This invention is directed to compounds of formula I: ##STR1## wherein the variables are as described herein. Compounds within the scope of the present invention possess useful properties, more particularly pharmaceutical properties. They are especially useful for inhibiting the production or physiological effects of TNF in the treatment of a patient suffering from a disease state associated with a physiologically detrimental excess of tumor necrosis factor (TNF). Compounds within the scope of the present invention also inhibit cyclic AMP phosphodiesterase, and are useful in treating a disease state associated with pathological conditions that are modulated by inhibiting cyclic AMP phosphodiesterase, such disease states including inflammatory and autoimmune diseases, in particular type IV cyclic AMP phosphodiesterase. Compounds within the scope of the present invention may also inhibit an MMP, and are useful in treating a disease state associated with pathological conditions that are modulated by inhibiting MMPs, such disease states involve tissue breakdown and those associated with a physiologically detrimental excess of TNF. The present invention is therefore also directed to the pharmaceutical use of the compounds, pharmaceutical compositions containing the compounds, intermediates leading thereto and methods for the preparation of the compounds and their intermediates.

FIELD OF THE INVENTION 
This invention is directed to (aryl, heteroaryl, arylmethyl or 
heteroarylmethyl)] hydroxamic acid compounds, their preparation, 
pharmaceutical compositions containing these compounds, and their 
pharmaceutical use in the treatment of disease states associated with 
proteins that mediate cellular activity which are capable of being 
modulated by inhibiting a matrix metalloproteinase (MMP), tumor necrosis 
factor (TNF) or cyclic AMP phosphodiesterase, or proteins associated 
therewith that mediate cellular activity. This invention is also directed 
to intermediates useful in preparing the (aryl, heteroaryl, aralkyl or 
heteroaralkyl) hydroxamic acid compounds. 
Disease states associated with abnormally high physiological levels of 
cytokines such as TNF are treatable according to the invention. TNF is an 
important pro-inflammatory cytokine which causes hemorrhagic necrosis of 
tumors and possesses other important biological activities. TNF is 
released by activated macrophages, activated T-lymphocytes, natural killer 
cells, mast cells and basophils, fibroblasts, endothelial cells and brain 
astrocytes among other cells. 
The principal in vivo actions of TNF can be broadly classified as 
inflammatory and catabolic. It has been implicated as a mediator of 
endotoxic shock, inflammation of joints and of the airways, immune 
deficiency states, allograft rejection, and in the cachexia associated 
with malignant disease and some parasitic infections. In view of the 
association of high serum levels of TNF with poor prognosis in sepsis, 
graft versus host disease and acute respiratory distress syndrome, and its 
role in many other immunologic processes, this factor is regarded as an 
important mediator of general inflammation. 
TNF primes or activates neutrophils, eosinophils, fibroblasts and 
endothelial cells to release tissue damaging mediators. TNF also activates 
monocytes, macrophages and T-lymphocytes to cause the production of colony 
stimulating factors and other pro-inflammatory cytokines such IL.sub.1, 
IL.sub.6, IL.sub.8 and GM-CSF, which in some case mediate the end effects 
of TNF. The ability of TNF to activate T-lymphocytes, monocytes, 
macrophages and related cells has been implicated in the progression of 
Human Immunodeficiency Virus (HIV) infection. In order for these cells to 
become infected with HIV and for HIV replication to take place the cells 
must be maintained in an activated state. Cytokines such as TNF have been 
shown to activate HIV replication in monocytes and macrophages. Features 
of endotoxic shock such as fever, metabolic acidosis, hypotension and 
intravascular coagulation are thought to be mediated through the actions 
of TNF on the hypothalamus and in reducing the anti-coagulant activity of 
vascular endothelial cells. The cachexia associated with certain disease 
states is mediated through indirect effects on protein catabolism. TNF 
also promotes bone resorption and acute phase protein synthesis. 
The discussion herein related to disease states associated with TNF include 
those disease states related to the production of TNF itself, and disease 
states associated with other cytokines, such as but not limited to IL-1, 
or IL-6, that are modulated by associated with TNF. For example, a IL-1 
associated disease state, where IL-1 production or action is exacerbated 
or secreted in response to TNF, would therefore be considered a disease 
state associated with TNF. TNF-.alpha. and TNF-.beta. are also herein 
referred to collectively as "TNF" unless specifically delineated 
otherwise, since there is a close structural homology between TNF-.alpha. 
(cachectin) and TNF-.beta. (lymphotoxin) and each of them has a capacity 
to induce similar biologic responses and bind to the same cellular 
receptor. 
Disease states associated with pathological conditions that are modulated 
by inhibiting enzymes, which are associated with secondary cellular 
messengers, such as cyclic AMP phosphodiesterase are also treatable 
according to the invention. Cyclic AMP phosphodiesterase is an important 
enzyme which regulates cyclic AMP levels and in turn thereby regulates 
other important biological reactions. The ability to regulate cyclic AMP 
phosphodiesterase, including type IV cyclic AMP phosphodiesterase, 
therefore, has been implicated as being capable of treating assorted 
biological conditions. In particular, inhibitors of type IV cyclic AMP 
phosphodiesterase have been implicated as being bronchodilators and 
asthma-prophylactic agents and as agents for inhibiting eosinophil 
accumulation and of the function of eosinophils, and for treating other 
diseases and conditions characterized by, or having an etiology involving, 
morbid eosinophil accumulation. Inhibitors of cyclic AMP phosphodiesterase 
are also implicated in treating inflammatory diseases, proliferative skin 
diseases and conditions associated with cerebral metabolic inhibition. 
Disease states associated with the activity of matrix metalloproteinases 
(MMPs), especially collagenase, stromelysin and gelatinase, or as 
described by Schwartz M A, Van Wart H E, Prog. Med. Chem., 29, 271-334 
(1992) are treatable according to the invention. Thus, the present 
invention provides compounds of formula I, and compositions containing 
compounds of formula I, which are of use in a method for treating a 
patient suffering from, or subject to, conditions which can be ameliorated 
or prevented by the administration of an inhibitor of an MMP. For example, 
compounds within the present invention are useful in inhibiting connective 
tissue breakdown and in the treatment or prophylaxis of conditions 
involving such tissue breakdown, for example rheumatoid arthritis, 
osteoarthritis, osteopenias such as osteoporosis, periodontitis, 
gingivitis, corneal epidermal or gastric ulceration, and tumor metastasis, 
invasion and growth. Compounds within the scope of the invention as MMP 
inhibitors may also inhibit the production of TNF (Mohler et al., Nature, 
370, 218-220 (1994); Gearing A J H et al., Nature, 370, 555-557 (1994); 
McGeehan G M et al., Nature, 370, 558-561 (1994)), and, thus are useful in 
the treatment or prophylaxis of conditions wherein the inhibition of the 
production or action of TNF are thought to be potentially useful for the 
treatment or prophylaxis of disease states associated with detrimental 
amounts of TNF, as described above. 
Reported Developments 
EP patent application publication No. 606046-A1 pertains to a compound of 
formula 
##STR2## 
is a matrix metalloproteinase inhibitor which is useful for treating 
rheumatoid arthritis, tissue ulceration, bone disease, tumor metastasis 
and HIV infection. The reference does not disclose or suggest that the 
compound inhibits TNF. 
Japanese patent application publication No. JP07196598-A disclose that a 
compound of formula 
##STR3## 
wherein R.sup.1 represents an alkyl group; R.sup.2 represents a hydrogen 
atom, a lower alkyl group or benzyl group; R.sup.3 represents a hydrogen 
atom or lower alkyl group; X may represent a sulfur atom, sulfinyl group 
or a sulfonyl group; Y represents an oxygen atom or NH; and n represents 
an integer from 1-3, and is a collagenase inhibitor which is useful for 
treating and preventing rheumatoid arthritis, osteoarthritis, neoplastic 
infiltration and bone resorption. The reference does not disclose or 
suggest that the compound inhibits TNF. 
SUMMARY OF THE INVENTION 
This invention is directed to a compound of formula I: 
##STR4## 
wherein 
R.sub.1 is hydrogen, optionally substituted alkyl, optionally substituted 
alkenyl, optionally substituted cycloalkyl, optionally substituted 
cycloalkenyl, optionally substituted aryl, optionally substituted 
heteroaryl, optionally substituted aralkyl, optionally substituted 
heteroaralkyl, optionally substituted aralkyloxyalkyl, optionally 
substituted aryloxyalkyl, hydroxy, optionally substituted alkoxy, 
optionally substituted aryloxy, optionally substituted aralkyloxy, Y.sup.3 
Y.sup.4 N--, Y.sup.1 Y.sup.2 NCO-alkyl, aryl-SO.sub.2 Y.sup.1 N-alkyl, 
arylsulfanylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, 
cyclocarbamoylalkyl or imidealkyl; 
R.sub.2, R.sub.4, R.sub.5, R.sub.6 are independently hydrogen or optionally 
substituted alkyl, or R.sub.2 and R.sub.4 taken together with the carbon 
atoms through which R.sub.2 and R.sub.4 are linked form optionally 
substituted cycloalkyl or optionally substituted cycloalkenyl, or R.sub.1 
and R.sub.2 taken together with the carbon atoms through which R.sub.1 and 
R.sub.2 are linked form optionally substituted cycloalkyl; 
R.sub.3 is optionally substituted alkyl, optionally substituted alkenyl, 
optionally substituted cycloalkyl, optionally substituted cycloalkenyl, 
optionally substituted aryl, optionally substituted heteroaryl, optionally 
substituted aralkyl, optionally substituted aralkenyl, optionally 
substituted aralkynyl, optionally substituted heteroaralkyl, optionally 
substituted heteroaralkenyl, optionally substituted heteroaralkynyl, 
optionally substituted alkyloxyalkyl, optionally substituted aryloxyalkyl, 
optionally substituted heteroaryloxyalkyl, optionally substituted 
aryloxyalkenyl, optionally substituted heteroaryloxyalkenyl, optionally 
substituted aralkyloxyalkyl, optionally substituted aralkyloxyalkenyl, 
optionally substituted heteroaralkyloxyalkyl, optionally substituted 
heteroaralkyloxyalkenyl, optionally substituted cycloalkyloxy, optionally 
substituted cycloalkyloxyalkyl, optionally substituted heterocyclyl, 
optionally substituted heterocyclyloxyalkyl or optionally substituted 
heterocyclyloxy, Y.sup.3 Y.sup.4 Nalkyl, Y.sup.1 Y.sup.2 NCO.sub.2 alkyl, 
Y.sup.1 Y.sup.2 NCO-alkyl, imidealkyl, or R.sub.3 and R.sub.4 taken 
together with the carbon to which R.sub.3 and R.sub.4 are attached form an 
optionally substituted cycloalkyl, or one of R.sub.1 and R.sub.2 and one 
of R.sub.3 and R.sub.4 taken together with the carbons through which the 
one of R.sub.1 and R.sub.2 and one of R.sub.3 and R.sub.4 are linked form 
a bond or optionally substituted cycloalkyl or optionally substituted 
cycloalkenyl; 
Ar is optionally substituted aryl or optionally substituted heteroaryl; 
Y.sup.1 and Y.sup.2 are independently hydrogen, optionally substituted 
alkyl, optionally substituted aryl or optionally substituted aralkyl, or 
Y.sup.1 and Y.sup.2 taken together with the nitrogen atom to which Y.sup.1 
and Y.sup.2 are attached form an optionally substituted heterocyclyl; 
Y.sup.3 and Y.sup.4 are independently Y.sup.1 and Y.sup.2, or optionally 
substituted acyl, optionally substituted aroyl, optionally substituted 
aralkyloxycarbonyl, optionally substituted heteroaralkyloxycarbonyl or 
optionally substituted alkoxycarbonyl; 
n is 0, 1 or 2; 
m is 0 or 1; 
p is 0 or 1; and 
q is 0 or 1, 
or an n-oxide thereof, solvate thereof, hydrate thereof or pharmaceutically 
acceptable salt thereof. 
Compounds within the scope of the present invention possess useful 
properties, more particularly pharmaceutical properties. They are 
especially useful for inhibiting the production or physiological effects 
of TNF in the treatment of a patient suffering from a disease state 
associated with a physiologically detrimental excess of tumor necrosis 
factor (TNF). Compounds within the scope of the present invention also 
inhibit cyclic AMP phosphodiesterase, and are useful in treating a disease 
state associated with pathological conditions that are modulated by 
inhibiting cyclic AMP phosphodiesterase, such disease states including 
inflammatory and autoimmune diseases, in particular type IV cyclic AMP 
phosphodiesterase. Compounds within the scope of the present invention 
also inhibit matrix metalloproteinases, and are useful in treating a 
disease state associated with pathological conditions that are modulated 
by inhibiting MMPs, such disease states involve tissue breakdown and those 
associated with a physiologically detrimental excess of TNF. The present 
invention is therefore also directed to the pharmaceutical use of the 
compounds, pharmaceutical compositions containing the compounds, 
intermediates leading thereto and methods for the preparation of the 
compounds and their intermediates. 
DETAILED DESCRIPTION OF THE INVENTION 
As used above, and throughout the description of the invention, the 
following terms, unless otherwise indicated, shall be understood to have 
the following meanings: 
Definitions 
"Patient" includes both human and other mammals. 
"Alkyl" means an aliphatic hydrocarbon group which may be straight or 
branched having about 1 to about 15 carbon atoms in the chain. Preferred 
alkyl groups have 1 to about 12 carbon atoms in the chain. Branched means 
that one or more lower alkyl groups such as methyl, ethyl or propyl are 
attached to a linear alkyl chain. "Lower alkyl" means about 1 to about 4 
carbon atoms in the chain which may be straight or branched. The alkyl 
group may be substituted by one or more hydroxy, halo, cycloalkyl, 
cycloalkenyl or heterocyclyl. Exemplary alkyl groups include methyl, 
fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropylmethyl, 
cyclopentylmethyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 
3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl. 
"Alkenyl" means an aliphatic hydrocarbon group containing a carbon-carbon 
double bond and which may be straight or branched having about 2 to about 
15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 
carbon atoms in the chain; and more preferably about 2 to about 4 carbon 
atoms in the chain. Branched means that one or more lower alkyl groups 
such as methyl, ethyl or propyl are attached to a linear alkenyl chain. 
"Lower alkenyl" means about 2 to about 4 carbon atoms in the chain which 
may be straight or branched. The alkenyl group may be substituted by one 
or more halo or cycloalkyl. Exemplary alkenyl groups include ethenyl, 
propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, 
octenyl, cyclohexylbutenyl and decenyl. 
"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system of about 
3 to about 10 carbon atoms. Preferred monocyclic cycloalkyl rings include 
cyclopentyl, fluorocyclopentyl, cyclohexyl and cycloheptyl; more preferred 
is cyclopentyl. The cycloalkyl group may be substituted by one or more 
halo, methylene (H.sub.2 C.dbd.), alkyl, aralkyl, heteroaralkyl, fused 
aryl or fused heteroaryl. Exemplary multicyclic cycloalkyl rings include 
1-decalin, adamant-(1- or 2-)yl and norbornyl. 
"Cycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system 
containing a carbon-carbon double bond and having about 3 to about 10 
carbon atoms. Preferred monocyclic cycloalkenyl rings include 
cyclopentenyl, cyclohexenyl or cycloheptenyl; more preferred is 
cyclopentenyl. A preferred multicyclic cycloalkenyl ring is norbornylenyl. 
The cycloalkenyl group may be substituted by one or more halo, methylene 
(H.sub.2 C.dbd.), alkyl, aralkyl or heteroaralkyl. 
"Aryl" means aromatic carbocyclic radical containing about 6 to about 10 
carbon atoms. Exemplary aryl include phenyl or naphthyl, or phenyl or 
naphthyl substituted with one or more aryl group substituents which may be 
the same or different, where "aryl group substituent" includes hydrogen, 
alkyl, aryl, aralkyl, hydroxy, alkoxy, aryloxy, aralkoxy, carboxy, acyl, 
aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, 
aralkoxycarbonyl, acylamino, aroylamino, alkylsulfonyl, arylsulfonyl, 
alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, aralkylthio, 
oxyalkylenyloxy, Y.sup.1 Y.sup.2 N--, Y.sup.1 Y.sup.2 NCO-- or Y.sup.1 
Y.sup.2 NSO.sub.2 --, where Y.sup.1 and Y.sup.2 are independently 
hydrogen, alkyl, aryl, and aralkyl. Preferred aryl group substituents 
include hydrogen, alkyl, hydroxy, acyl, aroyl, halo, nitro, cyano, 
alkoxycarbonyl, acylamino, alkylthio, Y.sup.1 Y.sup.2 N--, Y.sup.1 Y.sup.2 
NCO-- or Y.sup.1 Y.sup.2 NSO.sub.2 --, where Y.sup.1 and Y.sup.2 are 
independently hydrogen and alkyl. 
"Heteroaryl" means about a 5- to about a 10- membered aromatic monocyclic 
or multicyclic hydrocarbon ring system in which one or more of the carbon 
atoms in the ring system is/are element(s) other than carbon, for example 
nitrogen, oxygen or sulfur. The "heteroaryl" may also be substituted by 
one or more aryl group substituents. Exemplary heteroaryl groups include 
pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, 
isothiazolyl, quinolinyl, and isoquinolinyl. Preferred heteroaryl groups 
include pyrazinyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl and 
isothiazolyl. 
"Heterocyclyl" means an about 4 to about 10 member monocyclic or 
multicyclic ring system wherein one or more of the atoms in the ring 
system is an element other than carbon chosen amongst nitrogen, oxygen or 
sulfur. The heterocyclyl may be optionally substituted by one or more 
alkyl group substituents. Exemplary heterocyclyl moieties include 
quinuclidine, pentamethylenesulfide, tetrahydropyranyl, 
tetrahydrothiophenyl, pyrrolidinyl or tetrahydrofuranyl. 
"Aralkyl" means an aryl-alkyl- group in which the aryl and alkyl are as 
previously described. Preferred aralkyls contain a lower alkyl moiety. 
Exemplary aralkyl groups include benzyl, 2-phenethyl and naphthlenemethyl. 
"Aralkenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are 
as previously described. Preferred aralkenyls contain a lower alkenyl 
moiety. Exemplary aralkenyl groups include styryl and phenylallyl. 
"Aralkynyl" means an aryl-alkynyl- group in which the aryl and alkynyl are 
as previously described. Preferred aralkynyls contain a lower alkynyl 
moiety. An exemplary aralkynyl group is phenylacetylenyl. 
"Heteroaralkyl" means an heteroaryl-alkyl- group in which the heteroaryl 
and alkyl are as previously described. Preferred heteroaralkyls contain a 
lower alkyl moiety. An exemplary heteroaralkyl group is 4-pyridylmethyl. 
"Heteroaralkenyl" means an heteroaryl-alkenyl- group in which the 
heteroaryl and alkenyl are as previously described. Preferred 
heteroaralkenyls contain a lower alkenyl moiety. An exemplary aralkenyl 
group is 4-pyridylvinyl. 
"Heteroaralkynyl" means an heteroaryl-alkynyl- group in which the 
heteroaryl and alkynyl are as previously described. Preferred 
heteroaralkynyls contain a lower alkynyl moiety. An exemplary 
heteroaralkynyl group is 4-pyridylethynyl. 
"Heterocyclylalkyl" means an heterocyclyl-alkyl- group in which the 
heterocyclyl and alkyl are as previously described. Preferred 
heterocyclylalkyls contain a lower alkyl moiety. An exemplary 
heteroaralkyl group is tetrahydropyranylmethyl. 
"Heterocyclylalkyloxyalkyl" means an heterocyclyl-alkyl-O-alkyl- group in 
which the heterocyclyl and alkyls groups independently are as previously 
described. An exemplary heteroaralkyl group is 
tetrahydropyranylmethyloxymethyl. 
"Hydroxy substituted alkyl" means a HO-alkyl- group in which alkyl is as 
previously defined. Preferred hydroxyalkyls contain lower alkyl. Exemplary 
hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. 
"Acyl" means an H--CO-- or alkyl-CO-- group in which the alkyl group is as 
previously described. Preferred acyls contain a lower alkyl. Exemplary 
acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl 
and palmitoyl. 
"Aroyl" means an aryl-CO-- group in which the alkyl group is as previously 
described. Exemplary groups include benzoyl and 1- and 2-naphthoyl. 
"Alkoxy" means an alkyl-O-- group in which the alkyl group is as previously 
described. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, 
i-propoxy, n-butoxy and heptoxy. 
"Cycloalkyloxy" means an cycloalkyl-O-- group in which the cycloalkyl group 
is as previously described. Exemplary cycloalkyloxy groups include 
cyclopentyloxy and cyclohexyloxy. 
"Alkoxyalkyl" means an alkyl-O-alkyl- group in which the alkyl groups are 
independently as previously described. Exemplary alkoxy groups include 
methoxyethyl, ethoxymethyl, n-butoxymethyl and cyclopentylmethyloxyethyl. 
"Aryloxy" means an aryl-O-- group in which the aryl group is as previously 
described. Exemplary aryloxy groups include phenoxy and naphthoxy. 
"Aralkyloxy" means an aralkyl-O-- group in which the aralkyl group is as 
previously described. Exemplary aralkyloxy groups include benzyloxy and 1- 
or 2-naphthalenemethoxy. 
"Aralkyloxyalkyl" means an aralkyl-O-alkyl group in which the aralkyl and 
alkyl groups are as previously described. An exemplary aralkyloxyalkyl 
group is benzyloxyethyl. 
"Aralkyloxyalkenyl" means an aralkyl-O-alkenyl group in which the aralkyl 
and alkenyl groups are as previously described. An exemplary 
aralkyloxyalkenyl group is 3-benzyloxyallyl. 
"Aryloxyalkyl" means an aryl-O-alkyl- group in which the aryl or alkyl 
groups are as previously described. An exemplary aryloxyalkyl groups is 
phenoxypropyl. 
"Aryloxyalkenyl" means an aryl-O-alkenyl- group in which the aryl or 
alkenyl groups are as previously described. An exemplary aryloxyalkenyl 
groups is phenoxyallyl. 
"Heteroaralkyloxy" means an heteroaralkyl-O-- group in which the 
heteroaralkyl group is as previously described. An exemplary 
heteroaralkyloxy group is 4-pyridylmethyloxy. 
"Heteroaralkyloxyalkyl" means an heteroaralkyl-O-alkyl group in which the 
heteroaralkyl and alkyl groups are as previously described. An exemplary 
heteroaralkyloxy group is 4-pyridylmethyloxyethyl. 
"Heteroaralkyloxyalkenyl" means an heteroaralkyl-O-alkenyl group in which 
the heteroaralkyl and alkenyl groups are as previously described. An 
exemplary heteroaralkyloxyalkenyl group is 4-pyridylmethyloxyallyl. 
"Alkylthio" means an alkyl-S-- group in which the alkyl group is as 
previously described. Exemplary alkylthio groups include methylthio, 
ethylthio, i-propylthio and heptylthio. 
"Arylthio" means an aryl-S-- group in which the aryl group is as previously 
described. Exemplary arylthio groups include phenylthio and naphthylthio. 
"Aralkylthio" means an aralkyl-S-- group in which the aralkyl group is as 
previously described. An exemplary aralkylthio group is benzylthio. 
"Oxyalkylenyloxy" means a --O-lower alkyl-O-- group in which the lower 
alkyl group is as previously described. An exemplary alkylenedioxy group 
is --O--CH.sub.2 --O--. 
"Cyclocarbamoylalkyl" means a compound of formulae 
##STR5## 
in which the cyclocarbamoyl group consists of the oxooxazaheterocyclyl 
ring moiety, and the alkyl group is as previously described. The alkyl 
moiety may be attached to the carbamoyl through either a carbon atom or 
the nitrogen atom of the carbamoyl moiety. An exemplary 
cyclocarbamoylalkyl group is N-oxazolidinylpropyl. 
"Imidealkyl" means a compound of formulae 
##STR6## 
in which the imide group consists of the oxodiazaheterocyclyl ring moiety, 
and the alkyl group is as previously described. The alkyl moiety may be 
attached to the carbamoyl through either a carbon atom or nitrogen atom of 
the carbamoyl moiety. An exemplary imidealkyl group is 
n-phthalimidepropyl. 
"Y.sup.1 Y.sup.2 N--" means a substituted or unsubstituted amino group, 
wherein Y.sup.1 and Y.sup.2 are as previously described. Exemplary groups 
include amino (H.sub.2 N--), methylamino, ethylmethylamino, dimethylamino 
and diethylamino. 
"Alkoxycarbonyl" means an alkyl-O--CO-- group. Exemplary alkoxycarbonyl 
groups include methoxy- and ethoxycarbonyl. 
"Aryloxycarbonyl" means an aryl-O--CO-- group. Exemplary aryloxycarbonyl 
groups include phenoxy- and naphthoxycarbonyl. 
"Aralkoxycarbonyl" means an aralkyl-O--CO-- group. An exemplary 
aralkoxycarbonyl group is benzyloxycarbonyl. 
"Y.sup.1 Y.sup.2 NCO--" means a substituted or unsubstituted carbamoyl 
group, wherein Y.sup.1 and Y.sup.2 are as previously described. Exemplary 
groups are carbamoyl (H.sub.2 NCO--) and dimethylaminocarbamoyl (Me.sub.2 
NCO--). 
"Y.sup.1 Y.sup.2 NSO.sub.2 --" means a substituted or unsubstituted 
sulfamoyl group, wherein Y.sup.1 and Y.sup.2 are as previously described. 
Exemplary groups are aminosulfamoyl (H.sub.2 NSO.sub.2 --) and 
dimethylaminosulfamoyl (Me.sub.2 NSO.sub.2 --). 
"Acylamino" is an acyl-NH-- group wherein acyl is as defined herein. 
"Aroylamino" is an aroyl-NH-- group wherein aroyl is as defined herein. 
"Alkylsulfonyl" means an alkyl-SO.sub.2 -- group. Preferred groups are 
those in which the alkyl group is lower alkyl. 
"Alkylsulfinyl" means an alkyl-SO-- group. Preferred groups are those in 
which the alkyl group is lower alkyl. 
"Arylsulfonyl" means an aryl-SO.sub.2 -- group. 
"Arylsulfinyl" means an aryl-SO-- group. 
"Halo" means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro 
or bromo, and more preferred are fluoro or chloro. 
Preferred Embodiments 
A preferred compound aspect of the invention is the compound of formula I 
wherein 
R.sub.1 is hydrogen, optionally substituted alkyl, optionally substituted 
alkenyl, optionally substituted cycloalkyl, hydroxy, Y.sup.1 Y.sup.2 N--, 
arylsulfanylalkyl, arylsulfinylalkyl or arylsulfonylalkyl; 
R.sub.2, R.sub.4, R.sub.5, R.sub.6 are independently hydrogen or optionally 
substituted alkyl, or R.sub.4 is optionally substituted aryl or optionally 
substituted heteroaryl, or R.sub.2 and R.sub.4 taken together with the 
carbon atoms through which R.sub.2 and R.sub.4 are linked form optionally 
substituted cycloalkyl or optionally substituted cycloalkenyl, or R.sub.1 
and R.sub.2 taken together with the carbon atoms through which R.sub.1 and 
R.sub.2 are linked form optionally substituted cycloalkyl; 
R.sub.3 is optionally substituted alkyl, optionally substituted aryl, 
optionally substituted heteroaryl, optionally substituted aralkyl, 
optionally substituted heteroaralkyl, Y.sup.3 Y.sup.4 Nalkyl, Y.sup.1 
Y.sup.2 NCO.sub.2 alkyl, Y.sup.1 Y.sup.2 NCO-alkyl, imidealkyl, or R.sub.3 
and R.sub.4 taken together with the carbon to which R.sub.3 and R.sub.4 
are attached form an optionally substituted cycloalkyl, or one of R.sub.1 
and R.sub.2 and one of R.sub.3 and R.sub.4 taken together with the carbons 
through which the one of R.sub.1 and R.sub.2 and one of R.sub.3 and 
R.sub.4 are linked form a bond or optionally substituted cycloalkyl or 
optionally substituted cycloalkenyl; 
Ar is optionally substituted aryl or optionally substituted heteroaryl; 
Y.sup.1 and Y.sup.2 are independently hydrogen, optionally substituted 
alkyl or optionally substituted aryl, or Y.sup.1 and Y.sup.2 taken 
together with the nitrogen atom to which Y.sup.1 and Y.sup.2 are attached 
form an optionally substituted heterocyclyl, and 
Y.sup.3 and Y.sup.4 are independently Y.sup.1 or Y.sup.2, or optionally 
substituted aroyl or optionally substituted aralkyloxycarbonyl. 
Another preferred compound aspect of the invention is the compound wherein 
R.sub.1 is optionally substituted alkyl, optionally substituted alkenyl, 
optionally substituted aralkyl or optionally substituted heteroaralkyl. 
Another preferred compound aspect of the invention is the compound wherein 
R.sub.1 is optionally substituted alkyl. 
Another preferred compound aspect of the invention is the compound wherein 
R.sub.1 is hydroxy. 
Another preferred compound aspect of the invention is the compound wherein 
R.sub.1 is optionally substituted alkyl. 
Another preferred compound aspect of the invention is the compound wherein 
R.sub.1 is Y.sup.1 Y.sup.2 N-- and Y.sup.1 or Y.sup.2 are hydrogen. 
Another preferred compound aspect of the invention is the compound wherein 
R.sub.2 is hydrogen. 
Another preferred compound aspect of the invention is the compound wherein 
R.sub.1 and R.sub.2 are optionally substituted alkyl. 
Another preferred compound aspect of the invention is the compound wherein 
R.sub.3 is optionally substituted aryl, optionally substituted heteroaryl, 
optionally substituted aralkyl, optionally substituted heteroaralkyl or 
Y.sup.3 Y.sup.4 Nalkyl. 
Another preferred compound aspect of the invention is the compound wherein 
R.sub.3 is optionally substituted aralkyl. 
Another preferred compound aspect of the invention is the compound wherein 
R.sub.4 is hydrogen or optionally substituted alkyl. 
Another preferred compound aspect of the invention is the compound wherein 
R.sub.4 is optionally substituted alkyl. 
Another preferred compound aspect of the invention is the compound wherein 
R.sub.3 and R.sub.4 taken together with the carbon atom to which R.sub.3 
and R.sub.4 are attached form optionally substituted cycloalkyl. 
Another preferred compound aspect of the invention is the compound wherein 
Ar is optionally substituted aryl; more preferred is 4-methoxyphenyl or 
3,4-dimethoxyphenyl. 
Another preferred compound aspect of the invention is the compound wherein 
n is 0 or 2. 
Another preferred compound aspect of the invention is the compound wherein 
m is 0. 
Another preferred compound aspect of the invention is the compound wherein 
q is 1. 
Preferred compounds for use according to the invention are selected from 
the following species: 
A 7-Phenyl-3-phenylsulfonylheptanoic acid hydroxyamide; 
B 7-Phenyl-3-phenylsulfanylheptanoic acid hydroxyamide; 
C 3-(4-Acetoamidophenylsulfonyl)-7-phenylheptanoic acid hydroxyamide; 
D 3-(4-Acetoamidophenylsulfanyl)-7-phenylheptanoic acid hydroxyamide; 
E 3-(2-Naphthalenylsulfonyl)-7-phenylheptanoic acid hydroxyamide; 
F 3-(2-Naphthalenylsulfanyl)-7-phenylheptanoic acid hydroxyamide; 
G 3-(4-Methoxyphenylsulfonyl)-7-phenylheptanoic acid hydroxyamide; 
H 3-(4-Methoxyphenylsulfanyl)-7-phenylheptanoic acid hydroxyamide; 
I 3-(Benzylsulfonyl)-7-phenylheptanoic acid hydroxyamide; 
J 3-(Benzylsulfanyl)-7-phenylheptanoic acid hydroxyamide; 
K N-hydroxy-3-(4-methoxybenzenesulfonyl)-4-phenylbutyramide; 
L N-hydroxy-3-(4-methoxybenzenesulfanyl)-4-phenylbutyramide; 
M N-hydroxy-3-(4-methoxybenzenesulfonyl)-3-phenylpropionamide; 
N N-hydroxy-3-(4-methoxybenzenesulfanyl)-3-phenylpropionamide; 
O 3-(4-Methoxybenzenesulfonyl)-5-phenylpentanoic acid hydroxyamide; 
P 3-(4-Methoxybenzenesulfanyl)-5-phenylpentanoic acid hydroxyamide; 
Q 3-(4-Methoxybenzenesulfonyl)-6-phenylhexanoic acid hydroxamide; 
R 3-(4-Methoxybenzenesulfanyl)-6-phenylhexanoic acid hydroxamide; 
S 3-(4-Methoxybenzenesulfonyl)-3-methyl-7-phenylheptanoic acid hydroxamide 
T 3-(4-Methoxybenzenesulfanyl)-3-methyl-7-phenylheptanoic acid hydroxamide 
U (.+-.)-N-Hydroxy-3-(4-methoxyphenyl)sulfanyl-4-(4-biphenyl)butyramide; 
V 
(.+-.)-N-Hydroxy-3-(4-methoxyphenyl)sulfanyl-4-(4-phenyloxyphenyl)butyrami 
de; 
W 
(.+-.)-N-Hydroxy-3-(4-methoxyphenyl)sulfanyl-4-(4-benzyloxyphenyl)butyrami 
de; 
X 
(.+-.)-N-Hydroxy-3-(4-methoxyphenyl)sulfanyl-4-(4-n-butyloxyphenyl)butyram 
ide; 
Y (.+-.)-N-Hydroxy-3-(4-methoxyphenyl)sulfonyl-4-(4-biphenyl)butyramide; 
Z 
(.+-.)-N-Hydroxy-3-(4-methoxyphenyl)sulfonyl-4-(4-phenyloxyphenyl)butyrami 
de; 
AA 
(.+-.)-N-Hydroxy-3-(4-methoxyphenyl)sulfonyl-4-(4-benzyloxyphenyl)butyrami 
de; 
AB 
(.+-.)-N-Hydroxy-3-(4-methoxyphenyl)sulfonyl-4-(4-n-butyloxyphenyl)butyram 
ide; 
AC 3-(4-Methoxybenzenesulfonyl)-3-ethyl-7-phenylheptanoic acid hydroxamide; 
AD 3-(4-Methoxybenzenesulfonyl)-3,7-diphenylheptanoic acid hydroxamide; 
AE N-Hydroxy-3-(4-methoxybenzenesulfonyl)-3-methylbutyramide; 
AF N-Hydroxy-2-[1-(4-methoxybenzenesulfonyl)cyclopentyl]acetamide; 
AG N-Hydroxy-2-[1-(4-methoxybenzenesulfonyl)-4-phenylcyclohexyl]acetamide; 
AH (2R*,3R*)-2-Amino-3-(4-methoxybenzene)sulfonyl-7-phenylheptanoic acid 
hydroxy amide; 
AI N-Hydroxy-2-[(3,4-dimethoxyphenyl)sulfonyl]-6-phenylhexanamide; 
AJ (E)-N-Hydroxy-3-[(3,4-dimethoxyphenyl)thio]-7-phenyl-2-heptenamide; 
AK (E)-N-Hydroxy-3-[(3,4-dimethoxyphenyl)sulfonyl]-7-phenyl-2-heptenamide; 
AL (Z)-N-Hydroxy-3-[(3,4-dimethoxyphenyl)thio]-7-phenyl-2-heptenamide; 
AM 
N-hydroxy-3-(4-methoxyphenyl)thio-2-(1-propane-3-yl)-7-phenylheptanamide; 
AN 
N-Hydroxy-2-(1-propane-3-yl)-3-(4-methoxyphenyl)sulfonyl-7-phenylheptanami 
de; 
AO 
N-Hydroxy-2-[(3,4-dimethoxyphenyl)thio]-3-(3-phenylpropyl-1-yl)-1-cyclopen 
tenecarboxamide; 
AP 
N-Hydroxy-2-[(3,4-dimethoxyphenyl)sulfonyl]-3-(3-phenylpropyl-1-yl)-1-cycl 
opentenecarboxamide; 
AQ N-Hydroxy-3-(3,4-dimethoxyphenyl-7-phenyl-2-heptenamide; 
AR N-Hydroxy-3-(3,4-dimethoxyphenyl-7-phenylheptanamide; 
AS (-)-(2S, 
3R)-N-Hydroxy-2-(2-benzenesulfonylethyl)-3-(3,4-dimethoxyphenylsulfonyl)-7 
-phenylheptanamide; 
AT (+)-(2S, 
3R)-N-Hydroxy-2-(2-benzenesulfonylethyl)-3-(3,4-dimethoxyphenylsulfonyl)-7 
-phenylheptanamide; 
AU 
(-)-N-Hydroxy-2-(2-benzenesulfonylethyl)-3-(3,4-dimethoxyphenylsulfanyl)-7 
-phenylheptanamide; 
AV 
(+)-N-Hydroxy-2-(2-benzenesulfonylethyl)-3-(3,4-dimethoxyphenylsulfanyl)-7 
-phenylheptanamide; 
AW N-Hydroxy-3-(3,4-dimethoxybenzenesulfonyl)-4-phenylbutyramide; 
AX N-Hydroxy-3-(3,4-dimethoxyphenylsulfanyl)-4-phenylbutyramide; 
AY N-Hydroxy-3-(3,4-dimethoxybenzenesulfonyl)-3-phenylproprionamide; 
AZ N-Hydroxy-3-(3,4-dimethoxyphenylsulfanyl)-3-phenylpropionamide; 
BA 3-(3,4-Dimethoxyphenylsulfanyl)-5-phenylpentanoic acid hydroxamide; 
BB 3-(3,4-Dimethoxyphenylsulfonyl)-5-phenylpentanoic acid hydroxamide; 
BC 3-(3,4-Dimethoxybenzenesulfonyl)-6-phenylhexanoic acid hydroxamide; 
BD 3-(3,4-Dimethoxyphenylsulfanyl)-6-phenylhexanoic acid hydroxamide; 
BE 3-(3,4-Dimethoxybenzenesulfonyl)-6-phenylhexanoic acid hydroxamide; 
BF 3-(R*)-(3,4-Dimethoxybenzenesulfonyl)-2-(S*)-isopropyl-7-phenylheptanoic 
acid hydroxamide; 
BG 3-(3,4-Dimethoxybenzenesulfanyl)-2-isopropyl-7-phenylheptanoic acid 
hydroxamide; 
BH (+)-(2R,3R)-3-(3,4-Dimethoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic 
acid hydroxyamide; 
BI (+)-(2R,3R)-3-(3,4-Dimethoxyphenylsulfonyl)-2-methyl-7-phenylheptanoic 
acid hydroxyamide; 
BJ (+)-(2R,3S)-3-(3,4-Dimethoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic 
acid hydroxyamide; 
BK (+)-(2R,3S)-3-(3,4-Dimethoxyphenylsulfonyl)-2-methyl-7-phenylheptanoic 
acid hydroxyamide; 
BL 
1-[1-(3,4-Dimethoxyphenylsulfonyl)-5-phenylpentyl]cyclopentane-carboxylic 
acid hydroxyamide; 
BM 
1-[1-(3,4-Dimethoxyphenylsulfanyl)-5-phenylpentyl]cyclopentane-carboxylic 
acid hydroxyamide; 
BN 3-(3,4-Dimethoxybenzenesulfonyl)-2,2-dimethyl-7-phenylheptanoic acid 
hydroxyamide; 
BO 3-(4-Methoxybenzenesulfonyl)-2,2-dimethyl-7-phenylheptanoic acid 
hydroxyamide; 
BP 3-(4-Methoxybenzenesulfinyl)-7-phenylheptanoic acid hydroxamide; 
BQ (.+-.)-N-Hydroxy-3-(3,4-Dimethoxyphenyl)sulfonyl-7-phenylheptanamide; 
BR 
(.+-.)-N-Hydroxy-3-(3,4-methylenedioxyphenyl)sulfonyl-7-phenylheptanamide; 
BS (.+-.)-N-Hydroxy-3-(3,4-dimethoxyphenyl)sulfinyl-7-phenylheptanamide; 
BT (.+-.)-N-Hydroxy-3-(3,4-Dimethoxyphenyl)sulfanyl-7-phenylheptanamide; 
BU 
(.+-.)-N-hydroxy-3-(3,4-methylenedioxyphenyl)sulfanyl-7-phenylheptanamide; 
BV (-)-N-Hydroxy-3-(3,4-dimethoxyphenyl)sulfonyl-7-phenylheptanamide; 
BW (+)-N-hydroxy-3-(3,4-dimethoxyphenyl)sulfonyl-7-phenylheptanamide; 
BX 
(.+-.)-(2R*,3R*)-3-(4-Methoxybenzenesulfonyl)-7-phenyl-2-(2-phenoxyethyl)h 
eptanoic acid hydroxyamide; 
BY 
(.+-.)-(2R*,3R*)-3-(4-Methoxybenzenesulfonyl)-7-phenyl-2-(2-phenylsulfanyl 
ethyl)heptanoic acid hydroxyamide; 
BZ (2R*, 
3R*)-3-(4-Methoxybenzenesulfonyl)-7-phenyl-2-(2-phenylsulfanylethyl)heptan 
oic acid hydroxyamide; 
CA 
(.+-.)-(2R*,3S*)-3-(4-Methoxybenzenesulfonyl)-7-phenyl-2-(benzenesulfonylm 
ethyl)heptanoic acid hydroxyamide; 
CB 
(.+-.)-(2R*,3S*)-3-(4-methoxybenzenesulfonyl)-7-phenyl-2-(phenylsulfanylme 
thyl)heptanoic acid hydroxyamide; 
CC (.+-.) 2-Hydroxy-3-(4-methoxybenzenesulfonyl)-2-methyl-7-phenylheptanoic 
acid hydroxyamide; 
CD (.+-.)-3-(4-Methoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid 
hydroxyamide; 
CE (.+-.)-3-(4-Methoxybenzenesulfonyl)-2-methyl-7-phenylheptanoic acid 
hydroxyamide; 
CF 3-(3,4-Dimethoxybenzenesulfonyl)-5-methylhexanoic acid hydroxyamide; 
CG 5-(4-Butoxyphenyl)-3-(3,4-dimethoxybenzenesulfonyl)-pentanoic acid 
hydroxyamide; 
CH 3-(3,4-Dimethoxybenzenesulfonyl)hexanoic acid hydroxyamide; 
CI 3-(3,4-Dimethoxybenzenesulfonyl)-4-methylpentanoic acid hydroxyamide; 
CJ 3-(3,4-Dimethoxybenzenesulfonyl)-5-methylhexanoic acid hydroxyamide; 
CK 
3-(3-Benzyloxyphenyl)-3-(3,4-dimethoxybenzenesulfonyl)-N-hydroxypropionami 
de; 
CL 
3-(2-Benzyloxyphenyl)-3-(3,4-dimethoxybenzenesulfonyl)-N-hydroxypropionami 
de; 
CM 
3-(3-Benzyloxy-4-methoxyphenyl)-3-(3,4-dimethoxybenzenesulfonyl)-N-hydroxy 
propionamide; 
CN 
3-(3,4-Dimethoxybenzenesulfonyl)-N-hydroxy-3-(3-phenoxyphenyl)-propionamid 
e; 
CO 
3-(3-(4-Chlorophenoxy)phenyl)-3-(3,4-dimethoxybenzenesulfonyl)-N-hydroxypr 
opionamide; 
CP 
3-(3,4-Dimethoxybenzenesulfonyl)-N-hydroxy-3-(3-(4-methoxyphenoxy)phenyl)p 
ropionamide; 
CQ N-[2-(3,4-Dimethoxybenzenesulfonyl)-3-hydroxycarbamoyl-propyl]-N 
methylbenzamide; 
CR N-[2-(3,4-Dimethoxybenzenesulfonyl)-3-hydroxycarbamoyl-butyl]-N 
methylbenzamide; 
CS Methyl-phenyl-carbamic acid 
3-(3,4-dimethoxybenzenesulfonyl)-4-hydroxycarbamoyl-butyl ester; 
CT [3-(3,4-Dimethoxybenzenesulfonyl)-4-hydroxycarbamoylbutyl]methylcarbamic 
acid benzyl ester; 
CU 3-(3,4-Dimethoxybenzenesulfonyl)hexanedioic 
acid-1-hydroxyamide-6-(methylphenylamide); 
CV 3-(3,4-Dimethoxybenzenesulfonyl)heptanedioic 
acid-1-hydroxyamide-7-(methylphenylamide); 
CW 
3-(3,4-Dimethoxybenzenesulfonyl)-6-(1,3-dioxo-1,3-dihydroisoindol-2-yl)hex 
anoic acid hydroxyamide; 
CX 
7-(3,4-Dihydro-2H-quinolin-1-yl)-3-(3,4-dimethoxybenzenesulfonyl)-7-oxohep 
tanoic acid hydroxyamide; 
CY 
7-(3,4-Dihydro-2H-quinolin-1-yl)-3-(3,4-dimethoxybenzenesulfonyl)-6-oxohex 
anoic acid hydroxyamide; 
CZ 7-Benzo(1,3)dioxol-5-yl-3-(3,4-dimethoxybenzenesulfonyl)heptanoic acid 
hydroxyamide; 
DA 3-(3,4-Dimethoxybenzenesulfonyl)-3-(thien-3-yl)-N-hydroxypropionamide; 
DB 3-(3,4-Dimethoxybenzenesulfonyl)-5-phenylpentanoic acid hydroxyamide; 
DC 3-(3,4-Dimethoxybenzenesulfonyl)-5-(3-phenoxyphenyl)pentanoic acid 
hydroxyamide; 
DD 5-(4-Benzyloxyphenyl)-3-(3,4-dimethoxybenzenesulfonyl)pentanoic acid 
hydroxyamide; 
DE 
2-{(3,4-Dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxyphenyl]methyl}-4-me 
thylpentanoic acid hydroxyamide; 
DF 3-(3,4-dimethoxybenzenesulfonyl)-7-phenyl-2-(4-phenylbutyl)heptanoic 
acid hydroxyamide; 
DG 2-[1-(3-(3,4-dimethoxybenzenesulfonyl)-5-phenylpentyl]-N 1-hydroxy-N 
4-methyl-N 4-phenylsuccinamide; 
DH 3-(3,4-dimethoxybenzenesulfonyl)-7-phenyl-2-(3-phenylpropyl)heptanoic 
acid hydroxyamide; 
DI 3-(3,4-dimethoxybenzenesulfonyl)-2-isopropyl-7-phenylheptanoic acid 
hydroxyamide; 
DJ 3-(3,4-dimethoxybenzenesulfonyl)-2-isobutyl-7-phenylheptanoic acid 
hydroxyamide; 
DK 3-(3,4-dimethoxybenzenesulfonyl)-7-phenyl-2-propylheptanoic acid 
hydroxyamide; 
DL 3-(3,4-dimethoxybenzenesulfonyl)-7-phenyl-2-(4-phenylbutyl)heptanoic 
acid hydroxyamide; 
DM 
3-(3,4-dimethoxybenzenesulfonyl)-2-[2-(2-methoxyethoxy)ethyl]-7-phenylhept 
anoic acid hydroxyamide; 
DN 
3-(3,4-dimethoxybenzenesulfonyl)-2-benzenesulfonylethyl-7-phenylheptanoic 
acid hydroxyamide; 
DO 3-(3,4-dimethoxybenzenesulfonyl)-7-phenyl-2-(5-phenylpentyl)heptanoic 
acid hydroxyamide; 
DP 
4-Benzenesulfonyl-2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy) 
phenyl]methyl}-N-hydroxy-butyramide; 
DQ 
2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-N-h 
ydroxy-4-phenyl-butyramide; 
DR 
2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-N-h 
ydroxy-4-(2-methoxyethoxy)butyramide; 
DS 
2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-N-h 
ydroxy-butyramide; 
DT 
2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-pen 
tanoic acid hydroxyamide; 
DU 
2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-4-m 
ethylpentanoic acid hydroxyamide; 
DV 
2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-N-h 
ydroxy-3-methylbutyramide; 
DW 
2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-7-p 
henylheptanoic acid hydroxyamide; 
DX 
2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-5-p 
henylpentanoic acid hydroxyamide; 
DY 2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-N 
1-hydroxy-N 4-methyl-N 4-phenyl-succinimide; 
DZ 
2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-6-p 
henylhexanoic acid hydroxyamide; 
EA 2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-4-methylpentanoic 
acid hydroxyamide; 
EB 
2-[(3,4-Dimethoxybenzenesulfonyl)-(4-phenoxyphenyl)methyl]-N-hydroxy-4-(2- 
methoxyethoxy)butyramide; 
EC 
2-[(3,4-Dimethoxybenzenesulfonyl)-(4-phenoxyphenyl)methyl]-N-hydroxy-butyr 
amide; 
ED 
4-Benzenesulfonyl-2-[biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-N 
-hydroxybutyramide; 
EE 
2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-N-hydroxy-4-phenylb 
utyramide; 
EF 
2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-N-hydroxy-4-(2-meth 
oxyethoxy)butyramide; 
EG 
2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-N-hydroxybutyramide 
; 
EH 2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-4-methylpentanoic 
acid hydroxyamide; 
EI 
2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-N-hydroxy-3-methyl- 
butyramide; 
EJ 2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-7-phenylheptanoic 
acid hydroxyamide; 
EK 2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-5-phenylpentanoic 
acid hydroxyamide; 
EL 
2-[(3,4-Dimethoxybenzenesulfonyl)-(4-phenoxyphenyl)methyl]-N-hydroxy-3-met 
hylbutyramide; 
EM 
2-[(3,4-Dimethoxybenzenesulfonyl)-(4-phenoxyphenyl)methyl]-7-phenylheptano 
ic acid hydroxyamide; 
EN 3-(3,4-Dimethoxybenzenesulfonyl)-2-ethylhexanoic acid hydroxyamide; 
EO 3-(3,4-Dimethoxybenzenesulfonyl)-2-(3-phenyl-propyl)hexanoic acid 
hydroxyamide; 
EP 
2-[(3-Benzyloxyphenyl)-(3,4-dimethoxybenzenesulfonyl)methyl]-5-phenylpenta 
noic acid hydroxyamide; 
EQ 3-(4-Methoxybenzenesulfonyl)-3-(4-ethoxyphenyl)propionic acid 
hydroxyamide; 
ER 3-(4-methoxybenzenesulfonyl)-3-(4-biphenyl)propionic acid hydroxy 
amide); 
ES 3-(4-methoxybenzenesulfonyl)-3-(4-phenoxyphenyl)propionic acid hydroxy 
amide; 
ET 3-(4-methoxybenzenesulfonyl)-3-(4-benzyloxyphenyl)propionic acid hydroxy 
amide; 
EU 3-(4-methoxybenzenesulfonyl)-3-(4-fluorobenzyloxyphenyl)propionic acid 
hydroxy amide; and 
EV 
3-(4-methoxybenzenesulfonyl)-3-(4-(3-trifluoromethylphenoxy)phenylpropioni 
c acid hydroxy amide; 
EW (+)-3-(4-methoxyphenylsulfonyl)-7-phenylheptanoic acid hydroxamide; 
EX (-)-3-(4-methoxyphenylsulfonyl)-7-phenylheptanoic acid hydroxamide; 
EY (-)-(2S,3S)-3-(3,4-Dimethoxybenzenesulfanyl)-2-methyl-7-phenylheptanoic 
acid hydroxyamide; 
EZ (-)-(2S,3S)-3-(3,4-Dimethoxybenzenesulfonyl)-2-methyl-7-phenylheptanoic 
acid hydroxyamide; 
FA (-)-(2S,3R)-3-(3,4-dimethoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic 
acid hydroxyamide; and 
FB (-)-(2S,3R)-3-(3,4-dimethoxybenzenesulfonyl)-2-methyl-7-phenylheptanoic 
acid hydroxyamide. 
More preferred compounds include G, Z, AA, AE-AG, AI, AP, AU, BF, BH-BK, 
BN-BO, BQ, BS, BV-BW, CA, CZ, DI, DM-DN, ES-EU, EW-EZ, and FA-FB. 
The letters A to FB are allocated to compounds for easy reference in this 
specification. 
Compounds of formula I may be prepared by the application or adaptation of 
known methods, by which is meant methods used heretofore or described in 
the literature. 
General methods for preparing compounds according to the invention may also 
be prepared as described in the Schemes that follow. The variables in the 
Schemes are as described above, unless otherwise noted. 
One procedure for preparing compounds according to the invention, 
particularly .alpha.,.alpha.-disubstituted analogs, is shown in Scheme A. 
##STR7## 
For example, a dialkyl malonate such as diethyl (A1) or dimethyl may be 
monoalkylated using an appropriate alkyl halide (R.sub.1 --Cl, R.sub.1 
--I, R.sub.1 --Br, preferably R.sub.1 --I, R.sub.1 --Br) and a suitable 
base such as a carbonate (such as sodium or calcium carbonate), hydroxide 
(such as sodium or potassium hydroxide) or alkoxide (such as sodium 
methoxide or ethoxide) in a polar solvent such as ethanol at about 20 to 
about 90.degree. C. to give A2. 
A2 may then be alkylated using another appropriate alkyl halide (R.sub.2 
--Cl, R.sub.2 --I, R.sub.2 --Br, preferably R.sub.2 --I, R.sub.2 --Br), 
and similar reaction conditions as in the first alkylation to provide A3. 
A3 is then deprotected to the corresponding mono acid (A4) by using one 
equivalent of hydroxide (such as sodium or potassium hydroxide) in an 
aqueous alcohol or tetrahydrofuran solvent at about 20 to about 90.degree. 
C. 
The acid moiety of A4 is then reduced selectively using diborane in an 
organic solvent such as tetrahydrofuran at about 0 to about 40.degree. C. 
to give the alcohol (A5). 
A5 is then be converted to the corresponding sulfonate ester (A6) using a 
sulfonyl chloride (ClSO.sub.2 R.sub.b) such as p-toluenesulfonyl chloride, 
methanesulfonyl chloride or trifluoromethane sulfonyl chloride and a 
suitable base such as pyridine or triethylamine in an organic solvent. 
The sulfonate ester is then be reacted with a thiol in the presence of a 
trialkylamine base or hydroxide to give a sulfide (A7). 
The sulfide is then oxidized to a sulfone (A8) using a minimum of two 
equivalents of an oxidant such as oxone, m-chloroperbenzoic acid or 
hydrogen peroxide. 
When A8 is .alpha.,.alpha.-disubstituted then the sulfone may then be 
alkylated with an alkyl iodide or bromide using a base such as lithium 
diisopropylamine, lithium bis(trimethylsilyl)amine, sodium 
bis(trimethylsilyl)amine or n-butyllithium in a solvent such as 
tetrahydrofuran, hexamethylphosphoramide, diethyl ether, dimethoxyethane 
or a combination thereof at about -75 to about 20.degree. C. to give A9. 
A8 and A9 are then converted to the corresponding acids respectively A12 
and A10 using hydroxide in an aqueous alcohol or tetrahydrofuran solvent 
at about 20 to about 90.degree. C. 
A10 is then reacted using standard peptide coupling procedures with an 
O-protected hydroxylamine such as O-trimethylsilyl hydroxylamine, 
O-t-butyldimethylsilyl hydroxylamine, O-tetrahydropyranyl hydroxylamine 
followed by acid treatment to yield the hydroxamic acid A11. 
An alternative sequence for preparing A10 involves alkylating A12 with an 
alkyl iodide or bromide using two equivalents of a base such as lithium 
diisopropylamine, lithium bis(trimethylsilyl)amine, sodium 
bis(trimethylsilyl)amine or butyllithium in a solvent such as 
tetrahydrofuran, hexamethylphosphoramide, diethyl ether, dimethoxyethane 
or a combination thereof at about 75 to about 20.degree. C. to give A10. 
An alternative sequence for preparing A3, particularly where R.sub.1 aryl 
or heteroaryl, is from A13 by treatment with a suitable base such as 
trityl sodium, lithium diisopropylamine, lithium bis(trimethylsilyl)amine 
or sodium bis(trimethylsilyl)amine followed by a chloroformate at about 
-78 to about 25.degree. C. 
##STR8## 
An alternative sequence for preparing A4 involves a mixed ester malonate 
such as benzyl ethyl malonate (A14). Sequential alkylation using alkyl 
halide (R.sub.1 --I, R.sub.1 --Br) followed by (R.sub.2 --I, R.sub.2 --Br) 
and a suitable base such as carbonate, sodium hydride, hydroxide or 
alkoxide in a polar solvent such as ethanol at about 20 to about 
90.degree. C. can yield A15. Deprotection of the benzylester to the mono 
acid A4 may be accomplished using catalytic hydrogenation. 
##STR9## 
Another procedure for preparing compounds according to the invention is 
shown in Scheme B. 
##STR10## 
Another procedure for preparing compounds according to the invention is 
shown in Scheme C. 
##STR11## 
Following the procedures shown in Scheme B or C, except that the t-butyl 
diethylphosphonoacetate is substituted by a substituted t-butyl 
dialkylphosphonoacetate in step B, then a trisubstituted or 
tetrasubstituted olefin is produced respectively as shown in Scheme D. 
Those olefins may then be transformed according to the remaining 
procedures in Schemes B or C to an .alpha.-substituted hydroxamic acid. 
##STR12## 
An example according to Scheme D, step B may use t-butyl 
diethylphosphonopropionate to prepare a hydroxyamide using the remaining 
steps as outlined in Scheme A. In addition, a number of substituted 
t-butyl dialkylphosphonoacetates can be prepared by alkylation of t-butyl 
diethylphosphonoacetate with an appropriate alkyl halide in the presence 
of a base such as sodium hydride, lithium diisopropylamine or sodium 
bis(trimethylsilyl)amine in a solvent such as tetrahydrofuran. 
##STR13## 
These phosphonoacetates can then be substituted in step B of Scheme D. 
An alternative preparation of trisubstituted olefins is via an aldol 
reaction followed by elimination of the alcohol. Reaction of a t-butyl 
ester with an aldehyde in the presence of an appropriate base such as 
lithium diisopropylamine, lithium bis(trimethylsilyl)amine, sodium 
bis(trimethylsilyl)amine or butylithium in a solvent such as 
tetrahydrofuran, hexamethylphosphoramide, diethyl ether, dimethoxyethane 
or a combination thereof at about -75 to about 20.degree. C. may provide 
the aldol adduct which may be treated with a sulfonyl halide such as 
methanesulfonyl chloride and a trialkylamine base such as triethylamine to 
provide a sulfonate ester which may be directly eliminated with an 
additional base such as 1,8-diazabicyclo-[5.4.0]undec-7-ene to give the 
trisubstituted olefin. This olefin may then be used in Scheme B to yield 
hydroxamic acids. 
##STR14## 
Scheme E shows another means for preparing compounds according to the 
invention starting with an alkyl dialkylphosphonoacetate and 
aldehyde/ketone. The 
##STR15## 
moiety as represented therein and henceforth is Ar(CR.sub.5 R.sub.6).sub.m 
SH. 
##STR16## 
Scheme F shows another means for preparing .beta.,.beta.' disubstituted and 
.beta.,.beta.' spiro compounds according to the invention starting with an 
alkyl dialkylphosphonoacetate and aldehyde/ketone. 
##STR17## 
Scheme G shows a means for preparing ketone starting materials useful in 
the Schemes herein. 
##STR18## 
Scheme H shows alternative means for preparing hydroxamic acid compounds 
within the scope of the invention. 
##STR19## 
Scheme I shows alternative means for preparing hydroxamic acid compounds 
within the scope of the invention. 
##STR20## 
Scheme J shows alternative means for preparing hydroxamic acid compounds 
within the scope of the invention. X.sub.1 as used hereinbelow represents 
halo, preferably Cl, Br or I. 
##STR21## 
Scheme K shows alternative means for preparing hydroxamic acid compounds 
within the scope of the invention. 
##STR22## 
Scheme L shows alternative means for preparing hydroxamic acid compounds 
within the scope of the invention. 
##STR23## 
Scheme M shows alternative means for preparing hydroxamic acid compounds 
within the scope of the invention. 
##STR24## 
Scheme N shows alternative means for preparing hydroxamic acid compounds 
within the scope of the invention. 
##STR25## 
Scheme O shows alternative means for the preparation of hydroxamic acid 
compounds within the scope of the invention. 
##STR26## 
Scheme P shows alternative means for the preparation of hydroxamic acid 
compounds within the scope of the invention, particularly where R.sub.1 
and R.sub.2 taken together with the carbon atoms through which R.sub.1 and 
R.sub.2 are linked form optionally substituted cycloalkyl. 
##STR27## 
Scheme Q shows alternative means for the preparation of hydroxamic acid 
compounds within the scope of the invention. 
##STR28## 
Scheme R shows alternative means for preparing hydroxamic acid compounds 
within the scope of the invention, particularly wherein m is 0. The 
##STR29## 
moiety as represented therein and henceforth is Ar. 
##STR30## 
Scheme S shows alternative means for preparing hydroxamic acid compounds 
within the scope of the invention, which may be resolved using resolution 
methods. 
##STR31## 
Scheme T shows a means for preparing stereoisomerically hydroxamic acid 
compounds within the scope of the invention. 
##STR32## 
Scheme U shows alternative means for preparing stereoisomerically 
hydroxamic acid compounds within the scope of the invention. 
##STR33## 
Scheme V shows alternative means for preparing stereoisomerically acid 
compounds which can be converted to steroisomeric hydroxamic compounds 
within the scope of the invention. 
##STR34## 
Scheme W shows alternative means for preparing stereoisomerically acid 
compounds which can be converted to steroisomeric hydroxamic acid 
compounds within the scope of the invention. 
##STR35## 
Scheme X shows alternative means for preparing stereoisomerically 
hydroxamic acid compounds within the scope of the invention. 
##STR36## 
Scheme Y shows alternative means for preparing stereoisomerically 
hydroxamic acid compounds within the scope of the invention. 
##STR37## 
Scheme Z shows alternative means for preparing stereoisomerically 
hydroxamic acid compounds within the scope of the invention. 
##STR38## 
Scheme AA shows alternate means for preparing hydroxamic acid compounds 
within the scope of the invention employing a solid phase. 
##STR39## 
Resin III may then be coupled, as in Scheme AA, Step c, with an acid of 
formula (Ib), wherein A.sup.1 is (R.sup.5 R.sup.6 C).sub.m and Ar, n, 
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as hereinbefore defined, to give 
the hydroxamate ester resin (Resin IV). The coupling reaction may 
conveniently be carried out in the presence of a carbodiimide, such as 
EDCl, in an inert solvent such as dimethylformamide and at about room 
temperature. Resin IV may then be treated with an acid, such as 
trifluoroacetic acid, in an inert solvent such as dichloromethane to 
liberate the hydroxamic acid of formula (Ia). 
Scheme AB also shows an alternative means for preparing hydroxamic acid 
compounds within the scope of the invention employing a solid phase. 
##STR40## 
A resin such as Resin V may be used to prepare a compound of formula (Ib), 
wherein Ar, A.sup.1, n, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as 
hereinbefore defined, as shown in Scheme AC. 
##STR41## 
For example Wang resin (Resin V) is treated, in Scheme AC, Step 1, with 
diethylphosphonoacetic acid in an inert solvent such as dimethylformamide 
in the presence of 2,6-dichlorobenzoyl chloride and pyridine at about room 
temperature to give the esterified resin (Resin VI). 
The diethylphosphonoacetoxy-resin (Resin VI) is treated, in Scheme AC, Step 
2, with a base such as potassium bis (trimethylsilyl) amide in an inert 
solvent such as toluene, at about 0.degree. C., followed by reaction with 
an aldehyde of formula (II): 
EQU R.sup.3 --CHO (II) 
wherein R.sup.3 is as defined above, at about room temperature to give the 
alkenoate resin (Resin VII). 
Resin VII may then be reacted, as in Scheme AC, Step 3, with a thiol of 
formula (III): 
EQU Ar--A.sup.1 --SH (III) 
wherein Ar and A.sup.1 are as defined above, to give the alkanoate resin 
(Resin VIII). The Michael addition may be conveniently carried out under 
mild basic conditions, for example in the presence of lithium hydroxide 
and at about room temperature. 
Resin VIII may then be hydrolyzed by treatment with an acid, such as 
trifluoroacetic acid, in an inert solvent such as dichloromethane, to 
liberate acids of formula (Ib). 
Resin VIII may also be treated with an oxidizing agent such as 
m-chloro-perbenzoic acid in an inert solvent, such as dioxane, and at a 
temperature at about room temperature to give Resin IX. 
Resin IX may then be hydrolyzed by treatment with an acid, such as 
trifluoracetic acid, in an inert solvent such as dichloromethane, to 
liberate acids of formula (Ib). 
Resin V may also be converted to a hydroxylamine drivatized resin which may 
also be used in the preparation of compounds within the scope of the 
invention. The hydroxylamine drivatized resin is more acid stable and is 
synthesized as in Scheme AD. 
##STR42## 
N-hydroxyphthalimide is coupled to the resin using Mitsunobu conditions 
(Mitsunobu, O., Synthesis 1981, 1). The phthalimido protection is removed 
by methylaminolysis in THF at 40.degree. C. in about 2 hours or 
hydrazinolysis of the resin swelled in t-butanol or THF/t-butanol. The use 
of the methylamine to cleave the phthalimide protection offers a 
significant advantage over the commonly used hydrazinolysis procedure 
(Wolf, S. and Hasan, S. K. Can. J. Chem. 48, 3572 (1970). 
Scheme AE shows a means for preparing hydroxamic acid compounds within the 
scope of the invention. Carboxylic acids are readily coupled to the resin 
using procedures similar to those used in solid phase peptide synthesis. 
Thus, EDCl efficiently couples a carboxylic acid of formula Ib, for 
example wherein R.sub.1 and R.sub.2 are hydrogen, dissolved in DMF to the 
resin. The resulting O-resin bound -hydroxamic acid is then released from 
the solid support by reaction with 10% TFA in DCM for ten minutes. The 
Rink handle (H. Rink, Tet. Lett., 28, 3787-3790, 1987) has the advantage 
of being cleaved under mild acidolysis for short periods of time (i.e. 10% 
TFA in DCM for 10-15 minutes). 
##STR43## 
However, due to the cost of the resin it is desirable to synthesize the 
corresponding functional resin on the Wang solid support ((a) S. S. Wang, 
J. Am. Chem. Soc., 95, 1328 (1973); b) G. Lu, S. Mojsov, J. P. Tam, and R. 
B. Merrifield, J. Org. Chem., 46, 3433 (1981)). 
Scheme AF shows a means for preparing Ar moiety starting material useful in 
the Schemes herein. 
##STR44## 
The compounds of the present invention are useful in the form of the free 
base or acid or in the form of a pharmaceutically acceptable salt thereof. 
All forms are within the scope of the invention. 
Where the compound of the present invention is substituted with a basic 
moiety, acid addition salts are formed and are simply a more convenient 
form for use; and in practice, use of the salt form inherently amounts to 
use of the free base form. The acids which can be used to prepare the acid 
addition salts include preferably those which produce, when combined with 
the free base, pharmaceutically acceptable salts, that is, salts whose 
anions are non-toxic to the patient in pharmaceutical doses of the salts, 
so that the beneficial inhibitory effects on TNF inherent in the free base 
are not vitiated by side effects ascribable to the anions. Although 
pharmaceutically acceptable salts of said basic compounds are preferred, 
all acid addition salts are useful as sources of the free base form even 
if the particular salt, per se, is desired only as an intermediate product 
as, for example, when the salt is formed only for purposes of 
purification, and identification, or when it is used as intermediate in 
preparing a pharmaceutically acceptable salt by ion exchange procedures. 
Pharmaceutically acceptable salts within the scope of the invention are 
those derived from the following acids: mineral acids such as hydrochloric 
acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids 
such as acetic acid, citric acid, lactic acid, tartaric acid, malonic 
acid, methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid, 
p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the 
like. The corresponding acid addition salts comprise the following: 
hydrohalides, e.g. hydrochloride and hydrobromide, sulfate, phosphate, 
nitrate, sulfamate, acetate, citrate, lactate, tartarate, malonate, 
oxalate, salicylate, propionate, succinate, fumarate, maleate, 
methylene-bis-.beta.-hydroxynaphthoates, gentisates, mesylates, 
isethionates and di-p-toluoyltartratesmethanesulfonate, ethanesulfonate, 
benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, 
respectively. 
According to a further feature of the invention, acid addition salts of the 
compounds of this invention are prepared by reaction of the free base with 
the appropriate acid, by the application or adaptation of known methods. 
For example, the acid addition salts of the compounds of this invention 
are prepared either by dissolving the free base in aqueous or 
aqueous-alcohol solution or other suitable solvents containing the 
appropriate acid and isolating the salt by evaporating the solution, or by 
reacting the free base and acid in an organic solvent, in which case the 
salt separates directly or can be obtained by concentration of the 
solution. 
The acid addition salts of the compounds of this invention can be 
regenerated from the salts by the application or adaptation of known 
methods. For example, parent compounds of the invention can be regenerated 
from their acid addition salts by treatment with an alkali, e.g. aqueous 
sodium bicarbonate solution or aqueous ammonia solution. 
Where the compound of the invention is substituted with an acidic moiety, 
base addition salts may be formed and are simply a more convenient form 
for use; and in practice, use of the salt form inherently amounts to use 
of the free acid form. The bases which can be used to prepare the base 
addition salts include preferably those which produce, when combined with 
the free acid, pharmaceutically acceptable salts, that is, salts whose 
cations are non-toxic to the animal organism in pharmaceutical doses of 
the salts, so that the beneficial inhibitory effects on TNF inherent in 
the free acid are not vitiated by side effects ascribable to the cations. 
Pharmaceutically acceptable salts, including for example alkali and 
alkaline earth metal salts, within the scope of the invention are those 
derived from the following bases: sodium hydride, sodium hydroxide, 
potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium 
hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, trimethylammonia, 
triethylammonia, ethylenediamine, n-methyl-glucamine, lysine, arginine, 
ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, 
diethanolamine, procaine, n-benzylphenethylamine, diethylamine, 
piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium 
hydroxide, and the like. 
Metal salts of compounds of the present invention may be obtained by 
contacting a hydride, hydroxide, carbonate or similar reactive compound of 
the chosen metal in an aqueous or organic solvent with the free acid form 
of the compound. The aqueous solvent employed may be water or it may be a 
mixture of water with an organic solvent, preferably an alcohol such as 
methanol or ethanol, a ketone such as acetone, an aliphatic ether such as 
tetrahydrofuran, or an ester such as ethyl acetate. Such reactions are 
normally conducted at ambient temperature but they may, if desired, be 
conducted with heating. 
Amine salts of compounds of the present invention may be obtained by 
contacting an amine in an aqueous or organic solvent with the free acid 
form of the compound. Suitable aqueous solvents include water and mixtures 
of water with alcohols such as methanol or ethanol, ethers such as 
tetrahydrofuran, nitriles such as acetonitrile, or ketones such as 
acetone. Amino acid salts may be similarly prepared. 
The base addition salts of the compounds of this invention can be 
regenerated from the salts by the application or adaptation of known 
methods. For example, parent compounds of the invention can be regenerated 
from their base addition salts by treatment with an acid, e.g. 
hydrochloric acid. 
As well as being useful in themselves as active compounds, salts of 
compounds of the invention are useful for the purposes of purification of 
the compounds, for example by exploitation of the solubility differences 
between the salts and the parent compounds, side products and/or starting 
materials by techniques well known to those skilled in the art. 
Compounds of the present invention may contain asymmetric centers. These 
asymmetric centers may independently be in either the R or S 
configuration. It will also be apparent to those skilled in the art that 
certain compounds of formula I may exhibit geometrical isomerism. 
Geometrical isomers include the cis and trans forms of compounds of the 
invention having alkenyl moieties. The present invention comprises the 
individual geometrical isomers and stereoisomers and mixtures thereof. 
Such isomers can be separated from their mixtures, by the application or 
adaptation of known methods, for example chromatographic techniques and 
recrystallization techniques, or they are separately prepared from the 
appropriate isomers of their intermediates, for example by the application 
or adaptation of methods described herein. 
The starting materials and intermediates are prepared by the application or 
adaptation of known methods, for example methods as described in the 
Reference Examples or their obvious chemical equivalents, or by methods 
described according to the invention herein. 
The present invention is further exemplified but not limited by the 
following illustrative examples which illustrate the preparation of the 
compounds according to the invention. 
In the nuclear magnetic resonance spectra (NMR) the chemical shifts are 
expressed in ppm relative to tetramethylsilane. Abbreviations have the 
following significance: s=singlet; d=doublet; t=triplet; m=multiplet; 
dd=doublet of doublets; ddd=doublet of doublets of doublets; dt=doublet of 
triplets, b=broad.