U.S. patent application number 09/851123 was filed with the patent office on 2001-09-27 for amidino protease inhibitors.
This patent application is currently assigned to 3-Dimensional Pharmaceuticals, Inc.. Invention is credited to Illig, Carl R., Lu, Tianbao, Soll, Richard M., Tomczuk, Bruce E..
Application Number | 20010025041 09/851123 |
Document ID | / |
Family ID | 21737595 |
Filed Date | 2001-09-27 |
United States Patent
Application |
20010025041 |
Kind Code |
A1 |
Lu, Tianbao ; et
al. |
September 27, 2001 |
Amidino protease inhibitors
Abstract
Amidino and benzamidino compounds, including compounds of the
formula: 1 wherein R.sup.1-R.sup.4, R.sup.6-R.sup.9, Y, Z, n and m
are set forth in the specification, as well as hydrates, solvates
or pharmaceutically acceptable salts thereof, that inhibit a number
of proteolytic enzymes are described. Also described are methods
for preparing the compounds of Formula I.
Inventors: |
Lu, Tianbao; (Kennett
Square, PA) ; Tomczuk, Bruce E.; (Collegeville,
PA) ; Illig, Carl R.; (Phoenixville, PA) ;
Soll, Richard M.; (Lawrenceville, NJ) |
Correspondence
Address: |
STERNE, KESSLER, GOLDSTEIN & FOX PLLC
1100 NEW YORK AVENUE, N.W., SUITE 600
WASHINGTON
DC
20005-3934
US
|
Assignee: |
3-Dimensional Pharmaceuticals,
Inc.
|
Family ID: |
21737595 |
Appl. No.: |
09/851123 |
Filed: |
May 9, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09851123 |
May 9, 2001 |
|
|
|
09502005 |
Feb 11, 2000 |
|
|
|
09502005 |
Feb 11, 2000 |
|
|
|
09270734 |
Mar 16, 1999 |
|
|
|
6133315 |
|
|
|
|
09270734 |
Mar 16, 1999 |
|
|
|
08782894 |
Dec 27, 1996 |
|
|
|
6034127 |
|
|
|
|
60009431 |
Dec 29, 1995 |
|
|
|
Current U.S.
Class: |
514/218 ;
514/256; 514/534; 514/603; 514/626; 514/631 |
Current CPC
Class: |
A61P 9/10 20180101; C07D
295/195 20130101; A61P 1/18 20180101; C07D 211/26 20130101; C07C
309/73 20130101; A61P 29/00 20180101; A61P 1/00 20180101; C07D
211/22 20130101; C07C 311/21 20130101; A61P 7/00 20180101; A61P
9/00 20180101; A61P 43/00 20180101; A61P 7/02 20180101 |
Class at
Publication: |
514/218 ;
514/256; 514/534; 514/631; 514/626; 514/603 |
International
Class: |
A61K 031/551; A61K
031/505; A61K 031/155 |
Claims
What is claimed is:
1. A compound having the Formula I: 11or solvates, hydrates or
pharmaceutically acceptable salts thereof; wherein: Z is one of
--NR.sup.10SO.sub.2--, --SO.sub.2NR.sup.10--,
--NR.sup.10C(R.sup.yR.sup.z- )--, --C(R.sup.yR.sup.z)NR.sup.10--,
--OSO.sub.2--, --SO.sub.2O--, --OC(R.sup.yR.sup.z)--,
--C(R.sup.yR.sup.z)O--, -NR.sup.10CO-- or --CONR.sup.10--; R.sup.y
and R.sup.z are each independently one of hydrogen, alkyl,
cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl or carboxy; R.sup.1 is one
of alkyl, cycloalkyl, alkenyl, allynyl, aryl, aralkyl or
heteroaryl, any of which may be optionally substituted; R.sup.2,
R.sup.3 and R.sup.4 are each independently one of hydrogen, alkyl,
cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl,
trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamide,
--CO.sub.2R.sup.x, --CH.sub.2OR.sup.x or --OR.sup.x, or when
present on adjacent carbon atoms, R.sup.2 and R.sup.3 may also be
taken together to form one of --CH=CH--CH=CH-- or
--(CH.sub.2).sub.q--, where q is from 2 to 6, and R.sup.4 is
defined as above; R.sup.x, in each instance, is independently one
of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl
groups may optionally have one or more unsaturations; Y is one of
--O--, --NR.sup.10--, --S--, --CHR.sup.10-- or a covalent bond; W
is N or CR.sup.10; R.sup.6, in each instance, is independently one
of hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy,
alkoxycarbonyloxy, cyano or --CO.sub.2R.sup.w, where RW is alkyl or
cycloalkyl; R.sup.7 and R.sup.8 are each independently one of
hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl, or
R.sup.7 and R.sup.8 are taken together to form --CH.sub.2).sub.y--,
where y is zero, 1 or 2, with the proviso that when W is N, y
cannot be zero or 1; R.sup.9 is one of hydrogen, alkyl, cycloalkyl
or aryl, wherein said alkyl, cycloalkyl or aryl can be optionally
substituted with amino, monoalkylamino, dialkylamino, alkoxy,
hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl,
aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano or
trifluoromethyl; R.sup.10, in each instance, is independently one
of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl,
monoalkylamino(C.sub.2-10)alky1, dialkylamino (C.sub.2-10)alkyl or
carboxyalkyl; n is from zero to 8, with the proviso that when W is
N and Y is other than --CHR.sup.10--, then n is from 2 to 8; and m
is from 1 to 4, provided that when W is N, then m is not 1.
2. A compound of claim 1, wherein: Z is one of --SO.sub.2O--,
--SO.sub.2NR.sup.10--, (R.sup.yR.sup.z)O-- or --OC(R.sup.yR.sup.z),
where R.sup.y and R.sup.z are each hydrogen; R.sup.1 is one of
C.sub.6-10 aryl, pyridinyl, quinizolinyl, quinolinyl or
tetaahydroquinolinyl, any of which is optionally substituted by one
or two of hydroxy, nitro, trifluoromethyl, halogen, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, C.sub.1-6 arninoalkyl, C.sub.1-6
aminoalkoxy, amino, mono(C.sub.1-4)alkylamino,
di(C.sub.1-4)alkylamino, C.sub.2-6 alkoxycarbonylamino, C.sub.2-6
alkoxycarbonyl, carboxy, C.sub.1-6 hydroxyalkyl, C.sub.2-6
hydroxyalkoxy, C.sub.2-10 mono(carboxyalkyl)amino, di(C.sub.2-10
carboxyalkyl)amino, C.sub.6-14 ar(C.sub.1-6 alkoxycarbonyl,
C.sub.2-6 alkynylcarbonyl, C.sub.1-6 alkylsulfonyl, C.sub.2-6
alkenylsulfonyl, C.sub.2-6 alkynylsulfonyl, C.sub.1-6
alkylsulfinyl, C.sub.1-6 alkylsulfonamido, amidino, guanidino,
C.sub.1-6 alkyliminoamino, formyliminoamino, C.sub.2-6
carboxyalkyl, C.sub.2-6 carboxyalkoxy, C.sub.2-6 carboxyalkylamino,
cyano, trifluoromethoxy, or perfluoroethoxy; R.sup.2, R.sup.3 and
R.sup.4 are independently one of hydrogen, C.sub.1-6 alkyl,
C.sub.3-8 cycloalkyl, phenyl, benzyl, trifluoromethyl, halogen,
hydroxy(C.sub.1-8)alkyl, cyano, nitro, carboxamide, carboxy,
C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkoxymethyl or C.sub.1-4
alkoxy; or alternatively, R.sup.2 and R.sup.3, when present on
adjacent carbon atoms, may also be taken together to form one of
--CH=CH--CH=CH-- or --CH.sub.2).sub.q--, where q is from 2 to 6,
and R.sup.4 is as defied above; Y is one of --O--, --S--,
--NR.sup.10--, or a covalent bond; W is N or CR.sup.10; R.sup.6, in
each instance, is one of hydrogen, C.sub.1-4 alkyl, hydroxy,
C.sub.1-4 alkoxy, phenoxy, C.sub.1-4 alkyloxycarbonyl or cyano;
R.sup.7 and R.sup.8 are independently one of hydrogen, C.sub.1-6
alkyl, C.sub.2-10 carboxyalkyl or C.sub.2-10 hydroxyalkyl, or
R.sup.7 and R.sup.8 are taken together to form --(CH.sub.2).sub.y--
where y is 0, 1 or 2, provided that when W is N, y cannot be 0 or
1; R.sup.9 is hydrogen; or C.sub.1-10 alkyl, optionally substituted
with amino, mono(C.sub.1-4)alkylamino, C.sub.1-6 alkoxy, hydroxy,
carboxy, phenyl, alkyloxycarbonyl, aralkoxycarbonyl, C.sub.1-6
acylamino, cyano or trifluoromethyl; R.sup.10, in each instance, is
independently hydrogen, C.sub.1-6 alkyl, benzyl, phenyl, C.sub.2-10
hydroxyalkyl, C.sub.2-10 arinoalkyl, C.sub.1-4
monoalkylamio(C.sub.2-8)alkyl, C.sub.1-4
dialkylamino(C.sub.2-8)alkyl or C.sub.2-10 carboxyalkyl; n is from
zero to 8, with the proviso that when W is N, then n is from 2 to
8; and m is from 1 to 4, provided that when W is N, then m is not
1.
3. A compound of claim 1, wherein: Z is one of --SO.sub.2O--,
--SO.sub.2NR.sup.10--, --CH.sub.2O-- or --OCH.sub.2--; R.sup.1 is
one of phenyl or naphthyl, optionally substituted by one or two of
chloro or dimethylamino; R.sup.2 and R.sup.3 are each hydrogen or
R.sup.2 and R.sup.3 may also be taken together to form
--CH=CH--CH=CH--; R.sup.4 is one of hydrogen, methyl, methoxy or
trifluoromethyl; Y is one of O or NR.sup.10; W is N or CR.sup.10;
R.sup.6, in each instance is hydrogen or hydroxy; R.sup.7 and
R.sup.8 are independently one of hydrogen, C.sub.1-6 alky,
C.sub.2-10 hydroxyalkyl or C.sub.2-10 carboxyalkyl, or R.sup.7 and
R.sup.8 are taken together to form --(CH.sub.2).sub.y--, where y is
zero, 1 or 2, with the proviso that when W is N, y cannot be zero
or 1; R.sup.9 is hydrogen or C.sub.1-4 alkyl; R.sup.10, in each
instance, is independently hydrogen, C.sub.1-4 alkyl, C.sub.2-4
hydroxyalkyl, C.sub.2-4 carboxyalkyl, C.sub.2-4 aminoalkyl,
dimethylamino(C.sub.2-8)alk- yl, methylamino(C.sub.2-8)alkyl; n is
from zero to 4, with the proviso that when W is N, then n is 2 to
4; and m is 1, 2or3.
4. A compound having the Formula II: 12or solvates, hydrates or
pharmaceutically acceptable salts thereof; wherein: Z is one of
--NR.sup.10SO.sub.2--, --SO.sub.2NR.sup.10--,
--NR.sup.10C(R.sup.yR.sup.z- )--, --C(R.sup.yR.sup.z)NR.sup.10--,
--OSO.sub.2--, --SO.sub.2O--, --OC(R.sup.yR.sup.z)--,
--C(R.sup.yR.sup.z)O--, --NR.sup.10CO-- or --CONR.sup.10--; R.sup.y
and R.sup.z are each independently one of hydrogen, alkcyl,
cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl or carboxy; R.sup.1 is one
of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or
heteroaryl, any of which may be optionally substituted; R.sup.2,
R.sup.3 and R.sup.4 are each independently one of hydrogen, alkyl,
cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl,
trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamide,
--CO.sub.2R.sup.x, --CH.sub.2OR.sup.x or --OR.sup.x, or when
present on adjacent carbon atoms, R.sup.2 and R.sup.3 may also be
taken together to form one of --CH=CH--CH=CH-- or
--(CH.sub.2).sub.q--, where q is from 2 to 6, and R.sup.4 is
defined as above; R.sup.x, in each instance, is independently one
of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl
groups may optionally have one or more unsaturations; Y is one of
--O--, --NR.sup.10--, --S--, --CHR.sup.10-- or a covalent bond; W
is N or CR.sup.10; R.sup.6, in each instance, is independently one
of hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy,
alkoxycarbonyloxy, cyano or --CO.sub.2R.sup.w, where R.sup.w is
alkyl or cycloalkyl; R.sup.7 and R.sup.8 are each independently one
of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl, or
R.sup.7 and R.sup.8 are taken together to form
--(CH.sub.2).sub.y--, where y is zero, 1 or 2, with the proviso
that when W is N, y cannot be zero or 1; R.sup.10, in each
instance, is independently one of hydrogen, alkyl, aralkyl, aryl,
hydroxyalkyl, aminoalkyl, monoalkylamino(C.sub.2-10)alkyl,
dialkylamino (C.sub.2-10)alkyl or carboxyalkyl; n is from zero to
8, with the proviso that when W is N and Y is other than
--CHR.sup.10--, then n is from 2 to 8; and m is from 1 to 4,
provided that when W is N, then m is not 1.
5. A compound of claim 4, wherein: Z is one of --SO.sub.2O--,
--SO.sub.2NR.sup.10--, C(R.sup.yR.sup.z)O-- or
--OC(R.sup.yR.sup.z)--, where R.sup.y and R.sup.z are each
hydrogen; R.sup.1 is one of C.sub.6-10 aryl, pyridinyl,
quinizolinyl, quinolinyl or tetrahydroquinolinyl, any of which is
optionally substituted by one or two of hydroxy, nitro,
trifluoromethyl, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.1-6 aminoalkyl, C.sub.1-6 aminoalkoxy, amino,
mono(C.sub.1-4)alkylamino, di(C.sub.1-4)alkylamino, C.sub.2-6
alkoxycarbonylamino, C.sub.2-6 alkoxycarbonyl, carboxy, C.sub.1-6
hydroxyalkyl, C.sub.2-6 hydroxyalkoxy, C.sub.2-10
mono(carboxyalkyl)amino, di(C.sub.2-10 carboxyalkyl)amino,
C.sub.6-14 ar(C.sub.1-6)alkoxycarbonyl, C.sub.2-6 alkynylcarbonyl,
C.sub.1-6 alkylsulfonyl, C.sub.2-6 alkenylsulfonyl, C.sub.2-6
alkynylsulfonyl, C.sub.2-6 alkylsulfinyl, C.sub.1-6
alkylsulfonamido, amidino, guanidino, C.sub.1-6 alkyliminoamino,
formyliminoamino, C.sub.2-6 carboxyalkoxy, C.sub.2-6 carboxyalkyl,
C.sub.2-6 carboxyalkylamino, cyano, trifluoromethoxy, or
perfluoroethoxy; R.sup.2, R.sup.3 and R.sup.4 are independently one
of hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, phenyl, benzyl,
trifluoromethyl, halogen, hydroxy(C.sub.1-8)alkyl, cyano, nitro,
carboxamide, carboxy, C.sub.1-4 alkoxycarbonyl, C.sub.1-4
alkoxymethyl or C.sub.1-4 alkoxy; or alternatively, R.sup.2 and
R.sup.3, when present on adjacent carbon atoms, may also be taken
together to form one of --CH=CH--CH=CH-- or --(CH.sub.2).sub.q--,
where q is from 2 to 6, and R.sup.4 is as defined above; Y is one
of --O--, --S--, --NR.sup.10-- or a covalent bond; W is N or
CR.sup.10; R.sup.6, in each instance, is one of hydrogen, C.sub.1-4
alkyl, hydroxy, C.sub.1-4 alkoxy, phenoxy, C.sub.1-4
alkyloxycarbonyl or cyano; R.sup.7 and R.sup.8 are independently
one of hydrogen, C.sub.1-6 alkyl, C.sub.2-10 carboxyalkyl or
C.sub.2-10 hydroxyalkyl, or R.sup.7 and R.sup.8 are taken together
to form --CH.sub.2).sub.y-- where y is 0, 1 or 2, provided that
when W is N, y cannot be 0 or 1; R.sup.10, in each instance, is
independently hydrogen, C.sub.1-6 alkyl, benzyl, phenyl, C.sub.2-10
hydroxyalkyl, C.sub.2-10 aminoalkyl, C.sub.1-4
monoalkylammo(C.sub.2-8)alkyl, C.sub.1-4
dialkylamino(C.sub.2-8)alkyl or C.sub.2-10 carboxyalkyl; n is from
zero to 8, with the proviso that when W is N, then n is from 2 to
8; and m is from 1 to 4, provided that when W is N, then m is not
1.
6. A compound of claim 4, wherein: Z is one of --SO.sub.2O--,
--SO.sub.2NR.sup.10--, --CH.sub.2O -- or --OCH.sub.2--; R.sup.1 is
one of phenyl or naphthyl, optionally substituted by one or two of
chloro or dimethylamino; R.sup.2 and R.sup.3 are each hydrogen or
R.sup.2 and R.sup.3 may also be taken together to form
--CH=CH--CH=CH--; R.sup.4 is one of hydrogen, methyl, methoxy or
trifluoromethyl; Y is one of O or NR.sup.10; W is N or CR.sup.10;
R.sup.6, in each instance is hydrogen or hydroxy; R.sup.7 and
R.sup.8 are independently one of hydrogen, C.sub.1-6 alkyl,
C.sub.2-10 hydroxyalkyl or C.sub.2-10 carboxyalkyl, or R.sup.7 and
R.sup.8 are taken together to form --CH.sub.2).sub.y--, where y is
zero, 1 or 2, with the proviso that when W is N, y cannot be zero
or 1; R.sup.10, in each instance, is independently hydrogen,
C.sub.1-4 alkyl, C.sub.2-4 hydroxyalkyl, C.sub.2-4 carboxyalkyl,
C.sub.2-4 aminoalkyl, dimethylamino(C.sub.2-8)alkyl,
methylamino(C.sub.2-8)alkyl; n is from zero to 4, with the proviso
that when W is N, then n is 2 to 4; and m is 1, 2or 3.
7. A compound having the Formula III: 13or solvates, hydrates or
pharmaceutically acceptable salts thereof; wherein: Z is one of
--NR.sup.10SO.sub.2--, --SO.sub.2NR.sup.10--,
--NR.sup.10C(R.sup.yR.sup.z- )--, --C(R.sup.yR.sup.z)NR.sup.10--,
--OSO.sub.2--, --SO.sub.2O--, --OC(R.sup.yR.sup.z)O--,
--C(R.sup.yR.sup.z)O--, --NR.sup.10CO-- or --CONR.sup.10; R.sup.y
and R.sup.z are each independently one of hydrogen, alkyl,
cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl or carboxy; R.sup.1 is one
of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or
heteroaryl, any of which may be optionally substituted; R.sup.2,
R.sup.3 and R.sup.4 are each independently one of hydrogen, alkyl,
cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl,
trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamide,
--CO.sub.2R.sup.x, CH.sub.2OR.sup.x or --OR.sup.x, or when present
on adjacent carbon atoms, R.sup.2 and R.sup.3 may also be taken
together to form one of --CH=CH--CH=CH-- or --(CH.sub.2).sub.q--,
where q is from 2 to 6, and R.sup.4 is defined as above; R.sup.x,
in each instance, is independently one of hydrogen, alkyl or
cycloalkyl wherein said alkyl or cycloalkyl groups may optionally
have one or more unsaturations; Y is one of --O--, --NR.sup.10--,
--S--, --CHR.sup.10-- or a covalent bond; W is N or CR.sup.10;
R.sup.5 is one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or
carboxyalkyl; R.sup.6, in each instance, is independently one of
hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy,
alkoxycarbonyloxy, cyano or --CO.sub.2R.sup.w, where R.sup.w is
alkyl or cycloalkyl; R.sup.10, in each instance, is independently
one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl,
monoalkylamino(C.sub.2-10)alkyl, dialkylarnino(C.sub.2-10)alkyl or
carboxyalkyl; R' is one of hydrogen, alkyl, cycloalkyl, aryl,
aralkyl, heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano,
nitro, carboxamide, carboxy, alkoxycarbonyl or alkoxyalkyl; and n
is from zero to 8, with the proviso that when W is N and Y is other
than --CHR.sup.10--, then n is from 2 to 8.
8. A compound of claim 7, wherein: Z is one of --SO.sub.2O--,
--SO.sub.2NR.sup.10--, --C(R.sup.yR.sup.z)O-- or
--OC(R.sup.yR.sup.z)--, where R.sup.y and R.sup.z are each
hydrogen; R.sup.1 is one of C.sub.6-10 aryl, pyridinyl,
quinizolinyl, quinolinyl or tetrahydroquinolinyl, any of which is
optionally substituted by one or two of hydroxy, nitro,
trifluoromethyl, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.1-6 aminoalkyl, C.sub.1-6 aminoalkoxy, amino,
mono(C.sub.1-4)alkylamino, di(C.sub.1-4)alkylamino, C.sub.2-6
alkoxycarbonylamino, C.sub.2-6 alkoxycarbonyl, carboxy, C.sub.1-6
hydroxyalkyl, C.sub.2-6 hydroxyalkoxy, C.sub.2-10
mono(carboxyalkyl)amino, di(C.sub.2-10 carboxyalkyl)amino,
C.sub.6-14 ar(C.sub.1-6 alkoxycarbonyl, C.sub.2-6 alkynylcarbonyl,
C.sub.1-6 alkylsulfonyl, C2-6 alkenylsulfonyl, C.sub.2-6
alkynylsulfonyl, C.sub.1-6 alkylsulfinyl, C.sub.1-6
alkylsulfonamido, amidino, guanidino, C.sub.1-6 alkyliminoamino,
formyliminoamino, C.sub.2-6 carboxyalkyl, C.sub.2-6 carboxyalkoxy,
C.sub.2-6 carboxyalkylamino, cyano, trifluoromethoxy, or
perfluoroethoxy; R.sup.2, R.sup.3 and R.sup.4 are independently one
of hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, phenyl, benzyl,
trifluoromethyl, halogen, hydroxy(C.sub.1-8)alkyl, cyano, nitro,
carboxamide, carboxy, C.sub.1-4 alkoxycarbonyl, C.sub.1-4
alkoxymethyl or C.sub.1-4 alkoxy; or alternatively, R.sup.2 and
R.sup.3, when present on adjacent carbon atoms, may also be taken
together to form one of --CH=CH--CH=CH-- or --(CH.sub.2).sub.q--,
where q is from 2 to 6, and R.sup.4 is as defined above; Y is one
of --O--, --S--, --NR.sup.10 -- or a covalent bond; W is N or
CR.sup.10; R.sup.5 is one of hydrogen, C.sub.1-4 alkyl, C.sub.2-10
carboxyalkyl or C.sub.2-10 hydroxyalkyl; R.sup.6, in each instance,
is one of hydrogen, C.sub.1-4 alkyl, hydroxy, C.sub.1-4 alkoxy,
phenoxy, C.sub.1-4 alkyloxycarbonyLor cyano; R.sup.10, in each
instance, is independently hydrogen, C.sub.1-6 alkyl, benzyl,
phenyl, C.sub.2-10 hydroxyalkyl, C.sub.2-10 aminioalkyl, C.sub.1-4
monoalkylamino(C.sub.2-8)alkyl, C.sub.1-4
dialkylamino(C.sub.20-8)alkyl or C.sub.2-10 carboxyalkyl; R' is one
of hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, phenyl, benzyl,
trifluoromethyl, halogen, hydroxy(C.sub.1-8)alkyl, cyano, nitro,
carboxamide, carboxy, alkoxycarbonyl, alkoxymethyl or alkoxy; and n
is from zero to 8, with the proviso that when W is N, then n is
from 2 to 8.
9. A compound of claim 7, wherein: Z is one of --SO.sub.2O--,
--SO.sub.2NR.sup.10--, CH.sub.2O-- or --OCH.sub.2--; R.sup.1 is one
of phenyl or naphthyl, optionally substituted by one or two of
chloro or dimethylamino; R.sup.2 and R.sup.3 are each hydrogen or
R.sup.2 and R.sup.3 may also be taken together to form
--CH=CH--CH=CH--; R.sup.4 is one of hydrogen, methyl, methoxy or
trifluoromethyl; Y is one of O or NR.sup.10; W is N or CR.sup.10;
R.sup.5 is one of hydrogen, C.sub.1-6 alkyl, C.sub.2-10
hydroxyalkyl or C.sub.2-10 carboxyalkyl; R.sup.6, in each instance
is hydrogen or hydroxy; R.sup.10, in each instance, is
independently hydrogen, C.sub.1-4 alkyl, C.sub.2-4 hydroxyalkyl,
C.sub.2-4 carboxyalkyl, C.sub.2-4 aminoalkyl,
dimethylamino(C.sub.2-8)alk- yl, methylamino(C.sub.2-8)alkyl; R' is
hydrogen, methyl, methoxy or trifluoromethyl; and n is from zero to
4, with the proviso that when W is N, then n is 2 to 4.
10. The compound of claim 1, which is: chlorobenzenesulfonic acid
3-[(1-acetimidoylpiperidin-4-yl)methoxy]-5-methylphenyl ester
hydrochloride; 3-(2-chlorobenzyloxy)-5-methyl-1 -[2-[(1
-acetimidoyl)piperazin-4-yl]]ethoxybenzene diacetic acid salt;
N-[2-(N,N-dimethylamino)ethyl]-N-[2-[[4-(1-acetimidoyl)amino]butoxy]-4-me-
thylphenyl]benzenesulfonamide dihydrochloride;
N-benzyl-N-[[[3-(1-acetimid-
oyl)piperidin-4-yl]methylamino]phenyl]-benzenesulfonamide;
3-chlorobenzenesulfonic acid
3-[[(1-acetimidoyl)piperidin-4-yl]methoxy]-5- -methylphenyl ester
hydrochloride; 2,3-dichlorobenzenesulfonic acid
3-[[(1-acetimidoyl)piperidin-4-yl]methoxy]-5-methylphenyl ester
hydrochloride;
2-chloro-N-[[3-[(1-acetimidoyl)piperidin-4-yl]methoxy]-5-t-
rifluoromethylphenyl]benzenesulfonamide hydrochloride;
2-chloro-N-(5-carboxypentyl)-N-[[3-[(1-acetimidoyl)piperidin-4-yl]methoxy-
]-5-trifluoromethylphenyl]benzenesulfonamide;
1-5-(N,N-dimethylamino)napht- halenesulfonic acid 3-[[(l
-acetimidoyl)piperidin-3-yl]methoxy]-5-methoxyp- henyl ester
hydrochloride; 2-chlorobenzenesulfonic acid
1-[[(1-acetimidoyl)piperidin-4-yl]methoxy]naphthalen-3-yl ester
acetic acid salt; or
3-[(2-chlorophenoxy)methyl]-[[(1-acetimidoyl)piperidin-4-yl-
]methoxy]benzene acetic acid salt.
11. The compound of claim 4, which is: 2-chlorobenzenesulfonic acid
3-[3-amidinopropoxy]-5-methylphenyl ester hydrochloride; or
2-chlorobenzenesulfonic acid 3-[5-amidinopentyloxy]-5-methylphenyl
ester acetic acid salt.
12. The compound of claim 7, which is: 2-chlorobenzenesulfonic acid
3-[(3-amidinophenyl)methoxy]-5-methylphenyl ester hydrochloride;
2-chlorobenzenesulfonic acid
3-[[3-(N-hydroxy)amidinophenyl]methoxy]-5-me- thylphenyl ester
hydrochloride; 2-chlorobenzenesulfonic acid
3-[[3-(N-methylamidino)phenyl]methoxy]-5-methylphenyl ester
hydrochloride; 2-chlorobenzenesulfonic acid
3-[(4-amidinophenyl)methoxy]-- 5-methylphenyl ester hydrochloride;
or 2-chlorobenzenesulfonic acid 3-[(3-amidinophenyl)methoxy]phenyl
ester hydrochloride.
13. A pharmaceutical composition for inhibiting proteolysis in a
mammal, comprising an amount of a compound of claim 1 effective to
inhibit proteolysis.
14. The pharmaceutical composition of claim 13 further comprising a
pharmaceutically acceptable carrier or diluent.
15. The pharmaceutical composition of claim 13, comprising an
amount of a compound of claim 1 effective to inhibit a trypsin-like
protease.
16. A method of inhibiting proteolysis in a mammal, comprising
administering to the mammal a composition of claim 13.
17. The method of claim 16, wherein a trypsin-like protease is
inhibited.
18. A method of treating pancreatitis, thrombosis, ischemia,
stroke, restenosis, emphysema or inflammation in a mammal,
comprising administering to the mammal a composition of claim
13.
19. A method of inhibiting thrombin-induced platelet aggregation
and clotting of fibrinogen in plasma, comprising administering to
the mammal a composition of claim 13.
Description
[0001] This application claims the benefit, under 35 U.S.C. .sctn.
119(e), of the earlier filing date of U.S. provisional application,
application Ser. No. 60/009,431, filed Dec. 29, 1995.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to novel compounds that
function as enzyme inhibitors, and particularly to a new class of
non-peptidic inhibitors of proteolytic enzymes.
[0004] 2. Related Art
[0005] Proteases are enzymes that cleave proteins at single,
specific peptide bonds. Proteases can beclassified into four
generic classes: serine, thiol or cysteinyl, acid or aspartyl, and
metalloproteases (Cuypers et al., J. Biol. Chem. 257:7086 (1982)).
Proteases are essential to a variety of biological activities, such
as digestion, formation and dissolution of blood clots,
reproduction and the immune reaction to foreign cells and
organisms. Aberrant proteolysis is associated with a number of
disease states in man and other mammals. The human neutrophil
proteases, elastase and cathepsin G, have been implicated as
contributing to disease states marked by tissue destruction. These
disease states include emphysema, rheumatoid arthritis, comeal
ulcers and glomerular nephritis. (Barret, in Enzyme Inhibitors as
Drugs, Sandler, ed., University Park Press, Baltimore, (1980)).
Additional proteases such as plasmin, C-1 esterase, C-3 convertase,
urokinase, plasminogen activator, acrosin, and kallikreins play key
roles in normal biological fulnctions of mammals. In many
instances, it is beneficial to disrupt the fimction of one or more
proteolytic enzymes in the course of therapeutically treating a
mammal.
[0006] Serine proteases include such enzymes as elastase (human
leukocyte), cathepsin G, plasmin, C-1 esterase, C-3 convertase,
urokinase, plasminogen activator, acrosin, chymotrypsin, trypsin,
thrombin, factor Xa and kallikreins.
[0007] Human leukocyte elastase is released by polymorphonuclear
leukocytes at sites of inflammation and thus is a contributing
cause for a number of disease states. Cathepsin G is another human
neutrophil serine protease. Compounds with the ability to inhibit
the activity of these enzymes are expected to have an
anti-inflammatory effect useful in the treatment of gout,
rheumatoid arthritis and other inflammatory diseases, and in the
treatment of emphysema Chymotrypsin and trypsin are digestive
enzymes. Inhibitors of these enzymes are useful in treating
pancreatitis. Inhibitors of urokinase and plasminogen activator are
useful in treating excessive cell growth disease states, such as
benign prostatic hypertrophy, prostatic carcinoma and
psoriasis.
[0008] The serine protease thrombin occupies a central role in
hemostasis and thrombosis, and as a multifactorial protein, induces
a number of effects on platelets, endothelial cells, smooth muscle
cells, leukocytes, the heart, and neurons (Tapparelli et al.,
Trends in Pharmacological Sciences 14:366-376 (1993); Lefkovits and
Topol, Circulation 90(3):1522-1536 (1994); Harker, Blood
Coagulation and Fibrinolysis 5 (Suppl 1):S47-S58 (1994)).
Activation of the coagulation cascade through either the intrinsic
pathway (contact activation) or the extrinsic pathway (activation
by exposure of plasma to a non-endothelial surface, damage to
vessel walls or tissue factor release) leads to a series of
biochemical events that converge on thrombin. Thrombin cleaves
fibrinogen ultimately leading to a hemostatic plug (clot
formation), potently activates platelets through a unique
proteolytic cleavage of the cell surface thrombin receptor
(Coughlin, Seminars in Hematology 31(4):270-277 (1994)), and
autoamplifies its own production through a feedback mechanism.
Thus, inhibitors of thrombin function have therapeutic potential in
a host of cardiovascular and non-cardiovascular diseases,
including: myocardial infarction; unstable angina; stroke;
restenosis; deep vein thrombosis; disseminated intravascular
coagulation caused by trauma, sepsis or tumor metastasis;
[0009] hemodialysis; cardiopulmonary bypass surgery; adult
respiratory distress syndrome; endotoxic shock; rheumatoid
arthritis; ulcerative colitis; induration; metastasis;
hypercoagulability during chemotherapy; Alzheimer's disease; and
Down's syndrome.
[0010] Factor Xa is another serine protease in the coagulation
pathway. Factor Xa associates with factor Va and calcium on a
phospholipid membrane thereby forming a prothrombinase complex.
This prothrombinase complex then converts prothrombin to thrombin
(Claeson, Blood Coagulation and Fibrinolysis 5:411-436 (1994);
Harker, Blood Coagulation and Fibrinolysis 5 (Suppl 1):S47-S58
(1994)). Inhibitors of factor Xa are thought to offer an advantage
over agents that directly inhibit thrombin since direct thrombin
inhibitors still permit significant new thrombin generation
(Lefkovits and Topol, Circulation 90(3):1522-1536 (1994); Harker,
Blood Coagulation and Fibrinolysis S (Suppl 1):S47-S58 (1994)).
[0011] A need continues to exist for non-peptidic compounds that
are potent and selective protease inhibitors, and which possess
greater bioavailability and fewer side-effects than currently
available protease inhibitors. Accordingly, new classes of potent
protease inhibitors, characterized by potent inhibitory capacity
and low mammalian toxicity, are potentially valuable therapeutic
agents for a variety of conditions, including treatment of a number
of mammalian proteolytic disease states.
SUMMARY OF THE INVENTION
[0012] The present invention is directed to novel compounds having
one of Formulae I-III (below). Also provided are processes for
preparing compounds of Formulae I-III. The novel compounds of the
present invention are potent inhibitors of proteases, especially
trypsin-like serine proteases, such as chymotrypsin, trypsin,
thrombin, plasmin and factor Xa. Certain of the compounds exhibit
antithrombotic activity via direct inhibition of thrombin, or are
intermediates useful for forming compounds having antithrombotic
activity. Other compounds are inhibitors of trypsin and/or
chymotrypsin, and are therefore useful in treating pancreatitis.
Also provided are methods of inhibiting or treating aberrant
proteolysis in a mammal and methods of treating thrombosis,
ischemia, stroke, restenosis or inflammation in a mammal by
administering an effective amount of a compound of Formulae I-III.
Further provided are pharmaceutical compositions comprising a
compound of Formulae I-III and one or more pharmaceutically
acceptable carriers or diluents.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0013] Compounds of the present invention include compounds having
one of Formulae I-III: 2
[0014] or solvates, hydrates or pharmaceutically acceptable salts
thereof; wherein:
[0015] Z is one of --NR.sup.10SO.sub.2--,
--SO.sub.2NR.sup.10--,--NR.sup.1- 0C(R.sup.yR.sup.z)--,
--C(R.sup.yR.sup.z)NR.sup.10--, --OSO.sub.2--, --SO.sub.2O--,
--OC(R.sup.yR.sup.z)--, --(R.sup.yR.sup.z)O--, --NR.sup.10CO-- or
--CONR.sup.10--;
[0016] R.sup.y and R.sup.z are each independently one of hydrogen,
alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl,
aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxy;
[0017] R.sup.1 is one of allyl, cycloalkyl, alkenyl, alkynyl, aryl,
araLkyl or heteroaryl, any of which may be optionally
substituted;
[0018] R.sup.2, R.sup.3 and R.sup.4 are each independently one of
hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl,
heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro,
carboxamide, --CO.sub.2R.sup.x, --CH.sub.2OR.sup.x or --OR.sup.x,
or when present on adjacent carbon atoms, R.sup.2 and R.sup.3 may
also be taken together to form one of --CH=CH--CH=CH-- or
--(CH.sub.2).sub.q--, where q is from 2 to 6, and R.sup.4 is
defined as above;
[0019] R.sup.x, in each instance, is independently one of hydrogen,
alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may
optionally have one or more unsaturations;
[0020] Y is one of--O--, --NR.sup.10--, --S--, --CHR.sup.10-- or a
covalent bond;
[0021] W is N or CR.sup.10;
[0022] R.sup.5 is one of hydrogen, alkyl, aralkyl, aryl,
hydroxyalkyl or carboxyalkyl;
[0023] R.sup.6, in each instance, is independently one of hydrogen,
alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano
or --CO.sub.2R.sup.w, where R.sup.w is alkyl or cycloalkyl;
[0024] R.sup.7 and R.sup.8 are each independently one of hydrogen,
alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl, or R.sup.7 and
R.sup.8 are taken together to form --(CH.sub.2).sub.y--, where y is
zero, 1 or 2, with the proviso that when W is N, y cannot be zero
or 1;
[0025] R.sup.9 is one of hydrogen, alkyl, cycloalkyl or aryl,
wherein said alkyl, cycloalkyl or aryl can be optionally
substituted with amino, monoalkylamino, dialkylamino, alkoxy,
hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl,
aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano or
trifluoromethyl;
[0026] R.sup.10, in each instance, is independently one of
hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl,
monoalkylamino(C.sub.2-10- )alkyl, dialkylamino (C.sub.2-10)alkyl
or carboxyalkyl;
[0027] R' is one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl,
heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro,
carboxamide, carboxy, alkoxycarbonyl or alkoxyalkyl;
[0028] n is from zero to 8, with the proviso that when W is N and Y
is other than --CHR.sup.10--, then n is from 2 to 8; and
[0029] m is from 1 to 4, provided that when W is N, then m is not
1.
[0030] A preferred group of compounds falling within the scope of
the present invention include compounds of Formulae I-III
wherein:
[0031] Z is one of--SO.sub.2O--, --SO.sub.2NR.sup.10--,
--C(R.sup.yR.sup.z)O-- or --OC(R.sup.yR.sup.z)--, where R.sup.y and
R.sup.z are each hydrogen;
[0032] R.sup.1 is one of C.sub.6-10 aryl, pyridinyl, quinizolinyl,
quinolinyl or tetrahydroquinolinyl, any of which is optionally
substituted by one or two of hydroxy, nitro, trifluoromethyl,
halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 aminoalkyl,
C.sub.1-6 aminoalkoxy, amino, mono(C.sub.1-4)alkylamino,
di(C.sub.1-4)alkylamino, C.sub.2-6 alkoxycarbonylamino, C.sub.2-6
alkoxycarbonyl, carboxy, C.sub.1-6 hydroxyalkyl, C.sub.2-6
hydroxyalkoxy, C.sub.2-10 mono(carboxyalkyl)amino, di(C.sub.2-10
carboxyalkyl)amino, C.sub.6-14 ar(C.sub.1-6) aLkoxycarbonyl,
C.sub.2-6 alkynylcarbonyl, C.sub.1-6 alkylsulfonyl, C.sub.2-6
alkenylsulfonyl, C.sub.2-6 alkynylsulfonyl, C.sub.1-6
alkylsulfinyl, C.sub.1-6 alkylsulfonamido, amidino, guanidino,
C.sub.1-6 alkyliminoamino, formyliminoamino, C.sub.2-6
carboxyalkoxy, C.sub.2-6 carboxyalkyl, carboxyalkylamino, cyano,
trifluoromethoxy, and perfluoroethoxy;
[0033] R.sup.2, R.sup.3 and R.sup.4 are independently one of
hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, phenyl, benzyl,
trifluoromethyl, halogen, hydroxy(C.sub.1-8)alkyl, cyano, nitro,
carboxamide, carboxy, C.sub.1-4 alkoxycarbonyl, C.sub.1-4
alkoxymethyl or C.sub.1-4 alkoxy; or alternatively, R.sup.2 and
R.sup.3, when present on adjacent carbon atoms, may also be taken
together to form one of --CH=CH--CH=CH-- or --CH.sub.2).sub.q--,
where q is from 2 to 6, and R.sup.4 is as defined above;
[0034] Y is one of --O--, --S--, --NR.sup.10--, or a covalent
bond;
[0035] W is N or CR.sup.10;
[0036] R.sup.5 is one of hydrogen, C.sub.1-4 alkyl, C.sub.2-10
carboxyalkyl or C.sub.2-10 hydroxyalkyl;
[0037] R.sup.6, in each instance, is one of hydrogen, C.sub.1-4
alkyl, hydroxy, C.sub.1-4 alkoxy, phenoxy, C.sub.1-4
alkyloxycarbonyl or cyano;
[0038] R.sup.7 and R.sup.8 are independently one of hydrogen,
C.sub.1-6 alkyl, C.sub.2-10 carboxyalkyl or C.sub.2-10
hydroxyalkyl, or R.sup.7 and R.sup.8 are taken together to form
--CH.sub.2).sub.y-- where y is 0, 1 or 2, provided that when W is
N, y cannot be 0 or 1;
[0039] R.sup.9 is hydrogen; or C.sub.1-10 alkyl, optionally
substituted with amino, mono(C.sub.1-4)alkylamino, C.sub.1-6
alkoxy, hydroxy, carboxy, phenyl, alkyloxycarbonyl,
aralkoxycarbonyl, C.sub.1-6 acylamino, cyano or
trifluoromethyl;
[0040] R.sup.10, in each instance, is independently hydrogen,
C.sub.1-6 alkyl, benzyl, phenyl, C.sub.2-10 hydroxyalkyl,
C.sub.2-10 aminoalkyl, C.sub.1-4 monoalylamino(C.sub.2-8)alkyl,
C.sub.1-4 dialkylamino(C.sub.2-8)alkyl or C.sub.2-10
carboxyalkyl;
[0041] R' is one of hydrogen, C.sub.1-6 alkyl, C.sub.3-8,
cycloalkyl, phenyl, benzyl, trifluoromethyl, halogen,
hydroxy(C.sub.1-8)alkyl, cyano, nitro, carboxamide, carboxy,
alkoxycarbonyl, alkoxymethyl or alkoxy;
[0042] n is from zero to 8, with the proviso that when W is N, then
n is from 2 to 8; and
[0043] m is from 1 to 4, provided that when W is N, then m is not
1.
[0044] An especially preferred group of compounds include compounds
of Formulae I-III wherein:
[0045] Z is one of--SO.sub.2O--, --SO.sub.2NR.sup.10--,
--CH.sub.2O-- or --OCH.sub.2--;
[0046] R.sup.1 is one of phenyl or naphthyl, optionally substituted
by one or two of chloro or dimethylamino;
[0047] R.sup.2 and R.sup.3 are each hydrogen or R.sup.2 and R.sup.3
may also be taken together to form--CH=CH--CH=CH--;
[0048] R.sup.4 is one of hydrogen, methyl, methoxy or
trifluoromethyl;
[0049] Y is one of O or NR.sup.10;
[0050] W is N or CR.sup.10;
[0051] R.sup.5 is one of hydrogen, C.sub.1-6 alkyl, C.sub.2-10
hydroxyalkyl or C.sub.2-10 carboxyalkyl;
[0052] R.sup.6, in each instance is hydrogen or hydroxy;
[0053] R.sup.7 and R .sup.8 are independently one of hydrogen,
C.sub.1-6 alkyl, C.sub.2-10 hydroxyalkyl or C.sub.2-10
carboxyalkyl, or R.sup.7 and R.sup.8 are taken together to form
--(CH.sub.2).sub.y--, where y is zero, 1 or 2, with the proviso
that when W is N, y cannot be zero or 1;
[0054] R.sup.9 is hydrogen or C.sub.1-4 alkyl;
[0055] R.sup.10, in each instance, is independently hydrogen,
C.sub.1-4 alkyl, C.sub.2-4 hydroxyalkyl, C.sub.2-4 carboxyalkyl,
C.sub.2-4 aminoalkyl, dimethylamino(C.sub.2-8)alkyl,
methylamino(C.sub.2-8)alkyl;
[0056] R' is hydrogen, methyl, methoxy or trifluoromethyl;
[0057] n is from zero to 4, with the proviso that when W is N, then
n is 2 to 4; and m is 1, 2 or 3.
[0058] Useful compounds falling within the scope of Formula I
include compounds having one of Formulae IV-VI: 3
[0059] or solvates, hydrates or pharmaceutically acceptable salts
thereof; wherein:
[0060] Z, R.sup.1, R.sup.2, R.sup.3, R.sup.4, Y, R.sup.6, R.sup.9
and R.sup.10 are defined as above for Formulae I-III;
[0061] R.sup.18 is one of hydrogen, alkyl, aralkyl, aryl,
C.sub.2-10 hydroxyalkyl or C.sub.2-10 carboxyalkyl;
[0062] a is from 1 to 8, provided that when Y is other than
--CHR.sup.10--, then a is from 2 to 8;
[0063] b is from 1 to 8; and
[0064] c is from 1 to 13, provided that when Y is other than
--CHR.sup.10--, then c is from 2-13.
[0065] Preferred compounds falling within the scope of Formula II
include compounds having one of Formulae VII-IX: 4
[0066] or solvates, hydrates or pharmaceutically acceptable salts
thereof; wherein:
[0067] Z, R.sup.1, R.sup.2, R.sup.3, R.sup.4, Y, R.sup.6, R.sup.9
and R.sup.10 are defined as above for Formulae I-III;
[0068] R.sup.18 is one of hydrogen, alkyl, aralkyl, aryl,
C.sub.2-10 hydroxyalkyl or C.sub.2-10 carboxyalkyl;
[0069] a is from 1 to 8, provided that when Y is other than
--CHR.sup.10--, then a is from 2 to 8;
[0070] b is from 1 to 8; and
[0071] c is from 1 to 13, provided that when Y is other than
--CHR.sup.10--, then c is from 2-13.
[0072] Preferred compounds falling within the scope of Formula III
include compounds having one of Formulae X or XI: 5
[0073] or solvates, hydrates or pharmaceutically acceptable salts
thereof, wherein:
[0074] Z, R.sup.1, R.sup.2, R.sup.3, R.sup.4, Y, R.sup.6, R.sup.9
and R.sup.10 are defmed as above for Formulae I-III;
[0075] R.sup.18 is one of alkyl, aralkyl, aryl, C.sub.2-10
hydroxyalkyl or C.sub.2-10 carboxyalkyl;
[0076] d is from 1 to 8; and
[0077] e is from 1 to 8.
[0078] The moiety --Z--R.sup.1 of Formulae I-XI is attached to the
benzene ring in a position ortho-, meta- or para- to Y.
[0079] The amidino moiety (--C(=NR.sup.6)NR.sup.6R.sup.6) of
Formulae HI, X and lcan be attached in the ortho-, meta- orpara-
positions.
[0080] Preferred compounds of the present invention are those of
Formula I-XI wherein Y is one of divalent oxygen (--O--) or
--NR.sup.10-- and Z is one of --SO.sub.2NR.sup.10--, --SO.sub.2O--
or --CH.sub.2O--.
[0081] Preferred compounds of the present invention are those of
Formula I-XI wherein R.sup.1 is one of C.sub.1-12 alkyl, C.sub.4-7
cycloalkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl or C.sub.6-14
aryl, especially C.sub.6-10 aryl, any of which is optionally
substituted. Substituents that can be optionally present on the RI
moieties include one or more, preferably one or two, hydroxy,
nitro, trifluoromethyl, halogen, alkoxy, aminoalkoxy, aminoalkyl,
hydroxyalkyl, hydroxyalkoxy, cyano, amino, monoalkylamino,
dialkylamino, carboxy, carboxyalkyl, carboxyalkoxy,
mono(hydroxyalkyl)amino, di(hydroxyalkyl)amino,
mono(carboxyalkyl)amino, di(carboxyalkyl)amino,
alkoxycarbonylamino, alkoxycarbonyl, aralkoxycarbonyl,
alkenylcarbonyl, alkynylcarbonyl, alkylsulfonyl, alkenylsulfonyl,
alkynylsulfonyl, alkylsulfinyl, alkylsulfonamido, arnidino,
guanidino, alkyliminoamino, formyliminoamino, trifluoromethoxy or
perfluoroethoxy. A further substituent on aryl, cycloalkyl,
alkenyl, alkynyl and aralkyl moities of RI includes one or more,
preferably one or two, alkyl moieties. Preferred values of optional
substituents on R.sup.1 include hydroxy, nitro, trifluoromethyl,
halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C,.sub.1-6 aminoalkyl,
C.sub.1-6 aminoalkoxy, amino, mono(C.sub.1-4)alkylamino,
di(C.sub.1-4)alkylamino, C.sub.2-6 alkoxycarbonylamino, C.sub.2-6
alkoxycarbonyl, carboxy, C.sub.1-6 hydroxyalkyl, C.sub.2-10
mono(carboxyalkyl)amino, di(C.sub.2-10 carboxyalkyl)amino,
C.sub.6-14 ar(C.sub.1-6 alkoxycarbonyl, C.sub.2-6 alkynylcarbonyl,
C.sub.1-6 alkylsulfonyl, C.sub.2-6 alkenylsulfonyl, C.sub.2-6
alkynylsulfonyl, C.sub.1-6 alkylsulfinyl, C.sub.1-6
alkylsulfonamido, amidino, guanidino, C.sub.1-6 alkyliminoamino,
formyliminoamino, C.sub.2-6 carboxyalkoxy, carboxyalkylamino,
cyano, trifluoromethoxy, and perfluoroethoxy.
[0082] An additional preferred group of compounds are those
compounds of Formulae I-XI wherein R.sup.1 is heteroaryl or
substituted heteroaryl. Preferred R.sup.1 heteroaryl groups include
pyridyl, thienyl, chromenyl, benzoxazolyl, quinazolinyl, quinolinyl
and tetrahydroquinolinyl, with pyridyl, quinazolinyl, quinolinyl
and tetrahydroquinolinyl being most preferred. Preferred compounds
when R.sup.1 is substituted heteroaryl include those compounds
having one of the heteroaryl groups mentioned as preferred that
have one or more, preferably one or two, substituents that are
listed in the preceding paragraph.
[0083] Useful values of R.sup.1 include phenyl, chlorophenyl,
iodophenyl, dichlorophenyl, bromophenyl, trifluoromethylphenyl,
di(trifluoromethyl)phenyl, methylphenyl, t-butylphenyl,
methoxyphenyl, dimethoxyphenyl, hydroxyphenyl, carboxyphenyl,
aminophenyl, methylaminophenyl, n-butylaminophenyl, amidinophenyl,
guanidinophenyl, formyliminoaminophenyl, acetimidoylaminophenyl,
methoxycarbonylphenyl, ethoxycarbonylphenyl, carboxymethoxyphenyl,
naphthyl, hydroxynaphthyl, cyclohexyl, cyclopentyl, 2-propylbutyl,
quinolinyl and tetrahydroquinolinyl.
[0084] The groups R.sup.2, R.sup.3 and R.sup.4 in Formulae I-XI
substitute for any remaining hydrogen atoms on the benzene ring
after allowing for attachment of the moiety --Z--R.sup.1. Preferred
compounds are those where R.sup.2, R.sup.3 and R.sup.4 are
independently hydrogen, C.sub.1-4 alkyl, C.sub.4-7 cycloalkyl,
C.sub.6-14 aryl, especially C.sub.6-10, aryl, C.sub.6-10
ar(C.sub.1-4)alkyl, trifluoromethyl, halogen, hydroxyalkyl, cyano,
nitro, carboxamide, carboxy, alkoxycarbonyl, carboxymethyl,
alkoxycarbonylmethyl, or cycloalkyloxycarbonyl. Alternatively,
R.sup.2 and R.sup.3, when attached to adjacent carbon atoms on the
benzene ring, are one of --CH=CH--CH=CH-- or --(CH.sub.2).sub.q--,
where q is from 2 to 6, thereby forming a fused ring. Preferred
values of R.sup.2 together with R.sup.3 include --CH=CH--CH=CH--,
--CH.sub.2--CH.sub.2--CH.sub.2-- and
--CH.sub.2----CH.sub.2--CH.sub.2--CH.sub.2. When R.sup.2 and
R.sup.3 together form a fused ring, R.sup.4 is preferably
hydrogen.
[0085] Useful values of R.sup.2, R.sup.3 and R.sup.4 include
hydrogen, methyl, ethyl, chloro, bromo, trifluoromethyl,
hydroxymethyl, methoxy, ethoxy, carboxamide, nitro, phenyl,
cyclopropyl, hydroxy, isopropyl, methoxycarbonyl, ethoxycarbonyl
and benzyl. Useful values of R.sup.2, R.sup.3 and R.sup.4 also
include R.sup.2 and R.sup.3 together forming --CH=CH--CH=CH or
--CH.sub.2--CH.sub.2--CH.sub.2-- and R.sup.4 being hydrogen.
[0086] Preferred values of R.sup.6 in Formulae I-XI are hydrogen,
hydroxy, C .sub.1-6alkyl, C.sub.1-6 alkoxy, cyano or
--CO.sub.2R.sup.w, where R.sup.w, in each instance, is preferably
one of C.sub.1-4 alkyl or C.sub.4-7 cycloalkyl. Suitable values of
R.sup.6 include hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy,
methoxy, ethoxy, cyano, --CO.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.3 and --CO.sub.2CH.sub.2CH.sub.2CH.sub.3.
In the most preferred embodiments, each R.sup.6 is hydrogen.
[0087] Preferred compounds include compounds of Formulae I and II,
where R.sup.7 and R.sup.8 are independently one of hydrogen,
C.sub.1-6 alkyl, C.sub.6-10 ar(C.sub.1-6)alkyl, C.sub.6-10 aryl,
C.sub.2-10 hydroxyalkyl or C.sub.2-7 carboxyalkyl, or R.sup.7 and
R.sup.8 are taken together to form --CH.sub.2).sub.y--, where y is
most preferably 2. Useful values of R.sup.7 and R.sup.8 include
hydrogen, methyl, ethyl, propyl, n-butyl, benzyl, phenylethyl,
2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-carboxymethyl,
3-carboxyethyl and 4-carboxypropyl.
[0088] Preferred compounds are those of Formulae I, IV, Vand VI,
wherein R.sup.9 is C.sub.1-10 hydrogen or alkyl optionally
substituted by one, two or three of, preferably one of, amino,
monoalkylamino, dialkylamino, alkoxy, hydroxy, alkoxycarbonyl,
aryloxycarbonly, aralkoxycarbonyl, carboalkoxy, phenyl, cyano,
trifluoromethyl, acetylamino, pyridyl, thienyl, furyl, pyrrolyl or
imidazolyl.
[0089] Suitable values of R.sup.9 include hydrogen, methyl, ethyl,
propyl, n-butyl, benzyl, phenethyl, 2-hydroxyethyl,
3-hydroxypropyl, 4-hydroxybutyl, carboxymethyl and
carboxyethyl.
[0090] Preferred values of R.sup.10 in Formulae I-XI include
hydrogen, C.sub.1-6 alkyl, C.sub.6-10 ar(C.sub.1-6)alkyl,
C.sub.6-10 aryl, C.sub.2-10 hydroxyallyl C.sub.2-10 aminoalkyl,
C.sub.2-7 carboxyalkyl, mono(C.sub.1-4 alkyl)amino(C.sub.1-8)alkyl,
and di(C.sub.1-4 alkyl)amino (C.sub.1-8)alkyl. Suitable values of
R.sup.10 include methyl, ethyl, propyl, n-butyl, benzyl,
phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl,
2-aminoethyl, 2-carboxymethyl, 3carboxyethyl, 4-carboxypropyl and
2-(dimethylamino)ethyl.
[0091] Preferred values of n in Formulae I-III include from 1 to 6,
more preferably from 1 to 4, and most preferably 1 or 2, with the
proviso that when W is N and Y is other than --CHR.sup.10--, then n
is not 1. Preferred values of m include from 1 to 4, more
preferably 1, 2 or 3, provided that when W is N, then m is not
1.
[0092] Preferred values of R.sup.5 in Formula III include is one of
hydrogen, C.sub.1-4 alkyl, phenyl, benzyl, phenethyl, C.sub.2-10
carboxyalkyl and C.sub.2-10 hydroxyalkyl. Especially preferred
values are hydrogen, C.sub.1-6 alkyl, C.sub.2-10 hydroxyalkyl and
C.sub.2-10 carboxyalkyl. Suitable values of R.sup.5 include
hydrogen, methyl, hydroxymethyl, hydroxyethyl, carboxymethyl and
carboxyethyl.
[0093] Preferred values of R' in Formula III include hydrogen,
C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, phenyl, benzyl,
trifluoromethyl, halogen, hydroxy(C.sub.1-8)alkyl, cyano, nitro,
carboxamide, carboxy, alkoxycarbonyl, alkoxymethyl and alkoxy.
Suitable values of R' include hydrogen, methyl, methoxy and
trifluoromethyl;
[0094] Preferred values of "a" in Formulae IV and VII include from
1 to 6, more preferably from 1 to 4, and most preferably 1 or 2,
with the proviso that when Y is other than --CHR.sup.10--, then n
is not 1.
[0095] Preferred values of "b" in Formulae V and VIII include from
1 to 6, preferably from 1 to 4, and most preferably 1 or 2.
[0096] Preferred values of "c" in Formulae VI and IX include from 1
to 8, more preferably from 1 to 6, and most preferably 1, 2, 3, or
4.
[0097] Preferred values of "d" and "e" in Fromulae VandXI include
from 1 to 6, preferably from 1 to 4, and most preferably 1 or
2.
[0098] Preferred compounds of Formulae VI, IXandXI are those where
R.sup.18 is independently one of hydrogen, C.sub.1-6 alkyl,
C.sub.6-10 ar(C.sub.1-6)alkyl, C.sub.6-10 aryl, C.sub.2-10
hydroxyallyl and C.sub.2-7 carboxyalkyl. Useful values of R.sup.18
include hydrogen, methyl, ethyl, propyl, n-butyl, benzyl,
phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl,
2-carboxymethyl, 3-carboxyethyl and 4-carboxypropyl. Most preferred
compounds are those where R.sup.18 is hydrogen.
[0099] Specific compounds within the scope of the invention include
the following examples:
[0100] 2-chlorobenzenesulfonic acid
3-[(1-acetimidoylpiperidin-4-yl)methox- y]-5-methylphenyl ester
hydrochloride;
[0101] 3 -(2-chlorobenzyloxy)-5-methyl- 1- [2-(1
-acetimidoyl)piperazin-4-- yl]]ethoxybenzene diacetic acid
salt;
[0102]
N-[2-(N,N-dimethylamino)ethyl]-N-[2-[[4-(1-acetimidoyl)amino]butoxy-
]-4-methylphenyl]benzenesulfonamide dihydrochloride;
[0103] N-benzyl-N- [[[3 -(1
-acetimidoyl)piperidin-4-yl]methylamino]phenyl-
]-benzenesulfonamide; 3-chlorobenzenesulfonic acid
3-[[(1-acetimidoyl)pipe- ridin-4-yl]methoxy]-5-methylphenyl ester
hydrochloride;
[0104] 2-chlorobenzenesulfonic acid
3-[(3-amidinophenyl)methoxy]-5-methylp- henyl ester
hydrochloride;
[0105] 2-chlorobenzenesulfonic acid
3-[[3-(N-hydroxy)amidinophenyl]methoxy- ]-5-methylphenyl ester
hydrochloride;
[0106] 2,3-dichlorobenzenesulfonic acid
3-[[(l-acetimidoyl)piperidin-4-yl]- methoxy]-5-methylphenyl ester
hydrochloride;
[0107] 2-chloro-N-[[3 - [(1 -acetimidoyl)piperidin-4-yl] methoxy]
-5 -trifluoromethylphenyl]benzenesulfonamide hydrochloride;
[0108] 2-chloro-N-(5-carboxypentyl)-N-[[3-[(1
-acetimidoyl)piperidin-4-yl]-
methoxy]-5-trifluoromethylphenyl]benzenesulfonamide;
[0109] 1-(5-N,N-dimethylamino)naphthalenesulfonic acid
3-[[(1-acetimidoyl)piperidin-3-yl]methoxy]-5-methoxyphenyl ester
hydrochloride;
[0110] 2-chlorobenzenesulfonic acid 1 -[[(1
-acetimidoyl)piperidin-4-yl]me- thoxy]naphthalen-3-yl ester acetic
acid salt;
[0111] 3-[(2-chlorophenoxy)methyl]-[[(1
-acetimidoyl)piperidin-4-yl]methox- y]benzene acetic acid salt;
[0112] 2-Chlorobenzenesulfonic acid
3-[(4-amidinophenyl)methoxy]-5-methylp- henyl ester
hydrochloride;
[0113] 2-chiorobenzenesulfonic acid
3-[(3-amidinophenyl)methoxy]phenyl ester hydrochloride;
[0114] 2-chlorobenzenesulfonic acid
3-[5-amidinopentyloxy]-5-methylphenyl ester acetic acid salt;
[0115] 2-chlorobenzenesulfonic acid
3-[3-amidinopropoxy]-5-methylphenyl ester hydrochloride; and
[0116] 2-chlorobenzenesulfonic acid
3-[[3-(N-methylamidino)phenyl]methoxy]- -5-methylphenyl ester
hydrochloride.
[0117] It is also to be understood that the present invention is
considered to include stereoisomers as well as optical isomers,
e.g. mixtures of enantiomers as well as individual enantiomers and
diastereomers, which arise as a consequence of structural asymmetry
in selected compounds of the present series.
[0118] The compounds of Formulae I-XI may also be solvated,
especially hydrated. Hydration may occur during manufacturing of
the compounds or compositions comprising the compounds, or the
hydration may occur over time due to the hygroscopic nature of the
compounds.
[0119] The term "aryl" as employed herein by itself or as part of
another group refers to monocyclic or bicyclic aromatic groups
containing from 6 to 12 carbons in the ring portion, preferably
6-10 carbons in the ring portion, such as phenyl, naphthyl or
tetrahydronaphthyl.
[0120] The term "heteroaryl" as employed herein refers to groups
having 5 to 14 ring atoms; 6, 10 or 14 .pi. electrons shared in a
cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen,
nitrogen or sulfur heteroatoms (where examples of heteroaryl groups
are: thienyl, benzotb]thienyl, naphtho[2,3-b]thienyl, thianthrenyl,
fliryl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl,
xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl,
pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,
4H-quinolizinyl, isoquinolyl, quinolinyl, tetrahydroquinolinyl,
phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl,
4aH-carbazolyl, carbazolyl, .beta.-carbolinyl, phenanthridinyl,
acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl,
phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl groups).
[0121] The term "aralkyl" or "arylallyl" as employed herein by
itself or as part of another group refers to C.sub.1-6 alkyl groups
having an aryl substituent, such as benzyl, phenylethyl or
2-naphthylmethyl.
[0122] The term "cycloalkyl" as employed herein by itself or as
part of another group refers to cycloalllyl groups containing 3 to
9 carbon atoms, preferably 4 to 7 carbon atoms. Typical examples
are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl and cyclononyl.
[0123] The term "halogen" or "halo" as employed herein by itself or
as part of another group refers to chlorine, bromine, fluorine or
iodine with chlorine being preferred.
[0124] Scheme Ia illustrates but is not limited to the preparation
of compounds of Examples 1, 5, 8, 9, 11, and 12. 6
[0125] Each of R.sup.1 through R.sup.3, R.sup.6 through R.sup.9, n
and m is as defmed above; P.sup.a is a hydroxyl protecting group or
hydrogen, and P.sup.b is an amino protecting group.
[0126] Phenols 1 (where P is H) are converted to monosulfonates 2
by treatment with appropriate sulfonyl chlorides. Preferred
conditions include treating phenol 1 with a sulfonyl chloride in a
biphasic system composed of ether and an aqueous phase saturated
with NaHCO.sub.3. Alternatively, the reaction may be effected first
by deprotonating 1 with a strong base, most preferably NaH, in a
polar organic solvent, such as DMF or tetrahydrofliran, followed by
treating the deprotonated phenol with the sulfonyl chloride. Still
alternatively, phenol 1, in a typical organic solvent, such as
methylene chloride, may be converted to 2 by treating the phenol
with sulfonyl chloride in the presence of an amine base, such as
N-methylmorpholine.
[0127] Phenols 1 may be monoprotected (P.sup.a is a protecting
group) with a variety of protecting groups known in the art, such
as esters and benzyl ethers (Green, T. W. & Wuts, P. G. M.,
Protective Groups in Organic Synthesis, 2nd edition, John Wiley and
Sons, Inc., New York (1991)). Deprotection of the hydroxyl groups
is routinely accomplished using reaction conditions well-known in
the art. For example, deprotection of benzyl ethers may be effected
through catalytic hydrogenation using palladium on carbon as a
catalyst in solvents such as ethanol or tetrahydrofuran.
Deprotection of an acetate is accomplished by basic hydrolysis,
most preferably with sodium hydroxide in aqueous
tetrahydrofuran.
[0128] Phenols 2 are coupled to 3 (for L=OH) using a Mitsunobu
coupling procedure (Mitsunobu, O., Synthesis 1 (1981)) to provide
4. Preferred coupling conditions include using a trialkylphosphine
or triarylphosphine, such as triphenylphosphine, in a suitable
solvent such as tetrahydrofuran or methylene chloride, and a
dialkyl azodicarboxylate, such as diethyl azodicarboxylate. In some
cases, it is advantageous to add an amine base such as
N-methylmorpholine. The amine terminus of 3 is protected with a
protecting group P.sup.b that is readily removed from 4.
Amino-protecting groups are well known in the art (Greene, T. W.
& Wuts, P. G. M., Protective Groups in Organic Synthesis, 2nd
edition, John Wiley and Sons, Inc., New York (1991)). Deprotection
of the amino group is effected by employing reaction conditions
that are well known in the art. For example, the t-butoxycarbonyl
(BOC) may be removed by exposure to strongly acidic medium, such as
hydrogen chloride, in a suitable solvent, such as dioxane, or a
mixed trifluoroacetic acid/methylene chloride solvent system.
Benzyloxycarbonyl (CBz) groups may be removed by hydrogen using
palladium on carbon as a catalyst in solvents such as ethanol or
tetrahydrofuran. The resulting amine is then converted to amidine 5
in a manner similar to the procedure described by Nagahara et. al.,
J. Med. Chem. 37(8):1200-1207 (1994) wherein the amine is treated
with an appropriate imidate in the presence of a base such as
N,N-diisopropylethylamine in an appropriate solvent such as DMF.
Alternatively, the amine is treated with an appropriate imidate in
the presence of a base, such as sodium hydroxide, in an appropriate
solvent, such as methanol. Scheme Ib illustrates but is not limited
to the preparation of compounds of Examples 2 and 13. 7
[0129] R.sup.1-R.sup.3, R.sup.6-R.sup.8, n, m P.sup.a and P.sup.b
are each as defined above.
[0130] Aryl ethers 8 are synthesized in a fashion analogous to
synthesis of 5. Phenol 1 (P is H) is converted to derivative 6 by
treating 1 with a strong base, preferably NaH, in a suitable
solvent such as DMF, followed by addition of a reactive alkyl or
benzyl compound, R.sup.1CH.sub.2X (where X is a reactive finctional
group such as iodide, chloride, bromide or alkylsulfonate).
Alternatively, the Mitsunobu Reaction may be used with an
appropriate R.sup.1CH.sub.2X (X=OH) using the reaction conditions
described above. The use of suitable alcohol protecting groups
(P.sup.a), such as esters, to suppress over-alkylation, is well
known in the art (Greene, T. W. & Wuts, P. G. M., Protective
Groups in Organic Synthysis, 2nd edition, John Wiley and Sons,
Inc., New York (1991)). The protecting group may then be removed
using well-known techniques, for example by hydrolysis with aqueous
NaOH, when an ester protecting group is employed. Phenol 6 is then
converted to amidine 8 using the conditions described for formation
of 5.
[0131] Scheme II illustrates, but is not limited to, the
preparation of compounds exemplified by Examples 3, 9 and 10. 8
[0132] R.sup.1-R.sup.3, R.sup.6-R.sup.10, n, m, P.sup.a and P.sup.b
are as defined above.
[0133] According to Scheme II, a nitrophenol 9 may be coupled to
compound 3 by standard techniques. Preferably, the reaction is
effected by the Mitsunobu reaction (where L is OH). Alternatively,
9 may be treated with a base, such as NaH, in a suitable solvent
such as DMF or THF, followed by addition of 3 (where L is a
reactive group, such as Cl, Br, I or alkylsulfonate). The nitro
group is thereafter reduced, for example, by catalytic reduction
using palladium on carbon in a suitable solvent such as ethanol or
tetrahydroftnan. The resulting product in then treated with an
appropriate sulfonyl chloride (R.sup.1SO.sub.2Cl) to provide 11.
Removal of the amine protecting group P.sup.b is accomplished by
techniques known in the art. For example, the t-butoxycarbonyl
(BOC) is removed by exposure to a strongly acidic medium, such as
hydrogen chloride in a suitable solvent such as dioxane or
trfluoroacetic acid in methylene chloride. Benzyloxycarbonyl (CBz)
groups are removed by catalytic hydrogen using palladium on carbon
as a catalyst in solvents such as ethanol or tetrahydrofuran.
[0134] The resulting amine is then converted to amidine 12 in a
manner similar to the procedure described by Nagahara et. al., J.
Med. Chem. 37(8):1200-1207 (1994) wherein the amine is treated with
an appropriate imidate in the presence of a base such as
N,N-diisopropylethylamine in an appropriate solvent such as DMF.
Alternatively, the amine is treated with an appropriate imidate in
the presence of a base such as sodium hydroxide as base in an
appropriate solvent such as methanol. N-Substituted sulfonamide
derivative 13 is obtained by altylation of 11 employing a suitable
alkylating agent (R.sup.10X) in the presence of a base, most
preferably Cs.sub.2CO.sub.3 using a polar solvent such as DMF.
Deprotection and amidination are then executed in a manner similar
to the conversion of 11 to 12.
[0135] Scheme III illustrates but is not limited to the preparation
of compounds of Example 4. 9
[0136] R.sup.1-R.sup.3, R.sup.7-R.sup.10, n, m and P.sup.b are each
as defined above.
[0137] According to Scheme III, nitroaniline 14 is converted to a
sulfonamide by treatment with an appropriate sulfonyl chloride
R.sup.1SO.sub.2Cl in the presence of a weak base, such as
N-methylmorpholine. The resulting sulfonamide nitrogen is alkylated
with a suitable alkylating agent (R.sup.10X) in the presence of a
base, preferably an alkali metal carbonate such as Cs.sub.2CO.sub.3
or K.sub.2CO.sub.3, using a polar solvent, such as DMF, to provide
intermediate 15. After reduction of the nitro group, the resulting
aniline is coupled to a carboxylic acid, 16, to provide amide 17.
Amide coupling may be performed using any of a number of common
peptide coupling reagents. Preferably, one of
1,3-dicyclohexylcarbodiimide or Castro's reagent (BOP) are employed
(B. Castro et al., Tetrahedron Lett.:1219 (1975)). Alternatively,
17 may be formed by coupling the aniline with the corresponding
acid chloride of acid 16 in the presence of an acid scavenger, such
as N-methylmorpholine. Amide 17 is converted to amine 18 by
reduction of the amide functionality with an appropriate hydride
reagent, preferably borane-THF complex or chlorotrimethylsilane and
lithium borohydride. This reaction occurs in a suitable polar
solvent, such as THF. Removal of the amine protecting group P.sup.b
and formation of the amidine as described in Scheme II provides the
desired compound 19. Alternatively the amide nitrogen may be
alkylated using a strong base, such as sodium hydride, in a
suitable polar solvent such as DMF, followed by treatment with an
alkylating agent (R.sup.10X) to afford intermediate 20.
[0138] Reduction of the amide, as executed in the formation of 18,
to give 21 followed by deprotection and amidination as previously
described provides the analogous compound 22.
[0139] Scheme IV illustrates but is not limited to the preparation
of compounds of Examples 6, 7, 14, 15, 16, 17 and 18. 10
[0140] R.sup.1-R.sup.3, R.sup.6 and n are each as defined
above.
[0141] Monosulfonates 2 are converted to cyano derivatives 24 by
exposing 2 to a base, most preferably sodium hydride in a suitable
solvent such as DMF, followed by addition 23, where L is a reactive
group such as iodide, chloride, bromide, alkyl sulfonate, or aryl
sulfonate. Alternatively, the Mitsunobu Reaction may be used with
an appropriate alcohol 23, where L=OH. The nitrile is submitted to
arnidino formation conditions such as those described by Nagahara
et. al., J. Med Chem. 37(8):1200-1207 (1994), wherein the nitrile
is first exposed to a strong acid, preferably hydrogen chloride, in
a suitable alcoholic solvent, preferably methanol or ethanol, which
converts the nitrile to an imidate. Following brief isolation, the
imidate is treated with an appropriate amine HNR.sup.6R.sup.6 to
effect formation of 25. Similarly, benzamidines 28 are prepared
from 2 using appropriate benzonitrile derivatives 26.
[0142] It is to be understood that in each of the above-mentioned
schemes, an additional substituent, R.sup.4, may be present on the
phenyl ring of the starting material.
[0143] For medicinal use, the pharmaceutically acceptable acid
addition salts, those salts in which the anion does not contribute
significantly to toxicity or pharmacological activity of the
organic cation, are preferred. The acid addition salts are obtained
either by reaction of an organic base of Formulae I-XI with an
organic or inorganic acid, preferably by contact in solution, or by
any of the standard methods detailed in the literature available to
any practitioner skilled in the art. Examples of useful organic
acids are carboxylic acids such as maleic acid, acetic acid,
tartaric acid, propionic acid, fumaric acid, isethionic acid,
succinic acid, cyclamic acid, pivalic acid and the like; useful
inorganic acids are hydrohalide acids such as HCl, HBr, HI;
sulfuric acid; phosphoric acid and the like. Preferred acids for
forming acid addition salts include HCl and acetic acid.
[0144] The compounds of the present invention represent a novel
class of potent inhibitors of metallo, acid, thiol and serine
proteases. Examples of the serine proteases inhibited by compounds
within the scope of the invention include leukocyte neutrophil
elastase, a proteolytic enzyme implicated in the pathogenesis of
emphysema; chymotrypsin and trypsin, digestive enzymes; pancreatic
elastase, and cathepsin G, a chymotrypsin-like protease also
associated with leukocytes; thrombin and factor Xa, proteolytic
enzymes in the blood coagulation pathway. Inhibition of
thermolysin, a metalloprotease, and pepsin, an acid protease, are
also contemplated uses of compounds of the present invention. The
compounds of the present invention are preferably employed to
inhibit trypsin-like proteases.
[0145] An end use application of the compounds that inhibit
chymotrypsin and trypsin is in the treatment of pancreatitis. For
their end-use application, the potency and other biochemical
parameters of the enzyme-inhibiting characteristics of the
compounds of the present invention is readily ascertained by
standard biochemical techniques well-known in the art. Actual dose
ranges for their specific end-use application will, of course,
depend upon the nature and severity of the disease state of the
patient or animal to be treated, as determined by the attending
diagnostician. It is expected that a useful dose range will be
about 0.01 to 10 mg per kg per day for an effective therapeutic
effect.
[0146] Compounds of the present invention that are distinguished by
their ability to inhibit either factor Xa or thrombin may be
employed for a number of therapeutic purposes. As factor Xa or
thrombin inhibitors, compounds of the present invention inhibit
thrombin production. Therefore, these compounds are useful for the
treatment or prophylaxis of states characterized by abnormal venous
or arterial thrombosis involving either thrombin production or
action. These states include, but are not limited to, deep vein
thrombosis; disseminated intravascular coagulopathy which occurs
during septic shock, viral infections and cancer; myocardial
infarction; stroke; coronary artery bypass; hip replacement; and
thrombus formation resulting from either thrombolytic therapy or
percutaneous transluminal coronary angioplasty (PCTA). The
compounds of the present invention may also be used as an
anticoagulant in extracorporeal blood circuits.
[0147] By virtue of the effects of both factor Xa and thrombin on a
host of cell types, such as smooth muscle cells, endothelial cells
and neutrophils, the compounds of the present invention find
additional use in the treatment or prophylaxis of adult respiratory
distress syndrome; inflammatory responses, such as edema;
reperfusion damage; atherosclerosis; and restenosis following an
injury such as balloon angioplasty, atherectomy, and arterial stent
placement.
[0148] The compounds of the present invention may be useful in
treating neoplasia and metastasis as well as neurodegenerative
diseases, such as Alzheimer's disease and Parkinson's disease.
[0149] When employed as thrombin or factor Xa inhibitors, the
compounds of the present invention may be administered in an
effective amount within the dosage range of about 0.1 to about 500
mg/kg, preferably between 0.1 to 10 mg/kg body weight, on a regimen
in single or 2-4 divided daily doses.
[0150] When employed as inhibitors of thrombin, the compounds of
the present invention may be used in combination with thrombolytic
agents such as tissue plasminogen activator, streptokinase, and
urokinase. Additionally, the compounds of the present invention may
be used in combination with other antithrombotic or anticoagulant
drugs such as, but not limited to, fibrinogen antagonists and
thromboxane receptor antagonists.
[0151] Human leucocyte elastase is released by polymorphonuclear
leukocytes at sites of inflammation and thus is a contributing
cause for a number of disease states. Thus, compounds of the
present invention are expected to have an anti-inflammatory effect
useful in the treatment of gout, rheumatoid arthritis and other
inflammatory diseases, and in the treatment of emphysema. Cathepsin
G has also been implicated in the disease states of arthritis, gout
and emphysema, and in addition, glomerulonephritis and lung
infestations caused by infections in the lung. In their end-use
application the enzyme inhibitory properties of the compounds of
Formulae I-XI is readily ascertained by standard biochemical
techniques that are well-known in the art.
[0152] The neutrophil elastase inhibitory properites of compounds
within the scope of the present invention are determined by the
following method. Neutrophil elastase is prepared by the procedure
described by Baugh et aL, Biochemistry 15: 836 (1979). Enzyme
assays are conducted substantially according to the procedure
disclosed by Nakajima et al., J. Biol. Chem. 254: 4027 (1979), in
assay mixtures containing 0.10 M Hepes
(N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid) buffer, pH
7.5; 0.5 M NaCl; 10% dimethylsulfoxide; and 1.50.times.10.sup.-4 M
MeOSuc-Ala-Ala-Pro-Val-p-nitroanilide as substrate. Inhibitors are
evaluated by comparing enzymatic activity measured in the presence
and absence of inhibitor.
[0153] The Cathepsin G inhibitory properties of compounds within
the scope of the present invention are determined by the following
method. A preparation of partially purified human Cathepsin G is
obtained by the procedure of Baugh et al., Biochemistry 15: 836
(1979). Leukocyte granules are a major source for the preparation
of leukocyte elastase and cathepsin G (chymotrypsin-like activity).
Leukocytes are lysed and granules are isolated. The leukocyte
granules are extracted with 0.20 M sodium acetate, pH 4.0, and
extracts are dialyzed against 0.05 M Tris buffer, pH 8.0 containing
0.05 M NaCl overnight at 4.degree. C. A protein fraction
precipitates during dialysis and is isolated by centrifugation.
This fraction contains most of the chymotrypsin-like activity of
leukocyte granules. Specific substrates are prepared for each
enzyme, namely MeOSuc-Ala-Ala-Pro-Val-p-nitroanilide and
Suc-Ala-Ala-Pro-Phe-p-ni- troanilide. The latter is not hydrolyzed
by leukocyte elastase. Enzyme preparations are assayed in 2.00 mL
of 0.10 M Hepes buffer, pH 7.5, containing 0.50 M NaCl, 10%
dimethylsulfoxide and 0.0020 M Suc-Ala-Ala-Pro-Phe-pnitroanilide as
a substrate. Hydrolysis of the p-nitroanilide substrate is
monitored at 405 nm and at 25.degree. C.
[0154] Useful dose range for the application of compounds of the
present invention as neutrophil elastase inhibitors and as
Cathepsin G inhibitors will of course depend upon the nature and
severity of the disease state, as determined by the attending
diagnostician, with the range of 0.01 to 10 mg/kg of body weight,
per day, being useful for the aforementioned disease states.
[0155] Compounds of the present invention that inhibit urokinase or
plasminogen activator are potentially useful in treating excessive
cell growth disease state. As such the compounds of the present
invention may also be useful in the treatment of benign prostatic
hypertrophy and prostatic carcinoma, the treatment of psoriasis,
and in their use as abortifacients. For their end-use application,
the potency and other biochemical parameters of the enzyme
inhibiting characteristics of the compounds of the present
invention are readily ascertained by standard biochemical
techniques well-known in the art. Actual dose ranges for their
specific end-use application will, of course, depend upon the
nature and severity of the disease state of the patient or animal
to be treated as determined by the attending diagnostician. It is
to be expected that the general end-use application dose range will
be about 0.01 to 10 mg per kg per day for an effective therapeutic
effect.
[0156] Additional uses for compounds of the present invention
include analysis of commercial reagent enzymes for active site
concentration. For example, chymotrypsin is supplied as a standard
reagent for use in clinical quantitation of chymotrypsin activity
in pancreatic juices and feces. Such assays are diagnostic for
gastrointestinal and pancreatic disorders. Pancreatic elastase is
also supplied commercially as a reagent for quantitation of
.alpha..sub.1-antitrypsin in plasma. Plasma
.alpha..sub.1-antitrypsin increases in concentration during the
course of several inflammatory diseases, and
.alpha..sub.1-antitrypsin deficiencies are associated with
increased incidence of lung disease. Compounds of the present
invention can be used to enhance the accuracy and reproducibility
of this assay by titrametric standardization of the commercial
elastase supplied as a reagent. See, U.S. Pat. No. 4,499,082.
[0157] Protease activity in certain protein extracts during
purification of particular proteins is a recurring problem which
can complicate and compromise the results of protein isolation
procedures. Certain proteases present in such extracts can be
inhibited during purification steps by compounds of the present
invention, which bind tightly to various proteolytic enzymes.
[0158] The pharmaceutical compositions of the invention can be
administered to any animal that can experience the beneficial
effects of the compounds of the invention. Foremost among such
animals are humans, although the invention is not intended to be so
limited.
[0159] The pharmaceutical compositions of the present invention can
be administered by any means that achieve their intended purpose.
For example, administration can be by parenteral, subcutaneous,
intravenous, intramuscular, intraperitoneal, transdermal, buccal,
or ocular routes. Alternatively, or concurrently, administration
can be by the oral route. The dosage administered will be dependent
upon the age, health, and weight of the recipient, kind of
concurrent treatment, if any, frequency of treatment, and the
nature of the effect desired.
[0160] In addition to the pharmacologically active compounds, the
new pharmaceutical preparations can contain suitable
pharmaceutically acceptable carriers comprising excipients and
auxiliaries that facilitate processing of the active compounds into
preparations that can be used pharmaceutically.
[0161] The pharmaceutical preparations of the present invention are
manufactured in a manner that is, itself, known, for example, by
means of conventional mixing, granulating, dragee-making,
dissolving, or lyophilizing processes. Thus, pharmaceutical
preparations for oral use can be obtained by combining the active
compounds with solid excipients, optionally grinding the resulting
mixture and processing the mixture of granules, after adding
suitable auxiliaries, if desired or necessary, to obtain tablets or
dragee cores.
[0162] Suitable excipients are, in particular, fillers such as
saccharides, for example, lactose or sucrose, mannitol or sorbitol,
cellulose preparations and/or calcium phosphates, for example,
tricalcium phosphate or calcium hydrogen phosphate, as well as
binders, such as, starch paste, using, for example, maize starch,
wheat starch, rice starch, potato starch, gelatin, tragacanth,
methyl cellulose, hydroxypropylmethylcellulose, sodium
carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,
disintegrating agents can be added, such as, the above-mentioned
starches and also carboxymethyl-starch, cross-linked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof, such as,
sodium alginate. Auxiliaries are, above all, flow-regulating agents
and lubricants, for example, silica, talc, stearic acid or salts
thereof, such as, magnesium stearate or calcium stearate, and/or
polyethylene glycol. Dragee cores are provided with suitable
coatings that, if desired, are resistant to gastric juices. For
this purpose, concentrated saccharide solutions can be used, which
may optionally contain gum arabic, talc, polyvinyl pyrrolidone,
polyethylene glycol, and/or titanium dioxide, lacquer solutions and
suitable organic solvents or solvent mixtures. In order to produce
coatings resistant to gastric juices, solutions of suitable
cellulose preparations, such as, acetylcellulose phthalate or
hydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs or
pigments can be added to the tablets or dragee coatings, for
example, for identification or in order to characterize
combinations of active compound doses.
[0163] Other pharmaceutical preparations which can be used orally
include push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer, such as, glycerol or
sorbitol. The push-fit capsules can contain the active compounds in
the form of granules that may be mixed with fillers such as
lactose, binders such as starches, and/or lubricants such as talc
or magnesium stearate and, optionally, stabilizers. In soft
capsules, the active compounds are preferably dissolved or
suspended in suitable liquids, such as, fatty oils or liquid
paraffin. In addition, stabilizers may be added.
[0164] Suitable formulations for parenteral administration include
aqueous solutions of the active compounds in water-soluble form,
for example, water-soluble salts, alkaline solutions and
cyclodextrin inclusion complexes. Especially preferred alkaline
salts are ammonium salts prepared, for example, with Tris, choline
hydroxide, Bis-Tris propane, N-methylglucamine, or arginine. One or
more modified or unmodified cyclodextrins can be employed to
stabilize and increase the water solubility of compounds of the
present invention. Useful cyclodextrins for this purpose are
disclosed in U.S. Pat. Nos. 4,727,064, 4,764,604, and
5,024,998.
[0165] In addition, suspensions of the active compounds as
appropriate oily injection suspensions can be administered.
Suitable lipophilic solvents or vehicles include fatty oils, for
example, sesame oil, or synthetic fatty acid esters, for example,
ethyl oleate or triglycerides or polyethylene glycol-400 (the
compounds are soluble in PEG400). Aqueous injection suspensions can
contain substances that increase the viscosity of the suspension,
for example, sodium carboxymethyl cellulose, sorbitol, and/or
dextran. Optionally, the suspension may also contain
stabilizers.
[0166] The following examples are illustrative, but not limiting,
of the method and compositions of the present invention. Other
suitable modifications and adaptations of the variety of conditions
and parameters normally encountered and obvious to those skilled in
the art are within the spirit and scope of the invention.
EXAMPLE 1
[0167] 2-Chlorobenzenesulfonic acid
3-[(1-acetimidoylpiperidin-4-yl)metho]- -5-methylphenyl ester
hydrochloride
[0168] a) N-tert-butoxycarbonylisonipecotic acid
[0169] Di-tert-butyl dicarbonate (6.55 g, 30 mmol) was added to the
mixture of isonipecotic acid (3.90 g, 30 mmol) and NaHCO.sub.3
(5.05 g, 60 mmol) in 1:1 1,4-dioxane/water (100 iL), and the
mixture was stirred at room temperature overnight. The reaction
mixture was evaporated in vacuo, acidified to pH 6 using 10% citric
acid and extracted with ethyl acetate (3.times.100 mL). The organic
phase was washed with brine (2.times.50 mL) and dried over
Na.sub.2SO.sub.4. The solvent was evaporated to give the title
compound as a white solid (6.25 g, 91%). .sup.1H-NMR (300 MHz,
CDCl.sub.3) 67 1.43 (s, 9 H), 1.63 (m, 2 H), 1.88 (dd, 2 H, J =1.5,
6.6 Hz), 2.45 (m, 1 H), 2.83 (t,2H,J=11.4 Hz), and4.00 (d,2H,J=6.7
Hz).
[0170] b) N-tert-Butoxycarbonyl-4-piperidinemethanol
[0171] Borane-tetrahydrofuran (1 M, 25 mL, 25 mmol) was added
slowly to N-tert- butoxycarbonylisonipecotic acid (5.73 g, 25
mmol), as prepared in the preceding step, in tetrahydrofuran (50
mL) at 0.degree. C. (ice-bath) over 30 min. The mixture was stirred
at 0.degree. C. overnight and then warmed up to room temperature
for 6 h. Water (10 mL) was added slowly and then K.sub.2CO.sub.3 (5
g in 50 mL water) was added. The mixture was extracted with ethyl
acetate (3.times.50 mL). The organic phase was washed sequentially
with saturated NaHCO.sub.3 (2.times.50 mL) and brine (2.times.50
mL), and dried over Na.sub.2SO.sub.4. The solvent was removed in
vacuo, and the residue was purified by flash column chromatography
(1:1 hexane/ethyl acetate) to give the title compound as white
crystals (4.55 g, 84%). .sup.1H-NMR (300 MHz, CDC1.sub.3)
.delta.1.13 (m, 2 H), 1.42 (s, 9 H), 1.67 (m, 4 H), 2.67 (t, 2 H,
J=12.5 Hz), 3.46 (d, 2 H, J =3.0 Hz), and 4.09 (d, 2 H, J =3.6
Hz).
[0172] c) 2-Chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl
ester
[0173] Orcinol monohydrate (1.42 g, 10 mmol) and
2-chlorobenzenesulfonyl chloride (2.43 g,11 IImmol) were mixed in
saturated NaHCO.sub.3 (30 niL) and diethyl ether (30 mL). The
biphasic mixture was stirred vigorously at room temperature for 2
days. The reaction mixture was quenched with 50 mL of water and
extracted into ethyl acetate (3.times.50 mL). The organic phase was
washed with brine (2.times.50 mL) and dried over Na.sub.2SO.sub.4.
After removing the solvent in vacuo, the residue was purified by
flash column chromatography (2% ethyl acetate in methylene
chloride) to give the title compound as a pale-yellow liquid (2.15
g, 71%). .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.2.22 (s, 3 H),
5.24 (s, 1 H), 6.43 (s, 1 H), 6.52 (s, 2H), 7.38 (m, 1 H), 7.60 (m,
2 H), and 7.96 (dd, I H, J =0.6, 3.9 Hz).
[0174] d) 2-Chlorobenzenesulfonic acid
3-[[N-(tert-butoxycarbonyl)piperidi- n4-yl]methoxy]-5-methylphenyl
ester
[0175] Diethyl azodicarboxylate (349 mg, 2.0 mmol) was added to a
solution of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl
ester (600 mg, 2.0 mmol), as prepared in the preceding step,
N-tert-butoxylcarbonyl4-pip- eridinemethanol (430 mg, 2.0 mmol), as
prepared in step (b), and triphenylphosphine (525 mg, 2.0 mmol)
intetrahydrofuran (15 mL) at 0.degree. C. The reaction mixture was
stirred at 0.degree. C. for 2 h and at room temperature for 3 h.
The reaction mixture was quenched with water (50 mL) and was
extracted with ethyl acetate (3.times.50 mL). The organic phase was
washed with saturated NaHCO.sub.3 (2.times.50 mL), brine
(2.times.50 nmL) and dried over Na.sub.2SO.sub.4. The solvent
removed in vacuo and the residue was purified by flash column
chromatography (2:1 ethyl acetate/hexane) to give the title
compound as a colorless syrup (895 mg, 90%). .sup.1H-NMR (300 MHz,
CDC1.sub.3) .delta.1.24 (m, 2 H), 1.47 (s, 9 H), 1.76 (d, 2 H,
J=6.6 Hz), 1.89 (m, 1 H), 2.24 (s, 3 H), 2.72 (t, 2 H, J =2.4 Hz),
3.68 (d, 2 H, J=3.2 Hz), 4.13 (m, 2 H), 6.47 (t, 1 H, J =2.2 Hz),
6.52 (d, 1 H, J=0.7 Hz), 6.58 (d, 1 H, J=0.8 Hz), 7.38 (dd, 1 H,
J=0.6, 0.8 Hz), 7.61 (m, 2 H), and 7.97 (dd, 1 H, J=0.8,4.0
Hz).
[0176] e) 2-Chlorobenzenesulfonic acid
3-[(piperidin4-yl)methoxy]-5-methyl- phenyl ester
[0177] 2-Chlorobenzenesulfonic acid
3-[[N-(tert-butoxycarbonyl)piperidin-4- -yl]methoxy]-5-methylphenyl
ester (745 mg, 1.5 mmol), as prepared in the preceding step, was
treated with 4 N HCl in 1,4-dioxane (20 niL) at room temperature
for 2 h. The solvent was removed in vacuo and the residue was
purified by flash column chromatography (10% methanol in methylene
chloride saturated with NH3) to give the title compound as a
colorless syrup (570 mg, 95%). .sup.1H-NMR (300 MHz, CDCl.sub.3)
.delta.1.45 (m, 1 H), 1.94 (m, 3 H), 2.23 (s, 3 H), 2.45 (m, 1 H),
2.71 (dt, 2 H, J =1.2, 12.3 Hz), 3.51 (m, 2H), 3.76 (m, 2 H), 6.46
(t, 1 H, J =2.1 Hz), 6.53 (s, 1 H), 6.58 (s, 1 H), 7.40 (t, 1 H, J
=6.5 Hz), 7.62 (m, 2 H), and 7.97 (dd,1 H, J =1.4, 7.9 Hz). Mass
spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for
C.sub.19H.sub.22NO.sub.4SC1: 396.1 (M+H), Found: 396.4.
[0178] f) 2-Chlorobenzenesulfonic acid
3-[(1-acetimidoylpiperldin4-yl)meth- oxy]-5-methylphenyl ester
hydrochloride
[0179] Triethylamine (0.5 niL) and ethyl acetimidate hydrochloride
(247 mg, 2.0 mmol) were added to a solution of
2-chlorobenzenesulfonic acid
3-[(piperidin-4-yl)methoxy]-5-methylphenyl ester (396 mg, 1.0
mmol), as prepared in the preceding step, in N,N-dimethylformamide
(10 niL). The reaction mixture was stirred at room temperature
overnight. The N,N-dimethylformamide was removed in vacuo and the
residue partitioned between methylene chloride (200 mL) and 10%
K.sub.2CO.sub.3 (50 mL). The organic phase was washed with 10%
K.sub.2CO.sub.3 (2.times.50 mL) and dried over K.sub.2CO.sub.3. The
solvent was removed in vacuo, HCl-methanol (30 mL) was added, and
the solution was concentrated in vacuo. The residue was
crystallized from methanol-ethyl acetate to give the title compound
as white crystals (405 mg, 86%). .sup.1H-NMR (300 MHz, DMSO-d6)
.delta.1.30 (m,2 H), 1.82 (d,2H,J=7.0 Hz), 2.05 (m, 1 H), 2.20 (s,
3 H), 2.29 (s, 3 H), 3.16 (m, 2 H), 3.77 (d, 2 H, J=3.0 Hz), 3.92
(d, 1 H, J=6.5 Hz), 4.17 (d, 1 H, J=6.5Hz),6.46(d, 1 H,
J=2.5Hz),6.49(s, 1 H), 7.59 (t, 1 H.J=8.0 Hz), 7.87 (m, 2 H), 7.95
(d, 1 H, J=8.0 Hz), 8.77 (br s, 1 H), and 9.35 (br s, 1 H). Mass
spectrum (MALDI-TOF, sinapinic acid matrix) caled. for
C.sub.21,H.sub.25N.sub.2O.sub.4SCl: 437.1 (M+H). Found: 436.8.
EXAMPLE 2
[0180] 3-(2-Ch
lorobenzyloxy)-5-methyl-1-[2-(1-acetimidoyl)piperazin-4-yl]-
]ethoxybenzene diacetic acid saft
[0181] a) N-(tert-Butoxycarbonyl)-1-(2-hydroxyethyl)piperazine
[0182] To a solution of 1-(2-hydroxyethyl)piperazine (5.20 g, 40
mmol) and triethylamine (6 mL 43 mmol), in 1,4-dioxane (100 mL) was
added slowly di-tert-butyl dicarbonate (8.72 g, 40 mmol). The
reaction mixture was stirred at room temperature for 2 h . The
solvent was removed in vacuo and the residue was purified by flash
column chromatography (ethyl acetate to 2% methanol in ethyl
acetate) to give the title compound as colorless oil (8.32 g, 90%).
.sup.1H-NMR (300 MHz, CDC1.sub.3) .delta.1.46 (s, 9 H), 2.46 (t, 4
H), 2.55 (t, 2 H), 2.75 (br s,l H), 3.44 (t, 4 H), and 3.63 (t, 2
H).
[0183] b) 3-(2-Chlorobenzyloxy)-5-methylphenol
[0184] To 1.31 g (9.22 mmol) of orcinol monohydrate in 20 mL
anhydrous N,N-dimethylformamide under a nitrogen atmosphere was
added 220 mg (9.17 mmol) of NaH (100%). After 5 min, 1.30 mL (10.0
mmol) of 2-chlorobenzyl bromide was added. The reaction mixture was
stirred for 2 h and then quenched with 1 N HCl. The reaction
mixture was extracted into ethyl acetate (200 mL). The organic
phase was washed with water (4.times.100 mL), dried (MgSO.sub.4),
and concentrated in vacuo. Purification by flash chormatography
(diethyl ether/hexane (50:50 to 100:0) gave 656 mg of the title
compound as a glass. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.7.54
(dd, 1 H, J=3, 7 Hz), 7.39 (dd, 1 H, J=3, 7 Hz), 7.2-7.3 (m, 2 H),
6.41 (s, 1 H), 6.29-6.30 (m, 2 H), 5.29 (s, 2 H), and 2.28 (s, 3
H).
[0185] c)
3-(2-Chlorobenzyloxy)-5-methyl-1-[2-[N-(tert-butoxycarbonyl)
piperazin-4-yl]]ethoxybenzene
[0186] To a solution of 210 mg (0.845 mmol) of
3-(2-chlorobenzyloxy)-5-met- hylphenol as prepared in the preceding
step, 204 mg (0.887 mmol) of
N-(tert-butoxycarbonyl)-1-(2-hydroxyethyl)piperazine, as prepared
in step (a) of this Example, 287 mg (1.10 Immol) of
triphenylphosphine, and 280 .mu.L (2.5 mniol) of N-methylmorpholine
in 3 mL of tetrrhydrofuran was added 160,.mu.L (1.09 mmol) of
N,N-diethyl azodicarboxylate. After stirring overnight at ambient
temperature, the reaction mixture was quenched with water,
extracted into ethyl acetate, dried (NgSO.sub.4), and purified by
flash chromatography (methylene chloride/diethyl ether (8:1 to
4:1)) to give the 270 mg (59% yield) of the title compound as a
gum. .sup.1H-NMR (300 MHz, CDC1.sub.3) .delta.7.55 (dd, 1 H), 7.37
- 7.41 (m, 1 H), 7.22 - 7.3 (m, 2 H), 6.43 (s, 1 H), 6.37 (d, 2 H),
5.12 (d, 2 H), 4.08 (t, 2 H, J=6.7 Hz), 3.45 (t, 4 H), 2.80 (t, 2
H, J=6 Hz), 2.51 (t, 4 H), and 1.46 (s, 9 H). Mass spectrum
(MALDI-TOF; gentisic acid matri)Ox,ccd. for
C.sub.25H.sub.33ClN.sub.2O.sub.4: 461.2 (M+H). Found: 460.9.
[0187] d)
3-(2-Chlorobenzyloxy)-5-methyl-1-[2-[piperazin4-yl]]ethoxybenzen- e
dihydrochloride
[0188] A solutionof251 mg (0.544 mmol)
of3-(2-chlorobenzyloxy)-5-methyl-1--
[2-[N-(tert-butoxycarbonyl)piperazin-4-yl]]ethoxybenzene as
prepared in the preceding step, in 3 mL of methylene chloride and
500 .delta. of 4 N HCl in dioxane was stirred for 1 h. Another 1 mL
of 4 N HCl in dioxane was added. After stirring for another 15 min,
the reaction mixture was triturated with diethyl ether. The product
was collected by filtration to provide 127 mg of the title compound
as a colorless solid. .sup.1H-NMR (300 MHz, DMSO-d.sub.6)
.delta.9.50 (br s, 2 H), 7.58 -6.61 (m, 1 H), 7.51 - 7.57 (m, 1 H),
7.37 - 7.40 (m, 2 H), 6.53 (s, 1 H), 6.49 (s, 5 3 H), 5.12 (s, 2
H), 4.35 (br s, 2 H), and 2.27 (s, 3 H). Mass spectrum (MALDI-TOF;
.alpha.-cyano-4-hydroxycinnamic acid matrix) calcd. for
C.sub.20H.sub.25ClN.sub.2O.sub.2: 361.2 (M+H). Found: 360.9.
[0189] e)
3-(2-Chlorobenzyloxy)-5-methyl-1-[2-1-(acetymidoyl)piperazin4-yl-
]]ethoxybenzene diacetic acid salt
[0190] A solution of 104 mg (0.240 mmol) of
3-(2-chlorobenzyloxy)-5-methyl-
-1-2-[N-(tert-butoxycarbonyl)piperazin-4-yl]]ethoxybenzene, as
prepared in the preceding step, 90 mg (0.732 mmol) of ethyl
acetimidate hydrochloride in 1 mL of N,N-dimethylformamide
containing 260 .mu.L of N,N-diisopropylethylamine was stirred at
ambient temperature for 2 days. The solvent was removed in vacuo.
The residue was quenched with 1 N sodium hydroxide, extracted into
methylene chloride, dried (K.sub.2CO.sub.3), and concentrated. The
residue was dissolved in 1 mL methylene chloride and then treated
with 500 .mu.L glacial acetic acid. The solution was then purified
by preparative thin layer chromatography using methylene
chloride/glacial acetic acid/methanol (53:13:34) as developing
solvent to give 32.6 mg of the title compound as a colorless foam
after repeated concentrations from diethyl ether/methylene
chloride/hexane. .sup.1H-NMR (300 MHz, DMSO0) .delta.99-9.0 (br s,2
H), 7.50-7.60 (m, 2 H), 7.38-7.41 (m, 2 H), 6.48 (s, 1 H), 6.39 (s,
2H), 5.11 (s, 2 H), 4.06 (t, 2 H), 3.53 -3.56 (m, 4 H), 2.74 (t, 2
H), 2.60 (t, 4 H), 2.27 (s, 3 H), 2.24 (s, 3 H), and 1.85 (br s, 6
H). Mass spectrum (MALDI-TOF; .alpha.-cyano-4-hydroxycinnamic acid
matrix) calcd. for C.sub.22H.sub.28ClN.sub.3O.sub.2: 402.2 (M+H).
Found: 401.8.
EXAMPLE 3
[0191]
N-[2(N,N-dimethylamino)ethyl]-N-[2-[[4-(1-acetimidoyl)aminolbutoxy]-
-4-methylphenyl]benzenesulfonamide dihydrochloride.
[0192] a)
2-[(4-(tert-Butoxycarbonylamino)butoxy]-4-methylnitrobenzene.
[0193] To 252 mg (1.33 mmol) 4-(tert-butoxycarbonylamino)butanol,
407 mg (2.66 mmol) 4-methyl-2-nitrophenol and 383 mg (1.46 mmol)
triphenylphosphine in 1.0 mL of anhydrous tetrahydrofuran under
nitrogen was added 336 .mu.L (1.46 mmol) of diethyl
azodicarboxylate. After stirring for 1 h, the mixture was
concentrated to a yellow syrup. Chromatography on a Waters
Associates 10 g silica Sep-Pak SPE column eluting with 10-12% ethyl
acetate-hexane afforded 422 mg (98%) of the title compound as a
colorless oil. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.7.64 (d, 1
H, J=2.0 Hz), 7.30 (dd, 1 H, J=8.5,2.2 Hz), 6.95 (d, 1 H,
J=8.5Hz),4.64(brs, 1 H),4.09(t,2H,J=6.1 Hz),3.19(q,2H,J=6.5Hz),
2.34 (s, 3 H), 1.86 (m, 2 H), 1.69 (m, 2 H), and 1.44 (s, 9 H).
Mass spectrum (MALDI-TOF, gentisic acid matrix) calcd. for
C.sub.16H.sub.24N.sub.2O.sub- .5: 347.2 (M+H). Found: 347.3.
[0194] b)
2-[(4-(tert-Butoxycarbonylamino)butoxy]-4-methylaniline.
[0195] To a solution of 390 mg (1.20 mmol) of
2-[(4-(tert-butoxycarbonylam- ino) butoxy]-4-methylnitrobenzene, as
prepared in preceding step, in 1.5 mL of tetrahydrofuran was added
39 mg of 10% palladium on carbon and the mixture stirred under a
balloon of hydrogen for 20 h. The mixture was filtered (Celite)
washing with 3 mL of tetrhydrofiran and concentrated to 339 mg
(96%) of the title compound as a colorless oil. .sup.1H-NMR (300
MHz, CDCl.sub.3) .delta.6.66 (d, 1 H, J =8.0 Hz), 6.55 (dd, 1 H,
J=2.0 Hz), 6.49 (d, 1 H, J=8.0 Hz), 4.59 (br s, 1 H), 3.98 (t, 2 H,
J=6.3 Hz), 3.19 (q, 2 H, J=6.6 Hz), 2.21 (s, 3 H), 1.82 (m, 2 H),
1.67 (m, 2 H), 1.57 (br s, 2 H), and 1.44 (s, 9 H). Mass spectrum
(DI-TOF, gentisic acid matrix) calcd. for
C.sub.16H.sub.26N.sub.2O.sub.3: 317.2 (M+Na). Found: 317.2.
[0196] c)
N-[2-[4-(tert-Butoxycarbonylamino)-butoxy]-4-methylphenyl]benzen-
esulfonamide
[0197] To 216 mg (0.734 inmol) of
2-[(4-(tert-butoxycarbonylamino)butoxy]-- 4-methylaniline, as
prepared in preceding step, and 101 .mu.L (0.918 mmol) of
4-methylmorpholine in 3.0 mL of dichloromethane was added 143 .mu.L
(0.807 mmol) of benzenesulfonyl chloride. The solution was stirred
for 45 min, diluted with 30 mL of dichloromethane and washed with
10% citric acid (2.times.30 mL), saturated NaHCO.sub.3 (2.times.30
mL), and brine (30 mL). The solution was dried (Na.sub.2SO.sub.4)
and concentrated to 342 mg of a faintly amber solid. Chromatography
on a Waters Associates 10 g silica Sep-Pak SPE column eluting with
a gradient of 0-4% ethyl acetate-dichloromethane afforded 282 mg
(88%) of the title compound as a white crystalline solid.
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.7.72 (m, 2 H), 7.50 (m, 1
H), 7.40 (m, 3 H), 6.94 (s, 1 H), 6.83 (dd, 1 H, J 8.3, 2.1 Hz),
6.59 (d, 1 H, 3 =8.3 Hz), 4.54 (br s, 1 H), 3.70 (t, 2 H, 3 =6.3
Hz), 3.19 (q, 2 H, SH J=6.5 Hz), 2.27 (s, 3 H), 1.62 (m, 2 H), 1.48
(m, 2 H), and 1.46 (s, 9 H). Mass spectrum (MALDI-TOF, gentisic
acid matrix) calcd. for C.sub.22H.sub.30N.sub.2O.sub.5S: 457.2
(M+Na). Found: 457.7.
[0198] d)
N-[2-(714N-Dimethylamino)ethyl]-N-[2-[4-(tert-butoxycarbonylamin-
o)-butoxy]4-methylphenyl]benzenesulfonamide
[0199] To a solution of 82.2 mg (0.189 mmol) of
N-[2-[4-(tert-butoxycarbon-
ylamino)butoxy]-4-methylphenyl]benzenesulfonamide, as prepared in
preceding step, in 1.5 nL of anhydrous N,N-dimethylformamide was
added 78.3 mg (0.567 mmol) of powdered anhydrous potassium
carbonate and 30 mg (0.208 mmol) of N,N-dimethylaminoethyl chloride
hydrochloride. After stirring at 50.degree. C. for 21 h, the
mixture was partitioned between 10 mL of ethyl acetate and 10 mL of
water. The organic layer was washed with water (10 mL) and brine
(10 mL), dried (Na.sub.2SO.sub.4) and concentrated to give 93.7 mg
of a colorless oil. Chromatography on a 10 g Waters Associates
Sep-Pak silica SPE column with 50% ethyl acetate-dichloromethane
afforded a small amount of unreacted starting material (7.4 mg)
followed by 10% methanol-dichloromethane afforded 67.2 mg (77%
based on recovered starting material) of the title compound as a
colorless resin. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.7.67 (m,
2 H), 7.53 (m, 1 H), 7.43 (m, 2 H), 7.11 (d, 1 H, J=2.0 Hz), 7.06
(dd, 1 H, J=8A, 1.7 Hz), 6.66 (d, 1 H, J=8.4), 4.53 (br s, 1 H),
3.4-3.8 (br m, 4 H), 3.04 (q, 2 H, J=6.3 Hz), 2.88 (m, 2 H), 2.28
(s,3 H), 2.22 (s, 6 H), 1.46 (s, 9 H), and 1.33 (m, 4 H). Mass
spectrum (MALDI-TOF, .alpha.-cyano4fhydroxycinnamic acid matrix)
caled. for C.sub.26H.sub.39N.sub.3O.sub.5S: 506.3 (M+H), 528.3 (M
+Na). Found: 506.5, 528.8.
[0200] e) N-[2-(N,N-Dimethylamino) ethyl]-N-[2-[[4-(1-acetimidoyl)
amino]-butoxy]4-methylphenyl]benzenesulfonamide dihydrochloride
[0201] To a solution of 82.0 mg (0.162 mmol) of
N-[2-(NN-direthylamino) ethyl]-N-
[2-[4-(tert-butoxycarbonylamino)butoxy]-4-methylphenyl]
benzenesulfonamide, as prepared in preceding step, in 2.0 mL of
anhydrous dichloromethane was added 2.0 mL of trifluoroacetic acid.
After stirring for 15 min, the solution was concentrated and placed
under vacuum (0.5 torrtl h) to afford a colorless oil. This residue
in 0.75 mL of anhydrous N,N-dimethylformamide was treated with 30.0
mg (0.243 mmol) of ethyl acetimidate hydrochloride and 127 .mu.L
(0.729 mmol) of N,N-diisopropylethylamine and the mixture stirred
for 20 h at ambient temperature. 1 N NaOH (10 mL) was added and the
mixture extracted with ethyl acetate (3.times.10 mL). The combined
extracts were washed with 10 mL of brine-i N NaOH (9:1), dried
(Na.sub.2SO.sub.4) and concentrated to 88 mg of a pale yellow
resin. The above residue in 1.0 mL of anhydrous dichloromethane was
treated with 101 .mu.L (0.405 mmol) of 4 M HCl in dioxane and the
solution concentrated in vacuo to a pale yellow resin.
Concentration four more times from 2.0 mL of dichloromethane and
placement under vacuum (0.5 torr/3 h) afforded 77.0 mg (91%) of a
hard off-white foam. Mass spectrum (MALDI-TOF,
.alpha.-cyano4-hydroxy-cinnamic acid matrix) calcd. for
C.sub.23H.sub.34N.sub.4O.sub.3S: 447.2 (M+H). Found: 447.3.
EXAMPLE 4
[0202]
N-Benzyl-N-[[[3-(]-acetimidoyl)piperidin-4-yl]methylamino]phenyl]be-
nzene sulfonamide
[0203] a) N-(3-nitrophenyl)benzenesulfonamide
[0204] To 6.17 g (44.7 mmol) of 3-nitroaniline and 8.41 InL (48.2
mmol) ofN,N-diisopropylethylamine in 150 mL of anhydrous diethyl
ether was added 5.14 mL (40.2 mmol) of benzenesulfonyl chloride.
The mixture was heated to reflux under nitrogen with stirring for
16 h, cooled and the resulting two-phase mixture scratched to
crystallize the insoluble oil. After decanting the ether layer, the
derived solid was dissolved in 300 mL of dichloromethane and the
solution washed with 2 N HCl (3.times.200 mL), saturated
NaHCO.sub.3 (200 mL), brine (200 mL), dried (Na.sub.2SO.sub.4) and
concentrated to give 9.62 g (86%) of the title compound as a light
tan solid. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.7.96 (m, 2 H),
7.86 (m, 2 H), 7.41-7.63 (m, 5 1), and 7.30 (br s, 1 H). Mass
spectrum (LDI-TOF, gentisic acid matrix) calcd. for
Cl.sub.12H.sub.10N.sub.2O.sub.4S: 301.0(M+Na). Found: 301.1.
[0205] b) N-Benzyl-N-(3-nitrophenyl)benzenesulfonamide
[0206] To 6.00 g (21.6 mmol) of
N-(3-nitrophenyl)benzenesulfonamide, as prepared in preceding step,
in 15 mL of anhydrous N,N-dimethylformamide under nitrogen was
added 4.48 g (32.4 imtol) of powdered anhydrous potassium carbonate
and 2.83 mL (23.8 mmol) of benzyl bromide. After stirring for 3.5
h, the mixture was partitioned between 200 nIL of ethyl acetate and
250 mL of water. The aqueous layer was extracted with 50 mL of
ethyl acetate and the combined organic phases washed with 1 M
K.sub.2CO.sub.3 (2.times.100 mL). Hexane (50 mL) was added to the
organic phase which was then washed with water (3.times.150 mL),
brine (100 mL), dried (Na.sub.2SO.sub.4) and concentrated to give
8.2 g of a crystalline yellow solid. Recrystallization from ethyl
acetate-hexane afforded 7.45 g (94%) of the title compound as
cream-colored crystals. .sup.1H-NMR (300 MHz, CDCl.sub.3)
.delta.8.06 (d, 1 H, J=7.4 Hz), 7.76 (s, 1 11), 7.64 - 7.67 (m, 3
H), 7.51 - 7.56 (m, 2 H), 7.38-7.46 (m, 2 H ), 7.21 (s, 5 H), and
4.77 (s, 2 H). Mass spectrum (MALDI-TOF, gentisic acid matrix)
calcd. for C.sub.19H.sub.16N.sub.2O.sub.4S: 369.1 (M+H), 391.1
(M+Na), 407.0 (M+K). Found: 368.8, 391.3, 407.4.
[0207] c) N-Benzl-N-(3-aminophenyl)benzenesuyfonamide
[0208] To 3.01 g (8.17 mmol) of N-benzyl-N-(3-nitrophenyl)
benzenesulfonamide, as prepared in preceding step, in 60 mL of
methanol-tetrahydrofiran (1:1) was added 200 mg of 10 % palladium
on carbon. After stirring the mixture under a balloon of hydrogen
for 1.7 h, an additional 200 mg of 10 % palladium on carbon was
added and stirring was continued for another 2.5 h. Filtration
(Celite) and concentration afforded a dark green resin which was
dissolved in 40 mL of ethyl acetate-hexane (1:1), refiltered
(Celite) and concentrated to afford 2.9 g of a yellow solid.
Recrystallization from ethyl acetate-ether afforded 2.21 g (80%) of
the title compound as a light orange crystalline powder.
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.7.68 - 7.71 (m, 2 H),
7.56-7.62 (m, 1 H), 7.46-7.51 (m, 2H), 7.18-7.2 (m, 5 H), 6.97 (t,
1 H, J=8.0 Hz), 6.58 (dd, 1 H, J=8.0, 1.6 Hz), 6.47 (t, 1 H, J=2.1
Hz), 6.32 (dd, 1 H, J 8.0, 1.3 Hz), and 4.70 (s,1 H). Mass spectrum
(MALDI-TOF, gentisic acid matrix) calcd. for
C.sub.19H.sub.18N.sub.2O.sub.2S: 339.1 (M+H), 361.1 (M+Na). Found:
339.5, 361.5.
[0209] d)
N-Benzyl-N-[[3-(N-tert-butoxycarbonylpiperidin4-yl)carbonylamino-
l-phenyl]benzenesulfonamide
[0210] To 149 mg (0.650 rnmol) of N-tert-butoxycarbonylisonipecotic
acid, as prepared in step (a) in Example 1, and 287 mg (0.650 mmol)
of Castro's Reagent
(benzotriazole-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate, BOP) in 1.5 mL of anhydrous
N,N-dimethylformarnide was added 155 .mu.L (0.887 mmol) of
N,N-diisopropylethylarnine and the mixture stirred under nitrogen
for 5 min. A solution of 200 mg (0.591 mmol) of
N-benzyl-N-(3-aminophenyl) benzenesulfonamide, as prepared in
preceding step, in 0.5 mL of N,N-dimethylformamide was added. After
stirring for 16 h, 10 miL of saturated NaHCO.sub.3 was added. The
mixture was partitioned between 25 mL each of ethyl acetate and
water. The organic layer was washed with 10 % citric acid
(2.times.20 mL), brine (20 mL) and dried (Na.sub.2SO.sub.4).
Concentration afforded 360 mg of a yellow resin which was
chromatographed on a Waters Associates 10 g silica Sep-Pak SPE
column. Elution with a gradient of 5-10 % ethyl
acetate-dichloromethane afforded 268 mg (82%) of the title compound
as a white foam. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.7.56-7.66
(m, 4 H), 7.47 (m, 2 H), 7.09 - 7.22 (m, 8 H), 6.60 (br d, 1 H,
J=8.0 Hz), 4.70 (s, 2 H), 4.14 (br s, 2 H), 2.74 (br t, 2 H, J=12
Hz), 2.24-2.34 m, 1 H), 1.84 (br s, 1 H), 1.81 (br s, 1 H), 1.69
(td, 2 H, J=12.2, 4.1 Hz), and 1.44 (s, 9 H). Mass spectrum
(MALDI-TOF, gentisic acid matrix) calcd. for
C.sub.30H.sub.35N.sub.3O.sub.5S: 450.6 (M-BOC+2 H). Found:
450.3.
[0211] e)
N-Benzyl-N-[[[3-(1-tert-butoxycarbonyl)piperidin4-yl]methylamino-
]phenyl]benzenesulfonamide
[0212] To 404 .mu.L (0.807 mmol) of 2 M lithium borohydride in
tetrahydrofuran was added 1.0 mnL of tetrahydrofuran followed by
204 .mu.L (1.61 mmol) of chlorotrimethylsilane. After stirring for
4 min, 148 mg (0.269 mmol) of N-benzyl-N-[[3-(1
-tert-butoxycarbonyl)piperidin-4-ylc- arbonylamino]phenyl]
benzenesulfonamide, as prepared in preceding step, in 2.0 mL of
tetrahydrofuran was added and the mixture heated at 50.degree. C.
under nitrogen for 2 h. After quenching the reaction with 0.16 mL
of MeOH, 1.0 mL of 2 N NaOH was added, the mixture stirred for 10
min and then extracted with ethyl acetate (2.times.10 mL). The
combined extracts were washed with brine, dried (Na.sub.2SO.sub.4)
and concentrated to 150 mg of a pale yellow resin. Chromatography
on a Waters Associates 10 g silica Sep-Pak SPE column eluting with
5% ethyl acetate-dichloromethane afforded 143 mg (99%) of the title
compound as a colorless resin. .sup.1H-NMR (300 MHz, CDC1.sub.3)
.delta.7.70-7.74 (m, 2 H), 7.59 (m, 1 H), 7.48 (m, 2 H), 7.22 (m, 5
H), 6.95 (t, 1 H, J=8.0Hz), 6.40 (dd, 1 H, J=8.1,2.2 Hz), 6.25 (t,
1 H, J=2.1 Hz), 6.17 (dd, 1 H, J=7.2, 1.8Hz), 4.70 (s, 2 H), 4.11
(br s,2 H), 3.66 (br s, 1 H), 2.85 (br s,2H), 2.66 (t, 2 H, J=13.3
Hz), 1.65 (d, 2 H, J=13.3Hz), 1.47 (s, 9 H), and 1.09 (m, 2 H).
Mass spectrum (MALDI-TOF, gentisic acid matrix) calcd. for
C.sub.30H.sub.37N.sub.3O.sub.4S: 435.6 (M-BOC+H). Found: 435.6.
[0213] j)
N-Benzl-N-[[[3-(1-acetimidoyl)piperidin4-yl]methylamino[phenyl]--
benzenesulfonamide
[0214] To 140 mg (0.261 mmol) of
N-benzyl-N-[[[3-(1-tert-butoxycarbonyl)
piperidin-4-yl]methylamino]phenyl]benzenesulfonamide, as prepared
in preceding step, in 3.0 mL of anhydrous dichloromethane was added
0.75 mL of trifluoroacetic acid. After stirring for 15 min, the
solution was concentrated and placed under vacuum (0.1 torr/l h) to
afford a colorless resin. This residue in 1.0 mL of anhydrous
N,N-dimethylformamide was treated with 64.5 mg (0.522 mmol) of
ethyl acetimidate hydrochloride and 182 ,L (1.04 mmol) of
N,N-diisopropylethylamine and the mixture stirred for 48 h. An
additional 64.5 mg (0.522 mmol) of ethyl acetimidate hydrochloride
and 91.0 .mu.L (1.04 mmol) of N,N-diisopropylethylamine was added
and the mixture stirred at 50.degree. C. for 20 h. To the mixture
was added 20 mL of ethyl acetate and the solution washed with 0.1 N
NaOH (2.times.20 mL). The combined aqueous layers were extracted
with ethyl acetate (4.times.10 mL) and the five combined organic
layers washed with 25 mL of brine and dried (Na.sub.2SO.sub.4) and
concentrated to 91.4 mg of a pale yellow resin. This material was
crystallized obtaining three crops from methanol-ethyl acetate and
two crops from methanol-ethyl acetate-diethyl ether to afford 54.8
mg (44%) of the title compound as a cream-colored powder.
.sup.1H-NMR (300 MHz, CD.sub.3OD) .delta.7.65-7.72 (m, 3 H), 7.54 -
7.58 (m, 2 H), 7.18-7.24 (m, 5 H), 6.90 (t, 1 H,J=8.1 Hz), 6.46
(dd, 1 H,J=8.2,2.0Hz),6.25 (t, 1 H,J=2.1 Hz), 6.13 (d, 1 H, J=7.8
Hz), 4.73 (s, 2 H), 4.02 (m, 2 H), 3.05-3.25 (m, 2 H), 2.88 (d, 2
H, J=6.2 Hz), 2.31 (s, 3 H), 1.89 (m, 3 H), and 1.30 (m, 2 H). Mass
spectrum (MALDI-TOF, .alpha.-cyano-4-hydroxycinnamic acid matrix)
calcd. for C.sub.27H.sub.32N.sub.4O.sub.2S: 477.2 (M+H). Found:
477.2.
EXAMPLE 5
[0215] 3-Chlorobenzenesulfonic acid
3-[[(1-acetimidoyl)piperidin4-yl]metho- xyl-5-methylphenyl ester
hydrochloride
[0216] a) 3-Chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl
ester
[0217] Orcinol monohydrate (1.42 g, 10 mmol) and
3-chlorobenzenesulfonyl chloride (2.43 g, 11 mmol) were mixed in
saturated NaHCO.sub.3 (30 nlL) and diethyl ether (30 mL). The
biphasic mixture was stirred vigorously at room temperature for 2
days. After adding water (50 mL) to the mixture, the mixture was
extracted with ethyl acetate (3.times.50 mL). The organic phase was
then washed with brine (2.times.50 mL) and dried over
Na.sub.2SO.sub.4. The solvent was removed in vacuo and the residue
was purified by flash column chromatography (2% ethyl acetate in
methylene chloride) to give the title compound as a pale-yellow
liquid (2.08 g, 69%). .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.2.24
(s, 3 H), 5.32 (s, 1 H), 6.33 (t, 1 H, J=2.2 Hz), 6.40 (s, 1 H),
6.57 (s, 1 H), 7.48 (t, 1 H, J=8.0 Hz), 7.65 (m, 1 H), 7.73 (m, 1
H), and 7.86 (t, 1 H, J=1.8 Hz).
[0218] b) 3-Chlorobenzenesulfonic acid
3-[[N-(tert-butoxycarbonyl)piperidi- n-4-yl]methoxyl-5-methylphenyl
ester
[0219] Diethyl azodicarboxylate (349 mg, 2.0 mmol) was added to a
solution of 3-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl
ester (600 mg, 2.0 20 mmol), as prepared in the preceding step,
N-tert-butoxycarbonyl-4-- piperidinemethanol (430 mg, 2.0 mmol), as
prepared in step (b) of Example 1, and triphenylphosphine (525 mg,
2.0 mmol) in tetrahydrofuran (20 mL) at 0.degree. C. The mixture
was stirred at 0.degree. C. for 2 h and at room temperature for 3
h. The reaction was quenched with water (50 mL) and extracted with
ethyl acetate (3.times.50 mL). The organic phase was washed with
saturated NaHCO.sub.3 (2.times.50 mL), brine (2.times.50 mL) and
dried over Na.sub.2SO.sub.4. The solvent was removed in vacuo and
the residue was purified by flash column chromatography (1:3 ethyl
acetate/hexane) to give the title compound as a colorless liquid
(800 mg, 81%). .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.1.24 (m, 2
H), 1.47 (s, 9 H), 1.75 (m, 2 H), 1.90 (m, 1 H), 2.25 (s, 3 H),
2.73 (t, 2 H, J=12.5 Hz), 3.68 (d, 2 H, J=3.1 Hz), 4.13 (m, 2 H),
6.34 (t, .sup.1H, J=2.2 Hz), 6.39 (s, 1 H), 6.61 (s, 1 H), 7.49 (t,
1 H, J=7.8 Hz),7.63(d,1H,J=0.7Hz),- 7.75(d, 1H,J=3.9Hz),and7.86(t,
1H,J=1.8 Hz).
[0220] c) 3-Chlorobenzenesulfonic acid
3-[[(l-acetimidoyl)piperidin4-yl]me- thoxy]-5-methylphenyl ester
hydrochloride
[0221] 3-Chlorobenzenesulfonic acid
3-[[N-(tert-butoxycarbonyl)piperidin-4- -yl]methoxy]-5-methylphenyl
ester (496 mg, 1.0 mmol), as prepared in the preceding step, was
stirred with 4 N HCl in 1,4-dioxane (15 mL) at room temperature for
2 h. The solvent was removed in vacuo, and the residue was
co-evaporated with methylene chloride several times to give the
amine hydrochoride salt. The amine hydrochloride salt was then
treated with triethylamine (1.0 mL) and ethyl acetimidate
hydrochloride (247 mg, 2.0 mmol) in N,N-dimethylformamide (10 mL)
and stirred at room temperature overnight. The
N,N-dimethylformamide was removed in vacuo. The residue was
partitioned betveen methylene chloride (200 mL) and 10%
K.sub.2CO.sub.3 (50 mL). The organic phase was washed with 10%
K.sub.2CO.sub.3 (2.times.50 mL) and dried over K.sub.2CO.sub.3..
The solvent was removed in vacuo, the residue treated with
HCl-methanol (30 mL), and then concentrated in vacuo. The residue
was then purified by chromatography (15% methanol in methylene
chloride) and crystallized (methanol-ethyl acetate) to give the
title compound as white crystals (275 mg, 58%). .sup.1H-NMR(300
MHz, DMSO-d.sub.6) .delta.1.34 (m, 2 H), 1.84 (d, 2 H, J=7 Hz),
2.06 (m, 1 H), 2.22 (s, 3 H), 2.28 (s, 3 H),3.16 (m, 2 H), 3.78 (d,
2 H, J=3.1 Hz), 3.93 (d, 1 H, J=6.5 Hz), 4.12 (d, 1 H, J=6.5 Hz),
6.43 (t, 1 H, J=2.1 Hz), 6.49 (s, 1 H), 6.77 (s, 1 H), 7.72 (t, 1
H, J=7.5 Hz), 7.85 (t, 1 H, J=1.4 Hz,), 7.92 (m, 2 H), 8.67 (br s,
1 H), and 9.24 (br s, 1 H). Mass spectrun (MALDI-TOF, sinapinic
acid matrix) calcd. for C.sub.21H.sub.25N.sub.2O.sub.4SCl: 437.1
(M+H). Found: 436.8.
EXAMPLE 6
[0222] 2-Chlorobenzenesulfonic acid
3-[(3amidinophenyl)methoxy]-5-methylph- enyl ester
hydrochloride
[0223] a) 2-Chlorobenzenesulfonic acid
3-[(3cyanophenyl)methoxyl-5-methylp- henyl ester
[0224] Diethyl azodicarboxylate (349 mg, 2.0 mrnol) was added to a
solution of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl
ester (900 mg, 3.0 immol), as prepared in step (c) of Example 1,
3-cyanobenzyl alcohol (400 mg, 3.0 mmol; Yoon et al., J. Org. Chem.
38:2786-2792 (1973)), and triphenylphosphine (525 mg, 2.0 mmol) in
tetrahydrofuran (20 mL) at 0.degree. C. The mixture was stirred at
0.degree. C. for 2 h and at room temperature for 3 h. The reaction
mixture was quenched with water (50 mL) and extracted with ethyl
acetate (3.times.50 mL). The organic phase was washed with
saturated NaHCO.sub.3 (2.times.50 mL), brine (2.times.50 mL) and
dried over Na.sub.2SO.sub.4. The solvent was removed in vacuo and
the residue was purified by flash column chromatography (2:1 ethyl
acetate/hexane) to give the title compound as awhite solid (1.10 g,
89%). .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.2.26 (s, 3 H), 4.99
(s, 2 H), 6.55 (t, 1 H, J=2.3 Hz), 6.60 (t, 1 H, J=0.7 Hz), 6.67
(t, 1 H, J=0.7 Hz), 7.39 (m, 1 H), 7.50 (t, 1 H, J=7.7 Hz), 7.61
(m, 5 H), and 7.96 (d, 1 H, J=1.3 Hz).
[0225] b)
2-Chlorobenzenesulfonicacid3-[(3-amidinophenyl)methoxy]-5-methyl-
-phenyl ester hydrochloride
[0226] To a solution of 2-chlorobenzenesulfonic acid
3-[(3-cyanophenyl) methoxy]-5-methylphenyl ester (207 mg, 0.5
mmol), as prepared in the preceding step, in methylene chloride (10
mL) was added 37% HCl in ethanol (10 mL) at 0.degree. C. The
mixture was allowed to stand at 0.degree. C. for 3 days. The
solvent was evaporated in vacuo and the residue was co-evaporated
with methylene chloride several times. The residue was dissolved in
ethanol (10 mL) and ammonium carbonate (192 mg, 2.0 mmol) was added
at 0.degree. C. The mixture was stirred at room temperature
overnight. Methylene chloride (150 mL) was added to the mixture.
The methylene chloride solution was washed with 10% K.sub.2CO.sub.3
(2.times.50 mL) and dried over K.sub.2CO.sub.3. The solvent was
removed in vacuo, HCl in methanol (30 mL) was added, and the
solvent again removed in vacuo. The residue was purified by flash
chromatography (10% methanol in methylene chloride) to give the
title compound as a white solid (112 mg, 48%). .sup.1H-NMR (300
MHz, DMSO-d.sub.6) .delta.2.23 (s, 3 H), 5.11 (s, 2 H), 6.54 (s, 1
H), 6.56 (s, 1 H), 6.88 (s, 1 H), 7.58 (,t, 1 H, J=6.5 Hz), 7.61
(t, 1 H, J=12.2 Hz), 7.66 (d, I H, J=3.9 Hz), 7.73-7.95 (m, 5 H),
and 9.40 (br s, 4 H). Mass spectrum (MALDI-TOF, sinapinic acid
matrix) calcd. for C.sub.21H.sub.19N.sub.2O.sub.4SCl: 431.1 (M+H),
453.1 (M+Na). Found: 431.0, 452.9.
EXAMPLE 7
[0227] 2Chlorobenzenesutronic acid
3-[[3-(N-hydroxy)amidinophenyl]methoxy-- 5-methylphenyl ester
hydrochloride
[0228] To a solution of 2-chlorobenzenesulfonic acid
3-[(3-cyanophenyl) methoxy]-5-methylphenyl ester (207 mg, 0.5
mmol), as prepared in step (a) of the Example 6, in methylene
chloride (10 mL) was added 37% HCI in ethanol (IO mL) at 0.degree.
C. The mixture was allowed to stand at 0.degree. C. for 3 days. The
solvent was removed in vacuo and the residue was co-evaporated with
methylene chloride several times. The residue was dissolved in
ethanol (10 mL) and then treated with hydroxylamine hydrochloride
(140 mg, 2.0 mmol) and Na.sub.2CO.sub.3 (106 mg, 1.0 mmol). T he
reaction mixture was stirred at room temperature for 2 days.
Methylene chloride (150 mL) was added to the mixture, washed with
10% K.sub.2CO.sub.3 (2.times.50 mL), and dried over
K.sub.2CO.sub.3. The solvent was removed in vacuo, HCl in methanol
(30 mL) added and the solvent removed in vacuo. The residue was
purified by flash chromatography (1:1 ethyl acetate/methylene
chloride) to give the title compound as a white foam (95 mg, 39%).
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.2.25 (s, 3 H), 4.89 (br s,
1 H), 4.98 (d, 2 H, J=10.7 Hz), 5.58 (br s, 1 H), 6.15 (br s ,1 H),
7.33-7.64 (m, 6 H), 7.76-7.83 (m, 1 H), and 7.92 (d, 1 H, J=4.0
Hz).
[0229] Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for
C.sub.21H.sub.19N.sub.2O.sub.5SCl: 447.1 (M+H), 469.1 (M+Na).
Found: 447.1,469.2.
EXAMPLE 8
[0230] 2,3-Dichlorobenzenesulfonic acid
3-[[(1-acetimidoyl)piperidin4-yl]m- ethoxy]-5-methylphenyl ester
hydrochloride
[0231] a) 2,3-Dichlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl
ester
[0232] A solution of orcinol monohydrate (0.71 g, 5.0 mmol) and
2,3-dichlorobenzenesulfonyl chloride (1.23 g, 5.0 mmol) in
saturated NaHCO.sub.3 (20 nmL) and diethyl ether (20 mL was stirred
at room temperature for 2 days. The reaction mixture was quenched
with water (50 mL) and extracted with ethyl acetate (3.times.50
mL). The organic phase was washed with brine (2.times.50 mL) and
dried over Na.sub.2SO.sub.4. The solvent was evaporated in vacuo
and the residue was purified by flash column chromatography
(methylene chloride to 2% ethyl acetate in methylene chloride) to
give the title compound as a pale yellow oil (0.89 g, 55%).
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.2.24 (s, 3 H), 5.23 (s, 1
H), 6.43 (t, 1 H, J=2.2Hz), 6.54(d,2H,J=1.1 Hz),7.34(t, 1 H,J=8.1
Hz),7.75(dd, 1 H,J=0.8, 4.0 Hz), and 7.91 (dd, 1 H, J=0.8, 4.0
Hz).
[0233] b) 2,3-Dichlorobenzenesulfonic acid
3-[[N-(tert-butoxycarbonyl)pipe- ridin-4-yl]methoxy]-5-methylphenyl
ester
[0234] Diethyl azQdicarboxylate (349 mg, 2.0 nmuol) was added to a
solution of 2,3dichlorobenzenesulfonic acid
3-hydroxy-5-methylphenyl ester (644 mg, 2.0 mmol), as prepared in
the preceding step, N-tert-butoxylcarbonyl-4-piperidinemethanol
(430 mg, 2.0 mmol), as prepared in step (b) of Example 1, and
triphenylphosphine (525 mg, 2.0 mmol) in tetrahydrofuran (20 mL) at
0.degree. C. The mixture was stirred at 0.degree. C. for 2 h and at
room temperature for 3 h. The reaction mixture was quenched with
water (50 mL) and extracted with ethyl acetate (3.times.50 mL). The
organic phase was washed with saturated NaHCO.sub.3 (2.times.50
mL), brine (2.times.50 mL) and dried over Na.sub.2SO.sub.4. The
solvent was removed in vacuo and the residue was purified by flash
column chromatography (1:3 ethyl acetate/hexane) to give the title
compound as a colorless syrup (930 mg, 88%). .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.1.26 (m, 2 H), 1.47 (s, 9 H), 1.75 (m, 2 H),
1.90 (m, 1 H), 2.25 (s, 3 H), 2.73 (t, 2 H, J=2.0Hz), 3.68 (d, 2 H,
J=3.2 Hz), 4.13 (m, 2 H), 6.47 (d, 1 H, J=1.1 Hz), 6.53 (d, 1 H,
J=0.4 Hz), 6.59 (s, 1 H), 7.34 (t, 1 H, J=8.2 Hz), 7.75 (m, 1 H),
and 7.92 (m, 1 H).
[0235] c) 2,3-Dichlorobenzenesulfonic acid
3-1[(1-acetimidoyl)piperidin4-y- l]methoxy]-5-methylphenyl ester
hydrochloride
[0236]
2,3-Dichlorobenzenesulfonicacid3-[[N-(tert-butoxycarbonyl)piperidin-
4-yl]methoxy]-5-methylphenyl ester (530 mg, 1.0 mmol), as prepared
in the preceding step, was stirred with 4 N HCl in 1,4-dioxane (10
mL) at room temperature for 2 h. The solvent was evaporated in
vacuo, the residue was co-evaporated with methylene chloride
several times to give the amine HCl salt. Triethylamine (0.5 nmL)
and ethyl acetimidate hydrochloride (247 mg, 2.0 mmol) were added
to a solution of the above amine in N,Ndirnethylformamide (10 mL)
and the reaction mixture was stirred at room temperature for 2
days. The N,N-dimethylformamide was removed in vacuo and the
residue was partitioned between methylene chloride (200 mL) and 10%
K.sub.2CO.sub.3 (50 mL). The organic phase was washed with 10%
K.sub.2CO.sub.3 (2.times.50 mL) and dried over K.sub.2CO.sub.3.
After removing the solvent in vacuo, HCl-methanol (30 mL) was added
and the solution concentrated. The residue was then crystallized
from methanol-ethyl acetate to give the title compound as white
crystals (420 mg, 83%). .sup.1H-NMR (300 MHz, DMSO-d.sub.6)
.delta.1.34 (m, 2 H), 1.84 (d, 1 H, J=8.6 Hz), 2.04 (m, 1 H), 2.22
(s, 3 H), 2.29 (s, 3 H), 3.16 (m, 2 H), 3.78 (d, 2 H, J=3.2 Hz),
3.92 (d, 1 H, J=7.0Hz), 4.15 (d, I H, J=7.0 Hz), 6.46 (t, 1 H,
J=2.2Hz), 6.52 (s, 1 H), 6.77 (s, 1 H), 7.62(t, 1 H,J=8.1 Hz), 7.96
(d, 1 H,J=4.0 Hz), 8.14 (d, 1 H,J=4.0 Hz), 8.74 (br s, 1 H), and
9.32 (br s, 1 H). Mass spectrum (MALDI-TOF, sinapinic acid matrix)
calcd. for C.sub.21H.sub.24N.sub.2O.sub.4SCl.sub.2: 471.1 (M+H).
Found: 471.1.
EXAMPLE 9
[0237]
2-Chloro-N-[[3-[(1-acetimidoyl)piperidin-4-yl]methoxy]-5-trifluorom-
ethylphenyl]benzenesulfonamide hydrochloride
[0238] a) 3-(Trifluoromethyl)-5-nitrophenol
[0239] 3-Methoxy-5-nitrobenzotrifluoride (5 g, 23 mmol) was
dissolved in anhydrous methylene chloride (100 mL) and cooled to
-80.degree. C. under a nitrogen atmosphere. To this solution was
added via dropping fimnel a 1 M solution of BBr3 in methylene
chloride (68 mL, 68 mmol). This solution was allowed to warm to
room temperature and stirred for 3 days. Water was slowly added to
the mixture and mixed well to quench the excess BBr.sub.3. To this
mixture ether (500 mL) was added. The organic layer was separated
and extracted with 2 N NaOH (240 mL). The alkaline extract was
neutralized with dilute HC1 and extracted with diethyl ether
(3.times.300 mL). The ether extracts were combined, washed with
saturated NaCl and dried over anhydrous MgSO.sub.4. Evaporation of
diethyl ether gave a brownish yellow oil which was chromatographed
on a silica column to give 1.6 g (34%) of a yellow solid.
.sup.1H-NMR (CDCl.sub.3/CD.sub.3OD; 300 MHz) .delta.7.38-7.40 (m, 1
H), 7.82 (t, 1 H, J=2.2 Hz), and 7.95 - 7.96 (m, 1 H).
[0240] b)
3-[[1-(Tert-butoxycarbonyl)piperidin-4-yl]methoxy]-5-nitrobenzot-
rifluoride
[0241] The title compound was synthesized by treating
3-(trifluoromethyl)-5-nitrophenol (1.47 g, 7.1 mmol), as prepared
in the preceding step, in a manner analogous to step (d) of Example
1 to give 2.17 g (76%) as an oil. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta.1.24-1.38 (m, 2 H), 1.48 (s, 9 H), 1.82-1.87 (m, 2 H),
1.96-2.10 (m, 1 H), 2.73-2.81 (m, 2 H), 3.93 (d, 2 H, J=6.3 Hz),
4.09-4.21 (m, 2 H), 7.45-7.46 (m, 1 H), 7.89 (t, 1 H, J=2.2 Hz),
and 8.07-8.08 (m, 1 H).
[0242] c)
2-Chloro-N-[[3-[(1-tert-butoxycarbonyl)piperidin-4-yl]methoxy]-5-
-trifluoromethylphenyl]benzenesulfonamide
[0243] To a methanolic solution of
3-[(piperidin-4-yl)methoxy]-5-nitrobenz- otrifluoride (2.17 g in
200 mL), as prepared in the preceding step, and 10% Pd/C (300 mg)
was stirred under a hydrogen atmosphere for 20 h. The catalyst was
removed by filtration and the methanol was evaporated to give a
white foam. The foam was dried under high vacuum overnight and
dissolved in anhydrous methylene chloride (10 mL). The methylene
chloride solution was cooled in an ice bath under a nitrogen
atmosphere and 2-chlorobenzenesulfonyl chloride (1.17 g, 5.50 mmol)
and N-methylmorpholine (6.05 mmol) were added and the mixture
allowed to warm to room temperature. The mixture was stirred for 2
days at which time N-methylmorpholine (200 .mu.L) was added and the
mixture heated to reflux for 3 h. The methylene chloride solution
was diluted with another 50 mL of methylene chloride and extracted
with 10% citric acid and saturated NaHCO.sub.3. The organic layer
was separated, washed with saturated NaCl and dried over anhydrous
MgSO.sub.4. Evaporation of the methylene chloride gave an oil which
was chromatographed on a silica column to give 2.4 g (80 %) of a
white solid. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta.1.17-1.31 (m,
2 H), 1.47 (s, 9 H), 1.75-1.80 (m, 2 H), 1.83-1.98 (m, 1 H),
2.69-2.78 (m, 2 H), 3.74 (d, 1 H, J=6.2 Hz), 4.09-4.16 (m, 2 H),
6.81 (b s, 1 H), 6.87-6.89 (m,,1 H), 6.90 (br s, 1 H), 7.34-7.43
(m, 2 H), 7.50-7.54 (m, 2 H), and 8.05 - 8.08 (m, 1 H).
[0244] d)
2-Chloro-N-[[3-[piperidin-4-yl]methoxyl-5-trifluoromethylphenyl]-
-benzenesulfonamide trifluoroacetate
[0245] 2-Chloro-N-[[3-[(1
-tert-butoxycarbonyl)piperidin-4-yl]methoxy]-5-t-
rifiuoromethylphenyl]benzenesulfonamide (0.33 g, 0.64 mmol) was
treated with 25% trifluoroacetic acid in methylene chloride (5 mL)
at ambient temperature for 0.5 h. The reaction mixture was
evaporated to dryness and azeotroped with acetonitrile (3 times).
The residue was triturated with hexane (twice) and diethyl ether,
then placed under high vacuum overnight. Mass spectrum (MALDI-TOF,
gentisic acid matrix) calcd. for
C.sub.19H.sub.20N.sub.2O.sub.3SCIF.sub.3: 449.1 (M+H). Found:
449.8.
[0246] e)
2-Chloro-N-[[3-[(1-acetimidoyl)piperidin-4-yl]methoxy]-5-trifluo-
romethylphenyl]benzenesulfonamide hydrochloride
[0247]
2-Chloro-N-[[3-[piperidin-4-yl]methoxy]-5-trifluoromethylphenyl]
benzenesulfonamide trifluoroacetate from step (d) above was
dissolved in N,N-dimethylformamide (10 mL) and treated with ethyl
acetimidate hydrochloride (0.16 g, 1.28 mmol) and triethylamine
(0.27 mL, 1.92 mmol). The reaction mixture was stirred at ambient
temperature overnight. The reaction mixture was diluted with water
(cloud point) to initiate crystallization. The solid precipitate
was collected by filtration and washed with water. The solid was
dried under high vacuum overnight to give 0.218 g of the title
compound. .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.1.33 (m, 2 H),
1.84 (d, 3 H), 2.04-2.12 (m, 1 H), 2.26 (s, 3 H), 3.10-3.33 (m, 2
H), 3.74 (d, 2 H), 3.91-4.02 (m, 2 H), 6.32 (br s, 1 H), 6.57 (s, 1
H), 6.67 (br s, 1 H), 7.28-7.42 (mn, 3 H), 7.93 (dd, 1 H), 8.48 (br
s, 1 H), and 9.04 (br s, 1 H).
EXAMPLE 10
[0248]
2-Chloro-N-(5-carboxypentyl)-N-[[3-[(1-acetimidoyl)piperidin-4-yl]m-
ethoxy]-5-trifluoromethylphenyl]benzenesulfonamide
[0249] a)
2-Chloro-N-(5-ethoxycarbonylpentyl)-N-[[3-1(1-tert-butoxycarbony-
l)piperidin-4-yl]methoxyl-5-trifluoromethylphenyl]benzenesulfonamide
[0250] A solution of
2-chloro-N-[[3-[(1-tert-butoxycarbonyl)piperidin-4-yl-
]methoxy]-5-trifluoromethylphenyl]benzenesuifonamide (0.6 g, 1.1
mmol) in N,N-dimethylformamide (10 mL) was treated with potassium
carbonate (0.15 g, 1.1 mmol) and ethyl 6-bromohexanoate (0.20 mL,
1.1 Immol). The reaction was warmed at 50-60.degree. C. for 2 days.
The reaction mixture was diluted with water, neutralized with 5%
hydrochloric acid, and extracted with ethyl acetate (3.times.). The
ethyl acetate was washed with brine, dried (Na.sub.2SO.sub.4), and
evaporated to dryness. The residue was purified by solid phase
extraction using a 10 g Sep-Pak column (Waters Associates) and
elution with 20% ethyl acetate-hexanes to give 0.70 g (92% yield).
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta.1.26-1.43 (m, 2H), 1.44
(s, 9 H), 1.45-1.96 (m, 9 H), 2.24 (t, 2 H), 2.72 (br t, 2 H),
3.73-3.81 (m, 4 H), 4.05-4.16 (m, 4 H), 6.89 (br s, 1 H), 6.96 (m,
2 H), 7.24 (dt, 1 H), 7.40 - 7.50 (m, 2 H), and 7.81 (dd, 1 H).
[0251] b)
2Chloro-Ncarboxypentyl)-N-[[3-[(1-tert-butoxycarbonyl)piperidin--
4-yl]methoxy]-5-trifluoromethylphenyl]benzenesulfonamide
[0252] A solution of
2-chloro-N-(5-ethoxycarbonylpentyl)-N-[[3-[(1-tert-bu-
toxycarbonyl)piperidin-4-yl]methoxy]-5-trifluoromethylphenyl]
benzenesulfonamide, as prepared in the preceding step, (0.70 g, 1
mmol) was dissolved in a 4:1 dioxane/water mixture (12 mL) and
treated with lithium hydroxide monohydrate (0.042 g, 1 mmol). The
reaction mixture was allowed to stir at ambient temperature for 2
days, then warmed at 50.degree. C. overnight. An additional 0.042 g
of lithium hydroxide monohydrate was added and the temperature
maintained at 50.degree. C. for 5 h. The reaction mixture was
extracted with methylene chloride. The aqueous layer was acidified
with 5% hydrochloric acid and extracted with methylene chloride.
The combined methylene chloride extracts were washed with brine,
dried (Na.sub.2SO.sub.4), and evaporated to dryness to give 0.68 g
(quantitative) of the title compound. .sup.1H-NMR (CDCl.sub.3, 300
MHz) .delta.1.20-2.00 (m, 20 H), 2.32 (t, 2 H), 2.75 (br t, 2 H),
3.76-3.84 (m, 4 H), 4.16 (m, 2 H), 6.92 (br s, 1 H), 6.99 (m, 2 H),
7.28 (dt, 1 H), 7.44 (dd, 1 H), 7.49 (dd, 1 H), and 7.84 (dd, 1
H).
[0253] c)
2-Chloro-N-(5-carboxypentyl)-N-[[3-[(1-acetimidoyl)piperidin-4-y-
l]methoxy]-5-trifluoromethylphenyl]benzenesuofonamide
[0254] A solution of
2-chloro-N-(5-carboxypentyl)-N-[[3-[(1-tert-butoxycar-
bonyl)piperidin-4-yl]methoxy]-5-trifluoromethylphenyl]
benzenesulfonamide, as prepared in the preceding step, (0.68 g, 1
mmol) in 25% trifluoroacetic acid in methylene chloride (15 mL) was
stirred at ambient temperature for 0.5 h. The reaction mixture was
evaporated to dryness, azeotroped with acetonitrile (3 times), and
triturated with hexanes (twice) and 2:1 hexanes/diethyl ether
(twice). The residue was placed under high vacuum to give 0.6 g of
2-chloro-N-(5-carboxypentyl)-N-[[3-[pi-
peridin-4-yl]methoxy]-5-trifluoromethylphenyl]benzenesulfonamide
trifluoroacetate.
[0255] A solution of
2-chloro-N-(5-carboxypentyl)-N-[[3-[piperidin-4-yl]me-
thoxy]-5-trifluoromethylphenyl]benzenesulfonamide trifluoroacetate
(0.3 g, 0.5 mmol) in NN-dimethylformamide (10 mL) was treated with
triethylamine (0.21 mL, 1.5 mmol) and ethyl acetimidate
hydrochloride (0.13 g, 1 mmol) at ambient temperature. The reaction
mixure was diluted with water to produce an oily gum. The aqueous
layer was decanted and the oily gum was treated with a small amount
of methanol and diluted with water to initiate crystallization. The
solid was collected by filtration, washed with water, and dried
under high vacuum to give 7.4 mg of the title compounds as a white
solid. .sup.1H-NMR (CDCl.sub.3/TFA, 300 MHz) .delta.1.26-2.44 (m,
16 H), 2.9 - 3.4 (m, 2 H), 3.62-4.55 (m, 6 H), 6.90 (d, 1 H),
7.04-7.08 (m, 2 H), 7.33 (dt, 1 H), 7.55 (m, 2 H), and 7.84 (d, 1
H). Mass spectrum (MALDI-TOF, .alpha.-cyano-4-hydroxycinnamic acid
matrix) calcd. for C.sub.27H.sub.33N.sub.3O.sub.5SCIF.sub.3: 604.2
(M+H). Found: 604.3.
EXAMPLE 11
[0256] 1-(5-(N,N-Dimethylamino)naphthalenesulfonic acid
3-[[(1-acetimidoyl)piperidin-3-yl]methoxy]-5-methoxyphenyl ester
hydrochloride
[0257] a) 1-(5-(N,N-Dimethylamino)naphthalenesulfonic acid
3-hydroxy-5-methoxyphenyl ester
[0258] A biphasic solution of 1.08 g (7.78 mmol) of
5-methoxyresorcinol, 2.10 g (7.78 mmol) of dansyl chloride, 30 mL
of diethyl ether, and 30 mL of saturated sodium bicarbonate was
vigorously stirred at ambient temperature overnight. The reaction
mixture was quenched with pH 7 buffer, extracted into diethyl
ether, dried (MgSO.sub.4), and purified by flash chromatography
(1-2% ether/methylene chloride) to provide 605.5 mg (21% yield) of
the title compound was a bright yellow powder. .sup.1H-NMR (300
MHz, CDCl.sub.3) .delta.8.59 (d, 1 H, J=8.5 Hz), 8.43 (d, 1 H, J=8
Hz), 8.12 (dd, 1 H, J=1, 7 Hz), 7.66 (dd, 1 H, J=8, 8.5 hz), 7.46
(dd, 1 H, J=7.4, 8.5 Hz), 7.25 (d, 1 H, J=7.5 Hz), 6.20 (t, 1 H,
J=2.2 Hz), 6.04 (t, J=2.2 Hz), 6.01 (t, 1 H, J=2.2 Hz), 5.62 (br s,
1 H), 3.55 (s, 3 H), and 2.99 (s, 6 H). Mass spectrum (MALDI-TOF;
.alpha.-cyano-4-hydroxycinna- mic acid matrix) calcd. for
C.sub.19H.sub.19NO.sub.5S: 374.1 (M+H), 396.1 (M+Na). Found: 373.7,
395.7.
[0259] b) N-(tert-Butoxycarbonyl)-3-piperidinemethanol
[0260] To a solution of 3-piperidinemethanol (4.60 g, 40 mmol) and
triethylamine (6 mL) in 1,4-dioxane (100 mL) was added slowly
di-tert-butyl dicarbonate (8.72 g, 40 mmol). After stirring at room
temperature for 2 h, the solvent was removed in vacuo and the
residue purified by flash column chromatography (2:1 hexane/ethyl
acetate) to give the title compound as white solid (7.81 g, 91%).
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.1.25-1.39 (m, 2 H), 1.46
(s, 9 H), 1.60-1.81 (m, 3 H), 1.94 (br s,1 H), 2.98-3.08 (m, 2 H),
3.51 (d, 2 H), and 3.66-3.77 (m, 2 H).
[0261] c) 1-(5-(N,N-Dimethylamino)naphthalenesulfonic acid
3-[[N-(tert-butocxyarbonyl)piperidin-3-yl]methoxy]-5-methoxyphenyl
ester
[0262] To a solution of 379 mg (1.05 mmol) of
1-(5-(N,N-dimethylamino) naphthalenesulfonic acid
3-hydroxy-5-methoxyphenyl ester as prepared in Step a of this
Example, in tetrahydrofuran (10 mL) containing 275 mg (0.347 mmol)
of N-(tert-butoxycarbonyl)-3-piperidinemethanol, as prepared in the
preceding step, 358 mg (1.36 nunol) of triphenylphosphine, and 350
.mu.L (3.18 mmol) of N-methylmorpholine was added 215 .mu.L (1.36
mmol) of diethyl azodicarboxylate. The reaction mixture was stirred
at ambient temperature for 1 h, quenched with pH 7 buffer,
extracted into diethyl ether, dried (MgSO.sub.4), and concentrated
in vacuo. The product was purified by flash chromatography to
provide 245.7 mg (38% yield) ofthe title compound as a yellow foam.
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.8.60 (d, 1 H, J=8.6Hz),
8.45 (d, 1 H, J=8.7Hz), 8.13 (dd, 1 H, J=1.2,7.3 Hz), 7.67 (dd, 1
H), 7.47 (dd, 1 H, J=7.4, 8.5 Hz), 7.24 (1 H, J=8.5 Hz), 6.24 (t, 1
H, J=2.2 Hz), 6.10 (t, 1 H, J=1.9 Hz), 5.99 (t, 1 H, J=2.1 Hz),
3.88 (br d, 2 H), 3.55 (s, 3 H), 2.90 (s, 6 H), 1.58 (s, 3 H), and
1.44 (s, 9 H) . Mass spectrum (MALDI-TOF; .alpha.-cyano-4-hydroxy-
cinnamic acid matrix) calcd. for C.sub.39H.sub.38N.sub.2O.sub.7S:
593.2 (M+Na). Found: 593.0.
[0263] d) 1-(5-(N,N-Dimethylamino)naphthalenesulfonic acid
3-[(piperidin-3-yl)methoxy]-5-methoxyphenyl ester hydrochloride
[0264] To 245 mg of 1-(5-(N,N-dimethylamino)naphthalenesulfonic
acid
3-[[N-(tert-butoxycarbonyl)piperidin-3-yl]methoxy]-5-methoxyphenyl
ester, as prepared in the preceding step, in methylene chloride (1
mL) was added 500 .mu.L of 4 N HCl in dioxane. The reaction mixture
was stirred for 1 h. The reaction mixture was treated with another
1 mL of 4 N HCl in dioxane and stirring was continued for another 1
h. The reaction mixture was concentrated repeatedly from diethyl
ether/methanol/hexane to afford 237.7 mg of the title compound as a
hardened foam. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.9.19 (d,
I H), 9.03 (q, 1 H), 8.72 (d, 1 H, J=8.5 Hz), 8.35 (d, 1 H, J=8.6
Hz), 8.17 (dd, 1 H, J=1.1, 7.3 Hz), 7.84 (t, 1 H, J=7.9 Hz), 7.69
(dd, 1 H, J=7.6, 8.5 Hz), 7.51 (1, H, J=7.7 Hz), 6.41 (t, I H,
J=2.2Hz), 6.08 (t, 1 H, J=2.1 Hz), 5.92 (t, 1 H, J=2.1 Hz),
3.57-3.76 (m, 2 H), 3.53 (s, 3 H), 3.2-3.23 (m, 2 H), 2.94 (s, 6
H), 2.58-2.8 (m, 2 H), 2.14 (br s, 1 H), 1.62-1.80 (m, 2 H),
1.17-1.3 (m, 1 H). Mass spectrum (MALDI-TOF;
.alpha.-cyano-4-hydroxycinnamic acid matrix) calcd. for
C.sub.25H.sub.30N.sub.2O.sub.5S: 471.2 (M+H), 493.2 (M+Na). Formed:
470.9, 492.9.
[0265] e) 1-(5-(N,N-Dimethylamino)naphthalenesulfonic acid
3-[[1-acetimidoyl)piperidin-3-yl]methoxy]-5-methoxyphenyl ester
hydrochloride
[0266] To a solution of 204.7 mg of 1-(5-(N,N-dimethylamino)
naphthalenesulfonic acid
3-[(piperidin-3-yl)methoxy]-5-methoxyphenyl ester hydrochloride, as
prepared in the preceding step in 2 mL of N,N-dimethylformamide
containing 380 .mu.L (3.42 mmol) of N,N-diisopropylethylamine was
added 190 mg (1.54 numol) of ethyl acetimidate hydrochloride. The
reaction mixture was stirred at ambient temperature for 2 days. The
solvent was removed in vacuo and the residue was quenched with 2 N
sodium hydroxide. The reaction mixture was extracted into methylene
chloride, dried (K.sub.2CO.sub.3), and concentrated in vacuo. The
residue was dissolved in methylene chloride (1 mL), treated with
500 .mu.L of glacial acetic acid and then flash chromatographed
(methylene chloride/methanol/glacial acetic acid (92.6:6.5:0.9) to
afford the acetic acid salt of the product as a gum. The gum was
dissolved in methylene chloride and treated with 1 N sodium
hydroxide. The organic phase was dried (K.sub.2CO.sub.3) and
concentrated in vacuo. The residue was dissolved in methylene
chloride, treated with 1 mL of 4 N HCl in dioxane and repeatedly
concentrated from diethyl ether/methylene chloride/hexane to give
177 mg of the title compound as a pale yellow powder. .sup.1H-NMR
(300 MHz, DMSO-d.sub.6) .delta.9.37 and 9.33 (br s, 1 H), 8.78 (s,
I H), 8.71 (d, 1 H, J=7.8 Hz), 1S 8.34 (d, 1 H, J=8.6 Hz),
8.14-8.18 (m, 2 H), 7.84 (t, 1 H, J=7.8 Hz), 7.69 (dt, 1 H, J=1.1,
8.8 Hz), 7.49 (d, 1 H, J=7.6 Hz), 6.45 and 6.42 (t, 1 H), 6.16 and
6.10 (t, 1 H), 5.92 and 5.89 (t, 1 H), 3.53 (s, 3 H), 2.92 (t, 6
H), 2.28 and 2.22 (s, 3 H). Mass spectrum (MALDI-TOF;
.alpha.-cyano-4-hydroxycinna- mic acid matrix) calcd. for
C.sub.27H.sub.33N.sub.3O.sub.5S: 512.2 (M+H). Found: 511.5.
EXAMPLE 12
[0267] 2-Chlorobenzenesulfonic acid
1-[[(1-acetimidoyl)piperidin-4-yl]meth- oxy]naphthalen-3-yl ester
acetic acid salt
[0268] a) 2-Chlorobenzenesulfonic acid 1-hydroxynaphthalen-3-yl
ester
[0269] At 0.degree. C. to 1.0 g (6.24 nmuol) of 1,3-naphthalenediol
in tetrahydrofuran (20 mL) containing 1.5 mL of 2,6-lutidine was
added 1.35 g (6.40 mmol) of 2-chlorobenzenesulfonyl chloride. The
reaction mixture was stirred to ambient temperature overnight,
quenched with 3 N hydrochloric acid, extracted into methylene
chloride, and dried (MgSO.sub.4). Purification by flash
chromatography (2% ethyl acetate/methylene chloride) gave 277 mg
(13% yield) of the title compound as a colorless solid. .sup.1H-NMR
(300 MHz, DMSO-d.sub.6) .delta.10.75 (s, 1 H), 8.06 (d, 1 H, J=1.7
Hz), 7.78-7.95 (m, 4 H), 7.43 - 7.57 (m, 3 H), 7.11 (d, 1 H, J=2
Hz), and 6.63 (d, 1 H, J=2 Hz).
[0270] b) 2-Chlorobenzenesulfonic acid
1-[[1-N-(tert-butoxycarbonyl)piperi-
din-4-yl]methoxy]naphthalen-3-yl ester
[0271] To 277 mg (0.881 mmol) of 2-chlorobenzenesulfonic acid
1-hydroxynaphthalen-3-yl ester, as prepared in the preceding step,
180 mg (0.837 mmol) of N-tert-butoxycarbonyl-4-piperidinemethanol,
as prepared in step (b) of Example 1, 260 mg ((0.99 mmol) of
triphenylphosphine, and 270 .mu.L (2.45 mmol) of N-methylmorpholine
in 2 mL of tetrahydrofuran, was added 160 .mu.L (1.02 mmol) of
diethyl azodicarboxylate. The reaction mixture was stirred at
ambient temperature for 1 h. The reaction mixture was quenched with
water, extracted into diethyl ether, dried (MgSO.sub.4), and flash
chromatographed (2% diethyl ether/methylene chloride) to give 325
mg (79% yield) of a colorless foam. .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.8.17 (d, 1 H, J=7 Hz), 7.96 (dd, 1 H, J=1.4, 8
Hz), 7.41-7.67 (m, 5 H), 7.34 (dt, 1 H, J=1, 7 Hz), 7.08 (d, 1 H),
6.64 (d, 1 H), J=2Hz),4.18
(br,2H),3.89(d,2H,J=6.2Hz),2.79(t,2H,J=12H),2.0-2.2 (m, 1 H), 1.76
(d, 2 H, J=8 Hz), and 1.49 (s, 9 H). Mass spectrum (MALDI-TOF;
.alpha.-cyano-4-hydroxycinnamic acid matrix) calcd. for
C.sub.27H.sub.30ClNO.sub.6S: 554.1 (M+Na). Found: 554.2.
[0272] c) 2-Chlorobenzenesulfonic acid
1-[(piperidin4-yl)methoxy]naphthale- n-3-yl ester hydrochloride
[0273] To a solution of 319 mg (0.596 mmol) of
2-chlorobenzenesulfonic acid
1-[[1-N-(tert-butoxycarbonyl)piperidin-4-yl]methoxy]naphthalen-3-yl
ester, as prepared in the preceding step, in 2 mL of methylene
chloride was added 1.5 mL (6 mmol) of 4 N HCl in dioxane. The
reaction mixture was stirred for 1 h and triturated with diethyl
ether to afford 281 mg of the title compound as a colorless powder.
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.8.94 (bd, 1 H, J=9 Hz),
8.68 (bd, 1 H, J=10 Hz), 8.6 (d, 1 H, J=8 Hz), 7.8-7.98 (m, 4 Hz),
7.50-7.6 (m, 3 H), 7.18 (d, 1 H, J=2 Hz), 6.69 (d, 1 H, J=2 H),
3.94 (d, 2 H, J=7 Hz), 2.93 (q, 2 H), 2.16 (bm, 1 H), 1.96 (d, 2
H), and 1.57-1.71 (m, 2 H). Mass spectrum (MALDI-TOF; gentisic acid
matrix) calcd. for C.sub.22H.sub.22ClNO.sub.4S: 432.1 (M+H). Found:
431.5.
[0274] d) 2-Chlorobenzenesulfonic acid
1-[[(1-acetimidoyl)piperidin4-yl]me- thoxylnaphthalen-3-yl ester
acetic acid salt
[0275] A mixture of 100 mg (0.214 mmol) of 2-chlorobenzenesulfonic
acid 1-[(piperidin-4-yl)methoxy]naphthalen-3-yl ester
hydrochloride, as prepared in the preceding step, in
N,N-dimethylformamide (2 mL) containing 55 mg (0.45 mmol) of ethyl
acetimidate hydrochloride and 125 .mu.L of
N,N-diisopropylethylarnine was stirred at ambient temperature
overnight. To the reaction mixture was added another 125 .mu.L of
N,N-diisopropylethylamine and 55 mg (0.45 mmol) of ethyl
acetimidate hydrochloride. The reaction mixture was stirred for
another 4 h. The reaction mixture was concentrated to dryness,
quenched with 1 N sodium hydroxide (2 mL), extracted into methylene
chloride, dried (K.sub.2CO.sub.3), and concentrated in vacuo. The
residue was diluted with methylene chloride (1 mL), treated with 1
mL of glacial acetic acid and directly purified by preparative thin
layer chromatography using methylene chloride/methanol/glacial
acetic acid (93.6:6.5:0.5) as developing solvent to give the title
compound. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.8.14 (d, 1 H,
J=8 Hz), 7.8-7.97 (m,4H),7.50-7.59(m,3 H), 7.19 (s, 1 H), 6.68 (d,
I H,J=2Hz),4.11 (d, 2 H, J=6 Hz), 3.92 (d, 2 H, J=6 Hz), 3.11 (t, 2
H, J=2.6 Hz), 2.2 (m, 1 H), 1.92 (d, 2 H), 1.75 (br s,3 H), and
1.41 (q, 2 H). Mass spectrum (MALDI-TOF;
.alpha.-cyano4-hydroxycinnamic acid matrix) calcd. for
C.sub.23H.sub.24CIN.sub.3O.sub.4S: 474.1 (M +H). Found: 473.8.
EXAMPLE 13
[0276]
3-[(2-Chlorophenoxy)methyl]-[[(1-acetimidoyl)piperidin4-yl]methoxyl-
benzene acetic acid Salt
[0277] a) 3-[(2-Chlorophenoxy)methyl]phenol
[0278] At 0.degree. C. to 616 mg (2.35 mmol) of triphenylphosphine
and 400 .mu.L (3.84 mmol) of 2-chlorophenol in 20 mL of methylene
chloride was added 370 mL (2.35 mmol) of diethyl azodicarboxylate
followed by dropwise addition of a solution of 233 mg (1.9 mmol)
3-hydroxybenzyl alcohol in 2 mL of tetrahydrofuran. The reaction
mixture was stirred at 0.degree. C. to ambient temperature for 1 h.
The reaction mixture was quenched with water, extracted into
diethyl ether, dried (MgSO.sub.4), and purified by flash
chromatography (methylene chloride/hexane (2:1 to 4:1)) to provided
227 mg (44% yield) of the title compound as a colorless oil.
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.7.39 (dd, 1 H, J=1.6, 7.8
Hz), 7.25 (t, 1 H), 7.15-7.21 (m, 1 H), 6.88 -7.01 (m, 4 H), 6.79
(dd, 1 H, J=2.5, 8.1 Hz), 5.12 (s, 2 H), and 4.97 (s, 1 H).
[0279] b)
1-[(2-Chlorophenoxy)methyl]-3-[[N-(tert-butoxycarbonyl)piperidin-
4-yl]methoxy]benzene
[0280] To a solution of 272 mg (0.809 nunol) of
3-[(2-chlorophenoxy) methyl]phenol, as prepared in the preceding
step, in methylene chloride (5 mL) containing 275 mg (1.05 mmol) of
triphenylphosphine and 208 mg (0.97 mmol) of
N-(tertbutoxycarbonyl)-4-piperidinemethanol, as prepared in step
(b) of Example 1, was added slowly 165 .mu.L (1.04 mmol) of diethyl
azodicarboxylate. The reaction mixture was stirred at ambient
temperature for 1 h. The reaction mixture was quenched with water,
extracted into diethyl ether, dried (MgSO.sub.4), and flash
chromatographed (hexane/ethyl acetate (1:4 to 1:2)) to give 221 mg
(58% yield) of the title compound as a colorless oil. .sup.1H-NMR
(300 MHz, CDCl.sub.3) .delta.7.38 (dd, 1 H, J=1.5, 7.8 Hz), 7.28
(t, 1 H, J=8.1 Hz), 7.15-7.21 (m, 1 H), 8.82-7.03 (m, 5 H), 5.13
(s, 2 H), 3.82 (d, 2 H, J=6.4 Hz), 2.74 (t, 2 H), 1.91-2.00 (m, 1
H), 1.84 (d, 2 H), and 1.47 (s, 9 H). Mass spectrum (MALDI-TOF;
.alpha.-cyano-4-hydroxycinnamic acid matrix) calcd. for
C.sub.24H.sub.30CINO.sub.4S: 454.2 (M+Na). Found: 454.4.
[0281] c)
1-[(2-Chlorophenoxy)methyl]-3-[(piperidin-4-yl)methoxy]benzene
hydrochloride
[0282] A solution of 215 mg of
1-[(2-chlorophenoxy)methyl]-3-[[N-(tert-but-
oxycarbonyl)piperidin-4-yl]methoxy]benzene, as prepared in the
preceding step, in methylene chloride (2 mL) was treated with 1.5
mL of 4 N HCl in dioxane. The reaction mixture was stirred at
ambient temperature for 1 h, and then concentrated to provide 183
mg of the title compound as a colorless powder after repeated
concentrations from diethyl ether/hexane/methanol. .sup.1H-NMR (300
MHz, DMSO-d.sub.6) .delta.8.51 (br s, 2 H), 7.45 (dd, 1 H, J=1.3,
7.9 Hz), 7.27-7.35 (m, 2 H), 7.21 (d, 1 H), 6.90-7.05 (m, 4 H),
5.18 (s, 2 H), 3.87 (d, 2 H), 2.90 (t, 2 H, J=10Hz), 2.05 (m, 1 H),
1.91 (d, 2 H, J=13.8 Hz), and 1.5-1.54 (m, 2 H). Mass spectrum
(MALDI-TOF; .alpha.-cyano-4-hydroxycinnamic acid matrix) calcd. for
C.sub.19H.sub.22ClNO.sub.2: 332.1 (M+H). Found: 332.0.
[0283] d)
3-[(2-Chlorophenoxy)methyl]-[[(1-acetimidoyl)piperidin4-yl]metho-
xy benzene acetic acid salt
[0284] To 40 mg (0.109 mmol) of
1-[(2-chlorophenoxy)methyl]-3-[(piperidin4- -yl)methoxy]benzene
hydrochloride as prepared in the preceding step, in 1 mL of
N,N-dimethylformamide containing 100 .mu.L (0.908 mmol) of
N,N-diisopropylethylamine was added 40 mg (0.325 mmol) of ethyl
acetimidate hydrochloride. The reaction mixture was stirred at
ambient temperature for 3 days. The reaction mixture was
concentrated in vacuo and the residue was quenched with 1 N sodium
hydroxide, extracted into methylene choride, dried
(K.sub.2CO.sub.3), and concentrated. The residue was dissolved with
1 mL of methylene chloride and then treated with 500 .mu.L of
glacial acetic acid. The solution was then applied directly to
preparative thin layer chromatography using methylene
chloride/methanol/glacial acetic (83:15:2) as developing solvent to
provide 33.8 mg of the title compound as a gum. .sup.1H-NMR (300
MHz, DMSO-d.sub.6) .delta.7.45 (dd, 1 H, J=1.5, 7.9 Hz), 7.27-7.34
(m, 2 H), 7.20 - 7.23 (dd, 1 H, J=1.4, 8.3 Hz), 6.89-7.04(m,4
H),5.76 (s,2 H),4.07 (d,2H,J=14Hz),3.87(d,2 H, J=6.2 Hz), 3.05 (t,
2 H, J=13 Hz), 2.22 (s, 3 H), 2.05 -2.13 (m, 1 H), 1.85 (d, 2 H),
1.71 (br s , 3 H), and 1.18-1.38 (m, 2 H). Mass spectrum
(MALDI-TOF; .alpha.-cyano4-hydroxycinnamic acid matrix matrix)
calcd. for C.sub.21H.sub.25N.sub.2O.sub.2: 373.2 (M+H). Found:
373.0.
EXAMPLE 14
[0285] 2-Chlorobenzenesulfonic acid
3-[3-amidinopropoxy]-5-methylphenyl ester hydrochloride
[0286] a) 2-Chlorobenzenesulfonic
acid3-[3-cyanopropoxyl-5-methylphenyl ester
[0287] At 0.degree. C. to 250 mg (0.796 mmol) of
2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester, as
prepared in step (c) of Example 1 in NN-diimethylformamide (3 mL)
was added 20 mg (0.833 mmol) of 100% sodium hydride. The reaction
mixture was stirred for 5 min. To the reaction mixture was added
100 .mu.L (1.01 mmol) of 4-bromobutyronitrile. The reaction mixture
was stirred to ambient temperature overnight, quenched with 1 N
hydrochloric acid and extracted into diethyl ether. The reaction
mixture was dried MgSO.sub.4), placed on a silica gel flash colunm,
and eluted with methylene chloride to give 127 mg of impure
compound as an oil, which was used as is in the next reaction.
.sup.1H-NMR (300 Mz, DMSO-d.sub.6).delta.7.94 (dd, 1 H, J=1.5, 9
Hz), 7.54 - 7.63 (m, 2 H), 7.34-7.40 (m, 1 H), 6.57 (m, 1 H), 6.55
(m, 1 H), and 6.48 (t, 1 H, J=2 Hz). Mass spectrum (ALADI-TOF;
.alpha.-cyano-4-hydroxycinnamic acid matrix) calcd. for
C.sub.17H.sub.16ClNO.sub.4S: 388.0 (M+Na). Found: 387.8.
[0288] b) 2-Chlorobenzenesulfonic acid
3-[3-amidinopropoxy]-5-methylphenyl ester hydrochloride
[0289] A solution of 115 mg of 2-chlorobenzenesulfonic acid
3-[3-cyanopropoxy]-5-methylphenyl ester in 10 mL of 37% HC1 in
ethanol was stirred at 0.degree. C. overnight. The reaction was
concentrated to dryness, diluted with ethanol (5 mL) and treated
with 1 g of ammonium carbonate. The reaction mixture was stirred
for 40 min. The reaction mixture was quenched with 2 N sodium
hydroxide, extracted into methylene chloride, dried
(K.sub.2CO.sub.3), and concentrated to dryness. The residue was
triturated with a mixture of methylene chloride/methanol/hexane to
give 64 mg of the title compound as a colorless powder. .sup.1H-NMR
(300 MHz, DMSO-d.sub.6) .delta.9.02 (br s, 2 H), 8.68 (br s, 2 H),
7.95 (dd, 1 H, J=1, 7 Hz), 7.81-7.90 (m, 2 H), 7.56 - 7.62 (m, 1
H), 6.75 (s, 1 H), 6.50 (s, 1 H), 6.44 (t, 1 H, J=1 Hz), 3.89 (t, 2
H, J 6 Hz), 2.21 (s, 2 H), and 2.02 (pentet, 2 H). Mass Spectrum
(MALDI-TOF; .alpha.-cyano-4-hydroxycinnamic acid matrix) calcd. for
C.sub.17H.sub.19ClN.sub.2O.sub.4S: 383.1 (M+H). Found: 382.8.
EXAMPLE 15
[0290] 2-Chlorobenzenesulfonic acid
3-[[3-(N-methylamidino)phenyl]methoxy-- 5-methylphenyl ester
hydrochloride
[0291] To a solution of 2-chlorobenzenesulfonic acid
3-[(3-cyanophenyl)methoxy]-5-methylphenyl ester (414 mg, 1.0 mmol),
as prepared in step (a) of Example 6, in methylene chloride (10 mL)
was added 37% HCl in ethanol (15 mL) at 0.degree. C. The mixture
was allowed to stand at 0.degree. C. for 3 days. The solvent was
evaporated and the residue was concentrated in vacuo from methylene
chloride several times. The residue was dissolved in ethanol (10
mL), treated with methylamine hydrochloride (270 mg, 4.0 mmol) and
Na.sub.2CO.sub.3 (212 mg, 2.0 mmol), and then stirred at room
temperature for 2 days. The reaction mixture was partitioned
between methylene chloride (150 mL) and 10% K.sub.2CO.sub.3.
[0292] The organic phase was washed with 10% K.sub.2CO.sub.3 (50
mL) and dried over K.sub.2CO.sub.3. After removing the solvent in
vacuo, HCl in methanol (30 mL) was added and the solvent was
removed in vacuo. The residue was then purified by flash column
chromatography (10% methanol/methylene chloride) and crystallized
from methanol/ethyl acetate to give the title compound as white
crystals (145 mg, 30%) .sup.1H-NMR (300 MHz, DMSO-d.sub.6)
.delta.2.22 (s, 3 H), 3.01 (s, 3 H), 5.10 (s, 2 H), 6.53 (s, 1 H),
6.56 (s, 1 H), 6.87 (s, 1 H), 7.58 (t, 1 H, J=7.0 Hz), 7.63 (t, 1
H, J=7.6 Hz), 7.73 (m, 2 H), 7.86 (m, 3 H), 7.94 (d, I H, J=4.0
Hz), 9.05 (br s, 1 H), 9.55 (br s, 1 H), and 9.94 (br s, 1 H). Mass
spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for
C.sub.22H.sub.21N.sub.2O.sub.4SCl: 445.1 (M+H). Found: 445.0.
EXAMPLE 16
[0293] 2-Chlorobenzenesulfonic acid
3-[(4-amidinophenyl)methoxyl-5-methylp- henyl ester
hydrochloride
[0294] a) 2-Chlorobenzenesulfonic acid
3-[(4-cyanophenyl)methoxy-5-methyip- henyl ester
[0295] Diethyl azodicarboxylate (524 mg, 3.0 mmol) was added to a
solution of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl
ester (900 mg, 3.0 mmol), as prepared in step (c) of the Example
1,4-cyanobenzyl alcohol (400 mg, 3.0 mmol; Yoon et al., J. Org.
Chem. 38:2786-2792 (1973)), and triphenylphosphine (790 mg, 3.0
mmol) in tetrahydrofuran (20 miL) at 0.degree. C. The mixture was
stirred at 0.degree. C. for 2 h and at room temperature for 3 h.
The reaction mixture was quenched with water (50 mL) and extracted
with ethyl acetate (3.times.50 mL). The organic phase was washed
sequentially with saturated NaHCO.sub.3 (2.times.50 mL) and brine
(2.times.50 mL), and dried over Na.sub.2SO.sub.4. The solvent was
removed in vacuo and the residue was purified by flash column
chromatography (2:1 ethyl acetate:hexane) to give the title
compound as a white solid (0.95 g, 76%). .sup.1H-NMR (300 Mz
CDCl.sub.3) .delta.2.26 (s, 3H), 5.03 (s, 1 H), 6.57 (t, 1 H, 3=2.2
Hz), 6.59 (s, 1H), 6.67 (s, 1H), 7.38 (t, lH, J=5.8 Hz), 7.49 (d,
2H, J=4.2 Hz), 7.60 (m, 2H), 7.67 (d, 2H, J=3.5 Hz) and 7.96 (d,
1H, J=3.6 Hz).
[0296] b) 2-Chlorobenzenesulfonic acid
3-[4-amidinophenyl)methoxy]-5-methy- lphenyl ester
hydrochloride
[0297] To a solution of 2-chlorobenzenesulfonic acid
3-[(4-cyanophenyl)methoxy]-5-methylphenyl ester (414 mg, 1.0 mmol),
as prepared in the preceding step, in methylene chloride (10 mL)
was added 37% HCl in ethanol (20 mL) at 0.degree. C. The mixture
was stinred at room temperature for 2 days. The solvent was
evaporated and the residue was co-evaporated with methylene
chloride several times. The residue was then dissolved in ethanol
(20 mL) and ammonium carbonate (385 mg, 4.0 mmol) was added at
0.degree. C. The mixture was stirred at room temperature overnight.
The reaction mixture was partitioned between methylene chloride and
10% K.sub.2CO.sub.3 (50 mL). The organic phase was washed with 50
mL of 10% K.sub.2CO.sub.3 and dried over K.sub.2CO.sub.3. The
solvent was removed in vacuo. The residue was diluted with
CH.sub.2Cl.sub.2, treated with HCl in methanol (30 mL), and
concentrated. The residue was then purified by crystallization
(methanol and ethyl acetate) to give the title compound as a white
solid (345 mg, 74%). .sup.1H-NMR (300 MHz, DMSO-d.sub.6)
.delta.2.21 (s, 3H), 5.16 (s, 2 H), 6.53 (t, 2 H, J=9.3 Hz)), 6.86
(s, 1H), 7.55-7.62 (m, 3H), 7.82-7.89 (m, 4 H), 7.93 (d, 1 H, J=4.0
Hz), 9.24 (br s,2 H) and 9.44 (br s,2 H). Mass spectrum (MALDI-TOF,
sinapinic acid matrix) calcd. for
C.sub.21H.sub.19N.sub.2ClO.sub.4S: 431.1 (M+H). Found: 431.1.
EXAMPLE 17
[0298] 2-Chlorobenzenesulfonic acid
3-[(3-amidinophenyl)methoxylphenyl ester hydrochloride
[0299] a) 3-Benzyloxyphenyl acetate
[0300] Resorcinol monoacetate (6.10 g, 40 mmol) in DMF (10 mL) was
added dropwise to the mixture of NaH (95%, 0.92 g, 40 mmol) in DMF
(50 mL). The mixture was stirred at room temperature for 10 min.
Benzyl bromide (6.85 g, 40 mmol) in DMF (10 mL) was then added
dropwise, and the mixture was stirred at room temperature for 2 h.
The reaction mixture was quenched slowly with water (100 mL) and
then extracted with ethyl acetate (3.times.100 mL). The organic
phase was washed with brine (2.times.50 mL) and dried over
Na.sub.2SO.sub.4. The solvent was removed in vacuo and the residue
purified by flash column chromatography (1:1 hexane:methylene
chloride) to give the title compound as a white solid (5.30 g,
55%). .sup.1 H-NMR (300 MHz, CDCl.sub.3) .delta.2.28 (s, 3 H), 5.03
(s, 2 H), 6.72 (m, 2 H), 6.85 (dd, 1 H, J=1.2,4.1 Hz), 7.27 (t, 1
H, J=7.9Hz), and 7.41 (m, 5 H).
[0301] b) 3-Benzyloxyphenol
[0302] 3-Benzyloxyphenyl acetate (4.84 g, 20 mmol), as prepared in
the preceding step, in tetrahydrofuran (50 mL) was treated with 1 N
NaOH (30 mL) at room temperature for 3 h. The mixture was acidified
with 1 N HCl and extracted with ethyl acetate (3'100 nmL). The
organic phase was washed with brine (2.times.50 mL) and dried over
Na.sub.2SO.sub.4. The solvent was removed in vacuo and the residue
purified by flash column chromatography (methylene chloride) to
give the title compound as a colorless liquid (3.80 g, 96%).
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.5.01 (s, 2 H), 5.09 (s, 1
H), 6.47 (t, 2 H, J=2.2 Hz), 6.56 (dd, 1 H, 3=1.1, 4.1 Hz), 7.11
(t, 1 H), and 7.39 (m, 5 H).
[0303] c) 2-Chlorobenzenesulfonic acid 3-benzyloxyphenyl ester
[0304] 3-Benzyloxyphenol (2.97 g, 15 mmol), as prepared in the
preceding step, in methylene chloride (50 mL) was treated with
diisopropylethylamine (2 mL) and 2-chlorobenzenesulfonyl chloride
(3.27 g, 15.5 mmol) at 0.degree. C. for 2 h and at room temperature
for 2 h. The reaction mixture was diluted with 200 mL of methylene
chloride, washed sequentially with saturated NaHCO.sub.3
(2.times.50 mL) and brine (2.times.50 mL), and dried over
Na.sub.2SO.sub.4. The solvent was removed in vacuo and the residue
was purified by flash column chromatography (1:1 hexane:methylene
chloride) to give the title compound as a colorless liquid (5.35 g,
95%). .sup.1H-NMR (300 Mz, CDCl.sub.3) .delta.4.97 (s, 2 H), 6.71
(dd, 1 H, J=1.1, 4.1 Hz), 6.78 (t, 1 H, J=2.3 Hz), 6.85 (dd, 1 H,
J=1.1, 4.1 Hz), 7.17 (t, 1 H, J=8.3 Hz), 7.37 (m, 5 H), 7.58 (m, 2
H), and 7.91 (dd, 1 H, J=1.1, 4.1 Hz).
[0305] d) 2-Chlorobenzenesulfonic acid 3-hydroxyphenyl ester
[0306] 2-Chlorobenzenesulfonic acid 3-benzyloxyphenyl ester (3.75
g, 10 mmol), as prepared in the preceding step, Pd/C (10%) (350 mg)
in tetrahydrofuran (80 mL) was hydrogenated (balloon) for 3 h. The
catalyst was filtered through Celite and washed with
tetrahydrofuiran. The combined tetrahydrofuran solution was
evaporated in vacuo and the residue was then purified by flash
column chromatography (methylene chloride) to give the title
compound as a colorless oil (2.75 g, 95%). .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.6.68 (m, 3 H), 7.12 (t, 1H, J=6.5 Hz), 7.37 (t,
1 H, =7.1 Hz), 7.60 (m, 2 H), 7.94 (dd, .sup.1 H, J=0.6, 4.0
Hz).
[0307] e) 2-Chlorobenzenesulfonic acid
3-[(3-cyanophenyl)methoxyphenyl ester
[0308] Diethyl azodicarboxylate (174 mg, 1.0 mmol) was added to a
solution of 2-chlorobenzenesulfonic acid 3-hydroxyphenyl ester (285
mg, 1.0 mmol), as prepared in the preceding step, 3-cyanobenzyl
alcohol (133 mg, 1.0 mmol)(Yoon et al., J. Org. Chem. 38:2786-2792
(1973)), and triphenylphosphine (263 mg, 1.0 mmol) in
tetrahydrofuran (10 mL) at 0.degree. C. The mixture was stirred at
0.degree. C. for 2 hours and at room temperature for 3 hours. The
reaction mixture was quenched with water (30 mL) and extracted with
ethyl acetate (3.times.30 mL). The organic phase was washed with
saturated NaHCO.sub.3 (2.times.30 mL), brine (2.times.30 mL) and
dried over Na.sub.2SO.sub.4. The solvent was removed in vacuo the
residue was purified by flash column chromatography (2:1 ethyl
acetate:hexane) to give the title compound as a pale yellow oil
(375 mg, 93%). .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.5.02 (s, 2
H), 6.78 (m, 2 H), 6.85 (dd, 1 H, J=4.2, 1.3 Hz), 7.20 (t, .sup.1
H, J=8.2 Hz), 7.38 (t, 1 H, J=5.8 Hz), 7.51 (t, 1 H, J=7.7 Hz),
7.59-7.68 (m, 5 H) and 7.93 (dd, 1 H, J=4.0, 0.7 Hz).
[0309] f) 2-Chlorobenzenesulfonic acid
3-[(3-amidinophenyl)methoxy]phenyl ester hydrochloride
[0310] To a solution of 2-chlorobenzenesulfonic acid
3-[(3-cyanophenyl)methoxy]phenyl ester (280 mg, 0.7 mmol), as
prepared in the preceding step, in methylene chloride (10 mL) was
added 37% HCl in ethanol (15 mL) at 0.degree. C. The mixture was
stirred at room temperature for 2 days. The solvent was evaporated
and the residue was co-evaporated with methylene chloride several
times. The residue was then dissolved in ethanol (10 mL) and
ammonium carbonate (300 mg, 3.0 mmol) was added at 0.degree. C. The
mixture was stirred at room temperature overnight. The reaction
mixture was diluted with methylene chloride (150 mL), washed with
10% K.sub.2CO.sub.3 (2.times.50 mL), and dried over
K.sub.2CO.sub.3. The solvent was removed in vacuo, HCl in methanol
(30 mL) was added, and then concentrated in vacuo. The residue was
purified by flash chromatography (10% methanol in methylene
chloride) to give the title compound as a white foam (238 mg, 75%).
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.5.15 (s, 2 H), 6.67 (d,
1 H, J=4.0 Hz), 6.81 (s, 1 H), 7.03 (d, 1 H, J=4.0 Hz), 7.32 (t, 1
H, J=8.3 Hz), 7.58 (t, 1 H, J=7.5 Hz), 7.65 (t, 1 H, J=7.7 Hz),
7.75-7.94 (m, 6 H), 9.27 (br s, 2 H), and 9.45 (br s, 2 H). Mass
spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for
C.sub.20H.sub.17N.sub.2ClO.sub.4S: 417.1 (M+H), 439.0 (M+Na).
Found: 417.4,439.1.
EXAMPLE 18
[0311] 2-Chlorobenzenesulfonic acid
3-[5-amidinopentyloxy]-5-methylphlenyl ester acetic acid salt
[0312] a) 2-Chlorobenzenesulfonic acid
3-[5-cyanopentyloxy]-5-methylphenyl ester
[0313] Sodium hydride (24 mg, 1 mmol; 100%) was added to solution
of 250 mg (0.855 mmol) of 2-chlorobenzenesulfonic acid
3-hydroxy-5-methylphenyl ester, as prepared in step (c) of Example
1, in 2 mL of N,N-dimethylformamide. After 5 min, 130 .mu.L (0.93
mmol) of 6-bromohexanenitrile was added to the reaction mixture.
The reaction mixture was stirred for 2 h at ambient temperature,
quenched with brine ( 50 mL), extracted into diethyl ether (50 mL),
washed with water (3.times.10 mL), dried (MgSO.sub.4), and
concentrated in vacuo. The residue was purified by flash
chromatography (methylene chloride/petroleum ether 4:1 to 100:0) to
give 250 mg of the title compound as a colorless oil which
solidified upon standing. .sup.1H-NMR (300 MHz, CDCl.sub.3)
.delta.7.97 (dd, 1 H, J=1.4, 7.8 Hz), 7.56-7.65 (m, 2 H), 7.36-7.41
(m, 1 H), 6.59 (br s, 1 H), 6.53 (br, s 1 H), 6.48 (t, 1 H, J=1.1
Hz), 3.85 (t, 2 H), 2.38 (t, 2 H), 2.24 (s, 3 H), and 1.6-1.8 (m, 6
H). Mass spectrum (MALDI-TOF, .alpha.-cyano-4-hydroxycinnamic acid
matrix) calcd. for C.sub.19H.sub.20NClO.sub.4S: 416.1 (M+Na).
Found: 416.1.
[0314] b) 2-Chlorobenzenesulfonic acid
3-[5-anidinopentyloxy]-5-methylphen- yl ester acetic acid salt
[0315] A solution of 138 mg (0.351 mmol) of 2-chlorobenzenesulfonic
acid 3-[5-cyanopentyloxy]-5-methylphenyl ester, as prepared in the
preceding step, in 10 mL of 37% HCl ethanol was stirred at ambient
temperature overnight. The reaction mixture was concentrated to an
oil, diluted with 5 mL of ethanol and treated with 1.0 g of
ammonium carbonate. After stirring at ambient temperature for 30
min, the reaction mixture was quenched with 2 N NaOH, extracted
into methylene chloride, dried (K.sub.2CO.sub.3), and concentrated.
The residue was treated with 500 .mu.L of glacial acetic acid and
triturated from diethyl ether/methylene chloride to provide 3.9 mg
of the title compound. .sup.1H-NMR (300 MHz, DMSO-d.sub.6)
.delta.7.79-7.95 (m, 3 H), 7.55-7.60 (t, 1 H), 6.73 (s, 1 11), 6.49
(s, 1 H), 6.38 (s, 1 H), 3.85 (t, 2 H), 2.29 (t, 2 H), and 2.20 (s,
3 H). Mass spectrum (MALDI-TOF, .alpha.-cyano-4-hydroxycinnamic
acid matrix) calcd. for C.sub.19H.sub.23N.sub.2ClO.sub.4S: 411.1
(M+H). Found: 411.3.
EXAMPLE 19
[0316] In Vitro Inhibition of Purified Enzymes
[0317] Reagents
[0318] All buffer salts were obtained from Sigma Chemical Company
(St. Louis, Mo.), and were of the highest purity available. The
enzyme substrates, N-benzoyl-Phe-Val-Arg-p-nitroanilide
(SigmaB7632),N-benzoyl-I- le-Glu-Gly-Arg-p-nitroanilide (Sigma
B2291), N-p-tosyl-Gly-Pro-Lys-p-nitro- anilide (Sigma T6140), and
N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide (Sigma S7388) were all
obtained from Sigma.
[0319] Human .alpha.-thrombin and human factor Xa were obtained
from Enzyme Research Laboratories (South Bend, Indiana). Bovine
trypsin was obtained from Sigma.
[0320] K.sub.i Determinations
[0321] All assays are based on the ability of the test compound to
inhibit the enzyme catalyzed hydrolysis 6f a peptide p-nitroanilide
substrate. In a typical K.sub.i determination, substrate is
prepared in DMSO, and diluted into an assay buffer consisting of 50
mM HEPES, 200 mM NaCl, pH 7.5. The final concentration for each of
the substrates is listed below. In general, substrate
concentrations are lower than the experimentally determined value
for K.sub.m. Test compounds are prepared as a 0.16 mg/mL solution
in DMSO. Dilutions are prepared in DMSO yielding 8 final
concentrations encompassing a 200-fold concentration range. Enzyme
solutions are prepared at the concentrations listed below in assay
buffer.
[0322] In a typical K.sub.i determination, into each well of a 96
well plate is pipetted 280 uL of substrate solution, 10 .mu.L of
inhibitor solution, and the plate allowed to thermally equilibrate
at 37.degree. C. in a Molecular Devices plate reader for >10
minutes. Reactions were initiated by the addition of a 20 .mu.L
aliquot of enzyme, and the absorbance increase at 405 nm is
recorded for 15 minutes. Data corresponding to less than 10% of the
total substrate hydrolysis were used in the calculations. The ratio
of the velocity (rate of the change in absorbance as a function of
time) for a sample containing no inhibitor is divided by the
velocity of a sample containing inhibitor, and is plotted as a
finction of inhibitor concentration. The data are fit to a linear
regression, and the value of the slope of the line calculated. The
inverse of the slope is the experimentally determined K.sub.i
value.
[0323] Thrombin
[0324] Thrombin activity was assessed as the ability to hydrolyze
the substrate Suc-Ala-Ala-Pro-Arg-pNA. Substrate solutions were
prepared at a concentration of 20 .mu.M (20 uM<<K.sub.m=180
.mu.M) in assay buffer. Final DMSO concentration was 0.3%. Purified
human a-thrombin was diluted into assay buffer to a concentration
of 450 nM. Final reagent concentrations were: [thrombin] =0.5 nM,
[Suc-Ala-Ala-Pro-Arg-pNA] =20 .mu.M.
[0325] Factor Xa
[0326] Factor Xa activity was assessed as the ability to hydrolyze
the substrate Bz-Be-Glu-Gly-Arg-pNA. Substrate solutions were
prepared at a concentration of 51 .mu.M (51
.mu.M<<K.sub.m=1.3 mM) in assay buffer. Final DMSO
concentration was 0.3%. Purified activated human Factor Xa was
diluted into assay buffer to a concentration of 300 nM. Final
reagent concentrations were: [FXa] =20 rM, [Bz-]le-Glu-Gly-Arg-pNA]
=51 .mu.M.
[0327] Trypsin
[0328] Trypsin activity was assessed as the ability to hydrolyze
the substrate Bz-Phe-Val-Arg-pNA. Substrate solutions were prepared
at a concentration of 14 .mu.M (14 .mu.M<<K.sub.m=291 .mu.M)
in assay buffer. Final DMSO concentration was 0.3%. Purified bovine
trypsin was diluted into assay buffer to a concentration of 150 nM.
Final reagent concentrations were: [Trypsin] =10 nM,
[Bz-Phe-Val-Arg-pNA]=14 .mu.M.
[0329] Chymotrypsin
[0330] Chymotrypsin activity was assessed as the ability to
hydrolyze the substrate Suc-Ala-Ala-Pro-Phe-pNA. Substrate
solutions were prepared at a concentration of 14 .mu.M (14
.mu.M<<K.sub.m=6 .mu.M) in assay buffer. Final DMSO
concentration was 0.3%. Purified bovine x-chymotrypsin was diluted
into assay buffer to a concentration of 45 nM. Final reagent
concentrations were: [chymotrypsin] =3 nM,
[Suc-Ala-Ala-Pro-Phe-pNA] =14 .mu.M.
[0331] The results obtained employing synthesized compounds are
given in Table 1.
1TABLE 1 Product of Example Number Enzyme K.sub.i (.mu.M) 1
Thrombin 1.65 5 Thrombin 4.86 6 Factor Xa 2.72 7 Trypsin 5.23 8
Thrombin 1.72 14 Thrombin 0.57 18 Chymotrypsin 6.29
[0332] The results indicate that the compounds of the present
invention are inhibitors of proteases. Compounds of the present
invention inhibit a number of proteases, including factor Xa,
thrombin chymotrypsin and trypsin.
[0333] Having now fully described this invention, it will be
understood to those of ordinary skill in the art that the same can
be performed within a wide and equivalent range of conditions,
formulations, and other parameters without affecting the scope of
the invention or any embodiment thereof. All patents and
publications cited herein are filly incorporated by reference
herein in their entirety.
* * * * *