CA2260825A1 - Furan nitrone compounds - Google Patents

Abstract

Disclosed are furan nitrone compounds and pharmaceutical compositions containing such compounds. The disclosed compounds are useful as analytical reagents for detecting free radicals and as therapeutics for treating a wide variety of medical dysfunctions and diseases.

Description

WO 98/03496 PCr/US97111960 FURAN NITRONE COMPOUNDS

BACKGROUND OF THE INVENTION
Field of the Invention This invendon relates to novel furan nitrone co".~ lc and their use as free radical trapping agents and th~ ;r agents. More pardcularly, this invendon c~,nc~ s furan nitrone col..i ou~ds and their use as analytdcal reagents 5 for det~ting free r~ic~ls and as ther~reutics for treating various mPAic~
dysfi-nctions and ~ es State of the Art Nitrones, such as a-phenyl-N-teJt-butyl~ one (PBN) and 5,5~imethyl-10 1-pyrroline-N-oxide (DMPO), are h~own to be useful as analydcal l~gcr.ta for t,~ ;ng free radicals. Such co~ ounds function as "spin traps" by reacdng with unstable free radicals to form reladvely stable free radical spin adducts which are observable by electron spin r~sonal.ce (ESR) apC~ OSCOpy. Thus, spin trapping allows previously unobse.~able free radicals to be identifi~i and 15 studied using ESR and related techniques.

The use of nil~nes as spin traps for studying lln~t~bl- free radicals has been applied to bioloEi~l systems. In this regard, PBN, DMPO and related compounds have been used to idendfy s.lpero,.ide (~2--) and hydroxyl ratlic~l~
20 (HO ~ ) in biological systems. Ad~itio~ y~ such nit ones have been used to study lipid peroYi~l~tion and other free radical-induced biological çlru~-5~

W O 98t03496 PCTAUS97/11960 More recently, nitrone compounds, such as PBN and derivatives thereof, have been rl ~. Led as thP~peutics for the llr~ nt of a wide variety of disease c~n~itionc arising from or cha,~ t . ;7P.d by free radical-induce~d oxidative ~lqmqge Such disease con~iitiQns include, for ~ ...ple, disorders of the centra}S nervous system (CNS) and the pe.il.h~ 1 nervous system, such as stroke, P~uk;~conicm~ ;c nerve damage and the like, and disorders of the p ;phr.dl organs, such as athe.usclc~.,sis, cardiac infarction, ulcerative colitis and the like. Nitrones have also been l~ol~ed to treat certain inflq...."~to,y con~litionc~ such as arthritis.
Although various nitrone co",?ounds have been previously reported to be useful as analytical reagen~s or thel~c;ulic agents, a need exists for novel nitrone spin traps having improved effectiveness in these applic~tion~. For example, when using nil~ones as thelapeulic agents for treating acute 15 cQn~litiQnC~ such as stroke, cardiac infarction or the like, it is particularly desirable to be able to 3dminicter the nitrone spin trap at high doses, çspe~iqlly to the loc~li7~ area i~ q~ely ;"~"o~ ing the acute incident~ to minimi7~
the amount of free radical-in~uced oxidative damage that occurs. Thus, nitrone co~"po~"ds used to treat acute conditions should be non-toxic or have very low 20 toxicity.

Additionqlly~ when studying free r~ lc in biological systems or when tr~ting various disease cQn~litionc caused by free r~ c it is i~ t that the nitrone spin trap have sufficient solubility at the biological site where the 25 free radicals are gen~ted so that the radicals are trapped by the nitrone before they are quen~he~ or cause oxidative damage by their surroundingc. Thus, it would be particularly desirable to be able to readily optimize the solubility ofnitrone compounds for a particular biological environment ranging in nature, for example, from aqueous to lipophilic.

Accordingly, a need exists for new classes of effective nitrone spin traps having improved ~ ies such as low toxicity and increased solubility in a wide range of bio~ ql systems.

SUMMARY OF THE ~VENTION
This invention provides novel furan nitrone co,.,pounds which are effective free radical spin traps and, accordingly, are useful as analytical reagents for deh~ free rq.~1irq1~ Ad~litiQnqlly~ the furan nil,~,nes of this 10 invenlion have been found to be useful as the,~r~ s for treating various m.oAirq1 J~fi.~ ;OI~ and ~ Pq~s In this regard, the furan nitrone compounds have ;.~ isingly low toxicity even at relatively high dosage levels.
Struct~-rq-11y, the furan nillones of this invention are particularly useful as analytical reagents and/or lh~ tics since one or more sulfur-derived 15 filn~tinnql groups are qt1r~c1~ to the furan ring thereby llowing the lipophilicity of the col~pou~ c to be readily varied. This permits the U~ C to be used in a wide variety of biologirq1 envirofi...~ and/or optimized for a particular analytical or lh~ ic use.

Accordingly, in one of its co"",o~;tion qcpect~, this invention is di.~:~ed to cGIllpounds of formula I:

(Rl)n ~--C =N(o)R3 wherein each Rl is in~lependent1y se1e~led from the group con~isting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycl~qll~nyl and halo;

R2 is Cplp~t~d from the group consicting of hydrogen, alkyl, s.~b;,l;l~
alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cyclo. lkyl and cyclQqlkpnyl;
R3 is sPlP~ted from the group concicting of alkyl, s~lbs~;~ute~ ~kyl, S alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cyc1oqll~nyl;
each X is in~ep~Pndently s~l~l~ from the group concicting of -SO3Y, -S(o)R4, -So2R5 and -So2NR6R7;
wherein Y is hydrogen or a ph~.-.q~ ;c-q-lly ~~ce~t-qhle cation;
R4 is ~ d from the group concicting of alkyl, s ~bsti~ ~ alkyl, 10 alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cyrl~qlkPnyl;
R5 is s~l~Pd from the group cnnCi~tin~e of alkyl, '~)b ,~ alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycl~qlk~nyl;
R6 and R7 are in~le~ .l1y s~PI~P~t~Pd from the group concictirlg of hydrogen, alkyl, ~lbsl;l~lled alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, 15 cycloalkyl and cyclc~qlk~nyl; or R6 and R7 together with the nillogen atom towhich they are qtt~rhP~I can forrn a heterocyclic ring co..l~;nil-g from 2 to 8 carbon atoms and op~ion-qlly from 1 to 3 -qdd~ nql het.,oatollls s~l~tçd from the group concictirlg of oxygen, ~ ,o6en and sulfur;
m is an integer from 1 to 3; . nd n is an integer from 0 to 2, provided 20 that m + n = 3; or l,h~...-q-~el.~ic-q-lly ~~~ept~ le salts thereof.

~ fe.~bly, in the compo~m~s of formula I above, Rl is s~l~ted from the group concicting of hydrogen .,nd alkyl. More preferably, Rl is hydrogen.

R2 is p~efel~bly sele~ted from the group concicting of hyd~en, alkyl and aryl. More plt;Ç~I~bly, R2 is hydrogen or alkyl. Still more pl~r~ bly, R2 is hydrogen.

Preferably, R3 is s~ cted from the group collsicting of alkyl, alkaryl, aryl and cycloalkyl. More ~l~r~l~bly, R3 is alkyl or cycloa~kyl. Still more W O 98/03496 PCT~US97/11960 p~fe.dbly, R3 is cycloalkyl. F.spe~i~lly pfef~.led R3 groups are cyclohexyl and isopropyl.

R4 is prcre.ably ~ from tbe group concictin~ of alkyl, alkaryl, aryl 5 and cycloalkyl. More preferably, R4 is alkyl, aryl or cycloalkyl. Still more ef~.dbly, R4 is alkyl.

Preferably, Rs is s~ from the group concisting of alkyl, alkaryl, aryl and cycloalkyl. More p.cr~.dbly, R5 is alkyl, aryl or cycloalkyl. Still 10 more p~r~.ably, R5 is alkyl.

X is pl~fe.dl)ly -SO3Y, -So2R5 or -So2NR6R7, ~he.~.n Rs is alkyl, cycloalkyl or aryl and R6 and R7 are illdep ndently ~le~te~i from the group con~icting of hydrogen, alkyl and cycloalkyl. ~lt~ tively, R6 and R7 are 15 preferably joined together with the niL-ugel~ atom to which they are ~t~he~ to form a ~.et~ rocyclic ring having 4 to 6 carbon atoms. More pl~fe.~bly, when X
is -SO2NRsR6, Rs is hydrogen and R6 is sel~ted from the group concisting of l~yd~en, alkyl and cycloalkyl.

~,fe.ably, m in formula I above is 1 or 2. More pre~l~bly, m is 1.

In another of its co~ ~s;tinll ~q-ects, this invention is directed to a co...~ d of formula II:

II
O C =N(o)-R3 W O 98/03496 rCTAUS97/11960 wherein R2, R3, X and m are as defined above, inclu~ing the above defined pltfc,lcd embo-~inlentc; or pharm~eeutir~lly acceptable salts thereof.

In still another of its cG..-I o~ n ~p~P~tc~ this invention is directed to a S compound of formula III:

~ m 10YO3S O CH=N(O)-R8 wherein R8 is SPIP~t-P~ from the group consisting of alkyl, sl~hstitut~Pd alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cyclo~ pnyl; and 20Y .~PlP~ted from the group concictin~ of hydrogen and a ph~.............................. n~u~;r~lly acccptable cation.

Preferably, in formula III above, R8 is SPlP~t~P~ from the group c~nCicting of alkyl, alkaryl, aryl and cycloallyl. More plcfcl~bly, R8 is alkyl 25or cycloalkyl. Still more ~J~efe.dbly, R8 is alkyl.

Preferably, in formula III above, Y is hydrogen or a sodium cation.

In yet another of its cc....~ ;on ~ t~, this invention is dil~c~d to the 30 following individual compounds:
N-isopropyl-a-(2-sulfo~uldn-5-yl)~ ne N-n-propyl-a-(2-sulfofuran-5-yl)nitrone N-n-butyl-a-(2-sulfofuran-5-yl)nitrone N-tert-butyl-a-(2-sulfofuran-5-yl)nitrone CA 02260825 l999-0l-l8 W O 98/03496 PCT~US97/11960 N-n-hexyl-a-(2-sulfofuran-5-yl)..i~ne N-cyclohexyl-a-(2-sulro~u~an-s-y~ iL~)ne N-tert-octyl-a-(2-sulfofuran-5 -yl)nitrone N-benzyl-a-(2-sulfofuran-5-yl)nitrone S N-isopropyl-a-[2-(N-morphn1inosu1fonyl)furan-5-yl]nihone N-isopropyl-a-[2-(N,N-dimethylculf~moyl)furan-S-yl]nitrone N-isoplopyl-a-[2-(N,N-diethylclllf~moyl)furan-S-yl]ni~une N i~op,up~ l-a-[2-(N~-methylpi~zin- l-ylsulfonyl)furan-S-yl]niLIûne N-tert-butyl-a-[2-(N-3-trifluo,ul,.eLllylphenyls~lf~moyl)-furan-5 yl]nillone N-tert-butyl-a-[2-(methylsulfonyl)-furan-5-yl]nitrone, and ph~~ e.Jtic~11y acceptable salts thereof.

This invention is also dil~:Led to pharm~reutic~1 colll~c;l;onc 15 comI-risin~ a ~Ihal.~ 11y ~rcept~hle carrier and a phanr~~eutir~lly effective amount of a compound of formula I:

(Rl)n (X)., ~C =N(O)R3 wherein R~-R3, X, m and n are as defined above; or ph~...~e~ltic~l1y a~ept~'-le sa1ts thereof.

In ~ition~1 compositiQn ~pect~, this invention is dir~;Led to pharrn~reutir~l co,..lJociL;r~n~ comprising a pharrn~~,eutir~11y acceptable carrier and a pharrn~~eutir~11y effective amount of a coulpound of formula II or III
above.

CA 02260825 l999-0l-l8 W O 98t03496 PCTAUS97/11960 As previously mentioned, the furan nitrone compounds of this invention have been found to be effective free radical spin traps. As such, these co"lpounds are useful as analytical reagents for det~P~ting free radicals.
Addiffonqlly, the furan niL,ones of this invention have been discovered to be S useful as tl~w ~~ul;cs for treating a wide variety of mp~icql dysfunrtionc andfs inrln-lin~, but not limited to, acute central nervous system (CNS) disorders, acute cardiovascular diso.d~.~, neurodegenc.dti.~e cnn~itions inns .. ~t~ Pq~S and -qalt~immllnp cnn~litinn~

Accordingly, in one of its method ~pe~cts, this invention provides a method for llc~ti"g a patient with an acute central nervous system disorder, said method compri~in~ a ~ ini~ ing to said patient a pharnn;~.reuti~ql co",~ilion comprising a ph~.-.~u~;r-q-lly P~~eptql le carrier and an effective acute cent~al nervous system disor l~-t,~dling ~mollnt of a co",pound of forrnula I above. In 15 a plef~.led emhul;...~n~ of this meth~d, the acute central nervous system disorder treated is stroke.

In anotl,~ r of its method q~re~t~ this invention provides a method for treating a patient with an acute cardiovascular disorder, said method comprising20 1~ln~ini~tering to said patient a pharmqreuti~l co,l"~ition co",l"ising a ph~...Qs- u~;cqlly ~p~ le carrier and an effective acute cardiovascular disorder-l,~ating amount of a co...~ui-d of forrnula I above. In a pl~fc~
emho~ of this method, the acute cardiovascular disorder treated is cardiac infarction.
In still another of its method ~q-~pe~tc~ this invention is directed to a method for tl~dl.ing a patient with a n~.lr~degen~ ative disease which method c~n~l~liSes ~dmini~tering to said patient a pharm~euti~ ;on comprising a ph~.--~ cut~ lly acceptable carrier and an effective 30 neurodegencldlive disease-treating amount of a compound of forrnula I above.
Ad~lition~lly, this invention is directed to a method for preventing the onset of a WO 98/03496 PCTrUS97/11960 neurodegenc.a~ e disease in a patient at Ask for developing the neurodP~&e--f ~dti~e disease which metbod compAses ?~minictering to said patienta l ha~ ;rql c~",~sition compricing a pharmvq~euticqlly ~c~pt~' le carAer and an effective ne~l~d~Pg~l-P-dtive disease-preventing amount of a UJJIIPOUI1d of 5 formula I above.

In pn f~ d embodirnentc of this invention, the n~ ~,odPceen ~;dli~e disease treated and/or p~G~renled in the above mçthQIlc is ,~l7hPimPr~s ~iCPqC~,p..l~;ncon's Aicpqce~ HIV de...e ~I;q and the like.
In yet another of its method q-cpe~tC, this invention is directed to a method for treating a patient with an autoimmune disease which method comprises a~l~.,ini~t~ ~ ing to s id patient a pharm. ~euti~-ql co"~ ion ng a ph~..- ~ qlly ~~rept-qhle carrier and an effective ~q~utoimrnune 15 disease-treating amount of a c~",pound of formula I above. This invention is also dil~:~d to a method for p~ c.l~ g the onset of an autoimmnne disease in a patient at risk for developing the autoimml-ne dise. se which method c~mrri~s adminict~ring to said patient a pha,...~re~ l cl)...~c;l;r),~-comprising a pharm~reutic~lly accPpt~'-lç c~ier and an effective ~l.tc~immune 20 disease-pl~ ~nting amount of a compound of formula I above.

In plefe.l d embo~ of this invention, the ~utQimmllnp dise~e treated and/or ~ cnled in the above methods is systemic lupus, multiple sclerosis and the like.
In still another of its method ~Cpe~tc this invention is dil~:ted to a method for tseating a patient with an infl~mm~tory disease which method col~ ises ~mini~t~ring to said patient a pharm~~euti~l co",~o~i~on comrricing a pharm~~eutic~lly acceptable carrier and an effective infl~mm~tory 30 disease-treating amount of a colll~oulld of formula I above. A~ ition~lly, this invention is di~c~ed to a method for preventing the onset of an infl~ oly W O 98/03496 PCTrUS97/11960 disease in a patient at risk for developing the inflqmmqtory disease which method comprises ~qdminicte-ring to said patient a pharmqr~uti~ql co~ros;l;nn c~mrricing a pharm~q~euti--qlly acceptable carria and an effective inflqmmqtnry disease-plc~nLing amount of a compound of formula I above.
s In ~,r~f~ d embodimPntc of this invention, the inlls....~.~t~.ly disease treated and/or p,w_nted in the above ~Ptho~lc is ll.e~J...~t.~ arthritis, septicshock, erythema r~o~ leprosy, srpti~miq~ uveitis and the like.

This invention is also dilr~;Led to p,ocesses for p,~a,ing the furan nitrone co...~ s of formula I. Accordingly, in one of its process ~q-~pectc, this invention provides a process for p,~ l)~ing a colllpound of formula I:

(Rl)n (X)~ ~5 C =N(o)R3 wherein each Rl is ind~ del-~ly sekP~ed from the group concicting of hydrogen, alkyl, su~ d alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, 25 cycloalkyl, cyrloq-lkPnyl and halo;
R2 is ~l~d from the group conciCl;i~g of hydrogen, alkyl, ~ s~;l.l~d alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and CyC1~ ,qll~Pnyl;
R3 is s~lP~-lrd from the group cQn~ g of alkyl, substitut~l alkyl, 30 alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cyclnqlkpnyl;
each X is indepP~nd~Pnsly s~ ted from the group concicting of -SO3Y, -S(O)R4, -So2R5 and -So2NR6R7;
wherein Y is hydrogen or a pharmq~eutir-qlly acc~pt~ble cation;

W O 98103496 PCTrUS97/11960 R4 is cPl~Pct~Pd from the group corlcicting of . lkyl, substitu~d alkyl, alkenyl, . lkynyl, alkaryl, aryl, alkcyclo lkyl, cycloalkyl and cyc~o-qll~pnyl;
Rs is s~PlertPd from the group concicting of .,lkyl, subslilu~Pd ~kyl, alkenyl, alkynyl, alkaryl, aryl, alkcyclo. lkyl, cycloalkyl and cyclo~lkPnyl;
R6 and R7 are indep~Pndçntly s~Pl~Pct~P~I from the group c~ncicting of hyd~vgen, alkyl, s.Jhsl;Lu~ed alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cyclo-q-l~Pnyl; or R6 and R~ together with the nill.,g~ n atom towhich they are ~ hfd can form a hete.ùcyclic ring co~ n;n~ from 2 to 8 c3bon atoms and op ionqlly from 1 to 3 ~litionql hete~uatû~ls slect~d from the group a~nCicting of oxygen, nilr~6en and sulfur;
m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m + n = 3, said process comprising reacting a furan carbonyl compound of the formula:

(R )n ~)~C=O

with a hydroxylamine of the formula:

to provide a co,llpuund of formula I.

In another of its process qcpectC, the pre~nt invention provides a process for ~lc~d~ing a s~lf-q~moyl-substituted fur n nitrone of formula I':

W O 98/03496 PCT~US97/11960 (Rl)o S (X )m ~lC2=N(O)R3 I' 10 wherein each Rl is i~-dep~n~l~Pntly s~l~ted from the group concictin~ of hydrogen, alkyl, ,~l~,s~ilut~ alkyl, alkenyl, alkynyl, alk. ryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycloqll~Pnyl and halo;
R2 is C~~ l~ from the group concisting of hydrogen, alkyl, s.lbsl;~u~
15 alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cyclo~ Pnyl;
R3-iss~lP~ from the group concicting of alkyl, ~bsl;tliled .,lkyl, alkenyl, alkynyl, ~karyl, aryl, alkcycloalkyl, cycloalkyl and cy~loqlkpnyl;
each X' is -So2NR6R7; wh~ ~n R6 nd R7 are in~lepf ~der.tly Cfl~,l~
20 from the group cQnCicting of hydrogen, alkyl, snl~sl;~ d alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloqllfpnyl; or R6 and R7 togell-c- with the nillu2en atom to which they are ~ 'hP~ can form a he~.ucyclic ring c4nt~inil-g from 2 to 8 carbon atoms and optionally from 1 to 3 ~ 1~1itionql he~r~..~,..s s~ P~ from the group concicting of oxygen, nillugen 25 and sulfur;
m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m + n = 3, said process comprising the steps of:
(a) reacting a carbonyl-subslilul~d furan sulfonic acid compound of the formula:

(Rl)o ~
(HO3S)m ~ ll R2 W O 98/03496 PCT~US97/11960 with phosphQrous tri(~hloride and phosphorous pent~chloride to provide a gem-dichloride-substituted furan sulfonyl chloride co.,-l~ound of the forrnula:

(Rl)" Cl (Cl02S)",~ ll ;R2 (b) reacting the gem-dichloride-su~sl;l."ç~ furan sulfonyl chloride con.l~un~1 with an amine of the formula:

to provide a gem-dichloride-sub.l;lul-~ furan sulfon~mide co,llpound of the 25 formula:

(Rl)~ Cl (X')", ~ c-R2 (c) hydrolyzing the gem-dichloride-sub~ uled furan sulfon~mide co.,~ d to provide a carbonyl-s~lbst~ t~l furan sulfon~mi~le compound of the formula:

(R')" o (X')", ~c R2 10 and;
(d) reacting the carbonyl-s~lbstitllt~PA furan sulfonqmi~l~P with a hydroxylamine of the formula:

to provide a CO,llpOLll d of formula I'.

In another of its qcpectc~ this invention is di-~ted to the use of a co.,lpound of formula I, II or III above in the mqmlfqrtll~e of a formlllqtiQn or 20 rneAirqm~nt for a m~Aicinql ~ f~ably, the mPAirql t~ n~ nl is the IL.,d~.llic or prophylactic t.~n..r ~t of an acute central nervous system disorder, an acute cardiovascular disorder, a neurod~e~ .,n;~e ~iicPq~ an ~q~utoimmlln~p disease or an infl~qmm~q~tory ~iSPqc~

BRIEF DESCRImON OF THE DRAWINGS
Figure 1 is an ~ tlon spin ~nnqllre (ESR) spectra of the radical adduct of N-isopropyl-~Y-(2-sulfofuran-5-yl)nitrone sodium salt and a methyl radical.
Figure 2 is a bar graph illusllating the infarct volume for surgically-induc~Pd strokes in rodents treated with a furan nitrone of formula I (Co--,pound 1) or a saline control.

W O 98/03496 PCT~US97/11960 Figures 3A, 3B and 3C show the wanderings of rodents in a enclosecl grid. Spe~ifir~lly~ Figure 3A shows the wandering of a rodent treated with a 1% methylcell-llo~/saline control. Figure 3B shows the wandering of a rodent treated with 1~ methylc~llulosP/nilloa~ih~ine. And Figure 3C shows the S ~nd~.ing of a rodent treated with nit ua~inine and 10 mg/kg of a furan nitrone of formula I (Coln~ nd 1).

Figure 4 is a series of bar graphs itl,.Str~ti.lg the daily behavioral scores for rodents treated with myelin basic protein (MBP), myelin basic protein 10 (MBP) and a furan nitrone of formula I (Col.l~ound 1), or a control. The behavioral scores shown were obtained 10 to 14 days after ~ t~ t Figure 5 is a graph showing the weight change, over a 14 day period, for rodents treated with myelin basic protein (MBP), myelin basic protein 15 (MBP) and a furan nitrone of formula I (Compound 1), or a control.

DETAILED DESCRIPI ION OF THE INVEN IION
As ~lic~llc~d above, the furan nitrone con,l)ounds of this invention are 20 useful as free radical trapping agents. Accordingly, such compounds are useful as analytical reagents for det~P~ti-lg free radicals. Ad~lition~lly, the furan niLI.i~es of this invention have been discovered to be useful as thc~ .eu~;rs for lr~ting a wide variety of mPAit~l dy~r~n.~;Qnc and ~I;C~C~5 In the furan nitrone colll~unds of formula I, the S~ u~ may be located at any of the carbon atoms of the furan ring. The furan ring po~ition~
are sper-ified herein using conventior-ql furan nomPnc1qture~ i.e., the furan ring oxygen is the 1 position; the two carbon atoms i....~.e~ tPly ~~ ent the ring oxygen are designqtP-A the 2 and 5 positions; and the ~,..q;ning two carbons are30 decign~t~PA the 3 and 4 positio~ Thus, a ,c~"~ se~ e compound of formula I

W O 98/03496 PCTrUS97/11960 having a single sulfonate group at the 2 position and an isopropyl nitrone at the S position would be narned N-isopropyl-a-(2-sulfofuran-5-yl)nilrone.

Definiti~ ns S The term ",~-amyloid peptide" refers to a 39~3 amino acid peptide having a ~nQl-c~ q-r weight of about 4.2 kD, which peptide is s~ stAl~t;~lly homologous to the form of the protein described by Glenner, et al., Biochem.
BiopArys. Res. Con~mun., 120:885-890 (1984), including mutations and post-c~ nql motiifirqtion~ of the normal ~B-amyloid peptide~

The term "cytokines" refers to peptide protein ...f~ that are produced by ir .. n~ cells to mod~ q-~ cellul. r filnrti--nc Examples of cytokines inclll~e, int~rlP-ukin-l~B (IL-lO, interleukin-6 (IL-6) and tumor neclusis factor-a ('INFa).
"Alkyl" refers to monovalent lkyl groups IJ~cfc~bly having from 1 to . bout 12 carbon atoms, more plcr~.dbly 1 to 8 carbon atoms and still more plcf~bly 1 to 6 carbon atoms. This term is exemrlified by groups such as methyl, ethyl, n-propyl, isoprupyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-20 octyl, tert-octyl and the like. The term "lower alkyl" refers to alkyl groups having 1 to 6 carbon atoms.

"Sub~~ led alkyl" refers to an alkyl group l,rLf~,~bly having from 1 to about 12 carbon atoms, more preferably 1 to 8 carbon atoms and still more 25 p~f~.~.bly 1 to 6 carbon atoms, which is subsl;l~tr~l with from 1 to 3 s.ll!s~;~uentc ~l~t~ from the group con~i~ting of alkoxy, amino, mono- and dialkylamino, -A.~ yl, ~n~;nocAIl~onyl~ alkoxyc~l,onyl, aryl, carboxyl, cyano, halo, hete.u~;yclic, hydroxy, nitro, thioAll~xy and the like. A p~efe~t;ds~lbstitutç~d alkyl group is the trifluoromethyl group.

W O 98/03496 PCTrUS97/11960 "Alkylene" refers to divalent alkylene groups l,lel~ldbly having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms which can be straight chain or b".nche~. This term is eY~mplifi~l by groups such as methylene (-CH2-), ethylene (-CH2CH2-), the propylene isomers (e.g., -S CH2CH2CH2- and -CH(CH3)CH2-) and the like.

~Alkenylene" refers to divalent alkenylene groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms which can be straight chain or branched and having at least 1 and preferably from 1-2 sites of alkenyl l.nsdlll.dlion. This term is exemplified by groups such as ethenylene(-CH=CH-), the propenylene isomers (e.g., -CH=CHCH2- and -C(CH3)=CH-and -CH=C(CH3)-) and the like.

"Alkaryl~ refers to -alkylene-aryl groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 14 carbon atoms in the aryl moiety. Such alkaryl groups are exemplified by benzyl, I)h~ yl, and the like.

"Alkcycloalkyl" refers to -alkylene-cycloalkyl groups prefe.dbly having from 1 to 10 carbon atoms in the alkylene moiety and from 3 to 8 carbon atoms in the cycloalkyl moiety. Such alkcycloalkyl groups are ~Yemlllified by -CH2-cyclopropyl, -CH2-cyclopenl~l, -CH2CH2-cyclohexyl, and the like.

"Alkoxy" refers to the group "alkyl-O-". ~lcf~cd alkoxy groups incl~de, by way of eX~mrle~ methoxy, ethoxy, n-pro~Ay, iSop~opoAy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

"Alkoxycarbonyl" refers to the group -C(O)OR where R is alkyl.

"AlkenylN refers to alkenyl groups preferably having from 2 to 10 carbon atoms and more l,~efe,dbly 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl un~hlr~tion. ~rerel-~d alkenyl groups include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), isopl~nyl 5 (-C(CH3)=CH2), and the like.

"Alkynyl" refers to alkynyl groups 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 alkynyl ~nsdlu~dtion. ~erellcd alkynyl groups 10 include ethynyl (-C_CH), p,up~yl (-CH2C=CH), and the like.

"A"linoc~lonyl" refas to the group -C(O)NRR where each R is indepPn~Pntly hydrogen or alkyl.

"~min~r-cyl" refers to the ~roup -NRC(O)R where each R is in~le~ de~ y hydrogen or alkyl.

"A~yl" refers to an llns~lulatp-d aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl).or multiple cond~Pnc~ rings 20 (e.g., naphthyl or anthryl). ~. fc~l~d aryls include phenyl, naphthyl and thelike. Unless otherwise consk~ih~ed by the de-fini~ion for the individual ~"~,,,t;l~nt, such aryl groups can optionally be s.,bsLiLuled with from 1 to 3 s~.k~l;nlt~r.ni s~l~cted from the group con~i~tin~ of alkyl, sul,sl;l~ alkyl, aIkoxy, alkenyl, alkynyl, amino, ~incr~yl~ ~min~-~.l,onyl, alkuAyc;hbonyl, 25 aryl, carboxyl, cyano, halo, hydroxy, nitro, trihalomethyl and the like.

"Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 carbon atoms having a single cyclic ring or multiple con~en~ed rings which can be optionally substituted with from 1 to 3 alkyl groups. Such cycloalkyl groups include, by 30 way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, l-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple ring structures such as adal"an~nyl,and the like.

"Cycl~qll~enylN re&rs to cyclic alkenyl groups of from 4 to 10 carbon S atoms having a single cyclic ring and at least one point of internal unsatulalion which c n be optir~nqlly s~lb~l;nJ~d with from 1 to 3 alkyl groups. ~lples of suitable cyc~o~ nyl groups inrlude, for in~t~n~, cyclopent-3-enyl, cyclohex-2-enyl, cyclooct-3-enyl and the like.

"HaloH or "halogen" refers to fluoro, chloro, bromo and iodo.
efell d halo groups are either fluoro or chloro.

"IIet~,ucycle" or "hete~cyclic" refers to a monovalent ~qhlr~te~l or ul~tulat~d group having a single ring or multiple cond~Pnc~P~ rings, from 1 to 15 10 carbon atoms and from 1 to 4 hetero atoms selP~t~Pd from nitrogen, sulfur or oxygen within the ring. Fx~mpl~Ps of hcL.~ycles in~lude, but are not limited to, morphrJlin-P, pipeldzine, imi~tq7Oli~inP" pyrrolidine, piperidine and the like.

"Ph&~ ar~ ;rqlly acceptable salt" refers to pharmq~euticqlly arreFt~hle 20 salts which are derived from a variety of organic and inorganic counter ions well known in the art and inc1ude~ by way of example only, s(ulium~ pot~ccillm~
cqlr,i~lm, ..-~"~..c;l~.." qmmc~niUm, tetraalkylqmmoni~1m~ and the like; and when the molc~~lle co~ inc a basic f~nctionqlity, salts of org. nic or inorganic acids, such as hydrochlori~e, hydrobro,.,ide, tartrate, mesylate, acetate, maleate and 25 the like. The term "~ha~ iC-q-lly 5q~cept~ cation" refers to a p~"~ r,~lly ~~ce~ hle c~tiQniC counterion of an acidic functiQn~l group.
Such cations are eyemplifie~ by so~ m~ pot~csi~lm~ c~lrium~ Ill~n~;Ll-ll, ~.. or.;-,---, tetraalkyl~mmon~ c~tiorlc~ and the like. Ph;i~ l;r~lly :~c~ept~hle salts of the furan nitrones of this invention are l~rcpaled using 30 conventinnal pr~lur~s well known to those skilled in the art inC~ ing, for Ps~mplc, treating a sulfonic acid derivative with an appr~liate base.

. . .

"Thioqlk xy" refers to the group "alkyl-S-". Plefell~d thinq1h~Yy groups include, by way of eY~mple, thiomethoxy, thioethoxy, n-thiop~poAy, isothiol)r~po,.y, n-thiobutoxy and the like.

S Genera1 S~ .,th~t;c ~ oc~dul ~s The furan nitrone co...~un-is of this invention can be p,~ d from readily available starting materials using the following general metho lc and pr~l~ s. It will be ~preciat~d that where typical or p ~fe,l~d process con~itiorlc (i.e., reaction ~ c.atul~s, times, mole ratios of r~qrtqnts~ solvents, 10 pl~ s, etc.) are given, other process cor~litionc can also be used unless otherwise stated. O~ l-l reaction con~lit~ c may vary with the particular req~ tqntC or solvent used, but such con-iitiQnc can be det~r,.,ined by one skilled in the art by routine op~;.n;~ ';on procedures.

AdAitinna11y, as will be appa~ent to those skilled in the art, convention groups may be n~f~ to prevent certain function~1 groups from undelE,oing undesired re~tionC The choice of a suitable ~lu!P~l;n~ group for a particular functinn-q-l group as well as suitable cQn(litionc for p~u~C~in~ and d~ t~~ various functinnq1 groups are well known in the art. For example, 20 nu~ler~us ~,r~t~ groups, and their h~lnY~uc~;ol~ and removal, are described in T. W. Greene and G. M. Wuts, Protecring Groups in Organic Synthesis, Second F~iti(!n, Wiley, New York, l99l, and l. fel.,nces cited therein.

In a ~l~f. ll~d method of synthesis, the furan nitrone col.,~ounds of this 25 invention are ~ ~cd by couplin~ a furan carbonyl co...l~und of formula IV:

(R )D
(X)m~C=O IV

wherein R', R2, X, m and n are as defined above, with a hydroxylamine of forrnula V:

wl~ R3 is as defined above, under conventinn~l reaction Co"r~itionc The coupling reaction is typically conducte~ by cnnt~ting the furan 10 carbonyl compound IV with at least one equivalent, preferably about 1.1 to about 2 equivalents, of hydroxylamine V in an inert polar solvent such as nol, eth~no~ 4-~lioy~ne~ tetrahydrofuran, dimethylsulfoxide, dimethylfo~ ;de and the like. This reaction is preferably con~ cte~ at a te-..~ c of from about 0~C to about 100~C for about 1 to about 48 hours.
15 Optionally, a catalytic ~mount of an acid, such as acetic acid, p-tol~enes~lfonic acid and the like, may be employed in this r~ tiol- Upon completion of the re i~tion~ the furan nitrone of formula I is recovered by conventional m~tho lc inrlU~lin~ p~;p;l~t;on, chl~,...atogl~hy, filtration, ~lictill~tir,n and the like.

The furan carbonyl compounds of formula IV employed in the coupling l~action are either known co~llpoun~c or can be pl-;p~cd from known c~ O!~- ds by convl ntioll~l procedures. Ple~,lcd furan carbonyl co~ Jn-ic inc~lude~ but are not limited to, 5-formylfuran-2-sulfonic acid, 4-formylfuran-2-sulfonic acid, 3-formylfuran-2-sulfonic acid, 2-formylfuran-3-sulfonic acid, 4-formylfuran-3-sulfonic acid, 2-formylfuran-4-sulfonic acid, 5-acetylfuran-2-sulfonic acid, 4-acetylfuran-2-sulfonic acid, and the like. An especi~lly pleîCll~ furan carbonyl compound is 5-formylfuran-2-sulfonic acid.

- Particularly p~l~,led furan carbonyl compounds for use in this invention are those compounds of formula IV wherein X is -SO3Y and Y is as W 098/03496 PCTnUS97/11960 defined above. These co,~lpounds can be readily p.ep~d by sulfonating furan carbonyl compounds of formula VI:

(R')~
~C=O VI

wherein R~, R2 and n ,re as defined above, using reagel)ts and con~ nc vell 15 k~own to those skilled in the art. Any convention-q-l sulfonating reagent, such as sulfur trioxide pyridine complex, may be used in this reaction. Typically, the sulfonation r~ lion is conduc~l by cont ~~ting a furan carbonyl cG~Ilpound of forrnula VI with about 1 to about 5 molar equivalent of the sulfonating reagent in an inert solvent, such as 1,2-dichlor~~ n~, at a ~ an-~ ranging 20from about 50~C to about 200~C, l,lefe,~bly at about 100~C to about 150~C, for about 6 to about 48 hours. Upon co pl~ion of the re -tinn~ the sulfonated furan carbonyl colllpound is recovered by conven~ionql methods including p" ~ ;Qn, cl~ro",atogl~hy, filtration nd the like.

When a sulfonated furan carbonyl C~!~.pou~ is employed in the coupling reaction with hydroxylamine V, the sulfonate group is l)r~Ç~.~bly converted intoa suitable salt, such as the lithium, sodium or potqC~ m salt, prior to CQI~
the h~JroAylamine with the furan carbonyl co,.-~ . The sulfonate group is readily converted into the col~ -dil-g salt by cor~;- I;i-g the sulfonate with at le. st one equivalent of a suitable base, such as lithium hydroxide, sodium hydroxide, pol;~c~ hydroxide, sodium hydride and the like.

Another p~f~,ed group of furan carbonyl co",pollnds for use in this invention are those collll)ounds of formula IV wherein one or more X is W O 98/03496 PCT~USg7/11960 -So2NR6R7 wherein R6 and R7 are as defined above. These compounds can be readily plc~ d from the co,~syollding sulfonated furan carbonyl compound, i.e., col..pûunds of formula IV wherein X is -SO3H, by converting the sulfonate group into a sulfonyl chloride and then coupling the sulfonyl halide with an 5 amine of formula VII:

wL~.e;n R6 and R7 are as defined above. The arnines of formula VII are either known co~ uls or co...pou~1~c that can be prepared by known }~l~edu~s.
F~mp~c of suitnb1e amines for use in this reaction include, but are not limited to, ~m mnni~, N-methylamine, N-ethylamine, N-n-propylamine, N-isopropylamine, N-n-butylamine, N-isobutylamine, N-sec-butylamine, N-tert-butylarnine, N-n-pentylamine, N-cyclopentylamine, N-n-hexylamine, N-cyclohexylamine, N-n-octylamine, N-tert-octylamine, N,N-dimethylamine, N,N-20 diethylamine, N,N-di-n-propylamine, N,N-diisopropylamine, N,N-di-n-butylamine, N,N-diisobutylamine, N,N-di-sec-butylamine, N,N-di-n-hexylamine, N-methyl-N-ethylamine, N-methyl-N-n-propylamine, N-methyl-N-,r~ylamine, N-methyl-N-n-butylamine, N-methyl-N-tert-butylamine, N-methyl-N-tert-octylamine, N-methyl-N-cyclopentylamine, N-methyl-N-25 cyclohexy1amine, N-ethyl-N-n-propylamine, N-ethyl-N-isopropylamine, N-ethyl-N-n-butylamine, N-ethyl-N-cyclohexylamine, N-phenylamine, N-(4-methyl)phenylamine, pyrrolidine, piperidine, morpholine and the like.

The sulfonic acid, i.e., where X in formula IV is -SO3H, can be 30 converted into the co~ ng sulfonyl chloride using phosphorous trichloride and phos~Jhulo~Js pent~~h1Qride. In ~ tion to converting the sulfonic acid group(s) into the coll~yonding sulfonyl chloride, this reaction also converts the carbonyl group of compound IV into a gem-dichloride group.

W O 98/03496 PCTrUS97/11960 This transÇo~ ion ~rves to protect the carbonyl group during sub~quent sulfonqmi-le fortnation.

Generally, the reaction of co...l,ound IV with PCl3/PCl5 is conducted 5 using about 2 to 5 molar equivalents of phosphorous trichloride and pho~ho,ous pentq~hloride~ either neat or in an inert solvent, such as dichlorom~thqne, at te.,.~latul~, in the range of about 0~C to about 80~C for about 1 to about 48 hours.

The sulfonyl chloride is then col-t~ ed with about 1 to about 5 molar equivalents of amine VII to afford the COll~ ~l.ùn-ling sulfon-q- nide gem-dichloride compound. This reaction is preferably conducte~ at a tc.ll~lur r-qnging from about -70~C to about 40~C for about 1 to about 24 hours.
Typically, this reaction is conduct~ in the presence of a suitable base to 15 scavenge the acid gen~l~led during the re~~tiQrl. Suitable ba~s include, by way of eAalllp~C', triethylamine, diisoplu~ lethylarnine, N-methylmorpholine and thelike. Alt~lnati~ely, an excess of amine VII may be used to scavenge the acid geneldted during the re~q~ction.

The gem-dichloride group is then hydrolyzed to l~en~ e the carbonyl group. This reaction is preferably cnnducted by cont-q-rting the sulfonqmi~e gem-dichloride compound with an aqueous sol~ltinn of formic acid (p~r~ably about 75%) at a tL.Ilpel~lule ~ ~ei~e from about 50~C to about 150~C for about 1 to 24 hours. Upon comp'~ ion of the reaction, the resulti-l~
25 sulfonqmi~le furan carbonyl co---pound is recovered by conventinnql . ~ .o ls inclu~inv precipitalion, chromatography, fil~ration, and the like.

Another p-e~ell~;d group of furan carbonyl con~you~c for use in this invention are those co...~~ s of formula IV wherein one or more X is -S(O)R4 or -So2R5 wherein R4 and R5 are as defined above. These co.,.~~ ds can be readily pç~a~. d from the COl-. ~ondhlg sulfanyl furan carbonyl W O 98/03496 rCTrUS97/11960 compound, i.e. wherein X in formula IV is -SR4 or SR5, by oxid~tion using conventional reagents and reaction conditi~nc. Suitable reagents for oY-iAi7ing a sulfide co~ ~unA. to a sulfoxide incluAe~ by way of example, hydrogen peroxide, 3-chloroper~"ybenzoic acid (MCPBA), sodium periodate and the like.
5 Dep~nAing on the oYiAi7ing agent employed, the carbonyl group of the furan int~ Aiq~e is pr~fe.~bly p~t~led as, for example, an acetal or a ketal, to p~. ient undesired oYiAqtion.

The oyidqtion ., ~~tion is typically corlducteA by cont~ting the sulfanyl lO furan carbonyl c~ ~u~d with about 0.95 to about l.l equivalents of the oYiAi7in~ reagent in an inert diluent, such as dichlororneth~n~, at a tel"~;.~ture r~q-nging from about -50~C to about 75~C for about 1 to about 24 hours. The resu1ting sulfoxide can then be further o~iAi7~ to the cG.,~s~onding sulfone by contqrtin~ the sulfoxide with at least one ~d~litionql equivalent of an oyiAi7ing 15 reagent, such as hydrogen peroxide, MCPBA, pOtdSi~;UIII perrn~nglqn~t~ and the like. Alternatively, the sulfone can be p.~ar~ directly by cont~r~ing the sulfide with at le. st two equivalent, and plefeldbly an excess, of the oxidizing reagent. If desired, these oxidation r~rtior~c can also be conrluct~l after conrling the furan carbonyl compound of formula IV with the hydroxylamine 20 V.

Alternatively, the sulfone cornrounds of formula IV wherein one or more X is -So2R5 where R5 is as defined above, can be pr~a~cd by reacting the co~ ,~nAin~ bromo furan carbonyl compound with, for example, a 25 sulfinic acid sodium salt (i.e., a co".pollnd of the formula R5-SO2Na, wherein R5 is as defined above). This reaction is typically conducte~l by cont~rting thebromofuran carbonyl compoun-~c with an excess, p-eÇt dbly 1.2 to 3 equivalents, of the sulfinic acid in an inert solvent, such as 2-ethoxyethanol, at a ~."~.ature ranging from about 50~C to about l50~C for about 2 to 24 30 hours. The resu1ting sulfone furan carbonyl compound can then be coupled with a hydro~yl~u"ine compound of formula V using conventional reaction c~nrli~ion~

The hydroxylarnine compounds of forrnula V above are also known 5 compounds or co.--l,ou-~-lc which can be p~ a~cd from known co,-~ c by conve~ n~l pr~ull ... Typically, the hydroxylamine coclpounds of forrnula V are ~ cd by re~uGtion of the coll~;pon~lin~ nitro cG",pou"d (i.e., R3-No2, wherein R3 is as defined above) using a suitable catalyst such as an activated zinc/acetic acid catalyst or an ~ h~u~ llel~;uly ~m~lg~m catalyst.
10 This reaction is typically conductPd at a t~,."~lalure ranging from about 15~C
to about 100~C for about O.S to 12 hours, preferably about 2 to 6 hours, in an aqueous ,~c~ion media, such as an ~lcohol/water mi~lule in the case of the zinc catalyst or an ether/water Illi~-lul~ in the case of the ~ minum ~m~ m catalyst. Hydroxyl~mines can also be pr~p~c;d by reAnctiQn of oximes with 15 hydride re~ucin~ agents, such as sodium cy~,obG,uhydride. ~liph~tic nitro co Ipo~ c (in the form of their salts) can also be reduced to hydroxyl~min~s -using borane in tetrahydç~rL~ . Since some hydroxyl~...;n~~ have limited stability, such comroun~ are generally pr~d immeAi~t~ly prior to reaction with the furan carbonyl co,..l ound of formula IV. Altematively, 20 hyd~ cyl~minçs can often be stored (ûr pu,.;l.ased co!....,e~cially) as theirhydrochl~ride salts. In such cases, the free hydroxylarnine is typically 6-ne~ated i~...oeA;~cly prior to reaction with the furan carbonyl com~x>und by reaction ûf the hydrochloridç salt with a suitable base, such as sodium hydroxide, sodium mPtho~ide and the like.
~ f~.,cd hydroxyl~mimPs for use in this invention include, but are not limited to, N-methylhydroxylamine, N-ethylhydroxylamine, N-n-propylhydroxylamine, N-isopropylhydroxylarnine, N-n-butylhydroxylamine, N-isobutylhydroxylamine, N-sec-butylhydroxylamine, N-ter~-butylhydroxylamine, 30 N-n-pentylhydroxylamine, N-cyclopentylhydroxylamine, N-n-hexylhydroxylamine, N-cyclohexylhydroxylamine, N-n-octylhydroxylamine, N-tert-octylhydroxylamine, N-phenylhydroxylamine and the like.

In some cases, the furan r.iLlones of this invention will contain one or S more chiral centers. Typically, such cornpoun.lc will be prepared as a racemicmixture. If desired, however, such col,.pounds can be prepared or isolated as pure stereo~ mprs~ i.e., as individual enantiomers or diastereomers, or as stereQi~mer~nriched mixtures. All such stereoisomers (and enriched ,..i,~u,~s) of the furan nil.~nes of formula I are include~d within the scope of10 this invention. Pure stereQi~m~Prs (or c~.icl-ed mixtures) may be pl~ared using, for ~ ~ ple, optically active starting materials or ~ 4sele~tive reagentswell known in the art. Alternative}y, racemic mixtures of such compounds can be S~paldled using, for example, chiral column chromatography, chiral resolving agents and the like.
I..a. ~re~tical Cu "~,itions When employed as ph~...q~e~tirqlc, the furan nitrone compounds of this invention are typically ~minictlored in the form of a pha".l~re.ltirql co..-~silion comprising at least one active furan nitrone compound and a 20 camer or vehicle suitable for use in pharm~eutic-ql co.lll~sitionC, i.e., a pha"..zr~ lly ~ptAI-le carrier. Such carriers are well known in the ph~...~r~ l;r~l art as are procedures for ~,.~ing pharm~~eutirql ~PnPr~qlly, the co.. pounds of this invention are ~ 1minict~Pred in a pharm~reutir~lly effective ~mol)nt. The amount of the col,lpound actually a~minictpred will typically be dete-,l~ ed by a physician, in the light of the relevant cirCumct~ncçs~ including the con~itiQn to be treated, the chosen route Of arlminic~ration, the actual compo~md ~minictered, the age, weight, and 30 r~s~n~ of the individual patient, the severity of the patient's symptoms, and the like.

The ph~n~ uti~l co"~posi~ions of this invention can be ~dminictered by a variety of routes including oral, rectal, transdermal, s~-bcutq-nPous, intrdvenous, intrqm~lcc~lqr" nd intranasal. Depenrline on the intçndP~ route of delivery, the co",pou, ds of this invention are p~e,dbly form-ll~tPA as either 5 injectqhle or oral co...~ ;ons.

The co~ ;l;Qnc for oral ~minictration can take the form of bulk liquid sol~tionc or ~S~ inC~ or bulk powders. More commonly, however, the c~..pQ~;I;onc are p~sented in unit dosage forms to fq~ilitAqtP acculdte 10 dosing. The term "unit dosage forrns" refers to physically discrete units suitable as unitary do~ges for human subjects and other ,.. ~.. qlc, each unit col~i-inine a l,red~t~.",ined quantity of active material ~lrlll~tpd to produce the desired the~a~ulic effect, in ~C~o~ ;on with a suitable pharm~reuti~
excipient. Typical unit dosage forms include prefilled, l~le ..- ~c~ d ampules or 15 syringes of the liquid co"~po~ilions or pills, tablets, r~psulPs or the like in the case of solid con,l)osilions. In such co.nl os;l;- nc, the furan nitrone cGIllpound is usually a minor cO ~?on~nt (from about 0.1 to about 50% by weight or ps~f~àbly from about 1 to about 40% by weight) with the r~ der being various vehicles or carriers and ~ c;ne aids helpful for forrning the desired 20 dosing form.

Liquid forms suitable for oral ~ Iminictration may include a suitable aqueous or nonaqueous vehicle with buffers, suspen-line and ~licpPncine agents, c~lor~ntc, flavors and the like. Solid forms may include, for example, any of 25 the following ingreAiPntc~ or co.,.pounds of a similar nature: a binder such as ll.ic~ lline ~P~ osel gum t~ nth or gelatin; an excipient such as starch or lactose, a ~ ntegl~ling agent such as alginic acid, Primo~el, or corn starch; a lubricant such as rn~..e~;--..~ stearate; a glidant such as colloidal silicon dioxide; a sweet~lling agent such as sucrose or saccharin; or a flavoring 30 agent such as peppell..int, methyl salicylate, or orange flavoring.

W O 98/03496 PCT~US97/11960 Injectable compositions are typically based upon injectable sterile saline or phosphate-bufrered saline or other injectable carriers known in the art. As before, the furan nitrone compollnd in such co,l,posiLions is typically a minor con.f onent often being from about 0.05 to 10% by weight with the remqin~ler S being the injectable carrier and the like.

The above described cou.l ol~e~ for orally ~lminictrable or injectable c~...po~;tiQnS are merely le~s~nt~ti~e. Other materials as well as plOC~'';n~e techniques and the like are set forth in Part 8 of Remin~ton's Pharmaceutic-~l Sciences~ 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is inco~ t~d herein by reference.

The ro~npo~ c of this invention can also be dminictered in suct~in~d release forms or from s~ .ned release drug delivery systems. A des.;lipLion of 15 "pl"~"L~ e s-~ct~ined release materials can be found in the inco,~olated materials in Remin~ton's Pharmaceutical Sciences.

The following form~ tion ~y~mrlps illl-ct~t.o r~p,~se.,~1i~e pharm~reutic~l c~.n~ ;ons of this invention. The present invention, however, 20 is not limited to the following exemplif1e~ pharm~reutic~l co~;L;Qnc For.mulation 1 - Tablets A c4,--pou~d of formula I is ~imiyed as a dry powder with a dry gelatin binder in an approYimqtp- 1:2 weight ratio. A minor amount of m~n~cil.m s~te is added as a lubricant. The Illi~lu~ is formed into 240-270 mg tablets (80-90 mg of active furan nitrone co.llpound per tablet) in a tablet press Formulation 2 - Capsules A c~,npound of formula I is ~lmixed as a dry powder with a starch diluent in an approximqt~ 1:1 weight ratio. The mixture is filled into 250 mg c~rSllles (125 mg of active furan nitrone compound per capsule).

Formulation 3 - Liquid A compound of formula I (50 mg), sucrose (1.75 g) and ~ t.~n gum (4 mg) are blended passed tll.ougll a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline CP~ os~P and sodium S carboxymethyl c~ lose (11:89, 50 mg) in water. .So~ium ben~o~t~- (10 mg),flavor, and color are diluted with water and added with stirring. SuffiriPnt water is then added to ~,~xluoe a total volume of 5 mL.

Formulation 4 - Tablets The co!~po!~nd of formula I is ~ Imi~ed as a dry powder with a dry gelatin binder in an approxim~tP- 1:2 weight ratio. A minor ~moun~ of .. stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active furan nitrone co.--pound) in a tablet press.

15 Formulation S - Injection The co---puund of formula I is dissolved in a burr~d sterile salin injectable aqueous m~dinm to a conc~ntration of approYim~tPly S mg/ml.

Compound Utility The furan nitrone co.. pounds of this invention have been discovered to effectively trap or scavenge free radicals and, accordingly, such c~ poun~lC areuseful as ana1ytical reagents for dete;l;ng free radicals using, for example, ESR
s~cl-oscopy techniques. Ad~i~ion~lly, the furan nilrJIe~S of this invention havebeen discovered to be useful for treating a wide variety of m~Air~ f~nc!;onc 25 and ~ crc As analytical ~age.lts, the furan nitrone co...l~unds of this invention are useful as spin traps for det~ting unstable free ra~ir~lc using el~llun spin .~sonA~ce (ESR) ~ ,oscopy and related techniques. When used as analytical 30 r~ ntc, the furan nitrone compounds of this invention are typically cont~rt~
with the radical to be studied in solution and an ESR spectrum generated in a conventiQn~l manner. Any ESR ~,ecL,ol,leter, such as a JEOL JES-FE3XG
,Illeter, may be employed in these experiments. Typically, the solution c4~,t~ining the spin-trap will be deoxygenated by, for eY~mr'~, bubbling argon or nil-ogen through the solution before the ESR e~pc~ ent is cQnduct~Pd.
S F'~fwàbly~ an exccss of the furan nitrone is used in such ESR çyrçrimpntc-The actual experimental procedures employed in the spin-trapping nt will depend on a number of factors, such as the manner of radical pro~luction, the in~.lness of the solvent and reagents with respect to the spin 10 trap, the lifPtime of the spin adduct and the like. Spin trapping pn,cedu,~s are well known in the art and the exact I~lOCeJUlC employed can be del~.l.,ined by those skilled in the art. Typical ~l~lul~s and app~ual~ls for conductillg spin L,d~,~ing e~perim~n~c are described, for example, in C. A. Evans, "Spin Trappingn, Aldrichimica Acta, (1979), 12(2), 23-29, and references cited 15 therein.

As the. .r~ul;cs, the furan nit~ones of this invention have been found to be useful for treating a wide variety of mPdic~l dysfunctionc and ~lisç~ces~
While not wishing to be limited to theory, it is believed that one mode of action 20 for the furan nitrone comround~ of this invention is the trapping or scavenging of frec radicals. Accordingly, the furan nitrones of formula I are useful for treating m~Air~l dysfi)nctiQrls or ~ cPs arising from or char~rtçri7~ by free radical-ifi~ c~d oxidative ~m~e Such mçdic~l dy~rJ--~;~;ons or ~ es include, by way of ~ -- rle~
disorders of the central nervous system, such as stroke, aging, PO~L;~ icm, multipl~ sclerosis, concuc~ion~ aneurysm, ventricular hemorrhage and ~Cc~;~tçd v~osp~cm, migr~in~ and other vascular hç*d~hes, spinal cord trauma, ~ hetic l~l;n~ t~y, nc~ru~n~lhes;~ adjunct, and dçmçnti~ including age-related ~ .t;~"~17h~imçr's disease, multi-infarct demçnti~ HIV clemçnti~ and Parkinsonian dç~.,e~ ; disorders of the p~liphe,~l nervous system, such as rliq~ etiC pcli~he.~l n~ UPaIhY and tr~umqtic nerve damage; and disorders of the ~,i~)he.~l organs, such as atherosclerosis (both riiqhetir and ~ont;~ne~us),cardiac infarction, chronic obstructive pulmonq y disease (COPD), pancçcatilis, uveitis, pUlmQnqry fibrosis due to cl~*~..ot~ ul;r agents, angioplasty, S trauma, bums, iQrhPmic bowel ~licPqcP ~ounds, ulcers and bed sores, lupus, ulcerative colitis, organ tranQplqntqtiol~, renal hypertension, overexertion of ~IP1Ptql n~u.~le, and epict-qyic (pulmon-qry bleeding). Other conrlitionc that can be treated include infl~.. ~o~y ~iQpqQps~ such as arthritis; ~ de~ hle or altered o~Yi~-q-tinn of low density lipop~lcin; and dysfunctionc from eyl~osure to 10 r~ liqtirn, inclu~in~ X-ray, ultraviolet, gamma and beta rq-~liqtion~ and CylulO~-iC
c4.-.pou ~AQ, ii-clu-l;ng those used for chc,llothcl~y~ for cancer and viral in~ u~c ~ntinYir~qntQ may also provide ~)rot~ e effects against cancers and inhibit cell proliferation. See, for ~ e, K. Irani et al., Science, 27~:1649-1652 (1997).
Ad~iitiQT~qlly~ the furan ni~,nes of this invention have been discovered to effectively inhibit the release of cytokines, such a IL-l~B, IL-6 and TNFa.
Elevated levels of cytokines are qccor:a~l with a wide variety of ihflq..llll~to.
neurodeE~ t;~e and ~ltoimmunP- con-liti-nc inrludin~ h~ e-'s rlicP-q-ce~
20 AIDS ~ q~, septic shock, .h~ oj~ allh,ilis, erythema nodosum leprosy, ~l~cl~ingococcal l.~ g;tic7 mllltir'~ sclerosis, systemic lupus and the like. See, L. Sekut et al., Drug News ~c,~ccl. 1996, 9, 261; K. Shio~qki et al., "Chapter 4. Emerging O~pûlluniLies in Neuroinllq.. -st~ MPrhqnicmc of Neurodegeneration" Annual Reports in Me.lieinn~ Chc~ 7~l~, pp. 31-40, AC~1Pm;~ Press (1995) and ~c~er~nce cited therein; and A. Waage et al., J.
Ecp. A~ed. 1989, 170, 1859-1867. Accordingly, the furan nilloncs of formula I
are useful for tredting AicP~c~S Chdld~;lt;liL~,d by an ovell,r~ductinn or an unregulated producti~n of cytokinPC, particularly IL-l~, IL-6 and INFa, inclll-~ing neurodcgcnc.dti~/e, autoimmune and/or infl~mm~ory cQntli~ions W 0 98/034g6 PCT~US97/11960 Moreover, the furan nillones have been found to effectively inhibit the formation of A,B(1-40) beta-pleated sheets and/or protect against neuronal cell loss. Ad~itiQn~lly, in in vivo tests, such cGIllpounds have been found to reducethe locomotor i."pail",ent caused by A,~(25-35). The formation of A~(1-40) S beta-pleated sheets, r,e.llonal cell loss, and beta amyloid-induced loco"~otori."pair",cnt have been ~ccori~t~A with n~ od~encldti-/e con(~itiQns~ such as ~17.1.~ s~ ce~ and/or ~toimm~ne conrlitiQnc Accordingly, the furan r,it~ones of forrnula I are useful for preventing and/or tr~aling neurodege.- - ~L.~e and/or ~utoimmune con~itiQnc Among the various m~lit~l conditionc which may be prevented and/or treated, the furan nillones of this invention are particularly useful for treating contlitionc involving acute intense oxidative damage to a region of the central nervous system. Examples of such eon~litionc include stroke, con~litinnc 15 ~cco~ ~teA with stroke, conc~cci~n and sub~a~hnoid hemolll,age. When treating such conditinnc the furan nitrone co",l)ound will typically be ~dminict~red in a manner that allows the compound to enter the patient's bloodsl,~m as quicldy and directly as possible. Typically, this involves intravenous ~minictration.
Intravenous dose levels for treating these mP~ l con~itions range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour over a period of from about 1 to about 120 hours and esper;~lly 24 to 96 hours. P~cfelably~ an amount of at least about 0.2 mg/kg/hour is ~minictered to the patient. A pre~ }ing bolus 25 of from about 10 mg to about S00 mg may also be ~mini~t~-red to achieve adellua~ steady state levels.

While intravenous ~rlmini~tration is p.efe,~ed, other forms of parenteral ~~lmini~tration, such as intramuscular injection can be used, as well. In such 30 cases, dose levels similar to those described above may be employed.

Among other factors, a surprising and unexpected advantage of the furan nitrones of this invention is that such con~poullds can be ~minictPred at vastlyhigher levels than are possible with certain other known free radical traps, such as N-tert-butyl-a-phenylnitrone (PBN). Doses of up to 300 mglkg/hour and S higher or intravenous bolus doses of from l0 to l000 mg/kg may be employed using the C4~ ou~ c of this invention. In contrast, PBN causes death or acute toxicity at high dG; ~,;f 5 Acco~lingly, large doses of a furan nitrone co",pound may be ~-lmini~red innne~ r1y post stroke or other trauma to provide cignific~nt1y reduced oxidative r~ma~ in many cases. Such do~es, and the 10 acco..-~allying ben~ rl~., are not possible using PBN.

Another acute conriitinn which can be advantageously treated with the furan.nil.~.. es of this invention is acute oxidative d~"agc to the cardiovascular system, such as the ~ma~e which occurs in a patient who has s.lrr~ed a 15 cardiac infarction or the like. When treating such a co~-1iti-)n~ a pharm~r~uti comrosition co nrricin~ a furan nitrone is ~minict~red pa~ t~,~lly, e.g.
intravenously, at doses similar to those described above for stroke and other acute CNS conditi~-nc..

Other mPAic~1 con.liti~mc which may be prevented and/or treated with the furan nitrone co-npou..ds of this invention are neuç~deg~--e)~ .re con(lition such as ~ 's ~ c~, Parkinson's .dic~o~cel HIV-~e..,~ n~;~ and the like;
tQimm~ e conditions~ such as systemic lupus (eryth~ ,s~lc), multiple sclerosis and the like; and infl~mm~tory con-litiQnc~ such as inn~.. ~tol~ bowel25 ~ ce, .I--~-n~l~id arthritis, septic shock, e.~ll.e...a no~o~ . leprosy, septi~e-mi~ uveitis, and the like. With regard to these disease t-l~ccifi~tiol c, it will be a~ c;ated by those skilled in the art, that some disease con~litionc maybe c1~ccified as, for example, both autoimml~ne and inn~ to"r con-~itiQnc, such as multiple sclerosis and the like.

As ~ cucce~d above, the co.,~pounds described herein are suitable for use in a variety of drug delivery systems. Tnje~tion dose levels for treating neurod~n.-rdti~/e, ~utoinlmlln~ and infl~mm~tory contlitioll~ range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 S hours and çsI)erially 24 to 96 hours. A prelo~ling bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be adminictered to achieve ade~ steady state levels. The rn~ximum total do~ is not eYpe~ted to exceed about 2 g/day for a 40 to 80 kg human patient.

For the pr~ ntion and/or tr~ .t,.,.~t of long-term con~itiQns~ such as neurodege.-PIdti~re and ~utoimmllnp~ conditions, the regimen for tre~tmP-nt usually sh~tches over many months or years so oral dosing is plefe,l~d for patient convenience and tolerance. With oral dosing, one to five and e~peci~lly two to four and typically thre~e oral doses per day are ,~ ~,resentative regim-on~.
Using these dosing ~i.t~."s, each dose provides from about 0.02 to about 50 mg/kg of furan nitrone, with prer. .lt d doses each providing from about 0.04 toabout 30 mg/kg and eslleri~lly about 1 to about 10 mg/kg.

When used to prevent the onset of a neurode~nPrative, autoimmunr or 20 inll~...n~ol~ conditioll~ the furan nitrone cG---pounds of this invention will be ~lmini~tered to a patient at risk for dcvclo~ing the condition, typically on theadvice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular corl~liti~n generally include those that have a family history of the con~ition, or those who have been 25 identifi~d by genetic testing or scr~ning to be particularly ~,~scep~ible to developing the cQnr~ition. When used prophyl~cti~11y, a pharm~eutir~l c~,.~pos;~ n comprising a furan nitrone is admini~t~red orally to the predisposed patient The doses for this oral therapy will typically be the same as those set forth above for treating persons suffering from the neurodegenerative, 30 autoimmune or infl~mm~tory condition.

W 098/03496 rcTrusg7/ll960 The cG.,.~ounds of this invention can be ~Aminictered as the sole active agent or they can be ~dminictered in combination with other agents, innll~ding other active furan nitrone cG..-pounds.

S The following' synthetic and biolcgic~l eY~mrlos are offered to illl~c this invention and are not to be construed in any way as limitine the scope of this invention.

EXAMPLES
In the eY~mpl~ps below, the following abbreviations have the following m~ning.c Abbreviations not defined below have their generally ~ccept~d ning.
bd = broad doublet bs = broad singlet d = doublet dd = doublet of doublets DCF = dichlorofluorescc;n dec = deco.. ~s~
dH2O = dictill~d water ELISA = enzyme-linked imm~mo-sorbent assay EtOAc = ethyl acetate EtOH = ethanol FBS = fetal bovine serum g = grams h = hours Hz = hertz int,erleukin-l,B
IL-6 = interl~~ n-6 L = liter LPS = lipopolysaccharide m = mllltiplet min = mmlltes M = molar MEM = ,.,ini~ J.. ~ P.c~.~ l .. P.1;~n~ (or m~ifiPd Eagle's m~inm MeOH = meth~n~l mg = milligram MHz = m~h~rtz mL = millilit~.r mmol = millimole CA 02260825 l999-0l-l8 W O 98/03496 PCTrUS97/11960 m.p. = melting point N = normal q = quartet quint. = quintet ROS = reactive oxygen species s = singlet t = triplet ter~-octyl = 1,1,3,3-tetramethylbutyl THF = tetrahydrofuran ThT = thioflavin T
tlc = thin layer chlulllat~gl~hy TNFa = tumor necrosis factor-a ~g = microgram ,uL = microliter UV = ultraviolet In the eY~mpl~c below, all ~ t...~s are in degrees Celsius (unless otherwise in~ t~d). FY~p'es A-C below describe the synthesis of an 20 interm~i~te used to prepare the furan nitrone cû--.po~nds of this invention;
FY~mpl~r 1-17 describe the synthesis of furan nitrone compounds; and FY~mP'eS 18-29 ~escribe the in vf~ro and in vivo testing of such compounds.

~xample A
Synthesis of N-Isopropylh~ lamine Acetic acid (10.8 g) was added to a cooled solution of 2-nil,upropane (5.35 g) and zinc dust (5.89 g) in 95% ethanol (350 mL) at such a rate to ..i~in~in the le-..~ below 10~C. The reaction was stirred for three hours 30 and the solvent removed in vacuo. The residue was extracted three times with dichlor~.~ ,tl.~e. The combined eYt~?rts were dried over m~P~;~.... sulfate, filtered, and solvent stripped. The crude hydroxylamine product was used without further purifi~ ~tiorl. Other hydroxyl~mines may also be ~,l~ared by this pnxedu.c.

Example B
Synth_s~ of HY~rOAYI~ PC By Reduction of Ox~nes Various hydroxyl~min~s were pl~ar~;d according to the procedures of R. F. Borch et al., J. Amer. Chem. Soc., 1971, 93(3):2897 from the S col~ ~nding oxime. Specifically, a 3-necked round bottom flask e.luipped with a stirring motor, a pH meter probe and an ~-I({itiQn funnel is ch~E,ed witha solution of the oxime in ~ nol (ca. 0.4 M). To the stirring solution is added 0.68 equivalents of NaBH3CN in portions. The ~d~ition funnel is filled with 4M HCl in MeOH. The amount of the acid solution pl~;~ared should be 10 roughly 3l4 of the volume of MeOH used to dissolve the oxime. The HCl solution is then added slowly to the oxime until pH comes down to about i and stabilizes at that value. The solution is then allowed to stir at ambient ~Ill~l~tul~, for ca. 4 hours. HCl is added as n~sC~ry to keep the pH at 4.
(A small sample can be periodically removed and worked-up to det~.ll,ine if the 15 reaction is complete). When the reaction is complete, the solution is decanted into a l-necked round bottom flask and MeOH is removed in vacuo. (While removing the meth~lol by rotoevaporation, the solvent trap should be filled with NaOH (1 eq.) to quench HCN s~ ,ped off with MeOH). After the methanol has been removed, the residue is dissolved in water and extracted 20 with methylene chloride (4x). The organic phases are combined, dried over MgSO4 and ~ipped to dryness to provide the hydroxylamine product (as delcllllil~ed by NMR and DSC).

FY~mrlc C
Synthesis of N-Cy~!chPYylh~ ,A~l~,.i.. e N-Cyclohexylhydroxylamine hydrochloride (co~ ially available from Aldrich, 1001 West Saint Paul Avenue, Milwaukee, Wicl on~in 53233 U.S.A.) was susp~-nded in ether (about 200 mL of ether for 6 grams of the hydroxylamine salt) and extracted three times with 5% NaOH in brine. The 30 organic phase (white fluffy crystals of N-cyclohexylhydroxylamine suspended in ether) was transferred to a round bottom flask and the ether was removed in W O 98/034g6 PCT~US97/11960 vacuo. The res~lting crystals were dried under a high vacuum for about 20 min. to afford the title co-"~ound.

Example 1 Synthecis of N-Isopropyl-a-(2-sulfofuran-5-yl)nitrooe N-Isopropylhydroxylamine (from FY~mplP A above) and 5-formylfuran-2-sulfonic acid, sodium salt hydrate (5.94 g) were refluxed in meth~nol (200 mL) for 24 hours. Another portion of N-isopropylhydroxylamine was added and the reaction stirred for 24 hours. The solvent was stripped to provide a pale yellow solid which was recryst~lli7~d from ethyl acetate to afford 5.72 g (75% yield) of the title co...l o~ d, m.p. = 230~C (dc~,..~se,d). HPLC
analysis showed a major product of 88% by area. Depen~ing upon the pH, the title co,l,i)ou.-d was present as the free acid, or, if in the p~ ce of sodium cations and a higher pH, as the sodium salt. Other salt forms can be prepared by ch~ngin~ the cation.
Spe~ scupic data was as follows:
IR (KBr, cm'): 2984.5 (CH), 2940 (CH), 1637.0 (C=N), 1216.1 (SO3) and 1049.7 (N-O).
lH NMR (DMSO-d6, 270 MHz): ~ = 8.03 (lH, s, nitronyl H), 7.41 (lH, d, J = 3.5 Hz, 4-aryl H), 6.49 (lH, d, J = 3.3 Hz, 3-aryl H), 4.32 (lH, m, J = 6.5 Hz; C-H), 1.27 (6H, d, J = 6.5 Hz, CH3).
13C NMR (DMSO-d6, 270 MHz): ~ = 158.20, 147.03, 122.96, 113.89, 110.23, 65.23 and 20.63.
Example 2 S~ tl~ ;c Of N-Propyl-a-(2-sulfofuran-5-yl)nitrone Following the procedure of Fy~mple 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-propylhydroxylamine, the title W O 98/03496 PCT~US97/11960 col.,pollnd was ~.epared in 41% yield as the sodium salt, m.p. 230-233~C
(dec.).
S~;lros~opic data was as follows:
~H NMR (DMSO~6, 90 MHz~: ~ = 8.047 (lH, s, nitronyl CH), 7.459 (lH, d, J = 3.4 Hz, furan CH), 6.524 (lH, d, J = 3.4 Hz, furan CH), 3.865 (2H, t, J = 6.7 Hz, CH2), 1.805 (2H, m, CH2), and 0.862 (3H, t, 7.3 Hz, CH3).

FY~mp'~ 3 Synthesis of N-n-Butyl-a-(2-sulfofuran-5-yl)nitrone Following the pl~lu~ of FY~mrle 1 above and using 5-formylfuran-2-su}fonic acid, sodium salt hydrate and N-n-butylhydroxylamine, the title col"~llnd was p,~pared in 6.7% yield as the sodium salt, m.p. 212.8~C (dec).
Spectn~s~ol)ic data was as follows:
IR (KBr, cm~'): 2959.2 (CH), 2931.9 (CH), 1636 (C=N), 1246 (SO3), 1225.2 (SO3) and 1165.4 (N-O).
lH NMR (DMSO~6, 270 MHz): ~ = 8.139 (lH, s, nitronyl CH), 7.677 (lH, d, J = 3.7 Hz, furan CH), 7.047 (lH, d, J = 3.7 Hz, furan CH), 4.026 (2H, t, J = 6.9 Hz, CH2), 1.889 (2H, m, CH2), 1.373 (2H, m, CH2) and 0.950 (3H, t, J = 7.4 Hz, CH3).
'3C NMR (DMSO-d6, 270 MHz): ~ = 153.699, 146.774, 130.713, 118.037, 113.766, 64.742, 28.561, 18.540 and 12.438.

Example 4 Synthesis of N-tert-Butyl-cY-(2-sulfofuran-5-yl)lutrone Following the procedure of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-~ert-butylhydroxylamine, the title co",l,ound was pl~ed in 36% yield as the sodium salt, m.p. 117-120~C
(dec.).

Speclloscol)ic data was as follows:
'H NMR (DMSO-d6, 90 MHz): ~ = 7.908 (lH, s, nitronyl CH), 7.445 (lH, d, J = 3.3 Hz, furan CH), 6.486 (lH, d, J = 3.3 Hz, furan CH), and 1.430 (9H, s, 3 CH3).
s FY~mp'c 5 S~ ~ P-~ of N-n-Hexyl-~r-(2-sulfofuran-5-yl)nitrone Following the procedure of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-n-hexylhydroxylamine, the title ~und was p,~d in 76% yield as the sodium salt, m.p. 225.5~C (dec.).
S~c~sco~ic data was as follows:
IR (KBr, cm-l): 2956.8 (CH), 2927.1 (CH), 1617.2 (C=N), 1247.6 (SO3), 1222.7 (SO3) and 1171.2 (N-O).
'H NMR (DMSO-d6, 270 MHz): ~ = 8.050 (lH, s, nitronyl CH), 7.448 (lH, d, J = 2.2 Hz, furan CH), 6.517 (lH, d, J = 2.2 Hz, furan CH), 3.890 (2H, t, J = 6.6 Hz, CH2), 1.779 (2H, m, CH2), 1.263 (2H, m, CH2CH2CH2) and 0.850 (3H, t, CH3).
13C NMR (DMSO-d6, 270 MHz): ~ = 158.275, 146.866, 125.069, 113.964, 110.258, 64.772, 30.895, 27.142, 25.526, 22.078 and 13.948.

F.~.,.pl~ 6 Synthesis of N-Cyclohexyl-a-(2-sulfofuran-5-yl)nitrone Following the p~ucedule of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-cyclohexylhydroxylamine, the title co.l-pound was ~re~ ed in 84.3% yield as the sodium salt, m.p. 236.1~C
(dec.).
Spec~osc~ic data was as follows:
IR (KBr, cm-l): 2934.2 (CH), 2858.4 (CH), 1637.2 (C=N), 1215.5 (SO3) and 1168.9 (N-O).

CA 02260825 l999-0l-l8 W O 98/03496 PCTrUS97/11960 'H NMR (DMSO-d6, 270 MHz): ~ = 8.015 (lH, s, nitronyl CH), 7.439 (lH, d, J = 3.5 Hz, furan CH), 6.508 (lH, d, J = 3.5 Hz, furan CH), 4.053 (lH, m, NCH) and 1.814-1.097 (lOH, m, 5 CH2).
13C NMR (DMSO-d6, 270 MHz): ~ = 158.230, 147.049, 123.208, 113.858, 110.197, 72.597, 30.666, 24.839 and 24.534.

r.~...ple7 S~ th~ of N-tert-Octyl-a-(2-sulfofuran-5-yl)nitrone Following the pluc~lul~ of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-tert-octylhydroxylamine, the title co...pol~n~ was prel)~ in 98~o yield as the sodium salt, m.p. 216.9~C (dec.).
Specl,oscopic data was as follows:
IR (KBr, cm~'): 2954.3 (CH), 2905.4 (CH), 1634.8 (C=N), 1216 (SO3) and 1168.3 (N-O).
~H NMR (DMSO-d6, 270 MHz): ~ = 8.031 (lH, s, nitronyl CH), 7.492 (lH, d, J = 3.5 Hz, furan CH), 6.517 (lH, d, J = 3.5 Hz, furan CH), 1.844 (2H, s, CH2), 1.525 (6H, s, 2 CH3) and 0.885 (9H, s, 3 CH3).
~3C NMR (DMSO-d6, 270 MHz): ô = 158.336, 147.857, 122.079, 113.873, 110.182, 72.796, 50.983, 31.398, 30.452 and 28.332.

Exa~ple 8 S~nlh~.s of N-Adamantyl-a-(2-sulfofuran-5-yl)nitrone Following the procedure of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N~ ntylhydroxylamine, the title co,.li)oulld was ~repar~d in 59% yield as the sodium salt, m.p. 236.9~C (dec.).
Sp~scopic data was as follows:
IR (KBr, cm-'): 2910.7 (CH), 2853.0 (CH), 1638 (C=N), 1216.8 (SO3) and 1168.4 (N-O).

WO 98/03496 PCTrUS97/11960 IH NMR (DMSO-d6, 270 MHz): ~ = 7.849 (lH, s, nitronyl CH), 7.495 (lH, d, J = 3.5 Hz, furan CH), 6.518 (lH, d, J = 3.5 Hz, furan CH), 2.166 (3H, bs, 3 CH), 2.075 (6H, bs, 3 CH2) and 1.666 (6H, bs, 3 CH2).
~3C NMR (DMSO-d6, 270 MHz): ~ = 158.306, 147.644, 120.417, 5114.087, 110.288, 69.669, 35.639 and 29.2g3.

FY~mpl~ 9 Synthesis of N-Benzyl-~(2-sulfofuran-5-yl)nitrone 10Following the ~,r~ur~ of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-benzylhydroxylarnine, the title c4~ ~ n~1 was pl~)arcd in 82% yield as the sodium salt, m.p. 223.7~C (dec.).
S~;lluscopic data was as follows:
IR (KBr, cm~'): 3079.2 (aromatic CH), 1632.4 (C=N), 1242.2 (SO3), 151219 (SO3) and 1173.1 (N-O).
'H NMR (DMSO-d6, 270 MHz): ~ = 8.273 (lH, s, nitronyl CH), 7.500-7.371 (6H, m, C6H5 & furan CH), 6.519 (lH, d, J = 3.S Hz, furan CH) and 5.067 (2H, s, CH~).
13C NMR (DMSO-d6, 270 MHz): ~ = 158.596, 146.790, 135.319, 20129.752, 129.126, 125.084, 114.224, 110.304 and 68.738.

F.~mple 10 Synthesis of N-Isopropyl-a-(2,4-disulfofuran-5-yl)nitrone 25Following the p~c~u,e of Example 1 above and using 5-formylfuran-2,4-disulfonic acid f~ m salt and N-isopropylhydroxylamine, the title c4...po.)~d could be pr~d ac the ~~icodi~m salt.

W O 98/03496 PCT~US97/11960 Example 11 Synthesis of N-Isopropyl-~Y-[2-(N-morphclin~ .lfonyl)furan-S-yl]~ r~..c To a mixture of POC13, (16.0 mL, 171.66 mmol) and 5-formyl-2-filr~rs~lfonic acid sodium salt (15.0 g, 75.71 mmol) was added PCI5 (38.0 g, 182.48 mmol) in portions over a 20 min. period with cooling. The ~ ur~, was stirred at room te.ll~.dlul~ for ~lrlition~l 90 min. The solids (primarily NaCl) were removed by filtration and washed with CH2Cl2 (25 mL). Rotary evaporation of the filtrate gave crude 5-dichloromethyl-2-furansulfonyl chloride(16.43 g). This liquid was dissolved in Et2O or CH2CI2 (100 mL) and cooled to -45~C. A sQlutiQn of morpholine (12.0 mL, 138.20 mmol) in Et20 or CH2C12 (30 mL) was added dropwise during 15 min. After stirring for 1 h at room t~ e, the Illi~lul~ was filtered and the solid was washed with 2 x 60 mL
of the solvent. The co-..bh~ed filtrdtes were rotary e~a~ld~ed to provide crude 2-(N-morpholinos-llfonyl)-5-dichloromethylfuran (15.13 g) as a yellowish crystalline solid. Part of this solid (14.13 g, 47.07 mmol) was dissolved in 75% HCOOH (75 mL) and refluxed for 60 min. The solution was then rotary e~ ted to afford crude 2-(N-I,.ol~holinosl-lfonyl)-5-fu~aldehyde (12.58 g) as a brown solid. This solid was mixed with nlr'~ r sieves (55 g), silica gel (10 g) and Me2CHNHOH (6.0 g, 80 mmol) in CHCl3 (250 mL) under argon.
After stirring at room l~ e for 1 h, the ~ Lure was filtered and rotary e~ ted to produce a yellowish solid. This crude product was recryst~lli from hPY~nes and ethylene glycol dimethyl ether to give the title co."pound (6.92 g, 30.25~ overall yield) as a solid, m.p. = 163.7~C (R, = 0.31 on a silica gel plate using EtOAc as the eluant).
Sp~:~oscopic data was as follows:
IR (~CBr, cm~'): 2982 (CH), 2934 (CH), 2872 (CH), 1634 (C=N), 1584 (furan ring), 1364.8 (SO2), 1188.1 (N-O), 1149.3 (SO2), 1112.7 (C-O-C).
'H NMR (CDCl3, 270 MHz): ~ = 7.763 (lH, d, J = 3.6 Hz, furan CH), 7.649 (lH, s, nitronyl CH), 7.091 (lH, d, J = 3.6 Hz, furan CH), 4.218 W O 98/03496 PCT~US97/11960 (lH, septet, J = 6.6 Hz, CH), 3.718 (4H, m? CH2OCH2), 3.150 (4H, m, CH2NCH2) and 1.472 (6H, d, J = 6.6 Hz, 2 CH3).
~ 3C NMR (CDCl3, 270 MHz): ~ = 150.801, 145.920, 122.018, 119.349, 114.605, 67.457, 65.947, 45.614 and 20.538.
s FY~mple 12 SynthecLc of N-Lcopropyl-a-[2-(N,N-d;methylsulfamoyl)furan-5-yl]nitrone The title cc l~l~und was ~lepared using the procedure described in Example 11 above and using N,N-dimethylamine instead of morpholinP. The title col,lpo~nd was i~nl~ted in 32.1% yield as a solid, m.p. = 79.0~C (Rf =
0.35 on a silica gel plate using EtOAc as the eluant).
Sp~l,oscopic data was as follows:
IR (KBr, cm~1): 2980 (CH), 1640 (C=N), 1582 (furan ring), 1356.0 (SO2), 1177.6 (N-O) and 1136.9 (SO2).
IH NMR (CDCl3, 270 MHz): ~ = 7.747 (lH, d, J = 3.7 Hz, furan CH), 7.653 (lH, s, nitronyl CH), 7.056 (lH, d, J = 3.7 Hz, furan CH), 4.211 (lH, septet, J = 6.6 Hz, CH), 2.794 (6H, s, CH3NCH3) and 1.457 (6H, d, J
= 6.7 Hz, 2 CH3).
'3C NMR (CDCI3, 270 MHz): ~ = 150.435, 146.347, 122.186, 118.647, 114.575, 67.320, 37.469 and 20.507.

FY~m~'e 13 SynthecLc of N-Lcopropyl-ar-[2-(N~N-diethylcl~lr~ o~l)furan-s-yll~utrone The title coln~und was pl~ using the procedure described in F~ e 11 above and using N,N-diethylamine instead of morpholine. The title conlpo.md was iso~t~ in 40.4% yield as a solid, m.p. = 82.9~C (R~ = 0.34 on a silica gel plate using EtOAc as the eluant).
S~c~oscopic data was as follows:

W O 98/03496 rCT~US97/11960 IR (KBr, cm~l): 2981.2 (CH), 2938 (CH), 1633.2 (C=N), 1556.6 (furan ring), 1359.1 (SO2), 1172.4 (N-O) and 1135.4 (SO2).
'H NMR (CDCI3, 270 M~z): ~ = 7.706 (lH, d, J = 3.6 Hz, furan CH), 7.609 (lH, s, nitronyl CH), 7.002 (lH, d, J = 3.6 Hz, furan CH), 4.196 (lH, septet, J = 6.6 Hz, CH), 3.269 (4H, q, J = 7.2 Hz, CH2NCH2), 1.451 (6H, d, J = 6.6 Hz, 2 CH3) and 1.120 (6H, t, J = 7.2 Hz, 2 CH3).
13C NMR (CDCl3, 270 MHz): ~ = 149.703, 149.123, 122.201, 117.351, 114.758, 67.213, 42.030, 20.491 and 13.674.

FY~mple 14 Synthesis of N 1 DP~ o~ l-a-[2-(N 4 methylpi~ ~in-l-yLsulfonyl)furan-Syl]nitrone The title co.--l)ou~--l was ~r~p~d using the p~OCedUl-, described in Example 11 above and using l-methylpip~laLiuc instead of IIIG~hO~ ' The title CGI~ l d was isolated in 35.6% yield as a solid, m.p. = 111.5~C (R~ =
0.19 on a silica gel plate using EtOAc:EtOH (4:1, v:v) as the eluant).
Spc.:l.oscopic data was as follows:
IR (KBr, cm-'): 2982 (CH), 2858 (CH), 1634 (C=N), 1582 (furan ring), 1364.6 (SO2), 1182.8 (N-O) and 1142.6 (SO2).
~H NMR (CDCl3, 270 MHz): ~ = 7.739 (lH, d, J = 3.6 Hz, furan CH), 7.618 (lH, s, nitronyl CH), 7.071 (lH, d, J = 3.6 Hz, furan CH), 4.204 (lH, septet, J = 6.6 Hz, CH), 3.201 (4H, m, CH2NCH2), 2.450 (4H, m, CH2NCH2), 2.263 (3H, s, CH3) and 1.470 (6H, d, J = 6.6 Hz, 2 CH3).
13C NMR (CDCl3, 270 MHz): ~ = 150.557, 146.393, 121.957, 118.968, 114.559, 67.381, 53.821, 45.614, 45.523 and 20.538.

FY~mple 15 Synthesis of N-Isopropyl-~[2-(N q ~n~hylpip~ ylsulfonyl) furan-5-yl]nitrone Hydrochloride Hydrochloride gas was bubbled into a solution of the product from FY.~mple 14 above in CH2Cl2. The title co~ ow~d was i~o!~ l in 84.5% as a solid, m.p. = 212.6~C (dec.) (Rf = O on a silica gel plate using EtOAc:EtOH
(4:1, v:v) as the eluant).
Spac~ scop;c data was as follows:
IR (KBr, cm '): 3441.2 (NH), 2984 (CH), 2938 (CH), 2680 (NH+Cl-), 2594 (NH+Cl-), 2452 (NH~Cl-), 1636 (C=N), 1558 (furan ring), 1365.3 (SO2), 1188.7 (N-O) and 1141.2 (SO2) IH NMR (D2O, 270 MHz): ~ = 8.205 (lH, s, nitronyl CH), 7.741 (lH, d, J = 4.0 Hz, furan CH), 7.443 (lH, d, J = 4.0 Hz, furan CH), 4.431 (lH, septet, J = 6.5 Hz, CH), 4.018 (2H, broad s, CH2N), 3.613 (2H, broad s, CH2N), 3.270 (4H, broad s, CH2NCH~, 2.942 (3H, s, CH3) and 1.445 (6H, d, J = 6.5 Hz, 2 CH3).
'3C NMR (D2O, 270 MHz): ~ = 150.100, 145.874, 127.967, 120.615, 117.595, 67.243, 52.585, 42.884, 42.762 and 19.440.

Example 16 Synthesis of N-teJt-Butyl-~Y-[2-(N-3-trifluor~ ll.ylphenylclllf~mQy"-furan-5-yl]nitrone The title compound was p.~a~ using the procedure ~çscril~ed in FY~mple 1 1 above and using 3-trifluoromethylaniline instead of morpholine and N-ter~-butylhydroxylamine instead of N-isopropylhydroxylamine. The title co"~ nd was icol~tP~I in 14.9% yield as a solid, m.p. = 162.1~C (Rf = 0.08 on a silica gel plate using CH2Cl2 as the eluant).
Sp~l-uscopic data was as follows:
IR (KBr, cm-'): 3094 (aromatic CH), 2982.9 (alkyl CH), 1618.8 (C=N), 1363.0 (CF3), 1332.5 (SO2), 1178.8 (SO2), 1144.1 (C-F) and 1127.6 (N-O).
lH NMR (CDCl3, 270 MHz): ~ = 7.657-7.627 (3H, m, furan CH, nitronyl H & phenyl H), 7.433 (lH, s, NHSO2), 7.401-7.329 (3H, m, phenyl H's), 7.085 (lH, d, J = 3.5 Hz, furan CH) and 1.549 (9H, s, 3 CH3).

W O 98/03496 PCTrJS97/11960 13C N M.fR (CDCl3, 270 MHz): ô = 151.442, 146.622, 136.661, 132.154 (q, J = 32.8 Hz), 130.347, 124.260, 123.666 (q, J = 274.1 Hz), 122.415, 120.508, 119.852, 117.885, 114.392, 71.301 and 27.661.

Fl~mple 17 Synthesis of N-telt-Butyl-a-[2-(methylsulfonyl)-furan-5-yl]nitrone A s~ tion of 5-bromo-2-furaldehyde (20 g, 0.1143 mol) and ,,.~n~2.-lfinic acid sodium salt (25 g, 0.2427 mol) in 2-ethoxyethanol (300 mL) was refluxed for 3 h and poured into ice-water (1000 g) after cooling.
The Illixlu~e was extracted with CHCl3 and the CHCl3 solution was dried over Na2SO4, filtered and rotary e~d~làled. The res-llti~g residue (9.16 g) was reacted with N-ter~-butylhydroxylamine (7.0 g) in CHCl3 in the presence of rnole~ul~r sieves (4A, 50 g) and silica gel (10 g) at room ~---p~.dture for 21 hand at refluxing te.ll~ldlule for 3 h. After filtration and evaporation, the residue ob~in~d was purified by column chromatography eluted with hPY~nPs and ethyl acetate (1:1, v:v) to give the title cG---pound (5.37 g, 19.2% overal yield) as a solid, m.p. 137.5~C (R~ = 0.27 on a silica gel plate using h~ ~n~.c/EtOAc (1:1, v:v) as the eluant).
S~t~scopic data was as follows:
IR (KBr, cm~'): 3173.2 (furan CH), 2997.0 (alkyl CH), 2915.1 (allyl CH), 1636 (C=N), 1320.9 (SO2), 1173.0 (SO2) and 1127.6 (N-O).
lH NMR (CDCl3, 270 MHz): ~ = 7.792 (lH, s, nitronyl CH), 7.757 (lH, d, J = 3.6 Hz, furan CH), 7.204 (lH, d, J = 3.6 Hz, furan CH), 3.126 (3H, s, CH3) and 1.549 (9H, s, 3 CH3).
13C NMR (CDCl3, 270 MHz): ~ = 151.930, 148.818, 120.386, 119.181, 114.407, 71.270, 43.235 and 27.737.

CA 0226082~ 1999-01-18 Using the procedures described in Examples 1-17 above and the ~pr~"iate starting materials and reagents, the following furan nitrone compoun~s of formula I could be pr~,p~d:
N-methyl-a-(2-sulfofuran-3-yl)nitrone S N-methyl-a-(2-sulfofuran-4-yl)nitrone N-methyl-a-(2-sulfofuran-5-yl)nil ~ne N-methyl-a-(3-sulfofuran-2-yl)nitlone N-methyl-a-(3-sulfofuran-4-yl)nil,un N-methyl-a-(3-sulfofuran-5-yl)nillune N-ethyl-a-(2-sulforu~ -3-yl)ni~r~ne N-ethyl-a-(2-sulfofuran-4-yl)nil.~ne N-ethyl-a-(2-sulfofuran-5-yl)nil~une N-ethyl-a-(3-sulfofuran-2-yl)rliLIone N-ethyl-a-(3-sulfofuran-4-yl)ni~,une N-ethyl-a-(3-sulfofuran-5-yl)ni~-one N-n-propyl-a-(2-sulfofuran-3-yl)ni~ne N-n-propyl-a-(2-sulfofuran-4-yl)nitrone N-n-propyl-a-(3-sulfofuran-2-yl)nitrone N-n-propyl-a-(3-sulfofuran-4-yl)nitrone N-n-propyl-a-(3-sulfofuran-5-yl)n}trone N-isopropyl-a-(2-sulfofuran-3-yl)nitrone N-isoplop,~ l-a-(2-sulfûfuran-4-yl)nitrone N-isopropyl-a-(3-sulfofuran-2-yl)nitrone N-isoplopyl-a-(3-sulfofuran-4-yl)nitrone N-isupiopyl-a-(3-sulrûrul~n-5-yl)nillu"e N-n-butyl-a-(2-sulfofuran-3-yl)nitrone N-n-butyl-a-(2-sulfofuran-4-yl)nitrone N-n-butyl-a-(3-sulfofuran-2-yl)nitrone N-n-butyl-a-(3-sulfofuran-4-yl)nitrone - 30 N-n-butyl-a-(3-sulfofuran-5-yl)nitrone N-sec-butyl-a-(2-sulfofuran-3 -yl)nitrone N-sec-butyl-a-(2-sulforu~dn-4-yl)~ ,one N-sec-butyl-a-(2-sulfofuran-5-yl)nil,une N-sec-butyl-a-(3-sulfofuran-2-yl)nillone N-sec-butyl-a-(3-sulruÇu.dn-4-yl)nil,une S N-sec-butyl-a-(3-sulforuldn-S-yl)ni~lùnc N-isobulyl-a-(2-sulrc~ruldn-3-yl)nilrùne N-isobutyl-a-(2-sulfufuldn~-yl)nilrùne N-isobutyl-a-(2-sul-ol;lldn-5-yl)niLIùne N-isobutyl-a-(3-sul-uf~l~an-2-yl)nil~une N-isobutyl-a-(3-sulfofuran-4-yl)nitrone N-isobutyl-a-(3-sulfofurdn-5-yl)nillune N-tert-butyl-a-(2-sul~orll.dn-3-yl)nitrone N-tert-butyl-a-(2-sulfofurdn-4-yl)niLIone N-tert-butyl-a-(3-sulforu,~-2-yl)nil~one N-tert-butyl-a-(3-sulÇuru~ -4-yl)nitlûne N-tert-butyl-a-(3-sulroruldi~-5-yl)llil.ùne N-n-hexyl-a-(2-sulfofu,~-3-yl)nitrone N-n-hexyl-a-(2-sulfofuran-4-yl)nitrone N-n-hexyl-a-(3-sulfofuran-2-yl)llillone N-n-hexyl-a-(3-sulfofuran~-yl)nillune N-n-hexyl-a-(3-sulfofuran-5-yl)nitrone N-cyclohexyl-a-(2-sulforuldn-3-yl)nil,une N-cyclohexyl-a-(2-sulfofuran-4-yl)ni~l une N-c~/clohcAyl-a-(3-sulfofuran-2-yl)nillone N-cyclohexyl-a-(3-sulfofurdn-4-yl)nilrûne N-cyclohexyl-a-(3-sulfofuran-5-yl)nillone N-tert~ctyl-a-(2-sulÇoÇuldn-3-yl)nil,one N-tert-octyl-a-(2-sulÇoruldn-4-yl)nitrone N-tert-octyl-a-(3-sulÇoru.dn-2-yl)nitrone N-tert-octyl-a-(3-sulf(~ru~l-4-yl)nitlune W O 98/03496 PCT~US97/11960 N-lert-octyl-a-(3-sulfofuran-5-yl)nitrone N-benzyl-a-(2-sulÇofuldn-3-yl)nitrone N-benzyl-a-(2-sulfofuran-4-yl)nitrone N-benzyl-a-(3-sulfofuran-2-yl)nilr~ne N-benzyl-a-(3-sulfûrlllan-4-yl)nitlone N-benzyl-a-(3-sulÇofll~dn-S-yl)nillune N-methyl-a-[2-(N-methylcl~lf~moyl)furan-S-yl]nillùne N-ethyl-a-[2-(N-methylc~llf~moyl)furan-5-yl]nitlune N-n-propyl-a-[2-(N-methylc~lf~moyl)furan-S-yl]nitrone N-iso~ pyl-a-[2-(N-methylc~lf~moyl)furan-S-yl]niL~ne N-n-butyl-a-[2-(N-methylc~lfAmoyl)furan-S-yl]nillun N-isobutyl-a-[2-(N-methylc~lf~moyl)furan-S-yl]nitrone N-sec-butyl-a-[2-(N-methylc~-lf~moyl)furan-S-yl],-ilrone N-tert-butyl-a-[2-(N-methylculfamoyl)furan-S-yl]nitrone N-n-hexyl-a-[2-(N-methylculf~moyl)furan-5-yl]nitrone N-cyclohexyl-a-[2-(N-methylcl-lf~moyl)furan-S-yl]nit-ùne N-tert-octyl-a-[2-(N-methylc~lf~mQyl)furan-s-yl]ni~ùne N-benzyl-a-12-(N-methyl culf~moyl)furan-s-yl]nitlone N-methyl-a-(2,4-disulfofuran-5-yl)nitrone N-ethyl-a-(2,4-disulruruldn-5-yl)nitrone N-n-propyl-a-(2,4-disulfofuran-5-yl)nilro, e N-isoplupyl-a-(2,4-di~.llrorulan-5-yl)nitlone N-n-butyl-a-(2,4-disulÇoru,~ul-S-yl)nillùne N-isobutyl-a-(2,4-disulforuldn-5-yl)nitrone N-sec-butyl-a-(2,4-disulroru.dn-5-yl)nit~ne N-tert-butyl-a-(2,4-disulfofuran-5-yl)nitrone N-n-hexyl-a-(2,4-disulforuldn-5-yl)nitrone N-cyclohexyl-a-(2,4-disulfor lldn-S-yl)ni~one N-tert-octyl-a-(2,4-disulÇorul~n-S-yl)nitrone - 30 N-benzyl-a-(2,4-disulfofuran-5-yl)nitrone N-methyl-a-(2,3-disulfofuran-5-yl)nitrone N-ethyl-a-(2,3-disulfofuran-5-yl)nitrone N-n-propyl-a-(2,3-disulfofuran-5-yl)nil,one N-isoplupyl-a-(2,3-disulfofuran-5-yl)nillone N-n-butyl-a-(2,3-disulroÇul~dn-5-yl)nitrone N-isobutyl-a-(2,3-disulÇuru~ -S-yl)~ une N-sec-butyl-a-(2,3-disulfofuran-5-yl)nitrone N-tert-butyl-a-(2,3-disulfofuran-5-yl)niL.~ne N-n-hexyl-a-(2,3-disulfofuran-5-yl)nitrone N-cyclohexyl-a-(2,3-disulrorul~l-5-yl)nitrone N-tert~ctyl-a-(2,3-disulrofulan-5-yl)r,il.ùne N-benzyl-a-(2,3-disulfofuran-5-yl)nit.~,nc N-methyl-a-t2,4-di(N-methy~ f~mQyl)furan-S-yl]nitrone N-ethyl-a-[2,4-di(N-methylc~lf~moyl)furan-S-yl3nil.one N-n-prûpyl-a-[2~4-di(N-methylculf~moyl)furan-s-yl]niLlone N-isopropyl-a-[2,4-di(N-methylc~lf~m~yl)furan-5-yl]nitrone N-n-butyl-a-[2,4-di(N-methylc~lf~moyl)furan-s-yl]nitrone N-isobutyl-a-[2,4-di(N-methylc~lf~moyl)furan-S-yl]ni~rone N-sec-butyl-a-[2,4-di(N-methylc~lf~moyl)furan-S-yl]ni~n)ne N-tert-butyl-~-r2~4-di(N-methyl~lllf~moyl)furan-s-yl]l~ e N-n-hexyl-a-t2,4-di(N-methyl~ f~tnoyl)furan-S-yl]nitrone N-cyclohexyl-a-[2,4-di(N-methylc~lf~mQyl)furan-5-yl]nitloi~e N-tert-octyl-a-[2,4-di(N-methylc~lf~moyl)furan-5-yl]nil,one N-benzyl-a-[2,4-di(N-methyl~ulf~moyl)furan-5-yl]nitrone and the like; and ph~. .~e~ lly ~~cept~hle salts thereof, inellltling but not limited to, the so-lium, potassium, and c~lçium monoc~ te salts.

FY~mple 18 Free Radical Trapping In this ~A~llple, the ability of furan nitrones of formula I above to trap free radicals in vitro is demon~trated. Free radicals have been impli~tçd in ,~l7ht~im~r's disease and other long term neurodegenerative conrlitionc~ A
series of studies were co~duGted to determine the ability of furan nillo,les to trap free radicals in biological sPttin~c S Dichlorofluore3cein (DCF) is a cG.. po~nd that fluoresces when OYi(1i7f~d by reactive oxygen species (ROS), such as hydroxyl, peroxyl, or alkoxyl free ~lir~lc Test compounds were evaluated for their ability to scavenge r~ lc by dete~ ing their capacity to prevent the DCF oYid~tinn in a radical &.,.~ ;n~ envi~ n~ Two radical gene~ating systems were used: (i) ferrous 10 iron and (ii) ~ert-butyl hydru~hioAide. When ferrous iron is placed in normoxic solutinn, it auto-Q~ridi7Ps to produce ROS in the form of hydroxyl radicals, su~Aide anion free radicals, and hydrogen peroxide. Similarly, when tert-butyl h~dlu~x~uAide is placed in non-c-h~l~t~d media, trace metals cataly_e its oY~ tion to yield alkoxy, peroxyl, and alkyl free radicals.
In this a_say, either 100 ~M FeSO4 or 25 ~uM tert-butyl hydrupe.u~ide were mixed with 50 ~M DCF and 100 ~M of the test compound in MEM and the IlliAIU~ was in~ b~ at 37~C for 2 hrs. The fluolesee.lce wave1~ngthc "-e~.-,~d were 485 nm for eYcit~tion and 530 nm for çmiCcir n. In these tests, 20 N~ propyl-~-(2-sulfofuran-5-yl)nitrone sodium salt (p-cpa-cd in Example 1 above) reduced fluG~sce~ce by 20% in the Fe+2 assay and by 13% in the tert-butyl hyd,ùpe~Aide assay. In colnp~ison, a known free radical trap, N-tert-butyl-a-phenylnilrone (PBN) reduced fluo~scellce by 48% in the Fe+2 assay and by 9% in the tert-butyl hydlu~.oAide assay. These results ~len-ol-strate 25 that N-isoplop~ -(2-sulfofuran-5-yl)nitrone sodium salt was effective at trapping free radicals.

Example 19 Electron Spin R~o~nn~ (ESR) Study In this eApelil-.. nt, the ability of furan nitrones of formula I above to trap free radicals is demon~trated using ESR spin trapping techniques. See, for CA 02260825 l999-0l-l8 example, K. R. Maples et al., "In Vivo Detection of Free Radical l~t~holites", Free Rn~ n1r in Synthesis and Biology ~:. Mini,cci, ed.) pp. 423-436 (Kluwer ~c ~l~mic Publishers, Boston, 1989); and J. A. DeGray et al., "Biological Spin Trapping", Electron Spin Resonance 14:246-300 (1994). A t-butyl S h~dlo~roAide/ferrous iron free radical ge.~e.a~ing system was used in this c ~.i"lenl. This free radical gcne.dLing system pf~l~lces t-butyl-alkoxyl r~ lc, t-butyl-peroxyl prli~lc~ and methyl r~ c If the furan niLr~nes are capable of Lla~)ph~g any of these r~dic~lc, radical adducts should be ~et~t~hl~
by ESR s~:lloscopy.
To 490 ~1 of a 100 mM sollltiorl of N-isop~pyl-a-(2-sulÇoruldn-5-yl)nitrone sodium salt in water was added 5 ~ of 1 mM t-butyl hydr~.u--ide.
The reaction was initi:ltetl by the ~d~1itit)n of S ~1 of 1 mM ferrous sulfate and then the solution was quickly Llans~llGd into a quartz flat cell and this cell was 15 placed in the cavity of a Bruker ESP 300 ESR s~ecLl~,lleter. ESR s~Llull-~te ~ g~ were: 9.75 GHz G~ue,lcy, 10 dB power, 8 x 104 receiver gain, 0.20 G r~ odlll~tion ~mrlihlde, 0.080 sec time conct~-lt, 3480 G center field, 200 G
sweep width and 240 sec sweep time.

As shown in Figure 1, N-isopf~yl-~Y-(2-sulfofuran-5-yl)niLlunc sodium salt reacted with radicals 2en~laL~d by the t-butyl hydlu~ro..ide/ferrous iron system to produce a radical adduct. The adduct is ch~ tPrized as a 4.5 G
doublet of 4.5 G doublet of 16.5 G 1:1:1 triplets. The h~,Gne ~l.litl;i-g.~ arise from couplings of the clocLr~n with the In~nPtiC Ino~nlont of the hydr~gen 25 atoms ~t~~hP~ to the N-isopropyl group, the hydrogen atom ~tt~rh~d to the nitrone carbon and from the niLn)gen of the nitrone. Based on the large a~
spli~ting, and in co",l,alison to similar results previously le~lL~d for N-terr-butyl-a-phenylniLlune, the species trapped is most likely a methyl radical.
Thus, the ESR ~;LI.IIII shown in Figure 1 d~morlstrates that N-isopropyl-cY-(2-30 sul~fulan-5-yl)nitrone sodium salt was effective at trapping free radicals and can be used as an analytical reagent for ESR applications.

W 098/03496 PCTrUS97/11960 FY~mple 20 Tl~nl~-~f.-~ of Acute CNS Disor~
In this eY~mple, the ability of a furan nitrone of formula I above to reduce the infarct volume in an in vivo stroke model is demonstrated. A rat 5 pe.~ en~ middle cerebral artery occh~cion (MCAO) model was used to deb~ ne stroke 1~ ..c ~1~ efficacy. MCAO is a ~ ese ~t;-~e model of acute CNS diso~e.~. See, for PY~mple, M. D. Ginsberg et al., "Rodent Models of Cerebral ~-h~...jAn (1989) Stroke, 20:1627-1642. In this stroke model, the middle cerebral artery was ~" ,alle~ y occluded via caute.iication to produce a 10 focal stroke. N-isc-,~,lopyl-~Y-(2-sulfofuran-5-yl)nilrone, sodium salt (pr pa-~d in FY~ 1 above) was then ~ c~r~ed as a 10 mg/kg i.v. bolus dose three hours post MCAO through a c~ ; surgically implanted in the jugular vein.
Two days post MCAO, the rats were sacrificed and the extent of brain ~rnaee 5c~ using tetr~7Olillm st~ining (TTC ~h~ing) followed by cG~ Jut~ image 15 analysis to ~lu-nl;l;t~o- infarct volumes, i.e., the regions of dead tissue. The mean infarct volume for rats treated with the test compound was 24.7 mm3 whereas the mean infarct volume for rats not treated with the test col.-pound was 36.0 mm3. These results are illu~ ted in Figure 2. Thus, N-isopropyl-a-(2-sulfo~u,~-5-yl), il~one, sodium salt reduced the mean infarct volume of a 20 stroke by 32% when ~ulmini~ cd three hours post stroke Co~ )~cd to controls.

Example 21 Inhibition of A,~ Beta-Pleated Sheet Formation The deposition of arnyloid ,B-peptide (A~B) is ~csociAtrll with the 25 development of ~l7heim~or~s ~lise~. See, for e~mpl~, G. G. Glenner et al.
(1984) Biochem. Biophys. Res. Commun., 120:885-890; and R. E. Tanzi (1989) Ann. Med., 21:91-94. Accordingly, compounds which effectively disrupt the formation of A~(1-40) or A~(1-42) beta-pleated sheets are potentially useful forp.~,~e"ting and/or ,~ ing such amyloid deposits. Thioflavin T (ThT) is 30 known to rapidly ~Ccoci~te with beta-pleated sheets, particularly the aggregated fibrils of synthetic A~(1-40). This ~Ccoci~tion gives rise to a new e~çjt~tion W 098/03496 PCTrUS97tll960 rn~Ydml.m at 440 nm and to çnh~n~ed emic~ion at 490 nm. In this eJ.~.illlent, the ability of furan nitrones of formula I above to inhibit the ~ccoci~tinn of ThT
with synthetic A~B(1-40) or A,B(1~2) is clemof.s~ çd by m~cllrin~ ch~ne~cs in fluolesr~ce.

The eY~rim~ntc were ~ fUlll~ed using a CytoFluor II lluor~sGenc~ plate reader having the following pu~ let~

Filters: FYcit~tion 440 nml20 F.miccion 490 nm/40 Gain: 75 Cycle to Cycle Time: 30 min Run Time: 720 min (24 cycles) or dc~ ndç.-t on e~;.. c.~l design Plate: 96 well Into each well was aliquoted 95 ~1 of ThT (3 ~M) p~"~d in PBS (pH
6.0), 2 ~ L of the co.~pound to be tested (10 ~M) prep~t;d with 0.05% of methylce~ ose in PBS (pH 6.0), and 3 ~LL of AB(1~0)(3 ,ug) p~are~ with dH20 (the colul~ou~ds plep~ in F~ les 1, 3, 4, 5, 6, 7, 8, 9, 11 and 12 were tested). The fluGl~ sc$ ~ce mea~.lr~,.-ent began when the A,B(1-40) was added and ~n~ çd for a total of 12 hours. The percent inhibition of beta-pleated sheet fG.Illation was ç~l~ul~t~ from the relative lluol~se~.l-ce unit difference b~lw~l agg,~alion in the presence and in the ~hSçnce of the test cG...~ dc The data show that the cGI~lpounds pr~par~d in FY~ ~ 1, 5, 6, 7, 9, 11 and 12 above inhibited AB(1-40) beta-pleated sheet formation 15 to 71% co"-pal~d to the conl,-ls. At 10 ~M, the cU~.pounrlc pr~ cd in Fl~mp'es 3, 4, and 8 above did not cigrlific~ntly reduce AB(l~0) beta-pleated 30 sheet formation in this test.

In experiments cond~lct~i in a similar manner using A,~(1-42) instead of A~B(1-40), the co.,.pound ~lepaled in Examples 1, 13, 14 and 15 above inhibited A~ 42) beta-pleated sheet formation by 32 to 55% COlllp ~ ~ to the controls.

Example 22 S~ ~t~lion Against A,~(25-35)-Induced Neuronal Cell Loss Patients with A~ r's disease are known to suffer a pr~,~ i.;,;ve loss of neL~l~,ndl cells. See, for eY-q---. 'e, P. J. Wh;~*h~l-~ et al., (1982) Science, 215:1237-1239. In this experiment, the ability of certain furan nitrones of formula I above to protect against A~(25-35)-induce~ neuronal cell loss is 10 de ..ofi~ ttd. Sprague Dawley rat hippocampus of 18-day ges~Lion embryos was excised and then d~ by trituration to l,r~ primary ne~lonal/asLIu~ yt~ cultures. Cells (3x105) were plated on 35 mm poly-D-lysine-co~ted plates co~ -;ne Eagle's minimum e~ l meAium supplementrl1 with 109~i fetal bovine serum. After 3-5 hours, the originql medium was removed 15 and replaced with 1 mL of fresh medium. Cultures were ,~ ne~d at 37~C in a 5 % CO2/95 % air humi~lified incuhqtor.

To the cells (7 DIV) was added 30 ,uM of A~B(25-35) dissolved in dH20 (stored at -20~C) and }00 ~M of the test co...poul-d (i.e., a compound of FYqmple 1, 3, 4, 5, 6, 7, 8, 12 or 13 above) in 1% methyl~ ose~ Controls were also co~uct.~l without the test compound. The percentage of mo,~hologically viable neurons was dt;le.ll.ined counting the number of viable r,~ ns after 96 hours tre~tm~nt co,llpa~ed to the number of neurons before t in the same }~.. .l,alhed culture regions (three regions/culture, n = 6).
The data show that the co.ll~ounds p,e~ed in FY~mple 1, 3, 5, 6, 7, 8 and 13 above reduced A~(25-35)-induced ne.-ronal cell loss by 3 to 62% colll~d to the conllols. At 100 ~M, the co.,.younds pl~dred in Fy~mples 4 and 13 above did not si~nific~ntly reduce A~(25-35)-induced neuronal cell loss in this test.

CA 02260825 l999-0l-l8 W O 98/03496 PCT~US97/11960 In eypprimpnt~ conduct~ in a similar ~ mer using A~B(1-40) instead of A~B(25-35), the compound prepared in Example 1 above reduced A,~(1-40)-inducPd neur~Jnal cell loss by 46% cGI--l)~c;d to the controls.

F~ 23 R~ction of Inflammation In ~l~h~ t's f~icP~ce~ stroke and mllltirlP sclerosis, lC~S ~ e~ have implir~tP~ an inll~ o~ sl,once in the etiology of the rli~p~ce~ See, for eY~ p!~, P. S. Aisen et al., (1994) Am. J. Psychiatry, lSl:1105-1113; D. W.
Dickson et al., (1993) Glia, 7:75-83; and S. D. Yan et al., Proc. Natl. Acad.
Sci. USA, 94, 5296 (1997). This r~s~ has been mod~le~l in cell culture by utili7ing various factors to cim~ tP the infl~.,.,..~loly le~pOnSe. Such factors include lipopolyc~rr-h~ride (LPS), an agent known to cause the c AIul si~;on of riitric oxide and other cytokinPs and inte.re~n y (INF- y), another agent 15 impltr~tPd in the inll~ h,y/cytokine ~S~i~onse. In this ~Y~mple, the ability of furan n,l.unes of formula I above to reduce the infl~mm~tion caused by LPS
and INF-~y is demor-ctrated.

In this ~ t the cell culture system used was compose~ of E16 20 rat pure cortical neuronal cells (treated with 10 ~M Ara C to retard astrocyte growth) that had been plated on a col.nue ~ bed of two week old cortical glial cells p~el)~ed from the cortices ûf I day old rat pups and allowed to grow for one week. To these cells wa added LPS (20 ~g/mL), IL-l,B (40 mg/pg/mL), and INF~y (200 U/mL), either with or without 100 ~M of the test co...p~s~n-l (i.e., a co.. ~uu~d of Fy~mple 1, 6, 11, 12, 13, 14 or 15 above). Two days later, cell viability was ~cces~c~1 using the lactate dehyd~genase (LDH) assay to ...ofi;lor cytosolic protein leakage due to cell me...bl~ ne dqm~e The results show that the compounds of Fy~mpl~c 1, 6, 11, 12, 13, 14 and 15 above reduced the infl~mm~ion caused by LPS and INF- y by from S to 43%
30 co...~;d to the control.

W O 98/03496 PCTrUS97/11960 Example 24 Reduction of ~-Amyloid~ Jced ll.e. ~ J Cytokine Release In this ~ i...r"t, the ability of furan nitrones of formula I to reduce the ~-amyloid-induc~A increased release of cytol ineS~ such as intPrlellkin-l,B
S (IL-l,B) is demonctrated. THP-l cells, a human monocyte cell line from ~meric~n Type Culture CQ11~t;Cn, were grown in RPMI-1640 rn~Aium plus 10% fetal bovine serum (PBS, not heat-inactivated) in T-flasks. The m.~AilJm was changed every two days by s~;nnin~ down (800 rpm, 5 ~;n~l~s) the cells and added the same fresh ...eAi~ t~m~tively, the cultures were l..AintA.ned10 by the ~ itiQll of fresh .~ JUI. The cultures were maintained at a cell con~ dLion ranging from between lx105 and lxlO~ cells/mL. ne~ cc sera may contain unknown factors which can affect macr~,phdge/monocyte IL-1 production, the FBS was reduced to 5% for 24 hours. The FBS wa_ further r~l~ced to 2% over two days prior to starting each ~;~pe.i",cnt. The cells were 15 coll~tffl by centrifugation and rçs~cpe~ded to 2% FBS. Cell r,u,,lbc;.~ were c~ ul~t~ and cells were plated on 24-well plates (3 x 105 cells/0.6 mL/well).
Cells were then treated with LPS (0.5 ~g/ml or 0-lO~g/ml for LPS dose-~l~nce experiments) alone or in combination with A~B peptides (5~M or 0.05-S ~LM for dose~ on~ illlen~). When determining the effect of the test 20 compo~ndc on cytokine release, 100 ~M of the test cG.ll~und was added with the LPS and A,B25-35 and this mixture was i~Cub~t~d for 48 hours prior to pe.ron,ling EUSA.

IL~ secretions into medium by LPS-stim~ t~d THP-1 cells, in the 25 p~ncc or ahsence of amyloid peptides and a test col..pou~d, were a_sayed with a c4.~ ~ially available ELISA kit (R & D Systems). Briefly, a microtiter plate coated with a murine tnonoclon~l antibody to human IL-l,B was suppli~ by the ~ ur~ r. Standards and samples were pi~lled into the wells and any IL-l,B present was bound by the immobilized antibody. Unbound 30 proteins were washed away and a horseradish peroxidase-linked polyclonal antibody specific for IL-1~ was added to the wells to "sandwich" the IL-l,B

__59__ CA 02260825 l999-0l-l8 W O 98/03496 PCT~US97/11960 bound in the initial step. After washing to remove any unhound antibody-enzyme reagent, a s~sl~dte solution (1:1 hydrogen peroxide -~.i....~ Ihylhen7i~1ine, v/v) was added to the wells and color developed in p~ iol- to the amount of IL-1,l5 bound in the initial step. Color development 5 was stoppe~ with 2 N sulfuric acid and the optical density of the standard andthe test samples was l--~sul~d at 450 nm. The ~mount-C of IL-1,~ present in the samples were cq~ P~I based upon a standard curve. Assays were run in u~llup1ic~tP- wells. The data show that the co.--pounds pr~par d in Examples 1, 6, 12 and 13 above reduced the ~B-amyloid-induce~ increased release of interleukin-l~B by 22 to 48~ co.. ~pared to the controls. At 100 ~M, the po~ d pre;~ared in FY~mrles 11, 14 and 15 above did not ~ignific~ntly reduce the ,B-amyloid-induce~ incr~s~ release of interleukin-1,B in this test.

F~mp ~ 25 Reduction of Locomotor Impairment Due to A,B-Peptide In this ~ l the ability of a furan nitrone of formula I above to reduce the in vivo impairment of ~nim~lc treated with A~-peptide is ~ - On~l~aled. Male Sprague-Dawley rats (250-400 g) were given an ipcil~t inje~tion of 20 ~Lg of A,B(25-35) into their sul,s~ ia nigra. Prior to the 20 injection, the rats were fasted overnight and then each received an oral t-~ of N-isopropyl-a-(2-sulfofuran-5-yl)ni~one sodium salt (prepared in Example 1 above) (10-100 mg/kg) dissolved in aqueous 1% methyl celll~losf or the vehicle alone, one hour before and three hours post the A~-peptide ~t~ic injection. One week after lr~ the rats were dosed s.c. with 25 0.5 mg/kg a~ ollJhillc (dissolved in 0.1% vitamin C in iCotorlic saline) and the circling reflex was morlit~red using a Rotorat colllpulf ;7~d behavioral l ~o~ g a~p~alu~ for the time period between lS and 30 . ~;nv~f s of being - placed in the arena. Il--pail~llent of the ~nim~l~ due to A,B-peptide was d~te~lllined by measuring the nu...b. r of rotations over the 15 minute period. A
30 higher number of rotations per period intlir~te s more physical impairment. The data are shown in Table I below.

Table I
Locomotor Impairment Due to A,B(25-35) Test ~ t~tion~ Over 15 No. Tre~tmPnt Minute Period 16A Naive 4 16B Saline 7 16C A,B(25-35) 16 16D A,B(25-35) + 100 mg/kg of N-isopç~pyl-a- 6 (2-sulfofuran-5-yl)nillone sodium salt 16E A,~(25-35) + 10 mg/kg of N-isopropyl-~- 9 (2-sulfofuran-5-yl)nitrone sodium salt The data in Table I show that N-isoplul)yl-a-(2-sulfofuran-5-yl)niL-une sodium salt reduced the nll.,.be~ of rotations per period and hence, the loco,llo~or i.npail.. cnt, of rats injected with A~B(25-35) CGIllpaf~d to A~(25-35)-treated controls.

F~mple 26 RP~l~ction of Spatial Learning Deficit In this ~ f nt the ability of a furan nitrone of formula I above to reduce spatial learning ~efi~ ies in vivo is demollctrated. Tre~tm~nt of rats with N-nitro-L-ar~,inine, a nitric oxide synthase inhibitor, is known to cause adeficit in spatial le~rning. See, for example, G. A. Bohme et al., (1993) PNAS, 90:9191-9194. Rats treated with N-nitro-L-arginine wander ~iml~ssly throughout their enclQs~re whereas untreated rats spend most of their time in the 4uadl~t in which they are initially placed and stay away from the open area in the middle of the enclosu-e. This N-nitro-L-arginine-induoe~ spatial learning deficit is used as a model for learning deficits caused by Al7hPimer's disease and other de...el.

W O 98/03496 PCTnUS97/11960 In this experiment, 10 mglkg of N-isopropyl-a-(2-sulf~f~llan-5-yl)r~ onc sodium salt ~ d in FY~mrle 1 above) or a control was ~minictçred 30 min before each of nine doses of N-nitro-L-arginine (100 mg/kg. iip.). The w~n-lP in~.c of the rats were then mnnitnred. The results show that rats dosed 5 with N-nitro-L-ar~,inine wander equally around the perimeter of the ~nrlosu~e and readily cross the center of the field. These results are illnct-~tPA in Fig.2B. In c~nt~ct, rats treated with N-nitro-L-arginine and N-isopropyl-a-(2-sulÇoruldn-5-yl)l,illu~le sodium salt show a l,l. fe,ence for the area of the enrlos~e into which they were first placed and rarely cross the center of the 10 enrlos~e as illucl.~led in Figure 3C. This behavior is eccPnti~lly the same as rats treated with a saline control (i.e., without N-nitro-L-af~,,nine) (see Figure 3A). These results demo~ te that N-isopropyl-a-(2-sulf~fu.dn-5-yl)lliL,une sodium salt prevents the spatial 1~ ln~ deficit caused by N-nitro-L-arginine.

FY~mple 27 tion of MBP-Tn~ e~ tal Allergic Fnr~phsl~ ;c Multiple sclerosis (MS) is a chronic infl~.. ~t~ly CNS disorder caused by demyelin~tior~ in the brain and spinal cord. The disease is ch~act~.ized by pr~l~ s ,i~/e CNS d~runction, incl~l(ling muscul~r we~knPcc, tremor, 20 in-~o~ enc~, ocular dislu-l,~ces, and mental dysfunction, with remissi-~n~ and exac~.l,Gt;onc At present, the only Lr,~t---~n~ for MS is physical therapy.

.. n~l allergic e~ hAlomyelitis (EAE) induc~ by inie~ction of myelin basic protein ~MBP) or MBP peptide fra~mentc is ~ d to be a 25 useful model for MS. See, for example, D. E. McFarlin et al., "Re~;u,l~ nl ExperimPn~l Allergic rn~elJhAlQmyelitis in the Lewis Rat," 17te Journal of Irnmunology, 113(2): 712-715 (1974). In this e.AIJt;lilnl~l~l, the ability of a furan nitrone of fûrmula I above to prevent MBP-induced EAE is ~l~mon~lldted.

30Acc~ ed female Lewis rats, (Harlan; 200-250g) were used in this experiment since this strain of rat is geneti~lly highly susceptible to EAE. In W O 98/03496 PCT~US97/11960 the expe im~nt 100 mg/kg of N-isopropyl-a-(2-sulfofuran-5-yl)nitrone sodium salt (~n p~ed in Example 1 above) or a vehicle alone (control) was ~~..;n-~b cd po once a day from days 4 to 18. On day 1, the rats received an injection of 100 ~g of MBP peptirle~ from guinea pig brain, plus 500 ~g of S H37RA Mycoba.,t~,.;ulll in 0.10 ml complete Freund's adjuvant divided equally between the two hind foot-pads.

The rats were evaluated on a 0-6 scale every day after day 7 until day 18 (effects usually begin day 10 and peak day 15). See E. Heber-Katz, "The Ups and Downs of EAE," Internn~ion(r1 Reviews Immunology, 2: 277-285 (1992). The 0-6 ev~1u~tion scale is as follows: 0) normal; 1) abno.,nal gait, h.,~ing, flaccid tail; 2) definite we~knç~s in one or both hind legs, mild ataxia;

3) lllod~late p~aresis, severe ataxia; 4) minim~l hind leg movement after painful stimuli only; S) no hind leg movement; 6) moribund state with little or 15 no movement, i",l,aired res~ildtion. Results are exprcssed as a behavioral score ranging from 0 to 6.

The results are shown in Figure 4. These results show that N-isop-uy a-(2-sulfofuran-5-yl)nitrone sodium salt completely counter~ t~od the effect of 20 MBP in this test.

Example 28 Prevention of Weight Loss Animals eYposed to MBP or MBP peptide exhibit ~ignifi~nt weight loss 25 as co,.lpar~ to controls ~-pos~ to Freund's adjuvant alone. To det_.l"ine if the furan nitrones of formula I p~e.lted such weight loss, the ~nim~ls in the EAE model described in Example 27 above were weighed daily. The results show that those ~nim~ls receiving N-isopropyl-a-(2-sulfofuran-5-yl)nitrone sodium salt exhibited normal or above normal weight gain whereas the ~nim~l~
30 receiving MBP without the furan nitrone showed serious weight loss. These results are shown in Figure 5.

W O 98/03496 PCTrUS97/11960 Example 29 Reduction of Learning Deficit in Autoimmune Mice In this PY~rimPnt the ability of a furan nitrone of formula I . bove to reduce l~..ing dP-firiPnries in qlltoimm~me mice is demonstrrq-ted. Male S MRLJMpJ controls and FaslPr m--tqtion mice were either dosed orally with 1%
methylc~ lose ("MC") or with 100 mg/kg of N-isopropyl-a-(2-sulforul~ -5-yl)nh~, e sodium salt (pl~ared in T~ ple 1 above) ("test COI~l ou~lln) in 1%
methylcellulose for 9-10 weeks. Following dosing, qnimql~ of appro~imqtPly 4 months of age were tested in an active avoidance T-m-q.7P. In the one day test, 10 ~nin~qlc were analy_ed for ac luisilion to avoid shock within the first five trials of the test. When two ~ ents were cGI~bined (n=14-15), q~limqls ~1ministered N-isoplupyl-a-(2-sulfofuran-S-yl)nitrone sodium salt showed a 50% pr~ ;nn in acquisition l~ning deficit co",l)ared to Fas ...~ te~d ~nim~l~
receiving only 1% methylc~ llosP as shown in Table II.
Table II
Mean Acquisition Values (M~l~imum score of 5.0) ControV 1% MC' Fas~l 1% MC Fas~r/Test Co",~ound2 Mean = 2.13 Mean = 0.857 Mean = 1.467 n = 15 n = 14 n = 15 MC = methyl cPll~ s~P~
The test co,upûul~d was N-isopropyl-a-(2-sulruful~u -5-yl)ni~une sodium salt.
The results shown in Table II demon~trate that N-isopropyl-a-(2-sulÇurul~ -5-yl)nit une sodium salt reduces the learning deficiPn~ies developed in autoimmunP mice.

W O 98/03496 PCTrUS97/11960 From the ~oregoing des.;li~,tion, various modifications and changes in the co,~ osilions and methods of this invention will occur to those skilled in the art. All such mo~ific~tions coming within the scope of the appended claims are i~t~ ed to be inrlllded therein.

~ .

Claims (72)

WHAT IS CLAIMED IS:

1. A compound of formula I:

wherein each R1 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycloalkenyl and halo;
R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
each X is independently selected from the group consisting of -SO3Y, -S(O)R4, -SO2R5 and -SO2NR6R7;
wherein Y is hydrogen or a pharmaceutically acceptable cation;
R4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; or R6 and R7 together with the nitrogen atom to which they are attached can form a heterocyclic ring containing from 2 to 8 carbon atoms and optionally from 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;

m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m + n = 3; or pharmaceutically acceptable salts thereof.

2. The compound according to Claim 1 wherein R1 is hydrogen.

3. The compound according to Claim 1 wherein R2 is hydrogen.

4. The compound according to Claim 1 wherein R3 is selected from the group consisting of alkyl, alkaryl, aryl and cycloalkyl.

5. The compound according to Claim 4 wherein R3 is alkyl or cycloalkyl.

6. The compound according to Claim 1 wherein X is -SO3Y.

7. The compound according to Claim 1 wherein X is -SO2NR6R7, wherein R6 and R7 are independently selected from the group consisting of hydrogen, alkyl and cycloalkyl; or R6 and R7 are joined together with the nitrogen atom to which they are attached to form a heterocyclic ring having 4 to 6 carbon atoms.

8. The compound according to Claim 7 wherein R6 is hydrogen and R7 is selected from the group consisting of hydrogen, alkyl and cycloalkyl.

9. The compound according to Claim 1 wherein X is -SO2R5, wherein R5 is selected from the group consisting of alkyl, cycloalkyl and aryl.

10. The compound according to Claim 1 wherein m is 1.

11. A compound of formula II:

wherein R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
each X is independently selected from the group consisting of -SO3Y, -S(O)R4, -SO2R5 and -SO2NR6R7;
wherein Y is hydrogen or a pharmaceutically acceptable cation;
R4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; or R6 and R7 together with the nitrogen atom to which they are attached can form a heterocyclic ring containing from 2 to 8 carbon atoms and optionally from 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; and m is an integer from 1 to 3; or pharmaceutically acceptable salts thereof.

12. The compound according to Claim 11 wherein R2 is hydrogen.

13. The compound according to Claim 11 wherein R3 is selected from the group consisting of alkyl, alkaryl, aryl and cycloalkyl.

14. The compound according to Claim 13 wherein R3 is alkyl or cycloalkyl.

15. The compound according to Claim 11 wherein X is -SO3Y.

16. The compound according to Claim 11 wherein m is 1.

17. A compound of formula III:

wherein R8 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; and Y selected from the group consisting of hydrogen and a pharmaceutically acceptable cation.

18. The compound according to Claim 17 wherein R8 is selected from the group consisting of alkyl, alkaryl, aryl and cycloalkyl.

19. The compound according to Claim 18 wherein R8 is alkyl or cycloalkyl.

20. The compound according to Claim 17 wherein Y is hydrogen or a sodium cation.

21. A compound selected from the group consisting of:
N-isopropyl-.alpha.-(2-sulfofuran-5-yl)nitrone N-n-propyl-.alpha.-(2-sulfofuran-5-yl)nitrone N-n-butyl-.alpha.-(2-sulfofuran-5-yl)nitrone N-tert-butyl-.alpha.-(2-sulforuran-5-yl)nitrone N-n-hexyl-.alpha.-(2-sulforuran-5-yl)nitrone N-cyclohexyl-.alpha.-(2-sulfofuran-5-yl)nitrone N-tert-octyl-.alpha.-(2-sulfofuran-s-yl)nitrone N-benzyl-.alpha.-(2-sulfofuran-5-yl)nitrone N-isopropyl-.alpha.-[2-(N-morpholinosulfonyl)furan-5-yl]nitrone N-isopropyl-.alpha.-[2-(N,N-dimethylsulfamoyl)furan-5-yl]nitrone N-isopropyl-.alpha.-[2-(N,N-diethylsulfamoyl)furan-5-yl]nitrone N-isopropyl-.alpha.-[2-(N,-methylpiperazin-1-ylsulfonyl)furan-5-yl]nitrone N-tert-butyl-.alpha.-[2-(N-3-trifluoromethylphenylsulfamoyl)-furan-5-yl]nitrone N-tert-butyl-.alpha.-[2-(methylsulfonyl)-furan-5-yl]nitrone, and pharmaceutically acceptable salts thereof.

22. The compound according to Claim 21 wherein the compound is selected from the group consisting of N-isopropyl-.alpha.-(2-sulfofuran-5-yl)nitrone and pharmaceutically acceptable salts thereof.

23. The compound according to Claim 21 wherein the compound is selected from the group consisting of N-cyclohexyl-.alpha.-(2-sulfofuran-5-yl)nitrone and pharmaceutically acceptable salts thereof.

24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula I:

wherein each R1 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycloalkenyl and halo;
R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
each X is independently selected from the group consisting of -SO3Y, -S(O)R4, -SO2R5 and -SO2NR6R7;
wherein Y is hydrogen or a pharmaceutically acceptable cation;
R4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; or R6 and R7 together with the nitrogen atom to which they are attached can form a heterocyclic ring containing from 2 to 8 carbon atoms and optionally from 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;

m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m + n = 3; or pharmaceutically acceptable salts thereof.

25. The pharmaceutical composition according to Claim 24 wherein R1 is hydrogen and R2 is hydrogen.

26. The pharmaceutical composition according to Claim 24 wherein R3 is selected from the group consisting of alkyl, alkaryl, aryl and cycloalkyl.

27. The pharmaceutical composition according to Claim 26 wherein R3 is alkyl or cycloalkyl.

28. The pharmaceutical composition according to Claim 24 wherein X is -SO3Y.

29. The pharmaceutical composition according to Claim 24 wherein X is -SO2NR6R7, wherein R6 and R7 are independently selected from the group consisting of hydrogen, alkyl and cycloalkyl; or R6 and R7 are joined together with the nitrogen atom to which they are attached to form a heterocyclic ring having 4 to 6 carbon atoms.

30. The pharmaceutical composition according to Claim 29 wherein R6 is hydrogen and R7 is selected from the group consisting of hydrogen, alkyl and cycloalkyl.

31. The pharmaceutical composition according to Claim 24 wherein X is -SO2R5, wherein R5 is selected from the group consisting of alkyl, cycloalkyl and aryl.

32. The pharmaceutical composition according to Claim 24 wherein m is 1.

33. The pharmaceutical composition according to Claim 24 wherein the carrier is an oral carrier.

34. The pharmaceutical composition according to Claim 24 wherein the carrier is an injectable carrier.

35. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula III:

wherein R8 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; and Y selected from the group consisting of hydrogen and a pharmaceutically acceptable cation.

36. The pharmaceutical according to Claim 35 wherein R8 is selected from the group consisting of alkyl, alkaryl, aryl and cycloalkyl.

37. The pharmaceutical composition according to Claim 36 wherein R8 is alkyl or cycloalkyl.

38. The pharmaceutical composition according to Claim 35 wherein Y is hydrogen or a sodium cation.

39. The pharmaceutical composition according to Claim 35 wherein the carrier is an oral carrier.

40. The pharmaceutical composition according to Claim 35 wherein the carrier is an injectable carrier.

41. A method for treating a patient with an acute central nervous system disorder, said method comprising administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective acute central nervous system disorder-treating amount of a compound of formula I:

wherein each R1 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycloalkenyl and halo;
R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cyclolakenyl;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
each X is independently selected from the group consisting of -SO3Y, -S(O)R4, -SO2R5 and -SO2NR6R7;
wherein Y is hydrogen or a pharmaceutically acceptable cation;
R4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;

R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; or R6 and R7 together with the nitrogen atom to which they are attached can form a heterocyclic ring containing from 2 to 8 carbon atoms and optionally from 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m + n = 3; or pharmaceutically acceptable salts thereof.

42. The method according to Claim 41 wherein said acute central nervous system disorder is a stroke.

43. The method according to Claim 42 wherein said pharmaceutical compositional is administered parenterally to said patient in an amount of at least about 0.2 mg/kg/hour.

44. The method according to Claim 43 wherein said pharmaceutical composition is administered intravenously.

45. A method for treating a patient with an acute cardiovascular disorder, said method composition administering to said patient a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and an effective acute cardiovascular disorder-treating amount of a compound of formula I:

wherein each R1 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycloalkenyl and halo;
R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
each X is independently selected from the group consisting of -SO3Y, -S(O)R4, -SO2R5 and -SO2NR6R7;
wherein Y is hydrogen or a pharmaceutically acceptable cation;
R4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, selected alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl,cycloalkyl and cycloalkenyl; or R6 and R7 together with the nitrogen atom to which they are attached can form a heterocyclic ring containing from 2 to 8 carbon atoms and optionally from 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m + n = 3; or pharmaceutically acceptable salts thereof.

46. The method according to Claim 45 wherein said acute cardiovascular disorder is a cardiac infarction.

47. The method according to Claim 46 wherein said pharmaceutical composition is administered parenterally to said patient in an amount of at least about 0.2 mg/kg/hour.

48. The method according to Claim 47 wherein said pharmaceutical composition is administered intravenously.

49. A method for treating a patient with a neurodegenerative disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective neurodegenerative disease-treating amount of a compound of formula I:

wherein each R1 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycloalkenyl and halo;
R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
each X is independently selected from the group consisting of -SO3Y, -S(O)R4, -SO2R5 and -SO2NR6R7;
wherein Y is hydrogen or a pharmaceutically acceptable cation;
R4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; or R6 and R7 together with the nitrogen atom to which they are attached can form a heterocyclic ring containing from 2 to 8 carbon atoms and optionally from 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m + n = 3; or pharmaceutically acceptable salts thereof.

50. A method for preventing the onset of a neurodegenerative disease in a patient at risk for developing the neurodegenerative disease which method comprises administering to said patient a pharmaceutical composition comprises a pharmaceutically acceptable carrier and an effective neurodegenerative disease-preventing amount of a compound of formula I:

wherein each R1 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycloalkenyl and halo;
R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
each X is independently selected from the group consisting of -SO3Y, -S(O)R4, -SO2R5 and -SO2NR6R7;
wherein Y is hydrogen or a pharmaceutically acceptable cation;

R4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; or R6 and R7 together with the nitrogen atom to which they are attached can form a heterocyclic ring containing from 2 to 8 carbon atoms and optionally from 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m + n = 3; or pharmaceutically acceptable salts thereof.

51. The method according to Claim 49 or 50 wherein the neurodegenerative disease is Alzheimer's disease.

52. The method according to Claim 49 or 50 wherein the neurodegenerative disease is Parkinson's disease.

53. The method according to Claim 49 or 50 wherein the neurodegenerative disease is HIV dementia,

54. A method for treating a patient with an autoimmune disease which method comprises administering to said patient a pharmaceutically composition comprising a pharmaceutically acceptable carrier and an effective autoimmune disease-treating amount of a compound of formula I:

wherein each R1 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycloalkenyl and halo;
R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
each X is independently selected from the group consisting of -SO3Y, -S(O)R4, -SO2R5 and -SO2NR6R7;
wherein Y is hydrogen or a pharmaceutically acceptable cation;
R4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; or R6 and R7 together with the nitrogen atom to which they are attached can form a heterocyclic ring containing from 2 to 8 carbon atoms and optionally from 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m + n = 3; or pharmaceutically acceptable salts thereof.

55. A method for preventing the onset of an autoimmune disease in a patient at risk for developing the autoimmune disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective autoimmune disease-preventing amount of a compound of formula I:

wherein each R1 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycloalkenyl and halo;
R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
each X is independently selected from the group consisting of -SO3Y, -S(O)R4, -SO2R5 and -SO2NR6R7;
wherein Y is hydrogen or a pharmaceutically acceptable cation;
R4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkeyl;
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; or R6 and R7 together with the nitrogen atom to which they are attached can form a heterocyclic ring containing from 2 to 8 carbon atoms and optionally from 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m + n = 3; or pharmaceutically acceptable salts thereof.

56. The method according to Claim 54 or 55 wherein the autoimmune disease is systemic lupus.

57. The method according to Claim 54 or 55 wherein the autoimmune disease is multiple sclerosis.

58. A method for treating a patient with an inflammatory disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective inflammatory disease-treating amount of a compound of formula I:

wherein each R1 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycloalkenyl and halo;
R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
each X is independently selected from the group consisting of -SO3Y, -S(O)R4, -SO2R5 and -SO2NR6R7;
wherein Y is hydrogen or a pharmaceutically acceptable cation;
R4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;

R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; or R6 and R7 together with the nitrogen atom to which they are selected can form a heterocyclic ring containing from 2 to 8 carbon atoms and optionally from 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m + n = 3; or pharmaceutically acceptable salts thereof.

59. A method for preventing the onset of an inflammatory disease in a patient at risk for developing the inflammatory disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective inflammatory disease-preventing amount of a compound of formula I:

wherein each R1 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycloalkenyl and halo;
R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;

each X is independently selected from the group consisting of -SO3Y, -S(O)R4, -SO2R5 and -SO2NR6R7;
wherein Y is hydrogen or a pharmaceutically acceptable cation;
R4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; or R6 and R7 together with the nitrogen atom to which they are attached can form a heterocyclic ring containing from 2 to 8 carbon atoms and optionally from 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m + n = 3; or pharmaceutically acceptable salts thereof.

60. The method according to Claim 58 or 59 wherein the inflammatory disease is rheumatoid arthritis.

61. The method according to Claim 58 or 59 wherein the inflammatory disease is septic shock.

62. The method according to Claim 58 or 59 wherein the inflammatory disease is erythema nodosum leprosy.

63. The method according to Claim 58 or 59 wherein the inflammatory disease is septicemia.

64. The method according to Claim 58 or 59 wherein the inflammatory disease is uveitis.

65. A process for preparing a compound of formula I:

wherein each R1 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycloalkenyl and halo;
R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
each X is independently selected from the group consisting of -SO3Y, -S(O)R4, -SO2R5 and -SO2NR6R7;
wherein Y is hydrogen or a pharmaceutically acceptable cation;
R4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; or R6 and R7 together with the nitrogen atom to which they are attached can form a heterocyclic ring containing from 2 to 8 carbon atoms and optionally from 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;

m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m + n = 3, said process comprising reacting a furan carbonyl compound of the formula:

with a hydroxylamine of formula V:

to provide a compound of formula I.

66. A process for preparing a sulfamoyl-substituted furan nitrone of formula I':

wherein each R1 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycloalkenyl and halo;

R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
each X' is -SO2NR6R7; wherein R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; or R6 and R7together with the nitrogen atom to which they are attached can form a heterocyclic ring containing from 2 to 8 carbon atoms and optionally from 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m + n = 3, said process comprising the steps of:
(a) reacting a carbonyl-substituted furan sulfonic acid compound of the formula:

with phosphorous trichloride and phosphorous pentachloride to provide a gem-dichloride-substituted furan sulfonyl chloride compound of the formula:

(b) reacting the gem-dichloride-substituted furan sulfonyl chloride compound with an amine of the formula:

to provide a gem-dichloride-substituted furan sulfonamide compound of the formula:

(c) hydrolyzing the gem-dichloride-substituted furan sulfonamide compound to provide a carbonyl-substituted furan sulfonamide compound of the formula:

and;
(d) reacting the carbonyl-substituted furan sulfonamide with a hydroxylamine of the formula:

Ho-NH-R3 to provide a compound of formula I'.

67. The use of a compound of formula I:

wherein each R1 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycloalkenyl and halo;
R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
each X is independently selected from the group consisting of -SO3Y, -S(O)R4, -SO2R5 and -SO2NR6R7;
wherein Y is hydrogen or a pharmaceutically acceptable cation;
R4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; or R6 and R7 together with the nitrogen atom to which they are attached can form a heterocyclic ring containing from 2 to 8 carbon atoms and optionally from 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;

m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m + n = 3; or pharmaceutically acceptable salts thereof in the manufacture of a formulation for a medicinal treatment.

68. The use according to Claim 67 wherein the medicinal treatment is the therapeutic or prophylactic treatment of an acute central nervous system disorder.

69. The use according to Claim 67 wherein the medicinal treatment is the therapeutic or prophylactic treatment of an acute cardiovascular disorder.

70. The use according to Claim 67 wherein the medicinal treatment is the therapeutic or prophylactic treatment of a neurodegenerative disease.

71. The use according to Claim 67 wherein the medicinal treatment is the therapeutic or prophylactic treatment of an autoimmune disease.

72. The use according to Claim 67 wherein the medicinal treatment is the therapeutic or prophylactic treatment of an inflammatory disease.