syringe over 5 minutes. After 2 hours, another aliquot of 3-chloro-1-propanol (0.88 g, 9.32 mmol) was added dropwise. The reaction was held at this temperature for an additional 45 minutes, after which the temperature was reduced to 90° C. for 18 hours. The reaction was filtered hot and the solvent removed under high vacuum. Ethanol (100 mL) was added to the pasty white solid and the solution was heated in an 80° C. oil bath. The solution was filtered hot and the ethanol removed in vacuo to give a gummy semi-solid. This was triturated with MTBE three times and the resulting solid was placed under high vacuum to remove remaining traces of MTBE. The solid was heated with ethanol (70 mL) to give solid and liquid phases that were decanted from the solid. The solid was washed with 5% methanol / DCM (50 mL) and the liquid was combined with the ethanol solution and concentrated in vacuo. The resulting solid (8.05 g) was treated with acetone (50 mL), stirred for 30 minutes, filtered, and the solid was isolated and dried in vacuo to give 5.95 g of product.

[0169] LRMS(ESI) + m / z:239

[0170] [ka] 3-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl nicotinate was prepared in a manner similar to the preparation of 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethyl nicotinate.

[0171] 1-(3-Hydroxypropyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (5.95 g, 25.0 mmol), nicotinic acid (3.07 g, 25.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.03 g, 26.2 mmol), and dimethylaminopyridine (0.614 g, 5.02 mmol) were combined in a 100 mL 24 / 40 single neck round bottom flask equipped with a magnetic stir bar and a 24 / 40 rubber septum and placed under argon. DCM (40 mL) was added and the reaction was stirred at room temperature for 1.5 h. Workup with saturated sodium bicarbonate, dried over sodium sulfate, decanted, and concentrated in vacuo to give 7.47 g of product (87.2% yield).

[0172] LRMS(ESI) + m / z:344.

[0173] [ka] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((3-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate

[0174] It was prepared using a method similar to that used to prepare 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate.

[0175] 3-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl nicotinate (7.37 g, 21.5 mmol) and β-D-ribofuranose-1,2,3,5-tetraacetate (6.83 g, 21.5 mmol) were combined under argon and dry dioxane (40 mL) was added. Trimethylsilyl trifluoromethanesulfonate (9.76 g, 43.91 mmol) was added dropwise via syringe and the reaction was heated at 42° C. for 18 hours. This gave a biphasic reaction mixture which was added to well-stirred MTBE (150 mL). The resulting gummy solid was dissolved in a minimum amount of ACN and precipitated by adding the solution to MTBE with stirring three times and the resulting gummy solid was placed under high vacuum to give a yellow foam (16.62 g, 103% yield).

[0176] LRMS(ESI) + m / z:602.

[0177] [ka] 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((3-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate

[0178] Prepared using a procedure similar to that used to prepare 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((3-(2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetoxy)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate.

[0179] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((3-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate (16.62 g, 22.1 mmol) gave 10.83 g of crude product (78.4% yield).

[0180] A sample of this product (2.50 g) was purified using silica gel (25 g) and DCM-20% methanol / DCM as the eluent to give 1.15 g of purified product.

[0181] LRMS(ESI) + m / z: 476; 1 H NMR (DO) δ 9.70 (1H,s), 9.27 (1H,d), 9.03 (1H,s), 8.24 (1H, doublet of doublets), 7.82 (1H,s), 6.20 (1H,d), 4.50-4.44 (4H,m), 4.32 (1H,t), 4.13 (1H,t), 4.00 (1H, doublet of doublets), 3.98 (1H, doublet of doublets), 3.82 (3H,s), 2.98 (3H,s), 2.16 (2H,t).

[0182] Example 5P [ka]

[0183] Compound 5P ((2R,3S,4R,5R)-5-(3-((3-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)propoxy)carbonyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate

[0184] This was prepared using a modification of the procedure for the synthesis of compound 9P.

[0185] Compound 5 (2.5 g, 4.00 mmol) was reacted with a solution of phosphorus oxychloride (1.23 g, 8.00 mmol) in dry trimethyl phosphate (15 mL) at 0° C. for 7 hours. The reaction was quenched with water (3.36 g, 24.0 mmol) and neutralized with triethylamine (2.43 g, 24.0 mmol). The reaction mixture was added dropwise to isopropanol (400 mL) and the resulting precipitate was isolated by filtration and washed with isopropanol followed by MTBE. Upon drying, 2.00 g of crude product was obtained, a portion of which was purified by chromatography on a 40 g C-18 reverse phase column using a 5-30% methanol / water solvent gradient. This afforded 330 mg of purified product.

[0186] LRMS(ESI) + m / z: 556.1; 1 H NMR(D2O)δ9.44(s,1H),9.33(d,1H),9.01(d,1H),8.25(m,1H),7.80(s,1H),6.13(d,1H),4.59(m ,1H),4.49(m,3H),4.39(m,1H),4.21(m,1H),4.13(m,3H),3.81(s,3H),3.36(s,3H),2.16(m,2H).

[0187] Example 6 [ka]

[0188] compound 6 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((3-(2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)acetoxy)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate [ka]

[0189] 2-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)acetate 3-chloropropyl

[0190] 2-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)acetic acid (2.40 g, 10.1 mmol) was added to a 200 mL single neck 24 / 40 round bottom flask equipped with a magnetic stir bar and a 24 / 40 rubber septum. The flask was evacuated and placed under argon. Chloroform (25 mL) was added via syringe followed by thionyl chloride (3.44 g, 29 mmol) dropwise via syringe. A catalytic amount of dry DMF (1 mL) was then carefully added and the mixture was gently heated in a 60° C. oil bath. After 1 h the reaction was concentrated in vacuo and coevaporated with chloroform (25 mL) to give an orange glass. Additional chloroform (25 mL) was added to dissolve the glass and 3-chloropropanol (1.02 g, 10.8 mmol) was added via syringe. Triethylamine (2.04 g, 20.2 mmol) was added via syringe and an exotherm was observed during the second half of the addition and the color deepened to deep orange. The reaction was allowed to stir at room temperature for 48 hours and then quenched with saturated sodium bicarbonate (50 mL). The layers were separated and the organic phase was dried over sodium sulfate, decanted and concentrated in vacuo to give 3.6 g of crude product. This was purified using silica gel (40 g) eluting with DCM followed by EtOAc. This gave 1.90 g (60%) of product.

[0191] LRMS(ESI) + m / z:315.

[0192] [ka] 3-(2-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)acetoxy)propyl nicotinate was prepared from the above chloride in a similar manner as 3-(2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetoxy)propyl nicotinate, except that once complete the reaction was concentrated in vacuo, dissolved in DCM and filtered to give a glass, 2.77 g of crude product. This was purified utilizing silica gel (30 g) and DCM-4% MeOH / DCM as the eluent. Fractions were collected to give 1.90 g of product upon concentration.

[0193] LRMS(ESI) + m / z:402

[0194] [ka] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((3-(2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)acetoxy)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate was prepared in a similar manner to 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate, except that the reaction took 2 hours to complete. 3-(2-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)acetoxy)propyl nicotinate (1.90 g, 4.73 mmol) was reacted with a solution of β-D-ribofuranose-1,2,3,5-tetraacetate (1.51 g, 4.73 mmol) in dry dioxane (24 mL) and trimethylsilyl trifluorosulfonate (2.32 g, 10.4 mmol) was added dropwise. Workup as described above gave 4.32 g (113%) of crude product.

[0195] LRMS(ESI) + m / z:660.

[0196] [ka] 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((3-(2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)acetoxy)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate

[0197] Prepared in a similar manner as 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((3-(2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetoxy)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate.

[0198] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((3-(2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)acetoxy)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate (3.83 g, 4.73 mmol) was reacted in cold (2-6 °C) methanolic HCl for 18 h. After precipitation by addition of MTBE (120 mL), it was decanted, dissolved in a minimum amount of cold methanol, reprecipitated with MTBE (twice), and the resulting residue was placed under high vacuum to give 1.99 g (61.9%) of crude product. This was purified using silica gel (30 g) and DCM-20% methanol / DCM as the eluent to give 0.665 g of purified product.

[0199] LRMS(ESI) + m / z 534; 1 H NMR (DO) δ 9.96 (1H,s), 9.30 (1H,d), 9.07 (1H,d), 8.29 (1H, doublet of doublets), 7.98 (1H,s), 6.23 (1H,d), 5.19 (2H,s), 4.48-4.44 (2H,m), 4.41-4.38 (4H,m), 4.44 (1H,t), 4.02 (1H, doublet of doublets), 3.86 (1H, doublet of doublets), 3.51 (3H,s), 3.21 (3H,s), 2.16 (2H,m).

[0200] Example 6P [ka]

[0201] Compound 6P ((2R,3S,4R,5R)-5-(3-((3-(2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)acetoxy)propoxy)carbonyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate

[0202] It is prepared using a modification of the procedure for the synthesis of compound 9P.

[0203] Example 7 [ka]

[0204] compound 7 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((2-(3-methyl-2,6-dioxo-7-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate [ka]

[0205] 3-Methyl-7-propyl-3,7-dihydro-1H-purine-2,6-dione was synthesized as follows: 3-Methylxanthine (15.0 g, 90.3 mmol) and potassium carbonate (ground, 12.48 g, 90.3 mmol) were combined in a 200 mL, single-necked, round-bottom flask equipped with a magnetic stir bar and a 24 / 40 rubber septum, and the contents were placed under argon. Dry DMF (120 mL) was added via syringe, and the reaction was heated in a 70° C. oil bath for 10 minutes. 1-Iodopropane was added dropwise to the reaction mixture over 10 minutes, and after 1 hour, an additional 1.75 g (10.3 mmol) of 1-iodopropane was added dropwise, followed after 40 minutes by the addition of an additional 1.2 g (8.7 mmol) of ground potassium carbonate. After an additional hour, an additional 1.00 g (7.24 mmol) of ground potassium carbonate was added and the reaction was continued in a 70° C. oil bath for 18 hours. The reaction mixture was removed from the oil bath, filtered while warm, and the filtrate was concentrated in vacuo to give a white solid. This solid was washed with DMF, and then the product was recrystallized from ethanol / water after the solid was kept under high vacuum. This gave 8.28 g (44% yield) of product.

[0206] LRMS(ESI) + m / z 209.

[0207] [ka] 1-(2-Hydroxyethyl)-3-methyl-7-propyl-3,7-dihydro-1H-purine-2,6-dione was synthesized in a similar manner to 1-(2-hydroxyethyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione.

[0208] 3-Methyl-7-propyl-3,7-dihydro-1H-purine-2,6-dione (6.24 g, 30 mmol) was combined with potassium carbonate (ground, 4.14 g, 30 mmol), dry DMF (60 mL) was added and this was heated in a 100° C. oil bath for 2 hours. 2-Iodoethanol (5.16 g, 30 mmol) was added dropwise to the room temperature reaction mixture over 10 minutes. After 30 minutes it was placed back in a 100° C. oil bath and heated for an additional hour. An additional 0.90 g (5.2 mmol) of 2-iodoethanol was added dropwise to the hot reaction. The reaction was heated for an additional 2 hours, after which it was hot filtered and the filtrate concentrated in vacuo. The residue was co-evaporated with toluene (3×30 mL) to give 3.31 g of a white solid (43.8% yield).

[0209] LRMS(ESI) + m / z 253.

[0210] [ka] 2-(3-Methyl-2,6-dioxo-7-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl nicotinate was prepared in a similar manner to 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethyl nicotinate. Xanthine (3.23 g, 12.8 mmol), nicotinic acid (1.61 g, 13.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.58 g, 13.44 mmol), and dimethylaminopyridine (0.313 g, 2.56 mmol) were combined and DCM (30 mL) was added. The reaction was stirred and heated to reflux briefly (5 min) under argon and then allowed to stir at room temperature. An additional 0.5 g (2.61 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added, followed by an additional 0.22 g (0.87 mmol) of xanthine. After an additional 2.5 h, saturated sodium bicarbonate (30 mL) was added and the biphasic reaction was stirred for 10 min. The layers were separated and the organic phase was rewashed three times with bicarbonate solution. It was then dried over sodium sulfate, decanted, and concentrated in vacuo to give 4.91 g (107% yield) of a glass.

[0211] LRMS(ESI) + m / z.358

[0212] [ka] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((2-(3-methyl-2,6-dioxo-7-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate was prepared in a similar manner as 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate. 2-(3-Methyl-2,6-dioxo-7-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl nicotinate (4.57 g, 12.8 mmol) and β-D-ribofuranose-1,2,3,5-tetraacetate (4.28 g, 13.4 mmol) were placed in a 200 mL single neck round bottom flask equipped with a magnetic stir bar and a 24 / 40 rubber septum under argon. Dry dioxane (24 mL) was added via syringe followed by trimethylsilyl trifluoromethanesulfonate (3.13 g, 14.1 mmol) dropwise via syringe. After stirring at room temperature for 18 hours, saturated sodium bicarbonate (20 mL) and DCM (40 mL) were added and this was stirred for 10 minutes. The layers were separated and the lower organic phase was dried over sodium sulfate, decanted and concentrated in vacuo to give a yellow foam (10.22 g, 104% yield).

[0213] LRMS(ESI) + m / z 616

[0214] [ka] 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((2-(3-methyl-2,6-dioxo-7-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate

[0215] Prepared in a similar manner as 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((3-(2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetoxy)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate.

[0216] A cold HCl / methanol solution was prepared by carefully adding acetyl chloride (6.03 g, 76.8 mmol) to cold dry methanol (50 mL) under argon over 10 min. This solution was added to cold foamed 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((2-(3-methyl-2,6-dioxo-7-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate (9.80 g, 12.8 mmol) and the resulting solution was stirred in an ice-water bath for 10 min before being placed in the refrigerator (5° C.) for 18 h. MTBE (120 mL) was added, resulting in precipitation of the product. The solvent was decanted and the thick syrup was dissolved in a minimum amount of cold methanol and MTBE was again used to precipitate the product, which was repeated two more times until a solid was obtained, which was dried in vacuum to give 4.55 g (55.6% yield) of product.

[0217] LRMS(ESI) + m / z 490; 1 H NMR(D2O)δ9.75(1H,s),9.28(1H,d),9.01(1H,d),8.27(1H,m),7.94(1H,s),6.22(1H,d),4.78-4.74(1H,m),4.70-4.63(1H,m),4.44-4. 43(1H,t),4.41-4.33(3H,m),4.30(1H,t),4.12(2H,t),3.83(1H,double line of double line),3.77(1H,double line of double line),3.45(3H,s),1.62(2H,m),0.71(3H,t).

[0218] Example 7P [ka]

[0219] Compound 7P ((2R,3S,4R,5R)-3,4-dihydroxy-5-(3-((2-(3-methyl-2,6-dioxo-7-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium-1-yl)tetrahydrofuran-2-yl)methyl hydrogen phosphate

[0220] 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((2-(3-methyl-2,6-dioxo-7-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate (2.00 g, 3.12 mmol) was placed in a 100 mL single neck round bottom flask equipped with a magnetic stir bar under argon. TMP (12 mL) was added via syringe and the tan heterogeneous solution was cooled in an ice water bath for 10 min. The reaction mixture was degassed and placed under argon. Phosphorus oxychloride (0.960 g, 6.26 mmol) was added dropwise over 4 min. After 7.5 h, water (1.65 mL, 91.7 mmol) was carefully added dropwise over 10 min. The reaction was stirred in the cold bath for 5 minutes and then placed in the refrigerator (5° C.) overnight. Triethylamine (2.62 mL, 1.90 g, 18.8 mmol) was added to isopropyl alcohol (175 mL) in a 250 mL Erlenmeyer flask, which was cooled in an ice-water bath. After 10 minutes, the cold reaction mixture was added dropwise over 10 minutes to the isopropyl alcohol solution. This resulted in a precipitate. After stirring for 1 hour, the solution was filtered and the solid was washed with isopropyl alcohol followed by MTBE. The solid was dried to give 1.43 g of crude product. This was purified using reverse phase chromatography in a similar manner as ((2R,3S,4R,5R)-5-(3-((3-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)propoxy)carbonyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate.

[0221] LRMS(ESI)+ m / z.570.1

[0222] Example 8 [ka]

[0223] compound 8 [ka]

[0224] Compound 8P [ka] 3-Methyl-7-pentylxanthine was synthesized as follows: 3-Methylxanthine (2.00 g, 12.0 mmol) and cesium carbonate (3.92 g, 12.03 mmol) were placed in a 100 mL, single neck, round bottom flask equipped with an egg shaped magnetic stir bar and placed under argon. DMSO (25 mL) was added via syringe and the reaction mixture was degassed, placed under argon, and then stirred. This was placed in a 120° C. oil bath for 3 hours. The reaction was removed from the heating bath and allowed to cool to room temperature. 1-Iodopentane (1.57 mL, 2.38 g) was added dropwise over 3 minutes. The reaction was placed in an 83° C. oil bath for 30 minutes. At this point an additional 0.313 mL (0.5 g) of 1-iodopentane was added and the reaction was allowed to cool to room temperature. After 1.5 hours, methyl t-butyl ether (10 mL) and dichloromethane (70 mL) were added to give a solid and a liquid phase. It was filtered and the filtrate was concentrated in vacuo to give a thick liquid. It was poured into water (150 mL) to give a solid. After 30 minutes, the solid was isolated by filtration, washed with water and dried in vacuo. The solid was recrystallized from ethanol / water to give 1.68 g of product (59% yield).

[0225] 1 HNMR(DMSO-d6)δ11.1(s,1H),8.05(s,1H),4.20(t,2H),3.35(s,3H),1.77(quintet,2H),1.28(m,2H),1.19(m,2H),0.85(t,3H);LRMS(ESI) + m / z 237.

[0226] 1-Hydroxyethyl-7-pentyl-3-methylxanthine [ka] 3-Methyl-7-pentylxanthine (3.50 g, 14.8 mmol) and Cs2CO3 (6.08 g, 18.7 mmol) were placed in a 100 mL single neck round bottom flask equipped with an egg shaped magnetic stir bar and placed under argon. DMSO (25 mL) was added via syringe and the reaction mixture was degassed, placed under argon and then stirred. This was placed in a 120° C. oil bath for 3 hours. The reaction was removed from the heating bath and allowed to cool to room temperature. 2-Iodoethanol (1.57 mL, 2.38 g) was added dropwise over 3 minutes. The reaction was placed in an 83° C. oil bath for 30 minutes. At this point an additional 0.313 mL (0.5 g) of 2-iodoethanol was added and the reaction was allowed to cool to room temperature. After 1.5 hours, methyl t-butyl ether (10 mL) and dichloromethane (70 mL) were added to give a solid and liquid phase. This was filtered and the filtrate was concentrated in vacuo to give a thick liquid. This was poured into water (150 mL) to give a solid. After 30 minutes, the solid was isolated by filtration, washed with water and dried in vacuo. The solid was recrystallized from ethanol / water to give 1.68 g of product (59% yield).

[0227] 1 HNMR(DMSO-d6)δ11.1(s,1H),8.05(s,1H),4.20(t,2H),3.35(s,3H),1.77(quintet,2H),1.28(m,2H),1.19(m,2H),0.85(t,3H).LRMS(ESI) + m / z 281. [ka]

[0228] The reaction was carried out with 1-hydroxyethyl-7-pentyl-3-methylxanthine (3.90 g, 13.9 mmol), nicotinic acid (1.80 g, 14.6 mmol), EDAC.HCl (2.95 g, 15.4 mmol), and dimethylaminopyridine (0.170 g, 1.39 mmol) following the procedure described for hydroxymethyldimethylxanthine using dichloromethane as solvent.

[0229] Yield=87%; MS+=386. [ka]

[0230] The reaction was carried out with 2-(3-methyl-2,6-dioxo-7-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl nicotinate (4.66 g, 12.10 mmol); 1,2,3,5-tetraacetylribose (4.04 g, 12.70 mmol), and trimethylsilyl trifluoromethylsulfonate (2.96 g, 13.31 mmol) according to the procedure described for 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((3-(2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetoxy)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate.

[0231] Yield = 95%; LRMS (ESI) + m / z 644.6. [ka]

[0232] Compound 8. This reaction was carried out in a manner similar to that used to prepare 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((3-(2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetoxy)propoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate. in the same manner as above with 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((2-(3-methyl-2,6-dioxo-7-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium (9.00 g, 11.35 mmol) and acetyl chloride (6.60 g, 84.0 mmol).

[0233] Yield = 69%; LRMS (ESI) + m / z 518.22. [ka]

[0234] Compound 8P. This reaction was carried out in a manner similar to that used to prepare ((2R,3S,4R,5R)-5-(3-((2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate to give 1-((2R, 3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((2-(3-methyl-2,6-dioxo-7-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium (3.00 g, 4.50 mmol) and phosphorus oxychloride (1.38 g, 9.00 mmol). Yield=25.2%.

[0235] 1H NMR(D2O)δ9.43(s,1H),9.33(d,1H),8.97(d,1H),8.27(double of doublets,1H),7.90(s,1H),6.15(d,1H),4.71(m,1H),4.64(m,1H) ,4.55(bt,1H),4.48(t,1H),4.38(m,3H),4.14(bt,2H),4.08(m,2H),3.43(s,3H),1.62(m,2H),1.10(m,4H),0.71(bt,3H); 31 P NMR(DO)δ-0.26

[0236] LRMS(ESI) + m / z 598.0.

[0237] Example 9 [ka]

[0238] compound 9 [ka]

[0239] Compound 9P ((2R,3S,4R,5R)-5-(3-((2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)carbamoyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate [ka]

[0240] 1-(2-Chloroethyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione was synthesized as follows: 1-(2-Hydroxyethyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (7.00 g, 31.25 mmol) was added to a 500 mL single neck round bottom flask and placed under argon. Dry dioxane (150 mL) was added via syringe and the heterogeneous solution was stirred. Triethylamine (3.48 g, 34.4 mmol) was added followed by methanesulfonyl chloride (3.75 g, 32.8 mmol) dropwise over 5 minutes. The reaction was heated in a 70° C. bath overnight (16 hours). The reaction was concentrated in vacuo and the resulting solid was washed with water and then dried in vacuo. The reaction was incomplete and the solid was placed in a 200 mL round bottom flask and dry dioxane (25 mL) was added. This was stirred and 0.35 g (3.46 mmol) of triethylamine was added followed by 0.38 g of methanesulfonyl chloride (3.32 mmol) to the stirred reaction mixture. This was heated again in a 70° C. bath for 2 hours. The reaction was then concentrated in vacuo and the solid was washed with water followed by MTBE and dried in vacuo to give 6.12 g (80.9% yield) of 1-(2-chloroethyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione.

[0241] LRMS(ESI) + m / z 243. [ka]

[0242] 1-(2-Azidoethyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione was synthesized as follows: 1-(2-Chloroethyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (6.12 g, 24.6 mmol) and sodium azide (1.65 g, 25.3 mmol) were placed in a 200 mL round bottom flask equipped with a magnetic stir bar, dry DMF (30 mL) was added via syringe, and the reaction was placed under argon and heated in a 120° C. oil bath for 1.5 hours. The reaction mixture was hot filtered and the filtrate was concentrated in vacuo to give a white solid (6.30 g, 100% yield).

[0243] LRMS(ESI) + m / z 250.1. [ka]

[0244] 1-(2-aminoethyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione was synthesized as follows: 1-(2-azidoethyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (6.30 g, 25.3 mmol) and triphenylphosphine (6.97 g, 26.6 mmol) were placed in a 200 mL single neck round bottom flask equipped with a magnetic stir bar under argon. Dry THF (80 mL) was added and stirred. This was heated in a 50° C. water bath for 1 hour until it foamed. Water (4.77 g, 265 mmol) was added dropwise to the reaction over 5 minutes and the water bath temperature was increased to 75° C. After 1.5 hours the reaction was concentrated in vacuo to give a gummy solid. The solid was treated with hot water until only a small amount of solid was present. It was filtered hot and the filtrate was concentrated in vacuo to give 5.23 g of slightly impure product, which was sufficiently pure for use in the next reaction.

[0245] LRMS(ESI) + m / z 224. [ka]

[0246] N-(2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)nicotinamide was synthesized as follows: 1-(2-aminoethyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (1.65 g, 7.40 mmol), nicotinic acid (1.35 g, 10.97 mmol), and 3-(3-dimethylaminopropyl)-1-ethyl-carbodiimide hydrochloride (2.21 g, 11.53 mmol) were placed in a 200 mL single neck round bottom flask equipped with a magnetic stir bar under argon. Dry dioxane (30 mL) was added via syringe and allowed to stir. Triethylamine (1.10 g, 10.9 mmol) was added via syringe and the reaction was allowed to stir at room temperature overnight. The reaction mixture was concentrated in vacuo, dissolved in CHCl3, and washed with saturated NaHCO3 and saturated NaCl. The combined aqueous phase was back-extracted with CHCl3 and combined with the previous organic phase. The organic phase was dried over Na2SO4, decanted, and concentrated in vacuo to give 3.81 g of a glass. This was dissolved in DCM and purified using 75 g of silica gel and a gradient of 0-20% methanol / DCM. The product fractions were collected and concentrated in vacuo to give 1.28 g of product (52.7% yield).

[0247] LRMS(ESI) + m / z 329.1. [ka]

[0248] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)carbamoyl)pyridin-1-ium trifluoromethanesulfonate was synthesized as follows: N-(2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)nicotinamide (2.73 g, 8.22 mmol) and 1,2,3,5-tetraacetyl-bD-ribofuranose (2.91 g, 9.16 mmol) were added to a 500 mL single-neck round-bottom flask with a magnetic stir bar and placed under argon. Dry dioxane (30 mL) and DCM (45 mL) were added. Trimethylsilyl trifluoromethanesulfonate (2.14 g, 9.62 mmol) was added dropwise to the stirred reaction over 3 min. The reaction was stirred at room temperature for 6.5 h. Saturated NaHCO3 (30 mL) was added and this was stirred for 5 min. The layers were separated and the organic phase was washed with saturated NaCl solution (15 mL). The combined aqueous solutions were back-extracted with DCM and the combined organic phase was dried over Na2SO4. The solution was decanted and concentrated in vacuo to give a quantitative yield of the product. This material was carried forward to the next reaction without further purification.

[0249] LRMS(ESI) + m / z 587.2. [ka]

[0250] 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)carbamoyl)pyridin-1-ium trifluoromethanesulfonate was synthesized as follows: Anhydrous methanol (30 mL) was added via syringe to a 100 mL single neck round bottom flask equipped with a magnetic stir bar under argon. This was placed in an ice / water bath for 10 minutes and acetyl chloride (3.59 g, 45.7 mmol) was added dropwise via syringe. 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)carbamoyl)pyridin-1-ium trifluoromethanesulfonate in a 200 mL single neck round bottom flask equipped with a magnetic stir bar under argon was placed in a -25°C freezer for 10 minutes. Once the cold HCl / methanol solution was ready (5 minutes after the acetyl chloride was added), it was added in one portion to the cold foam of starting material. This was stirred in an ice water bath for 10 minutes and placed in the refrigerator (5°C) overnight (16 hours). The reaction was removed from the refrigerator and placed in an ice water bath and MTBE (150 mL) was added in a small portion-wise stream to the mixture resulting in a gum of product. The solvent was decanted from the gum, which was dissolved in methanol (30 mL) and an additional portion of MTBE was added with similar results. After decanting, the gum was dissolved in methanol (30 mL) and this solution was added dropwise to well-stirred MTBE (150 mL) to give 3.65 g of a nice solid (72.7% yield) after drying.

[0251] LRMS(ESI) + m / z.461.2. [ka]

[0252] ((2R,3S,4R,5R)-5-(3-((2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)carbamoyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate was synthesized as follows. 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)carbamoyl)pyridin-1-ium trifluoromethanesulfonate (3.00 g, 4.91 mmol) was placed in a 200 mL single neck round bottom flask equipped with a magnetic stir bar under argon and the flask was placed in an ice water bath. Dry cold (refrigerator) TMP (15 mL) was added via syringe to give a heterogeneous solution to which phosphorus oxychloride (1.51 g, 9.83 mmol) was added dropwise via syringe over 8 min. After 4 h, triethylamine (0.248 g, 2.5 mmol) was added dropwise. After 1 hour, water (2.65 g, 147 mmol) was slowly added dropwise to the cold reaction mixture. The reaction was stirred in the cold bath for 10 minutes and then placed in a -25°C freezer overnight. A solution of triethylamine (2.73 g, 27.0 mmol) in isopropyl alcohol (12 mL) was prepared and added dropwise to the cold reaction. This gave a heterogeneous solution with a pH of 3.0. After 30 minutes, the solid was filtered off and washed with isopropyl alcohol (30 mL) followed by MTBE (20 mL). The solid was dried in vacuo to give 4.46 g of crude product. A portion of this was purified using a 40 g reverse phase column with a gradient of 0-30% methanol / water. The appropriate fractions were collected, concentrated in vacuo and the resulting solid was lyophilized to give 0.530 g of product.

[0253] LRMS(ESI) + m / z.541.2.

[0254] Example 10 [ka]

[0255] compound 10 [ka]

[0256] Compound 10P ((2R,3S,4R,5R)-3,4-dihydroxy-5-(3-((2-(7-(1-methoxy-1-oxopropan-2-yl)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)ethoxy)carbonyl)pyridin-1-ium-1-yl)tetrahydrofuran-2-yl)methyl hydrogen phosphate

[0257] 3-Methyl-3,7-dihydro-1H-purine-2,6-dione (8.00 g, 48.2 mmol) and potassium carbonate (crushed, 6.66 g, 48.2 mmol) were placed in a 200 mL single neck round bottom flask with a magnetic stir bar and placed under argon. Dry DMF (80 mL) was added and the heterogeneous reaction mixture was placed in a 100° C. oil bath for 2 hours. It was removed from the oil bath and placed in a room temperature water bath for 10 minutes. Potassium iodide (crushed, 8.00 g, 48.2 mmol) was added and then 2-chloromethylpropionate (5.90 g, 48.2 mmol) was added dropwise to the stirred cooled reaction. It was stirred for 5 minutes and placed in a 100° C. oil bath and the reaction was allowed to continue for 1.25 hours. The reaction was removed from the hot oil bath and cooled to room temperature. It was filtered and the filtrate was concentrated in vacuo to give a solid. The solid was washed with MTBE and dried in vacuum. The solid was washed with water (20 mL), filtered and rinsed with additional water. The solid was co-evaporated with acetonitrile (20 mL) and dried in vacuum to give 7.80 g of product (64.2% yield).

[0258] LRMS(ESI) + m / z.253.1. [ka]

[0259] Methyl 2-(1-(2-hydroxyethyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)propanoate was synthesized as follows: Methyl 2-(3-methyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)propanoate (3.5 g, 13.9 mmol) and potassium carbonate (ground, 1.92 g, 13.9 mmol) were placed in a 200 mL single neck round bottom flask with a magnetic stir bar and placed under argon. Dry DMF (35 mL) was added via syringe and the heterogeneous reaction was placed in an 85° C. oil bath for 1 h. The reaction was cooled in an ice-water bath for 5 min and 2-chloroethanol (1.12 g, 13.9 mmol) was added dropwise over 3 min. It was then placed back into the 85° C. oil bath for 2 h. It was removed from the oil bath and allowed to cool to room temperature. An additional portion of 2-chloroethanol (0.55 g) was added and the reaction was allowed to continue in the 85° C. bath overnight. The reaction was filtered hot and the filtrate was concentrated in vacuo to give a glass. The glass was co-evaporated with methanol and acetonitrile to give 4.61 g of product which was used without further purification.

[0260] LRMS(ESI) + m / z.297.1. [ka]

[0261] 2-(7-(1-Methoxy-1-oxopropan-2-yl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl nicotinate was synthesized as follows: Methyl 2-(1-(2-hydroxyethyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)propanoate (4.61 g, 15.6 mmol), nicotinic acid (1.92 g, 15.6 mmol), 3-(3-dimethylaminopropyl)-1-ethyl-carbodiimide hydrochloride (3.30 g, 17.2 mmol), and dimethylaminopyridine (0.19 g, 1.56 mmol) were combined in a 200 mL single neck round bottom flask equipped with a magnetic stir bar and placed under argon. DCM (40 mL) was added and the reaction was stirred at room temperature. After 2 days the reaction was not complete and two more portions of 3-(3-dimethylaminopropyl)-1-ethyl-carbodiimide hydrochloride were added (1.21 g, then another 1.0 g after 2 hours). The reaction was stirred overnight and worked up by adding saturated NaHCO3 (2 x 30 mL). The organic phase was dried over Na2SO4, decanted, and concentrated in vacuo to give a glass. The reaction was not complete so further portions of nicotinic acid (0.94 g, 7.64 mmol), 3-(3-dimethylaminopropyl)-1-ethyl-carbodiimide hydrochloride (1.65 g, 8.61 mmol), and dimethylaminopyridine (0.133 g, 1.09 mmol) were added to the residue and DCM (50 mL) was added. After 1 hour the reaction was complete and saturated NaHCO3 (4 x 15 mL) was used to wash the reaction mixture. The DCM solution was dried using sodium sulfate, decanted, and concentrated in vacuo to give 6.12 g of crude product, which was purified using 50 g of silica gel and 0-2% MeOH DCM elution solvent to give 3.07 g of product (49% yield).

[0262] LRMS(ESI) + m / z.402.1. [ka]

[0263] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((2-(7-(1-methoxy-1-oxopropan-2-yl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate was synthesized as follows. 2-(7-(1-Methoxy-1-oxopropan-2-yl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl nicotinate (3.07 g, 7.65 mmol) and 1,2,3,5-tetraacetyl-bD-ribofuranose (2.56 g, 8.03 mmol) were added to a 300 mL single neck round bottom flask with a magnetic stir bar and placed under argon. DCM (40 mL) was added and the reaction was stirred. Trimethylsilyl trifluoromethanesulfonate (1.87 g, 8.42 mmol) was added dropwise to the stirred reaction over 3 min. After 4.5 hours the reaction was not complete and 1,2,3,5-tetraacetyl-bD-ribofuranose (0.200 g, 0.63 mmol) was added followed by trimethylsilyl trifluoromethanesulfonate (0.184 g, 0.83 mmol) and the reaction was allowed to stir overnight. Saturated NaHCO3 (2 x 20 mL) was used to wash the organic reaction mixture which was dried over sodium sulfate. The solution was decanted from the solids and concentrated in vacuo to give a quantitative yield of impure product.

[0264] LRMS(ESI) + m / z.598.2. [ka]

[0265] 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((2-(7-(1-methoxy-1-oxopropan-2-yl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate was synthesized as follows. 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((2-(7-(1-methoxy-1-oxopropan-2-yl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate (6.51 g, 7.65 mmol) in a 200 mL single neck round bottom flask with a magnetic stir bar under argon was placed in a -25°C freezer. Anhydrous methanol (40 mL) was added via syringe to a 100 mL single neck round bottom flask equipped with a magnetic stir bar under argon. This was placed in an ice / water bath for 10 minutes and acetyl chloride (3.82 g, 48.7 mmol) was added dropwise via syringe over 5 minutes. This solution was added all at once to the cold flask containing the substrate, which was stirred in an ice-water bath for 10 minutes and then placed in a 5° C. refrigerator overnight. The resulting solution was added over 30 minutes to a well-stirred solution of MTBE (350 mL) in a 500 mL Erlenmeyer flask. This gave a nice solid which was allowed to settle and washed with two portions of MTBE, and the resulting solid was placed in a 300 mL single-neck round bottom flask and placed under high vacuum to give 4.72 g of product.

[0266] LRMS(ESI) + m / z.534.2. [ka]

[0267] ((2R,3S,4R,5R)-3,4-Dihydroxy-5-(3-((2-(7-(1-methoxy-1-oxopropan-2-yl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium-1-yl)tetrahydrofuran-2-yl)methyl hydrogen phosphate was synthesized as follows. 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((2-(7-(1-methoxy-1-oxopropan-2-yl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate (4.00 g, 5.85 mmol) was placed in a 200 mL single neck round bottom flask and a magnetic stir bar was added. This was placed under argon and in an ice water cooling bath. Dry TMP (24 mL) was added via syringe and this was stirred for 10 minutes to give a pale yellow homogenous solution. Phosphorus oxychloride (1.79 g, 11.70 mmol) was added dropwise over 6 minutes. After 3.5 hours, triethylamine (0.301 mg, 2.97 mmol) was added dropwise. After an additional 1.5 hours, the reaction was deemed complete by HPLC and water (2.11 g, 117 mmol) was added dropwise over 10 minutes. The reaction was stirred in the cold bath for an additional 5 minutes and then placed in a 5° C. refrigerator overnight. The reaction was placed in an ice-water bath. Triethylamine (3.25 g, 32.1 mmol) was dissolved in dry dioxane (50 mL) and added slowly to the reaction mixture over 15 minutes. The reaction was stirred in the cold bath for 1 hour and then allowed to warm to room temperature and the pH was 3.0. The solid was filtered and washed with dioxane, MTBE. An oil appeared in the filtrate. As the solid isolated was not the desired product, sufficient MTBE was added to the filtrate to completely remove the oil from the product (200 mL). The liquid was decanted from the resulting oil, which was washed with MTBE (2 times). The oil was treated with IPA (50 mL) to give a solid, which was broken up with a spatula and then stirred using a magnetic stir bar for 30 minutes. The solid was isolated by filtration, washed with IPA, then MTBE, and dried in vacuo to give 3.60 g of crude product (quantitative yield).A portion of this was purified using a 40 g C-18 column using 5-30% methanol / water as the eluting solvent to give 120 mg of purified product.

[0268] LRMS(ESI) + m / z.614.1.

[0269] Example 11 [ka]

[0270] compound 11 [ka]

[0271] Compound 11P ((2R,3S,4R,5R)-5-(3-((2-(1,3-diethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethoxy)carbonyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate [ka]

[0272] 6-Amino-1,3-diethyl-5-nitrosopyrimidine-2,4(1H,3H)-dione was synthesized as follows: Diethylurea (11.6 g, 0.10 mol), cyanoacetic acid (8.50 g, 0.10 mol), and acetic anhydride (12.5 mL) were placed in a 200 mL single neck round bottom flask equipped with a magnetic stir bar. The flask was placed in an 80° C. oil bath and heated for 3 h. It was removed from the oil bath and concentrated in vacuo at 50° C. The resulting oil was coevaporated with toluene (4 times) to give a clear thick oil. 5% sodium hydroxide solution (50 mL) was added to the oil resulting in an exotherm and a thick precipitate. After 30 min, the reaction was placed in an ice-water bath for 15 min. Sodium nitrite (8.30 g, 0.12 mol) was dissolved in water (50 mL). Water (25 mL) was added to the thick reaction mixture to allow the mixture to stir. Sodium nitrite solution was added to the thick reaction mixture. Acetic acid (12.59 g, 0.21 mol) was added dropwise to the reaction. The reaction was transferred to a 500 mL round bottom flask and water (300 mL) was added to aid stirring. The reaction was allowed to stir at room temperature overnight. It was placed in an ice water bath for 30 minutes, then filtered and the solid was washed with water, a small amount of ethanol, then MTBE. The product was dried in vacuum to give 16.92 g of a deep purple solid. [ka]

[0273] 5,6-Diamino-1,3-diethylpyrimidine-2,4(1H,3H)-dione was synthesized as follows: 6-Amino-1,3-diethyl-5-nitrosopyrimidine-2,4(1H,3H)-dione (16.9 g, 79.7 mmol) was added to a 500 mL single neck round bottom flask equipped with a magnetic stir bar. Concentrated ammonium hydroxide (85 mL) was added and placed in a warm water bath to a temperature of 35° C. Sodium hydrosulfite (46.5 g, 267 mmol) was dissolved in water (211 mL). This solution was added to the stirred substrate solution over 20 minutes, after which the reaction was heated to near reflux for 20 minutes. After 1 hour, the reaction mixture was concentrated in vacuo at 30° C. until a large amount of solid was formed. The reaction mixture was cooled in an ice-water bath for 20 minutes and then filtered. The solid was washed with cold water and then MTBE. Drying under high vacuum gave 15.82 g of product.

[0274] LRMS(ESI) + m / z.199.1. [ka]

[0275] 1,3-Diethyl-3,7-dihydro-1H-purine-2,6-dione was synthesized as follows: 5,6-Diamino-1,3-diethylpyrimidine-2,4(1H,3H)-dione (4.00 g, 20.2 mmol) was added to a 100 mL single neck round bottom flask equipped with a magnetic stir bar and placed under argon. Dry DMF (20 mL) was added via syringe followed by trimethyl orthoformate (40 mL). The solution was stirred and placed in a 95° C. oil bath overnight. It was concentrated in vacuo and the resulting solid was recrystallized from water-isopropanol. This gave 2.25 g, 53.6% yield.

[0276] LRMS(ESI) + m / z.209. [ka]

[0277] 1,3-Diethyl-7-(2-hydroxyethyl)-3,7-dihydro-1H-purine-2,6-dione was synthesized as follows: 1,3-Diethyl-3,7-dihydro-1H-purine-2,6-dione (5.20 g, 25.0 mmol) and potassium carbonate (ground, 3.63 g, 26.3 mmol) and a magnetic stir bar were placed in a 200 mL single neck round bottom flask and placed under argon. Dry DMF (70 mL) was added via syringe and the stirred solution was heated in a 120° C. oil bath for 1 hour. The reaction was removed from the oil bath and allowed to cool for 15 minutes. 2-Chloroethanol (2.22 g, 26.3 mmol) was added to the reaction over 5 minutes using a syringe. The reaction was stirred for 10 minutes and then returned to the hot oil bath for 1 hour. It was hot filtered and the filtrate was concentrated in vacuo. This was co-evaporated with methanol, then acetonitrile, and the resulting solid was washed with MTBE to give 5.50 g, 87.3% yield.

[0278] LRMS(ESI) + m / z.253. [ka]

[0279] 2-(1,3-Diethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethyl nicotinate was synthesized as follows: 1,3-Diethyl-7-(2-hydroxyethyl)-3,7-dihydro-1H-purine-2,6-dione (1.26 g, 5.00 mmol), nicotinic acid (0.646 g, 5.25 mmol), 3-(3-dimethylaminopropyl)-1-ethyl-carbodiimide hydrochloride (1.06 g, 5.53 mmol), and dimethylaminopyridine (0.122 g, 1.00 mmol) were combined in a 100 mL single neck round bottom flask equipped with a magnetic stir bar and placed under argon. DCM (20 mL) was added via syringe and the reaction was stirred. After stirring overnight, the reaction was washed with saturated sodium bicarbonate solution (3×30 mL). The layers were separated and the organic phase was dried over sodium sulfate. The solution was decanted and concentrated in vacuo to give a tan foam (1.71 g, 95.5% yield).

[0280] LRMS(ESI) + m / z.358. [ka]

[0281] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((2-(1,3-diethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate was synthesized as follows: 2-(1,3-diethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethyl nicotinate (1.71 g, 4.79 mmol) and 1,2,3,5-tetraacetyl-bD-ribofuranose (1.60 g, 5.03 mmol) were added to a 100 mL single neck round bottom flask with a magnetic stir bar. DCM (20 mL) was added and the reaction was degassed and placed under argon. Trimethylsilyl trifluoromethanesulfonate (1.17 g, 5.27 mmol) was added dropwise over 2 min. After 7 h 20 min, the reaction was worked up by adding saturated sodium bicarbonate (20 mL) and the biphasic solution was stirred for 10 min. The phases were separated and the process was repeated. The organic phase was dried over sodium sulfate, decanted and concentrated in vacuo to give 3.66 g of product (quantitative yield).

[0282] LRMS(ESI) + m / z.616.2 [ka]

[0283] 3-((2-(1,3-diethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethoxy)carbonyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium trifluoromethanesulfonate was synthesized as follows. 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((2-(1,3-diethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethoxy)carbonyl)pyridin-1-ium trifluoromethanesulfonate (3.66 g, 4.79 mmol) was deprotected as described herein to give 2.68 g of product (87.6% yield).

[0284] LRMS(ESI) + m / z.490.2. [ka]

[0285] ((2R,3S,4R,5R)-5-(3-((2-(1,3-diethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethoxy)carbonyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate was synthesized as follows: 3-((2-(1,3-diethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethoxy)carbonyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium trifluoromethanesulfonate (1.00 g, 1.57 mmol) was phosphorylated using the procedure described herein to give 436 mg of crude product. This was purified using a 40 g C-18 column and a gradient of 5-30% methanol / water as eluent.

[0286] LRMS(ESI) + m / z.569.5.

[0287] Example B1: Biological testing Studies were conducted to assess the specificity of PDE4 inhibition by the compounds described herein, and the results are presented in FIG.

[0288] Controls in columns 1-4: 1) no inhibitor, 2) water, 3) RLPM 60 micromolar, 4) IBMX 60 micromolar. Columns 5-11 at 0.6 mM: 5) theophylline, 6) caffeine, 7) comparison compound, 8) NRCl, 9) compound 3, 10) compound 1, 11) compound 6. Columns 12-18 at 6 mM: 12) theophylline, 13) caffeine, 14) comparison compound, 15) NRCl, 16) compound 3, 17) compound 1, 18) compound 6.

[0289] IBMX is 3-isobutyl-1,7-bismethyl-xanthine. RLPM is rolipram. NRCl is nicotinamide riboside chloride. "No TRT" means no treatment.

[0290] Additional targets for enzyme inhibition include PDE1A1, PDE4A4B, and PDE5A1 at concentrations ranging from 0.4 mM to 10 mM.

[0291] Example B2: Biological testing Cisplatin-induced acute kidney injury (AKI) is an accepted model because it is rapid (72 hours), reproducible, similar to the human disease, and responsive to nicotinamide or NMN supplementation. The study design was 48 male C57BL / 6 mice randomized into six treatment groups (1-6) and subjected to cisplatin-induced AKI (cisplatin 25 mg / kg administered intraperitoneally on day 0) according to Tran et al., “PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection” Nature, 24 March 2016, vol 531, 528-532). Comparison and test compounds were gavaged 24 hours before injury and again at the time of injury, based on the protocol of Tran et al. The results are shown in Figure 2. The readouts from this study were (a) biliary urinary nitrogen (BUN), (b) serum creatinine (Cr), (c) histopathology of kidney sections assessed and graded for tubular necrosis, and (d) NAD concentration in the kidney. In each of (a)-(d), column 1 was cisplatin only, column 2 was niacinamide (Nam), column 3 was nicotinamide mononucleotide (NMN), and column 4 was compound 4.

[0292] Example B3: Biological testing Compounds were tested in the NAD cell assay according to the following protocol: Jurkat cells (50,000 in 100 microliters of RPMI medium) were added to wells of a 96-well conical bottom plate. The cells were allowed to recover in culture for 3 hours. A 16 microliter aliquot of 100 mM compound stock solution was diluted with 784 microliters of medium and 10% FBS to obtain 800 microliters of 2 mM compound treatment solution. Compound treatment solution was added to cells at a final compound concentration of 1 mM (n=6 wells per compound). As a parallel control, nicotinamide mononucleotide (NMN) was added to cells at a final concentration of 2 mM (n=6). Plates were incubated for 24 hours and then spun at 1000 rpm for 10 minutes. The medium was removed, then the cells were washed with fresh PBS and spun again. The PBS medium was removed, then the cells were washed once more with PBS and spun. Liquid was removed from each well using a pipette to avoid touching the cell pellet. Cells were lysed with 75 microliters of 0.5% DTAB. 25 microliters of lysate was added to each of two flat-bottom plates. One plate was used for BCA protein assay (clear) and the other plate was used for NAD assay (clear bottom, white wall). NAD concentration in each well was determined using a commercially available assay according to kit instructions (e.g., Promega NAD / NADH-Glo™ assay). Pierce BCA protein assay was performed according to kit instructions (e.g., ThermoScientific catalog number 23225). NAD levels were normalized to total protein and reported as fold of NAD levels in untreated cells.

[0293] Assays with other cell types were performed similarly using appropriate compound and NMN dilutions, with cell numbers adjusted as necessary to provide signals within the readout range of the protein and NAD assay kits.

[0294] The results of the NAD elevation assay are provided in the table below. [Table 1]

[0295] Incorporation by Reference All U.S. patents and U.S. and PCT published patent applications, and non-patent literature cited in this specification are herein incorporated by reference to the same extent as if each individual patent and publication was specifically and individually indicated to be incorporated by reference.

[0296] Equivalent While the foregoing written description of the invention will enable one of ordinary skill in the art to make and use what is presently considered to be its best mode, one of ordinary skill in the art will understand and appreciate the existence of variations, permutations, and equivalents to the specific embodiments, methods, and examples herein. Thus, the present invention should not be limited to the above-described embodiments, methods, and examples, but rather to all embodiments and methods within the scope and spirit of the present invention.

Claims

1. A compound having a structure represented by formula (I): 【Chemistry 1】 During the ceremony, Q is H or a phosphate group (-PO(OH) ２ or -PO(OH)(O － )) and Y is —NH— or —O—; L ２ is (C1-6) alkylene or 【Chemistry 2】 (In the formula, L ２ａ is alkylene, and R １ are each independently OH, O － , O-alkyl, NH-alkyl, or alkyl, Z is O or NH, n is 0 or 1, * is the point of attachment to the oxygen atom, and ** is the point of attachment to D; or Y and L ２ is absent, A compound, or a pharmaceutically acceptable salt thereof, wherein D is an optionally substituted xanthine.

2. The compound of claim 1, wherein Y is —O—.

3. The compound of claim 1 , wherein Y is —HN—.

4. L ２ａ The compound of claim 1 , wherein is (C1-3) alkylene.

5. L ２ａ The compound of claim 4, wherein is a C3 alkylene.

6. R １ are each OH or O － 2. The compound of claim 1, wherein:

7. The compound of claim 1 , wherein each Z is O.

8. 2. The compound of claim 1, wherein n is 1.

9. The compound of claim 1 , wherein n is 0.

10. Y and L ２ The compound of claim 1 , wherein is absent.

11. L ２ The compound of claim 1, wherein is (C1-6) alkylene or (C1-3) alkylene.

12. A compound having a structure represented by formula (II): 【Transformation 3】 During the ceremony, X is NH ２ or OH or O － and L １ but 【Chemistry 4】 (In the formula, R １ are each independently OH, O － , O-alkyl, NH-alkyl, or alkyl, Z is O or NH, n is 0 or 1, * is the point of attachment to the oxygen atom, and ** is the point of attachment to D; A compound, or a pharmaceutically acceptable salt thereof, wherein D is an optionally substituted xanthine.

13. X is OH or O － 13. The compound of claim 12, wherein:

14. X is NH ２ 13. The compound of claim 12, wherein:

15. R １ are each OH or O － 13. The compound of claim 12, wherein:

16. 13. The compound of claim 12, wherein each Z is O.

17. 13. The compound of claim 12, wherein n is 1.

18. 13. The compound of claim 12, wherein n is 0.

19. 10. The compound of claim 1, wherein D is an anti-inflammatory agent.

20. 2. The compound of claim 1, wherein D is a substituted xanthine.

21. 2. The compound of claim 1, wherein D is a methylxanthine.

22. 22. The compound of claim 21, wherein the methylxanthine is caffeine, theobromine, or theophylline.

23. 23. The compound of claim 22, wherein the methylxanthine is theobromine.

24. D is L at the 1st position of the xanthine ring. １ or L ２ The compound of claim 1 , wherein

25. D is L at the 3-position of the xanthine ring １ or L ２ The compound of claim 1 , wherein

26. D is L at the 7th position of the xanthine ring １ or L ２ The compound of claim 1 , wherein

27. D is represented by formula (III), 【Transformation 5】 During the ceremony, R １ , R ２ , R ３ , and R ４ are each independently H, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C3-7)cycloalkyl, aryl, heteroaryl, —C(═O)(C1-6)alkyl, C(═O)(O)(C1-6)alkyl, absent, or a point of attachment to L, with the proviso that R １ , R ２ , R ３ , and R ４ is the point of attachment, and R ４ is not absent or is the point of attachment to L, with the further proviso that the nitrogen to which it is attached is positively charged; R ５ is H, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C3-7)cycloalkyl, aryl, heteroaryl, or NR ６ R ７ and R ６ and R ７ 2. The compound of claim 1, wherein each is independently H, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, or aryl.

28. R １ and R ３ are each independently (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C3-7)cycloalkyl, aryl, heteroaryl, —C(═O)(C1-6)alkyl, C(═O)(O)(C1-6)alkyl, or the point of attachment to L.

29. R １ , R ２ , and R ３ are each independently (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C3-7)cycloalkyl, aryl, heteroaryl, -C(=O)(C1-6)alkyl, C(=O)(O)(C1-6)alkyl, or a point of attachment.

30. R １ , R ２ , R ３ , and R ４ 28. The compound of claim 27, wherein each is independently H, (C1-6) alkyl, or absent.

31. R １ , R ２ , R ３ , and R ４ 28. The compound of claim 27, wherein at least one of: is (C1-6) alkyl.

32. R １ , R ２ , R ３ , and R ４ At least one of the groups is —C(O)CH ３ 28. The compound of claim 27, wherein the alkyl is (C1-6) alkyl substituted with

33. R １ , R ２ , R ３ , and R ４ 28. The compound of claim 27, wherein at least one of is methyl.

34. R ４ 28. The compound of claim 27, wherein is H or absent.

35. R ５ is H or (C1-6) alkyl.

36. R ５ 36. The compound of claim 35, wherein is H.

37. R １ is the point of attachment to L.

38. R １ L ２ or L １ is the point of attachment to R ２ is CH ３ and R ３ is CH ３ and R ４ is absent, and R ５ 28. The compound of claim 27, wherein is H.

39. below: 【Transformation 6】 【change】 【change】 【change】 【change】 The compound of claim 1 having the structure of any one of or a pharmaceutically acceptable salt thereof.

40. A pharmaceutically acceptable salt of the compound of any one of claims 1 to 39, wherein the salt is H ＋ , Li ＋ , Na ＋ , K. ＋ , Mg ２＋ , and Ca ２＋ A pharmaceutically acceptable salt comprising a cation selected from:

41. A pharmaceutically acceptable salt of the compound of any one of claims 1 to 39, wherein the salt is an acetate, triflate, halide, trifluoroacetate, formate, H ２ P.O. ４ － , H.P.O. ４ ２－ , O.H. － , HSO ４ － , S.O. ４ ２－ , NO ３ － , HCO ３ － , and CO ３ ２－ A pharmaceutically acceptable salt comprising an anion selected from:

42. 40. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 39, and one or more pharmaceutically acceptable excipients.

43. 43. The pharmaceutical composition of claim 42, wherein the pharmaceutically acceptable excipient is selected from anti-adherents, binders, coatings, dyes, disintegrants, flavorings, glidants, lubricants, preservatives, adsorbents, sweeteners, dispersants, diluents, fillers, granulating agents, coating agents, waxes, suspending agents, wetting agents, vehicles, liquid carriers, and combinations thereof.

44. 44. The pharmaceutical composition of claim 43, wherein the composition is in a solid form selected from a tablet, pill, capsule, caplet, troche, granule, powder, sachet, dry powder inhalation form, chewable, pastille, and lozenge.

45. 45. The pharmaceutical composition of claim 44, wherein the composition is in the form of a tablet.

46. 43. The pharmaceutical composition of claim 42, wherein one or more of the compounds and pharmaceutically acceptable salts of claim 1 are present in the composition in an amount of about 0.001% to about 90% by weight.

47. A medicament comprising a compound or a pharmaceutically acceptable salt of any one of claims 1 to 39 for treating inflammation in a subject.

48. 48. The pharmaceutical of claim 47, wherein the inflammation is mediated by phosphodiesterase.

49. 48. The pharmaceutical agent of claim 47, wherein the inflammation is a symptom or cause of asthma, chronic obstructive pulmonary disease (COPD), psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), lupus, acute kidney injury (AKI), chronic kidney disease, or neuroinflammation.

50. A medicament comprising a compound or a pharmaceutically acceptable salt of any one of claims 1 to 39 for treating acute kidney injury in a subject.

51. A medicament for increasing NAD+ in a subject, comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 39.

52. 48. The method of claim 47, wherein the compound and / or the pharmaceutically acceptable salt is administered orally.

53. 53. The method of claim 52, wherein the oral administration occurs in an outpatient setting.

54. The pharmaceutical composition of claim 52, wherein the subject administers the oral administration.

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