Uridine phosphorylase (UPASE) inhibitors for treating liver conditions

Abstract

Provided is a method for treating a subject for liver conditions, such as NAFLD, NASH, and / or DILI.An embodiment of the method comprises administering an effective amount of a UPase inhibitor to the subject, optionally in combination with a uridine activator, such as auxiliary uridine (for example, uridine (UR), UR prodrug, or UR mimic), to treat the subject for liver conditions.Also provided is a composition for use in carrying out the subject method.

Description

[Background technology]

[0001] The prevalence of nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), is rapidly increasing worldwide. 1 NAFLD is characterized by hepatic fat accumulation (steatosis), sometimes fibrosis, and balloon-like hepatocytes as a result of the accumulation of fat (triglyceride) droplets without other causes of secondary hepatic fat accumulation (e.g., alcohol, infection, medications, etc.). 2 In addition to ballooning hepatocytes and fat accumulation, as seen in NALFD, NASH also features lobular inflammation, fibrosis, and hepatocyte degeneration. In NASH, fibrosis is typically followed by cirrhosis and end-stage liver disease, which is typically fatal without liver transplantation. 3 In addition to end-stage liver disease, individuals with NASH also often develop liver cancer (hepatocellular carcinoma, HCC) as a result of the condition. 4、5 .

[0002] The increased prevalence of both NALFD and NASH reflects the societal rise in obesity and type 2 diabetes (T2D) and the resulting altered metabolic state and liver manifestations. 6 Exposure of hepatocytes to high concentrations of lipids and carbohydrates, termed lipotoxicity and glucotoxicity, respectively, accounts for much of the hepatocellular injury observed in NAFLD / NASH. 7

[0003] Metabolic syndrome, defined as the cluster of obesity, insulin resistance, hyperglycemia, dyslipidemia, and hypertension, is a major risk factor that predisposes individuals to NAFLD and NASH. 8 Approximately 30% of North Americans suffer from NALFD and 4% from NASH. 9 Genetic, demographic, and ethnic factors may also contribute to the etiology of NAFLD. 10 for example NAFLD is associated with various genetic variants, including PNPLA-3, TM6SF2, and FDFT1. NAFLD is more common in older age groups and in men. Hispanics have the highest prevalence of NAFLD in the United States, followed by whites and African Americans.

[0004] There are no U.S. Food and Drug Administration (FDA)-approved medications to treat patients with NASH. Current recommended actions to treat the disease include weight loss and dietary changes, such as reducing fat and glucose consumption. 11 The only known "cure" for late-stage NASH and / or HCC is liver transplantation, and at this point, it is expected that NASH will soon surpass hepatitis as the single leading cause of liver transplantation. 9

[0005] Lipid droplets (LDs), also called lipid bodies, oil bodies, or adiposomes, are dynamic organelles that store neutral lipids during periods of energy excess and act as energy reservoirs during periods of depletion. 12 Many common metabolic diseases, such as metabolic syndrome and obesity, often result in elevated lipids and increased LD in the liver, also known as hepatic steatosis / NAFLD. LD, especially LD-associated proteins, are strongly associated with the pathophysiology of fatty liver disease. 13 Under normal physiological conditions, hepatic LDs are small and present in limited numbers. More substantial LD ​​formation is observed with tamoxifen (TAM), 14、15、16、17 cyclosporine, 18 valproic acid, 19、20 tetracycline, 21 clofibrate, 22 olanzapine, 23 and simavastin, 24 LDs appear to have a close relationship with mitochondria, involving physical contact and protein shuttling. 25 LDs also appear to have a similar close association with the cell nucleus. 26The content of LDs appears to determine their toxic potential—LDs containing unsaturated fatty acids such as arachidonic acid, a precursor of many inflammatory mediators. 27 is more toxic than LD, which contains saturated fatty acids. 28 LDs are coated with proteins from the perilipin family, some of which are involved in regulating lipid metabolism. 29

[0006] A major liver-related public health problem is drug-induced liver disease (DILI). It affects individuals who take pharmaceutical or dietary supplements. DILI has been associated with over 1000 drugs. 30 Although patients with less severe DILI are expected to make a complete recovery, associated symptoms (e.g., fatigue, itching, nausea) can be debilitating, recovery may be prolonged, and approximately 20% of patients have biochemical evidence of ongoing liver damage 6 months after diagnosis. 31 Cirrhosis and long-term liver-related morbidity and mortality occur in approximately 3% of cases. 32 Currently, no test is available that allows physicians to confidently diagnose DILI. 33 DILI, or even suspected DILI, can lead to the use of alternative treatments, exposing patients to the risk of new adverse drug events and potentially suboptimal treatment of the underlying disease. DILI is also a common cause of termination of clinical drug development programs. 34 DILI produces a wide range of pathologies, ranging from elevated serum transaminase levels detected by routine biochemical laboratory tests that resolve after removal of the chemical insult, to acute liver failure, defined as new, sudden, life-threatening liver dysfunction leading to coagulopathy and hepatic encephalopathy within 26 weeks of illness onset. 35 Acute liver failure is a devastating disease that primarily affects young, healthy individuals and results in death in approximately 30% of patients who undergo aggressive therapy, including liver transplantation.

[0007] There are two types of DILI: "toxic" and "idiosyncratic." Drugs that induce liver injury in a predictable, dose-dependent manner in both preclinical models and humans are said to cause toxic DILI. Acetaminophen is the most common cause of toxic DILI in the United States. Most other commercially available drugs do not cause life-threatening toxic DILI because this disadvantage is generally identified during preclinical or early clinical studies. Such drugs are often abandoned for further development, used at lower doses than would be expected to provide optimal efficacy but not cause liver injury, or administered in controlled or irreversible situations, such as chemotherapy. With the exception of N-acetylcysteine ​​for treating acetaminophen overdose, there are no available treatments for toxic DILI, and N-acetylcysteine ​​is useful only in limited clinical situations. Idiosyncratic DILI is the most problematic form of DILI. It rarely occurs among treated patients and often develops several months after treatment with the offending drug. Idiosyncratic DILI with new drugs is often only discovered when the drug enters general use. Idiosyncratic DILI, which has a latency period, likely reflects an immune attack on the liver. Consistent with this observation, when patients with DILI are rechallenged with the offending drug, idiosyncratic liver injury recurs shortly after complete recovery. The long latency period may be due to the time required for antigen-specific lymphocytes to be activated and proliferate to sufficient numbers to mediate DILI. The likely first step in the initiation of idiosyncratic DILI is the formation of hepatocellular stress, which induces neoantigens.

[0008] Both toxic and idiosyncratic liver injury appear to progress through similar processes. Proposed mechanisms include mitochondrial dysfunction, oxidative stress, and altered bile acid homeostasis. Mitochondria produce ATP, which is required to maintain all essential cellular functions. Drugs that cause DILI can inhibit mitochondrial function, resulting in reduced ATP levels, impaired cellular function, and ultimately cell death. 36Oxidative stress is a by-product of normal metabolism and a consequence of ROS, which have roles in cell signaling and homeostasis. However, some drugs that cause DILI can increase ROS accumulation through diverse mechanisms. 37 When the processes that regulate cellular levels of ROS are excessive, oxidative stress can cause damage to key cellular components and ultimately cell death. Finally, a major function of the liver is the transport of bile salts from the blood to bile. Drugs that cause DILI can interfere with this process in many ways, most importantly through the reduction of hepatic bile acid flow by inhibiting bile salt export proteins. 38 This results in the intracellular accumulation of toxic bile acids that can lead to hepatocyte death. In summary, in two distinct variants, toxic or idiosyncratic, DILI appears to have similar pathogenesis and etiology but likely multiple mechanisms of initiation and promotion.

[0009] There is a link between NAFLD / NASH and DILI that is not yet fully understood. 39、40、41、42、43、44 However, (1) in patients with NAFLD / NASH, DILI is a risk factor for many drugs, (2) DILI exists as a lesion similar to that of NAFLD / NASH, (3) DILI and NASH overlap pathophysiologically, (4) certain drugs induce hepatic steatosis (DIS) and / or steatohepatitis (DISH) by causing pathological events similar to those occurring in the development and progression of NAFLD / NASH, (5) DILI influences the development or accelerates the progression of NAFLD / NASH, and (6) NAFLD / NASH influences susceptibility to DILI and the consequences of DILI.

[0010] The deleterious effects from DILI not only mimic the physiological insults that cause the onset and / or progression of NAFLD in normal liver, but may also exacerbate similar pre-existing changes in fatty liver. Compared to NAFLD / NASH, DILI: ·Aggravating influencing factors (e.g. obesity, diabetes). Enhancement of fat-related factors (e.g., impairing lipid synthesis / uptake by the liver). Increased inflammatory factors (e.g., accumulation of lipotoxic fatty acids and oxidative stress). · Activating fibrogenic factors (e.g., enhancing collagen deposition). Alters the drug-metabolism pathway that occurs in the background of NAFLD. Based on the above, drugs that alleviate NAFLD / NASH are likely to also act to treat DILI, and vice versa.

[0011] NAFLD / NASH has become a significant, potentially fatal health condition in countries suffering from an increasing prevalence of obesity and related metabolic disorders, for which there are no approved treatments. DILI, another serious liver condition, appears to mimic the pathophysiology of NAFLD / NASH. Summary of the Invention

[0012] Provided is a method for treating a subject for liver conditions, such as NAFLD, NASH, and / or DILI.An embodiment of the method comprises administering to the subject an effective amount of a UPase inhibitor, optionally in combination with a uridine activator, such as auxiliary uridine (for example, uridine (UR), UR prodrug, or UR mimic), to treat the subject for liver conditions.Also provided is a composition for use in carrying out the subject method. [Brief explanation of the drawings]

[0013] [Figure 1] Figure 1 provides a regression analysis of plasma UR concentration versus plasma Compound I concentration determined after continuous infusion of various amounts of Compound I (TK-112690) into mice. The R2 of the line is 0.95, and the slope and intercept values ​​of the line are 0.010 and 0.051, respectively. Compound I is seen to linearly increase plasma UR. [Figure 2]Mouse weights measured during the experimental phase of the MCD study are provided. Six mice were studied per experimental group. All groups showed substantial weight loss. No variation in weight was observed between groups. Data are presented as mean + / - SEM. [Figure 3] This figure shows serum HDL cholesterol levels measured at the end of the experimental phase of the MCD study. Six mice were studied per experimental group. Mice treated with UR+Compound I (TK-112690) had significantly lower HDL cholesterol levels (p<0.05) compared with vehicle-treated controls. Data are presented as mean + / - SEM. [Figure 4] (A) Representative H&E images of liver sections from each experimental group are shown, and (B) fibrosis scores for the images shown in (A) are provided. The greatest effect was observed in the group of mice treated with UR + Compound I (TK-112690). This group showed significantly less liver fibrosis (p<0.001) compared to vehicle-treated controls (6 animals per experimental group). Data are presented as mean + / - SEM. DETAILED DESCRIPTION OF THE INVENTION

[0014] definition The following terms, when describing the compounds, pharmaceutical compositions containing such compounds, methods of using such compounds and compositions, and biological and pharmacological descriptions for using the compounds, have the following meanings, unless otherwise indicated: It is also to be understood that any of the defined moieties described below may be substituted with a variety of substituents, and that each definition is intended to include such substituted moieties within its scope.

[0015] "Acyl" refers to the radical -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

[0016] "Acylamino" refers to the radical -NR'C(O)R, where R' is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, and R is hydrogen, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl. Representative examples include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, benzylcarbonylamino, and the like.

[0017] "Acyloxy" refers to an -OC(O)H, -OC(O)-alkyl, -OC(O)-aryl, or -OC(O)-cycloalkyl group.

[0018] "Aliphatic" refers to hydrocarbyl organic compounds or groups characterized by a linear, branched, or cyclic arrangement of constituent carbon atoms and an absence of aromatic unsaturation. Aliphatic groups include, but are not limited to, alkyl, alkylene, alkenyl, alkynyl, and alkynylene. Aliphatic groups typically have from 1 or 2 to 6 or 12 carbon atoms.

[0019] "Alkenyl" refers to a monovalent olefinically unsaturated hydrocarbyl group, which may be straight-chained or branched, having up to about 11 carbon atoms, specifically 2 to 8 carbon atoms, more specifically 2 to 6 carbon atoms, and having at least one, specifically 1 or 2, sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (-CH=CH), n-propenyl (-CHCH=CH), isopropenyl (-C(CH)=CH), vinyl, and substituted vinyl.

[0020] "Alkoxy" refers to an -O-alkyl group. Particular alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0021] "Alkoxycarbonyl" refers to a radical -C(O)-alkoxy where alkoxy is defined herein.

[0022] "Alkoxycarbonylamino" refers to the group -NRC(O)OR' where R is hydrogen, alkyl, aryl, or cycloalkyl and R' is alkyl or cycloalkyl.

[0023] "Alkyl" refers specifically to monovalent saturated aliphatic hydrocarbyl groups having up to about 12 or 18 carbon atoms, more specifically 1 to 8 carbon atoms as lower alkyl, and even more specifically 1 to 6 carbon atoms. The hydrocarbon chain can be either straight or branched. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-hexyl, n-octyl, tert-octyl, and the like. The term "alkyl" also includes "cycloalkyl," as defined herein. The structures of some exemplary alkyl groups are provided in Table 1 below.

[0024] [Table 1]

[0025] "Alkylene" specifically refers to divalent saturated aliphatic hydrocarbyl groups which may be straight-chained or branched and have up to about 12 or 18 carbon atoms, more specifically 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH-), ethylene (-CHCH-), propylene isomers (e.g., -CHCHCH- and -CH(CH)CH-).

[0026] "Alkynyl" specifically refers to acetylenically unsaturated hydrocarbyl groups which may be straight-chained or branched, having up to about 12 or 18 carbon atoms, more specifically 2 to 6 carbon atoms, and having at least one, specifically 1 or 2, sites of alkynyl unsaturation. Specific non-limiting examples of alkynyl groups include acetylenic ethynyl (-C≡CH), propargyl (-CHC≡CH), and the like.

[0027] "Amino" refers to the radical -NH2.

[0028] "Amino acid" refers to any of the naturally occurring amino acids in D, L, or DL ​​form (e.g., Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val). The side chains of naturally occurring amino acids are well known in the art and include, for example, hydrogen (e.g., in glycine), alkyl (e.g., in alanine, valine, leucine, isoleucine, proline), substituted alkyl (e.g., in threonine, serine, methionine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, and lysine), alkaryl (e.g., in phenylalanine and tryptophan), substituted arylalkyl (e.g., in tyrosine), and heteroarylalkyl (e.g., in histidine).

[0029] "Aminocarbonyl" refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, aryl, or cycloalkyl, or the R groups are joined to form an alkylene group.

[0030] "Aminocarbonylamino" refers to the group -NRC(O)NRR where each R is independently hydrogen, alkyl, aryl, or cycloalkyl, or two R groups are joined to form an alkylene group.

[0031] "Aminocarbonyloxy" refers to the group -OC(O)NRR where each R is independently hydrogen, alkyl, aryl, or cycloalkyl, or the R groups are joined to form an alkylene group.

[0032] An "amino-containing saccharide group" refers to a saccharide group having an amino substituent. Representative amino-containing saccharides include L-vancosamine, 3-desmethyl-vancosamine, 3-epi-vancosamine, 4-epi-vancosamine, acosamine, actinosamine, daunosamine, 3-epi-daunosamine, ristosamine, N-methyl-D-glucamine, and the like.

[0033] "ARMD" refers to the eye disease age-related macular degeneration.

[0034] "Aralkyl" or "arylalkyl" refers to an alkyl group, as defined above, substituted with one or more aryl groups, as defined above.

[0035] "Aryl" refers to a monovalent aromatic hydrocarbon group derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like. Specifically, aryl groups contain 6 to 14 carbon atoms. Structures of some exemplary aryl groups are provided in Table 2.

[0036] [Table 2]

[0037] "Aryloxy" refers to the group --O-aryl, where "aryl" is as defined herein.

[0038] "Autoimmune disease" or "autoimmune condition" refers to a disease that occurs when the body's tissues are attacked by its own immune system. Examples of autoimmune diseases or conditions include multiple sclerosis, ankylosing spondylitis, Crohn's disease, arthritis, psoriasis, Behcet's disease, and psoriatic arthritis.

[0039] "Azide" refers to the radical -N3.

[0040] "Carbohydrate" refers to a mono-, di-, tri-, or polysaccharide, where the polysaccharide can have a molecular weight of up to about 20,000, e.g., hydroxypropyl-methylcellulose or chitosan. "Carbohydrate" also encompasses oxidized, reduced, or substituted saccharide monoradicals covalently bonded to an anhydropyrimidine (e.g., anhydrothymidine or anhydrouridine) or a derivative thereof via any atom of the saccharide moiety, e.g., a carbon atom of the aglycone. "Mono-, di-, tri-, or polysaccharide" can also include amino-containing saccharide groups. Representative "carbohydrates" include, for example, D-glucose, D-mannose, D-xylose, D-galactose, vancosamine, 3-desmethyl-vancosamine, 3-epi-vancosamine, 4-epi-vancosamine, acosamine, actinosamine, daunosamine, 3-epi-daunosamine, ristosamine, D-glucamine, N-methyl-D-glucamine, D-glucuronic acid, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine, sialic acid These include hexoses such as α-vancosaminyl)-β-D-glucopyranose, iduronic acid, and L-fucose; pentoses such as D-ribulose or D-arabinose; ketoses such as D-ribulose or D-fructose; disaccharides such as 2-O-(α-vancosaminyl)-β-D-glucopyranose, 2-O-(3-desmethyl-α-L-vancosaminyl)-β-D-glucopyranose, sucrose, lactose, or maltose; derivatives such as acetals, amines, acylated, sulfurized, and phosphorylated sugars; and oligosaccharides having 2 to 10 saccharide units. The saccharides can be in their open, r-pyranose, or furanose forms.

[0041] "Carboxyl" refers to the radical -C(O)OH.

[0042] "Cyano" refers to the radical -CN.

[0043] "Cycloalkenyl" refers to cyclic hydrocarbyl groups having from 3 to 10 carbon atoms, a single ring, or multiple condensed rings, including fused and bridged ring systems, and at least one, and specifically one or two, sites of olefinic unsaturation. Such cycloalkenyl groups include, for example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.

[0044] "Cycloalkyl" refers to cyclic hydrocarbyl groups having from 3 to about 10 carbon atoms and having a single ring or multiple condensed rings, including fused and bridged ring systems, which can be optionally substituted with 1 to 3 alkyl groups. Such cycloalkyl groups include, for example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, and multiple ring structures such as adamantanyl.

[0045] "DILI" refers to drug-induced liver injury.

[0046] "DIS" refers to drug-induced hepatic steatosis

[0047] "DISH" refers to drug-induced steatohepatitis.

[0048] "DR" refers to the eye condition diabetic retinopathy.

[0049] "FU" refers to 5-fluorouracil.

[0050] "Heterocycloalkyl" refers to stable heterocyclic non-aromatic rings and fused rings containing one or more heteroatoms independently selected from N, O, and S. Fused heterocyclic ring systems can include carbocyclic rings and must contain only one heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, piperazinyl, homopiperazinyl, piperidinyl, and morpholinyl. Some exemplary heterocyclyl structures are shown in Table 3.

[0051] [Table 3]

[0052] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo. A halo group can be either fluoro or chloro.

[0053] "HCC" refers to hepatocellular carcinoma.

[0054] "HDL" refers to high density lipoprotein.

[0055] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the above hydrocarbyl groups, including alkyl (e.g., heteroalkyl), cycloalkyl (e.g., heterocycloalkyl), aryl (e.g., heteroaryl), cycloalkenyl (e.g., heterocycloalkenyl), cycloheteroalkenyl (e.g., heterocycloheteroalkenyl), etc., having 1 to 5, specifically 1 to 3, heteroatoms. A heteroatom is any atom other than carbon or hydrogen, typically, but not limited to, nitrogen, oxygen, sulfur, phosphorus, boron, chlorine, bromine, or iodine. An unsubstituted heteroatom refers to a pendant heteroatom such as an amine, hydroxyl, or thiol. A substituted heteroatom refers to a heteroatom other than the pendant heteroatom.

[0056] "Heteroaryl" refers to a monovalent heteroaromatic group derived by removing one hydrogen atom from a single atom of a parent heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, etc. Heteroaryl groups can be 5 to 20 membered heteroaryl, or 5 to 10 membered heteroaryl. Particular heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole, and pyrazine.

[0057] "Hydroxyl" refers to the radical --OH.

[0058] "KO" refers to knockout as used in the phrase knockout animal.

[0059] "MCD" refers to methionine-choline deficient diet.

[0060] "NAFLD" refers to non-alcoholic fatty liver disease.

[0061] "NASH" refers to non-alcoholic steatohepatitis.

[0062] "Nitro" refers to the radical -NO2.

[0063] "Peptide" refers to a polyamino acid containing up to 2, 5, 10, or about 100 amino acid residues.

[0064] "Polypeptide" refers to a polyamino acid containing from about 100 to about 1,000 amino acid units, from about 100 to about 750 amino acid units, or from about 100 to about 500 amino acid units.

[0065] "ROP" refers to the eye condition infantile retinopathy of prematurity.

[0066] "SEM" refers to standard error of the mean.

[0067] "Side effect" means an unwanted and adverse consequence of drug administration.

[0068] "Stereoisomer" with respect to a given compound is well understood in the art and refers to another compound (e.g., an enantiomer, diastereomer, or geometric isomer) having the same molecular formula, where the atoms in the other compound are oriented in space differently, but the atoms in the other compound are like the atoms in the given compound with respect to which atoms are connected to which other atoms. See, e.g., Morrison and Boyd, Organic Chemistry, 1983, 4th ed., Allyn and Bacon, Inc., Boston, MA, p. 123.

[0069] "Substituted" refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). A "substituted" group specifically refers to a group having one or more substituents, for example, 1 to 5 substituents, specifically 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, aralkyl, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, imidate, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkylthio, (substituted alkyl)thio, arylthio, (substituted aryl)thio, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2. Typical substituents include -X, (where R 8 (provided that it is not hydrogen)-R 8 , -O-, =O, -OR 8 , -SR 8 , -S - , =S, -NR 8 R 9 , =NR 8 , -CX3, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2O - , -S(O)2OH, -S(O)2R 8 , -OS(O2)O - , -OS(O)2R 8 , -P(O)(O-)2, -P(O)(OR 8 )(O - ), -OP(O)(OR 8 )(OR 9 ), -C(O)R 8 , -C(S)R 8 , -C(O)OR 8 , -C(O)NR 8 R 9 , -C(O)O - , -C(S)OR 8 , -NR 10 C(O)NR 8 R9 , -NR 10 C(S)NR 8 R 9 , -NR 11 C(NR 10 )NR 8 R 9 , and -C(NR 10 )NR 8 R 9 (wherein X is not independently a halogen).

[0070] "Substituted amino" includes those groups recited in the definition of "substituted" herein, and specifically refers to the group -N(R)2, where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, and substituted cycloalkyl, and both R groups are joined to form an alkylene group.

[0071] "T2D" refers to type 2 diabetes.

[0072] "TG" refers to transgenic.

[0073] "Thioalkoxy" refers to the group --S-alkyl.

[0074] "Thioaryloxy" refers to the group --S-aryl.

[0075] "Thioketo" refers to the =S group.

[0076] "Thiol" refers to the group --SH.

[0077] "UR" refers to uridine.

[0078] In enzymology, "UPase (uridine phosphorylase)" refers to a phosphorylase (EC 2.4.2.3) that catalyzes the chemical reaction: uridine + phosphate → uracil + alpha-D-ribose 1-phosphate. The enzyme's two substrates are uridine and phosphate, and its two products are uracil and alpha-D-ribose 1-phosphate. This enzyme belongs to the family of glycosyltransferases, specifically pentosyltransferases. The systematic name for this enzyme class is uridine:phosphate alpha-D-ribosyltransferase. Other commonly used names include pyrimidine phosphorylase, UrdPase, UPH, and UPase. This enzyme is involved in pyrimidine metabolism.

[0079] "Uridine supplement" refers to either a compounded product containing UR or a compounded product containing a UR precursor, such as UR monophosphate or acetylated UR, which is converted to UR in the body. The compounded product can be a solution, capsule, tablet, or cream. The product can be administered po, ​​ip, sc, or iv. UR supplements can be administered as part of a more complex mixture, such as a nutritional supplement.

[0080] ip, po, and sc are intraperitoneal, oral, or subcutaneous administration, respectively. H&E is hematoxylin and eosin, a dye used to stain tissue. SD is standard deviation. SE is standard error. PBS is phosphate-buffered saline. qd and bid are daily and twice daily, respectively.

[0081] Those skilled in the art will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether aromatic or non-aromatic, is determined by the ring size, degree of unsaturation, and valence of the heteroatoms. Generally, a heterocyclic ring can have 1 to 4 heteroatoms, so long as the heteroaromatic ring is chemically feasible and stable.

[0082] Provided is a method for treating a subject for liver conditions, such as NAFLD, NASH, and / or DILI.An embodiment of the method comprises administering to the subject an effective amount of a UPase inhibitor, optionally in combination with a uridine activator, such as auxiliary uridine (for example, uridine (UR), UR prodrug, or UR mimic), to treat the subject for liver conditions.Also provided is a composition for use in carrying out the subject method.

[0083] Before the present invention is described in greater detail, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0084] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limits of that range, and any other stated or intervening value within this stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0085] Certain ranges are presented herein with numerical values ​​preceded by the term "about." The term "about" is used herein to provide literal support for the exact number it precedes, as well as a number that is close to or approximately the number it precedes. When determining whether a number is close to or approximately a specifically stated number, the number that is close to or approximately the unstated number may be a number that, in the context in which it is presented, provides a substantial equivalent to the specifically stated number.

[0086] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative exemplary methods and materials are now described.

[0087] All publications and patents cited herein are incorporated by reference to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference, and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the publication dates provided may be different from the actual publication dates, which may need to be independently confirmed.

[0088] It should be noted that, as used in this specification and the appended claims, the articles "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should be further noted that the claims may be drafted to exclude any element. Accordingly, this statement is intended to serve as a prior basis for using exclusive terminology, such as "solely," "solely," and the like, in connection with the recitation of claim elements or the use of a "negative" limitation.

[0089] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has distinct components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the invention. Any described method can be carried out in the order of events described or in any other order which is logically possible.

[0090] Although apparatus and methods have been or will be described with functional descriptions for the sake of grammatical fluidity, unless expressly recited under 35 U.S.C. 112, the claims are not necessarily to be construed as limited by constructions of "means" or "step" limitations, but are to be given the full scope of meaning and equivalents of the definitions provided by the claims under the doctrine of legal equivalents, with the express understanding that if a claim is expressly recited under 35 U.S.C. 112, it should be given its full legal equivalents under 35 U.S.C. 112.

[0091] In further describing the subject invention, the subject methods will first be described in more detail, followed by a discussion of various compositions, e.g., formulations and kits, that may find use in the subject methods, as well as a discussion of various representative applications in which the subject methods and compositions find use.

[0092] method As summarized above, methods of treating, including prophylactically treating (e.g., preventing the occurrence of) a liver condition in a subject are provided. Aspects of the method include administering a UPase inhibitor to a subject, either alone or in combination with a uridine (UR) activator (e.g., a UR, a UR prodrug, or a UR mimetic), to treat the subject for the liver condition. When a UPase inhibitor is administered in combination with a UR activator, i.e., simultaneously, the UPase inhibitor can be administered simultaneously with the UR activator. Alternatively, the UPase inhibitor and the UR activator can be administered sequentially, for example, when the UPase inhibitor is administered before or after the UR activator. In such embodiments, the UPase inhibitor and the UR activator can be administered simultaneously, for example, as two separate formulations or combined in a single composition. Alternatively, the UPase inhibitor and the UR activator can be administered sequentially to a subject in different formulations. Whether the UPase inhibitor and the UR activator are administered sequentially or simultaneously, or in any effective manner, the agents are considered to be administered together or in combination for the purposes of the present invention. The administration route of the two agents may vary. Representative administration routes are described below.

[0093] The subject treated according to the method of the present invention may be a subject suffering from or suspected of suffering from a liver condition such as NAFLD, NASH, or DILI.Treatment according to the disclosed method can be initiated prophylactically for subjects at risk of liver disease or for subjects after the diagnosis of a serious liver condition.Treatment can be performed at intervals determined by those skilled in the art as appropriate.For example, administration can be performed 1, 2, 3, 4 or more times per day.Ideally, treatment is expected to be constant qd.Treatment can also be initiated before, at the same time as, or approximately at the same time as the drug associated with the serious liver condition.

[0094] In the context of the present invention, the dose administered to animals, particularly humans, should be sufficient to affect preventive or therapeutic responses in animals over a reasonable time frame.Those skilled in the art will recognize that dosage depends on a variety of factors, including the strength of the specific compound used, the dosage regimen used, the condition and body weight of the animal, and the severity and stage of the disease.The size of the dose is also determined by the existence, nature and extent of any adverse side effects that may accompany the administration of a specific compound.

[0095] UPase inhibitors As summarized above, aspects of the present invention involve administering to a subject a UPase inhibitor. UPase (UPh; EC 2.4.2.3) is a member of the pyrimidine nucleoside phosphorylase family of enzymes that catalyzes the phosphorylative cleavage of the C-N glycosidic bond of UR with the formation of ribose 1-phosphate and uracil. 45 UPase inhibitors are agents that act to regulate uridine plasma levels in a subject, for example, agents that act to increase uridine (UR) plasma levels in a subject. The magnitude of any UR plasma level enhancement can vary, but in some cases, the enhancement is 2-fold or greater, such as 5-fold or greater, 10-fold or greater, 15-fold or greater, 20-fold or greater, 25-fold or greater, or 50-fold or greater.

[0096] In some cases, the UPase inhibitor is an anhydronucleoside. Anhydronucleosides are analogs of natural nucleosides, often used as intermediates in the synthesis of nucleoside derivatives. They are characterized by an N-glycosidic bond, plus a covalent bond between the 2', 3', or 5' carbon of the sugar and a carbon, oxygen, or nitrogen atom of the base (excluding the nitrogen of the glycosidic bond), either directly or via a bridging atom. Anhydropyrimidines are characterized by a pyrimidine base covalently bonded between the 2', 3', or 5' carbon of the sugar and a carbon, oxygen, or nitrogen atom of the pyrimidine base (excluding the nitrogen of the glycosidic bond), either directly or via a bridging atom.

[0097] In some embodiments, the UPase inhibitor is a 2,2'-anhydropyrimidine or a derivative thereof. In some embodiments, the 2,2'-anhydropyrimidine or a derivative thereof is a compound of formula (I):

[0098] [ka]

[0099] or pharmaceutically acceptable salts, solvates, hydrates, and prodrug forms thereof, and stereoisomers thereof; During the ceremony, Each R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted heteroatom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, hydroxyl, halogen, azide, amino, substituted amino, carbohydrate, nucleic acid, amino acid, peptide, dye, fluorophore, and polypeptide.

[0100] In certain embodiments, the compound is of formula (I) and R 1 , R 2 , R 3 , and R 4 are independently hydrogen, hydroxyl, heteroatoms, C1-C 18 Alkyl, C1-C 18 Substituted alkyl, C1-C 18 Alkenyl, C1-C 18Acyl, amino, substituted amino, where alkyl, alkenyl, or acyl is linear or branched and optionally substituted with hydroxyl, ester and its derivatives, carboxyl and its derivatives, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroatoms, and optionally containing in-chain or bridging heteroatoms such as nitrogen, oxygen, and sulfur.

[0101] Target R 1Examples of moieties include hydrogen; hydroxyl; sulfyhydryl; halogens such as fluorine, chlorine, bromine, or iodine, and pseudohalogens such as lower alkylsulfonyl groups of 1 to 5 carbons, such as methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, tert-butyl-, and pentasulfonyl or arylsulfonyl groups, such as benzene, p-toluene, and p-nitrobenzenesulfonyl groups; lower alkyls containing 1 to 20 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and pentyl, including substituted lower alkyls such as aminomethyl, hydroxymethyl, methoxy, ethyloxy, propyloxy, benzyloxy, imidate, alkylthio, (substituted alkyl)thio, arylthio, and (substituted aryl)thio; lower alkenyls containing 1 to 20 carbons, such as vinyl and substituted vinyls, ethynyl, and substituted ethynyls (substituted vinyls or substituted ethynyls). Nyl refers to substitution at the β-position of vinyl or ethynyl by a halogen such as bromine, chlorine, fluorine, or iodine, or by an alkyl of 1 to 5 carbon atoms such as methyl, ethyl, propyl, butyl, or pentyl, or by an aralkyl such as benzyl, p-chlorobenzyl, or p-nitrobenzyl, or by an aryl such as phenyl, p-nitrophenyl, p-tolyl, p-anisyl, or naphthyl; formyl, acetyl, propionyl, isopropionyl, Lower alkanoyl (acyl groups) containing 1 to 20 carbon atoms, such as butyryl, isobutyryl, tert-butyryl, valeryl, pivaloyl, caproyl, capryl, lauryl, myristyl, palmityl, stearyl, arachidyl, stilligyl, palmitoyl, oleyl, linolenyl, and arachidonyl; lower aryl groups containing 1 to 20 carbon atoms, such as phenyl, p-tolyl, p-chlorophenyl, p-aminophenyl, p-nitrophenyl, and p-anisyl;Lower aroyls containing 1 to 20 carbons, such as benzoyl and naphthoyl (wherein the aromatic group can be additionally substituted by an alkyl, alkoxy, halo, or nitro moiety, such as p-toluenesulfonyl, p-anisoyl, p-chlorobenzoyl, p-nitrobenzoyl, or 2,4-dinitrobenzoyl, pentafluorobenzoyl, or by another aroyl, such as benzyloxybenzoyl); lower aralkyls containing 1 to 20 carbons, such as benzyl, benzhydryl, p-chlorobenzyl, m-chlorobenzyl, p-nitrobenzyl, benzyloxybenzyl, and pentafluorobenzyl; aminos or alkylaminos containing 1 to 20 carbons, such as monoalkyl or monoaralkylamino groups, such as methylamino, ethylamino, propylamino, or benzamino; and dialkylaminos, such as dimethylamino, diethylamino, dibenzylamino, pyrrolidino, piperidino, or morpholino.

[0102] Thus, in certain embodiments, R 1 is hydrogen, hydroxyl, sulfhydryl, amino, substituted amino, hydroxymethyl, monomethoxy, halogen, pseudohalogen, or a lower hydrocarbon containing 1 to 20 atoms (the hydrocarbon can be substituted or unsubstituted). 1 is a lower hydrocarbon selected from alkyl, substituted alkyl, alkenyl, alkanoyl, aryl, aroyl, aralkyl, or alkylamino. 1 is a lower hydrocarbon substituted with alkoxy, substituted alkoxy, imidate, arylthio, or (substituted aryl)thio. 1 is a lower alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and pentyl. 1 is a lower alkenyl selected from vinyl, substituted vinyl, ethynyl, or substituted ethynyl. 1is a lower alkanoyl selected from formyl, acetyl, propionyl, isopropionyl, butyryl, isobutyryl, tert-butyryl, valeryl, pivaloyl, caproyl, capryl, lauryl, myristyl, palmityl, stearyl, arachidyl, styridyl, palmitoyl, oleyl, linolenyl, and arachidonyl. 1 is a lower aryl selected from phenyl, p-tolyl, p-chlorophenyl, p-aminophenyl, p-nitrophenyl, and p-anisyl. 1 is a lower aroyl selected from benzoyl and naphthoyl. In other embodiments, R 1 is a lower aralkyl selected from benzyl, benzhydryl, p-chlorobenzyl, m-chlorobenzyl, p-nitrobenzyl, benzyloxybenzyl, or pentafluorobenzyl. 1 is lower alkylamino selected from monoalkylamino, monoaralkylamino, dialkylamino, diaralkylamino, and benzylamino.

[0103] The target compounds are R 1 is selected from hydrogen, fluorine, trifluoromethyl, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, acetyl, propionyl, butyryl, 2-bromovinyl, phenyl, benzyl, benzoyl, benzyloxybenzyl, benzylamino, alkyloxyalkyl, benzyloxyalkyl, imidate alkyl, arylthio, and (substituted aryl)thio. Thus, in certain embodiments, the compound is of formula (I), wherein R 1is H, F, CF3, CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, (CH3)2CH2CH2, CH3(O)CCH2, CH3(O)CCH2CH2, Br-CH=CH, phenyl, benzyl, benzoyl, benzyloxybenzyl, benzyl-NH-, CH3CH2OCH2, benzyl-O-CH2, CHOCH2, CH3C(NH)-O-CH2, or CH3-phenyl-O-CH2.

[0104] Target R 2Examples of moieties include hydrogen; hydroxyl; sulfyhydryl; halogens such as fluorine, chlorine, bromine, or iodine; and pseudohalogens such as lower alkylsulfonyl groups of 1 to 5 carbons, such as methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, tert-butyl-, and pentasulfonyl or arylsulfonyl groups, such as benzene, p-toluene, and p-nitrobenzenesulfonyl groups; and substituted lower alkyls such as aminomethyl, hydroxymethyl, methoxy, ethyloxy, and propyloxy. lower alkyl containing 1 to 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, etc.; lower alkenyl containing 1 to 20 carbon atoms, such as vinyl and substituted vinyl, ethynyl and substituted ethynyl (wherein the substituted vinyl or substituted ethynyl is substituted at the β-position of the vinyl or ethynyl with a halogen such as bromine, chlorine, fluorine, or iodine, or with an alkyl of 1 to 5 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, or benzyl, p-chlorobenzyl, p-nitrobenzyl, etc.); or aryl, such as phenyl, p-nitrophenyl, p-tolyl, p-anisyl, or naphthyl; lower alkanoyl (acyl groups) or esters thereof having a main chain containing 1 to 20 carbon atoms, such as formyl, acetyl, propionyl, isopropionyl, butyryl, isobutyryl, tert-butyryl, valeryl, pivaloyl, caproyl, capryl, lauryl, myristyl, palmityl, stearyl, arachidyl, styridyl, palmitoyl, oleyl, linolenyl, or arachidonyl; phenyl lower aryl containing 1 to 20 carbons such as p-tolyl, p-tolyl, p-chlorophenyl, p-aminophenyl, p-nitrophenyl, p-anisyl; lower aroyl containing 1 to 20 carbons such as benzoyl and naphthoyl (wherein the aromatic group can be additionally substituted by an alkyl, alkoxy, halo, or nitro moiety such as p-tolunoyl, p-anisoyl, p-chlorobenzoyl, p-nitrobenzoyl, or 2,4-dinitrobenzoyl, pentafluorobenzoyl, or by another aroyl such as benzyloxybenzoyl);lower aralkyl containing 1 to 20 carbons such as benzyl, benzhydryl, p-chlorobenzyl, m-chlorobenzyl, p-nitrobenzyl, benzyloxybenzyl, pentafluorobenzyl; lower aryloxy containing 1 to 20 carbons such as phenyloxy (i.e., O-phenyl), benzyloxy (i.e., O-benzyl), benzhydryloxy (i.e., O-benzylhydryl), p-chlorobenzyloxy (i.e., O-(p-chlorobenzyl)), m-chlorobenzyloxy (i.e., O-(m-chlorobenzyl)), p-nitrobenzyloxy (i.e., O-(p-nitrobenzyl)), (4-benzyloxybenzyl)-oxy (i.e., O-benzyloxybenzyl), or pentafluorobenzyloxy (i.e., O-pentafluorobenzyl); benzoyloxy (i.e., O-benzoyl), diphenylacetyloxy (i.e., O-diphenylacetyloxy), aryloxy esters such as lower aroyloxy (i.e., O-aroyl) groups containing 1 to 20 carbons, such as (4-benzyloxybenzoyl)-oxy (i.e., O-benzyloxybenzoyl), p-chlorobenzoyloxy (i.e., O-(p-chlorobenzoyl)), m-chlorobenzoyloxy (i.e., O-(m-chlorobenzoyl)), p-nitrobenzoyloxy (i.e., O-(p-nitrobenzoyl)), (4-benzyloxybenzoyl)-oxy (i.e., O-benzyloxybenzoyl), or pentafluorobenzoyloxy (i.e., O-pentafluorobenzoyl); amino or alkylamino groups containing 1 to 20 carbons, such as monoalkyl or monoaralkylamino groups, such as methylamino, ethylamino, propylamino, or benzamino, dimethylamino, diethylamino, dibenzylamino, dialkylaquino such as pyrrolidino, piperidino, or morpholino;

[0105] Thus, in certain embodiments, R 2is hydrogen, hydroxyl, sulfhydryl, amino, hydroxymethyl, monomethoxy, halogen, pseudohalogen, or lower hydrocarbons containing 1 to 20 atoms (which hydrocarbons can be substituted or unsubstituted), and esters thereof. In certain embodiments, R 2 is a lower hydrocarbon selected from alkyl, alkenyl, alkanoyl, aryl, aroyl, aryloxy, aroyloxy, aralkyl, or alkylamino. 2 is a lower alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and pentyl. 2 is a lower alkenyl selected from vinyl, substituted vinyl, ethynyl, or substituted ethynyl. 2 is a lower alkanoyl selected from formyl, acetyl, propionyl, isopropionyl, butyryl, isobutyryl, tert-butyryl, valeryl, pivaloyl, caproyl, capryl, lauryl, myristyl, palmityl, stearyl, arachidyl, styridyl, palmitoyl, oleyl, linolenyl, and arachidonyl. 2 is a lower aryl selected from phenyl, p-tolyl, p-chlorophenyl, p-aminophenyl, p-nitrophenyl, and p-anisyl. 2 is a lower aroyl selected from benzoyl and naphthoyl. In other embodiments, R 2 is a lower aralkyl selected from benzyl, benzhydryl, p-chlorobenzyl, m-chlorobenzyl, p-nitrobenzyl, benzyloxybenzyl, or pentafluorobenzyl. 2 is a lower aryloxy selected from phenyloxy, benzyloxy, benzhydryloxy, p-chlorobenzyloxy, m-chlorobenzyloxy, p-nitrobenzyloxy, (4-benzyloxybenzyl)-oxy, or pentafluorobenzyloxy. 2is a lower aroyloxy selected from benzoyloxy, diphenylacetyloxy, p-chlorobenzoyloxy, m-chlorobenzoyloxy, p-nitrobenzoyloxy, (4-benzyloxybenzoyl)-oxy, or pentafluorobenzoyloxy. 2 is a lower alkylamino selected from monoalkylamino, monoaralkylamino, dialkylamino, and diaralkylamino. Thus, in certain embodiments, R 2 may be hydrogen or hydroxyl, as well as O-acyl, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, O-alkyl, O-alkylene, O-alkynyl, O-aralkyl, O-aryl, O-aryloxy, O-carbohydrate, O-cycloalkenyl, O-cycloalkyl, O-heterocycloalkyl, O-heteroaryl. Additionally, S may be substituted with O.

[0106] The target compounds are R 2 is selected from hydrogen, fluorine, trifluoromethyl, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, acetyl, propionyl, butyryl, 2-bromovinyl, phenyl, phenyloxy, benzyl, benzoyl, benzoyloxy, and benzyloxybenzyl. Thus, in certain embodiments, the compound is of formula (I), wherein R 2 is H, F, CF3, CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, (CH3)2CH2CH2, CH3(O)CCH2, CH3(O)CCH2CH2, Br-CH=CH, phenyl, phenyloxy, benzyl, benzoyl, benzoyloxy, or benzyloxybenzyl.

[0107] In certain embodiments of interest, the compound is of formula (I) and R 2 is hydrogen, hydroxyl, or an O-linked substituent. This includes R 2 is H, OH, or C6H5C(O)O.

[0108] Target R 3 Examples of alkanoyl include hydrogen, hydroxyl, azide, sulfhydryl, halogen, pseudohalogen, lower alkyl containing 1 to 20 carbons such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and the like, including substituted lower alkyl such as aminomethyl, hydroxymethyl, methoxy, ethyloxy, propyloxy, and the like; lower alkanoyl (acyl) including those esters of a main chain of 1 to 20 carbon atoms such as formyl, acetyl, propionyl, isopropionyl, butyryl, isobutyryl, tert-butyryl, valeryl, pivaloyl, caproyl, capryl, lauryl, myristyl, palmityl, stearyl, arachidyl, styridyl, palmitoyl, oleyl, linolenyl, arachidonyl, and the like; lower aryl such as phenyl, p-nitrophenyl, p-tolyl, p-anisyl, naphthyl, and the like; and lower aroyl (acyl of an aromatic acid) of 1 to 20 carbons such as benzoyl and naphthoyl. radicals) (wherein the aromatic group may be additionally substituted with alkyl, alkoxy, halo, or nitro moieties such as p-toluenesulfonyl, p-anisoyl, p-chlorobenzoyl, p-nitrobenzoyl, or 2,4-dinitrobenzoyl, pentafluorobenzoyl); lower aryloxy of 1 to 20 carbons such as phenyloxy, benzyloxy, benzhydryloxy, p-chlorobenzyloxy, m-chlorobenzyloxy, p-nitrobenzyloxy, (4-benzyloxybenzyl)-oxy, or pentafluorobenzyloxy; and esters of aryloxy such as lower aroyloxy (O-aroyl) of 1 to 20 carbons such as benzoyloxy, diphenylacetyloxy, p-chlorobenzyloxy, m-chlorobenzyloxy, p-nitrobenzyloxy, (4-benzyloxybenzoyl)-oxy, or pentafluorobenzoyloxy. R 3 can also be adamantoyl, or substituted adamantoyl.

[0109] Thus, in certain embodiments, R 3is hydrogen, hydroxyl, azido, sulfhydryl, hydroxymethyl, halogen, or pseudohalogen. 3 is a lower hydrocarbon selected from alkyl, alkanoyl, aryl, aroyl, aryloxy, aroyloxy, or aralkyl. 3 is a lower alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and pentyl. 3 is a lower alkanoyl selected from formyl, acetyl, propionyl, isopropionyl, butyryl, isobutyryl, tert-butyryl, valeryl, pivaloyl, caproyl, capryl, lauryl, myristyl, palmityl, stearyl, arachidyl, styridyl, palmitoyl, oleyl, linolenyl, and arachidonyl. 3 is a lower aryl selected from phenyl, p-tolyl, p-chlorophenyl, p-aminophenyl, p-nitrophenyl, p-anisyl, and the like. 3 is a lower aroyl selected from benzoyl and naphthoyl. In certain other embodiments, R 3 is a lower aralkyl selected from benzyl, benzhydryl, p-chlorobenzyl, m-chlorobenzyl, p-nitrobenzyl, benzyloxybenzyl, or pentafluorobenzyl. 3 is a lower aryloxy selected from phenyloxy, benzyloxy, benzhydryloxy, p-chlorobenzyloxy, m-chlorobenzyloxy, p-nitrobenzyloxy, (4-benzyloxybenzyl)-oxy, or pentafluorobenzyloxy. 3 is a lower aroyloxy selected from benzoyloxy, diphenylacetyloxy, p-chlorobenzoyloxy, m-chlorobenzoyloxy, p-nitrobenzoyloxy, (4-benzyloxybenzoyl)-oxy, or pentafluorobenzoyloxy. Thus, in certain embodiments, R 3may be hydrogen or hydroxyl, as well as O-acyl, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, O-alkyl, O-alkylene, O-alkynyl, O-aralkyl, O-aryl, O-aryloxy, O-carbohydrate, O-cycloalkenyl, O-cycloalkyl, O-heterocycloalkyl, O-heteroaryl. Additionally, S may be substituted with O.

[0110] The target compound is R 3 is hydrogen, hydroxyl, halogen, azide, or an O-linked substituent. 3 is selected from hydrogen, hydroxyl, n-butoxy, isobutyloxy, t-butyloxy, phenyloxy, benzyloxy, benzoyloxy, and pentafluorobenzoyloxy. Thus, in certain embodiments, the compound is of formula (I) and R 3 is selected from H, OH, CH3CH2CH2CH2O, (CH3)2CH2CH2O, (CH3)3CO, C6H5O, benzoyloxy, and pentafluorobenzoyloxy.

[0111] In certain embodiments of interest, the compound is R 3 is H, OH, F, Cl, Br, I, N, or C6H5C(O)O. Of particular interest are those of formula (I) where R 3 is OH, or O-acyl (e.g., an ester such as C6H5C(O)O).

[0112] R 4 Examples of R include, but are not limited to, hydrogen; hydroxyl; sulfhydryl; halogen, such as fluorine, chlorine, bromine, or iodine; amino, or lower alkylamino. 4is also exemplified by lower alkyl groups, including acyl groups, which may be lower alkanoyl groups of 1 to 7 carbon atoms, such as formyl, acetyl, propionyl, isopropionyl, butyryl, isobutyryl, tert-butyryl, and the like, and esters thereof. 4 can also be aroyl such as benzoyl and naphthoyl (and O-linked aroyl, i.e., O-arolyl, or esters thereof, such as aroyloxy), where the aromatic group can be additionally substituted with alkyl, alkoxy, halo, or nitro moieties such as p-tolunoyl, p-anisoyl, p-chlorobenzoyl, p-nitrobenzoyl, or 2,4-dinitrobenzoyl. Thus, in certain embodiments, R 4 may be hydrogen or hydroxyl, as well as O-acyl, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, O-alkyl, O-alkylene, O-alkynyl, O-aralkyl, O-aryl, O-aryloxy, O-carbohydrate, O-cycloalkenyl, O-cycloalkyl, O-heterocycloalkyl, O-heteroaryl. Additionally, S may be substituted with O.

[0113] Thus, in certain embodiments, R 4 is hydrogen; hydroxyl; sulfhydryl; halogen, aminoaminomethyl, or aminodimethyl. 4 is lower alkyl, acyl, aroyl, or aroyloxy. This includes compounds of formula (I) where R 4 is hydrogen, fluorine, hydroxyl, amino, aminomethyl, aminodimethyl, t-butyloxy, phenyloxy, or benzoyloxy (e.g., R 4 is H, F, OH, NH, NHCH, N(CH)(CH)CO, CHO, or CHC(O)O).

[0114] Compounds of particular interest are R 4is of formula (I), where R is hydrogen, hydroxyl, or an O-linked substituent. 4 is H, OH, or C6H5C(O)O. Of particular interest are those of formula (I) where R 4 is OH, or O-acyl (e.g., an ester such as C6H5C(O)O).

[0115] The target compound is R 1 is H, F, CF3, CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, (CH3)2CH2CH2, CH3(O)CCH2, CH3(O)CCH2CH2, Br-CH=CH, phenyl, benzyl, benzoyl, or benzyloxybenzyl; R 2 is H, OH, F, CF3, CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, (CH3)2CH2CH2, CH3(O)CCH2, CH3(O)CCH2CH2, Br-CH=CH, phenyl, phenyloxy, benzyl, benzoyl, benzoyloxy, or benzyloxybenzyl; R 3 and R 4and R are each hydroxyl. These include the following compounds: 2,2'-anhydrouridine, 2,2'-anhydro-5-fluorouridine, 2,2'-anhydro-5-trifluoromethyluridine, 2,2'-anhydro-5-methyluridine, 2,2'-anhydro-5-ethyluridine, 2,2'-anhydro-5-propyluridine, 2,2'-anhydro-5-isopropyluridine, 2,2'-anhydro-5-isobutyl ... 2'-anhydro-5-methylacyluridine, 2,2'-anhydro-5-propylacyluridine, 2,2'-anhydro-5-(2-bromovinyl)uridine, 2,2'-anhydro-5-phenyluridine, 2,2'-anhydro-5-benzyluridine, 2,2'-anhydro-5-benzyluridine, and 2,2'-anhydro-5-(benzyloxylbenzyl)uridine. Of particular interest is 2,2'-anhydro-5-methyluridine, or pharmaceutically acceptable salts, solvates, hydrates, and prodrug forms thereof, and stereoisomers thereof.

[0116] Additional compounds of interest are R 1 is H, F, CF3, CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, (CH3)2CH2CH2, CH3(O)CCH2, CH3(O)CCH2CH2, Br-CH=CH, phenyl, benzyl, benzoyl, or benzyloxybenzyl; R 2 is H, OH, F, CF3, CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, (CH3)2CH2CH2, CH3(O)CCH2, CH3(O)CCH2CH2, Br-CH=CH, phenyl, phenyloxy, benzyl, benzyloxy, benzoyl, benzoyloxy, or benzyloxybenzyl; R 3 is hydroxyl and R 4is benzoyloxy. These include the following compounds: 3'-O-benzoyl-2,2'-anhydrouridine, 3'-O-benzoyl-2,2'-anhydro-5-fluorouridine, 3'-O-benzoyl-2,2'-anhydro-5-trifluoromethyluridine, 3'-O-benzoyl-2,2'-anhydro-5-methyluridine, 3'-O-benzoyl-2,2'-anhydro-5-ethyluridine, 3'-O-benzoyl-2,2'-anhydro-5-propyluridine, 3'-O-benzoyl-2,2'-anhydro-5-isopropyluridine, 3'-O-benzoyl-2,2'-O-anhydro uridine, 3'-O-benzoyl-2,2'-anhydro-5-isobutyluridine, 3'-O-benzoyl-2,2'-anhydro-5-methylacyluridine, 3'-O-benzoyl-2,2'-anhydro-5-propylacyluridine, 3'-O-benzoyl-2,2'-anhydro-5-(2-bromovinyl)uridine, 3'-O-benzoyl-2,2'-anhydro-5-phenyluridine, 3'-O-benzoyl-2,2'-anhydro-5-benzyluridine, 3'-O-benzoyl-2,2'-anhydro-5-benzyluridine, 3'-O-benzoyl-2,2'-anhydro-5-benzyluridine, and 3'-O-benzoyl-2,2'-anhydro-5-(benzyloxybenzyl)uridine. Of particular interest is 3'-O-benzoyl-2,2'-anhydro-5-methyluridine, or pharmaceutically acceptable salts, solvates, hydrates, and prodrug forms thereof, and stereoisomers thereof.

[0117] In addition, the target compound is R 1 is H, F, CF3, CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, (CH3)2CH2CH2, CH3(O)CCH2, CH3(O)CCH2CH2, Br-CH=CH, phenyl, benzyl, benzoyl, or benzyloxybenzyl; R 2is H, OH, F, CF3, CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, (CH3)2CH2CH2, CH3(O)CCH2, CH3(O)CCH2CH2, Br-CH=CH, phenyl, phenyloxy, benzyl, benzyloxy, benzoyl, benzoyloxy, or benzyloxybenzyl; R 3 is benzoyloxy, and R 4 is hydroxyl. These include the following compounds: 5'-O-benzoyl-2,2'-anhydrouridine, 5'-O-benzoyl-2,2'-anhydro-5-fluorouridine, 5'-O-benzoyl-2,2'-anhydro-5-trifluoromethyluridine, 5'-O-benzoyl-2,2'-anhydro-5-methyluridine, 5'-O-benzoyl-2,2'-anhydro-5-ethyluridine, 5'-O-benzoyl-2,2'-anhydro-5-propyluridine, 5'-O-benzoyl-2,2'-anhydro-5-isopropyluridine, 5'-O-benzoyl-2,2'-O-anhydro uridine, 5'-O-benzoyl-2,2'-anhydro-5-isobutyluridine, 5'-O-benzoyl-2,2'-anhydro-5-methylacyluridine, 5'-O-benzoyl-2,2'-anhydro-5-propylacyluridine, 5'-O-benzoyl-2,2'-anhydro-5-(2-bromovinyl)uridine, 5'-O-benzoyl-2,2'-anhydro-5-phenyluridine, 5'-O-benzoyl-2,2'-anhydro-5-benzyluridine, 5'-O-benzoyl-2,2'-anhydro-5-benzyluridine, 5'-O-benzoyl-2,2'-anhydro-5-benzyluridine, and 5'-O-benzoyl-2,2'-anhydro-5-(benzyloxybenzyl)uridine. Of particular interest is 5'-O-benzoyl-2,2'-anhydro-5-methyluridine, or pharmaceutically acceptable salts, solvates, hydrates, and prodrug forms thereof, and stereoisomers thereof.

[0118] The 2,2'-anhydropyrimidine compounds of the present invention can be in a composition containing various derivatives thereof, which can occur as a single stereoisomer, a mixture of stereoisomers, and an equilibrium mixture of tautomers.For example, the 2,2'-anhydropyrimidine of formula (I) contains four stereocenters on the furano ring, including α and β anomers, and L or D mirror image configurations.Examples of stereoisomers of the 2,2'-anhydropyrimidine compounds of the present invention are tautomers and mixtures, including β-D-isomers, β-L-isomers, α-D-isomers, and α-L-isomers, and α,β-D-isomers, α,β-L-isomers, α-DL-isomers, and β-DL-isomers. Thus, in one embodiment, a composition is provided that consists essentially of a stereoisomer of 2,2'-anhydropyrimidine that is the β-D-isomer, β-L-isomer, α-D-isomer, or α-L-isomer.

[0119] Stereoisomers of particular interest include: 2,2'-anhydro-1-(β-D-arabinofuranosyl)uracil; 2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-fluorouracil; 2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-trifluoromethyluracil; 2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-trifluoromethyluracil; 2,2'-anhydro-1-(β-D-arabinofuranosyl) )-5-Methyluracil;2,2'-Anhydro-1-(β-D-arabinofuranosyl)-5-ethyluracil;2,2'-Anhydro-1-(β-D-arabinofuranosyl)-5-n-propyluracil;2,2'-Anhydro-1-(β-D-arabinofuranosyl)-5-isopropyluracil;2,2'-Anhydro-1-(β-D-arabinofuranosyl)-5-isobutyluracil Uracil;2,2'-Anhydro-1-(β-D-arabinofuranosyl)-5-methyacyluracil;2,2'-Anhydro-1-(β-D-arabinofuranosyl)-5-propylacyluracil;2,2'-Anhydro-1-(β-D-arabinofuranosyl)-5-(2-bromovinyl)uracil;2,2'-Anhydro-1-(β-D-arabinofuranosyl)-5-(2-bromovinyl)uracil 2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-phenyluracil; 2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-benzyluracil; 2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-benzyluracil; and 2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-(3-benzoxybenzyl)uracil.Additional stereoisomers of interest include: 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)uracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-fluorouracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-trifluoromethyluracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-trifluoromethyluracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-trifluoromethyluracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-methyluracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-ethyluracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-n-propyluracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-isopropyluracil, 3'-O-benzoyl-2,2'-anhydro-1- (β-D-arabinofuranosyl)-5-isobutyluracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-methylacyluracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-propylacyluracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-(2-bromovinyl)uracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-(2-bromovinyl)uracil, , 2'-anhydro-1-(β-D-arabinofuranosyl)-5-phenyluracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-benzyluracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-benzoyluracil, and 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-(3-benzyloxybenzyl)uracil.Additional stereoisomers of interest include: 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)uracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-fluorouracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-trifluoromethyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β -D-arabinofuranosyl)-5-methyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-ethyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-n-propyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-isopropyluracil, 5'-O-benzoyl-2,2'-anhydro-1-( β-D-arabinofuranosyl)-5-isobutyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-methylacyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-propylacyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-(2-bromovinyl)uracil, 5'-O-benzoyl-2, 2'-anhydro-1-(β-D-arabinofuranosyl)-5-phenyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-benzyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-benzyluracil, and 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-(3-benzyloxybenzyl)uracil.

[0120] Other examples of analogs or derivatives of 2,2'-anhydropyrimidines of the present invention, and their stereoisomers, include 3'-O-acetyl-2,2'-anhydro-5-propyluridine (3'-O-acetyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-propyluracil) and 3'-O-acetyl-2,2'-anhydro-5-isopropyluridine (3'-O-acetyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-isopropyluracil); and 2,2'-anhydrocytidine, and analogs and derivatives thereof, of which the stereoisomer 2,2'-anhydro-1-(β-D-arabinofuranosyl)cytosine is one example.

[0121] As noted above, stereoisomers and various 2,2'-anhydropyrimidines of particular interest are those that exhibit improved activity on a molar basis. Such compounds can be readily selected for this purpose by comparison against a matrix of compounds of particular interest, such as those shown in Table 4 (wherein the compounds are of Formula (I)).

[0122] [Table 4-1]

[0123] [Table 4-2]

[0124] As noted above, the compounds in Table 4 are exemplary, but not limiting. For example, R 4can be not only hydroxyl, but also O-acyl, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, O-alkyl, O-alkylene, O-alkynyl, O-aralkyl, O-aryl, O-aryloxy, O-carbohydrate, O-cycloalkenyl, O-cycloalkyl, O-heterocycloalkyl, O-heteroaryl. In addition, S can be replaced by O and other combinations of structural elements as described herein, and other stereochemical orientations are also possible.

[0125] In certain embodiments, acyl derivatives of 2,2'-anhydropyrimidines of formula (I) are of interest. Thus, compounds of formula (I) include those having R 1 , R 2 , R 3 , and R 4 is as defined above, and R 2 , R 3 , and R 4 At least one of R is an acyl derivative. 2 , R 3 , and R 4 is a substantially non-toxic organic acyl substituent obtainable from a carboxylic acid attached through an ester bond to a hydroxyl group on the ribose or pyrimidine ring of formula (I).

[0126] The acyl derivatives of the 2,2'-anhydropyrimidine compounds of formula (I) include R 1 is as defined above, and each R 2 , R 3 , and R 4 are independently hydrogen, hydroxyl, or an acyl radical, with the proviso that R 2 , R 3 , and R 4 In another embodiment, the acyl derivative of 2,2'-anhydropyrimidine is a 2,2'-anhydropyrimidine having at least one of R 1 and R 2is as defined above, except that R 2 is other than hydrogen, and each R 3 and R 4 is a compound of formula (I), provided that R is independently a hydroxyl or an acyl radical. In one embodiment, the acyl derivative of 2,2'-anhydropyrimidine is 1 is as defined above, and R 2 is hydrogen, and each R 3 and R 4 is independently a hydroxyl or acyl radical. Of particular interest are compounds of formula (I) where R 1 is methyl, and R 2 is hydrogen, and each R 3 and R 4 are independently hydroxyl or acyl radicals. Also of interest are acyl derivatives of the 2,2'-anhydropyrimidine compounds of formula (I), wherein R 1 is methyl, and R 2 is hydrogen, and each R 3 and R 4 is an acyl radical.

[0127] Generally, the ester bond of the acyl derivative of Formula (I) is cleavable under physiological conditions either in vitro, such as in a cell-based system, and / or in vivo, such as through metabolism in the body. Thus, in certain embodiments, the acyl radical is a radical of a metabolite. Such acyl substituents include, but are not limited to, those derived from acetic acid, fatty acids, amino acids, lipoic acid, glycolic acid, lactic acid, enolpyruvic acid, pyruvic acid, orotic acid, acetoacetic acid, beta-hydroxybutyric acid, creatic acid, succinic acid, fumaric acid, adipic acid, benzoic acid, and p-aminobenzoic acid. Specific acyl substituents of interest are compounds that are typically present in the body as either dietary components or intermediate metabolites and are essentially non-toxic when cleaved from the target 2,2'-anhydropyrimidine compound in vivo.

[0128] Of particular interest are compositions comprising 3'-O-acyl-2,2'-anhydropyrimidines or derivatives thereof. For example, acyl derivatives of interest include those in which each R 1 , R 2 , and R 3 are independently selected from hydrogen, hydroxyl, sulfhydryl, amino, hydroxymethyl, methoxy, halogen, pseudohalogen, and substituted or unsubstituted lower hydrocarbons containing 1 to 20 carbons, such as lower hydrocarbons selected from alkyl, alkenyl, alkanoyl, aryl, aroyl, aralkyl, and alkylamino, and esters thereof; R 4 is an O-acyl radical.

[0129] In certain embodiments, the acyl derivatives include R 4 is an O-acyl radical, the O-acyl radical containing 1 to 10 carbon atoms, such as an O-acyl radical selected from aroyloxy, aralkoyloxy, heteroaroyloxy, and cycloalkoyloxy.

[0130] Therefore, the acyl derivative of the 2,2'-anidropyrimidine compound of formula (I) includes 3'-O-acyl-2,2'-anidropyrimidine, 5'-O-acyl-2,2'-anidropyrimidine, 3',5'-O-acyl-2,2'-anidropyrimidine and their derivatives.For example, 3'-O-acyl-2,2'-anhydropyrimidine or its derivative includes 3'-O-aroyl-2,2'-anhydropyrimidine such as 3'-O-aroyl-2,2'-anhydrouridine or its derivative.A particularly interesting example is 3'-O-benzoyl-2,2'-anhydrouridine such as 3'-O-benzoyl-2,2'-anhydro-5-methyluridine or its derivative. Also of interest are compounds in which the 3'-O-benzoyl-2,2'-anhydro-5-methyluridine is the stereoisomer 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-methyluracil.

[0131] In some embodiments, the acyl derivatives of the 2,2′-anhydropyrimidine compounds of Formula (I) include R 1 is H, F, CF3, CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, (CH3)2CH2CH2, CH3(O)CCH2, CH3(O)CCH2CH2, Br-CH=CH, phenyl, benzyl, benzoyl, or benzyloxybenzyl; R 2 is H, OH, F, CF3, CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, (CH3)2CH2CH2, CH3(O)CCH2, CH3(O)CCH2CH2, Br-CH=CH, phenyl, phenyloxy, benzyl, benzyloxy, benzoyl, benzyloxybenzyl, or an acyl radical, and each R 3 and R 4are independently a hydroxyl or an acyl radical. These include the following compounds: 3'-O-benzoyl-2,2'-anhydrouridine, 3'-O-benzoyl-2,2'-anhydro-5-fluorouridine, 3'-O-benzoyl-2,2'-anhydro-5-trifluoromethyluridine, 3'-O-benzoyl-2,2'-anhydro-5-methyluridine, 3'-O-benzoyl-2,2'-anhydro-5-ethyluridine, 3'-O-benzoyl-2,2'-anhydro-5-propyluridine, 3'-O-benzoyl-2,2'-anhydro-5-iso ... isopropyluridine, 3'-O-benzoyl-2,2'-O-anhydro-5-isobutyluridine, 3'-O-benzoyl-2,2'-anhydro-5-methylacyluridine, 3'-O-benzoyl-2,2'-anhydro-5-propylacyluridine, 3'-O-benzoyl-2,2'-anhydro-5-(2-bromovinyl)uridine, 3'-O-benzoyl-2,2'-anhydro-5-phenyluridine, 3'-O-benzoyl-2,2'-anhydro-5-benzyluridine, 3'-O-benzoyl-2,2'-anhiuridine uridine, 5'-O-benzoyl-2,2'-anhydro-5-(benzyloxybenzyl)uridine, 5'-O-benzoyl-2,2'-anhydrouridine, 5'-O-benzoyl-2,2'-anhydro-5-fluorouridine, 5'-O-benzoyl-2,2'-anhydro-5-trifluoromethyluridine, 5'-O-benzoyl-2,2'-anhydro-5-methyluridine, 5'-O-benzoyl-2,2'-anhydro-5-ethyluridine, 5'-O-benzoyl-2,2'-anhydro-5-methyluridine, 5'-O-benzoyl-2,2'-anhydro-5-ethyluridine, 5'-O-benzoyl-2,2'-an Hydro-5-propyluridine, 5'-O-benzoyl-2,2'-anhydro-5-isopropyluridine, 5'-O-benzoyl-2,2'-O-anhydro-5-isobutyluridine, 5'-O-benzoyl-2,2'-anhydro-5-methylacyl lysine, 5'-O-benzoyl-2,2'-anhydro-5-propylacyl lysine, 5'-O-benzoyl-2,2'-anhydro-5-(2-bromovinyl)-uridine, 5'-O-benzoyl-2,2'-anhydro-5-phenyluridine, 5'-O-benzoyl-2,2'-anhydro-5-benzyluridine, 5'-O-benzoyl-2,2'-anhydro-5-benzyluridine, and 5'-O-benzoyl-2,2'-anhydro-5-(benzyloxybenzyl)-uridine, 3',5'-O-benzoyl-2,2'-anhydrouridine, 3',5'-O-benzoyl-2,2'-anhydro-5-fluorouridine, 3',5'-O-benzoyl-2 ,2'-anhydro-5-trifluoromethyluridine, 3',5'-O-benzoyl-2,2'-anhydro-5-methyluridine, 3',5'-O-benzoyl-2,2'-anhydro-5-ethyluridine, 3',5'-O-benzoyl-2,2'-anhydro-5-propyluridine, 3',5'-O-benzoyl-2,2'-anhydro-5-isopropyluridine, 3',5'-O-benzoyl 3',5'-O-benzoyl-2,2'-anhydro-5-isobutyluridine, 3',5'-O-benzoyl-2,2'-anhydro-5-methylacyluridine, 3',5'-O-benzoyl-2,2'-anhydro-5-propylacyluridine, 3',5'-O-benzoyl-2,2'-anhydro-5-(2-bromovinyl)uridine, 3',5'-O-benzoyl-2,2'-anhydro-5-phenyl Uridine, 3',5'-O-benzoyl-2,2'-anhydro-5-benzyluridine, 3',5'-O-benzoyl-2,2'-anhydro-5-benzyluridine, and 3',5'-O-benzoyl-2,2'-anhydro-5-(benzyloxybenzyl)-uridine, or pharmaceutically acceptable salts, solvates, hydrates, and prodrug forms thereof, and stereoisomers thereof.

[0132] Of particular interest are 3'-O-benzoyl-2,2'-anhydro-5-methyluridine, 5'-O-benzoyl-2,2'-anhydro-5-methyluridine, and 3',5'-O-benzoyl-2,2'-anhydro-5-methyluridine, or their pharmaceutically acceptable salts, solvates, hydrates, and prodrug forms, and their stereoisomers. Of particular interest are the β-D-arabinofuranosyl isomers of these compounds, or their pharmaceutically acceptable salts, solvates, hydrates, and prodrug forms.

[0133] In another embodiment, compounds according to formula (I) of particular interest are those having R 1 and R 4 is as defined above, and R 2 and / or R 3 is a cyclic hydrocarbyl. By "cyclic hydrocarbyl" is intended a hydrocarbon-based ring structure having from 3 to about 10 carbon atoms, and having a single cyclic ring or multiple fused rings, which may be substituted. Cyclic hydrocarbyls of interest are selected from aryl, aralkyl, aryloxy, aroyl, aroyloxy, heteroaryl, heteroaryloxy, heteroaroyloxy, cycloalkyl, cycloalkyloxy, and cycloalkoyloxy. Thus, cyclic hydrocarbyls of particular interest are those O-bonded to the ribose or pyrimidine ring of formula (I). R 2 and / or R 3 However, compounds that are cyclic hydrocarbyl exhibit improved activity on a molar basis.

[0134] Thus, certain compounds of the present invention include 5'-O-(cyclic hydrocarbyl)-2,2'-anhydropyrimidine, or a derivative thereof. 5 But R 1 (For example, "5(R 5 )" is R of formula (I) 1 refers to the same as R 5 =R 1 5'-O-(cyclic hydrocarbyl)-2,2'-anhydro-5(R 5)-uridine or its derivatives.

[0135] Compounds of interest are 5'-O-aryl-2,2'-anhydropyrimidines or derivatives thereof, including various 2,2'-anhydrouridine derivatives thereof, such as compounds in which the 5'-O-aryl-2,2'-anhydropyrimidine is a 5'-O-aroyl-2,2'-anhydropyrimidine, such as 5'-O-benzoyl-2,2'-anhydropyrimidine, 5'-O-chlorobenzyl-2,2'-anhydropyrimidine, 5'-O-nitrobenzyl-2,2'-anhydropyrimidine, 5'-O-hydroxybenzyl-2,2'-anhydropyrimidine, and the like.

[0136] In one embodiment, compounds that exhibit improved activity on a molar basis, or improved specificity with respect to not interfering with the efficacy of fluorouracil therapy, are 5'-O-aryl-2,2'-anhydro-5(R 4 )-uridine, 5'-O-aroyl-2,2'-anhydro-5(R 4and 5'-O-aryl-2,2'-anhydrouridine, 5'-O-aroyl-2,2'-anhydrouridine, and derivatives thereof, such as 5'-O-aryl-2,2'-anhydro-5-methyl-uridine, 5'-O-aryl-2,2'-anhydro-5-ethyl-uridine, 5'-O-aryl-2,2'-anhydro-5-propyl-uridine, 5'-O-aryl-2,2'-anhydro-5-benzyl-uridine, and 5'-O-aryl-2,2'-anhydro-5-(2-bromovinyl)-uridine, and derivatives thereof. Examples also include 5'-O-aroyl-2,2'-anhydro-5-methyl-uridine, 5'-O-aroyl-2,2'-anhydro-5-ethyl-uridine, 5'-O-aroyl-2,2'-anhydro-5-propyl-uridine, 5'-O-aroyl-2,2'-anhydro-5-benzyl-uridine, and 5'-O-aroyl-2,2'-anhydro-5-(2-bromovinyl)-uridine, and derivatives thereof. Compounds of particular interest include 5'-O-benzoyl-2,2'-anhydro-5(R)-uridine, such as 5'-O-benzoyl-2,2'-anhydro-5-methyl-uridine, 5'-O-benzoyl-2,2'-anhydro-5-ethyl-uridine, 5'-O-benzoyl-2,2'-anhydro-5-propyl-uridine, 5'-O-benzoyl-2,2'-anhydro-5-benzyl-uridine, and 5'-O-benzoyl-2,2'-anhydro-5-(2-bromovinyl)-uridine. 4 )-uridine.

[0137] Stereoisomers of interest include the β-D-isomers of 5'-O-(cyclic hydrocarbyl)-2,2'-anhydropyrimidines. Examples include, but are not limited to, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)uracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-fluorouracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-trifluoromethyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5- ... uracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-ethyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-n-propyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-isopropyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-isopropyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl) )-5-Isobutyluracil, 5'-O-Benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-methylacyluracil, 5'-O-Benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-propylacyluracil, 5'-O-Benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-(2-bromovinyl)uracil, 5'-O-Benzoyl-2,2'-anhydride r-1-(β-D-arabinofuranosyl)-5-phenyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-benzyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-benzyluracil, and 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-(3-benzyloxybenzyl)uracil.

[0138] As noted above, of interest are also analogs / derivatives of the above compounds.

[0139] The above-mentioned 2,2'-anhydropyrimidines and derivatives thereof can be commercially available or conventionally prepared by techniques known to those skilled in the art. For example, representative patents describing various 2,2'-anhydropyrimidines and derivatives, including intermediates and precursors, analysis, and their synthesis / preparation include U.S. Patent Nos. 3,975,367, 4,145,531, 4,230,698, 4,247,544, 4,544,740, 4,600,740, and 4,700,740. 4,382, 4,613,604, 4,681,933, 4,841,039, 4,916,122, 4,987,224, No. 5,008,384, No. 5,077,280, No. 5,084,445, No. 5,141,943, No. 5,190,926, No. 5,212,293 No. 5,278,167, No. 5,384,396, No. 5,455,339, No. 5,476,855, No. 5,596,093, No. 5,61 No. 0,292, No. 5,721,241, No. 5,723,449, No. 5,739,314, No. 5,760,202, No. 5,889,013, No. Nos. 5,861,493, 6,060,592, 6,090,932, 6,222,025, 6,369,040, 6,642,367, 6,670,461, 6,867,290, and 7,176,295, the disclosures of which are incorporated herein by reference.

[0140] Uridine phosphorylase (UPase) inhibitors also include benzyl acyclouridine, benzyloxyacylouridine, aminomethyl-benzylacylouridine, aminomethyl-benzyloxybenzylacyclouridine, hydroxymethyl-benzylacyclouridine, hydroxymethyl-benzyloxybenzylacyclouridine, and derivatives of 5-benzyl barbiturate such as 5-benzyloxybenzyl barbiturate, 5-benzyloxybenzyl-1-(1-hydroxy-2-ethoxy)methyl)barbiturate, 5-benzyloxybenzylacetyl-1-(1-hydroxy-2-ethoxy)methyl)barbiturate, and 5-benzyloxybenzyl-1-(1,3-dihydroxy-2-pro barbiturate, 5-benzyloxybenzyl-1-(2-(3-carboxypropionyloxy)ethoxy)methyl)barbiturate, 5-benzyloxybenzyl-1-(2-(3-carboxypropionyloxy)ethoxy)methyl)barbiturate, 5-benzyl-1-(1-hydroxy-2-ethoxy)methyl)barbiturate, 5-methoxybenzylacetyl barbiturate, 5-benzyl-1-(1,3-dihydroxy-2-propoxy)methyl)barbiturate, 5-benzyl-1-(1-hydroxy,3-amino-2-propoxy)methyl)barbiturate, and 5-benzyl-1-(2-(3-carboxypropionyloxy)ethoxy)methyl)barbiturate. Upase inhibitors that may be used in embodiments of the present invention include, but are not limited to, those described in U.S. Pat. Nos. 5,723,449, 5,141,943, 5,077,280, and 4,613,604, the disclosures of which compounds are incorporated herein by reference.

[0141] Uridine (UR) activator As summarized above, in some embodiments, a UPase inhibitor is administered to a subject in combination with a UR activator (e.g., uridine (UR), a UR prodrug, or a UR mimetic). Uridine is a nucleoside formed when uracil is attached to a ribose ring (also known as ribofuranose) via a β-N1-glycosidic bond. Uridine is available in phosphorylated forms, i.e., uridine-5'-monophosphate (also known as 5'-uridine acid and UMP), uridine 5'-monophosphate tris salt, uridine 5'-monophosphate dihydrate, uridine 5'-monophosphate solution, uridine 5'-monophosphate hydrate, uridine 13C 9. 15 N25'-monophosphate sodium salt solution, uridine- 15 N25'-monophosphate sodium salt solution, uridine 5'-monophosphate trisodium salt hydrate, uridine-N25'-monophosphate sodium salt solution, uridine-5'-diphosphate (UDP), uridine 5'-diphosphate tris salt, uridine 5'-diphosphate dihydrate, uridine 5'-diphosphate solution, uridine 5'-diphosphate hydrate, uridine 13C 9. 15 N25'-diphosphate sodium salt solution, uridine-5'-triphosphate (UTP), UTPγS, MRS2498, uridine 5'-triphosphate tris salt, uridine 5'-triphosphate dihydrate, uridine 5'-triphosphate solution, uridine 5'-triphosphate hydrate, uridine 13C 9. 15N2 5'-5'-triphosphate sodium salt solution, 2-diuridine tetraphosphate, thio-UTP tetrasodium salt, denufosol tetrasodium, or UTP.gamma.S trisodium salt, the prodrug known in the art as triacetyluridine (TAU) or uridine triacetate (PN501), acyl derivatives of uridine such as those described in U.S. Pat. No. 7,582,619 (i.e., 2',3',5'-tri-O-pyruvyluridine), 2,2'-anhydro-5-ethyluridine, 5-ethyl-2-de Acyclouridine compounds such as oxyuridine and 5-benzyl-substituted acyclouridine congeners, including, for example, benzyl acyclouridine, benzyloxybenzylacyclouridine, aminomethyl-benzylacyclouridine, aminomethylbenzyloxy-benzylacyclouridine, hydroxymethyl-benzyloxy-benzylacyclouridine (see also WO89 / 09603 and WO91 / 16315), and are available in dietary supplements such as Mitocnol and NucleomaxX, which are derived from sugarcane extracts.

[0142] UR and its sources include, but are not limited to, meat products such as fish, pig, and beef liver and pancreas; fungal products such as brewer's yeast, beer, and mushrooms; plant products such as sugarcane, tomato, oats, algae, and broccoli; and salts such as UR phosphate and acylated UR. UR and its sources that can be used in embodiments of the present invention include, but are not limited to, those described in U.S. Patent Nos. 9,579,337, 6,316,426, and 5,470,838, the disclosures of which are incorporated herein by reference.

[0143] UR precursors and sources thereof include, but are not limited to, UR prodrugs such as triphenyluridine and orotic acid; uridine 5'-monophosphate prodrugs such as mono- and di-alkyl esters, acyloxyalkyl esters, alkoxycarbonylmethyl esters, substituted ethyl and propyl esters, amidomethyl esters, benzyl esters, phenyl esters, phosphonamidates, and cyclophosphates; UR prodrugs containing UR mono-, di-, or tri-esters such as mono-, di-, and triacetyl UR; UR prodrugs containing UR monophosphate, diphosphate, or triphosphate such as UR monophosphate, UR diphosphate, and UR triphosphate; UR homodimers such as UPU and their esters; heterodimers of dideoxynucleoside compounds and UR or UPase inhibitors such as AZT-PU and AZT-P-BAU. Uridine precursors and sources thereof that can be used in embodiments of the present invention include, but are not limited to, those described in U.S. Patent Nos. 5,723,449 and 7,737,128, the disclosures of which are incorporated herein by reference.

[0144] Uridine (UR) processing regulator If desired, UR processing regulator can also be administered to the subject in combination with UPase inhibitor.UR secretion inhibitor compound includes but is not limited to drugs such as dilazep, hexobendine, etc.UR secretion inhibitor compound that can be used in the embodiments of the present invention includes but is not limited to those described in U.S. Patent No. 6,989,376 and U.S. Patent No. 5,567,689, the disclosure of which is incorporated herein by reference.

[0145] UR renal transport competitors include, but are not limited to, drugs such as L-uridine, L-2',3'-dideoxyuridine, and D-2',3'-dideoxyuridine. UR renal transport competitors that may be used in embodiments of the present invention include, but are not limited to, those described in U.S. Patent Nos. 6,989,376, 5,723,449, and 5,567,689, the disclosures of which compounds are incorporated herein by reference.

[0146] compound Also provided are pharmaceutical compositions that find use in embodiments of the present invention, containing a UPase inhibitor and / or a UR activator, for example, as described above. The active agents may be present in the pharmaceutical composition, for example, in the form of a pharmaceutically acceptable salt, and may be formulated for oral, topical, or parenteral administration for use in the subject methods, as described above. Formulations used in embodiments of the present invention may contain a single active agent or a combination of active agents. Thus, embodiments of the present invention include formulations containing a single active agent, such as a UPase inhibitor or a UR activator, as well as formulations containing two or more active agents, such as when both a UPase inhibitor and a UR activator are present together in a common formulation.

[0147] For example, the UPase inhibitor and, if desired, the UR activator (separately or in combination) can be mixed with conventional pharmaceutically acceptable carriers and excipients (e.g., vehicles) and used in the form of aqueous solutions, tablets, capsules, elixirs, suspensions, syrups, wafers, and the like. Such pharmaceutical compositions, in certain embodiments, contain from about 0.1% to about 90% by weight of the active compound, more typically from about 1% to about 30% by weight. Pharmaceutical compositions may contain common carriers and excipients such as corn starch or gelatin, lactose, dextrose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid. Disintegrants commonly used in the formulations of the present invention include croscarmellose, microcrystalline cellulose, corn starch, sodium starch glycolate, and alginic acid.

[0148] Liquid compositions generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier, for example, ethanol, glycerin, sorbitol, polyethylene glycol, oil, or a non-aqueous solvent such as water, containing a suspending agent, preservative, surfactant, wetting agent, flavoring, or coloring agent. Alternatively, liquid formulations can be prepared from reconstitutable powders.

[0149] For example, a powder containing the active compound, suspending agent, sucrose, and sweetener may be reconstituted with water to form a suspension, or a syrup may be prepared from a powder containing the active ingredient, sucrose, and sweetener.

[0150] The composition in the form of tablet can be prepared using any suitable pharmaceutical carrier that is usually used for preparing solid compositions.Examples of such carrier include magnesium stearate, starch, lactose, sucrose, microcrystalline cellulose, and binders such as polyvinylpyrrolidone.Tablet can also be provided with color film coating or coloring agent that is included as part of carrier.In addition, active compound can be formulated in controlled release dosage form as tablet that includes hydrophilic or hydrophobic matrix.

[0151] The composition in the form of capsule can be prepared by using the usual encapsulation procedure, for example, by incorporating active compound and excipient into hard gelatin capsule.Alternatively, the semi-solid matrix of active compound and high molecular weight polyethylene glycol can be prepared and filled into hard gelatin capsule, or the solution of active compound in polyethylene glycol or the suspension in edible oil, for example, liquid paraffin or fractionated coconut oil, can be prepared and filled into soft gelatin capsule.

[0152] Tablet binders that may be mentioned are acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (povidone), hydroxypropyl methylcellulose, sucrose, starch, and ethylcellulose.Lubricants that may be used include magnesium stearate or other metal stearates, stearic acid, silicone fluid, talc, waxes, oils, and colloidal silica.

[0153] Flavoring agents such as peppermint, oil of wintergreen, cherry flavor, etc. may also be used. Additionally, it may be desirable to add coloring agents to make the dosage form more visually appealing or to aid in product identification.

[0154] The compounds of the invention and their pharmaceutically acceptable salts that are active upon given parenteral administration may be formulated for intramuscular, intrathecal, or intravenous administration.

[0155] A typical composition for intramuscular or intrathecal administration is a suspension or solution of the active ingredient in oil, such as arachis oil or sesame oil. A typical composition for intravenous or intrathecal administration is, for example, a sterile isotonic aqueous solution containing the active ingredient and dextrose or sodium chloride, or a mixture of dextrose and sodium chloride. Other examples include lactated Ringer's injection, lactated Ringer's plus dextrose injection, Normosol-M and dextrose, Isolyte E, acylated Ringer's injection, etc. Optionally, cosolvents such as polyethylene glycol, chelating agents such as ethylenediaminetetraacetic acid, and antioxidants such as sodium metabisulfite may be included in the formulation. Alternatively, the solution may be lyophilized and then reconstituted with a suitable solvent immediately before administration.

[0156] The compounds of the present invention and their pharmaceutically acceptable salts that are active for rectal administration can be formulated as suppositories.A typical suppository formulation generally consists of an active ingredient with a binder and / or lubricant, such as gelatin or cocoa butter, or other low-melting vegetable or synthetic waxes or fats.

[0157] The compounds of the present invention and their pharmaceutically acceptable salts that are active upon topical administration can be formulated as transdermal compositions or transdermal delivery devices ("patches"). Such compositions include, for example, a backing, an active compound reservoir, a control membrane, a liner, and a contact adhesive. Such transdermal patches can be used to provide continuous or discontinuous infusion of a controlled amount of the compounds of the present invention. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, U.S. Pat. No. 5,023,252, which is incorporated herein by reference in its entirety. Such patches can be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0158] In certain embodiments of interest, the UPase inhibitor and the UR activator are administered as a single pharmaceutical formulation, which contains other suitable compounds and carriers in addition to the active agent, and may also be used in combination with other active agents. Thus, the present invention also includes pharmaceutical compositions containing pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, for example, any suitable vehicle, adjuvant, carrier, or diluent, and are readily available to the public. The pharmaceutical compositions of the present invention may further contain other active agents known in the art.

[0159] Those skilled in the art will understand that a variety of suitable methods are available for administering the formulations of the present invention to a subject or host, such as a patient, in need of the formulation, and that more than one route can be used to administer a particular formulation, with a particular route providing a more immediate and effective response than another route. Pharmaceutically acceptable excipients are also well known to those skilled in the art and readily available. The choice of excipient is determined in part by the specific compound and the specific method used to administer the composition. Therefore, suitable formulations of the pharmaceutical compositions of the present invention are diverse. The following methods and excipients are merely exemplary and are in no way limiting.

[0160] Formulations suitable for oral administration may consist of (a) liquid solutions, such as an effective amount of the compound dissolved in a diluent such as water, saline, or orange juice, (b) capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient as a solid or granules, (c) suspensions in a suitable liquid, and (d) suitable emulsions. Tablet forms may contain one or more of lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffers, wetting agents, preservatives, flavoring agents, and pharmacologically compatible excipients. Lozenge forms may comprise the active ingredient in a flavoring, which is usually sucrose and acacia or tragacanth, and pastilles, emulsions, gels, etc., containing the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia, containing, in addition to the active ingredient, such excipients as are known in the art.

[0161] The formulations of the present subject matter can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They can also be formulated as pharmaceuticals for non-pressurized preparations, such as for use in a nebulizer or atomizer.

[0162] Formulations suitable for parenteral administration include isotonic aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives. The formulations may be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid vehicle for injection, such as water, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the type described above.

[0163] Formulations suitable for topical administration may be presented as creams, gels, pastes, or foams containing, in addition to the active ingredient, any other such carriers known in the art to be appropriate.

[0164] Suppository formulations are also provided by mixing with a variety of bases, such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, or foams.

[0165] Unit dosage forms for oral or rectal administration, such as syrups, elixirs, and suspensions, may be provided, in which each dosage unit, e.g., teaspoon, tablespoon, tablet, or suppository, contains a predetermined amount of a composition containing one or more inhibitors. Similarly, unit dosage forms for injection or intravenous administration may contain the inhibitor(s) in a composition as a solution in sterile water, normal saline, or another pharmaceutically acceptable carrier.

[0166] The term "unit dosage form" as used herein refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of a compound of the present invention calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle. The specifications for the novel unit dosage forms of the present invention depend on the particular compound employed and the effect to be achieved, as well as the pharmacodynamics associated with each compound in the host.

[0167] Those of skill in the art will readily appreciate that dosage levels can vary as a function of the particular compound, the nature of the delivery vehicle, etc. Appropriate dosages for a given compound are readily determinable by those of skill in the art by a variety of means.

[0168] In the context of the present invention, the dose administered to an animal, particularly a human, should be sufficient to induce a prophylactic or therapeutic response in the animal over a reasonable time frame. Those skilled in the art will recognize that the dosage depends on a variety of factors, including the strength of the specific compound used, the condition and weight of the animal, and the severity and stage of the disease. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that may accompany the administration of a specific compound. Optionally, the pharmaceutical composition may contain other pharmaceutically acceptable components, such as buffers, surfactants, antioxidants, viscosity modifiers, preservatives, etc. Each of these components is well known in the art. See, for example, U.S. Patent No. 5,985,310, the disclosure of which is incorporated herein by reference.

[0169] Other ingredients suitable for use in the formulations of the present invention can be found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, Pa., 17th ed. (1985). In one embodiment, the aqueous solution of cyclodextrin also contains dextrose, e.g., about 5% dextrose.

[0170] availability The subject method finds use in the treatment of liver disease.Target liver disease can vary, but in some cases, liver disease is characterized by the presence of fibrosis features or the accumulation of extracellular matrix molecules that constitute scar tissue as toxic endpoint, and other diseases such as pulmonary fibrosis, renal fibrosis, systemic sclerosis (SSc), scleroderma graft-versus-host disease, radiation-induced fibrosis and cardiac fibrosis, among others.

[0171] In some cases, the liver disease is fatty liver disease. Fatty liver disease, also known as fatty liver or fatty liver disease (FLD), is a condition in which large vacuolar triglyceride fats accumulate in liver cells through the process of steatosis, or abnormal intracellular lipid retention. Despite having multiple causes, fatty liver is considered a single disease that frequently occurs in subjects with excessive alcohol consumption and in obese subjects (with or without the effects of insulin resistance). This condition is also associated with other diseases affecting fat metabolism. FLD can be classified into two separate conditions: alcoholic FLD and non-alcoholic FLD. Both conditions exhibit microdroplet and macrodroplet fatty changes at different stages of the disease. Fat accumulation can also be accompanied by progressive liver inflammation (hepatitis), referred to as steatohepatitis. Fatty liver is also known in the art as alcoholic steatosis and non-alcoholic fatty liver disease (NAFLD), and its more serious form is alcoholic steatohepatitis (a part of alcoholic liver disease) and non-alcoholic steatohepatitis (NASH).The cirrhosis associated with non-alcoholic fatty liver disease is the most serious form of the disease, characterized by liver inflammation, which leads to scarring of liver tissue, and eventually leads to liver failure.In some cases, liver condition is NAFLD, NASH or DILI.

[0172] Treatment means that at least the symptoms associated with the condition that the host suffers from are improved, and improvement is used in a broad sense to refer to the magnitude of a parameter, for example, the symptoms associated with the condition being treated, or at least the side effects resulting from the administration of a drug, at least reducing.Therefore, treatment also includes the situation where a pathological condition or at least the symptoms associated with it are completely inhibited, for example, prevented from occurring or stopped, for example, terminated, such that the host no longer suffers from the condition, or at least the symptoms that characterize the condition.Treatment also includes the prophylactic treatment of an object so that a liver condition does not occur in the object.Therefore, treatment includes preventing the occurrence of a liver condition in an object.

[0173] A variety of subjects can be treated according to the subject method. Generally, such hosts are "mammals" or "mammals," which terms are used broadly to describe organisms within the mammalian class, including carnivora (e.g., dogs and cats), rodents (e.g., mice, guinea pigs, and rats), and primates (e.g., humans, chimpanzees, and monkeys). In many embodiments, the subject is a human.

[0174] In certain embodiments, the subject is a subject who has been diagnosed with and is in need of administration of an active agent, and thus is in need of administration of an active agent. In certain embodiments, the method can include diagnosing the subject for the presence of a disease state that is treated by administration of an active agent.

[0175] When the liver disease is DILI, the method of the present invention can be used in combination with a therapeutic regimen suspected of causing DILI, for example, to treat DILI that has already occurred or to preventively treat DILI. When the compounds of the present invention are administered in conjunction with other therapies, the dosage of the co-administered compounds will, of course, vary depending on the type of co-drug used, the specific drug used, the condition being treated, etc. As used herein, the terms "combination treatment," "combination therapy," "combined treatment," or "combinatorial treatment," which are used interchangeably, refer to the treatment of an individual with at least two different therapeutic agents. As used herein, terms such as "co-administration" or "co-administration" are intended to encompass the administration of selected therapeutic agents to a single patient and are intended to include therapeutic regimens in which the agents do not necessarily need to be administered by the same route of administration or at the same time. The term "pharmaceutical combination" refers to a product resulting from the mixing or combination of two or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients. "Fixed combination" means that both the active ingredients, e.g., the compounds disclosed herein, and one or more additional therapeutic agents are administered to a patient simultaneously in the form of a single entity or dosage. "Non-fixed combination" means that both the active ingredients, e.g., the compounds disclosed herein, and one or more additional therapeutic agents are administered to a patient as separate entities, either simultaneously, concurrently, or sequentially, without specific time restrictions, such that such administration provides therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients. As used herein, the methods of the present invention include combinations of drugs for pulmonary hypertension, such as ambrisentan, bosentan, treprostinil, sildenafil, epoprostenol, treprostenol, and iloprost, aldosterone receptor antagonists such as spironolactone and eplerenone, trandolapril, fosinopril, and the like.angiotensin-converting enzyme inhibitors such as enalapril, captopril, ramipril, moexipril, lisinopril, quinapril, benazepril, and perindopril; angiotensin II inhibitors such as eprosartan, olmesmian, telmismian, losartan, valsmian, candesartan, and irbesmian; antianginal agents such as nitroglycerin, isosorbide mononitrate, and isosorbide dinitrate; moricizine, quinidine, disopyramine, antiarrhythmics, including phenyloin, propafenone, flecamide, mexilitene, lidocaine, procainamide, propranolol, acebutolol, amiodarone, dofetilide, dronedarone, sotalol, ibutilide, diltiazem, verapamil, nifedipine, nimodipine, felodipine, nicardipine, clevidipine, isradipine, bepridil, nisoldipine, adenosine, and digoxin, betaxolol, bisoprolol, metoprolol, atenolol, nebivolol, nadolol, carvedilol, Antidiabetic agents including secretagogues such as P-adrenergic receptor antagonists such as labetalol, timolol, carteolol, penbutolol, pindole, and esmolol, sulfonylureas, tolbutamide, acetohexamide, tolazamide, chlorpropamide, meglitinides such as glipizide, glyburide, glimepiride, glibenclamide, gliclazide, nateglinide, senaglinide, and repaglinide, biguanides, insulin sensitizers such as metformin, rosiglitazone, isaglitazone, darglitazone, englitazone, and pioglitazone α-glucosidase inhibitors such as miglitol, voglibose, emiglitate, and acarbose; glucagon-like peptide analogs and agonists such as exenatide, liraglutide, and taspglutide; dipeptidyl peptidase-4 inhibitors such as vildagliptin, sitagliptin, and saxagliptin; amylin analogs such as pramlintide; peroxisome proliferator-activated receptor (PPAR)-alpha, beta, delta, and gamma ligands or agonists, e.g.,Cholesterol-lowering agents such as hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, such as statins, including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin; agonists of the retinoid X receptor (RXR), such as ALRT-268, LG-1268, or LG-1069; glucokinase activators, which are inhibitors of hepatic enzymes involved in stimulating gluconeogenesis and / or glycogenolysis; acetazolamide, dichlorphenamide, methazolamide, torasemide, furosemide, bumetanide, ethoxycaproate, thiazolinone, thiazolinone; It may be used in combination with one or more additional therapeutic agents, including, but not limited to, diuretics such as clinic acid, amiloride, triamterene, indapamide, metolazone, methylclothiazide, hydrochlorothiazide, chlorothiazide, metolazone, bendroflumethiazide, polythiazide, and chlorthalidone; vasodilators such as alprostadil, hydralazine, minoxidil, nesiritide, and nitroprusside; and other antilipidemic agents such as cholestyramine, colestipol, clofibrate, gemfibrozil, probucol, or dextrothyroxine.

[0176] Kits and Systems Also provided are kits and systems that find use in practicing the subject methods described above. For example, kits and systems for practicing the subject methods may include one or more pharmaceutical formulations containing a UPase inhibitor and, in some embodiments, a UR activator. Thus, in certain embodiments, the kit may include a single pharmaceutical composition present as one or more unit dosages, the composition including both a UPase inhibitor and a UR activator. In yet other embodiments, the kit may include two or more separate pharmaceutical compositions, each containing a UPase inhibitor and, optionally, a UR activator.

[0177] In addition to the above components, the subject kits may further include instructions for practicing the subject methods. These instructions may be present in the subject kits in a variety of forms, one or more of which may be present in the kit. One form in which these instructions may be present is as information printed on a suitable medium or substrate, such as one or more sheets of paper on which the information is printed, within the kit packaging, within the packaging insert, etc. Yet another means may be a computer-readable medium, such as a disk, CD, etc., on which the information is stored. Yet another means may be a website address that can be used via the Internet to access information at a remote site. Any convenient means may be present in the kit. For example, a kit according to one embodiment includes, as a first component, (a) instructions for using the plasma UR level regulator, and, as a second component, (b) a pharmaceutical composition containing a uridine, a UR prodrug, or a UR mimetic.

[0178] Kits of particular interest include 2,2'-anhydropyrimidine pharmaceutical compositions of the invention and are suitable for practicing the subject methods, such as for alleviating serious liver conditions.

[0179] As used herein, the term "system" refers to a collection of UPase inhibitors and, optionally, UR activators, present in a single or different compositions, that are combined for the purpose of practicing the subject methods. For example, separately obtained dosage forms of a UPase inhibitor and a UR activator that are combined in accordance with the present invention and co-administered to a subject are systems according to the present invention.

[0180] The following examples further illustrate the present invention but should not be construed as in any way limiting its scope. [Example]

[0181] I. Increase in UR with increasing concentration of compound I UR allows for extremely rapid clearance in just a few minutes. 1 / 2 and 46Compound I elimination in mice 1 / 2 Because the release of UR after a separate dose of Compound I, such as that used for ip dosing, is only 1-2 h long, it is very difficult to measure the increase in UR concentration after each dose. For this reason, a continuous infusion of Compound I (genuine TK-112690, batch TCY90108) into BDF®-1 male mice was administered via an osmotic pump implanted sc, and UR plasma concentrations were measured.

[0182] A solution of Compound I was prepared at a concentration of 500 mg / mL in sterile PBS. Osmotic pumps (ALZET® Microosmotic Pumps 2001D and 1003D, Alza Co.) were filled with 200 μL (2001D osmotic pump) and / or 100 μL (1003D osmotic pump) of TK-112690 solution.

[0183] BDF-1 male mice (n=6) were treated with a constant infusion of Compound I at doses of 667, 833, or 3000 mg / kg / day delivered via subcutaneously implanted osmotic pumps. Prior to pump implantation, animals were anesthetized with 100 mg / kg ketamine. Using surgical scissors, an approximately 1 cm incision was made on the back of the animal near the shoulder blades. A hemostat was used to create a subcutaneous tunnel toward the front end of the animal. The osmotic pump was positioned inside the subcutaneous tunnel. The incision was then sealed with wound clips.

[0184] Blood samples were collected from animals anesthetized with ketamine (100 mg / kg i.p.). Blood samples from animals treated with a constant-rate TK-112690 infusion were collected 72 hours after pump implantation for 667 mg / kg / day and 833 mg / kg / day, and 24 hours after pump implantation for 3000 mg / kg / day. Whole blood (approximately 0.8 mL) was withdrawn through the retro-orbital sinus using heparin-coated micro-hematocrit tubes and collected in EDTA microtubes. Blood samples were transferred to unused 1.5 mL microcentrifuge tubes, centrifuged at 14,000 × g for 10 minutes using an Eppendorf Minispin Plus, and stored in a 4°C refrigerator. Exactly 0.4 mL of plasma was transferred to an unused microcentrifuge tube containing 2 μL of 10 mM 5-FU and vortexed at the highest setting for approximately 5 seconds. A final concentration of 50 μM 5-FU was used as an internal standard. Animals were sacrificed by cervical dislocation and disposed of appropriately.

[0185] Blood samples from animals treated with a constant-rate infusion of Compound I were collected 72 hours after pump implantation for 667 mg / kg / day and 833 mg / kg / day, and 24 hours for 3000 mg / kg / day. Whole blood (approximately 0.8 mL) was withdrawn through the retro-orbital sinus using heparin-coated micro-hematocrit tubes and collected in EDTA microtubes. Blood samples were transferred to unused 1.5 mL microcentrifuge tubes, centrifuged at 14,000 × g for 10 minutes using an Eppendorf Minispin Plus, and stored in a refrigerator at 4°C. Exactly 0.4 mL of plasma was transferred to unused microcentrifuge tubes containing 2 μL of 10 mM 5-FU and vortexed at the highest setting for approximately 5 seconds. A final concentration of 50 μM 5-FU was used as an internal standard. Animals were sacrificed by cervical dislocation and disposed of appropriately.

[0186] Solid-phase extraction (SPE) of the analytes (UR, Compound I, and 5-FU) from plasma was performed prior to HPLC analysis. A Supelco C8 SPE column was used for the extraction process. Positive pressure generated by a vacuum pressure pump (Barnant Company Model 400-1901) was used to force all solutions through the SPE column. The flow rate through the SPE column was approximately 2 drops per second. The SPE column was pre-washed with a total of 2.4 mL of sterile PBS (room temperature, pH = 7.4). Exactly 0.6 mL of PBS was added to the SPE column in four portions and forced through the column. Immediately after pre-wash, 0.4 mL of the plasma sample (spiked with 5-FU internal standard) was transferred onto the column and forced through the column. The analytes were separated from the SPE column by forcing through exactly 0.5 mL of 5 M NaCl (room temperature, pH ∼5). The eluted sample was collected in a fresh 1.5 mL microcentrifuge tube. The samples were transferred to fresh HPLC vials and analyzed.

[0187] HPLC analysis was performed at room temperature (RT) using a ThermoFinnigan Spectra System equipped with a degasser, pump, autosampler, and UV detector. Chromatograms were constructed from a chart recorder equipped with a pen. A Phenomenex C18 reverse-phase column (250 × 4.6 mm) was used to separate the analytes. Two separate mobile phase gradients were used for the HPLC analysis: (1) 5% methanol in nanowater containing 0.1% formic acid and (2) 5% methanol in acetonitrile containing 0.1% formic acid (flow rate = 0.5 mL per minute). The HPLC responses for Compound I and UR were divided by the 5-FU response. A calibration curve was used to convert these ratios to the concentration of Compound I.

[0188] A regression analysis of the data from the study (UR concentration vs. Compound I concentration) is provided in Figure 1. Higher concentrations of Compound I appear to be associated with higher levels of UR.

[0189] II. Methionine-Choline Diet (MCD) Model of NASH Mice fed the MCD diet are a standard model of diet-induced NASH. 47、48 All animals were housed in ventilated standard enclosure cages throughout the experimental phase. Tap water was provided ad libitum to all animals. Male 8-week-old C57BL / 6 mice from Charles River were maintained on a standard chow diet for 3 days for acclimation, and groups were housed in HEPA-filtered cages (5 animals per cage) with a normal 12-hour light cycle (lights on from 8 AM to 8 PM). Temperature and humidity were 22 ± 2 °C and 50 ± 10%, respectively. Cage bedding was changed once a week.

[0190] After acclimation, animals were randomized according to body weight into homogeneous treatment groups and fed ad libitum a methionine- and choline-deficient diet (4.2 kcal / g; MP Biomedicals, Solon, OH). Food and water intake was measured three times per week (at the same time as body weight measurements). After the acclimation period, 24 mice (n=6 / treatment group) were weighed three times per week until sacrifice.

[0191] The four treatment groups were: Group 1: Vehicle + MCD Group 2: MCD + 200 mg / kg UR Group 3: MCD + 60 mg / kg of Compound I Group 4: MCD + 60 mg / kg Compound I, plus UR at 200 mg / kg 30 minutes after Compound I

[0192] All Compound I and UR doses (mg / kg in 10 mL / kg vehicle) were administered i.p., bid, at least 8 hours apart for 28 days. Vehicle = PBS. Vehicle, UR, and Compound I ± UR were administered daily, starting 2 days before the animals were placed on the MCD diet. Mice were placed on the MCD diet for 26 days.

[0193] After 26 days on MCD, animals were sacrificed approximately 2 hours after the final dose, and nonfasting glucose was measured along with a plasma lipid panel, TNF-α, ALT, and AST. Total body weight was determined weekly. Total livers were weighed, and the medial lobes were excised, formalin-fixed, and stained with Oil Red O to assess lipid content. An intensity score was also determined for fixed tissue slides measured by an independent histopathologist.

[0194] As expected, 49 Body weight decreased by approximately 20% in all treatment groups (Figure 2; data presented as mean + / - SEM). There were no differences in body weight between groups. There were also no differences between groups 2, 3, and 4 for total triglycerides, cholesterol, AST, or ALT. There was a statistically significant difference in HDL-cholesterol levels between groups 1 and 4 (Figure 3). (Serum HDL cholesterol concentrations were measured at the end of the MCD study. Data are means + / - SEM. TK-90 is Compound I, also known as TK-112690). Most importantly, the findings of fibrosis were observed (Figure 4). ((A) Representative H&E images of liver sections from each experimental group. (B) Fibrosis scores for the images shown in (A). TK-90 is Compound I, also known as TK-112690. Data are means + / - SEM.) The significance of the data is that fibrosis is a pathological endpoint of NASH. In the data in Figure 4, groups 2, 3, and 4 were all statistically different from the group 1 control group.

[0195] Notwithstanding the scope of the appended claims, the present disclosure is also defined by the following notes. 1. A method of treating a subject for a liver condition, comprising: A method comprising administering to a subject an effective amount of 2,2'-anhydropyrimidine or a derivative thereof to treat the subject for a liver condition. 2. 2,2'-anhydropyrimidine or a derivative thereof is a compound of formula (I):

[0196] [ka]

[0197] or pharmaceutically acceptable salts, solvates, hydrates, and prodrug forms thereof, and stereoisomers thereof; During the ceremony, Each R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted heteroatom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, carbohydrate, nucleic acid, amino acid, peptide, dye, fluorophore, and polypeptide. 3.Each R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, hydroxyl, sulfhydryl, amino, hydroxymethyl, methoxy, halogen, pseudohalogen, and substituted or unsubstituted lower hydrocarbons containing 1 to 20 carbons. 4. The method of claim 2, wherein the lower hydrocarbon is selected from the group consisting of alkyl, alkenyl, alkanoyl, aryl, aroyl, aralkyl, and alkylamino, and esters thereof. 5.R 1 is hydrogen, fluorine, methyl, ethyl, propyl, benzyl, or 2-bromovinyl, and R 2 is hydrogen, hydroxyl, fluorine, methyl, ethyl, propyl, benzyl, benzoyl, benzoyloxy, or 2-bromovinyl, and each R 3 and R 4 is independently selected from the group consisting of hydroxyl and benzoyloxy.

[0198] 6.R 1 is hydrogen or methyl, and R 2 is hydrogen, and each R 3and R 4 is independently selected from the group consisting of hydroxyl and benzoyloxy. 7. The method of claim 1, wherein the 2,2'-anhydropyrimidine or a derivative thereof is selected from the group consisting of 2,2'-anhydro-5-methyluridine; 3'-O-benzoyl-2,2'-anhydrouridine; 3'-O-benzoyl-2,2'-anhydro-5-methyluridine; 5'-O-benzoyl-2,2'-anhydrouridine; and 5'-O-benzoyl-2,2'-anhydro-5-methyluridine. 8. The method according to Appendix 7, wherein the 2,2'-anhydropyrimidine or a derivative thereof is 2,2'-anhydro-5-methyluridine. 9. The method according to Appendix 7, wherein the 2,2'-anhydropyrimidine or a derivative thereof is 3'-O-benzoyl-2,2'-anhydro-5-methyluridine. 10. The method according to Appendix 7, wherein the 2,2'-anhydropyrimidine or a derivative thereof is 5'-O-benzoyl-2,2'-anhydro-5-methyluridine.

[0199] 11. The method according to Appendix 1, wherein the 2,2'-anhydropyrimidine or derivative thereof includes stereoisomers. 12. The method of claim 11, wherein the stereoisomer is selected from the group consisting of 2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-methyluracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-uracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-methyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-uracil, and 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-methyluracil. 13. The method of any one of appendices 1-12, wherein the liver condition is selected from the group consisting of NAFLD, NASH, and DILI. 14. The method of any one of appendices 1 to 13, wherein the treatment is prophylactic. 15. The method of claim 14, wherein the liver condition is DILI. 16. The method of any one of appendices 1-13, wherein the subject is suffering from a liver condition.

[0200] 17. A method of treating a subject for a liver condition, comprising: A method comprising administering to a subject an effective amount of a 2,2'-anhydropyrimidine or derivative thereof in combination with a uridine (UR) activator to treat the subject for a liver condition. 18. 2,2'-anhydropyrimidine or a derivative thereof is a compound of formula (I):

[0201] [ka]

[0202] or pharmaceutically acceptable salts, solvates, hydrates, and prodrug forms thereof, and stereoisomers thereof; During the ceremony, Each R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted heteroatom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, carbohydrate, nucleic acid, amino acid, peptide, dye, fluorophore, and polypeptide. 19.Each R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, hydroxyl, sulfhydryl, amino, hydroxymethyl, methoxy, halogen, pseudohalogen, and substituted or unsubstituted lower hydrocarbons containing 1 to 20 carbons. 20. The method of claim 18, wherein the lower hydrocarbon is selected from the group consisting of alkyl, alkenyl, alkanoyl, aryl, aroyl, aralkyl, and alkylamino, and esters thereof.

[0203] 21.R 1 is hydrogen, fluorine, methyl, ethyl, propyl, benzyl, or 2-bromovinyl, and R 2 is hydrogen, hydroxyl, fluorine, methyl, ethyl, propyl, benzyl, benzoyl, benzoyloxy, or 2-bromovinyl, and each R 3 and R 4 is independently selected from the group consisting of hydroxyl and benzoyloxy. 22.R 1 is hydrogen or methyl, and R 2 is hydrogen, and each R 3 and R 4 is independently selected from the group consisting of hydroxyl and benzoyloxy. 23. The method of claim 18, wherein the 2,2'-anhydropyrimidine or a derivative thereof is selected from the group consisting of 2,2'-anhydro-5-methyluridine; 3'-O-benzoyl-2,2'-anhydrouridine; 3'-O-benzoyl-2,2'-anhydro-5-methyluridine; 5'-O-benzoyl-2,2'-anhydrouridine; and 5'-O-benzoyl-2,2'-anhydro-5-methyluridine. 24. The method according to claim 23, wherein the 2,2'-anhydropyrimidine or a derivative thereof is 2,2'-anhydro-5-methyluridine. 25. The method according to claim 23, wherein the 2,2'-anhydropyrimidine or a derivative thereof is 3'-O-benzoyl-2,2'-anhydro-5-methyluridine.

[0204] 26. The method according to claim 23, wherein the 2,2'-anhydropyrimidine or a derivative thereof is 5'-O-benzoyl-2,2'-anhydro-5-methyluridine. 27. The method according to claim 18, wherein the 2,2'-anhydropyrimidine or derivative thereof includes stereoisomers. 28. The method of claim 27, wherein the stereoisomer is selected from the group consisting of 2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-methyluracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-uracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-methyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-uracil, and 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-methyluracil. 29. The method of any one of claims 17 to 28, wherein the liver condition is selected from the group consisting of NAFLD, NASH, and DILI. 30. The method of any one of claims 17 to 29, wherein the treatment is prophylactic. 31. The method of claim 30, wherein the liver condition is DILI. 32. The method of any one of claims 17 to 29, wherein the subject is suffering from a liver condition.

[0205] In at least some of the foregoing embodiments, one or more elements used in one embodiment may be used interchangeably in another embodiment unless such substitution is technically feasible. Those skilled in the art will appreciate that various other omissions, additions, and modifications may be made to the methods and structures described above without departing from the scope of the claimed subject matter. All such modifications and variations are intended to fall within the scope of the subject matter defined by the appended claims.

[0206] In general, it will be understood by those skilled in the art that the terms used herein, particularly in the appended claims (e.g., the body of the appended claims), are generally intended as "open" terms (e.g., the term "comprises" should be interpreted as "including, but not limited to," the term "having" should be interpreted as "having at least," the term "including" should be interpreted as "including, but not limited to," etc.). It will be further understood by those skilled in the art that where a specific number of introduced claim recitations are intended, such intention will be explicitly recited in the claim; in the absence of such recitation, such intention does not exist. For example, as an aid to understanding, the appended claims below may include the use of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be interpreted as meaning that the introduction of a claim recitation with the indefinite article "a" or "an" limits a particular claim that includes such introduced claim recitation to embodiments that include only one such recitation. The same claim may include the introductory phrase "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" means "at least one" or "one or more"). The same applies to the use of definite articles used to introduce claim recitations. Additionally, even if a specific number of recitations in an introduced claim is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., the bare recitation of "two recitations" without other modifiers means at least two recitations, or two or more recitations). Furthermore, when a convention similar to "at least one of A, B, and C, etc." is used, such a configuration is generally intended in the sense that one skilled in the art would understand the convention (e.g., "a system having at least one of A, B, and C" includes, but is not limited to, systems having only A, only B, only C, both A and B, both A and C, both B and C, and / or both A, B, and C, etc.).When a convention similar to "at least one of A, B, or C, etc." is used, generally such configuration is intended in the sense that one of ordinary skill in the art would understand the convention (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, systems having only A, only B, only C, both A and B, both A and C, both B and C, and / or both A, B, and C, etc.). It will be further understood by those skilled in the art that virtually any disjunction and / or phrase presenting two or more alternative terms, whether in the specification, claims, or drawings, should be understood to contemplate the possibility of including one of the terms, either of the terms, or both terms. For example, the phrase "A or B" is understood to include the possibilities of "A" or "B" or "A and B."

[0207] Furthermore, when features or aspects of the disclosure are described in terms of a Markush group, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member of the Markush group, or any subgroup of members of the Markush group.

[0208] As will be understood by those skilled in the art, for all purposes, including providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations thereof. Any listed range can be readily recognized as fully indicating and allowing for the same range to be broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third, upper third, etc. As will also be understood by those skilled in the art, all terms such as "up to," "at least," "greater than," "less than," etc., are inclusive of the recited numbers and refer to ranges that can subsequently be broken down into subranges as described above. Finally, as will be understood by those skilled in the art, a range includes each individual member. Thus, for example, a group having 1 to 3 items refers to a group having 1, 2, or 3 items. Similarly, a group having 1 to 5 items refers to a group having 1, 2, 3, 4, or 5 items, etc.

[0209] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those skilled in the art that, in light of the teachings of this invention, certain changes and modifications can be made thereto without departing from the spirit or scope of the appended claims.

[0210] Accordingly, the foregoing merely illustrates the principles of the present invention. It will be understood that those skilled in the art will be able to devise various arrangements, not explicitly described or shown herein, which embody the principles of the present invention and are within its spirit and scope. Furthermore, all examples and conditional language set forth herein are intended primarily to aid the reader in understanding the principles of the present invention and the concepts the inventors contributed to furthering the art, and should not be construed as being limited to such specifically described examples and conditions. Furthermore, all statements herein describing principles, aspects, and embodiments of the present invention, as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, such equivalents are intended to include both currently known equivalents and future-developed equivalents, regardless of structure, i.e., any elements developed to perform the same function, regardless of structure. Furthermore, nothing disclosed herein is intended to be dedicated to the public, regardless of whether such disclosure is expressly recited in the claims.

[0211] Accordingly, the scope of the present invention is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the present invention is embodied by the appended claims. In the claims, 35 U.S.C. 112(f) or 35 U.S.C. 112(6) is expressly defined as being invoked for a limitation in a claim only if the precise phrase "means for" or the precise phrase "step for" appears at the beginning of such limitation in the claim; if such precise phrases are not used in the limitation in the claim, 35 U.S.C. 112(f) or 35 U.S.C. 112(6) is not invoked.

[0212] CROSS-REFERENCE TO RELATED APPLICATIONS Under 35 U.S.C. §119(e), this application claims priority to the filing date of U.S. Provisional Patent Application No. 62 / 864,695, filed June 21, 2019, the disclosure of which is incorporated herein by reference.

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Claims

1. 1. Use of a 2,2'-anhydropyrimidine in the manufacture of a medicament for treating a subject for liver damage associated with fibrosis by ameliorating fibrosis, comprising: The 2,2'-anhydropyrimidine is a compound of formula (I): 【Chemistry 1】 or pharmaceutically acceptable salts, solvates, and hydrates thereof, and stereoisomers thereof; During the ceremony, The use wherein each R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted heteroatom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, halogen or pseudohalogen, carbohydrate, nucleic acid, amino acid, peptide, dye, fluorophore, and polypeptide.

2. Each R １ , R ２ , R ３ , and R ４ is independently selected from the group consisting of hydrogen, hydroxyl, sulfyhydryl, amino, hydroxymethyl, methoxy, halogen, pseudohalogen, and substituted or unsubstituted lower hydrocarbons containing 1 to 20 carbons.

3. 3. The use according to claim 2, wherein the lower hydrocarbon is selected from the group consisting of alkyl, alkenyl, alkanoyl, aryl, aroyl, aralkyl, and alkylamino, and esters thereof.

4. R １ is hydrogen, fluorine, methyl, ethyl, propyl, benzyl, or 2-bromovinyl, and R ２ is hydrogen, hydroxyl, fluorine, methyl, ethyl, propyl, benzyl, benzoyl, benzoyloxy, or 2-bromovinyl, and each R ３ and R ４ The use of claim 1 , wherein is independently selected from the group consisting of hydroxyl and benzoyloxy.

5. R １ is hydrogen or methyl, and R ２ is hydrogen, and each R ３ and R ４ The use of claim 4, wherein is independently selected from the group consisting of hydroxyl and benzoyloxy.

6. 2. The use according to claim 1, wherein the 2,2'-anhydropyrimidine is selected from the group consisting of 2,2'-anhydro-5-methyluridine, 3'-O-benzoyl-2,2'-anhydrouridine, 3'-O-benzoyl-2,2'-anhydro-5-methyluridine, 5'-O-benzoyl-2,2'-anhydrouridine, and 5'-O-benzoyl-2,2'-anhydro-5-methyluridine.

7. The use according to claim 1, wherein the 2,2'-anhydropyrimidine includes stereoisomers.

8. 8. The use according to claim 7, wherein the stereoisomer is selected from the group consisting of 2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-methyluracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-uracil, 3'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-methyluracil, 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-uracil, and 5'-O-benzoyl-2,2'-anhydro-1-(β-D-arabinofuranosyl)-5-methyluracil.

9. The use according to any one of claims 1 to 8, wherein the liver disorder is selected from the group consisting of NAFLD, NASH, and DILI.

10. The use according to any one of claims 1 to 9, wherein the treatment is prophylactic.

11. The use according to claim 10, wherein the liver disorder is DILI.

12. The use according to any one of claims 1 to 9, wherein the subject is suffering from liver damage.

13. 13. The use of any one of claims 1 to 12, wherein the 2,2'-anhydropyrimidine is used in combination with uridine (UR), phosphorylated uridine, triacetyluridine, uridine triacetate, an acyl derivative of uridine, or acyclouridine for the manufacture of a medicament for ameliorating fibrosis and treating a subject for liver damage associated with fibrosis.

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