3,4,5-TRISUBSTITUTED ARYL NITRONE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME

Abstract: Disclosed are 3,4,5-trisubstituted aryl nitrone compounds and pharmaceutical compositions containing such compounds. The 3,4,5-trisubstituted aryl nitrone compounds have formula (I); where R<1>-R<4> are as defined in the specification. The disclosed compositions are useful as therapeutics for inflammation-related conditions in mammals, such as arthritis, and as analytical reagents for detecting free radicals.

Description: 3 ,4 , 5-TRISUBSTITUTED ARYL NITRONE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME BACKGROUND OF THE INVENTION Field of the nvention This invention relates to novel 3,4,5-trisubstituted aryl nitrone compounds and their use as therapeutic agents for the treatment of inflammation-related conditions in mammals, such as arthritis, and as analytical reagents for detecting free radicals. State ofthe Art Arthritis and related inflammatory disease conditions occur in more than 100 different forms, including rheumatoid arthritis (RA), osteoarthritis (OA), an ylosing spondylitis and systemic lupus erythematosus (SLE). Most forms of arthritis are characterized by some type of chronic inflammation. For example, RA typically involves chronic inflammation of the lining of the j oints and/or the internal organs. Such chronic inflammation generally causes pain and swelling in the joints of those afflicted and may result in damage to cartilage, bone, tendons, ligaments and the like, ultimately leading to deformity and disability. Prostaglandins have long been known to be involved in the inflammation process. Accordingly, a number of inhibitors of prostaglandin synthesis have been developed for the treatment of arthritis and related inflammatory disease conditions. Such non-steroidal antiinflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen and indomethacin, typically prevent the production of prostaglandins by inhibiting enzymes in the arachidonic acid/prostaglandin pathway, including the enzyme cycloxygenase (COX). The enzyme COX catalyzes the conversion of arachidonic acid to prostaglandin H2, the first step in the biosynthesis of prostaglandins such as prostacyclin and thromboxanes. The enzyme COX is now known to exist in two forms. COX-1 is a constitutive form of the enzyme found in most tissues and organs. Among other properties, COX-1 produces relatively small amounts of prostoglandins necessary for maintaining the integrity ofthe gastrointestinal tract. COX-2, on the other hand, is an inducible form ofthe enzyme associated with the increased production of prostoglandins during inflammatory conditions. Since many NSAIDS inhibit both forms of COX, they interfere with prostaglandin-regulated processes not associated with the inflammation process. As a result, many NSAIDS cause severe side effects, such as stomach ulcers and renal damage, which limit their effectiveness as therapeutics. Accordingly, a need exists for novel classes of therapeutic compounds which effectively treat arthritis and other inflammation-related conditions without producing undesired side effects. SUMMARY OF THE INVENTION This invention provides novel 3,4,5-trisubstituted aryl nitrone compounds which are useful as therapeutics for reducing inflammation in mammals. In particular, the compounds of this invention are useful for treating arthritis and other inflammation-related conditions. Accordingly, in one of its composition aspects, this invention is directed to compounds of formula I: wherein R 1 is selected from the group consisting of: W W ψ R5— C— ' R 6 — N-C— and R8 — X-CH- ; R 7 each R 2 is independently selected from a group ofthe formula: R 3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl; R 4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; R 5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; R 6 and R 7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; or R 6 and R 7 can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms; R 8 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; R 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; or R 8 and R 9 can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms; R 10 is selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl; or R 1 and R 10 can be joined to form an alkylene, substituted alkylene, -C(O)- -S(O)- or -S(O) 2 - group; R 11 and R 12 are independently selected from the group consisting of lower alkyl and lower cycloalkyl; or R 11 and R 12 can be joined to form an alkylene group having from 2 to 10 carbon atoms; Nis oxygen, sulfur, -S(O)- or -S(O) 2 -; and W is oxygen or sulfur; and pharmaceutically-acceptable salts thereof. Preferably, R 3 is hydrogen or lower alkyl. More preferably, R 3 is hydrogen or alkyl having 1 to 4 carbon atoms, more preferably 1 or 2 carbon atoms. Still more preferably, R 3 is hydrogen. R 4 is preferably selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. More preferably, R 4 is alkyl having 3 to 6 carbon atoms or cycloalkyl having 5 to 6 carbon atoms. Particularly preferred R 4 groups include methyl, π-propyl, isopropyl, l-hydroxy-2-methylprop-2-yl, «-butyl, tert-butyl, 3- thiomethylpropyl, 3-(thiomethoxy)but-l-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl. R 5 is preferably selected from the group consisting of alkyl and cycloalkyl. More preferably, R 5 is lower alkyl. Particularly preferred R 5 groups include methyl, ethyl, n-propyl, isopropyl and ra-butyl. R 6 is preferably selected from the group consisting of alkyl and alkoxycarbonylalkyl (i.e., ROC(O)-alkyl-, where R is alkyl or cycloalkyl). Particularly preferred R δ groups include ethyl, «-propyl, isopropyl, «-butyl, ethoxycarbonylmethyl and 2-(ethoxycarbonyl)ethyl. R 7 is preferably hydrogen. Preferably, R 8 is alkyl or alkoxyalkyl (i.e., RO-alkyl-, where R is alkyl). Particularly preferred R 8 groups include methyl and methoxyethyl. R 9 is preferably hydrogen. Preferably, X is oxygen. Preferably, R 10 , R π and R 12 are independently lower alkyl. More preferably, R 10 , R π and R 12 are methyl. W is preferably oxygen. In a preferred embodiment, this invention is directed to a compound of formula II: wherein R 13 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; R 14 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; and pharmaceutically-acceptable salts thereof. Preferably, R 13 is lower alkyl. R 14 is preferably selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. More preferably, R 14 is alkyl having 3 to 6 carbon atoms or cycloalkyl having 5 to 6 carbon atoms. Particularly preferred R 14 groups include methyl, «-propyl, isopropyl, l-hydroxy-2-methylprop-2-yl, π-butyl, tert-butyl, 3- thiomethylpropyl, 3-(thiomethoxy)but-l-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl. In another preferred embodiment, this invention is directed to a compound of formula III: wherein R 15 and R 16 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl; or R 15 and R 16 can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms; R 17 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; and pharmaceutically-acceptable salts thereof. R 15 is preferably selected from the group consisting of alkyl and alkoxycarbonylalkyl (i.e., ROC(O)-alkyl-, where R is alkyl or cycloalkyl). Particularly preferred R 15 groups include ethyl, «-propyl, isopropyl, π-butyl, ethoxycarbonylmethyl and 2-(ethoxycarbonyl)ethyl. R 16 is preferably hydrogen. R is preferably selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. More preferably, R 17 is alkyl having 3 to 6 carbon atoms or cycloalkyl having 5 to 6 carbon atoms. Particularly preferred R 17 groups include methyl, n-propyl, isopropyl, l-hydroxy-2-methylprop-2-yl, w -butyl, tert-butyl, 3- fhiome hylpropyl, 3-(thiomethoxy)but-l-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl. In still another preferred embodiment, this invention is directed to a compound of formula IV: wherein R 18 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; R 19 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; or R 18 and R 19 can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms; R 20 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; and pharmaceutically-acceptable salts thereof. Preferably, R 18 is alkyl or alkoxyalkyl (i.e., RO-alkyl-, where R is alkyl). Particularly preferred R 18 groups include methyl and methoxyethyl. R 19 is preferably hydrogen. R is preferably selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. More preferably, R 20 is alkyl having 3 to 6 carbon atoms or cycloalkyl having 5 to 6 carbon atoms. Particularly preferred R 20 groups include methyl, «-propyl, isopropyl, l-hydroxy-2-methylprop-2-yl, «-butyl, tert-butyl, 3- thiomethylpropyl, 3-(thiomethoxy)but-l-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl. Particularly preferred 3,4,5-trisubstituted aryl nitrone compounds include those having the formulae shown in Tables I, II and III. Table I oε III w_ SI 01 6- t,fr8Z/66SflΛL3d t,9szε/oo OΛV Accordingly, in another of its composition aspects, this invention is directed to each of the individual compounds: α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone -(4-isobutanoyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone α-(4-w-butanoyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-isopropylnitrone α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-l-hydroxy-2-methylprop-2- ylnitrone α-(4-«-pentanoyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-4-trifluoromethylbenzylnitrone -(4-propionyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone α-(4-acetoxy-3 ,5-di-tert-butylphenyl)-N-methylnitrone α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-3,4,5-trimethoxybenzylnitrone α-[4-(ethylaminocarbonyloxy)-3,5-di-tert-butylphenyl]-N-tert-butylnitrone -[4-(n-propylaminocarbonyloxy)-3,5-di-tert-butylphenyl]-N-tert- butylnifrone -[4-(«-butylaminocarbonyloxy)-3,5-di-tert-butylphenyl]-N-tert- butylnifrone - [4-(2-ethoxycarbonyl)ethylaminocarbonyloxy)-3 ,5 -di-tert-butylphenyl] - N-tert-butylnitrone α-[4-(2-ethoxycarbonyl)methylaminocarbonyloxy)-3,5-di-tert- butylphenyl]-N-tert-butylnitrone α-(4-methoxymethoxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone -[4-(2-methoxy)ethoxymethoxy-3,5-di-tert-butylphenyl]-N-tert- butylnifrone α-(4-methoxymethoxy-3 ,5-di-tert-butylphenyl)-N-3-(thiomethoxy)but- 1 - ylnitrone α-(4-methoxymefhoxy-3,5-di-tert-butylphenyl)-N-3- thiomethoxypropylnitrone and pharmaceutically acceptable salts thereof. In another of its composition aspects, this invention is directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula I: wherein R -R are as defined above. In additional composition aspects, this invention is directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula II, III or IV above. Among other properties, the 3,4,5-trisubstituted aryl nitrone compounds of this invention are believed to inhibit the induction of cyclooxygenase associated with prostagladin E 2 (PGE 2 ) synthesis and inflammation. Compounds having such properties are useful for reducing inflammation, including inflammation resulting from arthritis and related inflammatory conditions. Accordingly, in one of its method aspects, this invention is directed to a method for treating a mammal with an inflammation-related condition which method comprises administering to said mammal a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective inflammation- reducing amount of a compound of formula I, II, III or IV above. In preferred embodiments of this invention, the inflammation-related condition treated in the above methods is rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriatic arthritis, and the like. DETAILED DESCRIPTION OF THE INVENTION For the purposes of this invention, the 3,4,5-trisubstituted aryl nitrone compounds of formula I are named using conventional nitrone nomenclature, i.e., the carbon atom ofthe carbon-nitrogen double bond (C=N) is designated the α- position and substituents on the nitrogen atom ofthe carbon-nitrogen double bond are given the N- prefix. In some cases, the 3,4,5,-trisubstituted aryl nitrones of this invention may contain one or more chiral centers. Typically, such compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) ofthe 3,4,5-trisubstituted aryl nitrones of formula I are included within the scope of this invention. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like. Additionally, all geometric isomers ofthe nitrone compounds of formula I are included within the scope of this invention including, for example, all isomers (i.e. E and Z isomers) ofthe carbon-nitrogen double bond ofthe nitrone functionality. Definitions When describing the 3,4,5-trisubstituted aryl nitrones, pharmaceutical compositions and methods of this invention, the following terms have the following meanings unless otherwise specified. " Acyl" refers to the group -C(O)R where R is hydrogen, alkyl, aryl or cycloalkyl. "Acylamino" refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, aryl or cycloalkyl. "Acyloxy" refers to the group -OC(O)R where R is hydrogen, alkyl, aryl or cycloalkyl. "Alkenyl" refers to a monvalent branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of carbon-carbon double bond unsaturation. Preferred alkenyl groups include ethenyl (-CH= H 2 ), «-propenyl (-CH 2 CH=CH 2 ), isopropenyl (-C(CH 3 )=CH 2 ), and the like. "Substituted alkenyl" refers to an alkenyl group having from 1 to 5 substituents, and preferably from 1 to 3 substiutents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, arnino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2 -. "Alkoxy" refers to the group -OR where R is alkyl. Preferred alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, tert-butoxy, sec-butoxy, «-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like. "Substituted alkoxy" refers to an alkoxy group having from 1 to 5 substituents, and preferably from 1 to 3 substiutents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2 -. "Alkoxycarbonyl" refers to the group -C(O)OR where R is alkyl or cycloalkyl. "Alkoxycarbonylamino" refers to the group -NRC(O)OR' where R is hydrogen, alkyl, aryl or cycloalkyl, and R' is alkyl or cycloalkyl. "Alkyl" refers to a monovalent branched or unbranched saturated hydrocarbon group preferably having from 1 to about 10 carbon atoms, more preferably from 1 to 8 carbon atoms and still more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, «-propyl, isopropyl, n- butyl, isobutyl, tert-butyl, n-hexyl, n-octyl, tert-octyl and the like. The term "lower alkyl" refers to an alkyl group having from 1 to 6 carbon atoms. "Substituted alkyl" refers to an alkyl group having from 1 to 5 substituents, and preferably from 1 to 3 substiutents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2 -. "Alkylene" refers to a divalent branched or unbranched saturated hydrocarbon group preferably having from 1 to 10 carbon atoms and more preferably from 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH 2 -), ethylene (~CH 2 CH 2 -), the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -) and the like. "Substituted alkylene" refers to an alkylene group having from 1 to 5 substituents, and preferably from 1 to 3 substiutents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2 -. "Alkynyl" refers to a monovalent branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of carbon-carbon triple bond unsaturation. Preferred alkynyl groups include ethynyl (-C≡CH), propargyl (-CH 2 C≡CH) and the like. "Substituted alkynyl" refers to an alkynyl group having from 1 to 5 substituents, and preferably from 1 to 3 substiutents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2 -. "Amino" refers to the group -NH 2 . "Substituted amino" refers to the group -N(R) 2 where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, and where both R groups are joined to form an alkylene group. When both R groups are hydrogen, -N(R) 2 is an amino group. "Aminocarbonyl" refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, aryl and cycloalkyl, or where the R groups are joined to form an alkylene group. "Aminocarbonylamino" refers to the group -NRC(O)NRR where each R is independently hydrogen, alkyl, aryl or cycloalkyl, or where two R groups are joined to form an alkylene group. "Aminocarbonyloxy" refers to the group -OC(O)NRR where each R is independently hydrogen, alkyl, aryl or cycloalky, or where the R groups are joined to form an alkylene group. "Aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like. Unless otherwise constrained by the definition for the individual substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkoxycarbonyl, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2 -. "Aryloxy" refers to the group -OR where R is aryl. "Cycloalkyl" refers to a cyclic alkyl group of from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed or bridged rings which can be optionally substituted with from 1 to 3 alkyl groups. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2- methylcyclooctyl, and the like, or multiple or bridged ring structures such as adamantanyl and the like. The term "lower cycloalkyl" refers to a cycloalkyl group having from 3 to 6 carbon atoms. "Substituted cycloalkyl" refers to a cycloalkyl group having from 1 to 5 substituents, and preferably from 1 to 3 substiutents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2 -. "Cycloalkoxy" refers to the group -OR where R is cycloalkyl. Such cycloalkoxy groups include, by way of example, cyclopentoxy, cyclohexoxy and the like. "Cycloalkenyl" refers to a cyclic alkenyl group of from 4 to 10 carbon atoms having a single cyclic ring and at least one point of internal unsaturation which can be optionally substituted with from 1 to 3 alkyl groups. Examples of suitable cycloalkenyl groups include, for instance, cyclopent-3-enyl, cyclohex-2- enyl, cyclooct-3-enyl and the like. "Substituted cycloalkenyl" refers to a cycloalkenyl group having from 1 to 5 substituents, and preferably from 1 to 3 substiutents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2 -. "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo. Preferred halo groups are either fluoro or chloro. "Hydroxyl" refers to the group -OH. "Keto" or "oxo" refers to the group =O. "Nitro" refers to the group -NO 2 . "Thioalkoxy" refers to the group -SR where R is alkyl. "Substituted thioalkoxy" refers to a thioalkoxy group having from 1 to 5 substituents, and preferably from 1 to 3 substiutents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2 -. "Thioaryloxy" refers to the group -SR where R is aryl. "Thioketo" refers to the group =S. "Thiol" refers to the group -SH. "Pharmaceutically-acceptable salt" refers to any salt of a compound of this invention which retains its biological properties and which is not biologically or otherwise undesirable. Such salts may be derived from a variety of organic and inorganic counter-ions well known in the art and include, by way of example illustration, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically- acceptable cation" refers to a pharmaceutically acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. General Synthetic Procedures The 3,4,5-trisubstituted aryl nitrones of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein. In a preferred method of synthesis, the 3,4,5-trisubstituted aryl nitrones of this invention are prepared by coupling an aryl carbonyl compound of formula V: wherein R 1 , R 2 and R 3 are as defined above, with a hydroxylamine of formula VI: HO-NH-R 4 VI wherein R is as defined above, under conventional reaction conditions. This coupling reaction is typically conducted by contacting the aryl carbonyl compound V with at least one equivalent, preferably about 1.1 to about 2 equivalents, of hydroxylamine VI in an inert polar solvent such as methanol, ethanol, 1 ,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide and the like. This reaction is preferably conducted at a temperature of from about 0°C to about 100°C for about 1 to about 48 hours. Optionally, a catalytic amount of an acid, such as hydrochloric acid, acetic acid, /?-toluenesulfonic acid, silica gel and the like, may be employed in this reaction. When R 1 in formula V is -C(O)R 3 , at least two equivalents of hydroxylamine VI are employed in this coupling reaction. Upon completion ofthe reaction, the 3,4,5-trisubstituted aryl nitrone of formula I is recovered by conventional methods including precipitation, chromatographic separation, filtration, distillation, sublimation, and the like. The aryl carbonyl compounds of formula V employed in the above- described coupling reaction are either known compounds or compounds that can be prepared from known compounds by conventional procedures. For example, aryl carbonyl compounds of formula V where R 1 is -C(O)R 5 are readily prepared by acylation ofthe corresponding 4-hydroxy derivative. For example, in a preferred embodiment, 3,5-di-tert-butyl-4-hydroxybenzaldehyde (available from Aldrich Chemical Co., 1001 W. St. Paul Avenue, Milwaukee, WI, USA 53233- 2641) is acetylated by contacting the benzaldehyde with excess acetic anhydride in the presence of an acid catalyst, such as perchloric acid, followed by hydrolysis of the intermediate acetal, to afford 4-acetoxy-3,5-di-tert-butylbenzaldehyde. Other carboxylic anhydrides may also be employed in this reaction including, by way of example, propionic anhydride, butyric anhydride, isobutyric anhydride and the like. Alternatively, such compounds can be prepared by acylation ofthe 4- hydroxy compound with other acylating agents, such as acyl halides, under conventional reaction conditions. The acyl halides employed in this reaction are preferably acyl chlorides or acyl bromides, such as acetyl chloride, acetyl bromide, propionyl chloride, «-butyryl chloride, isobutyryl chloride and the like. Typically, this reaction is conducted in the presence of a trialkylamine, such as triethylamine, to neutralize the acid generated during the reaction. Similarly, the aryl carbonyl compounds of formula V where R 1 is -C(O)NR 6 R 7 are readily prepared by reaction ofthe corresponding 4-hydroxy derivative with an isocyanate (i.e., R 6 R 7 N=C=O). For example, in a preferred embodiment, 3,5-di-tert-butyl-4-hydroxybenzaldehyde is reacted with ethylisocyanate to afford 4-(ethylaminocarbonyloxy)-3,5-di-tert- butylbenzaldehyde. Typically, this reaction is conducted at ambient temperature in an inert diluent, such as N,N-dimethylformamide, in the presence of an excess of a trialkylamine, such as triethylamine and the like. Other isocyantes may be employed in this reaction including, by way of illustration, n-propylisocyanate, n- butylisocyanate and the like. Additionally, the aryl carbonyl compounds of formula V where R 1 is -CHR 9 -X-R 8 are readily prepared by reacting the corresponding 4-hydroxy derivative with a compound ofthe formula L-CHR 9 -X-R 8 , where L is a leaving group, such as a halogen or a sulfonate ester, and R 8 , R 9 and X are as defined herein. Typically, this reaction is conducted by contacting the 4-hydroxy derivative with an excess ofthe alkylating agent in the presence of an equimolar amount of a trialkylamine, such as N,N-diisopropylefhylamine, in an inert diluent such as 1,2-dichloroethane. Preferred alkylating agents for use in this reaction include, by way of example, methoxymethyl chloride and 2-methoxyethoxymethyl (MEM) chloride. The hydroxylamine compounds of formula VI above are also known compounds or compounds which can be prepared from known compounds by conventional procedures. Typically, the hydroxylamine compounds of formula VI are prepared by reducing the corresponding nitro compound (i.e., R 4 -NO 2 , wherein R 4 is as defined above) using a suitable reducing agent such as activated zinc/acetic acid, activated zinc/ammonium chloride or an aluminum/mercury amalgam. This reaction is typically conducted at a temperature ranging from about 15°C to about 100°C for about 0.5 to 12 hours, preferably about 2 to 6 hours, in an aqueous reaction media, such as an alcohol/water mixture in the case ofthe zinc reagents or an ether/water mixture in the case ofthe aluminum amalgams. Aliphatic nitro compounds (in the form of their salts) can also be reduced to hydroxylamines using borane in tetrahydrofuran. Since some hydroxylamines have limited stability, such compounds are generally prepared immediately prior to reaction with the aryl carbonyl compound of formula V. Preferred hydroxylamines for use in this invention include, but are not limited to, N-isopropylhydroxylamine, N-n-propylhydroxylamine, N-n- butylhydroxylamine, N-tert-butylhydroxylamine, N-cyclohexylhydroxylamine and the like. Pharmaceutical Compositions When employed as pharmaceuticals, the 3,4,5-trisubstituted aryl nitrones of this invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one active compound. Generally, the compounds of this invention are administered in a pharmaceutically effective amount. The amount ofthe compound actually administered will typically be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity ofthe patient's symptoms, and the like. The pharmaceutical compositions of this invention can be administered by any suitable routes including, by way of illustration, oral, topical, rectal, transdermal, subcutaneous, intravenous, intramuscular, intranasal, and the like. Depending on the intended route of delivery, the compounds of this invention are preferably formulated as either oral, topical or injectable compositions. Pharmaceutical compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, such compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes ofthe liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the nitrone compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form. Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any ofthe following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. Topical compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example, an oil-in-water cream base. Such topical formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration or stability ofthe active ingredients or the formulation. All such known topical formulations and ingredients are included within the scope of this invention. The compounds of this invention can also be administered by a transdermal device. Accordingly, topical administration can be accomplished using a patch either of the reservoir or porous membrane type or of a solid matrix variety. Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the 3,4,5-trisubstituted aryl nitrone compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like. The above-described components for orally and topically administrable or injectable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences. 18th edition, 1990, Mack Publishing Company, Easton, Pennsylvania, 18042, which is incorporated herein by reference. The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in the incorporated materials in Remington's Pharmaceutical Sciences. The following formulation examples illustrate representative pharmaceutical compositions of this invention. The present invention, however, is not limited to the following pharmaceutical compositions. Formulation 1 - Tablets A compound of formula I is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active nitrone compound per tablet) in a tablet press. Formulation 2 - Capsules A compound of formula I is admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active nitrone compound per capsule). Formulation 3 - Liquid A compound of formula I (125 mg), sucrose (1.75 g) and xanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymefhyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water is then added to produce a total volume of 5 mL. Formulation 4 - Injection The compound of formula I is dissolved in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL. Formulation 5 - Ointment Stearyl alcohol (250 g) and white petrolatum (250 g) are melted at about 75 °C and then a mixture of a compound of formula I (50 g), methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) is added and the resulting mixture is stirred until it congeals. Compound Utility Among other properties, the 3,4,5-trisubstituted aryl nitrones of this invention have been discovered to inhibit the induction of inducible cylcooxygenase (COX-2) and/or to inhibit the release of physiologically active leukotrienes and/or to be effective in various in vivo arthritis models. Accordingly, the compounds and pharmaceutical compositions of this invention find use as therapeutics for treating inflammation-related conditions in mammals including humans. In particular, the compounds of this invention have been discovered to effectively inhibit the induction of inducible cyclooxygenase (COX-2), the release of which results in prostagladin E 2 (PGE 2 ) synthesis. PGE 2 is produced by the enzyme COX as part ofthe arachidonic acid pathway. The enzyme COX is now known to exist in two forms, COX-1 and COX-2. COX-1 is a constitutive form of the enzyme found in most tissues and organs. COX-2, on the other hand, is an inducible form ofthe enzyme associated with the production of PGE 2 and inflammation. Without being limited to theory, it is believed that selective inhibition of COX-2 formation will provide therapeutic agents which effectively reduce inflammation with fewer or none ofthe side effects associated with inhibition of COX-1 and/or COX-2. Since the compounds of this invention have been discovered to inhibit the release PGE 2 , such compounds are useful for treating diseases or conditions characterized by an overproduction or a dysregulated production of prostagladin E 2 including many inflammatory conditions. Among the inflammation-related conditions which may be treated with the 3,4,5-trisubstituted aryl nitrone compounds and pharmaceutical compositions of this invention are various forms of arthritis, including but not limited to, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriatic arthritis, and the like. Other inflammation-related conditions include, by way of illustration, inflammatory bowel disease (IBD), septic shock, erythema nodosum leprosy, septicemia, uveitis, adult respiratory distress syndrome (ARDS), organ rejection, neuro-inflammatory conditions, cardio-inflammatory conditions and the like. As discussed above, the compounds described herein are suitable for use in a variety of drug delivery systems. Injection dose levels for treating inflammation- related conditions range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient. For the treatment of long-term conditions, such as arthritis, the regimen for treatment may stretch over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.1 to about 20 mg/kg of the nitrone, with preferred doses each providing from about 0.1 to about 10 mg/kg and especially about 1 to about 5 mg/kg. The compounds of this invention can be administered as the sole active agent or they can be administered in combination with other active agents, such as cyclooxygenase inhibitors, 5-lipoxygenase inhibitors, non-steroidal antiinflammatory drugs (NSAIDs), steroids, peripheral analgesic agents such as zomepirac, diflunisol, and the like, and other active nitrone derivatives. The novel 3,4,5-trisubstituted aryl nitrones of this invention also find use as analytical reagents, i.e. as spin traps, for detecting unstable free radicals using electron spin resonance (ESR) spectroscopy and related techniques. When used as analytical reagents, the nitrone compounds of this invention are typically contacted with the radical to be studied in solution and an ESR spectrum generated in a conventional manner. In particular, the nitrones of this invention may be used to detect and identify free radicals in biological systems. Any ESR spectrometer, such as a JEOL JES-FE3XG spectrometer, may be employed in these experiments. Typically, the solution containing the spin-trap will be deoxygenated by, for example, bubbling argon or nitrogen through the solution before the ESR experiment is conducted. Preferably, an excess ofthe nitrone is used in such ESR experiments. The actual experimental procedures employed in the spin-trapping experiment will depend on a number of factors, such as the manner of radical production, the inertness ofthe solvent and reagents with respect to the spin trap, the lifetime ofthe spin adduct and the like. Spin trapping procedures are well known in the art and the exact procedure employed can be determined by those skilled in the art. Typical procedures and apparatus for conducting spin trapping experiments are described, for example, in C. A. Evans, "Spin Trapping", Aldrichimica Acta, (1979), 12(2), 23-29, and references cited therein. The following synthetic and biological examples are offered to illustrate this invention and are not to be construed in any way as limiting the scope of this invention. EXAMPLES In the examples below, the following abbreviations have the following meanings. Abbreviations not defined below have their generally accepted meaning. bd = broad doublet bs = broad singlet d = doublet dd = doublet of doublets dec = decomposed dH 2 O = distilled water ELISA = enzyme-linked immuno-sorbent assay EtOAc = ethyl acetate EtOH = ethanol g = grams h = hours Hz = hertz ip = intraperitoneal L = liter m = multiplet min = minutes M = molar MeOH - methanol mg = milligram MHz = megahertz mL = milliliter mmol = millimole m.p. = melting point N = normal po = per os, oral q = quartet quint. = quintet s = singlet t = triplet THF = tetrahydrofuran tic = thin layer chromatography μg = microgram μL = microliter UN = ultraviolet In the examples below, all temperatures are in degrees Celsius (unless otherwise indicated). Example A-Ν describe the synthesis of intermediates useful for preparing nitrones of this invention; Examples 1-19 describe the synthesis of various nitrones; and Examples I-NI describe the testing of such compounds. Example A Synthesis of N-tert-Butylhydroxylamine Zinc dust (648 g) was added in portions to a cooled mixture of 2-methyl-2- nitropropane (503 g) and ammonium chloride (207 g) in deionized water (6 L) at such a rate so as to maintain the temperature below 18°C. The reaction mixture was stirred mechanically for 15 hours and then filtered. The solid was washed with hot water (1.75 L). The combined filtrate was saturated with potassium carbonate (4.6 Kg) and extracted with ethyl acetate (2 x 1300 mL). The organic solution was dried over anhydrous sodium sulfate, filtered and rotary evaporated to give the title compound (329 g, 75.7% yield) as white crystals. This material was used without further purification. Spectroscopic data were as follows: Η ΝMR (CDC1 3 , 270 MHz) δ = 1.090 (s, 3 CH 3 ). Example B Synthesis of N-Isopropylhydroxylamine Using the procedure of Example A above and 2-nitropropane, the title compound was prepared. The crude hydroxylamine product was used without further purification. Example C Synthesis of N-Cyclohexylhydroxylamine Using the procedure of Example A above and nitrocyclohexane, the title compound can be prepared. Alternatively, N-cyclohexylhydroxylamine hydrochloride may be purchased commercially from Aldrich Chemical Company, Inc., Milwaukee, WI USA and neutralized with a base, such as potassium carbonate, to provide the title compound. Example D Synthesis of 4-Acetoxy-3,5-di-tert-butylbenzaldehyde 3,5-Di-tert-butyl-4-hydroxybenzaldehyde (100 g, 0.411 moles) was placed in a 5 L round-bottomed flask equipped with a mechanical stirrer. Acetic anhydride (300 mL) was added with stirring followed by 70% perchloric acid (0.600 mL). The solid immediate dissolved and a blue colored solution formed. The reaction mixture was stirred overnight under nitrogen. The reactions progress was determined by TLC. After completion ofthe reaction, the flask was cooled in an ice bath. While stirring the reaction mixture vigorously, ice water was added in small portions. The flask became warm during addition ofthe water. A total of 2 L of water was added. An oil separated and upon continuous stirring the oil solidified to provide brown lumps. The brown lumps were separated in a Buchner funnel and the solid was washed freely with water to remove acetic acid. The solid was then dried under vacuum. To a solution ofthe solid in ethanol (250 mL) was added concentrated hydrochloric acid (25 mL). The resulting solution was boiled for ten minutes and then left to cool. While stirring, the reaction mixture was poured into 2 L of water and an oil separated. Upon continuous stirring, the oil solidified to form brown lumps. The solid was separated and packed in Buchner funnel and washed freely with water (about one liter). The solid was then dried on a mechanical pump to afford the title compound in 99.4% yield as a light brown solid, m.p. 65.2-74.5 °C. Spectroscopic data were as follows: 'H NMR (CDC1 3 , 270 MHz): δ = 9.96 (IH, s, carbonyl H), 7.86 (2H, s, phenyl H), 2.38 (3H, s, 3CH 3 ), 1.39 (18H, s, 18 CH 3 ). Example E Synthesis of 4-Isobutanoyl-3,5-di-tert-butylbenzaldehyde 3,5-Di-tert-butyl-4-hydroxybenzaldehyde (10 g, 0.041 mol) was placed in a 500-mL round-bottomed flask fitted with a mechanical stirrer. Isobutyric anhydride (40 mL) was added with stirring, followed by 0.200 mL of 40% perchloric acid. The solid immediately dissolved to form a red color solution. The reaction mixture was stirred overnight under nitrogen. The reaction progress was determined by TLC. After completion of reaction, the reaction mixture was cooled in an ice bath and added to 400 mL of vigorously stirred ice water. The mixture became warm and an oil separated. The oil was extracted with methylene chloride and the organic layer was washed with 1.5M NaOH solution (2 X 100 mL), water ( 2 X 100 mL) and then dried over magnesium sulfate. The solvent was removed in vacuo to afford a red oil. To a solution ofthe red oil in ethanol (200 mL) was added concentrated hydrochloric acid (50 mL). The resulting solution was boiled for ten minutes and the solution was left to cool. While stirring, the mixture was then poured into 2 L of water and an oil separated. Upon continuous stirring, the oil solidified to brown lumps. The solid was separated and packed in Buchner funnel and then washed freely with water to remove acetic acid (about one liter). The solid was then dried on a mechanical pump to afford the title compound (56.7% yield) which was used without further purification. Example F Synthesis of 4-w-ButanoyI-3,5-di-tert-butylbenzaldehyde 3,5-Di-tert-butyl-4-hydroxybenzaldehyde (15 g, 0.062 mol) was placed in a 500-mL round-bottomed flask fitted with a mechanical stirrer. w-Butyric anhydride (50 mL) was added with stirring, followed by 0.200 mL of 40% perchloric acid. The solid immediately dissolved to form a blue colored solution. The reaction mixture was stirred overnight under nitrogen. The reaction progress was determined by TLC. After completion of reaction, the reaction mixture was cooled in an ice bath and added to 400 mL of vigorously stirred ice water. The mixture became warm and an oil separated. The oil was extracted with methylene chloride and the organic layer was washed with 5% NaOH (4 X 100 mL), brine (1 X 100 mL), water (4 X 100 mL) and dried over MgSO4. The solvent was removed in vacuo to afford a red oil. To a solution ofthe red oil in ethanol (200 mL) was added concentrated hydrochloric acid (40 mL). The resulting solution was boiled for ten minutes and left to cool. While stirring, the mixture was then poured into 2 L of water and an oil separated. Upon continuous stirring, the oil did not solidify, so the mixture was extracted with methylene chloride. The organic layer was washed with saturated NaHCO3 (2 X 100 mL), water (3 X 100 mL) and dried over MgSO4. The solvent was removed in vacuo to afford the title compound as a red oil (77.6%) yield) which was used without further purification. Example G Synthesis of 4-n-Pentanoyl-3,5-di-tert-butylbenzaldehyde 3,5-Di-tert-butyl-4-hydroxybenzaldehyde (10.0 g, 0.0.081 mol) was placed in a 500-mL round-bottomed flask fitted with a mechanical stirrer. Valeric anhydride (50 mL) was added with stirring, followed by 0.200 mL of 40% perchloric acid. The solid immediately dissolved to form a green colored solution. The reaction mixture was stirred overnight under nitrogen. The reaction progress was determined by TLC. After completion of reaction, the reaction mixture was cooled in an ice bath and added to 400 mL of vigorously stirred ice water. The mixture became warm and an oil separated. The oil was extracted with methylene chloride and the organic layer was washed with 5% NaOH (3 X 50 mL), brine (3 X 50 mL), water (3 X 100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo to afford a thick oil. To a solution ofthe oil in ethanol (200 mL) was added concentrated hydrochloric acid (50 mL). The resulting solution was boiled for ten minutes and left to cool. While stirring, the mixture was then poured into 2 L of water and an oil separated. Upon continuous stirring, the oil did not solidify, so the mixture was extracted with methylene chloride. The organic layer was washed with saturated NaHCOa (3 X 50 mL), water (5 X 100 mL) and dried over MgSO4. The solvent was removed in vacuo to afford the title compound as a red oil which was used without further purification. Example H Synthesis of 4-(Ethylaminocarbonyloxy)-3,5-di-tert-butylbenzaldehyde To a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (5 g, 20 mmol) in DMF (100 mL) was added triethylamine (3.5 mL, 25 mmol) and the solution was stirred for 15 min at room temperature. Ethyl isocyanate (1.95 mL, 25 mmol) was added and the reaction mixture was stirred for 2 h at room temperature until no more hydroxybenzaldehyde was detected by TLC (R f =0.78 for product and 0.89 for starting material using 1:1 hexanes/EtOAc). The reaction solution was concentrated by azeotropic removal of DMF with water. The resulting suspension was filtered, washed with water and dried in a vacuum oven to afford 96% ofthe title compound as a light buff solid. Spectroscopic data were as follows: 5 H NMR (OMSO-d 6 , 270 MHz): δ =9.96 (IH, s, aldehyde CHO), 8.04 (IH, t, carbamate NH), 7.83 (2H, s, phenyl H), 3.09 (2H, m, ethyl CH 2 ), 1.34 (18H, s, 6 CH 3 ), 1.07 (3H, t, ethyl CH 3 ). 1 C NMR (DMSO- 6 , 270 MHz): δ =193.4, 155.1, 154.2, 145.0, 133.3, 127.8, 35.9, 31.4, 30.5. Example I Synthesis of 4-(«-Propylaminocarbonyloxy)-3,5-di-tert-butyIbenzaldehyde The title compound was prepared in DMF using 3,5-di-tert-butyl-4- hydroxybenzaldehyde and n-propyl isocyanate according to the procedure described in Example H. The title compound was isolated in 100.0%> yield as an off-white solid. Example J Synthesis of 4-(«-Butylaminocarbonyloxy)-3,5-di-tert-butylbenzaldehyde The title compound was prepared in DMF using 3,5-di-tert-butyl-4- hydroxybenzaldehyde and «-butyl isocyanate according to the procedure described in Example H. The title compound was isolated in 87.5% yield as a buff solid. Example K Synthesis of 4-(2-Ethoxycarbonyl)ethylaminocarbonyloxy)-3,5-di-tert-butylbenzaldehyde The title compound was prepared in DMF using 3,5-di-tert-butyl-4- hydroxybenzaldehyde and ethyl 3-isocyanatopropionate according to the procedure described in Example H. The title compound was isolated in 100% yield as an off- white solid. Example L Synthesis of 4-(2-Ethoxycarbonyl)methylaminocarbonyloxy)-3,5-di-tert-butylbenzaldehyde The title compound was prepared in DMF using 3,5-di-tert-butyl-4- hydroxybenzaldehyde and ethyl 2-isocyanatoacetate according to the procedure described in Example H. The title compound was isolated in 100%> yield as an off- white solid. Example M Synthesis of 4-Methoxymethoxy-3,5-di-tert-butylbenzaldehyde To a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (10 g, 40 mmol) in 1 ,2-dichloroethane (200 mL) was added N,N-diisopropylethylamine (6.97 mL, 40 mmol) and the solution was stirred for 1 h at room temperature. Chloromethoxymethyl ether (3.77 mL, 50 mmol) was added and the reaction mixture was stirred for 1 h at room temperature and then refluxed for 16 h until no more hydroxybenzaldehyde was detected by TLC (R f = 0.78 for product and 0.70 for starting material using 1:1 hexanes/EtOAc). The reaction mixture was cooled to room temperature and washed with water. The organic layer was concentrated and the residue applied to a silica gel column and eluted with mixture of pentane/EtOAc. The title compound was isolated in 100 % yield as a brown oil. Spectroscopic data were as follows: Η NMR (DMSO-tf 6 , 270 MHz): δ = 9.89 (IH, s, aldehyde CHO), 7.80 (2H, s, phenyl H), 4.92 (2H, s, CH 2 ), 3.64 (3H, s, CH 3 ), 1.46 (18H, s, 6 CH 3 ). 13 C NMR (DMSO- 6 , 270 MHz): δ =192.11, 160.11, 145.77, 131.65, 128.55, 100.98, 57.66, 35.99 and 30.16. Example N Synthesis of 4-(2-Methoxy)ethoxymethoxy-3,5-di-tert-butylbenzaldehyde To a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (8 g, 33 mmol) in 1 ,2-dichloroethane (150 mL) was added N,N-diisopropylethylamine (6.97 mL, 40 mmol) and the solution was stirred for 1 h at room temperature. 2- Methoxyethoxymethyl (MEM) chloride (5.7 mL, 50 mmol) was added and the reaction mixture was stirred for 1 h at room temperature and then at reflux for 26 h until no more hydroxybenzaldehyde was detected by TLC (R f = 0.92 for product and 0.70 for starting material using 1 : 1 hexanes/EtOAc). The reaction mixture was cooled to room temperature and washed with water. The organic layer was concentrated and the residue applied to a silica gel column and eluted with mixture of pentane/EtOAc. The title compound was isolated (98 % yield) as a brown oil. Example 1 Synthesis of α-(4-Acetoxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone 4-Acetoxy-3,5-di-tert-butylbenzaldehyde (113.16 g, 0.41 mol) was placed in a 2 L round-bottomed flask fitted with a magnetic stirrer. Benzene (500 mL) was added and the mixture was stirred until the solids dissolved. To the resulting red solution was added tert-butylhydroxylamine (43.80 g, 0.49 mol) and silica gel (20 g). The mixture was refluxed overnight at which time TLC showed no remaining starting material (R f = 0.31 for product and 0.80 for starting material using 3:1 hexanes/EtOAc). The benzene was removed in vacuo on a rotovap to provide a grey solid. The solid was dissolved in a minimum amount of ethyl acetate and the flask was left to stand in the freezer. The white crystals which formed were separated, washed with hexanes and dried under vacuum to afford 105.78 g ofthe title compound as a crystalline white solid (74.4% yield), m.p. 227.0-248.9°C. Spectroscopic data were as follows: 'H ΝMR (CDCl j , 270 MHz): δ = 8.32 (IH, s, phenyl H), 7.50 (IH, s, nitronyl H). 2.35 (3H, s, 1 CH 3 ), 1.61 (9H, s, 3 CH 3 ), 1.37, s, 18 CH 3 ). 13 C ΝMR (CDCI 3 , 270 MHz): δ =170.7, 149.2, 142.6, 129.7, 128.4, 127.2, 70.7, 35.5, 31.4, 28.5, 22.6. Example 2 Synthesis of α-(4-Isobutanoyl-3,5-di-tert-butylphenyl)-N-tert-butylnitrone To a solution of 4-isobutanoyl-3,5-di-tert-butylbenzaldehyde (7.00 g, 0.023 mol) in benzene (200 mL) was added tert-butylhydroxylamine (2.56 g, 0.029 mol) and / toluenesulfonic acid (0.100 g). Using a Dean-Stark trap, the resulting mixture was refluxed until no more aldehyde was detected by TLC (R f = 0.30 for product and 0.89 for starting material using 3:1 hexanes/EtOAc). The solvent was removed in vacuo and the residue was thoroughly washed with hexanes. The title compound was isolated in 50.8% yield as a white solid, m.p. 197.1-208.1 °C. Spectroscopic data were as follows: Η NMR (CDC1 3 , 270 MHz): δ = 8.32 (2H, s, phenyl), 7.51 (IH, s, nitronyl H), 2.87 (IH, q, J=7.17Hz, isobutyryl H), 1.61 (9H, s, 9CH 3 ), 1.38 (6H, d, J=7.17, 6CH 3 ), 1.36 (18H, s, I8CH 3 ). 13 C NMR (CDC1 3 , 270 MHz): δ = 176.0, 150.2, 142.7, 129.9, 128.1, 127.1, 70.7, 35.5, 35.2, 31.3, 28.5, 18.7. Example 3 Synthesis of -(4-n-Butanoyl-3,5-di-tert-butylphenyl)-N-tert-butylnitrone To a solution of 4-«-butanoyl-3,5-di-tert-butylbenzaldehyde (9.63 g, 0.032 mol) in benzene (200 mL) was added tert-butylhydroxylamine (3.52 g, 0.040 mol) andjc-toluenesulfonic acid (0.100 g). Using a Dean-Stark trap, the resulting solution was refluxed until no more aldehyde was detected by TLC (R f = 0.30 for product and 0.91 for starting material using 3:1 hexanes/EtOAc). The solvent was removed in vacuo and the residue was crystallized from EtOAc and hexanes to afford the titled compound (50.2% yield) as a white solid, m.p. 216.9-236.5°C. Spectroscopic data were as follows: Η ΝMR (CDCI 3 , 270 MHz): δ = 8.32 (2H, s, phenyl H), 7.50 (IH, s, nitronyl H), 2.61 (2H, t, J=7.67Hz, 2CH 2 ), 1.78 (2H, m, J=4.70Hz, 2CH 2 ), 1.61 (9H, s, 9CH 3 ), 1.36 (18H, s, 18CH 3 ), 1.05 (3H, t, J=7.42Hz, 3CH 3 ). 13 C ΝMR (CDCI 3 , 270 MHz): δ =173.2, 149.5, 142.7, 129..8, 128.2, 127.1, 70.7, 37.6, 35.5, 31.4, 28.5, 17.7, 13.8. Example 4 Synthesis of α-(4-Acetoxy-3,5-di-tert-butylphenyl)-N-isobutylnitrone To a solution of 4-acetoxy-3,5-di-tert-butylbenzaldehyde (17.0 g, 0.0615 mol) in methanol (250 mL) was added isobutylhydroxylamme (5.36 g, 0.0714mol) and concentrated hydrochloric acid (10 drops ). Using a Dean-Stark trap, the resulting solution was refluxed until no more aldehyde was detected by TLC (R f = 0.23 for product and 0.84 for starting material using 3:1 hexanes/EtOAc) The solvent was removed in vacuo and the residue was a red oil which when triturated with hexanes it turned into solid. The solid was separated and washed completely with hexanes. The titled compound was isolated in 52.3%> yield as a white solid, m.p. 176.8-180.4°C. Spectroscopic data were as follows: 'H ΝMR (CDC1 3 , 270 MHz): δ =8.3 (2H, s, phenyl H), 7.42 (IH, s, nitronyl H), 4.20 (IH, q, J=6.50Hz, ICH), 2.35 (3H, s, 3CH 3 ), 1.50 (6H, d, J=6.43 Hz, 6CH 3 ), 1.37 (18H, s, 18CH 3 ). , C ΝMR (CDCI 3 , 270 MHz): δ =170.7, 150.1, 142.7, 131.9, 128.0, 127.0, 67.8, 35.5, 31.3, 22.6, 20.9. Example 5 Synthesis of α-(4-Acetoxy-3,5-di-tert-butylphenyl)-N-l-hydroxy-2-methylprop-2-ylnitrone To a solution of 4-acetoxy-3,5-di-tert-butylbenzaldehyde (10.0 g, 0.0362 mol) in benzene (200 mL) was added N-(l-hydroxy-2-methylprop-2-yl) hydroxylamine (5.55 g, 0.0543 mol) and / toluenesulfonic acid (0.090g). Using a Dean-Stark trap, the resulting mixture was refluxed until no more aldehyde was detected by TLC(R f = 0.20 for product and 0.98 for starting material using 1 : 1 hexanes/EtOAc). The solvent was removed in vacuo and the residue was washed with hot hexanes. The title compound was isolated (83.9 % yield) as a off white solid, m.p. 204.3-204.8 °C. Spectroscopic data were as follows: Η NMR (CDCI 3 , 270 MHz): δ=8.30 (2H, s, phenyl H), 7.46 (IH, s, nitronyl H). 3.79 (2H, s, 2 CH 2 ), 2.36 (3H, s, 3 CH 3 ), 1.60, s, 6 CH 3 ), 1.37 (18H, s, I8CH 3 ). 13 C NMR (CDCI 3 , 270 MHz): δ =171.1, 150.1, 142.9, 132.3, 127.7, 72.8, 69.8, 35.5, 31.6, 31.3, 23.9, 22.6. Example 6 Synthesis of α-(4-/ι-Pentanoyl-3,5-di-tert-butylphenyl)-N-tert-butyInitrone To a solution of 4-pentanoyl-3,5-di-tert-butylbenzaldehyde (17.48 g, 0.050 mol) in benzene (250 mL) was added tert-butylhydroxylamine (4.57 g, 0.0510 mol) and /j-toluenesulfonic acid (0.080 g). Using a Dean-Stark trap, the resulting mixture was refluxed until no more aldehyde was detected by TLC (R f = 0.43 for product using 1 :1 hexanes/EtOAc). The solvent was removed in vacuo and the residue was thoroughly washed with hexanes. The title compound was isolated (56.50 % yield) as a white solid, m.p. 195.5-204.8°C. Spectroscopic data were as follows: Η ΝMR (CDCI 3 , 270 MHz): δ= 8.31 (2H, s, phenyl H), 7.50 (IH, s, nitronyl H). 2.63 (2H, t, J=7.80 2CH), 1.85-1.67 (2H, m, 2CH 2 ), 1.61 (9H, s, 9CH 3 ), 1.52-1.36 (2H, m, 2CH 2 ), 1.36 (18H, s, 18CH 3 ), 0.97 (3H, t, J=7.30, 3CH 3 ). 13 C ΝMR (CDCI 3 , 270 MHz): δ =173.2, 149.4, 142.7, 129.8, 128.2, 127.1, 70.7, 35.5, 35.4, 31.4, 28.4, 26.2, 22.2, 13.8. Examples 7-10 Using the appropriate starting materials and the procedures described herein, the following additional compounds were prepared: α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-4-trifluoromethylbenzylnitrone (m.p. 217-232°C); -(4-propionyloxy-3 ,5-di-tert-butylphenyl)-N-tert-butylnitrone (m.p. 202-222°C); α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-methylnitrone (m.p. 136-143 °C); and α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-3,4,5-trimethoxybenzylnitrone (m.p. 231.7-235 °C). Example 11 Synthesis of -[4-(Ethylaminocarbonyloxy-3,5-di-tert-butyIphenyI]-N-tert-butylnitrone To a solution of 3, 5-di-tert-butyl-4-(ethylaminocarbonyloxy)- benzaldehyde (5 g, 16 mmol) in benzene (200 mL) was added tert- butylhydroxylamine (2.14 g, 24 mmol). The resulting solution was refluxed for 96 h until no more aldehyde was detected by TLC (R f = 0.57 for product and 0.78 for starting material using 1:1 hexanes/EtOAc). The solvent was removed in vacuo and the residue applied to a silica gel column and eluted with mixture of hexane/EtOAc. The title compound was isolated in 57 % yield as a white solid, m.p. 202.2-212.2°C. Spectroscopic data were as follows: Η ΝMR (DMSO-J 6 , 270 MHz): δ = 8.37 (2H, s, phenyl H), 7.86 (IH, t, J = 6.3 Hz, carbamate ΝH), 7.83 (IH, s, nitronyl H), 3.08 (2H, quintet, J = 6.3 Hz, ethyl CH 2 ), 1.49 (9H, s, 3 CH 3 ), 1.31 (18H, s, 6 CH 3 ), 1.06 (3H, t, J = 6.4 Hz, ethyl CH 3 ). 13 C ΝMR (DMSO- 6 , 270 MHz): δ = 155.8, 149.6, 143.30, 129.5, 128.7, 126.9, 70.6, 35.8, 31.6, 28.5 and 15.7. Example 12 Synthesis of -[4-(n-Propylaminocarbonyloxy-3,5-di-tert-butylphenyl]-N-tert-butylnitrone The title compound was prepared in benzene using 3,5-di-tert-butyl-4-(«- propylaminocarbonyloxy)benzaldehyde and tert-butylhydroxylamine according to the procedure described in Example 11. The title compound was isolated in 96.6% yield as a white solid, m.p. 206.5-214.0°C. Spectroscopic data were as follows: Η NMR (DMSO- 6 , 270 MHz): δ = 8.38 (2H, s, phenyl H), 7.90 (1H, t, J = 5.8 Hz, carbamate NH), 7.84 (IH, s, nitronyl H), 3.02 (2H, q, J = 6.5 Hz, propyl NCH 2 ), 1.50 (9H, s, 3 CH 3 ), 1.45 (3H, hextet, J = 7.2 Hz, propyl CH 2 ), 1.32 (18H, s, 6 CH 3 ), 0.88 (3H, t, J = 7.3 Hz, propyl CH 3 ). 13 C NMR (DMSO- 6 , 270 MHz): δ =155.7, 149.7, 143.3, 129.5, 128.7, 127.0, 70.6, 42.8, 35.8, 31.7, 28.5, 23.1 and 11.8. Example 13 Synthesis of -[4-(«-Butylaminocarbonyloxy-3,5-di-tert-butylphenyl]-N-tert-butylnitrone The title compound was prepared in benzene using 3,5-di-tert-butyl-4-(«- butylaminocarbonyloxy)benzaldehyde and tert-butylhydroxylamine according to the procedure described in Example 11. The title compound was isolated in 93.4%> yield as a white solid, m.p. 203.6-205.1 °C. Spectroscopic data were as follows: Η ΝMR (DMSO- 6 , 270 MHz): δ = 8.38 (2H, s, phenyl H), 7.88 (IH, t, J = 5.7 Hz, carbamate ΝH), 7.84 (IH, s, nitronyl H), 3.05 (2H, q, J = 6.3 Hz, n-butyl ΝCH 2 ), 1.50 (9H, s, 3 CH 3 ), 1.45-1.37 (4H, m, n-butyl 2 CH 2 ), 1.31 (18H, s, 6 CH 3 ), 0.87 (3H, t, J = 7.1 Hz, n-butyl CH 3 ). 13 C NMR (OMSO-d 6 , 270 MHz): δ =155.6, 149.7, 143.3, 129.5, 128.7, 127.0, 70.6, 40.7, 35.8, 31.9, 31.6, 28.5, 19.9 and 14.2. Example 14 Synthesis of α-[4-(2-Ethoxycarbonyl)ethylaminocarbonyloxy-3,5-di-tert-butylphenyl]-N- tert-butylnitrone The title compound was prepared in benzene using 3,5-di-tert-butyl-4-(2- ethoxycarbonyl)ethylaminocarbonyloxy)benzaldehyde and tert- butylhydroxylamine according to the procedure described in Example 11. The title compound was isolated in 88.4% yield as a white solid, m.p. 130.5-146.3 °C. Spectroscopic data were as follows: 'H NMR (OMSO-d 6 , 270 MHz): δ = 8.38 (2H, s, phenyl H), 8.01 (IH, t, J = 6.0 Hz, carbamate NH), 7.84 (IH, s, nitronyl H), 4.08 (2H, q, J = 7.0 Hz, ethyl OCH 2 ), 3.28 (2H, t, J = 6.0 Hz, propionate NCH 2 ), 2.50 (2H, t, J = 6.0 Hz, propionate COCH 2 ), 1.49 (9H, s, 3 CH 3 ), 1.26 (18H, s, 6 CH 3 ), 1.19 (3H, t, J = 7.0 Hz, ethyl CH 3 ). 13 C NMR (DMSO-J 6 , 270 MHz): δ =171.5, 155.6, 149.5, 143.3, 129.4, 128.8, 127.0, 70.6, 60.5, 37.2, 35.8, 34.6, 31.7, 28.5, and 14.7. Example 15 Synthesis of α-[4-(2-Ethoxycarbonyl)methylaminocarbonyloxy-3,5-di-tert-butylphenyl]-N- tert-butylnitrone The title compound was prepared in benzene using 3,5-di-tert-butyl-4-(2- ethoxycarbonyl)methylaminocarbonyloxy)benzaldehyde and tert- butylhydroxylamine according to the procedure described in Example 11. The title compound was isolated in 42%> yield as a white solid, m.p. 177.2-181.6°C. Spectroscopic data were as follows: Η ΝMR (DMSO-d 6 , 270 MHz): δ = 8.38 (2H, s, phenyl H), 8.35 (IH, t, J = 5.7 Hz, carbamate ΝH), 7.84 (IH, s, nitronyl H), 4.10 (2H, q, J = 7.0 Hz, ethyl OCH 2 ), 3.83 (2H, d, J = 5.7 Hz, ΝCH 2 ), 1.50 (9H, s, 3 CH 3 ), 1.32 (18H, s, 6 CH 3 ), 1.19 (3H, t, J = 7.0 Hz, ethyl CH 3 ). 13 C NMR (DMSO-- , 270 MHz): δ =170.3, 155.9, 143.3, 129.4, 128.9, 127.0, 70.7, 61.0, 42.9, 35.8, 31.7, 28.5, and 14.6. Example 16 Synthesis of α-(4-Methoxymethoxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone To a solution of 3,5-di-tert-butyl-4-methoxymethoxybenzaldehyde (11.42 g, 40 mmol) in benzene (200 mL) was added tert-butylhydroxylamine (4.0 g, 50 mmol). The resulting solution was refluxed for 72 h until no more aldehyde was detected by TLC (R f = 0.56 for product and 0.78 for starting material in 1 : 1 hexanes/EtOAc). The solvent was removed in vacuo and the residue was suspended in hexane/EtOAc. The suspension was filtered, washed with hexanes and dried to afford the title compound (69 % yield) as a white solid, m.p. 202.2- 205.9°C. Spectroscopic data were as follows: Η NMR (DMSO--7 6 , 270 MHz): δ = 8.37 (2H, s, phenyl H), 7.79 (IH, s, nitronyl H), 4.84 (2H, s, OCH 2 ), 3.54 (3H, s, OCH 3 ), 1.48 (9H, s, 3 CH 3 ), 1.40 (18H, s, 6 CH 3 ). 13 C NMR (DMSO-J 6 , 270 MHz): δ =155.3, 143.9, 129.4, 127.8, 127.4, 101.0, 70.5, 57.6, 36.0, 32.3, 28.5. Example 17 Synthesis of α-[4-(2-Methoxy)ethoxymethoxy-3,5-di-tert-butylphenyl]-N-tert-butylnitrone The title compound was prepared in benzene with 3,5-di-tert-butyl-4-(2- methoxy)ethoxymethoxybenzaldehyde and tert-butylhydroxylamine using the procedure described in Example 16. The title compound was isolated (70.1 % yield) as a white solid, m.p. 169.6-173.5 °C. Spectroscopic data were as follows: Η ΝMR (DMSO-c? 6 , 270 MHz): δ = 8.38 (2H, s, phenyl H), 7.80 (IH, s, nitronyl H), 4.91 (2H, s, OCH 2 ), 3.87 (2H, m, J = 4.76 Hz, ethoxy OCH 2 ), 3.54 (2H, m, J = 4.76 Hz, OCH 2 ), 3.28 (3H, s, OCH 3 ), 1.49 (9H, s, 3 CH 3 ), 1.40 (18H, s, 6 CH 3 ). 13 C ΝMR (OMSO-d 6 , 270 MHz): δ =155.3, 143.9, 129.4, 127.8, 127.4, 100.1, 71.7, 70.5, 69.3, 58.7, 36.0, 32.3, 28.5. Examples 18 and 19 Using the appropriate starting materials and the procedures described herein, the following additional compounds were prepared: -(4-methoxymethoxy-3 ,5 -di-tert-butylphenyl)-N-3 -(thiomethoxy)but- 1 - ylnitrone (m.p. 76.7-80.0°C); and α-(4-methoxymethoxy-3,5-di-tert-butylphenyl)-N-3- thiomethoxypropylnitrone (m.p. 55-63 °C). Example I Lack of Inhibition of COX-1 and COX-2 In this experiment, the compound of Example 1 was tested to determine if it inhibited the enzymes cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX- 2). The inhibition of COX-1 was measured by incubating arachidonic acid with COX-1 derived from ram seminal vesicles. The inhibition of COX-2 was measured by incubation of arachidonic acid with COX-2 derived from sheep placenta. These assays are further described in Evans et al., Biochem. Pharmacol, 36:2035, 1987. In each assay, the formation of prostaglandin E 2 (PGE 2 ) was measured by spectrophotometric quantitation of malondialdehyde. The compound of Example 1 was added to incubation solutions at a concentration of 300 μM. At this concentration, indomethacin, a known inhibitor of COX-1 and COX-2, completely inhibits both enzymes. Under the same conditions, the compound of Example 1 did not significantly affect COX-1 or COX-2 at a concentration of 300 μM. These results demonstrate that the compound of Example 1 is not an inhibitor ofthe enzymes cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). Example II Inhibition of PGE 2 In this experiment, the ability of nitrones of formula I to inhibit induction of prostaglandin E 2 (PGE 2 ) is demonstrated. For this assay, the test compounds were solubilized in 500 μL of EtOH and then adjusted to 10 mL with complete DMEM with lμg/mL lipopoplysaccharide (LPS) to obtain a lOmM solution. This solution was then diluted 1/100 to obtain a lOOμM. As a reference, indomethacin was solubilized in 500 μL DMSO and then adjusted to 50 mL with complete DMEM with l g/mL LPS. This 2 mM solution was then diluted 1/200 to obtain a lOμM solution. This solution was used as a reference. All dilutions were made with complete DMEM Macrophages (murine macrophages RAW 264.7) were obtained from American Type Culture Collection, Rockville, MD. They were cultured in 75 cm 3 flasks with DMEM (Dulbeco Modified Eagle Medium with 10% Fetal Bovine Serum, penicillin, streptomycin, and glutamine) and seeded into a 96 well plate at 20 x 10 6 cells/10 mL, 200μL per well. At 80-100% confluence, the macrophages were washed with HBSS (with penicillin, streptomycin, and glutamine) and incubated with the test compound or a reference diluted into DMEM (with 10% FCS, penicillin, streptomycin, and glutamine) with l g/mL LPS for 18 hours. The cells were then washed with HBSS and incubated with 30/ M arachidonic acid in HBSS for 15 minutes at 37°C. The supernatant was taken to determine PGE 2 levels using conventional procedures. Results were expressed as percent inhibition. Compounds reducing the induction of PGE 2 by at least about 30% compared to the control were considered effective in this assay. Initially, test compounds were screened at lOO M. Compounds showing activity were screened at lower concentrations to obtain an IC 50 . For such screening, the stock solution was diluted in a series 1 :10 dilutions to obtain 30μM, lOμM, lμM, O.l M solutions. The lO M solution was diluted 1 :3 to obtain a 3 M solution which is then diluted in a series to produce solutions of 0.3 M and 0.03 M. The serial dilutions are used to determine the IC 50 ofthe test compound. Example III Carrageenan Footpad Edema Assay In this example, the ability of compounds of formula I to reduce carrageenan footpad edema in rats is demonstrated. This assay is commonly used to screen and evaluate anti-inflammatory drug candidates. See, for example, C. A. Winter et al, "Carrageenin-induced Edema in Hind Paw ofthe Rat as an Assay for Anti-inflammatory Drugs," Proc. Sci. Exp. Biol. Med. Ill, 544-547 (1962) and references cited therein. In this assay, a carrageenan suspension (0.5%) was prepared by mixing 50 mg of carrageenan (Type IV, λ) in 10 mL of sterile saline solution. Male Sprague-Dawley rats (150-250 g) were then injected subcutaneously with 100 μL ofthe caπageenan suspension in the plantar portion ofthe right rear paw. The test compound (100 mg in 2 mL) or a vehicle control (2 mL) was then administered by po or ip. The initial foot paw volume was measured immediately before and 3 hours after caπageenan challenge using plethysmography (Ugo-Basile). The difference between the 3-hour and the initial paw volume was for each test group of animals was used to calculate the percent inhibition of edema achieved by the test compound at the test dose compared with vehicle control group. Compounds reducing edema by at least about 10% compared to the vehicle control group were considered to be effective in this assay. Example IV Adjuvant Assay In this example, the ability of compounds of formula I to reduce adjuvant- induced footpad edema in rats is demonstrated. This assay is a model for chronic inflammation. See, for example, B. M. Weichman, "Rat Adjuvant Arthritis: A Model of Chronic Inflammation," Pharmacological Methods in the Control of Inflammation, 363-380 (1989) and references cited therein. In this assay, Male Lewis rats weighing between 180-220 g were lightly anesthetized with an ip injection of 30 mg/kg of sodium pentobarbital (50 mg/mL). Desiccated Mycobacterium butyrium (Difco, 20 mg/mL) suspended in mineral oil was injected (50 μL) at both sides ofthe base ofthe tail under the skin. A line was tattooed on both rear paws at 5 mm above the angle ofthe ankle. The paw volumes, under the line, were measured by volume displacement using a plethysmometer (Ugo Basile) at the day of adjuvant injection (day 0) and on day 14. On day 14, animals with paw volumes equal to the mean of paw volumes ± SD were randomized into treatment groups. Rats which fell outside ± 1 SD were not used in the experiment. One group received vehicle (1% methyl cellulose) by the po route and the other group received indomethacin (3 mg/kg suspended in 1% methyl cellulose). Dosing began on day 14, and continued until final assessment on day 21 post-adjuvant injection. A separate group, which did not receive adjuvant or test compound, was also monitored as a control. This group has a slightly positive volume increase when paw volumes on day 21 are subtracted from day 0 values due to growth ofthe rat. Indomethacin (3 mg/kg, po), a known anti-inflammation compound, significantly reduced paw volume as compared to vehicle controls. Compounds reducing paw volume by at least about 30% compared to vehicle control group were considered effective in this test. Example V Collagen Arthritis Assay In this example, the ability of compounds of formula I to reduce collagen footpad edema in rats is demonstrated. This assay is commonly used to screen and evaluate anti-inflammatory drug candidates. See, for example, Larsson et al., Arthritis & Rheumatism, 33:693-701, 1990 and references cited therein. For these experiments, Female DA rats (7-8 weeks of age) were immunized with Type II collagen derived from bovine nasal septum as described in Cremer et al., J. of Immunology, 149:1045-1053, 1992. The collagen was dissolved and administered with incomplete Freund's adjuvant. Standard precautions were taken to avoid denaturing the collagen before its administration such as keeping the solution cold during preparation. Rats were immunized in the base ofthe tail on day 0. Dosing began on day 10 with rats scored on day 21 on a severity scale. Rats are scored for gait (0-3), swelling (metatarsals, ankle, carpals, metacarpals, 0- 3) with the highest scores given for the most swelling or impariment. All scoring was done in a blinded manner. Compounds reducing scores by at least about 30% compared to the controls were considered effective in this assay. The arthritis was also evaluated by comparing paw weights at day 21. Compounds reducing paw weight by at least about 30% compared to the controls were also considered effective in this assay. Assay Results: Each compound of formula I that was tested in the above assays was found to be effective for reducing the induction of PGE 2 and/or effective in the caπageenan, adjuvant and/or collagen assay. Example VI Electron Spin Resonance (ESR) Study Using the following procedures, the nitrones of this invention could be shown to trap free radicals using ESR spin trapping techniques. For additional experimental details, see, for example, K. R. Maples et al., "In Vivo Detection of Free Radical Metabolites", Eree Radicals in Synthesis and Biology (F. Minisci, ed.) pp. 423-436 (Kluwer Academic Publishers, Boston, 1989); and J. A. DeGray et al., "Biological Spin Trapping", Electron Spin Resonance 14:246-300 (1994). In this experiment, a t-butyl hydroperoxide/ferrous iron free radical generating system is used. This free radical generating system produces t-butyl-alkoxyl radicals, t-butyl-peroxyl radicals, and methyl radicals. If the nitrones of this invention are capable of trapping any of these radicals to form a stable radical adduct, such radical adducts should be detectable by ΕSR spectroscopy. To 490 μ\ of a 100 mM solution ofthe nitrone in water is added 5 μl of 100 mM feπous sulfate. The reaction is initiated by the addition of 5 μl of 100 mM t-butyl hydroperoxide. The final concentrations of reagents are 1 mM feπous iron, 1 mM t-butyl hydroperoxide and 98 mM ofthe nitrone compound in water. Once mixed, the solution is quickly transfeπed into a quartz flat cell and this cell is placed in the cavity of a Bruker ΕSP 300 ΕSR spectrometer, and scanned within 5 minutes of mixing. ΕSR spectrometer settings are: 3480 G center field, 200 G field width, 480 seconds sweep time, 9.76 GHz frequency, 10 dB power, 1.6 x 10 5 receiver gain, 0.200 G modulation amplitude, 0.320 second time constant, and 270° phase. The resulting ΕSR spectrum would show that the nitrone is effective at trapping free radicals and that such compounds can be used as analytical reagents for ΕSR applications. From the foregoing description, various modifications and changes in the compositions and methods of this invention will occur to those skilled in the art. All such modifications coming within the scope ofthe appended claims are intended to be included therein.

Claims: WHAT IS CLAIMED IS: 1. A compound of formula I: wherein R 1 is selected from the group consisting of: w W R 9 I I II I I R 5 — C— R 6 — N-C — and R 8 — x-CH— ; R 7 each R 2 is independently selected from a group ofthe formula: R 10 R U — C — R 3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl; R 4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; R 5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; R 6 and R 7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; or R 6 and R 7 can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms; R 8 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; R 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; or R 8 and R 9 can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms; R 10 is selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl; or R 1 and R 10 can be joined to form an alkylene, substituted alkylene, -C(O)- -S(O)- or -S(O) 2 - group; R 11 and R 12 are independently selected from the group consisting of lower alkyl and lower cycloalkyl; or R n and R 12 can be joined to form an alkylene group having from 2 to 10 carbon atoms; Nis oxygen, sulfur, -S(O)- or -S(O) 2 -; and W is oxygen or sulfur; and pharmaceutically-acceptable salts thereof. 2. The compound of Claim 1 wherein Wx ' s oxygen. 3. The compound of Claim 2 wherein R 3 is hydrogen or lower alkyl. 4. The compound of Claim 3 wherein R 3 is hydrogen. 5. The compound of Claim 4 wherein R 4 is selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. 6. The compound of Claim 5 wherein R 4 is selected from the group consisting of methyl, n-propyl, isopropyl, l-hydroxy-2-methylprop-2-yl, w-butyl, tert-butyl, 3-thiomethylpropyl, 3-(thiomethoxy)but-l-yl, cyclohexyl, 4- trifluoromethybenzyl and 3,4,5-trimethoxybenzyl. 7. The compound of Claim 4 wherein R 5 is selected from the group consisting of alkyl and cycloalkyl. 8. The compound of Claim 7 wherein R 5 is selected from the group consisting of methyl, ethyl, «-propyl, isopropyl and n-butyl. 9. The compound of Claim 4 wherein R 7 is hydrogen and R 6 is selected from the group consisting of alkyl and alkoxycarbonylalkyl. 10. The compound of Claim 9 wherein R 6 groups is selected from the group consisting of ethyl, n-propyl, isopropyl, rc-butyl, ethoxycarbonylmethyl and 2-(ethoxycarbonyl)ethyl. 11. The compound of Claim 4 wherein X is oxygen; R 9 is hydrogen; and R 8 is alkyl or alkoxyalkyl. 12. The compound of Claim 11 wherein R 8 is selected from the group consisting of methyl and methoxyethyl. 13. The compound of Claim 4 wherein R 10 , R 1 ' and R 12 are independently lower alkyl. 14. The compound of Claim 13 wherein R 10 , R 1 ' and R 12 are methyl. 15. A compound of formula II: wherein R 13 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; R 14 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; and pharmaceutically-acceptable salts thereof. 16. The compound of Claim 15 wherein R is lower alkyl 17. The compound of Claim 15 wherein R 14 is selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. 18. The compound of Claim 17 wherein R 14 is selected from the group consisting of methyl, «-propyl, isopropyl, l-hydroxy-2-methylprop-2-yl, n-butyl, tert-butyl, 3-thiomethylpropyl, 3-(thiomethoxy)but-l-yl, cyclohexyl, 4- trifluoromethybenzyl and 3,4,5-trimethoxybenzyl. 19. A compound of formula III: wherein R 15 and R 16 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl; or R 15 and R 16 can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms; R 17 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; and pharmaceutically-acceptable salts thereof. 20. The compound of Claim 19 wherein R 16 is hydrogen and R 15 is selected from the group consisting of alkyl and alkoxycarbonylalkyl. 21. The compound of Claim 20 wherein R 15 is selected from the group consisting of ethyl, w-propyl, isopropyl, w-butyl, ethoxycarbonylmethyl and 2- (ethoxycarbonyl)ethyl. 22. The compound of Claim 19 wherein R 17 is selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. 23. The compound of Claim 22 wherein R 17 is selected from the group consisting of methyl, « -propyl, isopropyl, l-hydroxy-2-methylprop-2-yl, « -butyl, tert-butyl, 3-thiomethylpropyl, 3-(thiomethoxy)but-l-yl, cyclohexyl, 4- trifluoromethybenzyl and 3,4,5-trimethoxybenzyl. 24. A compound of formula IV: wherein R 18 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; R 19 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; or R 18 and R 19 can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms; R 20 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; and pharmaceutically-acceptable salts thereof. 25. The compound of Claim 24 wherein R 19 is hydrogen and R 18 is alkyl or alkoxyalkyl. 26. The compound of Claim 25 wherein R is methyl or methoxyethyl. 27. The compound of Claim 24 wherein R 20 is selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. 28. The compound of Claim 27 wherein R 20 is selected from the group consisting of methyl, n-propyl, isopropyl, l-hydroxy-2-methylprop-2-yl, w-butyl, tert-butyl, 3-thiomethylpropyl, 3-(thiomethoxy)but-l-yl, cyclohexyl, 4- trifluoromethybenzyl and 3,4,5-trimethoxybenzyl. 29. A compound selected from the group consisting of: -(4-acetoxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone -(4-isobutanoyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone α-(4-«-butanoyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-isopropylnitrone α-(4-acetoxy-3 ,5-di-tert-butylphenyl)-N- 1 -hydroxy-2-methylprop-2- ylnitrone α-(4-«-pentanoyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-4-trifluoromethylbenzylnitrone α-(4-propionyloxy-3,5-di-tert-butylphenyl)-N-tert-butymitrone α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-methylnitrone α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-3,4,5-trimethoxybenzylnitrone α-[4-(ethylaminocarbonyloxy)-3,5-di-tert-butylphenyl]-N-tert-butylnitrone α-[4-(«-propylaminocarbonyloxy)-3,5-di-tert-butylphenyl]-N-tert- butylnifrone α-[4-(n-butylaminocarbonyloxy)-3,5-di-tert-butylphenyl]-N-tert- butylnifrone α-[4-(2-ethoxycarbonyl)ethylaminocarbonyloxy)-3,5-di-tert-butylphenyl]- N-tert-butylnitrone α-[4-(2-ethoxycarbonyl)methylaminocarbonyloxy)-3,5-di-tert- butylphenyl]-N-tert-butylnitrone -(4-methoxymethoxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone α-[4-(2-methoxy)ethoxymethoxy-3,5-di-tert-butylphenyl]-N-tert- butylnifrone α-(4-methoxymethoxy-3 ,5 -di-tert-butylphenyl)-N-3 -(thiomethoxy)but- 1 - ylnitrone α-(4-methoxymethoxy-3 ,5 -di-tert-butylphenyl)-N-3 - thiomethoxypropylnifrone and pharmaceutically acceptable salts thereof. 30. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula I: wherein R 1 is selected from the group consisting of: W W ψ R 5_c— ' R 6 — N-C— and R 8 — X-CH- R 7 each R 2 is independently selected from a group ofthe formula: R i o R U — C — R 12 R is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl; R 4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; R 5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; R δ and R 7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; or R 6 and R 7 can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms; R 8 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; R 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; or R 8 and R 9 can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms; R 10 is selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl; or R 1 and R 10 can be joined to form an alkylene, substituted alkylene, -C(O)- -S(O)- or -S(O) 2 - group; R 11 and R 12 are independently selected from the group consisting of lower alkyl and lower cycloalkyl; or R 11 and R 12 can be joined to form an alkylene group having from 2 to 10 carbon atoms; Nis oxygen, sulfur, -S(O)- or -S(O) 2 -; and W is oxygen or sulfur; and pharmaceutically-acceptable salts thereof. 31. The pharmaceutical composition of Claim 30 wherein W is oxygen. 32. The pharmaceutical composition of Claim 31 wherein R 3 is hydrogen or lower alkyl. 33. The pharmaceutical composition of Claim 3 wherein R 3 is hydrogen. 34. The pharmaceutical composition of Claim 33 wherein R 4 is selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. 35. The pharmaceutical composition of Claim 34 wherein R 4 is selected from the group consisting of methyl, «-propyl, isopropyl, l-hydroxy-2- methylprop-2-yl, n-butyl, tert-butyl, 3-thiomethylpropyl, 3-(thiomethoxy)but-l-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl. 36. The pharmaceutical composition of Claim 33 wherein R 5 is selected from the group consisting of alkyl and cycloalkyl. 37. The pharmaceutical composition of Claim 36 wherein R 5 is selected from the group consisting of methyl, ethyl, n -propyl, isopropyl and n- butyl. 38. The pharmaceutical composition of Claim 33 wherein R 7 is hydrogen and R 6 is selected from the group consisting of alkyl and alkoxycarbonylalkyl. 39. The pharmaceutical composition of Claim 38 wherein R 6 groups is selected from the group consisting of ethyl, H-propyl, isopropyl, w-butyl, ethoxycarbonylmethyl and 2-(ethoxycarbonyl)ethyl. 40. The pharmaceutical composition of Claim 33 wherein X is oxygen; R 9 is hydrogen; and R 8 is alkyl or alkoxyalkyl. 41. The pharmaceutical composition of Claim 40 wherein R 8 is selected from the group consisting of methyl and methoxyethyl. 42. The pharmaceutical composition of Claim 33 wherein R 10 , R 11 and R 12 are independently lower alkyl. 43. The pharmaceutical composition of Claim 42 wherein R 10 , R 1 ' and R 12 are methyl. 44. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula II: wherein R 13 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; R 14 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; and pharmaceutically-acceptable salts thereof. 45. The pharmaceutical composition of Claim 44 wherein R 13 is lower alkyl. 46. The pharmaceutical composition of Claim 44 wherein R 14 is selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. 47. The pharmaceutical composition of Claim 46 wherein R 14 is selected from the group consisting of methyl, n-propyl, isopropyl, l-hydroxy-2- mefhylprop-2-yl, «-butyl, tert-butyl, 3-thiomethylpropyl, 3-(thiomethoxy)but-l-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl. 48. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula III: wherein R 15 and R 16 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl; or R 15 and R 16 can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms; R 17 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; and pharmaceutically-acceptable salts thereof. 49. The pharmaceutical composition of Claim 48 wherein R 16 is hydrogen and R 15 is selected from the group consisting of alkyl and alkoxycarbonylalkyl. 50. The pharmaceutical composition of Claim 49 wherein R 15 is selected from the group consisting of ethyl, «-propyl, isopropyl, w-butyl, ethoxycarbonylmethyl and 2-(ethoxycarbonyl)ethyl. 51. The pharmaceutical composition of Claim 48 wherein R 17 is selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. 52. The pharmaceutical composition of Claim 51 wherein R 17 is selected from the group consisting of methyl, rc-propyl, isopropyl, l-hydroxy-2- methylprop-2-yl, w-butyl, tert-butyl, 3-thiomethylpropyl, 3-(thiomethoxy)but-l-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl. 53. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula IV: wherein R 18 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; R 19 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; or R 18 and R 19 can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms; R 20 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; and pharmaceutically-acceptable salts thereof. 54. The pharmaceutical composition of Claim 53 wherein R 19 is hydrogen and R 18 is alkyl or alkoxyalkyl. 55. The pharmaceutical composition of Claim 54 wherein R 18 is methyl or methoxyethyl. 56. The pharmaceutical composition of Claim 53 wherein R 20 is selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. 57. The pharmaceutical composition of Claim 56 wherein R 20 is selected from the group consisting of methyl, w-propyl, isopropyl, l-hydroxy-2- methylprop-2-yl, n-butyl, tert-butyl, 3-thiomethylpropyl, 3-(thiomethoxy)but-l-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl. 58. A method for treating a mammal with an inflammation-related condition which method comprises administering to said mammal a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective inflammation-reducing amount of a compound of formula I: wherein R 1 is selected from the group consisting of: each R 2 is independently selected from a group ofthe formula: R 3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl; R 4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; R 5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; R 6 and R 7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; or R 6 and R 7 can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms; R 8 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; R 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; or R 8 and R 9 can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms; R 10 is selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl; or R 1 and R 10 can be joined to form an alkylene, substituted alkylene, -C(O)- -S(O)- or -S(O) 2 - group; R 11 and R 12 are independently selected from the group consisting of lower alkyl and lower cycloalkyl; or R 11 and R 12 can be joined to form an alkylene group having from 2 to 10 carbon atoms; Nis oxygen, sulfur, -S(O)- or -S(O) 2 -; and Wxs oxygen or sulfur; and pharmaceutically-acceptable salts thereof. 59. The method according to Claim 58 wherein the inflammation- related condition is rheumatoid arthritis. 60. The method according to Claim 58 wherein the inflammation- related condition is osteoarthritis. 61. The method according to Claim 58 wherein the inflammation- related condition is ankylosing spondylitis. 62. The method according to Claim 58 wherein the inflammation- related condition is systemic lupus erythemoatosus.

Inventors: CARNEY JOHN M, DANIELZADEH ALBERT, MAVANDADI FARAH, WATERBURY L DAVID, WILCOX ALLAN L, CARNEY, JOHN M., DANIELZADEH, ALBERT, MAVANDADI, FARAH, WATERBURY, L. DAVID, WILCOX, ALLAN L.
Applicants: CARNEY JOHN M, CENTAUR PHARMACEUTICALS INC, DANIELZADEH ALBERT, MAVANDADI FARAH, WATERBURY L DAVID, WILCOX ALLAN L, CARNEY, JOHN M., CENTAUR PHARMACEUTICALS, INC., DANIELZADEH, ALBERT, MAVANDADI, FARAH, WATERBURY, L. DAVID, WILCOX, ALLAN L.
Application year: 1999
Main classification: C07C291
IPC codes: A61K31, A61P19, A61P25, A61P29, A61P37, C07C291, C07C323