CA2264000A1 - 5-substituted and 5,5-disubstituted-3,4-dihydroxy-2(5h)-furanones and methods of use therefor - Google Patents

5-substituted and 5,5-disubstituted-3,4-dihydroxy-2(5h)-furanones and methods of use therefor Download PDF

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CA2264000A1
CA2264000A1 CA002264000A CA2264000A CA2264000A1 CA 2264000 A1 CA2264000 A1 CA 2264000A1 CA 002264000 A CA002264000 A CA 002264000A CA 2264000 A CA2264000 A CA 2264000A CA 2264000 A1 CA2264000 A1 CA 2264000A1
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dihydroxy
furanone
phenyl
ethyl
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Allen T. Hopper
John A. Ziemniak
Robert E. Johnson
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Oxis International Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/62—Three oxygen atoms, e.g. ascorbic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • C07D405/02—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
    • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • C07D405/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • C07D417/02—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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms

Abstract

The present invention relates to synthetic methods for the production of both optically active and racemic 5,5-disubstituted-3,4-dihydroxy-2(5H)-furanones;
5-[(4-aryl)-3-butynyl]-3,4-dihydroxy-2(5H)-furanones; 5-(2-arylthio)ethyl-3,4-dihydroxy-2(5H)-furanones; and 5-(2-aryloxy)ethyl-3,4-dihydroxy-2(5H)-furanones. This invention further relates to the use of the above mentioned compounds as anti-inflammatory agents through their action as mixed inhibitors of lipid peroxidation, 5-lipoxygenase, cyclooxygenase-1 and cyclooxygenase-2.
The invention further relates to the use of such compounds in the treatment of chronic inflammatory disorders such as asthma, rheumatoid arthritis, inflammatory bowel diseas, atherosclerosis, acute respiratory distress syndrome, and central nervous system disorders such as Alzheimer's and Parkinson's diseases wherein reactive oxygen species and inflammatory mediators are contributing deleterious factors.

Description

?WO 98/07714U:10152025CA 02264000 l999-02- 19PCT/US97/148785-SUBSTITUTED AND 5,5-DISUBSTITUTED-3,4-DIHYDROXY-2(SH)-F URANONES AND METHODS OF USE THEREFORThis Application claims priority from Provisional Applications Serial Nos.60/024,440 and 60/024,586 both ?led on August 22, 1996.FIELD OE THE INVEN I IQNThe present invention relates generally to 5-substituted and 5,5-disubstituted—3,4-dihydroxy-2(5H)-furanones, methods of preparation therefor, and methods for theirUSC.BACKGROUND QF THE INVEN l [OL\_lThe aci—reductone 4—(4—chlorophenyl)—2-hydroxytetronic acid compound (CHTA)possesses antilipidemic and antiaggregatory properties which differ from those ofthe classical phenoxyactetic acids as has been disclosed in Witiak et al. _J_.Me_¢Qlienn, 1988, §_1_:1434-1445 and Kamanna et al. , 1989, 251125-32. Although.unsubstituted—, 2—a1kyl- and 2—acyltetronic acids are frequently found in nature, the2—hydroxy substituted tetronic acid redox system is found only in vitamin C and itsclosely related relatives (isoascorbic acid, erythroascorbic acid) and derivatives, andthe macrolide antibiotic, chlorothricin.The antiaggregatory activities of 2—hydroxytetronic acid aci-reductone compound(CHTA) are of interest since blood platelets are involved in the genesis ofatherosclerosis. 2-Hydroxytetronic acid aci-reductones inhibit collagen-inducedhuman platelet aggregation and secretion of [”C]-serotonin in a concentration-dependent manner at equivalent doses, as reported in Witiak et al. , J . Med. §;l_1em,,1982, 25:90-93. The CHTA compound inhibits platelet function by a similarmechanism, involving arachidonic acid release. Redox analogues, such as 2-hydroxytetronic acid, function as antioxidants in membranes or interfere with freeradical processes involved in the biosynthetic elaboration of cyclic prostaglandin.?10152025WO 98/07714CA 02264000 l999-02- 19PCT/US97/148782endoperoxides (PGG2 and PGH2), and, subsequently, thromboxane A, fromarachidonic acid.The development of dual antioxidant-arachidonic acid (AA) metabolism inhibitorsmay provide added bene?ts over existing drugs for the treatment of diseasesassociated with oxidative stress and in?ammation. Numerous conditions includingasthma, rheumatoid arthritis, irritable bowel disease (IBD), adult respiratory distresssyndrome (ARDS), atherosclerosis, ischemia/reper?ision injury, restenosis,neurodegenerative disorders and initiation and promotion of carcinogenesis correlatewith abnormally high levels of reactive oxygen species (ROS). Antioxidant- basedtherapies including both natural antioxidants (e.g., vitamin E, vitamin C and SOD),and synthetic antioxidants (e. g., 4-aryl-2-hydroxytetronic acids’, 2-0-alkyl ascorbicacids, probucol and tirilazad mesylate) have been, or are currently being, investigatedfor the treatment of a number of these conditions.Previously, the S-arachidonic acid aci-reductone analog (S)-3, 4-dihydroxy—5 [(all Z)««3, 6, 9, 12-octadecatraenyl]-2 (SH)-?iranone, was identi?ed as a stereoselective andpotent acachidonic acid metabolic inhibitor. This compound inhibits both PGE2 andLTB4 production in stimulated macrophages (IC50 = 20 uM) and blocks AA-inducedplatelet aggregation (AAIPA) with an IC50 < 10 pM. Dual cyclooxygenase (COX)and lipoxygenase (LO) activity could be important in preventing substrate shunting inthe arachidonic acid cascade. Although this compound demonstrates an encouragingbiological pro?le, both its instability and labored synthesis render this compound lessthan satisfactory as a therapeutic agent.Thus, there exists a need for new therapeutic agents which exhibit activity asantioxidants and arachidonic acid metabolism inhibitors. It is to this aim that thepresent invention is directed.SUMMARY OF THE INVENTION?101520253035CA 02264000 l999-02- 19W0 98/07714 PCT/US97/148783The present invention relates to 5—substituted and5 ,5—disubstituted-3,4-dihydroxy-2(5H)—furanones of the general formula IOR OAryl - (L) -— (CH OH (I)m 2 )nOHwherein R is hydrogen, phenyl or lower alkyl; L is a linker moiety selected from thegroup consisting of oxygen, sulfur, nitrogen, acetylene, a cis or trans carbon-carbondouble bond, an ester, carbonate, urea, amide and carbamate; m is O or 1; n is O to 4;Aryl is a mono-substituted or unsubstituted aryl group; with the proviso that when R ishydrogen, then either m or n is not zero, and the pharmaceutically acceptable saltsthereof.In various preferred embodiments of the present invention, these compounds arerepresented by four structural subclasses of compounds. Thus, in one preferredembodiment, the compounds are 5,5-disubstituted—3,4—dihydroxy-2(SH)—furanones ofthe structural formula la0Aryl OH (Ia)OHwherein R and Aryl are as hereinbefore defined. Most preferably, in the compounds offormula (Ia), R is a methyl, 1-propyl or 2-methylpropyl group; and Aryl is a phenyl, orsubstituted phenyl, such as 1, l1—biphenyl, 4-chlorophenyl or 2- methylpropylphenylgroup.In a second preferred embodiment, the compounds are 5-(arylalkynyl)-3,4-dihydroxy-2(5H)-furanones of the structural formula IbOH\OAry|—cE: c— (CH2)n 0“OH(lb)?101520253035CA 02264000 l999-02- 19wo 93/07714 PCT/US97/148784wherein n and Aryl are as hereinbefore defined. Most preferably, in the compounds offormula lb, n is 2 and Aryl is naphthyl or a substituted phenyl such as 2-methylphenyl, 2-hexenyl phenyl, 2—phenylthiomethylphenyl or pentylthiomethylphenyl.In a third preferred embodiment, the compounds are5-(arylthio)alkyl-3,4-dihydroxy—2(5H)-furanones of the structural formula Ic‘ OH OAryl -s— (CH2 )n 0H (10)OHwherein n and Aryl are as hereinbefore defined. Most preferably, in the compounds ofFormula Ic, n is 2 and the Aryl substituent is napthyl or 4, 5-diphenylisoxazole.In a fourth preferred embodiment, the compounds are5-(a1yloxy)alkyl-3,4-dihydroxy-2(5H)-furanones of the structural formula Id0H OAryl — 0- (CH2; OH (Id)OHwherein n and Aryl are as hereinbefore defined. Most preferably, in the compounds offormula Id, n is 2 and Aryl is a substituted phenyl or heteroaiyl compound such as 1,12biphenyl-4 yl, 4-phenoxyphenyl, flavonyl, dibenzofuranyl, quinolinyl and naphthyl.The racemic 5,5—disubstituted analogs of formula Ia are prepared by reacting an ethylbenzoylformate with a Grignard reagent and trapping the intermediate alkoxide anionwith benzyloxyacetyl chloride, and subsequently adding lithium diisopropylarnide togenerate the corresponding 3-benzyloxy-5,5-disubstituted-4—hydroxy-2(5H)-furanones. Cleavage of the benzyl group by hydrogenolysis provides racernic5,5-disubstituted-3,4-dihydroxy-2(5H)-furanones of formula Ia.?10152025WO 98/07714CA 02264000 l999-02- 19PCT/U S97/ 148785The enantiomerically pure 5,5-disubstituted analogs of formula Ia are synthesized byreacting ethyl benzoylformate with a Grignard reagent, followed by estersaponi?cation and resolution of the resultant 2-aryl-2—substituted-2—hydroxy acid bycrystallizing with a suitable optically pure chiral amine to provide the optically purecompounds with non-racemisable stereocenters. Acid esteri?cation, acylation of thehydroxyl group with benzyloxyacetyl chloride, LDA-induced intramolecular Claisencyclization and reductive cleavage of the benzyl protecting group generates the 5,5~disubstituted-3,4-dihydroxy-2(SH)-furanones of formula Ia having high enantiomericpurity.The 5-(aryl alkynyl)-3,4-dihydroxy-2(SH)-furanones of formula Ib are synthesized ina convergent manner by coupling 5-(alkynyl)-3,4-dihydroxy-2(5H)-furanone witharyliodides by employing a catalytic amount of Pd(PPh3)4. The starting material, 5—(alkynyl)-3,4-dihydroxy-2(5H)-?iranone, is synthesized in four steps. For instance,intermolecular Claisen reaction between or-trimethylsilyloxy-Y-butyrolactone andethyl benzyloxyacetate yields 3-benzyloxy-4-hydroxy-5-(2-hydroxyethyl)-2(5H)-furanone. Iodination (I2, PPh3, imidazole), subsequent iodo displacement with lithiumacetylide, and benzyl group cleavage yields, for instance, the 5-(3-butynyl)-3,4-dihydroxy—2(5H)-furanone coupling precursor.The 5-(arylthio)a1kyl-3,4-dihydroxy12(SH)-furanones of formula 1c are produced byreacting a 3,4-dihydroxy-5-(iodoalkyl)-2(5H)—furanone with the lithium salt of asubstituted arylthiol. The starting material, 3,4-dihydroxy-5-(2—iodoalkyl)—2(SH)-furanone is produced by benzyl group cleavage of 3-benzyloxy-4-hydroxy-5-(2-iodoalkyl)-2(5H)—furanone.The 5-(aryloxy)alky1-3,4-dihydroxy-2(SH)-furanones of formula Id are prepared bycoupling 3,4-dibenzyloxy-5-(hydroxyalkyl)-2(SH)-?iranone with an appropriatelysubstituted phenol according to the Mitsunoble reaction. Subsequent benzyl group?1020l\)(21W0 98/077141CA 02264000 l999-02- 19PCT/U S97/ 148786cleavage by hydrogenation yields the desired 5-(aryloxy) alkyl-3, 4—dihydroxy-2(5H)~furanone.DETAILEIQ DESQRIPTION QF THE INVENTIQ 2NAs used herein, the term "alkenyl" means an organic, alkanyl group containing one ormore double bonds and which can optionally be substituted by one or more halogen,lower alkanyl, alkoxy, aromatic or heteroaromatic groups. Examples of unsubstitutedalkenyl groups include those such as 3-butenyl, 3- or 4-pentenyl, and the like. In asimilar fashion, the term "alkynyl" refers to an organic, alkanyl group containing oneor more triple bonds, of which 3—butynyl, 3- or 4- pentynyl and the like arerepresentative.The term "substituted or unsubstituted aryl", as utilized herein, means an organic,aromatic group which can be unsubstituted or substituted by one or more lower alkyl,lower alkenyl, lower alkenynyl, loweralkylthio, loweralkylsulfonyl,loweralkylsulfonylamino, aromatic or heteroaromatic groups. Examples ofunsubstituted aryl groups include phenyl, pyridyl, thiophenyl, furyl, pyrrolyl and thelike. Examples of substituted aryl groups include those such as alkyl—substituted aryl,e.g., tolyl, 3-methylpyridyl, 2,3-dimethylphenyl, 4-ethylphenyl, 4-isobutylphenyl;alkoxysubstituted aryl, e.g., 4-methoxyphenyl; loweralkylthio or loweralkylsulfonyl-substituted aryl, e.g., 1-propylthiopihenyl, 1-pentylsulfonylphenyl, lower alkenylsubstituted phenyl, e.g., 4-(2-(ZZ-hexenyl] phenyl and aryl-substituted aryl, e.g., 1,1 '-biphenyl and naphthyl. Complex aryl groups such as those derived from ?avone,dibenzofuran, 1,8-natphthalimide, 1,8-naptholsultarn, quinoline, 4,5-diphenyl-2-thio-1, 3- isoxazole. and napthalenethiol can also be utilized as substituant groups.Particularly preferred are compounds wherein a 2- or 2,3—disubstitution pattern(relative to the alkenenyl or alkynenyl group) is present.?10I520253035W0 98/07714CA 02264000 l999-02- 19PCT/U S97/ 148787As used herein, the term lower "alkyl" means straight- or branched-chain saturatedaliphatic hydrocarbon groups preferably containing 1-6 carbon atoms. Representativeof such groups are methyl, ethyl, isopropyl, isobutyl, butyl, pentyl, hexyl and the like.The term "alkoxy" means a lower alkyl group attached to the remainder of the moleculeby oxygen. Examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy andthe like.The compounds of formula I can be formed as mixtures of enantiomers, as well ascis/trans isomers, due to the asymmetric carbon atoms of the ring structure and thedouble bonds present in the substituents. The present invention contemplates the use ofboth the individual isomers, as well as the racemic or cis/trans mixtures or both.The present invention relates to 5-substituted-and5,5-disubstituted-3,4—dihydroxy-2(5H)-furanones of the general formula,0OH (I)Aryl - (L) (CH2 )nmOHwherein R is hydrogen, phenyl, or a lower alkyl; L is a linker moiety selected from thegroup consisting of oxygen, sulfur, nitrogen, acetylene, a cis or trans carbon-carbondouble bond, an ester, carbonate, urea, amide and carbamate; m is O or 1, n is O to 4,Aryl is a substituted or unsubstituted aryl group; with the proviso that when R ishydrogen, then either In or n is not zero; and the pharmaceutically acceptable saltsthereof.In general, the compounds of formula I wherein m and n are zero are prepared by:a) reacting a benzoylformate of the formula,?101520253035WO 98/07714CA 02264000 l999-02- 19PCT/U S97/ 14878OAlk (11)wherein Alk is a lower alkyl group, Aryl is as hereinbefore defined with anorganometalic reagent RMX wherein M is a group I or group H metal, X is ahalogen, and R is as hereinbefore defined, to form an intermediate alkoxide of theformula,OMXOA|k(111)wherein Aryl, R, M, Alk and X are as hereinbefore defined. The intermediatealkoxide is treated with a benzyloxyacetyl chloride, wherein Bn is a protectinggroup such as benzyl or a substituted derivative thereof, to provide an intermediatediester of the formula,0)K/ OBnOR OA|k (Iv)Aryl ’O?101520253035W0 98/07714CA 02264000 l999-02- 19PCT/U S97/ 148789wherein Aryl, R and Alk are as hereinbefore de?ned;(b) Intramolecular Claisen cyclization of the diester of formula IV to the tetronicacid of the formula,(V)OBnOHwherein Aryl, R and Bn are as hereinbefore defined; and(c) cleaving the benzyl protecting group of formula V by catalytic hydrogenationto yield the desired 5,5-disubstituted—3,4-dihydroxy-2(5H)-furanone of the generalformula I wherein Aryl and R are as hereinbefore de?ned, and m and n are 0.Step (a) of the instant process utilizes as starting material, the appropriatebenzoyl forrnate of the formula H wherein Aryl and Alk are as hereinbefore de?nedwhich can be purchased through commercial suppliers, or, if not commerciallyavailable, synthesized according to literature procedures. Benzoylforrnates areprepared by mixing an aiyl compound, alkyl oxalylchloride and AICI3 (or suitableLewis acid) in a l.O/ 1.1/1.1 mixture in 1,2-dichloroethane (or suitable solvent) atO_ to 10__C with vigorous stirring and subsequently stirring the reaction mixture at25_C for 24 hours according to the method of Kuchar et al., Coll. Czech. Chem.Commun., 49: 122-136 (1984).A process for the synthesis of enantiomerically pure analogs of the formula Iwherein m and n are both zero comprises:(a) reacting an optically pure 2—hydroxyester of the formulaOHO‘ R OA|k?101520253035CA 02264000 l999-02- 19wo 9s/07714 PCT/US97/1487810wherein Aryl, R and Alk are as hereinbefore de?ned with a benzyloxyacetyl chloride,wherein Bn is as hereinbefore de?ned, to provide an intermediate diester of theformula,0)J\/ OBnOR OA|k (V11)Aryl I0wherein Aryl, R, Bn, Alk and R are as hereinbefore de?ned;(b) Intramolecular Claisen cyclization of the diester of formula VI] to the tetronicacid of the formula,OBn (VH1)OHwherein Aryl, R and Bn are as hereinbefore defined; and(c) cleaving the benzyl protecting group of formula VIII by catalytic hydrogenationto yield the desired optically pure 5,5-disubstituted-3,4-dihydroxy-2(5H)-furanone ofthe general formula I wherein Aryl and R are as hereinbefore defined, and m and n areboth zero.Step (a) of this process utilizes as starting material, an optically pure 2-hydroxyesterof the formula VI, wherein Aryl, R and Alk are as hereinbefore de?ned, which can bepurchased through commercial suppliers or, if not commercially available, synthesizedaccording to literature procedures. Reaction of a benzoylformate with an organometalicreagent RMX, wherein R, M, and X are as hereinbefore de?ned, produces racernic2-hydroxyesters of the formula VI, wherein aryl, R and Alk are as hereinbeforedefined. Ester saponification with, for example, 1.0M NaOH, resolution with 31:?CA 02264000 l999-02- 19W0 98/07714 PCT/US97/14878lloptically pure amine base using the method of Saigo et al., Bull. Chem. Soc. Jpn., 55:1 188-1190 (1982) and esterification of the acid with, for example an etheral solution ofCH2N2, provides optically pure 2-hydroxyesters of the formula VI.5 A process for the synthesis of analogs of formula I wherein R is hydrogen, Aryl isas hereinbefore de?ned, m is 1 n = 2, and L is an oxygen, ester, N-sulfonamide orN-irnide linkage comprises:(a) reacting a 3-Benzyloxy-4-hydroxy-5-(2-hydroxyethyl)—2(5H)-furanone of theformula,100(IX)HO OBn15 OHwherein Bn is as hereinbefore defined with one equivalent of BnBr and one equivalentof triethlyamine in THF for 5 hours at 65_C to provide 3,4-dibenzyloxy-5-(2-20 hydroxyethyl)-2(5H)-furanone of the formula,25 OBn (X) OBn30 wherein Bn is as hereinbefore de?ned;(b) reacting the 3,4—dibenzyloxy-2(5H)-furanone of the formula X with an arylalcohol (i.e. phenol), carboxylic acid, sulfonamide, or phthalirnide, wherein aryl is ashereinbefore defined, under Mitsunoble conditions to provide 3,4—dibenzyloxy-2(5H)--furanones of the formula,35?101520253035CA 02264000 l999-02- 19W0 98/07714 PCT/US97/1487812(X1)AWOBnwherein Aryl and Bri are as hereinbefore defined, L is an oxygen, ester, 5-sulfonamide or N_-imide linkage and n = 2; and(c) cleaving the benzyl protecting groups of formula XI by catalytic hydrogenationto yield the desired 5-substituted-3,4-dihydroxy-2(5H)-furanone of the general formulaI wherein R is hydrogen, Aryl is as hereinbefore defined, m is l, n = 2, and L is anoxygen, ester, N-sulfonamide or N-imide linkage.A process for the synthesis of analogs of the formula I wherein R is hydrogen, Aryl isas hereinbefore defined, m is 1, n = 2, and L is a sulfur linkage comprises:(a) Iododination of the 3-benzyloxy-4-hydroxy-5-(2-hydroxyethyl)—2(5H)-furanone of the formula IX with I2, PPh3 and imidazole in CH3CN/ether ( 1/5) toproduce the 3—benzyloxy-4-hydroxy—5-(2-iodoethyl)-2-(SH)-furanone of formula,OBn (XII)OHwherein Bn is as hereinbefore de?ned;(b) benzyl group cleavage by first treating the furanone of formula XII with acetylanhydride and pyridine in CI-I2Cl2 for 2 hours, followed by removal of all volatilesubstances in vacuo and subsequent treatment with boron trichloride to yield3,4—dihydroxy—5~(2—iodoethyl)—2(5H)-furanone of the formula;?1015202530CA 02264000 l999-02- 19wo 98/07714 PCT/US97/1487813OH O' QH (XIII)OH(c) reaction of a compound with the formula XIII with three mole equivalents of thelithium salt of an arylthiol, wherein aryl is as hereinbefore de?ned, providescompounds of the formulal wherein Aryl is as hereinbefore defined, n = 2, R = H, andL is sulfur.A process for the synthesis of analogs of the formula I wherein R is hydrogen, Arylis as hereinbefore de?ned, m is 1, n = 2, and L is an acetylene or carbon-carbon doublebond linkage comprises:(a) reaction of 5-(2-iodoethyl)-2-(5H)~furanone of the formula XII with lithiumacetylide ethylenediamine complex in HMPA at -5__C to make 3-benzy1oxy-4-hydroxy-5-(3—butyny1)-2—(5H)—furanone of formula,OBn (XIV)\\OHwherein Bn is as hereinbefore de?ned;(b) benzyl group cleavage by first treating the furanone of formula XIV with acetylanhydride and pyridine in CH2Cl2 for 2 hours, followed by removal of all volatile?101520253035CA 02264000 l999-02- 19W0 93/07714 PCT/US97/1487814substances in vacuo and subsequent treatment of the remaining residue with borontrichloride to yield compounds of the general formula;(XV)_/ OH/OH(c) coupling the 5-(3-butynyl)-2(5I-I)-furanone of formula XV with an aryliodide toprovide analogs of the formula I, wherein Aryl is as hereinbefore defined, n = 2, R = Hand L is an acetylene linker;(d) reduction of the acetylene moiety by the addition of 1 mole equivalent of H2 bycatalytic hydrogenation under Lindlar conditions to yield compounds of formula Iwherein Aryl is as hereinbefore defined, n = 2, R = H and L is a carbon-carbon cisdouble bond; and(e) reduction of the acetylene moiety by the addition of 2 mole equivalent of H2 bycatalytic hydrogenation to yield compounds of formula I wherein Aryl is ashereinbefore defined, m = O, n = 4, and R is hydrogen.In a composition aspect, the present invention encompasses novel pharmaceuticalcompositions comprising the compounds of the general formula I, together with aphysiologically acceptable carrier or excipient, in an amount sufficient to haveantilipidernic, antiaggregatory or antiin?ammatory activities in an animal or patient. Thecompounds and their compositions of the present invention are thus useful in thetreatment or prevention of atherosclerotic disorders, as well as in the treatment ofvarious pathologies in which acute and chronic in?ammation occur.The starting materials utilized in the synthesis of the compounds of formula I are knownin the art and/or are preparable by methods described herein. Where the pure opticalisomers of these compounds are desired, numerous methods exist for the manufactureof optically active and optically pure derivatives of the necessary starting materials.Also, a wide range of chiral bases can be used to starting materials and?10152025WO 98107714CA 02264000 l999-02- 19PCT/U S97/ 148781 5intermediate products. Partial separation of enantiomers can typically accomplished:with optically active solvents such as (-)-menthone, (—)-menthyl acetate and (+)—limonene. Anion-exchange chromatography using a chiral stationary phaseconstructed of 1-p-nitrophenyl-2-amino—l ,3-propanediol, or chromatography throughstarch successfully separates mandelic acid enantiomers.The invention also provides for pharmaceutical compositions comprising thecompounds of formula I above, as well as their physiologically acceptable salts (suchas, for example, Na", K*, NH,,*).The compounds of the invention have antilipidemic and antiaggregatory activity andare thus useful in the treatment or prevention of atherosclerotic disorders.Additionally, the compounds of the invention possess the ability to inhibit the activityof cyclooxygenase and 5-lipooxygenase in standardized assays for such activity, thusmaking them useful for the treatment of pathologies involving acute or chronicin?ammation, such as in?ammatory bowel disease, asthma, adult respiratory distresssyndrome (ARDS) and various forms of arthritis.BIOLOGICAL EVALUATIONThe compounds of the invention were screened for their anti—in?ammatory activityusing a series of in vitro tests the details of which are given below. The activity ofvarious compounds against 5—1ipoxygenase, cycloxygenase-1, cycloxygenase-2 andlipid peroxidase was evaluated. Results of the screening procedures are included inTABLE I, and the activity against 5-lipoxygenase at a test concentration of 1uM inTable II.5-Ll_EOXYGE[\_1ASE SQBEEN5-Lipoxygenase catalyzes the oxidative metabolism of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-I-IETE), the initial reaction leading to the?10152025W0 98/07714CA 02264000 l999-02- 19PCT/US97/148781 6formation of the leukotrienes. Brie?y, the testing procedure utilizes a crude enzymepreparation from rat basophilic leukemia cells (RBL-I) according to the methods of T.Shimuzu et al. Pro. Natl. Acad, Sci. 81:689-693 (1984) and R.W. Egan et al, J. Biol.Chem. 260: 11554-11559 ( 1985). Test compounds are pre-incubated with the enzymepreparation for 5 minutes at room temperature and the reaction is initiated by theaddition of arachidonic acid. Following an 8 minute incubation at room temperature,the reaction is terminated by the addition of citric acid and concentrations of 5-HETEare determined by RIA. Compounds are screened at 30uM. Under these conditions thereference compound phenidone has an IC50 of 30uM.CYCLQQXYQENASE-1 SQBEENCyclooxygenase-1 is involved in the formation of prostaglandins and thromboxane viathe oxidative metabolism of arachidonic acid. Brie?y, cyclooxygenase from ramseminal vesicles is incubated with arachidonic acid (100um) for 2 minutes at 37°C inthe presence or absence of test compounds according to the methods of A.T. Evans etal., Biochem. Pharm. 36:203 5-2037 (1987) and R. Boopathy et al., Biochem J.23 91371-3 77 (1968). The assay is terminated by the addition of trichloroacetic acidand cyclooxygenase activity is determined by reading the absorbance at 530nm.Compounds are screened at 300uM. Under these condition the reference compoundaspirin has an IC50 value of 240uM.CYCLOOXYGENASE-2 SCREENCyclooxygenase-2, also known as prostaglandin H synthetase—2, catalyzes the rate-limiting step in the synthesis of in?ammatory prostaglandins. In this reactioncyclooxygenase-2 catalyzes the oxygenation of unesteri?ed precursors to form cyclicendoperoxide derivatives, including prostaglandin H. Brie?y, cyclooxygenase-2 fromsheep placenta, 14ug/assay tube, is incubated with arachidonic acid (500uM) for 1.5minutes at 27°C in the absence or presence of test compounds according to themethods of A.T. Evans, et al., Biochem Pharm. 36:2035-2037 (1987) and M.G.O’Sullivan et al., Biochem. Biophys. Res. Cxomm. 187: 1123-1127 (1992). The assay?W0 98/077141015CA 02264000 l999-02- 19PCT/U S97/ 148781 7is terminated by the addition of trichloroacetic acid and cyclooxygenase activity isdetermined by reading the absorbance at 532nm. Compounds are screened at 300p.M.Under these conditions the reference compound NS—398 exhibited 77% inhibition at300uM.LI P OXID TI SLipid peroxidation is a consequence of various stimuli, including reactive freeradicals. Polyunsaturated fatty acids associated with plasma membranes are degradeddue to enzymatic induction by reactive agents such as CCI4, leading to cellulardamage. Brie?y, microsomes are prepared from rat livers and the proteinconcentration is determined according to the method of D. Mansuy et al., Biochem.Biophys. Res. Comm. 135: 101 5-1021 (1986). A reaction mixture consisting of 2mg ofthe microsomal preparation, an NADPH generating system, 20mM CCL, and testcompound are incubated for 12 minutes at 37°C. The reaction is terminated by theaddition of a mixture of thiobarbituric acid and trichloroacetic acid. The absorbanceis read at 535nm and is proportional to the concentration of malondialdehyde.Compounds are screened at 300uM. Under these conditions the reference compound,alpha-tocopherol has an IC5o value of 280uM.?CA 02264000 l999-02- 19PCT/US97/ 14878W0 98/07714188332:2:8N32:Z:2:S«aN38maN2.2:mmr?OOOOV'©t'\l("1©O\O\v-*('\l\D\Ogn\O?'-<00\Dl\l\lf)l\0Ol\l\l\OOl\\OI\\O a[\l\I\\Do\<roc~:<:-cog. ~51‘-—-m~———-—-—- n(\IC\l .mmmmEnoou E25 E33N _ -938$93 o._-m Snow ESQAzoEmEz_ ezmumma2§§e-Sn~-__>_s.2-E._e__£=_%.£.:-~_-m-ba.E___n-§2_2§e-$a~-__b_.u:xo§_%._-_V-~_-n-ba_E.__o-...mo=o:EE-$mvm->xo._PE_u-v.m-:x__.o9xo-~-:EEo~=o£9-3%ococE:.?$D~-:b_.u§xo-o-u:o>a_b-N_-m4?o€b__D-v.m30:83-53N-:b=o»xo:2_q§xo:2_a-E-N_-m:?o.PE_n_-v.m255:3-$mVS.ba._.:_Eoa_b_sE-u-:-m-_b_§._-w-?o§.__o-.%-3-@2_2§e-$a~-__:22_Eoa_§2=-u-:-2b.;.m£-?o._E__n_e.2-152.2.23-3a~-_b_sE-m-?o§.__3..m-__3-€:_2a_m-. _.:_-m-3-c:2.2.23-$3~-_Eze-m-basb__3.2_3-i5?_m-,_,E.2L-@o:o=E£-$Sm-_>=o__m-mA_b_2E_b_5om_-$-m4?o.PE_D-v.mo:o:E:.#$mvm-:\€oE. ~v-wA_>=2E_b=nom_-$-m->xo€»£Q-...mu=o=ee-$3N-_bs_a__.-m.m-bs.E._E-.~.M2_2_sa-Ee~-_ba_a-m-bs§___3..2_».i_>_2_em-. _ . _ VI0.5=2e-$3N-2Eoa_§2=-@-m-bs§.___.-§-__3-§5?_m-._.:_-m25..ea-$am-_Eoa-n-?eE.__3.m-E-1_b_2_.__m-. _ . _ VI2_o_§a-Ea~-_b_sE-m-ba§.__3.2_ba._._o.o_._u-$-mo=o=E€-$?~-:>:o__.5.&oE_b=uE-mYE-m-_~£$E-m-»xo.P£_D-v.m2s_§a-Ea~-_b_ms-m-ba._E___.-V.1_El_b_2a_m-. 1:3u:o=EE-$3m-_.€u.E-m-_b=oE-m-.?o.PE_D-v.mo?wz m:==EEoDH m?m?-~mv~n~¢I\°oa~2:.'.“.'2.‘£?E'.T.§Eo_nESn._?CA 02264000 l999-02- 19PCT/US97/14878W0 98/07714193HZHZHZHZ883.S..2.NoNH3anHH3.M:$vHwe38HZHZHZ_©nwcm83wMa32:5mm9::S.M:8a::5mmHZHZHZHZ2S8mmmm382em22we2S.2mmHZHZHZHZ8HoHmE3mm3onM:N_C-2.82e-$aw:b§B.~2_b§_%__€2a__.m©-@-§m-¢o.E;_o-.xmescee-ESN-5:33.~2_b_£&_b_sa-@.§m-?o§.__o-v,m2_o=e=._-$a~-__bs.Bmi.ba._.+§-m-?o§.._o-..mm2.2.23.Sa~-A_>a.3_b_2a-$-m.bs.E.__o-...m28:28-$a~-EbE.5-3-3_§_%_£332.b§_%§.=.:-3-a-m-?os.£_o-32_o._ee-Ea~,:>E3-m-iE._.5b_se:b_e_a_ae&-u-§-m.ba__a___o-v.m...=o=e.i:aN-:b§3-m-€__2_.5Es§o___._b_§_-_V-@-3_-m-b.o_..E_o-§2ss:e-SuN-__b5.:_-m-A_b_2_&_Ese§£_&oé-©-§-m-bssEa-v.M2_o=se-$3~-E_E3-2_b_:a2_-©i-m-?o.E___o-...M...=o.§e-$mK-Z_b_b=.Z-3bB.é-%_Sac:a_b_2a-s-..:-m-§o._E__a-_V,Mo=o=ea-$u~-=b§3.2_b_2a:b_sE8_5:5._e-u-§-m-ba._.E_o-.V.mas.§e-$am-=b_b.5-m-2E232_b§£.mu-@-§-n-baeb__a-.»m2_2§e-Ec~-__bE_s-2:__£._i__aE-c-§-m-?o§___o+.M2.2.23-$3~-__b_b3-webs._a-§-m-?o...£_a-v.M2_2§e-Sa~-__b§o_._.-~-_b_._.%5-u-m-basEo-§u=o=a=_-S3~-__b_§o_5-_-_b_:_%5-N_-m-ba__.b__Qea2_o_§a-Scm-..b_§o_e-~-2Ss.8_-4_-_b_2a__.-n3-N_-m-ba._§_o4‘.M...__2§a-$a~-__b_s:é-~-2___o=_=3-~_-m-?%E_o-225s:e-S3~-?o._§_3.2.Es:§-1_b_2a_m-. _. 9&3u=o:EE-$0m-:b=o¢O.o-~-o=a£uE_z:u;&3-&-m->xo._P£_m_inozosue-SmK-__b_m.2-€.s_ao__=_%=-w.:-~_-m-?%b__o-§2.amanHmonmmX2ScmHN3mmX223 ?CA 02264000 l999-02- 19PCT/US97/ 14878W0 98/07714208:.3SM:38%mm3an8amE8262we2E1 _:o .88:3 m S O.._-m no=oE£__=_ Eueom2_o=sa-$31_E§o_5-_-_22%5-a-m-ba__;.__o-,..m25:23-5a~-__bEE.=-~-o_8§8_-m._-_§__.€-m.$-~_-m-ba.E___o-...m2.2.23-5a~-?...E._3.m-E._?bs-1_ba._ems _ . §-~_-mo:o=8E-Q._5m-__\E.u§xo-m-o=§__uE_»:2_&3-~_-m->xo€b=Q-v.m2.9.23-5a~-__§o.2-E§_=8__=_%=-w._V-~_-m-bs.3___a-§2§§e-EcN-=Ei.oa__:_n_.:_-:-~_-w-b.o.E___o-...mu:o:E:._-$Cm->xo.?E_vé.m-:b=o¢O8-~-=EEo~:u£DY~_-mo=o:E:._-5SW:.£.u§xo-o-u:o>mcYN_-w:Qo€b__Q-v.mu:o=EE-53m-:>£Pc8:o:n_§xo:u._._-vY~_-w-b.cEb__O-v.m2§§e-SaN-=as._&.305.505-3-:-m-_EaE-m-?osE_o-v.23-52_o§e-$aN-__b§_2_Eo.n__b_ss6-:-m-_E.us-m-?o...b__o-v.2+9:..=§_ea-$a~-_§oe-m-?o._E__u-...1_3-§=2_.._m-._.:_-m-$-€2§§a-$3~-_b_§._-m-?.§._=.-...m-E-1_ba.a_m.M _,_:-2L-5ococ?éAtCm;>:o__a-wA_>:o:a_b:nom_-$-m-»xo€b__Q-v..m2_2§=._-S3N-cEoa-_YE_ba._.__bEa_-3-n-b.o._;_=new2.25e-Eu~-_?.._.E..m.m-ba.3.__m-§085:5-S3~-_bs._n_-m-?o§.__3..m-E-1_>_2a_m-. _.:_-m2§Ee-$3~-A_EoaE_se-e-m-bs._;____.-§-_;-i_b_2a_m-, 1:32§_ee-E3~-_Eoa-m-bs__%.%-.V.m-E-I_b_2a_m-. _ . :32_o_§e-$a~-_b_se.m.ba._.b__3.1_E.-§__2a_m-._,:_-me?az _=._:a=:.o2.: mo aoumbcuocoo 63 m an84-3 ommcmwmxo?a?m :o mwcogoswoiom m=otm> mo Soho och= msm?.mmom22?CA 02264000 l999-02- 19PCT/US97/14878W0 98/07714212.52 u go. i.82cmvm28:23-Sa~.:_bE_5-u-§_2ao_§_b_sE_baio.o=c-s-$-~_-n-ba.2£_o-v.m25:2e-$e2_b53-2_b_z%=-c-:-m-ba._.>__o+.m08=se-$u~-:é§p-2_ba_§_b_sa€_5:c?eé-§-m-ba§___o-§2§_ee-ScN-__bE_5-MA_b_u__aSb_u§._.~@-s-3.-m-ba.E___o-325._ee-Eam-=z__§o_£-~-_b_:_%5-~_-m-?§.Eo-v.M8anon38 ?1015202530W0 98/07714CA 02264000 l999-02- 19PCT/US97/1487822Nuclear factor—KB exists in the cytoplasm of most cells bound to a natural inhibitorprotein IKB. In a complex cascade, extracellular stimulation by cytokines such asTNF—oc or interleukin—1 (IL1), viruses, lipopolysaccharide (LPS) or UV-radiationresults in the production of second messenger reactive oxygen species (ROS).Increased ROS concentrations are important mediators, which instigate the processof IKB disassociation from the NF-KB complex enabling NF-KB to migrate into thecell nucleus. Recent ?ndings demonstrate that low levels of H202 activate NF-KBand that a number of antioxidants inhibit this activation process. The antioxidantspyrrolidone dithiocarbamate (PDTC) and N—acetyl-cysteine (NAC) inhibit both theH202 and extracellular cytokine—induced activation of NF-KB in a concentrationdependent manner. Steroids such as dexamethasone are potent anti~in?ammatoryagents in part, because they stimulate the gene synthesis of IKB, leading to inhibitionof NF-KB. The mechanism by which these aci-reductones block NF-KB nucleartranslocation is not clear, but is likely related to their antioxidant properties.However, the possibility that they speci?cally interact with a biomolecule involvedin NF-KB activation has not been disregarded.Test Compound Concentration % Inhibition3 ,4-Dihydroxy-5-[4—(2-naphthyl)—3—butynyl]—2(5H)—furanone 30nM 90 %Reference CompoundsDexamethasone lO00nM 60 %Pyrrolidone dithiocarbamate (PDTC) 10,000nM 50%N-Acetyl-cysteine (NAC) lO00nM 0%Experiments measuring test agents effect on N F-KB nuclear membrane translocationwere performed with NR8383 cells, which are transformed rat alveolarmacrophages. Cells were treated simultaneously with LPS (1 pg/ml) and the testcompounds (10 and 30 nM). In addition, some compounds were tested at doses of10 and 30 pLM. Untreated control cells and cells treated with LPS alone were testedin each experiment. Cells were harvested 6 hours after treatment. Nuclear protein:were extracted, frozen and quantified using the Bradford assay. Electrophoretic?101520W0 98/07714CA 02264000 l999-02- 19PCT/US97/1487823mobility shift assays (EMSA) were subsequently analyzed using a radiolabeled NF-KB probe. Nuclear proteins were reacted with the radiolabeled probe, run on a 5%polyacrylarnide gel, and subjected to audoradiography. Speci?city of proteinbinding for the NF-KB binding site was assayed by cold and nonspeci?c competitionusing the LPS treated sample in each experiment . All EMSA were duplicated atleast once to verify results. Laser densitometry of N F—KB bands was done onautoradiographs to'quantify NF—I<B binding activity.The human T lymphoid cell line Jurkat was transfected with a response element lacZreporter in which transcription of the B-galactosidase gene is directed by the bindingsite for the NF-KB transcription factor. The cell line containing KB-Z is stimulatedwith calcium ionophore A23187 and phorbol ester PMA; this stimulation is inhibitedby the immunosuppressive drug cyclosporin A. In the screening assay transfected KB-Z Jurkat cells (1 x 10“ cells/assay well) are incubated with 2uM A23l87, 20 ng/mLPMA and test compound or vehicle in the well of a microplate for at least 4 hoursaccording to the procedure of M.J. Lenardo and D. Baltimaore, NF—i<B: a pleiotropicmediator of inducible and tissure specific gene control. Cell 58, 227-229, (1989). Atthe end of the incubation, the cells are spun down and resuspended in the buffer andFDG (?uorescein di-[3-D-galactopyranoside) solution. The covered plates are furtherincubated in the dark for l6 hours at 25 °C. The ?uorescent product resulting from theend of reaction is read at 485/530 a Cyto2300 ?uorescence reader. Compoundswere screened at l0pM. The standard, cyclosporin A has an IC50 of 50nM in thisassay.?CA 02264000 l999-02- 19PCT/US97/14878WO 98/07714242.6 u 22 5$8$onQ232Somwe8E: o:9&2Azo:.:=:z_ bzmommaozon?a-£a~-:_>;=5-mZ2§_%_§_>_.2=_b§_%§:-$-3-~_-m-ba§_=m-.q,m0Same-S3N-__§2o_£-m-u_S§8_-m._-_b§_.€.m.$-~_-m-?o§.=n_+.m2§§e-$mV~.__b_2..5Eo_._:52.éi-m-_b_sE-m-ba§___o-.~.23-82_2=:e-$am-E__2_.5aoa_Es=_-@-:-E§ua-m-b.o§.._o+.2-152§a.e-S3~-_EnE-m-?o§____.-v.m-__El_b_u€_m-. _.::-$-€2.255-$mv~-_b_.oe-m-?o._;.___§.m-E-I_b_2a_m-. _.:_-m-3-5u=o:E=..-$mvm-_5.21.méxco;a_b:aom_-3-m-»xo:i£Dimo=o=EE-Q.~mvm-?€oE- _ Ym-£>:2_a_b:nom_-$-m->xo._PE_Q-w. m2.2.e=,_-$a~-_b§_.€-m.m-b8._s£_a-.xm2.2.2e-$n~-_>a€-m-?o§____.-_..m-E-I_b_2a_m-. _ ii2§§e-$c~-?aoa_b_sE-@-m-ba_E_%-.xm-E-I_b_2a_m-. _ . _ VI2_9Ee-$a~-_Eoa-m-ba.E.__3..m-__El_b_2a_m-. .532.2.2a-$u~-_>_se-m-b.osb___§..1;-I_>_2_em-. _ . _ VIo=_nZ _=_:c._E=Q3 8_._e€_ 283..m m&s_-.o§£ .3332 so mu:o§68-_om m:o:m> mo Soto ochE mqm?2.3V.2N.C3N|h©l\%uo_._:_S§22?102025WO 98/07714CA 02264000 l999-02- 19PCT/U S97/ 1487825The ability of the compounds of formula I to inhibit the action of variousin?ammatory cytokines make them useful in a wide variety of therapeutic methods.Speci?cally, their ability to mediate or inhibit the actions of TNF-on makes thesecompounds useful in the treatment of various invasive diseases, infections, andin?ammatory states. Particularly important is the inhibition of the large amount ofTNF produced during serious bacterial infections, which can trigger a state of shockand tissue injury (septic shock syndrome).A further important use of the compounds of formula I is to inhibit the TNF which isknown to mediate cachexia produced during chronic disease states. Thus, thesecompounds are particularly useful in adjunctive therapy for AIDS and cancer patientsto reduce and/or ameliorate the consequences of cachexia produced during thesechronic disease states.A further specific method of treatment for which the compounds of the instantinvention are particularly useful is in the treatment of rheumatoid arthritis whereinincreased amounts of the in?ammatory cytokines, TNF—oc and IL-1 are present. Byvirtue of their ability to mediate and/or inhibit the action of these cytokines,in?ammation and the severity of the disease state can be reduced or eliminated.The compounds of the instant invention can also be utilized in the treatment ofmultiple sclerosis (MS), Crohn's disease and ulcerative colitis by inhibiting and theactivity of the in?ammatory cytokines which underlie these disease states.The compounds of the invention may be formulated in a conventional manner,optionally together with one or more other active ingredients, for administration byany convenient route for example of oral, intravenous or intramuscular administration.Thus, according to another aspect, the invention provides a pharmaceuticalcomposition comprising a compound of formula I and/or a pharmaceutically?101520W0 98/07714CA 02264000 l999-02- 19PCT/US97/1487826acceptable salt thereof together with a pharmaceutically acceptable carrier orexcipient.For oral administration, the pharmaceutical composition may ta.ke the form of, forexample, tablets, capsules, powders, solutions, syrups or suspensions prepared byconventional means with physiologically acceptable excipients.The compounds may be formulated for intravenous or intramuscular administration indry form for reconstitution before use, or as a sterile solution or suspension.A proposed daily dose based on similar pharmacokinetic parameters to CHTA foradministration to man is about 10 to 25 mg/kg, for example, 700 mg to 1 gm daily,which may be conveniently administered in l to 3 doses per day. The precise doseadministered will, of course, depend on the age and condition of the patient.The following examples are illustrative of the present invention.EXAMELESGeneral Methods. Unless otherwise noted all reagents were purchased fromcommercial suppliers and used as received. Melting points were determined in opencapillaries with a Thomas-Hoover Uni-Melt Apparatus and are uncorrected. Nuclearmagnetic resonance spectra were obtained with either an IBM-Bruker model NRJI 00or Varian model 200 FT NMR spectrometer. Tetramethylsilane (TMS) in CDCI3,DMSO—d6, acetone-d6, CD3OD or D20 was used as internal standard. Chemical shiftsare reported on the 6 scale with peak multiplicities: s, singlet; d, doublet; dd, doubletof doublets; ddd doublet of doublet of doublets; t, triplet; q, quartet, in, multiplet.Anhydrous solvents were purchased from Aldrich Chemical, Inc., Milwaukee, WI andused as such. Optical rotations were performed on a Perkin-Elmer model 241?10152025WO 98/07714CA 02264000 l999-02- 19PCT/US97/1487827polarimeter using a 10 cm, lmL cell. Elemental Analyses were performed byQuantitative Technologies, Inc., Whitehouse, NJ.P PARA F G E SEXAMELE AEthyl 4-phenylbenzoylformateA mixture of 77g (500mmol) of biphenyl and 68mL (540mmol) of ethyloxalylchloride was dissolved in 300mL of 1,2—dichloroethane and cooled with stirringto between 0° and 10°C. AlCl3 (73 g, 550mmo1) was added at such a rate to maintainthe reaction temperature below 15°C. The mixture was stirred at 10°C for 1 hour andat 25 °C for 24 hours, then poured into l00OmL of a ice cold 10% HCI solution. Theaqueous suspension was extracted with 4 x 500mL of ether and the combined etherextracts were washed with 100mL of 10% HCI solution, 100mL of brine, dried(MgSO4) and concentrated to a yellow oil which was puri?ed by chromatography overSiO3 using initially acetone/hexanes (2/98) and increasing the polarity of the solventto acetone/hexanes (10/90) upon elution of the nonpolar impurities to liberate 82g(68% yield) of a yellow oil, which crystallized on standing.EXAMPLE BEthyl 4-isobutylbenzoylformateA mixture of 27g (200mmol) of isobutylbenzene and 24mL (215mmol) of ethyloxalylchloride underwent Friedel—Crafts acylation reaction in an analogous fashion asdescribed for the synthesis of ethyl 4-phenylbenzoylforrnate to yield 38g (81% yield)of ethyl 4—isobutylbenzoylformate as a colorless oil.EXAMPLE £23—Benzyloxy-4-hydroxy-5-(2-hydroxy)ethyl-2(SH)-furanoneA. A solution of 10.0g (98mmol) of oz-hydroxy-y-butyrolactone in l00mL ofanhydrous THF under argon was cooled to 0-5 °C with magnetic stirring. Addition 14mL (110mmol) of trimethylsilyl chloride and 16mL (1 15mmol) of triethylamine?101520WO 98/07714CA 02264000 l999-02- 19PCT/US97l1487828immediately produced a white precipitate. The suspension was warmed to roomtemperature and stirred for 4 hours. The suspension was poured into a separatoryfunnel containing l00mL of H20 and 500mL of ether. The organic layer was washedwith 50mL of H20, 50mL of brine, dried (MgSO4) and concentrated. Puri?cation(Kugelrohr distillation) provided 14.7g (90% yield) of ac-trimethylsilyloxy-y-butyrolactone bp 80-100°C (8 mm Hg).B. To a 500mL 2-necked ?ask ?ame dried under argon and equipped with a magneticstir bar, was added 200mL of THF and 18.7mL (89mmol) of hexamethyldisilazide.The ?ask was cooled to -78°C and 55.4mL (89mmol) ofa l.6M nBuLi solution inhexanes was added with stirring over 15 min. The light yellow solution was stirredfor an additional 15 min and l6.7g (86mmol) of ethyl benzyloxyacetate was addedover 5 min. The solution was stirred for 20 min at -78 °C, and l4.7g (84.4mmol) of ac-silyloxy—y-butyrolactone was added via syringe. The reaction mixture was quenchedafter 30 minutes by pouring into a mixture of l00mL of 10% aqueous HCI solutionand 500mL of ether. The aqueous layer was separated and washed with 2 x l00mL ofether. The combined ether extracts were washed with 50mL of brine, dried (MgSO4)and concentrated leaving a yellow oil, which was dried in vacuo for 15 hours.C. The yellow oil was placed under argon, diluted with 400mL of MeOH, cooled to0°C with stirring and 1 1.7g (85mmol) of anhydrous KZCO3 was added. After 30minutes the suspension was concentrated to a volume of about 75mL, diluted withl00mL of H20 and 50mL of saturated sodium bicarbonate solution, and washed with2 x 100 mL of ether. The aqueous phase was acidified with 37% HCl solution to a pHnear 1 and extracted with 10 x 150mL of ether. The combined ether extracts werewashed with l00mL of brine, dried (MgSO4) and concentrated to a yellow oil (18.7 g,86%) which solidi?ed upon standing. Recrystallization from benzene and hexanesprovided 15.8 g, (75% yield) of 3-benzyloxy-4-hydroxy-5-(2-hydroxy)ethyl-2(5H)-furanone as a white solid: mp 98-99°C, ‘H NMR (acetone- d6) 5 7.46-7.27 (m, 5H),?10152025WO 98/07714CA 02264000 l999-02- 19PCT/US97/14878295.06 (S. 2H), 4.83 (t, J = 6.3 Hz, 1H), 3.85-3.69 (m, 2H), 2.05-1.95 (m, 1H), 1.89-=l.76(m. IH). Anal Calcd for C,3H,4O5: C, 62.39; H, 5.64. Found: C, 62.51; H, 5.50.EXAMPLE D3,4-Dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanoneA mixture of 1.25g (5mmol) of 3-benzy1oxy-4-hydroxy-5-(2-hydroxyethy1)-2(5H)-furanone, l5mL of ‘THF, 871 uL (5.0mrnol) of diisopropylethylarnine and 631p.L(5.2mmol) of benzyl bromide were combined under argon. The reaction mixture waswarmed to re?ux for 5 hours, and upon cooling, a suspension formed which waspoured into 50mL of 5% aqueous HCl solution and extracted with l00mL of ether.The ether fraction was separated and sequentially washed with 30mL of 5% aqueousHCl, 30mL of H20, 30mL of saturated NaHCO3 solution, 30mL of H20, 30mL ofbrine, dried (MgSO.,) and concentrated to a colorless oil. Puri?cation over silica gelusing EtOAc/hexanes (2/3) provided 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone as a faint pink colored oil (1 .Og, 60% yield).EXAMPLE E3-Benzyloxy-4—hydroxy—5—(2-iodoethyl)-2(5H)-furanoneTo an oven dried 250mL round bottom ?ask ?ushed with argon was added 5.8g(22mmol) of PPh3, 1.5g (22mmol) of imidazole and 80mL of ether/CH3CN (3/1). Themixture was cooled in an ice waterlbath with magnetic stirring and 5.6g (22mrnol) ofiodine was added in 4 equal portions with vigorous stirring. The resulting slurry waswarmed at room temperature for 20 minutes, cooled to 0°C, and 5.0g (20mmol) of 3mbenzyloxy-4—hydroxy-5-(2-hydroxyethyl)-2(5H)—furanone dissolved in 20mL ofCH3CN/ether (1/1) was added in one portion and the remainder was rinsed in with5mL of ether. The mixture was stirred at 0°C for 10 minutes, then at roomtemperature for 30 minutes and quenched by pouring into 150mL of 10% HClsolution and extracting with 500mL of ether/hexanes (1/1). The aqueous layer wasseparated and extracted with l00mL of ether. The combined organic fractions werewashed with 50mL of H20 and extracted with 5 x 50mL of saturated NaHCO3?10152025WO 98/07714CA 02264000 l999-02- 19PCT/US97/1487830solution. The combined bicarbonate extracts were washed with 50mL ofether/hexanes (1/1), acidi?ed to pH below 2 with 10% HCl solution and extractedwith 3 x 200mL of ether. The combined ether extracts were washed with 100mL ofbrine, dried (MgSO4) and concentrated to give 6.7g, (93% yield) of 3-benzyloxy-4-hydroxy-5-(2-iodoethyl)-2(5H)-furanone as a white solid, which was not furtherpuri?ed: mp 101-104°C, ‘H NMR (CDCI3) 6 7.40-7.27 (m, 5H), 5.06, (dd, J = 11.4Hz, 2H), 4.69 (dd, ‘J = 3.4, 8.0 Hz, 1H), 3.06 (t, J = 7.3 Hz, 2H), 2.41-2.29 (m, 1H),2.02-1.90 (m, 1H); “C NMR (CDCI3) 5 170.33, 160.61, 136.32, 128.77, 128.69,128.58, 120.11, 75.76, 73.39, 35.77, -2.03; Anal Calcd for‘C,3H,3O4I: C, 43.35; H,3.64. Found: C, 43.94; H, 3.69.EXAM LE F3,4-Dihydroxy-5-(2-iodoethyl)-2(SH)-furanoneTo a dry ?ask ?ushed with argon was added 0.72g (2.0mmol) of 3-benzyloxy-4-hydroxy-5-(2—iodoethyl)-2(5H)-furanone and 10mL of CHZCI2. The solution wascooled with stirring in an ice-water bath, and 0.3 8mL (4.0mmol) of acetic anhydrideand 0.34mL (4.2mmol) of pyridine were added. The ice bath was removed and thesolution was stirred for 1 hour. All volatile substances were removed in vacuo (2h at1 mm Hg, 25 °C). Argon was introduced to the reaction ?ask and the residue wastaken up in 20mL of dry CH2Cl2, cooled to -78°C and 5.2mL (2.6mmol) of 1.0MBCI3 in CH2Cl2 was added with stirring. The reaction mixture was kept at -78 °C for 1hour and at room temperature for 30 minutes. The mixture was poured into 50mL ofbrine and extracted with 3 x 30mL of ether. The combined ether extracts were washedwith 5mL of H20 and extracted into saturated NaHCO3 solution (3 x l5mL). Thebicarbonate fractions were pooled and washed with l5mL of ether, acidi?ed to pH 1with 25% aqueous HCI solution, and extracted with 3 x 30mL of ether. The etherextracts were combined and washed with l5mL of brine, dried (MgSO4) andconcentrated to provide 360mg (67% yield) of 3,4-dihydroxy-5-(2-iodoethyl)-2(5I-[)-furanone as a white crystalline solid: mp 150-151 °C; ‘H NMR (acetone-d6) 6 4.80?WO 98/0771410152025CA 02264000 l999-02- 19PCT/U S97/ 148783 1(dd, 1H, J = 3.5, 8.0 Hz), 3.50-3.25 (m, 2H), 2.60-2.35 (m, 1H), 2.20-1.95 (m, 1H).Anal Calcd for C6H7O4I: C, 26.69; H, 2.61. Found: C, 26.54; H, 2.59.X PL G3-Benzyloxy-5-(3-butyne)-4-hydroxy-2(5H)-furanoneTo a ?ame-dried three-necked round bottom ?ask with magnetic stir bar, argon inlet,and septum containing 5.7g (55.8mmo1) of 90% lithium acetylide ethylenediaminecomplex, was added 20mL of HMPA. The suspension was stirred for 15 minutes atroom temperature. cooled in an ice bath (acetone/CO2) to between -5 °C and -10°C,and 6.7g (18.6 mmol) of 3-benzyloxy-4-hydroxy-5-(2-iodoethyl)-2(5H)-furanonedissolved in 15mL of HMPA was added over a two minute period. A dark brown-orange slurry formed and the temperature was maintained between 0°C and -5 °C for30 minutes. The mixture was quenched by the careful addition of 150mL of 10%aqueous HCl solution, which was immediately extracted with 2 x 200mL of ether.The combined ether extracts were washed with 2 x 50mL of 5% aqueous HCl solutionand extracted with 4 x 50mL of NaHCO3 solution. The combined bicarbonateextracts were washed with 50mL of ether, acidi?ed with 20% aqueous HC1 solution topH 1 and extracted with 3 x 150mL of ether. The combined ether extracts werewashed with 50mL of brine, dried (MgSO4) and concentrated leaving 4.1 g (85%crude yield) of 3-benzyloxy-5-(3—butyne)-4-hydroxy-2(5H)-furanone as a yellowsolid. This material was used without further puri?cation in subsequent steps: mp85-88°C; ‘H NMR (CDC13 ) 5 7.38-7.26 (m, 5H), 5.06, (q, Jab = 11.6 Hz, 2H), 4.75(dd, J = 3.5, 8.1 Hz, 1H), 2.27-2.20 (m, 2H), 2.12-2.01 (m, 1H), 1.98 (t, J = 2.6 Hz,1H), 1.73-1.62 (m, 111); “C NMR(CDC13) 6 169.93, 160.90, 136.39, 128.77, 128.73,128.64, 120.13, 82.31, 74.30, 73.43, 69.71, 30.78, 13.72.EXAMPLE L-15-(3-Butyne)-3,4-dihydroxy-2(5H)-furanoneAn oven dried 250mL ?ask equippedwith a magnetic stir bar was ?ushed with argonand charged with 2.6g (10.0mmol) of 3-benzyloxy-5-(3—butyne)—4—hydroxy-2(5H)-?W0 98l077141020t\)U)30CA 02264000 l999-02- 19PCT/U S97/ 1487832furanone and 50mL of anhydrous CH2Cl2. The solution was cooled in an ice bath to5°C with magnetic stirring and 1.9mL (20.0mmol) of acetic anhydride was addedfollowed by 1.7mL (2 lmmol) of pyridine. The ice bath was removed after 1 hour,and the mixture was concentrated on a rotary evaporator and dried at 0.5 mm Hg at25°C for 12 hours. Argon was introduced followed by 100mL of dry CHZCI2. Thesolution was cooled to —78°C with stirring and 25mL (25mmo1) of 1.0M BCI3 inCH2Cl2 was added.‘ The reaction mixture was allowed to gradually warm to 10°Cover a 2 hour period and maintained at 10°C for 1 hour. The mixture was poured into50mL of brine and extracted with 4 x 100mL of ether. The combined ether fractionswere extracted with 3 x 25mL of saturated NaHCO3 solution. The combinedbicarbonate extracts were washed with 25mL of ether and acidi?ed to pH 1 withaqueous HCl solution and extracted with 5 x 100mL of ether. The combined etherwashes were dried (MgSO4) and filtered through 100g of silica gel to remove a polarimpurity using IL of ether as eluant. Removal of solvent in vacuo left 1.4g (80%yield) of 5-(3-butyne)-3,4-dihydroxy-2(5H)-furanone as an off white solid: mp 124-128 °C dec.; ‘H NMR (acetone- d6) 6 4.79 (dd, J = 3.4, 8.3 Hz, 1H) 2.42 (t, J = 2.6Hz, 1 H) 2.37-2.30 (m, 2H), 2.20-2.09 (m, 1H), 1.81-1.67 (m, 1H); “C NMR(acetone- d5) 5 170, 153.7, 119, 83.4, 74.7, 70.9, 32.4, 14.4; Anal Calcd for C3H3O4:C, 57.14; H, 4.79. Found: C, 57.04; H, 5.01.EXAMPLE I2-(2Z-Hexenyl)iodobenzeneA dry 25mL 2-necked ?ask equipped with a magnetic stir bar, argon inlet and septumwas cooled to 0°C and 3 mL of 1.0M BH3 in THF was added. Cyclohexene, 607p.L(6 mmol) was added via syringe and the suspension stirred at 0-5 °C for 35 minutes.2—Hexyny1iodobenzene5 (0.852g, 3.0 mmol) was added to the reaction mixturedropwise over a 5 minute period, the ice bath was removed and the yellow reactionmixture stirred at room temperature for 1 hour. The solution was subsequently cooledin an ice bath, and 1.4 mL (25 mmol) of glacial ACOH was added. The mixturestirred at room temperature for 1 hour, was poured into 75mL of H20, and extracted?W0 98/0771410152025CA 02264000 l999-02- 19PCT/U S97/ 1487833with 3 x 30mL of hexanes. The combined hexanes fractions were washed with 25mLof I-130, 25mL of saturated NaHCO3 solution, 25mL of H20, 2 x 20mL of brine, dried(MgSO4) and concentrated to an oil (do not warm above 30°C to avoid isomerizationof the double bond). Puri?cation over 40g of silica gel using hexanes as eluantprovided 670 mg (78%) of 2-(2Z-hexenyl)iodobenzene as a colorless oil: ‘H NMR(CDCI3) 6 7.82 (d, J = 7.8 Hz, 1H), 7.30-7.20 (m, 2H), 6.91-6.86 (m, 1H), 5.62-5.46(m, 2H), 3.47 (d, J 5 6.5 Hz, 2H), 2.17-2.10 (m, 2H), 1.49-1.37 (m, 2H), 0.94 (t, J =7.3 Hz, 3H); “C NMR (CDCI3) 5 143.8, 139.3, 131.3, 129.2, 128.3, 127.7, 126.6,100.8, 38.8, 29.6, 22.7, 13.9; Anal Calcd for C,2H,5I: C, 50.37; H, 5.28. Found: C,49.97; H, 5.24.SYNTHESIS OF COMPOUNDS OF THE INVENTIONEXAMPLE I3,4-Dihydroxy-5-methyl-5-phenyl-2(SH)-furanoneA. To a 2-necked ?ask ?ame dried under argon with septum and charged with asolution of 3.6g (20mmol) of ethyl benzoylformate in 50mL of anhydrous THF at-30°C was slowly added 7 mL (21mmol) of a 3.0 M solution of methylmagnesiumiodide. The reaction mixture was stirred at 0°C for 45 minutes, then at roomtemperature for 30 minutes and again cooled to 0°C. Benzyloxyacetyl chloride(3.4mL, 21mmol) was added and the reaction mixture was stirred at room temperaturefor 1 hour, cooled to -78°C and 33mL of a 1.5M solution of LDA in THF was addedwith rapid stirring. The mixture was worked up after 1 hour by the addition of 100mL of aqueous 10% HCI solution and 300mL of ether. The layers were separated andthe organic phase was washed with 50mL aqueous 10% HCl solution, 30mL of H20,and extracted with 3 x 40mL of saturated NaHCO3 solution. The bicarbonate extractswere combined and washed with 40mL of ether, acidi?ed to pH 1 with 10% aqueousHCI solution, and extracted with 2 x 80mL of ether. The organic fractions werecombined, washed with 25 mL of H20, 25 mL of brine, dried (MgSO4), and?WO 98/0771410152025CA 02264000 l999-02- 19PCT/U S97/ 1487834concentrated leaving 1.2g (20% yield) of 4—hydroxy-5-methyl-5-phenyl-3-phenylmethoxy-2—(5H)—furanone as a yellow oil.B. The 4-hydroxy-5-methyl-5-phenyl-3-phenylmethoxy-2-(SH)-furanone (1 .2g) wassubjected to hydrogenation over 100 mg of 5% Pd/BaSO4 in 100 mL of MeOH atroom temperature and under 30 psi H2. The reaction was monitored periodically byTLC analysis. Thesuspension was ?ltered through two #1 ?lter papers, concentratedto a white solid and recrystallized from MeOH/H20 to give 3.4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone as a white crystalline material: mp 173-175 °C dec. ‘H NMR(acetone-d6) 6 7.53-7.36 (m, 5H), 1.84 (s, 3H). Anal Calcd for C , ,H,0O4 + 0.125 H20:C, 63.38; H, 4.96. Found: C, 63.30; H, 4.96.EXAMPLE 25- [(1,1 ’-Biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanoneA. A total of 3.4mL (10.2mmol) of 3.0M methylmagnesium iodide in THF wasadded to a THF solution of 2.4g (10mmol) of ethyl 4-phenylbenzoylformate in ananalogous manner as described for the synthesis of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to give prior to hydrogenolysis, 1.1g (30% yield) of 5-[(1,1’-biphenyl)-4-yl]-3-phenylmethoxy-4-hydroxy-5-methyl-2(5H)-furanone as a whitegranular solid: m.p. 182-183°C (benzene/hexanes) ‘H NMR (CDCI3) 5 7.56-7.26 (m,14H), 5.10 (ab quartet, 2H, J = 11.4.Hz), 1.79 (s, 3H). “C NMR (CDC13) 5 168.5,163.8, 141.5, 140.3, 137.0, 136.3, 129.0, 128.8, 128.8, 128.8, 127.6, 127.2, 127.1,125.6, 119.0, 81.1, 73.5, 24.3. Anal Calcd for C24H20O4: C, 77.40; H, 5.41. Found:C, 77.99; H, 5.61.B. Hydrogenolysis of 500 mg of the 5-[(1,1’-biphenyl)-4-yl]-3-phenylmethoxy-4-hydroxy-5-methyl-2(5H)—?Jranone was performed in a similar manner as described inthe synthesis of 3,4-dihydroxy-5-methy1-5-phenyl-2(5H)-furanone to provided 240mg(63% yield) of 5-[(1,1’-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl—2(5H)-furanone as awhite powder: mp 206-212 °C dec. (MeOH/H20), ‘H NMR (acetone-d6) 5 7.69-7.33(m, 9H), 1.88 (s, 3H). “C NMR (acetone-d6) 5 169.5, 157.1, 141.6, 141.0, 139.3,?WO 98/077142025CA 02264000 l999-02- 19PCT/U S97/ 148783 5129.6, 128.3, 127.6, 127.6, 126.6, 117.9, 81.2, 24.5. Anal Calcd for c,,H,,,o,,: C,72.33; H, 5.00. Found: C, 72.07; H, 5.14.EXAMPLE 33,4-Dihydroxy-5-methy1-5-[4-(2-methy1propy1)phenyl]-2(5H)-furanoneA. A total of 3.4mL (10.2mmol) of 3.0M methylmagnesium iodide in THF wasadded to a THF solution of 2.34 g (10 mmol) of ethyl 4-isobutylbenzoylformate in ananalogous manner as described for the synthesis of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to give prior to hydrogenolysis 4-hydroxy45—methy1-5-[4—(2—methy1propy1)pheny1]-3-phenylmethoxy-2(5H)-furanone in 45% yield as a yellow oil.‘CH NMR (CDC13) 5 7.37-7.02 (m, 9H), 5.01 (s, 2H), 2.42 (d, 2H, J = 7.2 Hz), 1.86-1.77 (m, 1H), 1.72 (s, 3H), 0.87 (d, 6H, J = 6.6 Hz). “C NMR (CDC13) 5 170.0,165.1, 142.1. 136.3, 135.2, 129.2, 128.9, 128.6, 127.2, 125.0, 118.6, 81.7, 73.5, 45.0,30.2, 24.1, 22.4. Anal Calcd for C22H24O4 + 0.5 H20: C, 73.11; H, 6.97. Found: C,72.92; H, 6.87.B. Hydrogenolysis of 800mg (2.3mmo1) of 4-hydroxy-5-methyl-5-[4—(2—methylpropyl)phenyl]—3-phenylmethoxy-2(SH)-furanone was performed in a similarmanner as described in the preparation of 3,4—dihydroxy-5-methyl-5-pheny1-2(5H)-furanone to provided 500mg (84% yield) of 3,4-dihydroxy-5—methyl-5-[4-(2-methy1propy1)phenyl]-2(5H)—furanone as a light yellow crystalline material: mp 135-150°C dec. ‘H NMR (acetone-d6) ('.5.7.40—7.17 (m, 4H), 2.46 (d, 2H, J = 7.1 Hz), 1.87-1.82 (m, 1H), 1.82 (s, 3H), 0.87 (d, 6H, J = 6.6 Hz). 13c NMR (acetone-d6) 6 169.5,157.2, 142.4, 138.0, 129.8, 125.9, 117.9, 81.3, 45.3, 30.8, 24.5. 22.5. Anal Calcd forC1:-,H,8O4 + 0.25 H20: C, 67.53; H, 6.99. Found: C, 67.78; H, 7.09.EXAMPLE 45-(4-Chlorophenyl)-3,4-dihydroxy-5-methyl-2(SH)-furanoneA. A total of 3.4mL (l0.2mmol) of 3.0M methylmagnesium iodide was added to asolution of 2.34g (10mmo1) of ethyl 4-chlorobenzoylforrnate in THF in an analogousmanner as described for the synthesis of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-?W0 98I077l4102025CA 02264000 l999-02- 19PCT/US97/1487836furanone to give prior to hydrogenolysis 1.3g (40% yield) of 5-(4-chlorophenyl)-4-=hydroxy-5-methyl—3-phenylmethoxy-2(5H)-furanone as a yellow oil: ‘H NMR(CDCI3) 5 7.37-7.21 (m, 9H), 5.10 (s, 2H), 1.73 (s, 3H).B. Hydrogenolysis of 330 mg of 5-(4-chlorophenyl)-4-hydroxy-5-methyl-3-phenylmethoxy-2(5H)-furanone was performed in a similar manner as described inthe preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provided1 10mg (46% yield) of 5-(4-chlorophenyl)-3,4-dihydroxy-5-methyl-2(5H)-?iranone alight tan solid: mp 154-155 °C dec.(benzene/hexanes) ‘H NMR (acetone-d6) 6 7.52-7.34 (m, 4H), 1.82 (s, 3H). “C NMR (acetone-d6) 6 169.0, 156.6, 139.8, 134.3,129.2, 127.8, 117.9, 80.8, 24.6. Anal Calcd for C1,H9ClO4: C, 54.90; H, 3.77. Found:C, 54.74; H, 4.08.EXAMPLE 55-[(l,1’-Biphenyl)-4-yl]-3,4-dihydroxy-5-propyl-2(SH)-furanoneA. A total of 5.2mL (10.4mmol) of 2.0M n-propylmagnesium bromide was added to asolution of 2.4 g (10 mmol) of ethyl 4-phenylbenzoylformate in THF in an analogousmanner as described for the synthesis of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to give prior to hydrogenolysis 0.30g (8% yield) of 5-[(1 ,1 ’-biphenyl)-4-yl]-4-hydroxy-3-phenylmethoxy-5-propyl-2(5H)—furanone as an off white solid aftercrystallization from CHCI3 and hexanes.B. Hydrogenolysis of 250 mg of 5.-i[(1,1’-biphenyl)-4—yl]-4-hydroxy-3-phenylmethoxy-5-propyl-2(5H)-furanone was performed in a similar manner asdescribed in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5I-I)-furanone toprovided 100mg (52% yield) of a white powder: mp 203-204°Cdec.(acetone/CHCI3/hexanes). ‘H NMR (acetone-d6) 6 7.65-7.40 (m, 9H), 2.25-1.95(m, 2H), 1.45-1.10 (m, 2H), 0.95 (t, J=6.9Hz, 3H). Anal Calcd for C,9H13O4 + 0.125H30: C, 73.01; H, 5.88. Found: C, 72.99; H, 5.86.EXAMPLE 65-[(1,] ’-Biphenyl)-4-yl]-3,4-dihydroxy-5-(2-methylpropyl)-2(5H)-furanone?WO 98/0771410152025CA 02264000 l999-02- 19PCT/U S97/ 1487837A. A total of 5.2mL (10.4mmol) of 2.0M isobutylmagnesium bromide was added to asolution of 2.4 g (10 mmol) of ethyl 4-phenylbenzoylformate in THF in an analogousmanner as described for the synthesis of 3,4-dihydroxy-5-methyl-5—phenyl-2(5H)-furanone to give prior to hydrogenolysis 0.35g (8% yield) of 5-[( 1,1 ’-biphenyl)-4-yl]-4-hydroxy-3—phenylmethoxy-5-(2-methylpropyl)-2(SH)-furanone as an off white solidafter crystallization from CHCI3 and hexanes.B. Hydrogenolysis of 350mg of 5-[(1 ,1 ’-biphenyl)-4-yl]-4-hydroxy-3-phenylmethoxy-5-(2-methylpropyl)-2(5I-1)-furanone was performed in a similarmanner as described in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provide 190mg (69% yield) of a white powder: mp 198-199°Cdec.(CHCl3/hexanes). ‘H NMR (acetone-d6) 5 7.73-7.34 (m, 9H), 2.44-2.28 (m, 1H),1.50-0.80 (m, 8H). “C NMR (acetone-d6) 5 169.21, 155.47, 140.81, 139.57, 129.17,127.73, 127.18, 127.08, 126.04, 118.47, 86.01, 40.66, 23.72, 12.11, 11.87. AnalCalcd for CZOHZOO4 + 0.125 H30: C, 73.55; H, 6.25. Found: C, 73.25; H, 6.36.EXAMPLE 75-[(1 ,1 ’-Biphenyl)-4-yl]-3,4-dihydroxy—5-phenyl-2(5H)-furanoneA. A total of 3.4mL (10.2 mmol) of 3.0M phenylmagnesium bromide was added to asolution of 2.4 g (10 mmol) of ethyl 4—phenylbenzoylformate in THF in an analogousmanner as described for the synthesis of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to give prior to hydrogenolysis 0.88g (20% yield) of 5-[(1,1’-biphenyl)-4-y1]- 4-hydroxy-3-phenylmethoxy-S-phenyl-2(5H)-furanone as an off white solid: mp190-195 °C (CHCI3/hexanes).B. Hydrogenolysis of 500mg of 5-[(1,1’-bipheny1)-4-yl]- 4-hydroxy-3-phenylmethoxy-5-phenyl-2(5H)-furanone was performed in a similar manner asdescribed in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone toprovide 150mg (38% yield) of 5-[(1,1’-biphenyl)-4-yl]-3,4-dihydroxy-5-phenyl-2(5H)-furanone as colorless needles: mp 188-191 °C dec.(CHCl3/hexanes). ‘H N1\/1.151.(acetone-d6) 6 7.75-7.36 (m, 14H). “C NMR (acetone-d6) 6 168.34, 154.84, 141.50,?W0 98/0771410152530CA 02264000 l999-02- 19PCT/US97/ 1487838140.66, 140.30, 139.42,129.18, 128.74, 128.59,127.92,127.40, 127.25,127.07,119.45, 84.59. Anal Calcd for c,2H,,o,,; c, 76.73;H, 4.68. Found: C, 76.44; H,4.50.EXAMELE 83,4-Dihydroxy-5,5-diphenyl-2(5H)-furanoneA. A total of 3.5mL (l0.5mmol) of 3.0M phenylmagnesium bromide was added to asolution of 1.6mL (10 mmol) of ethyl benzoylformate in THF in an analogous manneras described for the synthesis of 3,4-dihydroxy-5-methyl-5-phenyl-2(SH)-furanone togive 5,5—diphenyl-4-hydroxy-3-phenylmethoxy-2(5H)-furanone as an oil, which waspuri?ed over S102 using acetone/hexanes (3/7).B. Hydrogenolysis of 5,5-diphenyl-4-hydroxy—3—phenylmethoxy-2(5H)-furanone wasperformed in a similar manner as described in the preparation of 3,4-dihydroxy-5-methyl-5-pheny1—2(5H)—furanone to provide 150mg (5.6% overall yield) of 3,4-dihydroxy-5,5—diphenyl-2(5H)-furanone as colorless needles: mp 192-193 °Cdec.(CHCl3/hexanes). ‘H NMR (acetone-d6) 6 7.41 (s, 10H). 13C NMR (acetone-d6)6 168.38, 154.92, 140.44, 128.72, 128.58, 127.43, 119.46, 84.74. Anal Calcd forC,6H,2O4 + 0.25 H30 C, 70.46; H, 4.62. Found: C, 70.42; H, 4.52.EXAMPLE 93,4-Dihydroxy-5-(4-isoblitylphenyl)—5—(1-propyl)-2(5H)-furanoneA. A total of 5.2mL (10.4mmol) of 2.0M 1-propylmagnesium bromide was added toa solution of 2.3g (10 mmol) of ethyl 4-isobutylbenzoylformate in THF in ananalogous manner as described for the synthesis of 3,4-dihydroxy-5—methyl-5-phenyl-2(5H)-furanone to provide 4-hydroxy-5-(4-isobutylphenyl)-3-phenylmethoxy-5-(1—propyl)-2(5H)-furanone as an oil, which was puri?ed over SiO2 using acetone/hexanes(1/4).B. Hydrogenolysis of 4-hydroxy-5-(4-isobutylphenyl)-3-phenylmethoxy-5-(1-propyl)-2(5H)-furanone was performed in a similar manner as described in thepreparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provide 2000113;?W0 98/0771410152025CA 02264000 l999-02- 19PCT/US97/1487839(6.9% yield) of 3,4-dihydroxy-5-(4—isobutylpheny1)-5-(1-propyl)-2(5H)-furanone asan oil, which was puri?ed by preparative TLC using hexanes/acetone/acetic acid(70/29/1) as eluant: ‘H NMR (acetone-d6) 5 7.48-7.13 (m, 4H), 2.47 (d, J = 10.3112,2H), 2.10-1.66 (m, 1H), 1.29-0.85 (m, 13H). “C NMR (acetone-d6) 5 169.20, 155.54,141.58, 137.91, 129.24, 125.32, 118.25, 83.37, 45.02, 39.60, 30.26, 22.03, 16.84,13.63. Anal Calcd for CWHZZO4: C, 70.32; H, 7.64. Found: C, 70.01; H, 7.61.PL 103,4-Dihydroxy-5-(4-isobutylphenyl)-5-phenyl-2(SH)-furanoneA. A total of 3.5mL (10.5mmo1) of 3.0M phenylmagnesium bromide was added to asolution of 2.3g (10 mmol) of ethyl 4-isobutylbenzoylformate in THF in an analogousmanner as described for the synthesis of 3,4-dihydroxy-5-methyl-5-phenyl—2(5H)-furanone to provide an oil, which was puri?ed over 400g of SiO2 by eluting with500mL of CHCl3, 500mL of EtOH/CHCI, (3/97) and 500mL of EtOH/CHCl3 (8/92)to provide 1.2g (29% yield) of 4-hydroxy-5-(4-isobutylphenyl)-5-phenyl-3—phenylmethoxy-2(SH)-furanone as a tan powder recrystallized from CHC13 andhexanes.B. Hydrogenolysis of 500mg (1.2mmol) of 4-hydroxy-5-(4-isobutylphenyl)-5-phenyl-3-phenylmethoxy-2(5H)-furanone was performed in a similar manner asdescribed in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone toprovide 200mg (51% yield) of 3,4-idihydroxy-5-(4-isobutylphenyl)-5-phenyl-2(5H)-furanone as a white powder: mp 138-139 °C (CHCl3/hexanes). ‘H NMR (acetone-d6)5 7.40-7.15 (m, 9H), 2.49 (cl, .1 = 7.lHz, 2H), 1.94-1.74 (m, 1H), 0.89 (d, J = 6.5 Hz,6H). Anal Calcd for CZOHZOO4: C, 74.1; 1-1, 6.2. Found: C, 73.7; H, 6.3.EXAMBQH(S)-(+)-5-[(1,1’-Biphenyl)-4-yl]-3,4-dihydroxy-5-methyl—2(5H)-furanoneA. To a ?ame dried 500mL ?ask ?ushed with N2, was added 24g (100mmol) of ethyl4-phenylbenzoylformate and 300mL of anhydrous THF. The solution was cooledwith stirring to -25 °C and 37mL (110mmol) of a 3.0M solution of methylmagnesia. ?10152025W0 98/07714CA 02264000 l999-02- 19PCT/US97/1487840iodide was added at a rate to maintain the reaction temperature below -10°C. Thereaction progress was monitored by TLC and upon disappearance of starting material,100mL of saturated NH4Cl solution and 200mL of ether were added. The organiclayer was separated and washed with 2 x 50mL of brine, dried (MgSO4) andconcentrated leaving racemic ethyl 2-[(l,1’-biphenyl)-4-yl]-2—hydroxypropionate asan oil.B. The crude ethyl ‘2-[(1,1 ’-biphenyl)-4-yl]:2-hydroxypropionate was saponi?ed bytreating with 100mL of ethanol and 100mL of 4.0M NaOH solution. The suspensionwas stirred for 3 hours, after which a clear solution formed The solution wasconcentrated, diluted with 150mL of H20, washed with 2 x 50mL of ether, andacidi?ed to pH 1 with 10% HCI solution. The aqueous phase was extracted with 3 x100mL portions of ether and the combined ether extracts were washed with 50mL ofH20, 50mL of brine, dried (MgSO4) and concentrated leaving 18.3 g (72% yield) ofracemic 2-[(1 ,1 ’-biphenyl)-4-yl]-2-hydroxypropionic acid as a white solid after wasrecrystallization from CHCI3 and hexanes.C. Racemic 2-[(1,l ’-biphenyl)-4-yl]-2-hydroxypropionic acid l2.lg (50mmol) wasresolved by dissolving in 225mL of a 2:221 mixture of isopropanolzbenzenezhexanes.The solution was warmed to re?ux and 6.9g (50mmol) of (R)-(-)-phenylglycinol wasadded in one portion. The mixture was allowed to cool slowly over 15 hours duringwhich white crystals formed, which were isolated by ?ltration and washed withseveral small portions of isopropanol. The isolated white solid was recrystallized fouradditional times from isopropanol until a constant melting point of 189.5-191°C wasobserved, leaving 4.3g (45.3% yield for the resolution) of diastereomerically pure (S)-(+)-2-[(1,] ’-biphenyl)-4—yl]-2—hydroxypropionate (R)-(-)-phenylglycinol salt.D. Diastereomerically pure (S)-(+)—2-[(1,1’-biphenyl)-4-yl]-2-hydroxypropionate (R)-(-)-phenylglycinol salt (1 .9g, Smmol) was added to a separatory funnel containing70mL of 15% aqueous HCl solution and 150mL of ether. The suspension was shakenuntil completely solvated, and the aqueous layer was separated. The ether portion was?l0152025WO 98/07714CA 02264000 l999-02- 19PCT/U S97/ 148784 lwashed with 2 x 50mL of 15% aqueous HCI solution, 50mL of H20, 50mL of brine,dried (MgSO4) and ?ltered into a 500mL ?ask. The ether solution was cooled in anice bath and a freshly prepared etheral solution of diazomethane was added withstirring until the yellow color of the reagent persisted. The solution was concentratedleaving 1.3g (99%) of methyl (S)-(+)-2-[(1,1’-biphenyl)-4-yl]-2-hydroxypropionate asa white crystalline material.E. In a dry ?ask under argon, were mixed 1.3g (5mmol) of methyl (S)-(+)-2-[(1,l ’-biphenyl)-4-yl]-2-hydroxypropionate, 1.7mL (10mmol) of 95% benzyloxyacetylchloride and 6.1mL of pyridine. The reaction stirred for 48 hours and was quenchedby pouring into lO0mL of 10% aqueous HCl and 200mL of ether. The ether fractionwas separated and washed with 50mL of 10% aqueous HCl, 50mL of H20, 2 x 50mLof NaHCO3 solution, 50mL of H20, 50mL of brine, dried (MgSO4) and concentrated.The product was purified over 250g of SiO2 using initially EtOAc/hexanes (1/9)followed by EtOAc/hexanes ( 1.5/8.5) as eluant to yield 1.5g (80% yield) of methyl(S)-(+)-2-[(1 ,1 ’-biphenyl)-4—yl]—2-(2—phenylmethoxyacetoyl)oxypropionate.F. (S)-(+)-2-[(1 ,1 ’-Biphenyl)-4-y1]-2-(2-phenylmethoxyacetoyl)oxypropionate (1 .5 g,4mmol) was dissolved in l0mL of anhydrous THF and added to 33mL of a 0.3Msolution of LiHMDA in THF at —78°C. The light yellow solution stirred for 45minutes and was quenched by the addition of 30mL of 10% aqueous HCl solution.The mixture was taken into 200mL of ether and washed with 30mL of 10% aqueousHCI solution, 30mL of H20, 30mL of brine, dried (MgSO4) and concentrated. Theresultant oil was taken up in 50mL of ether and extracted with 4 x 30mL of saturatedNaHCO3 solution. The combined NaHCO3 fractions were washed with 25mL ofether, acidi?ed to pH below 1 with 10% aqueous HCl solution and extracted with 2 x100mL of ether. The combined ether extracts were washed with 25mL of H20, 25mLof brine, dried (MgSO,,) and concentrated to give (S)-(+)—5—[(1,l’-biphenyl)-4-yl]-4~hydroxy-5-methyl-3-phenylmethoxy-2(SH)-furanone.?10152025W0 98/07714CA 02264000 l999-02- 1942 PCT/US97/14878G. The (S)-(+)-5-[(1 ,1 ’—biphenyl)-4-yl]-4-hydroxy-5-methyl-3-phenylmethoxy-2(5H)-furanone was subjected to hydrogenation over 100 mg of 5% Pd/BaSO4 inl00mL of MeOH at room temperature under 30 psi of H2. The reaction wasmonitored periodically by TLC analysis. Upon reaction completion, the suspensionwas ?ltered through two #1 ?lter papers, concentrated and recrystallized from CHCI3and hexanes to provide 300mg (20% overall yield from methyl (S)-(+)-2—[(l,l ’-biphenyl)-4-yl]-2-lrydroxypropionate) of (S)-(+)-5—[( l , 1 ’-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone as a light weight white crystalline material: mp204-206°C dec.; [(Z]25D + 121° (c=0.66; MeOH); ‘H NMR (acetone-d6) 6 7.72-7.41(m, 9H), 1.89 (s, 3H). Anal Calcd for C17}-1,404 + 0.75 H20: C, 69.03; H, 5.28.Found: C, 68.69; H, 4.95.EXAMPLE 12(R)-(-)-5-[(1,1’-Biphenyl)-4-yl]-3,4-dihydroxy-5-methyl—2(5H)-furanoneA. The combined ?ltrates from the resolution of racemic 2-[(1 ,1 ’-biphenyl)-4—yl]-2-hydroxypropionic acid with (R)-(-)-phenylglycinol (example I 1, section C) wereconcentrated to a thick brown paste and partitioned between 100mL of 20% HCIsolution and 400mL of ether. The aqueous phase was separated and the ether layerwas subsequently washed with 4 x 30mL of 20% HCl solution, 50mL of brine, dried(MgSO4) and concentrated. A total of 8.5g (35mmol) of 2-[(l,l’-biphenyl)-4—yl]-2-hydroxypropionic acid was recovered and dissolved in 300mL of isopropanol bywarming to re?ux and 4.5g (35mmol) of (S)—(+)—phenylglycinol was added. Thediastereomeric salts were allowed to crystallize at 25 °C over a period of 72 hours andisolated by ?ltration and washed with 2 x 40mL of isopropanol to provide 6.7g oflight brown crystals. Two subsequent recrystallizations from isopropanol provided3.6g of the diastereomerically pure salt of (R)—(-)— 2-[(1,l ’-biphenyl)-4—yl]-2-hydroxypropionic acid with (S)-(+)-phenylglycinol.B. (R)-(-)-5-[(1 ,1 ’-Biphenyl)—4-yl]-3,4—dihydroxy-5-methyl—2(5H)-furanone wasprepared in an analogous manner as described for (S)-(+)-5-[(l,l’-biphenyl)-4-yl]=-3,4-?WO 98/077141015202530CA 02264000 l999-02- 1943 PC T/U S97/ 14878dihydroxy-5-methyl-2(5H)-furanone starting with 1.9g (5.0mmol) of thediastereomerically pure salt of (R)—(-)- 2-[(1,1’-biphenyl)-4-yl]-2-hydroxypropionicacid and (S)-(+)-phenylglycinol to provide 280mg ( 19% yield) of (R)-(-)-5-[(1,1 ’-biphenyl)-4-yl]-3,4-dihydroxy-5-methy1—2(5H)-furanone as a white crystallinematerial: mp 197-199 °C dec. (CHCI3/hexanes); [oa]25D -182° (c=1.42; MeOH); ‘HNMR (acetone-d6) 5 7.65-7.41 (m, 9H), 1.89 (s, 3H). Anal Calcd for C,7H,4O4 + 0.25H20: C, 71.20; I-I,*5.10. Found: C, 71.19; H, 4.74.EXAMPLE 1;(R)-(-)-3,4-Dihydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone(R)-(-)-3,4—Dihydroxy-5-methyl—5-[4-(2-methy1propyl)phenyl]—2(5H)-fu.ranone wassynthesized in an analogous manner used for the production of (S)-(+)-5-[(1 ,1 ’-biphenyl)-4-yl]—3,4-dihydroxy—5—methyl-2(5H)—furanone starting with ethyl 4-isobutylbenzoylformate. (R)-(-)-Phenylglycinol was used to resolve the methyl (R)—(-)-2-(4-isobutylphenyl)propionate enantiomer, of which 1.2g, (5mmol) was convertedinto 190mg (15% yield) of (R)-(-)-3,4-dihydroxy-5-methy1-5-[4-(2-methylpropyl)phenyl]—2(SH)-furanone as a white crystalline material: mp 180-181 °Cdec. (CHCI3/hexanes); [ot]25D —137° (c=1.27; MeOH); ‘H NMR (acetone-d6) 5 7.44-7.14 (m, 4H), 2.48 (d, 2H, J = 7.1 Hz), 1.87-1.82 (m, 1H), 1.83 (s, 3H), 0.88 (d, 6H, J= 6.5 Hz). Anal Calcd for C,5H,3O4: C, 68.68; H, 6.92. Found: C, 68.52; H, 7.01.EXAMPLE 14(S)-(+)-3,4-Dihydroxy-5-methyl—5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone(.S')-(+)-3,4-Dihydroxy-5-methyl-5-[4-(2-methylpropy1)phenyl]-2(5H)—furanone wassynthesized in an analogous manner used for the production of (R)-(-)-5-[(1,] ’-bipheny1)—4-yl]-3,4-dihydroxy—5-methyl—2(5H)-furanone starting with ethyl 4-isobutylbenzoylformate. (S)-(+)-Phenylglycinol was used to resolve the methyl (8)-(+)-2-(4-isobutylphenyl)propionate enantiorner, of which 1.2g (5mmo1) was convertedinto 250mg (19% yield) of (S)-(+)-3,4-dihydroxy-5-methyl-5-[4—(2-methy1propyl)phenyl]-2(5H)-furanone as a white crystalline material: mp 175-177°C?10152025W0 9s/07714 44CA 02264000 l999-02- 19PCT/U S9 7/ l 4878dec. (CHCI3/hexanes); [oc]25D +132° (c=1.55; MeOH) ‘H NMR (acetone-d6) 6 7.44-7.14 (m, 4H), 2.48 (d, 2H, J = 7.1 Hz), 1.87-1.82 (m, 1H), 1.83 (s, 3H), 0.88 (d, 6H, J= 6.5 Hz). Anal Calcd for C,5H1304: C, 68.68; H, 6.92. Found: C, 68.08; H, 6.90.EX L 153,4-Dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanoneA. A mixture consisting of 340mg (1 .0mmo1) of 3,4-dibenzyloxy-5-(2—hydroxyethyl)-2(5H)-furanone, 320mg (1 .3mmo1) of triphenylphosphine and 225mg (1.2mmol) of 4-phenoxyphenol was dissolved in 8mL of anhydrous THF under argon. Diisopropylazodicarboxylate (276uL 1.4mmol) was added to the solution dropwise with stirringat 25°C. After 36 hours the reaction mixture was poured into 30mL of H20 andextracted with two 30mL portions of ether. The combined ether fractions werewashed with 25mL of saturated NaHC03 solution, 25mL of H20, 25mL of aqueous10% HCI solution, 25mL of H20, 25mL of brine, dried (MgS0.,) and concentrated toan oil. The product was puri?ed over silica gel using Et0Ac/hexanes (2/3) as eluantto provide 3,4-dibenzyloxy-5-[2-(4-phenoxy)phenoxyethy1]-2(5H)-furanone as an oil.B. The 3,4-dibenzyloxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone washydrogenated in 50mL of MeOH over 50mg of 5% Pd/BaS0., under 30psi H3. Aftercompletion of the reaction, as determined by TLC analysis, the suspension was?ltered through celite, washed with"three 10mL portions of MeOH and concentratedto a white solid. Trituration with ether and hexanes provided 150mg (44% yield) of3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl}-2(SH)-furanone as a white powder: mp125-127 °C, 'H NMR (acetone-d6) 6 7.42-7.28 (m, 2H), 7.12-6.88 (m, 7H), 4.95 (dd,1H), 4.17 (q,,,, 2H), 2.55-2.36 (m, 1H), 2.05-1.87 (m, 1H); ”C NMR (acetone-d5) 6169.41, 158.91, 155.57, 153.39, 150.61, 129.98, 122.73, 120.94, 117.71, 116.32,115.99, 72.43, 63.97, 32.43; Anal Calcd for C,3H,606 + 0.5 H20; C, 64.12; H, 5.04:Found C, 64.28; H, 5.04.?W0 98/0771410152025CA 02264000 l999-02- 194 5 PCT/U S97/ 14878EXAMELEJQ3,4-Dihydroxy-5-[2-(?avone-6-oxy)ethyl]-2(SH)-furanoneMitsunoble coupling of 0.33 g (1.4mmo1) of 6—hydroxy?avone with 0.40g (1 .17mmo1)of 3,4—dibenzy1oxy-5-(2-hydroxyethyl)-2(5H)-?iranone and subsequent benzyl groupdeprotection by hydrogenation were performed in a similar manner as described in thesynthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)—furanone to provide3,4-dihydroxy-5-[2‘-(?avone-6-oxy)ethyl]-2(5H)-furanone as a tan solid: mp 200-220°C dec. (acetone/hexanes), ‘H NMR (DMSO-d,,) <3 8.13-7.36 (m, 8H), 7.01 (s,1H), 4.92 (dd, 1H), 4.17 (t, 2H), 2.47-2.27 (m, 1H), 1.98-1--.85 (m, 111). “C NMR(DMSO-d6) 6 177.23, 170.22, 162.71, 156.02, 155.36, 150.80, 132.06, 131.51,129.42, 126.59, 124.31, 123.85, 120.49, 117.44, 106.43, 105.85, 72.24, 64.20, 31.71.Anal Calcd for C2,H,6O7 + 0.25 H20: C, 65.55; H, 4.44. Found: C, 65.59; H, 4.49.EXAMPLE 175-[2-(Dibenzofuran-2-oxy)ethy1]-3,4-dihydroxy-2(5H)-furanoneMitsunoble coupling of 0.22g (1 .2mmol) of 2-hydroxydibenzofuran with 0.34g(1 .Ommo1) of 3,4-dibenzyloxy—5-(2-hydroxyethyl)-2(5H)-furanone and subsequentbenzyl group deprotection by hydrogenation were performed in a similar manner asdescribed in the synthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethy1]-2(5H)-furanone to provide 40 mg (10% yield) of 5-[2—(dibenzofuran-2-oxy)ethyl]—3,4-dihydroxy-2(5H)-furanone a white's'olid.: mp 191-192°C (ether/hexanes), ‘H NMR(acetone-d6) 5 8.23-8.18 (m, 1H), 7.83-7.44 (m, 5H), 7.28-7.23 (m, 1H), 5.12 (dd,J=5.3, 8.7Hz, 1H), 4.42 (dd, J=2.6, 4.7Hz, 2H), 2.69-2.59 (m, 1H), 2.21-2.08 (m, 1H).”C NMR (acetone-d6) 6 169.68, 157.31, 155.75, 153.70, 151.31, 127.76, 125.05,124.83, 123.07, 121.34, 118.46, 116.42, 112.39, 111.90, 105.40, 72.72, 64.57, 32.64.Ana1Ca1cd for C,3H,4O6 + 0.25 H20: C, 65.36; H, 4.57. Found: C, 65.52; H, 4.23. -...?10152025WO 98/07714CA 02264000 l999-02- 1946 PCT/US97/14878MPL 183,4-Dihydroxy-5-[2-(1-naphthoxy)ethyl]-2(5H)-furanoneMitsunoble coupling of O.17g (1.2mmol) of l-naphthol with 0.34g (1 .0mmol) of 3,4-dibenzy1oxy-5-(2-hydroxyethyl)-2(SH)-?iranone and subsequent benzyl groupdeprotection by hydrogenation were performed in a similar manner as described in thesynthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5I-I)-furanone to provide75mg (26% yield) of 3,4-dihydroxy-5-[2-(1-naphthoxy)ethyl]-2(5H)-furanone ascolorless cubes: mp 163-164°C (ether/hexanes) ‘H NMR (acetone-d6) 5 8.38-8.25 (m,1H), 7.92-7.79 (m, 1H), 7.60-7.34 (m, 4H), 7.05-6.93 (m, 1H), 5.1 1 (dd, J=5.3, 8.7Hz,1H), 4.39 (dd, J=2.6, 4.7Hz, 2H), 2.75-2.52 (m, 1H), 2.25-2.05 (m, IH). ”C NMR("acetone-d6) 5 169.62, 154.92, 153.61, 135.13, 127.83, 126.78, 126.50, 125.92,125.05, 122.41, 120.66, 118.53, 105.28, 72.85, 63.93, 32.58. Anal Calcd for CMHHO5:C, 67.11; H. 4.89. Found: C, 66.70; H, 4.88.EXAMPLE 193,4-Dihydroxy-5-[2-(1,8-naphthalimide)-N-ethyl]-2(5H)-furanoneMitsunoble coupling of O.24g (1 .2mmol) of 1,8—naphthalimide with 0.34g (1 .0mmol)of 3,4-dibenzyloxy-5—(2-hydroxyethyl)-2(SH)-?iranone and subsequent benzyl groupdeprotection by hydrogenation were performed in a similar manner as described in thesynthesis of 3,4-dihydroxy-5-[2-(4—phenoxy)phenoxyethy1]-2(5H)-furanone to provide150mg (45% yield) of 3,4-dihydro)'<'y-5-[2-(1,8-naphthalimide)-N-ethyl]-2(5H)-furanone as a white powder: mp 235-250°C dec. (acetone/hexanes), ‘H NMR(DMSO-d6) 5 8.62-8.35 (m, 4H), 7.92-7.82 (m, 2H), 4.82 (dd, J=5.3, 8.7Hz, 1H), 4.19(t, J=4.2Hz, 2H), 2.32-2.16 (m, 1H), 1.90-1.75 (m, 1H). “C NMR (DMSO-d6) 5170.29, 163.72, 154.91, 134.56, 131.52, 130.96, 127.60, 127.45, 122.29, 117.46,73.64, 36.03, 30.58. Anal Calcd for C,,,H,3NO6: C, 63.71; H, 3.86; N, 4.12. Found:C, 63.84; H, 3.83; N, 4.00.?WO 98/0771410152025CA 02264000 l999-02- 1947 PCT/U S97/ 14878_E_}_(.AMRLE2Q3,4—Dihydroxy-5-[2-(1,8-naphthosultam)-N-ethyl]-2(5H)-furanoneMitsunoble coupling of 0.28g (1.3mmol) of 1,8-naphthosultam with O.37g (1.1mmol)of 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5I-1)-furanone and subsequent benzyl groupdeprotection by hydrogenation were performed in a similar manner as described in thesynthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethy1]-2(5H)-furanone to provide100mg (29% yield) of 3,4-dihydroxy-5-[2-(1,8-naphthosultam)-N-ethyl]-2(5H)-furanone as a light yellow powder: mp 85-95 °C dec. (acetone/hexanes), ‘H NMR(acetone-d6) 6 8.29-7.55 (m, 5H), 7.12-7.01 (m, 1H), 4.97 (dd, J=4.9, 8.7Hz, 1H), 4.10(t, J=4.2Hz, 2H), 2.72-2.50 (m, 1H), 2.18-1.95 (m, 1H). “C NMR (acetone-d6) 6169.28, 152.93, 136.42, 131.65, 131.10, 130.84, 130.00, 128.82, 120.03, 119.10,118.60, 118.42, 103.71, 73.01, 37.72, 31.45. Anal Calcd for C,6H,3NO(,S + IHZO: C,52.60; H, 4.14; N, 3.83. Found: C, 52.62; H, 3.86; N, 3.56.E AM 213,4-Dihydroxy-5-[2-(diphenylmethane-2-oxy)ethyl]-2(5H)-furanoneMitsunoble coupling of 0.28g (1 .3mmol) of 2-hydroxy diphenylmethane with O.37g(1.1mmo1) of 3,4-dibenzyloxy-5-(2-hydroxyethy1)-2(5H)-furanone and subsequentbenzyl group deprotection by hydrogenation were performed in a similar manner asdescribed in the synthesis of 3,4—dihydroxy—5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone to provide 140mg (43% yield) of 3,4-dihydroxy-5-[2-(diphenylmethane-2-oxy)ethyl]-2(5H)-furanone as a white powder, which was puri?ed by trituration withether and hexanes: ‘H NMR (acetone-d6) 5 7.33-6.82 (m, 9H), 4.78 (dd, J=5.3, 8.7Hz,1H), 4.19 (dd, J=2.6, 4.7Hz, 2H), 3.96 (s, 2H); 2.57-2.36 (m, 1H), 2.10-1.82 (m, 1H).AnalCa1cd for C,9H,gO5: C, 69.9; H, 5.6. Found: C, 69.75; H, 5.52.EXAMPLE 225-[2-((1,1’-Biphenyl)-4-oxy)ethyl]-3,4-dihydroxy-2(5H)-furanoneMitsunoble coupling of 0.20g (1 .2mmol) of 4-hydroxy-1,1 ’-biphenyl with 0.34g(1 .0mmol) of 3,4-dibenzy1oxy-5-(2—hydroxyethyl)-2(5H)-furanone and subsequent?10152025WO 98107714CA 02264000 l999-02- 19T S97/1487848 PC /Ubenzyl group deprotection by hydrogenation were performed in a similar manner asdescribed in the synthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone to provide 100mg (32% yield) of 5-[2-(( 1,1 ’-biphenyl)-4-oxy)ethyl]-3,4-dihydroxy-2(5H)-furanone as a white powder after trituration with ether and hexanes:‘H NMR (acetone-d6) 5 7.71-7.02 (m, 9H), 4.97 (dd, J=4.9, 8.7Hz, 1H), 4.25 (dd,J=2.6, 4.7Hz, 2H), 2.58-2.41 (m, 1H), 2.10-1.92 (m, 1H). Anal Calcd for C,8H,6O5 +IHZO: C, 67.49; H, 5.66. Found: C, 67.34; H, 5.42.EXAMPLE 233,4-Dihydroxy-5-[2-(quinoline-2-oxy)ethyl]-2(5H)-furanoneMitsunoble coupling of 0. 1 7g (1 .2mmol) of 2-hydroxyquinoline with 0.34g(l.Ommol) of 3,4-dibenzy1oxy-5-(2-hydroxyethyl)-2(51-1)-furanone and subsequentbenzyl group deprotection by hydrogenation were performed in a similar manner asdescribed in the synthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone to provide 50mg (17% yield) of 3,4-dihydroxy-5-[2-(quinoline—2-oxy)ethyl]-2(5H)-furanone as a ?uffy white solid after recrystallization from ether and hexanes:‘H NMR (acetone-d6) 5 8.25-8.17 (m, 1H); 7.88-7.38 (m, 4H), 7.01-6.93 (m, 1H);4.97 (dd, J=4.9,i 8.7Hz, 1H), 4.81-4.55 (m, 2H); 2.62-2.45 (m, 1H), 2.20-1.95 (m, IH).Anal Calcd for C1,H,3NO5 + 0.5H2O: C, 60.81; H, 5.10; N, 4.72. Found: C, 61.04; H,5.04; N, 4.32.EXAMPLE 243,4-Dihydroxy-5-[2—(4,5-diphenyl-1,3-isoxazole—2-thio)ethyl]-2(5H)-furanoneA suspension of 3. 14g (l2.4mmol) 4,5-diphenyl-2-thio-1,3-isoxazole in 12mL of THFunder argon with stirring at -78°C was treated with 4.9mL (12.2mmol) of 2.5MnBuLi. The reaction mixture was warmed to -5 °C and 1.1 g (4mmol) of 3,4-dihydroxy-5-(2-iodoethyl)-2(5H)-furanone dissolved in 12mL of HMPA was added ata rate to maintain the reaction temperature below 0 °C. Stirring continued at 0 to -5 °Cfor 60 minutes followed by the addition of 100mL of saturated NH4Cl solution. Themixture was extracted with 2 x 100 mL portions of ether/EtOAc (1/1). The organic?W0 98/07714102025CA 02264000 l999-02- 19PCT/US97/1487849fractions were combined and extracted with 3 x 50 mL of saturated NaHCO3 solution.The bicarbonate extracts were combined, washed with 2 x 50mL of ether, acidi?ed topH 1 with 10% HCl solution and extracted into 2 x 100mL portions of ether. Theether extracts were combined and washed successively with 40mL of H30, 40mL ofbrine, dried (MgSO4) and concentrated to an oil.Puri?cation over SiO2 using acetone/hexanes (1 :1 to 2:3 to 7:3) provided abrown colored solid upon evaporation of solvent. The solid was taken up in 100mL ofether and extracted with 3 x 50mL of NaHCO3 solution. The combined aqueousextracts were acidi?ed with 10% HCI solution and extracted with 2 x 100mL portionsof ether. The organic portions were washed with 40mL of H20, 40mL of brine, dried(MgSO,,) and concentrated to provide 875mg (55% yield) of 3,4-dihydroxy-5-[2-(4,5-diphenyl-1,3-isoxazole-2—thio)ethyl]-2(5H)-furanone as a white foam: mp 88-91 °C,‘H NMR (acetone-d6) 6 7.67-7.39 (m, 10H), 4.95 (dd, J=3.7, 8.7Hz, 1H), 3.61-3.28(m, 2H), 2.72-2.19 (in, 2H). “C NMR (acetone-d,,) 6 169.17, 159.13, 152.70, 147.65,136.83, 132.60, 129.14 (2C), 128.85 (2C), 128.61, 128.11, 126.92, 118.91, 74.25,32.69, 27.32. Anal Calcd for C2,H,7NO5S + 0.25 H20: C, 63.07; H, 4.41; N, 3.50.Found: C, 63.23; H, 4.70; N, 3.24.EXAMP1 ,E 253,4-Dihydroxy-5-[2-(naphthyl-1-thio)ethy1]-2(5H)-furanone1-Naphthalenethiol (430uL, 3.1mrnol) and 0.27g (lmmol) of 3,4-dihydroxy-5-(2-iodoethyl)-2(5H)-furanone were reacted in an analogous manner as described for thesynthesis of 3,4-dihydroxy-5-[2-(4,5-diphenyl-1,3-isoxazole-2-thio)ethyl]-2(5H)-furanone to provide 90mg (30% yield) of 3,4-dihydroxy-5-[2-(naphthyl-1-thio)ethyl]-2(5H)-furanone as a colorless oil. Additional purification by chromatography overSiO2 was not necessary for this compound: ‘H NMR (acetone-d6) 5 8.44-8.32 (m, 1H),7.98-7.43 (m, 6H), 4.92 (dd, J=3.7, 8.7Hz, 1H), 3.28-3.06 (m, 2H), 2.39-2.19 (m, 1H),2.02-1.84 (m, 1H). Anal Calcd for C,6H,4O4S + 0.25 H20: C, 62.63; H, 4.76. Found:C, 63.06; H, 5.19.?10152025WO 98/07714 5 0CA 02264000 l999-02- 19PCT/US97/14878MP 63,4-Dihydroxy-5-[2-(naphthyl-2-thio)ethyl]-2(5H)-furanone2-Naphthalenethiol (430uL, 3. lmmol) and 0.27g ( lmmol) of 3,4-dihydroxy-5-(2-iodoethyl)-2(5H)-furanone were reacted in an analogous manner as described for thesynthesis of 3,4-dihydroxy-5-[2-(4,5—diphenyl-1,3-isoxazole-2-thio)ethyl]-2(5H)-furanone to provide 140mg (46% yield) of 3,4-dihydroxy-5-[2-(naphthyl-2-thio)ethyl]-2(5H)-furanone as a white powder after trituration with ether and hexanes.Additional puri?cation by chromatography over SiO3 was not necessary for thiscompound: ‘H NMR (acetone-d6) 5 7.95-7.82 (m, 4H), 7.58-7.40 (m, 3H), 4.92 (dd,J=3.7, 8.7Hz, 1H), 3.34-3.08 (m, 2H), 2.42-2.21 (m, 1H), 2.02-1.86 (m, IH). “CNMR (acetone-d6) 5 169.53, 153.03, 134.48, 134.09, 132.29, 128.99, 128.13, 127.49,127.41, 127.08, 126.65, 126.14, 118.68, 74.25, 32.33, 27.81. Anal Calcd forC,(,H,4O4S: C, 63.56; H, 4.67. Found: C, 63.44; H, 4.58.EXAMPLE 273,4-Dihydroxy-5-[(4-phenyl)-3-butynyl]-2(5H)-furanoneTo a ?ame dried reaction ?ask ?tted with an argon inlet, septum and magnetic stirbar, were added 58mg (0.05mmol) of Pd(PPh3)4, 225 uL (2.0 mmol) of iodobenzene,0.17g (1.0mmol) of 5-(3-butynyl)-3,4-dihydroxy-2(5H)-furanone, 2 mL of pyrrolidineand 20mg (0.10mmol) of copper (I) iodide. The ?ask was protected from light (foil)and the yellow mixture was stirred at room temperature until the starting 5-(3-butynyl)-3,4-dihydroxy-2(SH)-?rranone was not visible by TLC analysis(CHCl3:MeOH 9:1). The reaction mixture was poured into a mixture of 50g of iceand 10mL of 37% HCl, and extracted with 2 x 50mL of ether. The ether extracts werecombined and washed with 2 x 20mL of 10% aqueous HC1 solution, 20mL of H20,20mL of brine, dried (MgSO4) and concentrated.The residue was dissolved in 30mL of ether and extracted with 3 x 15mL of saturatedNaHCO3 solution. The bicarbonate extracts were pooled and washed with 10mL ofether, acidi?ed to pH 2 with 10% HCI solution and extracted with 2 x 25mL of ether.?10152025WO 98/07714CA 02264000 l999-02- 195 1 PCT/US97/ 14878The ether extracts were combined and washed with 10mL of H20, 3mL of 10%(w/w) Nal-ICO3 solution, 10mL of H20, 10mL of brine, dried (MgSO_,) andconcentrated to provide 3,4-dihydroxy-5-[(4-phenyl)-3-butynyl]-2(5H)-?iranone as awhite solid: mp 145-146°C; 'H NMR (acetone-d6) 6 7.35-7.15 (In, SH) 4.75 (dd,J=3.4, 8.2 Hz, 1H), 2.50-2.40 (m, 2H), 2.20-2.05 (m, 111), 1.75-1.60 (m, 1H); ‘3cNMR (acetone-d6) 6 170.2, 153.8, 132.3, 129.2, 128.7, 124.6, 119.0, 89.3, 82.1, 74.9,32.4, 15.3.EXAMELE 283,4-Dihydroxy-5-[(4-(2-methyl)phenyI)-3-butynyl]-2(5H)-furanone5-(3—Butynyl)-3,4-dihydroxy-2(5H)-furanone (O.17g, l.Ommol) and 256p.L (2.0mmol) of 2-iodotoluene were coupled in an analogous fashion as described for thesynthesis of 3,4-dihydroxy-5-[(4-phenyl)—3-butynyl]-2(5H)-furanone. The residuewas puri?ed over silica gel using CHCI3/MeOI-I (96/4) as eluant to provide 3,4-dihydroxy-5-[(4-(2-methyl)phenyl)-3-butynyl]-2(5H)-furanone as a light yellow solid:mp 111~112°C, ‘H NMR (CDC13) 5 7.37-7.07 (m, 4H), 5.01 (dd, J=3.5, 8.5 Hz, 1H),2.69-2.65 (m, 2H), 2.40 (s, 3H), 2.39-2.27 (m, 111), 1.97-1.86 (m, 1H); “C NMR(CDC13) 5 173.6, 155.8,140.0, 131.9,129.3. 127.9.125.5,123.1. 117.5, 91.5, 80.9,76.4, 31.3, 20.7, 15.3; Anal Calcd for C,5H,.,O,: C, 69.76; H, 5.46. Found: C. 69.41;H, 5.58.EXAMPLE 293,4-Dihydroxy-5-[(4-(2-(2Z-hexenyl))phenyl)-3-butynyl]-2(SH)-furanone5-(3-Butynyl)-3,4-dihydroxy-2(5H)-furanone (0.34g, 2.0mmol) and 1.1g (4.0 mmol)of 2-(2Z-hexenyl)iodobenzene were coupled in an analogous fashion as described forthe synthesis of 3,4-dihydroxy-5-[(4-phenyl)-3—butyny1]-2(5H)-furanone. The residuewas puri?ed over silica gel using CHCI3/MeOH (96/4) as eluant and dried at 0.05 mmHg at 58 °C for 2h to provide 100 mg (17% yield) of 3,4—dihydroxy-5-[(4-(2-(2Z-hexeny1))phenyl)-3-butynyl]-2(5H)-furanone as a yellow oil: ‘H NMR (acetone-d6) 67.43-7.15 (m, 4H), 5.70-5.45 (m, 2H), 4.91 (dd, 1H, J = 3.4, 8.3 Hz), 3.57 (d, 2H, J =?2025WO 98/07714CA 02264000 l999-02- 1952 PCT/US97/148785.9 Hz), 2.66 (t, 2H, J = 7.0 Hz), 2.37-2.11 (m, 3H), 2.00-1.85 (m, 1H), 1.48-1.29 (m2H), 0.93 (t, 3H, J = 7.3 Hz); Anal Calcd for C20H;,_2O4 +0.2 H20: C, 72.80; H, 6.84.Found: C, 72.99; H, 6.96.9EXAMPLE 303,4-Dihydroxy-S-[(4-(2-(phenylthio)methyl)phenyl)-3-butynyl]-2(5H)-furanone5-(3-Butynyl)-3,4-dihydroxy-2(5H)-furanone (0.12g, 0.71 mmol) and 0.35 g(1.1mmol) of 2-(phenylthio)methyl-1-iodobenzene were coupled in an analogousfashion as described for the synthesis of 3,4-dihydroxy-5-[(4-phenyl)-3-butynyl}2(5H)-furanone. The residue was puri?ed over silica gel using CHCI3/MeO1-I/AcOH('96/3/1) as eluant and dried at 0.05 mm Hg at 58°C for 2h to provide 180 mg (69%)of 3,4-dihydroxy-5-[(4-(2-(phenylthio)methyl)phenyl)-3-butynyl]-2(5H)-furanone alight yellow oil: ‘H NMR (acetone-d6) 5 7.44-7.19 (m, 9H), 4.90 (dd. J=3.3, 8.3 Hz,1H), 4.36 (s, 2H), 2.63 (t, J=7.6 Hz, 2H), 2.28-2.21 (m, 1H), 1.90-1.81 (m, 1H); AnalCalcd for C2,H,8O..S: C, 68.85; H, 4.95. Found: C, 68.63; H, 5.11.EXAMPLE 313,4-Dihydroxy-5-[(4-(2-phenylsulfonamide-(N-butyl))-3—butynyl]-2(5H)-furanone5-(3-Butynyl)-3,4-dihydroxy-2(5H)-furanone (0.17g, 1.0 mmol) and 400mg(1.2mmol) of 111-butyl-2-iodobenzenesulfonamide were coupled in an analogousfashion as described for the synthesis of 3,4-dihydroxy-5-[(4-phenyl)-3-butynyl]-2(5H)-furanone. The residue was puri?ed over silica gel using CHCl3/MCOH/ACOH(500/16/0.5) as eluant and dried at 0.05mm Hg at 58°C for 2h to provide 3,4-dihydroxy-5-[(4-(2-phenylsulfonamide-(N-butyl))-3—butynyl]-2(5H)-furanone as alight yellow oil: ‘H NMR (acetone-d6) 5 8.00-7.96 (m, 1H), 7.59-7.55 (m, 1H), 7.33-7.24(m, 2H), 6.66(s, 1H), 4.82 (dd, J=3.4, 8.3 Hz, 1H), 3.44-3.36 (m, 2H), 3.23-3.14(m, 2H), 2.52-2.45 (m, 1H), 2.00-1.94 (m, 1H), 1.69-1.53 (m, 2H), 1.43-1.29 (m, 2H),0.31 (t, J=7.2 Hz, 3H); “C NMR (acetone-d6) 5 169.8, 153.5, 141.6, 137.6, 130.0,124.2, 123.8, 120.9, 118.6, 114.4, 108.7, 74.8, 53.6, 32.0, 24.9, 24.1, 20.9, 12.9; AnalCalcd for C,3H3,NO6S: C, 56.99; H, 5.58; N, 3.69. Found: C, 56.71; H, 5.65; N, 3.48.?W0 98/0771410152025CA 02264000 l999-02- 1953 PCT/US97/14878 - lZ3,4-Dihydroxy-5-[4-(2-naphthyl)-3-butynyl]-2(5H)-furanone5-(3-Butynyl)-3,4-dihydroxy-2(5H)-furanone (0.17g, 1.0 mmol) and 300uL(2.0mmol) of 2-iodonaphthalene were coupled in an analogous fashion as describedfor the synthesis of 3,4-dihydroxy-5-[(4-phenyl)-3—butynyl]-2(5H)-furanone. Theresidue was puri?ed over silica gel using CHC13/1\/IBOH/ACOH (96/3/ 1) as eluant anddried at 0.05mm Hg at 58°C for 2h to provide 230 mg (75%) of 3,4-dihydroxy-5-[4-(2-naphthyl)-3-butynyl]-2(5I-1)-?iranone as a yellow wax: -‘H NMR (acetone-d6) 58.4-8.3 (m, 1H), 7.96-7.88 (m. 2H), 7.70-7.43 (m, 4H), 4.98 (dd, J=3.4, 8.3 Hz, 1H),2.82-2.75 (m, 2H), 2.48-2.29 (m, 1H), 2.00-1.85 (m, 1H); Anal Calcd for C,8H,4O,, +0.5 H30: C, 71.27; H, 4.98. Found: C, 71.33; H, 4.87.EXA E 333,4-Dihydroxy-5-[(4-(2-(propylthio)methyl)phenyl)-3-butynyl]-2(5H)-furanone5-(3-Butynyl)-3,4-dihydroxy-2(5H)-furanone (O.17g, 1.0 mmol) and 440mg(1 .5mmol) of 2—(propylthio)methyl]-iodobenzene were coupled in an analogousfashion as described for the synthesis of 3,4-dihydroxy-5-[(4-phenyl)-3-butynyl]-2(5H)-furanone. The residue was puri?ed over silica gel using CHCI3/MeOH/AcOH(500/16/0.5) as eluant and dried at 0.05mm Hg at 58°C for 2b to provide 240 mg(72% yield) of 3,4—dihydroxy-5-[(4-(2-(propylthio)methyl)phenyl)-3-butynyl]-2(5H)-furanone as a yellow oil: ‘H NMR (acetone-d6) 5 7.44-7.21 (m, 4H), 4.90 (dd, J=3.4,8.3 Hz, 1H), 3.89 (s, 2H), 2.70-2.63 (m, 2H), 2.48-2.41 (m, 2H), 2.26-2.21 (in, 1H),1.90-1.81 (m, 1H) 1.64-1.53 (m, 2H), 0.93 (t J=7.3 Hz, 3H); Anal Calcd forC,8H20O4S: C, 65.05; H, 6.07. Found: C, 64.51; H, 6.28.EXAMPLE 343,4-Dihydroxy-5-[(4-(2-(1-pentylthio)methyl)phenyl)-3-butynyI]-2(5_H_)-furanone5-(3-Butynyl)-3,4-dihydroxy-2(5H)-furanone (84mg, 0.5 mmol) and 240mg(O.75mrnol) of 2-(methyl-1-pentylsul?de?odobenzene were coupled in an analogous?10152025W0 98/07714 54CA 02264000 l999-02- 19PCT/U S97/ 14878fashion as described for the synthesis of 3,4—dihydroxy-5-[(4-phenyl)-3-butynyl}2(5H)-furanone. The residue was puri?ed over silica gel using CHCl3/MeOH/AcOH(500/16/0.5) as eluant and dried at 0.05mm Hg at 58°C for 2hours to provide 3,4-dihydroxy-5-[(4-(2-(pentylthio)methyl)phenyl)-3-butynyl]-2(5H)-furanone: ‘H NMR(acetone-d5) 6 7.43-7.21 (m, 4H), 4.95 (dd, J=3.4, 8.4 Hz, 1H), 3.89 (s, 2H), 2.70-2.63(m, 2H), 2.50-2.43 (m, 2H), 2.26-2.21 (m, 1H), 2.00-1.81 (m, 1H) 1.66-1.45 (m, 2H),1.43-1.20 (m, 4H), 0.87 (t, J=7.2 Hz, 3H); Anal Calcd for C20H24O,,S + 0.5 H20: C,65.02; H, 6.82. Found: C, 65.38; H, 6.69.EXAMPLE 353,4-Dihydroxy-5-[(4-(2-(propylsulfonyl)methyl)phenyl)-3-butynyl]-2(5H)-furanone5—(3-Butynyl)-3,4-dihydroxy-2(5H)-furanone (236mg, 1.2 mmol) and 600mg(1 .5mmol) of 2-methyl-(1-propylsulfone)iodobenzene were coupled in an analogousfashion as described for the synthesis of 3,4-dihydroxy-5-[(4-phenyl)-3 —butynyl]-2(5H)—furanone. The residue was puri?ed over silica gel using CHC13/MeOI-I/AcOH(500/I6/0.5) as eluant and dried at 0.05mm Hg at 58°C for 2h to provide 250 mg(50% yield) of 3,4-dihydroxy-5—[(4-(2-(propylsulfonyl)methyl)phenyl)—3-butynyl]-2(5H)-furanone as a light yellow oil: ‘H NMR (acetone-d6) 6 7.56-7.34 (rn, 4H), 4.96(dd, J=3.4_. 8.2 Hz, 1H), 4.57 (s, 2H), 3.03-2.95 (m, 2H), 2.71-2.64 (m, 2H), 2.35-2.26(m, 1H), 1.94-1.70 (m, 3H), 1.02 (i; J=7.4 Hz, 3H); “C NMR (acetone-d6) 5 169.9,153.5, 132.9, 132.1, 131.0, 128.9, 128.5, 125.3, 118.6, 94.0, 79.6, 74.4, 57.2, 54.0,31.5, 15.7, 14.8, 12.7; Anal Calcd for C,,,H2oO6S: C, 59.34; H, 5.53. Found: C, 58.93;H, 5.76.EXAMPLE 363,4-Dihydroxy-5-[2-(4-(4-?uorophenylmethyl)thiophene)-(3-butynyl)]-2(5H)-furanone5-(3-Butynyl)—3,4-dihydroxy—2(5H)-furanone (750mg, 4.5mmol) and 2.6g (8.2mmol)of 4-(4-?uorophenylmethyl)-2-iodothiophene were coupled in an analogous fashion as?WO 98107714102025CA 02264000 l999-02- 195 5 PCT/U S97/ 14878described for the synthesis of 3,4-dihydroxy-5-[(4-phenyl)-3-butyny1]-2(5I-1)-furanone. The residue was purified over silica gel using CHCI3/MeOI-I/ACOH(500/15/0.5) as eluant and dried at 0.05mm Hg at 58°C for 2h to provide 1.2g (75%yield) of 3,4-dihydroxy-5-[2-(4—(4-?uorophenylmethyl)thiophene)-(3-butynyl)]-2(5l-1)-furanone as a brown wax: mp 119-121 °C 1H NMR (acetone-d6) 6 7.38-7.25(m, 2H), 7.13-6.99 (m, 3H), 6.78-6.74 (m, 1H), 4.84 (dd, J=3.3, 8.1 Hz, 1H), 4.14 (s,2H), 2.59 (1, J=7.1 Hz, 2H), 2.38-2.14 (m, 1H), 1.90-1.69 (m, 1H); “C NMR(acetone-d6) 5 169.19. 164.04 157.29, 152.78, 145.79, 136.74, 131.80, 130.80,130.47, 125.54, 122.74, 118.84, 115.89, 115.03, 92.44, 74.90, 74.31, 35.14, 31.84,15.02; Anal Calcd for C,9H15FO,,S: C, 63.69; H, 4.22. Found: C, 63.42; H, 4.33._E_X1LME_LElZ3,4-Dihydroxy-5-(4-phenylbutanyl)—2(5H)-furanoneQuinoline (70 11L, 0.6 mmol), 15mg of 5% Pd/BaSO4 and 61mg (0.25mmol) of 3,4-dihydroxy-5-[(4-phenyl)-3-butynyl]-2(5H)-?iranone were combined in 20mL ofethanol and hydrogenated at atmospheric pressure until 12 mL (0.5mmol) of H2 wasconsumed as measured by a H20 ?lled burette. The catalyst was removed by?ltration through two #1 ?uted ?lter papers and the solution was concentrated to avolume of about 5mL, taken up in 50mL of ether and washed with 3 x 15mL of 5%aqueous HCI, 20mL of H20 and 20mL of brine, dried (MgSO4) and concentrated toprovide 3,4-dihydroxy-5-(4—phenylbutanyl)-2(5H)-furanone as a brown wax: ‘H NMR(acetone- d6) 6 7.28-7.13 (m, 5H), 4.66 (dd, J=3 .4, 7.2 Hz, 1H), 2.62 (t, J=7.7, 2H),2.00-1.93 (m, 1H), 1.69-1.42 (m, SH); “C NMR (acetone- .16) 5 170.7, 154.9, 143.3,129.2, 129.1, 126.5, 118.6, 76.2. 36.3, 32.7, 32.1, 24.6. Anal Calcd for C,4H.6O4 +0.25 H20: C, 66.52; H, 6.58. Found: C, 66.71; H, 6.75.E MPLE 383,4-Dihydroxy-5-[(4-phenyl)-3Z-butenyl]-2(5H)-furanoneQuinoline (70 1.1L, 0.6 mmol), 15mg of 5% Pd/BaSO4 and 62mg (0.25mmol) of3,4-dihydroxy-5-[(4-phenyl)-3-butynyl]-2(5H)-furanone were combined in 20mL of?WO 98/07714 5610152025CA 02264000 l999-02- 19PCT/US97/ 14878ethanol and hydrogenated at atmospheric pressure until 6 mL (0.25mmol) of Hz wasconsumed as measured by a H20 ?lled burette. The catalyst was removed by?ltration through 2 ?uted ?lter papers and the solution was concentrated, taken up in50mL of ether and washed with 3 x l5mL of 5% aqueous HC1, 20mL of H20 and20mL of brine, dried (MgSO4) and concentrated to give 3,4-dihydroxy-5-[(4-phenyl)—3Z-butenyl]-2(5I-I)-furanone as the major constituent in a mixture of alkyne, cis alkeneand alkane (1.0/5070.5) as determined by ‘H NMR spectra: ‘H NMR (CDCI3) 6 7.34-7.14 (m, 5H), 6.46 (d, J=11.5 Hz, 1H), 5.65-5.57 (m, 1H), 4.77 (dd, 3.5, 8.0 Hz, 1H),2.49 (dd, J,,b=7.6 Hz, 2H), 2.16-2.09 (m, 1H), 1.80-1.70 (m, 1H); ‘3C NMR (CDCI3) 6173.4, 155.9, 137.1, 130.4,130.3, 128.7,128.3, 128.3, 126.8, 117.5, 77.2, 31.8, 23.5.EXAMPLE 393,4-Dihydroxy-5[(4-(2-methyl)phenyl)-3Z-butenyl]-2(5H)-furanone3,4-Dihydroxy-5[(4-(2-methyl)phenyl)-3-butynyl]-2(5I-I)-furanone (65mg, O.25mmo1)was reduced in a similar manner as described for the synthesis of 3,4—dihydroxy-5-[(4-phenyl)-3Z—butenyl]-2(5H)-furanone to produce 3,4-dihydroxy-5[(4—(2-methyl)phenyl)-3Z-butenyl]-2(5H)-furanone as an oil consisting of only the cis isomeras observed by the ‘H NMR spectra. ‘H NMR (CDCI3) 6 7.34-7.20 (m, 4H), 6.59 (d,J=11.4 Hz, 1H), 5.81-5.73 (m, 1H), 4.81 (dd, J=3.4, 8.2 Hz, 1H), 2.49-2.35 (m, 2H),2.33 (s, 3H), 2.17-2.13 (m, 1H), 1.81-1.75 (tn, IH); ‘3C NMR (CDCI3) 6 173.6, 156.0,136.2, 136.2, 130.2, 129.9, 129.6, 128.8, 127.1, 125.5, 117.4, 77.3, 31.9, 23.4, 19.9.EXAMPLE 403,4-Dihydroxy-5[(4-(2-(2Z-hexenyl))phenyl)-3Z-butenyl]-2(5H)-furanone3,4-Dihydroxy-5 [(4-(2-(2-hexynyl))pheny1)-3Z-butenyl]-2(5H)-furanone (75mg,0.25mmol) was reduced in a similar manner as described for the synthesis of 3,4-dihydroxy-5-{(4-phenyl)-3Z-butenyl]-2(5H)-furanone to produce 3,4-dihydroxy—5[(4-(2-(2Z-hexenyl))phenyl)-3Z-butenyl]-2(5H)-furanone as an oil consisting of only thecis isomer as observed by the ‘H NMR spectra and contaminated with less than 5% ofstarting material, which was not separable from the product: ‘H NMR (acetone-d6) 5?CA 02264000 l999-02- 19WO 98/07714 5 7 PCT/US97/ 14878 ..10157.25-7.15 (m, 4H), 6.59 (d, 1H, J = 11.4 Hz), 5.81-5.76 (m, 1H), 5.51-5.43 (m, 2H),4.71 (dd, 1H, J = 3.5, 7.6 Hz), 3.44-3.25 (m, 2H), 2.40-1.90 (In, SH). 1.76-1.58 (m,1H), 1.50-1.32 (m. 2H), 0.94 (t, 3H, J = 7.3 Hz). Anal Calcd for C20H24O4 + 0.25 H20:C, 71.20; H, 7.47. Found: C, 70.97; H, 7.32.The following is a list of references related to the above disclosure. These referencesshould be considered as incorporated by reference in their entirety.1. Shimuzu, T., et al. Enzyme with dual lipoxygenase activities catalyzes leukotrieneA4 synthetase from arachidonic acid. Pro. Natl. Acag, Sci. 812689-693, (1984).2. Egan, RW and Gale PH, Inhibition of mammalian 5—1ipoxygenase by aromaticdisul?des, J. Biol. Qhem, 260: 11554-11559, (1985).3. Evans, AT, et al Actions of cannabis constituents on enzymes of arachidonicmetabobilismz anti-in?ammatory potential. Bigchem Pham. 36:2035-2037, (1987).4. Boopathy, R and Baiasubramanian AS. Puri?cation and characterization of sheepplatelet cyclooxygenase. Biochem J. 2392371-3 77, (1968).5. O’Sullivan, MG et al, Lipopolysaccharide induces prostaglandin H synthase-2 inalveolar macrophages. Biochem. Bio h s. Res. omm. 187: 1123-1127, (1992).6. Mansuy D. et al, A new potent inhibitor of lipid peroxidation in vitro and in vivo,the hepatoprotecticve drug anisyldithiolthione. Biochem. Biophys. Res. Comm.l35:1015-l02l,(l986).

Claims (66)

WHAT IS CLAIMED IS:
1. A racemic or optically active compound of the formula I:

wherein R is hydrogen, phenyl, or a lower alkyl; L is a linker moiety selected from the group consisting of oxygen, nitrogen, acetylene, a cis or trans carbon-carbon double bond, an ester, carbonate, urea, amide and carbamate; m is 0 or 1, n is 0 to 4, Aryl is a substituted or unsubstituted aryl group; with the proviso that when R is hydrogen, then either m or n is not zero; and with the further proviso that when R is hydrogen and L is sulfur, Aryl is substituted other than with a hydroxy or lower alkoxy group; or a pharmaceutically acceptable salt thereof.
2. A compound according to Claim 1 of the formula Ia wherein R is phenyl or a lower alkyl; and Aryl is a substituted or unsubstituted aryl group; or a pharmaceutically acceptable salt thereof.
3. A compound according to Claim 2 which is racemic 5-[(1,1'-diphenyl)-4-yl]-3,4-dihydroxy-5-phenyl-2(5H)-furanone; racemic 5-[(1,1'-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone; racemic 3,4-dihydroxy-5-methyl-5-[4'-(2'-methylpropyl)phenyl]-2(5H)-furanone; (S)-(+)-5-[(1,1'-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone; (R)-(-)-5-[(1,1'-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone; (S)-(+)-3,4-dihydroxy-5-methyl-5-[4'-(2'-methylpropyl)phenyl]-2(5H)-furanone; or (R)-(-)-3,4-dihydroxy-5-methyl-5-[4'-(2'-methylpropyl)phenyl]-2(5H)-furanone.
4. A compound according to Claim 1 of the formula Ib - wherein n is 0 to 4 and Aryl is a substituted or unsubstituted aryl group; or a pharmaceutically acceptable salt thereof.
5. A compound according to Claim 4 which is 3,4-dihydroxy-5-[(4-(2-(2Z-hexenyl))phenyl)-3-butynyl]-2(5H)-furanone.
6. A compound according to Claim 4 which is 3,4-dihydroxy-5-[(4-(2-(phenylthio)methyl)phenyl)-3 -butynyl]-2(5H)-furanone.
7. A compound according to Claim 4 which is 3,4-dihydroxy-5-[4-(2-naphthyl)-3-butynyl]-2(5H)-furanone.
8. A compound according to Claim 4 which is 3,4-dihydroxy-5-[2-(4-(4-fluorophenylmethyl)thiophene)-(3-butynyl)]-2(5H)-furanone.
9. A compound according to Claim 1 of the formula Ic wherein n is 0 to 4 and Aryl is a substituted or unsubstituted aryl group; or a pharmaceutically acceptable salt thereof.
10. A compound according to Claim 9 which is 3,4-dihydroxy-5-[2-(4,5-diphenyl-1,3-isoxazole-2-thio)ethyl]-2(5H)-furanone.
11. A compound according to Claim 9 which is 3,4-dihydroxy-5-[2-(naphthyl-1-thio)ethyl]-2(5H)-furanone.
12. A compound according to Claim 9 which is 3,4-dihydroxy-5-[2-(naphthyl-2-thio)ethyl]-2(5H)-furanone.
13. A compound according to Claim 1 of the general formula Id wherein n is 0 to 4 and Aryl is a substituted or unsubstituted aryl group; or a pharmaceutically acceptable salt thereof.
14. A compound according to Claim 13 which is 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone.
15. A compound according to Claim 10 which is 3,4-dihydroxy-5-[2-(flavone-6-oxy)ethyl]-2(5H)-furanone.
16. A compound according to Claim 10 which is 5-[2-(dibenzofuran-2-oxy)ethyl]-3,4-dihydroxy-2(5H)-furanone.
17. A compound according to Claim 10 which is 3.4-dihydroxy-5-[2-(1-naphthoxy)ethyl]-2(5H)-furanone.
18. A compound according to Claim 10 which is 3,4-dihydroxy-5-[2-(diphenylmethane-2-oxy)ethyl]-2(5H)-furanone.
19. A compound according to Claim 10 which is 5-[2-((1,1'-biphenyl)-4-oxy)ethyl]-3,4-dihydroxy-2(5H)-furanone.
20. A pharmaceutical composition comprising an effective amount of a racemic or optically active compound of the general formula I:

wherein R is hydrogen, phenyl, or a lower alkyl; L is a linker moiety selected from the group consisting of oxygen, nitrogen, acetylene, a cis or trans carbon-carbon double bond, an ester, carbonate, urea, amide and carbamate; m is 0 or 1, n is 0 to 4, Aryl is a substituted or unsubstituted aryl group; with the proviso that when R is hydrogen, then either m or n is not zero; and with the further proviso that when R is hydrogen and L is sulfur, Aryl is substituted other than with a hydroxy or lower alkoxy group; or a pharmaceutically acceptable salt thereof;
together with a pharmaceutically acceptable carrier therefor.
21. A composition according to Claim 20 of the formula Ia wherein R is phenyl or a lower alkyl; and Aryl is a substituted or unsubstituted aryl group; or a pharmaceutically acceptable salt thereof.
22. A composition according to Claim 21 which is racemic 5-[(1,1'-biphenyl)-4-yl]-3,4-dihydroxy-5-phenyl-2(5H)-furanone; racemic 5-[(1,1-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone; racemic 3,4-dihydroxy-5-methyl-5-[4'-(2'-methylpropyl)phenyl]-2(5H)-furanone; (S)-(+)-5-[(1,1'-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone; (R)-(-)-5-[(1,1'-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone; (S)-(+)-3,4-dihydroxy-5-methyl-5-[4'-(2'-methylpropyl)phenyl]-2(5H)-furanone; or (R)-(-)-3,4-dihydroxy-5-methyl-5-[4'-(2'-methylpropyl)phenyl]-2(5H)-furanone.
23. A composition according to Claim 20 of the formula Ib wherein n is 0 to 4, and Aryl is a substituted or unsubstituted aryl group; or a pharmaceutically acceptable salt thereof.
24. A composition according to Claim 23 which is 3,4-dihydroxy-5-[(4-(2-(2Z-hexenyl))phenyl)-3-butynyl]-2(5H)-furanone.
25. A composition according to Claim 23 which is 3,4-dihydroxy-5-[(4-(2-(phenylthio)methyl)phenyl)-3-butynyl]-2(5H)-furanone.
26. A composition according to Claim 23 which is 3,4-dihydroxy-5-[4-(2-naphthyl)-3-butynyl]-2(5H)-furanone.
27. A composition according to Claim 23 which is 3,4-dihydroxy-5-[2-(4-(4-fluorophenylmethyl)thiophene)-(3-butynyl)]-2(5H)-furanone.
28. A composition according to Claim 20 of the formula Ic wherein n is 0 to 4, and Aryl is a substituted or unsubstituted aryl group; or a pharmaceutically acceptable salt thereof.
29. A composition according to Claim 28 which is 3,4-dihydroxy-5-[2-(4,5-diphenyl-1.3-isoxazole-2-thio)ethyl]-2(5H)-furanone.
30. A composition according to Claim 28 which is 3,4-dihydroxy-5-[2-(naphthyl-1-thio)ethyl]-2(5H)-furanone.
31. A composition according to Claim 28 which is 3,4-dihydroxy-5-[2-(naphthyl-2-thio)ethyl]-2(5H)-furanone.
32. A composition according to Claim 20 of the general formula Id wherein n is 0 to 4, and Aryl is a substituted or unsubstituted aryl group; or a pharmaceutically acceptable salt thereof.
33. A composition according to Claim 32 which is 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone.
34. A composition according to Claim 27 which is 3,4-dihydroxy-5-[2-(flavone-6-oxy)ethyl]-2(5H)-furanone.
35. A composition according to Claim 27 which is 5-[2-(dibenzofuran-2-oxy)ethyl]-3,4-dihydroxy-2(5H)-furanone.
36. A composition according to Claim 27 which is 3,4-dihydroxy-5-[2-(1-naphthoxy)ethyl]-2(5H)-furanone.
37. A composition according to Claim 27 which is 3,4-dihydroxy-5-[2-(diphenylmethane-2-oxy)ethyl]-2(5H)-furanone.
38. A composition according to Claim 27 which is 5-[2-((1,1'-biphenyl)-4-oxy)ethyl]-3,4-dihydroxy-2(5H)-furanone.
39. A method of treating a pathology in which reactive oxygen species and inflammatory mediators are contributing deleterious factors which comprises administration to a patient in need of such therapy an effective amount of a racemic or optically active compound of the formula wherein R is hydrogen, phenyl, or a lower alkyl; L is a linker moiety selected from the group consisting of oxygen, nitrogen, acetylene, a cis or trans carbon-carbon double bond, an ester, carbonate, urea, amide and carbamate; m is 0 or 1. n is 0 to 4, Aryl is a substituted or unsubstituted aryl group; with the proviso that when R is hydrogen, then either m or n is not zero; and with the further proviso that when R is hydrogen and L is sulfur, Aryl is substituted other than with a hydroxy or lower alkoxy group; or a pharmaceutically acceptable salt thereof.
40. The method of claim 39 wherein said pathology comprises acute or chronic inflammatory disorders.
41. The method of claim 40 wherein said acute or chronic inflammatory disorder is asthma, rheumatoid arthritis, inflammatory bowel disease. or acute respiratory distress syndrome.
42. The method of claim 39 wherein said pathology comprises neurodegenerative disorders.
43. The method of claim 42 wherein said neurodegenerative disorder is Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, traumatic brain injury or multiple sclerosis.
44. The method of claim 39 wherein said pathology comprises cardiovascular disease.
45. The method of claim 44 wherein said cardiovascular disease is atherosclerosis.
46. The method of claim 39 wherein said pathology comprises a viral disease.
47. The method of claim 46 wherein said viral disease is AIDS.
48. The method of claim 39 wherein said pathology comprises a skin disease.
49. A method according to Claim 39 of the formula Ia wherein R is phenyl or a lower alkyl; and Aryl is a substituted or unsubstituted aryl group; or a pharmaceutically acceptable salt thereof.
50. A method according to Claim 49 which is racemic 5-[(1.1'-biphenyl)-4-yl]-3,4-dihydroxy-5-phenyl-2(5H)-furanone: racemic S-[(1,1'-biphenyl)-4-yl]-3.4-dihydroxy-5-methyl-2(5H)-furanone; racemic 3.4-dihydroxy-5-methy1-5-[4'-(2'-methylpropyl)phenyl]-2(5H)-furanone: (S)-(+)-5-[(1,1'-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone; (R)-(-)-5-[(1,1'-biphenyl)-4-yl]-3.4-dihydroxy-S-methyl-2(5H)-furanone; (S)-(+)-3,4-dihydroxy-5-methyl-5-[4'-(2'-methylpropyl)phenyl]-2(5H)-furanone; or (R)-(-)-3,4-dihydroxy-5-methyl-5-[4'-(2'-methylpropyl)phenyl]-2(5H)-furanone.
51. A method according to Claim 39 of the formula Ib wherein n is 0 to 4, and Aryl is a substituted or unsubstituted aryl group; or a pharmaceutically acceptable salt thereof.
52. A method according to Claim 51 in which said compound is 3,4-dihydroxy-5-[(4-(2-(2Z-hexenyl))phenyl)-3-butynyl]-2(5H)-furanone.
53. A method according to Claim 51 in which said compound is 3,4-dihydroxy-5-[(4-(2-(phenylthio)methyl)phenyl)-3-butynyl]-2(5H)-furanone.
54. A method according to Claim 51 in which said compound is 3,4-dihydroxy-5-[4-(2-naphthyl)-3-butynyl]-2(5H)-furanone.
55. A method according to Claim 51 in which said compound is 3,4-dihydroxy-5-[2-(4-(4-fluorophenylmethyl)thiophene)-(3-butynyl)]-2(5H)-furanone.
56. A method according to Claim 39 comprising a compound of the formula Ic wherein n is 0 to 4, and Aryl is a substituted or unsubstituted aryl group; or a pharmaceutically acceptable salt thereof.
57. A method according to Claim 56 in which said compound is 3,4-dihydroxy-5-[2-(4,5-diphenyl-1.3-isoxazole-2-thio)ethyl]-2(5H)-furanone.
58. A method according to Claim 56 in which said compound is 3.4-dihydroxy-5-[2-(naphthyl-1-thio)ethyl]-2(5H)-furanone.
59. A method according to Claim 56 in which said compound is 3.4-dihydroxy-5-[2-(naphthyl-2-thio)ethyl]-2(5H)-furanone.
60. A method according to Claim 39 comprising a compound of the general formula Id wherein n is 0 to 4, and Aryl is a substituted or unsubstituted aryl group; or a pharmaceutieally acceptable salt thereof.
61. A method according to Claim 60 in which said compound is 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone.
62. A method according to Claim 60 in which said compound is 3.4-dihydroxy-5-[2-(flavone-6-oxy)ethyl]-2(5H)-furanone.
63. A method according to Claim 60 in which said compound is 5-[2-(dibenzofuran-2-oxy)ethyl]-3,4-dihydroxy-2(5H)-furanone.
64. A method according to Claim 60 in which said compound is 3,4-dihydroxy-5-[2-(1-naphthoxy)ethyl]-2(5H)-furanone.
65. A method according to Claim 59 in which said compound is 3,4-dihydroxy-5-[2-(diphenylmethane-2-oxy)ethyl]-2(5H)-furanone.
66. A method according to Claim 59 in which said compound is 5-[2-((1,1'-biphenyl)-4-oxy)ethyl]-3,4-dihydroxy-2(5H)-furanone.
CA002264000A 1996-08-22 1997-08-22 5-substituted and 5,5-disubstituted-3,4-dihydroxy-2(5h)-furanones and methods of use therefor Abandoned CA2264000A1 (en)

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US08/915,099 1997-08-20
PCT/US1997/014878 WO1998007714A1 (en) 1996-08-22 1997-08-22 5-substituted and 5,5-disubstituted-3,4-dihydroxy-2(5h)-furanones and methods of use therefor

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