THIOL SULFONAMIDE METALLOPROTEASE INHIBITORS

INHIBITEURS DE METALLOPROTEASES A BASE DE SULFONAMIDE DE THIOL

English Abstract

This invention is directed to proteinase (protease) inhibitors, and more
particularly to thiol sulfonamide inhibitors for matrix metalloproteinase
13(MMP-13), compositions of proteinase inhibitors, intermediates for the
syntheses of proteinase inhibitors, processes for the preparation of
proteinase inhibitors and processes for treating pathological conditions
associated with phatological matrix metalloproteinase activity related to MMP-
13.

French Abstract

Cette invention se rapporte à des inhibiteurs de protéinases (protéases) et plus particulièrement à des inhibiteurs à base de sulfonamide de thiol pour les métalloprotéinases matricielles 13 (MMP-13), à des compositions d'inhibiteurs de protéinases, à des intermédiaires pour la synthèse de ces inhibiteurs de protéinases, à des procédés pour la préparation d'inhibiteurs de protéinases et à des procédés pour traiter des états pathologiques associés à une activité pathologique des métalloprotéinases matricielles de type MMP-13.

Claims

-277-
WHAT IS CLAIMED IS:
1. A matrix metalloprotease inhibitor
compound corresponding to the formula:
<IMG>
<IMG>
or
<IMG>
wherein
R1 is a radical having a length greater
than that of a saturated four carbon chain, and
shorter than that of a saturated eighteen carbon
chain, and when rotated about an axis drawn through
the SO2-bonded 1-position and the 4-position of a
6-membered ring or the SO2-bonded position and
substituent-bonded 3- or S-position of a 5-membered
ring defines a three-dimensional volume whose widest
dimension has the width of about one phenyl ring to

-278-
about three Dhenyl rings in a direction transverse to
that axis to rotation;
R2 is selected from the group consisting of
hydrido, a C1-C6 alkyl group, a C2-C4 alkyl group
substituted by amino, mono-substituted amino or
di-substituted amino, wherein the substituents on
nitrogen are chosen from C1-C6 alkyl, aralkyl, C5-C8
cycloalkyl and C1-C6 alkanoyl, or wherein the two
substitutents and the nitrogen to which they are
attached when taken together form a 5- to 8-membered
heterocyclo or heterozaryl ring containing zero or
one additional hetero atoms that are nitrogen, oxygen
or sulfur and a C1-C4 alkylaryl or C1-C4
alkylheteroaryl group having a single ring;
R4 is a hydroxycarbonyl, aminocarbonyl or
C1-C5 alkyl group;
W is oxygen or sulfur; and
R9 is a C1-C6 alkyl group, a C1-C6 alkoxy
group, or a single-ringed carbocyclic aryl or
heteroaryl group,
with the proviso that R2 is hydrido only
when R1 is 4-(phenylazo)phenyl.
2. The inhibitor compound according to
claim 1 wherein R1 has a length greater than that of
a pentyl group and less than that of a lauryl group.
3. The inhibitor compound according to
claim 1 wherein R1 is a single-ringed aryl or
heteroaryl group that is 5- or 6-membered, and is
itself unsubstituted or substituted at its own 4-position
when a 6-membered ring and at its own 3-position
when a 5-membered ring with a substituent
selected from the group consisting of one other
single-ringed aryl or hetroaryl group, an alkyl or

-279-
alkoxy group containing an unbranched chain of 3 to
about 7 carbon atoms, a phenoxy group, a thiophenoxy
group, a phenylazo group and a benzamido group.
4. A matrix metalloprotease inhibitor
corresponding to the formula:
<IMG>
<IMG>
or
<IMG>
wherein
Ph is phenyl substituted with R11 at the
4-position;
R11 is a substituent selected from the
group consisting of C3-C8 alkoxy, C3-C8 alkyl,
phenoxy, thiophenoxy, benzamido, phenylazo and
phenyl;
R2 is selected from the group consisting of
hydrido, a C1-C6 alkyl group, a C2-C3 alkylene

-280-
cycloamino group having five or six atoms in the ring
and zero or one additional heteroatom that is oxygen
or nitrogen, and a C1-C4 alkylheteroaryl group having
a single heteroaryl ring wherein said single
heteroaryl ring contains one or two nitrogen atoms;
R4 is a C1-C6 alkyl group, or carbamido
group; and
R9 is a C1-C6 alkyl, C1-C6 alkoxy, or a
single-ringed aryl or heteroaryl group,
with the proviso that R2 is hydrido only
when R11 is phenylazo.
5. The inhibitor compound according to
claim 4 wherein R9 is selected from the group
consisting of phenyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, thiophene-2-yl, 3-thiophene-3-yl, methyl,
ethyl, methoxy and ethoxy.
6. The inhibitor compound according to
claim 4 wherein the R11 substituent group is itself
substituted at the 3- or 4-position, or both, with a
single atom or a substituent containing a longest
chain of up to five atoms excluding hydrogen.
7. The inhibitor compound according to
claim 6 wherein the said R11 substituent is selected
from the group consisting of 4-substituted a halogen,
a C1-C4 alkoxy group, a C1-C4 alkyl group, a
dimethylamino group and a two or three carbon-containing
carboxyl group, or a 3,4-methylenedioxy
group.
8. A matrix metalloprotease inhibitor
corresponding to the formula:

-281-
<IMG> <IMG>
wherein
R1 is a radical having a length greater
than that of a saturated four carbon chain, and
shorter than that of a saturated eighteen carbon
chain, and when rotated about an axis drawn through
the SO2-bonded 1-position and the 4-position of a
6-membered ring or the SO2-bonded position and
substituent-bonded 3- or 5-position of a 5-membered
ring defines a three-dimensional volume whose widest
dimension has the width of about one phenyl ring to
about three phenyl rings in a direction transverse to
that axis to rotation;
R2 is selected from the group consisting of
hydrido, a C1-C6 alkyl group, a C2-C4 alkyl group
substituted by amino, mono-substituted amino or
di-substituted amino, wherein the substituents on
nitrogen are chosen from C1-C6 alkyl, aralkyl, C5-C8
cycloalkyl and C1-C6 alkanoyl, or wherein the two
substituents and the nitrogen to which they are
attached when taken together form a 5- to 8-membered
heterocyclo or heterozaryl ring containing zero or
one additional hetero atoms that are nitrogen, oxygen
or sulfur and a C1-C4 alkylaryl or C1-C4
alkylheteroaryl group having a single ring;
R4 is a hydroxycarbonyl, aminocarbonyl or
C1-C6 alkyl group; and

-282-
R9 is a C1-C6 alkyl group, a C1-C6 alkoxy
group, or a single-ringed carbocyclic aryl or
heteroaryl group.
9. The inhibitor compound according to
claim 8 wherein R1 is a single-ringed aryl or
heteroaryl group that is 5- or 6-membered, and is
itself substituted at its own 4-position when a 6-membered
ring and at its own 3-position when a 5-membered
ring with a substituent selected from the
group consisting of one other single-ringed aryl or
hetroaryl group, an alkyl or alkoxy group containing
an unbranched chain of 3 to about 7 carbon atoms, a
phenoxy group, a thiophenoxy group, a phenylazo group
and a benzamido group.
10. A matrix metalloprotease inhibitor
corresponding to the formula:
<IMG>
wherein
Ph is phenyl substituted with R11 at the
4-position;
R11 is a substituent selected from the
group consisting of C3-C8 alkoxy, C3-C8 alkyl,
phenoxy, thiophenoxy, benzamido, phenylazo and
phenyl;
R2 is selected from the group consisting of
hydrido, a C1-C6 alkyl group, a C2-C3 alkylene

-283-
cycloamino group having five or six atoms in the ring
and zero or one additional heteroatom that is oxygen
or nitrogen, and a C1-C4 alkylheteroaryl group having
a single heteroaryl ring wherein said single
heteroaryl ring contains one or two nitrogen atoms;
R4 is a C1-C6 alkyl group, or carbamido
group; and
R9 is a C1-C6 alkyl, C1-C6 alkoxy, or a
single-ringed aryl or heteroaryl group.
11. The inhibitor compound according to
claim 10 wherein R2 is a hydrido, a C1-C6 alkyl
group, a C2-C3 alkylene cycloamino group having five
or six atoms in the ring and zero or one additional
heteroatom that is oxygen or nitrogen, or a C2-C3
alkylheteroaryl group wherein the single aryl ring
contains one or two nitrogen atoms.
12. A process for treating a host mammal
having a condition associated with pathological
matrix metalloprotease activity that comprises
administering a metalloprotease inhibitor in an
effective amount to a mammalian host having such a
condition, said metalloprotease inhibitor
corresponding in structure to formulas I, II or III
below
<IMG>

-284-
<IMG>
or
<IMG>
wherein
x represents 0, 1 or 2;
W is oxygen or sulfur;
a starred R group or x is the same or
different from an unstarred R or x;
R9 is selected from the group consisting of
alkyl, aryl, alkoxy, cycloalkyl, aryloxy, aralkoxy,
aralkyl, aminoalkyl, heteroaryl and N-monosubstituted
or N,N-disubstituted aminoalkyl wherein the
substituent(s) on the nitrogen are selected from the
group consisting of alkyl, aryl, aralkyl, cycloalkyl,
aralkoxycarbonyl, alkoxycarbonyl, and alkanoyl, or
wherein the nitrogen and two substituents attached
thereto form a S to 8 member heterocyclo or
heteroaryl ring;
R1 is selected from the group consisting of
alkyl, cycloalkyl, heterocycloalkyl, aralkyl,
heteroaralkyl, aralkoxyalkyl, aryloxyalkyl,
hydroxyalkyl, alkanoylalkyl, aralkanoylalkyl,
arylcarbonylalkyl, haloalkyl, aralkylaryl,
aryloxyalkylaryl, aralkoxyaryl, arylazoaryl,
arylhydrazinoaryl, alkylthioalkyl, alkylthioaryl,

-285-
arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl,
and aralkylthioaryl, the sulfoxide or sulfone of any
of said thio substituents, aryl, heteroaryl, and a
fused ring structure comprising two or more 5- or
6-membered rings selected from the group consisting of
aryl, heteroaryl, carbocyclic and heterocyclic, the
aryl and heteroaryl substituents of which R1 may be
comprised being unsubstituted or substituted with one
or more substituents independently selected from
among halo, C1-C10 alkyl, C1-C10 alkoxy, nitro,
cyano, perfluoroalkyl, trifluoromethylalkyl, hydroxy,
thiol, hydroxycarbonyl, aryloxy, arylthio, arylamino,
aralkyl, aryl, heteroaryloxy, heteroarylthio,
heteroarylamino, heteroaralkyl, cycloalkyl,
heterocyclooxy, heterocyclothio, heterocycloamino,
cycloalkyloxy, cycloalkylthio, cycloalkylamino,
heteroaralkoxy, heteroaralkylthio,
heteroaralkylamino, aralkoxy, aralkylthio,
aralkylamino, heterocyclic, heteroaryl, arylazo,
hydroxycarbonylalkoxy, alkoxycarbonylalkoxy,
alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy,
aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy,
alkylthio, alkoxyalkylthio, alkoxycarbonyl,
aryloxyalkoxyaryl, arylthioalkylthioaryl,
aryloxyalkylthioaryl, arylthioalkoxyaryl,
hydroxycarbonylalkoxy, hydroxycarbonylalkylthio,
alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino,
alkanoylamino, arylcarbonylamino, aralkanoylamino,
heteroarylcarbonylamino, heteroaralkanoylamino, and
N-monosubstituted or N,N-disubstituted aminoalkyl
wherein the substituent(s) on the nitrogen are
selected from the group consisting of alkyl, aryl,
aralkyl, cycloalkyl, aralkoxycarbonyl,
alkoxycarbonyl, and alkanoyl, or wherein the nitrogen
and two substituents attached thereto form a 5 to 8
member heterocyclo or heteroaryl ring;

-286-
R2 is selected from the group consisting of
hydrogen, alkyl, aryl, aralkyl, heteroaryl,
heteroaralkyl, alkynylalkyl, alkenylalkyl, thioalkyl,
cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl,
alkoxyalkyl, aralkoxyalkyl, aminoalkyl,
alkoxyalkoxyalkyl, aryloxyalkyl, hydroxyalkyl,
hydroxycarbonylalkyl, hydroxycarbonylaralkyl, or
N-monosubstituted or N,N-disubstituted aminoalkyl
wherein the substituent(s) on the nitrogen are
selected from the group consisting of alkyl, aralkyl,
cycloalkyl and alkanoyl, or wherein the nitrogen and
two substituents attached thereto form a 5- to
8-member heterocyclo or heteroaryl ring;
R3 and R4 are independently selected from
the group consisting of hydrogen, alkyl, cycloalkyl,
cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl,
aryloxyalkyl, aralkoxyalkyl, aralkyl, aryl,
heteroaryl, heteroaralkyl, hydroxycarbonylalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
hydroxycarbonyl, alkoxycarbonyl, perfluoroalkyl,
trifluoromethylalkyl, thioalkyl, alkylthioalkyl,
arylthioalkyl, aralkylthioalkyl,
heteroaralkylthioalkyl, or a sulfoxide or sulfone of any of said
thio substituents, aminocarbonyl, aminocarbonylalkyl
and N-monosubstituted or N,N-disubstituted
aminocarbonyl or aminocarbonylalkyl wherein the
substituent(s) on the nitrogen are independently
selected from among alkyl, aralkyl, cycloalkyl and
alkanoyl, or wherein the nitrogen and two
substituents attached thereto form a 5- to 8-member
heterocyclo or heteroaryl ring, R2 and R4 together
with the atoms to which they are attached optionally
forming a 4- to 8-membered ring, or R3 and R4
together with the atoms to which they are attached
optionally forming a 3- to 8-membered ring;

-287-
R5 and R6 are independently selected from
the substituents that may constitute R3 and R4, R5
and R3 together with atoms to which they are attached
optionally forming a 3- to 8-membered ring, or R5 and
R2 together with the atoms to which they are attached
optionally forming a 4- to 8-membered ring, or R5 and
R6 together with atoms to which they are attached
optionally forming a 3- to 8-membered ring;
R7 and R8 are independently selected from
the substituents that may constitute R3 and R4, R7
and R2 together with the atoms to which they are
attached optionally forming a 4- to 8-membered ring,
or R7 and R8 together with the atoms to which they
are attached optionally forming a 3- to 8-membered
ring, or R7 and R3 or R7 and R5 together with the
atoms to which they are attached optionally forming a
3- to 8-membered ring
provided that no carbon atom is geminally
substituted with more than one sulfhydryl group.
13. The process according to claim 12
wherein X = 0 for the matrix metalloprotease
inhibitor compound.
14. A process for treating a host mammal
having a condition associated with pathological
matrix metalloprotease activity that comprises
administering a metalloprotease inhibitor in an
effective amount to a mammalian host having such a
condition, said metalloprotease inhibitor
corresponding in structure to a formula shown below

-288-
<IMG>
<IMG>
or
<IMG>
wherein
R1 is a radical having a length greater
than that of a saturated four carbon chain, and
shorter than that of a saturated eighteen carbon
chain, and when rotated about an axis drawn through
the SO2-bonded 1-position and the 4-position of a
6-membered ring or the SO2-bonded position and
substituent-bonded 3- or 5-position of a 5-membered
ring defines a three-dimensional volume whose widest
dimension has the width of about one phenyl ring to
about three phenyl rings in a direction transverse to
that axis to rotation;

-289-
R2 is selected from the group consisting of
hydrido, a C1-C6 alkyl group, a C2-C4 alkyl group
substituted by amino, mono-substituted amino or
di-substituted amino, wherein the substituents on
nitrogen are chosen from C1-C6 alkyl, aralkyl, C5-C8
cycloalkyl and C1-C6 alkanoyl, or wherein the two
substituents and the nitrogen to which they are
attached when taken together form a 5- to 8-membered
heterocyclo or heterozaryl ring containing zero or
one additional hetero atoms that are nitrogen, oxygen
or sulfur and a C1-C4 alkylaryl or C1-C4
alkylheteroaryl group having a single ring;
R4 is a hydroxycarbonyl, aminocarbonyl or
C1-C6 alkyl group;
W is oxygen or sulfur; and
R9 is a C1-C6 alkyl group, a C1-C6 alkoxy
group, or a single-ringed carbocyclic aryl or
heteroaryl group.
15. The process according to claim 14
wherein the inhibitor compound R1 substituent is a
single-ringed aryl or heteroaryl group that is 5- or
6-membered, and is itself substituted at its own
4-position when a 6-membered ring and at its own
3-position when a 5-membered ring with a substituent
selected from the group consisting of one other
single-ringed aryl or hetroaryl group, an alkyl or
alkoxy group containing an unbranched chain of 3 to
about 7 carbon atoms, a phenoxy group, a thiophenoxy
group, a phenylazo group and a benzamido group.
16. A process for treating a host mammal
having a condition associated with pathological
matrix metalloprotease activity that comprises
administering a metalloprotease inhibitor in an
effective amount to a mammalian host having such a

-290-
condition, said metalloprotease inhibitor
corresponding in structure to a formula shown below
<IMG>
<IMG>
or
<IMG>
wherein
Ph is phenyl substituted with R11 at the
4-position;
R11 is a substituent selected from the
group consisting of C3-C8 alkoxy, C3-C8 alkyl,
phenoxy, thiophenoxy, benzamido, phenylazo and
phenyl;
R2 is selected from the group consisting of
hydrido, a C1-C6 alkyl group, a C2-C3 alkylene

-291-
cycloamino group having five or six atoms in the ring
and zero or one additional heteroatom that is oxygen
or nitrogen, and a C1-C4 alkylheteroaryl group having
a single heteroaryl ring wherein said single
heteroaryl ring contains one or two nitrogen atoms;
R4 is a C1-C6 alkyl group, or carbamido
group; and
R9 is a C1-C6 alkyl, C1-C6 alkoxy, or a
single-ringed aryl or heteroaryl group.
17. A process for treating a host mammal
having a condition associated with pathological
matrix metalloprotease activity that comprises
administering a metalloprotease inhibitor in an
effective amount to a mammalian host having such a
condition, said metalloprotease inhibitor
corresponding in structure to a formula shown below
<IMG>
wherein
x is 0, 1 or 2
Y is selected from the group consisting of
hydrogen, halogen, alkyl, alkoxy, nitro, cyano,
carboxy and amino;
R10 is hydrogen or -C(O)-R9;
R9 is selected from the group consisting of
alkyl, aryl, alkoxy, cycloalkyl, aryloxy, aralkoxy,

-292-
aralkyl, aminoalkyl, heteroaryl and N-monosubstituted
or N,N-disubstituted aminoalkyl wherein the
substituent(s) on the nitrogen are selected from the
group consisting of alkyl, aryl, aralkyl, cycloalkyl,
aralkoxycarbonyl, alkoxycarbonyl, and alkanoyl, or
wherein the nitrogen and two substituents attached
thereto form a 5 to 8 member heterocyclo or
heteroaryl ring;
R1 is selected from the group consisting of
alkyl, cycloalkyl, heterocycloalkyl, aralkyl,
heteroaralkyl, aralkoxyalkyl, aryloxyalkyl,
hydroxyalkyl, alkanoylalkyl, aralkanoylalkyl,
arylcarbonylalkyl, haloalkyl, aralkylaryl,
aryloxyalkylaryl, aralkoxyaryl, arylazoaryl,
arylhydrazinoaryl, alkylthioalkyl, alkylthioaryl,
arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl,
and aralkylthioaryl, the sulfoxide or sulfone of any
of said thio substituents, aryl, heteroaryl, and a
fused ring structure comprising two or more 5- or
6-membered rings selected from the group consisting of
aryl, heteroaryl, carbocyclic and heterocyclic, the
aryl and heteroaryl substituents of which R1 may be
comprised being unsubstituted or substituted with one
or more substituents independently selected from
among halo, C1-C10 alkyl, C1-C10 alkoxy, nitro,
cyano, perfluoroalkyl, trifluoromethylalkyl, hydroxy,
thiol, hydroxycarbonyl, aryloxy, arylthio, arylamino,
aralkyl, aryl, heteroaryloxy, heteroarylthio,
heteroarylamino, heteroaralkyl, cycloalkyl,
heterocyclooxy, heterocyclothio, heterocycloamino,
cycloalkyloxy, cycloalkylthio, cycloalkylamino,
heteroaralkoxy, heteroaralkylthio,
heteroaralkylamino, aralkoxy, aralkylthio,
aralkylamino, heterocyclic, heteroaryl, arylazo,
hydroxycarbonylalkoxy, alkoxycarbonylalkoxy,
alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy,
aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy,

-293-
alkylthio, alkoxyalkylthio, alkoxycarbonyl,
aryloxyalkoxyaryl, arylthioalkylthioaryl,
aryloxyalkylthioaryl, arylthioalkoxyaryl,
hydroxycarbonylalkoxy, hydroxycarbonylalkylthio,
alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino,
alkanoylamino, arylcarbonylamino, aralkanoylamino,
heteroarylcarbonylamino, heteroaralkanoylamino, and
N-monosubstituted or N,N-disubstituted aminoalkyl
wherein the substituent(s) on the nitrogen are
selected from the group consisting of alkyl, aryl,
aralkyl, cycloalkyl, aralkoxycarbonyl,
alkoxycarbonyl, and alkanoyl, or wherein the nitrogen
and two substituents attached thereto form a 5- to
8-member heterocyclo or heteroaryl ring;
R2 is selected from the group consisting of
hydrogen, alkyl, aryl, aralkyl, heteroaryl,
heteroaralkyl, alkynylalkyl, alkenylalkyl, thioalkyl,
cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl,
alkoxyalkyl, aralkoxyalkyl, aminoalkyl,
alkoxyalkoxyalkyl, aryloxyalkyl, hydroxyalkyl,
hydroxycarbonylalkyl, hydroxycarbonylaralkyl, or
N-monosubstituted or N,N-disubstituted aminoalkyl
wherein the substituent(s) on the nitrogen are
selected from the group consisting of alkyl, aralkyl,
cycloalkyl and alkanoyl, or wherein the nitrogen and
two substituents attached thereto form a 5- to
8-member heterocyclo or heteroaryl ring;
R3 and R4 are independently selected from
the group consisting of hydrogen, alkyl, cycloalkyl,
cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl,
aryloxyalkyl, aralkoxyalkyl, aralkyl, aryl,
heteroaryl, heteroaralkyl, hydroxycarbonylalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
hydroxycarbonyl, alkoxycarbonyl, perfluoroalkyl,
trifluoromethylalkyl, thioalkyl, alkylthioalkyl,
arylthioalkyl, aralkylthioalkyl,
heteroaralkylthioalkyl, or a sulfoxide or sulfone of any of said

-294-
thio substituents, aminocarbonyl, aminocarbonylalkyl
and N-monosubstituted or N,N-disubstituted
aminocarbonyl or aminocarbonylalkyl wherein the
substituent(s) on the nitrogen are independently
selected from among alkyl, aralkyl, cycloalkyl and
alkanoyl, or wherein the nitrogen and two
substituents attached thereto form a 5- to 8-member
heterocyclo or heteroaryl ring, R2 and R4 together
with the atoms to which they are attached optionally
forming a 4- to 8-membered ring, or R3 and R4
together with the atoms to which they are attached
optionally forming a 3- to 8-membered ring;
R5 and R6 are independently selected from
the substituents that may constitute R3 and R4, R5
and R3 together with atoms to which they are attached
optionally forming a 3- to 8-membered ring, or R5 and
R2 together with the atoms to which they are attached
optionally forming a 4- to 8-membered ring, or R5 and
R6 together with atoms to which they are attached
optionally forming a 3- to 8-membered ring;
R7 and R8 are independently selected from
the substituents that may constitute R3 and R4, R7
and R2 together with the atoms to which they are
attached optionally forming a 4- to 8-membered ring,
or R7 and R8 together with the atoms to which they
are attached optionally forming a 3- to 8-membered
ring, or R7 and R3 or R7 and R5 together with the
atoms to which they are attached optionally forming a
3- to 8-membered ring
provided that no carbon atom is geminally
substituted with more than one sulfhydryl group.
18. A process for treating a host mammal
having a condition associated with pathological

-295-
matrix metalloprotease activity that comprises
administering a metalloprotease inhibitor in an
effective amount to a mammalian host having such a
condition, said metalloprotease inhibitor
corresponding in structure to formula IVa or IVb,
below,
<IMG> <IMG>
wherein
R1 is a radical having a length greater
than that of a saturated four carbon chain, and
shorter than that of a saturated eighteen carbon
chain, and when rotated about an axis drawn through
the SO2-bonded 1-position and the 4-position of a
6-membered ring or the SO2-bonded position and
substituent-bonded 3- or 5-position of a 5-membered
ring defines a three-dimensional volume whose widest
dimension has the width of about one phenyl ring to
about three phenyl rings in a direction transverse to
that axis to rotation;
R2 is selected from the group consisting of
hydrido, a C1-C6 alkyl group, a C2-C4 alkyl group
substituted by amino, mono-substituted amino or
di-substituted amino, wherein the substituents on
nitrogen are chosen from C1-C6 alkyl, aralkyl, C5-C8
cycloalkyl and C1-C6 alkanoyl, or wherein the two
substituents and the nitrogen to which they are
attached when taken together form a 5- to 8-membered
heterocyclo or heteroaryl ring containing zero or one

-296-
additional hetero atoms that are nitrogen, oxygen or
sulfur and a C1-C4 alkylaryl or C1-C4 alkylheteroaryl
group having a single ring;
R4 is a hydroxycarbonyl, aminocarbonyl or
C1-C6 alkyl group; and
R9 is a C1-C6 alkyl group, a C1-C6 alkoxy
group, or a single-ringed carbocyclic aryl or
heteroaryl group.
19. The process according to claim 18
wherein the inhibitor compound R1 substituent is a
single-ringed aryl or heteroaryl group that is 5- or
6-membered, and is itself substituted at its own
4-position when a 6-membered ring and at its own
3-position when a 5-membered ring with a substituent
selected from the group consisting of one other
single-ringed aryl or heteroaryl group, an alkyl or
alkoxy group containing an unbranched chain of 3 to
about 7 carbon atoms, a phenoxy group, a thiophenoxy
group, a phenylazo group and a benzamido group.

Description

CA 02260860 1999-01-12
W O 98/03166 _ PCT~US97/12873
THIOL SULFONAMIDE
METALLOPROTEASE INHIBITORS
Descri~tion
5 Technica~ Field
This invention is directed to proteinase
(proteas~) inhibitors, and more particu~arly to thiol
sulfonamide inhibitors for matrix metalloproteinases,
compositions of proteinase inhibitors, intermediates
ror the syntheses of proteinase inhibitors, processes
for the ~reparation of proteinase inhibitors and
processes for treating pathological conditions
~ssociated with pathological matrix metalloproteinase
activity.
Backcrou~.d of the Invention
Connective tissue, extracellular matrix
constit~nts and basemen. membranes are required
_omponer-s of all mammals. These components are _he
biologlcal materials that provide rigidity,
aifferen.iation, attachments and, in some cases,
elastic~'y to biological systems including human
beings Gnd other mammals. Connective tissues
componen~s include, for example, collagen, elastin,
proteog~vcans, fibronectin and laminin. These
biochemicals makeup, or are components OL StrUCtUreS!
such as skin, bone, teeth, tendon, cartilage,
basement membrane, blood vessels, cornea and vitreous
humor.
Under normal conditions, connective tissue
turnove~ and/or repair processes are controlled and
in e¢ui'ibrium. The loss of this balance for
whateve- reason leads to a number of disease states.
Inhibition or the enzymes responsible loss of
e¢uilibrium provides a control mechanism for this
~issue aecomposition and, therefore, a treatment for
these a~seases.

CA 02260860 1999-01-12
W O 98/03166 PCTrUS97/12873
Degradation of connective tissue or
connective tissue components is carried out by the
action of proteinase enzymes released from resident
tissue cells and/or invading inflammatory or tumor
cells. A major class of enzymes involved in this
function are the zinc metalloproteinases
(metalloproteases).
The metalloprotease enzymes are divided
into classes with some members having several
different names in common use. Examples are:
collagenase I (MMP-1, fibroblast collagenase; EC
3.4.24.3); collagenase II (MMP-8, neutrophil
collagenase; EC 3.4.24.34), collagenase III (MMP-13),
stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2
(MMP-10; EC 3.4.24.22), proteoglycanase, matrilysin
(MMP-7~, gelatinase A (MMP-2, 72kDa gelatinase,
basement membrane collagenase; EC 3.4.24.24),
gelatinase B (MMP-9, 92kDa gelatinase; EC 3.4.24.35),
stromelysin 3 (MMP-11), metalloelastase (MMP-12, HME,
human macrophage elastase) and membrane MMP (MMP-14).
MMP is an abbreviation or acronym representing the
term Matrix Metalloprotease with the attached
numerals providing differentiation between specific
members of the MMP group.
The uncontrolled breakdown of connective
tissue by metalloproteases is a feature of many
pathological conditions. Examples include rheumatoid
arthritis, osteoarthritis, septic arthritis; corneal,
epidermal or gastric ulceration; tumor metastasis,
invasion or angiogenesis; periodontal disease;
proteinuria; Alzheimers Disease; coronary thrombosis
and bone disease. Defective injury repair processes
also occur. This can produce improper wound healing
leading to weak repairs, adhesions and scarring.
These latter defects can lead to disfigurement and/or
permanent disabilities as with post-surgical
adhesions.

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WO98/03166 PCT~S97/12873
Matrix metalloproteases are also involved
in the biosynthesis of tumor necrosis factor (TNF),
and inhibition of the production or action of TNF and
related compounds is an important clinical disease
treatment mechanism. TNF-a, for example, is a
cytokine that at present is thought to be produced
initially as a 28 kD cell-associated molecule. It is
released as an active, 17 kD form that can mediate a
large number of deleterious effects in vitro and in
vivo. For example, TNF can cause and/or contribute
to the effects of inflammation, rheumatoid arthritis,
autoimmune disease, multiple sclerosis, graft
rejection, fibrotic disease, cancer, infectious
diseases, malaria, mycobacterial infection,
meningitis, fever, psoriasis,
cardiovascular/pulmonary effects such as post-
ischemic reperfusion injury, congestive heart
failure, hemorrhage, coagulation, hyperoxic alveolar
injury, radiation damage and acute phase responses
like those seen with infections and sepsis and during
shoc~ such as septic shock and hemodynamic shock.
Chronic release of active TNF can cause cachexia and
anorexia. TNF can be lethal.
TNF-a convertase is a metalloproteinase
involved in the formation of active TNF-a.
Inhibition of TNF-a convertase inhibits production of
active TNF-a. Compounds that inhibit both MMPs
activity have been disclosed in WIPO International
Publication Nos. WO 94/24140, WO 94/02466 and WO
97/20824. There remains a need for effective MMP and
TNF-a convertase inhibiting ~gents. Compounds that
lnhibit MMPs such as collagenase, stromelysin and
gelatinase have been shown to inhibit the release of
TNF (Gearing et al. Nature 376, 555-557 (1994),
McGeehan et al., Nature 376, 558-561 (1994)).
MMPs are involved in other biochemical
processes in mammals as well. Included is the

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control of ovulation, post-partum uterine involution,
possibly implantation, cleavage of APP (~-Amyloid
Precursor Protein) to the amyloid plaque and
inactivation of a1-protease inhibitor (a -PI).
Inhibition of these metalloproteases permits the
control of fertility and the treatment or prevention
of Alzheimers Disease. In addition, increasing and
maintaining the levels of an endogenous or
administered serine protease inhibitor drug or
biochemical such as al-PI supports the treatment and
prevention of diseases such as emphysema, pulmonary
diseases, inflammatory diseases and diseases of aging
such as loss of skin or organ stretch and resiliency.
Inhibition of selected MMPs can also be
desirable in other instances. Treatment of cancer
and/or inhibition of metastasis and/or inhibition of
angiogenesis are examples of approaches to the
treatment of diseases wherein the selective
inhibition of stromelysin, gelatinase, or collagenase
III are the relatively most important enzyme or
enzymes to inhibit especially when compared with
collagenase I (MMP-1). A drug that does not inhibit
collagenase I can have a superior therapeutic
profile. Osteoarthritis, another prevalent disease
wherein it is believed that cartilage degradation in
inflamed joints is at least partially caused by
MMP-13 released from cells such as stimulated
chrondrocytes, may be best treated by administration
of drugs one of whose modes of action is inhibition
of MMP-13. See, for example, Mitchell et al., J.
Clin. Invest., 97:761-768 (1996) and Reboul et al.,
J. Clin. Invest., 97:2011-2019 (1996).
Inhibitors of metalloproteases are known.
~xamples include natural biochemicals such as tissue
inhibitor of metalloproteinase (TIMP), a2-
macroglobulin and their analogs or derivatives.

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These are high molecular weight protein molecules
that form inactive complexes with metalloproteases.
A number of smaller peptide-like compounds that
inhibit metalloproteases have been described.
Mercaptoamide peptidyl derivatives have shown ACE
inhibition in vitro and in vivo. Angiotensin
converting enzyme (ACE) aids in the production of
angiotensin II, a potent pressor substance in mammals
and inhibition of this enzyme leads to the lowering
of blood pressure. Thiol group-containing amide or
peptidyl amide-based metalloprotease (MMP) inhibitors
are known as is shown in, for example, WO95/12389,
WO96/11209 and U.S. 4,595,700.
It is recognized that a compound that
inhibits a known member of the MMP group of enzymes
can inhibit members in that group and also new, yet
to be discovered, enzymes. Therefore, the skilled
person will presume that the novel inhibitors of this
invention can be useful in the treatment of the
diseases in which known and new MMP enzymes are
implicated.
Summary of the Invention
The present invention is directed to a
process for treating a mammal having a condition
associated with pathological matrix metalloprotease
(MMP) activity, as well as to molecules that
particularly inhibit the activity of MMP-13.
Briefly, therefore, one embodiment of the
present invention is directed to a process for
treating a mammal having a condition associated with
pathological matrix metalloprotease activity that
comprises administering a metalloprotease inhibitor
in an effective amount to a host having such a
condition. The administered enzyme inhibitor
corresponds in structure to one of formulae (I), (II)
or (III), below

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R6 Rs Rl 2
H ,S~N~SO2R
(I)
W ~ IR ~SO2R
(Il)
or
R1SO ~ ?~R8 ~ ~SO Rl'
(111)
where x represents 0, 1 or 2, and W is oxygen or
sulfur.
A contemplated R9 group is an alkyl, aryl,
alkoxy, cycloalkyl, aryloxy, aralkoxy, aralkyl,
aminoalkyl, heteroaryl and N-monosubstituted or
N,N-disubstituted aminoalkyl group wherein the
substituent(s) on the nitrogen are selected from the
group consisting of alkyl, aryl, aralkyl, cycloalkyl,
aralkoxycarbonyl, alkoxycarbonyl, and alkanoyl, or
wherein the nitrogen and two substituents attached

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thereto form a 5- to 8-mem~ered heterocyclic or
heteroaryl ring.
A contemplated R1 group is linked to the
S~2 portion of an inhibitor and is an alkyl,
cycloalkyl, heterocycloalkyl, aralkanoylalkyl,
arylcarbonylalkyl, hydroxyalkyl, alkanoylalkyl,
aralkylaryl, aryloxyalkylaryl, aralkoxyaryl,
arylazoaryl, arylhydrazinoaryl, haloalkyl,
alkylthioaryl, arylthioalkyl, alkylthioaralkyl,
aralkylthioalkyl, or aralkylthioaryl group, the
sulfoxide or sulfone of any of those thio
substituents, alkylthioalkyl, and preferably aryl and
heterocyclic (heteroaryl) rings such as aralkyl,
heteroaralkyl, aralkoxyalkyl, aryloxyalkyl, as well
as a fused ring structure comprising two or three 5-
or 6-membered aryl rings that can be carbocyclic or
heterocyclic rings. The aryl (carbocyclic) and
heteroaryl substituents of R1 are themselves
unsubstituted or substituted with one or two
substituents independently selected from among halo,
C1-C10 alkyl, C1 C10 alkoxy, nitro, cyano,
perfluoroalkyl, trifluoromethylalkyl, hydroxy, thiol,
hydroxycarbonyl, aryloxy, arylthio, arylamino,
aralkyl, arylcarboxamido, heteroarylcarboxamido,
azoaryl, azoheteroaryl, aryl, heteroaryloxy,
heteroarylthio, heteroarylamino, heteroaralkyl,
cycloalkyl, heterocyclooxy, heterocyclothio,
heterocycloamino, cycloalkyloxy, cycloalkylthio,
cycloalkylamino, heteroaralkoxy, heteroaralkylthio,
heteroaralkylamino, aralkoxy, aralkylthio,
aralkylamino, heterocyclic, heteroaryl, arylazo,
hydroxycarbonylalkoxy, alkoxycarbonylalkoxy,
alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy,
aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy,
alkylthio, alkoxyalkylthio, alkoxycarbonyl,
aryloxyalkoxyaryl, arylthioalkylthioaryl,
.

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aryloxyalkylthioaryl, arylthioalkoxyaryl,
hydroxycarbonylalkoxy, hydroxycarbonylalkylthio,
alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino,
alkanoylamino, arylcarbonylamino, aralkanoylamino,
heteroarylcarbonylamino, heteroaralkanoylamino, and
N-monosubstituted or N,N-disubstituted aminoalkyi
wherein the substituent(s) on the nitrogen are
selected from the group consisting of alkyl, aryl,
aralkyl, cycloalkyl, aralkoxycarbonyl,
alkoxycarbonyl, and alkanoyl, or wherein the nitrogen
and two substituents attached thereto together form a
5- to 8-membered heterocyclo or heteroaryl ring.
A contemplated R2 substituent can be
hydrogen (hydrido), an alkyl, aryl, aralkyl,
heteroaryl, heteroaralkyl, alkynylalkyl,
alkenylalkyl, thioalkyl, cycloalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, alkoxyalkyl, aralkoxyalkyl,
aminoalkyl, alkoxyalkoxyalkyl, aryloxyalkyl,
hydroxyalkyl, hydroxycarbonylalkyl,
hydroxycarbonylaralkyl, or N-monosubstituted or
N,N-disubstituted aminoalkyl group wherein the
substituent(s) on the nitrogen are selected from the
group consisting of alkyl, aralkyl, cycloalkyl and
alkanoyl, or wherein R2 and the nitrogen to which it
is bonded and another substituent(i.e., R2 and R4, or
R2 and R6 or R2 and R8) together form a 4- to
8-membered heterocyclo or heteroaryl ring.
Contemplated R3 and R4 groups are
independently selected. Those substituents can be
hydrogen (hydrido), an alkyl, cycloalkyl,
cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl,
aryloxyalkyl, aralkoxyalkyl, aralkyl, aryl,
heteroaryl, heteroaralkyl, hydroxycarbonylalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
hydroxycarbonyl, alkoxycarbonyl, perfluoroalkyl,
trifluoromethylalkyl, thioalkyl, alkylthioalkyl,

CA 02260860 1999-01-12
W O 98/03166 PCT~US97/12873
arylthioal~yl, aralkylthioalkyl,
heteroaralkylthioalkyl, or a sulfoxide or sulfone of
any of the thio substituents, aminocarbonyl,
aminocarbonylalkyl, N-monosubstituted or '
N,N-disubstituted aminocarbonyl or aminocarbonylalkyl
group wherein the substituent(s) on the nitrogen are
independently selected from among alkyl, aralkyl,
cycloalkyl and alkanoyl, or wherein the nitrogen and
two substituents attached thereto together form a 5-
to 8-membered heterocyclo or heteroaryl ring that can
contain one additional heteroatom, or R2 and R4
together with the atoms to which they are attached
form a 4- to 8-membered ring (as above), or R3 and R4
together with the atom to which they are attached
form a 3- to 8-membered ring or R4 and R8 together
with the atoms to which they are attached form a 5-
to 8-membered ring.
R5 and R6 substituents are also
independently selected. R5 and R6 substituents can
be a substituent that constitutes R3 and R4, or R6
and R4 together with atoms to which they are attached
form a 4- to 8-membered ring, or R6 and R2 together
with the atoms to which they are attached form a 5-
to 8-membered ring (as above), or R6 and R8 together
with the atoms to which they are attached form a 4-
to 8-membered ring, or R5 and R6 together with atom
to which they are attached form a 3- to 8-membered
rlng .
Contemplated R7 and R8 substituents are
also independently selected. R7 and R8 substituents
can also be a substituent that constitutes R3 and R4,
or R8 and R2 together with the atoms to which they
are attached ~orm a 6- to 8-membered ring (as above),
or R7 and R8 together with the atom to which they are
.

CA 02260860 1999-01-12
WO 98103166 PCTrUS97/12873
attached form a 3- to 8-membered ring, or R8 and R4
together with the atom to which they are attached
form a 5- to 8-membered ring (as above), or R8 and R6
together with the atoms to which they are attached
form a 4- to 8-membered ring (as above).
A provision to the above definitions is
that no carbon atom is geminally substituted with
more than one sulfhydryl group. Additionally, a
starred substituent "R" groups and "x" of formula III
are the same as or different from the unstarred "R"
groups and "x".
The present invention is also directed to a
more preferred sub-set of molecules of formulas I,
II, and III, above. Here, x is zero so that the
mercapto group is bonded directly to the carbon atom
that bears the R5 and R6 substituent radicals, which
are themselves both hydrido, as is R3. Here, also,
R2 is other than hydrogen (hydrido) unless Rl is
phenylazophenyl, R1 is an aryl, substituted aryl,
heteroaryl, or substituted heteroaryl group
containing one 5- or 6-membered ring; i.e. R1 is not
a fused aryl ring or heteroaryl group, and a compound
of formula III is a homodimer. These preferred
compounds are depicted by formulas Ia, IIa, and IIIa,
below, and the substituent "R" groups and W are as
otherwise defined before.
HS ~ ~SO2R
R4
(la)

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W O 98/03166 PCTAUS97/12873
11
R2
R9 ~ S ~ ~SO2R
W
(lla)
or
R2 R2
R1SO2~ ~\S S~/ ~SO2R
(Illa)
In most preferred practice, a contemplated
inhibitor compound constitutes another sub-set of the
compounds of formulas I, II and III. Here, R3, R~
and R6 are again hydrido, the SO2-linked R1
substituent is a 4-substituted phenyl group (PhR11),
and W is O. These most preferred compounds are
depicted by formulas Ib, IIb and IIIb, below.
Specifics of the depicted "R" groups are discussed
hereinafter.
HS ~ ~SO2PhR
R4
(Ib)

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12
R9 S/~/ ~SO2PhR
y R
(llb)
or
lR2 R, 2
R11PhSO2~ ~\S--S/~/ SO2PhR
R4 R4
(lll b)
Yet another aspect of the invention is
directed to a matrix metalloprotease inhibitor
corresponding to formula IV, below,
SO2R
(1~
where R10 is hydrogen (hydrido) or -C(O)-R9~ and R1,
R2, R3, R4, R5, R6, R9 and x are as defined above,
15 and Y represents hydrogen, halogen, alkyl, alkoxy,
nitro, cyano, carboxy or amino.
Among the several benefits and advantages
of the present invention are the provision of
compounds and compositions effective as inhibitors of
matrix metalloproteinase activity, the provision of

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13
such compounds and compositions that are effective
for the inhibition of metalloproteinases implicated
in diseases and disorders involving uncontrolled
breakdown of connective tissue.
More particularly, a benefit of this
invention is the provision of a compound and
composition effective for inhibiting
metalloproteinases, particularly MMP-13, associated
with pathological conditions such as, for example,
rheumatoid arthritis, osteoarthritis, septic
arthritis, corneal, epidermal or gastric ulceration,
tumor metastasis, invasion or angiogenesis,
periodontal disease, proteinuria, Alzheimer's
Disease, coronary thrombosis and bone disease.
An advantage of the invention is the
provision of a method for preparing such
compositions. Another benefit is the provision of a
method for treating a pathological condition
associated with abnormal matrix metalloproteinase
activity.
Another advantage is the provision of
compounds, compositions and methods effective for
treating such pathological conditions by selective
inhibition of a metalloproteinase, MMP-13, associated
2s with such conditions with minimal side effects
resulting from inhibition of other proteinases whose
activity is necessary or desirable for normal body
function.
Still further benefits and advantages of
the invention will be apparent to the skilled worker
from the disclosure that follows.
Description of the Preferred Embodiments
In accordance with the present invention,
it has been discovered that certain thiol
sulfonamides are effective for inhibition of matrix
metalloproteinases ("MMPs") believed to be associated
. . ~

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14
with uncontrolled or otherwise pathological breakdown
of connective tissue. In particular, it has been
found that these certain thiol sulfonamides are
effective for inhibition of collagenase III (MMP-13),
which can be particularly destructive to tissue if
present or generated in abnormal quantities or
concentrations, and thus exhibit a pathological
activity.
Moreover, it has been discovered that many
or these thiol sulfonamides are selective in the
inhibition of MMP-13, as well as other MMPs
associated with diseased conditions without excessive
~inhibition of other collagenases essential to normal
bodily function such as tissue turnover and repalr.
More particularly, it has been found that
particularly preferred the thiol sulfonamides of the
invention are particularly active in inhibiting of
MMP-13, while being selective for MMP-13, in having a
limited or minimal effect on MMP-1. This point is
discussed in detail hereinafter and is illustrated in
several examples.
One embodiment of the present invention is
directed to a process for treating a mammal having a
condition associated with pathological matrix
metalloprotease activity. That process comprises
administering a metalloprotease inhibitor in an
effective amount to a host having such a condition.
The administered enzyme inhibitor corresponds in
structure to one of formulas (I), (II) or (III),
below
R6 Rs R
H,S ~N ~SO2R
(I)

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W O 98/03166 PCT~US97/12873
g R6 Rs R2
R ~II~s~N~so2R1
(Il)
or
R1SO2~ ?~ S--S~ ~SO R1-
(111)
where x represents 0, 1 or 2, and W is oxygen or
sulfur.
A contemplated R9 group is an alkyl, aryl,
alkoxy, cycloalkyl, aryloxy, aralkoxy, aralkyl,
aminoalkyl, heteroaryl and N-monosubstituted or
N,N-disubstituted aminoalkyl group wherein the
substituent(s) on the nitrogen are selected from the
group consisting of alkyl, aryl, aralkyl, cycloalkyl,
aralkoxycarbonyl, alkoxycarbonyl, and alkanoyl, or
wherein the nitrogen and two substituents attached
thereto form a 5- to 8-membered heterocyclo or
heteroaryl ring;
A contemplated Rl group is linked to the
S~2 portion of an inhibitor and is an alkyl,
cycloalkyl, heterocycloalkyl, aralkanoylalkyl,
arylcarbonylalkyl, hydroxyalkyl, alkanoylalkyl,
aralkylaryl, aryloxyalkylaryl, aralkoxyaryl,
arylazoaryl, arylhydrazinoaryl, haloalkyl,
alkylthioaryl, arylthioalkyl, alkylthioaralkyl,

CA 02260860 1999-01-12
W O 98/03166 . PCTrUS97/12873
-16-
aralkylthioalkyl, or aralkylthioaryl group, the
sulfoxide or sul~one of any of those thio
substituents, alkylthioalkyl, and preferably aryl
(carbocyclicaryl) and heteroaryl rings such as
aralkyl, heteroaralkyl, aralkoxyalkyl, aryloxyalkyl,
as well as a fused ring structure comprising two or
three 5- or 6-membered aryl rings that can be
carbocyclic or heterocyclic rings. lhe aryl and
heteroaryl substituents of wnich R1 can be comprised
are unsubstituted or preferably substituted with one
(preferably) or two substituents independently
selected from among halo, C1-C10 alkyl, C1_C10
alkoxy, nitro, cyano, perfluoroalkyl,
trifluoromethylalkyl, hydroxy, thiol,
hydroxycarbonyl, aryloxy, arylthio, arylamino,
aralkyl, arylcarboxamido, heteroarylcarboxamido,
azoaryl, azoheteroaryl, aryl, heteroaryloxy,
heteroarylthio, heteroarylamino, heteroaralkyl,
cycloalkyl, heterocyclooxy, heterocycloth o,
heterocycloamino, cycloalkyloxy, cycloalkylthio,
cycloalkylamino, heteroaralkoxy, heteroaralkylthio,
heteroaralkylamino, aralkoxy, aralkylthio,
aralkylamino, heterocyclic, heteroaryl, arylazo,
hyaroxycarbonylalkoxy, alkoxycarbonylalkoxy,
alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy,
aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy,
alkylthio, alkoxyalkylthio, alkoxycarbonyl,
aryloxyalkoxyaryl, arylthioalkylthioaryl,
aryloxyalkylthioaryl, arylthioalkoxyaryl,
hydroxycarbonylalkoxy, hydroxycarbonylalkylthio,
alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino,
alkanoylamino, arylcarbonylamino, aralkanoylamino,
heteroarylcarbonylamino, heteroaralkanoylamino, and
N-monosubstituted or N,N-disubstituted aminoalkyl
wherein the substituent(s) on the nitrogen are
selected from the sroup consisting of alkyl, aryl,
aralkyl, cycloalkyl, aralkoxycarbonyl,

CA 02260860 1999-01-12
W O 98/03166 PCT~US97/12873
-17-
alkoxycarbonyl, and alkanoyl, or wherein the nitrogen
and two substituents attached thereto together form a
5- to 8-membered heterocyclo or heteroaryl ring.
A contemplated R2 substituent can be
hydrogen (hydrido), an alkyl, aryl, aralkyl,
heteroaryl, heteroaralkyl, alkynylalkyl,
alkenylalkyl, thioalkyl, cycloalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, alkoxyalkyl, aralkoxyalkyl,
aminoalkyl, alkoxyalkoxyalkyl, aryloxyalkyl,
hydroxyalkyl, hydroxycarbonylalkyl,
hydroxycarbonylaralkyl, or N-monosubstituted or
N,N-disubstituted aminoalkyl group wherein the
substituent(s) on the nitrogen are selected from the
group consisting of alkyl, aralkyl, cycloalkyl and
lS alkanoyl, or wherein R2 and the nitrogen to which it
is bonded and another substituent (i.e., R2 and R4,
or R2 and R6, or R2 and R8) together form a 4- to
8-membered heterocyclo or heteroaryl ring.
Contemplated R3 and R4 groups are
independently selected. Those substituents can be
hydrogen (hydrido), an alkyl, cycloalkyl,
cyc~oalkylalkyl, alkoxyalkyl, hydroxyalkyl,
aryloxyalkyl, aralkoxyalkyl, aralkyl, aryl,
heteroaryl, heteroaralkyl, hydroxycarbonylalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
hydroxycarbonyl, alkoxycarbonyl, perfluoroalkyl,
trifluoromethylalkyl, thioalkyl, alkylthioalkyl,
arylthioalkyl, aralkylthioalkyl, heteroaralkyl-
thioalkyl, or a sulfoxide or sulfone of any of the
thio substituents, aminocarbonyl, aminocarbonylalkyl,
N-monosubstituted or N,N-disubstituted aminocarbonyl
or aminocarbonylalkyl group wherein the
substituent(s) on the nitrogen are independently
selected from among alkyl, aralkyl, cycloalkyl and
alkanoyl, or wherein the nitrogen and two
substituents attached thereto together form a 5- to
.. . .

CA 02260860 1999-01-12
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-18-
8-membered heterocyclo or heteroaryl ring that can
contain one additional heteroatom, or R2 and R4
together with the atoms to which they are attached
form a 4- to 8-membered ring (as above), or R3 and R4
together with the atom to which they are attached
form a 3- to 8-membered ring, or R4 and R6 together
with the atoms to which they are attached form a 4-
to 8-membered ring, or R4 and R8 together with the
atoms to which they are attached form a 5- to
8-membered ring.
R5 and R6 substituents are also
~ndependently selected. R5 and R6 substituents can
be a substituent that constitutes R3 and R4.
Alternatively, R6 and R4 together with atoms to which
they are attached form a 4- to 8-membered ring, or R6
and R2 together with the atoms to which they are
attached form a 5- to 8-membered ring (as above), or
R6 and R8 together with the atoms to which they are
attached form a 4- to 8-membered ring, or R5 and R6
together with atom to which they are attached form a
3- to 8-membered ring;
Contemplated R7 and R8 substituents are
also independently selected. R7 and R8 substituents
can also be a substituent that constitutes R3 and R4.
Alternatively, R8 and R2 together with the atoms to
which they are attached form a 6- to 8-membered ring
(as above), or R7 and R8 together with the atom to
which they are attached form a 3- to 8-membered ring,
or R8 and R4 together with the atom to which they are
attached form a S- to 8-membered ring (as above), or
R8 and R6 together with the atoms to which they are
attached form a 4- to 8-membered ring (as above).

CA 02260860 1999-01-12
W O 98/03166 PCTrUS97/12873
--19-- ,
A provision to the above definitions is
provided that no carbon atom is geminally substituted
with more than one sulfhydryl group. In addition,
starred substituent "R" groups and "x" of 'formula III
are the same as or different from the unstarred "R"
groups and "x".
~ n generally increasing order of
preference, the following paragraphs summarize the
substituents which may most advantageously constitute
each of R1 through R10, as well as W and x.
R1 represents an aryl or heteroaryl ring
C1-C1o alkyl, wherein the aryl or heteroaryl ring can
optionally be substituted by one or more of the
following substltuents: C1-C10 alkyl, C1-C1o alkoxy,
aryloxy, heteroaryloxy, aryl, heteroaryl, aralkoxy,
heteroaralkoxy, C1-C10 alkylthio, arylthio,
heteroarylthio.
R1 represents a single aryl or heteroaryl
ring, wherein the single aryl or heteroaryl ring can
optionally be substituted by one or more of the
following substituents: C1-C6 alkyl, C1-C6 alkoxy,
arylcarboxamido, heteroarylcarboxamido,arylazo,
heteroarylazo, aryloxy, heteroaryloxy, aryl,
heteroaryl, aralkoxy, heteroaralkoxy, C1-C6
alkylthio, arylthio, heteroarylthio in which each
ring -containing substituent itself contains a single
ring.
R1 represents a 6-membered aryl ring,
wherein the aryl ring can optionally be substituted
in the para-position (4-position) by one of the
following substituents: C1-C6 alkyl, C1-C6 alkoxy,
arylcarboxamido, heteroarylcarboxamido, arylazo,
heteroarylazo, aryloxy, heteroaryloxy, aryloxy,
heteroaryloxy, aryl, heteroaryl, aralkoxy,
heteroaral~oxy, C1-C6 alkylthio, arylthio,
.

CA 02260860 1999-01-12
W O 98/03166 PCTrUS97/12873
-20-
heteroarylthio in which each ring-containing
substituent itself contains a single ring.
R1 represents a 6-membered aryl ring,
wherein the aryl ring is substituted in the para-
position by C1-C6 alkyl, C1-C6 alkoxy
arylcarboxamido, arylazo, aryloxy, arylthio and aryl
in which each ring-containing substituent itself
contains a single ring.
Rl represents phenyl, wherein the phenyl
ring is substituted in the para-position by n-propyl,
n-butyl, n-pentyl, n-hexyl, isobutyl, isoamyl,
ethoxy, n-propyloxy, n-butoxy, n-pentyloxy,
n-hexyloxy, isobutoxy, phenoxy, thiophenoxy
(phenylthio), phenyl, azophenyl or benzamido, in
which the para-substituted R1 phenyl substituent can
itself optionally contain a meta- or para-
substituent, or both containing one atom or a chain
of no more than five atoms other than hydrogen.
R2 Preferences:
R2 represents hydrogen, C1-C6 a7kyl,
aralkyl, heteroaralkyl, cycloalkylalkyl having 4-8
carbons in the ring and 1-3 carbons in the alkyl
chain, heterocycloalkylalkyl in which 4-8 atoms are
in the ring, one or two of which atoms can be
nitrogen, oxygen or sulfur and in which the alkyl
chain contains 1-3 carbons, C1-C5 alkyl substituted
by hydroxycarbonyl, amino, mono-substituted amino and
di-substituted amino, wherein the substituents on
nitrogen are chosen from C1_C4 alkyl, aralkyl, C5-C8
cycloalkyl and C1-C6 alkanoyl groups, or wherein the
two substituents and the nitrogen to which they are
attached when taken together form a 5- to 8-membered
heterocyclo or heteroaryl ring.

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R2 represents hydrogen, C1_C6 alkyl,
aralkyl, heteroaralkyl, cycloalkylalkyl having 4-8
carbons in the ring and 1-3 carbons in the alkyl
chain, heterocycloalkylalkyl in which 4-8 atoms are
in the ring, one or two of which atoms can be
nitrogen, oxygen or sulfur and in which the alkyl
chain contains 1-3 carbons.
R2 represents hydrogen or Cl-C6 alkyl.
R2 represents hydrogen, methyl, ethyl,
n-propyl, n-butyl, isobutyl.
R2 represents carbocyclic aralkyl or
heteroaralkyl as discussed above.
R2 represents benzyl, 2-pyridylmethyl,
3-pyridylmethyl, 4-pyridylmethyl, 2-thiazolylmethyl,
4-thiazolylmethyl, 5-thiazolylmethyl.
R2 represents cycloalkylalkyl having 4-8
carbons in the ring and 1-3 carbons in the alkyl
chain, heterocycloalkylalkyl in which 4-8 atoms are
ln the ring, one or two of which atoms can be
nitrogen, oxygen or sulfur and in which the alkyl
chain contains 1-3 carbons.
R2 represents cyclopropylmethyl,
cyclopentylmethyl, cyclohexylmethyl.
R2 represents alkyl substituted by
hydroxycarbonyl, amino, mono-substituted amino and
di-substituted amino, wherein the substituents on the
amino nitrogen are chosen from C1-C6 alkyl, aralkyl,
Cs-Cg cycloalkyl and C1-C6 alkanoyl, or wherein the
two substituents and the nitrogen to which they are
attached when taken together form a 5- to 8-membered
heterocyclo or heteroaryl ring containing zero or one
additional hetero atoms that are nitrogen, oxygen or
sulfur.
R2 represents C1-Cs alkyl substituted by
hydroxycarbonyl.
. . .

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-22-
R2 represents 5-pentanoic acid,
4-n-butanoic acid, 3-propanoic acid or 2-ethanoic
acid.
R2 represents hydrido, C1-C6 alkyl, C2-C4
alkyl substituted by amino, mono-substituted amir.o or
di-substituted amino, wherein the substituents on
nitrogen are chosen from Cl-C6 alkyl, aralkyl, C5-Cg
cycloalkyl and C1-C6 alkanoyl, or wherein the two
substituents and the nitrogen to which they are
attached when taken together form a 5- to 8-membered
heterocyclo or heteroaryl ring containing zero or one
additional hetero atoms that are nitrogen, oxygen or
sulfur, a C1-C4 alkylaryl or C1-C4 alkylheteroaryl
group having a single ring.
R2 represents methyl, 2-aminoethyl,
3-aminopropyl, 4-aminobutyl, N,N-dimethyl-2-
aminoethyl, 2-(4-morpholino)ethyl, 2-(1-
piperidino)ethyl, 2-(1-pyrrolidino~ethyl.
R3 and R4 Preferences:
R3 and R4 independently represent hydrogen,
hydroxycarbonyl, aminocarbonyl, C1-C6 alkyl, aralkyl,
aryl, heteroaryl, C5-C8 cycloalkyl, heteroaralkyl,
cycloalkylalkyl having 4-8 carbons in the ring and
1-3 carbons in the alkyl chain.
R3 is hydrido, and R4 is hydroxycarbonyl,
aminocarbonyl or C1-C6 alkyl.
R3 and R4 independently represents
hydrogen, aminocarbonyl, methyl.
R3 is hydrido and R4 represents methyl.
R3 is hydrido and R4 represents
hydroxycarbonyl or aminocarbonyl.
R3 represents hydrido and R4 represents
aminocarbonyl (carbamyl) or methyl.

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R5 and R6 Preferences:
R5 and R6 independently represent hydrogen
(hydrido), hydroxycarbonyl, aryl, heteroaryl, C1-C6
alkyl.
R5 and R6 are both hydrido.
R7 and R8 Preferences:
R7 and R8 independently represent hydrogen,
hydroxycarbonyl, C1-C6 alkyl.
x Preferences:
x is preferably zero.
W is preferably oxygen (O).
R9 Preferences:
R9 represents C1-C6 alkyl, aryl, C1-C6
alkoxy, heteroaryl, amino C1-C6 alkyl,
N-monosubstituted amino Cl-C6 alkyl and
N,N-disubstituted amino C1-C6 alkyl, wherein the
substituents on nitrogen are chosen from C1-C6 alkyl,
aralkyl, Cs-Cg cycloalkyl and C1-C6 alkanoyl, or
wherein the two substituents and the nitrogen to
which they are attached when taken together form a 5-
to 8-membered heterocyclo or heteroaryl ring.
R9 represents C1-C6 alkyl, C5-C8
cycloalkyl, aryl, C1-C6 alkoxy, heteroaryl, amino
C1-C6 alkyl, N-monosubstituted amino Cl-C6 alkyl and
N,N-disubstituted amino C1-C6 alkyl, wherein the
substituents on nitrogen are chosen from C1-C6 alkyl,
aralkyl, Cs-Cg cycloalkyl and C1-C6 alkanoyl, or
wherein the two substituents and the nitrogen to
which they are attached when taken together rorm a 5-
to 8-membered heterocyclo or heteroaryl ring.

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R9 represents C1-C6 alkyl, C1-C6 alkoxy, a
single-ringed aryl or heteroaryl.
R9 represents methyl, ethyl, n-propyl,
n-butyl, isopropyl, isobutyl.
R9 represents a 3- to 8-membered cycloalkyl
ring.
R9 represents cyclohexyl and cyclopentyl.
R9 represents aryl or heteroaryl.
R9 represents phenyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, thiophene-2-yl, 3-thiophene-3-yl.
R9 represents C1-C6 alkoxy.
R9 represents methoxy and ethoxy.
Starred substituents, R*, and x* are
preferably the same as unstarred substituents, R, and
x so that a compound of formula III is homodimer.
In particularly preferred practice, an
S02-linked R1 substituent is an aryl or heteroaryl
group that is a 5- or 6-membered single-ring, and is
itself substituted with one other single-ringed aryl
or heteroaryl group or, with an alkyl or alkoxy group
containing an umbranched chain of 3 to about 7 carbon
atoms, a phenoxy group, a thiophenoxy [C6Hs-S-]
group, a phenylazido [C6Hs-N2-] group or a benzamido
[-NHC(O)C6Hs] group. The S02-linked single-ringed
aryl or heteroaryl R1 group is substituted at its own
4-position when a 6-membered ring and at its own
3-position when a 5-membered ring.
The R1 group's substituent single-ringed
aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo
or benzamido group is unsubstituted or can itself be
substituted at the 4-position when a 6-membered ring
or the 3-position when a 5-membered ring. The 4- and
3-positions of rings discussed here are numbered from
the sites of substituent bonding as compared to

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formalized ring numbering positions used in
heteroaryl nomenclature. Here, single atoms such as
halogen moieties or substituents that contain one to
a chain of about five atoms other than hydrogen such
as C1-C4 alkyl, C1-C4 alkoxy or carboxyethyl groups
can be used. Exemplary substituted S02-linked R1
substituents include biphenyl, 4-phenoxyphenyl,
4-thiophenoxyphenyl, 4-butoxyphenyl, 4-pentylphenyl,
4-(4'-dimethylaminophenyl)azophenyl, and 2-~(2-
pyridyl)- 5- thienyl].
When examined along its longest chain of
~atoms, an R1 substituent including its own
substituent has a total length of greater than a
saturated chain of four carbon atoms and less than a
saturated chain of about 18 and preferably about 12
carbon atoms, even though many more atoms may be
present in ring structures or substituents. This
length requirement is discussed further below.
Looked at more generally, and aside from
specific moieties from which it is constructed, a
particularly preferred R1 radical (group or moiety)
has a length greater than that of an butyl group.
Such an R1 radical also has a length that is less
than that of a stearyl (octadecyl) group. That is to
say that a particularly preferred R1 is a radical
having a length greater than that of a saturated four
carbon chain, and shorter than that of a saturated
eighteen carbon chain, and more preferably, a length
greater than that of a pentyl group and less than
that of a lauryl group.
The radical chain lengths are measured
along the longest linear atom chain in the radical,
and each atom in the chain, e.g. oxygen or nitrogen,
is presumed to be carbon for ease in calculation.
Such lengths can be readily determined by using
published bond angles, bond lengths and atomic radii,

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as needed, to draw and measure a staggered chain, or
by building models using commercially available kits
whose bond angles, lengths and atomic radii are in
accord with accepted, published values. Radical
lengths can also be determined somewhat less exactly
by assuming that all atoms have bond lengths
saturated carbon, that unsaturated bonds have the
same lengths as saturated bonds and that bond angles
for unsaturated bonds are the same as those for
saturated bonds, although the above-mentioned modes
of measurement are preferred.
In addition, a particularly preferred R1
group when rotated about an axis drawn through the
SO2-bonded 1-position and the 4-position of a
6-membered ring or the SO2-bonded position and
substituent-bonded 3- or 5-position of a 5-membered
ring defines a three-dimensional volume whose widest
dimension has the width of about one phenyl ring to
about three phenyl rings in a direction transverse to
that axis to rotation.
As a consequence of these length and width
requirements, R1 substituents such as
4-(phenyl)phenyl [biphenyll,
4-(4'-methoxyphenyl)phenyl, 4-(phenoxy)phenyl,
4-(thiophenyl)phenyl [4-(phenylthio)phenyl],
4-(azophenyl)phenyl and 4-(benzamido)phenyl are
particularly preferred R1 substituents.
One sub-set of particularly preferred
MMP-13 inhibitor compounds useful in a before-
described process has structures depicted by formulasIa, IIa and IIIa, below.
HS ~ SO2R
R4
(la)

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Rl 2
R9 S/~/ ~SO2R
\/ R4
W
(lla)
or
lR2 IR2
R SO2 ~\S--S~/ ~SO2R
R4 R4
1 a)
In a particularly preferred compound of the
above structural formulas, the configuration about
the
R4-containing carbon atom is that of a naturally-
occurring amino acid. The substituent groups are
discussed below for these compounds.
An R1 group represents a single aryl or
heteroaryl ring, wherein the single aryl ring is
unsubstituted or can optionally be substituted by one
or more of the following substituents: C1-C6 alkyl,
C1-C6 alkoxy, aryloxy, heteroaryloxy, aryl,
heteroaryl, aralkoxy, heteroaralkoxy, C1-C6
alkylthio, arylthio, heteroarylthio in which each
rlng-containing substituent itself contains a single
rlng .
A single-ringed aryl or heteroaryl group is
5- or 6-membered, and is itself preferably
substituted at its own 4-position when a 6-membered
ring and at its own 3-position when a 5-membered ring
.. ... . .

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with a substituent selected from the group consistingof one other single-ringed aryl or hetroaryl group,
an alkyl or alkoxy group containing an umbranched
chain of 3 to about 7 carbon atoms, a phenoxy group,
a thiophenoxy group, a phenylazo group or a benzamido
group.
R2 represents hydrido, Cl-C6 alkyl, C2-C4
alkyl substituted by amino, mono-substituted amino or
di-substituted amino, wherein the substituents on
nitrogen are chosen from Cl-C6 alkyl, aralkyl, C5-C8
cycloalkyl and Cl-C6 alkanoyl, or wherein the two
substituents and the nitrogen to which they are
attached when taken together form a 5- to 8-membered
heterocyclo or heteroaryl ring containing zero or one
additional hetero atoms that are nitrogen, oxygen or
sulfur, a Cl-C4 alkylaryl or Cl-C4 alkylheteroaryl
group having a single ring.
An R4 group is hydroxyxcarbonyl,
aminocarbonyl or Cl-C6 alkyl.
W is sulfur or oxygen, but preferably
oxygen (O).
An R9 group represents a Cl-C6 alkyl group,
Cl-C6 alkoxy group, or a single-ringed carbocyclic
aryl or heteroaryl group.
A most preferred MMP-13 inhibitor sub-set
of compounds useful in a before-described process
also preferably has the configuration of a naturally-
occurring amino acid, and corresponds to the
structures depicted by formulas Ib, IIb and IIIb,
below.
R2
HS--Y ~SO2PhR
R4
(Ib)

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R9 ~ S ~ SO2PhR
(llb)
or
R2 R2
R11PhSO2~ \~\S S~/ ~SO2PhR
R4 R4
(Illb)
The substituents of these most preferred
MMP-13 inhi~itor compounds are as follows:
An R4 group is Cl-C6 alkyl, and
particularly methyl, or aminocarbonyl [-C(O)NH2].
An R2 group is C1-C6 alkyl and particularly
methyl, a C2-C3 alkyl cycloamino group having five or
six atoms in the ring and zero or one additional
heteroatom that is oxygen or nitrogen, and C1-C4
alkyl single-ringed aryl or heteroaryl, wherein the
single heteroaryl ring contains one or two nitrogen
atoms. Exemplary most preferred substituents in
addition to methyl include 2-(4-morpholino)ethyl,
2-(l-piperidino)ethyl~ 2-(1-pyrrolidino)ethyl and
(3-pyridyl)methyl. Hydrogen (hydrido) can also be a
most preferred R2 group as is discussed below.
The sulfonyl group (-SO2-) of a most
preferred sub-set of inhibitor compounds is linked to
a phenyl group (Ph), which itself is substituted at

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the 4-position by a substituent denominated R11 that
together with the phenyl group is referred to as
PhR11. A 4-substituted phenyl group substituent,
R11, can be C3-C8 alkoxy such as butoxy, C3-C8 alkyl
such as pentyl, as well as phenoxy, thiophenoxy
(phenylthio), benzamido, phenylazo or phenyl.
An R11 6-membered ring-containing
substituent group can itself also be substituted in a
3-(meta) or 4- (para-) position, or both, with a
halogen (fluorine, chlorine, bromine or iodine), a
C1-C4 alkoxy group such as methoxy or isopropoxy, a
C1-C4 alkyl group such as methyl, a two or three
carbon-containing carboxyl group such as
carboxymethyl or carboxyethyl an amine, or a mono- or
di-Ci-C4 alkyl-substituted amine such as dimethyl
amino. A 3,4-methylenedioxy substituent is a
contemplated 3,~-substituent, whereas methyl is a
contemplated 3-substituent. A substituent of such a
R11 ring para substituent has one atom or a longest
chain of up to five atoms, excluding hydrogen.
R9 represents a C1-C6 alkyl group, a C1-C6
alkoxy group, a single-ringed carbocyclic aryl or
heteroaryl group, and more particularly, a phenyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, thiophene-2-yl,
3-thiophene-3-yl, methyl, ethyl, methoxy or ethoxy
group.
With respect to compounds of the formula
R10~N,~R2
SO2R
(IV)
.

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R10 is hydrogen (hydrido) or -C(O)-R9~and R1, R2, R3,
R4, R5, R6, R9 and x are as defined above, and Y
represents hydrogen, halogen, alkyl, alkoxy, nitro,
cyano, carboxy or amino.
In particularly preferred and most
preferred practice, the substituent "R" groups and x
are as they have been previously described in regard
to formulas Ia-IIIa and Ib-IIIb, respectively, except
that R3 and R4 are both hydrido in most preferred
compounds. Additionally, x is zero so that R5 and R6
and the carbon to which they are bonded are absent, Y
is hydrogen, and the sulfur atom bonded to the
depicted phenyl ring is linked ortho to the
sulfonamide-bearing carbon atom. It is thus seen
that particularly preferred and most preferred
compounds of formula IV constitute compounds of
formulas I and II in which x is one, and the R6 and
R8 substituents together with the atoms to which they
are attached form a 6-membered, aromatic ring.
A particularly or most preferred R1 group
is a radical having a length greater than that of a
saturated four carbon chain, and shorter than that of
a saturated eighteen carbon chain. When rotated
about an axis drawn through the SO2-bonded R1 group
1-position and the 4-position of a 6-membered ring or
the SO2-bonded position and substituent-bonded 3- or
5-position of a 5-membered R1 ring, the substituent
defines a three-dimensional volume whose widest
dimension has the width of about one phenyl ring to
about three phenyl rings in a direction transverse to
that axis to rotation.
More specifically, an SO2-linked R1
substituent ls an aryl or heteroaryl group that is a
5- or 6-membered single-ring, and is itself

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-32- -
substituted with one other single-ringed aryl or
heteroaryl group or, with an alkyl or alkoxy group
containing an umbranched chain of 3 to about 7 carbon
atoms, a phenoxy group, a thiophenoxy [C6~s-S-]
group, a phenylazido [C6H5-N2-] group or a benzamido
[-NHC(O)C6HS] group. The S02-linked single-ringed
aryl or heteroaryl R1 group is substituted at its own
4-position when a 6-membered ring and at its own
3-position when a 5-membered ring
R2 represents hydrido, C1-C6 alkyl, C2-C4
alkyl substituted by amino, mono-substituted amino or
di-substituted amino, wherein the substituents on
nitrogen are chosen from C1-C6 alkyl, aralkyl, C5-C8
cycloalkyl and C1-C6 alkanoyl, or wherein the two
substituents and the nitrogen to which they are
attached when taken together form a 5- to 8-membered
heterocyclo or heteroaryl ring containing zero or one
additional hetero atoms that are nitrogen, oxygen or
sulfur, a C1-C4 alkylaryl or Cl-C4 alkylheteroaryl
group having a single ring.
An R3 group is hydrido, and R4 is
hydroxyxcarbonyl, aminocarbonyl or C1-C6 alkyl.
Again, R3 and R4 are both hydrido in most preferred
compounds.
An R9 group represents C1-C6 alkyl, C1-C6
alkoxy, a single-ringed carbocyclic aryl or
heteroaryl, and more particularly, phenyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, thiophene-2-yl, 3-thiophene-
3-yl, methyl, ethyl, methoxy and ethoxy.
Particularly preferred and most preferred
compounds correspond to formulas IVa, IVb, IVc and
IVd that are shown below:

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R4 R4
O=C O=C
R9 R9
(IVa) (IVb)
~\ SO2PhR ~N\'o phR11
O=C
R9
(IVc) (IVd)
The compounds described herein are useful
in a process described herein in that such compounds
can inhibit the activity of MMP-13. A particularly
preferred compound inhibits the enzyme with an IC50
value of about 1000 nm or less in the in vitro assay
discussed hereinafter. A most preferred compound
exhibits an ICso value in that assay of about 20 nm
or less, with some compounds exhibiting values of
about l nm or less.
In addition, while being highly active
against MMP-13, selectivity of inhibitory activity
toward MMP-l is also exhibited by many of these
particularly preferred and most preferred compounds.
That is, many compounds exhibit little or no
inhibition in the in vi tro assay against MMP-l so
that IC50 values are often found to be several
thousand to greater than 10,000 nm toward MMP-1.
- Exemplary ratios of IC50 values toward MMP-l and MMP-
13 (IC50 MMP-l/IC50 MMP-13) can range from about 5 to
about 20,000, with most preferred compounds

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-34-
exhibiting ratios of about 500 to about 20,000.
Inhibition data for several exemplary compounds are
provided in a table hereinafter.
A contemplated inhibitor compound is used
for treating a host mammal such as a mouse, rat,
rabbit, dog, horse, primate such as a monkey,
chimpanzee or human that has a condition associated
with pathological matrix metalloprotease activity.
Also contemplated is use of a contemplated
metalloprotease inhibitor compound in the treatment
of a disease state that can be affected by the
activity of metalloproteases TNF-a convertase.
Exemplary of such disease states are the acute phase
responses of shock and sepsis, coagulation responses,
hemorrhage and cardiovascular effects, fever and
inflammation, anorexia and cachexia.
In treating a disease condition associated
with pathological matrix metalloproteinase activity,
a contemplated MMP inhibitor compound can be used in
the form of an amine salt derived from an inorganic
or organic acid. Exemplary salts include but are not
limited to the following: acetate, adipate, alginate,
citrate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, camphorate, camphorsulfonate,
digluconate, cyclopentanepropionate, dodecylsulfate,
ethanesulfonate, glucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, fumarate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-
ethanesulfonate, lactate, maleate, methanesulfonate,
nicotinate, 2-naphthalenesulfonate, oxalate,
palmoate, pectinate, persulfate, 3-phenylpropionate,
picrate, pivalate, propionate, succinate, tartrate,
thiocyanate, tosylate, mesylate and undecanoate.
Also, a basic nitrogen-containing group can
be quaternized with such agents as lower alkyl
halides, such as methyl, ethyl, propyl, and butyl
chloride, bromides, and iodides; dial~yl sulfates
-

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like dimethyl, diethyl, dibuytl, and diamyl sulfates,
long chain halides such as decyl, lauryl, myristyl
and stearyl chlorides, bromides and iodides, aralkyl
halides like benzyl and phenethyl bromides, and
others to provide enhanced water-solubility. Water
or oil-soluble or dispersible products are thereby
obtained as desired. The salts are formed by
combining the basic compounds with the desired acid.
Other compounds useful in this invention
that are acids can also form salts. Examples include
salts with alkali metals or alkaline earth metals,
such as sodium, potassium, calcium or magnesium or
with organic bases or basic quaternary ammonium
salts.
In some cases, the salts can also be used
as an aid in the isolation, puri~ication or
resolution of the compounds of this invention.
Total daily dose administered to a host
mammal in single or divided doses can be in amounts,
for example, for 0.001 to 30 mg/kg body weight daily
and more usually 0.01 to 10 mg. Dosage unit
compositions can contain such amounts or submultiples
thereof to make up the daily dose. A suitable dose
can be administered, in multiple sub-doses per day.
Multiple doses per day can also increase the total
daily dose should this be desired by the person
prescribing the drug.
The dosage regimen for treating a disease
condition with a compound and/or composition of this
invention is selected in accordance with a variety of
factors, including the type, age, weight, sex, diet
and medical condition of the patient, the severity of
the disease, the route of administration,
pharmacological considerations such as the activity,
efficacy, pharmacokinetic and toxicology profiles of
the particular compound employed, whether a drug
delivery system is utilized and whether the compound

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-36- -
is administered as part of a drug combination. Thus,
the dosage regimen actually employed can vary widely
and therefore can deviate from the preferred dosage
regimen set forth above.
A compound useful in the present invention
can be formulated as a pharmaceutical composition.
Such a composition can then be administered orally,
parenterally, by inhalation spray, rectally, or
topically in dosage unit formulations containing
conventional nontoxic pharmaceutically acceptable
carriers, adjuvants, and vehicles as desired.
Topical administration can also involve the use of
transdermal administration such as transdermal
patches or iontophoresis devices. The term
parenteral as used herein includes subcutaneous
injections, intravenous, intramuscular, intrasternal
injection, or infusion techniques. Formulation of
drugs is discussed in, for example, Hoover, John E.,
Reminqton's Pharmaceutical Sciences, Mack Publishing
Co., Easton, Pennsylvania; 1975 and Liberman, H.A.
and Lachman, L., Eds., Pharmaceutical Dosaqe Forms,
Marcel Decker, New York, N.Y., 1980.
Injectable preparations, for example,
sterile injectable aqueous or oleaginous suspensions
can be formulated according to the known art using
suitable dispersing or wetting agents and suspending
agents. The sterile injectable preparation can also
be a sterile injectable solution or suspension in a
nontoxic parenterally acceptable diluent or solvent,
for example, as a solution in l,3-butanediol. Among
the acceptable vehicles and solvents that can be
employed are water, Ringer's solution, and isotonic
sodium chloride solution. In addition, sterile,
fixed oils are conventionally employed as a solvent
or suspending medium. For this purpose any bland
fixed oil can be employed including synthetic mono-
or diglycerides. In addition, fatty acids such as

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oleic acid find use in the preparation of
injectables. Dimethyl acetamide, surfactants
including ionic and non-ionic detergents,
polyethylene glycols can be used. Mixtures of
solvents and wetting agents such as those discussed
above are also useful.
Suppositories for rectal administration of
the drug can be prepared by mixing the drug with a
suitable nonirritating excipient such as cocoa
butter, synthetic mono- di- or triglycerides, fatty
acids and polyethylene glycols that are sold at
ordinary temperatures but liquid at the rectal
temperature and will therefore melt in the rectum and
release the drug.
Solid dosage forms for oral administration
can include capsules, tablets, pills, powders, and
granules. In such solid dosage forms, the compounds
of this invention are ordinarily combined with one or
more adjuvants appropriate to the indicated route of
administration. If administered per os, the
compounds can be admixed with lactose, sucrose,
starch powder, cellulose esters of alkanoic acids,
cellulose alkyl esters, talc, stearic acid, magnesium
stearate, magnesium oxide, sodium and calcium salts
of phosphoric and sulfuric acids, gelatin, acacia
gum, sodium alginate, polyvinylpyrrolidone, and/or
polyvinyl alcohol, and then tableted or encapsulated
for convenient administration. Such capsules or
tablets can contain a controlled-release formulation
as can be provided in a dispersion of active compound
in hydroxypropylmethyl cellulose. In the case of
capsules, tablets, and pills, the dosage forms can
also comprise buffering agents such as sodium
citrate, magnesium or calcium carbonate or
bicarbonate. Tablets and pills can additionally be
prepared with enteric coatings.

CA 02260860 1999-01-12
W O 98/03166 PCTrUS97/12873
-38-
For therapeutic purposes, formulations for
parenteral administration can be in the form of
aqueous or non-aqueous isotonic sterile injection
solutions or suspensions. These solutions and
suspensions can be prepared from sterile powders or
granules having one or more of the carriers or
diluents mentioned for use in the formulations for
oral administration. The compounds can be dissolved
in water, polyethylene glycol, propylene glycol,
ethanol, corn oil, cottonseed oil, peanut oil, sesame
oil, benzyl alcohol, sodium chloride, and/or various
buffers. Other adjuvants and modes of administration
are well and widely known in the pharmaceutical art.
Liquid dosage forms for oral administration
can include pharmaceutically acceptable emulsions,
solutions, suspensions, syrups, and elixirs
containing inert diluents commonly used in the art,
such as water. Such compositions can also comprise
adjuvants, such as wetting agents, emulsifying and
suspending agents, and sweetening, flavoring, and
perfuming agents.
The amount of active ingredient that can be
combined with the carrier materials to produce a
single dosage form varies depending upon the
mammalian host treated and the particular mode of
administration.
Certain compounds of this invention can
serve as prodrugs to other compounds of this
invention. Prodrugs are drugs that can be chemically
converted in vivo or in vi tro by biological systems
into an active derivative or derivatives. An example
from this invention are drugs of formula II (IIa or
IIb) where the acyl group is hydrolyzed to a compound
of formula I (or Ia or Ib). An additional example is
where a disulfide of this invention is reduced to its
thiol product or, in some cases, converted into an
active mixed disulfide.
. . .

CA 02260860 1999-01-12
W O 98/03166 . PCT~US97/12873
-39-
Table 1 through Table 80, below, show
several series of compounds useful in this invention.
Each case, class or group of compounds is illustrated
by a generic formula, or formulae, followed by a
series of preferred moieties or groups that
constitute various substituents that can be attached
at the position clearly shown in the generic
structure. The generic symbols, e.g., R1, R2 and the
like, are as defined before, except that R3 of the
following tables corresponds to particularly and must
preferred R4 discussed previously. This system is
well known in the chemical communication arts and is
widely used in scientific papers and presentations.
For example in Table 1, R2 is the variable group with
the structural variables that can substitute for R2
shown in the balance of the table. There are 40 R2
groups (including hydrogen) shown that are used to
represent, in a non-limiting manner, 40 distinct
compounds. In a similar manner, Table 43 for
example, illustrates a compound with a generic
structure containing two variable groups. The groups
are Rl and R2. Thus, this example shows a matrix of
12 Rl groups and 10 R2 groups (including hydrogen)
that represent 120 non-limiting compounds of this
invention that can be prepared.

CA 02260860 1999-01-12
W O 98/03166 PCT~US97/12873
-4 0 - -
TABLEI
R2 ,~D
HS N~ SJ~
CH3 0 0
- R2
- H 0 N--CH2CH2- CN CH2CH2
- C H3
- CH2CH3 ~N--CH2CH2- CH3
- CH2CH2CH3
- CH2CH2CH2CH3 IN--CH2CH2' ,N--CH2CH2-
11 CH3
-CH2CH2CH2CH2CH3
CH2CH2CH2CH2CH2CH3 H--N ~ CH2CH2 PhO~CH2CH2-
- CH2Ph
- CH2CH2Ph H3C--N~--N--CH2CH2- PhCH2--N~_~N--CH2CH2-
- C H2C H(C H3)2 CH2-
- CH2CF3 N~ ~ CH2- ~Sa--CH2-
- CH2CH20CH3
- CHzCH20H ¢~CH2- ~CH2- ~CH2-
- CH2C02H
- CH2CH2CO2H
D--CH2- 0--CH2- 3CH2' 0--CH2-
-CH2CH2CH2CO2H
- CH2CH2CH2CH2CO2H H3CO~CH2CH2- ~CH2-
-CH2CH2CH2CH2CH2CO2H
-- .

CA 02260860 1999-01-12
WO 98/03166 PCT/US97112873
--41--
TABLE 2
~O~
N
~ ~0 ~
HS~ ~ S
b\\
R3 ~ ~
CH3 o -- -- CF3
H
CH2CH3 H2N~ ~ _ CH2CF3
O _ _
- HO~O ~
- H3CO - CH20H
O
-, H2N O O~
-- H3C OH
HO~
~ H3CO O o~
N~
H2N~
¢~ - N=~
o ~ S
O~ N_ S

CA 02260860 1999-01-12
W O 98/03166 . PCT~US97/12873
-42- -
TABLE3
N~J J~
/A\
-
R3
:
_
,H3HO~I~ N~ G ~F3
- H
CH2CH3 H2N~ ~ _ CH2CF3
O _ _
- HO O ~
H3CO ~ .- _CH20H
O
H2N~o a --
H3C~ OH
HO
~ H3CO O
_ . , N~
H2N~
¢I' - - N=~
~ S
N~ S

CA 02260860 1999-01-12
W O 98/03166 PCT~US97/12873
-43- -
TABL~oN4
HS , 'S
H N'\~o
S~ ~'13
O H
~3, N ~3 ~0~0
~ J~ _
H3C H
~H CH3J~N~CF3 ~¢~,S
/~S~' '~J3' ~ ,0'
N ~ N J~ ~ J3' N
\=N

CA 02260860 1999-01-12
W O 98/03166 PCT~US97/12873
-44-
TABLE5
' ,e~
- /A\
R3 ~ ~
-
R3
-CH3HO~ --CF3
H
CH2CH3 H2N_¢ - CH2CF3
_
, HO~ O ~
H3CO_~ CH20H
.- - H2N O /--~ _
- ~- \J H3C~ OH
HO~
~ H3CO O ~
-H2N~o O V'
_
W Na~
~ S
N~ S
.

CA 02260860 1999-01-12
W O98/03166 PCTrUS97/12873
-45- -
T~AoB~E6
HS~ N~
CH3 o o
1 6
CH3 HO~ CF3
H
CH2CH3 H2N~ HO~O CH2CF3
H3CO~J CH20H
H2N O oJ H3Cl OH
HO l l
H3CO~ O Cl'
H2N [J
J
oJ H3CO ~ 0 ~3 ,_jJ
CO2H N~ S

CA 02260860 1999-01-12
W O 98/03166 PCTrUS97/12873
-46-
TABLE7
HS~ ~S~
CH3 o o
l6
CH3H~~J ~SJ CF3
CH2CH3 H2N~J h CH2CF3
HO O 1 1
CH20H
H3CO_,~
H2N10 O)
,J H3C OH
HO--~o H3CO O ~J
''J ~J 1 VJ '~J
H2N ~
oJH3CO sJ ~ J
CO2H N~ S

CA 02260860 1999-01-12
W O 98/03166 PCT~US97/12873
-47- -
TABLE8
R2 1~ ~ ~
HS~ ~ SJ~
-CH3d\\
R2
- H o N--CH2CH2- CN_CH2CH2-
-CH3
CH2CH3 GN--CH2CH2- CH3
- CH2CH2CH3 ~ ~
- CH2CH2CH2CH3 N--CH2CH2- N--CHzCH2-
H CH3
- CH2CH2CH2CH2CH3
CH2CH2CH2CH2CH2CH3 H--N N--CH2CH2- PhO~CH2CH2-
- CH2Ph
- CH2CH2PhH3C--N N--CH2CH2- PhCH2 N~ ~N--CH2CH2
-CH2CH(CH3)2 CH2-
CH2CF3 N~ ~ CH2 ~S~ CH2-
- CH2CH20CH3
CH2CH~OH ~,,CH2- N~CH2- ~,CH2-
- CH2CH2CO2H
- CH2CH2CH2CO2HD--CH2- <>--CH2- ~CH2- 0--CH2-
- CH2CH2CH2CH2CO2H HO2C
H3CO ~ CH2CH2 /=\ ~ CH2-
- CH2CH2CH2CH2CH2CO2H ~-- ~

CA 02260860 1999-01-12
W O 98/03166 PCT~US97/12873
-48- _
TAB~LoE~
HS , ~ sf
// \
R3 ~ ~
-R3
CH3HO~ -- -- CF3
- h
=
CH2CH3 H2N~I~ , CH2CF3
- . HO~O ~
- -- CH20H
H3CO~
,- H2N O 0/
H3C~ OH
HO~ - --
- ~ H3CO O ~
2 ~o b
H3CO--~ O ~D _
O' /~
N~ S

CA 02260860 1999-01-12
W O 98/03166 PCTrUS97/12873
TABLEI0
HS~ N~ S
I \
-
R3
--CH3 -- - -- --CF3
- H
CH2CH3 H2N_~ ,, _ CH2CF3
O
- HO~O ~
H3CO_~ CH20H
O
H2N~O ~
H3C--OH
HO
~ H3CO ~
H2N~ b ~ s
~ j
H3CO~o O ~ _
O~ N~ S

CA 02260860 1999-01-12
W O 98/03166 PCTtUS97tl2873
- 50- -
TABLEII
-
R3
_
CH3~ _ ~ -CF3
H
CH2CH3 2 ~ _ i CH2CF3
O
- - HO~ O ~
_
H3CO ~ , j, CH20H
H2N O 0~
H3C~ OH
HO ~
- ~ H3CO~ ~ a' r
N~
H2N~ O V~ S
- N=~
- ~ S
O~ N~ V S

CA 02260860 1999-01-12
W O 98/03166 , -51- PCT~US97112873
TABLE12
J ~ ~
/\\
R3 ~ ~
CH3HO~ ~- - =CF3
- _ H
CH2CH3 H2N~ , CH2CF3
O _ _
- HO O ~
CH OH
H3CO ~ , _ 2
O
, , H2N O O~ --
H3C OH
HO
~ H3CO O
- - N~
H2N~o O S
0~ ' - ,' N=~
~S
H3CO ~o O ~ _
~~ N~S

CA 02260860 1999-01-12
W O 98/03166 PCTAUS97/12873
-52-
TABLE13
HS , 'S~
CH3 ~ ~
,O~CI ~¢~,S~0
3' ~CI J3'
CH3
~''~ ~3~~~ ~0, S ~N
o~l3,CH3 ~13~0~¢~N ~3,S~
CH3 J3' ~N J3'
~¢~o~l3'CF3 ~¢~0~0~CH3 ,¢~'~'13

CA 02260860 1999-01-12
W O 98/03166 PCTAJS97/12873
-53-
TABLE14
~ N~,R~
- CH, ~ ~
~R
O~ C~ S~
~ 3 J~~~c~ ,~5~
CH,
~3 o~b ,¢~ ~'~ '¢I' S~N
~JO~ ~~¢~ CH' ~ O~N ~3~ S~¢l
CH3 J~ ~N ,¢
~3~ 0~¢~ C F, ~¢~ 0~ C F,

CA 02260860 1999-01-12
W O98/03166 . PCT~US97/12873
-54-
TABLE15
~N~ ~ R
- /A\
, ,
O~CI
~CI
CH3
~ b ,~ s ¢~
0~¢~,, CH, ~ N ~¢~ S~¢
CH3 J~ ~N ~ ~b
~3~O~CF3 ~O~CF3

CA 02260860 1999-01-12
W O 98/03166 PCTAUS97/12873
TABLE16
HS~N~ J~ ~
-CH3d\\
- R2
- H /--~
-CH3 ~ N-CH2CH2- ~ N-CH2CH2-
- CH2CH3 ~N--CH2CH2- CH3
- CH2CH2CH3
- CH2cH2cH2cH3,N--CH2CH2- ,N--CH2CH2-
H CH3
-CH2CH2CH2CH2CH3
- CH2CH2CH2CH2CH2CH3 H--N ~N--CH2CH2- PhO~CH2CH2-
- CH2Ph
- CH2CH2Ph H C--NN--CH2CH2- PhCH2--N~ N--CH2CH2-
- CH2CH(CH3 )2 CH2- .
- CH2CF3 N~ CH2- ~5~--CH2-
- CH2CH20CH3
- CH2CH20H ¢~CH2- NlJCH2 ~CH2-
- CH2CH2C02H D--CH2- 0--CH2- ~CH2- 0--CH2-
-CH2CH2CH2CO2H
- CH2CH2CH2CH2CO2H H3CO~CH2CH2- ~CH2-
-CH2CH2CH2CH2CH2CO2H

CA 02260860 1999-01-12
W O 98/03166 rCT~US97/12873
-56-
TABLE17
~O~
HS ~S
1/ ~\
R3 ~ ~
-
R3
-CH3 - - - ---CF3
H
CH2CH3 o _ _ CH2CF3
HO ~ ~
H3CO~ CH20H
O
~ H2N~ O ~
- - \~J H3C OH
HO
~ H3CO O
.
' ~
H3CO~ O ~ --
N~S

CA 02260860 1999-01-12
W O 98/03166 PCTAJS97/12873
TABLEI8
HS~ N~
-
R3
.
--CH3 HO~ ~ --CF3
- H
CH2CH3 H2N~n' - - CH2C~3
- HOi~ O A
H3CO~ - _ CH20H
O
H2N O O~
--_~-- H3C OH
HO
- ~ H3CO~O
--
- H2N~ O S
=~
H3Co~o- -~ b ~S
~ F~

CA 02260860 l999-0l-l2
W O 98/03166 PCTrUS97/12873
-58-
TABLEI9
HS~N~
//\\
-
- . ;
-,CH3 ~ CF3
CH2CH3 H2N~ CH2CF3
HO O ~
H3CO~ - CH20H
O
- H2N O O~
- ~- H3C~OH
HO~
- H3CO~O ~ ,-
N~
H2N~ O V~ S
-H3CO~ O 0
N~S

CA 02260860 1999-01-12
W O 98/03166 PCTAUS97/12873
-59- _
TABLE20
'~ o~o
HS . ~ S~
R3 ~ ~
-R3
_
GH3H~r 7~-- -- =CF3
CH2CH3
O
- ,- HO~ O ~
H3CO~ , CH20H
H2N ~ o a~
-- H3C OH
HO~
H3CO O
H2NI~ O V
H3CO ~ 0 ~3 -
N~ S

CA 02260860 1999-01-12
W O 98/03166 PCTrUS97/12873
-60-
TABLE21
R2 ,~
HS~ N~S
- h\\
CH3 O O
- R2
-H /--~
O N--CH2CH2- <~N--CH2CH2-
-CH3
CH2CH3 GN--CH2CH2- CH3
- CH2CH2CH3
-CH2CH2CH2CH3 N--CH2CH2- N--CH2CH2-
H CH3
- CH2CH2CH2CH2CH3
- CH~CH2CH2CH2CH2CH3 H--N ~N--CH2CH2- PhO~CH2CH2-
- CH2Ph
- CH2CH2Ph H3C--N ~N--CH2CH2- PhCH2--N~_~N--CH2CH2-
CH2CH(CH3)2 CH2-
CH2CF3 N~ ~ CH2- ~ CH2
- CH2CH20CH3
CH2CH2OH N CH2- N~CH2- ~CH2-
CH2CO2H ~ N
- CH2CH2CO2H
-CH2CH2CH2CO2H D--CH2- 0--CH2- [ ~ CH2- 0--CH2-
- CH2CH2CH2CH2CO2H HO2C
H3CO~CH2CH2- /=\ >--CH2-
- CH2CH2CH2CH2CH2C02H '-- ~
~ .

CA 02260860 1999-01-12
W O 98/03166 PCTAUS97/12873
-61- -
TABLE22
~ON~
HS~ ~ S
-
-
R3
-CH3HO~ -- ~ --CF3
-- h
CH2CH3 H2N~ , C~12CF3
o
HO~ ~ ~
---- CH OH
H3CO~ -' _ 2
-'.- H2N O ~
~ ~ H3C~OH
HO
~ H3COi~O
~ _ - _ ~
H3CO--~ O ~ _
~~ N~S

CA 02260860 1999-01-12
W O 98/03166 PCTrUS97/12873
-62-
TABLE23
HS ~S~
11~
R3 ~ ~
-
R3
CF3
H
CH2CH3 H2N_II~ CH2CF3
O
HO~ ~ ~
H3CO~ , ,. CH20H
O
- H2N O /--~ "
~J _
~ ~ H3C OH
HO~
H3CO ~ O
.
- H2N O
O
_ _ -' N=~
o~H3CO ~o
N~S

CA 02260860 1999-01-12
W O 98/03166 . PCTrUS97/12873
-63- -
TABLE24
HS~N~ S~)
- R3 ~ ~
R3
--CH3 o -- -- --CF3
- H
CH2CH3 H2N~ -' _ CH2CF3
,- HO~ O ~
H3CO _¢ - _ CH20H
H2N ~ a ~
H3C OH
HO~ - -
~ H3CO~O c~ ;
O
~J , N=~
l~s
H3CO~ O ~3
N~,~ S

CA 02260860 1999-01-12
W O98/03166 PCTrUS97/12873
-64-
TA~LE25
[~ON~
HS~ ~S
CH3 OAO
Rs
CH3HO~ ;5J <I> 1F3 CO H
CH2CH3 H2N~JH CH2CF3
HO O
CH20H
H3CO~ I
H2N O ,r
~J H3C OH
HO~
H~CO
oJ H,C~
N~ S

CA 02260860 1999-01-12
W O 98/03166 -65- PCTrUS97/12873
TABLE26
h~
F~3 ~ ~
-
R3
_
CH3HO ~ -- -- CF3
h
CH2CH3 H2N~ ~ ' CH2CF3
o
HO~ O ~
- - CH20H
H3CO
- H2N~O O~
-- -- H3C~ OH
HO
H3CO~ O
N~
-H2N~ O V/ S
_ ' - ~'5
N;~ S

CA 02260860 1999-01-12
W O 98/03166 , -66- PCT~US97112873
TABLE27
ON)
R'
//\\
CH3 ~ ~
,R1
CH3 ~ ~Cl ~O
Br ~,,F ~ O
CH3 ~,~OH ~ ~ NH~CH~
~¢~ CH3 ~~ ~ CO,H ~ HN~f CH3
~¢~ CH3 ~ N~ CH3
N CH3 o O, CH3 [~ ~f
~NH2 ~S~ 3~ N CH3
O H
H ~ H ~~

CA 02260860 1999-01-12
W O 98/03166 -67- PCTfUS97/12873
TABL~Eo~
R1
'' _ /~\
CH3
~Nb~ H~ H~
H H H ~N
N~ ~ N~¢~ ~¢~ N~
~N~
H H H
~3~ ~ ~¢I~N~CH3 ~N~ CH,
H b~9 H~ ~ N~f ~

CA 02260860 1999-01-12
PCTnUS97/12873
W O 98/03166 -68-
TABLE29
~o~
N~ R
h~
CH3R1
~0 CH3 ~ Ph ~S~ CH3
--CH3 ~--Ph ~S CH3
~,o~CH3 ~¢~, oJ~ S~CH3
~OCH3 ~ o~J~ ,SCH3
O Ph
~¢~ Ph ~SJ~ ~S ph
"~ CF3 ,,¢~SJ~3 ,~
, . .

CA 02260860 1999-01-12
W O 98/03166 PCT~US97/12873
-69-
TALLE30
~ON~
R~
CH3 ~ ~
,R1
N~l H3C~O~ Cl~ F3C~,~
CH3 Cl CF3
~GN ~CH3 ~C~JclJ~G,CF3
OCH 3
H3CO~ ~ OC H 3
~ r~

CA 02260860 1999-01-12
W O 98tO3166 PCTAUS97/12873
-70-
TABLE31
-- I~\
CH3 ~ ~
~R1
~N ~JCH3 ~aO~C~ 3~CF3
OCH 3
H,CO ~1~ ,~ OCH,
~) ~3 ~J

CA 02260860 1999-01-12
WO 98/03166 -71- PCTAUS97/12873
TABL 32
HS~N~S~RI
I~\
CH3 ~ ~
~R~
f~
~GN ~C~O~CH3 ~c~Jc~ cF~
OCH 3
OCH3

CA 02260860 1999-01-12
W O 98/03166 -72- _ PCT~US97/12873
TABLE33
~~s~ R1
HS ~
,R1
,~,OCH, ~CrO
~~~ ~ ~
~ ~Nb,CH3 H~3~ Hl CH3
o
. . .

CA 02260860 1999-01-12
WO 98/03166 PCT/US97/12873
TABLE 34
~ S~
HS~
.
~¢~ OCH3 ~¢~, o ~ "~
0~ S~¢~
H C ~3~ ~
~C~ ~ ~,0

CA 02260860 1999-01-12
WO 98/03166 PCT/US97/12873
--74--
TAE~LE 35
~S~
HS
~OCH3 ~¢~,O ,~
~~~ S~3
~ H~3~ N CH3
,o

CA 02260860 1999-01-12
W O 98/03166 . PCT~US97/12873
-75-
TABLE36
o~\\ ~R
HSJ~)
~OCH3 ~,,o ,~
~~~ ~ ~
~f ~ J~Nb~CH3 H~3~ N CH3
~J~ ~~ ,Q~,o

CA 02260860 1999-01-12
W O 98/03166 PCT~US97/12873
-76-
TABLE37
SH O O
~R
OCH3 ~[~
~~~ ~ ~
J~[3 Ji~ ~ H;~ NJI~ CH3
~ ~ ~0

CA 02260860 1999-01-12
W O98/03166 PCTrUS97/12873
-77-
TABLE38
~ ~S~
SH O O
~¢~OCH3 ,'C~'~
J~~~ ~ J3'~
~ ~ Nr CH3 H~3~ HJ~ CH3
~0 ~ ~0
. .

CA 02260860 1999-01-12
W O 98/03166 , -78- PCTrUS97/12873
TA~LE39
N~ 5, R1
~¢~OCH3 ~3"0 ~~cf 3
~,0~ S~0
J~ ~N~CH3 H~' N CH3
~N~ O
Çl N~ H3C~N,CH3 H
N
CH3 H

CA 02260860 1999-01-12
W O98/03166 PCT~US97/12873
-79-
TABLE40
Çl N,S~ R!
SH R2
,R1
~, OCH3 ~ ~~~ 'C~~
~~~ S~
3~ N~CH3 ~3~ o
1~ -~ ~,o
H3C~ N, CH3 H
~3 ~ CH3 H

CA 02260860 1999-01-12
W O 98/03166 PCTrUS97/12873
-80-
TABLE41
HS R2
S,
O O
,R1
~,OCH3 ,~3~0 ~ ~C~
~~~ s~G~
H,~3~ NHJl~ CH3
~o
Rl 2
~~) H3C~N,CH3 ~NH
N~
bN

CA 02260860 1999-01-12
W O 98/03166 PCTrUS97112873
-81-
TABLE42
~S~o
~3~OCH3 ~,O
~,0~ ,S~
J~ J~ ~ ~ NJI~CH
O
~0
H~C~N,CH, (~)
N

CA 02260860 1999-01-12
W O 98103166 -82- - PCTrUS97/12873
TABLE43
HS R2
~ '~S~
,~o~OCH3 ~,~0
0~ ,S~
J~ J~ ~ ~ NJI~CH
~0
l2
N Ç~ H3C~N,CH3 ~HN~
N
CH3 H

CA 02260860 1999-01-12
WO 98/03166 PCT/US97/12873
-83 - --
TABLE 44
HS~ R2
h, N~ S'
~ O O
~R1
~,OCH3 ~¢~.~~
~~ S~o
3 ~N~CH3 ~' NJ~CH
~0
H,C~ ,CH,
CH3 H

CA 02260860 1999-01-12
W O 98/03166 PCTrUS97/12873
-84- -
TABLE45
H ~ ~ H
/~ IA\
o o o o
HS ~ N S ~ ~ HS ~ N S
H3C CH30/~ o H3C CH301/\\o
N~ ~ ~ HS ~ N~
h~ h\\
o o o o
HS ~ N~ ~ ~ ~ N~ S
CH3 1 0 =CH //\\
N~ ~ ~ ~ N~S
CH3 o o CH3 o o
CH3 CH3 ~ ~ CH3 CH3
HS ~ ~ S HS ~ ~S
CH3 g o 3 o o

CA 02260860 1999-01-12
W O 98/03166 -85- PCTrUS97/12873
TABLE46
HS~N' J~
R
R3
--CH3 - - G --CF3
H
CH2CH3H2N~ ~ _ CH2CF3
HO~O
H3CO ~ , CH20H
O
H2N~o <~ ,
~3C OH
HO~ _ -
~ H3CO~O
N~
H2N~ O V~ S
- b ~
C~ N~,~ S

CA 02260860 1999-01-12
W O 98/03166 PCT~US97/12873
-86-
TABLE4
~N
HS~ ~/S~S~
3 O O
IH3 HO~IJ N~ IF3 lO H
IH2CH H2N~ H2CF3
o
HO~O ~
H3CO~J CH20H
H2N O ~J
~ I H C1 OH
HO--~0 l~ I
H3CO O [~
~J 1 J
C~ H2N~, IJ v--
OJ H3CO~

CA 02260860 1999-01-12
WO 98/03166 PCTrUS97/12873
-87-
T BLE48
HS~ 5J~
CH~ o/A\o
CH3HO~ J ~ CF, CO H
CH2CH, H2N_~J H CH2CF,
HO O
H,C(~J CH20H
H2N O oJ H,C OH
H ¦
H3CO~ O o~
o b
oJ H,C~

CA 02260860 1999-01-12
W O 98/03166 -88- PCTAUS97/12873
TABLE49
HS~ N~ J~
3 O O
- R2
- H /--~
O N--CH2CH2- ~--N--CH2CH2-
-CH3
CH2CH3 GN--CH2CH2- H3C'N--CH2CH2-
- CH2CH2CH3 .~ ~
- CH2cH2cH2cH3 ,N--CH2CH2- ,N--CH2CH2-
H CH3
- CH2CH2CH2CH2CH3
CH2CH2CH2CH2CH2CH3 H--N N--CH2CH2- PhO~CH2CH2'
- CH2Ph
~\ ~
- CH2CH2Ph H3C--N~ N--CH2CH2- PhCH2 N ~N--CH2CH2-
CH2CH(CH3)2 CH2-
- CH2CF3 N~ CH2- ~ CH2-
- CH2CH20CH3
CH:ZCH20H ~CH2- ,N~ N~
- CH2CH2C02H D--CH2- <~CH2- ~CH2- 0--CH2-
- CH2CH2CH2CO2H
-CHZcH2cH2cH2co2H H3CO ~ CH2CH2- ~ CH2-
- CH2CH2CH2CH2CH2CO2H

CA 02260860 1999-01-12
WO 98/03166 . PCT/US97/12873
-89-- --
TABLE 50
O CH3 ~ 13
CH3 ~ ~
J~
3R
o O O O
H3C~ ¢~ H2N~ HO~
O O O O
H3C~
o O O
H3C~~ ~ H2N~ O
N ~ ~~
O O I Me2NJ~J
H3G Jl~ ~=~ o
~S H2N~
~) H,CO
H3C~ ~ W
CH3 ~
o o H3CH2CO
~J-- ~ H3 H3C

CA 02260860 1999-01-12
W O 98/03166 PCT~US97/12873
-90-
TABLE51
O CH3 ~ S~¢~
CH~ ~ ~
9R~
o O O O
H3C~ ~ H2NJI~ HO~
H,C~ ~ H2N~ ~,cr'~
CH3H2N
o O O
H,C~~ ~
O O Me2N
3 ~ ~ O
~,~ S H2N~
H3~ ~ ~ H,CO
CH3 0 0
o o H3CH2CO
H3C~ H3CO~
CH3 CH3
,

CA 02260860 1999-01-12
W O 98/03166 PCTAUS97/12873
- 91-
TABLE 52
O CH, ~ --
9RJI~s~h~sJ~
CH3 ~ ~
O
9R~
O O O O
H,Cl ~ H2N~ HO~
O O O o
H3C~ N~
O O O
H3C~~ ~ H2N~
N ~J
O O I IVle2N~
H3C Jl~ _~1~ o
~ S H2N~I~' ~
H,C~ H3CO
CH3 0 0
o o H3CH2CO
~ H3C H3CO

CA 02260860 1999-01-12
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-92- -
TABLE53
O CH3 ~/
9R l S~ ~S~
CH3 ~ ~
J~
~R
H3CJI~ ¢~ H2N~ HO~
O O O O
H3CJI~ N~3
N~
o o Me2N
H3C ~1~ F~ O
~ S H2N~ o
O O ~ H3CO
H3C~ ~ ~J
CH3 ~~
~ H3CH2Co
~ ~ H, H,CO
O O ~ ~
~ ~ ~ CH3 CH3

CA 02260860 1999-01-12
WO 98/03166 PCT/US97/12873
-93- -
TABI,E 54
7 R 1 S~ ~ 5~ Q
- 11\\
CH~ ~ ~
o
~R Jl~
O O O O
H3CJ~ ~ H2N~ HO~
O O O o
H3C~JI~ N~
o O O
H3C~~ ~ H2N~D~ O
N
O O I Me2N~J
H3~ ~ O
~ S H2N~I~ o
H3C~ ~ 13/ H3CO
CH3 0 0
o o H3CH2CO
¢~ ~ H3C~ ~H3CO~~4j~
~ CH3 CH3
o

CA 02260860 1999-01-12
W O 98/03166 PCTAUS97/12873
-94-
TABLE55
~N)
9RJ~ S
- /A\
CH3
9RJ~
O O O O
H3CJI~ H2N~ HO~
O O O o
H,C~JI~ N~ H2N~
CH, H2N
o O O
H3C~ ~ H2N~ O
~ O ~ Me2N~
H3~ ~ ~
~ S H2N~ O
H3~ ,~ ~ H~CO
CH, O
o o H~CH2CO
H3C~ H3CO~
CH, CH3

CA 02260860 1999-01-12
WO 98/03166 PCT/US97/12873
- 9 5 - _
TABLE 56
N~
9R S~ ~sJ~ 5
' 1~
CH3 ~ ~
9R J'~
o O O O
H3CJ~ ~ H2N~ HO~
O O O o
H3C~J~ ~ H2N~
I~J CH, H2N~J~
o O O
H3C~ ~
O O Me2N
H3C
S H2N~
O O ~ / H3CO
H3C~ ~ ~ .
CH, ~ O
o o H3CH2CO
¢~ ~ H3 H3CO o

CA 02260860 1999-01-12
W O 98/03166 PCTrUS97/12873
-96-
TABLE57
[~,~~
o ~ ~o ~
~RJ~S~ ~5~J
- IA\
CH ~ ~
sR
O O O O
H,CJ~ ~ H2N~ HO~
CH3
O O O o
H,C~ ~ H2N
CH, HZN
o O O
H,C~~ f ~ HzN~
- N~ ~J Me2N
H,C~~~ _~
~ S H2N~ O
H,C~ ) H3CO~
CH3 0 0
o o H3CH2CO~

CA 02260860 1999-01-12
W O 98/03166 PCTrUS97/12873
-97- -
TABLE58
[~ON~
9R 1 S~ ~ 5
CH3 ~ ~
9R Jl~
o O O O
H,CJ~ ¢~ H2N~ HO~
CH3
O O O o
H3C~J~ N~ H2Nyl~ H2N}
O O O
H3C~~ ~ H2N~J~ O
N
O O Me2N~
H,C JL~ ,~ o
~ S H2N~I~
H3(~ ~ ~/ H3CO
CH, O O
o o H,CH2CO
~ H3C H3CO

CA 02260860 1999-01-12
WO 98/03166 PCT/US97/12873
--98--
TABLE 59
9R~S~ ~S~3
1/~
CH, ~ ~
9R
o O O O
H3CJ~ (~ H2N~ HO~
CH3
H3C~L~ ~H2N i H2N~
o O O
H3C~~ ~ .~
O O Me.N
SH2N~ O
H,C ~ / H,CO
CH, O O
o o H,CHZCO
¢~ ~H,C H,CO
} ~ ~ ~ ~ ~

CA 02260860 1999-01-12
WO 98/03166 PCT/US97/12873
_99_ _
TABLE60
9RJI~ S~ ~ S
~, _ ~\\
CH,
9RJ~
o O O O
H,CJ~ ~ H2N~ H(~
O O O o
H3C~ ~N3
o O O
H3C~~ N~
O O Me2N
H, ~ ,.~ O
~ S H2N~
H,C~,~ ) H,CO
CH, O O
o o H,CH2CO
o O ~ H3CO~CC~
CH3 CH,

CA 02260860 1999-01-12
W O98103166 PCT~US97/12873
-100-
TABLE61
3 R J~ S~ ~ 5J~ 5
- 6r\\
CH, ~ ~
3R
o O O O
H3CJ~ ~ H2N~ HO~
O O O O
H3C~J~ ~ H2N~I~ ~,
W CH3 H2NJ~J
o O O
H3C--Jl~ ~ HzN~
H3C ~ N ~J Me2N
H2N~D~ o
H3C~ 6~ ~/ H3CO
CH, O
o H3CH2CO
oJ~ ~ H,~ 11,CO~
-

CA 02260860 1999-01-12
W O98/03166 , PCTrUS97/12873
-101-
TABLE62
9R J'' S~ ~ 5
11~
CH3 ~ ~
9R
O O O O
H,CJ~¢~ H2N~ HO~
O O O o
H3C~Jl~N~ ~ _~
o O O
H3C~~ N~
H,C JL~ ~ Me2N
H2N~, O
H3C~ ~ 0/ H,CO
CH3 0 0
o o H3CH2CO
~ H, H3CO

CA 02260860 1999-01-12
W O 98/03166 PCTrUS97/12873
-102 -
T ~ LE63
~RJ~S~N~5~
h~
CH3
~RJ~
o O O O
H3C~ ~H2N~ HO~
O O O o
H3(~ N~
H3C~R ~R
O O Me2N
H3~ ~ o
~SH2N~ R
O O ~ / H3CO
CH3 ~ ~ O
o H3CH2CO
H3~ H3C~'CO'~i'
~,~ ~ CH3 CH3

CA 02260860 1999-01-12
W O98/03166 PCTAUS97/12873
-103-
TABLE64
~R J~ S~ ~ S~3
- /A\
CH, ~ ~
iRl
O O O O
H,CJ~ W~ H2N~ HO~
CH,
O O O o
H,C~ N~ H2N
W CH, H2N~W
o O O
H,C~~ N~
O O Me2N
3~ ~ O
~ SH2N~JI~ O
H,C~ ~ ~ H3CO
CH3 0 0
o H3CH2CO
~J~ ~ H,~

CA 02260860 1999-01-12
W O 98/03166 . PCT~US97/12873
-104-
TABLE65
9R~S~ ~sJ~ ~13
-- I~\
CH3 ~ ~
9R
O O O O
H,C~ ~ H2N~ HO~
CH3
O O O o
H3C~ ~ ~ ~ GJ~
O O O
H3C~~ ~ H2N~ O
H3~~l~ N ~J Me2N~
H2N I O
H3 ~ / H3CO
CH3 0 0
H3CH2CO
¢~ ~ H3 H3CO
O ~ ~ ~

CA 02260860 1999-01-12
WO 98/03166 PCT/US97/12873
-105-
TABLE 66
9R ~ S~ ~ S~ S~
CH3 ~ o~
9RJ~
o O O O
H3CJI~ ~ H2N~ HO~
O O O o
H3C~
o O O
H3C~~ ~ H2N~
O O ~ Me2N~
H3C Jl~ _~ o
~ S H2N~JI~ ~
H3C~ 6;~ ¢ ~/ H3CO
CH, O
o o H3CH2CO
H3 H3CO o

CA 02260860 1999-01-12
W O 98103166 PCTrUS97/12873
-106-
TABLE67
Jl~ ~N~ ~¢~
/1 \\
CH3
~R~
o O O O
H,CJ~ ~ H2N~ HO~
H3
O O O o
H3C~J~ N~
o O O
H3C~~ N~
O O Me2N
H3~ ~ H2N l O
O ~/ H3CO
H3C~ ~ I~J
CH, ~ O
H3CH2CO
~ ~ H3 H3CO o
O O ~ ~
~ ~ CHJ CH,
.

CA 02260860 1999-01-12
W O98/03166 PCTAUS97/12873
-107-
TABLE68
~R 1 S~ ~5
CH3 ~ ~
~RJ~
O O O O
H3C~ ~ H2N~ HO~
O O O O
H3C~ ~ H2N~
CH3 H2N
H,C~~ ~ H2N
N 'lJMe2N ~\
H, ~ ~_~ O
~ S HzN~l~ o
H3~ ~ ¢~ H3CO
CH3 0 0
O O H3CH2CO~
¢~ ~ H
3~f ~ H3CO~~~

CA 02260860 l999-0l-l2
W O 98/03166 PCTrUS97/12873
-108-
TABLE69
3R1S~
CH3 ~ ~
I~RJ~
o O O O
H,CJJ~ ~ H2N~ H~~J
O O O O
H3C~J~ ~ H2N~
CH, H2N
o O O
H3C--~P\ N~
O O Me2N
3~ ~ O
~ S H2N~ O
H3~ ~ ¢~ H3CO
CH3 0 0
~ H3CH2Co~
¢~ ~ H3 H3CO O

CA 02260860 1999-01-12
W O 98/03166 PCT~US97/12873
-109-
TABLE70
N O
HS , ~SJJ ~0
//\\
CH3 ~ _ -- -CF3
- H
CH2CH3H2N~ CH2CF3
O
HO~O /\
H3CO~ . CH20H
O
H2N ~0 O~
H3C~OH
HO~
~H3CO~O
_ N~
H2N~ O V~ S
N=~
H3CO~ O 0 S
O N~,S

CA 02260860 1999-01-12
W O 98/03166 PCTrUS97/12873
-110- -
TABLE 7l
,~
HS~N~S ~
H2N ~o ~ ~
- R2
-H O N--CH2CH2- CN_CH2CH2
-CH3
- CH2CH3 ~N--CH2CH2- H3C'N--CH2CH2-
-CH2CH2CH3 ~ ~
N--CH2CH2- N--CH2CH2-
CH2CH2CH2CH3 H CH3
-CH2CH2CH2CH2cH3 A
H--N N--CH2CH2- PhO~CH2CH2-
- CH2cH2cH2cH2cH2cH3
CH2Ph H3C--N N--CH2CH2- PhCH2--N N--CH2CH2-
- CH2CH2Ph
CH2-
CH2CH(CH3)2 N5 ~CH2- CS~CH2-
- CH2CF3 s
- CH2CH20CH3 ¢~CH2-N~CH2 ~,CH2-
CH2CH20H N
- CH2CO2H ~CH2- ~--CHz- 0-- C
- CH2CH2C02H
HO2C
- CH2CH2CH2C02H H3CO~CH2CH2- ~CH2-
- CH2CH2CH2CH2C02H
- CH2CH2CH2CH2CH2C02H

CA 02260860 1999-01-12
W O 98/03166 PCT~US97/12873
TABLE72
~ H
HS~N~S ~
- /1\\
--R3
CH3 ~ - C-F3
- H
CH2CH3 o _ _ CH2CF3
HO~O A
H3CO~ . CH20H
O
0/ ~
HO~ - - H3C OH
~H3CO~O ~
-H2N~o O S
0/ - N=~
H3CO ~ ~ ~I S
~ N ~ ~S

CA 02260860 1999-01-12
WO 98/03166 PCT/US97/12873
- 112 -
TABLE 73
~J
- /1~
R3 ~ ~
CH3 o _ -- CF3
H
CH2CH3H2N~ _ ' CH2CF3
O _ _
HO~O ~
H3CO~ _ CH20H
H2N ~0 0/
H3C~OH
HO~ _ -
~H3CO~O ~/
O O S
N=~
H3CO~ O 0
N ~,~S
.. . .

CA 02260860 1999-01-12
WO 98/03166 . PCT/US97/12873
- 113 -
TABLE 74
HS~ N 'S J~ ~
- 1/ ~\
R3 ~ ~
R3
CH3 . _ - --CF3
H
CH2CH3 H2N~ j CH2CF3
HO~O ~
H3CO~i . CH20H
O _ _
H2N~O O~
- H3C OH
HO~ ~ _ _
~ H3CO~O o~
~0 0 S
~ _ _ _ ~
- H3CO~o O 0
N~,S

CA 02260860 1999-01-12
W 098tO3166 PCTAUS97/12873
-114-
'.\131.':''
HS~N~ ~R'
O O
0~ S~
CH,
~'~' J~ ~~~1 ,0,,S~gN
O ~CH3 J3~ ~N ~3~5~¢~
CH3 /~ ~N J~ ~
~,O~CF3 ~l3~o~CF3 ~3~~~
,~,J 'i ~J~ 1~ ¢~o ~1N3H?

CA 02260860 1999-01-12
W O 98/03166 PCTrUSg7/12873
-115-
~'' .
HS~N~ ,R
11
R
0~ CI ~0~S~
J~ ~CI
CH.
f ~ 1 j ~ ~ ¢~ ~N
~O~ ~C~3 ~0~ ~N ~ \¢~
CH~ /~ ~N
¢~O~CF3 3~0~ 3~C'3 3~o~
~J-- li~ r- CH~ J~~~ CH,

CA 02260860 1999-01-12
W O 98/03166 , PCTrUS97/12873
~ .
HS~N~ ~R
11~
- O O
~ ~,O~CI ~3~S~
,~ ~U ~
J~ CI
CH.
O~ C H3 ~0~ ~N J~ S
CH3 /~ ~N ,, J3'
~3 ~O~ CF3 3~o~¢~
\= N
~~' [~"

CA 02260860 1999-01-12
WO 98/03166 PCT/US97/12873
- 117 -
TABLE 78
R2 0~O~3~N ~N
NH2~o ~ ~ bN~
- R2
- H O N--CH2CH2- CN_CH2CH2
- CH3
CH2CH3 GN--CH2CH2- H3C'N--CH2CH2-
- CH2CH2CH3 ~ ~
N--CH2CH2- N--CH2CH2-
CH2CH~CH2CH3 H CH3
-CH2CH~CH,CH2CH3 ~ ~
H--N N--CH2CH2- PhO~CH2CH2-
- CH2cH2cH2cH2cH2cH3
CH2Ph H3C--N N--CH2CH2- PhCH2--N N--CH2CH2-
- CH2CH2Ph
CH2CH(CH3)2 ~ CH2- ~S~CH2-
- CH2CH2OCH3 N CH2- N CH2- ~CH2-
- CH2CH20H ¢~ ~ N~
CH2CH~CO2H ~CH2 ~CH2 ~CH2~ C~CH2
- CH2CH2CH2C02H H3CO~CH2CH2- ~CH2-
- CH2CH2CH2CH2C02H
- CH2CH2CH2CH2CH2CO2H

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-118- -
TABLE79
HS~N~s/~ ~NH
NH2~o ~ ~ ~ CH3
- R2
- H A A
O N--CH2CH2- ~N--CH2cH2
-CH3
- CH2CH3 ~N--CH2CH2- 3 N--CH2CH2-
- CH2CH2CH3
N--CH2CH2- N--CH2cH2
- CH2CH2CH2CH3 H CH3
-CH2CH2CH2CH2CH3 A
H--N N--CH2CH2- Pho~cH2cH2
- CH2cH2cH2cH2cH2cH3
- CH2Ph H3C--N N--CH2CH2- PhCH2--N N--CH2cH2
- CH2CH2Ph
- CH2CH(CH3)2 ~ CH2- ~S~--CHz-
- CH2CH20CH3 N CH7- N~CH2- CH2-
- CH2CH20H ~ I~d N~
- CH2CO2H
D--CH2- 0--CH2- ~CH2- 0--CH2-
- CH2CH2C02H
H O H /==\ H02C
-C 2CH2CH2C 2 H3CO ~ CH2CH2- ~ CH2-
-CH2CH2CH2CH2CO2H
- CH2CH2CH2CH2CH2CO2H

CA 02260860 1999-01-12
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-119-
TABLE80
R2 ,~0~
- B"
- - R2
-H O N--CH2CH2- CN CH2CH2-
-CH3
CH2CH3 GN--CH2CH2- H3C'N--CH2CH2-
- CH2CH2CH3 ~ ~
N--CH2CH2- N--CH2CH2-
-CH2CH2CH2CH3 H CH3
-CH2CH2CH2CH2CH3 A
H--N N CH2CH2- PhO~CH2CH2-
- CH2CH2CH2CH2CH2CH3 --/ ~Y
- CH2Ph H3C--N N--CH2CH2- PhCH2--N ~N--CH2CH2-
- CH2CH2Ph
- CH~CH(CH3)2 ~ CH2- ~--CH2-
- CH2CH2OCH3 N CH2- N~CH2- ~ CH2-
CH2CH20H ~ N
-CH CH2CO2H ~CH2 ~CH2 ~ 2 C
H02C
- CH2CH2CH2C02H H3CO~CH2CH2- ~CH2-
- CH2CH2CH2CH2C02H
-CH2CH2CH2CH2CH2CO2H
In the written descriptlons of molecules
and groups, molecular descriptors can be combinea to
produce words or phrases that describe structurai

CA 02260860 1999-01-12
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-120-
groups or are combined to describe structural groups.
Such descriptors are used in this document. Common
illustrative examples include such terms as aralkyl
(or arylalkyl), heteroaralkyl, heterocycloalkyl,
cycloalkylalkyl, aralkoxyalkoxycarbonyl and the like.
A specific example of a compound encompassed with the
latter descriptor aralkoxyalkoxycarbonyl is C6Hs-CH2-
CH2-O-CH2-O-(C=O)- wherein C6Hs- is phenyl. It is
also to be noted that a structural group can have
more than one descriptive word or phrase in the art,
for example, heteroaryloxyalkylcarbonyl can also be
termed heteroaryloxyalkanoyl. Such combinations are
used above in the description of the compounds and
compositions of this invention and further examples
are described below. The following list is not
intended to be exhaustive or drawn out but provide
further illustrative examples of such words or
phrases.
As utilized herein, the term "alkyl", alone
or in combination, means a straight-chain or
branched-chain alkyl radical containing 1 to about 12
carbon atoms, preferably 1 to about 10 carbon atoms,
and more preferably 1 to about 6 carbon atoms.
Examples of such radicals include methyl, ethyl, n-
propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, iso-amyl, hexyl, octyl and the
like.
The term "alkenyl", alone or in
combination, means a straight-chain or branched-chain
hydrocarbon radical having one or more double bonds
and containing 2 to about 12 carbon atoms preferably
2 to about 10 carbon atoms, and more preferably, 2 to
about 6 carbon atoms. Examples of suitable alkenyl
radicals include ethenyl (vinyl), 2-propenyl, 3-
propenyl, 1,4-pentadienyl, 1,4-butadienyl, l-buten
2-butenyl, 3-butenyl, decenyl and the like.

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-121- -
The term "alkynyl", alone or in
combination, means a straight-chain hydrocarbon
radical having one or more triple bonds and
containing 2 to about 12 carbon atoms, prèferably 2
to about lO carbon atoms, and more preferably, 2 to
about 6 carbon atoms. Examples of alkynyl radicals
include ethynyl, 2-propynyl, 3-propynyl, decynyl, l-
butynyl, 2-butynyl, 3-butynyl, and the like.
The term "carbonyl", alone or in
combination, means a -C(=O)- group wherein the
remaining two bonds (valences) can be independently
substituted. The term "thiol" or "sulfhydryl", alone
or in combination, means a -SH group. The term
"thio" or "thia", alone or in combination, means a
thiaether group; i.e., an ether group wherein the
ether oxygen is replaced by a sulfur atom.
The term "amino", alone or in combination,
means an amine or -NH2 group whereas the term mono-
substituted amino, alone or in combination, means a
substituted amine -N(H)(substituent) group wherein
one hydrogen atom is replaced with a substituent, and
disubstituted amine means a -N(substituent)2 wherein
two hydrogen atoms of the amino group are replaced
with independently selected substituent groups.
Amines, amino groups and amides are
compounds that can be designated as primary (I~),
secondary (II~) or tertiary (III~) or unsubstituted,
mono-substituted or di-substituted depending on the
degree of substitution of the amino nitrogen.
Quaternary amine (ammonium)(IV~) means a nitrogen
with four substituents [-N+(substituent) 4] that is
positively charged and accompanied by a counter ion,
whereas N-oxide means one substituent is oxygen and
the group is represented as [-N+(substituent) 3-O-];
i.e., the charges are internally compensated.

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The term ~cyano", alone or in combination,
means a -C-triple bond-N (-C/N) group. The term
~azido", alone or in combination, means a -N-triple
bond-N (-N/N) group. The term "hydroxyl", alone or in
combination, means a -OH group. The term "nitro",
alone or in combination, means a -NO2 group. The
term "azo", alone or in combination, means a -N=N-
group wherein the bonds at the terminal positions can
be independently substituted.
The term "hydrazino", alone or in
combination, means a -NH-NH- group wherein the
depicted remaining two bonds (valences) can be
independently substituted. The hydrogen atoms of the
hydrazino group can be replaced, independently, with
substituents and the nitrogen atoms can form acid
addition salts or be quaternized.
The term "sulfonyl", alone or in
combination, means a -SO2- group wherein the depicted
remaining two bonds (valences) can be independently
substituted. The term ~sulfoxido", alone or in
combination, means a -SO- group wherein the remaining
two bonds (valences) can be independently
substituted.
The term "sulfonylamide", alone or in
combination, means a -SO2-N= group wherein the
depicted remaining three bonds (valences) can be
independently substituted. The term ~sulfinamido",
alone or in combination, means a -SON= group wherein
the remaining three depicted bonds (valences) can be
independently substituted. The term "sulfenamide",
alone or in combination, means a -S-N= group wherein
the remaining three bonds (valences) can be
independently substituted.
The term "alkoxy", alone or in combination,
means an alkyl ether radical wherein the term alkyl
s as defined above. Examples of suitable alkyl
ether radicals include methoxy, ethoxy, n-propoxy,

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isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-
butoxy and the like.
The term "cycloalkyl", alone or in
combination, means a cyclic alkyl radical that
S contains 3 to about 8 carbon atoms. The term
"cycloalkylalkyl" means an alkyl radical as defined
above that is substituted by a cycloalkyl radical
containing 3 to about 8, preferably 3 to about 6,
carbon atoms. Examples of such cycloalkyl radicals
include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and the like.
The term "aryl", alone or in combination,
means a 5- or 6-membered aromatic ring-containing
moiety or a fused ring system containing two or three
rings that have all carbon atoms in the ring; i.e., a
carbocyclic aryl radical, or a heteroaryl radical
containing one or more heteroatoms such as sulfur,
oxygen and nitrogen in the ring(s). Exemplary
carbocyclic aryl radicals include phenyl, indenyl and
naphthyl radicals. Examples of such heterocyclic or
heteroaryl groups are pyrrolidinyl, piperidinyl,
piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl,
imidazolyl (e.g., imidazol-4-yl,
1-benzyloxycarbonylimidazol-4-yl, and the like),
pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, furyl,
tetrahydrofuryl, thienyl, triazolyl, oxazolyl,
oxadiazoyl, thiazolyl, thiadiazoyl, indolyl (e.g.,
2-indolyl, and the like), quinolinyl, (e.g.,
2-quinolinyl, 3-quinolinyl, 1-oxido-2-quinolinyl, and
the like), isoquinolinyl (e.g., 1-isoquinolinyl,
3-isoquinolinyl, and the like), tetrahydroquinolinyl
(e.g., 1~2~3~4-tetrahydro-2-quinolyl~ and the like),
1,2,3,4-tetrahydroisoquinolinyl (e.g., 1,2,3,4-
tetrahydro-1-oxo-isoquinolinyl, and the like),
quinoxalinyl, ~-carbolinyl, 2-benzofurancarbonyl,
benzothiophenyl, 1-, 2-, 4- or 5-benzimidazolyl, and
the like.

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An aryl ring group optionally carries one
or more substituents selected from alkyl, alkoxy,
halogen, hydroxy, amino, nitro and the like, such as
phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-
butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-
hydroxyphenyl, 1-naphthyl, 2 -naphthyl, and the like.
The term "aralkyl", alone or in
combination, means an alkyl radical as defined above
in which one hydrogen atom is replaced by an aryl
radical as defined above, such as benzyl, 2-
phenylethyl and the like.
The term "aralkoxycarbonyl", alone or in
combination, means a radical of the formula -C(O)-O-
aralkyl in which the term "aralkyl~' has the
significance given above. An example of an
aralkoxycarbonyl radical is benzyloxycarbonyl.
The term "aryloxy" means a radical of the
formula aryl-O- in which the term aryl has the
significance given above.
The terms "alkanoyl" or "alkylcarbonyl",
alone or in combination, means an acyl radical
derived from an alkanecarboxylic acid, examples of
which include acetyl, propionyl, butyryl, valeryl,
4-methylvaleryl, and the like.
The term "cycloalkylcarbonyl~ means an acyl
group derived from a monocyclic or bridged
cycloalkanecarboxylic acid such as
cyclopropanecarbonyl, cyclohexanecarbonyl,
adamantanecarbonyl, and the like, or from a benz-
fused monocyclic cycloalkanecarboxylic acid that is
optionally substituted by, for example,
alkanoylamino, such as 1,2,3,4-tetrahydro-2-
naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-
naphthoyl.
3~ The terms ~'aralkanoyl" or ~'aralkylcarbonyl"
mean an acyl radical derived from an aryl-substituted
alkanecarboxylic acid such as phenylacetyl,

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3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl,
(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl,
4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl and
the like.
The terms ~aroyl" or "arylcarbonyl" means
an acyl radical derived from an aromatic carboxylic
acid. Examples of such radicals include aromatic
carboxylic acids, an optionally substituted benzoic
or naphthoic acid such as benzoyl, 4-chlorobenzoyl,
4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl,
1-naphthoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl,
6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-
2-naphthoyl, 3-hydroxy-2-naphthoyl,
3-(benzyloxyformamido)-2-naphthoyl, and the like.
The heterocyclic (heterocyclo) or
heterocycloalkyl portion of a heterocyclocarbonyl,
heterocyclooxycarbonyl, heterocycloalkoxycarbonyl, or
heterocycloalkyl group or the like is a saturated or
partially unsaturated monocyclic, bicyclic or
tricyclic heterocycle that contains one or more
hetero atoms selected from nitrogen, oxygen and
sulphur. Such a moiety can be optionally substituted
on one or more carbon atoms by halogen, alkyl,
alkoxy, oxo, and the like, and/or on a secondary
nitrogen atom (i.e., -NH-) by alkyl,
aralkoxycarbonyl, alkanoyl, aryl or arylalkyl or on a
tertiary nitrogen atom (i.e. =N-) by oxido and that
is attached via a carbon atom. The tertiary nitrogen
atom with three substituents can also attached to
form a N-oxide [=N(O)-] group.
The term "cycloalkylalkoxycarbonyl" means
an acyl group of the formula cycloalkylalkyl-O-CO-
wherein cycloalkylalkyl has the significance given
above. The term "aryloxyalkanoyl" means an acyl
radical of the formula aryl-O-alkanoyl wherein aryl
and alkanoyl have the significance given above. The
term "heterocyclooxycarbonyl" means an acyl group

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having the formula heterocyclo-O-CO- wherein
heterocyclo is as defined above. The term
"heterocycloalkanoyl" is an acyl radical of the
formula heterocyclo-substituted alkane carboxylic
acid wherein heterocyclo has the significance given
above. The term "heterocycloalkoxycarbonyl" means an
acyl radical of the formula heterocyclo-substituted
alkane-O-CO- wherein heterocyclo has the significance
given above. The term "heteroaryloxycarbonyl" means
an acyl radical represented by the formula
heteroaryl-O-CO- wherein heteroaryl has the
significance given above.
The term "aminocarbonyl" alone or in
combination, means an amino-substituted carbonyl
(carbamoyl) group derived from an amino-substituted
carboxylic acid (carboxamide) wherein the amino group
can be a primary or secondary amino (amido nitrogen)
group containing substituents selected from hydrogen,
and alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl
radicals and the like.
The term "aminoalkanoyl" means an acyl
group derived from an amino-substituted
alkanecarboxylic acid wherein the amino group can be
a primary or secondary amino group containing
substituents independently selected from hydrogen,
alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl
radicals and the like.
The term "halogen" means fluoride,
chloride, bromide or iodide. The term "haloalkyl"
means an alkyl radical having the significance as
defined above wherein one or more hydrogens are
replaced with a halogen. Examples of such haloalkyl
radicals include chloromethyl, 1-bromoethyl,
fluoromethyl, difluoromethyl, trifluoromethyl,
l~l,l-trifluoroethyl and the like.
The term perfluoroalkyl means an alkyl
group wherein each hydrogen has been replaced by a

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fluorine atom. Examples of such perfluoroalkyl
groups, in addition to trifluoromethyl above, are
perfluorobutyl, perfluoroisopropyl, perfluorododecyl
and perfluorodecyl.
The term "aromatic ring~ in combinations
such as substituted-aromatic ring sulfonamide,
substituted-aromatic ring sulfinamide or substituted-
aromatic ring sulfenamide means aryl or heteroaryl as
defined above.
M utilized in the reaction Schemes that
follow represents a leaving group such as halogen,
phosphate ester or sulfate ester.
Preparation of Useful ComPounds
Schemes 1 through 5 illustrate chemical
processes and transformations that can be useful for
the preparation of compounds useful in this
invention; i.e., compounds of formulas I-III, Ia-I_Ia
and Ib-IIIb. The groups ~1 through R9 shown in the
schemes are defined above.
These reactions can be carried out under a
dry inert atmosphere such a nitrogen or argon if
desired. Selected reactions known to those skilled
in the art, can be carried out under a dry atmosprere
such as dry air whereas other synthetic steps, for
example, aqueous acid or base ester or amide
hydrolysis, can be carried out under laboratory air.
In addition, some processes of this invention can be
carried out in a pressure apparatus at pressures
above, equal to or below atmospheric pressure. The
use of such an apparatus aids in the control of
gaseous reagents such as hydrogen, ammonia,
trimethylamine, methylamine, oxygen and the like. It
can also help prevent the leakage of air or humidity
into a reaction in progress. This discussion is not
intended to be exhaustive as it is readily noted that
additional or alternative methods, conditions,

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reactlons or systems can be identified and used by a
chemist of ordinary skill.
Step 1 in Scheme 1 illustrates conversion
of a hydroxyl group into compound 2 with an activated
carbon-M bond via hydroxyl activation or replacement
to provide intermediates useful as electrophilic
reagents or, when M is -SH, a product of this
invention of formula I is formed. M usually
represents leaving groups such as halides (Cl, Br,
I), fluorides (aromatic) or sulfate esters such as
tosylate (OTs), mesylate (OMs), triflate (OTs) and
the like, or epoxides. The preparations of epoxides,
sulfate esters or organic halides are well known in
the art. M can also represent groups such as -SH
(thiol) or, following treatment of a thiol with base
or with a pre-formed salt, an -S~ group. The
non-thiols are prepared from the alcohols by standard
methods such as treatment with HCl, HBr, thionyl
chloride or bromide, phosphorus trihalide, phosphorus
pentahalide, trifluoromethylsulfonyl chloride,
tosylchloride or methanesulfonyl chloride and the
like.
These reactions are usually carried out at
a temperature of about -25~C to solvent reflux under
an inert atmosphere such as nitrogen or argon. The
solvent or solvent mixture can vary widely depending
upon reagents and other conditions and can include
polar or dipolar aprotic solvents as listed or
mixtures of these solvents.
In some cases, amines such as triethyl
amine, pyridine or other non-reactive bases can serve
as reagents and/or solvents and/or co-solvents. In
some instances, in these reactions and other
reactions in these Schemes, protecting groups can be
used to maintain or retain groups in other parts of a
molecule(s) at locations that is(are) not desired
reactive centers. Examples of such groups that the
... . ..

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skilled person might want to maintain or retain
include, amines, other hydroxyls, thiols, acids and
the like. Such protecting groups can include acyl
groups, arylalkyl groups, carbamoyl groups, ethers,
alkoxyalkyl ethers, cycloalkyloxy ethers, arylalkyl
groups, silyl groups including trisubstituted silyl
groups, ester groups and the like. Examples of such
protecting groups include acetyl, trifluoroacetyl,
tetrahydropyran (THP), Benzyl, tert-butoxy carbonyl
(BOC or TBOC), benzyloxycarbonyl (Z or CBZ), tert-
butyldimethylsilyl (TBDMS) or methoxyethoxymethylene
(MEM) groups. The preparation of such protected
compounds as well as their removal is well known in
the art.
The second step in Scheme 1 illustrates
preparation of a sulfonamide 2. Sulfamidation
reactions are conveniently carried out by reacting an
amine with, for example, a sulfonyl chloride or
sulfonic anhydride. A suitable solvent or mixture of
solvents includes aprotic or dipolar aprotic solvents
as defined below with examples being acetone,
methylene chloride DMF, THF, tert-butylmethylether
(tBME) or mixtures of such solvents. Usually such
reactions are carried out under and inert or dry
atmosphere at a temperature of from about -25~C to
40~C preferably at about 0~C. A base for the
scavenging of acid is usually also present with non-
limiting examples being triethyl amine, pyridine,
DBU, N-ethyl morpholine (N~M), sodium carbonate and
the like. The sulfonyl chlorides are well know in
the art and are commercially available or can be
prepared by the reaction of a suitable organometallic
reagent with sulfuryl chloride or sulfur dioxide
followed by oxidation with a halogen such as
- 35 chlorine. Grignard and alkyl lithium reagents are
desirable organometallic reagents.

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In addition, thiols can be oxidized to
sulfonyl chlorides using chlorine and/or chlorine
with water. Sulfonic acids are available by the
oxidation of thiols, reaction of sulfur derivatives
with organometallic reagents and the like and can be
converted into sulfonyl chlorides by treatment with
thionyl chloride, PCls and the like. They are also
commercially available.
Many reactions or processes involve bases
that can act as reactants, reagents, deprotonating
agents, acid scavengers, salt forming reagents,
solvents, co-solvents and the like. Bases that can
be used include, for example, metal hydroxides such
as sodium, potassium, lithium, cesium or magnesium
hydroxide, oxides such as those of sodium, potassium,
lithium, calcium or magnesium, metal carbonates such
as those of sodium, potassium, lithium, cesium,
calcium or magnesium, metal bicarbonates such as
sodium bicarbonate or potassium bicarbonate, primary
(I~), secondary (II~) or tertiary (III~) organic
amines such as alkyl amines, arylalkyl amines,
alkylarylalkyl amines, heterocyclic amines or
heteroaryl amines, ammonium hydroxides or quaternary
ammonium hydroxides. As non-limiting examples, such
amines can include triethylamine, trimethylamine,
diisopropylamine, methyldiisopropylamine,
diazabicyclononane, tribenzylamine,
dimethylbenzylamine, morpholine, N-methylmorpholine,
N,N'-dimethylpiperazine, N-ethylpiperidine, 1,1,5,5-
tetramethylpiperidine, dimethylaminopyridine,pyridine, quinoline, tetramethylethylenediamine,
diazabicyclononane and the like. Non-limiting
examples of ammonium hydroxides, usually made from
amines and water, can include ammonium hydroxide,
triethyl ammonium hydroxide, trimethyl ammonium
hydroxide, methyldiiospropyl ammonium hydroxide,
tribenzyl ammonium hydroxide, dimethylbenzyl ammonium

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hydroxide, morpholinium hydroxide, N-
methylmorpholinium hydroxide,
N,N'-dimethylpiperazinium hydroxide,
N-ethylpiperidinium hydroxide, and the like. As non-
limiting examples, quaternary ammonium hydroxides can
~ include tetraethyl ammonium hydroxide, tetramethyl
ammonium hydroxide, dimethyldiiospropyl ammonium
hydroxide, benzymethyldiisopropyl ammonium hydroxide,
methyldiazabicyclononyl ammonium hydroxide,
methyltribenzyl ammonium hydroxide,
N,N-dimethylmorpholinium hydroxide,
N,N,N',N'-tetramethylpiperazenium hydroxide, and
N-ethyl-N'-hexylpiperidinium hydroxide and the like.
Metal hydrides, amides or alcoholates such
as calcium hydride, sodium hydride, potassium
hydride, lithium hydride, aluminum hydride,
diisobutylaluminum hydrice (DIBAL) sodium methoxide,
potassium tert-butoxide, calcium ethoxide, magnesium
ethoxide, sodium amide, potassium diisopropyl amide
and the like can also be suitable reagents.
Organometallic deprotonating agents such as alkyl or
aryl lithium reagents such as methyl lithium, phenyl
lithium, tert-butyl lithium, lithium acetylide or
butyl lithium, Grignard reagents such as
methylmagnesium bromide or methymagnesium chloride,
organocadium reagents such as dimethylcadium and the
like can also serve as bases for causing salt
formation or catalyzing the reaction. Quaternary
ammonium hydroxides or mixed salts are also useful
for aiding phase transfer couplings or serving as
phase transfer reagents. Pharmaceutically acceptable
bases and be reacted with acids to form
pharmaceutically acceptable salts of this invention.
It should also be noted that optically active bases
can be used to make optically active salts which can
be used for optical resolutions.

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Generally, reaction media can consist of a
single solvent, mixed solvents of the same or
different classes or serve as a reagent in a sing~e
or mixed solvent system. The solvents can be protic,
non-protic or dipolar aprotic. Non-limiting examples
of protic solvents include water, methanol (MeOH),
denatured or pure 95~ or absolute ethanol,
isopropanol and the like. Typical non-protic
solvents include acetone, tetrahydrofurane (THF),
dioxane, diethylether, tert-butylmethyl ether (TBME),
aromatics such as xylene, toluene, or benzene, ethyl
acetate, methyl acetate, butyl acetate,
trichloroethane, methylene chloride,
ethylenedichloride ~EDC), hexane, heptane, isooctane,
cyclohexane and the like. Dipolar aprotic solvents
include compounds such as dimethylformamide (~MF),
dimethylacetamiae (DMAc), acetonitrile, DMSO,
hexamethylphosphorus triamide (HMPA), nitromethane,
tetramethylurea, N-methylpyrrolidone and the like.
Non-limiting examples of reagents that might be used
as solvents or as part of a mixed solvent system
include organic or inorganic mono- or multi-protic
acids or bases such as hydrochloric acid, phosphoric
acid~ sulfuric acid, acetic acid, formic acid, citric
acid, succinic acid, triethylamine, morpholine,
N-methylmorpholine, piperidine, pyrazine, piperazine,
pyridine, potassium hydroxide, sodium hydroxide,
alcohols or amines for making esters or amides or
thiols for making the products of this invention and
the like.
Step 4 of Scheme 1 is sulfamidation of
compound 1 where R2 can be hydrogen or as otherwise
defined. The process of sulfamidation is discussed
above in reference to Step 2. The product is the
alcohol 4.
Scheme 1 shows in Step 5 the direct
conversion of an alcohol such as compound 4 into a

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contemplated sulfur-containing compound, 5. A
descriptive term for this process is activated azo
coupling. The process can be carried out by reacting
a phosphine such as triphenyl phosphine and an azo
compound such as diisopropylaziodicarboxylate (DIAD)
or diethylazodicarboxylate (DEAD), a starting alcohol
and a thiolcarboxylic acid or dithiocarboxylic acid.
The reaction is usually carried out under an inert
atmosphere such as nitrogen or argon at about -40~C
to about 50~C in an inert solvent such as methylene
chloride, THF or the others listed above.
The thioester or dithioester ~R9(C=S)-] 5
is a compound of Formula II. Compound 5 can be
hydrolyzed to form compound 8 in Scheme 1 or
compounds 15 or 16 as shown in Scheme 4. Compound 8
is a compound of formula I. This hydrolysis can be
carried out with bases such as a metal hydroxide
(LioH, NaOH, KOH), carbonate (Na2CO3, K2CO3) or a
bicarbonate (NaHCO3). Examples of other hydrolytic
reagents suitable for this reaction include alkoxides
such as sodium methoxide, potassium ethoxide and the
like, a thiolate such as sodium thiophenolate,
potassium methanethiolate and the like or by
hydrolytic exchange with an amine or ammonia.
These reactions can be carried out under an
inert atmosphere such as helium, nitrogen or argon at
temperatures of from about -50~C to about 100~C.
Temperatures from about 0~C to about 60~C are
preferred. Solvents, pure or mixed, include water,
alcohols especially for alcoholate hydrolysis or
dipolar aprotic solvents such as acetonitrile, DMSO
or DMF. Amine exchanges can occur under conditions
as discussed above. In addition, the amine can serve
if desired as the solvent or a co-solvent as, for
example, when diethylamine, morpholine, dimethyl

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amine (in a pressure system) or piperidine, are used
as exchange agents.
The preparation of compound 8 from compound
5 can also be carried out using reductive processes
if desired. Useful reducing agents may include
lithium aluminum hydride, aluminum hydride, DI~AL,
potassium borohydride, sodium borohydride, lithium
borohydride or a metal catalyzed hydrogenation with a
system such as the employing a Rosenmund catalyst.
Reductions of the hydride type are usually carried
out at between 80~C and -80~C in non-polar aprotic
solvents such as THF or ethers whereas hydrogenations
with hydrogen gas require containers (hydrogenation
bottles, Parr bombs, pressure kettles and the like)
with protic or non-protic solvents or solvent
mixtures at temperatures of between -20~C to 100~C.
Conversion of compound 3 in Scheme 1 into
the sulfur-containing compound 5 illustrates
displacement of an electrophile by a nucleophile;
i.e., the conversion of a intermediate containing our
activated leaving group M or a derivative into a
sulfur compound of this invention. This method of
synthesis is commonly called bimolecular nucleophilic
substitution. Solvolysis or SN1 reactions are also
possible and, if desired, can be used to provide
electrophilic substitutions to produce alcohols,
ethers, amines, carboxylate esters and the like. The
reagents that provide the above compounds via SN1
ractions are water, alcohols, amines and carboxylic
acids.
The nucleophilic displacement (SN2)
reaction can be used in Step 3 wherein group M is
displaced by a thiol compound or the salt of a thiol
compound to produce compounds of formula I (compound
8) or formula II (compound 5) directly or a compound
of formula I via conversion of II into I. The

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diagramatically reverse procedure; i.e., synthesis of
a compound of formula I followed by its conversion
into a compound of formula II or formula III can also
be accomplished. Either compounds of formula I or of
formula II can be direct or non-direct intermediates
- in the preparation of compounds III (e.g. compound
6).
Compounds of formula III can be converted
into a compound of either of formulas I or II with a
thiol reagent. Non-limiting examples of thiol
reagents or their salts useful for nucleophilic
displacement reactions are hydrogen sulfide (H2S),
sodium sulfide (NaSH), thiolacetic acid [HS(C=O)CH3],
sodium thiolacetate [NaS(C=O)CH3], dithioacetic acid
1~ [HS(C=S)CH3] and sodium dithiolacetate ~NaS(C=S)CH3].
A thiolate or other anion can be obtained from a
preformed salt such as sodium sulfide or sodium
thiolacetate or it can be formea in situ via addition
of a base to an acid such as hydrogen sulfide or
thiolacetic acid. The bases and solvents are
discussed above. Preferred bases are those that are
hindered or tertiary such that competition with a
sulfur anion as a nucleophile in a two stage reaction
is minimized, e.g., triethylamine, pyridine, DBU,
DMAP and the like. A strong inorganic base or
organometallic base can be used if desired.
The solvents, solvent mixtures or
solvent/reagent mixtures discussed above are
satisfactory but non-protic or dipolar aprotic
solvents such as acetone, acetonitrile, DMF,
acetonitrile and the like are examples of a preferred
class. Bases can also be used as solvents as well as
reagents. Mixtures of the above solvents or with a
solvent and a base such as pyridine or triethylamine
are also useful. These reactions are usually carried
out under an inert atmosphere (nitrogen, argon) at
temperatures varying from between about -10~C to

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about 80~C. In many cases, room temperature is
preferred due to cost or simplicity. Again,
procedures involving nucleophilic substitution
reactions are well know in the art and sul-fur based
anions are known to be excellent nucleophiles.
The oxidation/reduction sequence
illustrated in Scheme 1 Step 6 and Step 7 is also
well known in the art. In addition, in situ
hydrolysis of compound 5 by base, preferably protic,
reaction of the C=W group with a organometallic
reagent or its reductive removal can provide an -SH
compound 8. The thiol compound preformed or formed
in the reaction, can then be oxidized if desired
using, for example, air, oxygen, ozone, hypohalide
reagents, sodium plumbite, or other likely oxidation
agents-. Non-oxidizable solvents and a basic or
slightly basic pH value are preferred but not
required and the atmosphere of the reaction can be
air or another inert gas mentioned above. Preferred
temperature is O~C to 40~C, but lower or higher
temperatures can be used.
Mixed disulfides (heterodimers) can be made
if the starting materials have different structures
or by reaction of compound 6 (when R2 is H) with
different alkylating agents as is discussed below.
Reversal of the process ex vivo requires reduction of
the disulfide bond to the thiol of formula I
(compound 8). Compound 5 is formed by acylation of
compound 8 with a reagent such as a derivative of
HO(C=W)R9. Such a derivative can be an activated
carbonyl compounds prepared using reagents well know
in the art including the peptide and protein
synthesis and amino acid coupling or conjugation art.
Examples of such reagents are thionyl chloride,
oxalyl chloride, phosphorus oxychloride, HOBT
(hydroxybenzotriazole), isobutylchloroformate,
.... _ .

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carbodimide, azodicarboxylate compounds an the like
all of which are well known and established in the
art. Reduction of the disulfide to the corresponding
thiol can be carried out by, for example, treatment
with hydride reagents such as lithium aluminum
hydride, aluminum hydride, DIBAL, metal borohydrides
(Li+, Na+, K+, Ca++), sodium cyanoborohydride and the
like.
The aminoalcohol compound 7 in Scheme 2
illustrates a special case example of compound 1
wherein R2 is hydrogen. This series of reactions
-using, for example, compound 7, permits sulfamidation
by processes discussed above wherein one skilled in
the art can produce examples of compound 4 where ~2
is hydrogen. This intermediate or product can then
be alkylated or otherwise substituted to produce
compound 4 wherein R2 is other than hydrogen.
Alkylating agents include compounds that contain
groups that can be displaced by a nucleophile such as
a sulfamic acid salt.
Compound 4 with R2 = hydrogen is a sulfamic
acid and, as such, can be treated with a base to form
an anion. This anion can be reacted in an SN2 manner
with an intermediate or reagent containing a group
that can be displaced with such displaceable groups
including such non-limiting examples as epoxide,
chloride, bromide, iodide, tosylate, mesylate,
triflate, mesylate and the like. Examples of such
reagents or intermediates include benzyl bromide,
methyl iodide, n-butyl chloride, isoamyl tosylate,
N-chloroethylmorpholine, N-bromoethylpiperidine and
the like.
The anion can also be reacted (acylated)
with a carbonyl compound in an addition-elimination
sequence to provide a N-carbonyl compound. Such
acylated compounds might be reduced to desired

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intermediates or serve as protecting groups or both.
The anion can be formed with the bases listed and
discussed above if the affects of sulfamide structure
on pKa are accommodated. Sodium carbonate, potassium
carbonate, potassium methoxide or DMAP represent
bases sufficiently strong that they can be used to
deprotonate a sulfonamide such as 4. In some cases,
the use of a strong base such as an organometallic
base under argon in a aprotic solvent is desirable.
The reactions are normally carried out
under an inert atmosphere at temperatures of from
about 0~C to about 100~C using either protic or
dipolar aprotic solvents or with solvent mixtures.
The solvent mixtures can include reagents such as
amine bases that can also serve as part of a solvent
mixture. An alkylation or acylation reactions
involving salt formation are examples of the type
reaction wherein a non-participating group such as a
hydroxly group hydroxyl group on compound 4 can be
protected if desired by the skilled chemist.
A second process that can be used to place
an R2 group a sulfonamide with at least one hydrogen
atom is reductive amination. Treatment of compound 4
containing an active hydrogen on the nitrogen of the
sulfamide with an aldehyde or ketone and a reducing
agent such as LiAlH4, NaCNBH4, LiBH4, AlH4 or
hydrogen in the presence of controlled activity metal
catalyst may provide compounds with a R2 group. An
intermediate in this reductive process can be an
sulfimine, sulfimine derivative or a tautomer
thereof. The reducing agent can be present in the
initial reaction or the intermediate can be
subsquently reduced, i.e., the intermdiate carbonyl-
sulfamide compound can be isolatable or it may be
reduced further directly. A sulfamide salt can also
add to a carbonyl group (acylation) of an ester,

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amide, anhydride, acid halide, mixed anhydride or
similar compound and then be reduced.
Step 4 in Scheme 2 involves the hydroxyl
conversion step discussed in with regards to Step 1
in Scheme 1. Here again, protection of a non-
reactive group can be desirable. Once the hydroxyl
is converted into, for example, a halide or sulfate
ester, the sulfamide can be alkylated or reductively
alkylated to introduce the R2 group (Step 5) if such
is desired. This produces compound 3 which can be
treated with a nucleophile including -SH to produce
compounds 5 or 8. Note, these are the same compounds
as can be produced via the methods of Scheme ~.
Scheme 2 also illustrates the conversion of
compound 4 into compound 5, compound 4 into compound
9 and compound 9 into compound 3. The former
conversion is discussed above per Scheme 1. The
preparation of Compound 9 illustrates the preparation
of a sulfonamide compound where R2 is hydrogen and M
is a leaving group (activated intermediate).
The hydroxyl conversion process is well
discussed above under Step 1 of Scheme 1. In this
case, protection of groups that one does not wish to
participate in a reaction or process can be useful.
The use of reagents that convert hydroxyl groups into
halide type leaving groups is preferred. Examples of
such agents include hydrogen bromide, hydrogen
chloride, hydrogen iodide, hydrobromic acid,
hydrochloric acid or hydriodic acid. Agents that can
convert a sulfonamide nitrogen-hydrogen bond into a
nitrogen-halogen bond such as sodium hypochlorite can
serve as a method of protecting the sulfonamide from
further substitution on nitrogen. The halogen is
removable when desired by reduction.
Once formed, compound 9 can be alkylated or
acylated by processes as discussed for Step 2 in this

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Scheme to provide compound 3. Compound 3 can be
converted into a compound of this invention of
formula I or formula II (compound 5) via a
nucleophilic or electrophilic substitution process as
illustrated in Step 6. These processes and reactions
are discussed above.
An alternative synthetic process strategy
wherein one starts with an alcohol or protected
alcohol intermediate substituted with an M leaving
group is illustrated in Scheme 3. Conversion of
compound 10 into compound 7 or compound 11 or a
protected derivative is accomplished by amination at
the carbon-M bond with a ammonia or a I~ amine or
derivative.
Amination can be a nucleophilic
substitution process wherein the nucleophile is an
amine, amine anion or other amine derivative. If an
amine is the reagent desired, one can treat compound
10 directly with the amine at temperatures of from
about -60~C to reflux temperature in protic, non-
protic or dipolar aprotic solvents under an inert
atmospheres or air. Protic solvents can include
water wherein the reagent is usually an amine
hydroxide such as ammonium hydroxide, benzylamine
hydroxide and the like. Amine hydroxides are
discussed above. Solvents that can react with amines
such as ethyl acetate or acetone are not to be used.
A pressure containment system or a low temperature
system can be used for gaseous amines such as
ammonia, methyl amine ethyl amine and the like. For
example, reactions with or in ammonia can be run in
liquid ammonia at a temperature of about -33~C. The
SN2 reaction can also be carried out with an metal-
amine salt such as sodium amide, calcium amide,
potassium metylamide and the like.
Following synthesis of the alcohol-amine
compound 7 or 11 or a protected derivative thereof,
... .

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one can add the N-substituent R2 by reductive
amination or alkylation processes as discussed above.
Compound 7 represents compounds where R2 is hydrogen
whereas compound 11 represents compounds wherein R2
is any other group described earlier in this
specification.
Step 3 in this sequence illustrates
conversion of the unprotected alcohol group into the
sulfur compound 12, which can then be converted into
5, which is a sulfonamide of this invention if
formula II. Step 5 shows conversion of the M-
substituted carbinol 10 into the sulfur compound 13
via a before-discussed activated azo procedure as in
Step 3. Compound 13 can then be treated in Step 6 as
with Step 1 to convert the M-carbon bond in compound
13 into a carbon-nitrogen bond to produce compounds
12 or 14 wherein R2 is either hydrogen (compound
14)or not hydrogen (compound 12). When this product
is compound 14 and R2 is hydrogen, it can be
converted into compound 12 by alkylation or reductive
alkylation processes of Step 7 using the methods of
Step 2.
Scheme 4 presents an alternative synthetic
route to the compounds of this invention such as
compounds 5, 15 or 16. The amine R2NH2 is reacted
with a sulfonamide forming reagent such as a sulfonyl
chloride under sulfamidation conditions to provide a
sulfonamide. The sulfonamide can have two hydrogen
atoms on the nitrogen of the sulfonamide group or it
can have one nitrogen-carbon bond valence be occupied
by a group R2. In the latter case, the sulfonamide
can be alkylated (Step 3) by processes discussed
above using compound 13 as the electrophile.
Compound 13 was prepared in Scheme 3.

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The product of this alkylation is compound
5, which is a sulfur compound of formula II of this
invention. Hydrolysis of compound 5 can provide
compund 16, which is a compound of formula I
discussed above.
Step three displays the same process as
Step 1 except that the amine is replaced by ammonia
to provide an unsubstituted sulfonamide. This
unsubstituted sulfonamide can be alkylated with, for
example, compound 13 or compound 10, to produce
sulfonamide compound 14 or sulfonamide compound 4.
-~lkylation of compound 14 by procedures illustrated
above provides compound 5. Hydrolysis of compound 14
(Step 5) can produce compound 15 which is a compound
of this invention of formula I.
An extended example Step 3 or Step 2 is
provided by the procedure of Example 44. In this
case, the amine can be R2NH2 with R2 being methyl
followed by post sulfamidation alkylation with 2-
iodobenzylchloride to produce a dialkylatedsulfonamide that is subsequently converted into a
thiol compound of this invention of formula IV. The
inverse procedures can be carried out wherein the
product of reaction with iodobenzylchloride or
iodobenzylamine is the first sulfonamide that is then
alkylated with methyl iodide. Conversion of this
intermediate into the sulfur-containing product uses
a cobalt complex with thiourea followed by reduction
with sodium cyanoborohydride. This process is a
useful alternative for the synthesis of aromatic
sulfur compounds.
To further illustrate some of the general
principles of synthesis of the compounds of this
invention, Scheme 5 presents the preparation of the
product of Example 4lC. The carbinol amine a was
treated with the sulfonyl chloride b under
, . ~ .

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sulfamidation conditions to produce sulfonamide
compound c. The reaction was carried out under
nitrogen in THF and water as co-solvents and with
triethylamine as the base to act a the product
hydrochloric acid scavenger. The reaction
temperature was about 0~C in an ice bath.
The sulfonamide c in which R2 is H was
alkylated with methyl iodide to produce the product d
wherein R2 is methyl. The solvent for this reaction
was DMF with potassium carbonate base being
suspended/dissolved therein under an atmosphere of
-~nitrogen. The reaction mixture including the methyl
iodide was maintained at room temperature.
Nucleophilic displacement of fluoride with
an (ArS-)~ anion from the substituted aryl group on
the sulfonamide was the next step carried out to
produce compound e. Here, compound d was dissolved
in DMF solvent followed by cesium carbonate and
thiophenol. The reaction mixture was stirred for
about 15 hours at about 70~C under nitrogen to
produce the ArS-substituted aromatic N-methyl
sulfonamide compound e.
This alcohol was then converted via the
activated azo coupling procedure into the sulfur
compound f, which is a compound, useful in a process
of this invention. This reaction was carried out at
0~C in THF under nitrogen. The reagents
triphenylphosphine and diethyldiazodicarboxylate were
dissolved in the THF and thiolacetic acid was added.
The reaction was permitted to proceed for about one
hour to yield compound f which is the product of
Example 41B. Hydrolysis of compound f with sodium
methoxide in methanol at room temperature for about
one half hour provide compound g which is also the
product of Example ~lC. This product of this

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-144- -
invention is a potent MMP-13 inhibitor with an IC50 =
0.002 ~M (2 nM).
Optically active compound isomers as well
as mixed or non-optically active compound isomers are
specifically intended to be included in this
discussion. Examples of isomers are RS isomers,
enantiomers, diastereomers, racemates, cis isomers,
trans isomers, E isomers, Z isomers, syn- isomers,
anti- isomers, tautomers and the like. Aryl,
heterocyclo or heteroaryl tautomers, heteroatom
isomers and ortho, meta or para substitution isomers
are also included as isomers.
The chemical reactions described above are
generally disclosed in terms of their broadest
application to the preparation of the compounds
useful in this invention. Occasionally, the
reactions may not be applicable as described to a
particular compound included within the disclosed
scope or can be unsafe in a particular instance. In
addition, some preparations can be more desirable
than the alternatives due to cost or other economic
considerations. The compounds for which this occurs
are readily recognized by those skilled in the art.
In all such cases, either the reactions can be
successfully performed by conventional modifications
known to those skilled in the art, e.g., by
appropriate protection of interfering groups, by
changing to alternative conventional reagents, by
routine modification of reaction conditions, and the
like, or other reactions disclosed herein or
otherwise conventional, will be applicable to the
preparation of the corresponding compounds of this
invention. In all preparative methods, all starting
materials are known or readily preparable from known
starting materials.

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-145- -
SCHEME 1
F~8 R~R4 3 Step 1 ~8 R~R4
~Rs H Conversion M~N
Step 4 Step 2
Sultd~ n Sl.ltd---;dalion
H(o;~X~N~ R2 (R9 R~R4
R Rs SO R1 R Rs S02R'
4 / 3
Step 5
Activated Step 3 /
Azo
Compound
Coupling
(R8 R3R4
R9(C=VV)S ~ N
R Rs SO2R
Hydrolysis, Oxidation Rl8 ~ R4
Reduction Step 6 /~ _ s~ x_ RN~ R2
HS;<~X~'NR-R2 ~ R S SO2R
R Rs SO2R1
8 Step 7

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-146-
SCHEME 2
(R>~R~R~ R3 Step 1 ¦ ~ R3 SO R
R6 Rs HS~llrd~ d~iOI~~Rs H
4 (R2 = H)
Step 4 / Step 2
Alkylation
Hydroxyl
Conversion
(R~R4 HO~NR3 R2
R Rs so2R1 R R S02R
9 4
Step 3
Step 5 Activated
Alkylation Azo
Compound
Coupling
.;<~R4 Step 6 R9(C W) ( ~R,R2
R Rs S02R~Sllhst~ tion 5 ~2

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-147- -
SCHEME 3
H~( ~x~R3 Step 1 (R~R4
R6 Rs Amlnatlon R Rs h
70r11
Step 5
Activated Step 2 Alkylation/
Azo R2 - H Reductive
Compound () Amination
Coupling ~
R9(C=W) ~( ~x~ R3 HO~x~ R, R2
R6 Rs R6 Rs h
13 11
Step 3
Activated
Step 6 Azo
Amination Compound
Coupling
Step 7 (R 2 = H)
(RXR~ R3 Alkylation/ R9(C=v~ ~ 5X~X~ N~ R2
S 6~ N ReductiveR6 Rs h
R Rs H Amination
120r14(R2=H) 12
Step 4
SIJItdl 1 lil ,alion
R9(C=W) ~( ~X,~ R3 R2
R Rs S02R

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-148- -
SCHEME 4
Step 1
RlSO2CI + R2NH2 ~ R1SO2N(H)R 2
Step 3 +
2 = H)
Rl502NH2 ~S>$~X~M
+ R6 Rs
13 13
Step 2 Step 3
Alkylation Alkylation
R9(C=W) ~ X~X~R,SO2R' ~ R9(C=W) ~5R~CNR3R2
R Rs H Alkylation R 5 SO2R
14 5
Step 5 Step 6
H (~ ~ R, SO2R1 ~ S;~ R,R2
16

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-149-
SCHEME 5
~NH~ + OS~ THF/~O HO~ F
a b c
K2CO3
DMF
CH31
HO~ 5~, 5~ HO----~F
e C6HsSH d
Ph3P
[Et(C=O)N] 2=
H3C(C=O)SH
THF
J~s~S~ ~ H~ ~S~
Ex41B Ex41C
.

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3est Mode for Carr~inq Out the Invention
Without further elaboration, it is believed
tnat one skilled in the art can, using the preceding
Qescription, utilize the present invention to its
-ullest extent. The following preferred specific
embodiments are, therefore, to be construed as merely
illustrative, and not limitative of the remainder of
-he disclosure in any way whatsoever.
_xample 1: Preparation of N-(2-hydroxyethyl)-9-
methoxybenzenesulfonamide
HO--~ SJ~oCH3
1/\\
O O
To a solution of 3.5 mL (3.54 g, 58 mmol)
~f ethanolamine in 20 mL of THF and 5 mL of water,
.~as added 10.7 mL of triethylamine. After cooling in
an ice bath, 10.53 g (51 mmol) of para-
methoxybenzenesulfonyl chloride was slowly added over
~~n minutes. After stirring at room temperature for
: hour, the solvent was removed under reduced
pressure and ethyl acetate and water added. The
~rganic layer was separated, washed with 5% K~SO4 and
brine, dried over sodium sulfate, filtered and
stripped to afford 10.3 g of the desired N-(2-
hydroxyethyl)-9-methoxybenzenesulfonamide, m/e = 238
(M~Li).
_xample 2: Preparation of N-(2-hydroxyethyl)-4-(n-
butoxy)benzenesulfonamide

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H ~ ~ ~
HO--~N ~S
//\\
O O
To a solution of 4.0 mL (66 mmol) of
ethanolamine in 20 mL of tetrahydrofuran and 5 mL of
water, was added 11.3 mL (81 mmol) of triethylamine.
The solution was cooled to 0 C, and a solution of
15.0 g (54 mmol) of p-(n-butoxybenzene)sulfonyl
chloride in 10mL of tetrahydrofuran was slowly added.
After 2 hours at room temperature, the solution was
stripped, ethyl acetate added, washed with 5% KHSO4,
saturated sodium bicarbonate, brine and dried over
sodium sulfate, filtered and stripped to afford 15.3
g of crude material. This was crystallized from
ethyl acetate/hexane to afford 13.4 g of pure N-(2-
hydroxyethyl)-~-(n-butoxy)benzenesulfonamide.
~xample 3: Preparation of N-(2-hydroxy-lR-
methylethyl)-4-methoxybenzenesulfonamide.
H ~ OCH3
HO S~
2 0 CH3 1/\\
To a solution of 15.5 mL (15.0 g, 200 mmol)
of (R)-(-)-2-amino-1-propanol in 140 mL of THF and 47
mL of water, was added 32.9 mL (23.9 g, 236 mmole) of
triethylamine. After cooling in an ice bath, 37.5 g
(182 mmol) of 4-methoxybenzenesulfonyl chloride was
slowly added over 1 hour. After stirring at room
temperature for 2 hour, ~he reaction was concentrated
in vacuo, ethyl acetate and water were added, the

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organic layer was separated and washed with 5%
potassium hydrogen sulfate solution, saturated sodium
bicarbonate solution and brine, dried over sodium
sulfate, filtered and concentrated to afford 44 g of
the desired N-(2-hydroxy-lR-methylethyl)-4-
methoxybenzenesulfonamide, m/e = 252 ~M+Li).
Example 4: Preparation of N-(2-hydroxy-lR-
methylethyl)-4-~n-butoxy)benzenesulfonamide
H ~ ~ ~
HO ~ 'S
3 O O
To a solution of 4.83 g (64.3 mmol) of (R)-
(-)-2-amino-1-propanol in 22 mL of THF and 6 mL of
water, was added 12 mL (83.6 mmol) of triethylamine.
After cooling in an ice bath, a solution of 14.4 g
(57.9 mmol) of 4-(n-butoxy)benzenesulfonyl chloride
in 20 mL of tetrahydrofuran was slowly added over 0.5
hour. After stirring at room temperature for 2 hour,
the reaction was concentrated in vacuo, ethyl acetate
and water were added, the organic layer was separated
and washed with 5~ potassium hydrogen sulfate
soution, saturated sodium bicarbonate solution and
brine, dried over sodium sulfate, f ltered and
concentrated to afford 16.0 g of the desired
N-(2-hydroxy-lR-methylethyl)-4-(n-butoxy)benzene-
sulfonamide, m/e = 288 (M+H).
Example 5: Preparation of N-(2-hydroxy-lR-
methylethyl)(3-thiophenylpropyl)sulphonamide.

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-153- -
HO ~S ~ S
Part A: To a solution of (10.0 g, 133
mmol) 2R-amino-1-propanol in 120 mL of acetone and 50
mL of water, was added 35.8 mL of triethylamine.
After cooling in an ice bath, 23.5 g (133 mmol) of 3-
chloro propanesulfonyl chloride was slowly added over
15 minutes. After stirring at room temperature for 2
hours, the solvent was removed under reduced pressure
and ethyl acetate and water was added. The organic
layer was separated, washed with 5% KHSO4 and brine,
dried over sodium sulfate, filtered and stripped to
afford 8.5 g of the desired N-(2-hydroxy-lR-
methylethyl)(3-chloropropyl)sulphonamide, m/e = 222
(M+Li).
Part B: To a solution of 4.13 g (20 mmol)
of product from part A in (25 mL) of anhydrous
acetonitrile, was added (4.4 g, 40 mmol) of
triethylamine followed by (3.3 g, 30 mmol) of
benzenethiol. After stirring at room temperature for
16 hours, the reaction was diluted with (200 mL) of
dichloromethane. Washed with 2x60 mL saturated
aqueous sodium bicarbonate and 2x50 mL brine, dried
over sodium sulfate, filtered and solvent removed
under reduced pressure and the residue
chromatographed on 100 g of silica gel using 2:1
ethyl acetate:hexane to afford 2.1 g of the desired
N-(2-hydroxy-lR-methylethyl)(3-
thiophenylpropyl)sulphonamide, m/e = 296 (M+Li).
,

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Example 6: Preparation of N-(2-Hydroxy-lR-
methylethyl)-4-(n-pentyl)benzenesulfonamide.
H
HO ~ ~S
CH3 1 O
To a ice cooled solution of (2.5g, 30 mmol)
of (R)-(-)-2-amino-1-propanol in 50 mL of acetone, 25
mL of water , and 10 grams of triethylamine was added
( 7.7g, 30 mmol) of 4-(n-pentyl)benzenesulfonyl
chloride slowly over 10 minutes. After s~irring for
3 hours at room temperature, the solution was
concentrated by rotory evaporation and the contents
were partitioned between 200 mL of ethyl acetate and
200 mL of water. The organic layer was washed with
100 mL of 5% potassium hydrogen sulfate, followed by
saturated sodium chloride, dried over magnesium
sulfate, filtered and concentrated to yield 8.0 grams
of a c~ear oil, identified as N-(2-hydroxy-lR-
methylethyl)-4-(n-pentyl)benzenesulfonamide.
Example 7: Preparation of N-(2-mercaptoethyl)-N-
(phenylmethyl)-4-methoxybenzenesulfonamide.
~3
HS--~ 'SJ~OCH3
//~
O O
Part A: To a solution of 10.04 g (43 mmol)
of N-(2-hydroxyethyl)-9-methoxybenzenesulfonamide

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-155- -
from Example 1 in 85 mL of anhydrous DMF, was added
17.8 g (128 mmol) of powdered potassium carbonate and
then 8.2 g (48 mmol) of benzyl bromide. After 2~
hours, ethyl acetate and water was added, the organic
layer separated and washed 3xs with brine, dried with
sodium sulfate, filtered and stripped to afford 14.3
g of crude product. This was recrystallized from
tert-butylmethyl ether/hexane to afford 9.0 g of the
desired N-(hydroxyethyl)-N-(phenylmethyl)-4-
methoxybenzenesulfonamide.
Part B: To a solution of 2.0 g (6.2 mmoliof product from Part A and 1.79g (6.8 mmol) of
triphenylphosphine in 31 mL of anhydrous THF at 0 C,
lS was added 1.35 mL (6.8 mmol) of diisopropyla~odi-
carboxylate, followed by 0.50 mL (6.8 mmol) of
thiolacetic acid. After stirring at room temperature
for 15 hours, the reaction was concentrated and the
residue chromatographed on 150 g of silica gel using
20-30% ethyl acetate/hexane to afford 1.48 g of the
desired product, which was recrystallized from ethyl
acetate/hexane to afford 1.0 g of pure product,
identified as the desired product, m/e = 380 (M+H).
Part C: To a suspension of 0.57 g (1.5
mmol) of product from Part B above in 4 mL of
anhydrous methanol, was added 1.2 mL (5.4 mmol) of 25
weight % sodium methoxide in methanol. After 30
minutes, the solution was cooled in ice and 2%
hydrochloric acid added. Ethyl acetate was added and
the organic layer separated and washed with satura.ed
sodium bicarbonate, brine, dried over anhydrous
magnesium sulfate, filtered and stripped to afford
0.5 g of crude material. This was chromatographed on
50g of silica gel using 20%-40% ethyl acetate/hexane

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-156-
to yield 0.3 g of pure N-(mercaptoethyl)-N-
(phenylmethyl)-4-methoxybenzenesulfonamide.
Example 8: Preparation of N-(2-mercaptoethyl)-N-
pentyl-4-methoxybenzenesulfonamide.
HS ~ ~S
11\\
O O
Part A: To a solution of 2.0 g (8.6 mmol)
of N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide
from Example 1 in 20 mL of anhydrous DMF, was added
3.58 g (25.9 mmol) of powdered potassium carbonate
and then 1.96 g (13 mmol) of 1-bromopentane. After
24 hours, ethyl acetate and water was added, the
organic layer separated and washed 3xs with brine,
dried with sodium sulfate, filtered and stripped to
afford 2.3 g of crude product. This was
chromatographed on 150 g of silica gel using 20%-50%
ethyl acetate/hexane to afford 2.12 g of the desired
N-(hydroxyethyl)-N-pentyl-4-
methoxybenzenesulfonamide, m/e = 302 ~M+H).
Part B: To a solution of 2.1 g (7.0 mmol)of product from Part A and 2.03 g (7.7 mmol) of
triphenylphosphine in 28 mL of anhydrous THF at 0 C,
was added 1.2 mL (7.74 mmol) of
diethylazodicarboxylate, followed by 0.56 mL (7.7
mmol) of thiolacetic acid. After stirring at room
temperature for 15 minutes, the reaction was
concentrated and the residue chromatographed on 150 g
. .

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of silica gel using 10-50% ethyl acetate/hexane to
afford 2.06 g of the desired product, m/e = 360
(M+H).
Part C: To a solution of 2.06 g (6.3 mmol)
of product from Part B above in 13 mL of anhydrous
methanol, was added 5.2 mL (22.6 mmol) of 25 weight %
sodium methoxide in methanol. After 30 minutes, the
solution was cooled ln ice and 2% hydrochloric acid
added. Ethyl acetate was added and the organic
layuer separated and washed with saturated sodium
bicarbonate, brine, dried over anhydrous magnesium
sulfate, filtered and stripped to afford 1.26 g of
pure N-(2-mercaptoethyl)-N-pentyl-4-
methbxybenzenesulfonamide., m/e=324 (M+Li).
Example 9: Preparation of N-(2-mercapto~
methylethyl)-N-butyl-4-methoxybenzenesulfonamide.
~ ~ OCH3
HS~N 'S
CH3 //\O
Part A: To a solution of 3.0 g (12 mmol) of
N-(2-hydroxy-lR-methylethyl)-4-
methoxybenzenesulfonamlde from Example 3 in 40 mL of
anhydrous DMF, was added 5.1 g (37 mmol) of powdered
potassium carbonate, followed by 2.0 mL (2.5 g, 18
mmol) of 1-bromobutane. After 66 hours, and
additional 2.5 g (18 mmol) of powdered potassium
carbonate and 1.0 mL (1.3 g, 9 mmol) of 1-bromobutane
were added, and the reaction heated at 40~C. After

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48 hours at 40~C, the reaction was concentrated i~
vacuo, ethyl acetate and water were added, the
organic layer was separated and washed 3xs with
brine, dried with magnesium sulfate, filtered ana
concentrated to afford the crude product. This was
chromatographed on silica gel using 30%-40% ethyl
acetate/hexane to yield 2.8 g of pure N-(2-hydroxy-
lR-methylethyl)-N-butyl-4-methoxybenzenesulfonamide,
m/e= 302 (M+H).
Part B: To a solution of 2.8 g (9 mmoi) of
N-(2-hydroxy-lR-methylethyl)-N-butyl-4-
methoxybenzenesulfonamide from Part A and 2.7 g (10
mmol) of triphenylphosphine in 50 mL of anhydrous THF
at OCC, was added 1.6 mL (1.8 g, 10 mmol) of
diethylazodicarboxylate, followed after 5 min. by 0.7
mL (0.8 g, 10 mM) of thiolacetic acid. After 17
hours, the reaction was concentrated and the residue
was chromatographed on silica gel usinglO%-20% ethyl
acetate/hexane to yield 2.0 g of the desired product,
m/e = 366 (M+Li).
Part C: To a solution of 2.0 g (6 mmol) of
the product fro~ Part B in 50 mL of anhydrous
methanol, was added 0.5 g (21 mmol) of sodium metal.
After 1 hour, the reaction was cooled, lN HCl
solution was added, followed by ethyl acetate and
water, the organic layer was separated and washed
with saturated sodium bicarbonate solution and brine,
dried with magnesium sulfate, filtered and
concentrated to afford 1.6 g of crude product. This
was chromatographed on silica gel using 5~-15% ethyl
acetate/hexane to yield 0.9 g of pure N-(2-mercapto-
lR-methylethyl)-N-butyl-4-methoxybenzenesulfonamide,
m/e= 324 (M+Li).
... .

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~xample 10: Preparatlon of N-(2-mercaptopropyl)-4-
methoxybenzenesulfonamide
HS~N ~SJ~OCH3
/1\\
O O
Part A: To a solution of 10.04 g (43 mmol)
-~of N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide
from Example 1 in 85 mL of anhydrous DMF, was added
17.8 g (128 mmol) of powdered potassium carbonate and
then 8.2 g (48 mmol) of benzyl bromide. After 24
hours, ethyl acetate and water was added, the oragnic
layer separated and washed 3xs with brine, dried with
sodium sulfate, filtered and stripped to afford 14.3
g of crude product. This was recrystallized from
tert-butylmethyl ether/hexane to afford 9.0 g of the
desired N-(hydroxyethyl)-N-(phenylmethyl)-4-
methoxybenzene-sulfonamide.
Part B: To a solution of 4.0 g (12.4 mmol)
of N-(2-hydroxyethyl)-N-(phenylmethyl)-4-
methoxybenzenesulfonamide from Part A ln 6 mL of
anhydrous methylene chloride and 6 mL of anhydrous
dimethyl sulfoxide, was added 17.1 mL of
triethylamine, the solution cooled in an ice bath and
7.9 g (50 mmol) of sulfur trioxide/pyridine complex
in 38 mL of DMSO was added over 15 minutes. After 1
hour, the reaction mixture was poured intc ice,
extracted with ethyl acetate, washed with 5% KHSO4,
brine, dried over magnesium sulfate, filtered and
stripped to afford 4.0 g of N-(2-propanal)-4-

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methoxybenzenesulfonamide suitable for the nextreaction.
Part C: To 8.3 mL (25 mmol) of 3M methyl
magnesium bromide in diethyl ether at OC under
nitrogen, was added a solution of 4g (12.4 mmol) of
crude N-(2-propanal)-4-methoxybenzenesulfonamide from
Part B in 10 mL of anhydrous tetrahydrofuran. After
1 hour at room temperature, the reaction was cooled
in ice and quenched by the addition of saturated
ammonium chloride solution, extracted with ethyl
acetate, washed with 5% KHSO4, brine, dried and
stripped to afford 4.0 g of crude material. This was
chromatographed on silica gel using 20%-4Q% ethyl
acetate/hexane to afford 3.25 g of the desired N-(2-
hydroxypropyl)-4-methoxybenzenesulfonamide, m/e=336
(M+H).
Part D: To a solution of 2.0g (5.9 mmol) of
alcohol from Part C and 1.71g (6.5 mmol) of
triphenylphosphine in 30 mL of anhydrous
tetrahydrofuran at 0 C, was added 1.28 mL (1.32 g,
6.5 mmol) of diisopropylazodicarboxylate, then 0.47
mL (6.5 mmol) if thiolacetic acid. After 15 hours at
room temperature, the solution was stripped and
chormatographed on 150 g of silica gel using 20%-50%
ethyl acetate/hexane to afford 0.43 g of the desired
product, m/e=400 (M+Li).
Part E: To a solution of 0.43 g (1.1 mmol)
of the product of Part D in 5 mL of anhydrous
methanol, was added 0.9 mL (3.9 mmol) of 25 wt %
sodium methoxide/methanol. After 15 hours at room
temperature, an additional 0.9 mL of sodium
methoxide/methanol was added. After 2 hours, the

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solution was cooled, lN hydrochloric acid added,
extracted with ethyl acetate, washed with saturated
sodium bicarbonate, brine, dried and stripped to
afford crude product, which was chromatographed over
50 g of silica ge using 100% methylene chloride to
afford 117 mg of the desired N-(2-mercaptopropyl)-4-
methoxybenzenesulfonamide, m/e=358 (M+Li).
Example 11: Preparation of N-(2-mercapto-lR-
methylethyl)-N-methyl-4-methoxybenzenesulfonamide.
CH3 I~OCH3
HS - S
CH3 /I\\o
Part A: To a solution of 3.0 g (12.2 mmol)
of N-(2-hydroxy-lR-methylethyl)-4-
methoxybenzenesulfonamide from example 3, in 20 mL of
anhydrous DMF, was added 5.06 g (36.7 mmol) of
powdered potassium carbonate, and then 1.1 mL (17.7
mmol) of methyl iodide. After stirring at room
temperature for 48 hours, ethyl acetate and water was
added, the layers separated and the organic layer
washed 3xs with brine, dried with sodium sulfate,
filtered and stripped to afford 2.83 g of crude
material. This was chromatographed on 200 g of
silica gel using 50%-80% ethyl acetate/hexane to
afford 2.1 g of pure N-(2-hydroxy-lR-methylethyl)-N-
methyl-4-methoxybenzenesulfonamide, m/e=266(M+Li).
Part B: To a solution of 2.09 g (8.06 mmol)
of product from Part A and 2.32 g (8.86 mmol) of
triphenylphosphine in 32 mL of anhydrous THF at 0~C,
was added 1.4 mL (8.86 mmol) of

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diethylazodicarboxylate, folLowed after 5 min. by
0.64 mL (8.86 mmol) of thiolacetic acid. After 0.5
hour, the reaction was concentrated and the residue
was chromatographed on 200g of silica gel using 10%-
50~ ethyl acetate/hexane to yield 1.77 g of thedesired product, m/e = 324 (M+Li).
Part D: To a solution of 1.77 g (5.58 mmol)
of product from Part C in 20 mL of anhydrous
methanol, was added 4.6 mL (20 mmol) of a 25 weight %
solution of sodium methoxide in methanol. After 0.5
hour, the reaction was quenched with lN HCl solution,
~ollowed by ethyl acetate and water, the organic
layer was separated and washed wlth saturated sodium
1~ bicarbonate solution and brine, dried with magnesium
sulfate, filtered and concentrated to afford 1.2 g of
pure product, identified as N-(2-mercapto-lR-
methylethyl)-9-methoxy-N-methyl-4-
methoxybenzenesulfonamide, m/e= 282 (M+Li).
~xample 12: Preparation of N-(2-mercapto-lR-
methylethyl)-N-(phenylmethyl)-4-
methoxybenzenesulfonamide.
OCH 3
HS~ 'S
2 5 CH 3 l O
Part A: To a solution of 5.0 g (20mmol) of
N-(2-hydroxy-lR-methylethyl)-4-methoxybenzene-
sulfonamide from Example 3 in 40 mL of anhydrous DMF,
~as added 8.5 g (61 mmol) of powdered potassium

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carbonate, followed by 3.2 mL (4.5 g, 27 mmol) c~
benzyl bromide. After 16 hours, the reaclion was
concentrated in vacuo, ethyl acetate and water were
added, the organic layer was separated and washed 3xs
with brine, dried with magnesium sulfate, filterea
and concentrated to afford 7.1 g of crude product.
This was chromatographed on silica gel using 30%-50%
ethyl acetate/hexane to yield 4.1 g of pure N-(2-
hydroxy-lR-methylethyl)-N-(phenylmethyl)-4-
methoxybenzenesulfonamide, m/e= 342 (M+Li).
Part B: To a solution of 4.1 g (12 mmol) ofN-(2-hydroxy-lR-methylethyl)-N-(phenylmethyl)-4-
methoxybenzenesulfonamide from Part A and 3.6 g /14
mmole) of triphenylphosphine in 80 mL of anhydrous
T~F at 0~C, was added 2.1 mL (2.4 g, 14 mmol) of
diethylazodicarboxylate, followed after 5 min. by 1.0
mL (1.0 g, 14 mM) of thiolacetic acid. After 1 hour,
the reaction was concentrated and the residue was
chromatographed on silica gel using 20~-40% ethyi
acetate/hexane to yield 4.3 g of the desired proauct,
m/e = 400 (M+Li).
Part C: To a solution of 4.3 g (11 mmol) of
product from Part B in 100 mL of anhydrous methanol,
was added 0.9 g (40 mmol) of sodium metal. After 1
hour, the reaction was cooled, lN HCl solution was
added, followed by ethyl acetate and water, the
organic layer was separated and washed with saturated
sodium bicarbonate solution and brine, dried with
magnesium sulfate, filtered and concentrated to
afford 3.5 g of crude product. This was
chromatographed on silica gel using 15~-25~ ethyl
acetate/hexane to yield 1.9 g of pure N-(2-mercapto-

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lR-methylethyl)-N-(phenylmethyl)-4-
methoxybenzenesulfonamide, m/e= 358 (M+Li).
Example 13: Preparation of N-(2-mercapto-lS-
methylethyl)-N-(phenylmethyl)-4-
methoxybenzenesulfonamide.
HS ~ S
CH3 B~
Part A: To a solution of 15.5 mL (15.0 g,
200 mmol) of (S)-(+)-2-amino-1-propanol in 70 mL of
THF and 18 mL of water, was added 36 mL (259 mmol) of
triethylamine. After cooling in an ice bath, a
solution of 37.1 g (179 mmol) of 4-
methoxybenzenesulfonyl chloride in 30 mL of
tetrahydrofuran was slowly added over 15 minutes.
After stirring at room temperature for 2 hour, the
reaction was concentrated in vacuo, ethyl acetate and
water were added, the organic layer was separated and
washed with 5~ potassium hydrogen sulfate soution,
saturated sodium bicarbonate solution and brine,
dried over sodium sulfate, filtered and concentrated
to afford 43.3 g of the desired N-(2-hydroxy-lS-
methylethyl)-4-methoxybenzenesulfonamide, m/e = 246
(M+H)-
Part B: To a solution of 5.0 g (20 mmol) ofN-(2-hydroxy-lS-methylethyl)4-
methoxybenzenesulfonamide from part A in 40 mL of
anhydrous DMF, was added 8.5 g (61 mmol) of powdered
,

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potassium carbonate, followed by 3.2 mL (4.5 g, 27
mmol) of benzyl bromide. After 64 hours, the
reaction was concentrated in vacuo, ethyl acetate and
water were added, the organic layer was separated and
washed 3xs with brine, dried with magnesium sulfa~e,
filtered and concentrated to afford 7.0 g of crude
product. This was chromatographed on silica gel
using 20%-50% ethyl acetate/hexane to yield 4.2 g of
pure N- ( 2-hydroxy-lS-methylethyl)-N- ~ phenylmethyl)-4-
methoxybenzenesulfonamide, m/e= 342 (M+Li).
Part C: To a solution of 4.2 g (12.5 mmol)of N-(2-hydroxy-lS-methylethyl)-N- (phenylmethyl)-4-
methoxybenzenesulfonamide from Part B and 3.6 g (14
mmole) of triphenylphosphine in 50 mL of anhydrous
T~F at 0~C, was added 2.2 mL (13.8 mmol) of
diethylazodicarboxylate, followed after 5 min. by 1.0
mL (13.8 mmol) of thiolacetic acid. After 0.5 hour,
the reaction was concentrated and the residue was
chromatographed on silica gel using 20~-40% ethyl
acetate/hexane to yield 3.9 g of the desired product,
m/e = 394 (M+H).
Part D: To a solution of 3.8 g (9.7 mmol)
of product from Part C in 20 mL of anhydrous
methanol, was added 7.9 mL (34.8 mmol) of a 25 weight
% solution of sodium methoxide in methanol. After
0.5 hour, the reaction was quenched with lN HCl
solution, followed by ethyl acetate and water, the
organic layer was separated and washed with saturated
sodium bicarbonate solution and brine, dried with
magnesium sulfate, filtered and concentrated to
afford 2.78 g of pure product, identified as N-(2-
mercapto-1~-methylethyl)-N-(phenylmethyl)-4-methoxy-
benzenesulfonamide, m/e= 352 (M+H).

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Example 14: Preparation of N-(2-mercapto-lR-
methylethyl)-N-(2-methylpropyl)-4-
methoxybenzenesulfonamide.
HS ~ 'S
CH3 o/A\o
Part A: To a solution of 3.0 g (12.2 mmol)
.of N-(2-hydroxy-lR-methylethyl)-4-methoxybenzene-
sulfonamide from example 3, in 20 mL of anhydrous
DMF, was added 5.06 g (36.7 mmol) of powdered
potassium carbonate, and then 2.0 mL (18.3 mmol) of
sobutyl bromide. After stirring at room temperature
for 72 hours, ethyl acetate and water was added, the
layers separated and the organic layer washed 3xs
with brine, dried with sodium sulfate, filtered and
stripped to afford 3.35 g of crude material. This
was chromatographed on lS0 g of silica gel using 30%-
70% ethyl acetate/hexane to afford 2.1 g of pure N-
(2-hydroxy-lR-methylethyl)-N-(2-methylpropyl)-4-
methoxybenzenesulfonamide, m/e=308(M+Li).
Part B: To a solution of 1.3 g (4.3 mmol)of product from Part A and 1.24 g (4.7 mmol) of
triphenylphosphine in 17 mL of anhydrous THF at 0~C,
2~ was added 0.75 mL (4.7 mmol) of diethylazo-
dicarboxylate, followed after 5 min. by 0.34 mL (4.7
mmol) of thiolacetic acid. After 0.5 hour, the
reaction was concentrated and the residue was
chromatographed on lOOg of silica gel using 10%-30%
ethyl acetate/hexane to yield 0.73 g of the desired
product, m/e = 366 (M+Li).

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Part C: To a solution of 0.73 g (2.0 mmol)
of product from Part B in 10 mL of anhydrous
methanol, was added 1.7 mL (7.3 mmol) of a 25 weight
% solution of sodium methoxide in methanol. After
0.5 hour, the reaction was quenched with lN HCl
solution, followed by ethyl acetate and water, the
organic layer was separated and washed with saturated
sodium bicarbonate solution and brine, dried with
magnesium sulfate, filtered and concentrated to
afford 10.6 g of crude product. This was
chromatographed on lOOg of silica gel to afford 182
mg of pure product, identified as
~-(2-mercapto-lR-methylethyl)-N-(2-methylpropyl)-4-
methoxybenzenesulfonamide, m/e= 324 (M+Li).
Example 15: Preparation of N-(2-mercapto-lR-
methylethyl)-4-(n-butoxy)benzenesulfonamide.
H ~~--
HS~ ~S
2 0 CH3 /1\\
Part A: To a solution of 2.69 g (9.36 mmol)
of N-(2-hydroxy-lR-methylethyl)-4-(n-butoxy)benzene-
sulfonamide from example 4 and 2.7 g (10.3 mmol) of
triphenylphosphine in 37 mL of anhydrous THF at 0~C,
was added 1.6 mL (10.3 mmol) of diethylazodi-
carboxylate, followed after 5 minutes by 0.75 mL
(10.3 mmol) of thiolacetic acid. After 0.5 hour, the
reaction was concentrated and the residue was
chromatographed on 150g of silica gel using 10%-50%
ethyl acetate/hexane to yield 1.59 g of impure
material, which was carried into the next step.

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Part B: To a solution of 1.59 g (4.6 ~mol)
of product from Part A in 18 mL of anhydrous
methanol, was added 3.8 mL (16.6 mmol) of a 25 weight
% solution of sodium methoxide in methanol. After
0.5 hour, the reaction was quenched with lN HCl
solution, followed by ethyl acetate and water, the
organic layer was separated and washed with saturated
sodium bicarbonate solution and brine, dried with
magnesium sulfate, filtered and concentrated to
afford 1.4 g of crude product. This was
;chromatographed on 150g o~ silica gel using 1%-20%
methanol/methylene chloride to afford 230 mg of pure
product, identified as
N-(2-mercapto-lR-methylethyl)-4-(n-
butoxy)benzenesulfonamide, m/e= 304 (M+H).
Example 16: Preparation of N-(2-mercapto-lR-
methylethyl)-4-methoxybenzenesulfonamide.
H ~OCH3
HS - S~
CH3 ~
Part A: To a solution of 2.58 g (10.5 mmol)
of N-(2-hydroxy-lR-methylethyl)-4-methoxybenzene-
sulfonamide from example 3 and 3.03 g (11.6 mmol) oftriphenylphosphine in 40 mL of anhydrous T~F at 0~C,
was added 1.8 mL (11.6 mmol) of diethylazodi-
carboxylate, followed after 5 minutes by 0.83 mL
(11.6 mmol) of thiolacetic acid. After 0.5 hour, the
reaction was concentrated and the residue was
cnromatographed on silica gel using 20%-30% ethyl

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acetate/hexane to yield 1.5 g of pure material, m/e =
304 (M+H).
Part B: To a solution of 1.5 g (9.9 mmol)
of product from Part A in 20 mL of anhydrous
methanol, was added 4.0 mL (17.8 mmol) of a 25 weight
% solution of sodium methoxide in methanol. After
0.5 hour, the reaction was quenched with lN HCl
solution, followed by ethyl acetate and water, the
organic layer was separated and washed with saturated
sodium bicarbonate solution and brine, dried with
magnesium sulfate, filtered and concentrated to
afford 1.23 g of pure product, identified as N-(2-
mercapto-lR-methylethyl)-4-methoxybenzenesulfonamide,
m/e= 262 (M+H).
Example 17: Preparation of N-(2-mercapto-lR-
methylethyl)-N-phenylmethyl)-4-(n-
butoxy)benzenesulfonamide.
HS ~ ~S
CH3 O O
Part A: To a solut}on of 3.52 g (12.3 mmol)
of N-(2-hydroxy-lR-methylethyl)-4-(n-
butoxy)benzenesulfonamide from example 4 in 25 mL of
anhydrous DMF, was added 5.07 g (36.8 mmol) of
powdered potassium carbonate, followed by 1.9 mL
(2.7 g, 15.9 mmol) of benzyl bromide. After 63
hours, the reaction was concentrated in vacuo, ethyl

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acetate and water were added, the organic layer was
separated and washed 3xs with brine, dried with
magnesiu~L sulfate, filtered and concentrated to
afford the crude product. This was chromatographed
on 200g of silica ge~ using 20%-50% ethyl
acetate/hexane to yield 3.64 g of pure N-(2-hydroxy-
lR-methylethyl)-N-phenylmethyl)-4-(n-
butoxy)benzenesulfonamide, m/e= 384 (M+Li).
Part B: To a solution of 3.6 g (9.5 mmol)
of product from Part A and 2.74 g (10.5 mmol) of
~riphenylphosphine in 40 mL of anhydrous THF at 0~C,
was added 1.7 mL (10.5 mmol) of diethylazo-
dicarboxylate, followed after 5 min. by 0.75 mL ~10.5
mmol) of thiolacetic acid. After 0.5 hour, the
reaction was concentrated and the residue was
chromatographed on 200 g of silica gel using 10%-15%
ethyl acetate/hexane to yield 0.99 g of the desired
product, m/e = 442 (M+Li).
Part C: To a solution of 0.99 g (2.3 mmol)
of product from Part B in 10 mL of anhydrous
methanol, was added 1.9 mL ~8.2 mmol) of a 25 weight
% solution of sodium methoxide in methanol. After
0.5 hour, the reaction was quenched with lN HCl
solution, followed by ethyl acetate and water, the
organic layer was separated and washed with saturated
sodium bicarbonate solution and brine, dried with
magnesium sulfate, filtered and concentrated to
afford 0.75 g of pure product, identified as N-(2-
mercapto-lR-methylethyl)-N-phenylmethyl)-4-
(nbutoxy)benzenesulfonamide., m/e= 400 (M+Li).

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Example 18: Preparation of N-(2-mercapto-lR-
methylethyl)-N-phenylmethyl)-4-(n-
butoxy)benzenesulfonamide disulfide.
~ ~ CH3 CH3 ~ ~
~ S'N ~ 'S ~ ~S
~~'_~-~O ~ CH3 3 O O
To a solution of 0.42 g (1.32 mmol) of N-
l2-mercapto-lR-methylethyl)-N-phenylmethyl)-9-(n-
butoxy)benzenesulfonamide in 25 mL of methanol at 0
C, was added 174 mg (0.69 mmol) of iodine crystals.
After stirring for 30 minutes, aqueous sodium
thiosulfate was added to remove any unreacted iodine
and ethyl acetate was added. The organic layer was
separated and washed with saturaled sodium
bicarbonate, brine, dried with magnesium sulfate and
stripped to afford 0.40 g of crude product. This was
chromatographed on 100 g of silica gel using 20%-50%
ethyl acetate/hexane to afford 154 mg of pure N-(2-
mercapto-lR-methylethyl)-N-phenylmethyl)-4-(n-
butoxy)benzenesulfonamide disulfide, m/e=633 (M+H).
Example 19: Preparation of 1,3-benzodioxole-5-
sulfonyl chloride
O O
~//
~ O>
To a 22 liter round bottom flask fitted
with a mechanical stirrer, a cooling condenser, a
heating mantle and a pressure equalizing dropping

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funnel was added sulfur trioxide DMF complex (2778g,
18.1 moles). Dichloroethane (4 liters) was then added
and stirring initiated. 1,2-Benzodioxole (1905g, 15.6
moles) as then added through the dropping funnel over
a five minute period. The temperature was then
raised to 75~C and held for ~2 hours (NMR indicated
that the reaction was done after 9 hours.) The
reaction was cooled to 26~ and oxalyl chloride
(2290g, 18.1 moles) was added at a rate so as to
maintain the temperature below 40~C (1.5 hours). The
mixture was heated to 67~C for 5 hours followed by
cooling to 16~C with an ice bath. The reaction was
quenched with water (5 l) at a rate that kept the
temperature below 20~C. After the addition of water
was complete, the mixture was stirred for 10 minutes.
The layers were separated and the organic layer was
washed again twice with water (51). The organic
layer was dried with magnesium sulfate (500g) and
filtered to remove the drying agent. The solvent was
removed under vacuum at 50~C. The resulting warm
liquid was permitted to cool at which time a solid
began to form. After one hour, the solid was washed
wlth hexane (400 mL), filtered and dried to provide
sulfonyl chloride (2823g). The hexane wash was
concentrated and the resulting solid washed with 400
mL hexane to provide additional sulfonyl chloride
(464g). The total yield was 3287g (95.5% based upon
1,3- benzodioxole).
Example 20: Preparation of N-(2-mercapto-lR-
methylethyl)-N-methyl-5-(1,3-benzodioxol-5-
yl)sulfonamide.

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CH3 ~ ~~
CH3 //\\
Part A: To a solution of 5.4 g (72 mmol) of
(R)-2-amino-1-propanol in 25 mL of tetrahydrofuran
and 10 mL of water, was added 13 mL (93 mmol) of
triethylamine. The solution was cooled in an ice
bath and a solution of 13.3 g (60 mmol) of 1,3-
benzodioxole-5-sulfonyl chloride in 20 mL of
te~rahydrofuran was added over 20 minutes. The
reaction was stirred at room temperature for 21
hours, stripped, ethyl acetate added, washed with 5%
KHSO4 and brine, dried with sodium sulfate, filtered
and stripped to afford 12 g of crude material. This
was triturated with warm methylene chloride, hexane
added and the resulting solids collected, washed with
hexane and air dried to yield 7.7 g of pure N-(2-
hydroxy-lR-methylethyl)-5-(1,3-benzodioxol-5-
yl)sulfonamide, m/e=266(M+Li).
Part B: To a solution of 2.6 g (10 mmol) of
N-(2-hydroxy-lR-methylethyl)-5-(1,3-benzodioxol-5-
yl)sulfonamide from Part A, in 15 mL of anhydrous
DMF, was added 4.15 g (30 mmol) of powdered potassium
carbonate, and then 1.25 mL (20 mmol) of methyl
iodide. After stirring at room temperature for 17
hours, ethyl acetate and water was added, the layers
separated and the organic layer washed 3xs with
brine, dried with sodium sulfate, filtered and
stripped to afford 2.8 g of crude material. This was
- 30 chromatographed on 150 g of silica gel using 50%-80%
e~hyl acetate/hexane to afford 2.0 g of pure N-(2-

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hydroxy-lR-methylethyl)-Nmethyl-5-(1,3-benzodioxol-5-
yl)sulfonamide, m/e=280(M+Li).
Part C: To a solution of 2.0 g (7.3 mmol)
of product from Part B and 2.11 g (8.05 mmol) of
triphenylphosphine in 30 mL of anhydrous THF at 0~C,
was added 1.3 mL (8.05 mmol) of diethylazo-
dicarboxylate, followed after 5 minutes by 0.58 mL
(8.05 mmol) of thiolacetic acid. After 0.5 hour, the
reaction was concentrated and the residue was
chromatographed on 150 g of sllica gel using 20%-50%
ethyl acetate/hexane to yield 1.86 g of the desired
product, m/e = 332(M+H).
Part D: To a solution of 1.86 g (5.6 mmol)
of product from Part C in 20 mL of anhydrous
methanol, was added 4.6 mL (20 mmol) of a 25 weight %
solution of sodium methoxide in methanol. After 0.5
hour, the reaction was quenched with lN HCl solution,
followed by ethyl acetate and water, the organic
layer was separated and washed with saturated sodium
bicarbonate solution and brine, dried with magnesium
sulfate, filtered and concentrated to afford 1.53 mg
of pure product, identified as N-(2-mercapto-lR-
methylethyl)-N-methyl-5-(1,3-benzodioxol-5-
yl)sulfonamide, m/e= 290 (M+H).
Example 21: Preparation of N-(2-mercapto-lR-
methylethyl)-N-(phenylmethyl)-5-(1,3-benzodioxol-5-
yl)sulfonamide.
, . . .

CA 02260860 1999-01-12
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-175-
HS ~ N's ~ ~>
CH3 ~
Part A: To a solution of 5.4 g (72 mmol) of
(R)-2-amino-1-propanol in 25 mL of tetrahydrofuran
and 10 mL of water, was added 13 mL (93 mmol) of
triethylamine. The solution was cooled in an ice
;bath and a solution of 13.3 g (60 mmol) of 1,3-
benzodioxole-5-sulfonyl chloride in 20 mL of
tetrahydrofuran was added over 20 minutes. The
reaction was stirred at room temperature for 21
hours, stripped, ethyl acetate added, washed with 5%
KHSO4 and brine, dried with sodium sulfate, filtered
and stripped to afford 12 g of crude material. This
was triturated with warm methylene chloride, hexane
added and the resulting solids collected, washed with
hexane and air dried to yield 7.7 g of pure N-(2-
hydroxy-lR-methylethyl)-5-(1,3-benzodioxol-5-
yl)sulfonamide, m/e=266(M+Li).
Part B: To a solution of 2.5 g (9.6 mmol)
of N-(2-hydroxy-lR-methylethyl)-5-(1,3-benzodioxol-5-
yl)sulfonamide from Part A, in 20 mL of anhydrous
DMF, was added 3.99 g (29 mmol) of powdered potassium
carbonate, and then 1.5 mL (12.5 mmol) of benzyl
bromide. After stirring at room temperature for 17
hours, ethyl acetate and water was added, the layers
separated and the organic layer washed 3xs with
- brine, dried with sodium sulfate, filtered and
stripped to afford 3.15 g of crude material. This
was chromatographed on 150 g of silica gel using 20%-

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Part C: To a solution of 1.55 g (4.3 mmol)
of product from Part B in 18 mL of anhydrous
methanol, was added 3.6 mL (15.5 mmol) of a 25 weight
~ solution of sodium methoxide in methanol. After
0.5 hour, the reaction was quenched with lN HCl
solution, followed by ethyl acetate and water, the
organic layer was separated and washed with saturated
sodium bicarbonate solution and brine, dried with
magnesium sulfate, filtered and concentrated to
afford 1.3 g of crude product. This was
chromatographed on 100 g of silica gel using 1~
methanol/methylene chloride to afford 460 mg of pure
product, identified as N-(2-mercapto-lR-methylethyl)
N-methyl-4-(n-butoxybenzene)sulfonamide, m/e= 324
(M+Li).
Example 23: Preparation of N-(lR-
mercaptomethyl)propyl-N-methyl-4-(n-
butoxy)benzenesulfonamlde.
l ~3 ~~
HS~ 'S
- IA\
~ o o
Part A: To a solution of 3.91 g (44 mmol)
of (R)-2-amino-1-butanol in 20 mL of tetrahydrofuran
and 5 mL of water, was added 9.5 mL (68 mmol) of
triethylamine. The solution was cooled in an ice
bath and a solution of 9.85 g (40 mmol) of 4-(n-
butoxybenzene)sulfonyl chloride in 10 mL of
tetrahydrofuran was added over 10 minutes. The
reaction was stirred at room temperature for 5 hours,
stripped, ethyl acetate added, washed with 5~ KHS04
and brine, dried with sodium sulfate, filtered and
stripped to afford 12.1 g of crude material, which

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was identified as N-(lR-hydroxymethyl)propyl-4-(n-
butoxy)benzenesulfonamide, m/e=308 (M+Li).
.. .
Part B: To a solution of 3.0 g (9.85 mmol)
of N-(lR-hydroxymethyl)propyl-4-(n-butoxy)benzene-
sulfonamide from Part A, in 12 mL of anhydrous DMF,
was added 4.1 g (30 mmol) of powdered potassium
carbonate, and then 1.2 mL (20 mmol) of methyl
iodide. After stirring at room temperature for 21
hours, ethyl acetate and water was added, the layers
separated and the organic layer washed 3xs with
brine, dried with sodium sulfate, filtered and
stripped to afford 2.9 g of crude material. This was
chromatographed on 150 g of silica gel using 20~-80
ethyl acetate/hexane to afford 2.0 g of pure N-(lR-
hydroxymethyl)propyl-N-methyl-4-(n-
butoxy)benzenesulfonamide, m/e=322(M+Li).
Part C: To a solution of 2.4 g (7.6 mmol)
of product from Part B and 2.19 g (8.37 mmol) of
triphenylphosphine in 30 mL of anhydrous THF at 0~C,
was added 1.3 mL (8.37 mmol) of diethylazo-
dicarboxylate, followed after 5 minutes by 0.60 mL
(8.37 mmol) of thiolacetic acid. After 0.5 hour, the
reaction was concentrated and the residue was
chromatographed on silica gel using 20~-30~ ethyl
acetate/hexane to yield 2.12 g of pure material, m/e
= 374 (M+H).
Part D: To a solution of 2.12 g (5.7 mmol)
of product from Part C in 23 mL of anhydrous
methanol, was added 4.7 mL (20.4 mmol) of a 25 weight
solution of sodium methoxide in methanol. After
0.5 hour, the reaction was quenched with 'N HCl
solution, followed by ethyl acetate and water, the
organic layer was separated and washed with sa~urated
sodium bicarbonate solution and brine, dried with
-

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magnesium sulfate, filtered and concentrated to
G~ford 1.32 g of pure product, identified as N-(lR-
mercaptomethyl)propyl-N-methyl-4-(n-
butoxy)benzenesulfonamide, m/e= 332 (M+H).
Example 24: Preparation of N-(2-hydroxy-lR-
methylethyl)-N-(propyn-3yl)-4-(n-
butoxybenzene)sulfonamide.
~ H
~~
HO - S
lo CH3 //\\O
Part A: To a solution of 2.0 g (7 mmol) of
N-(2-hydroxy-lR-methylethyl)-4-(n-butoxy)benzene-
sulfonamide from example 4, in 10 mL of anhydrous
DMF, was added 2.9 g (21 mmol) of powdered potassium
carbonate, and then 1.6 mL of an 80 wt. % solution of
?ropargyl bromide in toluene (15 mmol). After
s~irring at room temperature for 24 hours, ethyl
acetate and water was added, the layers separated and
the organic layer washed 3xs with brine, dried with
sodium sulfate, filtered and stripped to afford 2.31
g of crude material. This was chromatographed on 100
g of silica gel using 20%-50% ethyl acetate/hexane to
afford 2.1 g of pure N-(2-hydroxy-lR-methylethyl)-(N-
propyn-3-yl)-4-(n-butoxy)benzenesulfonamide,
m/e=326(M+H).
Example 25: Preparation of N-(mercapto-lR-
methylethyl)-N-(propyn-3-yl)-4-(n-
butoxybenzene)sulfonamide disulfide.
._

CA 02260860 1999-01-12
W O 98/03166 PCTrUS97/12873
H
~.
N ~ S's ~ N'S
~~~_~~~ ~ ~ CH3 O/~\O
H
Part A: To a solution of 4.11 g (12.6
mmol) of N-(2-hydroxy-lR-methylethyl)-N-(propyn-3-
yl)-4-(n-butoxybenzene)sulfonamide and 3.64 g (13.9
mmol) of triphenylphosphine in 50 mL of anhydrous THF
at 0~C, was added 2.2 mL (13.9 mmol) of
diethylazodicarboxylate, followed after 5 minutes by
1.0 mL (13.9 mmol) of thiolacetic acid. After 0.5
hour, the reaction was concentrated and the residue
was chromatographed on silica gel using 10~-20% ethyl
acetate/hexane to yield 3.68 g of pure material, m/e
= 390 (M+Li).
Part B: To a solution of 1.1 g (2.9 mmol)
of product from Part A in 7 mL of anhydrous methanol,
was added 7.4 mL of 30~ aqueous ammonia. After 1
hour, the reaction was quenched with lN HCl solution,
followed by diethyl ether and water, the organic
layer was separated and washed with saturated sodium
bicarbonate solution and brine, dried with magnesium
sulfate, filtered and concentrated to afford 0.90 g
of crude product. This was chromatographed on silica
gel using 10~-15~ ethyl acetate/hexane to afford 200
mg of pure product, identified as N-(mercapto-lR-
methylethyl)-N-(propyn-3-yl)-4-(n-
butoxybenzene)sulfonamide disulfide, m/e= 687 (M+Li).
Example 26: Preparation of 1-[(4-
methoxyphenyl)sulfonyl]-3-mercaptopyrrolidine.

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-180-
O O
\\ //
~ N~ ~ OCH3
Part A: To a solution of 4.5 g (52 mmol) of
racemic 3-pyrrolidinol in 20 mL of tetrahydrofuran
and 5 mL of water, was added 10 mL of triethylamine.
The solution was cooled to 0 C, and 9.0 g (46 mmol)
of
4-(methoxybenzene)sulfonyl chloride was slowly added.
After 18 hours at room temperature, the solution was
stripped, ethyl acetate added, washed with 5~ KHSO4,
saturated sodium bicarbonate, brineand dried over
sodium sulfate, filtered and stripped to afford the
crude material., which was recrystrallized from warm
ethyl acetate/hexane to afford 7.0 g of pure
1-[(4-methoxyphenyl)sulfonyl~-3-hydroxypyrrolidine,
m/e=258 (M+H).
Part B: To a solution of 2.0 g (7.77 mmol)
of product from Part B and 2.24 g (8.54 mmol) of
triphenylphosphine in 35 mL of anhydrous THF at 0~C,
was added 1.35 mL (8.54 mmol) of diethylazo-
dicarboxylate, followed after 5 minutes by 0.62 mL
(8.54 mmol) of thiolacetic acid. After 0.5 hour, the
reaction was concentrated and the residue was
chromatographed on silica gel using 20~-30~ ethyl
acetate/hexane to yield 1.05 g of pure material, m/e
= 316 (M+H).
Part C: To a solution of 1.05 g (3.3 mmol)
of product from Part C in 6 mL of anhydrous methanol,
was added 8.6 mL of 30~ aqueous ammonia. After l
hour, the reaction was quenched with lN HCl solution,
followed by ethyl acetate and water, the organic
.. . ..

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layer was separated and washed with saturated sodium
bicarbonate solution and brine, dried with magnesium
sulfate, filtered and concentrated to afford 0.74 g
of crude product. This was crystallyzed from diethyl
ether/hexane to afford 220 mg of pure product,
identified as 1-[(4-methoxyphenyl)sulfonyl]-3-
mercaptopyrrolidine, m/e= 274 (M+H).
Example 27: Preparation of 1-[(4-
methoxyphenyl)sulfonyl~-3-hydroxypiperidine.
O O
~ N ~ OCH3
To a solution of 3.44 g (25 mmol) of
racemic 3-hydroxypiperidine hydrochloride in 10 mL of
tetrahydrofuran and 5 mL of water, was added 14 mL
(100 mmol) of triethylamine. The solution was cooled
to 0 C, and 4.64 g (22 mmol) of 4-
(methoxybenzene)sulfonyl chloride was slowly added.
After 21 hours at room temperature, the solution was
stripped, ethyl acetate added, washed with 5% KHS04,
saturated sodium bicarbonate, brineand dried over
sodium sulfate, filtered and stripped to afford the
crude material., which was triturated with hexane to
afford 5.39 g of pure 1-[(4-methoxyphenyl)sulfonyl]
3-hydroxypiperidine, m/e=272 (M+H).
Example 28: Preparation of 1-[(4-
methoxyphenyl)sulfonyl]pyrrolidine-2-methanethiol.
HS~ 0~ ~0
~Q OCH3

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Part A: To a solution of 10.27 g (89 mmol)
of D,L-proline in 100 mL of water and 60 mL of
acetone, was added 40 mL (287 mmol) of triethylamine.
After cooling in an ice bath, 17.6 g (85 mmol) of 4-
(methoxybenzene)sulfonyl chloride was slowly added.
After stirring at room temperature for 13 hours, the
acetone was stripped, the aqueous layer extracted
twice with toluene, then acidified with 25 mL of 6N
hydrochloric acid and extracted with ethyl acetate.
The organic layer was washed with 5% KHS04, brine,
dried with sodium sulfate, filtered and stripped to
afford 23.5 g of racemic 1-~(4-
methoxyphenyl)sulfonyl]-2-carboxypyrrolidine,
m/e=29 2( M+Li).
Part B: To a solution of 4.00 g (14 mmol)
of 1-[(4-methoxypheny~)sulfonyl]-2-
carboxypyrrolidine from part A in 50 mL of anhydrous
tetrahydrofuran at 0 C under a nitrogen atmosphere,
was slowly added over 15 minutes, 20 mL (20 mmol) of
a lM solution of lithium aluminum hydride in diethyl
ether. After stirring at room temperature for 2
hours, the solution was cooled in an ice bath, and
quenched by the slow sequential addition of 0.8 mL of
water, 0.8 mL of 10% sodium hydroxide and 2.4 mL of
water. The resulting suspension was filtered
through celite and the celite washed with ethyl
acetate. The combined organic filtrates were
stripped, the residue disolved in ethyl acetate,
which was washed with 5% KHS04, saturated sodium
bicarbonate, brine, dried with sodium sulfate,
filtered and stripped to afford 3.66 g of crude
material. This was chromatographed on 200g of silica
gel using 40~-75% ethyl acetate/hexane to yield pure
1-[(4-methoxyphenyl)sulfonyl]-2-(hydroxymethyl)
pyrrolidine, m/e=278(M+Li).

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Part C: To a solution of 1.78 g (6.6 mmol)
of product from Part B and 1.9 g (7.2 mmol) of
triphenylphosphine in 2 6 mL of anhydrous THF at 0~C,
was added 1.~4 mL (7.2 mmol) of
diethylazodicarboxylate, followed after 5 min. by
0.52 mL (7.2 mmol) of thiolacetic acid. After C.5
hour, the reaction was concentrated and the residue
was chromatographed on 200 g of silica gel using 50~-
80~ ethyl acetate/hexane to yield 1.5 g of thedesired product, m/e = 336 (M+Li).
Part D: To a solution of 1.5 g (4.6 mmol)
of product from Part C in 10 mL of anhydrous
methanol, was added 3.7 mL (16.4 mmol) of a 25 weight
solution of sodium methoxide in methanol. After
0.5 hour, the reaction was quenched with lN HCl
solution, followed by ethyl acetate and water, the
organic layer was separated and washed with saturated
sodium bicarbonate solution and brine, dried with
magnesium sulfate, filtered and concentrated to
afford 0.9 g of crude product. This was dissolved in
methylene chloride and passed down a short column of
silica gel using methylene chloride to afford 0.55 g
of pure product, identified as 1-[(4-
methoxyphenyl)sulfonyl]pyrrolidine-2-methanethiol,
m/e = 294 (M+Li).
Example 29: Preparation of Racemic N-[1-
(mercaptomethyl)-3-methylbutyl]-N-(phenylmethyl)-4-
methoxybenzenesulfonamide.

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-184-
~ ~ OCH3
HS~N~s
J IA\
~/ o o
Part A: To a solution of lO.0 g (76.2 mmol)
of D,L-leucine in 85 mL of water and 50 mL of
acetone, was added 30 m~ (215 mmol) of triethylamine.
This solution was cooled in an ice bath, and a
solution of 15.0 g (72.7 mmol) of 4-
methoxybenzenesulfonyl chloride in 50 mL of acetone
was slowly added over a 30 minute period. The
reaction was stirred at room temperature for 15
hours, concentrated, the remaining aqueous layer
extracted twice with toluene, then acidified with 20
mL of 6N hydrochloric acid, extracted with ethyl
acetate, which was washed with 5g6 KHS04, brine, dried
lS over sodium sulfate, filtered and stripped to afford
19.2 g of crude material, which was triturated with
warm hexane to afford 17.5 g of pure material, m/e =
308 (M+Li), suitable for use in the next step.
Part B: To a solution of 17.5 g of product
from part A in 45 mL of anhydrous methanol at 0 C,
was slowly added 5.5 mL (75 mmol) of thionyl chloride
over 15 minutes. The solution was then stirred for
15 hours at room temperature, concentrated, ethyl
acetate added, washed with water, saturated sodium
bicarbonate, brine, dried with sodium sulfate,
filtered and stripped to afford 18.6 g of crude
material. This was crys~allized from ethyl
acetate/hexane to afford 13.3 g of the desired
product, m/e= 322 (M+Li).
... .

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Part C: To a solution of 3.00 g (9.5 mmol)
of the product from Part B, in 20 mL of anhydrous
DMF, was added 4.0 g (29 mmol) of powdered potassium
carbonate, and then 1.5 mL (12.6 mmol) of benzyl
bromide. After stirring at room temperature for 16
hours, ethyl acetate and water was added, the layers
separated and the organic layer washed 3xs with
brine, dried with sodium sulfate, filtered and
stripped to afford 4.2 ~ of crude material. This was
recrystallized from ethyl acetate/hexane to afford
3.41 g of pure product, m/e=412(M+Li).
Part D: To a solution of 3.2 g (7.9 mmol)
of the product from part C in 30 mL of anhydrous
tetrahydrofuran at 0 C under a nitrogen atmosphere,
was slowly added over 15 minutes, 7.9 mL (7.9 mmol)
of a lM solution of lithium aluminum hydride in
diethyl ether. After stirring at room temperature
for 1 hour, the solution was cooled in an ice bath,
and quenched by the slow sequential addition of 0.3
mL of water, 0.3 mL of 10~ sodium hydroxide and 0.9
mL of water. The resulting suspension was filtered
through celite and the celite washed with ethyl
acetate. The combined organic filtrates were
stripped, the residue disolved in ethyl acetate,
which was washed with 5% KHSO4, saturated sodium
bicarbonate, brine, dried with sodium sulfate,
filtered and stripped to afford 2.71 g ofcrude
product identified as racemic N-[1-(hydroxymethyl)-3-
methylbutyl]-N-(phenylmethyl)-4-
methoxybenzenesulfonamide, m/e = 384 (M+Li).
Part E: To a solution of 2.7 g (7.2 mmol)
of product from Part D and 2.07 g (7.9 mmol) of
triphenylphosphine in 30 mL of anhydrous THF at 0~C,
was added 1.13 mL (7.2 mmol) of diethylazo-
dicarboxylate, followed after 5 min. by 0.52 mL (7.2

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-186-
mmol) of thiolacetic acid. After 0.5 hour, the
reaction was concentrated and the residue was
chromatographed on 200 g of silica gel using 20~-50
ethyl acetate/hexane to yield 2.0 g of pure product,
S m/e = 442 (M+Li).
Part F: To a solution of 2.0 g (4. 6 mmol)
of product from Part E in lO mL of anhydrous
methanol, was added 3.7 mL (16.4 mmol) of a 25 weight
~ solution of sodium methoxide in methanol. After
0.5 hour, the reaction was quenched with lN HCl
solution, followed by ethyl acetate and water, the
organic layer was separated and washed with saturated
sodium bicarbonate solution and brine, dried wlth
magnesium sulfate, filtered and concentrated to
afford 1.8 g of pure product, identified as racemic
N-[1-(mercaptomethyl)-3-methylbutyl]-N-
(phenylmethyl)-4-methoxybenzene-sulfonamiae. m/e =
400 ~M+Li).
EXAMPLE 30: Preparation of N-(4-methoxybenzene-
sulfonamide)-D-valine methyl ester.
O H ,~OCH3
H3COJ~ ~S J;~
A ~ O
Part A: To a solution of 20.0 g (170 mmol)
of D-valine in 170 mL of water and 95 mL of acetone,
was added 50 mL (360 mmol) of triethylamine. This
solution was cooled in an ice bath, and a solution of
35.2 g (170 mmol) of 4-methoxybenzenesulfonyl
chloride in 75 mL of acetone was slowly added over a
20 minute period. The reaction was stirred at room
temperature for 21 hours, concentrated, the remaining
aqueous layer extracted twice with toluene, then

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-187-
acidified with 25 mL of 6N hydrochloric acid,
extracted with ethyl acetate, which was washed with
5% KHS04, brine, dried over sodium sulfate, filtered
and stripped to afford 39.4 g of crude material, m/e
= 294 (M+Li), suitable for use in the next step.
Part B: To a solution of 35.04 g (122 mmol)
of product from part A in 125 mL of anhydrous
methanol at 0 C, was slowly added 10.0 mL (137 mmol)
of thionyl chloride over 15 minutes. The solution
;was then stirred for 14 hours at room temperature,
concentrated, ethyl acetate added, washed with water,
saturated sodium bicarbonate, brine, dried with
sodium sulfate, filtered and stripped to afford 37.1
g of crude material. This was triturated with hexane
to afford 32.9 g of the desired product, N- (4-
methoxybenzenesulfonamide)-D-valine methyl ester,
m/e= 308 (M+Li).
Example 31: Preparation of N-[(lR-mercaptomethyl)-2-
methylpropyl] -4 -methoxy-N-
(phenylmethyl)benzenesulfonamide.
~ OCH3
HS ~ N'S ~
/1 \
A O O
Part A: To a solution of 5.0 g (17 mmol) of
product from Example 30 in 40 mL of anhydrous DMF,
was added 6.9 g (50 mmol) of powdered potassium
carbonate, followed by 2.2 mL (3.1 g, 18 mmol) of
benzyl bromide. After 66 hours, ethyl acetate and
water were added to the reaction, the organic layer
was separated and washed 3xs with brine, dried with

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magnesium sulfate, filtered and concentrated to
afford 7.~ g of crude product. This was
chromatographed on silica gel using 15~-20~ ethyl
acetate/hexane to yield 6.3 g of pure product, m/e=
392 (M+H).
Part B: To a solution of 6.3 g (20mmol) of
product from Part A in 60 mL of anhydrous THF at 0~C
under nitrogen, was added 16.1 mL (0.6 g, 16 mmol) of
a 1.0 M solution of lithium aluminum hydride in
diethyl ether. After 1.5 hours, the reaction mixture
was cooled to 0~C and 0.7 mL of water was added,
followed by 0.7 mL of 2.5 ~ sodium hydroxide solution
and 2.1 mL of water, the reaction was filtered, the
filtrate concentrated in vacuo, ethyl acetate and 5
citric acid solution were added, the organic layer
was separated and washed with saturated sodium
bicarbonate solution and brine, dried with magnesium
sulfate, filtered and concentrated to afford 5.6 g of
pure N-[(lR-hydroxymethyl)-2-methylpropyl]-N-
(phenylmethyl)-4-methoxybenzenesulfonamide, m/e= 364
(M+H).
Part C: To a solution of 5.6 g (15 mmol) of
N-[(lR-hydroxymethyl)-2-methylpropyl]-N-
(phenylmethyl)-4-methoxybenzenesulfonamide from Part
B and 4.5 g (17 mmole) of triphenylphosphine in 100
mL of anhydrous THF at 0~C, was added 2.7 m~ (3.0 g,
17 mmol) of diethylazodicarboxylate, followed after 5
min. by 1.2 mL (1.3 g, 17 mM) of thiolacetic acid.
After 16 hours, the reaction was concentrated and the
residue was chromatographed on silica gel using 10~-
25~ ethyl acetate/hexane to yield 4.7 g of pure
product, m/e = 428 (M+Li).
Part D: To a solution of 4.7 g (11 mmol) of
product from Part C in 100 mL of anhydrous methanol,

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-189-
was added 1.0 g (41 mmol) of sodium metal. After 1
hour, the reaction was quenched using dry ice, ethyl
acetate and 5~ potassium hydrogen sulfate solution
were added, the organic layer was separated and
washed with saturated sodium bicarbonate solution and
brine, dried with magnesium sulfate, filterea and
concentrated to afford the crude product. This was
chromatographed on silica gel using 10~-20~ ethyl
acetate/hexane to yield 1.6 g of pure N-[(lR-
mercaptomethyl)-2-methylpropyl]-N-(phenylmethyl)-g-
methoxy~enzenesulfonamide, m/e= 386 (M+Li).
EXAMPLE 32: Preparation of N-(4-
methoxybenzenesulfonamide)-L-valine methyl ester.
O H ~ OCH3
H3CO ~ ~/S
O O
Part A: To a solution of 10.0 g (85 mmol)
of L-valine in 85 mL of water and 50 mL of acetone,
was added 25 mL (180 mmol) of triethylamine. This
solution was cooled in an ice bath, and a solution of
17.6 g (85 mmol) of 4-methoxybenzenesulfonyl chloride
in 35 mL of acetone was slowly added over a 20 minute
period. ~he reaction was stirred at room temperature
for 21 hours, concentrated, the remaining aqueous
layer extracted twice with toluene, then acidified
with 25 mL of 6N hydrochloric acid, extracted with
ethyl acetate, which was washed with 5~ KHS04, brine,
dried over sodium sulfate, filtered and stripped to
afford 22 g of crude material, m/e = 288 (M+H),
suitable for use in the next step.
Part B: To a solution of 18.9 g (65. 8 mmol)
of product from part A in 60 mL of anhydrous methanol

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at 0 C, was slowly added 6.0 mL (83 mmol) of thionyl
chloride over 15 minutes. The solution was then
stirred for 14 hours at room temperature,
concentrated, ethyl acetate added, washed with water,
saturated sodium bicarbonate, brine, dried with
sodium sulfate, filtered and stripped to afford the
crude material. This was recrystallized from ethyl
acetate/hexane to afford 16.5 g of the desired
product, N-(4-methoxy-benzenesulfonamide)-L-valine
methyl ester, m/e= 302 (M+H).
Example 33: Preparation of N-[(lS-mercaptomethyl)-2-
methylpropyl]-4-methoxy-N-
(phenylmethyl)benzenesulfonamide.
~ ~ OCH3
HS ,N~S
~ 1/\\
~ O O
Part A: To a solution of 4.07 g (13.5 mmol)
of the product from example 32 in 25 mL of anhydrous
DMF, was added 5.6 g (40.5 mmol) of powdered
potassium carbonate, followed by 2.0 mL (2.9 g, 17
mmol) of benzyl bromide. After 42 hours, ethyl
acetate and water were added to the reaction, the
organic layer was separated and washed 3xs with
brine, dried with magnesium sulfate, filtered and
concentrated to afford 5.85 g of crude product. This
was chromatographed on silica gel using 20%-40~ ethyl
acetate/hexane to yield 4.88 g of pure product, m/e=
392 (M+H).
Part B: To a solution of 4.88 g (12.5 mmol)
of product from Part A in 50 mL of anhydrous THF at
. . _

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OoC under nitrogen, was added 12.5 mL (12.5 mmol) of
a 1.0 M solution of lithium aluminum hydride in
diethyl ether. After 0.5 hours, the reaction mixture
was cooled to 0~C and 0.5 mL of water was added,
followed by 0.5 mL of 2.5 N sodium hydroxide solution
and 1.5 mL of water, the reaction was filtered, the
filtrate concentrated in vacuo, ethyl acetate and 5
citric acid solution were added, the organic layer
was separated and washed with saturated sodium
bicarbonate solution and brine, dried with magnesium
sulfate, filtered and concentrated to afford 4.0 g of
pure N-[(lS-hydroxymethyl)-2-methylpropyl]-N-
(phenylmethyl)-4-methoxybenzenesulfonamide, m/e= 364
(M+H).
Part C: To a solution of 3.94 g (10.8 mmol)
of N-[(lS-hydroxymethyl)-2-methylpropyl]-N-
(phenylmethyl)-4-methoxybenzenesulfonamide from Part
B and 3.12 g (11.9 mmole) of triphenylphosphine in 50
mL of anhydrous TH~ at 0~C, was added 1.9 mL (2.1 g,
11.9 mmol) of diethylazodicarboxylate, followed after
5 min. by 0.86 mL (0.91 g, ll.9 mmoles) of
thiolacetic acid. After 2 hours, the reaction was
concentrated and the residue was chromatographed on
silica gel using 20~-40~ ethyl acetate/hexane to
yield 2.7 g of pure product, m/e = 422 (M+H).
Part D: To a solution of 2.7 g (6.4 mmol)
of product from Part C in 20 mL of anhydrous
methanol, was added 5.3 mL (23 mmol~ of 25 weight %
sodium methoxide in methanol solution. After 0.5
hour, the reaction was quenched with lN hydrochloric
acid, ethyl acetate added and washed with 5~~
potassium hydrogen sulfate solution, saturated sodium
bicarbonate solution and brine, dried with magnesium
sulfate, filtered and concentrated to afford 2.05 g
of crude product. This was chromatographed on 100 g

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of silica gel using 20~-50~ ethyl acetate/hexane to
yield 1.5 g of pure N-[(lS-mercaptomethyl)-2-
methylpropyl]-4-methoxy-N-
(phenylmethyl)benzenesulfonamide, m/e= 386 (M+Li).
Example 34: Preparation of N-(2-mercaptoethyl)-N-
(phenylmethyl)-4-(n-butoxy)benzenesulfonamide.
N~ J~
lA\
O O
Part A: To a solution of 15.11 g (55 mmol)
of N-(2 -hydroxyethyl)-4-(n-butoxy)benzenesulfonamide
from Example 2 in 100 mL of anhydrous DMF, was added
22.9 g (165 mmol) of powdered potassium carbonate and
then 10.3 g (60 mmol) of benzyl bromide. After 16
hours, ethyl acetate and water was added, the oragnic
layer separated and washed 3xs with brine, dried with
sodium sulfate, filtered and stripped to afford 20.7
g of crude product. This was recrystallized from
ethyl acetate/hexane to afford 13.8 g of the desired
N- (hydroxyethyl)-N-(phenylmethyl)-4-~n-butoxy)-
benzenesulfonamide.
Part B: To a solution of 3.0 g (8.2 mmol)
of N-(2-hydroxyethyl)-N-(phenylmethyl)-4-(n-butoxy)-
benzenesulfonamide from Part A and 2.38 g (9.1 mmol)
of triphenylphosphine in 40 mL of anhydrous THF at 0
C, was added 1.4 mL (9.1 mmol) of diisopropylazo-
dicarboxylate, followed by 0.65 mL (9.1 mmol) of
thiolacetic acid. After stirring at room temperature
for 15 hours, the reaction was concentrated and the
residue chromatographed on 150 g of silica gel using

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20-50~ ethyl acetate/hexane to afford 2.4 ~ of the
desired product, which was recrystallized from ethyl
acetate/hexane to afford 1.7 g of pure product, m/e =
428 (M+Li~.
Part C: To a suspension of 1.7 g ~4.1 mmol)
of product from Part B above in 20 mL of anhydrous
methanol, was added 3.3 mL (14.6 mmol) of 25 weight
sodium methoxide in methanol. After 30 minutes, the
solution was cooled in ice and 2% hydrochloric acid
added. Ethyl acetate was added and the organic layer
separated and washed with saturated sodium
bicarbonate, brine, dried over anhydrous magnesium
sulfate, filtered and stripped to afford 1.42 g of
pure material, identified as N-(2-mercaptoethyl)-N-
(phenylmethyl)-4-(n-butoxy)benzenesulfonamide, m/e =
386 (M+Li).
Example 35: Preparation of 4-
(Benzyloxy)benzenesulfonyl chloride.
O O
\\//
~0~
To a suspension of 22.4 g (146 mmol) of
sulfur trioxide/DMF complex in 60 mL of anhydrous
1,2-dichloroethane at room temperature, was added a
solution of 30 g (162 mmol) of benzylphenyl ether in
30 mL of anhydrous 1~2-dichloroethane. The resulting
mixture was warmed to reflux and maintained there for
1 hour, cooled to room temperature and 10.8 mL (146
mmol) of thionyl chloride added. The reaction was
then warmed to 75 C for 1 hour, cooled in an ice
bath, 50 mL of water slowly added, then ethyl

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acetate. The layers were separated, washed with
saturated sodium bicarbonate, brine, dried with
magnesium sulfate, filtered and stripped. The
resulting solids were triturated with hexane to
afford 24.5 g of pure
4-(Benzyloxy)benzenesulfonyl chloride.
Example 36: Preparation of N-(2-hydroxy-lR-
methylethyl)-N-methyl-4-
hydroxybenzenesulfonamide.
~ N~ ~OH
CH3 l~o
Part A: To a solution of 7.4 mL (95.1 mmol)
of (R)-(-)-2-amino-1-propanol in 31 mL of THF and 9
mL of water, was added 17.2 mL (123 mmol) of
triethylamine. After cooling in an ice bath, a
solution of 24 .4 g (86.5 mmol) of 4- (benzyloxy)-
benzenesulfonyl chloride in 40 mL of tetrahydrofuran
was slowly added over 15 minutes. After stirring at
room temperature for 16 hours, the reaction was
concentrated in vacuo, ethyl acetate and water were
added, the organic layer was separated and washed
with 5~ potassium hydrogen sulfate solution,
saturated sodium bicarbonate solution and brine,
dried over sodium sulfate, filtered and concentrated
to afford a solid, which was triturated with hexane
to afford 23.4 g of the desired N-(2-hydroxy-lR-
methylethyl)-4-(benzyloxy)benzenesulfonamide, m/e =
322 (M+H).
Part B: To a solution of 18.25 g (56.8
mmol) of the product from Part A in 100 mL of
anhydrous DMF, was added 23.5 g (170 mmol) of

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powdered potassium carbonate and then 24.2 g (170
mmol) of methyl iodide. After 22 hours, ethyl
acetate and water was added, the oragnic layer
separated and washed 3xs with brine, dried with
sodium sulfate, filtered and stripped to afford 18.2
g of crude product, suitable for the next step and
identified as the desired N-(2-hydroxy-lR-
methylethyl)-N-methyl-4-
(benzyloxy)benzenesulfonamide, m/e = 333 (M+H).
Part C: A solution of 18.2 g (54 mmol) of
the product from Part B in 150 mL of tetrahydrofuran
was hydrogenated in the presence of 6.0 g of 4
palladium-on-carbon catalyst under 50 psig of
hydrogen at room temperature for 2 hours. The
catalyst was removed by filtering through celite and
concentrated. The resulting solids were triturated
with methylene chloride and hexane, collected and air
dried to afford 8.6 g of the desired N-(2-hydroxy-
lR-methylethyl)-N-methyl-4-hydroxybenzenesulfonamide,
m/e=246 (M+H).
Example 37: Preparation of N-(2-mercapto-lR-
methylethyl)-N-methyl-4-(n-
propyloxy)benzenesulfonamide.
CH3 ,~ ~
HS~ ~S
CH3 o/A\o
Part A: To a solution of 1.50 g (6.11 mmol)
of N-(2-hydroxy-lR-methylethyl)-4-hydroxybenzene-
sulfonamide from example 36, in 10 mL of anhydrous
DMF, was added 2.53 g (18.3 mmol) of powdered
potassium carbonate, and then 0.85 mL (9.3 mmol) of
bromopropane. After stirring at room temperature for

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14 hours, ethyl acetate and water was added, the
layers separated and the organic layer washed 3xs
with brine, dried with sodium sulfate, filtered and
stripped to afford 1.70 g of crude material, suitable
for use in the next step and identified as N-(2-
hydroxy-lR-methylethyl)-N-methyl-4-(n-
propyloxy)benzenesulfonamide, m/e=288 (M+H).
Part B: To a solution of 1.70 g (5.9 mmol)
of product from Part A and 1.70 g (6.5 mmol) of
triphenylphosphine in 23 mL of anhydrous THF at 0~C,
was added 1.0 mL (6. 5 mmol) of
diethylazodicarboxylate, followed after 5 minutes by
0.47 mL (6.5 mmol) of thiolacetic acid. After 0.5
hour, the reaction was concentrated and the resiaue
was chromatographed on 150 g of silica gel using 2096-
50~ ethyl acetate/hexane to yield 1. 02 g of pure
product, m/e = 352 (M+Li).
Part C: To a solution of 1. 02 g (2.95 mmol)
of product from Part B in 10 mL of anhydrous
methanol, was added 2.4 mL (10.5 mmol) of a 25 weight
solution of sodium methoxide in methanol. After
0.5 hour, the reaction was quenched with lN HCl
25 solution, followed by ethyl acetate and water, the
organic layer was separated and washed with saturated
sodium bicarbonate solution and brine, dried with
magnesium sulfate, filtered and concentrated to
afford 0.90 g of the desired product, identified as
N-(2-mercapto-lR-methylethyl)-N-methyl-4-(n-
propyloxy)benzene-sulfonamide, m/e= 304 (M+H).
Example 38: Preparation of N-(2-mercapto-lR-
methylethyl)-N-methyl-4-ethoxybenzenesulfonamide.

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CH3 ~ ~~/
HS~ ~S
CH3 o o
Part A: To a solution of 1.50 g (6.11 mmol)
of N-(2-hydroxy-lR-methylethyl)-4-
S hydroxybenzenesulfonamide from example 36, in 10 mLof anhydrous DMF, was added 2.53 g (18.3 mmol) of
powdered potassium carbonate, and then 0.70 mL (9.2
mmol) of bromoethane. After stirring at room
temperature for 15 hours, ethyl acetate and water was
added, the layers separated and the organic layer
washed 3xs with brine, dried with sodium sulfate,
filtered and stripped to afford 1.53 g of crude
material, suitable for use in the next step and
identified as N-(2-hydroxy-lR-methylethyl)-N-methyl-
4-ethoxybenzenesulfonamide, m/e=274 (M+H).
Part B: To a solution of 1.53 g (5.6 mmol)
of product from Part A and 1.61 g (6.15 mmol) of
triphenylphosphine in 20 mL of anhydrous THF at 0~C,
was added 0.97 mL (6.15 mmol) of diethylazo-
dicarboxylate, followed after 5 minutes by 0.44 mL
(6.15 mmol) of thiolacetic acid. After 0.5 hour, the
reaction was concentrated and the residue was
chromatographed on 150 g of silica gel using 20%-50~
ethyl acetate/hexane to yield 1.59 g of pure product,
m/e = 332 (M+H).
Part C: To a solution of 1.53 g (4.62 mmol)
of product from Part B in 20 mL of anhydrous
methanol, was added 3.8 mL (16.6 mmol) of a 25 weight
solution of sodium methoxide in methanol. After
0.5 hour, the reaction was ~uenched with lN HCl
solution, followed by ethyl acetate and water, the
organic layer was separated and washed with saturated

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sodium bicarbonate solution and brine, dried with
magnesium sulfate, filtered and concentrated to
afford 0.90 g of the desired product, identified as
N-(2-mercapto-lR-methylethyl)-N-methyl-4-
ethoxybenzenesulfonamide, m/e= 290 (M+H).
Example 39: Preparation of N-(2-mercapto-lR-
methylethyl)-N-methyl-4-(n-
pentyloxy)benzenesulfonamide.
CH3 ~ ~_~~~
CH3 O O
Part A: To a solution of 1.50 g (6.11 mmol)
of N-(2-hydroxy-lR-methylethyl)-4-
hydroxybenzenesulfonamide from example 36 in 10 mL ofanhydrous DMF, was added 2.53 g (18.3 mmol) of
powdered potassium carbonate, and then 1.13 mL (9.2
mmol) of 1-bromopentane. After stirring at room
temperature for 30 hours, ethyl acetate and water was
added, the layers separated and the organlc layer
washed 3xs with brine, dried with sodium sulfate,
filtered and stripped to afford 1.78 g of crude
material, suitable for use in the next step and
identified as N-(2-hydroxy-lR-methylethyl)-N-methyl-
4-(n-pentyloxyoxy)benzene-sulfonamide, m/e=316 (M+H).
Part B: To a solution of 1.78 g (5.64 mmol)
of product from Part A and 1.63 g (6.20 mmol) of
triphenylphosphine in 20 mL of anhydrous THF at 0~C,
was added 1.0 mL (6.2 mmol) of
diethylazodicarboxylate, followed after 5 minutes by
0.4S mL (6.2 mmol) of thiolacetic acid. After 0.5
hour, the reaction was concentrated and the residue
was chromatographed on 150 g of silica gel using 20~-
~ _ .

CA 02260860 1999-01-12
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50~ ethyl acetate/hexane to yield 1.48 g of pure
product, m/e = 374 (M+H).
Part C: To a solution of 1.48 g (3.96 mmol)
of product from Part B in 15 mL of anhydrous
methanol, was added 3.3 mL (14 mmol) of a 25 weight
solution of sodium methoxide in methanol. After 0.5
hour, the reaction was quenched with lN HCl solution,
followed ~y ethyl acetate and water, the organic
layer was separated and washed with saturated sodium
bicarbonate solution and brine, dried with magnesium
sulfate, filtered and concentrated to afford 1.14 g
of the desired product, identified as N-(2-mercapto-
lR-methylethyl)-N-methyl-4-ethoxybenzenesulfonamide,
m/e= 332 (M+H).
Example 0: Preparation of N-(2-mercapto-lR-
methylethyl)-N-methyl-4-(phenoxy)benzenesulfonamide.
~ N~
CH3 I/\\
Part A: To a solution of 5.02 g (66.8 mmol)
of (R)-(-)-2-amino-1-propanol in 28 mL of THF and 7
mL of water, was added 14.0 mL (100 mmol) of
triethylamine. After cooling in an ice bath, 11.7 g
(60 mmol) of 4-fluorobenzenesulfonyl chloride was
slowly added over 10 minutes. After stirring at room
temperature for 2 hour, the reaction was
- concentrated, ethyl acetate and water were added, the
organic layer was separated and washed with 5~
potassium hydrogen sulfate solution, saturated sodium
bicarbonate solution and brine, dried over sodium
sulfate, filtered and concentrated to afford 14.5 g
of the desired

CA 02260860 l999-0l-l2
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N-(2-hydroxy-lR-methylethyl)-4-fluorobenzene-
sulfonamide, m/e = 234 (M+H).
Part B: To a solution of 5.14 g (22.0 mmol)
of N-(2-hydroxy-lR-methylethyl)-4-fluorobenzene-
sulfonamide from Part A in 40 mL of anhydrous DMF,
was added 9.12 g (66.1 mmol) of powdered potassium
carbonate, and then 4.2 mL (66 mmol) of methyl
iodide. After stirring at room temperature for 4
hours, ethyl acetate and water was added, the layers
separated and the organic layer washed 3xs with
brine, dried with sodium sulfate, filtered and
stripped to afford 4.64 g of the desired N-(2-
hydroxy-lR-methylethyl)-N-methyl-4-
fluorobenzenesulfonamide, m/e=247 (M+H).
Part C: To a solution of 3.00 g (12.1 mmol)of the product from Part B in 25 mL of anhydrous DMF,
was added 5.02 g (36.4 mmol) of powdered potassium
carbonate, and then 2.3 g (24.3 mmol) of phenol. The
reaction mixture was heated to 100 C for 48 hours,
cooled and tert-butylmethyl ether and water added.
The organic layer was separated and washed with 10%
sodium hydroxide, brine, dried with sodium sulfate,
filtered and stripped to afford 3.0 g of crude
material. This was chromatographed on 150 g of
silica gel using 20%-30~ ethyl acetate/hexane to
provide 0.92 g of pure N-(2-hydroxy-lR-methylethyl)-
N-methyl-4-(phenoxy)-benzenesulfonamide, m/e=328
(M+Li).
Part D: To a solution of 742 mg (2.3 mmol)
of product from Part C and 0.67 g (2.54 mmol) of
triphenylphosphlne in 10 mL of anhydrous THF at 0~C,
was added 0.40 mL (2.54 mmol) of diethylazo-
dicarboxylate, followed after 5 min. by 0.18 mL (2.54
mmol) of thiolacetic acid. After 0.5 hour, the
. .

CA 02260860 1999-01-12
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~eaction was concentrated and the residue was
chromatographed on 100 g of silica gel using 10~-20
ethyl acetate/hexane to yield 0.77 g of the desired
product, m/e = 380 (M+H).
Part E: To a solution of 0.76 g (2.05 mmol)
of product from Part D in 5 mL of anhydrous methanol,
was added 1.8 mL (7.4 mmol) of a 25 weight ~ solution
of sodium methoxide in methanol. After 0.5 hour, the
reaction was quenched with lN HCl solution, followed
by ethyl acetate and water, the organic layer was
separated and washed with saturated sodium
bicarbonate solution and brine, dried with magnesium
sulfate, filtered and concentrated to afford the
crude product. This was chromatographed on 100 g of
silica gel using 100~ methylene chloride to provide
the pure
N-(2-mercapto-lR-methylethyl)-N-methyl-4-(phenoxy)-
benzenesulfonamide, m/e= 338 (M+H).
Example 41: Preparation of N-(2-mercapto-lR-
methylethyl)-N-methyl-4-
(thiophenyl)benzenesulfonamide.
HS ~ /S ~ ~S ~
Part A: To a solution of 1.72 g (6.95 mmol)
of N-(2-hydroxy-lR-methylethyl)-N-methyl-4-
'luorobenzenesulfonamide from Example 40, part B, in~lO mL of anhydrous DMF, was added 7.03 g (21.5 mmol)
of cesium carbonate, and then 1.0 mL (1.07 g, 9.73
mmol) of thiophenol. The reaction mixture was heated
to 70 C for 15 hours, cooled and ethyl acetate and

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water added. The organic layer was separated and
washed 3xs with brine, dried with sodium sulfate,
filtered and stripped to afford 2.5 g of crude
material. This was chromatographed on 100 g of
5 silica gel using 20~-60~6 ethyl acetate/hexane to
provide 1.37 g of pure N-(2-hydroxy-lRmethylethyl)-N-
methyl-4-(thiophenyl)-benzenesulfonamide, m/e=338
(M+H).
Part B: To a solution of 1.29 g (3.82 mmol)
of product from Part A and 1.10 g (4.20 mmol) of
triphenylphosphine in 19 mL of anhydrous THF at 0~C,
was added 0.60 mL (4.20 mmol) of diethylazo-
dicarboxylate, followed after 5 min. by 0.30 mL (4.20
15 mmol) of thiolacetic acid. After 1 hour, the
reaction was concentrated and the residue was
chromatographed on 150 g of silica gel using 100
methylene chloride to yield 1.0 g of the desired
product, m/e = 402 (M+Li).
Part C: To a solution of 1.0 g (2.53 mmol)
of product from Part B in 10 mL of anhydrous
methanol, was added 2.1 mL (9.1 mmol) of a 25 weight
~ solution of sodium methoxide in methanol. After
25 0.5 hour, the reaction was quenched with lN HC1
solution, followed by ethyl acetate and water, the
organic layer was separated and washed with saturated
sodium bicarbonate solution and brine, dried with
magnesium sulfate, filtered and concentrated to
30 afford the crude product. This was chromatographed
on 50 g of silica gel using 100~ methylene chloride
to pro~ride pure N-(2-mercapto-lR-methylethyl)-N-
methyl-4-(thiophenyl)benzene-sulfonamide, m/e= 354
~M+H).

CA 02260860 1999-01-12
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Example 42: Preparation of N-(2-hydroxy-lR-
methylethyl)-N-methyl-2-(pyrid-2-yl)thiophene-5-
sulfonamide.
HO ~ ~ ~ ~
Part A: To a solution of 1.97 g (26.2 mmol)
of (R)-(-)-2-amino-1-propanol in 10 mL of THF and 3.5
mL of water, was added 4.5 mL (32 mmol) of
triethylamine. After cooling in an ice bath, 5.44 g
(20.9 mmol) of 2-(pyrid-2-yl)thiophene-5-sulfonyl
chloride was slowly added over 10 minutes. After
stirring at room temperature for 3.5 hours, the
reaction was concentrated, ethyl acetate and water
were added, the organic layer was separated and
washed with 5~ potassium hydrogen sulfate soution,
saturated sodium bicarbonate solution and brine,
dried over sodium sulfate, filtered and concentrated
to afford 4.1 g crude product. This was crystallized
from acetone/diethyl ether to afford 0.95 of pure
N-(2-hydroxy-lR-methylethyl)-2-(pyrid-2-yl)thiophene-
5-sulfonamide.
Part B: To a solution of 0.94 g (3.15
mmol) of product from Part A in 10 mL of anhydrous
DMF, was added 1.31 g (9.45 mmol) of powdered
potassium carbonate, and then 0.60 mL (9.5 mmol~ of
methyl iodide. After stirring at room temperature
for 24 hours, ethyl acetate and water was added, the
layers separated and the organic layer washed 3xs
wlth brine, dried with sodium sulfate, filtered and
stripped to afford 0.93 g of the desired N-(2-
hydroxy-lR-methylethyl)-N-methyl-2-(pyrid-2
yl)thiophene-5-sulfonamide.

CA 02260860 l999-0l-l2
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Example 43: Preparation of N-(2-mercapto-1,1-
dimethylethyl)-N-(phenylmethyl)-4-
methoxybenzenesulfonamide.
~3
OCH3
H3C CH3 o/A\o
Part A: To a solution of 4. 47 g (50 mmol)
of 2-amino-2-methyl-1-propanol in 20 mL of THF and 5
mL of water, was added 10 mL (72 mmol) of
triethylamine. After cooling in an ice bath, 9.0 g
(44 mmol) of 4-methoxybenzenesulfonyl chloride was
slowly added over 10 minutes. After stirring at room
temperature for 12 hours, the reaction was
concentrated, ethyl acetate and water were added, the
organic layer was separated and washed with 5~
potassium hydrogen sulfate soution, saturated sodium
bicarbonate solution and brine, dried over sodium
sulfate, filtered and concentrated to afford 9.1 g of
the desired N-(2-hydroxy-1,1-dimethylethyl)-4-
methoxybenzenesulfonamide.
Part B: To a solution of 3.12 g ~12 mmol)of product from Part A in 25 mL of anhydrous DMF, was
added 5.0 g (36 mmol) of powdered potassium
carbonate, and then 2.2 m~ (18 mmol) of benzyl
bromide. After stirring at room temperature for 17
hours, ethyl acetate and water was added, the layers
separated and the organic layer washed 3xs with
brine, dried with sodium sulfate, filtered and
stripped to afford 3.2 g of crude product. This was
recrystallized from methylene chloride/hexane to
afford 1.51 g of the desired N-(2-hydroxy~
.

CA 02260860 l999-0l-l2
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dimethylethyl)-N-(pheny7methyl)-4-
methoxybenzenesulfonamide, m/e=356 (M+Li).
Part C: To a solution of 1.43 g (4.1 mmol)
of product from Part B and 1.18 g (4.5 mmol) of
triphenylphosphine in 16 mL of anhydrous THF at
zero ~C, was added 0.70 mL (4.5 mmol~ of diethylazo-
dicarboxylate, followed after 5 min. by 0.32 mL (4.5
mmol) of thiolacetic acid. After 3 hours, the
reaction was concentrated and the residue was
chromatographed on 150 g of silica gel using 20~-50~6
ethyl acetate/hexane to yield 0. 62 g of the desired
product, m/e = 414 (M+Li).
Part D: To a solution of 0.60 g (1.47 mmol)
of product from Part C in 10 mL of anhydrous
methanol, was added 1.2 mL (5.3 mmol) of a 25 weight
percent solution of sodium methoxide in methanol.
After 0. 5 hour, the reaction was quenched with lN HCl
solution, followed by ethyl acetate and water, the
organic layer was separated and washed with saturated
sodium bicarbonate solution and brine, dried with
magnesium sulfate, filtered and concentrated to
afford 0.38 g of pure N-(2-mercapto-1,1-
dimethylethyl)-N-(phenylmethyl)-4-
methoxybenzenesulfonamide, m/e= 366 (M+H).
Example 44: Preparation of N-[(2-
mercaptophenyl)methyl]-N-methyl- 4-
methoxybenzenesulfonamide.
. [~N~s)~
SH 1 0

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Part A: To a mixture of 50 mL of
tetrahydrofuran, 15 mL (108 mmol) of trtiethylamine
and 10 mL (116 mmol) of a 40% aqueous methylamine
solution at 0 C, was added 15.0 g (72.6 mmol) of 4-
methoxy-benzenesulfonyl chloride over a 15 minutes.
After 1 hour, the solvents were removed in vacuo, 5%
aqueous KHSO4 and ethyl acetate added, the organic
layer separted, washed with saturated aqueous sodium
bicarbonate, brine, dried with sodium sulfate,
filtered and stripped to afford a white solid. This
was recrystallized from hot ethyl acetate/hexane to
afford 13.4 g of N-methyl-4-
methoxybenzenesulfonamide, m/e=202 (M+H).
Part B: To a solution of 6.32 g (25.0 mmol)
of 2-iodobenzyl chloride in 40 mL of anhydrous DMF,
was added 5.04 g (25.0 mmol) of the product from Part
A, and then 10.4 g (75.3 mmol) of powdered potassium
carbonate was added. After stirring at room
temperature for 5 hours, ethyl acetate and water were
added, the organic layer separated and washed 3xs
with brine, dried with sodium sulfate, filtered and
stripped to afford 10.6 g of crude product. This was
recrystallized from ethyl acetate/hexane to afford
9.0 g of the desired N-[(2-iodophenyl)methyl]-~-
methyi-4-methoxybenzenesulfonamide.
Part C: To a mixture of 834 mg (2.0 mmol)
of the product from Part B, 236 mg (3.1 mmol) of
thiourea and 55 mg (0.10 mmol) of bis(tri-n-
butylphosphine)-nickel(II) chloride under a nitrogen
atmosphere at room temperature, was added 1 mL of
anhydrous DMF, and then 16 mg (0.25 mmol) of sodium
cyanoborohydride. The reaction was then warmed to 65
~ for 15 hours, cooled to room temperature and 2.0 mL
(5 mmol) of 2.5 N sodium hydroxide solution added.
After stirring for 15 minutes, lN hydrochloric acid

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and ethyl acetate were added, the organic layers
separated, washed 3 XS with brine, dried with sodium
sulfate, filtered and stripped to afford 650 mg of
crude product. This was chromatographed on 50 g of
silica gel using 20~-30% ethyl acetate/hexane to
afford 520 mg of purified product, which was then
recrystallized from methylene chloride/hexane to
afford 167 mg of the desired
N-[( 2 -mercaptophenyl)methyl]-N-methyl-4-
methoxybenzene-sulfonamide.
Example 45: Preparation of N-(2-mercapto-lR-
methylethyl) -N-[2- (4-morpholino)ethyl]-4-(n-
butoxy)benzenesulfonaml e
1~,~
HS "S~
lC
Part A: To a solution of 2. 87 g (10 mmol)
of N-(2-hydroxy-lR-methylethyl)-4-(n-butoxy)benzene-
sulfonamide from Example 4 in (10 ml) of anhydrous
DMF,was added 4.14 g (30 mmol) of powdered
potassium carbonate and then 2.04 g (11 mmol) of 4-
(2-Chloroethyl)morpholine hydrochloride. After 12
hours another batch of (2.0 g, mmo;) of powdered
potassium carbonate and 1.0 g (5.5 mmol) of 4-(2-
chloroethyl)-morpholine hydrochloride was added and
the reaction mixture stirred at room temperature for
an additional 12 hours, ethyl acetate and water was
added, the organic layer separated and washed 3x50 mL
with brine, dried with sodium sulfate, filtered and

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solvent removed under reduced pressure and the
residue chromatographed on 100 g of silica gel using
3:1 mixture of ethyl acetate:hexane to afford 2.1 g
of the desired N-(2-hydroxy-lR-methylethyl) -N-[2- (4-
morpholino)-ethyl]-4-(n-butoxy)benzenesulfonamide,
m/e = 407 (M+Li).
Part B: To a solution of 1.~ g (3.74 mmol)
of product from Part A and 983 mg (3.74 mmol) of
triphenylphosphine in 15 ml of anhydrous THF at room
temperature was added 0.588 mL (3.74 mmol) of diethyl
azodicarboxylate,followed by 0.8 mL (11.22 mmol) of
thiolacetic acid. After stirring at room temperature
for 1.5 hours, the reaction was concentrated and the
residue chromatographed on 100 g of silica gel using
a 1:1 mixture of ethyl acetate:hexane to afford 718
mg of the desired N-[2-(S-acetyl)mercapto-lR-
methylethyl] -N-[2- (4-morpholino)ethyl]-4-(n-
butoxy)benzenesulfonamide, m/e = 459 (M+H).
Part C: To a suspension of 0.63 g (1.7
mmol) of product from Part B in 20 mL of anhydrous
methanol, was added 0.5 mL (2. 3 mmol) of 25 wt. %
sodium methoxide in methanol. After 30 minutes at
room temperature, ethyl acetate and water was added,
the organic layer separated and washed 3X50 ml with
water and with brine and dried with sodium sulfate,
filtered and solvent removed under reduced pressure
and the residue chromatographed on lOOg of silica gel
using 3~ methanol/dichloromethane to afford 0.38 g of
N-(2-mercapto-lR-methylethyl)-N-[2-(4-
morpholino)ethyl)-4-(n-butoxy)benzenesulfonamide, m/e
= 417 (M+H).
Example 46: Preparation of N-(2-mercapto-lR-
methylethyl)-N-[2-(1-piperidino)ethyl]-4-(n-
butoxy)benzenesulfonamide.

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HS~N~s
CH3 ~
Part A: To a solution of 1.0 g (3.5 mmol)
of N-(2 -hydroxy-lR-methylethyl)-4-(n-butoxy)-benzene-
-sulfonamide from Example 4 in (30 ml) of anhydrous
DMF,was added 2.16 g ( 15.6 mmol) of powdered
potassium carbonate and then 0. 96 g (5.2 mmol) of 1-
(2- chloroethyl)piperidine hydrochloride. After 20
hours, ethyl acetate and water was added, the organic
layer separated and washed 2x50 mL with saturated
sodium bicarbonate and 2x50 mL with brine, dried with
sodium sulfate, filtered and solvent removed under
reduced pressure and the residue chromatographed on
200 g of silica gel using 3:1 mixture of ethyl
acetate:hexane to afford 0.98 g of the desired N-(2-
hydroxy-lR-methylethyl)-N-[2-(1-piperidino)ethyl]- 4-
(n-butoxy)-benzenesulfonamide, m/e = 399 (M+H)
Part B: To a solution of 0.9 g (2.26 mmol)
of product from Part A and 0. 6 g ( 2. 3 mmol) of
triphenylphosphine in 20 ml of anhydrous THF at room
~ temperature was added 0.3 6 mL (2.3 mmol) of diethyl
azodicarboxylate, followed by 0.48 mL (6.78 mmol) of
thiolacetic acid. After stirring at room temperature
for 6 hours, the reaction was concentrated and the
residue chromatographed on 60 g of silica gel using a
3:1:0.25 mixture of ethyl acetate:hexane:methanol to
afford 0.36 g of the desired N-[2-(S-
acetyl)mercapto-lR-methylethyl] -N-[2~

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pi~eridino)ethyl]-4-(n-butoxy)benzenesulfonamide, m/e
= 457 (M+H).
Part C: To a suspension of 0.36 g ~0.77
mmol) of product from Part B in 20 mL of anhydrous
methanol, was added 0.3 mL (1.4 mmol) of 25 wt. ~
sodium methoxide in methanol. After 30 minutes at
room temperature, ethyl acetate and water was added,
the organic layer separated and washed 3x50 ml with
water and with brine and dried with sodium sulfate,
filtered and solvent removed under reduced pressure
and the residue chromatographed on 20 g of silica gel
using 5~ methanol/ dichloromethane to afford 0.17 g
of N-( 2-mercapto-lR-methylethyl)-N-[2-(1-
piperidino)ethyl)-4-(n-butoxy)benzenesulfonamide, m/e
= 415 (M+H).
Example 47: Preparation of N-(2-mercapto-lR-
methylethyl)-N-[2-(1-pyrrolidino)ethyl]-4-(n-
butoxy)benzenesulfonamide.
HS~N~s
0~ ~
CH3 ~
Part A: To a solution of 2.87 g (10 mmol)
of N-( 2-hydroxy-lR-methylethyl)-4-(n-butoxy)benzene-
sulfonamide from Example 4 in (10 ml) of anhydrousDMF,'was added 4.14 g (30 mmol) of powdered
potassium carbonate and then 1.88 g (11 mmol) of 1-
(2-chloro-ethyl)pyrrolidine hydrochloride. After 12
hours, ethyl acetate and water was added, the organic

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layer separated and washed 3x50 mL with brine, dried
with sodium sulfate, filtered and solvent removed
under reduced pressure and the residue
chromatographed on 100 g of silica gel using 3:1:0.5
mixture of ethyl acetate:hexane:methanol to afford
1.6 g of the desired N-(2-hydroxy-lR-methylethyl)-N
[2-(l-pyrrolidino)-ethyl]-4-(n-
butoxy)benzenesulfonamide, m/e = 391 (M+Li).
lC Part B: To a solution of 1.2 g (3 mmol) of
product from Part A and 0.79 g (3 mmol) of
triphenylphosphine in 15 ml of anhydrous THF at room
temperature was added 0.47 mL (3 mmol) of diethyl
azodicarboxylate, followed by 0.7 mL (10 mmol) of
thiolacetic acid. After stirring at room temperature
for 2 hours, the reaction was concentrated and the
residue chromatographed on 100 g of silica gel using
a 3:1:1 mixture of ethyl acetate:hexane:methanol to
afford 0.4 g of the desired N-[2-(S-acetyl)mercapto-
lR-methylethyl]-N-[2-(l-pyrrolidino)ethyl]-4-(n
butoxy)benzenesulfonamide, m/e = 443 (M+H).
Part C: To a suspension of 0.39 g (0.87
mmol) of product from Part B in 15 mL of anhydrous
methanol, was added 0.3 mL (1.4 mmol) of 25 wt.
sodium methoxide in methanol. After 30 minutes at
room temperature, ethyl acetate and water was added,
the organic layer separated and washed 3x50 ml with
water and with brine and dried with sodium sulfate,
filtered and solvent removed under reduced pressure
and the residue chromatographed on 50 g of silica gel
using 5 ~ methanol/dichloromethane to afford 0.18 g
of the desired N-(2-mercapto-lR-methylethyl)-N-[2-(1-
pyrrolidino)ethyl)-4-(n-butoxy)benzenesulfonamide,
m/e = 401 (M+H).

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Example 48: Preparation of N-(2-mercapto-lR-
methylethyl)-N-pentyl-4-(n-butoxy)benzenesulfonamide.
~o
HS ~N~S
0 ~0
CH3
Part A:To a solution of 2.87 g ~lO mmol) of
N-(2-hydroxy-lR-methylethyl)-4-(n-
butoxy)benzenesulfonamide from Example 4 in (20 ml)
of anhydrous DMF, was added 4.2g (30 mmol) of
powdered potassium carbonate and then 2.3 g (15 mmol)
of l-Bromopentane. The reaction mixture was stirred
at 60~ C for 13 hours, ethyl acetate and water was
added, the organic layer separated and washedwith
water and with brine, dried with sodium sulfate,
filtered and solvent removed under reduced pressure
and the residue chromatographed on 100 g of silica
gel using 2:1 mixture of ethyl acetate:hexane to
afford 2.63 g of the desired N-(2-hydroxy-lR-
methylethyl)-N-pentyl-4-(n-
butoxy)benzenesulphonamide,m/e = 364 (M+Li).
Part B: To a solution of 2.0 g ( 5 . 6 mmol)of product from Part A and 1.58 g (6 mmol) of
triphenylphosphine in 20 ml of anhydrous THF at room
temperature was added 0.94 mL (6 mmol) of diethyl
azodicarboxylate, followed by 0.86 mL (12 mmol) of
thiolacetic acid. After stirring at room temperature
for 1 hour, the reaction was concentrated and the
residue chromatographed on 100 g of silica gel using

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a 4:1 mixture of hexane:ethyl acetate to afford 1.2 g
of the desired N-[2-(S-acetyl)mercapto-
l~methylethyl]-N-pentyl-4-(n-
butoxy)benzenesulfonamide, m/e = 416 (M+H)
Part C: To a suspension of 1.0 g (2.4
mmol) of product from Part B in 20 mL of anhydrous
methanol, was added 1.0 mL (4.6 mmol) of 25 wt.
sodium methoxide in methanol. After 30 minutes at
room temperature, ethyl acetate and water was added,
the organic layer separated and washed 3x50 ml with
water and with brine and dried with sodium sulfate,
filtered and solvent removed under reduced pressure
and the residue chromatographed on 50 g of silica gel
using dichloromethane to afford g of the desired N-
(2-mercapto-lR-methylethyl)-N-pentyl-4-(n-
butoxy)benzenesulfonamide, m/e = 380 (M+Li).
Example 49: N-(2-mercapto-1-R-methylethyl)-N-( 3-
pyridylmethyl)-4-methoxybenzenesulfonamide.
~~
HS ~ ~ S~
O O
CH3
Part A: To a solution of 3.69 g (15 mmol)
of N-(2-hydroxy-lR-methylethyl)-4-methoxybenzene-
2c sulfonamide from Example 3 in (25 ml) of anhydrous
. DMF, was added 6.3 g (45 mmol) of powdered potassium
carbonate and then 2.7 g (16. 5 mmol) of 3-picolyl
hydrochloride. The reaction mixture was stirred for
12 hours, ethyl acetate and water was added, the
3G organic layer separa~ed and washed with saturated

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sodium bicarbonate and with brine, dried with sodium
sulfate, filtered and solvent removed under reduced
pressure and the residue chromatographed on 100 g of
silica gel using 2:1 ethyl acetate:hexane to afford
1.12 g of the desired N-(2-hydroxy-lR-methylethyl)-
N-~3-pyridylmethyl)-4-methoxybenzenesulphonamide, m/e
= 343 (M+Li).
Part B: To a solution of 1.07 g (3.18
mmol) of product from Part A and 0.84 g (3.2 mmol) of
triphenylphosphine in 25 ml of anhydrous THF at room
temperature was added 0.5 mL (3.18 mmol) of diethyl
azodicarboxylate, followed by 0.68 mL (9.5 mmol) of
thiolacetic acid. After stirring at room temperature
for 1.5 hour, the reaction was concentrated and the
residue chromatographed on 80 g of silica gel using
1:2 hexane:ethyl acetate to afford 0.21 g of the
desired N-[2-(s-acetyl)mercapto-lR-methylethyl]-N-(3
pyridylmethyl)-4-methoxybenzenesulfonamide, m/e =395
(M+H).
Part C: To a suspension of 0.18 g (0.45
mmol) of product from Part B in 25 mL of anhydrous
methanol, was added 0.2 mL (1.2 mmol) of 25 wt. ~
sodi~m methoxide in methanol. After 30 minutes at
room temperature, ethyl acetate and water was added,
the organic layer separated and washed 2x50 ml with
water and with brine and dried with sodium sulfate,
filtered and solvent removed under reduced pressure
and the residue chromatographed on 50 g of silica gel
using 1~ methanol/dichloromethane to afford 0.1 g of
the desired N-(2-mercapto-lR-methylethyl)-N-(3-
pyridylmethyl)-4-methoxybenzenesulfonamide, m/e = 353
(M+H').
., _ .

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Example 50: Preparation of N-(2-mercapto-lR-
methylethyl)-N-methyl(3-
thiophenylpropyl)sulphonamide.
CH3
HS ~ N ~ /\/\ S
CH3 ~ ~
Part A: To a solution of 1.1 g (3.8 mmol)
of N-(2-hydroxy-lR-methylethyl)(3-thiophenoxypropyl)-
sulphonamide from Example 5 in (25 ml) of anhydrous
DMF, was added 2.1 g (15 mmol) of powdered potassium
carbonate and then 1.1 g (7.6 mmol) of methyl iodide.
The reaction mixture was stirred at room temperature
for 14 hours, ethyl acetate and water was added, the
organic layer separated and washed with saturated
sodium bicarbonate and with brine, dried with sodium
sulfate, filtered and solvent removed under reduced
pressure and the residue chromatographed on 100 g of
silica gel using 2:1 ethyl acetate:hexane to afford
0.93 g of the desired N-(2-hydroxy-lR-methylethyl)-
N-methyl(3-thiophenylpropyl)sulphonamide, m/e = 326
(M+Na).
Part B: To a solution of 0.9 g ~2.96 mmol)
of product from Part A and 0.78 g (2.96 mmol) of
triphenylphosphine in 25 ml of anhydrous THF at room
temperature was added 0.47 mL (2.96 mmol) of diethyl
azodicarboxylate, followed by 0.63 mL (8.8 mmol) of
thiolacetic acid. After stirring at room temperature
for 1.5 hour, the reaction was concentrated and the
residue chromatographed on 80 g of silica gel using
3:1 hexane:ethyl acetate to afford 0.85 g of the
desired
N-~2-(S-acetyl)mercapto-lR-methylethyl]-N-methyl(3-
thiophenylpropyl)sulfonamide, m/e = 368 (M+Li).

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-216-
Part C: To a suspension of 0.18 g (0.5
mmol) of product from Part B in 15 mL of anhydrous
methanol, was added 0.25 mL (1.12 mmol) of 25 wt.
sodium methoxide in methanol. After 25 minutes at
room temperature, neutralized with 0.2N hydrochloric
acid, ethyl acetate was added, the organic layer
separated and washed 2x50 ml with water and with
brine and dried over sodium sulfate,filtered and
lC solvent removed under reduced pressure and the
residue chromatographed on 50 g of silica gel using
dichloromethane to afford 72 mg of the desired N-(2-
mercapto-lR-methylethyl)-N-methyl-
(3-thiophenylpropyl)sulfonamide, m/e = 320 (M+H)
Example 51: N-(2-mercapto-lR-methylethyl)-N-benzyl(3-
thiophenylpropyl)sulphonamide.
CH~ ~ o ~S
2C Part A: To a solution of 0.86 g (3 mmol)
of N-(2-hydroxy-lR-methylethyl)(3-thiophenoxypropyl)-
sulphonamide from Example 5 in (25 ml) of anhydrous
DMF, was added 1.24 g (8.9 mmol) of powdered
potassium carbonate and then 0.62 g (3.6 mmol) of
benzyl bromide. The reaction mixture was stirred at
room temperature for 14 hours, ethyl acetate and
water was added, the organic layer separated and
washed with saturated sodium bicarbonate and with
brine, dried with sodium sulfate, filtered and
solvent removed under reduced pressure and the
.

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-217-
residue chromatographed on 100 g of silica gel using
1:2 ethyl acetate:hexane to afford 0.64 g of the
desired N-(2-hydroxy-lR-methylethyl)-N-benzyl)(3-
thiophenylpropyl)sulphonamide, m/e = 380 (M+H).
Part B: To a solution of 0.6g (1.58 mmol)
of product from Part A and 0.42 g (1.6 mmol) of
triphenylphosphine in 15 ml of anhydrous THF at room
temperature was added 0.25 mL (1.6 mmol) of diethyl
azodicarboxylate, followed by 0.34 mL (4.8 mmol) of
thiolacetic acid. After stirring at room temperature
for 1 hour, the reaction was concentrated and the
residue chromatographed on 80 g of silica gel using
2:1 hexane:ethyl acetate to afford 0.465 g of the
desired N-[2-(S-acetyl)mercapto-lR-methylethyl]-N-
benzyl(3-thiophenylpropyl)sulfonamide, m/e =444
(M+Li).
Part C: To a suspension of 0.17 g (0.39
mmol) of product from Part B in 15 mL of anhydrous
methanol, was added 0.2 mL (0.92 mmol) of 25 wt.
sodium methoxide in methanol. After 25 minutes at
room temperature, neutralized with 0.2N hydrochloric
acid, ethyl acetate was added, the organic layer
separated and washed 2x50 ml with water and with
brine and dried over sodium sulfate,filtered and
solvent removed under removed under reduced pressure
to afford 72 mg of the desired N-(2-mercapto-lR-
methylethyl)-N-benzyl(3-thiophenylpropyl)sulfonamide,
m/e = 396 (M+H).
Example 52: N-(2-mercapto-lR-methylethyl)-N-[2-(1-
piperidino)ethyl](3-thiophenylpropyl)sulphonamide.

CA 02260860 1999-01-12
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-218-
HS ~ N ~ ~ S
Part A: To a solution of 1.0 g (3.45 mmol)
of N-(2-hydroxy-lR-methylethyl)(3-thiophenoxypropy)-
sulphonamide from Example 5 in (30 ml) of anhydrous
DMF, was added 2.16 g (15.6 mmol) of powdered
potassium carbonate and then 0.96 g (5.2 mmol) of
methyl iodide. The reaction mixture was stirred at
room temperature for 10 hours, ethyl acetate and
water was added, the organic layer separated and
washed with saturated sodium bicarbonate and with
brine, dried with sodium sulfate, filtered and
solvent removed under reduced pressure and the
residue chromatographed on 100 g of silica gel using
3:1:0.5 mixture of ethyl acetate:hexane:methanol to
afford 0.9 g of the desired
N-(2-hydroxy-lR-methylethyl)-N-[2-(1-
piperidino)ethyl]-(3thiophenylpropyl)sulphonamide,
m/e = 401 (M+H).
Part B: To a solution of 0.83 g (2.07
mmol) of product from Part A and 0.54 g (2.07 mmol)
of triphenylphosphine in 25 ml of anhydrous THF at
room temperature was added 0.33 mL (2.07 mmol) of
diethyl azodicarboxylate, followed by 0.44 mL (6.21
mmol) of thiolacetic acid. After stirring at room
temperature for 1.5 hour, the reaction was
concentrated and the residue chromatographed on 100 g
of silica gel using a 3:1:0.25 mixture of ethyl
acetate:hexane:methanol to afford 0.45 g of the
. .

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-219-
desired N-[2-(S-acetyl)mercapto-lR-methylethyl]-N-~2-
(l-piperidino)ethyl](3-thiophenylpropyl)sulfonamide,
m/e =465 (M+Li).
Part C: To a suspension of 0.225 g (0.5
mmol) of product from Part B in 15 mL of anhydrous
methanol, was added 0.2 mL (0.9 mmol) of 25 wt. ~
sodium methoxide in methanol. After 25 minutes at
room temperature, ethyl acetate and water was added,
the organic layer separated and washed 2x50 ml with
water and with brine and dried over sodium
sulfate,filtered and solvent removed under reduced
pressure and the residue chromatographed on 50 g of
silica gel using dichloromethane to afford 112 mg of
the desired N-(2-mercapto-lR-methylethyl)-N-[2-(1-
piperidino)ethyl](3-thiophenylpropyl)sulfonamide, m/e
= 417 (M+H).
Example 53: Preparation of N-(2-mercapto-lR-
methylethyl)-N-methyl-4-(n-pentyl)benzenesulfonamide.
CH3
HS ~S
CH3 o o
Part A: Preparation of N-(2-hydroxy-lR-
methylethyl)-N-methyl-4-(n-pentyl)benzenesulfonamide.
To a stirred solution of ( 2.85g, 10 mmol) of N-(2-
Hydroxy-lR-methylethyl)-4-(n-
pentyl)benzenesulfonamide from example 6, in 30 mL of
dry dimethylfomamide was added ( 4.05g, 30 mmol) of
powdered potassium carbonate followed by ( 4.23g,
30mmol) of methyl iodide and the suspension stirred
for 16 hours. The contents were concentrated by
rotory evaporation and the residue was partitioned

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-220-
between 200 mL of ethyl acetate and 400 mL of water.
The organic phase was washed with saturated sodium
chloride, dried over magnesium sulfate, filtered and
concentrated to a dark yellow oil. The crude
material was purified by silica gel chromatography
using an eluant of 30 ~ ethyl acetate in hexane to
yield 1.53 grams of a clear oil.
Part B: Preparation of N-(2-thioacetyl-lR-
methylethyl)-N-methyl-4-(n-pentyl~benzenesulfonamide.
To an ice cooled, stirred solution of (1.53g, 5.1
mmol) of N-(2-hydroxy-lR methylethyl)-N-methyl-4-(n-
penty~)benzenesulfonamide and ( 1.46g, 5.6 mmol) of
triphenylphosphine in 20 mL of anhydrous
tetrahydrofuran was added ( 946 mg, 5.6 mmol) of
diethylazodicarbocylate, followed by (425 mg, 5.6
mmol) of thioacetic acid. After stirring for 1.5
hours at room temperature the contents were
concentrated by rotory evaporation and purified by
silica gel chromatography using an eluant of 25~
ethyl acetate in hexanes to yield 1.078 grams of a
clear oil. N-(2-thioacetyl-lR-methylethyl)-N-methyl-
4-(n-pentyl)benzenesulfonamide.
Part C: Preparation of N-(2-mercapto-lR-
methylethyl)-N-methyl-4-(n-pentyl)benzenesulfonamide.
To a stirred solution of ( 1.07g, 3 mmol) of N-(2-
thioacetyl-lR-methylethyl)-N-methyl-4-(n-pentyl)-
benzenesulfonamide in 25 mL of dry methanol was added
4.0 mL of 25~ sodium methoxide in methanol and the
solution stirred for 15 minutes. To the clear
solution was added 50 mL of 1 N hydrochloric acid and
the milky suspension was extracted with 100 mL of
ethyl acetate, dried over magnesium sulfate, filtered
and conc. to yield 700 mg of N-(2-mercapto-lR-

CA 02260860 1999-01-12
W O 98/03166 PCTAUS97/12873 -221-
methylethyl)-N-methyl-4-(n-pentyl)benzenesulfonamide
of purlfied product. m/e=322 (M+Li)
Example 54: Preparation of N-(2-mercapto-lR-
methylethyl)-N-[2-(4-morpholino)ethyl3-4-(n-
pentyl)benzenesulfonamide
o
HS~ ~S
CH3 o o
Part A: Preparation of N-(2-hydroxy-lR-
methylethyl)-N-[2-(4morpholino)ethyl]-4-
(n-pentyl)benzenesulfonamide.
To a stirred solution of ( 2.85g, 10 mmol) of N-(2-
Hydroxy-lR-methylethyl)-4-(n-
pentyl)benzenesulfonamide from example 6, in 30 mL ofdry dimethylformamide was added ( 5.40g, 40mmol) of
powdered potassium carbonate followed by ( 2.23g, 12
mmol) of 4-(2-chloroethyl)-morpholine hydrochloride
and the suspension stirred for 16 hours. Thin layer
chromatography, and H-NMR showed approximately 50
conversion, another 2.23 g of 4-(2-
chloroethyl)morpholine hydrochloride was added and
the reaction mixture stirred another 16 hours. The
contents were concentrated by rotory evaporation and
the residue was partitioned between 200 mL of ethyl
acetate and 400 mL of water. The organic phase was
washed with saturated sodium chloride, dried over
magnesium sulfate, filtered and concentrated to a
yellow oil. The crude material was purified by
silica gel chromatography using an eluant of 30
-

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ethyl acetate in hexane to yield 940 mg of a clear
oil.
Part B: Preparation of N-(2-thioacetyl-
lR-methylethyl)-N-[2-(4-morpholino)ethyl]-4-
(n-pentyl)benzenesulfonamide.
To a stirred, ice cooled solution of ( 940mg, 2.3
mmol) of N-(2-hydroxy-lR-methylethyl)-N-[(4-
morpholino)-ethyl]-4-(n-pentyl)benzenesulfonamide and
(740 mg, 2.8 mmol) of triphenylphosphine in 30 mL of
anhydrous tetrahydrofuran under nitrogen was added
(487 mg, 2.8 mmol) of diethylazodicarboxylate,
followed by (210 mg, 2.8 mmol) of thioacetic acid.
After warming to room temperature over two hours the
solution was concentrated by rotory evaporation and
sub3ected to silica gel column chromatography using
an eluant of 3:1:0.1 hexane:ethyl acetate: methanol
to yield 560 mg of purified product.
Part C: Preparation of N-(2-mercapto-lR-
methylethyl) -N-[2- (4-morpholino)ethyl]-4-'(n-pentyl)-
benzenesulfonamide.
To a stirred solution of ( 560 mg, 1.2 mmol) of N-(2-
thioacetyl-lR-methylethyl)-N[2-(4-morpholino)ethyl]-
4-(n-pentyl)benzenesulfonamide in 25 mL of dry
methanol was added 4.0 mL of 25% sodium methoxide in
methanol and the solution stirred for 15 minutes. To
the clear solution was added 1 N hydrochloric acid
until pH=7 and the milky suspension was extracted
with 100 mL of ethyl acetate, dried over magnesium
sulfate, filtered and conc. to yield 480 mg of N-(2-
thioacetyl-lR-methylethyl)-N[ 2-(4-morpholino)ethyl]-
4-(n-pentyl)benzenesulfonamide of purified product;
m/e=415 (M+H)

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Example 55: Preparation of N-(2-mercapto-lR-
methylethyl)-N-methyl-4-(phenyl)benzenesulfonamide.
I H3 ,~3
HS~ ~S
CH3 o o
Part A: Preparation of N-(2-Hydroxy-lR-
methylethyl)-4-bromo- benzenesulfonamide.
To a ice cooled solution of (5.0g, 60 mmol) of 2(R)-
methyl-ethanolamine in 25 mL of tetrahydrofuran, 10
mL of water , and 8.7 grams of triethylamine was
added ( 15.3 g , 54 mmol) of 4-bromobenzenesulfonyl
chloride slowly over 10 minutes. After stirring for
3 hours at room temperature , the solution was
concentrated by rotory evaporation and the contents
were partitioned between 200 mL of ethyl acetate and
200 mL of water. The organic layer was washed with
100 mL of 5% potassium hydrogen sulfate, followed by
saturated sodium chloride, dried over magnesium
sulfate, filtered and concentrated to yield 17.5
grams of a clear oil. The crude material was
crystallized from ethyl acetate and hexane to~yield
13.45 g of purified material.
Part B: Preparation of N-(2-Hydroxy-lR-
methylethyl)-4-(phenyl)benzenesulfonamide.
To a stirred solution of ( 2.54 g, 8.6 mmol) of N-(2-
Hydroxy-lR-methylethyl)-4-bromo- benzenesulfonamide
in 60 mL of toluene was added 40 mL of ethanol,
followed by (1.15 g, 9.0 mmol) of phenylboronic acid,
25 mL of 2M sodium carbonate, and (l.Og, 0.8mmol) of
tetrakis-(triphenylphosphine)palladium. The
subsequent heterogeneous solution was heated to

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-224-
reflux overnight. The solution was cooled and
extracted with ethyl acetate. The organic layer was
washed with saturated sodium bicarbonate and brine,
dried over magnesium sulfate, filtered and
concentrated to a dark oil, which contained
precipitated catalyst. The crude oil was purified by
silical gel chromatography using ethyl acetate hexane
as the eluant to yield 1.0 g of purified product.
Part C: Preparation of N-(2-Hydroxy-lR-
methylethyl)-N-methyl-4-~phenyl~benzenesulfonamide.
To a solution of (l.Og, 3.4 mmol) of N-~2-Hydroxy-lR-
methylethyl)-4-(phenyl)benzenesulfonamide in 10 mL of
dimethylformamide was added ( 1.35g, lO mmol) of
potassium carbonate and (1.41g, 10 mmol) of methyl
iodide and the suspension was stirred overnight under
nitrogen atmosphere. The contents were concentrated
by rotory evaporation and the residue was
crystallized from ether hexane to yield 535 mg of
purified product.
Part D: Preparation of N-(2-thioacetyl-lR-
methylethyl)-N-methyl-4-(phenyl)benzenesulfonamide.
To an ice cooled solution of (535 mg, 1.8 mmol) of N-
(2-Hydroxy-lR-methylethyl)-N-methyl-4-(phenyl)-
benzenesulfonamide and (524 mg, 2 mmol) of
triphenylphosphine in 15 mL of anhydrous
tetrahydrofuran was added (348 mg, 2 mmol) of
diethyldiazodicarboxylate followed by (152 mg, 2
mmol) of thioacetic acid. The resulting solution was
stirred for 1.5 hours to room temperature and then
concentrated by rotory evaporation to yield a crude
oil which was purified by column chromatography to
yield 328 mg of desired product.
.. ....... . ..

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Part E: Preparation of N-(2-mercapto-lR-
methylethyl)-N-methyl-4-~phenyl)benzenesulfonamide.
To a stirred solution of (328 mg, 0.9mmol) of N-(2-
thioacetyl-lR-methylethyl)-N-methyl-4-
(phenyl)benzene-sulfonamide in 5 mL of dry methanol
was added 1 mL of 25 wt~ sodium methoxide in
methanol. After 10 minutes the solution was diluted
with 10 mL of 1 N hydrochloric acid and extracted
lC with ethyl acetate. The organic layer was dried and
concentrated to yield N-(2-mercapto-lR-methylethyl)-
N-methyl-4-(phenyl)-benzenesulfonamide; m/e= 328
(M+Li)
Example 56: Preparation of N-(2-mercapto-lR,S-
methylethyl)-N-phenylmethyl-4-
methoxybenzenesulfonamide benzenesulfonamide.
~3
OCH3
HS--I~N~
CH3 //\\
Part A: To a stirred solution (lO.Og,36.6
mmol) of N-(4-methoxybenzenesulfonyl)-D,L-alanine
methyl ester in dimethylformamide in 200 mL of was
added (15.17g, 109 mmol) of powdered potassium
carbonate followed by (6.2 g, 36.6 mmol) of benzyl
bromide and the solution stirred for 20 hours. The
- contents were concentrated by rotory evaporation and
the residue was partition between 250 mL of ethyl
acetate and 250 ml of water.e organic layer was
washed with 100 mL 5~ aqueous potassium hydrogen
sulfate, 100 mL of saturated sodium bicarbonate,and
100 mL of saturated sodium chloride, dried over

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magnesium sulfate, filtered and concentrated to an
oil, which was crystallized from ethyl acetate and
hexanes to yield 10.16 g of purified N-phenylmethyl-
N-4-methoxybenzene-sulfonamide-D,L-alanine methyl
ester.
Part B: To an ice cooled, stirred solution
of (8.55g, 23.5mmol) of N-phenylmethyl-N-4-
methoxybenzene-sulfonamide-D,L-alanine methyl ester
~C in 100 mL of anhydrous tetrahydrofuran, under
nitrogen atmosphere was added (23 mL, 23 mmol) of lM
lithium aluminum hydride in diethyl ether and the
solution stirred at 0 C for three hours. The
solution was carefully quenched at 0 C by the
addition of 2 mL of 10~ sodium hydroxide dropwise ,
followed by 2 mL of water. The suspension was
filtered through celite and the filtrate was dried
over magnesium sulfate, filtered and concentrated to
yield 5.67g of crude N-phenylmethyl-N-4-
methoxybenzenesulfonamide-D,L-alaninol which was used
without purification.
Part C: To an ice cooled solution of ( 1.0
g, 3 mmol) of N-phenylmethyl-N-4-
methoxybenzenesulfonamide-D,L-alaninol and ( ~0 mg,
3.3 mmol) of triphenylphosphine in 20 mL of anhydrous
tetrahydrofuran was added (510 mg,3.3 mmol) of
diethyldiazodicarboxylate followed by ( 250 mg, 3.3
mmol) of thioacetic acid and the solution stirred to
room temperature for 2 hours. The contents were
concentrated by rotory evaporation and the crude oil
was subjected to silica gel chromatography to yield
730 mg of N-(2-thioacetyl-lR,S-methylethyl)-N-
phenylmethyl-4-methoxybenzenesulfonamide
benzenesulfonamide.

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Part D: To a stirred solution of ( 730 mg,
1.8 mmol) of N-(2-thioacetyl-lR,S-methylethyl)-N-
phenylmethyl-4-methoxybenzenesulfonamide
benzenesulfonamide in 10 mL of methanol was added 1.5
mL of 25 wt% sodium methoxide in methanol and the
solution stirred for 10 minutes. The contents were
diluted with 20 mL of 1 N hydrochloric acid and
extracted with ethyl acetate. The organic layer was
dried over magnesium sulfate, filtered and
concentrated to yield an oil which was crystallized
form ether/ethyl acetate/hexane to yield 300 mg of N-
(2-mercapto-lR,S-methylethyl)-N-phenylmethyl-4-
methoxybenzenesulfonamide benzenesulfonamide. m/e=358
~M+Li)
Example 57: Preparation of N-(2-mercapto-lR,S-
phenylmethyl)-N-phenylmethyl-4-methoxybenzene-
sulfonamide.
~3
~OCH3
HS~ ~SJ~
~ O O
2C
Part A: To a stirred solution
(2.03g,4.6mmol) of N-(4-methoxybenzenesulfonyl)-D,L-
phenylalanine methyl ester in dimethylformamide in 50
mL of was added (1.8g,13 mmol) of powdered potassium
carbonate followed by (789 mg,4.6 mmol) of benzyl
bromide and the solution stirred for 20 hours. The
contents were concentrated by rotory evaporation and
the residue was partition between 50 mL of ethyl
acetate and 50 ml of water.e organic layer was washed

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with 100 mL 5~ aqueous potassium hydrogen sulfate,
100 mL of saturated sodium bicarbonate,and 100 mL of
saturated sodium chloride, dried over magnesium
sulfate, filtered and concentrated to an oil, which
was crystallized from ethyl acetate and hexanes to
yield 1.55 g of purified N-phenylmethyl-N-4-
methoxybenzenesulfonamide-D,L-phenylalanine methyl
ester.
Part B: To an ice cooled, stirred solution
of (l.55g~3.5mmol ) of N-phenylmethyl-N-4-
methoxybenzene-sulfonamide-D,L-phenylalanine methyl
ester in 50 mL of anhydrous tetrahydrofuran, under
nitrogen atmosphere was added (4.2mL) of lM lithium
aluminum hydride in diethyl ether and the solution
stirred at O C for three hours. The solution was
carefully quenched at O C by the addition of 2 mL of
10~ sodium hydroxide dropwise , followed by 2 mL of
water. The suspension was filtered through celite
and the filtrate was dried over magnesium sulfate,
filtered and concentrated to yield 1.40 g of crude N-
phenylmethyl-N-4-methoxy-benzenesulfonamide-D,L-
phenylalaninol which was used without purification.
Part C: To an ice cooled solution of (
1.24g, 3.Ommol) of N-phenylmethyl-N-4-methoxybenzene-
sulfonamide-D,L-phenylalaninol and ( 949mg, 3.6 mmol)
of triphenylphosphine in 20 mL of anhydrous
tetrahydrofuran was added (630 mg, 3.6 mmol) of
diethyldiazodicarboxylate followed by ( 275mg, 3.6
mmol) of thioacetic acid and the solution stirred to
room temperature for 2 hours. The contents were
concentrated by rotory evaporation and the crude oil
was subjected to silica gel chromatography to yield
1.10 mg of N-(2-thioacetyl-lR~s-phenylmethyl)-N
phenylmethyl-4-methoxybenzenesulfonamide
benzenesulfonamide.

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Part D: To a stirred solution of ( 1.10 g,
2.3 mmol) of N-(2- thioacetyl-lR~s-phenylmethyl)-N
phenylmethyl-4-methoxybenzenesulfonamide
benzenesulfonamide in 10 mL of methanol was added 2.0
mL of 25 wt~ sodium methoxide in methanol and the
solution stirred for 10 minutes. The contents were
diluted with 20 mL of 1 N hydrochloric acid and
extracted with ethyl acetate. The organic layer was
dried over magnesium sulfate, filtered and
concentrated to yield an oil which was crystallized
form ether/ethyl acetate/hexane to yield 521 mg of N-
(2-mercapto-lR,S-phenylmethyl~-N-phenylmethyl-4-
methoxybenzene-sulfonamide; m/e=4 3 4 (M+Li~
Example 58: Preparation of N-N'-Bis-(4-
methoxybenzenesulfonyl)-L-cystine.
o O ~ ~OCH3
~ S ' N\r- S ~ S~/~xN ~ S
H3CO \~J H3CO O
To an ice cooled suspension of (3.41g, 10
mmol) of L-cystine methyl ester hydrochloride in
tetrahydrofuran was added 50 mL of saturated sodium
bicarbonate followed by (4.12g,20 mmol) of 4-
methoxybenzenesulfonyl chloride in 20 mL oftetrahydrofuran and the suspension stirred to room
temperature overnight. The contents were acidified
with lN hydrochloric acid and extracted with ethyl
acetate to yield 4.13 grams of product. m/e=615
(M+Li)
-
Example 59: Preparation of N-N'-Bis-(4-
methoxybenzenesulfonyl)-N,N'-dimethyl-L-cystine.
.

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O ~ H3 CH3 ~ ~ OCH3
H3CO ~ H3CO O
To a stirred solution of (1.3g,2.1 mmol) of
c N-N'-Bis-(4-methoxybenzenesulfonyl)-L-cystine in
dimethylformamide was added ( 635 mg, 4.6 mmol) of
potassium carbonate followed by ( 655mg, 4.6 mmol) of
methyl iodide and the suspension stirred overnight.
The contents were concentrated by rotory evaporation
lQ and the residue subjected to silica gel
chromatography to yield 890 mg of N-N'-Bis-(4-
mthoxybenzenesulfonyl)-N,N'-dimethyl-L-cystine as an
oil. m/e=643 (M+Li)
Example 60: 2R-(N-Fluorenylmethyloxycarbonyl)amino-
propanethiol
H
H3 0 ~
Part A: Preparation of 2R-(N-
Fluorenylmethyloxy-car~onyl)aminopropanol
To a stirred solution of (750mg, lOmmol ) of 2-R-
amino propanol in 15 mL dioxane containing 27 mL of
10~ aqueous potassium carbonate was added (2.58g,10
mmol~ of fluorenylmethyl chloroformate and the
solution was stirred vigorously for several hours.The
contents were diluted with ethyl acetate and the
organic layer was washed with lN hydrochloric acid,
. , ~ . . . . ..

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dried over magnesium sulfate, filtered and
concentrated to yield 2.97g of crude product which
was crystallized from ethyl acetate/ hexanes to yield
2.61g of purified 2R-(N-
fluorenylmethyloxycarbonyl)aminopropanol.
Part B: Preparation of 2R-(N-
Fluorenylmethyloxy-carbonyl)- aminopropanethiol-S-
acetate
1.0
To a ice cooled stirred solution of (13.9g,47 mmol)
of 2R-(N-fluorenylmethyloxycarbonyl)- aminopropanol
in 200 mL of anhydrous tetrahydrofuran was added
~13.5g,51mmol) of triphenylphosphine, followed by
(8.99g,51 mmol) of diethylazodicarboxylate, and the
(3.92g,51 mmol) of thioacetic acid and the reaction
stirred overnight to room temperature. The contents
were concentrated by rotory evaporation and the
residue was chromatographed on silica gel using ethyl
acetate / hexane as the eluant. The desired product
was crystallized to afford 7.8g of purified 2R-(N-
fluorenylmethyloxycarbonyl)- aminopropanethiol-S-
acetate.
Part C: Preparation of 2R-(N-
Fluorenylmethyloxy-carbonyl)- aminopropanethiol.
To an ice cooled, stirred solution of (355mg,1.Ommol)
of 2R-(N-fluorenylmethyloxycarbonyl)-
aminopropanethiol-S-acetate in 10 mL of anhydrous
methanol was added 1.2 equivalents of 25~ sodium
hydroxide in methanol and the solution stirred for 30
minutes. The reaction mixture was diluted with lN
hydrochloric acid and concentrated. _ The residue was
partitioned between ethyl acetate and water, and the
organic layer was dried over magnesium sulfate,

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filtered and concentrated to yield 300 mg of
mercaptan.
Example 61: Preparation of 2R-~N-Fluorenylmethyl-
carbamoyl)amino-propanethiol -conjugated-
chlorotrityl-polystyrene resin with l or 2~ cross-
linking
A solution of 5~ trifluorocacetic acid
(4Oml) in methylene chloride was added to dry 2-
chlorotrityl-chloride resin (5.84g, 7 mmoles) and
swirled. To this thick slurry was immediately added
14 mmoles (4.4 g) of ~-Fmoc-1-methyl-ethyl-2-
mercaptan. The suspension was swirled periodically
and incubated at RT under nitrogen for l hour. Nine
volumes methylene chloride were added and incubation
continued 30 minutes. Non-bound compound was then
removed by vacuum filtration through a centered glass
disk funnel and reserved for drying and quantitation.
The resin was washed with 300 mls methanol to cap any
unreacted sites, followed by 4 dimethylformamide
washes, 4 methylene chloride washes and 2-additional
methanol washes. The recovered resin was then dried
to constant weight under vacuum and loading was
~uanitated by l) mass balance 2) Fmoc release and/or
3) elemental analysis. Using this protocol, the
desired compound was loaded on approximately 92~ of
the available sites, as determined by resin
manufacturer's data sheet.
Dried resin was washed with methylene
chloride (about 250 mls) followed by
dimethylformamide (about 250 mls) and the Fmoc
protecting group was removed by incubation in a
solution of 20~ piperidine in dimethylformamide for
30-60 minutes. The resin was washed with
dimethylformamide, methanol, dimethylformamide. This
~ ... . .

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procedure was repeated one additional cycle. The
final wash included a methylene chloride wash
followed by methanol. The resin was dried to constant
weight and stored at 4 degrees. Prior to any
additional chemistry, the resin was always washed
with methylene chloride to ensure good swelling,
followed by the solvent of choice for the desired
protocol.
Alternatively, instead of loading the resin
with two equivalents of mercaptan for each equivalent
of resin sites, only 0.9 equivalents of available
(monomeric) compound was added. This resulted in
loading approximately 90-95~ of the target compound,
and the excess sites were capped as above. This
loading procedure had the advantage that less initial
compound had to be synthesized.
Example 62. Preparation of N-(2-mercapto-lR
methylethyl)-4-methoxybenzenesulfonamide.
To a slurry of 0.12g ~0.14 mmoles) deprotected resin
(Example 1) in 6ml 50~ pyridine: CH2C12 under
nitrogen was added 0.152g (0.74 mmoles) 4-
methoxybenzene-sulfonylchloride. The reaction ~as
agitated at room temperature for 20 hr. The resin was
then filtered and washed four times with 100 ml
dimethylformamide and four times with 100 ml CH2C12 .
The resin was treated with 80~ trifluoroacetic acid
in CH2Cl2 for 1 hour. It was then filtered and the
eluant stripped. The residue was extracted with
ethyl acetate, washed with lN HCl and dried with
Na2S04. The extract was stripped to dryness to afford
20 mg of the desired N-(2-mercapto-lR methylethyl)-4-
methoxybenzenesulfonamide.

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Example 63-90: By procedures analogous to Example
62, the following compounds were prepared:
Example 63: N-(2-mercapto-lR-methylethyl)-4-
fluorobenzenesulfonamide; m/e=256.3 (M+Li)
Example 64: N-(2-mercapto-lR-methylethyl)-4-
chlorobenzenesulfonamide; m/e=272.7 (M+Li)
Example 65: N-(2-mercapto-lR-methylethyl)-4-
bromobenzenesulfonamide; m/e=317.2 (M+Li)
Example 66: N-(2-mercapto-lR-methylethyl)-4-
iodobenzenesulfonamide; m/e=364.2 (M+Li)
Example 67: N-(2-mercapto-lR-methylethyl)-4
ethylbenzenesulfonamide; m/e=266.4 (M+Li)
Example 68: N-(2-mercapto-lR-methylethyl)-4-
methylbenzenesulfonamide; m/e=254.4 (M+Li)
Example 69: N-(2-mercapto-lR-methylethyl)-4-
(n-butyl)benzenesulfonamide; m/e=292.4 (M+Li)
Example 70: N-(2-mercapto-lR-methylethyl)-a-
~n-propyl)benzenesulfonamide; m/e=280.4 (M+Li)
Example 71: N-(2-mercapto-lR-methylethyl)-4-
n-pentyl)benzenesulfonamide; m/e=334.4 (M+Li)
Example 72: N-(2-mercapto-lR-methylethyl)-4-
isopropylbenzenesulfonamide; m/e=280.4 (M+Li)
Example 73: N-(2-mercapto-lR-methylethyl)-4-
(trifluoromethyl)-benzenesulfonamide; m/e=306.3
(M+Li)

CA 02260860 1999-01-12
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Example 74: N-( 2 -mercapto-lR-methylethyl)-4-(t-
butyl)benzenesulfonamide; m/e=294.4 (M+Li)
Example 75: N-(2 -mercapto-lR-methylethyl)-4-
5 (trifluoromethoxy)-benzenesulfonamide; m/e=322.3
(M+Li)
Example 76: N- (2-mercapto-lR-methylethyl)-4-
cyanobenzenesulfonamide; m/e=263.3 (M+Li)
1~
Example 77: N-( 2-mercapto-lR-methylethyl)-2-
(trifluoromethyoxy)-benzenesulfonamide; m/e=322.3
(M+Li)
Example 7 8: N-( 2-mercapto-lR-methylethyl)-2~4-
bis(trifluoromethyoxy)-benzenesulfonamide; m/e=434.4
(M+Li)
Example 79: N- (2-mercapto-lR-methylethyl)-2,4,6-
trimethyl-benzenesulfonamide; m/e=280.4 (M+Li)
Example 80: N-( 2-mercapto-lR-methylethyl)-2,4,6-
triisopropyl-benzenesulfonamide; m/e= 364. 6 (M+Li)
2c Example 81: N-( 2-mercapto-lR-methylethyl)-3,4-
difluoro-benzenesulfonamide; m/e=274.3 (M+Li)
Example 82: N-( 2-mercapto-lR-methylethyl)-
benzenesulfonamide.
Example 8 3: N-( 2-mercapto-lR-methylethyl)-2-
napthylenesulfonamide; m/e=288.4 (M+Li)
Example 84: N-( 2-mercapto-lR-methylethyl)-4-N-
acetylsulfanilamide; m/e=295.4 (M+Li)

CA 02260860 1999-01-12
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-236-
Example 85: N-(2-mercapto-lR-methylethyl)-5-bromo-2-
thiophenesulfonamide; m/e=323.3 (M+Li)
Example 86: N-(2-mercapto-lR-methylethyl)-5-chloro-
2-thiophenesulfonamide;
Example 87: N-(2-mercapto-lR-methylethyl)-3,5-
dibromo-2-thiophenesulfonamide; m/e=403.3 (M+Li)
Example 88: N-~2-mercapto-lR-methylethyl)-5-
(isoxazol-3-yl)-2-thiophenesulfonamide; m/e=311.4
(M+Li)
Example 89: N-(2-mercapto-lR-methylethyl)-4-
phenylazobenzenesulfonamide; m/e=342.4 (M+Li)
Example 90: N-(2-mercapto-lR-methylethyl)-2-
dibenzofuransulfonamide; m/e=328.4 (M+Li)
Example 91: Preparation of N-(2-mercapto-lR-
methylethyl)-N-[2-(4-morpholino)ethyl]-4-
(thiophenyl)benzenesulfonamide hydrochloride.
N~ HCI
N~
CH3 o/A\
Part A: To a solution of 8.38 g (35.9
mmol) of N-(2-hydroxy-lR-methylethyl)-4-
fluorobenzene-sulfonamide from Example 40, part A, in
70 mL of anhydrous DMF, was added 15.38 g (111 mmol)
of powdered potassium carbonate, and then 5.2 mL
(5.54 g, 50.3 mmol) of thiophenol. The reaction

CA 02260860 1999-01-12
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-237-
mixture was heated to 70 C for 15 hours, cooled and
ethyl acetate and water added. The organic layer was
separated and washed 3xs with brine, dried with
sodium sulfate, filtered and stripped to afford crude
material. This was chromatographed on a Waters Prep
2000 chromatograph over silica gel using 40%-60%
ethyl acetate/hexane to provide 9.0 g of pure N-(2-
hydroxy-lR-methylethyl)-4-
(thiophenyl)benzenesulfonamide, m/e=330 (M+Li).
Part B: To a solution of 3.0 g (9.3 mmol)
of N-(2-hydroxy-lR-methylethyl)-4-
(thiophenyl)benzene-sulfonamide from part A, in 18 mL
of anhydrous DMF, was added 3.85 g (27.8 mmol) of
powdered potassium carbonate, and then 2.42 g (13
mmol) of 4-(2-chloroethyl)morpholine hydrochloride.
The reaction mixture was stirred for 15 hours, ethyl
acetate and water added. The organic layer was
separated and washed 3xs with brine, dried with
sodium sulfate, filtered and stripped to afford 4.7 g
of crude material. This was chromatographed on a
Waters Prep 2000 chromatogram over silica gel using
50~-100% ethyl acetate/hexane, then 5~ methanol/ethyl
acetate, to provide 3.8 g of pure N-(2-hydroxy-lR-
methylethyl)-N-[2-(4-morpholino)ethyl]-4-
(thiophenyl)benzene-sulfonamide, m/e=437 (M+H).
Part C: To a solution of 3.4 g (7.8 mmol)
of product from Part B and 2.25 g (8.6 mmol) of
triphenylphosphine in 30 mL of anhydrous THF at 0~C,
was added 1.4 mL (8.6 mmol) of
diethylazodicarboxylate, followed after 5 min. by
0.62 mL (8.6 mmol) of thiolacetic acid. After 1
hour, the reaction was concentrated and the residue
was chromatographed on silica gel using 20%-80% ethyl
acetate/hexane to yield 1.4 g of the desired product,
m/e = 495 (M+H).

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Part D: To a solution of 1.4 g (2.83 mmol)
of product from Part C in 10 mL of anhydrous
methanol, was added 2.3 mL (10.2 mmol) of a 25 weight
~ solution of sodium methoxide in methanol. After
0.5 hour, the reaction was quenched the the addition
of dry ice, followed by ethyl acetate and water, the
organic layer was separated and washed with brine,
dried with magnesium sulfate, filtered and
concentrated to afford the crude product. This was
chromatographed on 75 g of silica gel using 50~ ethyl
acetate/hexane to provide 0.86 g of pure N-(2-
mercapto-lR-methylethyl)-N-[2-(4-morpholino)ethyl]-4-
(thiophenyl)benzenesulfonamide, m/e= 453 (M+H).
Part D: To a solution of 0.66 g (1.45
mmol) of the product of Part C in 10 mL of
acetonitrile was added 0.24 ml (2.88 mmol) of 12N
aqueous hydrochloric acid. After 10 minutes, the
solvent was removed in vacuo, acetonitrile added and
removed 3xs to afford 0.66 g of the desired N-(2-
mercapto-lR-methylethyl)-N-[2-(4-morpholino)ethyl]-4-
(thiophenyl)benzene-sulfonamide hydrochloride,
m/e=453 (M+H).
Example 92: Preparation of N-(2-mercapto-lR-
methylethyl)-N-[2-(1-piperidino)ethyl]-4-
(thiophenyl)benzenesulfonamide hydrochloride.
~ HCI
HS~N~
CH3 ol/\\

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-2 3 9 -
Part A: To a solution of 4.62 g (14.2 mmol~
of N-(2-hydroxy-lR-methylethyl)-4-
(thiophenyl)benzene-sulfonamide from example 91 part
A in 28 mL of anhydrous DMF, was added 5.92 g (42.8
mmol) of powdered potassium carbonate, and then 3.94
g (21.4 mmol) of 1-(2-chloroethyl)piperidine
hydrochloride. The reaction mixture was stirred for
17 hours at 50 C, then cooled and ethyl acetate and
water added. The organic layer was separated and
lC washed 3xs with brine, dried with sodium sulfate,
filtered and stripped to afford crude material. This
was chromatographed on 300g of silica gel using 100
tetrahydrofuran to provide 4.3 g of pure N-(2-
hydroxy-lR-methylethyl)-N-[2-(1-piperidinyl)-ethyl~-
4-(thiophenyl)benzenesulfonamide, m/e=435 (M+H).
Part B: To a solution of 3.7 g (8.5 mmol)
of product from Part A and 2.45 g (9.3 mmol) of
triphenylphosphine in 33 mL of anhydrous TH~ at 0~C,
was added 1.47 mL (9.3 mmol) of diethylazo-
dicarboxylate, followed after S min. by 0.67 mL (9.3
mmol) of thiolacetic acid. After 1 hour, the
reaction was concentrated and the residue was
chromatographed on basic alumina using 10%-50~ ethyl
acetate(5~methanol)/hexane to yield 2.3 g of the
desired product, m/e = 493 (M+H).
Part ~: To a solution of 2.3 g (G.67 mmol)
of product from Part B in 10 mL of anhydrous
methanol, was added 3.8 mL (16.8 mmol) of a 25 weight
solution of sodium methoxide in methanol. After
0.5 hour, the reaction was quenched the the addition
of dry ice, followed by ethyl acetate and water, the
organic layer was separated and washed with brine,
dried with magnesium sulfate, filtered and
concentrated to afford the crude product. This was
chromatographed on 150 g of silica gel using 50~

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-24~-
eth~.~ aceta~e(5~ methanol)/~ethylene chloride to
provide 1. 5 a of pure N-(2-mercapto-lR-mechylethyl)-
2 (1-plperidino)-ethyl]-4-
(~hi oDhen~l/ benzenesulfonamide, m/e= 451 (M+H).
',
Par_ D: To a solution of l.lg (2.44 mmol)
of Ihe product of Part C in 15 mL of acetonitrile was
added 0.~-10 ml (4.88 mmol) of 12N aqueous hydrochloric
acid. After 10 minutes, the solvent was removed in
vac~o, acetonitrile added and removed 3xs to afford
1.12 g of the desired N-(2-mercapto-lR-methylethyl)
N-~2-(1-piperidino)ethyl]-4-
(thiophellyl)~enzenesulfonamide hydrochloride, m/e=451
(M+~.).
ExamDle 93: Preparation of N-( 4-butoxyphenyl)-L-
cystei~e-N~i2.
Part A:
OMe OMe
MoO~ MeO~ O H
~Fmoc ~[~NJ~ Fmoc
Fmoc-L-Cys(Tr~)-Rink resin. Rink resin (0.88 g, 0.44
mmoles) was reacted with 5 mL of:4 piperidine/DMF for
30 mi~ llen w~slled with DMF (3 x 5 mL), MeOH (3 x 5
mL), and C~2C12 (3 x 5 mL). In a sep~rate 'lask,
Fmoc-L-C~Ys'mrt)OH (0.77 g, 1.3 mmol) in 5 mL
3~ anhydrou~ dimethylacetamide (DMA) was ~eacted with
diisopropvlcarbodiimide (0.21 mL, 1.3 mmol) and N-
. .

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-241-
hydroxysuc~in~mide (0.15 g, 1.3 mmol) for '5 min a.
rt. Then, this solution was added to the ~'ask
con~ainin~ Rink resin from above. The reac-ion
slurry was agitated using a tabletop shaker overnigh~
(16 h). The resin was then drained, washed with DMF
(3 x 5 mL), MeOH (3 x 5 mL), CH2Cl2 (3 x 5 mL), and
Et2O (3 Y ~ mL), and dried in vacuo tc yield 1.09 g
of tan polymeric solid. Theoretical loadins of
polymer = 0.43 mmol/g.
Part B: N-(4-Butoxyphenyl)sulfonyl-L-
Cys(Trt)-Rink resin. Fmoc-L-Cys(Trt)-Rink resin from
above (50 mg, 0.022 mmol) was reacted with 1 mL of :4
piperidine/DMF for 30 min, then washed wit~ DMF (3 x
1 mL), MeOH (3 x 1 mL), and CH2Cl2 (3 x 1 mL). Then,
0.5 mL of anhydrous CH2Cl2 was added to the resin
followed by 27 mg o, 4-butoxyphenylsulfonyl chloriae
(0.11 mmol), and the reaction slurry was shaken
overnight at r', (20 h). The resin was then drained,
washed with CH2Cl2 (3 x 1 mL), MeOH (3 x 1 mL),
CH2Cl2 (3 .~ l mL), and Et2O (3 x 1 mL), and dried in
vacuo to yield 105 mg brown polymeric solid.
Part C:
OMe ~
~ t,
N(4-Buto~Yyphenyl)sulfonyl-L-Cys-NH2. N-(4-
Butoxvphellyl~-- Sulfonyl-L-Cys(Tr,)-Rinl~ res ~..rom

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above was reacted with 1 mL of a 5:5:95 solution of
TFA/triethylsilane/CH2Cl2 at rt for one hour. The
resin was drained and washed with CH2Cl2 ~3 x 1 mL).
The resin was subsequently reacted with 0.5 mL of a
80:5:15 solution of TFA/triethylsilane/CH2Cl2 at rt
for one hour. The resin was drained, and the
filtrate collected. The resin was further washed
with 1:1 TFA/CH2Cl2 (3 x 0.5 mL) and CH2Cl2 (3 x 0.5
mL), again collecting the filtrates. The combined
filtrates were concentrated to yield 6.7 mg white
solid ~92~ crude yield). MS (FA~3) 333.2 (M+H).
Using procedures analogous to those used in Example
93, Examples 94, 95 and 96 were prepared.
Example 94: N-(4-methoxyphenyl)sulfonyl-L-cysteine-
NH2 .
Example 95: N-(4-iodophenyl)sulfonyl-L-cysteine-NH2.
Example 96:
N-[4-(n-pentyl)-phenyl]sulfonyl-L-cysteine-NH2.
Compounds of Example 97 to Example 223, tabulated
below, were prepared by the procedures presented
above. Exemplary additional specific syntheses are
also provided thereafter.

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EXAMPLE TABLE I
OH
HS --O' S" ~=~ o~ oG S"~3_ S
97 O CH3 103 b
~0 CH2cF3
S~ N' ~3 O~CH3~ "--b CH2CF3
H
HS~N~ ~3O~CH3 o'S"~3 C16H~3
99 1 05
H O--CH3
HS~ N~ ~ ~' CH HS~ N~ ~ C4Hg
100 r 106 o
HS ~ocS~ b ~ ~
107
H H
H C(C=0)5 ~ N' S~--5108 ~ CN

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EXAMPLE TABLE ll
~H NO2 0
HS~o_S~o~CH3 ~N~
109
~H HS~ 's~o
~N ~3 1'4 0
110 N
HN3 3 oeSIl~ b
; o=S,~3 CH3 0 \~
O~
o t-Bu
_ O ,l~o 3C(C O)S . ~551~3 b
~ O~ ~ ) \~ O
~ ~HCI
- ~ '~~ b 117 ~
O H

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EXAMPLETABLEIII
J ~HCI
r H3C H3~
oss~ b o~s~
118 122
O H HS~ N~ ~;~OCH3
HN3 123
o:: S~1~3 CH3 oc: 5~ OCH3
- 2 124
119
HN/~\N HN3 H3 l CF3
~N~ o~sl~q _ o l-lSI~
HN 120 ~o~
6~ 1 oS S~
b
121

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EXAMPLE TABLE IV
o
2 ~ ~ OCH(CH 3)2 ~o~ S"~ OCH3
o 126 130
N) N~
~HCI
; o=S~I~3n-csHl1 O .S,,~oCH3
~27 131
0
~_3~-8CsH" ¢~ ~ ~ 5,~}
N~ ~ N)
~HCI ~ ~HCI
,~o ~ n-CsH~ S~ N
..

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-247-
EXAMPLE TABLE \/
R2
'~SI~S
-~ b
EXAMPLEZ R2
fQ
134 >l~ ~N~J
135 G3? ~--N ~J
136 1~ ~J~
37I ~u~ o~ll~ NH N~O
OJ~ NH~ ~ N~
~O
H2N ~ ~ N~J
o ~ 2 HCI
140H2N~ ~ N~)
O ~ 2 HCI

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EXAMPLE TABLE Vl
Z's . oN'9~;~S
EXAMPLE Z R2
141 0 J~o--t-Bu
14~ ?
1~4 ~ I
/ N~ ~ HCI
145 ? --~

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-24 9-
EXAMPLE TABLE Vll
H' S ~,S~,
~ R4 ~ ~
EXAMPLE R 1 R2 R4
146 ~ NHbJ~¦ H CH 3
147 ~ S(O)2CH3 H CH 3
148 ~ CF3 H CH 3
CF3
149 ~ H CH 3
CH3
150 ~N H CH3
SCH3
151 ~ H CH3
152 ~3 :~r H CH 3
153 ~3 N~HDJ~CI H CH 3

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-250-
EXAMPLE TABLE Vll
R2
H' S ~S~
R4 ~ ~
E)(AMPLE R 1 R2 R4
146 ~3 NH~ H CH
147 ~ S~O).,CH3 H CH
148 ~ CF3 H CH 3
149 ~CF3 H CH3
N-- 'CH
150 ~N H CH 3
SCH3
151 ~r H CH 3
152 ~s Cl H CH3
153 ~3 NHbJ~ Cl H CH 3

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-251-
EXAMPLE TABLE Vlll
R2
H'S ~ ,~S~,
R4 ~ ~
EXAMPLE R 1 R2 R4
154 l~ H CH3
~,CF3 H CH 3
156 ~ CH3 CH3

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EXAMPLE TABLE IX
H~S~N~ R1
"S~
EXAMPLE R1 R2 R4
160 {~ O-n-C4Hg a OH
o
161 ~ O-n-C4Hg-(CH2)2CH(CH3)2 ~ NH2
162 ~ O-n-C4Hg ~ NH--O
163 {~O-n-C4Hg -CH3 ~~ NH2
16d {~ O-n-C4Hg-(CH2)C(C=O)OH a NH2
165 ~ O-n-C4HgN~HCI a NH2
~ O
166 ~ O-n-C4Hg NH

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-253-
EXAMPLE TABLE X
~ 5 - "S~
R4 ~ ~
EXAMPLE R1 R2 R4
167 ~O-n-C4Hg ~J~N NH2
168 ~O-n-C4Hg ~J~ HCI2
16g ~0~ ~ N~) l~~ NH2
~ ~ ~ N~) a NH
171 {~O-n-C4Hg H NHCH3
172 ~O-n-C4Hg NH~
173 ~O-n-C4Hg NH--~J
~HCI

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-254-
EXAMPLE TAE~LE Xl
H~ ~ N~ R
R4 ~ ~
EXAMPLE R1 R2 R4
174 ~ O-n-C4Hg J~N NH2
175 ~O-n-C4Hg ~J~ NH2
176 ~O-n-C4Hg N~O NHCH3
177 ~O-n-C4H9 ~N~) NH~
178 ~O-n-C4Hg H a N(cH~2
179 ~O-n-C4Hg NH ~
180 ~O-n-C4Hg H ~ H~NHCH3

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-255-
E)(AMPLE TABLE Xll
9S~
R4 ~ ~
EXAMPLE R1 R2 R4
~ o
181~O-n-C4Hs OH
182~ O-n-C4Hg ~J~ 1~~
183~ O-n-C4Hg N~J HCI a NHCH3
184~ o-n-C4Hg ~ N~JO ~
fo o
185~ O-n-C4Hg ~ N~J NH--
~HCI o
186~ o-n-C4Hg

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-256-
EXAMPLE TABLE Xlll
Rl2
H~ S~' N~,S~ R
R4 O O
EXAMPLE R 1 R2 R4
187 ~O-n-C4Hg H ~OH
Rl2
H~S N~,S~R
R4 ~ ~
EXAMPLE R1 R2 R4
188 ~ H CH3
189 --Q H CH3
Br
H CH3
9' {~Br H CH3
Br

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EXAMPLE TABLE XIV
s~N~,
,S~
R4 O o
EXAMPLE R1 R2 R4
192 ~ No2 H CH 3
~ \
193 ~ H CH 3
o
194 ~F H ~ NH2
H3C
1g5 23 Br H CH 3
196 ~ H CH3
F3C
197{~ OCH3 H ll
H3CO ~
198 ~ H CH 3

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EXAMPLE TABLE XV
S ~ ~ , R
~S~
R4 O o
EXAMPLE R 1 R2 R4
A
9~ ~ NH~ H
O NH2
20C ~S\ / ~ 1~~ NH2
201 ~O-n-Bu H 1~ NH
202 ~S~ ~HCI
~ o
203 ~ N~ CH 3 NH~
F3CO
204 ~3 Br H CH 3

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-259-
EXAMPLE TABLE XVI
.. R2
H S~ N~ S'
R4 ~ ~
EXAMPLE Rl R2 R4
206 ~ H CH3
n-Bu-O
207 ~G< H CH3
208 ~O-n-Bu -(CH2)2CH(CH3)2 ~ NH2
209 ~ O-n-Bu H NH--13
210 ~ O-n-Bu H
21~ ~o-n-CsH11 \~' N CH3
212 CI~CI H CH3

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-260-
EXAMPLE TABLE XVII
, N~
~, N~N,I~i
_ o_ S"~ O~ _ o "
213 -- 2 217
HS~ '~~N-CH~
H3C~N,CH3 H2N~o ~
J 218
S , o~
~ ~ _ ~ .
N ~HCI H2N ~o ~
_ ~5,, 219
H2N~o ~
216

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-261-
EXAMPLE TABLE XVIII
Cl ~HCI Br
~NH~ NH~
- o~S~J H'S~ ~S ~ ~
H2N~o ~ H2N~o
220 223
~HCI Cl
~ ~ J ~
H2N o
Z21
~ ~3, Br
H2N ~o ~
222
Example 126: N-(4-(4'-isopropoxyphenyljbenzene-
sulfonyl-N-(4-(morpholinoethyl))- L-cysteine amide.
Was prepared in a manner similar to Example 131, by
substitution of the sulfonyl chloride to 4-(4-
isopropoxyphenyl)phenylsulfonyl chloride prepared in
an analogous manner. Mass spec. m/z= 508.7 (M+H)

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Example 131: Preparation of N-(4-(4'methoxy henyl)-
benzenesulfonyl-N-(4-(morpholinoethyl))- L-cysteine
amide .
O ,0
N ~
~ N ~ OCH3
Part A: To a solution of 12.4 grams(5.0
mmol) of 4-(4'-bromophenyl)phenol in 50 mL of
dimethylformamide was added 10.1 grams of potassium
lC carbonate followed by 10.51 grams of iodomethane and
this stirred at room temperature for 48 hours. The
solution was diluted with 400 mL of water and
extracted with ethyl acetate. The organics were
dried over magnesium sulfate filtered and
concentrated to yield 14.1 grams of crude product.
Purification by recrystallization from ethyl acetate
hexane gave 8.2 grams of 4-(4'-bromophenyl)anisole as
a white crystalline solid.
Part B: 5.2 grams(20 mmol) of 4-(4'-
bromophenyl)-anisole was dissolved in 100 mL of
anhydrous tetrahydrofuran and placed under nitrogen
to cool to -78C. to this flask was added 8.0 mL of
2.5 molar butyl lithium over 10 minutes. In an
adjacent flask was added 100 mL of anhydrous
tetrahydrofuran which was cooled to -60C and a stream
of sulfur dioxide was added through a dispersion tube
while the system is under nitrogen atmosphere. After
the addition of approximately 10 mL of li~uid sulfur
dioxide the dispersion tube was removed and the cold

CA 02260860 1999-01-12
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-263- -
sulfur dioxide solution was transferred by a cannula
to the stirred aryl lithium solution over five
minutes. After one hour at -70C the contents were
warmed to room temperature and the solution ws
concentrated to dryness to yield a crude lithium
sulfinate. The crude lithium 4-(4'-
methoxyphenyl)phenylsulfinic acid was slurried in 100
mL of dry hexanes under nitrogen atmosphere and
cooled to OC. To this cooled suspension was added
2.45 grams(18.1 mmol) of sulfuryl chloride and the
suspension was allowed to warm to room temperature.
The contents were concentrated by rotory evaporation
to yield 5.1 grams of crude 4-(4'-methoxy-
phenyl)phenyl-sulfonyl chloride which ws purified by
recrystalli-zation from chloroform.
Part C: To a solution of 2.93 grams(8.1
mmol) of S-trityl-L-cysteine amide in 50 mL of dry
methylene chloride was added 2 equivalents of
triethylamine followed by 2.29 grams(8.1mmol) of 4-
(4'-methoxyphenyl)phenylsulfonyl chloride. The
solution was stirred at room temperature for one
hour, then concentrated on a rotory evaporator. The
resulting slurry was partitioned between ethyl
acetate and water. The organics were washed with 5
potassium hydrogen sulfate, saturated sodium
bicarbonate, and brine, dried over sodium sulfate,
filtered and concentrated to give 4.2grams of crude
product. The crude material was purified by silica
gel chromatography using 1:1 ethyl acetate : hexane
as the eluent to yield 3.36grams of pure N-(4-
(4'methoxyphenyl)-benzenesulfonyl- S-trityl-L-
cysteine amide as a white solid.
.,
Part D: To 3.36 gramst5.5mmol) of N-(4-
(4'methoxy-phenyl)-benzenesulfonyl- S-trityl-L-
cysteine amide in 12 mL of dry dimethylformamide was

CA 02260860 1999-01-12
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-264-
added 1.50 grams(8.3 mmol) of 4-( 2-
chloroethylmorpholine) hydrochloride followed by 2. 5
grams(17. mmol) of powdered potassium carbonate, and
the suspension was heated to 60C in an oil bath under
nitrogen atmosphere for 5 hours. The solution is
cooled to room temperature and diluted with 100 mL of
ethyl acetate and washed with water. The organic
layer was washed saturated brine and dried over
sodium sulfate, filtered and concentrated to yield
4.5 grams of crude material. Purification by flash
chromatography using ethyl acetate as the eluent gave
2.1 grams of purified N-(4-(4'methoxyphenyl)-
benzenesulfonyl-N-(4-(morpholinoethyl))-S-trityl-L-
cysteine amide.
Part E: 2.1 grams( 2.9 mmol) of N-(4-
(4'methoxy-phenyl)-benzenesulfonyl-N-(4-
(morpholinoethyl))-S-trityl-L-cysteine amide was
dissolved in lO mL of methylene chloride and lO mL of
triisopropylsilane was added followed by 40 mL of
trifluoroacetic acid and the solution is stirred for
1.5 hours. The contents were concentrated on a
rotory evaporator and the resultant material is
decanted three times with 50 mL of diethyl ether.
The resulting solid is slurried with a mixture of
ethyl acetate and sodium bicarbonate until the solids
dissolve. The organic layer is washed with saturated
sodium bicarbonate, dried over sodium sulfate,
filtered and concentrated to yield 1.87 grams of N-
(4-(4'methoxyphenyl)-benzenesulfonyl-N-(4-
(morpholinoethyl))- L-cysteine amide as a white
solid. Mass spec. m/z = 480 (M+H)
Example 218: Preparation of N-(4-benzoylamino)-
phenylsulfonyl-N-(4-(morpholinoethyl))-S-trityl-L-
cysteine amide hydrochloride

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-265-
H2N~O
- ro~,o
HS 'N-S~ O
N
~N~
Part A: To a cooled ( lOC) solution of
19.4grams(250 mmol) of chlorosulfonic acid under
nitrogen atmosphere was added lO grams (50. 7 mmol) of
benzanalide in portions over five minutes. The black
solution was heated to 60 C for one hour, then cooled
to room temperature and carefully poured over ice
slowly. The solid organic material was filtered and
dissolved in methylene chloride, washed with water
and dried over sodium sulfate. The solution was
concentrated on a rotory evaporator to 8.6 grams of a
tan solid.
Part B: To a solution of 4.0 grams(11.03
mmol) of S-trityl-L-cysteine amide in 50 mL of dry
methylene chloride was added 2.0 mL (14.33 mmol) of
triethylamine followed by 2.93 grams(9.93 mmol-) of 4-
benzoylamino-benzenesulfonyl chloride. The solution
was stirred at room temperature for one hour, then
concentrated on a rotory evaporator. The resulting
slurry was partitioned between ethyl acetate and
water. The organics were washed with 5~ potassium
hydrogen sulfate, saturated sodium bicarbonate, and
brine, dried over sodium sulfate, filtered and
concentrated to give7.0 grams of crude product. The
crude material was purified by silica gel
chromatography using 1:1 ethyl acetate : hexane as
the eluent to yield 3.5 grams of pure N-(4-

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benzoylamino)-phenylsulfonyl-s-trityl-L-cysteine as a
white solid.
Part C: To 3.5 grams(5.74mmol) Of N-(4-
benzoylamino)phenylsulfonyl-S-trityl-L-cysteine amide
in 12 mL of dry dimethylformamide was added 1.60
grams(8.61 mmol) of 4-(2-chloroethylmorpholine)
hydrochloride followed by 2.38 grams(17.22 mmol) of
powdered potassium carbonate, and the suspension was
lC heated to 60C in an oil bath under nitrogen
atmosphere for 5 hours. The solution is cooled to
room temperature and diluted with 100 mL of ethyl
acetate and washed with water. The organic layer was
wasned saturated brine and dried over sodium sulfate,
filtered and concentrated to yield 4.4 grams of crude
material. Purification by flash chromatography using
ethyl acetate as the eluent gave 3.5 grams of
purified N-(4-benzoylamino)-phenylsulfonyl-N-(4-
(morpholinoe{hyl))-S-trityl-L-cysteine amide.
Part D: 3.5 grams( 4.8 mmol) of N-(4-
benzoylamino)phenylsulfonyl-N-(4-(morpholinoethyl))-
S-trityl-L-cysteine amide was dissolved in 10 mL of
methylene chloride and 10 mL of triisopropylsilane
was added followed by 40 mL of trifluoroacetic acid
and the solution is s~irred for 1.5 hours. The
contents were concentrated on a rotory evaporator and
the resultant material is decanted three times with
50 mL of diethyl ether. The resulting solid is
slurried with a mixture of ethyl acetate and sodium
bicarbonate until the solids dissolve. The organic
layer is washed with saturated sodium bicarbonate,
dried over sodium sulfate, filtered and concentrated
to yield 1.87 grams of N-(4-
benzoylamino)phenylsulfonyl-N-(4-(morpholino-ethyl))-
-L-cysteine amide as a white solid. Mass spec. m/z =
493 (M+H~

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Example 219: 1.87 grams of N-(4-benzoylamino)-
phenylsulfonyl-N-(4-(morpholinoethyl))-S-t-ityl-L-
cysteine amide was dissolved in 20 mL of dry
acetonitrile and to this was added 630 uL of
concentrated HCl and the resulting solution was
concentrated to give a white foam solid which was
dried extensively under vacuum to obtain N-(4-
benzoylamino)-phenylsulfonyl-N-~4-(morpholinoethyl))-
lC L-cysteine amide hydrochloride.
Example 220: N-(4-(4'-chlorobenzoyl)aminoj-
phenylsulfonyl-N-(4-(morpholinoethyl)) -L-cysteine
amide. Preparation similar to Example 218, by
substitution of chlorobenzanalide in part a.
Example 221: N-(4-(4'-chlorobenzoyl)amino)-
phenylsulfonyl-N-(4-(morpholinoethyl)) -L-cysteine
amide. Preparation similar to Example219.
Example 222: N-(4-(4'-bromobenzoyl)amino)phenyl-
sulfonyl-N-(4-(morpholinoethyl)) -L-cysteine amide.
Prepared in a similar manner as Example 218, by
substitution of bromobenzanalide in part a.
Example 223: N-(4-(4'-bromobenzoyl)amino)phenyl-
sulfonyl-N-(4-(morpholinoethyl)) -L-cysteine amide
hydrochloride. Prepared in a similar manner as
Example 219.
Example 224: In vi tro Metalloprotease Inhibition.
Certain of the compounds prepared in the
manner described in Examples 1 to 223 were tested for
activity by an in vi tro assay. Following the
procedures of Knight et al., EEBS ~ett. 296(3):263
(1992). Briefly, 4-aminophenylmercuric acetate
(APMA) or trypsin activated MMPs were incubated with

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various conc~ntrations of the inhibitor compound at
room temperature for 5 minutes (0.02~ 2-mercapto-
ethanol added to buffer for thiol compounds with 5
minutes or overnight incubation). More specifically,
recombinant human MMP-13 and MMP-1 enzymes were
prepared in laboratories of the inventors' employer.
MMP-13 was expressed in baculovirus as a proenzyme,
and purified first over a heparin agarose column and
then over a chelating zinc chloride column. The
proenzyme was activated by APMA for use in the assay.
MMP-1 expressed in transfected ~T-1080 was provided
by Dr. Howard Welgus of Washington University, St.
Louis, MO. The enzyme was also activated using APMA
and was then purified over a hydroxamic acid column.
The enzyme substrate is a methoxycoumarin-
containing polypeptide having the following sequence:
MCA-ProLeuGlyLeuDpaAlaArgNH2, wheein MCA is
methoxycoumarin and Dpa is 3-(2,4-dinitrophenyl)-
L-2,3-diaminopropionyl alanine. This substrate is
commercially available from Baychem as product
M-1895.
The buffer used for assays contained 100 mM
Tris-HCl, 100 mM NaCl, 10 mM CaCl2 and 0.05 percent
polyethyleneglycol(23) lauryl ether at a pH value of
7.5. Assays were carried out at room temperat-ure,
and dimethyl sulfoxide (DMSO) at a final
concentration of 1 percent was used to dissolve
inhibitor compound.
The assayed inhibitor compound in
DMSO/buffer solution was compared to an equal amount
of DMSO/buffer with no inhibitor as control using
microfluorT~ white plates (Dynatech). The inhibitor
or control solution was maintained in the plate for
10 minutes and the substrate was added to provide a
final concentration of 4 uM.
Tn the absence of inhibitor activity, a
fluorogenlc peptide is cleaved at the gly-leu peptide

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bond, separating the highly fluorogenic peptide from
a 2, 4-dinitrophenyl quencher, resulting in an
increase of fluorescence intensity (excitation at 328
nm/emission at 415 nm). Inhibition was measured as a
reduction in fluorescent intensity as a function of
inhibitor concentration, using a Perkin Elmer L550
plate reader. The ICsO values were calculated from
those values. The results are set forth in the
Inhibition Table below, reported in terms of IC50 to
lC three significant figures.
Inhibition Table
Example Number MMP-1 MMP-13
ICso (nanomolar) ICso (nanomolar)
7B >10000 ~10000
7C 4000 300
8 4200 65
550
llD 300 32.5
12C 1300 38.5
13C >10000 2000
14C 1060 46
>10000 75
16B 7000 245
17C ~10000 260
18 >10000 390
20C 3000 110
21C 7000 200
22C 3400 13
23C 4000 150
26 >10000 250
28 >10000 800
29F 8000 1800
31D 2500 600

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33C >10000 345
33D >10000 >10000
37C 1500 5.0
38C 2500 31.0
39C >10000 21.5
40~ 309 0.61
41C >10000 1.8
42D >lO000 1800
44 >10000 400
45C 3200 3.0
46 3500 4.0
47C 4830 4.47
48C >10000 45.0
49 300 17.5
51 >10000 340
52 >10000 45
53 >10000 ll.0
54 9000 7.0
313 0.71
56 2000 67.5
57 >10000 5000
58 6000 200
59 lO00 13
63 300 2500
64 900
lO00 445
66 38
67 570
68 >lO000 1720
69 175
>10000 440
71 >10000 40
72 2300
73 2100
74 >10000

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5000 1000
76 3500 8800
77
~10000
79 >10000
~ 80 ~10000
81 6500
82 >10000 1200
83
1150
84 >10000 >10000
9000
86 1700
87
8500
88
365
89 >10000 90
600
91C >10000 0.6
91D >10000 0.7
9lE need need
92C need need
92D 6000 0.7
94 4400 34.0
800 20
96 >10000 17
97 4000
98
>10000
99 900 31.3
100 >10000 >10000
101 >10000 30
103 >10000 17
104
>10000
105
3500
107 4000 2.7
108
500
109
>10000
110 >10000 1600

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111 2000 40.0
112 4000 150
113 125 0.25
114 >10000 45
115 >10000 220
117 8000 15.0
118 7000 14.0
122 >10000 4250
123 >10000 115
124 2100 ~0.5
125 >10000 770
126 >100 3.5
128 5000 1.1
130 >10000 3300
131 70 cO.l
132 >10000 47.0
133 >10000 4200
141 >10000
142 >10000
146 >10000
147 >10000 >10000
148 >10000
149 >10000
150 9000 :
151 >10000
152 3000
153 >10000
154 9000
155 >10000 >10000
156 1070 7.3
163 500 0.3
164 >10000 40
165 1100 0.15
166 >10000 880
168 540 0.45

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170 30 0.2
171 ~10000 30
172 >10000 250
174 1700 2.5
175 400 0.7
176 2900 2.5
177 10000 20
178 >10000 300
179 2000 23.5
180 >10000 700
181 >lOOOO 3000
184 210 1.4
185 300 2.2
186 >10000 1100
187 >lO000 lOOO
188
>10000
189
>10000
l90 6500
191 >10000 >10000
192 >lOOOO >10000
193 >10000 >10000
195
464
196
>10000
197 4600 100
198 2300
199 >10000 350
200 2060 cO.l
201 7000 3-3
203 >10000 170
204
>10000
206
>10000
207
>10000
208 >10000 190
209 >10000 50
210 >10000 1320

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213 >10000 1.5
214 >10000
216 >10000 200
217 >10000 1.5
218 >10000 1.1
219
220 7000 1.4
221
222 5300 1.1
223
IN VIVO ANGIOGENESIS ASSAY
The study of angiogenesis depends on a
reliable and reproducible model for the stimulation
and inhibition of a neovascular response. The
corneal micropocket assay provides such a model of
angiogenesis in the cornea of a mouse. See, A Model
10 of Angiogenesis in the Mouse Cornea; Kenyon, BM,
et al., Investigative Ophthalmology & Visual Science,
July 1996, Vol. 37, No. 8
In this assay, uniformly sized HydronTM
pellets containing bFGF and sucralfate were prepared
and surgically implanted into the stroma mouse~cornea
adjacent to the temporal limbus. The pellets were
formed by making a suspension of 20 ~l sterile saline
containing 10 ~g recombinant bFGF, 10 mg of
sucralfate and 10 ~l of 12 percent HydronT~ in
ethanol. The slurry was then deposited on a 10 x
10 mm piece of sterile nylon mesh. After drying, the
nylon fibers of the mesh was separated to release the
pe~lets.
The corneal pocket was made by
anesthetizing a 7 week old C57Bl/6 female mouse, then
proptosing the eye with a jeweler's forceps. Using a
dissecting microscope, a central, intrastromal ~inear

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keratotomy of approximately 0.6 mm in length was
performed with a #15 surgical blade, parallel to the
insertion of the lateral rectus muscle. Using a
modified cataract knife, a lamellar micropocket was
dissected toward the temporal limbus. The pocket was
extended to within 1.0 mm of the temporal limbus. A
single pellet was placed on the corneal surface at
the base of the pocket with a jeweler's forceps. The
pellet was then advanced to the temporal end of the
pocket. Antibiotic ointment was then applied to the
eye.
Mice were dosed on a daily basis for the
duration of the assay. Dosing of the animals was
based on bioavailability and overall potency of the
compound. In the case of the compound of Example
218, dosing was 50 mg/kg bid, po. Neovascularization
of the corneal stroma began at about day three and
was permitted to continue under the influence of the
assayed compound until day five. At day five, the
degree of angiogenic inhibition was scored by viewing
the neovascular progression with a slit lamp
microscope.
The mice were anesthetized and the studied
eye was once again proptosed. The maximum vessel
2~ length of neovascularization, extending from the
limbal vascular plexus toward the pellet was
measured. In addition, the contiguous
circumferential zone of neovascularization was
measured as clock hours, where 30 degrees of arc
equals 1 clock hour. The area of angiogenesis was
calculated as
(0.4 x clock hours x 3.14 x vessel length (in mm))
where the vessel length is measured in millimeters.

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The studied mice were thereafter compared
to control mice and the difference in the area of
neovascularization was recorded. The compound of
Example 218 exhibited 37 percent inhibition, whereas
the vehicle control exhibited zero percent
inhibition.
From the foregoing, it will be observed
that numerous modifications and variations can be
effectuated without departing from the true spirit
and scope of the novel concepts of the present
invention. It is to be understood that no limitation
with respect to the specific example presented is
intended or should be inferred. The disclosure is
intended to cover by the appended claims all such
modifications as fall within the scope of the claims.
.. ...