WO2015191640A2

WO2015191640A2 - Bicyclic xanthine oxidase inhibitors and methods of use

Info

Publication number: WO2015191640A2
Application number: PCT/US2015/034975
Authority: WO
Inventors: Raghuram Selvaraju; Changyi Chen; Jian-ming LU; Qizhi Yao
Original assignee: Baylor College of Medicine
Current assignee: Baylor College of Medicine
Priority date: 2014-06-09
Filing date: 2015-06-09
Publication date: 2015-12-17
Anticipated expiration: 2016-12-09
Also published as: WO2015191640A3

Abstract

Xanthine oxidase inhibitors are provided, as well as compositions, methods for their use for treating disorders, mediated at least in part, by xanthine oxidase.

Description

BICYCLIC XANTHINE OXIDASE INHIBITORS AND METHODS OF USE

BACKGROUND OF THE INVENTION

Field of the Invention

[0001] This invention is directed to compounds, pharmaceutical compositions and methods. The methods of this invention are useful in treating a condition mediated at least in part by xanthine oxidase including by way of example, gout, hyperuricemia, hypoxia and the like.

State of the Art

[0002] Gout is caused by hyperuricemia, namely, abnormally high levels of uric acid in the blood. Gout is usually presented as acute inflammatory arthritis, as well as tophi, kidney stones, or urate nephropathy. Gout affects 1-2% of adults in developed countries and represents the most common case of inflammatory arthritis in men. In the United States, gouty arthritis accounts for millions of outpatient visits annually. Furthermore, gout and hyperuricemia are also associated with chronic diseases such as hypertension, diabetes mellitus, metabolic syndrome, and renal and cardiovascular disease.

[0003] Xanthine oxidase (XO) is a form of a molybdoflavin protein, xanthine oxidoreductase (XOR). It plays an important role in the catabolism of purines in humans, as it catalyzes the oxidation of hypoxanthine to xanthine and then catalyzes the oxidation of xanthine to uric acid. Meanwhile, reactive oxygen species (ROS), including superoxide and H₂0₂, are generated during this process. In a bioprotective role, uric acid can serve as an antioxidant to prevent macromolecular damage by ROS. However, overproduction of uric acid causes hyperuricemia which can lead to gout and other diseases or conditions. Therefore, maintaining uric acid at normal levels represents an important therapeutic goal for the prevention of gout and related disorders. For most patients with primary gout, the condition is directly related to the overproduction of uric acid (hyperuricemia).

[0004] Currently, two drugs have been developed to treat gout. Allopurinol is the most commonly used therapy for chronic gout and has been used clinically for more than 40 years. Allopurinol lowers uric acid production by inhibiting XO activity, and is used as a first-line urate-lowering phamacotherapy. Allopurinol, a structural isomer of hypoxanthine, is hydroxylated by XO to oxypurinol, which coordinates tightly to the reduced form of the molybdenum center, replacing the Mo-OH group of the native enzyme. Unfortunately, while rare, allopurinol has life-threatening side effects such as a hypersensitivity syndrome consisting of fever, skin rash, eosinophilia, hepatitis, and renal toxicity, for which the mortality rate approaches 20%. It also causes Stevens- Johnson syndrome (SJS) and toxic epidermal necrolysis (TENS), two life-threatening dermato logical conditions. Febuxostat, a non-purine xanthine oxidase inhibitor, has been approved for the management of gout in Europe and the United States. Side effects are also found with this drug including elevated serum liver enzymes, nausea, diarrhea, arthralgia, headache, and rash.

Notwithstanding the need for drugs with improved safety in the treatment of gout, hyperuricemia, and related disorders, drugs available for treatment and prevention of such disorders remain limited. Therefore, safe and effective xanthine oxidase inhibitors are needed for treating such disorders.

SUMMARY OF THE INVENTION

[0005] This invention is directed to compounds, pharmaceutical compositions, and methods of use in order to treat disorders mediated, at least in part, by xanthine oxidase. This invention is also directed to methods for treating, for example, hypoxia, gout and hyperuricemia and related conditions.

[0006] In one embodiment of its compound aspect, this invention provides or utilizes compounds of Formula I, IA-i, or II:

wherein ring A is phenyl or a 6-membered heteroaryl comprising one nitrogen atom in the ring; ring B is phenyl or a 5- or 6-membered heteroaryl comprising one or two ring

heteroatoms independently selected from nitrogen, oxygen and sulfur;

m is 1 or 2;

each A 1 , A2 , A 3 , A 4 is independently CR 1 or N, provided that no more than one of A 1 ,

A³, and A⁴ is N;

B¹, B², and B³ are independently CR¹, O, S, N or NR¹, provided no more than two of B¹, B², and B³ are O, S, N or NR¹;

X is CR¹ or N;

each R¹ is independently selected from the group consisting of hydrogen, nitro, aldehyde,

20 20 2 3 1

hydroxyl, OR , OCOR ,R and R , provided that at least two R are independently nitro, aldehyde, cyano, hydroxyl, or R³;

each R² is independently selected from halogen, nitroso, cyano, Ci to C₆ alkyl, -CH₂OH, halogenated Ci to C₄ alkyl, phenyl, -S0₂H, and -OR⁵;

each R³ is independently selected from the group consisting of:

-C=NOR⁴, -C(=0)NHR⁴, -C(=S)R⁴, -C(=S)NHR⁴, -C(=0)OR⁴, -C(=0)SR⁴, -C(=S)OR⁴, or OR;

each R is independently selected from the group consisting of:

(CH₂CH₂0)_nH,

-C(=0)R⁴, -C(=0)NHR⁴, -C(=S)R⁴, -C(=S)NHR⁴, -C(=0)OR⁴, -C(=0)SR⁴, -C(=S)OR⁴, -P(=0)R⁴, -P(=0)₂R⁴, -P(=0)NHR⁴, -P(=0)₂NHR⁴, -P(=S)NHR⁴, -P(=0)OR⁴,

-P(=0)₂OR⁴, -P(=0)SR⁴, -P(=0)₂SR⁴, -P(=S)OR⁴,

-S(=0)R⁴, -S(=0)₂R⁴, -S(=0)NHR⁴, -S(=0)₂NHR⁴, -S(=0)OR⁴, -S(=0)₂OR⁴,

-S(=0)SR⁴, -S(=0)₂SR⁴, -S(=NR⁴)R⁴, -S(=NR⁴)(=0)R⁴, -S(=NR⁴)₂R⁴, and -SiR⁴; R⁴ is selected from the group consisting of hydrogen, Ci-C₆ alkyl, C3-C7 cycloalkyl, C₂- C₆ alkenyl, C₄-C₇ cycloalkenyl, C₂-C₆ alkynyl, (CH₂CH₂0)_nH, phenyl, C₅-C₆ heterocycle having 1 to 3 heteroatoms selected from O, S, S0₂, N, and NR¹¹, and C5-C6 heteroaryl having 1 to 3 heteroatoms selected from O, S, N, and NR¹²;

n is an integer of from 1 to 10,000;

X¹ and Y¹ are independently selected from the group consisting of -0-, -S-, -S0₂-, and -N(R⁷)-;

L is -C(O)- or C₂ to C₄ alkylene group optionally substituted with one or two oxo; R⁵ is Ci to C₆ alkyl or halogenated Ci to C₆ alkyl;

R⁶ is hydrogen or R²;

R⁷ is selected from the group consisting of

hydrogen, (CH₂CH₂0)_nH, Ci to C₆ alkyl,

-C(=0)R⁴, -C(=0)NHR⁴, -C(=S)R⁴, -C(=S)NHR⁴, -C(=0)OR⁴, -C(=0)SR⁴, -C(=S)OR⁴,

-P(=0)R⁴, -P(=0)₂R⁴, -P(=0)NHR⁴, -P(=0)₂NHR⁴, -P(=S)NHR⁴, -P(=0)OR⁴, -P(=0)₂OR⁴, -P(=0)SR⁴, -P(=0)₂SR⁴, -P(=S)OR⁴,

-S(=0)R⁴, -S(=0)₂R⁴, -S(=0)NHR⁴, -S(=0)₂NHR⁴, -S(=0)OR⁴, -S(=0)₂OR⁴, -S(=0)SR⁴, -S(=0)₂SR⁴, -S(=NR⁴)R⁴, -S(=NR⁴)(=0)R⁴, -S(=NR⁴)₂R⁴, - SiR⁴;

R¹¹ is hydrogen or Ci to C₆ alkyl, or two R¹¹ on a same carbon form =0;

R¹² is hydrogen or Ci to C₆ alkyl; and

R²⁰ is a saturated fatty chain or an unsaturated fatty chain or -OR²⁰ is a hydroxy group esterified with a phospholipid,

or a tautomer, and/or a pharmaceutically acceptable salt and/or solvate thereof.

[0007] Preferably, the saturated fatty chain or the unsaturated fatty contains 10-30 chain carbons, or more preferably, 12-18 chain carbons. In some embodiment, the unsaturated fatty chain contains up to 4, preferably, up to 2, more preferably, a single carbon carbon double bond within the fatty chain. In some embodiments, the saturated fatty chain or the unsaturated fatty chain contains less than 10 chain carbons.

[0008] In one embodiment of its compound aspect, this invention provides or utilizes compounds of Formula III or IV:

wherein

X³ is CR³⁰ or N;

Y³ is NR³¹, O or S;

R is selected from the group consisting of hydrogen, nitro, OH, OR, and

selected from hydrogen and Ci to C₆ alkyl;

is independently selected from the group consisting of:

q is 0, 1, 2 or 3;

each R is independently selected from the group consisting of:

(CH₂CH₂0)_nH,

-P(=0)₂OR⁴, -P(=0)SR⁴, -P(=0)₂SR⁴, -P(=S)OR⁴,

-S(=0)SR⁴, -S(=0)₂SR⁴, -S(=NR⁴)R⁴, -S(=NR⁴)(=0)R⁴, -S(=NR⁴)₂R⁴ , and -SiR⁴; R⁴ is selected from the group consisting of hydrogen, Ci-C₆ alkyl, C3-C7 cycloalkyl, C₂- C₆ alkenyl, C4-C7 cycloalkenyl, C₂-C₆ alkynyl, (CH₂CH₂0)_nH, phenyl, C₅-C₆ heterocycle having 1 to 3 heteroatoms selected from O, S, S0₂, N, and NR¹¹, and C5-C6 heteroaryl having 1 to 3 heteroatoms selected from O, S, N, and NR¹²;

n is an integer of from 1 to 10,000;

X¹ and Y¹ are independently selected from the group consisting of -0-, -S-, -S0₂-, and -N(R³)-;

L is -C(O)- or C₂ to C₄ alkylene group;

R⁷ is hydrogen, (CH₂CH₂0)„H, or Ci to C₆ alkyl;

R¹¹ is hydrogen or Ci to C₆ alkyl, or two R¹¹ on a same carbon form =0;

R¹² is hydrogen or Ci to C₆ alkyl; and R²⁰ is a saturated fatty chain or an unsaturated fatty chain or -OR²⁰ is a hydroxy group esterified with a phospholipid,

[0009] Preferably, the saturated fatty chain or the unsaturated fatty chain contains 10-30 chain carbons, or more preferably, 12-18 chain carbons. In some embodiments, the saturated fatty chain or the unsaturated fatty chain contains less than 10 chain carbons.

[0010] In another embodiment, provided or utilized are compounds selected from the group consisting of:

or a tautomer, solvate and/or a pharmaceutically acceptable salt thereof.

[0011] In another embodiment, provided or utilized are compounds selected from the group consisting of:

where X¹¹ is O, S or NH,

or a tautomer, solvate and/or a pharmaceutically acceptable salt thereof.

[0012] In another embodiment, provided or utilized are compounds selected from the group consisting of:

or a tautomer, solvate and/or a pharmaceutically acceptable salt thereof.

[0013] In preferred embodiments, the hydroxy groups, preferably, one or two hydroxy groups, present in the compounds described herein can be esterified with a saturated fatty acid chain or an unsaturated hydrocarbon chain of fatty acid or a phospholipid, as disclosed herein.

[0014] Compounds described herein are contemplated to inhibit the activity of xanthine oxidase and reduce production of uric acid. In some embodiments, the compounds can be degraded in vivo, such as by hydrolysis and/or oxidation, to provide a metabolite that inhibit the activity of xanthine oxidase and reduce production of uric acid.

[0015] In one embodiment, this invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula I, II, III or IV above or a tautomer, and/or a pharmaceutically acceptable salt and/or solvate thereof.

[0016] In one embodiment of its method aspect, there is a provided a method for treating a condition mediated at least in part by xanthine oxidase which method comprises administering to a patient suffering from such a condition a therapeutically effective amount of a compound of any of Formulae I, II, III or IV above or a tautomer or a pharmaceutically acceptable salt and/or solvate thereof.

[0017] In one embodiment the compound utilized herein is 3,4-dihydroxy-5- cyanobenzaldehyde (DHCB) or 3,5-dinitrosalicylaldehyde (DNS A).

[0018] In one embodiment of its method aspect, there is provided a method for treating a condition mediated at least in part by xanthine oxidase which method comprises administering to a patient suffering from such a condition a therapeutically effective amount of DHCB or DNSA.

[0019] In one of its embodiments, this invention is directed to a method for

treating, for example, gout, hypoxia, or hyperuricemia in a patient which method comprises administering to the patient in need thereof a therapeutically effective amount of a

compound of any of Formulae I, II, III or IV above or a tautomer or a pharmaceutically acceptable salt and/or solvate thereof, or a therapeutically effective amount of DHCB or

DNSA.

DETAILED DESCRIPTION

[0020] Provided herein are bicyclic xanthine oxidase inhibitors and methods for their use in treating conditions mediated, at least in part, by xanthine oxidase in a patient. The xanthine oxidase inhibitors are administered in an effective amount to treat, for example, gout, hypoxia, or hyperuricemia in a subject.

[0021] 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.

[0022] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application.

DEFINITIONS

[0023] As used herein, the following definitions shall apply unless otherwise indicated. Further, if any term or symbol used herein is not defined as set forth below, it shall have its ordinary meaning in the art.

[0024] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH₃-, or Me), ethyl

(CH₃CH₂-, or Et), n-propyl (CH₃CH₂CH₂-, or n-Pr), isopropyl ((CH₃)₂CH-, or i-Pr), n-butyl (CH₃CH₂CH₂CH₂-, or n-Bu), isobutyl ((CH₃)₂CHCH₂-, or i-Bu), sec-butyl ((CH₃)(CH₃CH₂)CH-, or s-Bu), t-butyl ((CH₃)₃C-, or t-Bu), n-pentyl (CH₃CH₂CH₂CH₂CH₂-), and neopentyl

((CH₃)₃CCH₂-). C_x alkyl refers to an alkyl group having x number of carbon atoms.

[0025] "Alkylene" refers to a divalent alkyl group, such as -CH₂-, -CH₂CH₂-,

-CH₂CH₂CH₂-, -CH(CH₃)CH₂-, etc.

[0026] "Alkenyl" refers to straight or branched hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of vinyl (>C=C<) unsaturation. Such groups are exemplified, for example, by vinyl, allyl, and but-3-en-l-yl. Included within this term are the cis and trans isomers or mixtures of these isomers. C_x alkenyl refers to an alkenyl group having x number of carbon atoms. [0027] "Alkynyl" refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic (-C≡ C-) unsaturation. Examples of such alkynyl groups include acetylenyl (-C≡ CH), and propargyl (-CH₂C≡ CH). C_x alkynyl refers to an alkynyl group having x number of carbon atoms.

[0028] "Aryl" refers to a monovalent aromatic carbocyclic group of from 6 to 10 carbon atoms having a single ring (e.g., phenyl (Ph)) or multiple condensed rings (e.g., naphthyl) which condensed rings may or may not be aromatic (e.g. , 2-benzoxazolinone,

2H-l ,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.

[0029] "Cycloalkyl" refers to a saturated or unsaturated but nonaromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. C_x cycloalkyl refers to a cycloalkyl group having x number of ring carbon atoms. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more the rings can be aryl, heteroaryl, or heterocyclic provided that the point of attachment is through the non-aromatic, non-heterocyclic ring saturated carbocyclic ring.

[0030] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.

[0031] "Hydroxy" or "hydroxyl" refers to the group -OH.

[0032] "Heteroaryl" refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g. , pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N→0), sulfmyl, or sulfonyl moieties. Preferred heteroaryls include 5 or 6 membered heteroaryls such as pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.

[0033] "Heterocycle" or "heterocyclic" refers to a saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, phosphorus, sulfur, or oxygen. C_x cycloalkyl refers to a heterocycle group having x number of ring atoms including the ring heteroatoms. Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems. In fused ring systems, one or more the rings can be cycloalkyl, aryl or heteroaryl provided that the point of attachment is through the non-aromatic ring. In one embodiment, the nitrogen, phosphorus and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, P(O), P(0)₂, P(0)₃, sulfmyl, or sulfonyl moieties.

[0034] "Aldehyde" refers to the group -CHO.

[0035] "Nitro" refers to the group -N0₂.

[0036] "Nitroso" refers to the group -N=0.

[0037] "Oxo" refers to the atom (=0) or (-0 ).

[0038] " " represents a single bond or a double bond.

[0039] When used in the context of a chemical group, "hydrogen" means -H;

"hydroxyamino" means -NHOH; imino means =NH; "cyano" and "nitrile" can be used interchangeably and mean -CN; "isocyanate" means -N=C=0; "azido" means -N₃; in a monovalent context "phosphate" means -OP(0)(OH)₂ or a deprotonated form thereof; in a divalent context "phosphate" means -OP(0)(OH)0- or a deprotonated form thereof; "sulfonyl" means -S(0)₂-; and "sulfmyl" means -S(O)-.

[0040] "Stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.

[0041] "Tautomer" refer to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

[0042] "Treating" or "treatment" of a disease in a patient refers to 1) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease.

[0043] Treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of one or more symptoms of the disease or condition. For example, a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms or signs of the disease in a subject as compared to a control. As used herein, control refers to the untreated condition. Thus the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition.

[0044] As used herein, the terms prevent, preventing, and prevention of a disease or disorder refer to an action, for example, administration of a composition or therapeutic agent, that occurs before or at about the same time a subject begins to show one or more symptoms of the disease or disorder, which inhibits or delays onset or severity of one or more symptoms of the disease or disorder.

[0045] As used herein, references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a control level. Such terms can include, but do not necessarily include, complete elimination.

[0046] As used herein, subject means primarily mammals. Mammals include, for example, humans; non-human primates, e.g., apes and monkeys; cattle; horses; sheep; rats;

mice; pigs; and goats.

[0047] As used herein, the term "condition" or "disorder" refers to a state of a patient

(or an organ or tissue of the patient) that deviates from the normal state and may at least cause discomfort, such as pain or abnormal appearance, such as redness in color, or can lead to a condition which may cause discomfort such that treatment is desired.

[0048] It is understood that the above definitions are not intended to include

impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.

COMPOUNDS

[0049] In one embodiment of its compound aspect, this invention provides compounds of Formula I or IA:

wherein

ring A is phenyl or a 6-membered heteroaryl comprising one nitrogen atom in the ring; ring B is phenyl or a 5- or 6-membered heteroaryl comprising one or two ring

heteroatoms selected from nitrogen, oxygen and sulfur;

m is 1 or 2;

each A¹, A², A³, and A⁴ is independently CR¹ or N, provided that no more than one of A¹, A², A³, and A⁴ is N;

20 20 2 3 1

hydroxyl, OR , OCOR , R and R , provided that at least two R are independently nitro, aldehyde, hydroxyl, or R³;

each R³ is independently selected from the group consisting of:

each R is independently selected from the group consisting of:

-(CH₂CH₂0)_nH,

-P(=0)R⁴, -P(=0)₂R⁴, -P(=0)NHR⁴, -P(=0)₂NHR⁴, -P(=S)NHR⁴, -P(=0)OR⁴,

-P(=0)₂OR⁴, -P(=0)SR⁴, -P(=0)₂SR⁴, -P(=S)OR⁴,

-S(=0)SR⁴, -S(=0)₂SR⁴, -S(=NR⁴)R⁴, -S(=NR⁴)(=0)R⁴, -S(=NR⁴)₂R⁴, and -SiR⁴;

R⁴ is selected from the group consisting of hydrogen, Ci-C₆ alkyl, C3-C7 cycloalkyl, C₂- C₆ alkenyl, C4-C7 cycloalkenyl, C₂-C₆ alkynyl, (CH₂CH₂0)_nH, phenyl, C5-C6 heterocycle having 1 to 3 heteroatoms selected from O, S, S0₂, N, and NR¹¹, and C5-C6 heteroaryl having 1 to 3 heteroatoms selected from O, S, N, and NR¹²;

n is an integer of from 1 to 10,000;

L is -C(O)- or C₂ to C₄ alkylene group optionally substituted with one or two oxo;

R⁵ is Ci to C₆ alkyl or halogenated Ci to C₆ alkyl;

R⁷ is selected from the group consisting of

hydrogen, (CH₂CH₂0)_nH, Ci to C₆ alkyl,

-P(=0)R⁴, -P(=0)₂R⁴, -P(=0)NHR⁴, -P(=0)₂NHR⁴, -P(=S)NHR⁴, -P(=0)OR⁴, -P(=0)₂OR⁴, -P(=0)SR⁴, -P(=0)₂SR⁴, -P(=S)OR⁴, R is hydrogen or Ci to C₆ alkyl; and

R²⁰ is a saturated fatty chain or an unsaturated fatty chain or -OR²⁰ is a hydroxy group esterified with a phospholipid , or a tautomer, and/or a pharmaceutically acceptable salt and/or solvate thereof.

[0050] Preferably, the saturated fatty chain or the unsaturated fatty chain contains 10-30 chain carbons, or more preferably, 12-18 chain carbons. In some embodiments, the saturated fatty chain or the unsaturated fatty chain contains less than 10 chain carbons

[0051] In one embodiment of its compound aspect, this invention provides compounds of Formula I A, or IB:

or a tautomer, a solvate, and/or a pharmaceutically acceptable salt thereof, wherein A¹, A², A³,

A⁴, B², and B³ are as defined in Formula I.

[0052] In one embodiment of its compound aspect, this invention provides compounds of Formula II:

wherein ring B is phenyl or a 5- or 6-membered heteroaryl comprising one or two ring heteroatoms selected from nitrogen, oxygen and sulfur;

m is 1 or 2;

X is CR¹ or N;

each R¹ is independently selected from the group consisting of hydrogen, nitro, aldehyde, hydroxyl, OR 20 , OCOR 20 , R 2 and R 3 ; provided that at least two R 1 are independently nitro, aldehyde, hydroxyl, or R³;

each R³ is independently selected from the group consisting of:

each R is independently selected from the group consisting of:

(CH₂CH₂0)_nH,

-P(=0)₂OR⁴, -P(=0)SR⁴, -P(=0)₂SR⁴, -P(=S)OR⁴,

-S(=0)SR⁴, -S(=0)₂SR⁴, -S(=N)R⁴, -S(=NR⁴)(=0)R⁴, -S(=NR⁴)₂R⁴, and -SiR⁴;

R⁴ is selected from the group consisting of hydrogen, Ci-C₆ alkyl, C3-C7 cycloalkyl, C₂- C₆ alkenyl, C₄-C₇ cycloalkenyl, C₂-C₆ alkynyl, (CH₂CH₂0)_nH, phenyl, C5-C6 heterocycle having 1 to 3 heteroatoms selected from O, S, S0₂, N, and NR¹¹, and C5-C6 heteroaryl having 1 to 3 heteroatoms selected from O, S, N, and NR¹²;

n is an integer of from 1 to 10,000; X¹ and Y¹ are independently selected from the group consisting of -0-, -S-, -SO₂-, and -N(R⁷)-;

R⁵ is Ci to C₆ alkyl or halogenated Ci to C₆ alkyl;

R⁶ is hydrogen or R²;

R⁷ is selected from the group consisting of

hydrogen, (CH₂CH₂0)„H, Ci to C₆ alkyl,

-P(=0)₂OR⁴, -P(=0)SR⁴, -P(=0)₂SR⁴, -P(=S)OR⁴,

-S(=0)SR⁴, -S(=0)₂SR⁴, -S(=NR⁴)R⁴, -S(=NR⁴)(=0)R⁴, -S(=NR⁴)₂R⁴, and

-SiR⁴;

R¹¹ is hydrogen or Ci to C₆ alkyl, or two R¹¹ on a same carbon form =0;

R¹² is hydrogen or Ci to C₆ alkyl; and

R²⁰ is a saturated fatty acid chain or an unsaturated fatty acid chain or -OR²⁰ is a hydroxy group esterified with a phospholipid,

[0053] Preferably, the saturated fatty chain or the unsaturated fatty chain (each including the carbonyl carbon) contains 10-30 chain carbons, or more preferably, 12-18 chain carbons. In some embodiments, the saturated fatty chain or the unsaturated fatty chain contains less than 10 chain carbons.

[0054] In one embodiment of its compound aspect, this invention provides compounds of Formula IIA, IIB, IIC or IID:

or a tautomer, a solvate, and/or a pharmaceutically acceptable salt thereof, wherein R¹, R⁶, B¹, B², and B³ are as defined in Formula II.

[0055] In some embodiments, one of R¹ is hydrogen or Ci to C₄ alkyl.

[0056] In some embodiments, one of R¹ is phenyl.

[0057] In some embodiments, at least one of R¹ is C(=NOR⁴)H. In some embodiments, at least one of R¹ is CHO.

[0058] In some embodiments, at least one of R¹ is selected from -OC(=0)R⁴,

-OC(=0)NHR⁴, -OC(=S)R⁴, -OC(=S)NHR⁴, -OC(=0)OR⁴, -OC(=0)SR⁴, and -OC(=S)OR⁴.

[0059] In some embodiments, at least one of R¹ is selected from -OP(=0)R⁴ , -OP(=0)₂R⁴, -OP(=0)NHR⁴, -OP(=0)₂NHR⁴, -OP(=S)NHR⁴, -OP(=0)OR⁴, -OP(=0)₂OR⁴, -OP(=0)SR⁴, -OP(=0)₂SR⁴, and -OP(=S)OR⁴.

[0060] In some embodiments, at least one of R¹ is selected from -OS(=0)R⁴,

-OS(=0)₂R⁴, -OS(=0)NHR⁴, -S(=0)₂NHR⁴, -OS(=0)OR⁴, -OS(=0)₂OR⁴, -OS(=0)SR⁴, -OS(=0)₂SR⁴, -OS(=N)R⁴ , -OS(=NR⁴)(=0)R⁴ , -OS(=NR⁴)₂R⁴ , and -OSiR⁴. [0061] In some embodiments, at least one of R is

[0062] In some embodiments, at least one of R is

[0063] In some embodiments, at least one of R is

[0064] In some embodiments, R is a saturated fatty chain or an unsaturated fatty chain or -OR²⁰ is a hydroxy group esterified with a phospholipid.

[0065] In some embodiments, L is -C(O)-. In some embodiments, L is C₂ to C₄ alkylene group. In some embodiments, L is C₂ to C₄ alkylene group substituted with one oxo. In some embodiments, L is C₃ to C₄ alkylene group substituted with two oxo. In some

embodiments, L is -C(0)CH₂-. In some embodiments, L is -C(0)CH₂CH₂-.

[0066] In some embodiments, R⁷ is selected from the group consisting of hydrogen, (CH₂CH₂0)„H, and Ci to C₆ alkyl,

[0067] In some embodiments, at least one of R¹ is selected from: yV , V, yV, yV, yQ, yQ, y LallUyV

[0068] In some embodiments, two R¹ are independently selected from the group consisting of hydroxy, nitro, and aldehyde and the rest of R¹ are hydrogen. In some

embodiments, three R¹ are independently selected from the group consisting of hydroxy, nitro, and aldehyde and the rest of R¹ are hydrogen. In some embodiments, four R¹ are independently selected from the group consisting of hydroxy, nitro, and aldehyde and the rest of R¹ are hydrogen. In some embodiments, two R¹ are independently selected from the group consisting of hydroxy, nitro, and aldehyde, one R¹ is phenyl and the rest of R¹ are hydrogen. [0069] In one embodiment of its compound aspect, ring A and ring B are selected from the group consisting of

or a tautomer, and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein p is 2, 3, 4, or 5, or 6, each R^la can be present on any available position on either or both rings and is independently selected from the group consisting of nitro, aldehyde, hydroxyl, R² and R³, provided that at least two R^la are independently nitro, aldehyde, hydroxyl or R³, and R¹, R², R³ and R⁶ are as defined in Formula I.

[0070] In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6.

[0071] In some embodiments, one of R^la is Ci to C₄ alkyl.

[0072] In some embodiments, one of R^la is phenyl.

[0073] In some embodiments, R¹ is hydrogen. In some embodiments, R¹ is Ci to C₄ alkyl. In some embodiments, R¹ is phenyl.

[0074] In some embodiments, at least one of R^la is C(=NOR⁴)H. In some embodiments, at least one of R^la is CHO.

[0075] In some embodiments, at least one of R^la is selected from -OC(=0)R⁴,

[0076] In some embodiments, at least one of R^la is selected from -OP(=0)R⁴ -OP(=0)₂R⁴, -OP(=0)NHR⁴, -OP(=0)₂NHR⁴, -OP(=S)NHR⁴, -OP(=0)OR⁴, -OP(=0)₂OR⁴, -OP(=0)SR⁴, -OP(=0)₂SR⁴, and -OP(=S)OR⁴.

[0077] In some embodiments, at least one of R^la is selected from -OS(=0)R⁴,

-OS(=0)₂R⁴, -OS(=0)NHR⁴, -S(=0)₂NHR⁴, -OS(=0)OR⁴, -OS(=0)₂OR⁴, -OS(=0)SR⁴, -OS(=0)₂SR⁴, -OS(=N)R⁴ , -OS(=NR⁴)(=0)R⁴ , -OS(=NR⁴)₂R⁴ , and -OSiR⁴.

[0078] In some embodiments, at least one of R^la is

[0079] In some embodiments, at least one of R

[0080] In some embodiments, at least one of R^la is

[0081] In some embodiments, at least one of R^la is selected from:

[0082] In some embodiments, R¹ is hydrogen or phenyl, p is 2 and the two R^la are independently selected from the group consisting of hydroxy, nitro, and aldehyde. In some embodiments, R¹ is hydrogen or phenyl, p is 3, and the three R^la are independently selected from the group consisting of hydroxy, nitro, and aldehyde. In some embodiments, R¹ is hydrogen or phenyl, p is 4 and the four R^la are independently selected from the group consisting of hydroxy, nitro, and aldehyde. In some embodiments, R¹ is hydrogen, p is 3 and two R^la are independently selected from the group consisting of hydroxy, nitro, and aldehyde and one R^la is phenyl.

[0083] In another embodiment of its compound aspect, this invention provides compounds of Formula III or IV:

wherein

X³ is CR³⁰ or N;

Y³ is NR³¹, O or S;

R is selected from the group consisting of hydrogen, nitro, OH, OR, and

selected from hydrogen and Ci to C₆ alkyl;

is independently selected from the group consisting of:

q is 0, 1, 2 or 3;

each R is independently selected from the group consisting of:

(CH₂CH₂0)_nH,

-P(=0)₂OR⁴, -P(=0)SR⁴, -P(=0)₂SR⁴, -P(=S)OR⁴,

-S(=0)SR⁴, -S(=0)₂SR⁴, -S(=NR⁴)R⁴, -S(=NR⁴)(=0)R⁴, -S(=NR⁴)₂R⁴ , and -SiR⁴; R⁴ is selected from the group consisting of hydrogen, Ci-C₆ alkyl, C3-C₇ cycloalkyl, C₂- C₆ alkenyl, C₄-C₇ cycloalkenyl, C₂-C₆ alkynyl, (CH₂CH₂0)_nH, phenyl, C₅-C₆ heterocycle having 1 to 3 heteroatoms selected from O, S, S0₂, N, and NR¹¹, and C5-C6 heteroaryl having 1 to 3 heteroatoms selected from O, S, N, and NR¹²;

n is an integer of from 1 to 10,000;

L is -C(O)- or C₂ to C₄ alkylene group;

R⁷ is hydrogen, (CH₂CH₂0)„H, or Ci to C₆ alkyl;

R¹¹ is hydrogen or Ci to C₆ alkyl, or two R¹¹ on a same carbon form =0; and

R¹² is hydrogen or Ci to C₆ alkyl;

[

0085] In some embodiments, -C=NOR⁴.

[0086] In some embodiments,

[0087] In some embodiments,

[0088] In some embodiments,

[0089] In some embodiments, n is 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some embodiments, n is an integer from 10 to 100. In some embodiments, n is an integer from 100 to 200. In some embodiments, n is an integer from 200 to 300. In some embodiments, n is an integer from 300 to 400. In some embodiments, n is an integer from 400 to 500. In some embodiments, n is an integer from 500 to 1000.

[0090] In another embodiment, there is provide a compound selected from the group consisting of:

or their solvates, tautomers, and/or a pharmaceutically acceptable salt thereof.

[0091] In another embodiment, provided are compounds selected from the group consisting of:

where X¹¹ is O, S or NH, or a tautomer, solvate and/or a pharmaceutically acceptable salt thereof.

[0092] In another embodiment, provided are compounds selected from the group consisting of:

or a tautomer, solvate and/or a pharmaceutically acceptable salt thereof.

[0093] In preferred embodiments, the hydroxy groups, preferably, one or two hydroxy groups, present in the compounds described herein can be esterified with a saturated fatty acid or an unsaturated fatty acid or a phospholipid, as disclosed herein.

[0094] In one aspect, the compounds are effective at improving the bioavailability of any such compound resulting from metabolism as xanthine inhibitors. These compounds are particularly useful as anti-gout, anti-hypoxia, and anti-hyperuricemia drugs. The solubility and/or bioavailabilty, controlled for example by absorption thru a tissue membrane, may be substantially increased by administration of the appropriate compound as described herein. In some embodiments, these compounds exhibit significantly enhanced pharmacokinetic properties in comparison to other xanthine inhibitors such as long half life. These

improvements result in more of the drug being absorbed and reaching the target; thus, pill burden, overall cost of the therapy, and dosing intervals are be reduced.

PHARMACEUTICAL FORMULATIONS

[0095] The compounds described herein and derivatives thereof can be provided in a pharmaceutical composition. Depending on the intended mode of administration, the pharmaceutical composition can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, or suspensions, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions will include a therapeutically effective amount of the compound described herein or derivatives thereof in combination with a pharmaceutically acceptable carrier and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, or diluents. By pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, which can be administered to an individual along with the selected compound without causing unacceptable biological effects or interacting in a deleterious manner with the other components of the pharmaceutical composition in which it is contained.

[0096] As used herein, the term carrier encompasses any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations. The choice of a carrier for use in a composition will depend upon the intended route of administration for the composition. The preparation of pharmaceutically acceptable carriers and formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 21st Edition, ed. University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia Pa., 2005. Examples of physiologically acceptable carriers include buffers, such as phosphate buffers, citrate buffer, and buffers with other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; and/or nonionic surfactants, such as TWEEN® (ICI, Inc.; Bridgewater, New Jersey), polyethylene glycol (PEG), and PLURONICSTM (BASF; Florham Park, NJ).

[0097] Compositions containing the compounds described herein or derivatives thereof suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

[0098] These compositions may also contain adjuvants, such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be promoted by various antibacterial and antifungal agents, for example, parabens,

chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents, for example, sugars, sodium chloride, and the like may also be included. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0099] Solid dosage forms for oral administration of the compounds described herein or derivatives thereof include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds described herein or derivatives thereof is admixed with at least one inert customary excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin,

polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example, paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

[0100] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.

[0101] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others known in the art. They may contain opacifying agents and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0102] Liquid dosage forms for oral administration of the compounds described herein or derivatives thereof include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like.

[0103] Besides such inert diluents, the composition can also include additional agents, such as wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents.

[0104] Suspensions, in addition to the active compounds, may contain additional agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and

tragacanth, or mixtures of these substances, and the like.

[0105] Compositions of the compounds described herein or derivatives thereof for rectal administrations are optionally suppositories, which can be prepared by mixing the compounds with suitable non-irritating excipients or carriers, such as cocoa butter,

polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and, therefore, melt in the rectum or vaginal cavity and release the active component.

[0106] Dosage forms for topical administration of the compounds described herein or derivatives thereof include ointments, powders, sprays, and inhalants. The compounds described herein or derivatives thereof are admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, ointments, powders, and solutions are also contemplated as being within the scope of the compositions.

[0107] The compositions can include one or more of the compounds described herein and a pharmaceutically acceptable carrier. As used herein, the term pharmaceutically acceptable salt refers to those salts of the compound described herein or derivatives thereof that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds described herein. The term salts refers to the relatively non-toxic, inorganic and organic acid addition salts of the compounds described herein. These salts can be prepared in situ during the isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, methane sulphonate, and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. {See S.M. Barge et al., J. Pharm. Sci. (1977) 66, 1, which is incorporated herein by reference in its entirety, at least, for compositions taught therein).

[0108] A solvate of a compound is a so lid- form of the compound that crystallizes with less than one, one, or more than one molecules of solvent inside in the crystal lattice. A few examples of solvents that can be used to create solvates, such as pharmaceutically acceptable solvates, include, but are not limited to, water, C1-C6 alcohols (such as methanol, ethanol, isopropanol, butanol, and can be optionally substituted) in general, tetrahydrofuran, acetone, ethylene glycol, propylene glycol, acetic acid, formic acid, and solvent mixtures thereof. Other such biocompatible solvents which may aid in making a pharmaceutically acceptable solvate are well known in the art. Additionally, various organic and inorganic acids and bases can be added to create a desired solvate. Such acids and bases are known in the art. When the solvent is water, the solvate can be referred to as a hydrate. In some embodiments, one molecule of a compound can form a solvate with from 0.1 to 5 molecules of a solvent, such as 0.5 molecules of a solvent (hemisolvate, such as hemihydrate), one molecule of a solvent (monosolvate, such as monohydrate) and 2 molecules of a solvent (disolvate, such as dihydrate).

[0109] Administration of the compounds and compositions described herein or pharmaceutically acceptable salts thereof can be carried out using therapeutically effective amounts of the compounds and compositions described herein or pharmaceutically acceptable salts thereof as described herein for periods of time effective to treat a disorder. The effective amount of the compounds and compositions described herein or pharmaceutically acceptable salts thereof as described herein may be determined by one of ordinary skill in the art and includes exemplary dosage amounts for a mammal of from about 0.5 to about 200 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. Alternatively, the dosage amount can be from about 0.5 to about 150 mg/kg of body weight of active compound per day, about 0.5 to 100 mg/kg of body weight of active compound per day, about 0.5 to about 75 mg/kg of body weight of active compound per day, about 0.5 to about 50 mg/kg of body weight of active compound per day, about 0.5 to about 25 mg/kg of body weight of active compound per day, about 1 to about 20 mg/kg of body weight of active compound per day, about 1 to about lOmg/kg of body weight of active compound per day, about 20 mg/kg of body weight of active compound per day, about 10 mg/kg of body weight of active compound per day, or about 5mg/kg of body weight of active compound per day. The drug can be administered at a suitable schedule such as once a day, twice a day, three times a day. Those of skill in the art will understand that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.

[0110] Although compositions suitable for oral, intravenous or intraarterial delivery will probably be used most frequently, other routes that may be used include peroral, pulmonary, rectal, nasal, vaginal, lingual, intramuscular, intraperitoneal, intracutaneous, transdermaland subcutaneous routes. The choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance. [0111] In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors well known to the skilled artisan.

[0112] The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt % ) basis, from about 0.01 to 99.99 wt% of a compound of this invention based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. In some embodiments, the compound is present at a level of about 1 to 80 wt %. In a liquid composition, a compound of this invention should generally be present in such compositions at a concentration of between about 0.1 and 20 mg/ml.

Formulation Examples

[0113] The following are representative pharmaceutical formulations containing a compound described herein.

Formulation Example 1— Tablet formulation

[0114] The following ingredients are mixed intimately and pressed into single scored

Ingredient tablet, mg

compound of this invention 400

cornstarch 50

croscarmellose sodium 25

lactose 120

magnesium stearate 5 Formulation Example 2— Capsule formulation

[0115] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.

Ingredient Quantity per capsule, mg

compound of this invention 200

lactose, spray-dried 148

magnesium stearate 2

Formulation Example 3— Suspension formulation

[0116] The following ingredients are mixed to form a suspension for oral administration.

Ingredient Amount

compound of this invention 1.0 g

fumaric acid 0.5 g

sodium chloride 2.0 g

methyl paraben 0.15 g

propyl paraben 0.05 g

granulated sugar 25.0 g

sorbitol (70% solution) 13.00 g

Veegum K (Vanderbilt Co.) 1.0 g

flavoring 0.035 mL

colorings 0.5 mg

distilled water q.s. to 100 mL

Formulation Example 4— Injectable formulation [0117] The following ingredients are mixed to form an injectable formulation.

Ingredient Amount

compound of this invention 0.2 mg-20 mg

sodium acetate buffer solution, 0.4 M 2.0 mL

HC1 (IN) or NaOH (IN) q.s. to suitable pH

water (distilled, sterile) q.s. to 20 mL Formulation Example 5— Suppository Formulation

[0118] A suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:

Ingredient Amount

Compound of the invention 500 mg

Witepsol® H-15 balance

METHODS OF USE

[0119] Also provided herein are methods for treating a disorder mediated, at least in part, by xanthine oxidase. Examples of such disorders include, but are not limited to: gout, hypoxia, or hyperuricemia in a subject.

[0120] A method of treating gout, hypoxia, or hyperuricemia in a subject includes administering to the subject an effective amount of a xanthine oxidase inhibitor as described herein. Optionally, the methods for treating gout, hypoxia, or hyperuricemia in a subject can further include administering a second therapeutic agent, such as an anti-gout agent (e.g., allopurinol, benzbromarone, colchicine, probenecid, or sulfinpyrazone), an antiinflammatory agent, or an antioxidant, to the subject. Optionally, the compound may be administered orally to the subject.

[0121] Further provided herein are methods for reducing uric acid production and/or reactive oxygen species production in a subject. The methods include administering to the subject an effective amount of a xanthine oxidase inhibitor as described herein.

[0122] Optionally, the methods for reducing uric acid production and/or reactive oxygen species production further comprise selecting a subject having gout, hypoxia, or hyperuricemia.

[0123] Methods of inhibiting xanthine oxidase activity in a cell are also provided herein. The methods include contacting a cell with an effective amount of a xanthine

oxidase inhibitor as described herein. Optionally, the contacting is performed in vivo. Optionally, the contacting is performed in vitro.

[0124] The compounds described herein or their tautomers, solvates and/or

pharmaceutically acceptable salts thereof can effectively act as inhibitors of xanthine oxidase and reduce uric acid and/or reactive oxygen species production. In one aspect of this invention, the invention provides a method for inhibiting xanthine oxidase and/or a method for treating a condition, mediated at least in part by xanthine oxidase, for example, gout, hypoxia, or hyperuricemia, with an effective amount of one or more compound described herein or their tautomers, solvates and/or pharmaceutically acceptable salts as provided herein.

[0125] In one of its method aspects, this invention is directed to a method for inhibiting xanthine oxidase in a cell which method comprises contacting the cell with an effective amount of one or more compound described herein or their tautomers, solvates and/or pharmaceutically acceptable salts as described herein.

[0126] In another of its method aspects, this invention is directed to a method for treating a disorder, mediated at least in part by xanthine oxidase, which method comprises administering to a patient in need of the treatment an effective amount of one or more compounds described herein or their tautomers, solvates and/or pharmaceutically acceptable salts.

[0127] Disorders mediated at least in part by xanthine oxidase include, but are not limited to, those selected from the group consisting of gout, hypoxia, and complications thereof.

[0128] Other disorders or conditions treatable by xanthine oxidase include by way of example

• tumor lysis syndrome associated with tumor chemotherapy, or allopurinol

hypersensitivity syndrome;

• ischemia-reperfusion injury such as ischemic bowel injury, myocardial ischemia- reperfusion injury, myocardial infarction, stroke, splanchnic ischemia-reperfusion injury, gut reperfusion injury, ischemia-reperfusion of liver, kidney, lung, other organs and whole body; • Circulatory shock, hemorrhagic shock, hepatic damage, vascular injury and progressive hemodynamic decompensation;

• Chronic heart failure;

• Hypertension, hypercholesterolemia, atherosclerosis, diabetes;

• Inflammatory bowel diseases and other inflammatory diseases;

• Rheumatoid arthritis;

• Sickle cell disease;

• Pneumonia;

• Acute respiratory distress syndrome;

• Chronic obstructive pulmonary disease;

• Pancreatitis;

• Peritonitis and peritoneal adhesions;

• Uveitis;

• Dermatitis; and

• Various forms of toxic organ injury, including various forms of liver injury, e.g., ones induced by ionizing radiation, ethanol, cocaine, thioacetamide, acetaminophen, and aluminum.

[0129] The compounds of this invention are useful in the diagnosis and treatment of a variety of human disorders including, but are not limited to, those selected from the group consisting of gout, hypoxia, and complications thereof. For example, the compounds of the present invention are particularly useful in treating disorders such as gout and other disorders arising therefrom.

[0130] Compounds of this invention have improved safety and potency, such as the potency of inhibiting xanthine oxidase at low micromolar and even nanomolar concentrations.

[0131] The expression "effective amount," when used to describe an amount of compound in a method, refers to the amount of a compound that achieves the desired pharmacological effect or other effect, for example, an amount that results in uric acid production reduction. The compounds and compositions described herein or pharmaceutically acceptable salts thereof are useful for treating gout, hypoxia, or hyperuricemia in humans, including, without limitation, pediatric and geriatric populations, and in animals, e.g., veterinary applications. Optionally, the methods are used to treat conditions associated with elevated uric acid levels, including chronic gouty arthritis, acute inflammatory arthritis, uric acid nephropathy, kidney stones, or tophi.

[0132] In another of its method aspects, this invention is directed to a method for the treatment of patients having a condition due at least in part to over-sensitivity to uric acid by reducing the production of uric acid which method comprising administering to a patient in need of the treatment an effective amount of one or more compounds described herein or their tautomers, solvates and/or pharmaceutically acceptable salts. In some embodiments, the patient has gout.

[0133] The methods described herein can further comprise administering to the subject a second therapeutic agent. Thus, the provided compositions and methods can include one or more additional agents. The one or more additional agents and the compounds described herein or pharmaceutically acceptable salts thereof can be administered in any order, including concomitant, simultaneous, or sequential administration. Sequential administration can be temporally spaced order of up to several days apart. The methods can also include more than a single administration of the one or more additional agents and/or the compounds described herein or pharmaceutically acceptable salts thereof. The administration of the one or more additional agents and the compounds described herein or pharmaceutically acceptable salts thereof can be by the same or different routes and concurrently or sequentially.

[0134] Therapeutic agents include, but are not limited to, anti-gout agents. For example, the anti-gout agent can be allopurinol, benzbromarone, colchicine, probenecid, or sulfinpyrazone. Therapeutic agents also include anti-inflammatory agents. Examples of suitable anti-inflammatory agents include, for example, steroidal and nonsteroidal antiinflammatory drugs (e.g., ibuprofen and prednisone). The therapeutic agent can also be, for example, an antioxidant. Examples of suitable antioxidants include, for example, a- tocopherol, beta-carotene, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), caffeic acid, lutein, lycopene, selenium, tert-butylhydroquinone (TBHQ), Vitamin A, Vitamin C, and Vitamin E. Further examples of suitable antioxidants include putative antioxidant botanticals, such as, for example, grape seeds, green tea, Scutellaria baicalensis, American ginseng, ginkgo biloba, and the like.

[0135] In addition, non-human uric acid enzymes that degrade uric acid can be used as a complementary therapy. Thus, in another aspect, there is provided a method for treating hyperuricemia, or a condition related thereto, by co-administration of a xanthine oxidase inhibitor described herein in combination with an effective amount of an enzyme that degrades uric acid. Examples of such enzymes are described in, e.g., WO 2007052326.

[0136] Any of the aforementioned therapeutic agents can be used in any combination with the compositions described herein. Combinations are administered either concomitantly (e.g., as an admixture), separately but simultaneously (e.g., via separate intravenous lines into the same subject), or sequentially (e.g., one of the compounds or agents is given first followed by the second). Thus, the term combination is used to refer to concomitant, simultaneous, or sequential administration of two or more agents.

[0137] The methods and compounds as described herein are useful for both

prophylactic and therapeutic treatment. For prophylactic use, a therapeutically effective amount of the compounds and compositions or pharmaceutically acceptable salts thereof as described herein are administered to a subject prior to onset (e.g., before obvious signs of gout or hyperuricemia), during early onset (e.g., upon initial signs and symptoms of gout or hyperuricemia), or after the development of gout or hyperuricemia. Prophylactic

administration can occur for several days to years prior to the manifestation of symptoms of gout or hyperuricemia. Therapeutic treatment involves administering to a subject a

therapeutically effective amount of the compounds and compositions or pharmaceutically acceptable salts thereof as described herein after gout or hyperuricemia is diagnosed.

[0138] The amount of active compound administered will vary depending upon the disease treated, the mammalian species, and the particular mode of administration, etc. Suitable doses for the compounds of the present invention can be, for example, between 0.1 mg to about 1000 mg, between 1 mg to about 500 mg, between 1 mg to about 300 mg, or between 1 mg to about 100 mg per day. Such doses can be administered once a day or more than once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day. In some embodiments, the total dosage for a 70 kg adult is in the range of 0.001 to about 15 mg per kg weight of subject per administration or 0.01 to about 1.5 mg per kg weight of subject per administration, and such therapy can extend for a number of days, a number of weeks or months, and in some cases, years. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those of skill in the area.

KITS

[0139] Also provided herein are kits for treating or preventing gout or hyperuricemia in a subject. A kit can include any of the compounds or compositions described herein. For example, a kit can include a compound described herein. A kit can further include one or more additional agents, such as anti-gout agents (e.g., allopurinol, benzbromarone, colchicine, probenecid, or sulfinpyrazone), anti- inflammatory agents, or antioxidants. A kit can include an oral formulation of any of the compounds or compositions described herein. A kit can additionally include directions for use of the kit (e.g., instructions for treating a subject), a container, a means for administering the compounds or compositions, and/or a carrier.

PREPARATION OF THE COMPOUNDS OF THE INVENTION

[0140] The compounds described herein can be prepared by methods described herein or in a variety of ways known to one skilled in the art of organic synthesis or variations thereon as appreciated by those skilled in the art. The compounds described herein can be prepared from readily available starting materials. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art.

[0141] Variations on the compounds described herein include the addition,

subtraction, or movement of the various constituents as described for each compound. Similarly, when one or more chiral centers are present in a molecule, the chirality of the molecule can be changed. Additionally, compound synthesis can involve the temporary protection and deprotection of various chemical functional groups. The use of protection and deprotection, and the selection of appropriate protecting groups can be determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Ed., Wiley & Sons, 2006, which is incorporated herein by reference in its entirety.

[0142] Reactions to produce the compounds described herein can be carried out in solvents, which can be selected by one of skill in the art of organic synthesis. Solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products under the conditions at which the reactions are carried out, i.e., temperature and pressure.

Reactions can be carried out in one solvent or a mixture of more than one solvent. Product or intermediate formation can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear

1 13

magnetic resonance spectroscopy (e.g., H or C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0143] In one aspect, the compounds described herein may be obtained, where available, from commercial sources. Some of the compounds herein can be obtained from, for example, Sigma Chemical Co. (St. Louis, MO), VWR International (Radnor, PA), or Oakwood Products, Inc. (West Columbia, SC).

[0144] If the compounds of this invention contain one or more chiral centers, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column

chromatography, chiral resolving agents and the like.

[0145] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials, such as substituted naphthalene, quinoline, isoquinoline, indole, IH-benzoimidazole, benzooxazole, benzothiazole, imidazopyridine, quinazoline, etc., are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), ChemicalBook Inc. (China,

http://www.chemicalbook.com/ProductIndex_EN.aspx), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5^th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0146] It will be understood that particular syntheses described herein are shown by way of illustration and not as limitations on the syntheses of differently substituted aryl compounds. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents or synthetic strategies in order to the make the compounds described herein. Such synthetic methodologies are considered to be within the ability and knowledge of one skilled in art and are contemplated by the inventors of this application.

[0147] The compounds used as starting material to prepare the compounds of the invention described herein are either commercially available, or can be prepared from

commercially available starting materials. Those that are not commercially available can be made by a variety of synthetic methodologies, related to the particular moieties and the particular substitution pattern on the aryl ring which is desired. The variation in synthetic methodology will be readily apparent to those of skill in the art of organic synthesis. [0148] Compounds of the invention can be readily prepared from substituted benzaldehydes, particularly useful starting are 2-hydroxy-4-thio-benzaldehyde, l-hydroxy-2- amino-benzene, and 4-amino-3-thio-benzaldehyde. A skilled artisan would appreciate that the reactivity of the phenol groups and the aldehyde are each different so that selectivity can be achieved by selecting suitable reagents and suitable reaction conditions for one of them to react but leaving the other intact to form the desired product.

[0149] It is within the purview of the skilled artisan to combine steps in terms of functional group manipulation. For instance, selective functionalization of the phenol moiety, if desired, may occur in the first step and then that functionality may be carried thru to the end of the synthesis.

[0150] In one general embodiment as depicted in Scheme 1, the synthesis of compounds of the invention may involve, first, treating a naphthalenol with an electrophile in order to direct the placement of substituent(s), for instance, X-LG, wherein LG is a leaving group such as halo, sulfonate esters, such as tosylate (CH₃Ph0₃ or TsCT) and mesylate (CH₃S0₃ or MsCT) to five compound 1-2. Next, compound 1-2 is formylated and then undergoes a nitration reaction followed by reaction with R-LG to give compound 1-5, wherein R is as defined in Formula I.

Scheme 1

I, CN, and NO

1-5

[0151] Certain compounds may be prepared according to Scheme 2 wherein the R^2a is hydrogen, phenyl, hydroxy or R as defined in Formula I.

Scheme 2

[0152] In one aspect, certain compounds of Formula I can be prepared according to methods illustrated in Scheme 3 wherein the R^2a is hydrogen, phenyl, hydroxy or R² as defined in Formula I.

Scheme 3

[0153] In one aspect, certain compounds of Formula II can be prepared according to methods illustrated in Scheme 4, wherein R^la is as defined herein and p is 2, 3 or 4. In Scheme

4, compound 4-1 undergoes nitration to provide compound 4-2, which is reduced by, for example hydrogenation with hydrogen in the presence of a catalyst, such as Pd on carbon or Pt0₂ to give the amino compound 4-3. Compound 4-3 reacts with formamidine to give compound

4-5.

Scheme 4

4-5

[0154] In another general embodiment, the synthesis of compounds of the invention involves attaching polyethylene glycol (PEG) substituents. For example, Scheme 5 shows transformation of the compounds III-A and IV-A to compounds III-B and IV-B, respectively.

Scheme 5

IV-A IV-B

[0155] It is also provided that the preceding reaction schemes and syntheses are illustrative, but by no means the only way the compounds of the invention can also be made. EXAMPLES

[0156] The following examples are set forth below to illustrate the methods and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate

representative methods and results. These examples are not intended to exclude equivalents and variations of the subject matter described herein which are apparent to one skilled in the art. Unless otherwise stated, all temperatures are in degrees Celsius (°C).

[0157] In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

MS mass spectrometry

g gram

h hours

HC1 hydrochloric acid

HPLC high-performance liquid chromatography

M molar

mg milligrams

ml or mL milliliters

min minutes

mM micromolar

mmol millimols

mU/ml milliunit(s)per milliliter

m/z mass to charge ratio

NaOH sodium hydroxide

nM nanomolars

nm nanometers

UV ultraviolet

wt % weight percent

μΜ micromolar

[0158] Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures, and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions. [0159] Xanthine oxidase from bovine milk, xanthine, allopurinol, phosphate buffered saline (PBS) solution, potassium nitrite (K 0₂), dioxide manganese (Mn0₂), diethylene- triamine-pentaacetic acid (DTP A), EDTA, ferrous ammonium sulfate, hydrogen peroxide (H₂0₂), sodium hypochlorite, DPPH, 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB), sodium borohydride, potassium persulfate, ascorbic acid, and (±)-a-tocopherol can be obtained from Sigma Chemical Co. (St. Louis, MO). 3,4-Dihydroxy-5-nitrobenzaldehyde, 3,4- dimethoxybenzyl alcohol, 3,4- dihydroxyphenyl ethanol, caffeic acid, 3,4-dihydroxyphenyl ethanol, 3,4,5- trihydroxybenzaldehyde hydrate, 4-hydroxy-3-methoxybenzyl alcohol, and 3,4- dihydroxybenzoic acid can be obtained from VWR International (Radnor, PA).

Example 1: XO Inhibition Assay

[0160] XO activity can be determined by the method of continuous

spectrophotometric rate determination by monitoring the increase of absorption at 295 nm of uric acid in 67 mM phosphate buffer (pH 7.4) containing 20 nM xanthine oxidase with an activity of 5 mU/ml, with or without the compounds as described herein. After pre-incubation for 1 to 5 min at 25 °C, the formation of uric acid in the reaction mixture can be initiated by the addition of 50 μΜ xanthine. Allopurinol is used as a positive control. The compounds, including allopurinol, can be dissolved in H₂0 or an aqueous solution. H₂0 is used as the negative control.

[0161] XO inhibition - The inhibitory activity of xanthine oxidase by the compounds described herein can be determined in vitro by the formation of uric acid, which is measured spectrophotometrically by following the increase in absorbance of uric acid at 295 nm. When 20 nM XO is mixed with increasing concentrations of allopurinol, or a test compound, the initial rate of uric acid formation and IC₅₀ value are measured. After the test compound and XO are pre -incubated for 1 min, xanthine is added to initiate the reaction. The initial rate of uric acid formation is measured with increasing concentrations of xanthine.

Example 2:

[0162] The reaction kinetics of test compound with XO at different pH values can be measured using a spectrophotometer by monitoring the decay of the compound at 327 nm in a system of 30 nM XO with 30 μΜ of the compound in phosphate buffer with pH 6.5 to 8.5. The extinction coefficient of the compound can be measured. The sample for product analysis by mass spectroscopy and HPLC is prepared by mixing 0.3 U XO with 4 mg of the compound in 1 mL phosphate buffer (pH 7.4). The compound/XO samples are analyzed by HPLC (Bio-Rad BioLogic DuoFlow; Hercules, CA) equipped with a 250 x 4.6 mm, 5 micron Phenomenex C-18 (2) Luna column, with a mobile phase of 40% acetonitrile/water. The compound and its product are monitored by the optical absorption.

[0163] Negative electrospray ionization-mass spectrometry (ESI-MS) and tandem (MSMS) are applied to detect and confirm the reaction products of the compound with XO. Mass spectrometric experiments can be performed on an API 3200-Qtrap triple quadrupole mass spectrometer (Applied Biosystem/MDS SCIEX; Foster City, CA) equipped with a turbolonSprayTM source.

[0164] Reaction ofXO and test compound - To determine how a compound described herein inhibits XO enzyme activity, 30 μΜ DHNB is incubated with 15 mU/ml (or 30 nM) XO in phosphate buffer (pH 7.4) and xanthine is then added to initiate the reaction as discussed above. After a period of reaction, the enzymatic activity of XO is recovered. The optical spectral change of the compound is measured in a system without xanthine, i.e., 30 μΜ of the compound with 15 mU/ml (or 30 nM) XO in phosphate buffer.

Example 3: Antioxidant Activity

[0165] Antioxidant activity is determined by testing the ability of the compounds to scavenge DPPH, HOC1, peroxynitrite, and the superoxide ion.

[0166] DPPH scavenging assay - The abilities of the polyphenols described herein to scavenge the DPPH radical are measured optically by monitoring the decreases of their absorptions at 429 nm. The DPPH scavenging activities of the test compound and allopurinol are assayed at a concentration of 20 μΜ. DPPH is used at a concentration of 100 μΜ. Their scavenging activities are compared with that of vitamin C.

[0167] HOCl scavenging assay - HOC1 is prepared immediately before use by adjusting the pH of a 1% (v/v) solution of NaOCl to pH 6.2 with 0.6 M sulfuric acid. The concentration is further determined spectrophotometrically at 235 nm using the molar extinction coefficient of 100 M^_1crn \ 5-Thio-2-nitrobenzoic acid (TNB) is prepared by reducing 5,5'- dithio-bis(2-nitrobenzoic acid) (DTNB) with sodium borohydride in phosphate buffer. The final concentrations of reagents used in the assay are as follows: 25 μΜ HOCl, 70 μΜ TNB, 0 to 200 μΜ antioxidants, phosphate buffer, 50 mM, pH 6.6. The HOCl scavenging assay is based on the inhibition of TNB oxidation to DTNB induced by HOCl.

[0168] Peroxynitrite scavenging assay - Peroxynitrite (ONOO-) is generated by mixing 5 mL acidic solution (0.6 M HC1) of H₂0₂ (0.7 M) and 5 mL of 0.6 M KN0₂ in an ice bath for 1 second and the reaction is quenched with 5 mL of ice-cold 1.2 M NaOH. Residual H₂0₂ can be removed using granular Mn0₂ prewashed with 1.2 M NaOH and the reaction mixture is then left overnight at -20°C. Concentrations of ONOO can be determined before each experiment at 302 nm using a molar extinction coefficient of 1,670 M^"1 cm^"1. The final concentrations of reagents used in the assay can be as follows: 25 μΜ ONOO , 10 μΜ DTPA, 5 μΜ DHR 123, 0.1 M phosphate buffer, pH 7.4. The ONOO- scavenging assay is performed by monitoring the oxidation of dihydrorhodamine (DHR 123) by ONOO spectrophotometrically at 500 nm. The abilities of test compound to scavenge peroxynitrite can be compared with that of vitamin C.

[0169] Superoxide scavenging assay - Superoxide (0₂ ^') scavenging activity is assayed in the xanthine-xanthine oxidase system and determined by the inhibition of the reduction of nitro blue tetrazolium (NBT) to form blue formazan which has an absorption at 560 nm. The final concentrations of reagents used in the assay are as follows: 16.8 mU xanthine oxidase, 25 μΜ xanthine, 50 μΜ NBT, and 0.1 M phosphate buffer (pH 8.5). 0₂ ^° production and xanthine oxidase activity are measured as NBT reduction (at 560 nm) and uric acid production (at 295 nm), respectively. The abilities of polyphenols to scavenge 0₂ ^~" are compared with that of GSH.

Example 4: Hypouricemic effect of DHNB in allantoxanamide induced

hyperuricemic mice

[0170] A hyperuricemia mouse model can be used. Allantoxanamide, a potent uricase inhibitor, is used to induce hyperuricemia in mice in this study. Briefly, adult C57BL/6 mice (15-25 g, 6-8 weeks old, 6 per group) are administrated DHNB at a concentration of 100 mg/kg in 1.0% polyethylene glycol 400 (PEG400 in a volume of 0.1 ml/ 10 g mouse body weight) via oral gavage. The mice are subsequently intraperitoneally injected with allantoxanamide at 200 mg/kg in 0.5% CMC-Na in a volume of 0.1 ml/10 g mouse body weight just after the tested drug oral administration to increase the serum uric acid level. Positive control mice are administered allopurinol at the same concentration as a compound described herein followed by i.p. allantoxanamide. The negative control mice are administered PEG400 only followed by i.p. allantoxanamide. The normal group mice are administered PEG400 only followed by i.p. CMC- Na only. Food and water are withheld overnight prior to the study. Whole blood samples are collected from mice through orbital vein bleeding at the end of the study. The mice are anaesthetized with diethyl ether inside a chamber. The blood is allowed to clot for 1 h at room temperature and then centrifuged at 2350 x g for 4 min to obtain the serum. The serum is kept on ice and assayed immediately. Serum uric acid is determined with the phosphotungstate method, as known to those of skill in the art.

Example 5: Acute toxicity studies of DHNB in mice

[0171] To determine whether DFiNB has any acute toxicity in mice, C57BL/6 mice are randomized into 3 groups (12/group). Groups 1 to 3 received an oral vehicle solution (PEG400), DFiNB (500 mg/kg), and allopurinol (500 mg/kg), respectively. Each mouse is monitored for general health conditions on a daily basis for 28 days, including examination of mortality, body weights, and behavior of the mice.

[0172] A compound described herein or allopurinol at 500 mg/kg are administrated to 12 mice, respectively, via oral gavage. Control mice receive the vehicle solution. The animals are observed daily up to 28 days for any symptoms of general toxicity, such as behavior changes and hair loss. Body weight is measured. Histology analysis for the liver, kidney, and heart is performed. The offspring of the mice are also observed.

[0173] The compounds and methods of the appended claims are not limited in scope by the specific compounds and methods described herein, which are intended as illustrations of a few aspects of the claims and any compounds and methods that are functionally equivalent are within the scope of this disclosure. Various modifications of the compounds and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative compounds, methods, and aspects of these compounds and methods are specifically described, other compounds and methods and combinations of various features of the compounds and methods are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein; however, all other combinations of steps, elements, components, and constituents are included, even though not explicitly stated.

Claims

WHAT IS CLAIMED IS:

1. A method for reducing uric acid and/or reactive oxygen species production in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formula I, IA-I, or II:

wherein

heteroatoms independently selected from nitrogen, oxygen and sulfur;

m is 1 or 2;

A³, and A⁴ is N;

X is CR¹ or N;

20 20 2 3 1

hydroxyl, OR , OCOR , R and R , provided that at least two R are independently nitro, cyano, aldehyde, hydroxyl, or R³;

each R³ is independently selected from the group consisting of:

each R is independently selected from the group consisting of:

-(CH₂CH₂0)_nH,

-P(=0)₂OR⁴, -P(=0)SR⁴, -P(=0)₂SR⁴, -P(=S)OR⁴,

n is an integer of from 1 to 10,000;

R⁵ is Ci to C₆ alkyl or halogenated Ci to C₆ alkyl;

R⁶ is hydrogen or R²;

R⁷ is selected from the group consisting of

hydrogen, (CH₂CH₂0)_nH, Ci to C₆ alkyl,

-P(=0)₂OR⁴, -P(=0)SR⁴, -P(=0)₂SR⁴, -P(=S)OR⁴,

-SiR⁴;

R¹¹ is hydrogen or Ci to C₆ alkyl, or two R¹¹ on a same carbon form =0;

R¹² is hydrogen or Ci to C₆ alkyl; and R is a saturated fatty chain or an unsaturated fatty chain or -OR is a hydroxy group esterified with a phospholipid, or a tautomer, and/or a pharmaceutically acceptable salt and/or solvate thereof.

2. The method of claim 1, wherein the compound of Formula I is of Formula I:

a tautomer, and/or a pharmaceutically acceptable salt and/or solvate thereof. The method of claim 2, wherein the compound is of Formula IA or IB

or a tautomer, and/or a pharmaceutically acceptable salt and/or a solvate thereof, wherein A¹,

and B 3^J are as defined in Formula I. 4. The method of claim 1, wherein the compound is of Formula II:

5. The method of claim 4, wherein the compound of Formula II is of Formula IIA, IIB, IIC, or IID:

7. The method of claim 1, wherein the compound is selected from the group consisting of:

8. The method of claim 7 wherein one or more of the hydroxy groups are esterified with a saturated fatty acid or an unsaturated fatty acid or a phospholipid.

9. A method for reducing uric acid and/or reactive oxygen species production in a patient in need thereof, comprising administering to the patient an effective amount of a compound selected from the group consisting of 3,4-dihydroxy-5-cyanobenzaldehyde and 3 ,5 -dinitrosalicylaldehyde .

10. A method for treating a condition, mediated at least in part by xanthine oxidase, in a patient in need thereof, comprsing administering to the patient an effective amount of a compound of Formula I, IA-i or II:

wherein

heteroatoms independently selected from nitrogen, oxygen and sulfur;

m is 1 or 2;

each A 1 , A2 , A 3 , A 4 is independently CR 1 or N, provided that no more than one

A³, and A⁴ is N;

X is CR¹ or N;

20 20 2 3 1

each R³ is independently selected from the group consisting of:

each R is independently selected from the group consisting of:

(CH₂CH₂0)_nH,

-P(=0)₂OR⁴, -P(=0)SR⁴, -P(=0)₂SR⁴, -P(=S)OR⁴,

-S(=0)SR⁴, -S(=0)₂SR⁴, -S(=NR⁴)R⁴, -S(=NR⁴)(=0)R⁴, -S(=NR⁴)₂R⁴, and -SiR⁴; R⁴ is selected from the group consisting of hydrogen, Ci-C₆ alkyl, C3-C₇ cycloalkyl, C₂- C₆ alkenyl, C4-C₇ cycloalkenyl, C₂-C₆ alkynyl, (CH₂CH₂0)_nH, phenyl, C₅-C₆ heterocycle having 1 to 3 heteroatoms selected from O, S, S0₂, N, and NR¹¹, and C5-C6 heteroaryl having 1 to 3 heteroatoms selected from O, S, N, and NR¹²;

n is an integer of from 1 to 10,000;

L is -C(O)- or C₂ to C₄ alkylene group optionally substituted with oxo;

R⁵ is Ci to C₆ alkyl or halogenated Ci to C₆ alkyl;

R⁶ is hydrogen or R²;

R⁷ is hydrogen, (CH₂CH₂0)_nH, or Ci to C₆ alkyl;

R¹¹ is hydrogen or Ci to C₆ alkyl, or two R¹¹ on a same carbon form =0;

R¹² is hydrogen or Ci to C₆ alkyl; and

or a tautomer, and/or a pharmaceutically acceptable salt and/or solvate thereof. 11. The method of claim 10, wherein the compound is of Formula I

or a tautomer, a pharmaceutically acceptable salt and/or solvate thereof.

12. The method of claim 10, wherein the compound is of Formula IA or IB:

and B 3^J are as defined in Formula I.

13. The method of claim 10 wherein the compound is of Formula II:

14. The method of claim 10, wherein the compound is of Formula IIA, IIB, IIC, or IID:

16. The method of claim 10, wherein the compound is selected from the group consisting of:

where X¹¹ is O, S or NH,

or a tautomer, solvate and/or a pharmaceutically acceptable salt thereof.

17. The method of claim 16 wherein one or more of the hydroxy groups are esterified with a saturated fatty acid or an unsaturated fatty acid or a phospholipid.

18. A method for reducing uric acid and/or reactive oxygen species production in a patient in need thereof, comprising administering to the patient an effective amount of a compound selected from the group consisting of 3,4-dihydroxy-5-cyanobenzaldehyde and 3 ,5 -dinitrosalicylaldehyde .

19. The method of any one of claims 10-18, wherein the condition is gout or a

complication thereof.

20. The method of any one of claims 10-18, wherein the condition is hypoxia or a complication thereof.

21. A method for treating hyperuricemia in a patient in need thereof, comprising

administering to the patient an effective amount of a compound of Formula I, IA-i or II:

wherein

ring A is phenyl or a 6-membered heteroaryl comprising one nitrogen atom in the ring; ring B is phenyl or a 5- or 6-membered heteroaryl comprising one or two ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

m is 1 or 2;

A³, and A⁴ is N;

X is CR¹ or N; each R¹ is independently selected from the group consisting of hydrogen, nitro, aldehyde,

20 20 2 3 1

each R³ is independently selected from the group consisting of:

each R is independently selected from the group consisting of:

(CH₂CH₂0)_nH,

-P(=0)₂OR⁴, -P(=0)SR⁴, -P(=0)₂SR⁴, -P(=S)OR⁴,

R⁴ is selected from the group consisting of hydrogen, Ci-C₆ alkyl, C3-C7 cycloalkyl, C₂- C₆ alkenyl, C₄-C₇ cycloalkenyl, C₂-C₆ alkynyl, (CH₂CH₂0)_nH, phenyl, C5-C6 heterocycle having 1 to 3 heteroatoms selected from O, S, S0₂, N, and NR¹¹, and C₅-C₆ heteroaryl having 1 to 3 heteroatoms selected from O, S, N, and NR¹²;

n is an integer of from 1 to 10,000;

L is -C(O)- or C₂ to C₄ alkylene group optionally substituted with oxo;

R⁵ is Ci to C₆ alkyl or halogenated Ci to C₆ alkyl;

R⁶ is hydrogen or R²;

R⁷ is hydrogen, (CH₂CH₂0)_nH, or Ci to C₆ alkyl;

R¹¹ is hydrogen or Ci to C₆ alkyl, or two R¹¹ on a same carbon form =0; R is hydrogen or Ci to C₆ alkyl; and

22. The method of claim 21 , wherein the compound is of Formula I

or a tautomer, solvate, and/or a pharmaceutically acceptable salt thereof. The method of claim 21, wherein the compound is of Formula I A or IB:

or a tautomer, a solvate, and/or a pharmaceutically acceptable salt thereof, wherein A¹, A², A³, A⁴, B², and B³ are as defined in Formula I.

24. The method of claim 21 , wherein the compound is of Formula II:

25. The method of claim 21, wherein the compound is selected from Formula IIA, IIB, IIC or IID:

or a tautomer, and/or a pharmaceutically acceptable salt and a solvate thereof, wherein R¹, R⁶, B¹, B², and B³ are as defined in Formula II.

26. The method of claim 21 , wherein the compound of is selected from the group consisting of:

27. The method of claim 21, wherein the compound is selected from the group consisting

28. The method of claim 27 wherein one or more of the hydroxy groups are esterified with a saturated fatty acid or an unsaturated fatty acid or a phospholipid.

29. A method for treating hyperuricemia in a patient in need thereof, comprising administering to the patient an effective amount of a compound selected from the group consisting of 3,4-dihydroxy-5-cyanobenzaldehyde and 3,5-dinitrosalicylaldehyde.

30. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula I, IA-i or II:

wherein

heteroatoms independently selected from nitrogen, oxygen and sulfur;

m is 1 or 2;

A³, and A⁴ is N;

X is CR¹ or N;

20 20 2 3 1

each R³ is independently selected from the group consisting of:

each R is independently selected from the group consisting of:

(CH₂CH₂0)_nH,

-P(=0)₂OR⁴, -P(=0)SR⁴, -P(=0)₂SR⁴, -P(=S)OR⁴,

n is an integer of from 1 to 10,000;

R⁵ is Ci to C₆ alkyl or halogenated Ci to C₆ alkyl;

R⁶ is hydrogen or R²;

R⁷ is hydrogen, (CH₂CH₂0)_nH, or Ci to C₆ alkyl;

R¹¹ is hydrogen or Ci to C₆ alkyl, or two R¹¹ on a same carbon form =0;

R¹² is hydrogen or Ci to C₆ alkyl; and

31. The pharmaceutical composition of claim 30, wherein the compound is of Formula I

32. The pharmaceutical composition of claim 30, wherein the compound is of Formula I A or IB:

or a tautomer, and/or a pharmaceutically acceptable salt and/or a solvate thereof, wherein A¹, A 4 , B 1 , B 2", and B 3^J are as defined in Formula I.

33. The pharmaceutical composition of claim 30, wherein the compound is of Formula II:

34. The pharmaceutical composition of claim 30, wherein the compound is selected from the group consisting of:

NO, , and OH or a tautomer, and/or a pharmaceutically acceptable salt and/or solvate thereof.

35. The pharmaceutical composition of claim 30, wherein the compound is selected from the group consisting of:

36. The pharmaceutical composition of claim 35 wherein one or more of the hydroxy groups are esterified with a saturated fatty acid or an fatty acid or a phospholipid.