U.S. patent application number 12/633286 was filed with the patent office on 2010-04-08 for substituted n-arylsulfonylheterocyclic amines as gamma-secretase inhibitors.
This patent application is currently assigned to Schering Corp.. Invention is credited to Thomas A. Bara, John W. Clader, Hubert B. Josien, Hongmei Li, Dmitri A. Pissarnitaki, Ruo Xu, Zhiqiang Zhao.
Application Number | 20100087425 12/633286 |
Document ID | / |
Family ID | 35783342 |
Filed Date | 2010-04-08 |
United States Patent
Application |
20100087425 |
Kind Code |
A1 |
Josien; Hubert B. ; et
al. |
April 8, 2010 |
Substituted N-Arylsulfonylheterocyclic Amines As Gamma-Secretase
Inhibitors
Abstract
This invention discloses novel gamma secretase inhibitors of the
formula: ##STR00001## wherein: L is --O--, --N(R.sup.6)--, --S--,
--S(O)--, or --S(O.sub.2)--; R.sup.1 is selected from the group
consisting of aryl and heteroaryl; R.sup.2 is selected from the
group consisting of alkyl, --C(O)--Y, --X--C(O)--Y,
-alkylene-X--C(O)--Y, -alkylene-C(O)--Y,
-alkylene-cycloalkylene-X--C(O)--Y,
-alkylene-cycloalkylene-C(O)--Y,
-cycloalkylene-alkylene-X--C(O)--Y,
-cycloalkylene-alkylene-C(O)--Y, -cycloalkylene-X--C(O)--Y,
-cycloalkylene-C(O)--Y,
-alkylene-cycloalkylene-alkylene-X--C(O)--Y,
-alkylene-cycloalkylene-alkylene-C(O)--Y, aryl, and heteroaryl;
R.sup.3 is selected from the group consisting of aryl, heteroaryl,
alkyl, cycloalkyl, arylalkyl, arylcycloalkyl, heteroarylalkyl,
heteroarylcycloalkyl, arylheterocycloalkyl, and alkoxyalkyl; each
R.sup.4 and R.sup.5 is independently selected from the group
consisting of H and alkyl; and Y is selected from the group
consisting of --NR.sup.8R.sup.9,
--N(R.sup.6)--(CH.sub.2).sub.b--NR.sup.8R.sup.9, aryl, heteroaryl,
alkyl, cycloalkyl, arylalkyl, arylcycloalkyl, heteroarylalkyl,
heteroarylcycloalkyl, and aryl heterocycloalkyl; or Y is selected
from the group consisting of: ##STR00002## One or more compounds of
formula I, or formulations comprising such compounds, may be
useful, e.g. in treating Alzheimer's Disease.
Inventors: |
Josien; Hubert B.; (Jersey
City, NJ) ; Clader; John W.; (Crawford, NJ) ;
Bara; Thomas A.; (Linden, NJ) ; Xu; Ruo;
(Watchung, NJ) ; Li; Hongmei; (Warren, NJ)
; Pissarnitaki; Dmitri A.; (Scotch Plains, NJ) ;
Zhao; Zhiqiang; (Scotch Plains, NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION;PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Assignee: |
Schering Corp.
|
Family ID: |
35783342 |
Appl. No.: |
12/633286 |
Filed: |
December 8, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11168797 |
Jun 28, 2005 |
|
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12633286 |
|
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60584010 |
Jun 30, 2004 |
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Current U.S.
Class: |
514/227.8 ;
514/231.8; 514/233.2; 514/235.8; 514/237.2; 544/116; 544/121;
544/130; 544/141; 544/58.2; 544/85 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 451/02 20130101; A61P 25/28 20180101; C07D 265/30 20130101;
A61P 25/00 20180101; C07D 487/08 20130101; C07D 413/12
20130101 |
Class at
Publication: |
514/227.8 ;
544/130; 544/121; 544/141; 544/85; 544/116; 544/58.2; 514/237.2;
514/235.8; 514/231.8; 514/233.2 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 413/14 20060101 C07D413/14; C07D 413/12 20060101
C07D413/12; C07D 417/12 20060101 C07D417/12; C07D 417/14 20060101
C07D417/14; A61K 31/541 20060101 A61K031/541; A61P 25/00 20060101
A61P025/00; A61P 25/28 20060101 A61P025/28 |
Claims
1. A compound of the formula I: ##STR00289## or a pharmaceutically
acceptable salt and/or solvate thereof, wherein: L is --O--,
--N(R.sup.6)--, --S--, --S(O)--, or --S(O.sub.2)--; R.sup.1 is
selected from the group consisting of unsubstituted aryl, aryl
substituted with one or more substituents R.sup.7 which can be the
same or different, unsubstituted heteroaryl, and heteroaryl
substituted with one or more substituents R.sup.7 which can be the
same or different; R.sup.2 is selected from the group consisting of
alkyl, alkyl substituted with one or more substituents R.sup.7
which can be the same or different, --C(O)--Y, --X--C(O)--Y,
-alkylene-X--C(O)--Y, -alkylene-C(O)--Y,
-alkylene-cycloalkylene-X--C(O)--Y,
-alkylene-cycloalkylene-C(O)--Y,
-cycloalkylene-alkylene-X--C(O)--Y,
-cycloalkylene-alkylene-C(O)--Y, -cycloalkylene-alkylene-C(O)--Y
substituted on the alkylene moiety with one or more hydroxy groups,
-cycloalkylene-X--C(O)--Y, -cycloalkylene-C(O)--Y,
-alkylene-cycloalkylene-alkylene-X--C(O)--Y,
-alkylene-cycloalkylene-alkylene-C(O)--Y, unsubstituted aryl, aryl
substituted with one or more substituents R.sup.7 which can be the
same or different, unsubstituted heteroaryl, and heteroaryl
substituted with one or more substituents R.sup.7 which can be the
same or different; R.sup.3 is selected from the group consisting of
unsubstituted aryl, aryl substituted with one or more substituents
R.sup.7 which can be the same or different, unsubstituted
heteroaryl, heteroaryl substituted with one or more substituents
R.sup.7 which can be the same or different, unsubstituted alkyl,
alkyl substituted with one or more substituents R.sup.7 which can
be the same or different, unsubstituted cycloalkyl, cycloalkyl
substituted with one or more substituents R.sup.7 which can be the
same or different, alkylene-cycloalkyl, alkylene-cycloalkyl
independently substituted on the cycloalkyl moiety with one or more
substituents R.sup.7, unsubstituted arylalkyl, arylalkyl optionally
independently substituted on the aryl moiety with one or more
substituents R.sup.7 which can be the same or different,
unsubstituted arylcycloalkyl, arylcycloalkyl independently
substituted on the aryl moiety with one or more substituents
R.sup.7 which can be the same or different, unsubstituted
heteroarylalkyl, heteroarylalkyl independently substituted on the
heteroaryl moiety with one or more substituents R.sup.7 which can
be the same or different, unsubstituted heteroarylcycloalkyl,
heteroarylcycloalkyl independently substituted on the heteroaryl
moiety with one or more substituents R.sup.7 which can be the same
or different, unsubstituted arylheterocycloalkyl,
arylheterocycloalkyl independently substituted on the aryl moiety
with one or more substituents R.sup.7 which can be the same or
different, and unsubstituted alkoxyalkyl; each R.sup.4 and R.sup.5
is independently selected from the group consisting of H, alkyl,
and alkyl independently substituted with one or more substituents
R.sup.7 which can be the same or different; or R.sup.3 and R.sup.4
together with the carbon atoms to which they are shown attached can
be linked to form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; R.sup.6 is selected from the group consisting of H, alkyl,
alkyl independently substituted with one or more substituents
R.sup.7 which can be the same or different, unsubstituted aryl, and
aryl independently substituted with one or more substituents
R.sup.7 which can be the same or different; R.sup.7 is selected
from the group consisting of halo, --CF.sub.3, --OH, alkyl, alkyl
substituted with 1 to 4 hydroxy groups, --O-alkyl, --OCF.sub.3,
--CN, --NH(alkyl), --N(alkyl).sub.2, --NH(aryl), --N(aryl).sub.2,
--N(aryl)(alkyl), --C(O)O-alkyl, -alkylene-NH(alkyl),
-alkylene-N(alkyl).sub.2, -alkylene-NH(aryl),
-alkylene-N(aryl).sub.2, -alkylene-N(aryl)(alkyl), --NHC(O)-alkyl,
--N(alkyl)C(O)-alkyl, --N(aryl)C(O)-alkyl, --NHC(O)-aryl,
--N(alkyl)C(O)-aryl, --N(aryl)C(O)-aryl, --NHC(O)-heteroaryl,
--N(alkyl)C(O)-heteroaryl, --N(aryl)C(O)-heteroaryl,
--NHC(O)--NH.sub.2, --NHC(O)--NH(alkyl), --NHC(O)--N(alkyl).sub.2,
--NHC(O)--NH(aryl), --NHC(O)--N(aryl).sub.2,
--NHC(O)--N(alkyl)(aryl), --N(alkyl)C(O)--NH.sub.2,
--N(alkyl)C(O)--NH(alkyl), --N(alkyl)C(O)--N(alkyl).sub.2,
--N(alkyl)C(O)--NH(aryl), --N(alkyl)C(O)--N(aryl).sub.2,
--N(alkyl)C(O)--N(alkyl)(aryl), --N(aryl)C(O)--NH.sub.2,
--N(aryl)C(O)--NH(alkyl), --N(aryl)C(O)--N(alkyl).sub.2,
--N(aryl)C(O)--NH(aryl), --N(aryl)C(O)--N(aryl).sub.2, and
--N(aryl)C(O)--N(alkyl)(aryl); R.sup.8 and R.sup.9 are each
independently selected from the group consisting of H, alkyl,
cycloalkyl, arylalkyl, heteroarylalkyl, ##STR00290## each R.sup.10
is independently selected from the group consisting of H, --OH,
alkyl, alkyl substituted with 1 to 4 hydroxy groups, --O-alkyl,
--O-alkyl substituted with 1 to 4 hydroxy groups, cycloalkyl,
cycloalkyl substituted with 1 to 4 hydroxy groups, --C(O)O-alkyl,
-alkylene-C(O)--OH, unsubstituted heterocycloalkyl,
heterocycloalkyl substituted with one or more groups R.sup.7,
-alkylene-C(O)--NH.sub.2, -alkylene-C(O)--NH(alkyl),
-alkylene-C(O)--N(alkyl).sub.2, -alkylene-C(O)--NH(aryl),
-alkylene-C(O)--N(aryl).sub.2, -alkylene-C(O)--N(alkyl)(aryl),
--C(O)--NH.sub.2, --C(O)--NH(alkyl), --C(O)--N(alkyl).sub.2,
--C(O)--NH(aryl), --C(O)--N(aryl).sub.2, --C(O)--N(alkyl)(aryl),
--O-cycloalkyl, and --O-cycloalkyl substituted with 1 to 4 hydroxy
groups; or two R.sup.10 groups together with the ring carbon atoms
to which they are shown attached form a 4- to 7-membered cycloalkyl
or heterocycloalkyl ring; or two R.sup.10 groups together with the
ring carbon atom to which they are attached form a carbonyl group;
R.sup.11 is H, alkyl, alkyl substituted with 1 to 4 hydroxy groups,
cycloalkyl, cycloalkyl substituted with 1 to 4 hydroxy groups,
arylalkyl, heteroarylalkyl, --C(O)O-alkyl, --C(O)-alkyl,
--C(O)-alkyl wherein said alkyl moiety is substituted with one or
more hydroxyl groups, --C(O)-cycloalkyl, --O(O)--NH.sub.2,
--C(O)--NH(alkyl), --C(O)--N(alkyl).sub.2, --C(O)--NH(aryl),
--C(O)--N(aryl).sub.2, --C(O)--N(alkyl)(aryl),
--C(O)-alkylene-NH.sub.2, --C(O)-alkylene-NH(alkyl),
--C(O)-alkylene-N(alkyl).sub.2, --C(O)-alkylene-NH(aryl),
--C(O)-alkylene-N(aryl).sub.2, --C(O)-alkylene-N(alkyl)(aryl),
--S(O.sub.2)-alkyl, -alkylene-C(O)--OH, alkylene-O-alkylene-OH,
unsubstituted aryl, aryl independently substituted with one or more
substituents R.sup.7, unsubstituted heteroaryl, heteroaryl
independently substituted with one or more substituents R.sup.7,
and -alkylene-C(O)O-alkyl; X is selected from the group consisting
of --O--, --N(R.sup.6)--, --O-alkylene- and -alkylene-O--; Y is
selected from the group consisting of --NR.sup.8R.sup.9,
--N(R.sup.6)--(CH.sub.2).sub.b--NR.sup.8R.sup.9 wherein b is an
integer of from 2 to 6, unsubstituted aryl, aryl independently
substituted with one or more substituents R.sup.7 which may be the
same or different, unsubstituted heteroaryl, heteroaryl
independently substituted with one or more substituents R.sup.7
which may be the same or different, alkyl, cycloalkyl,
unsubstituted arylalkyl, arylalkyl independently substituted on the
aryl moiety with one or more substituents R.sup.7 which may be the
same or different, unsubstituted arylcycloalkyl, arylcycloalkyl
independently substituted on the aryl moiety with one or more
substituents R.sup.7 which may be the same or different,
unsubstituted heteroarylalkyl, heteroarylalkyl independently
substituted on the heteroaryl moiety with one or more substituents
R.sup.7 which may be the same or different, unsubstituted
heteroarylcycloalkyl, heteroarylcycloalkyl independently
substituted on the heteroaryl moiety with one or more substituents
R.sup.7 which may be the same or different, unsubstituted
heterocycloalkyl, heterocycloalkyl independently substituted with
one or more substituents R.sup.7 which may be the same or
different, unsubstituted arylheterocycloalkyl, and
arylheterocycloalkyl independently substituted on the aryl moiety
with one or more substituents R.sup.7 which may be the same or
different; or Y is selected from the group consisting of:
##STR00291## Z is selected from the group consisting of H, --OH,
--O-alkyl, unsubstituted heterocycloalkyl, heterocycloalkyl
optionally independently substituted with one or more substituents
R.sup.14 which may be the same or different, --NR.sup.8R.sup.9,
--NR.sup.8R.sup.13, unsubstituted benzo-fused heterocycloalkyl, and
benzo-fused heterocycloalkyl optionally independently substituted
on the benzo- or heterocycloalkyl moiety with one or more
substituents R.sup.14 which may be the same or different; each
R.sup.12 is independently H or alkyl; R.sup.13 is selected from the
group consisting of H, unsubstituted heterocycloalkyl,
heterocycloalkyl independently substituted with one or more
substituents R.sup.14 which may be the same or different,
unsubstituted arylalkyl, arylalkyl independently substituted on the
aryl moiety with one or more substituents R.sup.14 which may be the
same or different, unsubstituted heteroarylalkyl, heteroarylalkyl
optionally independently substituted on the heteroaryl moiety with
one or more substituents R.sup.14 which may be the same or
different, unsubstituted cycloalkyl, cycloalkyl optionally
independently substituted with one or more substituents R.sup.14
which may be the same or different, unsubstituted
-alkylene-cycloalkyl, -alkylene-cycloalkyl independently
substituted on the cycloalkyl moiety with one or more substituents
R.sup.14 which may be the same or different, unsubstituted
-alkylene-heterocycloalkyl, and -alkylene-heterocycloalkyl
independently substituted on the heterocycloalkyl moiety with one
or more substituents R.sup.14 which may be the same or different;
R.sup.14 is selected from the group consisting of halo, --CF.sub.3,
--OH, --OCF.sub.3, --CN, --NR.sup.8R.sup.9, --C(O)-alkyl,
--C(O)-aryl, --C(O)--NR.sup.8R.sup.9, --C(O)O-alkyl,
-alkylene-NR.sup.8R.sup.9, -alkylene-C(O)O-alkyl,
--N(R.sup.8)C(O)-alkyl, --N(R.sup.8)C(O)-aryl,
--N(R.sup.8)C(O)-heteroaryl, --N(R.sup.8)C(O)--NR.sup.8R.sup.9,
piperidinyl, pyrrolidinyl, aryl, heteroaryl, and
--O--CH.sub.2--CH.sub.2--O--, wherein both oxygen atoms of said
--O--CH.sub.2--CH.sub.2--O-- are bound to the same carbon atom and
with the proviso that aryl and heteroaryl moieties are not
substituted with said --O--CH.sub.2--CH.sub.2--O-group; m and n can
be the same or different and are integers of from 0 to 3; p is an
integer of from 1 to 4; r is an integer of from 1 to 3; and t is an
integer of from 0 to 2.
2. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, wherein: R.sup.1 is aryl or heteroaryl
substituted with one or more substituents R.sup.7; R.sup.2 is
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.6)cycloalkylene-(C.sub.0-C.sub-
.6)alkylene-X--C(O)--Y,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.6)cycloalkylene-(C.sub.0-C.sub-
.6)alkylene-C(O)--Y, or
--(C.sub.3-C.sub.6)cycloalkylene-(C.sub.1-C.sub.6)alkylene-C(O)--Y
substituted on the alkylene moiety with one or more hydroxy groups;
R.sup.3 is aryl, alkyl, or cycloalkyl, each of which may be
unsubstituted or substituted with one or more substituents R.sup.7
which can be the same or different; L is --O-- or --N(R.sup.6)--; X
is --O-- or --N(R.sup.6)--; and m and n are independently 0, 1, or
2, with the proviso that m+n is 1 or 2.
3. The compound of claim 2, or a pharmaceutically acceptable salt
and/or solvate thereof, wherein: R.sup.1 is phenyl, pyridyl, or
thiophenyl substituted with one or more substituents R.sup.7;
R.sup.2 is --(C.sub.1-C.sub.6)alkylene-X--C(O)--Y,
--(C.sub.3-C.sub.6)cycloalkylene-X--C(O)--Y,
--(C.sub.3-C.sub.6)cycloalkylene-(C.sub.1-C.sub.6)alkylene-C(O)--Y,
or
--(C.sub.3-C.sub.6)cycloalkylene-(C.sub.1-C.sub.6)alkylene-C(O)--Y
substituted on the (C.sub.1-C.sub.6)alkylene moiety with one or
more hydroxy groups; R.sup.3 is phenyl, ethyl, n-propyl,
iso-propyl, cyclopropyl, or --CH.sub.2-cyclopropyl, each of which
may be unsubstituted or substituted with one or more substituents
R.sup.7 which can be the same or different; and m and n are each
1.
4. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, wherein L is --O--.
5. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, wherein L is
--N((C.sub.1-C.sub.6)alkyl).
6. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, wherein L is --S--.
7. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, wherein L is --S(O)--.
8. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, wherein R.sup.2 is selected from the group
consisting of --(C.sub.1-C.sub.6)alkylene-X--C(O)--Y,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.6)cycloalkylene-(C.sub.0-C.sub-
.6)alkylene-X--C(O)--Y, and
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.6)cycloalkylene-(C.sub.0-C.sub-
.6)alkylene-C(O)--Y.
9. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, wherein R.sup.2 is
--CH.sub.2--X--C(O)--Y.
10. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, wherein R.sup.2 is
--CH.sub.2--O--C(O)--Y.
11. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, wherein R.sup.2 is
-1,1-cyclopropylene-O--C(O)--Y.
12. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, wherein R.sup.2 is
-1,1-cyclopropylene-CH.sub.2--C(O)--Y or
-1,1-cyclopropylene-CH(OH)--C(O)--Y.
13. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, wherein R.sup.3 is selected from the group
consisting of 3,5-difluorophenyl, cyclopropyl, methyl, ethyl,
iso-propyl, n-propyl, --CH.sub.2-cyclopropyl,
--CH.sub.2-(2,2-difluorocyclopropyl).
14. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, wherein R.sup.1 is 4-chlorophenyl.
15. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, wherein Y is selected from the group
consisting of --NR.sup.8R.sup.9, ##STR00292##
16. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, selected from the group consisting of:
##STR00293## ##STR00294## ##STR00295## ##STR00296## ##STR00297##
##STR00298## ##STR00299## ##STR00300## ##STR00301## ##STR00302##
##STR00303## ##STR00304## ##STR00305## ##STR00306## ##STR00307##
##STR00308## ##STR00309## ##STR00310## ##STR00311## ##STR00312##
##STR00313## ##STR00314## ##STR00315## ##STR00316## ##STR00317##
##STR00318## ##STR00319## ##STR00320## ##STR00321## ##STR00322##
##STR00323##
17. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, having the following structure:
##STR00324##
18. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, having the following structure:
##STR00325##
19. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, having the following structure:
##STR00326##
20. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, having the following structure:
##STR00327##
21. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, having the following structure:
##STR00328##
22. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, having the following structure:
##STR00329##
23. (canceled)
24. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, having the following structure:
##STR00330##
25. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, having the following structure:
##STR00331##
26. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, having the following structure:
##STR00332##
27. The compound of claim 1, A compound, or a pharmaceutically
acceptable salt and/or solvate thereof, having the following
structure: ##STR00333##
28. (canceled)
29. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, having the following structure:
##STR00334##
30. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, having the following structure:
##STR00335##
31. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, having the following structure:
##STR00336##
32. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, having the following structure:
##STR00337##
33. (canceled)
34. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, having the following structure:
##STR00338##
35. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, having the following structure:
##STR00339##
36. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, having the following structure:
##STR00340##
37. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, having the following structure:
##STR00341##
38. The compound of claim 1, or a pharmaceutically acceptable salt
and/or solvate thereof, having the following structure:
##STR00342##
39. A pharmaceutical composition comprising at least one compound
of claim 1 and at least one pharmaceutically acceptable
carrier.
40. A method of inhibiting gamma-secretase in a patient in need of
such treatment comprising administering to said patient a
therapeutically effective amount of one or more compounds of claim
1.
41. A method of treating one or more neurodegenerative diseases in
a patient in need of such treatment comprising administering to
said patient a therapeutically effective amount of one or more
compounds of claim 1.
42. A method of inhibiting the deposition of beta amyloid protein
in a patient in need of such treatment comprising administering to
said patient a therapeutically effective amount of one more
compounds of claim 1.
43. A method of treating Alzheimer's disease in a patient in need
of such treatment comprising administering to said patient a
therapeutically effective amount of one or more compounds of claim
1.
44. The compound of claim 1 in purified form.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/584,010, filed Jun. 30, 2004.
BACKGROUND
[0002] WO 00/50391, published Aug. 13, 2000, discloses compounds
having a sulfonamide moiety that are useful for the treatment and
prevention of Alzheimer's Disease and other diseases relating to
the deposition of amyloid protein.
[0003] In view of the present interest in the treatment or
prevention of neurodegenerative diseases, such as Alzheimer's
Disease, a welcome contribution to the art would be compounds for
use in such treatment or prevention. This invention provides such a
contribution.
SUMMARY OF THE INVENTION
[0004] This invention provides compounds that are inhibitors (e.g.,
antagonists) of gamma-secretase (also termed ".gamma.-secretase")
and have the formula I:
##STR00003##
[0005] or a pharmaceutically acceptable salt and/or solvate
thereof, wherein:
[0006] L is --O--, --N(R.sup.6)--, --S--, --S(O)--, or
--S(O.sub.2)--;
[0007] R.sup.1 is selected from the group consisting of
unsubstituted aryl, aryl substituted with one or more substituents
R.sup.7 which can be the same or different, unsubstituted
heteroaryl, and heteroaryl substituted with one or more
substituents R.sup.7 which can be the same or different;
[0008] R.sup.2 is selected from the group consisting of alkyl,
alkyl substituted with one or more substituents R.sup.7 which can
be the same or different, --C(O)--Y, --X--C(O)--Y,
-alkylene-X--C(O)--Y, -alkylene-C(O)--Y,
-alkylene-cycloalkylene-X--C(O)--Y,
-alkylene-cycloalkylene-C(O)--Y,
-cycloalkylene-alkylene-X--C(O)--Y,
-cycloalkylene-alkylene-C(O)--Y, -cycloalkylene-alkylene-C(O)--Y
substituted on the alkylene moiety with one or more hydroxy groups,
-cycloalkylene-X--C(O)--Y, -cycloalkylene-C(O)--Y,
-alkylene-cycloalkylene-alkylene-X--C(O)--Y,
-alkylene-cycloalkylene-alkylene-C(O)--Y, unsubstituted aryl, aryl
substituted with one or more substituents R.sup.7 which can be the
same or different, unsubstituted heteroaryl, and heteroaryl
substituted with one or more substituents R.sup.7 which can be the
same or different;
[0009] R.sup.3 is selected from the group consisting of
unsubstituted aryl, aryl substituted with one or more substituents
R.sup.7 which can be the same or different, unsubstituted
heteroaryl, heteroaryl substituted with one or more substituents
R.sup.7 which can be the same or different, unsubstituted alkyl,
alkyl substituted with one or more substituents R.sup.7 which can
be the same or different, unsubstituted cycloalkyl, cycloalkyl
substituted with one or more substituents R.sup.7 which can be the
same or different, alkylene-cycloalkyl, alkylene-cycloalkyl
independently substituted on the cycloalkyl moiety with one or more
substituents R.sup.7, unsubstituted arylalkyl, arylalkyl optionally
independently substituted on the aryl moiety with one or more
substituents R.sup.7 which can be the same or different,
unsubstituted arylcycloalkyl, arylcycloalkyl independently
substituted on the aryl moiety with one or more substituents
R.sup.7 which can be the same or different, unsubstituted
heteroarylalkyl, heteroarylalkyl independently substituted on the
heteroaryl moiety with one or more substituents R.sup.7 which can
be the same or different, unsubstituted heteroarylcycloalkyl,
heteroarylcycloalkyl independently substituted on the heteroaryl
moiety with one or more substituents R.sup.7 which can be the same
or different, unsubstituted arylheterocycloalkyl,
arylheterocycloalkyl independently substituted on the aryl moiety
with one or more substituents R.sup.7 which can be the same or
different, and unsubstituted alkoxyalkyl;
[0010] each R.sup.4 and R.sup.5 is independently selected from the
group consisting of H, alkyl, and alkyl independently substituted
with one or more substituents R.sup.7 which can be the same or
different; or
[0011] R.sup.3 and R.sup.4 together with the carbon atoms to which
they are shown attached form a 4- to 8-membered cycloalkyl or
heterocycloalkyl ring;
[0012] R.sup.6 is selected from the group consisting of H, alkyl,
alkyl independently substituted with one or more substituents
R.sup.7 which can be the same or different, unsubstituted aryl, and
aryl independently substituted with one or more substituents
R.sup.7 which can be the same or different;
[0013] R.sup.7 is selected from the group consisting of halo,
--CF.sub.3, --OH, alkyl, alkyl substituted with 1 to 4 hydroxy
groups, --O-alkyl, --OCF.sub.3, --CN, --NH(alkyl),
--N(alkyl).sub.2, --NH(aryl), --N(aryl).sub.2, --N(aryl)(alkyl),
--C(O)O-alkyl, -alkylene-NH(alkyl), -alkylene-N(alkyl).sub.2,
-alkylene-NH(aryl), -alkylene-N(aryl).sub.2,
-alkylene-N(aryl)(alkyl),), --NHC(O)-alkyl, --N(alkyl)C(O)-alkyl,
--N(aryl)C(O)-alkyl, --NHC(O)-aryl, --N(alkyl)C(O)-aryl,
--N(aryl)C(O)-aryl, --NHC(O)-heteroaryl, --N(alkyl)C(O)-heteroaryl,
--N(aryl)C(O)-heteroaryl, --NHC(O)--NH.sub.2, --NHC(O)--NH(alkyl),
--NHC(O)--N(alkyl).sub.2, --NHC(O)--NH(aryl),
--NHC(O)--N(aryl).sub.2, --NHC(O)--N(alkyl)(aryl),
--N(alkyl)C(O)--NH.sub.2, --N(alkyl)C(O)--NH(alkyl),
--N(alkyl)C(O)--N(alkyl).sub.2, --N(alkyl)C(O)--NH(aryl),
--N(alkyl)C(O)--N(aryl).sub.2, --N(alkyl)C(O)--N(alkyl)(aryl),
--N(aryl)C(O)--NH.sub.2, --N(aryl)C(O)--NH(alkyl),
--N(aryl)C(O)--N(alkyl).sub.2, --N(aryl)C(O)--NH(aryl),
--N(aryl)C(O)--N(aryl).sub.2, and
--N(aryl)C(O)--N(alkyl)(aryl);
[0014] R.sup.6 and R.sup.9 are each independently selected from the
group consisting of H, alkyl, cycloalkyl, arylalkyl,
heteroarylalkyl,
##STR00004##
[0015] each R.sup.10 is independently selected from the group
consisting of H, --OH, alkyl, alkyl substituted with 1 to 4 hydroxy
groups, --O-alkyl, --O-alkyl substituted with 1 to 4 hydroxy
groups, cycloalkyl, cycloalkyl substituted with 1 to 4 hydroxy
groups, --C(O)O-alkyl, -alkylene-C(O)--OH, unsubstituted
heterocycloalkyl, heterocycloalkyl substituted with one or more
groups R.sup.7, -alkylene-C(O)--NH.sub.2,
-alkylene-C(O)--NH(alkyl), -alkylene-C(O)--N(alkyl).sub.2,
-alkylene-C(O)--NH(aryl), -alkylene-C(O)--N(aryl).sub.2,
-alkylene-C(O)--N(alkyl)(aryl), --C(O)--NH.sub.2,
--C(O)--NH(alkyl), --C(O)--N(alkyl).sub.2, --C(O)--NH(aryl),
--C(O)--N(aryl).sub.2, --C(O)--N(alkyl)(aryl),
-alkylene-C(O)--O-cycloalkyl, --O-cycloalkyl, and --O-cycloalkyl
substituted with 1 to 4 hydroxy groups; or
[0016] two R.sup.10 groups together with the ring carbon atoms to
which they are shown attached form a 4- to 7-membered cycloalkyl or
heterocycloalkyl ring; or
[0017] two R.sup.10 groups together with the ring carbon atom to
which they are attached form a carbonyl group;
[0018] R.sup.11 is H, alkyl, alkyl substituted with 1 to 4 hydroxy
groups, cycloalkyl, cycloalkyl substituted with 1 to 4 hydroxy
groups, arylalkyl, heteroarylalkyl, --C(O)O-alkyl, --C(O)-alkyl,
--C(O)-alkyl wherein said alkyl moiety is substituted with one or
more hydroxyl groups, --C(O)-cycloalkyl, --C(O)--NH.sub.2,
--C(O)--NH(alkyl), --C(O)--N(alkyl).sub.2, --C(O)--NH(aryl),
--C(O)--N(aryl).sub.2, --C(O)--N(alkyl)(aryl),
--C(O)-alkylene-NH.sub.2, --C(O)-alkylene-NH(alkyl),
--C(O)-alkylene-N(alkyl).sub.2, --C(O)-alkylene-NH(aryl),
--C(O)-alkylene-N(aryl).sub.2, --C(O)-alkylene-N(alkyl)(aryl),
--S(O.sub.2)-alkyl, -alkylene-C(O)--OH, alkylene-O-alkylene-OH,
unsubstituted aryl, aryl independently substituted with one or more
substituents R.sup.7, unsubstituted heteroaryl, heteroaryl
independently substituted with one or more substituents R.sup.7,
and -alkylene-C(O)O-alkyl;
[0019] X is selected from the group consisting of --O--,
--N(R.sup.6)--, --O-alkylene- and -alkylene-O--;
[0020] Y is selected from the group consisting of
--NR.sup.8R.sup.9, --N(R.sup.6)--(CH.sub.2).sub.b--NR.sup.8R.sup.9
wherein b is an integer of from 2 to 6, unsubstituted aryl, aryl
independently substituted with one or more substituents R.sup.7
which may be the same or different, unsubstituted heteroaryl,
heteroaryl independently substituted with one or more substituents
R.sup.7 which may be the same or different, alkyl, cycloalkyl,
unsubstituted arylalkyl, arylalkyl independently substituted on the
aryl moiety with one or more substituents R.sup.7 which may be the
same or different, unsubstituted arylcycloalkyl, arylcycloalkyl
independently substituted on the aryl moiety with one or more
substituents R.sup.7 which may be the same or different,
unsubstituted heteroarylalkyl, heteroarylalkyl independently
substituted on the heteroaryl moiety with one or more substituents
R.sup.7 which may be the same or different, unsubstituted
heteroarylcycloalkyl, heteroarylcycloalkyl independently
substituted on the heteroaryl moiety with one or more substituents
R.sup.7 which may be the same or different, unsubstituted
heterocycloalkyl, heterocycloalkyl independently substituted with
one or more substituents R.sup.7 which may be the same or
different, unsubstituted arylheterocycloalkyl, and
arylheterocycloalkyl independently substituted on the aryl moiety
with one or more substituents R.sup.7 which may be the same or
different; or
[0021] Y is selected from the group consisting of:
##STR00005##
[0022] Z is selected from the group consisting of H, --OH,
--O-alkyl, unsubstituted heterocycloalkyl, heterocycloalkyl
optionally independently substituted with one or more substituents
R.sup.14 which may be the same or different, --NR.sup.8R.sup.9,
--NR.sup.8R.sup.13, unsubstituted benzo-fused heterocycloalkyl, and
benzo-fused heterocycloalkyl optionally independently substituted
on the benzo- or heterocycloalkyl moiety with one or more
substituents R.sup.14 which may be the same or different;
[0023] each R.sup.12 is independently H or alkyl;
[0024] R.sup.13 is selected from the group consisting of H,
unsubstituted heterocycloalkyl, heterocycloalkyl independently
substituted with one or more substituents R.sup.14 which may be the
same or different, unsubstituted arylalkyl, arylalkyl independently
substituted on the aryl moiety with one or more substituents
R.sup.14 which may be the same or different, unsubstituted
heteroarylalkyl, heteroarylalkyl optionally independently
substituted on the heteroaryl moiety with one or more substituents
R.sup.14 which may be the same or different, unsubstituted
cycloalkyl, cycloalkyl optionally independently substituted with
one or more substituents R.sup.14 which may be the same or
different, unsubstituted -alkylene-cycloalkyl, -alkylene-cycloalkyl
independently substituted on the cycloalkyl moiety with one or more
substituents R.sup.14 which may be the same or different,
unsubstituted -alkylene-heterocycloalkyl, and
-alkylene-heterocycloalkyl independently substituted on the
heterocycloalkyl moiety with one or more substituents R.sup.14
which may be the same or different;
[0025] R.sup.14 is selected from the group consisting of halo,
--CF.sub.3, --OH, --O-alkyl, --OCF.sub.3, --CN, --NR.sup.8R.sup.9,
--C(O)-alkyl, --C(O)-aryl, --C(O)--NR.sup.8R.sup.9, --C(O)O-alkyl,
-alkylene-NR.sup.8R.sup.9, -alkylene-C(O)O-alkyl,
--N(R.sup.8)C(O)-alkyl, --N(R.sup.8)C(O)-aryl,
--N(R.sup.8)C(O)-heteroaryl, --N(R.sup.8)C(O)--NR.sup.8R.sup.9,
piperidinyl, pyrrolidinyl, aryl, heteroaryl, and
--O--CH.sub.2--CH.sub.2--O--, wherein both oxygen atoms of said
--O--CH.sub.2--CH.sub.2--O-- are bound to the same carbon atom and
with the proviso that aryl and heteroaryl moieties are not
substituted with said --O--CH.sub.2--CH.sub.2--O-- group;
[0026] m and n can be the same or different and are integers of
from 0 to 3;
[0027] p is an integer of from 1 to 4;
[0028] r is an integer of from 1 to 3; and
[0029] t is an integer of from 0 to 2.
[0030] This invention also provides a pharmaceutical composition
comprising an effective amount of one or more compounds of Formula
I and at least one pharmaceutically acceptable carrier.
[0031] This invention also provides a method for inhibiting
gamma-secretase comprising administering an effective (i.e.,
therapeutically effective) amount of one or more compounds of
formula I to a patient in need of treatment.
[0032] This invention also provides a method of treating one or
more neurodegenerative diseases comprising administering an
effective (i.e., therapeutically effective) amount of one or more
compounds of formula I to a patient in need of treatment.
[0033] This invention also provides a method of inhibiting the
deposition of amyloid protein (e.g., amyloid beta protein) in, on
or around neurological tissue (e.g., the brain) comprising
administering an effective (i.e., therapeutically effective) amount
of one or more compounds of formula I to a patient in need of
treatment.
[0034] This invention also provides a method of treating
Alzheimer's disease comprising administering an effective (i.e.,
therapeutically effective) amount of one or more compounds of
formula I to a patient in need of treatment.
DETAILED DESCRIPTION OF THE INVENTION
[0035] In a first embodiment, the present invention is directed to
compounds of Formula I, or pharmaceutically acceptable salts and/or
solvates thereof, as described herein above.
[0036] In another embodiment of the compounds of Formula I, R.sup.1
is aryl or heteroaryl substituted with one or more substituents
R.sup.7;
[0037] R.sup.2 is
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.6)cycloalkylene-(C.sub.0-C.sub-
.6)alkylene-X--C(O)--Y,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.6)cycloalkylene-(C.sub.0-C.sub-
.6)alkylene-C(O)--Y, or
--(C.sub.3-C.sub.6)cycloalkylene-(C.sub.1-C.sub.6)alkylene-C(O)--Y
substituted on the alkylene moiety with one or more hydroxy
groups;
[0038] R.sup.3 is aryl alkyl, or cycloalkyl, each of which may be
unsubstituted or substituted with one or more substituents R.sup.7
which can be the same or different;
[0039] L is --O-- or --N(R.sup.6)--;
[0040] X is --O-- or --N(R.sup.6)--; and
[0041] m and n are independently 0, 1, or 2, with the proviso that
m+n is 1 or 2.
[0042] In another embodiment of the compounds of Formula I, m and n
are each 1;
[0043] each R.sup.4 and R.sup.5 is H; and
[0044] R.sup.1 is phenyl substituted with one or more substituents
R.sup.7.
[0045] In another embodiment of the compounds of Formula I, R.sup.1
is phenyl, pyridyl, or thiophenyl substituted with one or more
substituents R.sup.7;
[0046] R.sup.2 is --(C.sub.1-C.sub.6)alkylene-X--C(O)--Y,
--(C.sub.3-C.sub.6)cycloalkylene-X--C(O)--Y,
--(C.sub.3-C.sub.6)cycloalkylene-(C.sub.1-C.sub.6)alkylene-C(O)--Y,
or
--(C.sub.3-C.sub.6)cycloalkylene-(C.sub.1-C.sub.6)alkylene-C(O)--Y
substituted on the (C.sub.1-C.sub.6)alkylene moiety with one or
more hydroxy groups;
[0047] R.sup.3 is phenyl ethyl, n-propyl, iso-propyl, cyclopropyl,
or --CH.sub.2-cyclopropyl, each of which may be unsubstituted or
substituted with one or more substituents R.sup.7 which can be the
same or different;
[0048] L is --O-- or --N(R.sup.6)--;
[0049] X is --O-- or --N(R.sup.6)--; and
[0050] m and n are each 1.
[0051] In another embodiment of the compounds of Formula I, L is
--O--.
[0052] In another embodiment of the compounds of Formula I, L is
--NH--.
[0053] In another embodiment of the compounds of Formula I, L is
--N((C.sub.1-C.sub.6)alkyl).
[0054] In another embodiment of the compounds of Formula I, L is
--S--.
[0055] In another embodiment of the compounds of Formula I, L is
--S(O)--.
[0056] In another embodiment of the compounds of Formula I, L is
--S(O).sub.2--.
[0057] In another embodiment of the compounds of Formula I, R.sup.2
is selected from the group consisting of
--(C.sub.1-C.sub.6)alkylene-X--C(O)--Y,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.6)cycloalkylene-(C.sub.0-C.sub-
.6)alkylene-X--C(O)--Y, and
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.6)cycloalkylene-(C.sub.0-C.sub-
.6)alkylene-C(O)--Y.
[0058] In another embodiment of the compounds of Formula I, R.sup.2
is --CH.sub.2--X--C(O)--Y.
[0059] In another embodiment of the compounds of Formula I, R.sup.2
is --CH.sub.2--O--C(O)--Y.
[0060] In another embodiment of the compounds of Formula I, R.sup.2
is -1,1-cyclopropylene-O--C(O)--Y.
[0061] In another embodiment of the compounds of Formula I, R.sup.2
is -1,1-cyclopropylene-CH.sub.2--C(O)--Y or
-1,1-cyclopropylene-CH(OH)--C(O)--Y.
[0062] In another embodiment of the compounds of Formula I, R.sup.3
is phenyl substituted with one or more substituents R.sup.7.
[0063] In another embodiment of the compounds of Formula I, R.sup.3
is cycloalkyl.
[0064] In another embodiment of the compounds of Formula I, R.sup.3
is cyclopropyl.
[0065] In another embodiment of the compounds of Formula I, R.sup.3
is alkyl.
[0066] In another embodiment of the compounds of Formula I, R.sup.3
is methyl.
[0067] In another embodiment of the compounds of Formula I, R.sup.3
is ethyl.
[0068] In another embodiment of the compounds of Formula I, R.sup.3
is propyl.
[0069] In another embodiment of the compounds of Formula I, R.sup.3
is iso-propyl.
[0070] In another embodiment of the compounds of Formula I, R.sup.3
is n-propyl.
[0071] In another embodiment of the compounds of Formula I, R.sup.3
is 3,5-difluorophenyl.
[0072] In another embodiment of the compounds of Formula I, R.sup.3
is cyclopropyl.
[0073] In another embodiment of the compounds of Formula I, R.sup.3
is --CH.sub.2-cyclopropyl.
[0074] In another embodiment of the compounds of Formula I, R.sup.3
is --CH.sub.2-(2,2-difluorocyclopropyl).
[0075] In another embodiment of the compounds of Formula I, R.sup.1
is 4-chlorophenyl.
[0076] In another embodiment of the compounds of Formula I, R.sup.1
is p-tolyl.
[0077] In another embodiment of the compounds of Formula I, Y is
selected from the group consisting of --NR.sup.8R.sup.9,
##STR00006##
[0078] In yet another embodiment of the compounds of Formula I,
each R.sup.4 is independently H or methyl.
[0079] In yet another embodiment of the compounds of Formula I,
each R.sup.5 is independently H or methyl.
[0080] In yet another embodiment of the compounds of Formula I,
each R.sup.4 is methyl.
[0081] In yet another embodiment of the compounds of Formula I,
each R.sup.4 and each R.sup.5 is H.
[0082] In yet another embodiment of the compounds of Formula I,
each R.sup.4 and each R.sup.5 is independently selected from the
group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl,
sec-butyl, and t-butyl.
[0083] In yet another embodiment of the compounds of Formula I,
R.sup.3 and R.sup.4 together with the carbon atoms to which they
are shown attached form a 4- to 8-membered cycloalkyl or
heterocycloalkyl ring.
[0084] In yet another embodiment of the compounds of Formula I,
R.sup.6 is selected from the group consisting of H, methyl, ethyl,
propyl, butyl, phenyl, chlorophenyl, fluorophenyl, difluorophenyl,
trifluoromethylphenyl, and bis(trifluoromethyl)phenyl.
[0085] In yet another embodiment of the compounds of Formula I,
R.sup.7 is selected from the group consisting of chloro, bromo,
fluoro, --CF.sub.3, --OH, methyl, ethyl, propyl, butyl,
hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxy,
propoxy, butoxy, --OCF.sub.3, --CN, --NH(methyl),
--N(methyl).sub.2, --NH(ethyl), --N(ethyl).sub.2, --C(O)O-methyl,
--C(O)O-ethyl, --CH.sub.2--N(methyl).sub.2,
--CH.sub.2--N(ethyl).sub.2, --CH.sub.2--NH.sub.2,
--N(methyl)C(O)-methyl, --NHC(O)-methyl, --N(methyl)C(O)-phenyl,
--NHC(O)-phenyl, --N(methyl)C(O)-pyridyl, --NHC(O)-pyridyl, and
--N(methyl)C(O)--N(methyl).sub.2, --N(methyl)C(O)--NH.sub.2,
--NHC(O)--N(methyl).sub.2, and --NHC(O)--NH.sub.2.
[0086] In yet another embodiment of the compounds of Formula I,
R.sup.8 and R.sup.9 are independently selected from the group
consisting of H, methyl, ethyl, propyl, butyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, benzyl,
##STR00007##
[0087] In yet another embodiment of the compounds of Formula I,
each R.sup.10 is independently selected from the group consisting
of H, --OH, methyl, ethyl, propyl, butyl, HO--CH.sub.2--,
HO--CH.sub.2CH.sub.2--, --C(CH.sub.3).sub.2CH.sub.2--OH, methoxy,
ethoxy, HO--CH.sub.2--CH.sub.2--O--, cyclopentyl, cyclohexyl,
hydroxycyclopentyl, hydroxycyclohexyl, cyclopentyloxy,
cyclohexyloxy, hydroxycyclopentyloxy, hydroxycyclohexyloxy,
--C(O)--CH.sub.3, --C(O)--CH.sub.2CH.sub.3, --CH.sub.2--C(O)--OH,
--CH.sub.2CH.sub.2--C(O)--OH, unsubstituted piperidinyl,
piperidinyl substituted with one or more groups R.sup.7,
piperazinyl, piperazinyl substituted with one or more groups
R.sup.7, diazepanyl, diazepanyl substituted with one or more groups
R.sup.7, --CH.sub.2--C(O)--NH.sub.2,
--CH.sub.2--C(O)--NH(CH.sub.3),
--CH.sub.2--C(O)--NH(CH.sub.2CH.sub.3),
--CH.sub.2--C(O)--NH(CH(CH.sub.3).sub.2),
--CH.sub.2--C(O)--NH(phenyl),
--CH.sub.2--C(O)--N(CH.sub.3)(phenyl),
--CH.sub.2--C(O)--N(CH.sub.2CH.sub.3)(phenyl),
--CH.sub.2--C(O)--N(phenyl).sub.2,
--CH.sub.2--C(O)--N(CH.sub.3).sub.2, --C(O)--NH(CH.sub.3),
--C(O)--NH(CH.sub.2CH.sub.3), --C(O)--NH(CH(CH.sub.3).sub.2),
--C(O)--NH(phenyl), --C(O)--N(CH.sub.3)(phenyl),
--C(O)--N(CH.sub.2CH.sub.3)(phenyl), --C(O)--N(phenyl).sub.2, and
--C(O)--N(CH.sub.3).sub.2.
[0088] In yet another embodiment of the compounds of Formula I, two
R.sup.10 together with the ring carbon atoms to which they are
shown attached form a 4- to 7-membered cycloalkyl or
heterocycloalkyl ring.
[0089] In yet another embodiment of the compounds of Formula I, two
R.sup.10 together with the ring carbon atoms to which they are
shown attached form a spiro-fused lactam ring.
[0090] In yet another embodiment of the compounds of Formula I, two
R.sup.10 together with the ring carbon atoms to which they are
shown attached form a spiro-fused 4-membered lactam ring.
[0091] In yet another embodiment of the compounds of Formula I,
R.sup.11 is selected from the group consisting of H, methyl, ethyl,
propyl, butyl, HO--CH.sub.2--, HO--CH.sub.2CH.sub.2--,
--C(CH.sub.3).sub.2CH.sub.2--OH, cyclopentyl, cyclohexyl,
hydroxycyclopentyl, hydroxycyclohexyl, cyclopentyloxy,
cyclohexyloxy, hydroxycyclopentyloxy, hydroxycyclohexyloxy,
benzyl,
##STR00008##
--(O)O-methyl, --C(O)O-ethyl, --C(O)--O-t-butyl, --C(O)-methyl,
--C(O)-ethyl, --C(O)--CH.sub.2CH.sub.2--OH, --C(O)-cyclopropyl,
--C(O)-cyclobutyl, --C(O)-cyclopentyl, --C(O)-cyclohexyl,
--C(O)--NH.sub.2, --C(O)--NH(CH.sub.3),
--C(O)--NH(CH.sub.2CH.sub.3), --C(O)--N(CH.sub.3).sub.2,
--C(O)--N(CH.sub.2CH.sub.3).sub.2, --C(O)--NH(phenyl),
--C(O)--N(phenyl).sub.2, --C(O)--N(CH.sub.3)(phenyl),
--C(O)--CH.sub.2--NH.sub.2, --C(O)--CH.sub.2--NH(CH.sub.3),
--C(O)--CH.sub.2--NH(CH.sub.2CH.sub.3),
--C(O)--CH.sub.2--N(CH.sub.3).sub.2,
--C(O)--CH.sub.2--N(CH.sub.2CH.sub.3).sub.2,
--C(O)--CH.sub.2--NH(phenyl), --C(O)--CH.sub.2--N(phenyl).sub.2,
--C(O)--CH.sub.2--N(CH.sub.3)(phenyl), --S(O.sub.2)-methyl,
--S(O.sub.2)-ethyl, --CH.sub.2--C(O)-OH,
--CH.sub.2CH.sub.2--C(O)--OH, --CH.sub.2--O--CH.sub.2--OH,
--CH.sub.2CH.sub.2--O--CH.sub.2CH.sub.2--OH, phenyl, chlorophenyl,
fluorophenyl, difluorophenyl, trifluoromethylphenyl,
bis(trifluoromethyl)phenyl, pyridyl, trifluoromethylpyridyl,
--CH.sub.2--C(O)O--CH.sub.3, --CH.sub.2CH.sub.2--C(O)O--CH.sub.3,
--CH.sub.2--C(O)O--CH.sub.2CH.sub.3, and
--CH.sub.2CH.sub.2--C(O)O--CH.sub.2CH.sub.3.
[0092] In yet another embodiment of the compounds of Formula I,
each R.sup.12 is independently selected from the group consisting
of H, methyl, ethyl, propyl, and butyl.
[0093] In yet another embodiment of the compounds of Formula I,
R.sup.13 is selected from the croup consisting of H, piperazinyl,
piperidinyl, tetrahydrothiophenyl, benzyl,
##STR00009##
cyclopropyl, cyclopentyl, cyclohexyl, --CH.sub.2-cyclohexyl,
--CH.sub.2CH.sub.2-cyclohexyl, --CH.sub.2-cyclopenty,
--CH.sub.2CH.sub.2-cyclopentyl, and --CH.sub.2-piperidinyl.
[0094] In yet another embodiment of the compounds of Formula I,
R.sup.14 is selected from the group consisting of chloro, fluoro,
bromo, --CF.sub.3, --OH, methoxy, ethoxy, --OCF.sub.3, --CN,
--NH(methyl), --N(methyl).sub.2, --NH(ethyl), --N(ethyl).sub.2,
--C(O)-methyl, --C(O)-ethyl, --C(O)-phenyl,
--C(O)--N(methyl).sub.2, --C(O)O-methyl, --C(O)O-ethyl,
--CH.sub.2--N(methyl).sub.2, --CH.sub.2CH.sub.2--N(methyl).sub.2,
--CH.sub.2--C(O)O-methyl, --N(methyl)C(O)-methyl, --NHC(O)-methyl,
--N(methyl)C(O)-phenyl, --NHC(O)-phenyl, --N(methyl)C(O)-pyridyl,
--NHC(O)-pyridyl, and --N(methyl)C(O)--N(methyl).sub.2,
--N(methyl)C(O)--NH.sub.2, --NHC(O)--N(methyl).sub.2,
--NHC(O)--NH.sub.2, piperidinyl, pyrrolidinyl, phenyl, and
piperidinyl;
[0095] In yet another embodiment of the compounds of Formula I, R15
is selected from the group consisting of chloro, fluoro, bromo,
--CF.sub.3, --OH, methoxy, ethoxy, --OCF.sub.3, --CN, methyl,
ethyl, propyl, and butyl.
[0096] In yet another embodiment of the compounds of Formula I, X
is selected from the group consisting of --O--, --NH--,
--N(methyl)-, --N(ethyl)-, --O--CH.sub.2--,
--O--CH.sub.2CF.sub.2--, --CH.sub.2--O--, and
--CH.sub.2CH.sub.2--O--.
[0097] In yet another embodiment of the compounds of Formula I, X
is --O--.
[0098] In yet another embodiment of the compounds of Formula I, Y
is selected from the group consisting of --NH(methyl), --NH(ethyl),
--N(methyl).sub.2, --N(ethyl).sub.2,
##STR00010## ##STR00011## ##STR00012##
[0099] In still another embodiment, the compound of Formula I has a
structure according to Formula (II), wherein L, Q, Y, and R.sup.3
are as shown in Table 1:
TABLE-US-00001 TABLE 1 ##STR00013## Structure L Q Y R.sup.3 i --O--
--CH.sub.2-- ##STR00014## ##STR00015## ii --O-- --CH.sub.2--
##STR00016## ##STR00017## iii --O-- --CH.sub.2-- ##STR00018##
##STR00019## iv --O-- ##STR00020## ##STR00021##
--CH.sub.2CH.sub.2CH.sub.3 v --O-- ##STR00022## ##STR00023##
--CH.sub.2CH.sub.2CH.sub.3 vi --O-- ##STR00024## ##STR00025##
--CH.sub.2CH.sub.2CH.sub.3 vii --O-- ##STR00026## ##STR00027##
--CH.sub.2CH.sub.2CH.sub.3 viii --O-- ##STR00028## ##STR00029##
--CH.sub.2CH.sub.2CH.sub.3 ix --O-- ##STR00030## ##STR00031##
--CH.sub.2CH.sub.2CH.sub.3 x --O-- ##STR00032## ##STR00033##
--CH.sub.2CH.sub.2CH.sub.3 xi --O-- ##STR00034## ##STR00035##
--CH.sub.2CH.sub.2CH.sub.3 xii --O-- ##STR00036## ##STR00037##
--CH.sub.2CH.sub.2CH.sub.3 xiii --O-- ##STR00038## ##STR00039##
##STR00040## xiv --O-- ##STR00041## ##STR00042## ##STR00043## xv
--O-- ##STR00044## ##STR00045## ##STR00046## xvi --O-- ##STR00047##
##STR00048## ##STR00049## xvii --O-- ##STR00050## ##STR00051##
##STR00052## xviii --O-- ##STR00053## ##STR00054## ##STR00055## xix
--O-- ##STR00056## ##STR00057## ##STR00058## xx --O-- ##STR00059##
##STR00060## ##STR00061## xxi --O-- ##STR00062## ##STR00063##
##STR00064## xxii --O-- ##STR00065## ##STR00066## ##STR00067##
xxiii --O-- ##STR00068## ##STR00069## ##STR00070## xxiv --O--
##STR00071## ##STR00072## ##STR00073## xxv --O-- ##STR00074##
##STR00075## ##STR00076## xxvi --O-- --CH.sub.2-- ##STR00077##
##STR00078## xxvii --O-- --CH.sub.2-- ##STR00079## ##STR00080##
xxviii --O-- --CH.sub.2-- ##STR00081## ##STR00082## xxix --S--
##STR00083## ##STR00084## --CH.sub.2CH.sub.3 xxx --S(O)--
##STR00085## ##STR00086## --CH.sub.2CH.sub.3 xxxi --S(O)--
##STR00087## ##STR00088## --CH.sub.2CH.sub.3 xxxii --S--
##STR00089## ##STR00090## --CH.sub.2CH.sub.3 xxxiii --S--
##STR00091## ##STR00092## --CH.sub.2CH.sub.3 xxiv
--N(CH.sub.2CH.sub.3)-- --CH.sub.2-- ##STR00093## ##STR00094##
[0100] In still another embodiment, the compound of Formula I is
selected from the group consisting of:
##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099##
##STR00100## ##STR00101## ##STR00102## ##STR00103## ##STR00104##
##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109##
##STR00110## ##STR00111## ##STR00112## ##STR00113## ##STR00114##
##STR00115## ##STR00116## ##STR00117## ##STR00118## ##STR00119##
##STR00120## ##STR00121## ##STR00122## ##STR00123## ##STR00124##
##STR00125##
[0101] As used above, and throughout this disclosure, the following
terms, unless otherwise indicated, shall be understood to have the
following meanings:
[0102] "Patient" includes both human and animals.
[0103] "Mammal" means humans and other mammalian animals.
[0104] "Alkyl" means an aliphatic hydrocarbon group, which may be
straight or branched and comprising about 1 to about 20 carbon
atoms in the chain. Preferred alkyl groups contain about 1 to about
12 carbon atoms in the chain. More preferred alkyl groups contain
about 1 to about 6 carbon atoms in the chain. Branched means that
one or more lower alkyl groups such as methyl, ethyl or propyl, are
attached to a linear alkyl chain. "Lower alkyl" means a group
having about 1 to about 6 carbon atoms in the chain, which may be
straight or branched. The term "substituted alkyl" means that the
alkyl group may be substituted by one or more substituents which
may be the same or different, each substituent being independently
selected from the group consisting of halo, alkyl, aryl,
cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, --NH(alkyl),
--NH(cycloalkyl), --N(alkyl).sub.2, carboxy and --C(O)O-alkyl
(unless expressly defined otherwise). Non-limiting examples of
suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl
and t-butyl.
[0105] "Alkylene" means a divalent aliphatic hydrocarbon radical
derived from an alkyl group, as defined above. Both "open" valences
may be on the same carbon atom, or on different carbon atoms.
Non-limiting examples of alkylene groups include --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --CH(CH.sub.3)--, etc.
[0106] "Alkynyl" means an aliphatic hydrocarbon group containing at
least one carbon-carbon triple bond and which may be straight or
branched and comprising about 2 to about 15 carbon atoms in the
chain. Preferred alkynyl groups have about 2 to about 12 carbon
atoms in the chain; and more preferably about 2 to about 4 carbon
atoms in the chain. Branched means that one or more lower alkyl
groups such as methyl, ethyl or propyl, are attached to a linear
alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon
atoms in the chain, which may be straight or branched. Non-limiting
examples of suitable alkynyl groups include ethynyl, propynyl,
2-butynyl and 3-methylbutynyl. The term "substituted alkynyl" means
that the alkynyl group may be substituted by one or more
substituents which may be the same or different, each substituent
being independently selected from the group consisting of alkyl,
aryl and cycloalkyl.
[0107] "Aryl" means an aromatic monocyclic or multicyclic ring
system comprising about 6 to about 14 carbon atoms, preferably
about 6 to about 10 carbon atoms. The aryl group can be optionally
substituted with one or more "ring system substituents" which may
be the same or different, and are as defined herein. Non-limiting
examples of suitable aryl groups include phenyl and naphthyl.
[0108] "Heteroaryl" means an aromatic monocyclic or multicyclic
ring system comprising about 5 to about 14 ring atoms, preferably
about 5 to about 10 ring atoms, in which one or more of the ring
atoms is an element other than carbon, for example nitrogen, oxygen
or sulfur, alone or in combination. Preferred heteroaryls contain
about 5 to about 6 ring atoms. The "heteroaryl" can be optionally
substituted by one or more "ring system substituents" which may be
the same or different, and are as defined herein. The prefix aza,
oxa or thia before the heteroaryl root name means that at least a
nitrogen, oxygen or sulfur atom respectively, is present as a ring
atom. A nitrogen atom of a heteroaryl can be optionally oxidized to
the corresponding N-oxide. Non-limiting examples of suitable
heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl,
pyrimidinyl, pyridone (including N-substituted pyridones),
isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl,
furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl,
pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,
imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,
indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,
imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,
pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,
1,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl"
also refers to partially saturated heteroaryl moieties such as, for
example, tetrahydroisoquinolyl, tetrahydroquinolyl and the
like.
[0109] "Arylalkyl" (or "aralkyl") means an aryl-alkyl-group in
which the aryl and alkyl are as previously described. Preferred
arylalkyls comprise a lower alkyl group. Non-limiting examples of
suitable arylalkyl groups include benzyl, 2-phenethyl and
naphthalenylmethyl. The bond to the parent moiety is through the
alkyl.
[0110] "Alkylaryl" means an alkyl-aryl-group in which the alkyl and
aryl are as previously described. Preferred alkylaryls comprise a
lower alkyl group. Non-limiting example of a suitable alkylaryl
group is tolyl. The bond to the parent moiety is through the
aryl.
[0111] "Cycloalkyl" means a non-aromatic mono- or multicyclic ring
system comprising about 3 to about 10 carbon atoms, preferably
about 5 to about 10 carbon atoms. Preferred cycloalkyl rings
contain about 5 to about 7 ring atoms. The cycloalkyl can be
optionally substituted with one or more "ring system substituents"
which may be the same or different, and are as defined herein.
Non-limiting examples of suitable saturated monocyclic cycloalkyls
include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the
like, and non-limiting examples of non-aromatic, unsaturated
monocyclic cycloalkyls include cyclopentenyl, cyclohexenyl, etc.
Non-limiting examples of suitable multicyclic cycloalkyls include
1-decalinyl, norbornyl, adamantyl and the like, as well as
partially saturated species such as, for example, indanyl,
tetrahydronaphthyl and the like.
[0112] "Cycloalkylene" means a divalent cycloalkyl radical derived
from a cycloalkyl group, as defined above. Both open valences may
be on the same ring carbon atom, or may be on different ring carbon
atoms. Non-limiting examples of cycloalkylenes include
##STR00126##
etc.
[0113] "Arylcycloalkyl means an aryl-cycloalkyl-group in which the
aryl and cycloalkyl are as previously described. Non-limiting
examples of suitable arylcycloalkyl groups include
phenylcyclopentyl and indanyl.
[0114] "Heteroarylalkyr means a heteroaryl-alkyl-group in which the
heteroaryl and alkyl are as previously described. Preferred
heteroarylalkyls comprise a lower alkyl group. The bond to the
parent moiety is through the alkyl group.
[0115] "Heteroarylcycloalkyl" means a heteroaryl-cycloalkyl-group
in which the heteroaryl and cycloalkyl are as previously described.
Non-limiting examples of suitable heteroarylcycloalkyl groups
include
##STR00127##
The bond to the parent moiety is through the cycloalkyl group.
[0116] "Arylheterocycloalkyl" means an aryl-heterocycloalkyl-group
in which the aryl and heterocycloalkyl are a previously described.
Non-limiting examples of suitable arylheterocycloalkyls include
##STR00128##
The bond to the parent moiety is through the heterocycloalkyl
group.
[0117] "Benzo-fused heterocycloalkyl" means an arylheterocycloalkyl
group as previously defined in which a benzene ring of the aryl
group is fused (i.e., shares two ring carbon atoms) with the
heterocycloalkyl group. Suitable benzo-fused heterocycloalkyls
include
##STR00129##
etc.
[0118] "Halogen" or "halo" means fluorine, chlorine, bromine, or
iodine. Fluorine, chlorine and bromine are preferred.
[0119] "Ring system substituent" means a substituent attached to an
aromatic or non-aromatic ring system, which, for example, replaces
an available hydrogen on the ring system. Ring system substituents
may be the same or different, each being independently selected
from the group consisting of alkyl, alkenyl, alkynyl, aryl,
heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl,
heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy,
aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,
alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio,
heteroarylthio, arylalkylthio, heteroarylalkylthio, cycloalkyl,
heterocycloalkyl, --C(.dbd.N--CN)--NH.sub.2,
--C(.dbd.NH)--NH.sub.2, --C(.dbd.NH)--NH(alkyl), Y.sub.1Y.sub.2N--,
Y.sub.1Y.sub.2N-alkyl-, Y.sub.1Y.sub.2NC(O)--,
Y.sub.1Y.sub.2NSO.sub.2-- and --SO.sub.2NY.sub.1Y.sub.2, wherein
Y.sub.1 and Y.sub.2 can be the same or different and are
independently selected from the group consisting of hydrogen,
alkyl, aryl, cycloalkyl, and aralkyl (unless expressly defined
otherwise). The term "ring system substituent" may also mean a
single moiety in which two available hydrogens on two adjacent
carbon atoms are simultaneously replaced (e.g., one H on each
carbon) on a ring system. Examples of such moiety are
methylenedioxy, ethylenedioxy, --C(CH.sub.3).sub.2-- and the like
which form moieties such as, for example:
##STR00130##
[0120] "Heterocycloalkyl" means a non-aromatic monocyclic or
multicyclic ring system comprising about 3 to about 10 ring atoms,
preferably about 5 to about 10 ring atoms, in which one or more of
the atoms in the ring system is an element other than carbon, for
example nitrogen, oxygen or sulfur, alone or in combination. There
are no adjacent oxygen and/or sulfur atoms present in the ring
system. Preferred heterocycloalkyls contain about 5 to about 6 ring
atoms. The prefix aza, oxa or thia before the heterocycloalkyl root
name means that at least a nitrogen, oxygen or sulfur atom
respectively is present as a ring atom. Any --NH in a
heterocycloalkyl ring may exist in protected form, for example, as
an --N(Boc), --N(CBz), --N(Tos) group and the like; such protected
forms are also considered part of this invention. The
heterocycloalkyl can be optionally substituted by one or more "ring
system substituents" which may be the same or different, and are as
defined herein. The nitrogen or sulfur atom of the heterocycloalkyl
can be optionally oxidized to the corresponding N-oxide, S-oxide or
S,S-dioxide. Non-limiting examples of suitable monocyclic
heterocycloalkyl rings include piperidyl, pyrrolidinyl,
piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,
1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam,
lactone, and the like. Non-limiting examples of non-aromatic,
unsaturated monocyclic heterocycloalkyl rings include thiazolinyl,
2,3-dihydrofuranyl, 2,3-dihydrothiophenyl, etc.
[0121] It should be noted that in the hetero-atom containing ring
systems of this invention, there are no hydroxyl groups on carbon
atoms adjacent to a N, O or S, as well as there are no N or S
groups on carbon atoms adjacent to another heteroatom. Thus, for
example, in the ring:
##STR00131##
[0122] there is no --OH attached directly to carbons marked 2 and
5.
[0123] It should also be noted that tautomeric forms such as, for
example, the moieties:
##STR00132##
[0124] are considered equivalent in this invention.
[0125] "Heteroaralkyl" means a heteroaryl-alkyl-group in which the
heteroaryl and alkyl moieties are as previously described.
Preferred heteroaralkyls contain a lower alkyl group. Non-limiting
examples of suitable aralkyl groups include pyridylmethyl, and
quinolin-3-ylmethyl. The bond to the parent moiety is through the
alkyl.
[0126] "Hydroxyalkyl" means a HO-alkyl-group in which alkyl is as
previously defined. Preferred hydroxyalkyls contain lower alkyl.
Non-limiting examples of suitable hydroxyalkyl groups include
hydroxymethyl and 2-hydroxyethyl.
[0127] "Acyl" means an H--C(O)--, alkyl-C(O)-- or
cycloalkyl-C(O)--, group in which the various groups are as
previously described. The bond to the parent moiety is through the
carbonyl. Preferred acyls contain a lower alkyl. Non-limiting
examples of suitable acyl groups include formyl, acetyl and
propanoyl.
[0128] "Aroyl" means an aryl-C(O)-group in which the aryl group is
as previously described. The bond to the parent moiety is through
the carbonyl. Non-limiting examples of suitable groups include
benzoyl and 1-naphthoyl.
[0129] "Alkoxy" means an alkyl-O-group in which the alkyl group is
as previously described. Non-limiting examples of suitable alkoxy
groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
The bond to the parent moiety is through the ether oxygen.
[0130] "Aryloxy" means an aryl-O-group in which the aryl group is
as previously described. Non-limiting examples of suitable aryloxy
groups include phenoxy and naphthoxy. The bond to the parent moiety
is through the ether oxygen.
[0131] "Alkylthio" means an alkyl-S-group in which the alkyl group
is as previously described. Non-limiting examples of suitable
alkylthio groups include methylthio and ethylthio. The bond to the
parent moiety is through the sulfur.
[0132] "Arylthio" means an aryl-S-group in which the aryl group is
as previously described. Non-limiting examples of suitable arylthio
groups include phenylthio and naphthylthio. The bond to the parent
moiety is through the sulfur.
[0133] "Arylalkylthio" means an aralkyl-S-group in which the
arylalkyl group is as previously described. Non-limiting example of
a suitable arylalkylthio group is benzylthio. The bond to the
parent moiety is through the sulfur.
[0134] "Alkoxycarbonyl" means an alkyl-O--CO-group. Non-limiting
examples of suitable alkoxycarbonyl groups include methoxycarbonyl
and ethoxycarbonyl. The bond to the parent moiety is through the
carbonyl.
[0135] "Aryloxycarbonyl" means an aryl-O--C(O)-group. Non-limiting
examples of suitable aryloxycarbonyl groups include phenoxycarbonyl
and naphthoxycarbonyl. The bond to the parent moiety is through the
carbonyl.
[0136] "Arylalkoxycarbonyl" means an arylalkyl-O--C(O)-group. A
non-limiting example of a suitable arylalkoxycarbonyl group is
benzyloxycarbonyl. The bond to the parent moiety is through the
carbonyl.
[0137] "Alkylsulfonyl" means an alkyl-S(O.sub.2)-group. Preferred
groups are those in which the alkyl group is a lower alkyl. The
bond to the parent moiety is through the sulfonyl.
[0138] "Arylsulfonyl" means an aryl-S(O.sub.2)-group. The bond to
the parent moiety is through the sulfonyl.
[0139] The term "substituted" means that one or more hydrogens on
the designated atom is replaced with a selection from the indicated
group, provided that the designated atom's normal valency under the
existing circumstances is not exceeded, and that the substitution
results in a stable compound. Combinations of substituents and/or
variables are permissible only if such combinations result in
stable compounds. By "stable compound' or "stable structure" is
meant a compound that is sufficiently robust to survive isolation
to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[0140] When a group is substituted with "one or more" substituents,
the indicated group may be substituted with one substituent, two
substituents, etc., provided that the resulting substituted group
forms a stable structure, as described above.
[0141] The term "optionally substituted" means optional
substitution with the specified groups, radicals or moieties. For
example, an aryl optionally substituted with an indicated group of
substituents includes unsubstituted aryl as well as aryl
substituted with any of the indicated substituents.
[0142] The term "isolated" or "in isolated form" for a compound
refers to the physical state of said compound after being isolated
from a synthetic process or natural source or combination thereof.
The term "purified" or "in purified form" for a compound refers to
the physical state of said compound after being obtained from a
purification process or processes described herein or well known to
the skilled artisan, in sufficient purity to be characterizable by
standard analytical techniques described herein or well known to
the skilled artisan.
[0143] It should also be noted that any carbon atom as well as any
heteroatom with unsatisfied valences in the text, schemes,
examples, Tables, etc. herein is assumed to have the sufficient
number of hydrogen atom(s) to satisfy the valences.
[0144] When a functional group in a compound is termed "protected",
this means that the group is present in modified form to preclude
undesired side reactions at the protected site when the compound is
subjected to a reaction. Suitable protecting groups will be
recognized by those with ordinary skill in the art as well as by
reference to standard textbooks such as, for example, T. W. Greene
et al, Protective Groups in Organic Synthesis (1991), Wiley, New
York, herein incorporated by reference in its entirety.
[0145] When any variable (e.g., aryl, heterocycloalkyl, R.sup.2,
etc.) occurs more than one time in any constituent or in Formula I,
its definition on each occurrence is independent of its definition
at every other occurrence (unless otherwise expressly
indicated).
[0146] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts.
[0147] Prodrugs and solvates of the compounds of the invention are
also contemplated herein. The term "prodrug", as employed herein,
denotes a compound that is a drug precursor that, upon
administration to a subject, undergoes chemical conversion by
metabolic or chemical processes to yield a compound of Formula I or
a salt and/or solvate thereof. A discussion of prodrugs is provided
in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems
(1987) 14 of the A.C.S. Symposium Series, and in Bioreversible
Carriers in Drug Design, (1987) Edward B. Roche, ed., American
Pharmaceutical Association and Pergamon Press, both of which are
incorporated herein by reference thereto.
[0148] "Solvate" means a physical association of a compound of this
invention with one or more solvent molecules. This physical
association involves varying degrees of ionic and covalent bonding,
including hydrogen bonding. In certain instances the solvate will
be capable of isolation, for example when one or more solvent
molecules are incorporated in the crystal lattice of the
crystalline solid. "Solvate" encompasses both solution-phase and
isolatable solvates. Non-limiting examples of suitable solvates
include ethanolates, methanolates, and the like. A "hydrate" is a
solvate wherein the solvent molecule(s) is/are H.sub.2O.
[0149] "Effective amount" or "therapeutically effective amount" is
meant to describe an amount of compound or a composition of the
present invention effective in preventing the formation and/or
deposition of amyloid protein, and thus producing the desired
therapeutic, ameliorative, inhibitory or preventative effect.
[0150] The compounds of Formula I can form salts, which are also
within the scope of this invention. Reference to a compound of
Formula I herein is understood to include reference to salts
thereof, unless otherwise indicated. The term "salt(s)", as
employed herein, denotes acidic salts formed with inorganic and/or
organic acids, as well as basic salts formed with inorganic and/or
organic bases. In addition, when a compound of Formula I contains
both a basic moiety, such as, but not limited to a pyridine or
imidazole, and an acidic moiety, such as, but not limited to a
carboxylic acid, zwitterions ("inner salts") may be formed and are
included within the term "salt(s)" as used herein. Pharmaceutically
acceptable (i.e., non-toxic, physiologically acceptable) salts are
preferred, although other salts are also useful. Salts of the
compounds of the Formula I may be formed, for example, by reacting
a compound of Formula I with an amount of acid or base, such as an
equivalent amount, in a medium such as one in which the salt
precipitates or in an aqueous medium followed by
lyophilization.
[0151] Exemplary acid addition salts include acetates, ascorbates,
benzoates, benzenesulfonates, bisulfates, borates, butyrates,
citrates, camphorates, camphorsulfonates, fumarates,
hydrochlorides, hydrobromides, hydroiodides, lactates, maleates,
methanesulfonates, naphthalenesulfonates, nitrates, oxalates,
phosphates, propionates, salicylates, succinates, sulfates,
tartarates, thiocyanates, toluenesulfonates (also known as
tosylates,) and the like. Additionally, acids which are generally
considered suitable for the formation of pharmaceutically useful
salts from basic pharmaceutical compounds are discussed, for
example, by P. Stahl et al, Camille G. (eds.) Handbook of
Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:
Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences
(1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics
(1986) 33 201-217; Anderson et al, The Practice of Medicinal
Chemistry (1996), Academic Press, New York; and in The Orange Book
(Food & Drug Administration, Washington, D.C. on their
website). These disclosures are incorporated herein by reference
thereto.
[0152] Exemplary basic salts include ammonium salts, alkali metal
salts such as sodium, lithium, and potassium salts, alkaline earth
metal salts such as calcium and magnesium salts, salts with organic
bases (for example, organic amines) such as dicyclohexylamines,
t-butyl amines, and salts with amino acids such as arginine, lysine
and the like. Basic nitrogen-containing groups may be quarternized
with agents such as lower alkyl halides (e.g. methyl, ethyl, and
butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g.
decyl, lauryl, and stearyl chlorides, bromides and iodides),
aralkyl halides (e.g. benzyl and phenethyl bromides), and
others.
[0153] All such acid salts and base salts are intended to be
pharmaceutically acceptable salts within the scope of the invention
and all acid and base salts are considered equivalent to the free
forms of the corresponding compounds for purposes of the
invention.
[0154] Compounds of Formula I, and salts, solvates and prodrugs
thereof, may exist in their tautomeric form (for example, as an
amide or imino ether). All such tautomeric forms are contemplated
herein as part of the present invention.
[0155] All stereoisomers (for example, geometric isomers, optical
isomers and the like) of the present compounds (including those of
the salts, solvates and prodrugs of the compounds as well as the
salts and solvates of the prodrugs), such as those which may exist
due to asymmetric carbons on various substituents, including
enantiomeric forms (which may exist even in the absence of
asymmetric carbons), rotameric forms, atropisomers, and
diastereomeric forms, are contemplated within the scope of this
invention, as are positional isomers (such as, for example,
4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds
of the invention may, for example, be substantially free of other
isomers, or may be admixed, for example, as racemates or with all
other, or other selected, stereoisomers. The chiral centers of the
present invention can have the S or R configuration as defined by
the IUPAC 1974 Recommendations. The use of the terms "salt",
"solvate" "prodrug" and the like, is intended to equally apply to
the salt, solvate and prodrug of enantiomers, stereoisomers,
rotamers, tautomers, positional isomers, racemates or prodrugs of
the inventive compounds.
[0156] Polymorphic forms of the compounds of Formula I, and of the
salts, solvates and prodrugs of the compounds of Formula I, are
intended to be included in the present invention.
[0157] The compounds according to the invention have
pharmacological properties; in particular, the compounds of Formula
I can inhibit gamma-secretase, and are therefore useful in the
treatment or prevention of neurodegenerative diseases, e.g.,
Alzheimer's Disease.
[0158] Representative compounds of the invention include but are
not limited to the compounds of Examples 1-35.
[0159] Pharmaceutical compositions can comprise one or more of the
compounds of formula I. For preparing pharmaceutical compositions
from the compounds described by this invention, inert,
pharmaceutically acceptable carriers can be either solid or liquid.
Solid form preparations include powders, tablets, dispersible
granules, capsules, cachets and suppositories. The powders and
tablets may be comprised of from about 5 to about 95 percent active
compound. Suitable solid carriers are known in the art, e.g.
magnesium carbonate, magnesium stearate, talc, sugar or lactose.
Tablets, powders, cachets and capsules can be used as solid dosage
forms suitable for oral administration. Examples of
pharmaceutically acceptable carriers and methods of manufacture for
various compositions may be found in A. Gennaro (ed.), Remington's
Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co.,
Easton, Pa., herein incorporated by reference in its entirety.
[0160] Liquid form preparations include solutions, suspensions and
emulsions. Water or water-propylene glycol solutions for parenteral
injection or addition of sweeteners and opacifiers for oral
solutions, suspensions and emulsions are examples. Liquid form
preparations may also include solutions for intranasal
administration.
[0161] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier, such as an inert
compressed gas, e.g. nitrogen.
[0162] Also included are solid form preparations that are intended
to be converted, shortly before use, to liquid form preparations
for either oral or parenteral administration. Such liquid forms
include solutions, suspensions and emulsions.
[0163] The compounds of the invention may also be deliverable
transdermally. The transdermal compositions can take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
[0164] Preferably, the pharmaceutical preparation is in a unit
dosage form. In such form, the preparation is subdivided into
suitably sized unit doses containing appropriate quantities of the
active compound, e.g., an effective amount to achieve the desired
purpose.
[0165] The quantity of active compound in a unit dose of
preparation may be varied or adjusted from about 0.01 mg to about
1000 mg, preferably from about 0.01 mg to about 750 mg, more
preferably from about 0.01 mg to about 500 mg, and most preferably
from about 0.01 mg to about 250 mg, according to the particular
application.
[0166] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage regimen for a
particular situation is within the skill of the art. For
convenience, the total daily dosage may be divided and administered
in portions during the day as required.
[0167] The amount and frequency of administration of the compounds
of the invention and/or the pharmaceutically acceptable salts
thereof will be regulated according to the judgment of the
attending clinician considering such factors as age, condition and
size of the patient as well as severity of the symptoms being
treated. A typical recommended daily dosage regimen for oral
administration can range from about 0.04 mg/day to about 4000
mg/day, in one to four divided doses.
Examples
[0168] The invention disclosed herein is exemplified by the
following preparations and examples, which should not be construed
to limit the scope of the disclosure. Alternative mechanistic
pathways and analogous structures will be apparent to those skilled
in the art.
[0169] Where NMR data are presented, .sup.1H spectra were obtained
on either a Varian Gemini-300 (300 MHz) or XL-400 (400 MHz) and are
reported as ppm down field from Me.sub.4Si with number of protons,
multiplicities, and coupling constants in Hertz indicated
parenthetically. Where LC/MS data are presented, analyses was
performed using an Applied Biosystems API-100 mass spectrometer and
Shimadzu SCL-10A LC column: Alltech platinum C18, 3 micron, 33
mm.times.7 mm ID; gradient flow: 0 min-10% CH.sub.3CN in water, 5
min-95% CH.sub.3CN in water, 7 min-95% CH.sub.3CN in water, 7.5
min-10% CH.sub.3CN in water, 9 min. The retention time and observed
parent ion are given.
[0170] The following solvents and reagents may be referred to by
their abbreviations in parenthesis:
[0171] "AcOH" means acetic acid.
[0172] "Boc" means tert-butoxycarbonyl.
[0173] "BOP reagent" means
benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphat-
e.
[0174] "CBz" means the protecting group carbobenzyloxy.
[0175] "DCM" means dichloromethane.
[0176] "DCE" means 1,2-dichloroethylene.
[0177] "DDQ" means 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
[0178] "DIBAH" means diisobutylaluminum hydride.
[0179] "DEAD" means diethylazodicarboxylate.
[0180] "DMF" means dimethylformamide.
[0181] "EDCl" means
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
[0182] "Et.sub.2O" means diethyl ether.
[0183] "EtOAc" means ethyl acetate.
[0184] "EtOH" means ethyl alcohol.
[0185] "HOBT" means 1-hydroxybenzotriazole.
[0186] "LAH" or "LiAlH.sub.4" means lithium aluminum hydride.
[0187] "LCMS" means liquid chromatography with low resolution mass
spectrometry.
[0188] "mCPBA" means meta-chloroperbenzoic acid.
[0189] "Me" means methyl.
[0190] "MeOH" means methanol.
[0191] "MS" means mass spectrometry.
[0192] "NaOH" means sodium hydroxide.
[0193] "NMR" means nuclear magnetic resonance.
[0194] "HRMS" means high resolution mass spectrometry.
[0195] "OTBDMS" means t-butyldimethylsilyloxy (or
t-butyldimethylsilyl ether).
[0196] "OTBDPS" means t-butyldiphenylsilyloxy (or
t-butyldiphenylsilyl ether).
[0197] "P" means a protecting group (except as otherwise noted,
e.g., when P refers to a phosphorous atom, as in PPh.sub.3).
[0198] "Ph" means phenyl.
[0199] "PMBCl" means 4-methoxybenzylchloride,
[0200] "PPh.sub.3" means triphenyiphosphine.
[0201] "RT" means room temperature.
[0202] "TBAF" means tetrabutylammonium fluoride.
[0203] "TBDMS" means represent t-butyldimethylsilyl.
[0204] "TBDMSCl" means t-butyldimethylsilyl chloride.
[0205] "TBDMSOTf" means t-butyldimethylsilyl triflate.
[0206] "TBDPSCl" means t-butyldiphenylsilylchloride.
[0207] "TBDMS" or "TBS" means represent t-butyldimethylsilyl.
[0208] "TFA" means trifluroacetic acid.
[0209] "THF" means tetrahydrofuran.
[0210] "TMS" means trimethylsilane.
[0211] "TMSCl" means trimethylsilyl chloride.
[0212] "Tos" or "tosyl" means toluene sulfonyl.
[0213] Compounds of Formula I can be prepared by various methods
well known to those skilled in the art, and by the methods
described below. The following methods are typical:
Method 1
[0214] In Method 1, compounds of Formula I having the structure A
are prepared.
##STR00133##
[0215] An aminoalcohol 1 is converted to a sulfonamide 2 by
reaction with a sulfonyl halide in the presence of a base such as
triethylamine or potassium carbonate. The sulfonamide 2 is then
reacted with a diazoketone 3 in the presence of a catalyst such as
indium (III) triflate. The resulting ketone 4 is then reduced using
a reducing agent such as sodium borohydride, and the intermediate
sulfonamide alcohol 5 is cyclized to the final compound of
structure A using a phosphine such as triphenylphosphine and a
diazoester such as DEAD or a diazoamide.
Method 2
[0216] In Method 2, compounds of Formula I having the structure B
are prepared.
##STR00134##
[0217] A serine ester such as serine methyl ester 6 is converted to
a sulfonamide by reaction with a sulfonyl halide, followed by
protection of the alcohol using a typical protecting group such as
a t-butyldiphenylsilyl (TBDPS) ether. The resulting ester 7 is then
reduced using a typical reducing agent such as lithium aluminum
hydride, and the intermediate 8 is subjected to the sequences of
steps described in Method 1 to give a cyclic morpholine sulfonamide
9. The alcohol protecting group is then removed under standard
conditions such as treatment with TBAF. The resulting alcohol 10
can be converted to a variety of compounds of type B using methods
well-known to those skilled in the art. For example, carbamates can
be prepared by reaction of 10 with 4-Nitrophenylchloroformate
followed by reaction of the resulting carbonate with a primary or
secondary amine.
Method 3
[0218] Method 3 illustrates another method to prepare compounds of
Formula I having the structure B.
##STR00135## ##STR00136##
[0219] A serine protected at its nitrogen with a protecting group
such as Boc is protected at the alcohol with a typical protecting
group such as a t-butyldiphenylsilyl ether, and the resulting acid
is reacted with either a haloalkylketone (such as 12-a) in the
presence of a base such as potassium hydroxide, or alternatively
with a hydroxyalkylketone (such as 12-b) in the presence of
activating agents such as N,N'-dicyclohexycarbodiimide and
4-dimethylaminopyridine, to give ketoester 13. The serine
N-protecting group is then removed under standard conditions such
as TFA in case of a Boc-protecting group followed optionally by
neutralization with a base such as potassium carbonate, and the
intermediate 14 is reduced with a typical reducing agent such as
sodium triacetoxy borohydride, with or without the help of an
activation agent such as TMSCl to provide an amine 15. The amine 15
is then converted to a sulfonamide 16 by reacting with a sulfonyl
halide, or alternatively by reacting with a sulfinyl halide
followed by oxidation with an oxidizing agent such as mCPBA. The
ester part of the sulfonamide 16 is then opened and reduced with a
typical reducing agent such as sodium borohydride with calcium
chloride, and the resulting diol is cyclized back to a morpholine
17 using a variety of methods known to those skilled in the art,
for example using triphenylphosphine and DEAD (Mitsunobu-type
procedure), or tosylchloride and pyridine. Morpholine 9 can then be
converted into compounds of structure B using procedures described
in Method 2.
Method 4
[0220] In Method 4, compounds of Formula I having the structure C
are prepared.
##STR00137##
[0221] Protected alcohol intermediate 17 is deprotected with a
typical deprotection agent such as TBAF, then oxidized to an acid
18 using a standard procedure such as sodium periodate and
ruthenium chloride. The acid is then converted to an ester such as
methyl ester 19 using a standard esterification procedure such as
thionyl chloride and methanol. The ester 19 is then converted to a
cyclopropanol 20 using standard procedures such as the Kulinkovich
reaction using conditions such as ethylmagnesium bromide and
titanium IV isopropoxide. This alcohol 20 is finally converted into
compounds of structure C using procedures described in Method
2.
Method 5
[0222] In Method 5, compounds of Formula I having the structure D
are prepared.
##STR00138##
[0223] A cysteine ester such as cysteine methyl ester 21 is reacted
with a halomethylketone such as bromoketone 12 in the presence of a
base such as potassium hydroxide and the intermediate imine is
reduced with a typical reducing agent such as sodium
triacetoxyborohydride to give a thiomorpholine 22. This
thiomorpholine 22 is then converted to a sulfonamide 23 by reaction
with a sulfonyl halide and the ester part of the molecule is then
converted to a cyclopropane alcohol 24 using a Kulinkovich reaction
(Kulinkovich, O. G. Chem Review 100 (2000), 2789; incorporated
herein by reference in its entirety). Finally, the alcohol 24 is
converted into compounds of structure D using procedures described
in Method 2.
[0224] Chiral compounds of this invention can be resolved using
known methods, for example by chromatography over a chiral
stationary phase.
[0225] The invention disclosed herein is further exemplified by the
following examples, which should not be construed as limiting the
scope of the invention. Alternative mechanistic pathways and
analogous structures within the scope of the invention will be
apparent to those skilled in the art.
Example 1
4-(2-Hydroxy-ethyl)-piperazine-1-carboxylic acid
4-(4-chloro-benzenesulfonyl)-5-(3,5-difluoro-phenyl)-morpholin-3-ylmethyl
ester
##STR00139## ##STR00140##
[0226] Step 1
[0227] To a solution of DL-serine methyl ester hydrochloride (30 g,
0.19 mol) in water (150 mL) at 0.degree. C. was added potassium
carbonate (79 g, 0.57 mol) then 4-chlorobenzenesulfonyl chloride
(44 g, 0.21 mol) in THF (150 mL) and the reaction was allowed to
warm to RT for 3 h. The mixture was then diluted with water and
extracted with Et.sub.2O and EtOAc. The combined organic layers
were washed with 5% citric acid solution, brine, then dried over
sodium sulfate and concentrated to give 48.5 g (88%) of
sulfonamide.
Step 2
[0228] A solution of sulfonamide product from Step 1 (10 g, 34.0
mmol), TBDPSCl (10.3 g, 37.4 mmol) and imidazole (2.8 g, 41 mmol)
in DMF (50 mL) was stirred at RT overnight. The mixture was poured
into a mixture of water and brine (1:1), extracted with Et.sub.2O,
washed with brine, dried over sodium sulfate and concentrated. The
residue was purified by flash-chromatography over silica gel
(eluted with hexanes/DCM 1:1 to DCM) to obtain 16.0 g (89%) of
O-protected sulfonamide.
Step 3
[0229] To a solution of O-protected sulfonamide product of Step 2
(55.8 g, 0.10 mol) in THF (600 mL) was added LAH 1N in DCM (100 mL,
0.10 mol) at 0.degree. C. and the solution was allowed to warm to
RT for 1 h. The mixture was quenched with excess EtOAc and 0.5 N
NaOH, diluted with EtOAc, filtered over Celite, then extracted with
EtOAc and DCM, dried over sodium sulfate and concentrated. The
residue was purified by flash-chromatography over silica gel
(eluted with DCM/EtOAc 100:0 to 70:30) to give 39.5 g (75%) of
alcohol.
Step 4
[0230] To a solution of alcohol product of Step 3 (28.8 g, 0.057
mol) in DCM (200 mL), was added
2-diazo-1-(3,5-difluorophenyl)-ethanone (9.6 g, 0.052 mol) and the
reaction mixture was stirred at RT for 15 minutes. Indium (Ill)
triflate (5.7 g, 0.012 mol) was then added in four equal portions
every hour over 4 hr and the mixture was stirred at RT overnight.
Additional Indium (III) triflate (1.4 g, 0.0028 mol) was again
added to the reaction in four portions, as before, and the mixture
was stirred at room temperature overnight. After concentration of
the solvent, the residue was purified by flash-chromatography over
silica gel (eluted with hexanes/EtOAc 100:0 to 1:1) to provide 4.0
g of ketone product as well as 23.5 g of recovered alcohol starting
material (from Step 3). This alcohol (23.5 g) was then subjected to
the same conditions described above to provide another 3.30 g of
ketone product as well as 18.5 g of recovered alcohol starting
material from Step 3. This alcohol (18.5 g) was finally subjected
to the same conditions described above to provide another 2.60 g of
ketone product as well as 14.8 g of recovered starting material
alcohol from Step 3 (51% recovery). 9.90 g (26%) of the combined
ketone product was obtained.
Step 5
[0231] To a solution of the ketone product of Step 4 (12.2 g, 18.5
mmol) in MeOH (150 mL) at 0.degree. C. was added sodium borohydride
(700 mg, 18.5 mmol) and the reaction mixture was stirred for 1 h.
The mixture was then diluted with half-brine, extracted with DCM
and EtOAc, dried over sodium sulfate and concentrated. The residue
was purified by flash-chromatography over silica gel (eluted with
DCM/EtOAc 100:0 to 40:60) to give 8.0 g (67%) of alcohol.
Step 6
[0232] To a solution of the alcohol product of Step 5 (9.5 g, 14.4
mmol) and triphenylphosphine (5.7 g, 21.7 mmol) in THF (90 mL) was
added DEAD (3.4 mL, 21.7 mmol), and the mixture was stirred at RT
overnight then concentrated. The residue was purified by
flash-chromatography over silica gel (eluted with a gradient of
hexanes/EtOAc) to give 6.0 g (65%) of O-protected morpholine.
Step 7
[0233] To a solution of the O-protected morpholine product of Step
6 (9.5 g, 14.4 mmol) in THF (100 mL) was added TBAF 1N in THF (9.3
mL, 9.3 mmol) and the reaction was stirred 1 h at RT. It was then
concentrated, diluted with DCM and 50% NaHCO.sub.3, then extracted
with DCM and EtOAc. The combined organic layers were dried over
sodium sulfate, concentrated, and the residue was purified by
flash-chromatography over silica gel (eluted with a gradient of
DCM/EtOAc) to afford, in order of elution, 1.5 g (41%) of
cis-morpholine alcohol, followed by 1.5 g (41%)of trans-morpholine
alcohol.
Step 8
[0234] To a solution of cis-morpholine alcohol product of Step 7
(52 mg, 0.13 mmol) in acetonitrile/THF (1/1 mL) was added pyridine
(50 .mu.L) then 4-nitrophenyl chloroformate (40 mg, 0.2 mmol) and
the reaction was heated at 65.degree. C. overnight. The mixture was
concentrated, and then purified by flash-chromatography over silica
gel (eluted with a gradient of hexanes/DCM) to provide 61 mg of
nitrophenylcarbonate.
Step 9
[0235] To a solution of nitrophenylcarbonate product of Step 8 (19
mg, 0.033 mmol) in DCE (1 mL) was added
N-(2-hydroxyethyl)piperazine (100 mg), and the reaction was stirred
at RT overnight. The final mixture was diluted with DCM and 0.5 N
NaOH, extracted with EtOAc and DCM, dried over sodium sulfate and
concentrated, and the residue was purified over preparative silica
gel (eluted with DCM/MeOH 9:1) followed by treatment with 1N HCl in
Et.sub.2O to obtain 20.2 mg of product, i.e., Example 1, as a
hydrochloride salt. .sup.1H NMR (CDCl.sub.3 400 MHz) .delta. 7.82
(d, J=8.8 Hz, 2H), 7.55 (d, J=8.8 Hz, 2H), 7.22 (m, 2H), 6.77
(m,1H), 4.85 (m, 1H), 4.38 (d, 1H), 4.10 (m, 1H), 3.91 (m, 1H),
3.40-3.75 (m, 10H), 3.15-3.30 (m, 2H), 2.40-2.65 (m, 5H); HRMS
(MH.sup.+)=560.1434.
[0236] Following procedures similar to those of Example 1 and using
either cis-morpholine alcohol or trans-morpholine alcohol, i.e.,
the products of Step 7, the compounds in Table 2 were prepared:
TABLE-US-00002 TABLE 2 Mass Spec Example (M.sup.+); retention No.
COMPOUND time (min) 2 ##STR00141## 598.1; 3.73 3 ##STR00142##
598.1; 3.77 4 ##STR00143## 560.1; 3.44 5 ##STR00144## 573.1;
4.51
Example 6
4-Hydroxy-piperidine-1-carboxylic acid
1-[4-(4-chloro-benzenesulfonyl)-5-propyl-morpholin-3-yl]-cyclopropyl
ester
##STR00145##
[0238] 5-Methoxy-morpholine-3,4-dicarboxylic acid 4-tert-butyl
ester 3-methyl ester (product of Step 1) was prepared according to
the procedures described in U.S. Patent Publication Nos. 2003236296
and 2004014753 which are herein incorporated by reference.
Step 1
[0239] A solution of N-(tert-butoxycarbonyl)-O-allyl-D-serine
methyl ester (9.55 g, 36.8 mmol) in DCM (100 mL) and MeOH (50 mL)
was cooled to -78.degree. C. and treated with ozone until the
greenish color persisted. The solution was then purged with
nitrogen gas, treated with dimethylsulfide (11.2 mL) and allowed to
warm to RT overnight. After concentration, the crude product was
taken up in MeOH (120 mL) and treated with p-toluenesulfonic acid
(150 mg) for 4 h, then concentrated. The residue was purified by
flash-chromatography over silica gel (eluted with hexanes/EtOAc
90:10 to 50:50) to afford 5.02 g (50%) of aminal.
Step 2
[0240] To a solution of aminal product from Step 1 (5.02 g, 18.2
mmol) in DCM (80 mL) at -78.degree. C. were successively added
allyltrimethylsilane (6.00 mL, 37.8 mmol) then boron trifluoride
diethyletherate (560 .mu.L) and the reaction was stirred 1 h at
-78.degree. C. The solution was then quenched in water, extracted
twice with DCM, dried over sodium sulfate and concentrated. The
crude product was purified by flash-chromatography over silica gel
(eluted with hexanes/EtOAc 90:10 to 60:40) to give 3.16 g (61%) of
allyl product.
Step 3
[0241] A solution of allyl product from Step 2 (3.00 g, 10.5 mmol)
and palladium 10% over charcoal (300 mg) in EtOAc (10 mL) and MeOH
(10 mL) was hydrogenated at 1 atm for 6 h, filtered over Celite and
concentrated to yield 3.02 g (100%) of n-propyl product.
Step 4
[0242] A solution of n-propyl product from Step 3 (1.96 g, 6.82
mmol) in DCM (15 mL) and TFA (5 mL) was stirred at RT for 2 h then
concentrated. The residue was taken up in DCM and ice-cooled 0.1 N
NaOH, extracted with DCM and EtOAc, dried over sodium sulfate and
concentrated. The residue was taken up in DCM (20 mL), treated with
triethylamine (2.00 mL, 14.3 mmol) and 4-chlorobenzenesulfonyl
chloride (2.07 g, 10.6 mmol), and stirred overnight at RT. It was
then diluted with water and extracted with DCM, dried over sodium
sulfate and concentrated. The residue was purified by
flash-chromatography over silica gel (eluted with hexanes/EtOAc
95:5 to 40:60) to give 712 mg of sulfonamide isomer A and 434 mg of
isomer B (total yield 49%).
Step 5
[0243] A solution of sulfonamide isomers A and B products of Step 4
(1.15 g, 3.33 mmol) in DCM (20 mL) was treated with mCPBA (1.20 g,
6.96 mmol) and the reaction was stirred at RT overnight. The
solution was then poured into 5% sodium carbonate and extracted
with DCM, dried over sodium sulfate and concentrated. The residue
was purified by flash-chromatography over silica gel (eluted with
hexanes/EtOAc 90:10 to 50:50) to give 1.08 g (89%) of ester
sulfonamide.
Step 6
[0244] To a solution of ester sulfonamide product of Step 5 (653
mg, 1.80 mmol) in THF (22 mL) at 0.degree. C. was slowly added a 1
N solution in toluene of Tebbe's reagent (Aldrich) (14.5 mL)
followed, 10 min later, by pyridine (1.20 mL, 14.5 mmol) and the
reaction mixture was allowed to warm to RT for 4 h. The reaction
mixture was then quenched with EtOAc, and slowly poured onto ice.
Celite and brine were then added and the resulting slurry was
stirred 30 min at RT. The slurry was then filtered over Celite,
rinsed with EtOAc/MeOH (9:1) and brine, then extracted with EtOAc,
dried over sodium sulfate and concentrated. The resulting residue
was purified by flash-chromatography over silica gel (eluted with
hexanes/DCM 75:25 to 0:100) to give 352 mg of an intermediate enol
ether. This enol ether (352 mg) was taken up in THF (10 mL) and
treated with HCl 1N (10 mL) at RT for 2 h. The crude product was
then diluted with water, extracted with DCM and EtOAc, dried over
sodium sulfate and concentrated to give 335 mg (54%) of ketone.
Step 7
[0245] To a solution of the ketone product of Step 6 (345 mg, 1.00
mmol) and triethylamine (310 .mu.L, 0.22 mmol) in DCM (4 mL) at
0.degree. C. was slowly added t-butydimethysilyl triflate (250
.mu.L, 1.10 mmol) and the reaction was allowed to warm at RT
overnight. The final mixture was concentrated and purified by
flash-chromatography over silica gel (eluted with hexanes/DCM 7:3
to DCM) to provide 417 mg (91%) of enol silyl ether.
Step 8
[0246] To a solution of diethylzinc 1N in hexanes (6.4 mL, 6.4
mmol) in DCM (12 mL) at 0.degree. C. was slowly added
chloroiodomethane (465 .mu.L, 6.4 mmol) followed, 10 min later, by
the enol silyl ether product of Step 7 (417 mg, 0.91 mmol) in DCM
(12 mL). The solution was slowly allowed to warm to RT and stirred
3 h. It was then poured into 20% ammonium chloride solution,
extracted with DCM, dried over sodium sulfate and concentrated to
give 417 mg (97%) of O-protected cyclopropanol.
Step 9
[0247] A solution of the O-protected cyclopropanol product of Step
8 (417 mg, 0.88 mmol) and TBAF 1 N (2.0 mL, 2.0 mmol) in THF (4 mL)
was stirred at RT overnight, then concentrated. The residue was
directly purified by flash-chromatography over silica gel (eluted
with hexanes/EtOAc 85:15 to 0:100) to give 257 mg (81%) of
cyclopropanol.
Step 10
[0248] The cyclopropanol product of Step 9 was subjected to
conditions similar to those described in Example 1, Steps 8 and 9,
using 4-hydroxypiperidine instead of N-(2-hydroxyethyl)piperazine
in the last step, to give the desired product, i.e., Example 6.
.sup.1H NMR (CDCl.sub.3 400 MHz) .delta. 7.76 (d, J=8.8 Hz, 2H),
7.47 (d, J=8.8 Hz, 2H), 4.55 (m, 1H), 3.65-4.10 (m, 3H), 3.50-3.65
(m, 2H), 3.38 (d, 1H), 3.26 (m, 1H), 2.80-3.00 (m, 3H), 1.40-2.20
(m, 9H), 1.20-1.40 (m, 2H), 1.05-1.15 (m, 2H), 0.99 (t, J=7.5 Hz,
3H); HRMS (MH.sup.+)=487.1658.
[0249] The compounds in Table 3 were prepared following procedures
similar to those of Example 6:
TABLE-US-00003 TABLE 3 Mass Spec Example (M.sup.+); retention No.
COMPOUND time (min) 7 ##STR00146## 554.3; 3.37 8 ##STR00147##
516.3; 2.95 9 ##STR00148## 473.3; 3.69 10 ##STR00149## 487.3; 4.12
11 ##STR00150## 473.3; 4.29 12 ##STR00151## 544.3; 3.12 13
##STR00152## 529.3; 5.18 14 ##STR00153## 545.3; 3.88 15
##STR00154## 542.1; 3.06
Example 16
4-(2-Hydroxy-1,1-dimethyl-ethyl)-piperazine-1-carboxylic acid
1-[4-(4-chloro-benzenesulfonyl)-5-(3,5-difluoro-phenyl)-morpholin-3-yl]-c-
yclopropyl ester
##STR00155##
[0250] Step 1
[0251] To a solution of the cis-morpholine alcohol product of
Example 1, Step 7 (520 mg, 1.3 mmol) in EtOAc (4 mL), acetonitrile
(4 mL) and water (8 mL), was added sodium periodate (770 mg, 3.6
mmol) then ruthenium (III)chloride hydrate (50 mg) and the mixture
was stirred at RT overnight. The reaction was filtered over Celite,
and the filtrate was extracted with EtOAc, dried over sodium
sulfate and concentrated to provide 580 mg of crude acid.
Step 2
[0252] To a solution of the crude acid from Step 1 (477 mg, 1.15
mmol) in MeOH (10 mL) was added thionyl chloride (0.25 ml, 3.5
mmol), and then the reaction was heated at 60.degree. C. for 2 h.
The mixture was then concentrated, neutralized with saturated
sodium bicarbonate, extracted with DCM and EtOAc, dried over sodium
sulfate and concentrated to give 453 mg (92%) of ester.
Step 3
[0253] The ester product of Step 2 was subjected to conditions
similar to those described in Example 6, Steps 6 to 10, using
2-methyl-2-piperazin-1-yl-propan-1-ol instead of
N-(2-hydroxyethyl)piperazine in the last step, to give the desired
product, i.e., Example 16. .sup.1H NMR (CDCl.sub.3 400 MHz) .delta.
7.84 (d, J=8.7 Hz, 2H), 7.55 (d, J=8.7 Hz, 2H), 4.90 (m, 1H), 4.76
(m, 1H), 4.36 (m, 1H), 3.20-3.70 (m, 4H), 2.95-3.15 (m, 2H),
2.40-2.80 (m, 2H), 1.40-1.80 (m, 6H), 1.08 (s, 6H), 0.70-0.90 (m,
2H), 0.84 (m, 1H), -0.10 (m, 1H); HRMS (MH.sup.+)=614.1892.
[0254] The compounds in Table 4 were prepared following procedures
similar to those of Example 16:
TABLE-US-00004 TABLE 4 Mass Spec Example (M.sup.+); retention No.
COMPOUND time (min) 17 ##STR00156## 624.1; 3.84 18 ##STR00157##
586.1; 3.42 19 ##STR00158## 557.1; 4.25 20 ##STR00159## 543.1; 4.15
21 ##STR00160## 557.1; 4.55 22 ##STR00161## 543.1; 4.78 23
##STR00162## 585.1; 4.69 24 ##STR00163## 599.1; 5.52 25
##STR00164## 611.1; 4.81 26 ##STR00165## 625.1; 5.76 27
##STR00166## 650.2; 4.02 28 ##STR00167## 583.3; 4.00
Example 29
3-Hydroxy-pyrrolidine-1-carboxylic acid
4-(4-chloro-benzenesulfonyl-5-cyclopropyl-morpholin-3-ylmethyl
ester
##STR00168##
[0255] Step 1
[0256] To a solution of Boc-L-serine (12.95 g, 63.1 mmol) in DCM
(150 mL) was added triethylamine (19.7 mL, 140 mmol) followed by
TBDPSCl (16.7 mL, 65 mmol) and the reaction mixture was stirred at
RT over 2 days. The mixture was then treated with ice-cooled 5%
citric acid, extracted with DCM, EtOAc, dried over sodium sulfate
and concentrated to provide 28.0 g (100%) of O-protected
serine.
Step 2
[0257] To a solution of the O-protected serine product of Step 1
(18.71 g, 42.2 mmol) in MeOH (100 mL) and DCM (30 mL) was slowly
added potassium hydroxide (2.37 g, 42.2 mmol) in MeOH (100 mL),
then the reaction mixture was concentrated. The resulting solid and
potassium iodide (700 mg, 4.2 mmol) was taken up in DMF (70 rriL)
and a solution of 2-broo-1-cyclopropyl-ethanone (6.88 g, 42.2 mmol)
in DMF (30 mL) was slowly added. The reaction was stirred at RT
over 2 days. It was then concentrated, diluted with DCM and washed
twice with water, dried over sodium sulfate and concentrated. The
residue was purified by flash-chromatography over silica gel
(eluted with hexanes/EtOAc 85:15 to 50:50) to provide 22.3 g (100%)
of ketone.
Step 3
[0258] A solution of the ketone product of Step 2 (22.3 g, 42.2
mmol) was stirred in TFA (30 mL) and DCM (100 mL) for 2 h then
concentrated. The resulting residue was taken up in DCM (250 mL),
excess potassium carbonate was added, and the reaction was stirred
at RT overnight. The mixture was then filtered over Celite and
concentrated to provide 16.7 g (97%) of imine.
Step 4
[0259] To a mixture of the imine product of Step 3 (16.7 g, 41.0
mmol) and sodium triacetoxyborohydride (12.2 g, 57.5 mmol) in
acetonitrile (200 mL) at 0.degree. C. was slowly added TMSCl (5.6
mL, 44.0 mmol), then the reaction mixture was allowed to warm to RT
and stirred for 3 h. The reaction mixture was then filtered over
Celite, concentrated, and the residue was taken up in saturated
sodium bicarbonate solution, extracted with EtOAc and DCM, dried
over sodium sulfate and concentrated to provide 16.3 g (97%) of
amine.
Step 5
[0260] To a mixture of the amine product of Step 4 (18.07 g, 44.1
mmol) in pyridine (100 mL) was added 4-chlorobenzenesulfonyl
chloride (11.60 g, 55 mmol) and the reaction was stirred at RT for
6 h then concentrated. The residue was purified by
flash-chromatography over silica gel (eluted with hexanes/EtOAc
90:10 to 70:30) to provide 19.50 g (76%) of sulfonamide.
Step 6
[0261] To a solution of the sulfonamide product of Step 5 (4.50 g,
7.7 mmol) and calcium chloride (5.10 g, 46.2 mmol) in THF (45 mL)
and EtOH (65 mL) was added sodium borohydride (0.87 g, 23.1 mmol)
in one portion. The reaction was stirred at 0.degree. C. for 20 min
then heated to 60.degree. C. for 1 h. The final mixture was diluted
with EtOAc, treated with ice-cooled aqueous 5% citric acid
solution, extracted with EtOAc and DCM, dried over sodium sulfate
and concentrated. The residue was purified by flash-chromatography
over silica gel (eluted with hexanes/EtOAc 98:2 to AcOEt) to afford
3.21 g (71%) of diol.
Step 7
[0262] To a solution of the diol product of Step 6 (1.68 g, 2.86
mmol) and triphenylphosphine (1.57 g, 6.00 mmol) in toluene (20 mL)
was added DEAD (1.05 g, 6.00 mmol), and the solution was stirred
overnight at RT. The reaction mixture was then concentrated and
subjected to flash-chromatography over silica gel (eluted with
hexanes/DCM 75:25 to 0:100) to provide 1.03 g (63%) of morpholine
protected alcohol.
Step 8
[0263] The morpholine protected alcohol product of Step 7 was
subjected to conditions similar to those described in Example 1,
Step 7 to Step 9, using (R)-3-hydroxypyrrolidine instead of
N-(2-hydroxyethyl)piperazine in the last step, to afford the
desired product, i.e., Example 28. .sup.1H NMR (CDCl.sub.3 400 MHz)
.delta. 7.72 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 4.40-4.55
(m, 2H), 4.31 (m, 1H), 3.97 (m, 1H), 3.70-3.85 (m, 2H), 3.40-3.70
(m, 4H), 3.05-3.20 (m, 2H), 2.99 (m, 1H), 1.90-2.05 (m, 2H), 1.68
(m, 1H), 1.39 (m, 1H), 0.60-0.75 (m, 3H), 0.36 (m, 1H). LCMS
(MH.sup.+)=445.2 purity >99%.
[0264] The compounds in Table 5 were prepared following procedures
similar to those of Example 29:
TABLE-US-00005 TABLE 5 Mass Spec Example (M.sup.+); retention No.
COMPOUND time (min) 30 ##STR00169## 526.3; 2.88 31 ##STR00170##
459.3; 3.70 32 ##STR00171## 560.1; 3.27 33 ##STR00172## 549.6; 3.04
34 ##STR00173## 549.3; 2.86
Example 35
4-(2-Hydroxy-1,1-dimethyl-ethyl)-piperazine-1-carboxylic acid
1-[4-(4-chloro-benzenesulfonyl)-5-cyclopropyl-morpholin-3-yl]-cyclopropyl
ester
##STR00174##
[0265] Step 1
[0266] The morpholine protected alcohol product of Example 29, Step
7 was deprotected following conditions similar to those described
in Example 1, Step 7 and the resulting alcohol was subjected to
conditions similar to those described in Example 16, Steps 1 to 2,
to give an ester.
Step 2
[0267] To a solution of ester product of Step 1 (1.90 g, 5.3 mmol)
in THF (100 mL) was added titanium(IV)isopropoxide (1.50 g, 5.3
mmol) and the solution was cooled to 0.degree. C. Ethylmagnesium
bromide 3N in ether (9.0 mL, 26.5 mmol) was then added via syringe
pump over 1 hr period and the reaction was stirred for an
additional 30 min at this temperature. The final mixture was
diluted with EtOAc, treated with saturated sodium bicarbonate
solution, extracted with EtOAc and DCM, dried over sodium sulfate
and concentrated. The residue was purified by flash-chromatography
over silica gel (eluted with hexanes/EtOAc 95:5 to AcOEt) to give
1.16 g (61%) of morpholine cyclopropanol.
Step 3
[0268] The morpholine cyclopropanol product of Step 2 was subjected
to conditions similar to those described in Example 1, Steps 8 and
9, using 2-methyl-2-piperazin-1-yl-propan-1-ol instead of
N-(2-hydroxyethyl)piperazine in the last step, to give the desired
product, i.e., Example 35. .sup.1H NMR (CDCl.sub.3 400 MHz) .delta.
7.71 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 4.56 (m, 1H),
3.60-3.75 (m, 3H), 3.30-3.50 (m, 4H), 2.85-3.00 (m, 2H), 2.45-2.85
(m, 5H), 1.60-1.85 (m, 3H), 1.38 (m, 1H), 0.90-1.25 (m, 3H), 1.05
(s, 6H), 0.88 (m, 1H), 0.55-0.70 (m, 2H), 0.30 (m, 1H); HRMS
(MH.sup.+)=542.2079.
[0269] The compounds in Table 6 were prepared following procedures
similar to those of Example 35:
TABLE-US-00006 TABLE 6 Mass Spec Example (M.sup.+); retention No.
COMPOUND time (min) 36 ##STR00175## 513.1; 3.85 37 ##STR00176##
528.1; 2.95 38 ##STR00177## 539.1; 3.88 39 ##STR00178## 578.1; 3.43
40 ##STR00179## 485.1; 3.64 41 ##STR00180## 471.1; 3.36 42
##STR00181## 552.1; 3.30 43 ##STR00182## 540.1; 2.97 44
##STR00183## 482.1; 2.89 45 ##STR00184## 496.3; 2.95 46
##STR00185## 541.3; 4.77 47 ##STR00186## 527.3; 3.89 48
##STR00187## 510.1; 3.21 49 ##STR00188## 538.1; 3.91 50
##STR00189## 540.1; 3.10 51 ##STR00190## 510.1; 3.15 52
##STR00191## 512.1; 3.84 53 ##STR00192## 526.1; 2.99 54
##STR00193## 484.3; 3.28 55 ##STR00194## 568.3; 3.42 56
##STR00195## 498.1; 3.81 57 ##STR00196## 568.3; 4.69 58
##STR00197## 588.3; 4.41 59 ##STR00198## 581.3; 3.06 60
##STR00199## 496.3; 3.00 61 ##STR00200## 588.3; 4.41 62
##STR00201## 564.3; 4.17 63 ##STR00202## 538.1; 4.29 64
##STR00203## 581.3; 3.43 65 ##STR00204## 524.3; 3.39 66
##STR00205## 560.3; 3.15 67 ##STR00206## 558.3; 3.09 68
##STR00207## 568.3; 4.20 69 ##STR00208## 485.1; 4.13 70
##STR00209## 554.1; 3.01 71 ##STR00210## 552.3; 4.01 72
##STR00211## 485.3; 4.57 73 ##STR00212## 513.3; 4.35 74
##STR00213## 485.1; 4.02 75 ##STR00214## 554.1; 2.95 76
##STR00215## 510.1; 3.17 77 ##STR00216## 469.3; 4.94 78
##STR00217## 544.1; 2.93 79 ##STR00218## 501.3; 4.12 80
##STR00219## 473.3; 3.85
Example 81
3-Hydroxy-pyrrolidine-1-carboxylic acid
1-[4-(4-chloro-benzenesulfonyl)-5,6,6-trimethyl-morpholin-3-yl]-cycloprop-
yl ester
##STR00220##
[0270] Step 1
[0271] A solution of O-protected L-serine product of Example 29,
Step 1 (37.8 g, 85.2 mmol), 3-hydroxy-3-methyl-2-butanone (9.05 mL,
86 mmol), DCC (17.8 g, 86 mmol) and DMAP (10.5 g, 86 mmol) in DCM
(200 mL) was stirred at RT overnight. The reaction mixture was then
diluted with water, extracted with DCM, dried and concentrated. The
residue was filtered with a fritted disk and purified by
flash-chromatography over silica gel (eluted with Hexanes/EtOAc
95:5 to 80:20) to give 29.95 g (67%) of ketone.
Step 2
[0272] The ketone product of Step 1 was subjected to conditions
similar to those described in Example 29, Steps 3 to 7, and the
resulting protected morpholine alcohol was subjected to conditions
similar to those described in Example 35, Steps 1 to 3, using
(R)-3-hydroxypyrrolidine in the last step, to give the desired
product, i.e., Example 81. .sup.1H NMR (CDCl.sub.3 400 MHz) .delta.
7.76 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 4.55-4.70 (m, 1H),
4.20-4.50 (m, 1H), 3.20-3.90 (m, 6H), 3.05-3.20 (m, 1H), 1.80-2.10
(m, 2H), 1.54 (d, J=7.2 Hz, 3H), 0.80-1.65 (m, 5H), 1.06 (br s,
3H), 0.56 (m, 3H); LCMS (MH.sup.+)=473.3, purity >99%.
[0273] The compounds in Table 7 were prepared following procedures
similar to those of Example 81:
TABLE-US-00007 TABLE 7 Mass Spec Example (M.sup.+); retention No.
COMPOUND time (min) 82 ##STR00221## 503.3; 3.58 83 ##STR00222##
473.3; 4.50 84 ##STR00223## 542.3; 3.29 85 ##STR00224## 498.3; 3.38
86 ##STR00225## 544.3; 3.38 87 ##STR00226## 540.1; 4.02 88
##STR00227## 514.3; 3.59
Examples 89
3-Hydroxy-pyrrolidine-1-carboxylic acid
1-[4-(4-chloro-benzenesulfonyl)-5-ethyl-thiomorpholin-3-yl]-cyclopropyl
ester and Example 90: 3-Hydroxy-pyrrolidine-1-carboxylic acid
1-[4-(4-chloro-benzenesulfonyl)-5-ethyl-1-oxo-1[4-thiomorpholin-3-yl]-cyc-
lopropyl ester
##STR00228##
[0275] 5(R)-Ethyl-1,4-thiomopholinyl-3(S)-carboxylic acid methyl
ester was synthesized according to Sakai's method (Kazuo Sakai and
Naoto Yoneda, Chem. Pharm. Bull. 29 (1981), 1554; herein
incorporated by reference in its entirety).
Step 1
[0276] 5(R)-Ethyl-1,4-thiomopholinyl-3(S)-carboxylic acid methyl
ester (2.6 g, 13.7 mmol), 4-chlorobenzenesulfonyl chloride (3.5 g,
16.5 mmol) and pyridine (100 mL) were heated to 80.degree. C.
overnight. Pyridine was removed and EtOAc (100 mL) was added. The
organic layer was washed with saturated sodium carbonate solution
(100 mL), 1N HCl solution (100 mL), brine (100 mL) and then dried
over sodium sulfate. After the solvent was removed, the resulting
residue was purified by flash-chromatography (eluted with
hexanes/EtOAc 100:0 to 75:25). The product was further purified by
recrystallization from a hexanes/EtOAc mixture to give 1.75 g (35%)
of sulfonamide.
Step 2
[0277] The sulfonamide product of Step 1 (1.0 g, 2.75 mmol) and
titanium(IV) isopropoxide (234 mg, 0.8 mmol) were dissolved in THF
(30 mL), and the solution was cooled to 0.degree. C. Ethyl
magnesium bromide (3.0 M in ether, 2.8 mL, 8.3 mmol) was then added
via a syringe pump over 30 minutes. After stirring for additional
30 minutes, the reaction mixture was quenched by adding EtOAc (50
mL), and then the mixture was poured into a saturated sodium
bicarbonate solution (50 mL). The precipitate was filtered though a
pad of Celite. The organic layer was washed with brine (50 mL) and
dried over sodium sulfate. After the solvent was removed, the
resulting residue was purified by flash-chromatography over silica
gel (eluted with hexanes/EtOAc 100:0 to 75:25) to give 0.60 g (60%)
of cyclopropanol.
Step 3
[0278] The cyclopropanol product of Step 2 (1.0 g, 2.75 mmol) and
titanium (IV) (450 mg, 1.25 mmol) was dissolved in DCM (10 mL).
Pyridine (4 mL) and 20% phosgene in toluene (3 mL) were added and
the reaction mixture was stirred for an additional 3 h. DCM (50 mL)
was added and the organic layer was washed with 1N hydrogen
chloride solution (50 mL), and dried over sodium sulfate. After the
solvent was removed, the resulting residue was purified by
flash-chromatography over silica gel (eluted with hexanes/EtOAc
100:0 to 75:25) to give 0.20 g of carbonyl chloride product and 70
mg of unreacted starting material (cyclopropanol product of Step
2).
Step 4
[0279] The carbonyl chloride product of Step 3 (70 mg, 0.16 mmol)
was dissolved in DCM (5 mL) and 3(S)-hydroxypyrrolidine (28 mg,
0.32 mmol) was then added. After stirring at room temperature for
ten minutes, DCM (50 mL) was added and the organic layer was washed
with brine (25 mL), dried over sodium sulfate and concentrated. The
product, i.e., Example 89, was purified by flash-chromatography
over silica gel (eluted with hexanes/EtOAc 100:0 to 50:50). .sup.1H
NMR (CDCl.sub.3 400 MHz) .delta. 7.74 (d, J=8.4 Hz, 2H), 7.47 (d,
J=8.4 Hz, 2H), 4.8-4.9 (m, 1H), 4.3-4.5 (m, 1H), 3.9-4.05 (m, 1H),
3.2-3.8 (m, 4H), 1.7-2.5 (m, 8H), 1.0-1.2 (m, 7H). HRMS
(MH.sup.+)=475.1128.
Step 5
[0280] The product of Step 4 (34 mg, 0.072 mmol) was dissolved in
DCM (5 mL), and mCPBA (77%, 16.1 mg, 0.72 mmol) was added. The
mixture was stirred at room temperature for 10 minutes. DCM (40 mL)
and 1N sodium hydroxide solution (40 mL) were then added. The
organic and aqueous layers were separated, and the organic layer
was dried over sodium sulfate and concentrated. The product, i.e.,
Example 90, was purified by flash-chromatography over silica gel
(eluted with EtOAc). .sup.1H NMR (CDCl.sub.3 400 MHz) .delta. 7.76
(dd, J=8.8 Hz and 2 Hz, 2H), 7.52 (dd, J=8.8 Hz and 2 Hz, 2H), 4.86
(dd, J=6.4 Hz and 5.2 Hz, 1H), 4.3-4.5 (m, 2H), 3.2-3.8 (m, 6H),
1.75-2.1 (m, 6H), 1.05-1.3 (m, 7H). LCMS (MH.sup.+)=491.3,
purity=99%.
[0281] The compounds in Table 8 were prepared following procedures
similar to those of Examples 89 and 90:
TABLE-US-00008 TABLE 8 Mass Spec Example (M.sup.+); retention No.
COMPOUND time (min) 91 ##STR00229## 505.3; 3.21 92 ##STR00230##
489.3; 4.28 93 ##STR00231## 556.3; 3.58
Example 94
4-(2-Hydroxy-1,1-dimethyl-ethyl)-piperazine-1-carboxylic acid 1
-[4-(4-chloro-benzenesulfonyl)-5-cyclopropylmethyl-morpholin-3-yl]-cyclop-
ropyl ester
##STR00232##
[0282] Step 1
[0283] The product of Example 6, Step 2 (6.9 g, 24.2 mmol) and 4 N
HCl in dioxane (50 mL) were stirred at room temperature for 1 hour.
The solvent was removed and the residue was partitioned between
EtOAc (200 mL) and saturated sodium carbonate solution (200 mL).
The organic layer was washed with water (100 mL) and dried over
sodium sulfate. The solvent was removed and the residue was dried
under vacuum for 2 hours. 4-chlorobenzenesulfonyl chloride (7.6 g,
36.3mmol) and pyridine (100 mL) were added and the reaction was
heated to 80.degree. C. overnight. The solvent was removed and the
residue was partitioned between EtOAc (100 mL) and 1 N HCl aqueous
solution (100 mL). The organic layer was washed with brine (100
mL), dried over sodium sulfate and concentrated. The product was
purified by flash chromatography over silica gel (eluted with a
gradient EtOAc/hexanes 0:100 to 25:75) to give 5.3 g (61%) of
sulfonamide.
Step 2
[0284] Diethyl zinc 1 N in hexanes (44.2 mL, 44.2 mmol) was added
to DCM (200 mL) at 0.degree. C. TFA (5.0 g, 44.2 mmol) in DCM (20
mL) was added slowly in one minute and the reaction was stirred for
5 minutes. Diiodomethane (11.8 g, 44.2 mmol) in DCM (20 mL) was
then added and the reaction was stirred for 5 more minutes. The
sulfonamide product of Step 1 (5.3 g, 14.8 mmol) in DCM (50 mL) was
then added and the reaction was slowly allowed to warm to RT
overnight. Saturated ammonium chloride solution (100 mL) was added
to quench the reaction and the organic layer was washed with brine
(100 mL), dried over sodium sulfate and concentrated. The residue
was purified by flash chromatography over silica gel (eluted with a
gradient EtOAc/hexanes 0:100 to 25:75) to give 5.2 g (94%) of
cyclopropylmethyl product.
Step 3
[0285] The cyclopropylmethyl product of Step 2 (4.5 g, 12 mmol) was
subjected to conditions similar to those described in Example 35,
Step 2 to give 2.7 g (60%) of cyclopropanol.
Step 4
[0286] The cyclopropanol product of Step 3 (2.7 g, 7.3 mmol) was
dissolved in DCM (30 mL) and pyridine (2 mL) and phosgene (20% in
toluene) were added and the reaction was stirred at room
temperature for 10 minutes. DCM (20 mL) was added and the reaction
was quenched by slowly adding water (10 mL). The reaction was
further diluted with DCM (50 mL) and the organic layer was washed
with 1 N aqueous HCl solution (50 mL) and dried over sodium
sulfate. After evaporation of the solvent, the residue was purified
by flash chromatography over silica gel (eluted with a gradient
EtOAc/hexanes 0:100 to 25:75) to give 2.4 g (76%) of carbonyl
chloride.
Step 5
[0287] The carbonyl chloride product from Step 4 (40 mg, 0.092
mmole) was dissolved in DCM (5 mL) and
4-(2-hydroxy-1,1-dimethylethyl)-1-piperazine dihydrochloride (23
mg, 0.1 mmole) and a few drops of diisopropylethylamine were added.
The mixture was stirred at room temperature for 30 minutes then
diluted with DCM (40 mL) and saturated sodium carbonate solution
(40 mL). The organic layer was separated, dried over sodium sulfate
and concentrated. The product was purified by chromatography over
silica gel (eluted with a gradient EtOAc/hexanes 50:50 to 100:0) to
furnish the desired product, e.g. Example 94. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.77 (d, J=8.06 Hz, 2H), 7.47 (d, J=8.06 Hz,
2H), 4.55 (d, J=4.39 Hz, 1H), 3.76(d, J=11.7 Hz, 1H), 3.60 (m, 1H),
3.50 (m, 2H), 3.41 (d, J=12.4 Hz, 1H), 3.40(m, 2H), 3.30 (s, 2H),
2.99 (dd, J=12.4, 4.4 Hz, 1H), 2.89 (dd, J=12.4, 4.4 Hz, 1H), 2.63
(m, 2H), 2.42 (m, 2H), 1.88 (m, 2H), 1.23 (m, 2H), 1.10 (m, 2H),
1.00 (s, 6H), 0.99 (m, 2H), 0.72 (m, 1H), 0.50 (m, 2H), 0.15 (m,
2H). HRMS (MH.sup.+)=556.2250.
[0288] Following procedures similar to those of Examples 94, the
compounds in Table 9 were prepared:
TABLE-US-00009 TABLE 9 Mass Spec Example (M.sup.+); retention No.
COMPOUND time (min) 95 ##STR00233## 566.1; 3.51 96 (diastereo-
isomer 1) ##STR00234## 592.1; 3.26 97 (diastereo- isomer 2)
##STR00235## 592.1; 3.25 98 ##STR00236## 540.1; 3.47 99
##STR00237## 554.1; 1.25 100 ##STR00238## 556.1; 3.14 101
##STR00239## 538.1; 4.02 102 ##STR00240## 556.1; 3.40 103
##STR00241## 554.1; 3.36 104 ##STR00242## 610.3; 5.33 105
##STR00243## 510.3; 3.22 106 ##STR00244## 552.1; 3.97 107
##STR00245## 581.1; 3.97 108 ##STR00246## 485.3; 5.18 109
##STR00247## 485.3; 3.77 110 ##STR00248## 512.1; 4.15 111
##STR00249## 512.3; 3.33 112 ##STR00250## 512.3; 3.38 113
##STR00251## 498.1; 3.07 114 ##STR00252## 570.1; 3.16 115
##STR00253## 568.1; 4.62 116 ##STR00254## 604.1; 4.98 117
##STR00255## 513.3; 4.19 118 ##STR00256## 526.3; 3.78 119
##STR00257## 542.3; 3.21 120 ##STR00258## 498.3; 3.25 121
##STR00259## 527.3; 4.34 122 ##STR00260## 512.3; 3.25 123
##STR00261## 516.1; 3.01 124 ##STR00262## 560.3; 3.16 125
##STR00263## 562.3; 3.22 126 ##STR00264## 516.3; 3.56 127
##STR00265## 560.3; 3.59 128 ##STR00266## 518.3; 4.24 129
##STR00267## 520.3; 3.65 130 ##STR00268## 490.3; 3.23 131
##STR00269## 558.1; 3.30 132 ##STR00270## 556.1; 3.24 133
##STR00271## 542.1; 3.13 134 ##STR00272## 555.1; 4.64 135
##STR00273## 512.1; 3.24 136 ##STR00274## 514.1; 3.33 137
##STR00275## 556.3; 3.11
Example 138
[1,4']Bipiperidinyl-1'-carboxylic acid
1-(4-chloro-benzenesulfonyl)-6-(3,5-difluoro-phenyl)-4-ethyl-piperazin-2--
yl methyl ester
##STR00276##
[0289] Step 1
[0290] A solution of 1,3-difluoro-5-(2-nitro-vinyl)-benzene (11.3
g, 61 mmol) in THF (100 mL) was treated with allylamine (18.3 mL,
240 mmol) at RT for 2 h. The reaction mixture was then
concentrated, diluted with water and treated with an excess of
concentrated HCl, then concentrated to yield 16.02 g (100%) of
crude nitroamine hydrochloride.
Step 2
[0291] To a suspension of the nitroamine hydrochloride product of
Step 1(16.02 g, 61 mmol) in EtOH (120 mL) and concentrated HCl (120
mL) at 0.degree. C. was slowly added zinc (20.0 g) and the reaction
mixture was stirred 5 min at 0.degree. C. then 2 h at RT. The
reaction mixture was then filtered over Celite and concentrated.
The residue was diluted with water, treated with an excess of
concentrated ammonium hydroxide, extracted with DCM, dried over
sodium sulfate and concentrated to give 11.08 g (86%) of
diamine.
Step 3
[0292] To a solution of the diamine product of Step 2 (10.31 g,
48.6 mmol) in DCM (100 mL) was added di-tert-butyldicarbonate (11.2
g, 51 mmol) and the reaction was stirred at RT for 90 min then
concentrated. The residue was purified by flash-chromatography over
silica gel (eluted with hexanes/EtOAc 85:15 to 60:40) to afford
9.12 g (60%) of allyl mono-protected diamine.
Step 4
[0293] To a suspension of NaH (60% in hexanes, 1.28 g, 32 mmol) in
DMF (30 mL) was added the allyl mono-protected diamine product of
Step 3 (9.10 g, 29.1 mmol) in DMF (10 mL), and the reaction mixture
was stirred 30 min at RT. Then bromoethane (2.45 mL, 33 mmol) was
added and the mixture was stirred 30 min at RT and 2 h at
70.degree. C. The final mixture was poured into EtOAc and water,
extracted with EtOAc, washed with water, dried over sodium sulfate
and concentrated. The residue was purified by flash-chromatography
over silica gel (eluted with hexanes/EtOAc 90:10 to 70:30) to
afford 7.31 g (74%) of allylethyl mono-protected diamine.
Step 5
[0294] A solution of the allylethyl mono-protected diamine product
of Step 4 (7.31 g, 21.44 mmol) in DCM (20 mL) and TFA (10 mL) was
stirred at RT for 2 h then concentrated. The resulting crude
residue was treated with diluted NaOH, extracted with EtOAc, dried
over sodium sulfate and concentrated to give 5.35 g (100%) of
allylethyl diamine.
Step 6
[0295] To a solution of allylethyl diamine product of Step 5 (5.35
g, 21.44 mmol) and diisopropylethylamine (9.75 mL, 54 mmol) in DCE
(25 mL) at 0.degree. C. was slowly added
ethyl-2,3-dibromopropionate (3.44 mL, 23.6 mmol) in DCE (25 mL),
and the reaction was stirred at RT overnight. After workup, the
residue was purified by flash-chromatography over silica gel
(eluted with hexanes/ether 90:10 to 10:90) to provide, in order of
elution, 2.68 g (37%) of trans-allylpiperazine ester and 1.69 g
(23%) of cis-allylpiperazine ester.
Step 7
[0296] A solution of the cis-allylpiperazine ester product of Step
6 (1.80 g, 5.32 mmol) and chlorotris(triphenylphosphine)rhodium(I)
(700 mg) in EtOH (20 mL) and water (2 mL) was stirred at
100.degree. C. for 3 days. After filtration and concentration, the
residue was purified by flash-chromatography over silica gel
(eluted with hexanes/EtOAc 85:15 to 40:60) to provide 1.29 g (75%)
of cis-piperazine ester.
Step 8
[0297] A solution of cis-piperazine ester product of Step 7 (1.28
g, 4.29 mmol), 4-chlorobenzenesulfonyl chloride (1.10 g, 5.2 mmol)
and pyridine (865 .mu.L, 10.7 mmol) in DCE (15 mL) was heated at
40.degree. C. for 6 h then cooled down. The mixture was poured into
saturated sodium bicarbonate solution, extracted with DCM and
EtOAc, dried over sodium sulfate and concentrated. The residue was
purified by flash-chromatography over silica gel (eluted with
DCM/hexanes 50:50 to DCM) to give 674 mg (33%) of
cis-piperazinesulfonamide ester.
Step 9
[0298] A solution of the cis-piperazinesulfonamide ester product of
Step 8 (307 mg, 0.65 mmol) in THF (3 mL) at 0.degree. C. was
treated with LAH (1N in THF, 0.65 mL, 0.65 mmol), and the reaction
mixture was allowed to warm to RT for 30 min. It was then quenched
with EtOAc, diluted with water, filtered over Celite, and extracted
with EtOAc, dried over sodium sulfate and concentrated. The residue
was purified by flash-chromatography over silica gel (eluted with
DCM to DCM/EtOAc 1:1) to afford 257.7 mg (92%) of
cis-piperazinesulfonamide alcohol.
Step 10
[0299] The cis-piperazinesulfonamide alcohol product of Step 9 was
subjected to conditions similar to those described in Example 1,
Step 8 and Step 9, using 4-(N-piperidino)piperidine instead of
N-(2-hydroxyethyl)piperazine in the last step, to afford the
desired product, e.g. Example 138. .sup.1H NMR (CDCl.sub.3 400 MHz)
.delta. 7.80 (d, J=8.7 Hz, 2H), 7.52 (d, J=8.7 Hz, 2H), 7.22 (m,
2H), 6.72 (m, 1H), 4.99 (br s, 1H), 4.10-4.35 (m, 3H), 3.88 (m,
1H), 3.57 (t, 1H), 3.30 (d, 1H), 2.40-2.90 (m, 8H), 2.20-2.35 (m,
2H), 1.40-1.95 (m, 10H) 1.20-1.35 (m, 2H), 1.06 (t, J=7.2 Hz, 3H).
LCMS (MH.sup.+)=625.1, purity >99%.
Example 139
4-[[1-[cis-4-[(4-chlorophenyl)sulfonyl]-5-cyclopropyl-3-morpholinyl]cyclop-
ropyl]acetyl]-beta,beta-dimethyl-1-piperazineethanol
##STR00277## ##STR00278## ##STR00279##
[0300] Step 1
[0301] To 14.7 g (0.368 mol) of 60% dispersion of NaH in mineral
oil was added quickly DMF (300 mL). To the resulting suspension was
added dropwise with stirring a solution of
(1-hydroxymethyl-cyclopropyl)-methanol (35.8 g, 0.350 mol) in DMF
(400 mL). The mixture was stirred for an additional 20 min until
hydrogen evolution ceased, and cooled in an ice bath. A solution of
PMBCl in DMF (300 mL) was added dropwise. The mixture was stirred
for 2 h at 0.degree. C., then at RT overnight. It was then filtered
over Celite and concentrated. The residue was dissolved in DCM
(1000 mL) and washed twice with water (300 mL) and brine (300 mL).
The aqueous washes were then extracted twice with DCM. Combined
organic phases were dried over sodium sulfate and concentrated. The
product was isolated by flash-chromatography over silica gel,
eluted with 10-30% EtOAc/hexanes first to elute the bis-alkylated
by-product of the reaction, and then 43.96 g of the desired
monoprotected alcohol.
Step 2
[0302] To a solution of 23.3 mL of oxalyl chloride in DCM (750 mL)
cooled to -65.degree. C. to -70.degree. C. was added a solution of
DMSO (23.6 mL) in DCM (106 mL) dropwise. The reaction mixture was
stirred for an additional 1 hr prior to the addition of a solution
of the mono-protected alcohol product from Step 1 (29.6 g) in DCM
(372 mL), maintaining the internal temperature below -60.degree. C.
The mixture was stirred 20 more min followed by the rapid addition
of triethylamine (186 mL) while maintaining the internal
temperature between -55 and -60.degree. C. The reaction was allowed
to warm to 0.degree. C. over 1 h then worked up and purified by
flash-chromatography over silica gel, eluted using a mixture of 20%
EtOAc in hexanes to give 23.65 g of aldehyde.
Step 3
[0303] A mixture of the aldehyde product of Step 2 (18.2 g, 0.083
mol), potassium cyanide (8.1 g, 0.124 mol), ammonium carbonate
(23.9 g, 0.249 mol), triethylamine (50 mL) and 50% aqueous ethanol
(100 mL) was placed in a 350 mL glass pressure vessel. After 2 min
of ultrasonication, the mixture was stirred at 60.degree. C.
overnight, followed by cooling and DCM/water workup. A second
reaction batch starting from freshly prepared aldehyde product of
Step 2 was processed similarly. The crude product of the two
combined batches was recrystallized from solvent containing MeOH,
DCM and hexanes to furnish 32.99 g of hydantoin.
Step 4
[0304] A mixture of hydantoin product of Step 3 (21.4 g, 73.7
mmol), barium hydroxide (20.82 g, 147.4 mmol) and 275 mL of water
was refluxed overnight. The resulting precipitate was filtered out
through glass filter while the mixture was hot. The filtrate was
allowed to cool to 60.degree. C. and treated with ammonium
carbonate (16.4 g, 171 mmol). The mixture was boiled for 1 h and
the formed precipitate of barium hydroxide was filtered out through
glass filter while the mixture was hot. The filtrate was boiled for
1 hr in an open flask in fume hood to destroy the excess of
ammonium carbonate, while the volume of solution was maintained at
300 mL by adding water to account for evaporation. The desired
product precipitated upon cooling the mixture to 5.degree. C. and
was collected by filtration to afford 11.6 g of amino acid.
Step 5
[0305] To a suspension of amino acid from Step 4 (26.3 g, 99.2
mmol) in a mixture of dioxane (80 mL) and water (80 mL) was added
Boc.sub.2O (38.98 g, 179 mmol) and triethylamine (27.9 mL). After
overnight stirring, the volatiles were evaporated, the resulting
residue was dissolved in DCM, washed with 20% citric acid, and the
aqueous phase was back-extracted with DCM. The organic phase was
dried over sodium sulfate and concentrated. The residue was
purified by flash-chromatography over silica gel, eluted with
hexanes to 20% EtOAc/hexanes to elute non-polar admixtures, and
then 5-10% MeOH/DCM to elute the desired Boc-protected amino
acid.
Step 6
[0306] To a mixture of Boc-protected amino acid from Step 5 (113.5
g, 0.391 mol) in DCM (250 mL) and MeOH (750 mL) at 0.degree. C. was
added a solution of KOH (22.0 g, 0.39 mol) in MeOH (500 mL). After
concentration of the solvents, the residue was dissolved in DMF
(250 mL) and was added with ice cooling a mixture of
2-bromo-1-cyclopropyl-ethanone (63.8 g, 0.391 mol) in DMF (150 mL).
The mixture was stirred at RT overnight. After standard aqueous
workup (DCM/water) the product was isolated by flash-chromatography
over silica gel, eluted with 30% ethyl acetate/hexanes, to furnish
114.7 g of ester.
Step 7
[0307] To a mixture of ester product from Step 6 (15.2 g, 33.96
mmol) in DCM (240 mL) and water (4.8 mL) was added DDQ (8.4 g, 37.0
mmol). The reaction was stirred overnight, solids were filtered
out, and the solution was concentrated. Two more batches were
prepared in a similar manner, each containing 50 g of ester product
from Step 6. The crude products were combined and purified by
flash-chromatography over silica gel, eluted with 0-30% gradient of
EtOAc/hexanes, followed by 40% EtOAc/hexanes, and the final product
was recrystallized in DCM, EtOAc and hexanes to give 61.88 g of
alcohol.
Step 8
[0308] To a solution of alcohol product from Step 7 (61.88 g, 189
mmol) in THF (500 mL) was added imidazole (25.75 g, 378 mmol)
followed by TBDPSCl (62.38 g, 227 mmol) in THF (100 mL). The
reaction was stirred at RT overnight, the solids were filtered out
using Celite and the filtrate was concentrated. The residue was
partitioned between EtOAc and water. The aqueous phase was
extracted with EtOAc. The combined organic phases were dried over
sodium sulfate and concentrated. The residue was recrystallized
from EtOAc and hexanes to furnish 83 g of protected alcohol. An
additional 12.5 g of protected alcohol was isolated from mother
liquor by flash-chromatography over silica gel.
Step 9
[0309] To a mixture of protected alcohol from Step 8 (30 g, 53
mmol) in 300 mL of DCM was added TFA (90 mL). After 1 h of stirring
the volatiles were evaporated. The product was re-dissolved in 300
mL of DCM, shaken with 250 mL of saturated sodium bicarbonate, and
further extracted with DCM. The combined organic phases were dried
over sodium sulfate. The solvent was evaporated, the resulting
residue co-evaporated 2 times with EtOAc, and was kept on rotovapor
on a hot bath (60.degree. C.) for 20 min. The product was
recrystallized from EtOAc/hexanes to furnish 17.0 g of imine.
Additionally, 4.41 g of imine was isolated from mother liquor by
flash-chromatography over silica gel.
Step 10
[0310] To a mixture of imine product of Step 9 (4.41 g, 9.86 mmol)
and NaHB(OAc).sub.3 (2.19 g, 10.35 mmol) in 50 mL of DCM at
0.degree. C. was slowly added TMSCl (1.37 mL, 10.84 mmol). The
mixture was stirred overnight, worked up using saturated sodium
bicarbonate and DCM, and the resulting amine (2.90 g) was isolated
by flash-chromatography over silica gel (eluted with 20%
EtOAc/hexanes).
Step 11
[0311] A mixture of of amine product from Step 10 (12.3 g, 27.4
mmol) and 4-chlorobenzenesulfonylchloride (28.9 g, 137 mmol) in 230
mL of pyridine was heated at 85.degree. C. overnight in a pressure
vessel. Concentration of the solvents followed by
flash-chromatography over silica gel (eluted with a gradient from 0
to 30% EtOAc in hexanes) furnished 9.01 g of sulfonamide.
Step 12
[0312] To a mixture of sulfonamide product from Step 11 (8.82 g,
14.15 mmol), calcium chloride (9.4 g, 84.9 mmol), 70 mL of THF and
105 mL of ethanol was added in portions sodium borohydride (2.67 g,
70.76 mmol). The reaction was stirred overnight, quenched with 20%
aq. citric acid, extracted with DCM, dried (MgSO.sub.4) and
concentrated. The product was purified by flash-chromatography over
silica gel (eluted with a gradient 0 to 30% of EtOAc in hexanes) to
furnish 8.2 g of diol.
Step 13
[0313] A mixture of diol product from Step 12 (8.2 g, 13.1 mmol),
triphenylphosphine (10.3 g, 39.3 mmol) and 1.5 g of molecular
sieves (4 A) in toluene (120 mL) was stirred for a few minutes
prior to slow addition of DEAD. The reaction was stirred at RT
overnight. The desired morpholine product (5.44 g) was isolated
after flash chromatography over silica gel (eluted with a gradient
0-20% EtOAc/Hexanes).
Step 14
[0314] To a mixture of morpholine product from Step 13 (5.44 g,
8.93 mmol) in 75 mL of THF was added 1 N TBAF solution in THF
(17.86 mL, 17.86 mmol). The mixture was stirred overnight, quenched
with water and extracted with ethyl acetate. The organic phase was
washed with brine, dried over MgSO.sub.4 and concentrated. The
desired morpholine alcohol (3.4 g) was isolated after
flash-chromatography over silica gel (eluted with a gradient 0-30%
EtOAc/hexanes).
Step 15
[0315] To a mixture of morpholine alcohol product from Step 14 (478
mg, 1.29 mmol) in 4.0 mL acetonitrile and 8.0 mL of toluene was
added triphenylphosphine (406 mg, 1.55 mmol), iodine (393 mg, 1.55
mmol) and imidazole (263.5, 3.87 mmol). The reaction was stirred at
RT for 1 h, quenched with 20% aq. ammonium chloride, extracted
twice with diethyl ether. The organic phase was washed with
saturated sodium bicarbonate, brine, dried over magnesium sulfate
and concentrated. The residue was purified by flash-chromatography
over silica gel (eluted with a gradient 0 to 80% DCM/hexanes) to
furnish 550 mg of iodide.
Step 16
[0316] A suspension of the iodide product from Step 15 (550 mg,
1.14 mmol) and tetrabutylammonium cyanide (371 mg (1.38 mmol) in 10
mL of acetonitrile was stirred for 1.5 h. Water was added to the
reaction mixture and it was extracted twice with EtOAc. The organic
phase was washed with brine, dried over magnesium sulfate and
concentrated. The product was purified by flash-chromatography over
silica gel (eluted with a gradient from 0 to 30% EtOAc/hexanes) to
furnish 393 mg of nitrile.
Step 17
[0317] A solution of nitrile product from Step 16 (393 mg, 1.03
mmol) in DCM (7.0 mL) was treated at -78.degree. C. with a 1 M
solution of DIBAL in DCM (1.55 mL). The reaction was stirred at
-78.degree. C. for 4 h, quenched with methanol (2.0 mL). After
stirring for 10 minutes, 1 M sulfuric acid (2.0 mL) was added, and
stirring was continued for 45 min. The product was extracted twice
with DCM, washed with water and brine. The organic phase was dried
over magnesium sulfate, and concentrated. The product was purified
by flash-chromatography over silica gel (eluted with a gradient
from 0 to 30% ethyl acetate/hexanes) to fu rriish 393 mg of
aldehyde.
Step 18
[0318] To a mixture of aldehyde product from Step 17 (325 mg, 0.85
mmol) in ten-butanol (12.0 mL) and water (3.0 mL), were added
2-methyl-2-butene (0.361 mL, 3.4 mmol) and sodium chlorite (246 mg,
2.72 mmol). The reaction was stirred at RT for 2 h, then quenched
with saturated ammonium chloride and extracted with EtOAc. The
organic phase was washed with brine, dried over magnesium sulfate,
and concentrated to furnish 390 mg of crude carboxylic acid which
was used in the next step without further purification.
Step 19
[0319] To the carboxylic acid product from Step 18 (60 mg, 0.15
mmol) in 2.0 mL of DCM was added oxalyl chloride (0.105 mL, 1.2
mmol). The mixture was stirred for 20 min. The solvent was removed
in vacuum. The residue was transferred to a vial containing 70 mg
(0.30 mmol) of hydrochloride salt of
2-methyl-2-piperazin-1-yl-propan-1-ol and triethylamine (0.126 mL)
in 1.0 mL of DCM. The mixture was stirred overnight, diluted with
DCM, washed with saturated sodium bicarbonate, water and brine. The
organic phase was dried over magnesium sulfate, concentrated, and
the product was purified by prep. silica gel TLC plate using 7%
MeOH/DCM as solvent to furnish 62 mg of Example 139. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 7.70 (d, J=8.8 Hz, 2H), 7.46 (d,
J=8.8 Hz, 2H), 4.31 (m, 1H), 3.74-3.30 (ser m, 9H), 2.91 (m, 1H),
2.81-2.45 (ser m, 6H), 2.20 (br, 1H), 1.78 (m, 1H), 1.70 (m, 1H),
1.28 (m, 1H), 1.03 (s, 3H), 1.02 (s, 3H), 0.85-0.61 (ser m, 5H),
0.48 (m, 1H), 0.28 (m, 1H); LCMS (M+H.sup.+) m/z=540.3, retention
time 2.91 min.
[0320] The compounds in Table 9 were prepared following procedures
similar to those used to prepare Example 139:
TABLE-US-00010 TABLE 10 Mass Spec Example (M.sup.+); retention No.
COMPOUND time (min) 140 ##STR00280## 538.1; 2.91 141 (diastereo-
isomer 1) ##STR00281## 576.1; 3.35 142 (diastereo- isomer 2)
##STR00282## 576.1; 3.31 143 ##STR00283## 494.3; 2.89 144
##STR00284## 556.3; 3.89 145 ##STR00285## 536.3; 3.68
Example 146
alpha-[1-[4-[(4-chlorophenyl)sulfonyl-5(r)-cyclopropyl-3(s)-morpholinyl]cy-
clopropyl]-beta-oxo-3,8-diazabicyclo[3.2.1]octane-3-ethanol
##STR00286## ##STR00287##
[0321] Step 1
[0322] To a solution of the morpholine alcohol product from Example
139, Step 14 in DCM (12 mL) was added Dess-Martin periodinane (633
mg, 1.49 mmol) as a solid. After 1 h of stirring, the mixture was
quenched with 15 mL of saturated sodium bicarbonate and 600 mg of
solid Na.sub.2S.sub.2O.sub.3. The mixture was stirred until a clear
liquid-liquid biphasic mixture was obtained (1 hr). The organic
layer was separated and the aqueous phase was extracted with DCM.
The combined organic phases were dried over sodium sulfate and
concentrated to furnish 435 mg of crude aldehyde, used in the next
step without purification.
Step 2
[0323] A mixture of aldehyde product from Step 1 (800 mg, 2.16
mmol), potassium cyanide (843 mg, 12.98 mmol), TBSCl (488 mg, 3.24
mmol) and zinc iodide (34.5 mg, 0.108 mmol) in acetonitrile (15 mL)
was heated at 55.degree. C. overnight. An additional portion of
above mentioned amounts of potassium cyanide, TBSCl and 200 mg
(0.627 mmol) of zinc iodide was added and the reaction was heated
at 55.degree. C. for another 48 h. After standard aqueous workup
(DCM/water), the residue was purified by flash-chromatography over
silica gel (eluted with a gradient 0-30% ethyl acetate in hexanes)
to give 393 mg of protected cyanohydrin.
Step 3
[0324] A solution of the cyanohydrin product from Step 2 (393 mg,
0.76 mmol) in DCM (10 mL) at -78.degree. C. was treated with a 1 N
solution of DIBAL in hexanes (1.38 mL, 1.38 mmol). After stirring
at this temperature for 4 h, the reaction was quenched with 40 mL
of tartrate buffer. The mixture was diluted with 50 mL of DCM and
stirred at RT for 1 h to hydrolyze the intermediate imine. The
aldehyde (140 mg) was isolated upon DCM extraction and
flash-chromatography over silica gel (eluted with a gradient 0-30%
EtOAc/hexanes).
Step 4
[0325] To a mixture of aldehyde product from Step 3 (140 mg, 0.272
mmol) in tert-butanol (2.0 mL) and water (0.4 mL) was added a 2 N
solution of 2-methyl-2-butene in THF (0.87 mL, 1.74 mmol),
NaH.sub.2PO.sub.4H.sub.2O (75 mg, 0.544 mol) and NaClO.sub.2 (78.7
mg, 0.87 mmol). The mixture was stirred overnight and partitioned
between DCM and 20% citric acid. The aqueous phase was re-extracted
with DCM. The combined organic phases were dried over sodium
sulfate and evaporated to furnish 125 mg of carboxylic acid.
Step 5
[0326] To a solution of carboxylic acid product from Step 4 (125
mg, 0.236 mmol) in THF (3 mL) was added 1 N TBAF solution in THF
(0.54 mL, 0.54 mmol). The mixture was stirred at RT overnight,
diluted with 20% citric acid and extracted with ethyl acetate to
furnish 125 mg of crude hydroxycarboxylic acid.
Step 6
[0327] To a mixture of hydroxycarboxylic acid product from Step 5
(60 mg, 0.144 mmol) and 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester (61 mg, 0.29 mmol) in DCM (1.0 mL) was added
BOP reagent (65 mg, 0.144 mmol) followed by N-methylmorpholine (47
.mu.L, 0.43 mmol). The mixture was stirred at RT for 5 h. The
mixture was quenched with brine, extracted with EtOAc and DCM.
Combined organic phases were dried over magnesium sulfate and
concentrated. The residue was purified by flash-chromatography over
silica gel (eluted with 4% MeOH in DCM) to furnish 60 mg of
hydroxyamide.
Step 7
[0328] To a mixture of hydroxyamide product from Step 6 (60 mg,
0.0984 mmol) in DCM (5 mL) was added 0.5 mL of TFA. The mixture was
stirred for 50 minutes and the solvent was removed. The residue was
re-dissolved in DCM and washed with 2 N NaOH, water and brine. The
organic phase was dried over sodium sulfate, concentrated and
purified by prep. TLC over silica gel (eluted with 10% MeOH in DCM)
to furnish 37.9 mg of Example 146, as a 2:3 mixture of
diastereomers. .sup.1H NMR (CDCl.sub.3 400 MHz) .delta. 7.73 (d,
J=8.8 Hz, 0.8H), 7.72 (d, J=8.8 Hz, 1.2H), 7.48 (d, J=8.8 Hz, 2H),
5.29 (br d, 7.3 Hz, 0.4H), 5.14 (br d, 7.3 Hz, 0.6H), 4.18 (d, 11.7
Hz, 0.6H), 4.06-3.88 (ser m, 1.7H), 3.77-3.45(ser m, 5.8H),
3.40-3.30 (ser m, 2.9H), 3.15 (dd, J=6.6, 11.0 Hz, 0.6H), 2.96 (m,
1H), 2.86 (m, 0.4H), 2.75(dd, J=5.1, 10.2 Hz, 0.7H), 2.06 (m,
0.4H), 1.87-1.51 (ser m, 8H), 1.14-1.03 (ser m, 1H), 0.84-0.65 (ser
m, 5.4H), 0.56 (m, 0.4H), 0.47 (m, 0.6H), 0.26 (m, 1H);
LCMS(M+H.sup.+) m/z=510.3, retention time 2.65 min (single
peak).
Example 147
exo-alpha-[1-[4-[(4-chlorophenyl)sulfonyl]-5(r)-cyclopropyl-3(s)-morpholin-
yl]cyclopropyl]-beta-oxo-3-(1-piperidinyl)-8-azabicyclo[3.2.1]octane-8-eth-
anol
##STR00288##
[0330] The compound of Example 147 was prepared following
procedures similar to those of Example 146. LCMS(M.sub.+H.sup.+)
m/z=592.3, retention time 3.11 min.
ASSAY:
[0331] The pharmacological properties of the compounds of this
invention may be evaluated by a number of pharmacological assays.
The exemplified pharmacological assays, which are described later,
have been carried out with the compounds according to the present
invention, as well as with salts thereof.
[0332] Gamma-secretase activity was determined as described by
Zhang et al. (Biochemistry, 40 (16), 5049 -5055, 2001), which is
herein incorporated by reference. Activity is expressed either as a
percent inhibition or as the concentration of compound producing
50% inhibition of enzyme activity.
[0333] Reagents. Antibodies W02, G2-10, and G2-11 were obtained
from Dr. Konrad Beyreuther (University of Heidelberg, Heidelberg,
Germany). W02 recognizes residues 5-8 of A.beta. peptide, while
G2-10 and G2-11 recognize the specific C-terminal structure of
A.beta. 40 and A.beta. 42, respectively. Biotin-4G8 was purchased
from Senetec (St. Louis, Mo.). All tissue culture reagents used in
this work were from Life Technologies, Inc., unless otherwise
specified. Pepstatin A was purchased from Roche Molecular
Biochemicals; DFK167 was from Enzyme Systems Products (Livermore,
Calif.).
[0334] cDNA Constructs, Tissue Culture, and Cell Line Construction.
The construct SPC99-lon, which contains the first 18 residues and
the C-terminal 99 amino acids of APP carrying the London mutation,
has been described (Zhang, L., Song, L., and Parker, E. (1999) J.
Biol. Chem. 274, 8966-8972). Upon insertion into the membrane, the
17 amino acid signal peptide is processed, leaving an additional
leucine at the N-terminus of A.beta.. SPC99-lon was cloned into the
pcDNA4/TO vector (Invitrogen) and transfected into 293 cells stably
transfected with pcDNA6/TR, which is provided in the T-REx system
(Invitrogen). The transfected cells were selected in Dulbecco's
modified Eagle's media (DMEM) supplemented with 10% fetal bovine
serum, 100 units/mL penicillin, 100 g/mL streptomycin, 250 g/mL
zeocin, and 5 g/mL blasticidin (Invitrogen). Colonies were screened
for A.beta. production by inducing C99 expression with 0.1 g/mL
tetracycline for 16-20 h and analyzing conditioned media with a
sandwich immunoassay (see below). One of the clones, designated as
pTRE.15, was used in these studies.
[0335] Membrane Preparation. C99 expression in cells was induced
with 0.1 g/mL tetracycline for 20 h. The cells were pretreated with
1 M phorbol 12-myristate 13-acetate (PMA) and 1 M brefeldin A (BFA)
for 5-6 h at 37 C before harvesting. The cells were washed 3 times
with cold phosphate-buffered saline (PBS) and harvested in buffer A
containing 20 mM Hepes (pH 7.5), 250 mM sucrose, 50 mM KCl, 2 mM
EDTA, 2 mM EGTA, and Complete protease inhibitor tablets (Roche
Molecular Biochemicals). The cell pellets were flash-frozen in
liquid nitrogen and stored at -70 C before use.
[0336] To make membranes, the cells were resuspended in buffer A
and lysed in a nitrogen bomb at 600 psi. The cell lysate was
centrifuged at 1500 g for 10 min to remove nuclei and large cell
debris. The supernatant was centrifuged at 100000 g for 1 h. The
membrane pellet was resuspended in buffer A plus 0.5 M NaCl, and
the membranes were collected by centrifugation at 200000 g for 1 h.
The salt-washed membrane pellet was washed again in buffer A and
centrifuged at 100000 g for 1 h. The final membrane pellet was
resuspended in a small volume of buffer A using a Teflon-glass
homogenizer. The protein concentration was determined, and membrane
aliquots were flash-frozen in liquid nitrogen and stored at
-70.degree. C.
[0337] .gamma.-Secretase Reaction and A.beta. Analysis. To measure
.gamma.-secretase activity, membranes were incubated at 37.degree.
C. for 1 h in 50 .mu.L of buffer containing 20 mM Hepes (pH 7.0)
and 2 mM EDTA. At the end of the incubation, A.beta. 40 and A.beta.
42 were measured using an electrochemiluminescence (ECL)-based
immunoassay. A.beta. 40 was identified with antibody pairs
TAG-G2-10 and biotin-W02, while A.beta. 42 was identified with
TAG-G2-11 and biotin-4G8. The ECL signal was measured using an
ECL-M8 instrument (IGEN International, Inc.) according to the
manufacturer's instructions. The data presented were the means of
the duplicate or triplicate measurements in each experiment. The
characteristics of .gamma.-secretase activity described were
confirmed using more than five independent membrane
preparations.
[0338] The compounds of Examples 4, 34, 90 and 91 had an IC.sub.50
higher than about 1 .mu.M. All other compounds from the other
Examples had an IC.sub.50 within the range of about 1 nM to about 1
.mu.M. The compounds of Examples 2, 15, 16, 30, 35, 36, 43, 47, 51,
59, 69, 75, 78, 88, 94, 98, 99, 110, 122, 135, 142, 146 had an
IC.sub.50 within the range of about 1 nM to about 25 nM, i.e., 6.8,
3.6, 1.4, 11.1, 9.5, 13.3, 7.9, 24.5, 6.2, 8.9, 5.2, 0.9, 3.9, 6.7,
2.1, 3.6, 0.9, 5.7, 4.2, 4.2, 12.4 and 10.1, respectively.
[0339] While the present invention has been described in
conjunction with the specific embodiments set forth above, many
alternatives, modifications and variations thereof will be apparent
to those of ordinary skill in the art. All such alternatives,
modifications and variations are intended to fall within the spirit
and scope of the present invention.
* * * * *