The invention provides compounds which are useful as inhibitors of metalloproteases, and which are effective in treating conditions characterized by excess activity of these enzymes. In particular, the present invention relates to a compound having a structure according to Formula (I) ##STR1## as described in the claims, or an optical isomer, diastereomer or enantiomer thereof, or a pharmaceutically-acceptable salt, or biohydrolyzable alkoxyamide, ester, acyloxyamide, or imide thereof. Also disclosed are compounds, pharmaceutical compositions and methods of treating diseases characterized by metalloprotease activity using these compounds or the pharmaceutical compositions containing them.

TECHNICAL FIELD 
This invention is directed to compounds which are useful in treating 
diseases, disorders and conditions associated with unwanted 
metalloprotease activity. 
BACKGROUND 
A number of structurally related metalloproteases [MPs] effect the 
breakdown of structural proteins. These metalloproteases often act on the 
intercellular matrix, and thus are involved in tissue breakdown and 
remodeling. Such proteins are referred to as metalloproteases or MPs. 
There are several different families of MPs, classified by sequence 
homology. Several families of known MPs, as well as examples thereof, are 
disclosed in the art. 
These MPs include Matrix-Metallo Proteases [MMPs], zinc metalloproteases, 
many of the membrane bound metalloproteases, TNF converting enzymes, 
angiotensin-converting enzymes (ACEs), disintegrins, including ADAMs (See 
Wolfsberg et al, 131 J. Cell Bio. 275-78 October, 1995), and the 
enkephalinases. Examples of MPs include human skin fibroblast collagenase, 
human skin fibroblast gelatinase, human sputum collagenase, aggrecanse and 
gelatinase, and human stromelysin. Collagenase, stromelysin, aggrecanase 
and related enzymes are thought to be important in mediating the 
symptomatology of a number of diseases. 
Potential therapeutic indications of MP inhibitors have been discussed in 
the literature. See for example, U.S. Pat. No. 5,506,242 (Ciba Geigy 
Corp.); U.S. Pat. No. 5,403,952 (Merck & Co.); PCT published application 
WO 96/06074 (British Bio Tech Ltd); PCT Publication WO 96/00214 (Ciba 
Geigy); WO 95/35275 (British Bio Tech Ltd); WO 95/35276 (British Bio Tech 
Ltd); WO 95/33731 (Hoffinan-LaRoche); WO 95/33709 (Hoffman-LaRoche); WO 
95/32944 (British Bio Tech Ltd); WO 95/26989 (Merck); WO 9529892 (DuPont 
Merck); WO 95/24921 (Inst. Opthamology); WO 95/23790 (SmithKline Beecham); 
WO 95/22966 (Sanofi Winthrop); WO 95/19965 (Glycomed); WO 95 19956 
(British Bio Tech Ltd); WO 95/19957 (British Bio Tech Ltd); WO 95/19961 
(British Bio Tech Ltd) WO 95/13289 (Chiroscience Ltd.); WO 95/12603 
(Syntex); WO 95/09633 (Florida State Univ); WO 95/09620 (Florida State 
Univ.); WO 95/04033 (Celltech); WO 94/25434 (Celltech); WO 94/25435 
(Celltech); WO 93/14112 (Merck); WO 94/0019 (Glaxo); WO 93/21942 (British 
Bio Tech Ltd); WO 92/22523 (Res. Corp. Tech. Inc.); WO 94/10990 (British 
Bio Tech Ltd); WO 93/09090 (Yamanouchi); and British patents GB 2282598 
(Merck) and GB 2268934 (British Bio Tech Ltd); 
Published European Patent Applications EP 95/684240 (Hoffman LaRoche); EP 
574758 (Hoffman LaRoche); EP 575844 (Hoffinan LaRoche); Published Japanese 
applications; JP 08053403 (Fujusowa Pharm. Co. Ltd.); JP 7304770 (Kanebo 
Ltd.); and Bird et al J. Med Chem vol. 37, pp. 158-69 (1994). Examples of 
potential therapeutic uses of MP inhibitors include rheumatoid arthritis 
(Mullins, D. E., et al., Biochim. Biophys. Acta. (1983) 695:117-214); 
osteoarthritis (Henderson, B., et al., Drugs of the Future (1990) 
15:495-508); the metastasis of tumor cells (ibid, Broadhurst, M. J., et 
al., European Patent Application 276,436 (published 1987), Reich, R., et 
al., 48 Cancer Res. 3307-3312 (1988); and various ulcerations or 
ulcerative conditions of tissue. For example, ulcerative conditions can 
result in the cornea as the result of alkali bums or as a result of 
infection by Pseudomonas aeruginosa, Acanthamoeba, Herpes simplex and 
vaccinia viruses. 
Other examples of conditions characterized by undesired metalloprotease 
activity include periodontal disease, epidermolysis bullosa, fever, 
inflammation and scleritis (Cf. DeCicco et al, WO 95 29892 published Nov. 
9, 1995). 
In view of the involvement of such metalloproteases in a number of disease 
conditions, attempts have been made to prepare inhibitors to these 
enzymes. A number of such inhibitors are disclosed in the literature. 
Examples include U.S. Pat. No. 5,183,900, issued Feb. 2, 1993 to Galardy; 
U.S. Pat. No. 4,996,358, issued Feb. 26, 1991 to Handa, et al.; U.S. Pat. 
No. 4,771,038, issued Sep. 13, 1988 to Wolanin, et al.; U.S. Pat. No. 
4,743,587, issued May 10, 1988 to Dickens, et al., European Patent 
Publication Number 575,844, published Dec. 29, 1993 by Broadhurst, et al.; 
International Patent Publication No. WO 93/09090, published May 13, 1993 
by Isomura, et al.; World Patent Publication 92/17460, published Oct. 15, 
1992 by Markwell et al.; and European Patent Publication Number 498,665, 
published Aug. 12, 1992 by Beckett, et al. 
Metalloprotease inhibitors are useful in treating diseases caused, at least 
in part, by breakdown of structural proteins. Though a variety of 
inhibitors have been prepared, there is a continuing need for potent 
metalloprotease inhibitors useful in treating such diseases. Applicants 
have found that the compoundss of the present invention are potent 
metalloprotease inhibitors. 
OBJECTS OF THE INVENTION 
Thus it is an object of the present invention to provide compounds useful 
for the treatment of conditions and diseases which are characterized by 
unwanted MP activity. 
It is also an object of the invention to provide potent inhibitors of 
metalloproteases. 
It is a further object of the invention to provide pharmaceutical 
compositions comprising such inhibitors. 
It is also an object of the invention to provide a method of treatment for 
metalloprotease related maladies. 
SUMMARY OF THE INVENTION 
The invention provides compounds which are useful as inhibitors of 
metalloproteases, and which are effective in treating conditions 
characterized by excess activity of these enzymes. In particular, the 
present invention relates to a compound having a structure according to 
Formula (I) 
##STR2## 
wherein n is an integer from 1 to 3, and 0 to 2 additional heteroatoms, 
chosen from O, N, or S may occur in the backbone of the ring in the place 
of carbon, and where S occurs it may be in the form S, SO, or SO.sub.2 and 
where N occurs it is in the form NR.sub.5 and R.sub.5 is chosen from 
hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO.sub.2 R.sub.10, 
COR.sub.11, CSR.sub.12, PO(R.sub.13).sub.2 ; 
Z is independently one or more of (CH.sub.2).sub.m (CR.sub.1 R.sub.2).sub.o 
SR.sub.3 ; and 
R.sub.1 is independently hydrogen, alkyl, CH.sub.2 SR.sub.3 or CH.sub.2 
C(W)R.sub.4, and R.sub.4 is alkoxy, hydroxy, NR.sub.5, alkylthio, or thio; 
and R.sub.5 is independently one or more of heterocyclylalkyl, alkyl, 
aryl, heteroalkyl, heteraryl, hydrogen or ma with W form a heterocyclic 
ring; 
R.sub.2 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, 
heterocycloalkylene, aryl or heteroaryl, 
W is O or S, 
R.sub.3 is hydrogen, alkyl, aryl, heteroaryl; 
and m and o are integers, independently chosen from 0, 1 and 2; 
Y is independently one or more of hydrogen, hydroxy, oxo, a spiro moiety, 
SOR.sub.6, SO.sub.2 R.sub.10, alkoxy, aryloxy, alkyl aryl, heteroaryl, 
COR.sub.22 CSR.sub.12, amino, wherein amino is of formula 
NR.sub.8,R.sub.9, wherein R.sub.8 and R.sub.9 are independently chosen 
from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, OR.sub.3, SO.sub.2 
R.sub.10, COR.sub.11, CSR.sub.12, PO(R.sub.13).sub.2 ; and 
R.sub.6 is alkyl, aryl, heteroaryl; 
R.sub.10 is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, 
dialkylamino, arylamino, diarylamino and alkylarylamino; 
R.sub.11 is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, 
heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino and 
alkylarylamino; 
R.sub.12 is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, 
dialkylamino, arylamino, diarylamino and alkylarylamino; 
R.sub.13 is alkyl, aryl, heteroaryl, heteroalkyl; 
Ar is substituted or unsubstituted; alkyl, aryl, carbocyclyl, heterocyclyl, 
or heteroaryl; 
This structure also includes an optical isomer, diastereomer or enantiomer 
for Formula (I), or a pharmaceutically-acceptable salt, or biohydrolyzable 
alkoxyamide, ester, acyloxyamide, or imide thereof. 
These compounds have the ability to inhibit at least one mammalian matrix 
metalloprotease. Accordingly, in other aspects, the invention is directed 
to pharmaceutical compositions containing the compounds of Formula (I), 
and to methods of treating diseases characterized by metalloprotease 
activity using these compounds or the pharmaceutical compositions 
containing them. 
Metalloproteases active at a particularly undesired location (e.g., an 
organ or certain types of cells) can be targeted by conjugating the 
compounds of the invention to a targeting ligand specific for a marker at 
that location such as an antibody or fragment thereof or a receptor 
ligand. Conjugation methods are known in the art. 
The invention is also directed to various other processes which take 
advantage of the unique properties of these compounds. Thus, in another 
aspect, the invention is directed to the compounds of Formula (I) 
conjugated to solid supports. These conjugates can be used as affinity 
reagents for the purification of a desired metalloprotease. 
In another aspect, the invention is directed to the compounds of Formula 
(I) conjugated to label. As the compounds of the invention bind to at 
least one metalloprotease, the label can be used to detect the presence of 
relatively high levels of metalloprotease in vivo or in vitro cell 
culture. 
In addition, the compounds of Formula (I) can be conjugated to carriers 
which permit the use of these compounds in immunization protocols to 
prepare antibodies specifically immunoreactive with the compounds of the 
invention. Typical conjugation methods are known in the art. These 
antibodies are then useful both in therapy and in monitoring the dosage of 
the inhibitors. 
DETAILED DESCRIPTION 
The compounds of the present invention are inhibitors of mammalian 
metalloproteases. Preferably, the compounds are those of Formula (I) or a 
pharmaceutically-acceptable salt, or biohydrolyzable alkoxyamide, 
acyloxyamide, or imide thereof. 
Definitions and Usage of Terms: 
The following is a list of definitions for terms used herein. 
"Acyl" or "carbonyl" is described as a radical which could be formed by 
removal of the hydroxy from a carboxylic acid (i.e., R--C(.dbd.O)--). 
Preferred acyl groups include (for example) acetyl, formyl, and propionyl. 
"Acyloxy" is an oxy radical having an acyl substituent (i.e., --O--acyl); 
for example,--O--C(.dbd.O)-alkyl. 
"Alkoxyacyl" is an acyl radical (--C(.dbd.O)--) having an alkoxy 
substituent (i.e., --O--R), for example, --C(.dbd.O)--O-alkyl. This 
radical can be referred to as an ester. 
"Acylamino" is an amino radical having an acyl substituent (i.e., 
--N-acyl); for example, --NH--C(.dbd.O)-alkyl. 
"Alkenyl" is an unsubstituted or substituted hydrocarbon chain radical 
having 2 to 15 carbon atoms; preferably from 2 to 10 carbon atoms; more 
preferably from 2 to 8; except where indicated. Alkenyl substituents have 
at least one olefinic double bond (including, for example, vinyl, allyl 
and butenyl). 
"Alkynyl" is an unsubstituted or substituted hydrocarbon chain radical 
having 2 to 15 carbon atoms; preferably from 2 to 10 carbon atoms; more 
preferably from 2 to 8; except where indicated. The chain has at least one 
carbon-carbon triple bond. 
"Alkoxy" is an oxygen radical having a hydrocarbon chain substituent, where 
the hydrocarbon chain is an alkyl or alkenyl (i.e., --O-alkyl or 
--O-alkenyl). Preferred alkoxy groups include (for example) methoxy, 
ethoxy, propoxy and allyloxy. 
"Alkoxyalkyl" is an unsubstituted or substituted alkyl moiety substituted 
with an alkoxy moiety (i.e., -alkyl-O-alkyl). Preferred is where the alkyl 
has 1 to 6 carbon atoms (more preferably 1 to 3 carbon atoms), and the 
alkyoxy has 1 to 6 carbon atoms (more preferably 1 to 3 carbon atoms). 
"Alkyl" is an unsubstituted or substituted saturated hydrocarbon chain 
radical having 1 to 15 carbon atoms; preferably from 1 to 10 carbon atoms; 
more preferably 1 to 4; except where indicated. Preferred alkyl groups 
include (for example) substituted or unsubstituted methyl, ethyl, propyl, 
isopropyl, and butyl. 
As referred to herein, "spiro cycle" or "spiro cyclic" refers to a cyclic 
moiety sharing a carbon on another ring. Such cyclic moiety may be 
carbocyclic or heterocyclic in nature. Preferred heteroatoms included in 
the backbone of the heterocyclic spirocycle include oxygen, nitrogen and 
sulfur. The spiro cycles may be unsubstituted or substituted. Preferred 
substituents include oxo, hydroxy, alkyl, cycloalkyl, arylalkyl, alkoxy, 
amino, heteroalkyl, aryloxy, fused rings (e.g., benzothiole, cycloalkyl, 
heterocycloalkyl, benzimidizoles, pyridylthiole, etc., which may also be 
substituted) and the like. In addition, the heteroatom of the heterocycle 
may be substituted if valence allows. Preferred spirocyclic ring sizes 
include 3-7 membered rings. 
Alkylene refers to an alkyl, alkenyl or alkynyl which is diradical, rather 
than a radical. "Hetero alkylene" is likewise defined as a (diradical) 
alkylene having a heteroatom in its chain. 
"Alkylamino" is an amino radical having one (secondary amine) or two 
(tertiary amine) alkyl substituents (i.e., --N-alkyl). For example, 
methylamino (--NHCH.sub.3), dimethylamino (--N(CH.sub.3).sub.2), 
methylethylamino (--N(CH.sub.3)CH.sub.2 CH.sub.3). 
"Aminoacyl" is acyl radical having an amino substituent (i.e., 
--C(.dbd.O)--N); for example, --C(.dbd.O)--NH.sub.2. The amino group of 
the aminoacyl moiety may be unsubstituted (i.e., primary amine) or may be 
substituted with one (secondary amine) or two (i.e., tertiary amine) alkyl 
groups. 
"Aryl" is an aromatic carbocyclic ring radical. Preferred aryl groups 
include (for example) phenyl, tolyl, xylyl, cumenyl, naphthyl, biphenyl 
and fluorenyl. Such groups may be substituted or unsubstituted. 
"Arylalkyl" is an alkyl radical substituted with an aryl group. Preferred 
arylalkyl groups include benzyl, phenylethyl, and phenylpropyl. Such 
groups may be substituted or unsubstituted. "Arylalkylamino" is an amine 
radical substituted with an arylalkyl group (e.g., --NH-benzyl). Such 
groups may be substituted or unsubstituted. 
"Arylamino" is an amine radical substituted with an aryl group (i.e., 
--NH-aryl). Such groups may be substituted or unsubstituted. 
"Aryloxy" is an oxygen radical having an aryl substituent (i.e., --O-aryl). 
Such groups may be substituted or unsubstituted. 
"Carbocyclic ring" is an unsubstituted or substituted, saturated, 
unsaturated or aromatic, hydrocarbon ring radical. Carbocyclic rings are 
monocyclic or are fused, bridged or spiro polycyclic ring systems. 
Monocyclic carbocyclic rings generally contain 4 to 9 atoms, preferably 4 
to 7 atoms. Polycyclic carbocyclic rings contain 7 to 17 atoms, preferably 
from 7 to 12 atoms. Preferred polycyclic systems comprise 4-, 5-, 6- or 
7-membered rings fused to 5-, 6-, or 7-membered rings. 
"Carbocycle-alkyl" is an unsubstituted or substituted alkyl radical 
substituted with a carbocyclic ring. Unless otherwise specified, the 
carbocyclic ring is preferably an aryl or cycloalkyl; more preferably an 
aryl. Preferred carbocycle-alkyl groups include benzyl, phenylethyl and 
phenylpropyl. 
"Carbocycle-heteroalkyl" is an unsubstituted or substituted heteroalkyl 
radical substituted with a carbocyclic ring. Unless otherwise specified, 
the carbocyclic ring is preferably an aryl or cycloalkyl; more preferably 
an aryl. The heteroalkyl is preferably 2-oxa-propyl, 2-oxa-ethyl, 
2-thia-propyl, or 2-thia-ethyl. 
"Carboxyalkyl" is an unsubstituted or substituted alkyl radical substituted 
with a carboxy (--C(.dbd.O)OH) moiety. For example, --CH.sub.2 
--C(.dbd.O)OH. 
"Cycloalkyl" is a saturated carbocyclic ring radical. Preferred cycloalkyl 
groups include (for example) cyclopropyl, cyclobutyl and cyclohexyl. 
"Cycloheteroalkyl" is a saturated heterocyclic ring. Preferred 
cycloheteroalkyl groups include (for example) morpholinyl, piperadinyl, 
piperazinyl, tetrahydrofuryl and hydantoinyl. 
"Fused rings" are rings that are superimposed together such that they share 
two ring atoms. A given ring may be fused to more than one other ring. 
Fused rings are contemplated in heteroaryl, aryl and heterocycle radicals 
or the like. 
"Heterocycle-alkyl" is an alkyl radical substituted with a heterocyclic 
ring. The heterocyclic ring is preferably a heteroaryl or 
cycloheteroalkyl; more preferably a heteroaryl. Preferred heterocycle 
alkyl include C.sub.1 -C.sub.4 alkyl having preferred heteroaryl appended 
to them. More preferred is, for example, pyridyl alkyl, and the like. 
"Heterocycle-heteroalkyl" is an unsubstituted or substituted heteroalkyl 
radical substituted with a heterocyclic ring. The heterocyclic ring is 
preferably an aryl or cycloheteroalkyl; more preferably an aryl. 
"Heteroatom" is a nitrogen, sulfur or oxygen atom. Groups containing one or 
more heteroatoms may contain different heteroatoms. 
"Heteroalkenyl" is an unsubstituted or substituted unsaturated chain 
radical having 3 to 8 members comprising carbon atoms and one or two 
heteroatoms. The chain has at least one carbon-carbon double bond. 
"Heteroalkyl" is an unsubstituted or substituted saturated chain radical 
having 2 to 8 members comprising carbon atoms and one or two heteroatoms. 
"Heterocyclic ring" is an unsubstituted or substituted, saturated, 
unsaturated or aromatic ring radical comprised of carbon atoms and one or 
more heteroatoms in the ring. Heterocyclic rings are monocyclic or are 
fused, bridged, spiro or polycyclic ring systems. Monocyclic heterocyclic 
rings contain 3 to 9 atoms, preferably 4 to 7 atoms. Polycyclic rings 
contain 7 to 17 atoms, preferably from 7 to 13 atoms. 
"Heteroaryl" is an aromatic heterocyclic ring, either monocyclic or 
bicyclic radical. Preferred heteroaryl groups include (for example) 
thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, 
quinolinyl, and tetrazolyl, benzo thiazolyl, benzofuryl, indolyl and the 
like. Such groups may be substituted or unsubstituted. 
"Halo", "halogen", or "halide" is a chloro, bromo, fluoro or iodo atom 
radical, bromo, chloro and fluoro are preferred halides. 
Also, as referred to herein, a "lower" hydrocarbon moiety (e.g., "lower" 
alkyl) is a hydrocarbon chain comprised of 1 to 6, preferably from 1 to 4, 
carbon atoms. 
Also, as referred to herein, a "lower" hydrocarbon moiety (e.g., "lower" 
alkyl) is a hydrocarbon chain comprised of 1 to 6, preferably from 1 to 4, 
carbon atoms. 
As used herein the term "parent ring system" or "parent ring" refers to the 
ring system that forms the core of the structure described in the Summary 
of the Invention; 
##STR3## 
This ring system is of from about 5 to about 7 members and many contain 
from 0-2 additional heteroatoms chosen from O, S, or N, providing for 
rings such as morpholine, diazepine, piperidine, thiamorpholine,, and the 
like. The position of the heteroatom is limited by those ring which are 
known in the art. 
A "pharmaceutically-acceptable salt" is a cationic salt formed at any 
acidic (e.g., carboxyl) group, or an anionic salt formed at any basic 
(e.g., amino) group. Many such salts are known in the art, as described in 
World Patent Publication 87/05297, Johnston et al., published Sep. 11, 
1987 (incorporated by reference herein). Preferred cationic salts include 
the alkali metal salts (such as sodium and potassium), and alkaline earth 
metal salts (such as magnesium and calcium) and organic salts. Preferred 
anionic salts include the halides (such as chloride salts). 
"Biohydrolyzable alkoxyamide" and "Biohydrolyzable acyloxyamide" are amides 
of a hydroxamic acid that do not essentially interfere with the inhibitory 
activity of the compound, or that are readily converted in vivo by a human 
or lower animal subject to yield an active hydroxamic acid. 
A "biohydrolyzable hydroxy imide" is an imide of a Formula (I) compound 
that does not interfere with the metalloprotease inhibitory activity of 
these compounds, or that is readily converted in vivo by a human or lower 
animal subject to yield an active Formula (I) compound. Such hydroxy 
imides include those that do not interfere with the biological activity of 
the Formula (I) compounds. 
A "biohydrolyzable ester" refers to an ester of a Formula (I) compound that 
does not interfere with the metalloprotease inhibitory activity of these 
compounds or that is readily converted by an animal to yield an active 
Formula (I) compound. 
A "solvate" is a complex formed by the combination of a solute (e.g., a 
hydroxamic acid) and a solvent (e.g., water). See J. Honig et al., The Van 
Nostrand Chemist's Dictionary, p. 650 (1953). Pharmaceutically-acceptable 
solvents used according to this invention include those that do not 
interfere with the biological activity of the hydroxamic acid (e.g., 
water, ethanol, acetic acid, N,N-dimethylformamide and others known or 
readily determined by the skilled artisan). 
"Optical isomer", "stereoisomer", "diastereomer" as referred to herein have 
the standard art recognized meanings (Cf., Hawley's Condensed Chemical 
Dictionary, 11th Ed.). 
The illustration of specific protected forms and other derivatives of the 
Formula (I) compounds is not intended to be limiting. The application of 
other useful protecting groups, salt forms, etc. is within the ability of 
the skilled artisan. 
As defined above and as used herein, substituent groups may themselves be 
substituted. Such substitution may be with one or more substituents. Such 
substituents include those listed in C. Hansch and A. Leo, Substituent 
Constants for Correlation Analysis in Chemistry and Biology (1979), 
incorporated by reference herein. Preferred substituents include (for 
example) alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl 
(e.g., aminomethyl, etc.), cyano, halo, carboxy, alkoxyacyl (e.g., 
carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl 
(e.g., piperidinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo, 
hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof. 
As used herein, "mammalian metalloprotease" means any metal-containing 
enzyme found in mammalian sources which is capable of catalyzing the 
breakdown of collagen, gelatin or proteoglycan under suitable assay 
conditions. Appropriate assay conditions can be found, for example, in 
U.S. Pat. No. 4,743,587, which references the procedure of Cawston, et 
al., Anal Biochem (1979) 99:340-345, use of a synthetic substrate is 
described by Weingarten, H., et al., Biochem. Biophy. Res. Comm. (1984) 
139:1184-1187. Any standard method for analyzing the breakdown of these 
structural proteins can, of course, be used. The metalloprotease enzymes 
referred to herein are all zinc-containing proteases which are similar in 
structure to, for example, human stromelysin or skin fibroblast 
collagenase. The ability of candidate compounds to inhibit metalloprotease 
activity can, of course, be tested in the assays described above. Isolated 
metalloprotease enzymes can be used to confirm the inhibiting activity of 
the invention compounds, or crude extracts which contain the range of 
enzymes capable of tissue breakdown can be used. 
Compounds: 
Compounds of the invention include, 
##STR4## 
as described in the Summary of the Invention, above. One class of 
preferred compounds are of formula; 
##STR5## 
as described above. Of this class, preferred Z includes compounds of 
formula; 
##STR6## 
Preferably R.sub.3 is hydrogen and n is 1 or 2. Where R.sub.4 appears, 
preferably R.sub.4 is alkoxy. 
Another preferred class of compounds include those of formula 
##STR7## 
Where Z is SR.sub.3 
More preferred compounds have two Z moieties at the preferred positions 
shown above. 
Compound Preparation: 
The compounds of Formula (I) can be prepared using a variety of procedures. 
For clarity, Y is not shown. A preferred method of making the compounds of 
formula I is illustrated by the scheme below; 
##STR8## 
Of course, one of the examples of a Z moiety is exemplified here, but 
others may be made using known methodologies. It is preferred that the 
thiol moiety is introduced later in the synthesis for reason that are 
apparent to the skilled artisan. 
In the scheme above, preferably a piperidine, azepine, diazepine, proline 
or like compound (A) is converted to the sulfonamide by standard methods 
to produce (B) which may optionally be converted to an aldehyde (C) and 
transformed to the a-p unsaturated carbonyl compound (D). This unsaturated 
compound is thiolated using standard methods to produce a compound of 
Formula I (E). 
Of course, Y may be present in (A), masked in (A) or introduced at the 
appropriate time during synthesis. The order of synthesis, reagents used 
and methodologies employed may be varied or may deviate from the scheme 
above. 
For example Y can be introduced via a derivatizable group which can be 
manipulated or substituted. Such compounds are known or are prepared by 
known methods. For example, when R is OH, and n is 1, hydroxyproline (A) 
is converted to its analogous sulfonamide and the hydroxyl is then 
manipulated to give (B) during this or a subsequent step Y can be added or 
altered. It is expected that the skilled artisan will employ protecting 
groups or any other moieties the skilled artisan prefers, provided that 
ultimately the method provides the compounds of the invention. A variety 
of compounds can be generated in a similar fashion, using the guidance of 
the scheme above. 
It is recognized that it is preferable to use a protecting group for any 
reactive functionality such as a carboxyl, hydroxyl and the like, during 
the formation of the sulfonamide. This is standard practice, well within 
the normal practice of the skilled artisan. For example, in the above 
schemes, alkoxy or alkylthio, yield the corresponding hydroxy or thiol 
compounds by using a standard dealkylating procedure (Bhatt, et al., 
"Cleavage of Ethers", Synthesis, 1983, pp. 249-281). 
Preparation of the Y Moiety 
For the manipulation of Y it is understood that the skilled artisan may 
choose to prepare Y before, after or concurrent with the preparation of Z. 
It is to be understood that more than one Y and Z may be present in the 
compounds of formula (I). 
A preferred method of introducing Y includes choosing a starting material 
with a derivatizable group which can be manipulated or substituted into Y. 
Such compounds are known or are prepared by known methods. Preferred 
derivatizable groups include hydroxy, alkoxy, oxo, ammo, thiol and many 
others immediately recognizable to the skilled artisan. The skilled 
artisan will appreciate that judicious choice of starting materials and 
reactions is essential to preparing any molecules, including those of the 
invention. For example, where Y is adjacent to the ring nitrogen, a 
preferred starting material for the preparation of Y includes a lactam, 
where the derivatizable group is oxo, adjacent to the nitrogen. 
Where Y is a ketal or thioketal (including spiroketals) the compounds of 
the invention may be prepared from the analogous oxo compound using 
standard protecting group methodologies. Of course, hydroxy, amino, imino, 
alkoxy, oxo or many other groups can be manipulated into a carbonyl 
compound. A preferred method of making the spiro compounds of the 
invention is via a carbonyl compound, using "protecting group" technology 
known in the art, such as a thioketal or ketal, and the like. Ketals, 
acetals and the like are prepared from carbonyl compounds by methods known 
in the art. Such carbonyl compounds can be made of cyclic hydroxy alkylene 
amines via oxidation to a ketone, or of lactams, which provide for 2-amino 
spiro functionality. The order of elaborating the ketal, Z or the 
sulfonamide may be reordered to optimize yield and avoid undesired 
reactions. 
A preferred method for making compounds of the invention with Y as a 
carbocycle or a heterocycle which does not employ ketal formation is shown 
below. In the scheme below Y is depicted as a carbocyclic spirocycle, but 
one or more heteratoms may be interspersed in the backbone of the 
spirocyclic ring. The omission of heteroatoms is meant to add clarity and 
to aid the reader. It is not meant to limit the claims: 
##STR9## 
R is any group that may give rise to Y or to Z. L is a leaving Group. COB 
is a group that can be manipulated into Z. Of course, one can elaborate Y, 
Z, the sulfonamide, and any other groups as previously illustrated or as 
will be apparent to the skilled artisan. 
Preparation of Heterocyclic Parent Ring Systems 
For the preparation and elaboration of the parent ring system as a 
heterocyclic ring it is understood that the skilled artisan may choose to 
prepare Y before, after or concurrent with the preparation of the 
heterocyclic ring. Of course, more than one Y and Z may be present in the 
compounds of formula (I). 
For the purposes of illustration, these parent ring systems include; 
##STR10## 
where X is independently chosen from NR.sub.5, S, SO, SO.sub.2, or O. Also 
contemplated in this invention are cyclic sulfonamides and the like. 
For compounds where X is NR.sub.5, the preferred method for the 
manipulation of R.sub.5 is shown. In the scheme below, L is any acceptable 
leaving group, and B is a blocking group as above, Boc is an example of a 
preferred, and art recognized blocking group. The skilled artisan will 
recognize that the choice of blocking group is within the skill of the 
artisan working in organic chemistry. Thus the choice of Boc is not 
required, but preferred. 
##STR11## 
For compounds containing a sulfur in the heterocyclic ring the preferred 
methods of ring formation are shown. For the preparation and elaboration 
of the heterocyclic ring it is understood that the skilled artisan may 
choose to prepare Y before, after or concurrent with the preparation of 
the heterocyclic ring. 
##STR12## 
Another acceptable strategy for making the invention having X as sulfur 
includes the following scheme. The method allows for formation of the 
sulfonamide and subsequent reaction with a bifunctional moiety. Preferably 
the OH described in the scheme below is a primary hydroxyl. Closure of the 
ring uses standard methods. Functionalization and elaboration of the 
molecule proceeds as described above. 
##STR13## 
Where X is sulfur, further elaboration of the heterocyclic ring can be 
accomplished after the ring has been formed. For example, oxidation of the 
ring sulfur atom using known methods can provide the corresponding 
sulfoxides and sulfones as shown. Upon oxidation of the ring sulfur, 
elaboration of the invention proceeds as described above. 
##STR14## 
For compounds containing an oxygen in the heterocyclic ring the preferred 
methods of ring formation are shown. A bifunctional moiety, for example a 
halo hydroxy species is reacted with an aziridine as shown below. The halo 
moiety serves as a leaving group, and may be any appropriate leaving 
group. Upon formation of the ring, elaboration of the invention proceeds 
as described above. 
##STR15## 
Preparation of the Z Moiety 
Of course the skilled artisan will recognize that some of the schemes 
applicable to the preparation of Y may be useful in the preparation of Z 
as noted above. Other preferred methods are provided for the reader. In 
the above schemes, alkoxy or alkylthio yield the corresponding hydroxy or 
thiol compounds by using a standard dealkylating procedures (Bhatt, et 
al., "Cleavage of Ethers", Synthesis, 1983, pp. 249-281). 
The ordering of steps may be varied to increase yield of desired product. 
The skilled artisan will also recognize the judicious choice of reactants, 
solvents, and temperatures is an important component in successful 
synthesis. While the determination of optimal conditions, etc. is routine, 
it will be understood that to make a variety of compounds can be generated 
in a similar fashion, using the guidance of the scheme above. 
The starting materials used in preparing the compounds of the invention are 
known, made by known methods, or are commercially available as a starting 
material. 
It is recognized that the skilled artisan in the art of organic chemistry 
can readily carry out standard manipulations of organic compounds without 
further direction; that is, it is well within the scope and practice of 
the skilled artisan to carry out such manipulations. These include, but 
are not limited to, reduction of carbonyl compounds to their corresponding 
alcohols, oxidations, acylations, aromatic substitutions, both 
electrophilic and nucleophilic, etherifications, esterification and 
saponification and the like. Examples of these manipulations are discussed 
in standard texts such as March, Advanced Organic Chemistry (Wiley), Carey 
and Sundberg, Advanced Organic Chemistry (Vol. 2) and other standard 
texts. 
The skilled artisan will readily appreciate that certain reactions are best 
carried out when other functionality is masked or protected in the 
molecule, thus avoiding any undesirable side reactions and/or increasing 
the yield of the reaction. Often the skilled artisan utilizes protecting 
groups to accomplish such increased yields or to avoid the undesired 
reactions. These reactions are found in the literature and are also well 
within the scope of the skilled artisan. Examples of many of these 
manipulations can be found for example in T. Greene, Protecting Groups in 
Organic Synthesis. Of course, amino acids used as starting materials with 
reactive side chains are preferably blocked to prevent undesired side 
reactions. 
The compounds of the invention may have one or more chiral centers. As a 
result, one may selectively prepare one optical isomer, including 
diastereomer and enantiomer, over another, for example by chiral starting 
materials, catalysts or solvents, or may prepare both stereoisomers or 
both optical isomers, including diastereomers and enantiomers at once (a 
racemic mixture). Since the compounds of the invention may exist as 
racemic mixtures, mixtures of optical isomers, including diastereomers and 
enantiomers, or stereoisomers may be separated using known methods, such 
as chiral salts, chiral chromatography and the like. 
In addition, it is recognized that one optical isomer, including 
diastereomer and enantiomer, or stereoisomer may have favorable properties 
over the other. Thus when disclosing and claiming the invention, when one 
racemic mixture is disclosed, it is clearly contemplated that both optical 
isomers, including diastereomers and enantiomers, or stereoisomers 
substantially free of the other are disclosed and claimed as well. 
Methods of use 
Metalloproteases (MPs) found in the body operate, in part, by breaking down 
the extracellular matrix, which comprises extracellular proteins and 
glycoproteins. These proteins and glycoproteins play an important role in 
maintaining the size, shape, structure and stability of tissue in the 
body. Inhibitors of metalloproteases are useful in treating diseases 
caused, at least in part, by breakdown of such proteins. It is known that 
MPs are intimately involved in tissue remodeling. As a result of this 
activity they have been said to be active in many disorders involving 
either the: 
breakdown of tissues; including degenerative diseases, such as arthritis, 
multiple sclerosis and the like; metastasis or mobility of tissues in the 
body: 
the remodeling of tissues, including fibrotic disease, scarring, benign 
hyperplasia, and the like. 
The compounds of the present invention treat disorders, diseases and/or 
unwanted conditions which are characterized by unwanted or elevated 
activity by that class of proteases. For example the compounds can be used 
to inhibit proteases which 
destroy structural proteins (i.e. the proteins that maintain tissue 
stability and structure); 
interfere in inter/intracellular signaling, including those implicated in 
cytokine up-regulation, and/or cytokine processing and/or inflammation, 
tissue degradation and other maladies [Mohler KM, et al, Nature 370 (1994) 
218-220, Gearing A J H, et al, Nature 370 (1994) 555-557 McGeehan GM, et 
al, Nature 370 (1994) 558-561], and/or 
facilitate processes which are undesired in the subject being treated, for 
example, the processes of sperm maturation, egg fertilization and the 
like. 
As used herein, a "MP related disorder" or "a MP related disease" is one 
that involves unwanted or elevated MP activity in the biological 
manifestation of the disease or disorder; in the biological cascade 
leading to the disorder; or as a symptom of the disorder. This 
"involvement" of the MP includes; 
The unwanted or elevated MP activity as a "cause" of the disorder or 
biological manifestation, whether the activity was elevated genetically, 
by infection, by autoimmunity, trauma, biomechanical causes, lifestyle 
[e.g. obesity] or by some other cause; 
The MP as part of the observable manifestation of the disease or disorder. 
That is, the disease or disorder is measurable in terms of the increased 
MP activity, or from a clinical standpoint, unwanted or elevated MP levels 
indicate the disease. MPs need not be the "hallmark" of the disease or 
disorder; 
The unwanted or elevated MP activity is part of the biochemical or cellular 
cascade that results or relates to the disease or disorder. In this 
respect, inhibition of the MP activity interrupts the cascade, and thus 
controls the disease. 
Advantageously, many MPs are not distributed evenly throughout the body. 
Thus the distribution of MPs expressed in various tissues are often 
specific to those tissues. For example, the distribution of 
metalloproteases implicated in the breakdown of tissues in the joints, is 
not the same as the distribution of metalloproteases found in other 
tissues. Thus, though not essential for activity or efficacy, certain 
disorders preferably are treated with compounds that act on specific MPs 
found in the affected tissues or regions of the body. For example, a 
compound which displays a higher degree of affinity and inhibition for a 
MP found in the joints (e.g. chondrocytes) would be preferred for 
treatment of disease found there than other compounds which are less 
specific. 
In addition, certain inhibitors are more bioavailable to certain tissues 
than others, and this judicious choice of inhibitor, with the selectivity 
described above provides for specific treatment of the disorder, disease 
or unwanted condition. For example, compounds of this invention vary in 
their ability to penetrate into the central nervous system. Thus compounds 
may be selected to produce effects mediated through MPs found specifically 
outside the central nervous system. 
Determination of the specificity of a MP inhibitor of a certain MP is 
within the skill of the artisan in that field. Appropriate assay 
conditions can be found in the literature. Specifically assays are known 
for stromelysin and collagenase. For example, U.S. Pat. No. 4,743,587 
references the procedure of Cawston, et al., Anal Biochem (1979) 
99:340-345. The use of a synthetic substrate in an assay is described by 
Weingarten, H., et al., Biochem Biophy Res Comm (1984) 139:1184-1187. Any 
standard method for analyzing the breakdown of structural proteins by MPs 
can, of course, be used. The ability of compounds of the invention to 
inhibit metalloprotease activity can, of course, be tested in the assays 
found in the literature, or variations thereof. Isolated metalloprotease 
enzymes can be used to confirm the inhibiting activity of the invention 
compounds, or crude extracts which contain the range of enzymes capable of 
tissue breakdown can be used. 
As a result of the MP inhibitory effect of the compounds of the invention, 
the compounds of the invention are also useful in treating the following 
disorders by virtue of their metalloprotease activity. 
The compounds of this invention are also useful for the prophylactic or 
acute treatment. They are administered in any way the skilled artisan in 
the fields of medicine or pharmacology would desire. It is immediately 
apparent to the skilled artisan that preferred routes of administration 
will depend upon the disease state being treated, and the dosage form 
chosen. Preferred routes for systemic administration include 
administration perorally or parenterally. 
However, the skilled artisan will readily appreciate the advantage of 
administering the MP inhibitor directly to the affected area for many 
disorders. For example, it may be advantageous to administer MP inhibitors 
directly to the area of the disease or condition as in area affected by 
surgical trauma (e.g., angioplasty), area affected by scarring or burn 
(e.g., topical to the skin), 
Because the remodeling of bone involves MPs, the compounds of the invention 
are useful in preventing prosthesis loosening. It is known in the art that 
over time prostheses loosen, become painful, and may result in further 
bone injury, thus demanding replacement. The need for replacement of such 
prostheses includes those such as in, joint replacements (for example hip, 
knee and shoulder replacements), dental prosthesis, including dentures, 
bridges and prosthesis secured to the maxilla and/or mandible. 
MPs are also active in remodeling of the cardiovascular system (for 
example, in congestive heart failure). It has been suggested that one of 
the reasons angioplasty has a higher than expected long term failure rate 
(reclosure over time) is that MP activity is not desired or is elevated in 
response to what may be recognized by the body as "injury" to the basement 
membrane of the vessel. Thus regulation of MP activity in indications such 
as dilated cardiomyopathy, congestive heart failure, atherosclerosis, 
plaque rupture, reperfusion injury, ischemia, chronic obstructive 
pulmonary disease, angioplasty restenosis and aortic aneurysm may increase 
long term success of any other treatment, or may be a treatment in itself. 
In skin care, MPs are implicated in the remodeling or "turnover" of skin. 
As a result, the regulation of MPs improves treatment of skin conditions 
including but not limited to, wrinkle repair, regulation and prevention 
and repair of ultraviolet induced skin damage. Such a treatment includes 
prophylactic treatment or treatment before the physiological 
manifestations are obvious. For example, the MP may be applied as a 
pre-exposure treatment to prevent ultraviolet damage and/or during or 
after exposure to prevent or minimize post-exposure damage. In addition, 
MPs are implicated in skin disorders and diseases related to abnormal 
tissues that result from abnormal turnover, which includes metalloprotease 
activity, such as epidermolysis bullosa, psoriasis, scleroderma and atopic 
dermatitis. The compounds of the invention are also useful for treating 
the consequences of "normal" injury to the skin including scarring or 
"contraction" of tissue, for example, following bums. MP inhibition is 
also useful in surgical procedures involving the skin for prevention of 
scarring, and promotion of normal tissue growth including in such 
applications as limb reattachment and refractory surgery (whether by laser 
or incision). 
In addition, MPs are related to disorders involving irregular remodeling of 
other tissues, such as bone, for example, in otosclerosis and/or 
osteoporosis, or for specific organs, such as in liver cirrhosis and 
fibrotic lung disease. Similarly in diseases such as multiple sclerosis, 
MPs may be involved in the irregular modeling of blood brain barrier 
and/or myelin sheaths of nervous tissue. Thus regulating MP activity may 
be used as a strategy in treating, preventing, and controlling such 
diseases. 
MPs are also thought to be involved in many infections, including 
cytomegalovirus; [CMV] retinitis; HIV, and the resulting syndrome, AIDS. 
MPs may also be involved in extra vascularization where surrounding tissue 
needs to be broken down to allow new blood vessels such as in angiofibroma 
and hemangioma. 
Since MPs break down the extracellular matrix, it is contemplated that 
inhibitors of these enzymes can be used as birth control agents, for 
example in preventing ovulation, in preventing penetration of the sperm 
into and through the extracellular milieu of the ovum, implantation of the 
fertilized ovum and in preventing sperm maturation. 
In addition they are also contemplated to be useful in preventing or 
stopping premature labor and delivery. 
Since MPs are implicated in the inflammatory response, and in the 
processing of cytokines the compounds are also useful as 
anti-inflammatories, for use in disease where inflammation is prevalent 
including, inflammatory bowel disease, Crohn's disease, ulcerative 
colitis, pancreatitis, diverticulitis, asthma or related lung disease, 
rheumatoid arthritis, gout and Reiter's Syndrome. 
Where autoimmunity is the cause of the disorder, the immune response often 
triggers MP and cytokine activity. Regulation of MPs in treating such 
autoimmune disorders is a useful treatment strategy. Thus MP inhibitors 
can be used for treating disorders including, lupus erythmatosis, 
ankylosing spondylitis, and autoimmune keratitis. Sometimes the side 
effects of autoimmune therapy result in exacerbation of other conditions 
mediated by MPs, here MP inhibitor therapy is effective as well, for 
example, in autoimmune-therapy-induced fibrosis. 
In addition, other fibrotic diseases lend themselves to this type of 
therapy, including pulmonary disease, bronchitis, emphysema, cystic 
fibrosis, acute respiratory distress syndrome (especially the acute phase 
response). 
Where MPs are implicated in the undesired breakdown of tissue by exogenous 
agents, these can be treated with MP inhibitors. For example, they are 
effective as rattle snake bite antidote, as anti-vessicants, in treating 
allergic inflammation, septicemia and shock. In addition, they are useful 
as antiparasitics (e.g., in malaria) and antiinfectives. For example, they 
are thought to be useful in treating or preventing viral infection, 
including infection which would result in herpes, "cold" (e.g., rhinoviral 
infection), meningitis, hepatitis, HIV infection and AIDS. 
MP inhibitors are also thought to be useful in treating Alzheimer's 
disease, amyotrophic lateral sclerosis (ALS), muscular dystrophy, 
complications resulting from or arising out of diabetes, especially those 
involving loss of tissue viability, coagulation, Graft vs. Host disease, 
leukemia, cachexia, anorexia, proteinuria, and perhaps regulation of hair 
growth. 
For some diseases, conditions or disorders MP inhibition is contemplated to 
be a preferred method of treatment. Such diseases, conditions or disorders 
include, arthritis (including osteoarthritis and rheumitoid arthritis), 
cancer (especially the prevention or arrest of tumor growth and 
metastasis), ocular disorders (especially corneal ulceration, lack of 
corneal healing, macular degeneration, and pterygium), and gum disease 
(especially periodontal disease, and gingivitis) 
Compounds preferred for, but not limited to, the treatment of arthritis 
(including osteoarthritis and rheumatoid arthritis) are those compounds 
that are selective for the metalloproteases and the disintegrin 
metalloproteases. 
Compounds preferred for, but not limited to, the treatment of cancer 
(especially the prevention or arrest of tumor growth and metastasis) are 
those compounds that preferentially inhibit gelatinases or type IV 
collagenases. 
Compounds preferred for, but not limited to, the treatment of ocular 
disorders (especially corneal ulceration, lack of corneal healing, macular 
degeneration, and pterygium) are those compounds that broadly inhibit 
metalloproteases. Preferably these compounds are administered topically, 
more preferably as a drop or gel. 
Compounds preferred for, but not limited to, the treatment of gum disease 
(especially periodontal disease, and gingivitis) are those compounds that 
preferentially inhibit collagenases. 
Compositions: 
The compositions of the invention comprise: 
(a) a safe and effective amount of a compound of Formula (I); and 
(b) a pharmaceutically-acceptable carrier. 
As discussed above, numerous diseases are known to be mediated by excess or 
undesired metalloprotease activity. These include tumor metastasis, 
osteoarthritis, rheumatoid arthritis, skin inflammation, ulcerations, 
particularly of the cornea, reaction to infection, periodontitis and the 
like. Thus, the compounds of the invention are useful in therapy with 
regard to conditions involving this unwanted activity. 
The invention compounds can therefore be formulated into pharmaceutical 
compositions for use in treatment or prophylaxis of these conditions. 
Standard pharmaceutical formulation techniques are used, such as those 
disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Company, 
Easton, Pa., latest edition. 
A "safe and effective amount" of a Formula (I) compound is an amount that 
is effective, to inhibit metalloproteases at the site(s) of activity, in a 
mammal subject, without undue adverse side effects (such as toxicity, 
irritation, or allergic response), commensurate with a reasonable 
benefit/risk ratio when used in the manner of this invention. The specific 
"safe and effective amount" will, obviously, vary with such factors as the 
particular condition being treated, the physical condition of the patient, 
the duration of treatment, the nature of concurrent therapy (if any), the 
specific dosage form to be used, the carrier employed, the solubility of 
the Formula (I) compound therein, and the dosage regimen desired for the 
composition. 
In addition to the subject compound, the compositions of the subject 
invention contain a pharmaceutically-acceptable carrier. The term 
"pharmaceutically-acceptable carrier", as used herein, means one or more 
compatible solid or liquid filler diluents or encapsulating substances 
which are suitable for administration to a mammal. The term "compatible", 
as used herein, means that the components of the composition are capable 
of being commingled with the subject compound, and with each other, in a 
manner such that there is no interaction which would substantially reduce 
the pharmaceutical efficacy of the composition under ordinary use 
situations. Pharmaceutically-acceptable carriers must, of course, be of 
sufficiently high purity and sufficiently low toxicity to render them 
suitable for administration to the aminal, preferably mammal being 
treated. 
Some examples of substances which can serve as pharmaceutically-acceptable 
carriers or components thereof are sugars, such as lactose, glucose and 
sucrose; starches, such as corn starch and potato starch; cellulose and 
its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, 
and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid 
lubricants, such as stearic acid and magnesium stearate; calcium sulfate; 
vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, 
corn oil and oil of theobroma; polyols such as propylene glycol, 
glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; 
emulsifiers, such as the TWEENS"; wetting agents, such sodium lauryl 
sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; 
antioxidants; preservatives; pyrogen-free water; isotonic saline; and 
phosphate buffer solutions. 
The choice of a pharmaceutically-acceptable carrier to be used in 
conjunction with the subject compound is basically determined by the way 
the compound is to be administered. 
If the subject compound is to be injected, the preferred 
pharmaceutically-acceptable carrier is sterile, physiological saline, with 
blood-compatible suspending agent, the pH of which has been adjusted to 
about 7.4. 
In particular, pharmaceutically-acceptable carriers for systemic 
administration include sugars, starches, cellulose and its derivatives, 
malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, 
polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic 
saline, and pyrogen-free water. Preferred carriers for parenteral 
administration include propylene glycol, ethyl oleate, pyrrolidone, 
ethanol, and sesame oil. Preferably, the pharmaceutically-acceptable 
carrier, in compositions for parenteral administration, comprises at least 
about 90% by weight of the total composition. 
The compositions of this invention are preferably provided in unit dosage 
form. As used herein, a "unit dosage form" is a composition of this 
invention containing an amount of a Formula (I) compound that is suitable 
for administration to a aminal, preferably mammal subject, in a single 
dose, according to good medical practice. These compositions preferably 
contain from about 5 mg (milligrams) to about 1000 mg, more preferably 
from about 10 mg to about 500 mg, more preferably from about 10 mg to 
about 300 mg, of a Formula (I) compound. 
The compositions of this invention may be in any of a variety of forms, 
suitable (for example) for oral, rectal, topical, nasal, ocular or 
parenteral administration. Depending upon the particular route of 
administration desired, a variety of pharmaceutically-acceptable carriers 
well-known in the art may be used. These include solid or liquid fillers, 
diluents, hydrotropes, surface-active agents, and encapsulating 
substances. Optional pharmaceutically-active materials may be included, 
which do not substantially interfere with the inhibitory activity of the 
Formula (I) compound. The amount of carrier employed in conjunction with 
the Formula (I) compound is sufficient to provide a practical quantity of 
material for administration per unit dose of the Formula (I) compound. 
Techniques and compositions for making dosage forms useful in the methods 
of this invention are described in the following references, all 
incorporated by reference herein: Modem Pharmaceutics, Chapters 9 and 10 
(Banker & Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage 
Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage 
Forms 2d Edition (1976). 
In addition to the subject compound, the compositions of the subject 
invention contain a pharmaceutically-acceptable carrier. The term 
"pharmaceutically-acceptable carrier", as used herein, means one or more 
compatible solid or liquid filler diluents or encapsulating substances 
which are suitable for administration to a aminal, preferably mammal. The 
term "compatible", as used herein, means that the components of the 
composition are capable of being commingled with the subject compound, and 
with each other, in a manner such that there is no interaction which would 
substantially reduce the pharmaceutical efficacy of the composition under 
ordinary use situations. Pharmaceutically-acceptable carriers must, of 
course, be of sufficiently high purity and sufficiently low toxicity to 
render them suitable for administration to the aminal, preferably mammal 
being treated. 
Some examples of substances which can serve as pharmaceutically-acceptable 
carriers or components thereof are sugars, such as lactose, glucose and 
sucrose; starches, such as corn starch and potato starch; cellulose and 
its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, 
and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid 
lubricants, such as stearic acid and magnesium stearate; calcium sulfate; 
vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, 
corn oil and oil of theobroma; polyols such as propylene glycol, 
glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; 
emulsifiers, such as the TWEENS.TM.; wetting agents, such sodium lauryl 
sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; 
antioxidants; preservatives; pyrogen-free water; isotonic saline; and 
phosphate buffer solutions. 
The choice of a pharmaceutically-acceptable carrier to be used in 
conjunction with the subject compound is basically determined by the way 
the compound is to be administered. 
If the subject compound is to be injected, the preferred 
pharmaceutically-acceptable carrier is sterile, physiological saline, with 
blood-compatible suspending agent, the pH of which has been adjusted to 
about 7.4. 
Various oral dosage forms can be used, including such solid forms as 
tablets, capsules, granules and bulk powders. These oral forms comprise a 
safe and effective amount, usually at least about 5%, and preferably from 
about 25% to about 50%, of the Formula (I) compound. Tablets can be 
compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, 
or multiple-compressed, containing suitable binders, lubricants, diluents, 
disintegrating agents, coloring agents, flavoring agents, flow-inducing 
agents, and melting agents. Liquid oral dosage forms include aqueous 
solutions, emulsions, suspensions, solutions and/or suspensions 
reconstituted from non-effervescent granules, and effervescent 
preparations reconstituted from effervescent granules, containing suitable 
solvents, preservatives, emulsifying agents, suspending agents, diluents, 
sweeteners, melting agents, coloring agents and flavoring agents. 
The pharmaceutically-acceptable carrier suitable for the preparation of 
unit dosage forms for peroral administration are well-known in the art. 
Tablets typically comprise conventional pharmaceutically-compatible 
adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, 
mannitol, lactose and cellulose; binders such as starch, gelatin and 
sucrose; disintegrants such as starch, alginic acid and croscarmelose; 
lubricants such as magnesium stearate, stearic acid and talc. Glidants 
such as silicon dioxide can be used to improve flow characteristics of the 
powder mixture. Coloring agents, such as the FD&C dyes, can be added for 
appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, 
menthol, peppermint, and fruit flavors, are useful adjuvants for chewable 
tablets. Capsules typically comprise one or more solid diluents disclosed 
above. The selection of carrier components depends on secondary 
considerations like taste, cost, and shelf stability, which are not 
critical for the purposes of the subject invention, and can be readily 
made by a person skilled in the art. 
Peroral compositions also include liquid solutions, emulsions, suspensions, 
and the like. The pharmaceutically-acceptable carriers suitable for 
preparation of such compositions are well known in the art. Typical 
components of carriers for syrups, elixirs, emulsions and suspensions 
include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid 
sucrose, sorbitol and water. For a suspension, typical suspending agents 
include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, 
tragacanth and sodium alginate; typical wetting agents include lecithin 
and polysorbate 80; and typical preservatives include methyl paraben and 
sodium benzoate. Peroral liquid compositions may also contain one or more 
components such as sweeteners, flavoring agents and colorants disclosed 
above. 
Such compositions may also be coated by conventional methods, typically 
with pH or time-dependent coatings, such that the subject compound is 
released in the gastrointestinal tract in the vicinity of the desired 
topical application, or at various times to extend the desired action. 
Such dosage forms typically include, but are not limited to, one or more 
of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl 
methyl cellulose phthalate, ethyl cellulose, Eudragit" coatings, waxes and 
shellac. 
Compositions of the subject invention may optionally include other drug 
actives. 
Other compositions useful for attaining systemic delivery of the subject 
compounds include sublingual, buccal and nasal dosage forms. Such 
compositions typically comprise one or more of soluble filler substances 
such as sucrose, sorbitol and mannitol; and binders such as acacia, 
microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl 
methyl cellulose. Glidants, lubricants, sweeteners, colorants, 
antioxidants and flavoring agents disclosed above may also be included. 
The compositions of this invention can also be administered topically to a 
subject, e.g., by the direct laying on or spreading of the composition on 
the epidermal or epithelial tissue of the subject, or transdermally via a 
"patch". Such compositions include, for example, lotions, creams, 
solutions, gels and solids. These topical compositions preferably comprise 
a safe and effective amount, usually at least about 0.1%, and preferably 
from about 1% to about 5%, of the Formula (I) compound. Suitable carriers 
for topical administration preferably remain in place on the skin as a 
continuous film, and resist being removed by perspiration or immersion in 
water. Generally, the carrier is organic in nature and capable of having 
dispersed or dissolved therein the Formula (I) compound. The carrier may 
include pharmaceutically-acceptable emolients, emulsifiers, thickening 
agents, solvents and the like. 
Methods of Administration: 
This invention also provides methods of treating or preventing disorders 
associated with excess or undesired metalloprotease activity in an animal, 
preferably mammal subject, by administering a safe and effective amount of 
a Formula (I) compound to said subject. As used herein, a "disorder 
associated with excess or undesired metalloprotease activity" is any 
disorder characterized by degradation of proteins. The methods of the 
invention are useful in treating disorders such as (for example) 
osteoarthritis, periodontitis, corneal ulceration, tumor invasion, and 
rheumatoid arthritis. 
The Formula (I) compounds and compositions of this invention can be 
administered topically or systemically. Systemic application includes any 
method of introducing Formula (I) compound into the tissues of the body, 
e.g., intra-articular (especially in treatment of rheumatoid arthritis), 
intrathecal, epidural, intramuscular, transdermal, intravenous, 
intraperitoneal, subcutaneous, sublingual, rectal, and oral 
administration. The Formula (I) compounds of the present invention are 
preferably administered orally. 
The specific dosage of inhibitor to be administered, as well as the 
duration of treatment, and whether the treatment is topical or systemic 
are interdependent. The dosage and treatment regimen will also depend upon 
such factors as the specific Formula (I) compound used, the treatment 
indication, the ability of the Formula (I) compound to reach minimum 
inhibitory concentrations at the site of the metalloprotease to be 
inhibited, the personal attributes of the subject (such as weight), 
compliance with the treatment regimen, and the presence and severity of 
any side effects of the treatment. 
Typically, for a human adult (weighing approximately 70 kilograms), from 
about 5 mg to about 3000 mg, more preferably from about 5 mg to about 1000 
mg, more preferably from about 10 mg to about 100 mg, of Formula (I) 
compound are administered per day for systemic administration. It is 
understood that these dosage ranges are by way of example only, and that 
daily administration can be adjusted depending on the factors listed 
above. 
A preferred method of administration for treatment of rheumatoid arthritis 
is oral or parenterally via intra-articular injection. As is known and 
practiced in the art, all formulations for parenteral administration must 
be sterile. For mammals, especially humans, (assuming an approximate body 
weight of 70 kilograms) individual doses of from about IO mg to about 
I1000 mg are preferred. 
A preferred method of systemic administration is oral. Individual doses of 
from about 10 mg to about 1000 mg, preferably from about 10 mg to about 
300 mg are preferred. 
Topical administration can be used to deliver the Formula (I) compound 
systemically, or to treat a subject locally. The amounts of Formula (I) 
compound to be topically administered depends upon such factors as skin 
sensitivity, type and location of the tissue to be treated, the 
composition and carrier (if any) to be administered, the particular 
Formula (I) compound to be administered, as well as the particular 
disorder to be treated and the extent to which systemic (as distinguished 
from local) effects are desired. 
The inhibitors of the invention can be targeted to specific locations where 
the metalloprotease is accumulated by using targeting ligands. For 
example, to focus the inhibitors to metalloprotease contained in a tumor, 
the inhibitor is conjugated to an antibody or fragment thereof which is 
immunoreactive with a tumor marker as is generally understood in the 
preparation of immunotoxins in general. The targeting ligand can also be a 
ligand suitable for a receptor which is present on the tumor. Any 
targeting ligand which specifically reacts with a marker for the intended 
target tissue can be used. Methods for coupling the invention compound to 
the targeting ligand are well known and are similar to those described 
below for coupling to carrier. The conjugates are formulated and 
administered as described above. 
For localized conditions, topical administration is preferred. For example, 
to treat ulcerated cornea, direct application to the affected eye may 
employ a formulation as eyedrops or aerosol. For corneal treatment, the 
compounds of the invention can also be formulated as gels, drops or 
ointments, or can be incorporated into collagen or a hydrophilic polymer 
shield. The materials can also be inserted as a contact lens or reservoir 
or as a subconjunctival formulation. For treatment of skin inflammation, 
the compound is applied locally and topically, in a gel, paste, salve or 
ointment. The mode of treatment thus reflects the nature of the condition 
and suitable formulations for any selected route are available in the art. 
In all of the foregoing, of course, the compounds of the invention can be 
administered alone or as mixtures, and the compositions may further 
include additional drugs or excipients as appropriate for the indication. 
Some of the compounds of the invention also inhibit bacterial 
metalloproteases although generally at a lower level than that exhibited 
with respect to mammalian metalloproteases. Some bacterial 
metalloproteases seem to be less dependent on the stereochemistry of the 
inhibitor, whereas substantial differences are found between diastereomers 
in their ability to inactivate the mammalian proteases. Thus, this pattern 
of activity can be used to distinguish between the mammalian and bacterial 
enzymes. 
Preparation and Use of Antibodies: 
The invention compounds can also be utilized in immunization protocols to 
obtain antisera immunospecific for the invention compounds. As the 
invention compounds are relatively small, they are advantageously coupled 
to antigenically neutral carriers such as the conventionally used keyhole 
limpet hemocyanin (KLH) or serum albumin carriers. For those invention 
compounds having a carboxyl functionality, coupling to carrier can be done 
by methods generally known in the art. For example, the carboxyl residue 
can be reduced to an aldehyde and coupled to carrier through reaction with 
sidechain amino groups in protein-based carriers, optionally followed by 
reduction of imino linkage formed. The carboxyl residue can also be 
reacted with sidechain amino groups using condensing agents such as 
dicyclohexyl carbodiimide or other carbodiimide dehydrating agents. 
Linker compounds can also be used to effect the coupling; both 
homobifunctional and heterobifunctional linkers are available from Pierce 
Chemical Company, Rockford, Ill. The resulting immunogenic complex can 
then be injected into suitable mammalian subjects such as mice, rabbits, 
and the like. Suitable protocols involve repeated injection of the 
immunogen in the presence of adjuvants according to a schedule which 
boosts production of antibodies in the serum. The titers of the immune 
serum can readily be measured using immunoassay procedures, now standard 
in the art, employing the invention compounds as antigens. 
The antisera obtained can be used directly or monoclonal antibodies may be 
obtained by harvesting the peripheral blood lymphocytes or the spleen of 
the immunized animal and immortalizing the antibody-producing cells, 
followed by identifying the suitable antibody producers using standard 
immunoassay techniques. 
The polyclonal or monoclonal preparations are then useful in monitoring 
therapy or prophylaxis regimens involving the compounds of the invention. 
Suitable samples such as those derived from blood, serum, urine, or saliva 
can be tested for the presence of the administered inhibitor at various 
times during the treatment protocol using standard immunoassay techniques 
which employ the antibody preparations of the invention. 
The invention compounds can also be coupled to labels such as scintigraphic 
labels, e.g., technetium 99 or I-131, using standard coupling methods. The 
labeled compounds are administered to subjects to determine the locations 
of excess amounts of one or more metalloproteases in vivo. The ability of 
the inhibitors to selectively bind metalloprotease is thus taken advantage 
of to map the distribution of these enzymes in situ. The techniques can 
also be employed in histological procedures and the labeled invention 
compounds can be used in competitive immunoassays. 
The following non-limiting examples illustrate the compounds, compositions, 
and uses of the present invention.

EXAMPLES 
Compounds are analyzed using .sup.1 H and .sup.13 C NMR, Elemental 
analysis, mass spectra and/or IR spectra, as appropriate. 
Typically inert solvents are used, preferably in dried form. For example, 
tetrahydrofuran (THF) is distilled from sodium and benzophenone, 
diisopropylamine is distilled from calcium hydride and all other solvents 
are purchased as the appropriate grade. Chromatography is performed on 
silica gel (70-230 mesh; Aldrich) or (230-400 mesh; Merck) as appropriate. 
Thin layer chromatography analysis (TLC) is performed on glass mounted 
silica gel plates (200-300 mesh; Baker) and visualized with UV or 5% 
phosphomolybdic acid in EtOH. 
Example 1 
Synthesis of 
2(R)-Thiomethyl-4-(S)-thio-1-[(4-methoxyphenyl)sulfonyl]pyrrolidine 
##STR16## 
1-[(4-Methoxyphenyl)sulfonyl]-cis-4-hydroxy-D-proline (1a): 
Cis-4-hydroxy-D-proline (9.0 g, 68.6 mmol) is dissolved in 100 mL mixture 
of water and p-dioxane (1:1) and then triethyl amine (19.1 mL, 137.3 
mmol), 4-methoxyphenylsulfonyl chloride (15.6 g, 75.5 mmol), and 
4-dimethylaminopyridine (0.86 g, 6.86 mmol) are added. The solution is 
stirred at room temperature overnight. The reaction mixture is washed with 
sodium bicarbonate and extracted once with ether. The water layer is 
acidified with 1N HCl until pH.about.2 is achieved and then the solution 
is extracted three times with ethyl acetate. The ethyl acetate layers are 
washed with ammonium chloride, and dried (MsSO.sub.4), filtered and 
evaporated to give the crude acid. Cl.sup.+ MS: m/z (rel intensity) 
302.0(M.sup.+ +H, 100). 
1-[(4-Methoxyphenyl)sulfonyl]-cis-4-hydroxy-D-prolinol (1b): The acid (0.60 
g, 1.99 mmol) is dissolved in 10 mL of anhydrous THF followed by the slow 
addition of 1.0 M borane-etrahydrofuran complex (3.98 mL, 3.98 mmol) at 
room temperature. After stirring for 30 minutes, another 1 mL of the 
borane-THF complex is added and the solution is stirred for an additional 
1.5 hours. The reaction is quenched by the slow addition of water and 
acidified with 1N HCl to pH=2. The resulting solution is extracted with 
ethyl acetate three times. The combined organic layers are washed with 
ammonium chloride, dried (MgSO.sub.4), filtered and evaporated to give the 
of crude product. Cl.sup.+ MS: m/z (rel intensity) 289.0 (M.sup.+ +H, 
100). 
2(R)-Acetylthiomethyl-4-(S)-acetylthio-1-[(4-methoxyphenyl)sulfonyl]pyrroli 
dine (1e): In flask 1, triphenylphosphine (1.09 g, 4.18 mmol) is dissolved 
in 25 mL of anhydrous THF at -10.degree. C. and stirred. The diethyl 
azodicarboxylate (0.658 mL, 4.18 mmol), is then added and the resulting 
solution is stirred for 30 minutes. In flask 2, the alcohol (0.300 g, 1.04 
mmol) and thiolacetic acid (0.373 mL, 5.22 mmol) are dissolved in 7 mL of 
anhydrous THF. The contents of flask 2 are cannulated into flask 1. The 
resulting solution is stirred at 0.degree. C. for 4 hours and then at room 
temperature overnight. The reaction is treated with sodium bicarbonate 
until pH.about.9 is achieved and then the solution is extracted three 
times with ethyl acetate. The organic layers are washed with 1N HCl, 
sodium bicarbonate, and ammonium chloride, dried (MgSO.sub.4), filtered 
and evaporated to give a crude solid which is chromatographed on silica 
gel with hexanes/ethyl acetate/methylene chloride (4.5/1/1) to afford the 
desired product. Cl.sup.+ MS: m/z (rel intensity) 403.0 (M.sup.+ +H, 
100). 
2(R)-Thiomethyl-4-(S)-thio-1-[(4-methoxyphenyl)sulfonyl]pyrrolidine (1d): 
The dithiol acetate (0.085 g, 0.211 mmol) is dissolved in 10 mL of 
methanol and the solution is thoroughly degassed. Anhydrous ammonia gas is 
passed through the solution for 8 minutes and the solution is stirred for 
minutes. The solution is evaporated down to give the crude product which 
is chromatographed on silica gel with hexanes/ethyl acetate/methylene 
chloride/formic acid (70/5/6/0.1) to give the final product as an oil. 
Cl.sup.+ MS: m/z (rel intensity) 320.0 (M.sup.+ +H, 100). 
Example 2 
Synthesis of (2R)-2-Thiomethyl-1-[(4-methoxyphenyl)sulfonyl]pyrrolidine 
##STR17## 
1-[(4-Methoxyphenyl)sulfonyl]-D-proline (2a): D-proline (15 g, 130.3 mmol) 
is dissolved in a 1:1 mixture of water (150 mL) and p-dioxane (150 mL) and 
then triethyl amine (40 mL, 287 mmol), 4-methoxyphenylsulfonyl chloride 
(29.0 g, 140.3 mmol), and the 4-dimethylaminopyridine (1.5 g, 13.0 mmol) 
are added. The solution is stirred at room temperature overnight. The 
reaction mixture is then treated with 1N HCl until the solution is acidic 
(pH=2). The resulting solution is extracted three times with ethyl 
acetate. The ethyl acetate layers are washed with ammonium chloride, dried 
(MgSO.sub.4), filtered and evaporated to give the crude compound. Cl.sup.+ 
MS: m/z (rel intensity) (M.sup.+ +H 286, 100 ). 
1-[(4-Methoxyphenyl)sulfonyl]-D-prolinol (2b): The acid (5.0 g, 17.5 mmol) 
is dissolved in 100 mL of anhydrous THF followed by the slow addition of 
1.0 M borane-tetrahydrofuran complex (26.5 mL, 26.5 mmol) at room 
temperature. The reaction mixture is stirred for 2 hours. The reaction is 
quenched by the slow addition of water and acidified with 1N HCl to pH=2. 
The resulting solution is extracted with ethyl acetate 3 times. The 
organic layers are washed with ammonium chloride, dried (MgSO.sub.4), 
filtered and evaporated to give the crude product. Cl.sup.+ MS: m/z (rel 
intensity) (M.sup.+ +H 272, 100). 
2R-2-Acetylthiomethyl-1-[(4-methoxyphenyl)sulfonyl]pyrrolidine (2c): In 
flask 1, triphenylphosphine (0.782 g, 2.98 mmol) is dissolved in 20 mL of 
anhydrous THF at -10.degree. C. and stirred. The diethyl azodicarboxylate 
(0.470 mL, 2.98 mmol) is then added and the resulting solution is stirred 
for 30 minutes. In flask 2, the alcohol (0.404 g, 1.49 mmol) and 
thiolacetic acid (0.266 mL, 3.73 mmol) are dissolved in 10 mL of anhydrous 
THF. The contents of flask 2 are cannulated into flask 1. The resulting 
solution is stirred at 0.degree. C. for 4 hours and then at room 
temperature overnight. The reaction is treated with sodium bicarbonate 
until pH.about.9 is achieved and then the solution is extracted three 
times with ethyl acetate. The organic layers are washed with 1N HCl, 
sodium bicarbonate, and ammonium chloride, dried (MgSO.sub.4), filtered 
and evaporated to give a crude solid. Purification of the solid is 
accomplished by chromatography on silica gel using ethyl acetate/methylene 
chloride (1.5/500) as the eluent to afford the desired product. Cl.sup.+ 
MS: m/z (rel intensity) (M.sup.+ +H 329.9, 100). 
2-Thiomethyl-1-[(4-methoxyphenyl)sulfonyl]pyrrolidine (2d): The thiol 
acetate (0.110 g, 0.334 mmol) is dissolved in 15 mL of methanol and the 
solution is thoroughly degassed. Anhydrous ammonia gas is passed through 
the solution for 8 minutes and the solution stirred for an additional 15 
minutes. The solution is evaporated down to give the crude product which 
is chromatographed on silica gel with hexanes/ethyl acetate/methylene 
chloride(5/1/1) to provide the final product. Cl.sup.+ MS: m/z (rel 
intensity) (M.sup.+ +H 288.0, 100). 
Example 3 
Synthesis of (2R,4S)-Methyl 4-thio-1-[(4-methoxyphenyl)sulfonyl]proline 
##STR18## 
Methyl 1-[(4-methoxyphenyl)sulfonyl]-cis-hydroxy-D-proline (3a): 
1-[(4-methoxyphenyl)sulfonyl]-cis-hydroxy-D-proline (5 g, 16.6 mmol) is 
dissolved in 150 mL of ether and 20 mL of p-dioxane and treated with a 0.7 
M solution of diazomethane. The addition is stopped once the color 
remained yellow. The solution is stirred for an additional hour. The 
reaction mixture is diluted with 300 mL of ethyl acetate and washed with 
sodium bicarbonate and ammonium chloride and dried over magnesium sulfate. 
Cl.sup.+ MS: m/z (rel intensity) 316 (M.sup.+ +H, 100). 
(2R,4S)-Methyl 4-acetylthio-1-[(4-methoxyphenyl)sulfonyl]proline (3b): In 
flask 1, triphenylphosphine (5.16 g, 19.68 mmol) is dissolved in 150 mL of 
anhydrous THF at -10.degree. C. and stirred The diethyl azodicarboxylate 
(3.1 mL, 19.68 mmol) is added and the resulting solution is stirred for 30 
minutes. In flask 2, the alcohol 1 (3.1 g, 9.84 mmol) and thiolacetic acid 
(1.76 mL, 24.60 mmol) are dissolved in 30 mL of anhydrous THF. The 
contents of flask 2 are cannulated into flask 1. The resulting solution is 
stirred at 0.degree. C. for 4 hours and at room temperature over night. 
The reaction mixture is treated with sodium bicarbonate and extracted 
three times with ethyl acetate. The organic layers are washed with 1N HCl, 
sodium bicarbonate, and ammonium chloride, dried (MgSO.sub.4), filtered 
and evaporated to give a crude solid which is chromatographed on silica 
gel with ethyl acetate/methylene chloride (1/30). Cl.sup.+ MS: m/z (rel 
intensity) 374 (M.sup.+ +H, 100). 
(2R,4S)-Methyl 4-thio-1-[(4-methoxyphenyl)sulfonyl]proline (3c): The thiol 
acetate (0.120 g, 0.321 mmol) is dissolved in 5 mL of methanol and the 
solution is thoroughly degassed. Anhydrous ammonia gas is passed through 
the solution for 8 minutes and the solution stirred for an additional 15 
minutes. The solution is evaporated down to a crude product which is 
chromatographed on silica gel with hexanes/ethyl acetate/methylene 
chloride(4/1/1) to give the pure product. Cl.sup.+ MS: m/Z (rel 
intensity) 331.9 (M.sup.+ +H, 100). 
Example 4 
Synthesis of 2(R,S)-Thiomethyl-1-[(4-n-butoxyphenyl)sulfonyl]piperidine 
##STR19## 
1-[(4-n-Butoxyphenyl)sulfonyl]pipecolinic acid (4a): Pipecolinic acid 
(0.331 g, 2.56 mmol) is dissolved in 16 mL mixture of water and p-dioxane 
(1:1) followed by the addition of triethyl amine (0.78 mL, 5.64 mmol), 
4-butoxyphenylsulfonyl chloride (0.67 g, 2.69 mmol), and 
4-dimethylaminopyridine (0.031 g, 0.25 mmol). The resulting solution is 
stirred at room temperature overnight. The reaction mixture is acidified 
with 1N HCl and extracted three times with ethyl acetate. The combined 
organic extracts are washed with ammonium chloride, dried (MgSO.sub.4), 
filtered and evaporated to give the crude compound. Cl.sup.+ MS: m/z (rel 
intensity) 342 (M.sup.+ +H, 100). 
2-Hydroxymethyl-1-[(4-n-butoxyphenyl)sulfonyl]piperidine (4b): The acid 
(0.650 g, 1.90 mmol) is dissolved in 15 mL of anhydrous THF followed by 
the slow addition of 1.0 M borane-tetrahydrofuran complex (3.8 mL, 3.81 
mmol) at room temperature. The reaction is stirred for 2 hours and then 
quenched by the slow addition of water. The resulting solution is 
acidified with 1N HCl to pH=2 and extracted with ethyl acetate three 
times. The organic layers are washed with ammonium chloride, dried 
(MgSO.sub.4) and evaporated to give the crude product. Cl.sup.+ MS: m/z 
(rel intensity) 328.1 (M.sup.+ +H, 100). 
2-Acetylthiomethyl-1-[(4-n-butoxyphenyl)sulfonyl]piperidine (4c): In flask 
1, triphenylphosphine (0.528 g, 2.01 mmol) is dissolved in 20 mL of 
anhydrous THF at -10.degree. C. and stirred. The diethyl azodicarboxylate 
(0.317 mL, 2.01 mmol) is then added, and the resulting solution is stirred 
for 30 minutes. In flask 2, the alcohol (0.325 g, 1.00 mmol) and 
thiolacetic acid (0.179 mL, 2.51 mmol) are dissolved in 10 mL of anhydrous 
THF. The contents of flask 2 are cannulated into flask 1. The resulting 
solution is stirred at 0.degree. C. for 4 hours and at room temperature 
over night. The reaction is treated with sodium bicarbonate and then 
extracted three times with ethyl acetate. The organic layers are washed 
with 1N HCl, sodium bicarbonate, and ammonium chloride, dried 
(MgSO.sub.4), filtered and evaporated to give a crude solid which is 
chromatographed on silica gel with hexane/ethyl acetate/methylene chloride 
(7/1/1). Cl.sup.+ MS: m/z (rel intensity) 386.0 (M.sup.30 +H, 100). 
2(R,S)-Thiomethyl-1-[(4-n-butoxyphenyl)sulfonyl]piperidine (4d): The thiol 
acetate (0.105 g, 0.272 mmol) is dissolved in 10 mL of methanol and the 
solution is thoroughly degassed. Anhydrous ammonia gas is passed through 
the solution for 8 minutes and the solution stirred for an additional 15 
minutes. The solution is evaporated down to give a crude product which is 
chromatographed on silica gel with hexanes/ethyl acetate/methylene 
chloride(10/1/1) to afford 0.070 g (75.0%) of a pure product. Cl.sup.+ 
MS: m/z (rel intensity) 344 (M.sup.+ +H, 100). 
Example 5 
Synthesis of 2(R,S)-Thiomethyl-1-[(4-methoxyphenyl)sulfonyl]piperidine 
##STR20## 
Methyl-1-[(4-methoxyphenyl)sulfonyl]piperidine-2(R,S)-carboxylate (Sa): 
Methyl pipecolinate hydrochloride (10.0 g, 55.6 mmol), triethylamine (14.1 
g, 19.4 mL, 139.2 mmol, 2.5 equiv), 1,4-dioxane (75 mL), and water (75 mL) 
are stirred at room temperature and then p-methoxyphenylsulfonyl chloride 
(13.8 g, 66.8 mmol, 1.2 equiv) is added. The resulting solution is stirred 
at room temperature overnight. The solution is then poured into water and 
extracted with CH.sub.2 Cl.sub.2. The combined organic extracts are dried 
(Na.sub.2 SO.sub.4) and concentrated to an oil under reduced pressure. 
Purification of the oil is accomplished by chromatography on silica gel 
using 7/3 hexane/EtOAc as the eluent. The product is obtained as a 
colorless oil which solidified upon standing. 
2(R,S)-1-[(4-Methoxyphenyl)sulfonyl]piperidinemethanol (5b): The 
sulfonamide (4.0 g, 12.7 mmol) in THF (50 mL) is stirred at room 
temperature and then diisobutylaluminum hydride in THF (25.5 mL, 25.5 
mmol, 2 equiv) is added. The resulting solution is stirred at room 
temperature for 2 hours and then the reaction mixture is quenched by the 
addition of water. The solution is extracted with CH.sub.2 Cl.sub.2 
(3.Yen.100 mL). The combined organic extracts are dried (Na.sub.2 
SO.sub.4) and concentrated to an oil under reduced pressure. Purification 
of the oil is accomplished by chromatography using 1/1 hexane/EtOAc as the 
eluent. The product is obtained as a clear colorless oil. 
2(R,S)-Acetylthiomethyl-1-[(4-methoxyphenyl)sulfonyl]piperidine (5c): The 
alcohol (2.90 g, 10.1 mmol) in CH.sub.2 Cl.sub.2 (10 mL) is added to a 
solution of triphenylphosphine (3.19 g, 12.2 mmol, 1.2 equiv) and 
diethylazodicarboxylate (1.94 g, 11.1 mmol, 1.1 equiv) in CH.sub.2 
Cl.sub.2 (20) at -78.degree. C. The solution is stirred at -78.degree. C. 
and then the thiolacetic acid (1.55 g, 20.3 mmol, 2.0 equiv) is added. The 
resulting solution is warmed to room temperature and then stirred for 2 h. 
The reaction mixture is concentrated to an oil and then silica gel (20 g) 
is added. The resulting powder is purified by chromatography on silica gel 
using 7/3 hexane/EtOAc as the eluent to afford the desired thiolacetate as 
a clear colorless oil. MS (CI, NH.sub.3):344 (M+H.sup.+). 
2(R,S)-Thiomethyl-1-[(4-methoxyphenyl)sulfonyl]piperidine (5d): The 
thiolacetate 3 (0.295 g, 0.86 mmol) in methanol (20 mL) is stirred under 
an argon atmosphere at room temperature. The solution is then bubbled with 
ammonia gas for 20 minutes at room temperature and then the solution is 
purged with argon gas. The solvent is removed under reduced pressure to 
leave a colorless oil. Purification of the oil is accomplished by 
chromatography using 7/3 hexane/EtOAc as the eluent. The product is 
obtained as a colorless oil. MS (electron spray):302 (M+H.sup.+). 
Example 6 
Synthesis of 
2(R)-Thiomethyl-4-(S)-thio-1-[(4-n-butoxyphenyl)sulfonyl]pyrrolidine 
##STR21## 
1-[(4-Butoxyphenyl)sulfonyl]-cis-4-hydroxy-D-proline (6a): 
Cis-4-hydroxy-D-proline (0.308 g, 2.67 mmol) is dissolved in 16 mL of a 
1:1 mixture of water and p-dioxane and then triethyl amine (0.819 mL, 5.89 
mmol), 4-butoxyphenylsulfonyl chloride (0.700 g, 2.81 mmol), and 
4-dimethylaminopyridine (0.033 g, 0.268 mmol) are added. The resulting 
solution is stirred at room temperature overnight. The reaction is then 
washed with sodium bicarbonate and extracted once with ether. The water 
layer is acidified with 1N HCl to pH=2 and extracted three times with 
ethyl acetate. The ethyl acetate layers are washed with ammonium chloride, 
dried (MgSO.sub.4), filtered and evaporated to give the crude compound. 
Cl.sup.+ MS: m/z (rel intensity) 361 (M.sup.+ +H, 40). 
1-[(4-Butoxyphenyl)sulfonyl]-cis-4-hydroxy-D-prolinol (6b): The sulfonamide 
(0.750 g, 2.18 mmol) is dissolved in 10 mL of anhydrous THF followed by 
the slow addition of 1.0 M borane-tetrahydrofuran complex (4.4 mL, 4.37 
mmol) at room temperature. The solution is stirred for 1.5 hours at room 
temperature. The reaction is quenched by the slow addition of water, 
acidified with 1N HCl to pH=2 and extracted with ethyl acetate three 
times. The organic layers are washed with ammonium chloride, dried 
(MgSO.sub.4), filtered and evaporated to give the crude product. Cl.sup.+ 
MS: m/z (rel intensity) 347.1 (M.sup.+ +H, 40). 
2(R)-Acetylthiomethyl-4-(S)-acetylthio-1-[(4-butoxyphenyi)sulfonyl]pyrrolid 
ine (6c): In flask 1, triphenylphosphine (1.35 g, 5.14 mmol) is dissolved 
in 25 mL of anhydrous THF at -10.degree. C. and stirred. The diethyl 
azodicarboxylate (0.809 mL, 5.14 mmol) is then added and the resulting 
solution is stirred for 30 minutes. In flask 2, the alcohol (0.423 g, 1.28 
mmol) and thiolacetic acid (0.459 mL, 6.43 mmol) are dissolved in 10 mL of 
anhydrous THF. The contents of flask 2 are cannulated into flask 1. The 
resulting solution is stirred at 0.degree. C. for 4 hours and then at room 
temperature overnight. The reaction mixture is washed with sodium 
bicarbonate and extracted three times with ethyl acetate. The organic 
layers are washed with 1N HCl, sodium bicarbonate, and ammonium chloride, 
dried MgSO.sub.4), filtered and evaporated to give a crude solid which is 
chromatographed on silica gel with hexanes/ethyl acetate/methylene 
chloride (8/1/1). Cl.sup.+ MS: m/z (rel intensity) 446 (M.sup.+ +H, 100). 
2(R)-Thiomethyl-4-(S)-thio-1-[(4-butoxyphenyl)sulfonyl]pyrrolidine (6d): 
The dithiol acetate (0.150 g, 0.337 mmol) is dissolved in 10 mL of 
methanol and the solution is thoroughly degassed. Anhydrous ammonia gas is 
passed through the solution for 8 minutes and the solution stirred for 15 
minutes. The solution is evaporated down to the crude product which is 
chromatographed on silica gel with hexanes/ethyl acetate/methylene 
chloride/formic acid (10/1/1/0.1) to give the desired product as a pure 
white solid. Cl.sup.+ MS: m/z (rel intensity) 362 (M.sup.+ +H, 100). 
Example 7 
Synthesis of 3(R)-Thio-1-[(4-methoxyphenyl)sulfonyl]pyrrolidine 
##STR22## 
(3S)-3-Hydroxy-1-[(4-methoxyphenyl)sulfonyl]pyrrolidine (7a): The 
3(S)-hydroxy-pyrrolidine (1.0 g, 11.5 mmol), triethylamine (2.32 g, 22.9 
mmol, 2.0 equiv) in 1,4-dioxane (30 mL) and water (10 mL) is stirred at 
room temperature and then 4-methoxyphenylsulfonyl chloride (2.61 g, 12.6 
mmol, 1.10 equiv) is added. The resulting solution is stirred at room 
temperature for 3 h. and then the solution is acidified to pH.about.1 with 
1 N HCl. The solution is poured into water and then extracted with 
CH.sub.2 Cl.sub.2. The organic extracts are dried (Na.sub.2 SO.sub.4) and 
concentrated o an oil. The oil is purified by chromatography using 1/1 
hexane/EtOAc as the eluent to afford 2.62 g (81%) of the desired product 
as a colorless oil. 
(3R)-3-Acetylthio-1-[(4-methoxyphenyl)sulfonyl]pyrrolidine (7b): The 
alcohol (1.30 g, 5.05 mmol) in CH.sub.2 Cl.sub.2 (30 mL) is added to a 
solution of triphenylphosphine (1.59 g, 6.06 mmol, 1.2 equiv) and 
diethylazodicarboxylate (0.97 g, 5.56 mmol, 1.1 equiv) in CH.sub.2 
Cl.sub.2 (30 mL) at 0.degree. C. The solution is stirred at 0.degree. C. 
and then the thiolacetic acid (0.77 g, 10.1 mmol, 2.0 equiv) is added. The 
resulting solution is warmed to room temperature and then stirred for 2 h. 
The reaction mixture is concentrated to an oil and then silica gel (20 g) 
is added. The resulting powder is purified by chromatography on silica gel 
using 7/3 hexane/EtOAc as the eluent to afford 1.18 g (74%) of the desired 
thiolacetate as a clear colorless oil. 
(3R)-3-Thio-1-[(4-methoxyphenyl)sulfonyl]pyrrolidine (7c): The thiolacetate 
(0.46 g, 1.46 mmol) in methanol (30 mL) and THF (10 mL) is stirred under 
an argon atmosphere at room temperature. The solution is then bubbled with 
ammonia gas for 20 minutes at room temperature and then the solution is 
purged with argon gas. The solvent is removed under reduced pressure to 
leave a colorless oil. Purification of the oil is accomplished by 
chromatography using 8/2 hexane/EtOAc as the eluent. The product is 
obtained as a colorless oil. MS (electron spray): 274 (M+H.sup.+). 
Example 8 
Synthesis of 3(S)-Thiomethyl-1-[(4-methoxyphenyl)sulfonyl]pyrrolidine 
##STR23## 
(1R,3S) Methyl 5-oxo-1-(1-phenylethyl)3-pyrrolidinecarboxylic acid (8a): 
Itaconic acid (16.1 g, 124 mmol), (R)-a-methylbenzylamine (15.0 g, 124 
mmol) and xylenes (150 mL) are heated to reflux for 6 h. Water is removed 
from the reaction by a Dean-Stark trap. The reaction mixture is cooled to 
room temperature and then the xylenes are removed under reduced pressure. 
The product, a white solid, is dissolved in methanol (350 mL) and a 
catalytic amount of H.sub.2 SO.sub.4 is added (0.7 g). The resulting 
solution is heated to reflux for 18 h. The solvent is removed and the 
product is purified by chromatography on silica gel (65/35 hexane/EtOAc as 
eluent) to afford both diastereomers as single entities. The low R.sub.f 
material is used in the following sequence of reactions. 
(1R,3S) 5-oxo-1-(1-phenylethyl)-3-hydroxymethylpyrrolidine (8b): The ester 
(2.27 g, 9.18 mmol) in THF (50 mL) is stirred at room temperature and then 
the LiA1H.sub.4 (0.7 g, 18.3 mmol, 2.0 equiv) is slowly added. After the 
addition is complete the solution is stirred at reflux for 4 h. The 
reaction mixture is cooled to room temperature and the EtOAc is slowly 
added (.about.5 mL). The reaction is quenched by the cautious addition of 
water (0.7 mL), 15% NaOH (0.7 mL) and water (3 mL). The solution is 
stirred at room temperature for 10 minutes and then filtered. The solvent 
is removed to leave the desired product as a colorless oil which needed no 
further purification. 
(3S) 3-Hydroxymethylpyrrolidine (8c): The amine (1.85 g, 9.01 mmol), Pd-C 
(10%) (185 mg) in methanol (25 mL) is placed under a hydrogen atmosphere 
(50 psi) for 72 h. The product is filtered over celite with the aid of 
methanol (50 mL) and then the resulting solution is concentrated to afford 
the desired amine as a light yellow oil. No further purification is 
performed. 
(3S)-3-Hydroxymethyl-1-[(4-methoxyphenyl)sulfonyl]pyrrolidine (8d): The 
3(S)-hydroxymethylpyrrolidine (0.9 g, 8.90 mmol), triethylamine (1.80 g, 
17.8 mmol, 2.0 equiv) in 1,4-dioxane (30 mL) and water (10 mL) is stirred 
at room temperature and then 4-methoxyphenylsulfonyl chloride (2.02 g, 
9.80 mmol, 1.10 equiv) is added. The resulting solution is stirred at room 
temperature for 3 h. and then the solution is acidified to pH.about.1 with 
1 N HCl. The solution is poured into water and then extracted with 
CH.sub.2 Cl.sub.2. The organic extracts are dried (Na.sub.2 SO.sub.4) and 
concentrated to an oil. The oil is purified by chromatography using 1/1 
hexane/EtOAc as the eluent to afford the desired product as a colorless 
oil. 
(3S)-3-Acetylthiomethyl-1-[(4-methoxyphenyl)sulfonyl]pyrrolidine (8e): The 
alcohol (0.8 g, 2.95 mmol) in CH.sub.2 Cl.sub.2 (20 mL) is added to a 
solution of triphenylphosphine (0.93 g, 3.54 mmol, 1.2 equiv) and 
diethylazodicarboxylate (0.57 g, 3.24 mmol, 1.1 equiv) in CH.sub.2 
Cl.sub.2 (20 mL) at room temperature. The solution is stirred 15 minutes 
at room temperature and then the thiolacetic acid (0.45 g, 5.90 mmol, 2.0 
equiv) is added. The resulting solution is stirred at room temperature for 
2 h. The reaction mixture is concentrated to an oil and then silica gel 
(20 g) is added. The resulting powder is purified by chromatography on 
silica gel using 8/2 hexane/EtOAc as the eluent to afford the desired 
thiolacetate as a clear colorless oil. 
(3S)-3-Thiomethyl-1-[(4-methoxyphenyl)sulfonyl]pyrrolidine (8f): The 
thiolacetate (0.45 g, 1.37 mmol) in methanol (30 mL) is stirred under an 
argon atmosphere at room temperature. The solution is then bubbled with 
ammonia gas for 20 minutes at room temperature and then the solution is 
purged with argon gas. The solvent is removed under reduced pressure to 
leave a colorless oil. Purification of the oil is accomplished by 
chromatography using 8/2 hexane/EtOAc as the eluent. The product is 
obtained as a colorless oil. MS (electron spray): 288 (M+H.sup.+). 
Example 9 
Synthesis of 
2-(1-Thiol-1-(2-thiazolyl)methyl)-1-[(4-methoxyphenyl)sulfonyl]piperidine 
##STR24## 
2-(R,S)-1-[(4-methoxyphenyl)sulfonyl]piperidinemethanal (9a): The 
2(R,S)-1-[(4-Methoxyphenyl)sulfonyl]piperidinemethanol (16.5 g, 57.9 mmol) 
is dissolved in 400 mL of dichloromethane at room temperature, followed by 
the addition of PDC (32.67 g, 86.8 mmol, 15 equiv). The reaction is 
stirred at room temperature overnight. In the morning, another 0.5 
equivalents of PDC is added and the reaction mixture is stirred for an 
additional 4 hours. The reaction is diluted with ether and passed through 
a short plug silica gel column with CH.sub.2 Cl.sub.2 as eluent to 
eliminate the color providing the pure product. Cl.sup.+ MS: m/z (rel 
intensity) 284.0 (M.sup.+ +H, 100). 
2-[1-Hydroxy-1-(2-thiazolyl)methyl]-1-[(4-methoxyphenyl)sulfonyl]piperidine 
(9b): Thiazole (0.576 mL, 8.13 mmol) is dissolved in 150 mL of THF and 
cooled to -78.degree. C. in a dry ice acetone bath. N-butyllithium (5.0 
mL, 8.13 mmol) is added slowly and this solution stirred for 30 minutes. 
Next, the aldehyde (2.0 g, 7.07 mmol) is dissolved in 15 mL of THF and 
cannulated into the solution at -78.degree. C. The resulting solution is 
stirred at -78.degree. C. for 1 hour and at room temperature for 2 hours. 
The reaction is quenched with 1N HCl and extracted with ethyl acetate 3 
times, the organic layer is washed with saturated sodium chloride and 
dried over magnesium sulfate and evaporated down. Chromatography is 
performed on silica gel using ethyl acetate/hexane (1/1.5) to give the 
pure compound. Cl.sup.+ MS: m/z (rel intensity) 397.0 (M.sup.+ +H, 100). 
2-[1-Thioacetyl-1-(2-thiazolyl)methyl]-1-[(4-methoxyphenyl)sulfonyl]piperid 
ine (9c): In flask 1, the azeotropically dried alcohol (0.270 g, 0.73 mmol) 
is dissolved in 20 mL of anhydrous methylene chloride, followed by the 
addition of 2,6-lutidine (0.126 mL, 1.08 mmol) and the reaction is cooled 
to -78.degree. C. in a dry ice/acetone bath. Then, the 
trifluromethanesulfonic anhydride (0.135 mL, 0.80 mmol) is added and the 
mixture stirred at -78.degree. C. for 45 minutes, then at 0 OC for five 
minutes. In a separate flask (flask 2), the thiolacetic acid (0.174 mL, 
2.44 mmol) and 2,6-lutidine (0.28 mL, 2.44 mmol) are dissolved in 10 mL of 
anhydrous methylene chloride. Flask 2 is cannulated into flask 1 at 
0.degree. C. The reaction then stirred at room temperature overnight. The 
reaction is quenched with saturated sodium bicarbonate and water, then it 
is extracted 3 times with ethyl acetate and washed with saturated ammonium 
chloride, dried over magnesium sulfate and evaporated. A silica gel column 
is run using hexanes/ethyl acetate (3/1) to give the pure compound. 
2-[1-Thiol-1-(2-thiazolyl)methyl]-[(4-methoxyphenyl)sulfonyl]piperidine 
(9d): The thiol acetate (0.100 g, 0.234 mmol) is dissolved in 8 mL of 
methanol and the solution is thoroughly degassed. Anhydrous ammonia gas is 
passed through the solution for 8 minutes and the solution stirred for an 
additional 15 minutes. The solution is evaporated down to a crude product 
which is chromatographed on silica gel with hexanes/ethyl acetate(3/1) to 
give the pure product. 
Example 10 
Synthesis of 
2-[1-thiol-2-(5-methyl-1,3,4-thiadiazol-2-yl)thio]ethyl-1-[(4-methoxypheny 
l)sulfonyl]piperidine 
##STR25## 
2-Ethenyl-1-[(4-methoxyphenyl)sulfonyl]piperidine (10a): 
Triphenylphosphinemethyliodide (22.5 g , 55.6 mmol) is suspended in 400 mL 
of THF and cooled to 0.degree. C. in an ice bath and potassium t-butoxide 
(8.33 g, 74.2 mmol) is added and the reaction mixture is stirred for 1 
hour. This produced a suspension of yellow solid in yellow solution. The 
aldehyde 9a (10.5 g, 37.1 mmol) is dissolved in 40 mL of THF and then 
added to the reaction mixture. The reaction stirred at 0.degree. C. for 4 
hours. The reaction is quenched with 1N HCl and water. This is extracted 
with ethyl acetate 3 times and the organic layers are washed with 
saturated sodium bicarbonate and ammonium chloride, dried over magnesium 
sulfate, and evaporated to provide the product. Chromatography is 
performed on silica gel using hexanes/ethyl acetate (3/1) to give the pure 
compound. Cl.sup.+ MS: m/z (rel intensity) 331.9 (M.sup.+ +H, 100). 
2-Ethylene oxide-1-[(4-methoxyphenyl)sulfonyl]piperidine (1Ob): The alkene 
(4.5 g, 16.0 mmol) is dissolved in 200 mL of dichloromethane followed by 
the addition of MCPBA (50-75% pure) (17 g, 64 mmol). The reaction mixture 
is stirred at room temperature for 26 hours. The reaction is quenched with 
sodium sulfite (10.1 g, 64.0 mmol) in water and diluted with saturated 
sodium bicarbonate. This is extracted with ethyl acetate 3 times and the 
organic layers are washed with 1N HCl, sodium bicarbonate, and ammonium 
chloride, dried over magnesium sulfate and evaporated down. Chromatography 
is performed on silica gel using hexanes/ethyl acetate/methylene chloride 
(11/3/3) to give two different diastereomers as single pure compounds. 
Cl.sup.+ MS: (rel intensity) 298 (M+ +H, 100) 
2-(1-Hydroxy-2-(5-methyl-1,3,4-thiadiazol-2-yl)thio)ethyl-1-[(4-methoxyphen 
yl)sulfonyl]piperidine (10c): The more polar epoxide (0.270 g, 0.908 mmol) 
is dissolved in 10 mL of dichloromethane and cooled to 0.degree. C. 
followed by the addition of lithium perchlorate (0.363 mL, 1.81 mmol). 
This mixture is stirred for 5 minutes then the 
5-methyl-1,3,4-thiadiazole-2-thiol (0.480 g, 3.63 mmol) is added. The 
reaction mixture is stirred from 0.degree. C. to room temperature 
overnight. The reaction is quenched with 1N HCl and extracted with ethyl 
acetate 3 times. The organic layers are washed with ammonium chloride, 
dried over magnesium sulfate and evaporated down. Chromatography is 
performed silica gel using hexanes/ethyl acetate (1/1.5) to give the pure 
compound. Cl.sup.+ MS: m/z (rel intensity)430 (M.sup.+ +H , 70). 
2-(1-Acetylthio-2-(5-methyl-1,3,4-thiadiazol-2-yl)thio)ethyl-1-[(4-methoxyp 
henyl)sulfonyl]piperidine (10d): In flask 1, the azeotropically dried 
alcohol (0.300 g, 0.698 mmol) is dissolved in 10 mL of anhydrous methylene 
chloride, followed by the addition of 2,6-lutidine (0.122 mL, 1.04 mmol) 
and the reaction is cooled down to -78.degree. C. in a dry ice/acetone 
bath. Then, the trifluromethanesulfonic anhydride (0.129 mL, 0.768 mmol) 
is added and the mixture stirred at -78.degree. C. for 45 minutes, then at 
0.degree. C. for five minutes. In a separate flask (flask 2), the thiol 
acetic acid (0.498 mL, 6.93 mmol) and 2,6-lutidine (0.81 mL, 6.93 mmol) 
are dissolved in 10 mL of anhydrous methylene chloride. Flask 2 is 
cannulated into flask 1 at 0.degree. C. The reaction then stirred at room 
temperature overnight. The reaction is quenched with saturated sodium 
bicarbonate and water, then it is extracted 3 times with ethyl acetate and 
washed with saturated ammonium chloride, dried over magnesium sulfate and 
evaporated. A silica gel column is run using hexanes/ethyl acetate (1/2.5) 
to give the pure compound. Cl.sup.+ MS: m/z (rel intensity) (M.sup.+ +H, 
100). 
2-(1-Thiol-2-(5-methyl-1,3,4-thiadiazol-2-yl)thio)ethyl-1-[(4-methoxyphenyl 
)suifonyl]piperidine (10e): The thiol acetate (0.050 g, 0.102 mmol) is 
dissolved in 5 mL of methanol and the solution is thoroughly degassed. 
Anhydrous ammonia gas is passed through the solution for 2 minutes and the 
solution stirred for an additional 5 minutes. The solution is evaporated 
under reduced pressure to leave a crude product which is chromatographed 
on silica gel with hexanes/ethyl acetate (1/2) to give the desired thiol. 
Cl.sup.+ MS: m/z (rel intensity) (M.sup.+ +H, 100). 
Example 11 
Synthesis of 
2-(R,S)-(2-methoxycarbonyl-1-(R,S)-mercapto)ethyl-1-[(4-methoxyphenyl)sulf 
onyl]piperidine 
##STR26## 
2-(2-Methoxycarbonyl)ethenyl-1-[(4-methoxyphenyl)sulfonyl]piperidine 11a: 
The aldehyde (450 mg, 1.59 mmol) is dissolved in 20 mL of acetonitrile. 
Methyl (triphenylphosphoranylidene)acetate (1.06 g, 3.18 mmol) is added. 
The solution is warmed to reflux and stirred for 20 hours. After cooling 
to room temperature, the solvent is removed by rotary evaporation. 
Chromatography is performed on silica gel using hexanes/ethyl acetate 
(2/1) to give pure compound. Cl.sup.+ MS: m/z (rel intensity) 340 (M.sup.+ 
+H, 53). 
2-(R,S)-(2-Methoxycarbonyl-1-(R,S)-thiacetyl)ethyl-1-[(4-methoxyphenyl)sulf 
onyl]piperidine 11b: The a,b-unsaturated ester (462 mg, 1.36 mmol) is 
dissolved in 25 mL of thiolacetic acid. The solution is warmed to 
80.degree. C. and stirred for 5 days. After cooling to room temperature, 
the solvent is removed by rotary evaporation. Chromatography is performed 
on silica gel using methanol/dichloromethane (3%) to give pure compound. 
Cl.sup.+ MS: m/z (rel intensity) 416 (M.sup.+ +H, 100). 
2-(R,S)-(2-Methoxycarbonyl-1-(R,S)-mercapto)ethyl-1-[(4-methoxyphenyl)sulfo 
nyl]piperidine 11c: The thiolacetate is dissolved in 25 mL of methanol and 
the solution degassed with argon for 20 minutes. The solution is cooled to 
-50.degree. C. and ammonia is bubbled in at such a rate as to keep the 
temperature below -20.degree. C. When the addition of ammonia is no longer 
exothermic, the flow is stopped and the mixture is stirred under argon at 
-60.degree. C. for 1 hour. The mixture is warmed to room temperature and 
the solvent removed by rotary evaporation. Chromatography is performed on 
silica gel using methanol/dichloromethane (0.5%) to give pure compounds as 
separable diastereomers. Cl.sup.+ MS: m/z (rel intensity) 374 (M.sup.+ +H, 
65). 
Example 12 
Synthesis of 
2-(R,S)-(2-methylthio-1-(R,S)-mercapto)ethyl-1-[(4-methoxyphenyl)sulfonyl] 
piperidine 
##STR27## 
2-(R,S)-(2-ethylene sulfide)-1-[(4-methoxyphenyl)sulfonyl]piperidine 12a: 
The epoxide (0.124 mg, 0.415 mmol) is dissolved in 3.7 mL of methanol 
under argon. Thiourea (63.3 mg, 0.831 mmol) is added and the mixture 
stirred for 7 days. The solvent was removed by rotary evaporation. 
Chromatography is performed on silica gel using hexanes/ethyl acetate 
(2/1) to give pure compound. FAB.sup.+ MS: m/z (rel intensity) 374 
(M.sup.+ +H, 23). 
2-(R,S)-(2 
-methylthio-1-(R,S)-mercapto)ethyl-1-[(4-methoxyphenyl)sulfonyl]piperidine 
12b: The episulfide (25.7 mg, 0.0798 mmol) is dissolved in 4 mL of DMF 
under argon. Triethylamine (53 mL, 0.383 mmol) is added and the mixture is 
cooled to -55.degree. C. Methyl mercaptan is passed through the solution 
for 15 minutes and the mixture stirred at -55.degree. C. for 4 hours. The 
bath is removed and the mixture stirred at room temperature for 16 hours. 
The solvent is removed by rotary evaporation. The crude product is 
purified by radial chromatography using hexanes/ethyl acetate (6/1). ion 
spray MS: m/z (rel intensity) 362 (M.sup.+ +H, 42). 
Example 13 
Synthesis of 
2-(R,S)-(1-(R,S)-methylthio-2-mercapto)ethyl-1-[(4-methoxyphenyl)sulfonyl] 
piperidine 
##STR28## 
2-(R,S)-( 
1-(R,S)-methylthio-2-chloro)ethyl-1-[(4-methoxyphenyl)sulfonyl]piperidine 
13a: Methyl disulfide (32 mL, 0.355 mmol) is dissolved in 5 mL of 
1,2-dichloroethane and cooled to -40.degree. C. Sulfuryl chloride (29 mL, 
0.355 mmol) is added via syringe. The mixture is warmed -10.degree. C. and 
cooled to -40.degree. C. A solution of the alkene in 1 mL of 
1,2-dichloroethane is added via syringe. The cold bath is removed and the 
mixture stirred at room temperature for 16 hours. The solvent is removed 
by rotary evaporation. Chromatography is performed on silica gel using 
hexanes/ethyl acetate (4/1) to give pure compound. Cl.sup.+ MS: m/z (rel 
intensity) 364 (M.sup.+ +H, 100). 
2-(R,S)-(1-(R,S)-methylthio-2-mercapto)ethyl-1-[(4-methoxyphenyl)sulfonyl]p 
iperidine 13b: The chlorosulfide (50.0 mg, 0.137 mmol) is dissolved in 5 mL 
of 95% ethanol. Thiourea (12.6 mg, 0.165 mmol) is added and the mixture 
warmed to reflux temperature for 4 hours. After cooling to room 
temperature, the solvent is removed by rotary evaporation. The residue is 
treated with 5 mL of concentrated ammonium hydroxide at 85.degree. C. for 
1 hour. The mixture is cooled to room temperature, diluted with water, and 
extracted with two portions of ethyl acetate. The combined organic layers 
are washed three times with water, dried over MgSO.sub.4, filtered, and 
the solvent removed by rotary evaporation. The crude product is purified 
by radial chromatography using hexanes/ethyl acetate (4/1). ion spray MS: 
m/z (rel intensity) 362 (M.sup.+ +H, 100). 
Example 14 
Synthesis of 
2-(R,S)-(1-(R,S)-2-dithio)ethyl-1-[(4-methoxyphenyl)sulfonyl]piperidine 
##STR29## 
2-(R,S)-(2-thioacetyl-1-(R,S)-mercapto)ethyl-1-[(4-methoxyphenyl)sulfonyl]p 
iperidine 14a: The episulfide (25 mg, 0.0798 mmol) is dissolved in 2 mL of 
ethyl acetate. Triethylamine (40 mL, 0.287 mmol) and thiolacetic acid (25 
mL, 0.251 mmol) are added and the mixture stirred for 16 hours at room 
temperature and 4.5 hours at 50.degree. C. The reaction mixture is diluted 
with ethyl acetate and washed with three portions of 5% NaHCO.sub.3. The 
organic layer is dried over Na.sub.2 SO.sub.4, filtered, and the solvent 
removed by rotary evaporation. The crude product is purified by radial 
chromatography using hexanes/ethyl acetate (4/1). 
2-(R,S)-(1-(R,S)-2-dithio)ethyl-1-[(4-methoxyphenyl)sulfonyl]piperidine 
14b: The thiolacetate is dissolved in 25 mL of methanol and the solution 
degassed with argon for 20 minutes. The solution is cooled to -50.degree. 
C. and ammonia is bubbled in at such a rate as to keep the temperature 
below -20.degree. C. When the addition of ammonia is no longer exothermic, 
the flow is stopped and the mixture is stirred under argon at -60.degree. 
C. for 1 hour. The mixture is warmed to room temperature and the solvent 
removed by rotary evaporation. The crude product is purified by radial 
chromatography using methanol/dichloromethane (0.5%). ion spray.sup.+ MS: 
m/z (rel intensity) 348 (M.sup.+ +H, 100). 
The following compounds are made using the methods described and 
exemplified above. For the purpose of illustration, Y is shown as R2 and Z 
is shown as R1 
__________________________________________________________________________ 
#STR30## 
Z Y (n) 
Ar 
__________________________________________________________________________ 
Example 15 
--CH.sub.2 SH 
--OH 1 4-MeOC.sub.6 H.sub.4 -- 
Example 16 --CH.sub.2 SH --SC.sub.6 H.sub.6 OMe 1 4-MeOC.sub.6 H.sub.4 
-- 
Example 17 H SH 2 4-MeOC.sub.6 H.sub.4 -- 
Example 18 MeO.sub.2 CCH.sub.2 CH(SH)-- OH 1 4-MeOC.sub.6 H.sub.4 -- 
Example 19 MeO.sub.2 CCH.sub.2 CH(SH)-- 
SH 1 4-MeOC.sub.6 H.sub.4 -- 
Example 20 MeO.sub.2 CCH.sub.2 CH(SH)CH.sub.2 -- H 2 4-MeOC.sub.6 
H.sub.4 -- 
Example 21 t-BuO.sub.2 CCH.sub.2 CH(SH)-- H 2 4-MeOC.sub.6 H.sub.4 -- 
Example 22 HO.sub.2 CCH.sub.2 CH(SH)-- H 
2 4-MeOC.sub.6 H.sub.4 -- 
Example 23 MeSCH.sub.2 CH(SMe)-- H 2 4-MeOC.sub.6 H.sub.4 -- 
Example 24 (N-morpholinyl)- H 2 4-MeOC.sub.6 H.sub.4 -- 
(CH.sub.2).sub.2 NHCOCH.sub.2 CH(SH)-- 
Example 25 MeO.sub.2 CCH.sub.2 CH(SH)-- --OCH.sub.2 CH.sub.2 O-- 1 
C.sub.6 H.sub.5 -- 
Example 26 MeO.sub.2 CCH.sub.2 CH(SH)-- --SCH.sub.2 CH.sub.2 S-- 1 
4-MeOC.sub.6 H.sub.4 -- 
Example 27 MeO.sub.2 CCH.sub.2 CH(SH)-- --SCH.sub.2 CH.sub.2 CH.sub.2 
S-- 1 4-MeOC.sub.6 H.sub.4 -- 
Example 28 HSCH.sub.2 OH 1 n-HEXYL 
Example 29 HSCH.sub.2 CH(SMe)-- OMe 1 n-BUTYL 
Example 30 MeSCH.sub.2 CH(SMe)-- (2-benzathiazole) 2 2-PYRIDYL 
Example 31 HSCH.sub.2 (2-imidazole) 2 4-MeOC.sub.6 H.sub.4 -- 
Example 32 PhSCH.sub.2 OPh 3 4-MeOC.sub.6 H.sub.4 -- 
Example 33 HSCH.sub.2 HO(C.sub.6 H.sub.4)OCH.sub.2 Ph 1 4-MeOC.sub.6 
H.sub.4 -- 
Example 34 HSCH.sub.2 O(2-(C.sub.6 H.sub.4)NHPh) 2 4-MeOC.sub.6 H.sub.4 
-- 
Example 35 HSCH.sub.2 OXY(2-PYRIDYL) 1 2-PYRIDYL 
Example 36 PhSCH.sub.2 SPh 2 4-MeOC.sub.6 H.sub.4 -- 
Example 37 HSCH.sub.2 S(4-C.sub.6 H.sub.4 OMe) 2 4-MeOC.sub.6 H.sub.4 
-- 
Example 38 HSCH.sub.2 SPh 2 4-MeOC.sub.6 H.sub.4 -- 
Example 39 MeO.sub.2 CCH.sub.2 CH(SH)CH.sub.2 -- H 2 4-MeOC.sub.6 
H.sub.4 -- 
Example 40 HSCH.sub.2 NH(CH.sub.2).sub.5 CH.sub.3 2 4-MeOC.sub.6 
H.sub.4 -- 
__________________________________________________________________________ 
Me = methyl, 
Ph = phenyl; 
C.sub.6 H.sub.4 = phenyl diradical 
The following compounds are made using the methods described and 
exemplified above. All compounds exemplified below have Z (or R.sub.1) as 
MeO.sub.2 CCH.sub.2 
______________________________________ 
#STR31## 
Y Ar n 
______________________________________ 
Example 41 
--NHCO(pyridyl) --C.sub.6 H.sub.4 OCH.sub.3 
1 
Example 42 --NHCOCH.sub.3 --C.sub.6 H.sub.4 OCH.sub.3 1 
Example 43 --NHCOCH.sub.2 C.sub.6 H.sub.5 --C.sub.6 H.sub.4 OCH.sub.3 1 
Example 44 --NHSO.sub.2 NHCH.sub.2 CH.sub.3 --C.sub.6 H.sub.4 OCH.sub.3 
1 
Example 45 --NHSO.sub.2 NH.sub.2 --C.sub.6 H.sub.4 OCH.sub.3 1 
Example 46 --NHSO.sub.2 N(CH.sub.3).sub.2 --C.sub.6 H.sub.4 OCH.sub.3 1 
Example 47 --NHSO.sub.2 CH.sub.3 --C.sub.6 H.sub.4 OCH.sub.3 1 
Example 48 --NHSO.sub.2 C.sub.6 H.sub.4 OCH.sub.3 --C.sub.6 H.sub.4 
OCH.sub.3 1 
Example 49 --NHP(O)(CH.sub.3)C.sub.6 H.sub.5 --C.sub.6 H.sub.4 OCH.sub.3 
1 
Example 50 --N(CH.sub.3)COC.sub.6 H.sub.5 --C.sub.6 H.sub.4 OCH.sub.3 1 
Example 51 --N(CH.sub.3)(CH.sub.2 CH.sub.2 CH.sub.3) --C.sub.6 H.sub.4 
OCH.sub.3 1 
Example 52 --N(CH.sub.2 CH.sub.2 CH.sub.3).sub.2 --C.sub.6 H.sub.4 
OCH.sub.3 1 
Example 53 --N(CH.sub.2 CH.sub.3)SO.sub.2 CH.sub.3 --C.sub.6 H.sub.4 
OCH.sub.3 1 
Example 54 --CH.sub.2 NHSO.sub.2 CH.sub.3 --C.sub.6 H.sub.4 OCH.sub.3 1 
Example 55 --CH.sub.2 NHSO.sub.2 C.sub.6 H.sub.5 --C.sub.6 H.sub.4 
OCH.sub.3 1 
Example 56 --CH.sub.2 NHCOC.sub.6 H.sub.5 --C.sub.6 H.sub.4 OCH.sub.3 1 
Example 57 --CH.sub.2 NHCOCH.sub.2 CH.sub.2 CH.sub.3 --C.sub.6 H.sub.4 
NO.sub.2 1 
Example 58 --CH.sub.2 N(CH.sub.3)COCH.sub.3 --C.sub.6 H.sub.4 Br 1 
Example 59 --CH.sub.2 N(CH.sub.3)S 
O.sub.2 C.sub.6 H.sub.5 OMe 
--C.sub.6 H.sub.4 Br 1 
Example 60 --CH.sub.2 N(CH.sub.2 C.sub.6 H.sub.5)SO.sub.2 CH.sub.3 
--C.sub.6 H.sub.4 Br 1 
Example 61 --OH --C.sub.6 H.sub.4 OCH.sub.3 2 
Example 62 --S--C.sub.6 H.sub.5 --C.sub.6 H.sub.4 OCH.sub.3 2 
Example 63 --H --C.sub.6 H.sub.4 OCH.sub.3 2 
Example 64 --OH --C.sub.6 H.sub.4 OCH.sub.3 1 
Example 65 --(OH)[CH(CH.sub.3).sub.2 ] --C.sub.6 H.sub.4 OCH.sub.3 1 
Example 66 --(OH)(C.sub.6 
H.sub.5) --C.sub.6 H.sub.4 
OCH.sub.3 1 
Example 67 --(OH)(2-thiophenyl) --C.sub.6 H.sub.4 OCH.sub.3 1 
______________________________________ 
These examples provide the skilled artisan with sufficient guidance as to 
making the present invention and do not limit it in any way. 
Composition and Method of Use Examples 
The compounds of the invention are useful to prepare compositions for the 
treatment of ailments and the like. The following composition and method 
examples do not limit the invention, but provide guidance to the skilled 
artisan to prepare and use the compounds, compositions and methods of the 
invention. In each case the compounds formula I may be substituted for the 
example compound shown below with similar results. 
The methods of use exemplified do not limit the invention, but provide 
guidance to the skilled artisan to use the compounds, compositions and 
methods of the invention. The skilled practitioner will appreciate that 
the examples provide guidance and may be varied based on condition and the 
patient. 
Example A 
A tablet composition for oral administration, according to the present 
invention, is made comprising: 
______________________________________ 
Component Amount 
______________________________________ 
Example 9 15. mg 
Lactose 120. mg 
Maize Starch 70. mg 
Talc 4. mg 
Magnesium Stearate 1. mg 
______________________________________ 
Other compounds having a structure according to Formula (I) are used with 
substantially similar results. 
A human female subject weighing 60 kg (132 lbs), suffering from rheumatoid 
arthritis, is treated by a method of this invention. Specifically, for 2 
years, a regimen of three tablets per day is administered orally to said 
subject. 
At the end of the treatment period, the patient is examined and is found to 
have reduced inflammation, and improved mobility without concomitant pain. 
Example B 
A capsule for oral administration, according to the present invention, is 
made comprising: 
______________________________________ 
Component Amount (% w/w) 
______________________________________ 
Example 3 15% 
Polyethylene glycol 85% 
______________________________________ 
Other compounds having a structure according to Formula (I) are used with 
substantially similar results. 
A human male subject weighing 90 kg (198 lbs), suffering from 
osteoarthritis, is treated by a method of this invention. Specifically, 
for 5 years, a capsule containing 70 mg of Example 3 is administered daily 
to said subject. 
At the end of the treatment period, the patient is examined via orthoscopy, 
and found to have no further advancement of erosion/fibrillation of the 
articular cartilage. 
Example C 
A saline-based composition for local administration, according to the 
present invention, is made comprising: 
______________________________________ 
Component Amount (% w/w) 
______________________________________ 
Example 13 5% 
Polyvinyl alcohol 15% 
Saline 80% 
______________________________________ 
Other compounds having a structure according to Formula (I) are used with 
substantially similar results. 
A patient having deep corneal abrasion applies the drop to each eye twice a 
day. Healing is speeded, with no visual sequelae. 
Example D 
An topical composition for local administration, according to the present 
invention, is made comprising: 
______________________________________ 
Component Composition (% w/v) 
______________________________________ 
Compound of Example 3 
0.20 
Benzalkonium chloride 0.02 
Thimerosal 0.002 
d-Sorbitol 5.00 
Glycine 0.35 
Aromatics 0.075 
Purified water g.s. 
Total = 100.00 
Total = 100.00 
______________________________________ 
Any of the other compounds having a structure according to Formula (I) are 
used with substantially similar results. 
A patient suffering from chemical bums applies the composition at each 
dressing change (b.i.d.). Scarring is substantially diminished. 
Example E 
A inhalation aerosol composition, according to the present invention, is 
made comprising: 
______________________________________ 
Component Composition (% w/v) 
______________________________________ 
Compound of Example 2 
5.0 
Alcohol 33.0 
Ascorbic acid 0.1 
Menthol 0.1 
Sodium Saccharin 0.2 
Propellant (F12, F114) g.s. 
Total = 100.0 
______________________________________ 
Any of the other compounds having a structure according to Formula (I) are 
used with substantially similar results. 
An asthma sufferer sprays 0.01 mL via a pump actuator into the mouth while 
inhaling. Asthma symptoms are diminished. 
Example F 
A topical opthalmic composition, according to the present invention, is 
made comprising: 
______________________________________ 
Component Composition (% w/v) 
______________________________________ 
Compound of Example 5 0.10 
Benzalkonium chloride 0.01 
EDTA 0.05 
Hydroxyethylcellulose (NATROSOL M .TM.) 0.50 
Sodium metabisulfite 0.10 
Sodium chloride (0.9%) g.s. 
Total = 100.0 
______________________________________ 
Any of the other compounds having a structure according to Formula (I) are 
used with substantially similar results. 
A human male subject weighing 90 kg (198 lbs), suffering from corneal 
ulcerations, is treated by a method of this invention. Specifically, for 2 
months, a saline solution containing 10 mg of Example 5 is administered to 
said subject's affected eye twice-daily. 
Example G 
A composition for parenteral administration is made comprising: 
______________________________________ 
Component Amount 
______________________________________ 
Example 4 100 mg/ml carrier 
Carrier: 
sodium citrate buffer with (percent 
by weight of carrier): 
lecithin 0.48% 
carboxymethylcellulose 0.53 
povidone 0.50 
methyl paraben 0.11 
propyl paraben 0.011 
______________________________________ 
The above ingredients are mixed, forming a suspension. Approximately 2.0 ml 
of the suspension is administered, via injection, to a human subject with 
a premetastatic tumor. The injection site juxtaposes the tumor. This 
dosage is repeated twice daily, for approximately 30 days. After 30 days, 
symptoms of the disease subside, and dosage is gradually decreased to 
maintain the patient. 
Other compounds having a structure according to Formula I are used with 
substantially similar results. 
Example H 
A mouthwash composition is prepared; 
______________________________________ 
Component % w/v 
______________________________________ 
Example 1 3.00 
SDA 40 Alcohol 8.00 
Flavor 0.08 
Emulsifier 0.08 
Sodium Fluoride 0.05 
Glycerin 10.00 
Sweetener 0.02 
Benzoic acid 0.05 
Sodium hydroxide 0.20 
Dye 0.04 
Water balance to 100% 
______________________________________ 
A patient with gum disease uses 1 ml of the mouthwash thrice daily to 
prevent further oral degeneration. 
Other compounds having a structure according to Formula I are used with 
substantially similar results. 
Example I 
A lozenge composition is prepared; 
______________________________________ 
Component % w/v 
______________________________________ 
Example 3 0.01 
Sorbitol 17.50 
Mannitol 17.50 
Starch 13.60 
Sweetener 1.20 
Flavor 11.70 
Color 0.10 
Corn Syrup balance to 100% 
______________________________________ 
A patient uses the losenge to prevent loosening of an implant in the 
maxilla. . Other compounds having a structure according to Formula I are 
used with substantially similar results. 
Example J 
Chewing Gum Composition 
______________________________________ 
Component w/v % 
______________________________________ 
Example 1 0.03 
Sorbitol crystals 38.44 
Paloja-T gum base* 20.00 
Sorbitol (70% aqueous solution) 22.00 
Mannitol 10.00 
Glycerine 7.56 
Flavor 1.00 
______________________________________ 
A patient chews the gum to prevent loosening to prevent loosening of 
dentures. 
Other compounds having a structure according to Formula I are used with 
substantially similar results. 
Example K 
______________________________________ 
Components w/v % 
______________________________________ 
USP Water 54.656 
Methylparaben 0.05 
Propylparaben 0.01 
Xanthan Gum 0.12 
Guar Gum 0.09 
Calcium carbonate 12.38 
Antifoam 1.27 
Sucrose 15.0 
Sorbitol 11.0 
Glycerin 5.0 
Benzyl Alcohol 0.2 
Citric Acid 0.15 
Coolant 0.00888 
Flavor 0.0645 
Colorant 0.0014 
______________________________________ 
Example 1 is prepared by first mixing 80 kg of gylcerin and all of the 
benzyl alcohol and heating to 65 C, then slowly adding and mixing together 
methylparaben, propylparaben, water, xanthan gum, and guar gum. Mix these 
ingredients for about 12 minutes with a Silverson in-line mixer. Then 
slowly add in the following ingredients in the following order: remaining 
glycerin, sorbitol, antifoam C, calcium carbonate, citric acid, and 
sucrose. Separately combine flavors and coolants and then slowly add to 
the other ingredients. Mix for about 40 minutes. 
The patient takes the formulation to prevent flare up of colitis. 
All references described herein are hereby incorporated by reference. 
While particular embodiments of the subject invention have been described, 
it will be obvious to those skilled in the art that various changes and 
modifications of the subject invention can be made without departing from 
the spirit and scope of the invention. It is intended to cover, in the 
appended claims, all such modifications that are within the scope of this 
invention.