WO2004009563A1 - 5-aryltetrazole compounds, compositions thereof, and uses therefor - Google Patents

5-aryltetrazole compounds, compositions thereof, and uses therefor Download PDF

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Publication number
WO2004009563A1
WO2004009563A1 PCT/US2003/022462 US0322462W WO2004009563A1 WO 2004009563 A1 WO2004009563 A1 WO 2004009563A1 US 0322462 W US0322462 W US 0322462W WO 2004009563 A1 WO2004009563 A1 WO 2004009563A1
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alkyl
nhc
heteroaryl
compound
independently
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PCT/US2003/022462
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French (fr)
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Alex Nivorozhkin
John Van Duzer
Andrew Salzman
Garry Southan
Siya Ram
Qi Zeng
Csaba Szabo
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Inotek Pharmaceuticals Corporation
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Priority to HU0500871A priority Critical patent/HUP0500871A3/en
Priority to CA002492847A priority patent/CA2492847A1/en
Priority to EP03765715A priority patent/EP1542980A1/en
Priority to BR0312768-0A priority patent/BR0312768A/en
Priority to NZ538313A priority patent/NZ538313A/en
Priority to AU2003249313A priority patent/AU2003249313A1/en
Priority to MXPA05000765A priority patent/MXPA05000765A/en
Priority to JP2004523556A priority patent/JP2005535678A/en
Publication of WO2004009563A1 publication Critical patent/WO2004009563A1/en
Priority to IL16633105A priority patent/IL166331A0/en

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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to 5-Aryltetrazole Compounds, compositions comprising an effective amount of a 5-Aryltetrazole Compound, and methods for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia comprising administering to an animal in need thereof an effective amount of a 5-Aryltetrazole Compound.
  • Superoxide radical can be generated by xanthine oxidase and NADPH oxidase from the partial reduction of molecular oxygen. Neutrophils and macrophages are known to produce O 2 " and hydrogen peroxide (H 2 O 2 ), which normally are involved in the killing of ingested or invading microbes (T. Oda et al, Science, 244:974-976). Under physiologic conditions XO is ubiquitously present in the form of a xanthine dehydrogenase (XDH).
  • XDH xanthine dehydrogenase
  • XDH is a molybdenum iron-sulfur flavin dehydrogenase that uses NAD + as an electron acceptor to oxidize purines, pyrimidines, pteridins, and other heterocyclic nitrogen- containing compounds. In mammals, XDH is converted from the NAD-dependent dehydrogenase form to the oxygen-dependent oxidase form, either by reversible sulfhydryl oxidation or irreversible proteolytic modification (S. Tan et al, Free Radic. Biol. Med. 15:407-414).
  • Xanthine oxidase then no longer uses NAD as an electron acceptor, but transfers electrons onto oxygen, generating O 2" , H O 2 , and hydroxyl radical (OH) as purines are degraded to uric acid (J.M. McCord et al, New Engl. J. Med. 312:159-163; R. Miesel et al, Inflammation, 18:597-612).
  • Inflammatory activation converts XDH to XO, mainly by oxidizing structurally important thiolates. Inflammation also markedly up-regulates the conversion of xanthine dehydrogenase (T.D. Engerson et al, J. Clin. Invest. 79:1564-1570).
  • Inhibition of XO activity blocks the formation of O 2 ⁇ and prevents loss of purine nucleotides, and is therefore salutary in a variety of shock and ischemia reperfusion disorders.
  • Pharmacologic inhibition of XO can also be beneficial by blocking the pro- inflammatory effect of O 2 " on gene expression (M.D. Schwartz et al, Am. J. Respir. Cell Mol. Biol. , 12:434-440).
  • O 2 " has been implicated in the nuclear translocation of NF-kappa B and the expression of NF-icB-dependent genes.
  • mice subjected to hemorrhagic shock depletion of XO by a tungsten-enriched diet decreased mononuclear mRNA levels of IX- 113 and TNF-a. Similar results were obtained after pharmacologic inhibition of XO by in vivo administration of allopurinol.
  • a vicious cycle can be created by oxidant stress, in which O 2 " induction of pro-inflammatory cytokines results in greater XDH to XO conversion, and thus more O 2 " production. This suggests that XO inhibitors can exert important anti-inflammatory actions by interrupting this process at multiple points, in particular, by blocking pro-inflammatory gene expression.
  • Pharmacologic inhibition of XO can also be beneficial in hemorrhagic shock by preserving the intracellular nucleotide pool.
  • high energy phosphate nucleotides are sequentially degraded to inosine monophosphate, xanthine, and hypoxanthine.
  • xanthine and hypoxanthine degrade to uric acid, thereby depleting the purine pool.
  • the loss of available purines with which to form ATP accelerates the loss of intracellular energetics and contributes to cell necrosis and organ failure.
  • XO inhibitors block this terminal degradative pathway and permit the cell to recover and reestablish adequate stores of high energy phosphate nucleotides.
  • pre-treatment with allopurinol resulted in a 6-fold increase in survival (J.W. Crowell et al, Am. J. Phys. 216: 744-748) .
  • allopurinol exerted no benefit.
  • Infusion of the purine base hypoxanthine after the onset of shock similarly provided no benefit.
  • the invention encompasses compounds having the formula (la):
  • Ri is CO 2 R 4 ; each R 2 is independently -halo, -NO 2 , -CN, -OH, -N(R 5 )(R 5 ), -OR 5 , -C(O)R 5 , -OC(O)R 5 , -C(O)NHC(O)R 5 , -(C 1 -C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C 1 o)cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 5 -C 10 )cycloalkenyl, -(C 3 -C 10 )heterocycle, -phenyl, -naphthyl, -benzyl, -CO 2 R 5 , -C(O)OCH(R 5 )(R 5 ), -
  • R 3 is -H, -halo, -NO 2 , -CN, -OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)N(R 5 )(R 5 ), -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(d-C ⁇ alky!, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 5 -C 10 )cycloalkenyl, -naphthyl, -(C 3 -C 10 )heterocycle, -CO 2
  • R4 is -(C 5 )heteroaryl, -(C - 6 ) ⁇ heteroaryl, phenyl, naphthyl, or benzyl; each R 5 is independently -H, -CF 3 , -(C 1 -C 10 )alkyl, -benzyl, -adamantyl, -morpholinyl, -pyrrolidyl, -pyrridyloxide, -pyrrohdinyldione, -piperdidyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 3 -C 10 )heterocycle, or
  • each R 6 is independently -H, -halo, -NO 2 , -CN, -OH, -CO 2 H, -N((C ⁇ -C ⁇ o)al yl(C ⁇ -C ⁇ o)al yl).
  • a compound of formula (la) or a pharmaceutically acceptable salt or hydrate thereof is useful for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia in an animal.
  • the invention also relates to pharmaceutical compositions comprising an effective amount of a compound of formula (la) or a pharmaceutically acceptable salt or hydrate thereof; and a pharmaceutically acceptable carrier or vehicle. These compositions are useful for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia in an animal.
  • the invention also relates to compounds of formula (lb):
  • Ri is -H, -CO 2 R4, -C(O)R 5 , or -C(O)N(R 5 )(R 5 );
  • R 2 is -(C 1 -C 10 )alkyl or -O(C 1 -C 10 )alkyl;
  • T is -(C 5 )heteroaryl, -(C 6 )heteroaryl, phenyl, naphthyl, or benzyl; and eachR 5 is independently -H, -CF 3 , -benzyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C 1 o)cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 3 -C 10 )heterocycle.
  • a compound of formula (lb) or a pharmaceutically acceptable salt or hydrate thereof is useful for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia in an animal.
  • the invention also relates to pharmaceutical compositions comprising an effective amount of a compound of formula (lb) or a pharmaceutically acceptable salt or hydrate thereof; and a pharmaceutically acceptable carrier or vehicle. These compositions are useful for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia in an animal.
  • the invention further relates to methods for treating or preventing an inflammation disease, comprising administering to an animal in need thereof an effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt or hydrate thereof.
  • the invention further relates to methods for treating or preventing a reperfusion disease, comprising administering to an animal in need thereof an effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt or hydrate thereof.
  • the invention further relates to methods for treating or preventing hyperuricemia, comprising administering to an animal in need thereof an effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt or hydrate thereof.
  • the invention further relates to methods for treating or preventing tumor- lysis syndrome, comprising admimstering to an animal in need thereof an effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt or hydrate thereof.
  • the invention further relates to methods for treating or preventing an inflammatory bowel disorder, comprising administering to an animal in need thereof an effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt or hydrate thereof.
  • the invention further relates to methods for inhibiting xanthine oxidase activity, comprising administering to an animal in need thereof an effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt or hydrate thereof.
  • the invention further relates to methods for treating or preventing an inflammation disease, comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic):
  • Ri is -H, -CQ2R4, -C(O)R 5 , or -C(O)N(R 5 )(R 5 ); each R 2 is independently -halo, -NO 2 , -CN, -OH, -N(R 5 )(R 5 ), -OR 5 , -C(O)R 5 , -OC(O)R 5 , -C(O)NHC(O)R 5> ⁇ (C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl,
  • R 4 is -CF 3 , -(C 1 -C 10 )alkyl, -benzyl, -adamantyl, -morpholinyl, -pyrrolidyl, -pyrridyloxide, -pyrrohdinyldione, -piperdidyl, -(C5)heteroaryl, -(C 6 )heteroaryl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 3 -C 10 )heterocycle, or
  • each R 5 is independently -H or R ; each Rg is independently -H, -halo, -NO 2 , -CN, -OH, -CO 2 H, -N((C 1 -C 1 o)alkyl(C 1 -C 10 )alkyl), -O(C ⁇ -C ⁇ o)alkyl, -C(O)(d-C 10 )alkyl, -C(O)NH(CH 2 ) m (C 1 -C 10 )alkyl, -OCF 3 , -benzyl, -CO 2 (CH 2 ) m CH((C 1 -C 10 )alkyl(C 1 -
  • C 10 )alkyl ), -C(O)H, -CO 2 (C 1 -C 10 )alkyl, -(d-C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 5 -C 1 o)cycloalkenyl, -(C 5 )heteroaryl, -(C 6 )heteroaryl, -phenyl, naphthyl, -(C 3 -C 10 )heterocycle, -CO 2 (CH 2 ) m (C 1 -C 1 o)alkyl, -CO 2 (CH 2 ) m H, -NHC(O)(C 1 -C ⁇ o)alkyl, -NHC(O)NH(
  • the invention further relates to methods for treating or preventing hyperuricemia, comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic) or a pharmaceutically acceptable salt or hydrate thereof.
  • the invention further relates to methods for treating or preventing tumor- lysis syndrome, comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic) or a pharmaceutically acceptable salt or hydrate thereof.
  • the invention further relates to methods for treating or preventing an inflammatory bowel disorder, comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic) or a pharmaceutically acceptable salt or hydrate thereof.
  • the invention further relates to methods for inhibiting xanthine oxidase activity, comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic) or a pharmaceutically acceptable salt or hydrate thereof.
  • kits comprising a container containing a compound of formula (la), (lb), or (Ic) or a pharmaceutically acceptable salt or hydrate thereof (each being a "5-Aryltetrazole Compound").
  • saturated straight chain alkyl means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms.
  • Representative saturated straight chain alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n-decyl; while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3 -methylhexyl,
  • alkyl groups has its standard meaning known to those of ordinary skill in the art, for example, "Me” means methyl or -CH 3 , “Et” means ethyl or -CH 2 CH 3 , "n-Pr” means n-propyl or -CH 2 CH 2 CH 3 , “i-Pr” means iso-propyl or -CH(CH 3 ) 2 , "n-Bu” means n-butyl or -CH 2 (CH 2 ) 2 CH 3 , “t-Bu” means tert-butyl or -C(CH 3 ) 3 .
  • -(C 2 -C 10 )alkenyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at least one carbon-carbon double bond.
  • Representative straight chain and branched (C 2 -C 10 )alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3 -methyl- 1-butenyl, -2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1-n
  • -(C -do)alkyny ⁇ means a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at lease one carbon-carbon triple bond.
  • Representative straight chain and branched -(C 2 -C 10 )alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3 -methyl- 1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl, -6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl,
  • the term "-(C 3 -do)cycloalky ⁇ " means a saturated cyclic hydrocarbon having from 3 to 10 carbon atoms.
  • Representative (C 3 -C 1 o)cycloalkyls include -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl, and -cyclodecyl.
  • the term "-(C 8 -C 14 )bicycloalkyl” means a bi-cyclic hydrocarbon ring system having from 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring.
  • Representative -(C 8 -C 14 )bicyclocycloalkyls include -indanyl, -1,2,3,4-tetrahydronaphthyl, -5,6,7,8-tetrahydronaphthyl, -perhydronaphthyl and the like.
  • -(C 5 -C 1 o)cycloalkenyl means a cyclic non- aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 5 to 10 carbon atoms.
  • Representative (C 5 -C 10 )cycloalkenyls include -cyclopentenyl, -cyclop entadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl, -cyclononadienyl, -cyclodecenyl, -cyclodecadienyl and the like.
  • -(C 3 -do)heterocycle or "-(C 3 -C 10 )heterocyclo” means a 3- to 10-membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic.
  • a 3-membered -(C 3 -C 7 )heterocycle can contain up to 3 heteroatoms, and a 4- to 10-membered -(C 3 -C 10 )heterocycle can contain up to 4 heteroatoms.
  • Each heteroatom is independently selected from nitrogen, which can be quatemized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the -(C 3 -C 10 )heterocycle may be attached via any heteroatom or carbon atom.
  • Representative -(C 3 -do)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, xriazinyl, morpholinyl, pyrrohdinonyl, pyrrolidinyl, piperidinyl, piperazinyl, benzo[l ,3]dioxolyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindiny
  • a heteroatom may be substituted with a protecting group known to those of ordinary skill in the art, for example, the hydrogen on a nitrogen may be substituted with a tert-butoxycarbonyl group or the hydrogen on an oxygen may be substituted with a methoxymethyl.
  • -(C5)heteroaryl means an aromatic heterocycle ring of 5 members, wherein at least one carbon atom of the ring is replaced with a heteroatom such as, for example, nitrogen.
  • Representative -(C 5 )heteroaryls include furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyrazinyl, triazolyl, thiadiazolyl, and the like.
  • -(C 6 )heteroaryl means an aromatic heterocycle ring of 6 members, wherein at least one carbon atom of the ring is replaced with a heteroatom such as, for example, nitrogen.
  • One of the -(C 6 )heteroaryl's rings contain at least one carbon atom.
  • Representative (C 6 )heteroaryls include pyridyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, pyrimidyl, and the like.
  • saturated straight chain alkyl means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms.
  • Representative saturated straight chain alkyls include -methyoxy, -ethyoxy, -n-propyloxy, -n-butyloxy, -n-pentyloxy, -n-hexyloxy, -n-heptyloxy, -n-octyloxy, -n-nonyloxy and -n-decyloxy; while saturated branched alkyls include -isopropyloxy, -sec-butyloxy, -isobutyloxy, -tert-butyloxy, -isopentyloxy, -2-methylbutyloxy, -3-methylbutyloxy, -2-methylpentyloxy, -3-methylpentyloxy, -4-methylpentyloxy,
  • alkyloxy groups has its standard meaning known to those of ordinary skill in the art, for example, "OMe” means methoxy, methoxyl, or -OCH 3 , “OEt” means ethoxy, ethoxyl, or -OCH 2 CH 3 , "n-OPr” means n-propyloxy or -CH 2 CH 2 CH 3 , “i- OPr” means iso-propyloxy or -OCH(CH 3 ) , "n-OBu” means n-butyloxy or -OCH 2 (CH 2 ) 2 CH 3 , “t-OBu” means tert-butyloxy or -OC(CH 3 ) 3 .
  • -Halogen or "-Halo" means -F, -Cl, -Br or -I.
  • animal includes, but is not limited to, a cow, monkey, chimpanzee, baboon, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig and human.
  • adamantyl includes 1-adamantyl, 2-adamantyl, and 3-adamantyl.
  • naphthyl includes 1 -naphthyl and 2-naphthyl.
  • morpholinyl includes N-morpholinyl
  • pyrridyloxide includes 2-pyrridyloxide, 3 -pyrridyloxide, and 4-pyrridyloxide.
  • pyrrohdinyldione includes N-pyrrolidinyl-2, 3-dione, N-pyrrolidinyl-2,4-dione, N-pyrrolidinyl-2,5-dione, N-pyrrolidinyl-3,5-dione,
  • piperdinyl includes N-piperdinyl, 2-piperdinyl, and 3-piperdinyl.
  • pharmaceutically acceptable salt is a salt formed from an acid and a basic nitrogen group of one of the 5-Aryltetrazole Compounds.
  • Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,/?-toluenesulfonate, and pamoate (z.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
  • Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl) amine, 2-hydroxy-
  • the term "pharmaceutically acceptable hydrate,” is a hydrate formed from the association of one or more water molecules with a 5-Aryltetrazole Compound.
  • the term “hydrate” includes a mono-hydrate, dihydrate, trihydrate, tetrahydrate, and the like.
  • the term "effective amount” means an amount effective for: (a) treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia; or (b) inhibiting xanthine oxidase activity.
  • n is 0. In another embodiment n is 0 and R 3 is -halo.
  • n is 0 and R 3 is -C(O)R 5 ,
  • n is 0 and R 3 is -C(O)NHC(O)R 5 .
  • n is 0 and R 3 is -C(O)N(R 5 )(R 5 ).
  • n is 0 and R 3 is -CO 2 (CH 2 ) m (R 5 ). In another embodiment n is 0 and R 3 is -H.
  • n is 0 and R 3 is -NHC(O)N(R 5 )(R5).
  • n is 0 and R 3 is -C(O)NHR 5 .
  • p is an integer from 1 to 3.
  • p is 2; and each Re is independently -halo.
  • p 2; each Re is independently halo; and one R 6 is in the para position and the other Re is in a meta position.
  • p is 2; each Re is independently halo; and one Re is in the para position and the other Re is in an ortho position.
  • each Re is independently halo; and each Re is in a meta position.
  • Illustrative subclasses of the compounds of formula (la) have the following formulas, wherein R is -(C 5 )heteroaryl, -(Ce)heteroaryl, phenyl, naphthyl, or benzyl:
  • the invention also encompasses compounds of formula (lb):
  • R 1 is -H.
  • R ⁇ is -H and R 2 is -(C 1 -C 1 o)alkyl.
  • Ri is -H and R 2 is -O(C 1 -C 10 )alkyl.
  • Ri is -H and R 2 is methyl.
  • Ri is -H and R 2 is ethyl.
  • Ri is -H and R 2 is n-propyl. In another embodiment, Ri is -H and R 2 is iso-propyl. hi another embodiment, R ⁇ is -H and R 2 is n-butyl. hi another embodiment, Ri is ⁇ H and R 2 is iso-butyl. h another embodiment, Ri is •H and R 2 is sec-butyl. hi another embodiment, Ri is ⁇ H and R 2 is tert-butyl. hi another embodiment, Ri is -H and R 2 is n-pentyl. In another embodiment, Ri is -H and R 2 is isopentyl. hi another embodiment, Ri is ⁇ H and R 2 is n-hexyl.
  • Ri is ⁇ H and R 2 is n-heptyl. h another embodiment, Ri is -H and R 2 is n-octyl. In another embodiment, R ⁇ is -H and R 2 is n-nonyl. h another embodiment, Ri is -H and R 2 is n-decyl. h another embodiment, Ri is ⁇ H and R 2 is 2-methylbutyl. In another embodiment, Ri is -H and R is 3-methylbutyl. In another embodiment, Ri is -C(O)R 5 and R 2 is methyl. h another embodiment, Ri is -C(O)R 5 and R 2 is ethyl.
  • Ri is -C(O)R 5 and R 2 is n-propyl. In another embodiment, Ri is -C(O)R 5 and R 2 is iso-propyl h another embodiment, Ri is -C(O)R 5 andR 2 is n-butyl. In another embodiment, Ri is -C(O)R 5 and R 2 is iso-butyl. h another embodiment, Ri is -C(O)R 5 and R 2 is sec-butyl, hi another embodiment, Ri is -C(O)R 5 andR 2 is tert-butyl. In another embodiment, Ri is -C(O)R 5 and R 2 is n-pentyl.
  • Ri is -C(O)R 5 andR 2 is isopentyl. In another embodiment, Ri is -C(O)R 5 and R 2 is n-hexyl. In another embodiment, Ri is -C(O)R 5 and R 2 is n-heptyl. In another embodiment, Ri is -C(O)R 5 andR 2 is n-octyl. In another embodiment, Ri is -C(O)R 5 and R 2 is n-nonyl. hi another embodiment, R] is -C(O)R 5 and R 2 is n-decyl. In another embodiment, Ri is -C(O)R 5 and R 2 is 2-methylbutyl.
  • Ri is -C(O)R 5 and R 2 is 3-methylbutyl. h another embodiment, Ri is -CO R 4 and R 2 is methyl. In another embodiment, Ri is -CO 2 R 4 and R 2 is ethyl. In another embodiment, Ri is -CO 2 R 4 and R is n-propyl. In another embodiment, Ri is -CO 2 R 4 and R 2 is iso-propyl. h another embodiment, Ri is -CO ⁇ and R 2 is n-butyl. In another embodiment, Ri is -CO ⁇ and R 2 is iso-butyl. hi another embodiment, Ri is -CO 2 R 4 and R is sec-butyl. h another embodiment, R ⁇ is -CO 2 R 4 and R 2 is tert-butyl.
  • Ri is -CO 2 R 4 and R 2 is n-pentyl.
  • Ri is -CO ⁇ and R 2 is isopentyl.
  • Ri is -CO ⁇ and R 2 is n-hexyl.
  • Ri is -CO ⁇ and R 2 is n-heptyl.
  • Ri is -CO ⁇ E and R 2 is n-octyl.
  • Ri is -CO ⁇ and R 2 is n-nonyl.
  • Ri is -CO ⁇ and R is n-decyl. In another embodiment, Ri is -CO ⁇ and R 2 is 2-methylbutyl. h another embodiment, R ⁇ is -CO ⁇ and R 2 is 3-methylbutyl. h another embodiment, Ri is -C(O)N(R5)(R 5 ) and R 2 is methyl.
  • Ri is -C(O)N(R 5 )(R 5 ) and R is ethyl.
  • Ri is -C(O)N(R 5 )(R 5 ) and R 2 is n-propyl. In another embodiment, Ri is -C(O)N(R5)(R 5 ) and R 2 is iso-propyl.
  • Ri is -C(O)N(R 5 )(R 5 ) and R is n-butyl.
  • Ri is -C(O)N(R 5 )(R 5 ) and R 2 is iso-butyl.
  • Ri is -C(O)N(R 5 )(R 5 ) and R 2 is sec-butyl.
  • Ri is -C(O)N(R 5 )(R 5 ) and R 2 is tert-butyl.
  • Ri is -C(O)N(R 5 )(Rs) and R is n-pentyl.
  • R ⁇ is -C(O)N(R 5 )(Rs) and R is isopentyl.
  • Ri is -C(O)N(R 5 )(R5) and R is n-hexyl.
  • Ri is -C(O)N(R 5 )(R 5 ) and R is n-heptyl.
  • Ri is -C(O)N(R 5 )(R5) and R 2 is n-octyl.
  • R ⁇ is -C(O)N(R 5 )(R 5 ) and R 2 is n-nonyl.
  • Ri is -C(O)N(R 5 )(Rs) and R 2 is n-decyl.
  • Ri is -C(O)N(R 5 )(Rs) and R is 2-methylbutyl.
  • Ri is -C(O)N(R 5 )(R5) and R 2 is 3-methylbutyl.
  • Ri is -H and R 2 is methoxy. In another embodiment, Ri is -H and R 2 is ethoxy.
  • Ri is -H and R 2 is n-propyloxy.
  • Ri is -H and R 2 is iso-propyloxy.
  • Ri is -H and R 2 is n-butyloxy.
  • Ri is -H and R 2 is iso-butyloxy. In another embodiment, Ri is -H and R 2 is sec-butyloxy. In another embodiment, Ri is -H and R 2 is tert-butyloxy. hi another embodiment, Ri is -H and R 2 is n-pentyloxy. h another embodiment, Ri is -H and R 2 is isopentyloxy. hi another embodiment, Ri is -H and R 2 is n-hexyloxy. In another embodiment, Ri is -H and R 2 is n-heptyloxy. hi another embodiment, R ⁇ is -H and R 2 is n-octyloxy. hi another embodiment, Ri is -H and R 2 is n-nonyloxy.
  • Ri is -H and R 2 is n-decyloxy.
  • Ri is -H and R is 2-methylbutyloxy. In another embodiment, Ri is -H and R 2 is 3-methylbutyloxy. hi another embodiment, Ri is -C(O)R 5 and R 2 is methoxy.
  • Ri is -C(O)R 5 and R 2 is ethoxy.
  • Ri is -C(O)R 5 and R 2 is n-propyloxy.
  • Ri is -C(O)R 5 and R 2 is iso-propyloxy. In another embodiment, Ri is -C(O)R 5 and R 2 is n-butyloxy. hi another embodiment, Ri is -C(O)R 5 and R 2 is iso-butyloxy. h another embodiment, Ri is -C(O)R 5 and R 2 is sec-butyloxy. hi another embodiment, Ri is -C(O)R 5 and R 2 is tert-butyloxy.
  • Ri is -C(O)R 5 and R 2 is n-pentyloxy.
  • Ri is -C(O)R 5 and R 2 is isopentyloxy.
  • Ri is -C(O)R 5 and R 2 is n-hexyloxy.
  • Ri is -C(O)R 5 and R 2 is n-heptyloxy.
  • Ri is -C(O)R 5 and R 2 is n-octyloxy.
  • Ri is -C(O)R 5 and R 2 is n-nonyloxy.
  • Ri is -C(O)R 5 and R 2 is n-decyloxy.
  • R ⁇ is -C(O)R 5 and R 2 is 2-methylbutyloxy.
  • Ri is -C(O)R 5 and R 2 is 3-methylbutyloxy.
  • Ri is -CO R t and R 2 is methoxy. h another embodiment, Ri is -CO ⁇ and R 2 is ethoxy. hi another embodiment, Ri is -CO 2 R 4 and R 2 is n-propyloxy.
  • R ⁇ is -CO ⁇ and R 2 is iso-propyloxy.
  • Ri is -CO ⁇ and R 2 is n-butyloxy.
  • Ri is -CO ⁇ and R 2 is iso-butyloxy.
  • Ri is -CO 2 R 4 and R 2 is sec-butyloxy.
  • Ri is -CO 2 R 4 and R 2 is tert-butyloxy.
  • Ri is -CO 2 R 4 and R 2 is n-pentyloxy.
  • Ri is -CO 2 R 4 and R 2 is isopentyloxy.
  • Ri is -CO ⁇ and R is n-hexyloxy.
  • Ri is -CO R t and R 2 is n-heptyloxy.
  • Ri is -CO ⁇ and R 2 is n-octyloxy.
  • Ri is -CO 2 R 4 and R 2 is n-nonyloxy.
  • Ri is -CO ⁇ and R is n-decyloxy.
  • Ri is -CO ⁇ and R 2 is 2-methylbutyloxy.
  • Ri is -CO R]. and R 2 is 3-methylbutyloxy.
  • Ri is -C(O)N(R 5 )(R 5 ) and R 2 is methyloxy.
  • R ⁇ is -C(O)N(R 5 )(R5) and R is ethyloxy.
  • Ri is -C(O)N(Rs)(R 5 ) and R 2 is n-propyloxy.
  • Ri is -C(O)N(R5)(R 5 ) and R 2 is iso-propyloxy.
  • Ri is -C(O)N(R 5 )(R 5 ) and R 2 is n-butyloxy.
  • Ri is -C(O)N(Rs)(R 5 ) and R 2 is iso-butyloxy.
  • Ri is -C(O)N(R 5 )(R 5 ) and R 2 is sec-butyloxy.
  • Ri is -C(O)N(R 5 )(R 5 ) and R 2 is tert-butyloxy.
  • Ri is -C(O)N(R 5 )(R 5 ) and R 2 is n-pentyloxy.
  • Ri is -C(O)N(R 5 )(R 5 ) and R 2 is isopentyloxy.
  • Ri is -C(O)N(R 5 )(R5) and R 2 is n-hexyloxy.
  • Ri is -C(O)N(R 5 )(R 5 ) and R 2 is n-heptyloxy.
  • Ri is -C(O)N(R 5 )(R 5 ) and R 2 is n-octyloxy.
  • R ⁇ is -C(O)N(Rs)(R 5 ) and R 2 is n-nonyloxy.
  • Ri is -C(O)N(R 5 )(R5) and R 2 is n-decyloxy. In another embodiment, Ri is -C(O)N(R 5 )(R 5 ) and R 2 is 2-methylbutyloxy. hi another embodiment, Ri is -C(O)N(R 5 )(R 5 ) and R 2 is 3-methylbutyloxy.
  • Illustrative compounds of formula (lb) are:
  • the invention further relates to methods for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic):
  • Ri is -H. hi another embodiment R ⁇ is -H; n is 0 and R 3 is -(Ci-Cio)alkyl. In another embodiment Ri is -H; n is 0 and R 3 is -O(CH 2 ) m R 5 . In another embodiment Ri is -H; n is 0 R 3 is -O(CH 2 ) m R 5 ; and R 5 is -H. In another embodiment Ri is -H; n is 0 and R 3 is -halo. In another embodiment Ri is -H; n is 0 and R 3 is -C(O)R 5 .
  • Ri is -H; n is 0 and R 3 is -C(O)NHC(O)R 5 . In another embodiment Ri is -H; n is 0 and R 3 is -C(O)N(R 5 )(R 5 ). In another embodiment Ri is -H; n is 0 and R 3 is -H. In another embodiment Ri is -H; n is 0 and R 3 is -CO 2 (CH 2 ) m (R 5 ). In another embodiment Ri is -H; n is 0 and R 3 is -NHC(O)N(R 5 )(R 5 ). In another embodiment Ri is -H; n is 0 andR 3 is -C(O)NHR 5 . In another embodiment Ri is -H; n is 0 R 3 is -C(O)NHR 5 ; In another embodiment Ri is -H; n is 0 R 3 is -C(O)NHR 5 ; and R 5 is
  • Ri is -H; n is 0; R 3 is -C(O)NHR 5 ; R 5 is
  • p is an integer from 1 to 3.
  • Ri is -H; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • Ri is -H; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • Ri is -H; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • Ri is -H; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • R 6 is halo and is in an ortho position.
  • Ri is -H; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • Ri is -H; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • Ri is -H; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • p is 2; and one Re is in an ortho position and the other Re is in a meta position, hi another embodiment, Ri is -CO ⁇ .
  • h another embodiment and n is 0.
  • hi another embodiment R is -CO ⁇ ; n is 0 and R 3 is -halo.
  • hi another embodiment R is -CO ⁇ ; n is 0 and R 3 is -C(O)R 5 .
  • h another embodiment R is -CO ⁇ ; n is 0 and R 3 is -C(O)NHC(O)R 5 .
  • hi another embodiment R is -CORt; n is 0 and R 3 is -H.
  • R is -CO 2 Rt; n is 0 and R 3 is -CO 2 (CH 2 ) m (R 5 ). In another embodiment R is -CO ⁇ ; n is 0 and R 3 is -NHC(O)N(R 5 )(R 5 ). In another embodiment R is -CO ⁇ ; n is 0 and R 3 is -C(O)N(R 5 )(R 5 ). In another embodiment R is -CO ⁇ ; n is 0 and R 3 is -C(O)NHR 5 .
  • R is -CO ⁇ ; n is 0 R 3 is -C(O)NHR 5 .
  • R 5 is
  • Ri is -CO 2 R4; n is 0; R 3 is -C(O)NHR 5 ; R 5 is
  • p is an integer from 1 to 3.
  • Ri is -CO 2 R t ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • Ri is -CO 2 R 4 ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • p 1
  • Re is halo and is in a meta position.
  • Ri is -CO ⁇ ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • R 6 is halo and is in an ortho position.
  • Ri is -CO 2 R 4 ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • -G° p is 2; and each ⁇ is independently -halo.
  • Ri is -CO 2 R 4 ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • each R 6 is independently halo; and one Re is in the para position and the other R 6 is in a meta position.
  • Ri is -CO 2 R 4 ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • Ri is -CO2R4; n s 0; R 3 is -C(O)NHR 5; R 5 is
  • Ri is -C(O)R 5 .
  • R is -C(O)R 5 ; n is 0 andR 3 is -CO 2 (CH 2 ) m (R 5 ). In another embodiment R is-C(O)R 5 ;nisO andR 3 is -NHC(O)N(R 5 )(R 5 ). In another embodiment R is -C(O)R 5 ; nis 0 andR 3 is C(O)N(R 5 )(R 5 ). hi another embodiment R is -C(O)R 5 ; n is 0 and R 3 is -C(O)NHR 5 . In another embodiment R is -C(O)R 5 ; n is 0 R 3 is -C(O)NHR 5 ; and R 5 is
  • R ⁇ is -C(O)R 5 ; n is 0; R 3 is -C(O)NHR 5 ; R 5 is
  • p is an integer from 1 to 3.
  • Ri is -C(O)R 5 ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • Ri is -C(O)R5; n is 0; R 3 is -C(O)NHR 5 ; R 5 is
  • Ri is -C(O)R 5 ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • Ri is -C(O)R 5 ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • Ri is -C(O)R 5 ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • p is 2; and each Re is independently -halo.
  • Ri is -C(O)R 5 ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • Ri is -C(O)R 5 ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • p 2; each Re is independently -halo; and one Re is in the para position and the other Re is in an ortho position.
  • Ri is -C(O)Rs; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • p 2; and one Re is in an ortho position and the other Re is in a meta position.
  • Ri is -C(O)NR 5 R 5 .
  • Ri is -C(O)NR 5 R5; n is 0; and R 3 is -halo.
  • Ri is -C(O)NR5Rs; n is 0; and R 3 is -C(O)R 5 .
  • Ri is -C(O)NRsR5; n is 0; and R 3 is -C(O)NHC(O)R 5 .
  • Ri is -C(O)NR5R 5 ; n is 0; and R 3 is -H.
  • Ri is -C(O)NR 5 R 5 ; n is 0; and R 3 is -CO 2 (CH 2 ) m (R 5 ).
  • Ri is -C(O)NRsR 5 ; n is 0; and R 3 is -NHC(O)N(R 5 )(R 5 ).
  • Ri is -C(O)NR 5 R 5 ; n is 0; and R 3 is -C(O)N(R 5 )(R 5 ).
  • Ri is -C(O)NR 5 R 5 ; n is 0; and R 3 is -C(O)NHR 5 .
  • R x is -C(O)NR 5 R 5 ; n is 0; R 3 is -C(O)NHR 5 ; and R 5 is
  • Ri is -C(O)NR 5 R 5 ; n is 0; R 3 is -C(O)NHR 5 ; R 5 is
  • p is an integer from 1 to 3.
  • Ri is -C(O)NR 5 R 5 ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • Ri is -C(O)NR 5 R 5 ; n is 0; R 3 is -C(O)NHR 5; R 5 is -o ⁇ (Rs) P
  • Ri is -C(O)NR 5 R 5 ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • Ri is -C(O)NR 5 R 5 ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • Ri is -C(O)NR 5 R 5 ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • p 2; and each R 6 is independently -halo.
  • R t is -C(O)NR 5 R 5 ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • p 2; each Re is independently -halo; and one Re is in the para position and the other Re is in a meta position.
  • Ri is -C(O)NR 5 R 5 ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • R p is 2; each R 6 is independently -halo; and one R 6 is in the para position and the other Re is in an ortho position.
  • R x is -C(O)NR 5 R 5 ; n is 0; R 3 is -C(O)NHR 5; R 5 is
  • p 2; and one R 6 is in an ortho position and the other Re is in a meta position.
  • the compounds of formula (Ic) are the compounds of formula (la) and pharmaceutically acceptable salts and hydrates thereof, above.
  • the compounds of formula (Ic) are the compounds of formula (lb) and pharmaceutically acceptable salts and hydrates thereof, above.
  • Illustrative compounds of formula (Ic) are:
  • the 5-Aryltetrazole Compounds can be made using conventional organic synthesis and/or by the following illustrative methods. General procedures for the synthesis of aryl tetrazoles are provided in, Butler, R.N., Comprehensive Heterocyclic Chemistry Vol. IV, pp. 664-668 (Katritzky et al. eds., 1996).
  • the 5-Aryltetrazole Compounds of formula (Ic) wherein ⁇ is -H can be obtained by contacting a compound of formula A with an with an azide (e.g., sodium azide (“NaN 3 ”)) at reflux, (e.g., about 100 °C), in the presence of zinc bromide (“ZnBr 2 ") using water as a solvent as shown below in Scheme A.
  • an azide e.g., sodium azide (“NaN 3 ")
  • ZnBr 2 zinc bromide
  • Compounds of formula A can be obtained commercially (e.g., commercially available from Sigma- Aldrich Co., http://www.sigmaaldrich.com) or made readily by those skilled in the art.
  • a 5-Aryltetrazole Compound of formula (Ic) wherein R ⁇ is -CO ⁇ , -C(O)R 5 , or -C(O)N(R 5 )(R 5 ) can be obtained by contacting a 5-Aryltetrazole Compound of formula (Ic), wherein R t is -H with an acyl compound (e.g., XCO ⁇ , XC(O)R 5 , or XC(O)N(R 5 )(R 5 ), wherein X is Br or Cl) in triethylamine (NEt 3 ).
  • an acyl compound e.g., XCO ⁇ , XC(O)R 5 , or XC(O)N(R 5 )(R 5 ), wherein X is Br or Cl
  • a 5-Aryltetrazole Compounds of formula (Ic) wherein Ri is H can be obtained by contacting a compound of formula A with an azide, (e.g., azidotrimethylsilane (“TMSN 3 ”)) and a catalytic amount of dibutyl tin oxide ("n-Bu 2 SnO") in refluxing toluene as a solvent as shown below in Scheme B.
  • an azide e.g., azidotrimethylsilane (“TMSN 3 ”
  • n-Bu 2 SnO dibutyl tin oxide
  • -C(O)N(Rs)(R 5 ) can be obtained by contacting a 5-Aryltetrazole Compound of formula (Ic), wherein R! is -H with an acyl compound (e.g., XCO ⁇ , XC(O)R 5 , or XC(O)N(R 5 )(R 5 ), wherein X is Br or Cl) in triethylamine (NEt 3 ).
  • R 5 is -H
  • protecting group chemistry can be used.
  • the 5-Aryltetrazole Compounds of formula (Ic) wherein Ri is -H can be converted to 5-Aryltetrazole compounds of formula (la) by contacting the compound of formula (Ic) wherein Ri is -H with an alkyl chlorocarbonate or carbonic acid anhydride under conditions suitable for the formation of a carbamate as shown in Scheme C.
  • Methods for obtaining carbamates from amines and carbonates are provided in, for example, Raucher et al, Synthetic Commun. 1985, 15, 1025.
  • illustrative compounds AA-AZ, BA-BZ, CA-CZ, DA-DZ, EA-EG can be made using this method.
  • a 5-Aryltetrazole Compound of formula (lb) wherein Ri is -H can be obtained by contacting a compound of formula B with a 4- substituted aniline (e.g., 4-methylaniline or 4-methoxyaniline) to obtain a compound of formula D'.
  • the compound of formula D' is then contacted with azide, (e.g., azidotrimethylsilane ("TMSN 3 ")) and a catalytic amount of dibutyl tin oxide (“n-Bu 2 SnO”) in refluxing toluene as a solvent as shown below in Scheme B.
  • azide e.g., azidotrimethylsilane (“TMSN 3 ")
  • n-Bu 2 SnO dibutyl tin oxide
  • a 5-Aryltetrazole Compound of formula (lb) wherein Ri is -H is contacted with an acyl derivative (e.g. , XCO ⁇ , XC(O)R 5 , or XC(O)N(R 5 )(R 5 ), wherein X is Br or Cl) in triethylamine (NEt 3 ) to provide a 5-Aryltetrazole Compound of formula (lb).
  • R 5 is -H
  • protecting group chemistry can be used.
  • illustrative compounds EH- FE can be made using this method.
  • 5-Aryltetrazole Compounds can have asymmetric centers and therefore can exist in particular enantiomeric and or diastereomeric forms.
  • a 5-Aryltetrazole Compound can be in the form of an optical isomer or a diastereomer. Accordingly, the invention encompasses 5-Aryltetrazole Compounds and their uses as described herein in the form of their optical isomers, diastereomers, and mixtures thereof, including a racemic mixture.
  • one or more hydrogen, carbon or other atoms of a 5- Aryltetrazole Compound can be replaced by an isotope of the hydrogen, carbon, or other atom.
  • an effective amount of a 5-Aryltetrazole Compound or a pharmaceutical composition comprising an effective amount of a 5-
  • Aryltetrazole Compound is administered to an animal in need of treatment or prevention of an inflammation disease, a reperfusion disease, or hyperuricemia.
  • an effective amount of a 5-Aryltetrazole Compound can be used to treat or prevent any condition that is treatable or preventable by inhibiting xanthine oxidase.
  • Examples of cells that express xanthine oxidase include, but are not limited to, lung, liver, and intestinal cells.
  • Examples of conditions that are treatable or preventable by inhibiting xanthine oxidase include, but are not limited to, an inflammation disease, a reperfusion disease, or hyperuricemia.
  • an effective amount of a 5-Aryltetrazole Compound can be used to treat or prevent an inflammation disease, a reperfusion disease, or hyperuricemia.
  • inflammation diseases include, but are not limited to, chronic inflammatory disorders of the joints including arthritis, e.g., rheumatoid arthritis and osteoarthritis; respiratory distress syndrome; inflammatory bowel disorders; and inflammatory lung disorders such as asthma and chronic obstructive airway disease, inflammatory disorders of the eye such as corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis, and endophthalmitis; inflammatory disorders of the gum, e.g., periodontitis and gingivitis; tuberculosis; leprosy; inflammatory diseases of the kidney including glomerulonephritis and nephrosis; inflammatory disorders of the skin including acne, sclerodermatitis, psoriasis, eczema, photoaging and wrinkles; inflammatory diseases of the central nervous system, including AIDS-related neurodegeneration, stroke, neurotrauma, Alzheimer's disease, encephalomyelitis and viral or
  • inflammatory bowel disorders include, but are not limited to, ileitis, including, but not limited to, regional ileitis; colitis, including, but not limited to, ulcerative colitis, collagenous/microscopic colitis, and enterocolitis; Crohn's disease; and pouchitis.
  • reperfusion diseases include, but are not limited to, shock and sepsis.
  • Shock can be septic shock, e.g., gram positive bacteria-mediated circulatory shock, gram negative bacteria-mediated circulatory shock, hemorrhagic shock, anaphylactic shock, shock associated with systemic inflammation, shock associated with pro-inflammatory cytokines, and shock associated with systemic inflammatory response syndrome (SIRS).
  • SIRS systemic inflammatory response syndrome
  • the 5-Aryltetrazole Compounds can also be used to prevent or treat circulatory shock, such as shock occurring as a result of gram negative and gram positive sepsis, trauma, hemorrhage, burn injury, anaphylaxis, cytokine immunotherapy, organ failure (particularly kidney or liver failure), or systemic inflammatory response syndrome.
  • circulatory shock such as shock occurring as a result of gram negative and gram positive sepsis, trauma, hemorrhage, burn injury, anaphylaxis, cytokine immunotherapy, organ failure (particularly kidney or liver failure), or systemic inflammatory response syndrome.
  • reperfusion disease are disease arising from cell or solid-organ transplantation, cardiopulmonary bypass surgery, compartment syndrome, crush injury, splanchnic ischemia-reperfusion, myocardial infarction and stroke.
  • hyperuricemia examples include, but are not limited to, gout; tumor-lysis syndrome; idiopathic hyperuricemia; hyperuricemia inherited including, but not limited to, hyperuricemia due to PP-ribose-P synthetase overactivity; hypoxanthine-gaunine phosphoribosyltransferase deficiency; glucose-6-phosphate deficiency; Gierke's glycogen storage disease; chronic hemolytic hyperuricemia including, but not limited to, erythroid, myeloid, and lymphoid proliferative hyperuricemia; renal mechanistic hyperuricemia including, but not limited to, familial progressive renal insufficiency, acquired chronic renal insufficiency, drug related renal insufficiency, and endogenous renal production disorders.
  • tumor-lysis syndrome examples include, but are not limited to, tumor-lysis syndrome resulting from chemotherapy treatment in patients with cancer, including but not limited to, leukemias, lyrnphomas, small cell lung cancer, and breast cancer.
  • the rumor-lysis syndrome is that which results from chemotherapy, particularly for treating cancer.
  • the 5-Aryltetrazole Compounds are advantageously useful in veterinary and human medicine. As described above, the 5-Aryltetrazole Compounds are useful for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia.
  • an effective amount of a 5-Aryltetrazole Compound can be administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle.
  • the present compositions, which comprise a 5-Aryltetrazole Compound are in one embodiment administered orally.
  • the compositions of the invention can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal, and intestinal mucosa, etc.) and may be administered together with another therapeutic agent. Administration can be systemic or local.
  • Various delivery systems are known, e.g. , encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer the 5-Aryltetrazole Compounds.
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin.
  • the mode of administration is left to the discretion of the practitioner. In most instances, administration will result in the release of the 5-Aryltetrazole Compounds into the bloodstream.
  • the 5- Aryltetrazole Compounds may be desirable to administer the 5- Aryltetrazole Compounds locally. This may be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. In certain embodiments, it may be desirable to introduce the 5-Aryltetrazole
  • Compounds into the central nervous system by any suitable route including intraventricular, intrathecal, and epidural injection, hitraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
  • Pulmonary administration can also be employed, e.g. , by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
  • the 5-Aryltetrazole Compounds can be formulated as a suppository, with traditional binders and excipients such as triglycerides.
  • the 5-Aryltetrazole Compounds can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990) and Treat et al., Liposomes in the Therapy of Infectious Disease and Cancer 311 -311 and 353-365 (1989).
  • the 5-Aryltetrazole Compounds can be delivered in a controlled-release system (see, e.g., Goodson, in Medical Applications of Controlled
  • a controlled-release system can be placed in proximity of a target of the 5-Aryltetrazole Compound, e.g., the spinal column or brain, thus requiring only a fraction of the systemic dose.
  • compositions can optionally comprise a suitable amount of a pharmaceutically acceptable carrier or vehicle so as to provide the form for proper administration to the animal.
  • Such pharmaceutical carriers or vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like, h addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents may be used.
  • the pharmaceutically acceptable carriers or vehicle s are preferably sterile. Water is a particularly useful vehicle when the 5-Aryltetrazole Compound of the invention is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions.
  • suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like.
  • the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
  • the composition is in the form of a capsule (see e.g., U.S. Patent No. 5,698,155).
  • suitable pharmaceutical excipients are described in Remington 's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporated herein by reference.
  • compositions for oral delivery may be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example.
  • Orally administered compositions may contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
  • compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time.
  • Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions.
  • fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture.
  • delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
  • a time delay material such as glycerol monostearate or glycerol stearate may also be used.
  • Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose and magnesium carbonate. Such excipients are preferably of pharmaceutical grade.
  • compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the compositions may also include a solubilizing agent. Compositions for intravenous administration may optionally include a local anesthetic such as lignocaine to lessen pain at the site of the injection.
  • a local anesthetic such as lignocaine to lessen pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • the 5-Aryltetrazole Compounds are to be administered by infusion, they can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the 5-Aryltetrazole Compounds are administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • the 5-Aryltetrazole Compounds of the invention can be administered by controlled-release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S.
  • dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention.
  • the invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
  • the amount of the 5-Aryltetrazole Compound that is effective in the treatment or prevention of an inflammation disease, a reperfusion disease, or hyperuricemia and/or for inhibiting xanthine oxidase activity can depend on the nature of the disorder or condition causing the inflammation disease, reperfusion disease, or hyperuricemia, or the need for inhibiting xanthine oxidase activity and can be determined by standard clinical techniques.
  • in vitro or in vivo assays may optionally be employed to help identify dosage ranges.
  • the effective amount to be employed will also depend on the route of administration, and the seriousness of the inflammation disease, reperfusion disease, or hyperuricemia and/or need for inhibiting xanthine oxidase activity and can be decided according to the judgment of the practitioner and each patient's circumstances.
  • Administration can be at an effective amount ranging from about 0.1 to about 500 mg/kg/day of the 5-Aryltetrazole Compound to animal in need thereof. Suitable effective amounts can range from about 0.1 milligrams to about 500 milligrams about every 4 h, although typically about 100 mg or less.
  • the effective amounts range from about 0.01 milligrams to about 500 milligrams of a 5-Aryltetrazole Compound about every 4 h, in another embodiment about 0.020 milligrams to about 50 milligrams about every 4 h, and in another embodiment about 0.025 milligrams to about 20 milligrams about every 4 h.
  • the effective amounts described herein refer to total amounts administered; that is, if more than one 5-Aryltetrazole Compound is administered, the effective amounts correspond to the total amount administered.
  • the 5-Aryltetrazole Compounds can be assayed in vitro or in vivo, tor the desired therapeutic or prophylactic activity, prior to use in humans. Animal model systems can be used to demonstrate safety and efficacy.
  • the present methods for treating or preventing inflammation disease, a reperfusion disease, or hyperuricemia in an animal in need thereof can further comprise administering to the animal being administered a 5-Aryltetrazole Compound an effective amount of another therapeutic agent.
  • Effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective-amount range, h one embodiment of the invention where another therapeutic agent is administered to an animal, the effective amount of the 5-Aryltetrazole Compound is less than its effective amount would be where the other therapeutic agent is not administered. In another embodiment, the 5-Aryltetrazole Compound and the other therapeutic agent act synergistically to treat an inflammation disease, a reperfusion disease, or hyperuricemia.
  • the methods comprise administering an effecitve amount of a 5-Aryltetrazole Compound and another therapeutic agent
  • the 5-Aryltetrazole Compound is adminstered when the other therapeutic agent exerts its therapeutic effect, or the other therapeutic agent is administered when the 5-Aryltetrazole Compound exerts its therapeutic or prophylactic effect.
  • the other therapeutic agent can be a non-steroidal anti-inflammatory agent.
  • Useful non-steroidal anti-inflammatory agents include, but are not limited to, aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenaniic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, difluris
  • the other therapeutic agent can be an anticonvulsant.
  • useful anticonvulsants include, but are not limited to, acetylpheneturide, albutoin, aloxidone, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate, calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam, decimemide, diethadione, dimethadione, doxenitroin, eterobarb, ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate, mephenytoin, mephobarbital, metharbital, methetoin, methsuximide, 5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phen
  • the other therapeutic agent can be an anti-depressant.
  • useful antidepressants include, but are not limited to, binedaline, caroxazone, citalopram, dimethazan, fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone, benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomipramine, demex
  • the other therapeutic agent can be an anti-hyperuricemic agent.
  • Useful anti- hyperuricemic agents also include, but are not limited to, allopurinol.
  • the other therapeutic agent can be an agent useful in treating or preventing tumor-lysis syndrome.
  • Therapeutic agents useful for treating or preventing tumor-lysis syndrome also include, but are not limited to, Lasix or Zyloprim.
  • the other therapeutic agent can be an agent useful in treating or preventing an inflammatory bowel disorder.
  • Therapeutic agents useful for treating or preventing an inflammatory bowel disorder include, but are not limited to, sulfasalazine, olsalazine, and mesalamine.
  • a 5-Aryltetrazole Compound and the other therapeutic agent can act additively or, more preferably, synergistically.
  • Compound is administered concurrently with another therapeutic agent.
  • a composition comprising an effective amount of a 5-Aryltetrazole Compound and an effective amount of another therapeutic agent can be administered.
  • a composition comprising an effective amount of a 5-Aryltetrazole Compound and a different composition comprising an effective amount of another therapeutic agent can be concurrently administered.
  • an effective amount of a 5- Aryltetrazole Compound is administered prior or subsequent to administration of an effective amount of another therapeutic agent.
  • kits that can simplify the administration of a 5- Aryltetrazole Compound to an animal.
  • a typical kit of the invention comprises a unit dosage form of a 5-
  • the unit dosage form is a container, which can be sterile, containing an effective amount of a 5-Aryltetrazole Compound and a pharmaceutically acceptable carrier or excipient.
  • the kit can further comprise a label or printed instructions instructing the use of the 5-Aryltetrazole Compound to treat or prevent inflammation disease, reperfusion disease, or hyperuricemia.
  • the kit can also further comprise a unit dosage form of another therapeutic agent, for example, a container containing an effective amount of the other therapeutic agent.
  • the kit comprises a container containing an effective amount of a 5-Aryltetrazole Compound and an effective amount of another therapeutic agent. Examples of other therapeutic agents include, but are not limited to, those listed above.
  • Kits of the invention can further comprise devices that are useful for administering the unit dosage forms.
  • devices include, but are not limited to, syringes, drip bags, patches, enema bags, and inhalers.
  • Compounds FT, HA-HC, HK, HL, HS, HT, HW-IF, IH-IM, IO, IS, IX- JA, JG-JI, and JK-JN were prepared according to the method of example 1 using the corresponding amine in place of aniline.
  • Compounds JO, IP, and IG were prepared according to the method of examples 1 and 2 using the corresponding amine in place of aniline.
  • Compound FR was synthesized by reacting a commercially available 4-aminobenzonitrile with acetic anhydride as described in Vogel's Textbook of Practical Organic Chemistry 5th Ed., p. 917 and then converting a resulting 4-acetylaminobenzo- nitrile to Compound FR following the Method B.
  • Compound HN was prepared by reacting commercially available 5-aminotetrazole with cinnamoyl chloride as described in Vogel's Textbook of Practical Organic Chemistry 5th Ed., p. 917.
  • Compound IT was prepared by benzoylation of 4-aminobenzonitrile as described in Vogel 's Textbook of Practical Organic Chemistry 5th Ed., p. 917 and then converting a resulting N-benzoyl-4-cyanoaniline to Compound IT following the Method B (Sect. 4.4).
  • a typical assay showing of xanthine oxidase inhibitory activity of illustrative 5-Aryltetrazole Compounds involved the use of a 96 well plate setup. Analysis of the sample utilized a Spectrophotometer with a SoftMax Pro Program set at a kinetic reading at a wavelength of 295 run with a runtime of 10 minutes taking a reading at 12 second intervals. Before the first reading the sample was mixed using an automixer for five seconds and between readings the sample was mixed for three seconds.
  • Well Plate Preparation Four to eight wells were used for each 5- Aryltetrazole Compound, h each well was added 200 mL of Phosphate-buffered saline (50 mM), 20 mL of xanthine (0.5 mg/mL in water), 10 mL of the 2.5 mM solution of 5- Aryltetrazole Compound (prepared as described above), and 20 mL of xanthine oxidase (1/100 x 40 mL PBS). The xanthine oxidase was kept on ice and was added immediately before the plate was run on the spectrophotometer. A control well was also prepared using only DMSO.
  • the following table shows concentrations of illustrative 5-Aryltetrazole Compounds providing xanthine-oxidase inhibition. Without being limited by theory, compounds that inhibit xanthine oxidase are useful for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia.
  • NT means that the compound was not tested at the indicated concentration.
  • Compounds FF-HK, HM-HT, HW- IL, IN, IP-IZ, JB-JI, and JL-JR, illustrative 5-Aryltetrazole Compounds inhibit xanthine oxidase activity and, accordingly are useful for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia.
  • Compounds HL, HU, HV, IM, IO, JA, JJ, and JK are useful for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia.
  • EXAMPLE 14 TOXIC LIVER INJURY MODEL Illustrative 5-Aryltetrazole Compounds exert hepatoprotective effects in a thioacetamide model of hepatic failure.
  • An illustrative 5-Aryltetrazole Compound exerts protective effects in a model of collagen-induced arthritis in mice. Results are expressed as incidence and severity over time. Studies were conducted as described in Inflamm. Res. 50(11):561-569 (2001). The results illustrate that the administration of Compound JO, an illustrative 5- Aryltetrazole Compound, reduced incidence of collagen-induced arthritis in mice.
  • mice that were administered Compound JO showed a significant decrease in the incidence of collagen-induced arthritis.
  • Compound JO an illustrative 5- Aryltetrazole Compound, inhibits collagen-induced arthritis and accordingly, is useful for treating or preventing arthritis.
  • Illustrative 5-Aryltetrazole Compounds exert protective effects in various models of organ ischemia and reperfusion.
  • intraperitoneal administration of illustrative 5-Aryltetrazole Compounds retards the progression of gut ischemia reperfusion- induced hyperpermeability and mortality in mice. Results are expressed as % decrease in gut hyperpermeability and as mortality as observed after 6 hours and 2 days of reperfusion. Studies were conducted as described in Shock, 14(2):134-141 (2000). There was a notable dose-dependent effect on gut hyperpermeability and there was an improvement in survival rate, as tested at the highest dose of both levels.

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Abstract

The present invention relates to 5-Aryltetrazole Compounds, compositions comprising an effective amount of a 5-Aryltetrazole Compound, and methods for treating an inflammation disease, a reperfusion disease, or hyperuricemia in an animal in need thereof comprising administering to the animal an effective amount of a 5-Aryltetrazole Compound.

Description

5-ARYLTETRAZOLE COMPOUNDS, COMPOSITIONS THEREOF. AND USES THEREFOR
This application is a continuation-in-part of U.S. application no. 10/197,609, filed July 18, 2002, which is currently pending, the entirety of which is incorporated herein by reference.
GOVERNMENTAL SUPPORT
The research leading to the invention was supported, at least in part, by a grant from: the National Institute of General Medical Sciences Grant No. 1R43 GM63274- 01 Al; the National Heart, Lung, and Blood institute Grant No. 1R43HL70342-01; the National Institute of General Medical Sciences Grant No. 2R44GM59017-02; and the
National Institute of General Medical Sciences Grant No. 1R43GM59017-01. Accordingly, the U.S. Government may have certain rights in the invention.
1. FIELD OF THE INVENTION
The present invention relates to 5-Aryltetrazole Compounds, compositions comprising an effective amount of a 5-Aryltetrazole Compound, and methods for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia comprising administering to an animal in need thereof an effective amount of a 5-Aryltetrazole Compound.
2. BACKGROUND OF THE INVENTION The level of xanthine oxidase ("XO") in an animal increases markedly
- (>400-fold in bronchoalveolar fluid in pneumonitis) during inflammation, ischemia- reperfusion injury, and atherosclerosis. Particularly, due to the spillover of tissue XO into the circulation, plasma levels of XO maybe detected in an animal experiencing adult respiratory distress syndrome, ischemia-reperfusion injury, arthritis, sepsis, hemorrhagic shock, and other inflammatory conditions. Inflammation-induced histamine release by mast cells andbasophils also enhances the activity of XO.
Superoxide radical (O2 ") can be generated by xanthine oxidase and NADPH oxidase from the partial reduction of molecular oxygen. Neutrophils and macrophages are known to produce O2 " and hydrogen peroxide (H2O2), which normally are involved in the killing of ingested or invading microbes (T. Oda et al, Science, 244:974-976). Under physiologic conditions XO is ubiquitously present in the form of a xanthine dehydrogenase (XDH). XDH is a molybdenum iron-sulfur flavin dehydrogenase that uses NAD+ as an electron acceptor to oxidize purines, pyrimidines, pteridins, and other heterocyclic nitrogen- containing compounds. In mammals, XDH is converted from the NAD-dependent dehydrogenase form to the oxygen-dependent oxidase form, either by reversible sulfhydryl oxidation or irreversible proteolytic modification (S. Tan et al, Free Radic. Biol. Med. 15:407-414). Xanthine oxidase then no longer uses NAD as an electron acceptor, but transfers electrons onto oxygen, generating O2", H O2, and hydroxyl radical (OH) as purines are degraded to uric acid (J.M. McCord et al, New Engl. J. Med. 312:159-163; R. Miesel et al, Inflammation, 18:597-612). Inflammatory activation converts XDH to XO, mainly by oxidizing structurally important thiolates. Inflammation also markedly up-regulates the conversion of xanthine dehydrogenase (T.D. Engerson et al, J. Clin. Invest. 79:1564-1570). Inhibition of XO activity blocks the formation of O2 ~ and prevents loss of purine nucleotides, and is therefore salutary in a variety of shock and ischemia reperfusion disorders. Pharmacologic inhibition of XO can also be beneficial by blocking the pro- inflammatory effect of O2 " on gene expression (M.D. Schwartz et al, Am. J. Respir. Cell Mol. Biol. , 12:434-440). O2 " has been implicated in the nuclear translocation of NF-kappa B and the expression of NF-icB-dependent genes. In mice subjected to hemorrhagic shock, depletion of XO by a tungsten-enriched diet decreased mononuclear mRNA levels of IX- 113 and TNF-a. Similar results were obtained after pharmacologic inhibition of XO by in vivo administration of allopurinol. A vicious cycle can be created by oxidant stress, in which O2 " induction of pro-inflammatory cytokines results in greater XDH to XO conversion, and thus more O2 " production. This suggests that XO inhibitors can exert important anti-inflammatory actions by interrupting this process at multiple points, in particular, by blocking pro-inflammatory gene expression.
Pharmacologic inhibition of XO can also be beneficial in hemorrhagic shock by preserving the intracellular nucleotide pool. Under conditions of energetic failure, induced by hypoxia or by oxidant-induced poly(ADP-ribose) synthetase activation, high energy phosphate nucleotides are sequentially degraded to inosine monophosphate, xanthine, and hypoxanthine. In the presence of XO and molecular oxygen, xanthine and hypoxanthine degrade to uric acid, thereby depleting the purine pool. The loss of available purines with which to form ATP accelerates the loss of intracellular energetics and contributes to cell necrosis and organ failure. XO inhibitors block this terminal degradative pathway and permit the cell to recover and reestablish adequate stores of high energy phosphate nucleotides. In a canine model of severe hemorrhagic shock, pre-treatment with allopurinol resulted in a 6-fold increase in survival (J.W. Crowell et al, Am. J. Phys. 216: 744-748) . When the administration of allopurinol was delayed until after shock had been produced, allopurinol exerted no benefit. Infusion of the purine base hypoxanthine after the onset of shock similarly provided no benefit. When allopurinol and hypoxanthine were co-infused, however, there was a dramatic increase in survival (no survival in control group at 16 hours post-shock vs. a 40 % survival in the treated group at 48 hours). Similar results were obtained in a canine model of hemorrhagic shock in which allopurinol significantly improved survival, whereas a cocktail of free-radical scavengers (superoxide dismutase, catalase, dimethylsulfoxide, and alpha tocopherol) had no effect (D. Mannion, et al, Circ. Shock, 42:39-43). Thus, XO blockade appears to be beneficial by three independent mechanisms: blockade of O2 " formation; inhibition of O2 " mediated pro- inflammatory gene expression; and preservation of the nucleotide pool available for ATP formation.
Accordingly, there is a clear need for compounds that inhibit the levels of xanthine oxidase in an animal and, accordingly, that are useful for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia. Citation of any reference in Section 2 of this application is not an admission that the reference is prior art to the application.
3. SUMMARY OF THE INVENTION
The invention encompasses compounds having the formula (la):
Figure imgf000004_0001
(la)
and pharmaceutically acceptable salts and hydrates thereof, wherein:
Ri is CO2R4; each R2 is independently -halo, -NO2, -CN, -OH, -N(R5)(R5), -OR5, -C(O)R5, -OC(O)R5, -C(O)NHC(O)R5, -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C1o)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-C10)cycloalkenyl, -(C3-C10)heterocycle, -phenyl, -naphthyl, -benzyl, -CO2R5, -C(O)OCH(R5)(R5), -NHC(O)R5, -NHC(O)NHR5, -C(O)NHR5, -OC(O)R5, -OC(O)OR5, -SR5, -S(O)R5, or -S(O)2R5;
R3 is -H, -halo, -NO2, -CN, -OH, -N(R5)(R5), -O(CH2)mR5, -C(O)R5, -C(O)N(R5)(R5), -C(O)NH(CH2)m(R5), -OCF3, -benzyl, -CO2CH(R5)(R5), -(d-C^alky!, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-C10)cycloalkenyl, -naphthyl, -(C3-C10)heterocycle, -CO2(CH2)mR5, -NHC(O)R5, -N(R5)C(O)R5, -NHC(O)NHR5, -OC(O)(CH2)mCHR5R5, -CO2(CH2)mCHR5R5,-OC(O)OR5, -SR5, -S(O)R5, -S(O)2R5, -S(O)2NHR5, or
R4 is -(C5)heteroaryl, -(C -6)σheteroaryl, phenyl, naphthyl, or benzyl; each R5 is independently -H, -CF3, -(C1-C10)alkyl, -benzyl, -adamantyl, -morpholinyl, -pyrrolidyl, -pyrridyloxide, -pyrrohdinyldione, -piperdidyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C3-C10)heterocycle, or
each R6 is independently -H, -halo, -NO2, -CN, -OH, -CO2H, -N((Cι-Cιo)al yl(Cι-Cιo)al yl). -O(C1-C10)alkyl, -C(O)(Cι-Cιo)alkyL -C(O)NH(CH2)m(C1-C10)alkyl, -OCF3, -benzyl, -CO2(CH2)mCH((C1-C10)alkyl(C1- C10)alkyl), -C(O)H, -CO2(C1-C10)alkyl, -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C1o)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-C10)cycloalkenyl, -(C5)heteroaryl, -(C6)heteroaryl, -phenyl, naphthyl, -(C3-C10)heterocycle, -CO2(CH2)m(C1-C10)alkyl, -CO2(CH2)mH, -NHC(O)(C1-C10)alkyl, -NHC(O)NH(C1-C10)alkyl, -OC(O)(CrC10)alkyl,
Figure imgf000005_0001
n is an integer ranging from 0 to 4; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging from 0 to 5. A compound of formula (la) or a pharmaceutically acceptable salt or hydrate thereof is useful for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia in an animal. The invention also relates to pharmaceutical compositions comprising an effective amount of a compound of formula (la) or a pharmaceutically acceptable salt or hydrate thereof; and a pharmaceutically acceptable carrier or vehicle. These compositions are useful for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia in an animal. The invention also relates to compounds of formula (lb):
Figure imgf000006_0001
(lb)
and pharmaceutically acceptable salts and hydrates thereof, wherein: Ri is -H, -CO2R4, -C(O)R5, or -C(O)N(R5)(R5);
R2 is -(C1-C10)alkyl or -O(C1-C10)alkyl;
T is -(C5)heteroaryl, -(C6)heteroaryl, phenyl, naphthyl, or benzyl; and eachR5 is independently -H, -CF3,
Figure imgf000006_0002
-benzyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C1o)cycloalkyl, -(C8-C14)bicycloalkyl, -(C3-C10)heterocycle. A compound of formula (lb) or a pharmaceutically acceptable salt or hydrate thereof is useful for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia in an animal.
The invention also relates to pharmaceutical compositions comprising an effective amount of a compound of formula (lb) or a pharmaceutically acceptable salt or hydrate thereof; and a pharmaceutically acceptable carrier or vehicle. These compositions are useful for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia in an animal.
The invention further relates to methods for treating or preventing an inflammation disease, comprising administering to an animal in need thereof an effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt or hydrate thereof.
The invention further relates to methods for treating or preventing a reperfusion disease, comprising administering to an animal in need thereof an effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt or hydrate thereof.
The invention further relates to methods for treating or preventing hyperuricemia, comprising administering to an animal in need thereof an effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt or hydrate thereof. The invention further relates to methods for treating or preventing tumor- lysis syndrome, comprising admimstering to an animal in need thereof an effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt or hydrate thereof. The invention further relates to methods for treating or preventing an inflammatory bowel disorder, comprising administering to an animal in need thereof an effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt or hydrate thereof.
The invention further relates to methods for inhibiting xanthine oxidase activity, comprising administering to an animal in need thereof an effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt or hydrate thereof.
The invention further relates to methods for treating or preventing an inflammation disease, comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic):
Figure imgf000007_0001
(Ic)
or a pharmaceutically acceptable salt or hydrate thereof, wherein: Ri is -H, -CQ2R4, -C(O)R5, or -C(O)N(R5)(R5); each R2 is independently -halo, -NO2, -CN, -OH, -N(R5)(R5), -OR5, -C(O)R5, -OC(O)R5, -C(O)NHC(O)R5>
Figure imgf000007_0002
~(C2-C10)alkenyl, -(C2-C10)alkynyl,
-(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-C10)cycloalkenyl, -(C3-C10)heterocycle, -(Cs)heteroaryl, -(C6)heteroaryl, -phenyl, -naphthyl, -benzyl, -CO2R5, -C(O)OCH(R5)(R5), -NHC(O)R5, -NHC(O)NHR5, -C(O)NHR5, -OC(O)R5, -OC(O)OR5, -SR5, -S(O)R5, or -S(O)2R5; R3 is -H, -halo, -NO2, -CN, -OH, -N(R5)(R5), -O(CH2)mR5, -C(O)R5,
-C(O)N(R5)(R5), -C(O)NH(CH2)m(R5), -OCF3, -benzyl, -CO2CH(R5)(R5), -(d-C^alkyl, -(C2-C10)alkenyl, -(C2-C1o)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-C10)cycloalkenyl, -(C5)heteroaryl, -(C6)heteroaryl, -naphthyl, -(C3-C10)heterocycle, -CO2(CH2)mR5, -NHC(O)R5, -N(R5)C(O)R5, -NHC(O)NHR5, -OC(O)(CH2)mCHR5R5, -CO2(CH2)mCHR5R5,-OC(O)OR5, -SR5, -S(O)R5, -S(O)2R5, -S(O)2NHR5, or
Figure imgf000008_0001
R4 is -CF3, -(C1-C10)alkyl, -benzyl, -adamantyl, -morpholinyl, -pyrrolidyl, -pyrridyloxide, -pyrrohdinyldione, -piperdidyl, -(C5)heteroaryl, -(C6)heteroaryl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C3-C10)heterocycle, or
Figure imgf000008_0002
each R5 is independently -H or R ; each Rg is independently -H, -halo, -NO2, -CN, -OH, -CO2H, -N((C1-C1o)alkyl(C1-C10)alkyl), -O(Cι-Cιo)alkyl, -C(O)(d-C10)alkyl, -C(O)NH(CH2)m(C1-C10)alkyl, -OCF3, -benzyl, -CO2(CH2)mCH((C1-C10)alkyl(C1-
C10)alkyl), -C(O)H, -CO2(C1-C10)alkyl, -(d-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-C1o)cycloalkenyl, -(C5)heteroaryl, -(C6)heteroaryl, -phenyl, naphthyl, -(C3-C10)heterocycle, -CO2(CH2)m(C1-C1o)alkyl, -CO2(CH2)mH, -NHC(O)(C1-Cιo)alkyl, -NHC(O)NH(C1-C10)alkyl, -OC(O)(d-C10)alkyl, -OC(O)O(C1-C10)alkyl, -SO2NHR5, or -SO2NH2; n is an integer ranging from 0 to 4; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging from 0 to 5. The invention further relates to methods for treating or preventing a reperfusion disease, comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic) or a pharmaceutically acceptable salt or hydrate thereof.
The invention further relates to methods for treating or preventing hyperuricemia, comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic) or a pharmaceutically acceptable salt or hydrate thereof. The invention further relates to methods for treating or preventing tumor- lysis syndrome, comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic) or a pharmaceutically acceptable salt or hydrate thereof. The invention further relates to methods for treating or preventing an inflammatory bowel disorder, comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic) or a pharmaceutically acceptable salt or hydrate thereof.
The invention further relates to methods for inhibiting xanthine oxidase activity, comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic) or a pharmaceutically acceptable salt or hydrate thereof.
The invention also relates to kits comprising a container containing a compound of formula (la), (lb), or (Ic) or a pharmaceutically acceptable salt or hydrate thereof (each being a "5-Aryltetrazole Compound").
The invention can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention.
4. DETAILED DESCRIPTION OF THE INVENTION
4.1. DEFINITIONS As used herein, the term "-(C1-C1o)alkyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms. Representative saturated straight chain alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n-decyl; while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3 -methylhexyl,
4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. In addition, chemical nomenclature used to define alkyl groups has its standard meaning known to those of ordinary skill in the art, for example, "Me" means methyl or -CH3, "Et" means ethyl or -CH2CH3, "n-Pr" means n-propyl or -CH2CH2CH3, "i-Pr" means iso-propyl or -CH(CH3)2, "n-Bu" means n-butyl or -CH2(CH2)2CH3, "t-Bu" means tert-butyl or -C(CH3)3. As used herein, the term "-(C2-C10)alkenyl" means a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Representative straight chain and branched (C2-C10)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3 -methyl- 1-butenyl, -2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl, -2-decenyl, -3-decenyl and the like.
As used herein, the term "-(C -do)alkynyι" means a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at lease one carbon-carbon triple bond. Representative straight chain and branched -(C2-C10)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3 -methyl- 1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl, -6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl, -1-decynyl, -2-decynyl, -9-decynyl and the like.
As used herein, the term "-(C3-do)cycloalkyι" means a saturated cyclic hydrocarbon having from 3 to 10 carbon atoms. Representative (C3-C1o)cycloalkyls include -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl, and -cyclodecyl. As used herein, the term "-(C8-C14)bicycloalkyl" means a bi-cyclic hydrocarbon ring system having from 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring. Representative -(C8-C14)bicyclocycloalkyls include -indanyl, -1,2,3,4-tetrahydronaphthyl, -5,6,7,8-tetrahydronaphthyl, -perhydronaphthyl and the like. As used herein, the term "-(C5-C1o)cycloalkenyl" means a cyclic non- aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 5 to 10 carbon atoms. Representative (C5-C10)cycloalkenyls include -cyclopentenyl, -cyclop entadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl, -cyclononadienyl, -cyclodecenyl, -cyclodecadienyl and the like.
As used herein, the term "-(C3-do)heterocycle" or "-(C3-C10)heterocyclo" means a 3- to 10-membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic. A 3-membered -(C3-C7)heterocycle can contain up to 3 heteroatoms, and a 4- to 10-membered -(C3-C10)heterocycle can contain up to 4 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quatemized; oxygen; and sulfur, including sulfoxide and sulfone. The -(C3-C10)heterocycle may be attached via any heteroatom or carbon atom. Representative -(C3-do)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, xriazinyl, morpholinyl, pyrrohdinonyl, pyrrolidinyl, piperidinyl, piperazinyl, benzo[l ,3]dioxolyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. A heteroatom may be substituted with a protecting group known to those of ordinary skill in the art, for example, the hydrogen on a nitrogen may be substituted with a tert-butoxycarbonyl group or the hydrogen on an oxygen may be substituted with a methoxymethyl.
As used herein, the term "-(C5)heteroaryl" means an aromatic heterocycle ring of 5 members, wherein at least one carbon atom of the ring is replaced with a heteroatom such as, for example, nitrogen. Representative -(C5)heteroaryls include furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyrazinyl, triazolyl, thiadiazolyl, and the like.
As used herein, the term "-(C6)heteroaryl" means an aromatic heterocycle ring of 6 members, wherein at least one carbon atom of the ring is replaced with a heteroatom such as, for example, nitrogen. One of the -(C6)heteroaryl's rings contain at least one carbon atom. Representative (C6)heteroaryls include pyridyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, pyrimidyl, and the like.
As used herein, the term "-O(C1-C10)alkyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms. Representative saturated straight chain alkyls include -methyoxy, -ethyoxy, -n-propyloxy, -n-butyloxy, -n-pentyloxy, -n-hexyloxy, -n-heptyloxy, -n-octyloxy, -n-nonyloxy and -n-decyloxy; while saturated branched alkyls include -isopropyloxy, -sec-butyloxy, -isobutyloxy, -tert-butyloxy, -isopentyloxy, -2-methylbutyloxy, -3-methylbutyloxy, -2-methylpentyloxy, -3-methylpentyloxy, -4-methylpentyloxy, -2-methylhexyloxy, -3-methylhexyloxy, -4-methylhexyloxy, -5-methylhexyloxy, -2,3-dimethylbutyloxy, -2,3-dimethylpentyloxy, -2,4-dimethylpentyloxy, -2,3-dimethylhexyloxy, -2,4-dimethylhexyloxy, -2,5-dimethylhexyloxy, 2,2-dimethylpentyloxy, -2,2-dimethylhexyloxy, -3,3-dimtheylpentyloxy, -3,3-dimethylhexyloxy, -4,4-dimethylhexyloxy, -2-ethylpentyloxy, -3-ethylpentyloxy, -2-ethylhexyloxy, -3-ethylhexyloxy, -4-ethylhexyloxy, -2-methyl-2-ethylpentyloxy, -2-methyl-3-ethylpentyloxy, -2-methyl-4-ethylpentyloxy, -2-methyl-2-ethylhexyloxy, -2-methyl-3-ethylhexyloxy, -2-methyl-4-ethylhexyloxy, -2,2-diethylpentyloxy, -3,3-diethylhexyloxy, -2,2-diethylhexyloxy, -3,3-diethylhexyloxy and the like. In addition, chemical nomenclature used to define alkyloxy groups has its standard meaning known to those of ordinary skill in the art, for example, "OMe" means methoxy, methoxyl, or -OCH3, "OEt" means ethoxy, ethoxyl, or -OCH2CH3, "n-OPr" means n-propyloxy or -CH2CH2CH3, "i- OPr" means iso-propyloxy or -OCH(CH3) , "n-OBu" means n-butyloxy or -OCH2(CH2)2CH3, "t-OBu" means tert-butyloxy or -OC(CH3)3.
As used herein, the term "-Halogen" or "-Halo" means -F, -Cl, -Br or -I.
As used herein, the term "animal," includes, but is not limited to, a cow, monkey, chimpanzee, baboon, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig and human.
As used herein, the term "adamantyl" includes 1-adamantyl, 2-adamantyl, and 3-adamantyl.
As used herein, the term "naphthyl" includes 1 -naphthyl and 2-naphthyl. As used herein, the term "morpholinyl" includes N-morpholinyl,
2-morpholinyl, and 3 -morpholinyl.
As used herein, the term "pyrridyloxide" includes 2-pyrridyloxide, 3 -pyrridyloxide, and 4-pyrridyloxide.
As used herein, the term "pyrrohdinyldione" includes N-pyrrolidinyl-2, 3-dione, N-pyrrolidinyl-2,4-dione, N-pyrrolidinyl-2,5-dione, N-pyrrolidinyl-3,5-dione,
N-pyrrolidinyl-3,4-dione, 2-pyrrolidinyl-3,4-dione, or 3-pyrrolidinyldione-2,4-dione, and 3- -pyrrolidinyl-2,5-dione.
As used herein, the term "piperdinyl" includes N-piperdinyl, 2-piperdinyl, and 3-piperdinyl. As used herein, the term "pharmaceutically acceptable salt," is a salt formed from an acid and a basic nitrogen group of one of the 5-Aryltetrazole Compounds. Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,/?-toluenesulfonate, and pamoate (z.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a 5-Aryltetrazole Compound having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl) amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N, N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like.
As used herein, the term "pharmaceutically acceptable hydrate," is a hydrate formed from the association of one or more water molecules with a 5-Aryltetrazole Compound. The term "hydrate" includes a mono-hydrate, dihydrate, trihydrate, tetrahydrate, and the like. As used herein in connection with a 5-Aryltetrazole Compound, the term "effective amount" means an amount effective for: (a) treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia; or (b) inhibiting xanthine oxidase activity.
4.2. COMPOUNDS OF FORMULA (la)
As stated above, the invention encompasses compounds of formula (la):
Figure imgf000013_0001
(la)
and pharmaceutically acceptable salts and hydrates thereof, wherein Rls R2, R3, and n are defined above for the compounds of formula (la).
In one embodiment n is 0. In another embodiment n is 0 and R3 is -halo.
In another embodiment n is 0 and R3 is -C(O)R5,
In another embodiment n is 0 and R3 is -C(O)NHC(O)R5.
In another embodiment n is 0 and R3 is -C(O)N(R5)(R5).
In another embodiment n is 0 and R3 is -CO2(CH2)m(R5). In another embodiment n is 0 and R3 is -H.
In another embodiment n is 0 and R3 is -NHC(O)N(R5)(R5).
In another embodiment n is 0 and R3 is -C(O)NHR5.
In another embodiment n is 0; R3 is -C(O)NHRs; and R5 is
Figure imgf000014_0001
In another embodiment n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000014_0002
and p is an integer from 1 to 3.
In another embodiment n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000014_0003
and p is 1 or 2.
In another embodiment n is 0; R3 is -C(O)NHR5; R5 is
=^(RS)P ^ /)
p is 1 ; and R is in the para position. hi another embodiment n is 0; R3 is -C(O)NHRs; R5 is
= Rs)P \\ /)
p is 1; and Rδ is in a meta position.
In another embodiment n is 0; R3 is -C(O)NHR5; R5 is
■ ( 5)p \\ /) p is 1; and Re is in an ortho position.
In another embodiment n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000015_0001
and each Re is independently -halo. In another embodiment n is 0; R3 is -C(O)NHR5; R5 is
- =V(Re)P
p is 2; and each Re is independently -halo.
In another embodiment n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000015_0002
p is 2; each Re is independently halo; and one R6 is in the para position and the other Re is in a meta position.
In another embodiment n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000015_0003
p is 2; each Re is independently halo; and one Re is in the para position and the other Re is in an ortho position.
In another embodiment n is 0; R3 is -C(O)NHR5; R5 is
-ø =V1(Rs)P
p is 2; each Re is independently halo; and one Re is in an ortho position and the other ^ is in a meta position. In another embodiment n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000016_0001
p is 2; each Re is independently halo; and each Re is in an ortho position. In another embodiment n is 0; R3 is -C(O)NHR5; R5 is
- p is 2; each Re is independently halo; and each Re is in a meta position.
Illustrative subclasses of the compounds of formula (la) have the following formulas, wherein R is -(C5)heteroaryl, -(Ce)heteroaryl, phenyl, naphthyl, or benzyl:
Figure imgf000016_0002
Formula AA;
Figure imgf000016_0003
Formula AB;
Figure imgf000016_0004
Formula AC;
Figure imgf000016_0005
Formula AD
Figure imgf000017_0001
Formula AE:
Figure imgf000017_0002
Formula AF;
Figure imgf000017_0003
Formula AG;
Figure imgf000017_0004
Formula AH;
Figure imgf000017_0005
10 Formula Al;
Figure imgf000018_0001
Formula AJ;
Figure imgf000018_0002
Formula AK;
Figure imgf000018_0003
Formula AL;
Figure imgf000018_0004
Formula AM;
Figure imgf000018_0005
10 Formula AN;
Figure imgf000019_0001
Formula AO;
Figure imgf000019_0002
Formula AP;
Figure imgf000019_0003
Formula AQ;
Figure imgf000019_0004
Formula AR;
Figure imgf000019_0005
10 Formula AS;
Figure imgf000020_0001
Formula AT;
Figure imgf000020_0002
Formula AU;
Figure imgf000020_0003
Formula AV;
Figure imgf000020_0004
Formula AW;
Figure imgf000020_0005
10 Formula AX;
Figure imgf000020_0006
Formula AY;
Figure imgf000021_0001
Formula AZ;
Figure imgf000021_0002
Formula BA;
Figure imgf000021_0003
Formula BB;
Figure imgf000021_0004
Formula BC;
Figure imgf000021_0005
Formula BD;
Figure imgf000022_0001
Formula BE;
Figure imgf000022_0002
Formula BF;
Figure imgf000022_0003
Formula BG;
Figure imgf000022_0004
Formula BH;
Figure imgf000022_0005
10 Formula BI
Figure imgf000023_0001
Formula BJ;
Figure imgf000023_0002
Formula BK;
Figure imgf000023_0003
Formula BL;
Figure imgf000023_0004
Formula BM;
Figure imgf000023_0005
10 Formula BN;
Figure imgf000024_0001
Formula BO;
Figure imgf000024_0002
Formula BP;
Figure imgf000024_0003
Formula BQ;
Figure imgf000024_0004
Formula BR;
Figure imgf000024_0005
10 Formula BS;
Figure imgf000025_0001
Formula BT;
Figure imgf000025_0002
Formula BU;
Figure imgf000025_0003
Formula BV;
Figure imgf000025_0004
Formula BW;
Figure imgf000025_0005
10 Formula BX;
Figure imgf000026_0001
Formula BY;
Figure imgf000026_0002
Formula BZ;
Figure imgf000026_0003
Formula CA;
Figure imgf000026_0004
Formula CB;
Figure imgf000026_0005
10 Formula CC;
Figure imgf000027_0001
Formula CD;
Figure imgf000027_0002
Formula CE;
Figure imgf000027_0003
Formula CF;
Figure imgf000027_0004
Formula CG;
Figure imgf000027_0005
10 Formula CH;
Figure imgf000028_0001
Formula Cl;
Figure imgf000028_0002
Formula CJ;
Figure imgf000028_0003
Formula CK;
Figure imgf000028_0004
Formula CL;
Figure imgf000028_0005
10 Formula CM;
Figure imgf000029_0001
Formula CN;
Figure imgf000029_0002
Formula CO;
Figure imgf000029_0003
Formula CP;
Figure imgf000029_0004
Formula CQ;
Figure imgf000029_0005
10 Formula CR;
Figure imgf000030_0001
Formula CS;
Figure imgf000030_0002
Formula CT;
Figure imgf000030_0003
Formula CU;
Figure imgf000030_0004
Formula CV;
Figure imgf000030_0005
10 Formula CW;
Figure imgf000031_0001
Formula CX;
Figure imgf000031_0002
Formula CY;
Figure imgf000031_0003
Formula CZ;
Figure imgf000031_0004
Formula DA;
Figure imgf000031_0005
10 Formula DB;
Figure imgf000032_0001
Formula DC;
Figure imgf000032_0002
Formula DD;
Figure imgf000032_0003
Formula DE;
Figure imgf000032_0004
Formula DF;
Figure imgf000032_0005
10 Formula DG;
Figure imgf000033_0001
Formula DH;
Figure imgf000033_0002
Formula Dl;
Figure imgf000033_0003
Formula DJ;
Figure imgf000033_0004
Formula DK;
Figure imgf000033_0005
10 Formula DL;
Figure imgf000034_0001
Formula DM;
Figure imgf000034_0002
Formula DN;
Figure imgf000034_0003
Formula DO;
Figure imgf000034_0004
Formula DP;
Figure imgf000034_0005
10 Formula DQ;
Figure imgf000035_0001
Formula DR;
Figure imgf000035_0002
Formula DS;
Figure imgf000035_0003
Formula DT;
Figure imgf000035_0004
Formula DU;
Figure imgf000035_0005
10 Formula DV;
Figure imgf000036_0001
Formula DW;
Figure imgf000036_0002
Formula DX;
Figure imgf000036_0003
Formula DY;
Figure imgf000036_0004
Formula DZ;
Figure imgf000036_0005
10 Formula EA;
Figure imgf000037_0001
Formula EB;
Figure imgf000037_0002
Formula EC;
Figure imgf000037_0003
Formula ED;
Figure imgf000037_0004
Formula EE;
10
Figure imgf000038_0001
Formula EF:
Figure imgf000038_0002
Formula EG;
and pharmaceutically acceptable salts or hydrates thereof.
4.3. COMPOUNDS OF FORMULA qb)
The invention also encompasses compounds of formula (lb):
Figure imgf000038_0003
(lb)
and pharmaceutically acceptable salts and hydrates thereof, wherein R\ and R2 are defined above for the compounds of formula (lb).
In one embodiment R1 is -H. In another embodiment R\ is -H and R2 is -(C1-C1o)alkyl. hi another embodiment Ri is -H and R2 is -O(C1-C10)alkyl.
In another embodiment, Ri is -H and R2 is methyl.
In another embodiment, Ri is -H and R2 is ethyl.
In another embodiment, Ri is -H and R2 is n-propyl. In another embodiment, Ri is -H and R2 is iso-propyl. hi another embodiment, R\ is -H and R2 is n-butyl. hi another embodiment, Ri is ■H and R2 is iso-butyl. h another embodiment, Ri is •H and R2 is sec-butyl. hi another embodiment, Ri is ■H and R2 is tert-butyl. hi another embodiment, Ri is -H and R2 is n-pentyl. In another embodiment, Ri is -H and R2 is isopentyl. hi another embodiment, Ri is ■H and R2 is n-hexyl. h another embodiment, Ri is ■H and R2 is n-heptyl. h another embodiment, Ri is -H and R2 is n-octyl. In another embodiment, R\ is -H and R2 is n-nonyl. h another embodiment, Ri is -H and R2 is n-decyl. h another embodiment, Ri is ■H and R2 is 2-methylbutyl. In another embodiment, Ri is -H and R is 3-methylbutyl. In another embodiment, Ri is -C(O)R5 and R2 is methyl. h another embodiment, Ri is -C(O)R5 and R2 is ethyl. In another embodiment, Ri is -C(O)R5 and R2 is n-propyl. In another embodiment, Ri is -C(O)R5 and R2 is iso-propyl h another embodiment, Ri is -C(O)R5 andR2 is n-butyl. In another embodiment, Ri is -C(O)R5 and R2 is iso-butyl. h another embodiment, Ri is -C(O)R5 and R2 is sec-butyl, hi another embodiment, Ri is -C(O)R5 andR2 is tert-butyl. In another embodiment, Ri is -C(O)R5 and R2 is n-pentyl. In another embodiment, Ri is -C(O)R5 andR2 is isopentyl. In another embodiment, Ri is -C(O)R5 and R2 is n-hexyl. In another embodiment, Ri is -C(O)R5 and R2 is n-heptyl. In another embodiment, Ri is -C(O)R5 andR2 is n-octyl. In another embodiment, Ri is -C(O)R5 and R2 is n-nonyl. hi another embodiment, R] is -C(O)R5 and R2 is n-decyl. In another embodiment, Ri is -C(O)R5 and R2 is 2-methylbutyl. hi another embodiment, Ri is -C(O)R5 and R2 is 3-methylbutyl. h another embodiment, Ri is -CO R4 and R2 is methyl. In another embodiment, Ri is -CO2R4 and R2 is ethyl. In another embodiment, Ri is -CO2R4 and R is n-propyl. In another embodiment, Ri is -CO2R4 and R2 is iso-propyl. h another embodiment, Ri is -CO^ and R2 is n-butyl. In another embodiment, Ri is -CO^ and R2 is iso-butyl. hi another embodiment, Ri is -CO2R4 and R is sec-butyl. h another embodiment, R\ is -CO2R4 and R2 is tert-butyl.
In another embodiment, Ri is -CO2R4 and R2 is n-pentyl. hi another embodiment, Ri is -CO^ and R2 is isopentyl. In another embodiment, Ri is -CO^ and R2 is n-hexyl.
In another embodiment, Ri is -CO^ and R2 is n-heptyl. hi another embodiment, Ri is -CO^E and R2 is n-octyl.
In another embodiment, Ri is -CO^ and R2 is n-nonyl.
In another embodiment, Ri is -CO^ and R is n-decyl. In another embodiment, Ri is -CO^ and R2 is 2-methylbutyl. h another embodiment, R\ is -CO^ and R2 is 3-methylbutyl. h another embodiment, Ri is -C(O)N(R5)(R5) and R2 is methyl.
In another embodiment, Ri is -C(O)N(R5)(R5) and R is ethyl.
In another embodiment, Ri is -C(O)N(R5)(R5) and R2 is n-propyl. In another embodiment, Ri is -C(O)N(R5)(R5) and R2 is iso-propyl.
In another embodiment, Ri is -C(O)N(R5)(R5) and R is n-butyl.
In another embodiment, Ri is -C(O)N(R5)(R5) and R2 is iso-butyl. h another embodiment, Ri is -C(O)N(R5)(R5) and R2 is sec-butyl.
In another embodiment, Ri is -C(O)N(R5)(R5) and R2 is tert-butyl. h another embodiment, Ri is -C(O)N(R5)(Rs) and R is n-pentyl. hi another embodiment, R\ is -C(O)N(R5)(Rs) and R is isopentyl.
In another embodiment, Ri is -C(O)N(R5)(R5) and R is n-hexyl.
In another embodiment, Ri is -C(O)N(R5)(R5) and R is n-heptyl. hi another embodiment, Ri is -C(O)N(R5)(R5) and R2 is n-octyl. hi another embodiment, R\ is -C(O)N(R5)(R5) and R2 is n-nonyl. hi another embodiment, Ri is -C(O)N(R5)(Rs) and R2 is n-decyl.
In another embodiment, Ri is -C(O)N(R5)(Rs) and R is 2-methylbutyl. h another embodiment, Ri is -C(O)N(R5)(R5) and R2 is 3-methylbutyl.
In another embodiment, Ri is -H and R2 is methoxy. In another embodiment, Ri is -H and R2 is ethoxy.
In another embodiment, Ri is -H and R2 is n-propyloxy.
In another embodiment, Ri is -H and R2 is iso-propyloxy.
In another embodiment, Ri is -H and R2 is n-butyloxy.
In another embodiment, Ri is -H and R2 is iso-butyloxy. In another embodiment, Ri is -H and R2 is sec-butyloxy. In another embodiment, Ri is -H and R2 is tert-butyloxy. hi another embodiment, Ri is -H and R2 is n-pentyloxy. h another embodiment, Ri is -H and R2 is isopentyloxy. hi another embodiment, Ri is -H and R2 is n-hexyloxy. In another embodiment, Ri is -H and R2 is n-heptyloxy. hi another embodiment, R\ is -H and R2 is n-octyloxy. hi another embodiment, Ri is -H and R2 is n-nonyloxy.
In another embodiment, Ri is -H and R2 is n-decyloxy.
In another embodiment, Ri is -H and R is 2-methylbutyloxy. In another embodiment, Ri is -H and R2 is 3-methylbutyloxy. hi another embodiment, Ri is -C(O)R5 and R2 is methoxy.
In another embodiment, Ri is -C(O)R5 and R2 is ethoxy. hi another embodiment, Ri is -C(O)R5 and R2 is n-propyloxy.
In another embodiment, Ri is -C(O)R5 and R2 is iso-propyloxy. In another embodiment, Ri is -C(O)R5 and R2 is n-butyloxy. hi another embodiment, Ri is -C(O)R5 and R2 is iso-butyloxy. h another embodiment, Ri is -C(O)R5 and R2 is sec-butyloxy. hi another embodiment, Ri is -C(O)R5 and R2 is tert-butyloxy.
In another embodiment, Ri is -C(O)R5 and R2 is n-pentyloxy. hi another embodiment, Ri is -C(O)R5 and R2 is isopentyloxy. h another embodiment, Ri is -C(O)R5 and R2 is n-hexyloxy.
In another embodiment, Ri is -C(O)R5 and R2 is n-heptyloxy.
In another embodiment, Ri is -C(O)R5 and R2 is n-octyloxy. h another embodiment, Ri is -C(O)R5 and R2 is n-nonyloxy. i another embodiment, Ri is -C(O)R5 and R2 is n-decyloxy. hi another embodiment, R\ is -C(O)R5 and R2 is 2-methylbutyloxy.
In another embodiment, Ri is -C(O)R5 and R2 is 3-methylbutyloxy.
In another embodiment, Ri is -CO Rt and R2 is methoxy. h another embodiment, Ri is -CO^ and R2 is ethoxy. hi another embodiment, Ri is -CO2R4 and R2 is n-propyloxy.
In another embodiment, R\ is -CO^ and R2 is iso-propyloxy. hi another embodiment, Ri is -CO^ and R2 is n-butyloxy.
In another embodiment, Ri is -CO^ and R2 is iso-butyloxy. hi another embodiment, Ri is -CO2R4 and R2 is sec-butyloxy. In another embodiment, Ri is -CO2R4 and R2 is tert-butyloxy. hi another embodiment, Ri is -CO2R4 and R2 is n-pentyloxy.
In another embodiment, Ri is -CO2R4 and R2 is isopentyloxy. h another embodiment, Ri is -CO^ and R is n-hexyloxy. hi another embodiment, Ri is -CO Rt and R2 is n-heptyloxy. hi another embodiment, Ri is -CO^ and R2 is n-octyloxy.
In another embodiment, Ri is -CO2R4 and R2 is n-nonyloxy.
In another embodiment, Ri is -CO^ and R is n-decyloxy. hi another embodiment, Ri is -CO^ and R2 is 2-methylbutyloxy.
In another embodiment, Ri is -CO R]. and R2 is 3-methylbutyloxy. hi another embodiment, Ri is -C(O)N(R5)(R5) and R2 is methyloxy.
In another embodiment, R\ is -C(O)N(R5)(R5) and R is ethyloxy.
In another embodiment, Ri is -C(O)N(Rs)(R5) and R2 is n-propyloxy.
In another embodiment, Ri is -C(O)N(R5)(R5) and R2 is iso-propyloxy.
In another embodiment, Ri is -C(O)N(R5)(R5) and R2 is n-butyloxy. hi another embodiment, Ri is -C(O)N(Rs)(R5) and R2 is iso-butyloxy.
In another embodiment, Ri is -C(O)N(R5)(R5) and R2 is sec-butyloxy.
In another embodiment, Ri is -C(O)N(R5)(R5) and R2 is tert-butyloxy.
In another embodiment, Ri is -C(O)N(R5)(R5) and R2 is n-pentyloxy.
In another embodiment, Ri is -C(O)N(R5)(R5) and R2 is isopentyloxy. hi another embodiment, Ri is -C(O)N(R5)(R5) and R2 is n-hexyloxy. hi another embodiment, Ri is -C(O)N(R5)(R5) and R2 is n-heptyloxy.
In another embodiment, Ri is -C(O)N(R5)(R5) and R2 is n-octyloxy.
In another embodiment, R\ is -C(O)N(Rs)(R5) and R2 is n-nonyloxy.
In another embodiment, Ri is -C(O)N(R5)(R5) and R2 is n-decyloxy. In another embodiment, Ri is -C(O)N(R5)(R5) and R2 is 2-methylbutyloxy. hi another embodiment, Ri is -C(O)N(R5)(R5) and R2 is 3-methylbutyloxy.
Illustrative compounds of formula (lb) are:
Figure imgf000042_0001
Compound EH;
Figure imgf000043_0001
Compound El;
Figure imgf000043_0002
Compound EJ;
Figure imgf000043_0003
Compound EK;
Figure imgf000043_0004
Compound EL;
Figure imgf000043_0005
10 Compound EM;
Figure imgf000043_0006
Compound EN;
Figure imgf000044_0001
Compound EO;
Figure imgf000044_0002
Compound EP;
Figure imgf000044_0003
Compound EQ;
Figure imgf000044_0004
Compound ER;
Figure imgf000044_0005
10 Compound ES;
Figure imgf000044_0006
Compound ET;
Figure imgf000045_0001
Compound EU;
Figure imgf000045_0002
Compound EV;
Figure imgf000045_0003
Compound EW;
Figure imgf000045_0004
Compound EX;
Figure imgf000045_0005
Compound EY;
Figure imgf000045_0006
Compound EZ;
Figure imgf000046_0001
Compound FA;
Figure imgf000046_0002
Compound FB;
Figure imgf000046_0003
Compound FC;
Figure imgf000046_0004
Compound FD;
Figure imgf000046_0005
Compound FE;
and pharmaceutically acceptable salts and hydrates thereof.
4.4. COMPOUNDS OF FORMULA flc)
As stated above, the invention further relates to methods for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic):
Figure imgf000047_0001
or a pharmaceutically acceptable salt or hydrate thereof, wherein Rl5 R2, R3 and n are defined above for the compounds of formula (Ic).
In one embodiment Ri is -H. hi another embodiment R\ is -H; n is 0 and R3 is -(Ci-Cio)alkyl. In another embodiment Ri is -H; n is 0 and R3 is -O(CH2)mR5. In another embodiment Ri is -H; n is 0 R3 is -O(CH2)mR5; and R5 is -H. In another embodiment Ri is -H; n is 0 and R3 is -halo. In another embodiment Ri is -H; n is 0 and R3 is -C(O)R5. In another embodiment Ri is -H; n is 0 and R3 is -C(O)NHC(O)R5. In another embodiment Ri is -H; n is 0 and R3 is -C(O)N(R5)(R5). In another embodiment Ri is -H; n is 0 and R3 is -H. In another embodiment Ri is -H; n is 0 and R3 is -CO2(CH2)m(R5). In another embodiment Ri is -H; n is 0 and R3 is -NHC(O)N(R5)(R5). In another embodiment Ri is -H; n is 0 andR3 is -C(O)NHR5. In another embodiment Ri is -H; n is 0 R3 is -C(O)NHR5; and R5 is
Figure imgf000047_0002
In another embodiment Ri is -H; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000047_0003
and p is an integer from 1 to 3.
In another embodiment Ri is -H; n is 0; R3 is -C(O)NHR5; R5 is
- y* and p is 1 or 2.
In another embodiment Ri is -H; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000048_0001
p is 1; and Re is halo and is in the para position. h another embodiment Ri is -H; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000048_0002
p is 1 ; and R6 is halo and is in a meta position. hi another embodiment Ri is -H; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000048_0003
p is 1 ; and R6 is halo and is in an ortho position.
In another embodiment Ri is -H; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000048_0004
p is 1; and each Re is independently -halo. hi another embodiment Ri is -H; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000048_0005
p is 1; each Re is independently -halo; and one Re is in the para position and the other e is in a meta position. hi another embodiment Ri is -H; n is 0; R3 is -C(O)NHR5; R5 is
-o = (Rβ)P p is 2; each Rό is independently -halo; and one Re is in the para position and the other Re is in an ortho position. hi another embodiment Ri is -H; n is 0; R3 is -C(O)NHR5; R5 is
-G =^( e)p
p is 2; and one Re is in an ortho position and the other Re is in a meta position, hi another embodiment, Ri is -CO^. h another embodiment
Figure imgf000049_0001
and n is 0. hi another embodiment R is -CO^; n is 0 and R3 is -halo. hi another embodiment R is -CO^; n is 0 and R3 is -C(O)R5. h another embodiment R is -CO^; n is 0 and R3 is -C(O)NHC(O)R5. hi another embodiment R is -CORt; n is 0 and R3 is -H. hi another embodiment R is -CO2Rt; n is 0 and R3 is -CO2(CH2)m(R5). In another embodiment R is -CO^; n is 0 and R3 is -NHC(O)N(R5)(R5). In another embodiment R is -CO^; n is 0 and R3 is -C(O)N(R5)(R5). In another embodiment R is -CO^; n is 0 and R3 is -C(O)NHR5. hi another embodiment R is -CO^; n is 0 R3 is -C(O)NHR5; and R5 is
_ /= <fl*h
hi another embodiment Ri is -CO2R4; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000049_0002
and p is an integer from 1 to 3.
In another embodiment Ri is -CO2Rt; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000049_0003
and p is 1 or 2. hi another embodiment Ri is -CO2R4; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000050_0001
p is 1 ; and Re is halo and is in the para position. hi another embodiment Ri is -CO^; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000050_0002
p is 1 , and Re is halo and is in a meta position.
In another embodiment Ri is -CO^; n is 0; R3 is -C(O)NHR5; R5 is
^Q^
p is 1, and R6 is halo and is in an ortho position.
In another embodiment Ri is -CO2R4; n is 0; R3 is -C(O)NHR5; R5 is
-G° p is 2; and each ^ is independently -halo.
In another embodiment Ri is -CO2R4; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000050_0003
p is 2; each R6 is independently halo; and one Re is in the para position and the other R6 is in a meta position.
In another embodiment Ri is -CO2R4; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000050_0004
p is 2; each R6 is independently halo; and one Re is in the para position and the other Re is in an ortho position. In another embodiment Ri is -CO2R4; n s 0; R3 is -C(O)NHR5; R5 is
Figure imgf000051_0001
p is 2; each Re is independently halo; and one Re is in the ortho position and the other R6 is in a meta position. hi another embodiment, Ri is -C(O)R5. hi another embodiment R is -C(O)R5; n is 0: and R is -halo. hi another embodiment R is -C(O)R5; n is 0 and R3 is -C(O)R5, In another embodiment R is -C(O)R5; n is 0 andR3 is -C(O)NHC(O)R5, In another embodiment R is -C(O)R5; n is 0 and R3 is -H. In another embodiment R is -C(O)R5; n is 0 andR3 is -CO2(CH2)m(R5). In another embodiment R is-C(O)R5;nisO andR3 is -NHC(O)N(R5)(R5). In another embodiment R is -C(O)R5; nis 0 andR3 is C(O)N(R5)(R5). hi another embodiment R is -C(O)R5; n is 0 and R3 is -C(O)NHR5. In another embodiment R is -C(O)R5; n is 0 R3 is -C(O)NHR5; and R5 is
Figure imgf000051_0002
hi another embodiment R\ is -C(O)R5; n is 0; R3 is -C(O)NHR5; R5 is
-O =X<fl*k
and p is an integer from 1 to 3.
In another embodiment Ri is -C(O)R5; n is 0; R3 is -C(O)NHR5; R5 is
- ^ ^
and p is 1 or 2. h another embodiment Ri is -C(O)R5; n is 0; R3 is -C(O)NHR5; R5 is
- "^(Re)? p is 1; and Re is halo and is in the para position. h another embodiment Ri is -C(O)R5; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000052_0001
p is 1 ; and Re is halo and is in a meta position.
In another embodiment Ri is -C(O)R5; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000052_0002
p is 1 ; and Re is halo and is in an ortho position.
In another embodiment Ri is -C(O)R5; n is 0; R3 is -C(O)NHR5; R5 is
_^
p is 2; and each Re is independently -halo.
In another embodiment Ri is -C(O)R5; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000052_0003
p is 2; each Re is independently -halo; and one R6 is in the para position and the other Re is in a meta position. hi another embodiment Ri is -C(O)R5; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000052_0004
p is 2; each Re is independently -halo; and one Re is in the para position and the other Re is in an ortho position.
In another embodiment Ri is -C(O)Rs; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000053_0001
p is 2; and one Re is in an ortho position and the other Re is in a meta position.
In another embodiment, Ri is -C(O)NR5R5. hi another embodiment Ri is -C(O)NR5R5; n is 0; and R3 is -halo.
In another embodiment Ri is -C(O)NR5Rs; n is 0; and R3 is -C(O)R5.
In another embodiment Ri is -C(O)NRsR5; n is 0; and R3 is -C(O)NHC(O)R5.
In another embodiment Ri is -C(O)NR5R5; n is 0; and R3 is -H.
In another embodiment Ri is -C(O)NR5R5; n is 0; and R3 is -CO2(CH2)m(R5).
In another embodiment Ri is -C(O)NRsR5; n is 0; and R3 is -NHC(O)N(R5)(R5). h another embodiment Ri is -C(O)NR5R5; n is 0; and R3 is -C(O)N(R5)(R5). In another embodiment Ri is -C(O)NR5R5; n is 0; and R3 is -C(O)NHR5. In another embodiment Rx is -C(O)NR5R5; n is 0; R3 is -C(O)NHR5; and R5 is
Figure imgf000053_0002
In another embodiment Ri is -C(O)NR5R5; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000053_0003
and p is an integer from 1 to 3.
In another embodiment Ri is -C(O)NR5R5; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000053_0004
and p is 1 or 2. hi another embodiment Ri is -C(O)NR5R5; n is 0; R3 is -C(O)NHR5; R5 is -o ^ (Rs)P
p is 1; and Re is halo and is in the para position.
In another embodiment Ri is -C(O)NR5R5; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000054_0001
p is 1 ; and Re is halo and is in a meta position. h another embodiment Ri is -C(O)NR5R5; n is 0; R3 is -C(O)NHR5; R5 is
-σ = (Rs)P
p is 1 ; and Re is halo and is in an ortho position. h another embodiment Ri is -C(O)NR5R5; n is 0; R3 is -C(O)NHR5; R5 is
a=¥X<Pek
p is 2; and each R6 is independently -halo.
In another embodiment Rt is -C(O)NR5R5; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000054_0002
p is 2; each Re is independently -halo; and one Re is in the para position and the other Re is in a meta position.
In another embodiment Ri is -C(O)NR5R5; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000054_0003
p is 2; each R6 is independently -halo; and one R6 is in the para position and the other Re is in an ortho position. hi another embodiment Rx is -C(O)NR5R5; n is 0; R3 is -C(O)NHR5; R5 is
Figure imgf000055_0001
p is 2; and one R6 is in an ortho position and the other Re is in a meta position.
In another embodiment, the compounds of formula (Ic) are the compounds of formula (la) and pharmaceutically acceptable salts and hydrates thereof, above. In another embodiment, the compounds of formula (Ic) are the compounds of formula (lb) and pharmaceutically acceptable salts and hydrates thereof, above. Illustrative compounds of formula (Ic) are:
Figure imgf000055_0002
Compound FF;
Figure imgf000055_0003
Compound FG;
H
Figure imgf000055_0004
Compound FH;
H
Figure imgf000055_0005
Compound FI;
Figure imgf000056_0001
Compound FJ;
Figure imgf000056_0002
Compound FK;
Figure imgf000056_0003
Compound FL;
Figure imgf000056_0004
Compound FM;
Figure imgf000056_0005
10 Compound FN;
H
Figure imgf000056_0006
Compound FO;
Figure imgf000057_0001
Compound FP;
Figure imgf000057_0002
Compound FQ;
Figure imgf000057_0003
Compound FR;
H
Figure imgf000057_0004
Compound FS;
H
Figure imgf000057_0005
10 Compound FT;
H
Figure imgf000057_0006
Compound FU;
Figure imgf000058_0001
Compound FV;
H
Figure imgf000058_0002
Compound FW;
H
Figure imgf000058_0003
Compound FX;
H
Figure imgf000058_0004
Compound FY;
Figure imgf000058_0005
10 Compound FZ;
Figure imgf000058_0006
Compound GA;
Figure imgf000059_0001
Compound GB;
H
Figure imgf000059_0002
Compound GC;
Figure imgf000059_0003
Compound GD;
Figure imgf000059_0004
Compound GE;
H
Figure imgf000059_0005
0 Compound GF;
Figure imgf000059_0006
Compound GG; H
Compound GH;
Figure imgf000060_0002
Compound Gl;
H
Figure imgf000060_0003
Compound GJ;
Figure imgf000060_0004
Compound GK;
Figure imgf000060_0005
Compound GL;
Figure imgf000061_0001
Compound GM;
Figure imgf000061_0002
Compound GN;
Figure imgf000061_0003
Compound GO;
Figure imgf000061_0004
Compound GP;
Figure imgf000061_0005
10 Compound GQ;
Figure imgf000062_0001
Compound GR;
Figure imgf000062_0002
Compound GS;
Figure imgf000062_0003
Compound GT;
Figure imgf000062_0004
Compound GU;
Figure imgf000062_0005
10 Compound GV;
Figure imgf000063_0001
Compound GW;
Figure imgf000063_0002
Compound GX;
Figure imgf000063_0003
Compound GY;
Figure imgf000063_0004
Compound GZ;
Figure imgf000063_0005
10 Compound HA;
Figure imgf000064_0001
Compound HB;
Figure imgf000064_0002
Compound HC;
H
Figure imgf000064_0003
Compound HD;
Figure imgf000064_0004
Compound HE;
Figure imgf000064_0005
10 Compound HF;
Figure imgf000065_0001
Compound HG;
Figure imgf000065_0002
Compound HH;
Figure imgf000065_0003
Compound HI;
Figure imgf000065_0004
Compound HJ;
Figure imgf000065_0005
10 Compound HK;
Figure imgf000066_0001
Compound HL;
Figure imgf000066_0002
Compound HM;
Figure imgf000066_0003
Compound HN;
Figure imgf000066_0004
Compound HO;
Figure imgf000066_0005
10 Compound HP; H
Figure imgf000067_0001
Compound HQ;
H
Figure imgf000067_0002
Compound HR;
Figure imgf000067_0003
Compound HS;
Figure imgf000067_0004
Compound HT;
Figure imgf000067_0005
10 Compound HU;
Figure imgf000068_0001
Compound HV;
Figure imgf000068_0002
Compound HW;
Figure imgf000068_0003
Compound HX;
Figure imgf000068_0004
Compound HY;
Figure imgf000068_0005
10 Compound HZ;
Figure imgf000069_0001
Compound IA;
Figure imgf000069_0002
Compound IB;
Figure imgf000069_0003
Compound IC;
Figure imgf000069_0004
10 Compound ID;
Figure imgf000070_0001
Compound IE;
Figure imgf000070_0002
Compound IF;
Figure imgf000070_0003
Compound IG;
Figure imgf000070_0004
Compound IH;
Figure imgf000070_0005
10 Compound II;
Figure imgf000071_0001
Compound IJ;
Figure imgf000071_0002
Compound IK;
Figure imgf000071_0003
Compound IL;
Figure imgf000071_0004
Compound IM;
Figure imgf000071_0005
10 Compound IN;
Figure imgf000072_0001
Compound IO;
Figure imgf000072_0002
Compound IP;
Figure imgf000072_0003
Compound IQ;
Figure imgf000072_0004
Compound IR;
Figure imgf000072_0005
10 Compound IS; H
Figure imgf000073_0001
Compound IT;
Figure imgf000073_0002
Compound IU;
Figure imgf000073_0003
Compound IV;
Figure imgf000073_0004
Compound IW;
Figure imgf000073_0005
10 Compound IX;
Figure imgf000074_0001
Compound IY;
Figure imgf000074_0002
Compound IZ;
Figure imgf000074_0003
Compound JA;
Figure imgf000074_0004
Compound JB;
Figure imgf000074_0005
10 Compound JC;
Figure imgf000075_0001
Compound JD;
Figure imgf000075_0002
Compound JE;
Figure imgf000075_0003
Compound JF;
Figure imgf000075_0004
Compound JG;
Figure imgf000075_0005
10 Compound JH;
Figure imgf000076_0001
Compound JI;
Figure imgf000076_0002
Compound JJ;
Figure imgf000076_0003
Compound JK;
O-£ Lςj~
Compound JL;
Figure imgf000076_0004
10 Compound JM;
Figure imgf000077_0001
Compound JN;
Figure imgf000077_0002
Compound JO;
H
Figure imgf000077_0003
Compound JP;
Figure imgf000077_0004
Compound JQ;
Figure imgf000077_0005
Compound JR;
and pharmaceutically acceptable salts or hydrates thereof. 4.4. METHODS FOR MAKING THE
5-ARYLTETRAZOLE COMPOUNDS
The 5-Aryltetrazole Compounds can be made using conventional organic synthesis and/or by the following illustrative methods. General procedures for the synthesis of aryl tetrazoles are provided in, Butler, R.N., Comprehensive Heterocyclic Chemistry Vol. IV, pp. 664-668 (Katritzky et al. eds., 1996).
4.4.1. METHOD A
The 5-Aryltetrazole Compounds of formula (Ic) wherein \ is -H can be obtained by contacting a compound of formula A with an with an azide (e.g., sodium azide ("NaN3")) at reflux, (e.g., about 100 °C), in the presence of zinc bromide ("ZnBr2") using water as a solvent as shown below in Scheme A. Compounds of formula A can be obtained commercially (e.g., commercially available from Sigma- Aldrich Co., http://www.sigmaaldrich.com) or made readily by those skilled in the art. A representative procedure for obtaining a 5-Aryltetrazole Compounds of formula (Ic) from a substituted phenyl nitrile in the presence of sodium azide is provided in Sharpless et al, J. Org. Chem. 7945-7950 (2001).
Figure imgf000078_0001
A Formula Ic
Scheme A A 5-Aryltetrazole Compound of formula (Ic) wherein R\ is -CO^, -C(O)R5, or -C(O)N(R5)(R5) can be obtained by contacting a 5-Aryltetrazole Compound of formula (Ic), wherein Rt is -H with an acyl compound (e.g., XCO^, XC(O)R5, or XC(O)N(R5)(R5), wherein X is Br or Cl) in triethylamine (NEt3).
4.4.2. METHOD B
In another embodiment, a 5-Aryltetrazole Compounds of formula (Ic) wherein Ri is H can be obtained by contacting a compound of formula A with an azide, (e.g., azidotrimethylsilane ("TMSN3")) and a catalytic amount of dibutyl tin oxide ("n-Bu2SnO") in refluxing toluene as a solvent as shown below in Scheme B. Methods for obtaining tetrazoles from nitriles and TMSN3 are provided in, for example, Curran et al. Tetrahedron, 1999, 55, 8997-9006.
Figure imgf000079_0001
Scheme B
A 5-Aryltetrazole Compound of formula (Ic) wherein \ is -CO^, -C(O)R5, or
-C(O)N(Rs)(R5) can be obtained by contacting a 5-Aryltetrazole Compound of formula (Ic), wherein R! is -H with an acyl compound (e.g., XCO^, XC(O)R5, or XC(O)N(R5)(R5), wherein X is Br or Cl) in triethylamine (NEt3). Where R5 is -H, protecting group chemistry can be used.
4.4.3. METHOD C
The 5-Aryltetrazole Compounds of formula (Ic) wherein Ri is -H can be converted to 5-Aryltetrazole compounds of formula (la) by contacting the compound of formula (Ic) wherein Ri is -H with an alkyl chlorocarbonate or carbonic acid anhydride under conditions suitable for the formation of a carbamate as shown in Scheme C. Methods for obtaining carbamates from amines and carbonates are provided in, for example, Raucher et al, Synthetic Commun. 1985, 15, 1025. For example, illustrative compounds AA-AZ, BA-BZ, CA-CZ, DA-DZ, EA-EG can be made using this method.
Figure imgf000079_0002
Formula Ic Formula la
Scheme C 4.4.4. METHOD D
In another embodiment, a 5-Aryltetrazole Compound of formula (lb) wherein Ri is -H can be obtained by contacting a compound of formula B with a 4- substituted aniline (e.g., 4-methylaniline or 4-methoxyaniline) to obtain a compound of formula D'. The compound of formula D' is then contacted with azide, (e.g., azidotrimethylsilane ("TMSN3")) and a catalytic amount of dibutyl tin oxide ("n-Bu2SnO") in refluxing toluene as a solvent as shown below in Scheme B. Methods for obtaining tetrazoles from nitriles and TMSN3 are provided in, for example, Curran et al. (see, e.g., section 4.4.2, above).
Figure imgf000080_0001
D' Formula lb
Scheme D
To obtain a 5-Aryltetrazole Compound of formula (lb) wherein Ri is -CO2R4, -C(O)R5, or -C(O)N(R5)(R5), a 5-Aryltetrazole Compound of formula (lb) wherein Ri is -H is contacted with an acyl derivative (e.g. , XCO^, XC(O)R5, or XC(O)N(R5)(R5), wherein X is Br or Cl) in triethylamine (NEt3) to provide a 5-Aryltetrazole Compound of formula (lb). Where R5 is -H, protecting group chemistry can be used. For example, illustrative compounds EH- FE can be made using this method.
5-Aryltetrazole Compounds can have asymmetric centers and therefore can exist in particular enantiomeric and or diastereomeric forms. A 5-Aryltetrazole Compound can be in the form of an optical isomer or a diastereomer. Accordingly, the invention encompasses 5-Aryltetrazole Compounds and their uses as described herein in the form of their optical isomers, diastereomers, and mixtures thereof, including a racemic mixture. In addition, one or more hydrogen, carbon or other atoms of a 5- Aryltetrazole Compound can be replaced by an isotope of the hydrogen, carbon, or other atom. Such compounds, which are encompassed by the present invention, are useful as research and diagnostic tools in metabolism pharmokinetic studies and binding assays. 4.5. PROPHYLACTIC AND/OR THERAPEUTIC USES OF THE 5-ARYLTETRAZOLE COMPOUNDS
In accordance with the invention, an effective amount of a 5-Aryltetrazole Compound, or a pharmaceutical composition comprising an effective amount of a 5-
Aryltetrazole Compound, is administered to an animal in need of treatment or prevention of an inflammation disease, a reperfusion disease, or hyperuricemia. h one embodiment, an effective amount of a 5-Aryltetrazole Compound can be used to treat or prevent any condition that is treatable or preventable by inhibiting xanthine oxidase. Examples of cells that express xanthine oxidase include, but are not limited to, lung, liver, and intestinal cells. Examples of conditions that are treatable or preventable by inhibiting xanthine oxidase include, but are not limited to, an inflammation disease, a reperfusion disease, or hyperuricemia. In another embodiment, an effective amount of a 5-Aryltetrazole Compound can be used to treat or prevent an inflammation disease, a reperfusion disease, or hyperuricemia.
Examples of inflammation diseases include, but are not limited to, chronic inflammatory disorders of the joints including arthritis, e.g., rheumatoid arthritis and osteoarthritis; respiratory distress syndrome; inflammatory bowel disorders; and inflammatory lung disorders such as asthma and chronic obstructive airway disease, inflammatory disorders of the eye such as corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis, and endophthalmitis; inflammatory disorders of the gum, e.g., periodontitis and gingivitis; tuberculosis; leprosy; inflammatory diseases of the kidney including glomerulonephritis and nephrosis; inflammatory disorders of the skin including acne, sclerodermatitis, psoriasis, eczema, photoaging and wrinkles; inflammatory diseases of the central nervous system, including AIDS-related neurodegeneration, stroke, neurotrauma, Alzheimer's disease, encephalomyelitis and viral or autoimmune encephalitis; autoimmune diseases including immune-complex vasculitis, systemic lupus and erythematodes; systemic lupus erythematosus (SLE); and inflammatory diseases of the heart such as cardiomyopathy. Examples of inflammatory bowel disorders include, but are not limited to, ileitis, including, but not limited to, regional ileitis; colitis, including, but not limited to, ulcerative colitis, collagenous/microscopic colitis, and enterocolitis; Crohn's disease; and pouchitis. Examples of reperfusion diseases include, but are not limited to, shock and sepsis. Shock can be septic shock, e.g., gram positive bacteria-mediated circulatory shock, gram negative bacteria-mediated circulatory shock, hemorrhagic shock, anaphylactic shock, shock associated with systemic inflammation, shock associated with pro-inflammatory cytokines, and shock associated with systemic inflammatory response syndrome (SIRS). The 5-Aryltetrazole Compounds can also be used to prevent or treat circulatory shock, such as shock occurring as a result of gram negative and gram positive sepsis, trauma, hemorrhage, burn injury, anaphylaxis, cytokine immunotherapy, organ failure (particularly kidney or liver failure), or systemic inflammatory response syndrome. Other examples of reperfusion disease are disease arising from cell or solid-organ transplantation, cardiopulmonary bypass surgery, compartment syndrome, crush injury, splanchnic ischemia-reperfusion, myocardial infarction and stroke.
Examples of hyperuricemia include, but are not limited to, gout; tumor-lysis syndrome; idiopathic hyperuricemia; hyperuricemia inherited including, but not limited to, hyperuricemia due to PP-ribose-P synthetase overactivity; hypoxanthine-gaunine phosphoribosyltransferase deficiency; glucose-6-phosphate deficiency; Gierke's glycogen storage disease; chronic hemolytic hyperuricemia including, but not limited to, erythroid, myeloid, and lymphoid proliferative hyperuricemia; renal mechanistic hyperuricemia including, but not limited to, familial progressive renal insufficiency, acquired chronic renal insufficiency, drug related renal insufficiency, and endogenous renal production disorders. Examples of tumor-lysis syndrome include, but are not limited to, tumor- lysis syndrome resulting from chemotherapy treatment in patients with cancer, including but not limited to, leukemias, lyrnphomas, small cell lung cancer, and breast cancer. In one embodiment, the rumor-lysis syndrome is that which results from chemotherapy, particularly for treating cancer.
4.6. METHODS FOR ADMINISTRATION
Due to their activity, the 5-Aryltetrazole Compounds are advantageously useful in veterinary and human medicine. As described above, the 5-Aryltetrazole Compounds are useful for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia.
When administered to an animal, an effective amount of a 5-Aryltetrazole Compound can be administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle. The present compositions, which comprise a 5-Aryltetrazole Compound, are in one embodiment administered orally. The compositions of the invention can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal, and intestinal mucosa, etc.) and may be administered together with another therapeutic agent. Administration can be systemic or local. Various delivery systems are known, e.g. , encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer the 5-Aryltetrazole Compounds.
Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the practitioner. In most instances, administration will result in the release of the 5-Aryltetrazole Compounds into the bloodstream.
In specific embodiments, it may be desirable to administer the 5- Aryltetrazole Compounds locally. This may be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. In certain embodiments, it may be desirable to introduce the 5-Aryltetrazole
Compounds into the central nervous system by any suitable route, including intraventricular, intrathecal, and epidural injection, hitraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, e.g. , by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant. In certain embodiments, the 5-Aryltetrazole Compounds can be formulated as a suppository, with traditional binders and excipients such as triglycerides. In another embodiment, the 5-Aryltetrazole Compounds can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990) and Treat et al., Liposomes in the Therapy of Infectious Disease and Cancer 311 -311 and 353-365 (1989).
In yet another embodiment, the 5-Aryltetrazole Compounds can be delivered in a controlled-release system (see, e.g., Goodson, in Medical Applications of Controlled
8Z Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussed in the review by Langer, Science 249:1527-1533 (1990) may be used. In one embodiment, a pump maybe used (Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); and Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials can be used (see
Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); and Howard et al., J. Neurosurg. 71:105 (1989)). In yet another embodiment, a controlled-release system can be placed in proximity of a target of the 5-Aryltetrazole Compound, e.g., the spinal column or brain, thus requiring only a fraction of the systemic dose.
The present compositions can optionally comprise a suitable amount of a pharmaceutically acceptable carrier or vehicle so as to provide the form for proper administration to the animal.
Such pharmaceutical carriers or vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like, h addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents may be used. When administered to an animal, the pharmaceutically acceptable carriers or vehicle s are preferably sterile. Water is a particularly useful vehicle when the 5-Aryltetrazole Compound of the invention is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The present compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In one embodiment, the composition is in the form of a capsule (see e.g., U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington 's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporated herein by reference.
In one embodiment, the 5-Aryltetrazole Compounds are formulated in accordance with routine procedures as a composition adapted for oral administration to human beings. Compositions for oral delivery may be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. Orally administered compositions may contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions. In these later platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time delay material such as glycerol monostearate or glycerol stearate may also be used. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose and magnesium carbonate. Such excipients are preferably of pharmaceutical grade.
In another embodiment, the 5-Aryltetrazole Compounds can be formulated for intravenous admimstration. Typically, compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the compositions may also include a solubilizing agent. Compositions for intravenous administration may optionally include a local anesthetic such as lignocaine to lessen pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the 5-Aryltetrazole Compounds are to be administered by infusion, they can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the 5-Aryltetrazole Compounds are administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration. The 5-Aryltetrazole Compounds of the invention can be administered by controlled-release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release. The amount of the 5-Aryltetrazole Compound that is effective in the treatment or prevention of an inflammation disease, a reperfusion disease, or hyperuricemia and/or for inhibiting xanthine oxidase activity can depend on the nature of the disorder or condition causing the inflammation disease, reperfusion disease, or hyperuricemia, or the need for inhibiting xanthine oxidase activity and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays may optionally be employed to help identify dosage ranges. The effective amount to be employed will also depend on the route of administration, and the seriousness of the inflammation disease, reperfusion disease, or hyperuricemia and/or need for inhibiting xanthine oxidase activity and can be decided according to the judgment of the practitioner and each patient's circumstances. Administration can be at an effective amount ranging from about 0.1 to about 500 mg/kg/day of the 5-Aryltetrazole Compound to animal in need thereof. Suitable effective amounts can range from about 0.1 milligrams to about 500 milligrams about every 4 h, although typically about 100 mg or less. In one embodiment the effective amounts range from about 0.01 milligrams to about 500 milligrams of a 5-Aryltetrazole Compound about every 4 h, in another embodiment about 0.020 milligrams to about 50 milligrams about every 4 h, and in another embodiment about 0.025 milligrams to about 20 milligrams about every 4 h. The effective amounts described herein refer to total amounts administered; that is, if more than one 5-Aryltetrazole Compound is administered, the effective amounts correspond to the total amount administered. The 5-Aryltetrazole Compounds can be assayed in vitro or in vivo, tor the desired therapeutic or prophylactic activity, prior to use in humans. Animal model systems can be used to demonstrate safety and efficacy.
The present methods for treating or preventing inflammation disease, a reperfusion disease, or hyperuricemia in an animal in need thereof can further comprise administering to the animal being administered a 5-Aryltetrazole Compound an effective amount of another therapeutic agent.
Effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective-amount range, h one embodiment of the invention where another therapeutic agent is administered to an animal, the effective amount of the 5-Aryltetrazole Compound is less than its effective amount would be where the other therapeutic agent is not administered. In another embodiment, the 5-Aryltetrazole Compound and the other therapeutic agent act synergistically to treat an inflammation disease, a reperfusion disease, or hyperuricemia. It is to be understood that where the methods comprise administering an effecitve amount of a 5-Aryltetrazole Compound and another therapeutic agent, the 5-Aryltetrazole Compound is adminstered when the other therapeutic agent exerts its therapeutic effect, or the other therapeutic agent is administered when the 5-Aryltetrazole Compound exerts its therapeutic or prophylactic effect. The other therapeutic agent can be a non-steroidal anti-inflammatory agent.
Useful non-steroidal anti-inflammatory agents, include, but are not limited to, aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenaniic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam; salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; para-aminophennol derivatives including acetaminophen and phenacetin; indole and indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates), including mefenaniic acid, and meclofenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone); and alkanones, including nabumetone and pharmaceutically acceptable salts thereof and mixtures thereof. For a more detailed description of the NSAIDs, see Paul A. Insel, Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed in the Treatment of Gout, in Goodman & Gilman 's The Pharmacological Basis of Therapeutics 617-57 (Perry B. Molinhoff and Raymond W. Ruddon eds., 9th ed 1996) and Glen R. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs in Remington: The Science and Practice of Pharmacy Vol II
1196-1221 (A.R. Gennaro ed. 19th ed. 1995) which are hereby incorporated by reference in their entireties.
The other therapeutic agent can be an anticonvulsant. Useful anticonvulsants include, but are not limited to, acetylpheneturide, albutoin, aloxidone, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate, calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam, decimemide, diethadione, dimethadione, doxenitroin, eterobarb, ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate, mephenytoin, mephobarbital, metharbital, methetoin, methsuximide, 5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin, narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide, phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassium bromide, pregabaline, primidone, progabide, sodium bromide, solanum, strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine, topiramate, trimethadione, valproic acid, valpromide, vigabatrin, and zonisamide. The other therapeutic agent can be an anti-depressant. Useful antidepressants include, but are not limited to, binedaline, caroxazone, citalopram, dimethazan, fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone, benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine, imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine, nortriptyline, noxiptilin, opipramol, pizotyline, propizepine, protriptyline, quinupramine, tianeptine, trimipramine, adrafinil, benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, levophacetoperane, medifoxamine, milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline, prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride, sulphide, tandospirone, thozalinone, tofenacin, toloxatone, tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.
The other therapeutic agent can be an anti-hyperuricemic agent. Useful anti- hyperuricemic agents also include, but are not limited to, allopurinol. The other therapeutic agent can be an agent useful in treating or preventing tumor-lysis syndrome. Therapeutic agents useful for treating or preventing tumor-lysis syndrome also include, but are not limited to, Lasix or Zyloprim.
The other therapeutic agent can be an agent useful in treating or preventing an inflammatory bowel disorder. Therapeutic agents useful for treating or preventing an inflammatory bowel disorder include, but are not limited to, sulfasalazine, olsalazine, and mesalamine.
A 5-Aryltetrazole Compound and the other therapeutic agent can act additively or, more preferably, synergistically. In one embodiment, a 5-Aryltetrazole
Compound is administered concurrently with another therapeutic agent. In one embodiment, a composition comprising an effective amount of a 5-Aryltetrazole Compound and an effective amount of another therapeutic agent can be administered. Alternatively, a composition comprising an effective amount of a 5-Aryltetrazole Compound and a different composition comprising an effective amount of another therapeutic agent can be concurrently administered. In another embodiment, an effective amount of a 5- Aryltetrazole Compound is administered prior or subsequent to administration of an effective amount of another therapeutic agent.
4.7. KITS
The invention encompasses kits that can simplify the administration of a 5- Aryltetrazole Compound to an animal. A typical kit of the invention comprises a unit dosage form of a 5-
Aryltetrazole Compound, h one embodiment, the unit dosage form is a container, which can be sterile, containing an effective amount of a 5-Aryltetrazole Compound and a pharmaceutically acceptable carrier or excipient. The kit can further comprise a label or printed instructions instructing the use of the 5-Aryltetrazole Compound to treat or prevent inflammation disease, reperfusion disease, or hyperuricemia. The kit can also further comprise a unit dosage form of another therapeutic agent, for example, a container containing an effective amount of the other therapeutic agent. In one embodiment, the kit comprises a container containing an effective amount of a 5-Aryltetrazole Compound and an effective amount of another therapeutic agent. Examples of other therapeutic agents include, but are not limited to, those listed above.
Kits of the invention can further comprise devices that are useful for administering the unit dosage forms. Examples of such devices include, but are not limited to, syringes, drip bags, patches, enema bags, and inhalers.
The following examples are set forth to assist in understanding the invention and should not, of course, be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or minor changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein.
EXAMPLES
5.1. EXAMPLE 1; SYNTHESIS OF COMPOUND IC
Figure imgf000091_0001
B D
Figure imgf000091_0002
A solution of 4-cyanobenzoylchloride B (0.82 g, 5 mmol) (commercially available from Sigma- Aldrich Co., http://www.sigmaaldrich.com) was stirred in dry toluene (20 mL). Aniline (0.5 mL, 0.55 mmol) was added dropwise, and following the initial exothermic reaction, the suspension was refluxed for 2 h. After cooling to room temperature, hexane (100 mL) was added to the reaction mixture and the precipitate was filtered and washed with hexane to afford Compound D: Yield 2.0 g (90 %), 1H NMR
(DMSO-D6): δ 7.1 (t, lH,/?-H- NHPh) 7.35 (t, 2H, m-H, NHPh) , 7.75 (d, 2H, o-H, NHPh); 8.15 (AA'BB', Δ=27 Hz, 4H, C(O)Ar), 10.45 (s, IH, C(O)NH).
A mixture of Compound D (2.2 g, 10 mmol), azidotrirnethylsilane (2 mL, 15 mmol) and dibutyltin oxide (0.5 g, 2 mmol) in anhydrous toluene (40 mL) was heated at 100 °C for 5 h. The progress of the reaction was monitored by Thin-Layer
Chromatography. After completion of the reaction the organic phase was extracted with 1 M NaOH (20 mL). The aqueous layer was washed with ethyl acetate (2 x 20 mL) and acidified to pH 2 using 2 M HC1. The separated white solid was collected by filtration to provide Compound IC: Yield 1.95 g (75 %). 1H NMR (DMSO-D6): δ 5 7.1 (t, lH,/?-H, NHPh) 7.35 (t, 2H, m-H, NHPh), 7.8 (d, 2H, o-H, NHPh); 8.15 (AA'BB', Δ=12 Hz, 4H, C(O)Ar), 10.4 (s, IH, C(O)NH). ES/MS: m/z+ 263 (M+ + 1, 100 %). 5.2. EXAMPLE 2: ALTERNATIVE SYNTHESIS OF COMPOUND IC
Figure imgf000092_0001
Compound IC
A mixture of Compound D (2.2 g, 10 mmol), sodium azide (1.3 g, 20 mmol), zinc bromide (1.15 g, 10 mmol) and isopropanol (5 mL) in water (20 mL) was stirred at reflux for 48 h. After the mixture was cooled to 60 °C, 50 mL of 2 M NaOH was added and the suspension was stirred for additional 30 min at this temperature. The precipitate was filtered and the aqueous solution was extracted with ethyl acetate (2 x 50 mL). The aqueous layer was separated and acidified to pH 2 using 2 M HCl. The precipitate was filtered and washed thoroughly with water to provide Compound IC. Yield 1.3 g (50 %).
Experimental data for illustrative 5-Aryltetrazoles Compounds prepared using the methods analogous to those above are given below.
5.3. EXAMPLE 3: COMPOUNDS FT, HA-HC,
HK, HL, HS, HT, HW-IM, IO, IP, IS, IX-JA, JG-JL AND JK-JO
Compounds FT, HA-HC, HK, HL, HS, HT, HW-IF, IH-IM, IO, IS, IX- JA, JG-JI, and JK-JN were prepared according to the method of example 1 using the corresponding amine in place of aniline. Compounds JO, IP, and IG were prepared according to the method of examples 1 and 2 using the corresponding amine in place of aniline.
Experimental data for illustrative 5-Aryltetrazoles Compounds prepared using the method in Section 5.1 are given below.
5.3.1. Compound HX: 1H NMR (DMSO-D6): δ 7.2 (t, 2H, m-H, NHAr), 7.8 (q, 2H, o-H, NHAr), 8.05 (AA'BB', Δ=10 Hz, 4H, C(O)Ar), 10.4 (s, IH, C(O)NH).
5.3.2. Compound IA: 1H NMR (DMSO-D6): δ 2.6 (S, 3H, CH3), 7.5 (d, IH 3-H, NHAr), 7.7 (d, IH, 4-H, NHAr), 8.1 (m, 5H, 2-H NAr+C(O)Ar), 8.4
(s, IH, 6-H, NHAr), 10.6 (s, IH, C(O)NH). 5.3.3. Compound IP: 1H NMR (DMSO-D6): δ 1.2 (d, 6H, 2CH3), 2.8 (m, IH, CH(CH3)2), 7.4 (AA'BB', Δ = 140 Hz, 4H, C(O)Ar), 8.05 (AA'BB', m, 4H, C(O)Ar), 10.6 (s, IH, C(O)NH).
5.3.4. Compound IS: 1H NMR (DMSO-D6): δ 6 7.9 (s, 4H, NHAr), 8.1 (AA'BB', Δ = 34 Hz, 4H, C(O)Ar), 10.6 (s, IH, C(O)NH).
5.3.5. Compound JN: 1H NMR (DMSO-D6): δ 2.2 (s, 3H, CH3), 7.4 (AA'BB', Δ - 154 Hz, 4H, NHAr), 8.05 (AA'BB', Δ = 14 Hz, 4H, C(O)Ar), 10.3 (s, IH, C(O)NH).
5.4. EXAMPLE 4: SYNTHESIS OF COMPOUNDS FV-FX, FZ-GZ, HO-HR, AND JO Compounds FV-FX, FZ-GZ, HO-HR, AND JQ were prepared according to
Method B (described in Section 4.4 above) from the corresponding esters of 4-cyanobenzoic acid. These esters were obtained from 4-cyanobenzoyl chloride and an alcohol or a halide as described in Vogel's Textbook of Practical Organic Chemistry 5th Ed., p. 695. Such alcohols and halides are commercially available.
5.5. EXAMPLE 5: SYNTHESIS OF COMPOUNDS IN. IR IV, IW, AND JB-JE
To a solution of 4-cyanophenol (1.2 g, 10 mmol) in dry DMF (20 mL) was added triethylamine (20 mmol) followed by /-butyl bromide (2.7 g, 20 mmol). The resulting reaction mixture was stirred at 100 °C for 6 h. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2x40 mL). The organic layer was washed with 4 M KOH (3x30 mL) and then with water, dried over Na2SO and concentrated under vacuum to provide 1.5 g (85%) 4-iso-butoxybenzo- nitrile that was used for the next step without further purification. 1H NMR (DMSO-D6): δ 0.95 (d, 6H, 2CH3), 2.0 (m, IH, CH(CH3)2), 3.8 (d, 2H, CH2), 7.4 (AA'BB', Δ = 270 Hz, 4H, Ar).
A mixture of 4-wo-butoxybenzonitrile (1.75 g, 10 mmol), azidotrimethyl- silane (2 mL, 15 mmol) and dibutyltinoxide (0.5 g, 2 mmol) in anhydrous toluene (40 mL) was heated at 100 °C for 18 h. While still hot, the organic phase was extracted with 20 mL 1 M NaOH, aqueous layer was washed with ethyl acetate (2x20 mL) and acidified to pH 2 using 2 M HCL The resulting white solid was collected by filtration to provide Compound IR: Yield 1.2 g (55 %). 1H NMR (DMSO-D6): δ 0.95 (d, 6H, 2CH3), 2.0 (m, IH, CH(CH3)2), 3.8 (d, 2H, CH2), 7.5 (AA'BB', Δ = 295 Hz, 4H, Ar).
Compounds IN, IV, IW, JB, JC, and JD were prepared analogously starting from the commercially available substituted 4-cyanophenols. 3-Bromocyanophenol used in the synthesis of the compound JC was prepared by bromination of 4-cyanophenol in acetic acid using bromine as described in Minoshima et. al, JP 10139770 (1998). Compound JE was prepared be reacting Compound JC with potassium cyanide in the presence of catalytic amount of Ni[(PPh3)4] in N-methylpyrrolidone as described in Minoshima et. al, JP 10139770 (1998).
5.6. EXAMPLE 6: COMPOUNDS FF-FQ,
FU, FY, HE, HF, HG-HJ, HM, JP, AND JR These compounds were obtained from the commercially available substituted benzonitriles using the Method B.
5.7. EXAMPLE 7: COMPOUNDS OF FORMULA DL
Compounds of the Formula DL = Bzl, Et, tert-Bu) were obtained from Compound HE using Method C (described in Section 4.4), using commercially available CbzCl, ClCO2Et, and Boc2O, respectively.
5.8. EXAMPLE 8; COMPOUND FR
Compound FR was synthesized by reacting a commercially available 4-aminobenzonitrile with acetic anhydride as described in Vogel's Textbook of Practical Organic Chemistry 5th Ed., p. 917 and then converting a resulting 4-acetylaminobenzo- nitrile to Compound FR following the Method B.
5.9. EXAMPLE 9: COMPOUNDS FS AND IU
Compounds FS and IU were synthesized by reacting 4-aminobenzonitrile with methylisocyanate or phenylisocyanate, respectively, as described in Vishnyakova et al, Russ. Chem. Rev., 1985, 54, 249 and then converting the resulting urea derivative to the respective 5-Aryltetrazole Compound following Method B. 5.10. EXAMPLE 10: COMPOUND HN
Compound HN was prepared by reacting commercially available 5-aminotetrazole with cinnamoyl chloride as described in Vogel's Textbook of Practical Organic Chemistry 5th Ed., p. 917.
5.11. EXAMPLE 11: COMPOUNDSHUANDHV
Compounds HU and HV were prepared by reacting commercially available 4-cyanobenzoylsulfonyl chloride with adamantyl amine and cyclohexylamine, respectively, and then converting a resulting amide to a tetrazole as described in Example 5.1. above.
5.12. EXAMPLE 12: COMPOUND IT
Compound IT was prepared by benzoylation of 4-aminobenzonitrile as described in Vogel 's Textbook of Practical Organic Chemistry 5th Ed., p. 917 and then converting a resulting N-benzoyl-4-cyanoaniline to Compound IT following the Method B (Sect. 4.4).
5.13. EXAMPLE 13: XANTHINE OXIDASE
INHIBITORY ACTIVITY OF ILLUSTRATIVE 5-ARYL TETRAZOLE COMPOUNDS
A typical assay showing of xanthine oxidase inhibitory activity of illustrative 5-Aryltetrazole Compounds involved the use of a 96 well plate setup. Analysis of the sample utilized a Spectrophotometer with a SoftMax Pro Program set at a kinetic reading at a wavelength of 295 run with a runtime of 10 minutes taking a reading at 12 second intervals. Before the first reading the sample was mixed using an automixer for five seconds and between readings the sample was mixed for three seconds.
Sample Preparation: Approximately 1-2 mg of a 5-Aryltetrazole Compound was placed in a 5 mL vial and dissolved in about 1 mL of DMSO resulting in a 2.5 mM solution.
Well Plate Preparation: Four to eight wells were used for each 5- Aryltetrazole Compound, h each well was added 200 mL of Phosphate-buffered saline (50 mM), 20 mL of xanthine (0.5 mg/mL in water), 10 mL of the 2.5 mM solution of 5- Aryltetrazole Compound (prepared as described above), and 20 mL of xanthine oxidase (1/100 x 40 mL PBS). The xanthine oxidase was kept on ice and was added immediately before the plate was run on the spectrophotometer. A control well was also prepared using only DMSO. The following table shows concentrations of illustrative 5-Aryltetrazole Compounds providing xanthine-oxidase inhibition. Without being limited by theory, compounds that inhibit xanthine oxidase are useful for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia.
PERCENT XANTHINE OXIDASE INHIBITION
5-Aryltetrazole Compound Concentration (uM)
Compound 100 10 1 0 0.05 0.03 0.01
FF 10 NT NT NT NT NT NT
FG 34 NT NT NT NT NT NT
FH 69 27 NT NT NT NT NT
FI 67 21 NT NT NT NT NT
FJ 7 5 NT NT NT NT NT
FK 71 30 NT NT NT NT NT
FL 55 14 NT NT NT NT NT
FM 78 19 NT NT NT NT NT
FN 32 3 NT NT NT NT NT
FO 30 3 NT NT NT NT NT
FP 21 3 NT NT NT NT NT
FQ 99 81 34 NT NT NT NT
FR 40 NT NT NT NT NT NT
FS 10 NT NT NT NT NT NT
FT 67 70 15 NT NT NT NT
FU 92 54 9 NT NT NT NT
FV 100 92 64 NT NT NT NT
FW 100 82 39 NT NT NT NT
FX 95 95 73 NT NT NT NT
FY 91 56 11 NT NT NT NT
FZ 100 97 88 NT NT NT NT
GA 100 100 78 NT NT NT NT
GB 100 97 82 NT NT NT NT
GC NT NT 100 97 52 NT NT
GD 100 82 79 NT NT NT NT
GE NT NT 100 100 59 NT NT PERCENT XANTHINE OXIDASE INHIBITION
5-Arvltetrazole Compound Concentration fulV I)
Compound 100 10 1 0.05 0.03 0.01
GF 97 79 28 NT NT NT NT
GG 89 97 90 NT NT NT NT
GH NT NT 100 91 NT 65 NT
Gl NT NT 100 95 NT 75 NT
GJ NT NT 99 59 NT NT 12
GK NT NT 46 12 NT NT 3
GL NT NT 4 NT NT NT NT
GM NT NT 76 28 NT NT 8
GN NT NT 9 NT NT NT NT
GO NT NT 82 18 NT NT 6
GP NT NT 92 65 NT NT 9
GQ NT NT 78 35 NT NT 0
GR NT NT 48 8 NT NT 0
GS NT NT 95 68 NT NT 13
GT NT NT 94 53 NT NT 8
GU NT NT 94 69 NT NT 17
GV NT NT 95 73 NT NT 14
GW NT NT 39 9 NT NT 5
GX NT NT 100 84 NT NT 19
GY NT NT 76 11 NT NT 19
GZ NT NT 8 NT NT NT NT
HA NT NT 61 10 NT NT NT
HB NT NT 25 NT NT NT NT
HC NT NT 25 NT NT NT NT
HD 60 NT NT NT NT NT NT
HE 33 NT NT NT NT NT NT
HF 80 NT NT NT NT NT NT
HG 22 NT NT NT NT NT NT
HH 48 NT NT NT NT NT NT
HI 70 24 14 NT NT NT NT
HJ 2 NT NT NT NT NT NT PERCENT XANTHINE OXIDASE INHIBITION
5-Arvltetrazole Compound Concentration (μM)
Compound 100 10 1 0.05 0.03 0.01
HK 43 NT NT NT NT NT NT
HL 0 NT NT NT NT NT NT
HM 27 NT NT NT NT NT NT
HN 42 13 10 NT NT NT NT
HO NT NT 98 95 46 NT NT
HP NT NT 100 91 41 NT NT
HQ NT NT 95 97 53 NT NT
HR NT NT 95 95 34 NT NT
HS NT NT 55 16 NT 8 NT
HT NT NT 62 23 NT 15 NT
HU NT NT 0 NT NT NT NT
HV NT NT 0 NT NT NT NT
HW NT NT 89 62 NT 32 NT
HX NT NT 92 59 NT 37 NT
HY NT NT 86 45 NT 20 NT
HZ NT NT 88 41 NT 20 NT
IA NT NT 90 54 NT 31 NT
IB NT NT 94 64 NT 38 NT
IC NT NT 100 81 NT 60 NT
ID NT NT 72 37 NT 13 NT
IE NT NT 87 38 NT 22 NT
IF NT NT 16 NT NT NT NT
IG NT NT 93 59 NT 33 NT
IH NT NT 95 63 NT 33 NT
II NT NT 90 45 NT 20 NT
IJ NT NT 93 58 NT 27 NT
IK NT NT 55 17 NT 9 NT
IL NT NT 86 46 NT 21 NT
IM NT NT 0 NT NT NT NT
IN NT NT 68 21 NT NT NT
IO NT NT 0 NT NT NT NT PERCENT XANTHINE OXIDASE INHIBITION
5-Arvltetrazole Compound Concentration CUM [)
Compound 100 10 1 0Λ 0.05 0.03 0.01
IP NT NT 92 52 NT 28 NT
IQ NT NT 64 33 NT 36 NT
IR NT NT 88 47 NT 28 NT
IS NT NT 97 68 NT 44 NT
IT NT NT 56 15 NT 7 NT
IU NT NT 42 9 NT 3 NT
IV NT NT 35 10 NT NT NT
IW NT NT 22 9 NT NT NT
IX NT NT 98 74 NT 46 NT
IY NT NT 86 47 NT 26 NT
IZ NT NT 89 52 NT 23 NT
JA NT NT NT 0 NT NT NT
JB NT NT 32 15 NT NT NT
JC NT NT 31 6 NT NT NT
JD NT NT 28 0 NT NT NT
JE NT NT 82 32 NT 12 NT
JF NT NT 34 6 NT NT NT
JG NT NT 93 61 NT 33 NT
JH NT NT 86 41 NT 23 NT
JI NT NT 79 30 NT 19 NT
JJ NT NT 0 NT NT NT NT
JK NT NT 0 NT NT NT NT
JL NT NT 95 68 NT 34 NT
JM NT NT 89 38 NT 16 NT
JN NT NT 88 41 NT 20 NT
JO NT NT 83 36 NT 18 NT
JP NT NT 98 74 NT 46 NT
JQ NT NT 100 89 NT NT 18
JR 85 56 14 NT NT NT NT
The term "NT" means that the compound was not tested at the indicated concentration. The above example demonstrates that Compounds FF-HK, HM-HT, HW- IL, IN, IP-IZ, JB-JI, and JL-JR, illustrative 5-Aryltetrazole Compounds, inhibit xanthine oxidase activity and, accordingly are useful for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia. In addition, Applicants believe that Compounds HL, HU, HV, IM, IO, JA, JJ, and JK, illustrative 5-Aryltetrazole Compounds, are useful for treating or preventing an inflammation disease, a reperfusion disease, or hyperuricemia.
5.14. EXAMPLE 14: TOXIC LIVER INJURY MODEL Illustrative 5-Aryltetrazole Compounds exert hepatoprotective effects in a thioacetamide model of hepatic failure. The table below shows the efficacy of various illustrative 5-Aryltetrazole Compounds for their hepatoprotective activity in mice. Illustrated are percent inhibition of the increased serum AST levels resulting from an intraperitoneal injection of thioacetamide (400mg/kg) following a single oral dose (3 mL/kg or 10 mL/kg) of various doses of 5-Aryltetrazole Compounds. Results are expressed as percent inhibtion, mean ±SEM (n = 7-10). Studies were conducted as described in Biochim. Biophys. Acta. 1536(l):21-30 (2001).
Figure imgf000100_0001
Accordingly, the above example demonstrates that Compounds IC, IG, IP, IS, JM-JO, and IX, illustrative 5-Aryltetrazole Compounds, inhibit serum AST levels and, accordingly, are useful for treating or preventing organ failure.
5.15. EXAMPLE 15: COLLAGEN-INDUCED ARTHRITIS
An illustrative 5-Aryltetrazole Compound exerts protective effects in a model of collagen-induced arthritis in mice. Results are expressed as incidence and severity over time. Studies were conducted as described in Inflamm. Res. 50(11):561-569 (2001). The results illustrate that the administration of Compound JO, an illustrative 5- Aryltetrazole Compound, reduced incidence of collagen-induced arthritis in mice.
Specifically, after 33 days 100 % of the untreated mice exhibited arthritis; however, mice that were administered Compound JO showed a significant decrease in the incidence of collagen-induced arthritis.
Time (days) 25 27 29 31 33
% Incidence 35 45 55 90 100
Vehicle
Compound JO 20 35 45 75 85
Time (days) 25 27 29 31 33
Mean Severity 0 0 8 10 12
Vehicle
Compound JO 0 0 3 8 8
The above example demonstrates that Compound JO, an illustrative 5- Aryltetrazole Compound, inhibits collagen-induced arthritis and accordingly, is useful for treating or preventing arthritis.
5.16. EXAMPLE 16: REPERFUSION INJURY
Illustrative 5-Aryltetrazole Compounds exert protective effects in various models of organ ischemia and reperfusion. For example, intraperitoneal administration of illustrative 5-Aryltetrazole Compounds retards the progression of gut ischemia reperfusion- induced hyperpermeability and mortality in mice. Results are expressed as % decrease in gut hyperpermeability and as mortality as observed after 6 hours and 2 days of reperfusion. Studies were conducted as described in Shock, 14(2):134-141 (2000). There was a notable dose-dependent effect on gut hyperpermeability and there was an improvement in survival rate, as tested at the highest dose of both levels.
Dose 3mg/kg 10 mg/kg 30 mg/kg 30 mg/kg
Compound Control IG IG IG JO
Gut 100% 73% 69% 47% 39%
Permeability
Dose 30 mg/kg 30 mg/kg
Compound Control IG JO
Survival % (6h) 60 87 87
Survival % (2days) 0 20 13
The above example demonstrates that Compound IG and JO, illustrative 5- Aryltetrazole Compounds, are useful for treating or preventing a reperfusion disease in an animal.
The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims. A number of references have been cited, the entire disclosures of which have been incorporated herein in their entirety.

Claims

What is claimed is:
1. A compound of formula la:
Figure imgf000103_0001
(la)
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
Figure imgf000103_0002
each R2 is independently -halo, -NO2, -CN, -OH, -N(R5)(R5), -OR5, -C(O)R5, -OC(O)R5, -C(O)NHC(O)R5, -(Ci-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C1o)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-C10)cycloalkenyl, -(C3-Cι0)heterocycle, -phenyl, -naphthyl, -benzyl, -CO2R5, -C(O)OCH(R5)(R5), -NHC(O)R5, -NHC(O)NHR5, -C(O)NHR5, -OC(O)R5, -OC(O)OR5, -SR5, -S(O)R5, or -S(O)2R5;
R3 is -H, -halo, -NO2, -CN, -OH, -N(R5)(R5), -O(CH2)mR5, -C(O)R5, -C(O)NR5R5, -C(O)NH(CH2)m(R5), -OCF3, -benzyl, -CO2CH(R5)(R5), -(C1-C10)alkyl, -(C2-C1o)alkenyl, -(C2-C10)alkynyl, -(C3-Ci0)cycloalkyl, -(C8-C1 )bicycloalkyl, -(C5-Cιo)cycloalkenyl, -naphthyl, -(C3-C10)heterocycle, -CO2(CH2)mR5, -NHC(O)R5,
-N(R5)C(O)R5, -NHC(O)NHR5, -OC(O)(CH2)mCHR5R5, -CO2(CH2)raCHR5R5,-OC(O)OR5, -SR5, -S(O)R5, -S(O)2R5, -S(O)2NHR5, or
Figure imgf000103_0003
R is -(C5)heteroaryl, -(C6)heteroaryl, phenyl, naphthyl, or benzyl; each R5 is independently -H, -CF3, -(Ci-Ci0)alkyl, -benzyl, -adamantyl,
-morpholinyl, -pyrrolidyl, -pyrridyloxide, -pyrrolidinyldione, -piperdidyl, -(C2-C10)alkenyl, -(C2-Cio)alkynyl, -(C3-Cιo)cycloalkyl, -(C8-C14)bicycloalkyl, -(C3-Cio)heterocycle, or
Figure imgf000103_0004
each R6 is independently -H, -halo, -NO2, -CN, -OH, -CO2H, -N((Cι-Cιo)alkyl(Cι-Cιo)alkyl), -O(C1-C10)alkyl, -C(O)(Ci-C10)alkyl, -C(O)NH(CH2)m(Ci-
Ci0)alkyl, -OCF3, -benzyl, -CO2(CH2)mCH((Ci-C10)alkyl(Ci-C10)alkyl), -C(O)H, -CO2(Ci-C10)alkyl, -(C1-Cιo)alkyl, -(C2-C10)alkenyl, -(C2-Cιo)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-Cι0)cycloalkenyl, -(C5)heteroaryl, -(C6)heteroaryl, -phenyl, naphthyl, -(C3-C10)heterocycle, -CO2(CH2)m(Ci-C10)alkyl, -CO2(CH2)mH, -NHC(O)(Ci- C10)alkyl, -NHC(O)NH(C1-Cio)alkyl, -OC(O)(Ci-C10)alkyl, -OC(O)O(Ci-C10)alkyl, -SO2NHR5, or -SO2NH2; n is an integer ranging from 0 to 4; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging from 0 to 5.
2. A pharmaceutical composition comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier or excipient.
3. A method for treating an inflammation disease in an animal, comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic):
Figure imgf000104_0001
(Ic) or a pharmaceutically acceptable salt or hydrate thereof, wherein: Ri is -H, -CO2R4; -C(O)R5, or -C(O)N(R5)(R5); each R2 is independently -halo, -NO2, -CN, -OH, -N(R5)(R5), -OR5, -C(O)R5, -C(O)NHC(O)(R5), -OC(O)R5, -(d-C^alkyl, -(C2-C10)aιkenyl, -(C2-Ci0)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-Cι0)cycloalkenyl,-(C3-C7)heterocycle, -(C5)heteroaryl, -(C6)heteroaryl, phenyl, -naphthyl, -benzyl, -CO2R5, -C(O)OCH(R5)(R5), -NHC(O)R5, -NHC(O)NHR5, -C(O)NHR5, -OC(O)R5, -OC(O)OR5, -SR5, -S(O)R5, or -S(O)2R5;
R3 is -H, -halo, -NO2, -CN, -OH, -N(R5)(R5), -O(CH2)mR5, -C(O)R5, -C(O)NR5R5, -C(O)NH(CH2)m(R5), -OCF3, -benzyl, -CO2CH(R5)(R5), -(Ci-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-Cio)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-Cio)cycloalkenyl, -(C5)heteroaryl, -(C6)heteroaryl, -naphthyl, -(C3-Cio)heterocycle, -CO2(CH2)mR5, -NHC(O)R5, -NHC(O)R5, -NHC(O)NHR5, -OC(O)(CH2)mCHR5R5, -CO2(CH2)mCHR5R5,-OC(O)OR5, -SR5, -S(O)R5, -S(O)2R5, -S(O)2NHR5, or
Figure imgf000105_0001
R is -CF3, -(Ci-C10)alkyl, -benzyl, -adamantyl, -morpholinyl, -pyrrolidyl, -pyrridyloxide, -pyrrolidinyldione, -piperdidyl, -(C5)heteroaryl, -(C6)heteroaryl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C3-Cιo)heterocycle, or
-σ (R6)p
each R5 is independently H or R ; each Re is independently -halo, -NO2, -CN, -OH, -CO2H, -N(Cι- Cιo)alkyl(Cι-Cιo)al yl. -O(Cι-Cιo)alkyl, -C(O)(Cι-Cιo)alkyl, -C(O)NH(CH2)m(Cι-Cιo)alkyl, -OCF3,-benzyl, -CO2(CH2)mCH((Ci-Cio)alkyl(Ci-Ci0)alkyl), -C(O)H, -CO2(Ci-C10)alkyl, -(Ci-Cio)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-Ci4)bicycloalkyl,-(C5-CiQ)cycloalkenyl, -(C5)heteroaryl, -(C6)heteroaryl, -phenyl, naphthyl, -(C3-C10)heterocycle, -CO2(CH2)m(C1-C10)alkyl, -CO2(CH2)mH, -NHC(O)(Ci-C10)alkyl, -NHC(O)NH(Cι-Cιo)al yl, -OC(O)(Cι-C10)alkyl, -OC(O)O(d- C10)alkyl, or -SO2NH2; n is an integer ranging from 0 to 4; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging from 0 to 5.
4. The method of claim 3, wherein the inflammation disease is arthritis, psoriasis, gingivitis, colitis, uveitis, diabetes, adult respiratory distress syndrome, autoimmune disease, lupus erythematosus, ileitis, ulcerative colitis, Crohn's disease, asthma, periodontitis, ophthal itis, endophthalmitis, nephrosis, AJDS-related eurodegeneration, stroke, neurotrauma, Alzheimer's disease, encephalomyelitis, cardio- myopathy, or transplant rejection.
5. A method for treating a reperfusion disease in an animal, comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic):
Figure imgf000106_0001
(Ic) or a pharmaceutically acceptable salt or hydrate thereof, wherein: Ri is -H, -CO2R4; -C(O)R5, or -C(O)N(R5)(R5); each R2 is independently -halo, -NO2, -CN, -OH, -N(R5)(R5), -OR5, -C(O)R5,
-OC(O)R5, -C(O)NHC(O)R5, -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C1o)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-Cio)cycloalkenyl, -(C3-C7)heterocycle, -(C5)heteroaryl, -(C6)heteroaryl, phenyl, -naphthyl, -benzyl, -CO2R5, -C(O)OCH(R5)(Rs), -NHC(O)R5, -NHC(O)NHR5, -C(O)NHR5, -OC(O)R5, -OC(O)OR5, -SR5, -S(O)R5, or -S(O)2R5;
R3 is -H, -halo, -NO2, -CN, -OH, -N(R5)(R5), -O(CH2)mR5, -C(O)R5, -C(O)NR5R5, -C(O)NH(CH2)m(R5), -OCF3, -benzyl, -CO2CH(R5)(R5), -(C1-C10)alkyl, -(C2-C1o)alkenyl, -(C -C1o)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-C10)cycloalkenyl, -(C5)heteroaryl, -(C6)heteroaryl, -naphthyl, -(C3-C10)heterocycle, -CO2(CH2)mR5, -NHC(O)R5, -NHC(O)R5, -NHC(O)NHR5, -OC(O)(CH2)raCHR5R5, -CO2(CH2)mCHR5R5,-OC(O)OR5, -SR5, -S(O)R5, -S(O)2R5, -S(O)2NHR5, or
Figure imgf000106_0002
R4 is -CF3, -(C1-C1o)alkyl, -benzyl, -adamantyl, -morpholinyl, -pyrrolidyl, -pyrridyloxide, -pyrrolidinyldione, -piperdidyl, -(Cs)heteroaryl, -(C6)heteroaryl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C3-C10)heterocycle, or
Figure imgf000106_0003
each R5 is independently H or i; each Re is independently -halo, -NO2, -CN, -OH, -CO2H, -N(d- C10)alkyl(C1-C10)alkyl, -O(d-C10)alkyl, -C(O)(d-C10)alkyl, -C(O)NH(CH2)m(d-C10)alkyl, -OCF3, -benzyl, -CO2(CH2)mCH((C1-Cι0)alkyl(C1-C10)alkyl), -C(O)H, -CO2(C1-C10)alkyl, -(d-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-Cιo)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-C10)cycloalkenyl, -(C5)heteroaryl, -(C6)heteroaryl, -phenyl, naphthyl,-(C3-C10)heter©cycle, -CO2(CH2)m(C1-C10)alkyl, -CO2(CH2)mH, -NHC(O)(d- C10)alkyl, -NHC(O)NH(d-Cιo)alkyl, -OC(O)(C1-C10)alkyl, -OC(O)O(C1-C10)alkyl, or -SO2NH2; n is an integer ranging from 0 to 4; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging from 0 to 5.
6. The method of claim 5, wherein the reperfusion disease is hemorrhagic shock, sepsis, septic shock, myocardial infarction, or stroke.
7. A method for inhibiting xanthine oxidase activity in an animal, comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic):
Figure imgf000107_0001
(Ic) or a pharmaceutically acceptable salt or hydrate thereof, wherein: Ri is -H, -CO2R4; -C(O)R5, or -C(O)N(R5)(R5); each R2 is indepedently -halo, -NO2, -CN, -OH, -N(R5)(R5), -OR5, -C(O)R5, -OC(O)R5, -C(O)NHC(O)R5, -(d-C10)alkyl, -(C2-Cι0)alkenyl, -(C2-C1o)alkynyl, -(C3-C10)cycloalkyl, -(C8-Cι4)bicycloalkyl, -(C5-C10)cycloalkenyl,-(C3-C7)heterocycle,
-(C5)heteroaryl, -(C6)heteroaryl, phenyl, -naphthyl, -benzyl, -CO2R5, -C(O)OCH(R5)(R5), -NHC(O)R5, -NHC(O)NHR5, -C(O)NHR5, -OC(O)R5, -OC(O)OR5, -SR5, -S(O)R5, or -S(O)2R5;
R3 is -H, -halo, -NO2, -CN, -OH, -N(R5)(R5), -O(CH2)mR5, -C(O)R5, -C(O)NR5R5, -C(O)NH(CH2)m(R5), -OCF3, -benzyl, -CO2CH(R5)(R5), -(d-d^alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-C10)cycloalkenyl, -(C5)heteroaryl, -(C6)heteroaryl, -naphthyl, -(C3-C10)heterocycle, -CO2(CH2)mR5, -NHC(O)R5, -NHC(O)R5, -NHC(O)NHR5, -OC(O)(CH2)mCHR5R5, -CO2(CH2)mCHR5R5,-OC(O)OR5, -SR5, -S(O)R5, -S(O)2R5, -S(O)2NHR5, or
Figure imgf000107_0002
4 is -CF3, -(C1-C1o)alkyl, -benzyl, -adamantyl, -morpholinyl, -pyrrolidyl,
-pyrridyloxide, -pyrrolidinyldione, -piperdidyl, -(C5)heteroaryl, -(C6)heteroaryl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C1 )bicycloalkyl, -(C3-C10)heterocycle, or
5 is independently - HΌ ^ '(R6)p
each R or R4; each Re is independently -halo, -NO2, -CN, -OH, -CO2H, -N(d- Cιo)alkyl(C1-C10)alkyl, -O(Cι-Cιo)alkyl, -C(O)(C1-Cι0)alkyl, -C(O)NH(CH2)m(C1-C10)alkyl, -OCF3, -benzyl, -CO2(CH2)mCH((C1-C10)alkyl(Cι-C10)alkyl), -C(O)H, -CO2(d-C10)alkyl, -(d-C10)alkyl, -(C2-Cιo)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8- C14)bicycloalkyl, -(C5-C10)cycloalkenyl, -(C5)heteroaryl, -(C6)heteroaryl, -phenyl, naphthyl, -(C3-C10)heterocycle, -CO2(CH2)m(d-C10)alkyl, -CO2(CH2)mH, -NHC(O)(C1-C10)alkyl, -NHC(O)NH(C1-C10)alkyl, -OC(O)(d-C10)alkyl, -OC(O)O(Cι-C10)alkyl, or -SO2NH2; n is an integer ranging from 0 to 4; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging from 0 to 5.
8. A method for treating hyperuricemia in an animal, comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic):
Figure imgf000108_0001
(Ic) or a pharmaceutically acceptable salt or hydrate thereof, wherein: Ri is -H, -CO^; -C(O)R5, or -C(O)N(R5)(R5); each R2 is independently -halo, -NO2, -CN, -OH, -N(R5)(R5), -OR5, -C(O)R5, -OC(O)R5, -C(O)NHC(O)R5, -(Ci-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl,
-(C3-do)cycloalkyl, -(C8-C1 )bicycloalkyl, -(C5-C10)cycloalkenyl, -(C3-C7)heterocycle, -(C5)heteroaryl, -(C6)heteroaryl, phenyl, -naphthyl, -benzyl, -CO2R5, -C(O)OCH(R5)(R5), -NHC(O)R5, -NHC(O)NHR5, -C(O)NHR5, -OC(O)R5, -OC(O)OR5, -SR5, -S(O)R5, or -S(O)2R5; R3 is -H, -halo, -NO2, -CN, -OH, -N(R5)(R5), -O(CH2)mR5, -C(O)R5,
-C(O)NR5R5, -C(O)NH(CH2)m(R5), -OCF3, -benzyl, -CO2CH(R5)(R5), -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-C10)cycloalkenyl, -(C5)heteroaryl, -(C6)heteroaryl, -naphthyl, -(C3-C10)heterocycle, -CO2(CH2)mR5, -NHC(O)R5, -NHC(O)R5, -NHC(O)NHR5, -OC(O)(CH2)mCHR5R5, -CO2(CH2)mCHR5R5,-OC(O)OR5, -SR5, -S(O)R5, -S(O)2R5, -S(O)2NHR5, or
Figure imgf000108_0002
is -CF3, -(Crd^alkyl, -benzyl, -adamantyl, -morpholinyl, -pyrrolidyl, -pyrridyloxide, -pyrrohdinyldione, -piperdidyl, -(C5)heteroaryl, -(C6)heteroaryl, -(C2-C1o)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C3-do)heterocycle, or
Figure imgf000109_0001
each R5 is independently H or R^ each Re is independently -halo, -NO2, -CN, -OH, -CO2H, -N(d- Cιo)alkyl(Cι-Cιo)alkyl, -O(C1-C10)alkyl, -C(O)(d-C10)alkyl, -C(O)NH(CH2)m(C1-C10)alkyl, -OCF3, -benzyl, -CO2(CH2)mCH((C1-C10)alkyl(C1-C10)alkyl), -C(O)H, -CO2(C1-C10)alkyl, -(d-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-
C14)bicycloalkyl, -(C5-C10)cycloalkenyl, -(C5)heteroaryl, -(C6)heteroaryl, -phenyl, naphthyl, -(C3-C10)heterocycle, -CO2(CH2)m(d-Cιo)alkyl, -CO2(CH2)mH, -NHC(O)(d-C10)alkyl, -NHC(O)NH(C1-C10)alkyl,
Figure imgf000109_0002
or -SO2NH2; n is an integer ranging from 0 to 4; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging from 0 to 5.
9. The method of claim 8, wherein the hyperuricemia is gout.
10. A method for treating tumor-lysis syndrome in an animal, comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic):
Figure imgf000109_0003
(Ic) or a pharmaceutically acceptable salt or hydrate thereof, wherein: R! is -H, -CO2R4; -C(O)R5, or -C(O)N(R5)(R5); each R2 is independently -halo, -NO2, -CN, -OH, -N(R5)(R5), -OR5, -C(O)R5, -OC(O)R5, -C(O)NHC(O)R5, -(d-C^alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-do)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-do)cycloalkenyl, -(C3-C7)heterocycle, -(C5)heteroaryl, -(C6)heteroaryl, phenyl, -naphthyl, -benzyl, -CO2R5, -C(O)OCH(R5)(R5), -NHC(O)R5, -NHC(O)NHR5, -C(O)NHR5, -OC(O)R5, -OC(O)OR5, -SR5, -S(O)R5, or -S(O)2R5;
R3 is -H, -halo, -NO2, -CN, -OH, -N(R5)(R5), -O(CH2)mR5, -C(O)R5, -C(O)NR5R5, -C(O)NH(CH2)m(R5), -OCF3, -benzyl, -CO2CH(R5)(R5), -(d-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl,
-(C5-C10)cycloalkenyl, -(C5)heteroaryl, -(C6)heteroaryl, -naphthyl, -(C3-C10)heterocycle, -CO2(CH2)mR5, -NHC(O)R5, -NHC(O)R5, -NHC(O)NHR5, -OC(O)(CH2)mCHR5R5, -CO2(CH2)mCHR5R5,-OC(O)OR5, -SR5, -S(O)R5, -S(O)2R5, -S(O)2NHR5, or
Figure imgf000110_0001
t is -CF3, -(d-d^alkyl, -benzyl, -adamantyl, -morpholinyl, -pyrrolidyl, -pyrridyloxide, -pyrrolidinyldione, -piperdidyl, -(C5)heteroaryl, -(C6)heteroaryl, -(C2-C1o)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C3-C10)heterocycle, or
Figure imgf000110_0002
each R5 is independently H or j; each R6 is independently -halo, -NO2, -CN, -OH, -CO2H, -N(d-
C10)alkyl(C1-C10)alkyl, -O(d-C10)alkyl, -C(O)(C1-C10)alkyl, -C(O)NH(CH2)m(C1-C10)alkyl, -OCF3, -benzyl, -CO2(CH2)mCH((C1-C1o)alkyl(C1-C10)alkyl), -C(O)H, -CO2(C1-C10)alkyl, -(d-C10)alkyl, -(C2-C10)alkenyl, -(C2-C1o)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-C1o)cycloalkenyl, -(C5)heteroaryl, -(C6)heteroaryl, -phenyl, naphthyl, -(C3-C10)heterocycle, -CO2(CH2)m(d-C10)aUcyl, -CO2(CH2)mH, -NHC(O)(d- C10)alkyl, -NHC(O)NH(Cι-C10)alkyl, -OC(O)(C1-C10)alkyl, -OC(O)O(d-C10)alkyl, or -SO2NH2; n is an integer ranging from 0 to 4; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging from 0 to 5.
11. A method for treating an inflammatory bowel disorder in an animal, comprising administering to an animal in need thereof an effective amount of a compound of formula (Ic):
Figure imgf000110_0003
(Ic) or a pharmaceutically acceptable salt or hydrate thereof, wherein: R! is -H, -CO2R4; -C(O)R5, or -C(O)N(R5)(R5); each R2 is independently -halo, -NO2, -CN, -OH, -N(R5)(R5), -OR5, -C(O)R5, -OC(O)R5, -C(O)NHC(O)R5, -(C1-C10)alkyl, -(C2-Cιo)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-C10)cycloalkenyl, -(C3-C7)heterocycle, -(C5)heteroaryl, -(C6)heteroaryl, phenyl, -naphthyl, -benzyl, -CO2R5, -C(O)OCH(R5)(R5), -NHC(O)R5, -NHC(O)NHR5, -C(O)NHR5, -OC(O)R5, -OC(O)OR5, -SR5, -S(O)R5, or -S(O)2R5;
R3 is -H, -halo, -NO2, -CN, -OH, -N(R5)(R5), -O(CH2)mR5, -C(O)R5, -C(O)NR5R5, -C(O)NH(CH2)m(R5), -OCF3, -benzyl, -CO2CH(R5)(R5), -(d-d^alkyl, -(C2-C10)alkenyl, -(C -Cio)alkynyl, -(C3-C10)cycloalkyl, -(C8-C1 )bicycloalkyl, -(C5-C10)cycloalkenyl, -(C5)heteroaryl, -(C6)heteroaryl, -naphthyl, -(C3-do)heterocycle, -CO2(CH2)mR5, -NHC(O)R5, -NHC(O)R5, -NHC(O)NHR5, -OC(O)(CH2)mCHR5R5, -CO2(CH2)mCHR5R5,-OC(O)OR5, -SR5, -S(O)R5, -S(O)2R5, -S(O)2NHR5, or
Figure imgf000111_0001
i is -CF3, -(d-dt^alkyl, -benzyl, -adamantyl, -morpholinyl, -pyrrolidyl, -pyrridyloxide, -pyrrohdinyldione, -piperdidyl, -(C5)heteroaryl, -(C6)heteroaryl, -(C2-C10)alkenyl, -(C2-Cι0)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C3-C10)heterocycle, or
Figure imgf000111_0002
each R5 is independently H or j; eachR6 is independently -halo, -NO2, -CN, -OH, -CO2H, -N(d- Cι0)alkyl(C1-C10)alkyl, -O(d-C10)aιkyl, -C(O)(C1-C10)alkyl, -C(O)NH(CH2)m(C1-C10)alkyl, -OCF3, -benzyl, -CO2(CH2)mCH((Cι-C10)alkyl(C1-C10)alkyl), -C(O)H, -CO2(C1-C10)alkyl,
Figure imgf000111_0003
-(C2-C10)alkenyl, -(C2-Cι0)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C5-C10)cycloalkenyl, -(C5)heteroaryl, -(C6)heteroaryl, -phenyl, naphthyl, -(C3-C10)heterocycle, -CO^CFb d-dc alkyl, -CO2(CH2)mH, -NHC(O)(d- C10)alkyl, -NHC(O)NH(C1-C10)alkyl, -OC(O)(d-Cι0)alkyl, -OC^O^ d^alkyl, or -SO2NH2; n is an integer ranging from 0 to 4; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging from 0 to 5.
12. The method of claim 11 , wherein the inflammatory bowel disorder is regional ileitis, colitis, Crohn's disease, or pouchitis.
13. The method of claim 12, wherein the colitis is collagenous or microscopic colitis, ulcerative colitis, or enterocolitis.
14. A compound of formula (lb):
Figure imgf000112_0001
(lb)
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
Ri is -H, -CO2R4, -C(O)R5, or -C(O)N(R5)(R5);
R2 is -(C1-C10)alkyl or -O(C1-C10)alkyl;
Ri is -(C5)heteroaryl, -(C6)heteroaryl, phenyl, naphthyl, or benzyl; and each R5 is independently -H, -CF3, -(C1-C1o)alkyl, -benzyl, -(C2-C1o)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C1 )bicycloalkyl, or -(C3-C10)heterocycle.
15. The compound or pharmaceutically acceptable salt or hydrate of claim 13 , wherein R\ is -H.
16. A method for treating an inflammation disease in an animal, comprising administering to an animal in need thereof an effective amount of a compound or a pharmaceutically acceptable salt or hydrate of the compound of claim 13.
17. The method of claim 15, wherein the inflammation disease is arthritis, psoriasis, gingivitis, colitis, uveitis, diabetes, adult respiratory distress syndrome, autoimmune disease, lupus erythematosus, ileitis, ulcerative colitis, Crohn's disease, asthma, periodontitis, ophthalmitis, endophthalmitis, nephrosis, ATDS-related eurodegeneration, stroke, neurotrauma, Alzheimer's disease, encephalomyelitis, cardio- myopathy, or transplant rejection. ill
18. A method for treating a reperfusion disease in an animal, comprising administering to an animal in need thereof an effective amount of a compound or a pharmaceutically acceptable salt or hydrate of the compound of claim 13.
19. The method of claim 17, wherein the reperfusion disease is hemorrhagic shock, sepsis, septic shock, myocardial infarction, or stroke.
20. The compound of claim 13, wherein the animal is human.
21. A method for inhibiting xanthine oxidase activity in an animal, comprising administering to an animal in need thereof an effective amount of a compound or a pharmaceutically acceptable salt or hydrate of the compound of claim 13.
22. A method for treating hyperuricemia in an animal, comprising administering to an animal in need thereof an effective amount of a compound or a pharmaceutically acceptable salt or hydrate of the compound of claim 13.
23. The method of claim 22, wherein the hyperuricemia is gout.
24. A method for treating tumor-lysis syndrome in an animal, comprising administering to an animal in need thereof an effective amount of a compound or a pharmaceutically acceptable salt or hydrate of the compound of claim 13.
25. A method for treating an inflammatory bowel disorder in an animal, comprising administering to an animal in need thereof an effective amount of a compound, or a pharmaceutically acceptable salt or hydrate of the compound of claim 13.
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