U.S. patent application number 14/735798 was filed with the patent office on 2015-10-01 for methods for treating or preventing cancer and neurodegenerative diseases.
The applicant listed for this patent is Sloan-Kettering Institute for Cancer Research. Invention is credited to Yueming Li, Lei Zhu.
Application Number | 20150272962 14/735798 |
Document ID | / |
Family ID | 41692962 |
Filed Date | 2015-10-01 |
United States Patent
Application |
20150272962 |
Kind Code |
A1 |
Zhu; Lei ; et al. |
October 1, 2015 |
METHODS FOR TREATING OR PREVENTING CANCER AND NEURODEGENERATIVE
DISEASES
Abstract
Provided are methods of treating or preventing a
neurodegenerative disease comprising administering to a subject
having a neurodegenerative disease an effective amount of a
compound of Formula I: ##STR00001## where X, R.sup.1, R.sup.2,
subscript m, subscript n and subscript v are as defined herein.
Inventors: |
Zhu; Lei; (Schenectady,
NY) ; Li; Yueming; (New York, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sloan-Kettering Institute for Cancer Research |
New York |
NY |
US |
|
|
Family ID: |
41692962 |
Appl. No.: |
14/735798 |
Filed: |
June 10, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13140741 |
Feb 22, 2012 |
9056857 |
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PCT/US2009/068937 |
Dec 21, 2009 |
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14735798 |
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61139751 |
Dec 22, 2008 |
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Current U.S.
Class: |
514/221 ;
514/445 |
Current CPC
Class: |
A61P 43/00 20180101;
A61K 31/5513 20130101; C07D 333/34 20130101; A61P 35/00 20180101;
A61K 31/381 20130101; A61P 35/02 20180101; A61P 25/28 20180101;
A61P 25/00 20180101; C07D 409/12 20130101; A61P 25/16 20180101;
A61P 21/00 20180101 |
International
Class: |
A61K 31/5513 20060101
A61K031/5513; A61K 31/381 20060101 A61K031/381 |
Claims
1. A method for treating or preventing cancer, comprising
administering to a subject in need of treatment or prevention of
the cancer an effective amount of a compound of Formula I
##STR00043## or a pharmaceutically acceptable salt thereof,
wherein: X is H, halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, or cyano; each R.sup.1 is
independently H, halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, or cyano; R.sup.2 is
##STR00044## each R.sup.3 is independently H, halo, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or cyano;
Z.sup.1 is NH, O, or CH.sub.2; Z.sup.2 is --(C.sub.1-C.sub.6
alkylene)-, --(C.sub.2-C.sub.6 alkenylene)-, or
--(O--(C.sub.2-C.sub.6 alkylene))-; m is 3; n is 1; p is an integer
from 1 to 5; q is 0 or 1; and v is an integer from 1 to 3.
2. The method of claim 1, wherein the compound of Formula I has the
following Formula Ia ##STR00045## wherein: X is H, halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, or cyano; each R.sup.1 is independently H, halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, or cyano; each R.sup.3 is independently H, halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, or cyano; Z.sup.1 is NH, O, or CH.sub.2; Z.sup.2 is
--(C.sub.1-C.sub.6 alkylene)-, --(C.sub.2-C.sub.6 alkenylene)-, or
--(O--(C.sub.2-C.sub.6 alkylene))-; m is 3; p is an integer from 1
to 5; q is 0 or 1; and v is an integer from 1 to 3.
3. The method of claim 2, wherein the compound of Formula Ia has
the following Formula Iaa ##STR00046## wherein: X is halo; each
R.sup.1 is independently H, halo, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 haloalkyl; each R.sup.3 is independently H, halo,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl; Z.sup.2 is
--(C.sub.1-C.sub.6 alkylene)-, --(C.sub.2-C.sub.6 alkenylene)-, or
--(O--(C.sub.2-C.sub.6 alkylene))-; m is 3; p is an integer from 1
to 5; q is 0 or 1; and v is an integer from 1 to 3.
4. The method of any one of claims 1 to 3, wherein each R.sup.1 is
H.
5. The method of any one of claims 1 to 4, wherein q is 0.
6. The method of any one of claims 1 to 5, wherein v is 1 and X is
in the 5-position of the thiopheno group.
7. The method of any one of claims 1 to 6, wherein p is 1 and
R.sup.3 is in the 4-position of the phenyl group.
8. The method of claim 3, wherein the compound of Formula Iaa has
the structure: ##STR00047## or a pharmaceutically acceptable salt
thereof.
9. The method of claim 3, wherein the compound of Formula Iaa has
the structure: ##STR00048## or a pharmaceutically acceptable salt
thereof.
10. A method for treating or preventing cancer, comprising
administering to a subject in need of treatment or prevention of
the cancer an effective amount of a compound of Formula II
##STR00049## or a pharmaceutically acceptable salt thereof,
wherein: X is H, halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, or cyano; each R.sup.1 is
independently H, halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, or cyano; R.sup.4 is
##STR00050## each R.sup.3 is independently H, halo, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or cyano;
R.sup.5 is H, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl;
Z.sup.1 is NH, O, or CH.sub.2; Z.sup.2 is --(C.sub.1-C.sub.6
alkylene)- or --(C.sub.2-C.sub.6 alkenylene)-; m is 3; n is 1; p is
5; t is 4; q is 0 or 1; and v is an integer from 1 to 3.
11. The method of claim 10, wherein the compound of Formula II has
the following Formula IIa ##STR00051## wherein: X is H, halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, or cyano; each R.sup.1 is independently H, halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, or cyano; each R.sup.3 is independently H, halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, or cyano; R.sup.5 is H, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 haloalkyl; Z.sup.1 is NH, O or CH.sub.2; Z.sup.2 is
--(C.sub.1-C.sub.6 alkylene)- or --(C.sub.2-C.sub.6 alkenylene)-; m
is 3; p is 5; t is 4; q is 0 or 1; and v is an integer from 1 to
3.
12. The method of claim 11, wherein the compound of Formula IIa has
the following Formula IIaa ##STR00052## wherein: X is halo; each
R.sup.1 is independently H, halo, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 haloalkyl; each R.sup.3 is independently H, halo,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl; Z.sup.2 is
--(C.sub.1-C.sub.6 alkylene)- or --(C.sub.2-C.sub.6 alkenylene)-;
R.sup.5 is H, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl;
m is 3; p is 5; t is 4; q is 0 or 1; and v is an integer from 1 to
3.
13. The method of any one of claims 10 to 12, wherein each R.sup.1
is H.
14. The method of any one of claims 10 to 13, wherein R.sup.5 is H
or methyl.
15. The method of any one of claims 10 to 14, wherein R.sup.5 is
methyl.
16. The method of any one of claims 10 to 15, wherein q is 0.
17. The method of any one of claims 10 to 16, wherein v is 1 and X
is in the 5-position of the thiopheno group.
18. The method of claim 12, wherein the compound of Formula IIaa
has the structure: ##STR00053## or a pharmaceutically acceptable
salt thereof.
19. The method of claim 12, wherein the compound of Formula IIaa
has the structure: ##STR00054## or a pharmaceutically acceptable
salt thereof.
20. A method for treating or preventing a neurodegenerative
disease, comprising administering to a subject in need of treatment
or prevention of the neurodegenerative disease an effective amount
of a compound of Formula I ##STR00055## or a pharmaceutically
acceptable salt thereof, wherein: X is H, halo, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or cyano;
each R.sup.1 is independently H, halo, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or cyano;
R.sup.2 is ##STR00056## each R.sup.3 is independently H, halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, or cyano; Z.sup.1 is NH, O, or CH.sub.2; Z.sup.2 is
--(C.sub.1-C.sub.6 alkylene)-, --(C.sub.2-C.sub.6 alkenylene)-, or
--(O--(C.sub.2-C.sub.6 alkylene))-; m is 3; n is 1; p is an integer
from 1 to 5; q is 0 or 1; and v is an integer from 1 to 3.
21. The method of claim 20, wherein the compound of Formula I has
the following Formula Ia ##STR00057## wherein: X is H, halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, or cyano; each R.sup.1 is independently H, halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, or cyano; each R.sup.3 is independently H, halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, or cyano; Z.sup.1 is NH, O, or CH.sub.2; Z.sup.2 is
--(C.sub.1-C.sub.6 alkylene)-, --(C.sub.2-C.sub.6 alkenylene)-, or
--(O--(C.sub.2-C.sub.6 alkylene))-; m is 3; p is an integer from 1
to 5; q is 0 or 1; and v is an integer from 1 to 3.
22. The method of claim 21, wherein the compound of Formula Ia has
the following Formula Iaa ##STR00058## wherein: X is halo; each
R.sup.1 is independently H, halo, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 haloalkyl; each R.sup.3 is independently H, halo,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl; Z.sup.2 is
--(C.sub.1-C.sub.6 alkylene)-, --(C.sub.2-C.sub.6 alkenylene)-, or
--(O--(C.sub.2-C.sub.6 alkylene))-; m is 3; p is an integer from 1
to 5; q is 0 or 1; and v is an integer from 1 to 3.
23. The method of any one of claims 20 to 22, wherein each R.sup.1
is H.
24. The method of any one of claims 20 to 23, wherein q is 0.
25. The method of any one of claims 20 to 24, wherein v is 1 and X
is in the 5-position of the thiopheno group.
26. The method of any one of claims 20 to 25, wherein p is 1 and
R.sup.3 is in the 4-position of the phenyl group.
27. The method of claim 22, wherein the compound of Formula Iaa has
the structure: ##STR00059## or a pharmaceutically acceptable salt
thereof.
28. The method of claim 22, wherein the compound of Formula Iaa has
the structure: ##STR00060## or a pharmaceutically acceptable salt
thereof.
29. The method of any one of claims 20 to 28, wherein the
neurodegenerative disease is Alzheimer's disease, Parkinson's
disease, ALS, or MS.
30. The method of any one of claims 20 to 29, wherein the
neurodegenerative disease is Alzheimer's disease.
31. A method for treating or preventing a neurodegenerative
disease, comprising administering to a subject in need of treatment
or prevention of the neurodegenerative disease an effective amount
of a compound of Formula II ##STR00061## or a pharmaceutically
acceptable salt thereof, wherein: X is H, halo, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or cyano;
each R.sup.1 is independently H, halo, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or cyano; each
R.sup.3 is independently H, halo, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or cyano;
R.sup.4 is ##STR00062## R.sup.5 is H, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 haloalkyl; Z.sup.1 is NH, O, or CH.sub.2; Z.sup.2
alkylene)- or --(C.sub.2-C.sub.6 alkenylene)-; m is 3; n is 1; p is
5; t is 4; q is 0 or 1; and v is an integer from 1 to 3.
32. The method of claim 31, wherein the compound of Formula II has
the following Formula IIa ##STR00063## wherein: X is H, halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, or cyano; each R.sup.1 is independently H, halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, or cyano; each R.sup.3 is independently H, halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, or cyano; R.sup.5 is H, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 haloalkyl; Z.sup.1 is NH, O or CH.sub.2; Z.sup.2
alkylene)- or --(C.sub.2-C.sub.6 alkenylene)-; m is 3; p is 5; t is
4; q is 0 or 1; and v is an integer from 1 to 3.
33. The method of claim 32, wherein the compound of Formula IIa has
the following Formula IIaa ##STR00064## wherein: X is halo; each
R.sup.1 is independently H, halo, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 haloalkyl; each R.sup.3 is independently H, halo,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl; Z.sup.2 is
--(C.sub.1-C.sub.6 alkylene)- or --(C.sub.2-C.sub.6 alkenylene)-; m
is 3; p is 5; t is 4; q is 0 or 1; and v is an integer from 1 to
3.
34. The method of any one of claims 31 to 33, wherein each R.sup.1
is H.
35. The method of any one of claims 31 to 34, wherein R.sup.5 is H
or methyl.
36. The method of any one of claims 31 to 35, wherein R.sup.5 is
methyl.
37. The method of any one of claims 31 to 36, wherein q is 0.
38. The method of any one of claims 31 to 37, wherein v is 1 and X
is in the 5-position of the thiopheno group.
39. The method of claim 33, wherein the compound of Formula IIaa
has the structure: ##STR00065## or a pharmaceutically acceptable
salt thereof.
40. The method of claim 33, wherein the compound of Formula IIaa
has the structure: ##STR00066## or a pharmaceutically acceptable
salt thereof.
41. The method of any one of claims 31 to 40, wherein the
neurodegenerative disease is Alzheimer's disease, Parkinson's
disease, ALS, or MS.
42. The method of any one of claims 31 to 41, wherein the
neurodegenerative disease is Alzheimer's disease.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent
Application Ser. No. 61/139,751, filed Dec. 22, 2008, the entire
content of which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The invention relates to methods of treatment or prevention
of cancer and neurodegenerative diseases comprising administering
an effective amount of a Sulfonamide-Based Compound to a
subject.
BACKGROUND OF THE INVENTION
[0003] Alzheimer's disease (AD) is the most prevalent form of
dementia. It is a neurodegenerative disorder, clinically
characterized by progressive loss of memory and general cognitive
function, and pathologically characterized by the deposition of
extracellular proteinaceous plaques in the cortical and associative
brain regions of sufferers. These plaques mainly comprise fibrillar
aggregates of beta-amyloid peptide (A.beta.). A.beta. is formed
from amyloid precursor protein (APP). APP is a ubiquitous
membrane-spanning (type 1) glycoprotein, of which three major
isoforms (APP695, APP751, and APP770) are known, that undergoes a
variety of proteolytic processing events (Selkoe, 1998, Trends Cell
Biol. 8:447-453).
[0004] Generation of A.beta. from APP occurs via separate
intracellular proteolytic events involving the enzymes
bet-secretase and .gamma.-secretase. Beta-secretase first cleaves
APP within the extracellular domain to create soluble APP-beta and
beta-CTF (C-terminal fragment), which is then further processed by
.gamma.-secretase to release A.beta. and .gamma.-CTF. Given that
.gamma.-secretase cleaves beta-CTF, beta-CTF has widely been used
to monitor .gamma.-secretase activity in cell based and in vitro
assays. The cleavage site of APP by .gamma.-secretase appears to be
situated within a transmembrane domain, and variability in the site
of .gamma.-secretase mediated proteolysis results in A.beta. of
varying chain lengths comprising heterogeneous C-termini, e.g.
A.beta. (1-38, "A.beta.38"), A.beta. (1-40, "A.beta.40") and
A.beta. (1-42, "A.beta.42"). After secretion into the extracellular
medium, the initially-soluble A.beta. forms aggregate, ultimately
resulting in the insoluble deposits and dense neuritic plaques
which are the pathological characteristics of AD. A.beta.42 is more
prone to aggregation than A.beta.40 and is the major component of
amyloid plaque (Jarrett, et al., 1993, Biochemistry 32:4693-4697;
Kuo, et al., 1996, J. Biol. Chem. 271:4077-4081).
[0005] Alternatively, APP can be sequentially cleaved by
alpha-secretase and .gamma.-secretase to produce soluble APP-alpha,
P3 and .gamma.-CTF. Alpha-secretase cleavage precludes the
formation of A.beta. peptides.
[0006] Various interventions in the plaque-forming process have
been proposed as therapeutic treatments for AD (see, e.g., Hardy
and Selkoe, 2002, Science 297:353-356). One such method of
treatment that has been proposed is that of blocking or attenuating
the production of A.beta., for example, by inhibition of beta- or
.gamma.-secretase. Other proposed methods of treatment include
administering a compound(s) which blocks the aggregation of
A.beta., or administering an antibody which selectively binds to
A.beta.. Activation of .alpha.-secretase is also an appealing
strategy for the development of AD therapy, in that increased
alpha-secretase cleavage might lend to lessened A.beta.
generation.
[0007] .gamma.-secretase is a macromolecular aspartyl protease
composed of at least four proteins: presenilin (PS), nicastrin
(NCT), PEN-2 and APH-1 (De Strooper, 2003, Neuron 38:9-12).
Recently, CD147 and TMP21 have been found to be associated with the
.gamma.-secretase complex (Chen, et al., 2006, Nature
440:1208-1212; Zhou et al., 2005, Proc. Natl. Acad. Sci. USA,
102:7499-7504). Among these known components, PS is believed to
contain the active site of .gamma.-secretase (Esler et al., 2000,
Nat. Cell. Biol., 2:428:434; Li et al., 2000, Nature 405:689-694;
Wolfe et al., 1999, Nature 398:513-517). Considerable effort has
been made to understand the process of .gamma.-secretase substrate
recognition and its catalytic machinery. A PS-dependent protease
can process any single-pass transmembrane (TM) protein regardless
of its primary sequence as long as the TM protein extracellular
domain is smaller than 300 amino acids. Moreover, the size of the
extracellular domain appears to determine the efficiency of
substrate cleavage (Struhl and Adachi, 2000, Mol. Cell
6:625-636).
[0008] The sequential cleavage of APP by two proteases (beta- or
alpha-secretase followed .gamma.-secretase) is analogous to a
recently defined signaling paradigm, known as regulated
intramembrane proteolysis (RIP) (Brown et al., 2000, Cell
100:391-398). RIP generally requires two proteolytic steps to
initiate its signaling cascade, whereby the second intramembrane
cleavage is dependent on the first cleavage. Indeed, Notch, a type
I transmembrane protein employs RIP and is a substrate for
.gamma.-secretase cleavage. Activation of Notch (which is
.gamma.-secretase dependent) has been implicated in cancer
development. As such, inhibitors of .gamma.-secretase activity
might not only have implications in the treatment of AD, but may
also have benefit in treatment of all diseases in which
.gamma.-secretase plays a role.
[0009] Cancer also affects a significant number of people. It is
currently believed that the Notch signaling pathway is implicated
in cancer biology. The Notch signaling pathway involves cell-cell
communication, and aberrant Notch signaling has been observed in
cancer cells. Such aberrant Notch signaling has been linked to
tumor formation. .gamma.-Secretase inhibitors have been found to
prevent the generation of the active domain of Notch molecules,
thereby suppressing Notch signaling.
[0010] There is a need in the art for additional treatments for
cancer and neurodegenerative diseases, such as Alzheimer's
disease.
SUMMARY OF THE INVENTION
[0011] In one embodiment, the invention provides methods for
treating or preventing cancer, comprising administering to a
subject an effective amount of a compound of the following Formula
I
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein:
[0012] X is H, halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, or cyano;
[0013] each R.sup.1 is independently H, halo, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or
cyano;
[0014] R.sup.2 is
##STR00003##
[0015] each R.sup.3 is independently H, halo, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or
cyano;
[0016] Z.sup.1 is NH, O, or CH.sub.2;
[0017] Z.sup.2 is --(C.sub.1-C.sub.6 alkylene)-, --(C.sub.2-C.sub.6
alkenylene)-, --(NH-- (C.sub.1-C.sub.6 alkylene))- or
--(O--(C.sub.2-C.sub.6 alkylene))-;
[0018] m is 3;
[0019] n is 1;
[0020] p is an integer from 1 to 5;
[0021] q is 0 or 1; and
[0022] v is an integer from 1 to 3.
[0023] In another embodiment, the invention provides methods for
treating or preventing cancer, comprising administering to a
subject an effective amount of a compound of the following Formula
II
##STR00004##
or a pharmaceutically acceptable salt thereof, wherein:
[0024] X is H, halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, or cyano;
[0025] each R.sup.1 is independently H, halo, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or
cyano;
[0026] R.sup.4 is
##STR00005##
[0027] each R.sup.3 is independently H, halo, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or
cyano;
[0028] R.sup.5 is H, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6
haloalkyl;
[0029] Z.sup.1 is NH, O, or CH.sub.2;
[0030] Z.sup.2 alkylene)- or --(C.sub.2-C.sub.6 alkenylene)-;
[0031] m is 3;
[0032] n is 1;
[0033] p is 5;
[0034] t is 4;
[0035] q is 0 or 1; and
[0036] v is an integer from 1 to 3.
[0037] In one embodiment, the invention provides methods for
treating or preventing a neurodegenerative disease, comprising
administering to a subject an effective amount of a compound of the
following Formula I
##STR00006##
or a pharmaceutically acceptable salt thereof, wherein:
[0038] X is H, halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, or cyano;
[0039] each R.sup.1 is independently H, halo, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or
cyano;
[0040] R.sup.2 is
##STR00007##
[0041] each R.sup.3 is independently H, halo, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or
cyano;
[0042] Z.sup.1 is NH, O, or CH.sub.2;
[0043] Z.sup.2 is --(C.sub.1-C.sub.6 alkylene)-, --(C.sub.2-C.sub.6
alkenylene)-, --(NH-- (C.sub.1-C.sub.6 alkylene))- or
--(O--(C.sub.2-C.sub.6 alkylene))-;
[0044] m is 3;
[0045] n is 1;
[0046] p is an integer from 1 to 5;
[0047] q is 0 or 1; and
[0048] v is an integer from 1 to 3.
[0049] In another embodiment, the invention provides methods for
treating or preventing a neurodegenerative disease, comprising
administering to a subject an effective amount of a compound of the
following Formula II
##STR00008##
or a pharmaceutically acceptable salt thereof, wherein:
[0050] X is H, halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, or cyano;
[0051] each R.sup.1 is independently H, halo, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or
cyano;
[0052] R.sup.4 is
##STR00009##
each R.sup.3 is independently H, halo, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or cyano;
[0053] R.sup.5 is H, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6
haloalkyl;
[0054] Z.sup.1 is NH, O, or CH.sub.2;
[0055] Z.sup.2 alkylene)- or --(C.sub.2-C.sub.6 alkenylene)-;
[0056] m is 3;
[0057] n is 1;
[0058] p is 5;
[0059] t is 4;
[0060] q is 0 or 1; and
[0061] v is an integer from 1 to 3.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
[0062] The following definitions are used in connection with the
Sulfonamide-Based Compounds:
[0063] The term "C.sub.1-C.sub.6 alkyl," as used herein unless
otherwise defined, refers to a straight chain or branched
non-cyclic hydrocarbon having from 1 to 6 carbon atoms, wherein one
of the hydrocarbon's hydrogen atoms has been replaced by a single
bond. Representative straight chain C.sub.1-C.sub.6 alkyls include
-methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and n-heptyl.
Representative branched C.sub.1-C.sub.6 alkyls include -isopropyl,
-sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl,
1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl and
1,2-dimethylpropyl.
[0064] The term "C.sub.1-C.sub.6 haloalkyl," as used herein unless
otherwise defined, refers to a C.sub.1-C.sub.6 alkyl, as defined
above, wherein one or more of the --C.sub.1-C.sub.6 alkyl's
hydrogen atoms has been replaced with --F, --Cl, --Br, or --I.
Representative examples of a C.sub.1-C.sub.6 haloalkyl include, but
are not limited to --CCl.sub.3, --CF.sub.3, --CI.sub.3,
--CBr.sub.3, --CHCl.sub.2, --CHF.sub.2, --CHI.sub.2, --CHBr.sub.2,
--CH.sub.2Cl, --CH.sub.2Br, --CH.sub.2F, --CH.sub.2I,
--CH.sub.2CH.sub.2Br, --CH.sub.2CH.sub.2I, --CH.sub.2CH.sub.2F,
--CH.sub.2CH.sub.2Cl, --CH.sub.2CH.sub.2CH.sub.2Br,
--CH.sub.2CH(Br)CH.sub.3, --CH.sub.2CH.sub.2CH.sub.2Cl,
--CH.sub.2CH.sub.2CH.sub.2F, --CH.sub.2CH.sub.2CH.sub.2I,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2Br,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2Cl,
--CH.sub.2CH(Cl)CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2F,
--CH(F)CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2I,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2Br,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2Cl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2F,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2I,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2Br,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2Cl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2F,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2I, and
--CH.sub.2CH.sub.2CH(I)CH.sub.2CH.sub.2CH.sub.3.
[0065] The term "C.sub.1-C.sub.6 alkoxy," as used herein unless
otherwise defined, refers to --O--(C.sub.1-C.sub.6 alkyl), wherein
C.sub.1-C.sub.6 alkyl is as defined above. Representative examples
of a C.sub.1-C.sub.6 alkoxy include, but are not limited to,
--OCH.sub.3, --OCH.sub.2CH.sub.3, --OCH.sub.2CH.sub.2CH.sub.3,
--OCH(CH.sub.3)CH.sub.3, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH(CH.sub.3)CH.sub.3, --OCH(CH.sub.3)CH.sub.2CH.sub.3,
--OC(CH.sub.3).sub.3, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3, and
--OCH.sub.2CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3.
[0066] The term "C.sub.1-C.sub.6 alkylene," refers to a
C.sub.1-C.sub.6 alkyl where a hydrogen atom of the C.sub.1-C.sub.6
alkyl's terminal --CH.sub.3 group is replaced with a bond.
Representative examples of a C.sub.1-C.sub.6 alkylene include, but
are not limited to, --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH(CH.sub.3)CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3--,
--CH.sub.2CH(CH.sub.3)CH.sub.2--, --CH(CH.sub.3)CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and
--CH.sub.2CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.2--.
[0067] The term "C.sub.2-C.sub.6 alkenylene," refers to a
C.sub.2-C.sub.6 alkylene, as defined above, but having one or more
carbon-carbon double bonds. Representative examples of a
C.sub.2-C.sub.6 alkenylene include, but are not limited to
--HC.dbd.CH--, --HC.dbd.CH--CH.sub.2--,
--HC.dbd.CH--CH.sub.2--CH.sub.2--,
--CH.sub.2--HC.dbd.CH--CH.sub.2--,
--HC.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--HC.dbd.CH--CH.sub.2--,
--HC.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, and
--CH.sub.2--HC.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--.
[0068] The term "halo," as used herein unless otherwise defined,
refers to --F, --Cl, --Br or --I.
[0069] The term "subject," as used herein unless otherwise defined,
is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat,
horse, cow, pig, or non-human primate, such as a monkey,
chimpanzee, or baboon. In one embodiment, the subject is a
human.
[0070] The term "pharmaceutically acceptable salt," as used herein
unless otherwise defined, is a salt of a basic group, such as an
amino group, on the Sulfonamide-Based Compounds. Illustrative salts
of a basic group include, but are not limited, to sulfate, citrate,
acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate,
phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid
citrate, tartrate, oleate, tannate, pantothenate, bitartrate,
ascorbate, succinate, maleate, gentisinate, fumarate, gluconate,
glucaronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate, camphorsulfonate, and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
[0071] An "effective amount" when used in connection with a
Sulfonamide-Based Compound is an amount that is effective for
treating or preventing cancer or a neurodegenerative disease.
[0072] An "effective amount" when used in connection with another
anti-cancer agent is an amount that is effective for treating or
preventing cancer alone or in combination with a Sulfonamide-Based
Compound. An "effective amount" when used in connection with
another anti-neurodegenerative disease agent is an amount that is
effective for treating or preventing a neurodegenerative disease
alone or in combination with a Sulfonamide-Based Compound. "In
combination with" includes administration within the same
composition and via separate compositions; in the latter instance,
the other anti-neurodegenerative disease agent is effective for
treating or preventing a neurodegenerative disease during a time
when the Sulfonamide-Based Compound exerts its prophylactic or
therapeutic effect, or vice versa, and the other anti-cancer agent
is effective for treating or preventing cancer during a time when
the Sulfonamide-Based Compound exerts its prophylactic or
therapeutic effect, or vice versa.
[0073] The language "substantially free of its corresponding
opposite enantiomer" means having no more than about 10 mol %, in
another embodiment no more than about 5 mol %, in another
embodiment no more than about 2 mol %, in another embodiment no
more than about 1 mol %, in another embodiment no more than about
0.5 mol % and in another embodiment no more than about 0.1 mol %,
of its corresponding opposite enantiomer.
[0074] As used herein, the term "amyloid precursor protein" ("APP")
refers to an integral membrane protein that is expressed in tissues
and concentrated in the synapses of neurons. As used herein, the
term APP is meant to encompass all isoforms and forms of APP, both
wild-type and synthetic. Exemplary APP isoforms include, but are
not limited to, APP695 (SEQ ID NO:1), the 695 amino acid splice
variant of APP (see GenBank accession no. Y00264 and Kang, et al.,
1987, Nature 325:733-736), APP 751 (SEQ ID NO:2), the 751 amino
acid splice variant of APP (see Ponte, et al., 1988, Nature
331:525-527), and APP770 (SEQ ID NO:3), the 770 amino acid splice
variant of APP (see Kitaguchi, et al., 1988, Nature 331:530-532).
Other isoforms of APP include APP714, L-APP752, L-APP733, L-APP696,
L-APP677, APP563 and APP365. Use of the term APP herein is meant to
include all isoforms containing mutations found in familial AD and
other amyloidosis conditions. For example, these mutations include,
but are not limited to, the Swedish double mutation (Lys670Asn,
Met671 Leu); the London mutation (Val717Ile); the Indiana mutation
(Val717Leu); naturally occurring mutations including Val717Phe,
Val717Gly, Ala713Thr, and Ala713Val; the Austrian mutation
(Thr714Ile); the Iranian mutation (Thr714Ala); the French mutation
(Val715Met); the German mutation (Val715Ala); the Florida mutation
(Ile716Val); the Australian mutation (Leu723Pro); the Flemish
mutation (Ala692Gly); the Dutch mutation (Glu693Gln); the Arctic
mutation (Glu693Gly); the Italian mutation (Glu693Lys); the Iowa
mutation (Asp694Asn); and the amyloidosis-Dutch type mutation
(Glu693Gln). (All numbering herein is relative to the APP770 form).
Use of the term APP herein further includes proteins containing one
or more additions, deletions, insertions, or substitutions relative
to the isoforms described above, and APP proteins from humans and
other species. Unless a specific isoform is specified, APP when
used herein generally refers to any and all isoforms of APP, with
or without mutations, from any species.
[0075] As used herein, the term "amyloid-beta ("A.beta.")" refers
to a peptide derived from the proteolytic cleavage of APP. Cleavage
of A.beta. by beta-secretase generates two APP fragments, referred
to herein as "beta-CTF" and "soluble beta-APP." Beta-CTF is an
approximately 100 amino acid fragment, wherein the N-terminus of
beta-CTF defines the N-terminus of A.beta.. An example of a
naturally occurring beta-CTF sequence, i.e., the beta-CTF of
APP695, is provided in SEQ ID NO:5. Derivatives of the beta-CTF
portion of APP provided in SEQ ID NO:5 are well known in the art
(see, e.g., Lichtenthaler, et al., 1997, Biochemistry
36:15396-15403; and Selkoe, 1999, Nature 399:A23-A31). Such
derivatives can themselves provide a beta-CTF domain or can serve
as a starting point for creating additional derivatives. Examples
of naturally occurring derivatives of SEQ ID NO:5 are provided by
SEQ ID NOs:12-17. Subsequent .gamma.-secretase cleavage of beta-CTF
generates the C-terminus of A.beta.. Because .gamma.-secretase
cleavage of the beta-CTF fragment occurs over a short stretch of
amino acids rather than at a single peptide bond, A.beta. ranges in
size from, e.g., 39 to 43 peptides. However, A.beta. peptides of 40
and 42 amino acids in length ("A.beta.40" and "A.beta.42,"
respectively) predominate.
[0076] As used herein, the term ".gamma.-secretase" refers to an
enzyme(s) with the ability to cleave at the .gamma.-secretase site
of a protein having a .gamma.-secretase cleavage site, e.g., APP.
As used herein, .gamma.-secretase includes all recombinant forms,
mutations, and other variants of .gamma.-secretase so long as these
maintain a functional capability to catalyze the cleavage of
molecules or substrates bearing .gamma.-secretase cleavage
sites.
[0077] As used herein, the term "about" or "approximately," when
used in conjunction with a number, refers to any number within 1, 5
or 10% of the referenced number.
[0078] As used herein, the term "elderly human" refers to a human
65 years or older.
[0079] As used herein, the term "human adult" refers to a human
that is 18 years or older.
[0080] As used herein, the term "human child" refers to a human
that is 1 year to 18 years old.
[0081] As used herein, the term "human toddler" refers to a human
that is 1 year to 3 years old.
[0082] As used herein, the term "human infant" refers to a newborn
to 1 year old year human.
[0083] As used herein, the term "premature human infant" refers to
a human infant born at less than 37 weeks of gestational age.
[0084] Concentrations, amounts, percentages and other numerical
values may be presented herein in a range format. It is to be
understood that such range format is used merely for convenience
and brevity and should be interpreted flexibly to include not only
the numerical values explicitly recited as the limits of the range
but also to include all the individual numerical values or
sub-ranges encompassed within that range as if each numerical value
and sub-range is explicitly recited.
II. Sulfonamide-Based Compounds of Formulas I and II
[0085] In accordance with the invention, a compound or
pharmaceutically acceptable salt of the compound of Formula I or II
set forth above (a "Sulfonamide-Based Compound") is useful for
treating or preventing cancer or a neurodegenerative disease.
[0086] In one embodiment, the Sulfonamide-Based Compounds are
compounds of the following Formula I.
##STR00010##
or pharmaceutically acceptable salts thereof, wherein X, R.sup.1,
R.sup.2, R.sup.3, Z.sup.1, Z.sup.2, m, n, p, q, and v are as
defined above for the compounds and pharmaceutically acceptable
salts of Formula I.
[0087] Formula I above depicts relative stereochemistry, and
includes the enantiomers of the following Formulas I' and I'', and
mixtures of the enantiomers, including a racemic mixture of the
enantiomers of Formulas I' and I'':
##STR00011##
[0088] Formula I'' is the corresponding opposite enantiomer of
Formula I' when R.sup.1, R.sup.2, X, m, n, and v of Formula I'' are
the same as R.sup.1, R.sup.2, X, m, n, and v of Formula I' and
R.sup.1, R.sup.2, and X of Formula I'', when present, are in the
same positions as R.sup.1, R.sup.2, and X of Formula I'. Formula I'
is the corresponding opposite enantiomer of Formula I'' when
R.sup.1, R.sup.2, X, m, n, and v of Formula I' are the same as
R.sup.1, R.sup.2, X, m, n, and v of Formula I'' and R.sup.1,
R.sup.2, and X of Formula I', when present, are in the same
positions as R.sup.1, R.sup.2, and X of Formula I''.
[0089] In some embodiments, the compound of Formula I' is
substantially free of its corresponding opposite enantiomer of
Formula I''. In other embodiments, the compound of Formula I'' is
substantially free of its corresponding opposite enantiomer of
Formula I'.
[0090] In some embodiments, the compounds of Formula I are those
where X is halo. In other embodiments, the compounds of Formula I
are those where X is chloro. In other embodiments, the compounds of
Formula I are those where v is 1. In other embodiments, v is 1 and
X is at the 5-position of the thiopheno group. In other
embodiments, v is 1, X is halo, and X is at the 5-position of the
thiopheno group. In other embodiments, v is 1, X is chloro, and X
is at the 5-position of the thiopheno group.
[0091] In some embodiments, the compounds of Formula I are those
where Z.sup.1 is NH. In some embodiments, the compounds of Formula
I are those where Z.sup.2, when present, is --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --HC.dbd.CH--, or --OCH.sub.2--CH.sub.2--.
In other embodiments, the compounds of Formula I are those where
Z.sup.2 is trans --HC.dbd.CH--. In yet other embodiments, the
compounds of Formula I are those where Z.sup.2 is cis
--HC.dbd.CH--. In some embodiments, the compounds of Formula I are
those where q is 1. In some embodiments, the compounds of Formula I
are those where q is 0. In some embodiments, Z.sup.1 is NH, q is 1
and Z.sup.2 is --CH.sub.2--, --CH.sub.2--CH.sub.2--, --HC.dbd.CH--,
or --OCH.sub.2--CH.sub.2--
[0092] In some embodiments, the compounds of Formula I are those
where each R.sup.1 is hydrogen. In some embodiments, the compounds
of Formula I are those where p is 1 and R.sup.3 is in the
4-position of the phenyl group. In other embodiments, the compounds
of Formula I are those where at least one of R.sup.1 and R.sup.3 is
halo or C.sub.1-C.sub.6 haloalkyl. In certain embodiments, R.sup.3
is halo or C.sub.1-C.sub.6 haloalkyl. In some embodiments, the
C.sub.1-C.sub.6 haloalkyl is trihalomethyl, such as
trifluoromethyl, trichloromethyl, tribromomethyl, or triiodomethyl.
In some embodiments, halo is fluorine, chlorine, bromine, or
iodine. In some embodiments, the compounds of Formula Ia are those
where each R.sup.1 is hydrogen, p is 1, and R.sup.3 is in the
4-position of the phenyl group. In some embodiments, R.sup.1 and
R.sup.3 are C.sub.1-C.sub.6 haloalkyl, p is 1, and R.sup.3 is in
the 4-position of the phenyl group. In some embodiments, each
R.sup.1 is hydrogen, p is 1 or 2 and each R.sup.3 is halo or
C.sub.1-C.sub.6 haloalkyl.
[0093] In other embodiments, the compounds of Formula I have the
following Formula Ia
##STR00012##
wherein:
[0094] X is H, halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, or cyano;
[0095] each R.sup.1 is independently H, halo, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or
cyano;
[0096] each R.sup.3 is independently H, halo, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or
cyano;
[0097] Z.sup.1 is NH, O, or CH.sub.2;
[0098] Z.sup.2 is --(C.sub.1-C.sub.6 alkylene)-, --(C.sub.2-C.sub.6
alkenylene)-, or --(O--(C.sub.2-C.sub.6 alkylene))-;
[0099] m is 3;
[0100] p is an integer from 1 to 5;
[0101] q is 0 or 1; and
[0102] v is an integer from 1 to 3.
[0103] Formula Ia above depicts relative stereochemistry, and
includes the enantiomers of the following Formulas Ia' and Ia'',
and mixtures of the enantiomers, including a racemic mixture of the
enantiomers of Formulas Ia' and Ia'':
##STR00013##
[0104] Formula Ia'' is the corresponding opposite enantiomer of
Formula Ia' when R.sup.1, R.sup.3, X, Z.sup.1, Z.sup.2, q, m, p,
and v of Formula Ia'' are the same as R.sup.1, R.sup.3, X, Z.sup.1,
Z.sup.2, q, m, p, and v of Formula Ia' and R.sup.1, R.sup.3, and X
of Formula Ia'', when present, are in the same positions as
R.sup.1, R.sup.3, and X of Formula Ia'. Formula Ia' is the
corresponding opposite enantiomer of Formula Ia'' when R.sup.1,
R.sup.3, X, Z.sup.1, Z.sup.2, q, m, p, and v of Formula Ia' are the
same as R.sup.1, R.sup.3, X, Z.sup.1, Z.sup.2, q, m, p, and v of
Formula Ia'' and R.sup.1, R.sup.3, and X of Formula Ia', when
present, are in the same positions as R.sup.1, R.sup.3, and X of
Formula Ia''.
[0105] In some embodiments, the compound of Formula Ia' is
substantially free of its corresponding opposite enantiomer of
Formula Ia''. In other embodiments, the compound of Formula Ia'' is
substantially free of its corresponding opposite enantiomer of
Formula Ia'.
[0106] In some embodiments, the compounds of Formula Ia are those
where X is halo. In other embodiments, the compounds of Formula Ia
are those where X is chloro. In other embodiments, the compounds of
Formula Ia are those where v is 1. In other embodiments, v is 1 and
X is at the 5-position of the thiopheno group. In other
embodiments, v is 1 and X is halo, and X is at the 5-position of
the thiopheno group. In other embodiments, v is 1 and X is chloro,
and X is at the 5-position of the thiopheno group.
[0107] In some embodiments, the compounds of Formula Ia are those
where Z.sup.1 is NH. In some embodiments, the compounds of Formula
Ia are those where Z.sup.2, when present, is --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --HC.dbd.CH--, or --OCH.sub.2--CH.sub.2--.
In other embodiments, the compounds of Formula Ia are those where
Z.sup.2 is trans --HC.dbd.CH--. In yet other embodiments, the
compounds of Formula Ia are those where Z.sup.2 is cis
--HC.dbd.CH--. In some embodiments, the compounds of Formula Ia are
those where q is 1. In some embodiments, the compounds of Formula
Ia are those where q is 0. In some embodiments, the compounds of
Formula Ia are those where Z.sup.1 is NH and Z.sup.2 is
--CH.sub.2--, --CH.sub.2--CH.sub.2--, --HC.dbd.CH--, or
--OCH.sub.2--CH.sub.2--.
[0108] In some embodiments, the compounds of Formula Ia are those
where each R.sup.1 is hydrogen. In some embodiments, the compounds
of Formula Ia are those where p is 1 and R.sup.3 is in the
4-position of the phenyl group. In other embodiments, the compounds
of Formula Ia are those where at least one of R.sup.1 and R.sup.3
is halo or C.sub.1-C.sub.6 haloalkyl. In certain embodiments,
R.sup.3 is halo or C.sub.1-C.sub.6 haloalkyl. In some embodiments,
the C.sub.1-C.sub.6 haloalkyl is trihalomethyl, such as
trifluoromethyl, trichloromethyl, tribromomethyl, or triiodomethyl.
In some embodiments, halo is fluorine, chlorine, bromine, or
iodine. In some embodiments, the compounds of Formula Ia are those
where each R.sup.1 is hydrogen, p is 1, and R.sup.3 is in the
4-position of the phenyl group. In some embodiments, R.sup.1 and
R.sup.3 are C.sub.1-C.sub.6 haloalkyl, p is 1, and R.sup.3 is in
the 4-position of the phenyl group. In some embodiments, each
R.sup.1 is hydrogen, p is 1 or 2 and each R.sup.3 is halo or
C.sub.1-C.sub.6 haloalkyl.
[0109] In other embodiments, the compounds of Formula Ia have the
following Formula Iaa
##STR00014##
wherein:
[0110] X is halo;
[0111] each R.sup.1 is independently H, halo, C.sub.1-C.sub.6
alkyl, or C.sub.1-C.sub.6 haloalkyl;
[0112] each R.sup.3 is independently H, halo, C.sub.1-C.sub.6
alkyl, or C.sub.1-C.sub.6 haloalkyl;
[0113] Z.sup.2 is --(C.sub.1-C.sub.6 alkylene)-, --(C.sub.2-C.sub.6
alkenylene)-, or --(O--(C.sub.2-C.sub.6 alkylene))-; m is 3;
[0114] p is an integer from 1 to 5;
[0115] q is 0 or 1; and
[0116] v is an integer from 1 to 3.
[0117] Formula Iaa above depicts relative stereochemistry, and
includes the enantiomers of the following Formulas Iaa' and Iaa'',
and mixtures of the enantiomers, including a racemic mixture of the
enantiomers of Formulas Iaa' and Iaa'':
##STR00015##
[0118] Formula Iaa'' is the corresponding opposite enantiomer of
Formula Iaa' when R.sup.1, R.sup.3, X, Z.sup.2, q, m, p, and v of
Formula Iaa'' are the same as R.sup.1, R.sup.3, X, Z.sup.2, q, m,
p, and v of Formula Iaa' and R.sup.1, R.sup.3, and X of Formula
Iaa'', when present, are in the same positions as R.sup.1, R.sup.3,
and X of Formula Iaa'. Formula Iaa' is the corresponding opposite
enantiomer of Formula Iaa'' when R.sup.1, R.sup.3, X, Z.sup.2, q,
m, p, and v of Formula Iaa' are the same as R.sup.1, R.sup.3, X,
Z.sup.2, q, m, p, and v of Formula Iaa'' and R.sup.1, R.sup.3, and
X of Formula Iaa', when present, are in the same positions as
R.sup.1, R.sup.3, and X of Formula Iaa''.
[0119] In some embodiments, the compound of Formula Iaa' is
substantially free of its corresponding opposite enantiomer of
Formula Iaa''. In other embodiments, the compound of Formula Iaa''
is substantially free of its corresponding opposite enantiomer of
Formula Iaa'.
[0120] In some embodiments, the compounds of Formula Iaa are those
where X is chloro. In other embodiments, the compounds of Formula
Iaa are those where v is 1. In other embodiments, v is 1 and X is
at the 5-position of the thiopheno group. In other embodiments, the
compounds of Formula Iaa are those where v is 1, X is chloro, and X
is at the 5-position of the thiopheno group.
[0121] In some embodiments, the compounds of Formula Iaa are those
where R.sup.3 is halo or (trihalo)methyl. In other embodiments, the
compounds of Formula Iaa are those where R.sup.3 is fluoro or
(trifluoro)methyl. In other embodiments, the compounds of Formula
Iaa are those where v is 1, X is chloro, X is at the 5-position of
the thiopheno group, and R.sup.3 is fluoro or
(trifluoro)methyl.
[0122] In some embodiments, the compounds of Formula Iaa are those
where Z.sup.2, when present, is --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --HC.dbd.CH--, or --OCH.sub.2--CH.sub.2--.
In other embodiments, the compounds of Formula Iaa are those where
Z.sup.2 is trans --HC.dbd.CH--. In yet other embodiments, the
compounds of Formula Iaa are those where Z.sup.2 is cis
--HC.dbd.CH--. In some embodiments, the compounds of Formula Iaa
are those where q is 1. In some embodiments, the compounds of
Formula Iaa are those where q is 0. In some embodiments, the
compounds of Formula Iaa are those where q is 1 and Z.sup.2 is
--CH.sub.2--, --CH.sub.2--CH.sub.2--, --HC.dbd.CH--, or
--OCH.sub.2--CH.sub.2--.
[0123] In some embodiments, the compounds of Formula Iaa are those
where each R.sup.1 is hydrogen. In some embodiments, the compounds
of Formula Iaa are those where p is 1 and R.sup.3 is in the
4-position of the phenyl group. In other embodiments, the compounds
of Formula Iaa are those where at least one of R.sup.1 and R.sup.3
is C.sub.1-C.sub.6 haloalkyl. In certain embodiments, R.sup.3 is
C.sub.1-C.sub.6 haloalkyl. In some embodiments, the C.sub.1-C.sub.6
haloalkyl is trihalomethyl, such as trifluoromethyl,
trichloromethyl, tribromomethyl, or triiodomethyl. In some
embodiments, the compounds of Formula Iaa are those where each
R.sup.1 is hydrogen, p is 1, and R.sup.3 is in the 4-position of
the phenyl group. In some embodiments, R.sup.1 and R.sup.3 are each
C.sub.1-C.sub.6 haloalkyl, p is 1, and R.sup.3 is in the 4-position
of the phenyl group. In some embodiments, each R.sup.1 is hydrogen,
p is 1 or 2 and each R.sup.3 is C.sub.1-C.sub.6 haloalkyl.
[0124] In some embodiments, a compound of Formula Iaa has the
structure:
##STR00016##
, or a pharmaceutically acceptable salt thereof.
[0125] In other embodiments, the compounds of Formula Iaa have the
Formula Iaaa, set forth below. In some embodiments, the compounds
of Formula Iaaa are those where q is 0 or 1. In some embodiments,
the compounds of Formula Iaaa are those where Z.sup.2, when
present, is CH.sub.2, CH.sub.2CH.sub.2, O--CH.sub.2CH.sub.2, or
HC.dbd.CH. In some embodiments, the compounds of Formula Iaaa are
those where Ar is 4-fluorophenyl, 4-bromophenyl, 4-chlorophenyl,
4-iodophenyl, 4-methylphenyl, or 4-(trifluromethyl)phenyl. In other
embodiments, the compounds of Formula Iaaa are those where q is 1,
Z.sup.2 is CH.sub.2, CH.sub.2CH.sub.2, O--CH.sub.2CH.sub.2, or
HC.dbd.CH, and Ar is 4-fluorophenyl, 4-bromophenyl, 4-chlorophenyl,
4-iodophenyl, 4-methylphenyl, or 4-(trifluromethyl)phenyl.
[0126] Illustrative examples of the compounds of Formula Iaaa are
set forth in Table 1 below.
TABLE-US-00001 TABLE 1 Illustrative examples of compounds of
Formula Iaaa Formula Iaaa ##STR00017## Compound X q Z.sup.2 Ar 1 Cl
0 absent 4-fluorophenyl 2 Cl 0 absent 4-chlorophenyl 3 Cl 0 absent
4-bromophenyl 4 Cl 0 absent 4-iodophenyl 5 Cl 0 absent
4-(trifluoromethyl)phenyl 6 Cl 0 absent 4-methylphenyl 7 Cl 1
CH.sub.2 4-fluorophenyl 8 Cl 1 CH.sub.2 4-chlorophenyl 9 Cl 1
CH.sub.2 4-bromophenyl 10 Cl 1 CH.sub.2 4-iodophenyl 11 Cl 1
CH.sub.2 4-(trifluoromethyl)phenyl 12 Cl 1 CH.sub.2 4-methylphenyl
13 Cl 1 CH.sub.2CH.sub.2 4-fluorophenyl 14 Cl 1 CH.sub.2CH.sub.2
4-chlorophenyl 15 Cl 1 CH.sub.2CH.sub.2 4-bromophenyl 16 Cl 1
CH.sub.2CH.sub.2 4-iodophenyl 17 Cl 1 CH.sub.2CH.sub.2
4-(trifluoromethyl)phenyl 18 Cl 1 CH.sub.2CH.sub.2 4-methylphenyl
19 Cl 1 CH.sub.2CH.sub.2 2,5-di-(trifluoromethyl) phenyl 20 Cl 1
CH.sub.2CH.sub.2 2,5-dimethylphenyl 21 Cl 1 CH.sub.2CH.sub.2
2,5-difluorophenyl 22 Cl 1 CH.sub.2CH.sub.2 2,5-dichlorophenyl 23
Cl 1 CH.sub.2CH.sub.2 2,5-dibromophenyl 24 Cl 1 CH.sub.2CH.sub.2
2,5-diodophenyl 25 Cl 1 O-CH.sub.2CH.sub.2 4-fluorophenyl 26 Cl 1
O-CH.sub.2CH.sub.2 4-chlorophenyl 27 Cl 1 O-CH.sub.2CH.sub.2
4-bromophenyl 28 Cl 1 O-CH.sub.2CH.sub.2 4-iodophenyl 29 Cl 1
O-CH.sub.2CH.sub.2 4-(trifluoromethyl)phenyl 30 Cl 1
O-CH.sub.2CH.sub.2 4-methylphenyl 31 Cl 1 HC.dbd.CH 4-fluorophenyl
32 Cl 1 HC.dbd.CH 4-chlorophenyl 33 Cl 1 HC.dbd.CH 4-bromophenyl 34
Cl 1 HC.dbd.CH 4-iodophenyl 35 Cl 1 HC.dbd.CH
4-(trifluoromethyl)phenyl 36 Cl 1 HC.dbd.CH 4-methylphenyl 37 F 0
absent 4-fluorophenyl 38 F 0 absent 4-chlorophenyl 39 F 0 absent
4-bromophenyl 40 F 0 absent 4-iodophenyl 41 F 0 absent
4-(trifluoromethyl)phenyl 42 F 0 absent 4-methylphenyl 43 F 1
CH.sub.2 4-fluorophenyl 44 F 1 CH.sub.2 4-chlorophenyl 45 F 1
CH.sub.2 4-bromophenyl 46 F 1 CH.sub.2 4-iodophenyl 47 F 1 CH.sub.2
4-(trifluoromethyl)phenyl 48 F 1 CH.sub.2 4-methylphenyl 49 F 1
CH.sub.2CH.sub.2 4-fluorophenyl 50 F 1 CH.sub.2CH.sub.2
4-chlorophenyl 51 F 1 CH.sub.2CH.sub.2 4-bromophenyl 52 F 1
CH.sub.2CH.sub.2 4-iodophenyl 53 F 1 CH.sub.2CH.sub.2
4-(trifluoromethyl)phenyl 54 F 1 CH.sub.2CH.sub.2 4-methylphenyl 55
F 1 CH.sub.2CH.sub.2 2,5-di-(trifluoromethyl) phenyl 56 F 1
CH.sub.2CH.sub.2 2,5-dimethylphenyl 57 F 1 CH.sub.2CH.sub.2
2,5-difluorophenyl 58 F 1 CH.sub.2CH.sub.2 2,5-dichlorophenyl 59 F
1 CH.sub.2CH.sub.2 2,5-dibromophenyl 60 F 1 CH.sub.2CH.sub.2
2,5-diodophenyl 61 F 1 O-CH.sub.2CH.sub.2 4-fluorophenyl 62 F 1
O-CH.sub.2CH.sub.2 4-chlorophenyl 63 F 1 O-CH.sub.2CH.sub.2
4-bromophenyl 64 F 1 O-CH.sub.2CH.sub.2 4-iodophenyl 65 F 1
O-CH.sub.2CH.sub.2 4-(trifluoromethyl)phenyl 66 F 1
O-CH.sub.2CH.sub.2 4-methylphenyl 67 F 1 HC.dbd.CH 4-fluorophenyl
68 F 1 HC.dbd.CH 4-chlorophenyl 69 F 1 HC.dbd.CH 4-bromophenyl 70 F
1 HC.dbd.CH 4-iodophenyl 71 F 1 HC.dbd.CH 4-(trifluoromethyl)phenyl
72 F 1 HC.dbd.CH 4-methylphenyl 73 Br 0 absent 4-fluorophenyl 74 Br
0 absent 4-chlorophenyl 75 Br 0 absent 4-bromophenyl 76 Br 0 absent
4-iodophenyl 77 Br 0 absent 4-(trifluoromethyl)phenyl 78 Br 0
absent 4-methylphenyl 79 Br 1 CH.sub.2 4-fluorophenyl 80 Br 1
CH.sub.2 4-chlorophenyl 81 Br 1 CH.sub.2 4-bromophenyl 82 Br 1
CH.sub.2 4-iodophenyl 83 Br 1 CH.sub.2 4-(trifluoromethyl)phenyl 84
Br 1 CH.sub.2 4-methylphenyl 85 Br 1 CH.sub.2CH.sub.2
4-fluorophenyl 86 Br 1 CH.sub.2CH.sub.2 4-chlorophenyl 87 Br 1
CH.sub.2CH.sub.2 4-bromophenyl 88 Br 1 CH.sub.2CH.sub.2
4-iodophenyl 89 Br 1 CH.sub.2CH.sub.2 4-(trifluoromethyl)phenyl 90
Br 1 CH.sub.2CH.sub.2 4-methylphenyl 91 Br 1 CH.sub.2CH.sub.2
2,5-di-(trifluoromethyl) phenyl 92 Br 1 CH.sub.2CH.sub.2
2,5-dimethylphenyl 93 Br 1 CH.sub.2CH.sub.2 2,5-difluorophenyl 94
Br 1 CH.sub.2CH.sub.2 2,5-dichlorophenyl 95 Br 1 CH.sub.2CH.sub.2
2,5-dibromophenyl 96 Br 1 CH.sub.2CH.sub.2 2,5-diodophenyl 97 Br 1
O-CH.sub.2CH.sub.2 4-fluorophenyl 98 Br 1 O-CH.sub.2CH.sub.2
4-chlorophenyl 99 Br 1 O-CH.sub.2CH.sub.2 4-bromophenyl 100 Br 1
O-CH.sub.2CH.sub.2 4-iodophenyl 101 Br 1 O-CH.sub.2CH.sub.2
4-(trifluoromethyl)phenyl 102 Br 1 O-CH.sub.2CH.sub.2
4-methylphenyl 103 Br 1 HC.dbd.CH 4-fluorophenyl 104 Br 1 HC.dbd.CH
4-chlorophenyl 105 Br 1 HC.dbd.CH 4-bromophenyl 106 Br 1 HC.dbd.CH
4-iodophenyl 107 Br 1 HC.dbd.CH 4-(trifluoromethyl)phenyl 108 Br 1
HC.dbd.CH 4-methylphenyl 109 I 0 absent 4-fluorophenyl 110 I 0
absent 4-chlorophenyl 111 I 0 absent 4-bromophenyl 112 I 0 absent
4-iodophenyl 113 I 0 absent 4-(trifluoromethyl)phenyl 114 I 0
absent 4-methylphenyl 115 I 1 CH.sub.2 4-fluorophenyl 116 I 1
CH.sub.2 4-chlorophenyl 117 I 1 CH.sub.2 4-bromophenyl 118 I 1
CH.sub.2 4-iodophenyl 119 I 1 CH.sub.2 4-(trifluoromethyl)phenyl
120 I 1 CH.sub.2 4-methylphenyl 121 I 1 CH.sub.2CH.sub.2
4-fluorophenyl 122 I 1 CH.sub.2CH.sub.2 4-chlorophenyl 123 I 1
CH.sub.2CH.sub.2 4-bromophenyl 124 I 1 CH.sub.2CH.sub.2
4-iodophenyl 125 I 1 CH.sub.2CH.sub.2 4-(trifluoromethyl)phenyl 126
I 1 CH.sub.2CH.sub.2 4-methylphenyl 127 I 1 CH.sub.2CH.sub.2
2,5-di-(trifluoromethyl) phenyl 128 I 1 CH.sub.2CH.sub.2
2,5-dimethylphenyl 129 I 1 CH.sub.2CH.sub.2 2,5-difluorophenyl 130
I 1 CH.sub.2CH.sub.2 2,5-dichlorophenyl 131 I 1 CH.sub.2CH.sub.2
2,5-dibromophenyl 132 I 1 CH.sub.2CH.sub.2 2,5-diodophenyl 133 I 1
O-CH.sub.2CH.sub.2 4-fluorophenyl 134 I 1 O-CH.sub.2CH.sub.2
4-chlorophenyl 135 I 1 O-CH.sub.2CH.sub.2 4-bromophenyl 136 I 1
O-CH.sub.2CH.sub.2 4-iodophenyl 137 I 1 O-CH.sub.2CH.sub.2
4-(trifluoromethyl)phenyl 138 I 1 O-CH.sub.2CH.sub.2 4-methylphenyl
139 I 1 HC.dbd.CH 4-fluorophenyl 140 I 1 HC.dbd.CH 4-chlorophenyl
141 I 1 HC.dbd.CH 4-bromophenyl 142 I 1 HC.dbd.CH 4-iodophenyl 143
I 1 HC.dbd.CH 4-(trifluoromethyl)phenyl 144 I 1 HC.dbd.CH
4-methylphenyl and the enantiomer having the Formula Iaaa', the
enantiomer having the Formula Iaaa'', and mixtures thereof, of each
of Compounds 1-144, and pharmaceutically acceptable salts
thereof
[0127] The structures of Formulas Iaaa' and Iaaa'' are depicted
below:
##STR00018##
[0128] Formula Iaaa'' is the corresponding opposite enantiomer of
Formula Iaaa' when Ar, X, Z.sup.2, and q of Formula Iaaa'' are the
same as Ar, X, Z.sup.2, and q of Formula Iaaa'. Formula Iaaa' is
the corresponding opposite enantiomer of Formula Iaaa'' when Ar, X,
Z.sup.2, and q of Formula Iaaa' are the same as Ar, X, Z.sup.2, and
q of Formula Iaaa''.
[0129] In one embodiment, Z.sup.2 of Compound 31-36, 67-72,
103-108, or 139-144 is cis. In another embodiment, Z.sup.2 of
Compound 31-36, 67-72, 103-108, or 139-144 is trans.
[0130] In another embodiment, the Sulfonamide-Based Compounds are
compounds of the following Formula II
##STR00019##
or pharmaceutically acceptable salts thereof, wherein X, R.sup.1,
R.sup.3, R.sup.4, R.sup.5, Z.sup.1, Z.sup.2, m, n, p, t, q, and v
are as defined above for the compounds and pharmaceutically
acceptable salts of Formula II.
[0131] Formula II above depicts relative stereochemistry, and
includes the enantiomers of the following Formulas II' and II'',
and mixtures of the enantiomers, including a racemic mixture of the
enantiomers of Formulas II' and II'':
##STR00020##
[0132] Formula II'' is the corresponding opposite enantiomer of
Formula II' when R.sup.1, R.sup.4, X, m, n, and v of Formula II''
are the same as R.sup.1, R.sup.4, X, m, n, and v of Formula II' and
R.sup.1, R.sup.4, and X of Formula II'', when present, are in the
same positions as R.sup.1, R.sup.4, and X of Formula I'. Formula
II' is the corresponding opposite enantiomer of Formula II'' when
R.sup.1, R.sup.4, X, m, n, and v of Formula II' are the same as
R.sup.1, R.sup.4, X, m, n, and v of Formula II'' and R.sup.1,
R.sup.4, and X of Formula II', when present, are in the same
positions as R.sup.1, R.sup.4, and X of Formula II''.
[0133] In some embodiments, the compound of Formula II' is
substantially free of its corresponding opposite enantiomer of
Formula II''. In other embodiments, the compound of Formula II'' is
substantially free of its corresponding opposite enantiomer of
Formula II'.
[0134] In some embodiments, the compounds of Formula II are those
where X is halo. In other embodiments, the compounds of Formula II
are those where X is chloro. In other embodiments, the compounds of
Formula II are those where v is 1. In other embodiments, v is 1 and
X is at the 5-position of the thiopheno group. In other
embodiments, v is 1, X is halo, and X is at the 5-position of the
thiopheno group. In other embodiments, v is 1, X is chloro, and X
is at the 5-position of the thiopheno group.
[0135] In some embodiments, the compounds of Formula II are those
where Z.sup.1 is NH. In some embodiments, the compounds of Formula
II are those where Z.sup.2, when present, is
--CH.sub.2--CH.sub.2--, or --HC.dbd.CH--. In other embodiments, the
compounds of Formula II are those where Z.sup.2 is trans
--HC.dbd.CH--. In yet other embodiments, the compounds of Formula
II are those where Z.sup.2 is cis --HC.dbd.CH--. In some
embodiments, the compounds of Formula II are those where q is 1. In
some embodiments, the compounds of Formula II are those where q is
0. In some embodiments, Z.sup.1 is NH, q is 1 and Z.sup.2 is
--CH.sub.2--CH.sub.2--, --HC.dbd.CH--, or
--OCH.sub.2--CH.sub.2--.
[0136] In some embodiments, the compounds of Formula II are those
where each R.sup.1 is hydrogen. In other embodiments, the compounds
of Formula II are those where at least one of R.sup.1 and R.sup.3
is C.sub.1-C.sub.6 haloalkyl. In some embodiments, the
C.sub.1-C.sub.6 haloalkyl is trihalomethyl, such as
trifluoromethyl, trichloromethyl, tribromomethyl, or
triiodomethyl.
[0137] In other embodiments, the compounds of Formula II are those
where R.sup.5 is hydrogen or methyl. In other embodiments, the
compounds of Formula II are those where R.sup.5 is methyl. In other
embodiments, the compounds of Formula II are those where each
R.sup.1 is hydrogen and R.sup.5 is hydrogen or methyl. In other
embodiments, the compounds of Formula II are those where R.sup.1
and R.sup.3 are C.sub.1-C.sub.6 haloalkyl and R.sup.5 is hydrogen
or methyl.
[0138] In other embodiments, the compounds of Formula II have the
following Formula IIa
##STR00021##
wherein:
[0139] X is H, halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, or cyano;
[0140] each R.sup.1 is independently H, halo, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or
cyano;
[0141] each R.sup.3 is independently H, halo, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or
cyano;
[0142] R.sup.5 is H, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6
haloalkyl;
[0143] Z.sup.1 is NH, O or CH.sub.2;
[0144] Z.sup.2 alkylene)- or --(C.sub.2-C.sub.6 alkenylene)-;
[0145] m is 3;
[0146] p is 5;
[0147] t is 4;
[0148] q is 0 or 1; and
[0149] v is an integer from 1 to 3.
[0150] Formula IIa above depicts relative stereochemistry, and
includes the enantiomers of the following Formulas IIa' and IIa'',
and mixtures of the enantiomers, including a racemic mixture of the
enantiomers of Formulas IIa' and IIa'':
##STR00022##
[0151] Formula IIa'' is the corresponding opposite enantiomer of
Formula IIa' when R.sup.1, R.sup.3, R.sup.5, X, Z.sup.1, Z.sup.2,
m, p, t, and v of Formula IIa'' are the same as R.sup.1, R.sup.3,
R.sup.5, x, Z.sup.1, Z.sup.2, q, m, p, t, and v of Formula IIa' and
R.sup.1, R.sup.3, and X of Formula IIa'', when present, are in the
same positions as R.sup.1, R.sup.3, and X of Formula IIa'. Formula
IIa' is the corresponding opposite enantiomer of Formula IIa'' when
R.sup.1, R.sup.3, R.sup.5, X, Z.sup.1, Z.sup.2, q, m, p, t, and v
of Formula IIa' are the same as R.sup.1, R.sup.3, R.sup.5, X,
Z.sup.1, Z.sup.2, q, m, p, t, and v of Formula IIa'' and R.sup.1,
R.sup.3, and X of Formula IIa', when present, are in the same
positions as R.sup.1, R.sup.3, and X of Formula IIa''.
[0152] In some embodiments, the compound of Formula IIa' is
substantially free of its corresponding opposite enantiomer of
Formula IIa''. In other embodiments, the compound of Formula IIa''
is substantially free of its corresponding opposite enantiomer of
Formula IIa'.
[0153] In some embodiments, the compounds of Formula IIa are those
where X is halo. In other embodiments, the compounds of Formula IIa
are those where X is chloro. In other embodiments, the compounds of
Formula IIa are those where v is 1. In other embodiments, v is 1
and X is at the 5-position of the thiopheno group. In other
embodiments, v is 1, X is halo, and X is at the 5-position of the
thiopheno group. In other embodiments, v is 1, X is chloro, and X
is at the 5-position of the thiopheno group.
[0154] In some embodiments, the compounds of Formula IIa are those
where Z.sup.1 is NH. In some embodiments, the compounds of Formula
IIa are those where Z.sup.2, when present, is
--CH.sub.2--CH.sub.2--, or --HC.dbd.CH--. In other embodiments, the
compounds of Formula IIa are those where Z.sup.2 is trans
--HC.dbd.CH--. In yet other embodiments, the compounds of Formula
IIa are those where Z.sup.2 is cis --HC.dbd.CH--. In some
embodiments, the compounds of Formula IIa are those where q is 1.
In some embodiments, the compounds of Formula IIa are those where q
is 0. In some embodiments, Z.sup.1 is NH, q is 1 and Z.sup.2 is
--CH.sub.2--CH.sub.2--, --HC.dbd.CH--, or
--OCH.sub.2--CH.sub.2--.
[0155] In some embodiments, the compounds of Formula IIa are those
where each R.sup.1 is hydrogen. In other embodiments, the compounds
of Formula IIa are those where at least one of R.sup.1 and R.sup.3
is C.sub.1-C.sub.6 haloalkyl. In certain embodiments, R.sup.3 is
C.sub.1-C.sub.6 haloalkyl. In some embodiments, the C.sub.1-C.sub.6
haloalkyl is trihalomethyl, such as trifluoromethyl,
trichloromethyl, tribromomethyl, or triiodomethyl.
[0156] In other embodiments, the compounds of Formula IIa are those
where R.sup.5 is hydrogen or methyl. In other embodiments, the
compounds of Formula IIa are those where R.sup.5 is methyl. In
other embodiments, the compounds of Formula II are those where each
R.sup.1 is hydrogen and R.sup.5 is hydrogen or methyl. In other
embodiments, the compounds of Formula II are those where R.sup.1
and R.sup.3 are C.sub.1-C.sub.6 haloalkyl and R.sup.5 is hydrogen
or methyl.
[0157] In other embodiments, the compounds of Formula IIa have the
following Formula IIaa
##STR00023##
wherein:
[0158] X is halo;
[0159] each R.sup.1 is independently H, halo, C.sub.1-C.sub.6
alkyl, or C.sub.1-C.sub.6 haloalkyl;
[0160] each R.sup.3 is independently H, halo, C.sub.1-C.sub.6
alkyl, or C.sub.1-C.sub.6 haloalkyl;
[0161] Z.sup.2 is --(C.sub.1-C.sub.6 alkylene)- or
--(C.sub.2-C.sub.6 alkenylene)-;
[0162] R.sup.5 is H, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6
haloalkyl;
[0163] m is 3;
[0164] p is 5;
[0165] t is 4;
[0166] q is 0 or 1; and
[0167] v is an integer from 1 to 3.
[0168] Formula IIaa above depicts relative stereochemistry, and
includes the enantiomers of the following Formulas IIaa' and
IIaa'', and mixtures of the enantiomers, including a racemic
mixture of the enantiomers of Formulas IIaa' and IIaa'':
##STR00024##
[0169] Formula IIaa'' is the corresponding opposite enantiomer of
Formula IIaa' when R.sup.1, R.sup.3, R.sup.5, X, Z.sup.2, q, m, p,
t, and v of Formula IIaa'' are the same as R.sup.1, R.sup.3,
R.sup.5, X, Z.sup.2, q, m, p, t, and v of Formula IIaa' and
R.sup.1, R.sup.3, and X of Formula IIaa'', when present, are in the
same positions as R.sup.1, R.sup.3, and X of Formula IIaa'. Formula
IIaa' is the corresponding opposite enantiomer of Formula Iaa''
when R.sup.1, R.sup.3, R.sup.5, X, Z.sup.2, q, m, p, t, and v of
Formula IIaa' are the same as R.sup.1, R.sup.3, R.sup.5, X,
Z.sup.2, q, m, p, t, and v of Formula IIaa'' and R.sup.1, R.sup.3,
and X of Formula IIaa', when present, are in the same positions as
R.sup.1, R.sup.3, and X of Formula IIaa''.
[0170] In some embodiments, the compound of Formula IIaa' is
substantially free of its corresponding opposite enantiomer of
Formula IIaa''. In other embodiments, the compound of Formula
IIaa'' is substantially free of its corresponding opposite
enantiomer of Formula IIaa'.
[0171] In some embodiments, the compounds of Formula IIaa are those
where X is chloro. In other embodiments of the compound of Formula
IIaa, v is 1. In other embodiments, v is 1 and X is at the
5-position of the thiopheno group. In other embodiments, v is 1, X
is chloro, and X is at the 5-position of the thiopheno group.
[0172] In some embodiments, the compounds of Formula IIaa are those
where Z.sup.2, when present, is --CH.sub.2--,
--CH.sub.2--CH.sub.2--, or --HC.dbd.CH--. In other embodiments, the
compounds of Formula IIaa are those where Z.sup.2 is trans
--HC.dbd.CH--. In yet other embodiments, the compounds of Formula
IIaa are those where Z.sup.2 is cis --HC.dbd.CH--. In some
embodiments, the compounds of Formula IIaa are those where q is 1.
In some embodiments, the compounds of Formula IIaa are those where
q is 0. In some embodiments, Z.sup.1 is NH, q is 1 and Z.sup.2 is
--CH.sub.2--, --CH.sub.2--CH.sub.2--, --HC.dbd.CH--, or
--OCH.sub.2--CH.sub.2--.
[0173] In some embodiments, the compounds of Formula IIaa are those
where each R.sup.1 is hydrogen. In other embodiments, the compounds
of Formula IIaa are those where at least one of R.sup.1 and R.sup.3
is halo or C.sub.1-C.sub.6 haloalkyl. In certain embodiments,
R.sup.3 is halo or C.sub.1-C.sub.6 haloalkyl. In some embodiments,
the C.sub.1-C.sub.6 haloalkyl is trihalomethyl, such as
trifluoromethyl, trichloromethyl, tribromomethyl, or triiodomethyl.
In some embodiments, halo is fluorine, chlorine, bromine, or
iodine.
[0174] In other embodiments, the compounds of Formula IIaa are
those where R.sup.5 is hydrogen or methyl. In other embodiments,
the compounds of Formula IIaa are those where R.sup.5 is methyl. In
other embodiments, the compounds of Formula II are those where each
R.sup.1 is hydrogen and R.sup.5 is hydrogen or methyl. In other
embodiments, the compounds of Formula II are those where R.sup.1
and R.sup.3 are C.sub.1-C.sub.6 haloalkyl and R.sup.5 is hydrogen
or methyl.
[0175] In some embodiments, a compound of Formula IIaa has the
structure:
##STR00025##
or a pharmaceutically acceptable salt thereof.
[0176] In other embodiments, the compounds of Formula IIaa have the
Formula IIaaa, set forth below. In some embodiments, the compounds
of Formula IIaaa are those where q is 0 or 1. In some embodiments,
the compounds of Formula IIaaa are those where Z.sup.2 is CH.sub.2.
In some embodiments, the compounds of Formula IIaaa are those where
R.sup.5 is H or CH.sub.3. In some embodiments, the compounds of
Formula IIaaa are those where R.sup.3a, R.sup.3b, and R.sup.3c are
independently H, fluoro, CH.sub.3, or CF.sub.3. In some
embodiments, the compounds of Formula IIaaa are those where q is 1,
Z.sup.2 is CH.sub.2, R.sup.5 is H or CH.sub.3, and R.sup.3a,
R.sup.3b, and R.sup.3c are independently H, fluoro, CH.sub.3, or
CF.sub.3.
[0177] Illustrative examples of the compounds of Formula IIaaa are
set forth in Table 2 below.
TABLE-US-00002 TABLE 2 Illustrative examples of compounds of
Formula IIaaa ##STR00026## Compound X R.sup.5 q Z.sup.2 R.sup.3a
R.sup.3b R.sup.3c 145 Cl H 0 absent H H H 146 Cl H 0 absent F H H
147 Cl H 0 absent H F H 148 Cl H 0 absent H H F 149 Cl H 0 absent
CH.sub.3 H H 150 Cl H 0 absent H CH.sub.3 H 151 Cl H 0 absent H H
CH.sub.3 152 Cl H 0 absent CF.sub.3 H H 153 Cl H 0 absent H
CF.sub.3 H 154 Cl H 0 absent H H CF.sub.3 155 Cl H 1 CH.sub.2 H H H
156 Cl H 1 CH.sub.2 F H H 157 Cl H 1 CH.sub.2 H F H 158 Cl H 1
CH.sub.2 H H F 159 Cl H 1 CH.sub.2 CH.sub.3 H H 160 Cl H 1 CH.sub.2
H CH.sub.3 H 161 Cl H 1 CH.sub.2 H H CH.sub.3 162 Cl H 1 CH.sub.2
CF.sub.3 H H 163 Cl H 1 CH.sub.2 H CF.sub.3 H 164 Cl H 1 CH.sub.2 H
H CF.sub.3 165 Cl CH.sub.3 0 absent H H H 166 Cl CH.sub.3 0 absent
F H H 167 Cl CH.sub.3 0 absent H F H 168 Cl CH.sub.3 0 absent H H F
169 Cl CH.sub.3 0 absent CH.sub.3 H H 170 Cl CH.sub.3 0 absent H
CH.sub.3 H 171 Cl CH.sub.3 0 absent H H CH.sub.3 172 Cl CH.sub.3 0
absent CF.sub.3 H H 173 Cl CH.sub.3 0 absent H CF.sub.3 H 174 Cl
CH.sub.3 0 absent H H CF.sub.3 175 Cl CH.sub.3 1 CH.sub.2 H H H 176
Cl CH.sub.3 1 CH.sub.2 F H H 177 Cl CH.sub.3 1 CH.sub.2 H F H 178
Cl CH.sub.3 1 CH.sub.2 H H F 179 Cl CH.sub.3 1 CH.sub.2 CH.sub.3 H
H 180 Cl CH.sub.3 1 CH.sub.2 H CH.sub.3 H 181 Cl CH.sub.3 1
CH.sub.2 H H CH.sub.3 182 Cl CH.sub.3 1 CH.sub.2 CF.sub.3 H H 183
Cl CH.sub.3 1 CH.sub.2 H CF.sub.3 H 184 Cl CH.sub.3 1 CH.sub.2 H H
CF.sub.3 185 F H 0 absent H H H 186 F H 0 absent F H H 187 F H 0
absent H F H 188 F H 0 absent H H F 189 F H 0 absent CH.sub.3 H H
190 F H 0 absent H CH.sub.3 H 191 F H 0 absent H H CH.sub.3 192 F H
0 absent CF.sub.3 H H 193 F H 0 absent H CF.sub.3 H 194 F H 0
absent H H CF.sub.3 195 F H 1 CH.sub.2 H H H 196 F H 1 CH.sub.2 F H
H 197 F H 1 CH.sub.2 H F H 198 F H 1 CH.sub.2 H H F 199 F H 1
CH.sub.2 CH.sub.3 H H 200 F H 1 CH.sub.2 H CH.sub.3 H 201 F H 1
CH.sub.2 H H CH.sub.3 202 F H 1 CH.sub.2 CF.sub.3 H H 203 F H 1
CH.sub.2 H CF.sub.3 H 204 F H 1 CH.sub.2 H H CF.sub.3 205 F
CH.sub.3 0 absent H H H 206 F CH.sub.3 0 absent F H H 207 F
CH.sub.3 0 absent H F H 208 F CH.sub.3 0 absent H H F 209 F
CH.sub.3 0 absent CH.sub.3 H H 210 F CH.sub.3 0 absent H CH.sub.3 H
211 F CH.sub.3 0 absent H H CH.sub.3 212 F CH.sub.3 0 absent
CF.sub.3 H H 213 F CH.sub.3 0 absent H CF.sub.3 H 214 F CH.sub.3 0
absent H H CF.sub.3 215 F CH.sub.3 1 CH.sub.2 H H H 216 F CH.sub.3
1 CH.sub.2 F H H 217 F CH.sub.3 1 CH.sub.2 H F H 218 F CH.sub.3 1
CH.sub.2 H H F 219 F CH.sub.3 1 CH.sub.2 CH.sub.3 H H 220 F
CH.sub.3 1 CH.sub.2 H CH.sub.3 H 221 F CH.sub.3 1 CH.sub.2 H H
CH.sub.3 222 F CH.sub.3 1 CH.sub.2 CF.sub.3 H H 223 F CH.sub.3 1
CH.sub.2 H CF.sub.3 H 224 F CH.sub.3 1 CH.sub.2 H H CF.sub.3 225 Br
H 0 absent H H H 226 Br H 0 absent F H H 227 Br H 0 absent H F H
228 Br H 0 absent H H F 229 Br H 0 absent CH.sub.3 H H 230 Br H 0
absent H CH.sub.3 H 231 Br H 0 absent H H CH.sub.3 232 Br H 0
absent CF.sub.3 H H 233 Br H 0 absent H CF.sub.3 H 234 Br H 0
absent H H CF.sub.3 235 Br H 1 CH.sub.2 H H H 236 Br H 1 CH.sub.2 F
H H 237 Br H 1 CH.sub.2 H F H 238 Br H 1 CH.sub.2 H H F 239 Br H 1
CH.sub.2 CH.sub.3 H H 240 Br H 1 CH.sub.2 H CH.sub.3 H 241 Br H 1
CH.sub.2 H H CH.sub.3 242 Br H 1 CH.sub.2 CF.sub.3 H H 243 Br H 1
CH.sub.2 H CF.sub.3 H 244 Br H 1 CH.sub.2 H H CF.sub.3 245 Br
CH.sub.3 0 absent H H H 246 Br CH.sub.3 0 absent F H H 247 Br
CH.sub.3 0 absent H F H 28 Br CH.sub.3 0 absent H H F 249 Br
CH.sub.3 0 absent CH.sub.3 H H 250 Br CH.sub.3 0 absent H CH.sub.3
H 251 Br CH.sub.3 0 absent H H CH.sub.3 252 Br CH.sub.3 0 absent
CF.sub.3 H H 253 Br CH.sub.3 0 absent H CF.sub.3 H 254 Br CH.sub.3
0 absent H H CF.sub.3 255 Br CH.sub.3 1 CH.sub.2 H H H 256 Br
CH.sub.3 1 CH.sub.2 F H H 257 Br CH.sub.3 1 CH.sub.2 H F H 258 Br
CH.sub.3 1 CH.sub.2 H H F 259 Br CH.sub.3 1 CH.sub.2 CH.sub.3 H H
260 Br CH.sub.3 1 CH.sub.2 H CH.sub.3 H 261 Br CH.sub.3 1 CH.sub.2
H H CH.sub.3 262 Br CH.sub.3 1 CH.sub.2 CF.sub.3 H H 263 Br
CH.sub.3 1 CH.sub.2 H CF.sub.3 H 264 Br CH.sub.3 1 CH.sub.2 H H
CF.sub.3 265 I H 0 absent H H H 266 I H 0 absent F H H 267 I H 0
absent H F H 268 I H 0 absent H H F 269 I H 0 absent CH.sub.3 H H
270 I H 0 absent H CH.sub.3 H 271 I H 0 absent H H CH.sub.3 272 I H
0 absent CF.sub.3 H H 273 I H 0 absent H CF.sub.3 H 274 I H 0
absent H H CF.sub.3 275 I H 1 CH.sub.2 H H H 276 I H 1 CH.sub.2 F H
H 277 I H 1 CH.sub.2 H F H 278 I H 1 CH.sub.2 H H F 279 I H 1
CH.sub.2 CH.sub.3 H H 280 I H 1 CH.sub.2 H CH.sub.3 H 281 I H 1
CH.sub.2 H H CH.sub.3 282 I H 1 CH.sub.2 CF.sub.3 H H 283 I H 1
CH.sub.2 H CF.sub.3 H 284 I H 1 CH.sub.2 H H CF.sub.3 285 I
CH.sub.3 0 absent H H H 286 I CH.sub.3 0 absent F H H 287 I
CH.sub.3 0 absent H F H 288 I CH.sub.3 0 absent H H F 289 I
CH.sub.3 0 absent CH.sub.3 H H 290 I CH.sub.3 0 absent H CH.sub.3 H
291 I CH.sub.3 0 absent H H CH.sub.3 292 I CH.sub.3 0 absent
CF.sub.3 H H 293 I CH.sub.3 0 absent H CF.sub.3 H 294 I CH.sub.3 0
absent H H CF.sub.3 295 I CH.sub.3 1 CH.sub.2 H H H 296 I CH.sub.3
1 CH.sub.2 F H H 297 I CH.sub.3 1 CH.sub.2 H F H 298 I CH.sub.3 1
CH.sub.2 H H F 299 I CH.sub.3 1 CH.sub.2 CH.sub.3 H H 300 I
CH.sub.3 1 CH.sub.2 H CH.sub.3 H 301 I CH.sub.3 1 CH.sub.2 H H
CH.sub.3 302 I CH.sub.3 1 CH.sub.2 CF.sub.3 H H 303 I CH.sub.3 1
CH.sub.2 H CF.sub.3 H 304 I CH.sub.3 1 CH.sub.2 H H CF.sub.3 and
the enantiomer having the Formula IIaaa', the enantiomer having the
Formula IIaaa'', and mixtures thereof, of each of Compounds
145-304, and pharmaceutically acceptable salts thereof
[0178] The structures of Formulas IIaaa' and IIaaa'' are depicted
below:
##STR00027##
[0179] Formula IIaaa'' is the corresponding opposite enantiomer of
Formula IIaaa' when X, R.sup.5, Z.sup.2, q, R.sup.3a, R.sup.3b, and
R.sup.3c of Formula IIaaa'' are the same as X, R.sup.5, Z.sup.2, q,
R.sup.3a, R.sup.3b, and R.sup.3c of Formula IIaaa'. Formula IIaaa'
is the corresponding opposite enantiomer of Formula IIaaa'' when X,
R.sup.5, Z.sup.2, q, R.sup.3a, R.sup.3b, and R.sup.3c of Formula
IIaaa' are the same as X, R.sup.5, Z.sup.2, q, R.sup.3a, R.sup.3b,
and R.sup.3c of Formula IIaaa''.
III. Methods for Making the Sulfonamide-Based Compounds
[0180] Methods useful for making the Sulfonamide-Based Compounds
and pharmaceutically acceptable salts of Formula I are set forth in
the Examples below and generalized in Scheme 1 below.
##STR00028##
wherein R.sup.1, R.sup.2, X, m, n, and v are as defined above for
the compounds or pharmaceutically acceptable salts of Formula
I.
[0181] Methods useful for making the Sulfonamide-Based Compounds
and pharmaceutically acceptable salts of Formula II are generalized
in Scheme 2 below.
##STR00029##
[0182] Scheme 3a-b below provides a method for synthesizing a
particular compound of Formula I or II where an appropriately
substituted 1,2-bis(bromomethyl)benzene is not available as a
starting material for preparation of the given compound according
to Scheme 1 or 2. For instance, Scheme 3a is the synthesis and
addition of NO.sub.2 group to the benzobicyclo[4.2.1]nonane
core.
##STR00030##
[0183] Scheme 3b exemplifies preparation of compounds of Formula I
or II from nitrobenzobicyclo[4.2.1]nonane. R in Scheme 3b can be
R.sup.2 or R.sup.4 as defined above in the definitions for Formulas
I and II, respectively.
##STR00031##
[0184] A Sulfonamide-Based Compound can be obtained, isolated, or
purified such that it is substantially free of its corresponding
opposite enantiomer using methods known to one of skill in the art,
including chiral high performance liquid chromatography, selective
crystallization, and reaction with a chiral resolving agent or
chiral auxiliary.
IV. Treatment or Prevention of a Condition with the
Sulfonamide-Based Compounds
[0185] In accordance with the invention, a Sulfonamide-Based
Compound is useful for treating or preventing cancer or a
neurodegenerative disease.
[0186] A. Treatment or Prevention of Cancer
[0187] The Sulfonamide-Based Compounds are useful for treating or
preventing cancer. Accordingly, the invention provides methods for
treating or preventing cancer, comprising administering an
effective amount of a Sulfonamide-Based Compound to a subject. In
one embodiment, the subject is in need of treatment or prevention
of the cancer. In one embodiment, the methods further comprise
administering an effective amount of another anticancer agent.
Examples of cancers that the Sulfonamide-Based Compounds disclosed
herein are useful for treating or preventing include, but are not
limited to, the cancers disclosed below in Table 27 and metastases
thereof.
TABLE-US-00003 TABLE 27 Solid tumors, including but not limited to:
fibrosarcoma basal cell carcinoma myxosarcoma adenocarcinoma
liposarcoma sweat gland carcinoma chondrosarcoma sebaceous gland
carcinoma osteogenic sarcoma papillary carcinoma chordoma papillary
adenocarcinomas angiosarcoma cystadenocarcinoma endotheliosarcoma
medullary carcinoma lymphangiosarcoma bronchogenic carcinoma
lymphangioendotheliosarcoma renal cell carcinoma synovioma hepatoma
mesothelioma bile duct carcinoma Ewing's tumor choriocarcinoma
leiomyosarcoma seminoma rhabdomyosarcoma embryonal carcinoma colon
cancer Wilms' tumor colorectal cancer cervical cancer kidney cancer
uterine cancer pancreatic cancer testicular cancer bone cancer
small cell lung carcinoma breast cancer bladder carcinoma ovarian
cancer lung cancer prostate cancer epithelial carcinoma esophageal
cancer skin cancer stomach cancer melanoma oral cancer metastatic
melanoma nasal cancer neuroblastoma throat cancer retinoblastoma
squamous cell carcinoma Blood-borne cancers, including but not
limited to: acute lymphoblastic leukemia acute myelomonocytic
leukemia ("ALL") acute lymphoblastic B-cell acute nonlymphocyctic
leukemia leukemia acute lymphoblastic T-cell acute undifferentiated
leukemia leukemia acute myeloblasts leukemia chronic myelocytic
leukemia ("AML") ("CML") acute promyelocyte leukemia chronic
lymphocytic leukemia ("APL") ("CLL") acute monoblastic leukemia
hairy cell leukemia acute erythroleukemic leukemia multiple myeloma
acute megakaryoblastic leukemia Acute and chronic leukemias,
including but not limited to: lymphoblastic lymphocytic myelogenous
myelocytic leukemias CNS and brain cancers, including but not
limited to: glioma acoustic neuroma pilocytic astrocytoma
oligodendroglioma astrocytoma meningioma anaplastic astrocytoma
vestibular schwannoma glioblastoma multiforme adenoma
medulloblastoma metastatic brain tumor craniopharyngioma meningioma
ependymoma spinal tumor pinealoma medulloblastoma
hemangioblastoma
[0188] In one embodiment, the cancer is lung cancer, breast cancer,
colorectal cancer, prostate cancer, a leukemia, a lymphoma,
non-Hodgkin's lymphoma, skin cancer, a brain cancer, a cancer of
the central nervous system, ovarian cancer, uterine cancer, stomach
cancer, pancreatic cancer, esophageal cancer, kidney cancer, liver
cancer, or a head and neck cancer. In another embodiment, the
cancer is metastatic cancer.
[0189] In yet another embodiment, the cancer is brain cancer or
melanoma. In one embodiment, the brain cancer is metastatic brain
cancer or a glioma. In one embodiment, the glioma is pilocytic
astrocytoma, astrocytoma, anaplastic astrocytoma or glioblastoma
multiforme. In one embodiment, the cancer is
homologous-recombination deficient, such as BRCA-I or BRCA-2
deficient, or is deficient in one or more proteins of the Fanconi
family. In one embodiment, the deficiency is caused by a genetic
mutation. In another embodiment, the phenotype resulting from the
deficiency is caused by abnormally low expression of BRCA-I or
BRCA-2 protein. In another embodiment, the phenotype resulting from
the deficiency is caused by abnormally low expression of one or
more proteins of the Fanconi family.
[0190] In another embodiment, the cancer is leukemia, such as but
not limited to, acute leukemia, acute lymphocytic leukemia, acute
myelocytic leukemias, such as, myeloblastic, promyelocytic,
myelomonocytic, monocytic, and erythroleukemia leukemias and
myelodysplastic syndrome; chronic leukemia, such as but not limited
to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic
leukemia, hairy cell leukemia; polycythemia vera; lymphoma such as
but not limited to Hodgkin's disease, non-Hodgkin's disease;
multiple myeloma such as but not limited to smoldering multiple
myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell
leukemia, solitary plasmacytoma and extramedullary plasmacytoma;
Waldenstrom's macroglobulinemia; monoclonal gammopathy of
undetermined significance; benign monoclonal gammopathy; heavy
chain disease; dendritic cell cancer, including plasmacytoid
dendritic cell cancer, NK blastic lymphoma (also known as cutaneous
NK/T-cell lymphoma and agranular (CD4+/CD56+) dermatologic
neoplasms); basophilic leukemia; bone and connective tissue
sarcomas such as but not limited to bone sarcoma, osteosarcoma,
chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor,
fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue
sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's
sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma,
neurilemmoma, rhabdomyosarcoma, synovial sarcoma; a brain tumor
such as but not limited to, glioma, astrocytoma, brain stem glioma,
ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma,
craniopharyngioma, medulloblastoma, meningioma, pineocytoma,
pineoblastoma, primary brain lymphoma; breast cancer including but
not limited to ductal carcinoma, adenocarcinoma, lobular (small
cell) carcinoma, intraductal carcinoma, medullary breast cancer,
mucinous breast cancer, tubular breast cancer, papillary breast
cancer, Paget's disease, and inflammatory breast cancer; adrenal
cancer such as but not limited to pheochromocytom and
adrenocortical carcinoma; thyroid cancer such as but not limited to
papillary or follicular thyroid cancer, medullary thyroid cancer
and anaplastic thyroid cancer; pancreatic cancer such as but not
limited to, insulinoma, gastrinoma, glucagonoma, vipoma,
somatostatin-secreting tumor, and carcinoid or islet cell tumor;
pituitary cancer such as but limited to Cushing's disease,
prolactin-secreting tumor, acromegaly, and diabetes insipius; eye
cancer such as but not limited to ocular melanoma such as iris
melanoma, choroidal melanoma, and cilliary body melanoma, and
retinoblastoma; vaginal cancer such as squamous cell carcinoma,
adenocarcinoma, and melanoma; vulvar cancer such as squamous cell
carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma,
and Paget's disease; cervical cancer such as but not limited to,
squamous cell carcinoma, and adenocarcinoma; uterine cancer such as
but not limited to endometrial carcinoma and uterine sarcoma;
ovarian cancer such as but not limited to, ovarian epithelial
carcinoma, borderline tumor, germ cell tumor, and stromal tumor;
esophageal cancer such as but not limited to, squamous cancer,
adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma,
adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous
carcinoma, and oat cell (small cell) carcinoma; stomach cancer such
as but not limited to, adenocarcinoma, fungating (polypoid),
ulcerating, superficial spreading, diffusely spreading, malignant
lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon
cancer; rectal cancer; liver cancer such as but not limited to
hepatocellular carcinoma and hepatoblastoma; gallbladder cancer
such as adenocarcinoma; cholangiocarcinomas such as but not limited
to papillary, nodular, and diffuse; lung cancer such as non-small
cell lung cancer, squamous cell carcinoma (epidermoid carcinoma),
adenocarcinoma, large-cell carcinoma and small-cell lung cancer;
testicular cancer such as but not limited to germinal tumor,
seminoma, anaplastic, classic (typical), spermatocytic,
nonseminoma, embryonal carcinoma, teratoma carcinoma,
choriocarcinoma (yolk-sac tumor), prostate cancer such as but not
limited to, prostatic intraepithelial neoplasia, adenocarcinoma,
leiomyosarcoma, and rhabdomyosarcoma; penile cancer; oral cancer
such as but not limited to squamous cell carcinoma; basal cancer;
salivary gland cancer such as but not limited to adenocarcinoma,
mucoepidermoid carcinoma, and adenoidcystic carcinoma; pharynx
cancer such as but not limited to squamous cell cancer, and
verrucous; skin cancer such as but not limited to, basal cell
carcinoma, squamous cell carcinoma and melanoma, superficial
spreading melanoma, nodular melanoma, lentigo malignant melanoma,
acral lentiginous melanoma; kidney cancer such as but not limited
to renal cell carcinoma, adenocarcinoma, hypernephroma,
fibrosarcoma, transitional cell cancer (renal pelvis and/or
uterer); Wilms' tumor; bladder cancer such as but not limited to
transitional cell carcinoma, squamous cell cancer, adenocarcinoma,
carcinosarcoma. In addition, cancer include myxosarcoma, osteogenic
sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma,
mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma,
cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma,
sebaceous gland carcinoma, papillary carcinoma and papillary
adenocarcinomas (for a review of such disorders, see Fishman et
al., 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia and
Murphy et al., 1997, Informed Decisions: The Complete Book of
Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin
Books U.S.A., Inc., United States of America).
[0191] In a specific of this embodiment, the cancer is one that is
associated with cleavage of notch by .gamma.-secretase including,
but not limited to, leukemia, non small cell lung cancer, ovarian
cancer, breast cancer, or brain cancer.
[0192] In still another embodiment, the subject in need of
treatment has previously undergone or is presently undergoing
treatment for cancer. The treatment includes, but is not limited
to, chemotherapy, radiation therapy, surgery or immunotherapy, such
as administration of a cancer vaccine.
[0193] The Sulfonamide-Based Compounds are also useful for treating
or preventing a cancer caused by a virus. Such viruses include
human papilloma virus, which can lead to cervical cancer (see,
e.g., Hernandez-Avila et al., Archives of Medical Research (1997)
28:265-271); Epstein-Barr virus (EBV), which can lead to lymphoma
(see, e.g., Herrmann et al., J. Pathol. (2003) 199(2):140-5);
hepatitis B or C virus, which can lead to liver carcinoma (see,
e.g., El-Serag, J. Clin. Gastroenterol. (2002) 35(5 Suppl.
2):572-8); human T cell leukemia virus (HTLV)-I, which can lead to
T-cell leukemia (see, e.g., Mortreux et al., Leukemia (2003)
17(1):26-38); human herpesvirus-8 infection, which can lead to
Kaposi's sarcoma (see, e.g., Kadow et al., Curr. Opin. Investig.
Drugs (2002) 3(11): 1574-9); and Human Immune deficiency Virus
(HIV) infection, which can lead to cancer as a consequence of
immunodeficiency (see, e.g., Dal Maso et al., Lancet Oncol (2003)
4(2): 110-9). Each of these references is incorporated herein by
reference.
[0194] The Sulfonamide-Based Compounds are also useful for
preventing cancer, or preventing progression of a cancer, including
but not limited to the cancers listed in Table 27. Such
prophylactic use includes that in which non-neoplastic cell growth
such as hyperplasia, metaplasia, or most specifically, dysplasia
has occurred. Alternatively or in addition to the presence of
abnormal cell growth characterized as hyperplasia, metaplasia, or
dysplasia, the presence of one or more characteristics of a
transformed phenotype, or of a malignant phenotype, displayed in
vivo or displayed in vitro by a cell sample from a subject, can
indicate the desirability of prophylactic or therapeutic
administration of a Sulfonamide-Based Compound. Such
characteristics of a transformed phenotype include morphology
changes, looser substratum attachment, loss of contact inhibition,
loss of anchorage dependence, protease release, increased sugar
transport, decreased serum requirement, expression of fetal
antigens, disappearance of the 250,000 dalton cell surface protein,
etc. In a specific embodiment, leukoplakia, a benign-appearing
hyperplastic or dysplastic lesion of the epithelium, or Bowen's
disease, a carcinoma in situ, is treatable or preventable according
to the present methods.
[0195] In another embodiment, fibrocystic disease (cystic
hyperplasia, mammary dysplasia, specifically adenosis (benign
epithelial hyperplasia)) is treatable or preventable according to
the present methods.
[0196] In other embodiments, a subject that has one or more of the
following predisposing factors for malignancy can be treated by
administration of an effective amount of a Sulfonamide-Based
Compound: a chromosomal translocation associated with a malignancy
(e.g., the Philadelphia chromosome for chronic myelogenous
leukemia; t(14;18) for follicular lymphoma); familial polyposis or
Gardner's syndrome; benign monoclonal gammopathy; a first degree
kinship with persons having a cancer or precancerous disease
showing a Mendelian (genetic) inheritance pattern (e.g., familial
polyposis of the colon, Gardner's syndrome, hereditary exostosis,
polyendocrine. adenomatosis, medullary thyroid carcinoma with
amyloid production and pheochromocytoma, Peutz-Jeghers syndrome,
neurofibromatosis of Von Recklinghausen, retinoblastoma, carotid
body tumor, cutaneous melanocarcinoma, intraocular melanocarcinoma,
xeroderma pigmentosum, ataxia telangiectasia, Chediak-Higashi
syndrome, albinism, Fanconi's aplastic anemia, and Bloom's
syndrome); and exposure to carcinogens (e.g., smoking, second-hand
smoke exposure, and inhalation of or contacting with certain
chemicals).
[0197] In one aspect, the present methods for treating or
preventing cancer can further comprise the administration of
another anticancer agent.
[0198] In one embodiment, the present invention provides methods
for treating or preventing cancer, comprising the administration of
an effective amount of a Sulfonamide-Based Compound and another
anticancer agent to a subject in need thereof. The
Sulfonamide-Based Compound and another anticancer agent can be
administered concurrently. In this embodiment, the
Sulfonamide-Based Compound and another anticancer agent can be
administered within the same composition, or can be administered
from different compositions, via the same or different routes of
administration. In another embodiment, the Sulfonamide-Based
Compound is administered during a time when the other anticancer
agent exerts its prophylactic or therapeutic effect, or vice
versa.
[0199] In another embodiment, the Sulfonamide-Based Compound or
other anticancer agent is administered in doses commonly employed
when such agents are used as monotherapy for the treatment of
cancer.
[0200] In one embodiment, the Sulfonamide-Based Compound or other
anticancer agent is administered in doses that are lower than the
doses commonly employed when such agents are used as monotherapy
for the treatment of cancer.
[0201] In another embodiment, the Sulfonamide-Based Compound and
other anticancer agent act synergistically and are administered in
doses that are lower than the doses commonly employed when such
agents are used as monotherapy for the treatment of cancer. The
dosage of the Sulfonamide-Based Compound or other anticancer agent
administered as well as the dosing schedule can depend on various
parameters, including, but not limited to, the cancer being
treated, the subject's general health, and the administering
physician's discretion. A Sulfonamide-Based Compound can be
administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45
minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48
hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5
weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or
subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes,
1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72
hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6
weeks, 8 weeks, or 12 weeks after) the administration of the other
anticancer agent, to a subject in need thereof. In various
embodiments a Sulfonamide-Based Compound and the other anticancer
agent are administered 1 minute apart, 10 minutes apart, 30 minutes
apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours
apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours
to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours
apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours
to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours
apart, no more than 24 hours apart or no more than 48 hours apart.
In one embodiment, a Sulfonamide-Based Compound and the other
anticancer agent are administered within 3 hours. In another
embodiment, a Sulfonamide-Based Compound and the other anticancer
agent are administered at 1 minute to 24 hours apart.
[0202] In one embodiment, an effective amount of a
Sulfonamide-Based Compound and an effective amount of other
anticancer agent are present in the same composition. In one
embodiment, this composition is useful for oral administration, in
another embodiment, this composition is useful for intravenous
administration.
[0203] In one embodiment, the compositions comprise an amount of a
Sulfonamide-Based Compound and the other anticancer agent which
together are effective to treat or prevent cancer.
[0204] In another embodiment, the compositions comprise an
effective amount of temozolomide, procarbazine, dacarbazine,
interleukin-2, irinotecan, or doxorubicin, a physiologically
acceptable carrier, diluent, excipient, or vehicle, and an
effective amount of a Sulfonamide-Based Compound.
[0205] In one embodiment, the amount of a Sulfonamide-Based
Compound and the other anticancer agent is at least about 0.01% of
the combined combination chemotherapy agents by weight of the
composition. When intended for oral administration, this amount can
be varied from about 0.1% to about 80% by weight of the
composition. Some oral compositions can comprise from about 4% to
about 50% of combined amount of a Sulfonamide-Based Compound and
the other anticancer agent by weight of the composition. Other
compositions of the present invention are prepared so that a
parenteral dosage unit contains from about 0.01% to about 2% by
weight of the composition.
[0206] Cancers that can be treated or prevented by administering a
Sulfonamide-Based Compound and the other anticancer agent include,
but are not limited to, the list of cancers set forth above in
Table 27.
[0207] In one embodiment, the cancer is brain cancer. In specific
embodiments, the brain cancer is pilocytic astrocytoma,
astrocytoma, anaplastic astrocytoma, glioblastoma multiforme or a
metastatic brain tumor.
[0208] In one embodiment, the cancer is melanoma. In a specific
embodiment, the melanoma is metastatic melanoma.
[0209] The Sulfonamide-Based Compound and other anticancer agent
can act additively or synergistically. A synergistic combination of
a Sulfonamide-Based Compound and the other anticancer agent, might
allow the use of lower dosages of one or both of these agents
and/or less frequent administration of the agents to a subject with
cancer. The ability to utilize lower dosages of one or both of the
Sulfonamide-Based Compound and other anticancer agent and/or to
administer the agents less frequently can reduce any toxicity
associated with the administration of the agents to a subject
without reducing the efficacy of the agents in the treatment of
cancer. In addition, a synergistic effect might result in the
improved efficacy of these agents in the treatment of cancer and/or
the reduction of any adverse or unwanted side effects associated
with the use of either agent alone.
[0210] In one embodiment, the administration of an effective amount
of a Sulfonamide-Based Compound and an effective amount of another
anticancer agent inhibits the resistance of a cancer to the other
anticancer agent. In one embodiment, the cancer is a tumor.
[0211] Suitable other anticancer agents useful in the methods and
compositions of the present invention include, but are not limited
to temozolomide, a topoisomerase I inhibitor, procarbazine,
dacarbazine, gemcitabine, capecitabine, methotrexate, taxol,
taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine,
cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin,
mitomycin, dacarbazine, procarbizine, etoposide, teniposide,
campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin,
dactinomycin, plicamycin, mitoxantrone, L-asparaginase,
doxorubicin, epirubicin, 5-fluorouracil, taxanes such as docetaxel
and paclitaxel, leucovorin, levamisole, irinotecan, estramustine,
etoposide, nitrogen mustards, BCNU, nitrosoureas such as carmustine
and lomustine, vinca alkaloids such as vinblastine, vincristine and
vinorelbine, platinum complexes such as cisplatin, carboplatin and
oxaliplatin, imatinib mesylate, hexamethylmelamine, topotecan,
tyrosine kinase inhibitors, tyrphostins herbimycin A, genistein,
erbstatin, and lavendustin A.
[0212] In one embodiment, the other anticancer agent is, but is not
limited to, a drug listed in Table 28.
TABLE-US-00004 TABLE 28 Alkylating agents, including but not
limited to: Nitrogen mustards: Cyclophosphamide Trofosfamide
Ifosfamide Chlorambucil Nitrosoureas: Carmustine (BCNU) Lomustine
(CCNU) Alkylsulfonates: Busulfan Treosulfan Triazenes: Dacarbazine
Temozolomide Procarbazine Platinum containing complexes: Cisplatin
Aroplatin Carboplatin Oxaliplatin Plant alkaloids, including but
not limited to: Vinca alkaloids: Vincristine Vindesine Vinblastine
Vinorelbine Taxoids: Paclitaxel Docetaxel DNA topoisomerase
inhibitors, including but not limited to: Epipodophyllins:
Etoposide 9-aminocamptothecin Teniposide Camptothecin Topotecan
Crisnatol Mitomycins: Mitomycin C Anti-metabolites Anti-folates,
including but not limited to: DHFR inhibitors: Methotrexate
Trimetrexate IMP dehydrogenase inhibitors: Mycophenolic acid EICAR
Tiazofurin Ribavirin Ribomiclotide reductase inhibitors:
Deferoxamine hydroxyurea Pyrimidine analogs, including but not
limited to: Uracil analogs: 5-Fluorouracil Doxifluridine
Fluoxuridine Ralitrexed Cytosine analogs: Cytarabine (ara C)
Gemcitabine Cytosine arabinoside Capecitabine Fludarabine Purine
analogs: Mercaptopurine Thioguanine DNA anti-metabolites: 3-HP
beta-TGDR 2'-deoxy-5- cyclocytidine fluorouridine 5-HP guanazole
alpha-TGDR inosine glycodialdehyde aphidicolin glycinate macebecin
II ara-C Pyrazoloimidazole 5-aza-2'-deoxycytidine Hormonal
therapies, including but not limited to: Receptor antagonists:
Anti-estrogen: Tamoxifen Megestrol Raloxifene LHRH agonists:
Goscrclin Leuprolide acetate Anti-androgens: Flutamide Bicalutamide
Retinoids/deltoids, including but not limited to: Cis-retinoic acid
Vitamin A derivative: All-trans retinoic acid (ATRA-IV) Vitamin D3
analogs: EB 1089 KH 1060 CB 1093 Photodvnamic therapies, including
but not limited to: Vertoporfm (BPD-MA) Demethoxy-hypocrellin A
Plithalocyanine (2BA-2-DMHA) Photosensitizer Pc4 Cytokines,
including but not limited to: Interferon-.alpha. Tumor necrosis
factor Interferon-.beta. Interleukin-2 Interferon-.gamma.
Angiogenesis inhibitors, including but not limited to: Angiostatin
MoAb IMC-ICl 1 (plasminogen fragment) antiangiogenic Neovastat
antithrombin III Angiozyme NM-3 ABT-627 Panzem Bay 12-9566 PI-88
Benefin Placental ribonuclease inhibitor Bevacizumab Plasminogen
activator inhibitor BMS-275291 Platelet factor-4 (PF4)
cartilage-derived Prinomastat inhibitor (CDI) CAI Prolactin 16 kD
fragment CD59 complement Proliferin-related fragment protein (PRP)
CEP-7055 PTK 787/ZK 222594 Col 3 Retinoids Combretastatin A-4
Solimastat Endostatin (collagen Squalamine XVIII fragment)
Fibronectin fragment SS 3304 Gro-beta SU 5416 Halofuginone SU 6668
Heparinases SUl 1248 Heparin hexasaccharide Tetrahydrocortisol-S
fragment HMV833 Tetrathiomolybdate Human chorionic Thalidomide
gonadotropin (hCG) IM-862 Thrombospondin-1 (TSP-I) Interferon
.alpha./.beta./.gamma. TNP-470 Interferon inducible Transforming
growth protein (IP-10) factor-beta (TGF-.beta.) Interleukin-12
Vasculostatin Kringle 5 (plasminogen Vasostatin (calreticulin
fragment) fragment) Marimastat ZD6126 Metalloproteinase ZD 6474
inhibitors (TIMPs) 2-Methoxyestradiol farnesyl transferase
inhibitors (FTI) MMI 270 (CGS 27023A) Bisphosphonates Antimitotic
agents, including but not limited to: Allocolchicine Maytansine
Halichondrin B Rhizoxin Colchicine Thiocolchicine colchicine
derivative trityl cysteine dolstatin 10 Others: Isoprenylation
inhibitors: Dopaminergic neurotoxins: 1-methyl-4- phenylpyridinium
ion Cell cycle inhibitors: Staurosporine Actinomycins: Actinomycin
D Dactinomycin Bleomycins: Bleomycin A2 Peplomycin Bleomycin B2
Anthracyclines: Daunorubicin Pirarabicin Doxorubicin Zorabicin
(adriamycin) Idarubicin Mitoxantrone Epirubicin MDR inhibitors:
Verapamil Ca.sup.2+ATPase inhibitors: Thapsigargin
[0213] Other additional anticancer agents that are useful in the
compositions and methods of the present invention include, but are
not limited to: acivicin; aclarubicin; acodazole hydrochloride;
acronine; adozelesin; aldesleukin; altretamine; ambomycin;
ametantrone acetate; aminoglutethimide; amsacrine; anastrozole;
anthramycin; asparaginase; asperlin; azacitidine; azetepa;
azotomycin; batimastat; benzodepa; bicalutamide; bisantrene
hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;
brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;
caracemide; carbetimer; carboplatin; carmustine; carubicin
hydrochloride; carzelesin; cedefmgol; chlorambucil; cirolemycin;
cisplatin; cladribine; crisnatol mesylate; cyclophosphamide;
cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride;
decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;
diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;
droloxifene; droloxifene citrate; dromostanolone propionate;
duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin;
enloplatin; enpromate; epipropidine; epirubicin hydrochloride;
erbulozole; esorubicin hydrochloride; estramustine; estramustine
phosphate sodium; etanidazole; etoposide; etoposide phosphate;
etoprine; fadrozole hydrochloride; fazarabine; fenretinide;
floxuridine; fludarabine phosphate; fluorouracil; flurocitabine;
fosquidone; fostriecin sodium; gemcitabine hydrochloride;
hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine;
interleukin-2 (including recombinant interleukin-2, or rIL2),
interferon alfa-2.alpha.; interferon alfa-2.beta.; interferon
alfa-n1; interferon alfa-n3; interferon beta-I.alpha.; interferon
.gamma.-I.beta.; iproplatin; irinotecan hydrochloride; lanreotide
acetate; letrozole; leuprolide acetate; liarozole hydrochloride;
lometrexol sodium; lomustine; losoxantrone hydrochloride;
masoprocol; maytansine; mechlorethamine hydrochloride; megestrol
acetate; melengestrol acetate; melphalan; menogaril;
mercaptopurine; methotrexate; methotrexate sodium; metoprine;
meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;
mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; mycophenolic acid; nocodazole; nogalamycin;
ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin;
pentamustine; peplomycin sulfate; perfosfamide; pipobroman;
piposulfan; piroxantrone hydrochloride; plicamyciii; plomestane;
porfimer sodium; porfiromycin; prednimustine; procarbazine
hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin;
riboprine; rogletimide; safingol; safingol hydrochloride;
semustine; simtrazene; sparfosate sodium; sparsomycin;
spirogermanium hydrochloride; spiromustine; spiroplatin;
streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan
sodium; tegafur; teloxantrone hydrochloride; temoporfin;
teniposide; teroxirone; testolactone; thiamiprine; thioguanine;
thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone
acetate; triciribine phosphate; trimetrexate; trimetrexate
glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard;
uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine
sulfate; vindesine; vindesine sulfate; vinepidine sulfate;
vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;
vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;
zinostatin; and zorubicin hydrochloride.
[0214] Further anticancer drugs that are useful in the methods and
compositions of the invention include, but are not limited to:
20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;
aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin;
ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonist D; antagonist
G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta Lactam
Derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF
inhibitor; bicalutamide; bisantrene; bisaziridinylspermme;
bisnafide; bistratene A; bizelesin; breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C;
camptothecin derivatives; canarypox IL-2;
carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN
700; cartilage derived inhibitor; carzelesin; casein kinase
inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;
chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin Analogue;
conagenin; crambescidin 816; crisnatol; cryptopliycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemniii B; didox; diethylnorspermine;
dihydro-5-acytidine; dihydrotaxol; dioxamycin; diphenyl
spiromustine; docetaxel; docosanol; dolasetron; doxifluridine;
droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;
edelfosine; edrecolomab; eflornithine; elemene; emitefur;
epirubicin; epristeride; estramustine analogue; estrogen agonists;
estrogen antagonists; etanidazole; etoposide phosphate; exemestane;
fadrozole; fazarabine; fenretinide; filgrastim; finasteride;
flavopiridol; flezelastine; fluasterone; fludarabine;
fluorodaunorunicin hydrochloride; forfenimex; formestane;
fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;
galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;
glutathione inhibitors; hepsulfam; heregulin; hexamethylene
bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;
idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod;
immunostimulant peptides; insulin-like growth factor-1 receptor
inhibitor; interferon agonists; interferons; interleukins;
iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine;
isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;
lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia
inhibiting factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine Analogue; lipophilic disaccharide
peptide; lipophilic platinum complexes; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
lovastatin; loxoribine; lurtotecan; lutetium texaphyrin;
lysofylline; lytic peptides; maitansine; mannostatin A; marimastat;
masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase
inhibitors; menogaril; merbarone; meterelin; methioninase;
metoclopramide; MIF inhibitor; mifepristone; miltefosine;
mirimostim; mismatched double stranded RNA; mitoguazone;
mitolactol; mitomycin Analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
monoclonal antibody, human chorionic gonadotrophin; monophosphoryl
lipid A+myobacterium cell wall sk; mopidamol; multiple drag
resistance gene inhibitor; multiple tumor suppressor 1-based.
therapy; mustard anticancer agents; mycaperoxide B; mycobacterial
cell wall extract; myriaporone; N-acetyldinaline; N-substituted
benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;
naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;
neutral endopeptidase; nilutamide; nisamycin; nitric oxide
modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine;
octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;
oxaliplatin; oxaunomycin; paclitaxel; paclitaxel Analogues;
paclitaxel derivatives; palauamiiie; palmitoylrhizoxin; pamidronic
acid; panaxytriol; panomifene; parabactin; pazelliptine;
pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;
pentrozole; perflubron; perfosfamide; perillyl alcohol;
phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;
pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A;
placetin B; plasminogen activator inhibitor; platinum complex;
platinum complexes; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylene conjugate; raf
antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RII retinamide; rogletimide; rohitukine; romurtide;
roquinimex; rubiginone B1; raboxyl; safingol; saintopin; SarCNU;
sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence
derived inhibitor 1; sense oligonucleotides; signal transduction
inhibitors; signal transduction modulators; single chain antigen
binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium
phenylacetate; solverol; somatomedin binding protein; sonermin;
sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stem cell inhibitor; stem-cell division
inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;
superactive vasoactive intestinal peptide antagonist; suradista;
suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;
tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;
tegafur; tellurapyrylium; telomerase inhibitors; temoporfm;
temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;
thaliblastine; thiocoraline; thrombopoietin; thrombopoietin
mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan;
thyroid stimulating hormone; tin ethyl etiopurpurirt; tirapazamine;
titanocene bichloride; topsentin; toremifene; totipotent stem cell
factor; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; vector system,
erythrocyte gene therapy; velaresol; ver amine; verdins;
verteporfm; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone;
zeniplatin; zilascorb; and zinostatin stimalamer.
[0215] In another embodiment, the other anticancer agent is
interferon-.alpha.. In another embodiment, the other anticancer
agent is interleukin-2. In one embodiment, the other anticancer
agent is an alkylating agent, such as a nitrogen mustard, a
nitrosourea, an alkylsulfonate, a triazene, or a
platinum-containing agent. In one embodiment, the other anticancer
agent is a triazene alkylating agent. In one embodiment, the other
anticancer agent is O-6-benzylguanine. In another embodiment, the
other anticancer agent is O-6-benzylguanine and temozolomide. In
another embodiment, the other anticancer agent is O-6-benzylguanine
and procarbazine. In still another embodiment, the other anticancer
agent is O-6-benzylguanine and dacarbazine.
[0216] The Sulfonamide-Based Compounds can be administered to a
subject that has undergone or is currently undergoing one or more
additional anticancer therapies including, but not limited to,
surgery, radiation therapy, or immunotherapy, such as cancer
vaccines.
[0217] In one embodiment, the invention provides methods for
treating or preventing cancer comprising administering to a subject
in need thereof an effective amount of a Sulfonamide-Based Compound
to treat or prevent cancer and another anticancer therapy
including, but not limited to, surgery, radiation therapy, or
immunotherapy, such as a cancer vaccine.
[0218] In one embodiment, the other anticancer therapy is radiation
therapy. In another embodiment, the other anticancer therapy is
surgery. In still another embodiment, the other anticancer therapy
is immunotherapy.
[0219] In a specific embodiment, the present methods for treating
or preventing cancer comprise administering an effective amount of
a Sulfonamide-Based Compound and radiation therapy. The radiation
therapy can be administered concurrently with, prior to, or
subsequent to the Sulfonamide-Based Compound, in one embodiment at
least an hour, five hours, 12 hours, a day, a week, a month, in
another embodiment several months (e.g., up to three months), prior
or subsequent to administration of the Sulfonamide-Based Compound.
Where the other anticancer therapy is radiation therapy, any
radiation therapy protocol can be administered depending upon the
type of cancer to be treated. For example, but not by way of
limitation, X-ray radiation can be administered; specifically,
high-energy megavoltage (radiation of greater that 1 MeV energy)
can be administered for deep tumors, and electron beam and
orthovoltage X-ray radiation can be administered for skin cancers.
Gamma-ray emitting radioisotopes, such as radioactive isotopes of
radium, cobalt and other elements, can also be administered.
[0220] Additionally, the invention provides methods of treatment of
cancer comprising administering a Sulfonamide-Based Compound as an
alternative to chemotherapy or radiation therapy where the
chemotherapy or the radiation therapy results in a negative side
effect in the subject being treated. The subject being treated can,
optionally, be treated with another anticancer therapy such as
surgery, radiation therapy, or immunotherapy.
[0221] The Sulfonamide-Based Compounds can also be administered in
vitro or ex vivo, such as for the treatment of certain cancers,
including, but not limited to leukemias and lymphomas, such
treatment involving autologous stem cell transplants. This can
involve a process in which the subject's autologous hematopoietic
stem cells are harvested and purged of all cancer cells, the
subject's remaining bone-marrow cell population is then eradicated
via the administration of a Sulfonamide-Based Compound and/or
radiation, and the resultant stem cells are infused back into the
subject. Supportive care can be subsequently provided while bone
marrow function is restored and the subject recovers.
[0222] B. Treatment or Prevention of a Neurodegenerative
Disease
[0223] The invention provides methods for treating or preventing a
neurodegenerative disease, comprising administering an effective
amount of a Sulfonamide-Based Compound to a subject. In one
embodiment, the subject is in need treatment or prevention of the
neurodegenerative disease. Examples of neurodegenerative diseases
include, but are not limited to, Alexander's disease, Alper's
disease, Alzheimer's disease, Amyotrophic lateral sclerosis
("ALS"), Ataxia telangiectasia. Batten disease (also known as
Spielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiform
encephalopathy, Canavan disease, Cockayne syndrome, Corticobasal
degeneration, Creutzfeldt-Jakob disease, Huntington's disease,
HIV-associated dementia, Kennedy's disease, Krabbe's disease, Lewy
body dementia, Machado-Joseph disease (Spinocerebellar ataxia type
3), Multiple sclerosis ("MS"), Multiple System Atrophy, Narcolepsy,
Neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher
Disease, Pick's disease, Primary lateral sclerosis, Prion diseases,
Progressive Supranuclear Palsy, Refsum's disease, Sandhoff's
disease, Schilder's disease, Subacute combined degeneration of
spinal cord secondary to Pernicious Anaemia, Spinocerebellar
ataxia, Spinal muscular atrophy, Steele-Richardson-Olszewski
disease, and Tabes dorsalis. In one embodiment, the
neurodegenerative disease is Alzheimer's disease. Other examples of
neurdegenerative diseases include, but are not limited to, diffuse
Lewy body disease, multisystem degeneration (Shy-Drager syndrome),
motor neuron diseases including amyotrophic lateral sclerosis,
degenerative ataxias, cortical basal degeneration,
ALS-Parkinson's-Dementia complex of Guam, subacute sclerosing
panencephalitis, Huntington's disease, synucleinopathies, primary
progressive aphasia, striatonigral degeneration, Machado-Joseph
disease/spinocerebellar ataxia type 3 and olivopontocerebellar
degenerations, Gilles De La Tourette's disease, bulbar and
pseudobulbar palsy, spinal and spinobulbar muscular atrophy
(Kennedy's disease), primary lateral sclerosis, familial spastic
paraplegia, Werdnig-Hoffmann disease, Kugelberg-Welander disease,
Tay-Sach's disease, Sandhoff disease, familial spastic disease,
Wohifart-Kugelberg-Welander disease, spastic paraparesis,
progressive multifocal leukoencephalopathy, prion diseases
(including Creutzfeldt-Jakob, Gerstmann-Straussler-Scheinker
disease, Kuru and fatal familial insomnia), age-related dementia
and other conditions with memory loss, such as vascular dementia,
diffuse white matter disease (Binswanger's disease), dementia of
endocrine or metabolic origin, dementia of head trauma and diffuse
brain damage, dementia pugilistica and frontal lobe dementia,
cerebral ischemia or infaction including embolic occlusion and
thrombotic occlusion as well as intracranial hemorrhage of any type
(including, but not limited to, epidural, subdural, subarachnoid
and intracerebral), and intracranial and intravertebral lesions
(including, but not limited to, contusion, penetration, shear,
compression and laceration).
[0224] In one aspect, the present methods for treating or
preventing a neurodegenerative disease can further comprise the
administration of another anti-neurodegenerative disease agent.
[0225] In one embodiment, the present invention provides methods
for treating or preventing a neurodegenerative disease, comprising
the administration of an effective amount of a Sulfonamide-Based
Compound and another anti-neurodegenerative disease agent to a
subject in need of treatment or prevention of the neurodegenerative
disease. The Sulfonamide-Based Compound and another
anti-neurodegenerative disease agent can be administered
separately. The Sulfonamide-Based Compound and another
anti-neurodegenerative disease agent can also be administered
concurrently. In this embodiment, the Sulfonamide-Based Compound
and another anti-neurodegenerative disease agent can be
administered within the same composition, or can be administered
from different compositions, via the same or different routes of
administration. In another embodiment, the Sulfonamide-Based
Compound is administered during a time when the other
anti-neurodegenerative disease agent exerts its prophylactic or
therapeutic effect, or vice versa.
[0226] In another embodiment, the Sulfonamide-Based Compound or
other anti-neurodegenerative disease agent is administered in doses
commonly employed when such agents are used as monotherapy for the
treatment of a neurodegenerative disease.
[0227] In one embodiment, the Sulfonamide-Based Compound or other
anti-neurodegenerative disease agent is administered in doses that
are lower than the doses commonly employed when such agents are
used as monotherapy for the treatment of a neurodegenerative
disease.
[0228] In another embodiment, the Sulfonamide-Based Compound and
other anti-neurodegenerative disease agent act synergistically and
are administered in doses that are lower than the doses commonly
employed when such agents are used as monotherapy for the treatment
of a neurodegenerative disease. The dosage of the Sulfonamide-Based
Compound or other anti-neurodegenerative disease agent administered
as well as the dosing schedule can depend on various parameters,
including, but not limited to, the neurodegenerative disease being
treated, the subject's general health, and the administering
physician's discretion. A Sulfonamide-Based Compound can be
administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45
minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48
hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5
weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or
subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes,
1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72
hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6
weeks, 8 weeks, or 12 weeks after) the administration of the other
anti-neurodegenerative disease agent, to a subject in need of
treatment or prevention of the neurodegenerative disease. In
various embodiments a Sulfonamide-Based Compound and the other
anti-neurodegenerative disease agent are administered 1 minute
apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart,
1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3
hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6
hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8
hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11
hours apart, 11 hours to 12 hours apart, no more than 24 hours
apart or no more than 48 hours apart. In one embodiment, a
Sulfonamide-Based Compound and the other anti-neurodegenerative
disease agent are administered within 3 hours. In another
embodiment, a Sulfonamide-Based Compound and the other
anti-neurodegenerative disease agent are administered at 1 minute
to 24 hours apart.
[0229] In one embodiment, an effective amount of a
Sulfonamide-Based Compound and an effective amount of other
anti-neurodegenerative disease agent are present in the same
composition. In one embodiment, this composition is useful for oral
administration. In another embodiment, this composition is useful
for intravenous administration.
[0230] In one embodiment, the compositions comprise an amount of a
Sulfonamide-Based Compound and the other anti-neurodegenerative
disease agent which together are effective to treat or prevent a
neurodegenerative disease.
[0231] The Sulfonamide-Based Compound and other
anti-neurodegenerative disease agent can act additively or
synergistically. A synergistic combination of a Sulfonamide-Based
Compound and the other anti-neurodegenerative disease agent, might
allow the use of lower dosages of one or both of these agents
and/or less frequent administration of the agents to a subject with
a neurodegenerative disease. The ability to utilize lower dosages
of one or both of the Sulfonamide-Based Compound and other
anti-neurodegenerative disease agent and/or to administer the
agents less frequently can reduce any toxicity associated with the
administration of the agents to a subject without reducing the
efficacy of the agents in the treatment of a neurodegenerative
disease. In addition, a synergistic effect might result in the
improved efficacy of these agents in the treatment of a
neurodegenerative disease and/or the reduction of any adverse or
unwanted side effects associated with the use of either agent
alone.
[0232] In one embodiment, the administration of an effective amount
of a Sulfonamide-Based Compound and an effective amount of another
anti-neurodegenerative disease agent inhibits the resistance of a
neurodegenerative disease to the other anti-neurodegenerative
disease agent.
[0233] Suitable other anti-neurodegenerative disease agents useful
in the methods and compositions of the present invention include,
but are not limited to: anti-Alzheimer's agents, such as
cholinesterase inhibitors (e.g., tacrine, donepezil hydrochloride,
rivastigmine, or galantamine) or partial glutamate antagonists
(e.g., memantine); anti-Parkinson's agents, such as levodopa,
carbidopa, tolcapone, bromocriptine, pergolide, pramipexole,
ropinirole, selegiline, or amantadine; anti-ALS agents, such as
riluzole; and anti-MS agents, such as interferon beta-1a,
interferon beta-1b, glatiramer acetate, mitoxantrone, or
natalizumab.
[0234] C. Combination Therapy
[0235] Additional agents that can be used in a combination product
with Sulfonamide-Based Compounds for the treatment or prevention of
diseases associated with .gamma.-secretase activity or prevention
of diseases associated with .gamma.-secretase activity include, but
are not limited to, a small molecule, a synthetic drug, a peptide
(including a cyclic peptide), a polypeptide, a protein, a nucleic
acid (e.g., a DNA and RNA nucleotide including, but not limited to,
an antisense nucleotide sequence, a triple helix, RNAi, and a
nucleotide sequence encoding a biologically active protein,
polypeptide or peptide), an antibody, a synthetic or natural
inorganic molecule, a mimetic agent, and a synthetic or natural
organic molecule. Specific examples of such agents include, but are
not limited to, an immunomodulatory agent (e.g., interferon),
anti-inflammatory agent (e.g., an adrenocorticoid, a corticosteroid
(e.g., beclomethasone, budesonide, flunisolide, fluticasone,
triamcinolone, methylprednisolone, prednisolone, prednisone,
hydrocortisone), a glucocorticoid, a steroid, and a non-steriodal
anti-inflammatory drug (e.g., aspirin, ibuprofen, diclofenac, and a
COX-2 inhibitor), a pain reliever, a leukotreine antagonist (e.g.,
montelukast, a methyl xanthine, zafirlukast, and zileuton), a
beta2-agonist (e.g., albuterol, biterol, fenoterol, isoetharie,
metaproterenol, pirbuterol, salbutamol, terbutalin formoterol,
salmeterol, and salbutamol terbutaline), an anticholinergic agent
(e.g., ipratropium bromide and oxitropium bromide), sulphasalazine,
penicillamine, dapsone, an antihistamine, an anti-malarial agent
(e.g., hydroxychloroquine), an anti-viral agent (e.g., a nucleoside
analog (e.g., zidovudine, acyclovir, gangcyclovir, vidarabine,
idoxuridine, trifluridine, and ribavirin), foscarnet, amantadine,
rimantadine, saquinavir, indinavir, ritonavir, and AZT) and an
antibiotic (e.g., dactinomycin (formerly actinomycin), bleomycin,
erythomycin, penicillin, mithramycin, and anthramycin (AMC)).
[0236] Any therapy which is known to be useful, or which has been
used, will be used or is currently being used for the treatment or
prevention of diseases associated with .gamma.-secretase activity
can be used in combination with the Sulfonamide-Based Compounds in
accordance with the invention described herein.
V. Therapeutic or Prophylactic Administration and Compositions of
the Invention
[0237] Due to their activity, Sulfonamide-Based Compounds are
advantageously useful in veterinary and human medicine. As
described above, the Sulfonamide-Based Compounds are useful for
treating or preventing cancer or a neurodegenerative disease in a
subject, including a subject that is in need of treatment or
prevention of the cancer or neurodegenerative disease. Without
being bound by theory, it is believed that the Sulfonamide-Based
Compounds exert their therapeutic or prophylactic effect by
inhibiting .gamma.-secretase.
[0238] The Sulfonamide-Based Compounds can be administered in
amounts that are effective to treat or prevent cancer or a
neurodegenerative disease in a subject in need of treatment or
prevention of the neurodegenerative disease.
[0239] When administered to a subject, the Sulfonamide-Based
Compounds can be administered as a component of a composition that
comprises a pharmaceutically acceptable carrier, diluent,
excipient, or vehicle. The present compositions, which comprise a
Sulfonamide-Based Compound, can be administered orally. The
Sulfonamide-Based Compounds can also be administered by any other
convenient route, for example, by infusion or bolus injection, by
absorption through epithelial or mucocutaneous linings (e.g., oral,
rectal, or intestinal mucosa) and can be administered together with
another biologically active agent. Administration can be systemic
or local. Various delivery systems are known, e.g., encapsulation
in liposomes, microparticles, microcapsules and capsules.
[0240] Methods of administration include, but are not limited to,
intradermal, intramuscular, intraperitoneal, intravenous,
subcutaneous, intranasal, epidural, oral, sublingual,
intracerebral, intravaginal, transdermal, rectal, by inhalation, or
topical, specifically to the ears, nose, eyes, or skin. In some
instances, administration will result in the release of a
Sulfonamide-Based Compound into the bloodstream.
[0241] In one embodiment, the Sulfonamide-Based Compounds are
administered orally. In other embodiments, it can be desirable to
administer the Sulfonamide-Based Compounds locally. This can be
achieved, for example, and not by way of limitation, by local
infusion during surgery, topical application, e.g., in conjunction
with a wound dressing after surgery, by injection, by means of a
catheter, by means of a suppository or enema, or by means of an
implant, said implant being of a porous, non-porous, or gelatinous
material, including membranes, such as sialastic membranes, or
fibers.
[0242] In certain embodiments, it can be desirable to introduce the
Sulfonamide-Based Compounds into the central nervous system or
gastrointestinal tract by any suitable route, including
intraventricular, intrathecal, and epidural injection, and enema.
Intraventricular injection can be facilitated by an
intraventricular catheter, for example, attached to a reservoir,
such as an Ommaya reservoir.
[0243] Pulmonary administration can also be employed, e.g., by use
of an inhaler of nebulizer, and formulation with an aerosolizing
agent, or via perfusion in a fluorocarbon oar, synthetic pulmonary
surfactant. In certain embodiments, the Sulfonamide-Based Compounds
can be formulated as a suppository, with traditional binders and
excipients such as triglycerides.
[0244] In another embodiment Sulfonamide-Based Compounds can be
delivered in a vesicle, specifically a liposome (see Langer,
Science 249:1527-1533 (1990) and Liposomes in Therapy of Infectious
Disease and Cancer 317-327 and 353-365 (1989)).
[0245] In yet another embodiment, the Sulfonamide-Based Compounds
can be delivered in a controlled-release system or
sustained-release system (see, e.g., Goodson, in Medical
Applications of Controlled Release, supra, vol. 2, pp. 115-138
(1984)). Other controlled or sustained-release systems discussed in
the review by Langer, Science 249: 1527-1533 (1990) can be used. In
one embodiment a pump can be used (Langer, Science 249: 1527-1533
(1990); Sefton, CRC Crit. Ref Biomed. Eng. 14:201 (1987); Buchwald
et al, Surgery 88:507 (1980); and Saudek et al., N. Engl. J Med.
321:574 (1989)). In another embodiment polymeric materials can be
used (see Medical Applications of Controlled Release (Langer and
Wise eds., 1974); Controlled Drug Bioavailability, Drug Product
Design and Performance (Smolen and Ball eds., 1984); Ranger and
Peppas, J. Macromol. Sd. Rev. Macromol. Chem. 2:61 (1983); Levy et
al, Science 228:190 (1935); During et al, Ann. Neural. 25:351
(1989); and Howard et al, J. Neurosurg. 71:105 (1989)).
[0246] In yet another embodiment a controlled- or sustained-release
system can be placed in proximity of a target of the
Sulfonamide-Based Compounds, e.g., the spinal column, brain, skin,
lung, or gastrointestinal tract, thus requiring only a fraction of
the systemic dose.
[0247] The present compositions can optionally comprise a suitable
amount of a pharmaceutically acceptable excipient so as to provide
the form for proper administration to the subject.
[0248] Such pharmaceutical excipients can be liquids, such as water
and oils, including those of petroleum, animal, vegetable, or
synthetic origin, such as peanut oil, soybean oil, mineral oil,
sesame oil and the like. The pharmaceutical excipients can be
saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal
silica, urea and the like. In addition, auxiliary, stabilizing,
thickening, lubricating, and coloring agents can be used. In one
embodiment, the pharmaceutically acceptable excipients are sterile
when administered to a subject. Water is a useful excipient when
the Sulfonamide-Based Compound is administered intravenously.
Saline solutions and aqueous dextrose and glycerol solutions can
also be employed as liquid excipients, specifically for injectable
solutions. Suitable pharmaceutical excipients also include starch,
glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,
silica gel, sodium stearate, glycerol monostearate, talc, sodium
chloride, dried skim milk, glycerol, propylene, glycol, water,
ethanol and the like. The present compositions, if desired, can
also contain minor amounts of wetting or emulsifying agents, or pH
buffering agents.
[0249] The present compositions can take the form of solutions,
suspensions, emulsion, tablets, pills, pellets, capsules, capsules
containing liquids, powders, sustained-release formulations,
suppositories, emulsions, aerosols, sprays, suspensions, or any
other form suitable for use. In one embodiment, the composition is
in the form of a capsule (see e.g. U.S. Pat. No. 5,698,155). Other
examples of suitable pharmaceutical excipients are described in
Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro
eds., 19th ed. 1995), incorporated herein by reference.
[0250] In one embodiment, the Sulfonamide-Based Compound is
formulated in accordance with routine procedures as a composition
adapted for oral administration to human beings. Compositions for
oral delivery can be in the form of tablets, lozenges, aqueous or
oily suspensions, granules, powders, emulsions, capsules, syrups,
or elixirs for example. Orally administered compositions can
contain one or more agents, for example, sweetening agents such as
fructose, aspartame or saccharin; flavoring agents such as
peppermint, oil of wintergreen, or cherry; coloring agents; and
preserving agents, to provide a pharmaceutically palatable
preparation. Moreover, where in tablet or pill form, the
compositions can be coated to delay disintegration and absorption
in the gastrointestinal tract thereby providing a sustained action
over an extended period of time. Selectively permeable membranes
surrounding an osmotically active driving a Sulfonamide-Based
Compound are also suitable for orally administered compositions. In
these latter platforms, fluid from the environment surrounding the
capsule is imbibed by the driving compound, which swells to
displace the agent or agent composition through an aperture. These
delivery platforms can provide an essentially zero order delivery
profile as opposed to the spiked profiles of immediate release
formulations. A time-delay material such as glycerol monostearate
or glycerol stearate can also be useful. Oral compositions can
include standard excipients such as mannitol, lactose, starch,
magnesium stearate, sodium saccharin, cellulose, and magnesium
carbonate. In one embodiment, the excipients are of pharmaceutical
grade.
[0251] In another embodiment, the Sulfonamide-Based Compounds can
be formulated for intravenous administration. Typically,
compositions for intravenous administration comprise sterile
isotonic aqueous buffer. Where necessary, the compositions can also
include a solubilizing agent. Compositions for intravenous
administration can optionally include a local anesthetic such as
lignocaine to lessen pain at the site of the injection.
[0252] Generally, the ingredients are supplied either separately or
mixed together in unit dosage form, for example, as a dry
lyophilized-powder or water-free concentrate in a hermetically
sealed container such as an ampule or sachette indicating the
quantity of active agent. Where the Sulfonamide-Based Compounds are
to be administered by infusion, they can be dispensed, for example,
with an infusion bottle containing sterile pharmaceutical grade
water or saline. Where the Sulfonamide-Based Compounds are
administered by injection, an ampule of sterile water for injection
or saline can be provided so that the ingredients can be mixed
prior to administration.
[0253] Sulfonamide-Based Compounds can be administered by
controlled-release or sustained-release means or by delivery
devices that are well known to those of ordinary skill in the art.
Examples include, but are not limited to, those described in U.S.
Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719;
5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476;
5,354,556; and 5,733,556, each of which is incorporated herein by
reference in its entirety. Such dosage forms can be useful for
providing controlled- or sustained-release of one or more active
ingredients using, for example, hydropropylmethyl cellulose, other
polymer matrices, gels, permeable membranes, osmotic systems,
multilayer coatings, microparticles, liposomes, microspheres, or a
combination thereof to provide the desired release profile in
varying proportions. Suitable controlled- or sustained-release
formulations known to those skilled in the art, including those
described herein, can be readily selected for use with the active
ingredients of the invention. The invention thus provides single
unit dosage forms suitable for oral administration such as, but not
limited to, tablets, capsules, gelcaps, and caplets that are
adapted for controlled- or sustained-release.
[0254] In one embodiment a controlled- or sustained-release
composition comprises a minimal amount of a Sulfonamide-Based
Compound to treat or prevent the neurodegenerative disease over a
period of time. Advantages of controlled- or sustained-release
compositions include extended activity of the drug, reduced dosage
frequency, and increased subject compliance. In addition,
controlled- or sustained-release compositions can favorably affect
the time of onset of action or other characteristics, such as blood
levels of the Sulfonamide-Based Compound, and can thus reduce the
occurrence of adverse side effects. Controlled- or
sustained-release compositions can initially release an amount of a
Sulfonamide-Based Compound that promptly produces the desired
therapeutic or prophylactic effect, and gradually and continually
release other amounts of the Sulfonamide-Based Compound to maintain
this level of therapeutic or prophylactic effect over an extended
period of time. To maintain a constant level of the
Sulfonamide-Based Compound in the body, the Sulfonamide-Based
Compound can be released from the dosage form at a rate that will
replace the amount of Sulfonamide-Based Compound being metabolized
and excreted from the body.
[0255] Controlled- or sustained-release of an active ingredient can
be stimulated by various conditions, including but not limited to,
changes in pH, changes in temperature, concentration or
availability of enzymes, concentration or availability of water, or
other physiological conditions or compounds. The amount of the
Sulfonamide-Based Compounds that is effective in the treatment or
prevention of a neurodegenerative disease can be determined by
standard clinical techniques. In addition, in vitro or in vivo
assays can optionally be employed to help identify optimal dosage
ranges. The precise dose to be employed can also depend on the
route of administration, and the seriousness of the condition being
treated and can be decided according to the judgment of the
practitioner and each subject's circumstances in view of, e.g.,
published clinical studies. Suitable effective dosage amounts,
however, range from about 10 micrograms to about 5 grams about
every 4 hours, although they are typically about 500 mg or less per
every 4 hours. In one embodiment, the effective dosage is about
0.01 mg, 0.5 mg, about 1 mg, about 50 mg, about 100 mg, about 200
mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about
700 mg, about 800 mg, about 900 mg, about 1 g, about 1.2 g, about
1.4 g, about 1.6 g, about 1.8 g, about 2.0 g, about 2.2 g, about
2.4 g, about 2.6 g, about 2.8 g, about 3.0 g, about 3.2 g, about
3.4 g, about 3.6 g, about 3.8 g, about 4.0 g, about 4.2 g, about
4.4 g, about 4.6 g, about 4.8 g, and about 5.0 g, every 4 hours.
Equivalent dosages can be administered over various time periods
including, but not limited to, about every 2 hours, about every 6
hours, about every 8 hours, about every 12 hours, about every 24
hours, about every 36 hours, about every 48 hours, about every 72
hours, about every week, about every two weeks, about every three
weeks, about every month, and about every two months. The effective
dosage amounts described herein refer to total amounts
administered; that is, if more than one Sulfonamide-Based Compound
is administered, the effective dosage amounts correspond to the
total amount administered.
[0256] Compositions can be prepared according to conventional
mixing, granulating or coating methods, respectively, and the
present compositions can contain, in one embodiment, from about
0.1% to about 99%; and in another embodiment from about 1% to about
70% of the Sulfonamide-Based Compound by weight or volume.
[0257] The dosage regimen utilizing the Sulfonamide-Based Compound
can be selected in accordance with a variety of factors including
type, species, age, weight, sex and medical condition of the
subject; the severity of the condition to be treated; the route of
administration; the renal or hepatic function of the subject; and
the specific Sulfonamide-Based Compound employed. A
Sulfonamide-Based Compound can be administered in a single daily
dose, or the total daily dosage can be administered in divided
doses of two, three or four times daily. Furthermore, a
Sulfonamide-Based Compound can be administered in intranasal form
via topical use of suitable intranasal vehicles, or via transdermal
routes, using those forms of transdermal skin patches well known to
those of ordinary skill in that art. To be administered in the form
of a transdermal delivery system, the dosage administration can be
continuous rather than intermittent throughout the dosage regimen.
Other illustrative topical preparations include creams, ointments,
lotions, aerosol sprays and gels, wherein the concentration of
Sulfonamide-Based Compound ranges from about 0.1% to about 15%, w/w
or w/v. The Sulfonamide-Based Compounds can be assayed in vitro or
in vivo for the desired therapeutic or prophylactic activity prior
to use in humans. Animal model systems can be used to demonstrate
safety and efficacy.
[0258] In certain embodiments, a Sulfonamide-Based Compound or
pharmaceutical composition thereof is administered to a human that
has an age in a range of from about 0 months to about 6 months old,
from about 6 to about 12 months old, from about 6 to about 18
months old, from about 18 to about 36 months old, from about 1 to
about 5 years old, from about 5 to about 10 years old, from about
10 to about 15 years old, from about 15 to about 20 years old, from
about 20 to about 25 years old, from about 25 to about 30 years
old, from about 30 to about 35 years old, from about 35 to about 40
years old, from about 40 to about 45 years old, from about 45 to
about 50 years old, from about 50 to about 55 years old, from about
55 to about 60 years old, from about 60 to about 65 years old, from
about 65 to about 70 years old, from about 70 to about 75 years
old, from about 75 to about 80 years old, from about 80 to about 85
years old, from about 85 to about 90 years old, from about 90 to
about 95 years old or from about 95 to about 100 years old.
[0259] In some embodiments, a Sulfonamide-Based Compound or
pharmaceutical composition thereof is administered to a human
infant. In other embodiments, a Sulfonamide-Based Compound or
pharmaceutical composition thereof is administered to a human
toddler. In other embodiments, a Sulfonamide-Based Compound or
pharmaceutical composition thereof is administered to a human
child. In other embodiments, a Sulfonamide-Based Compound or
pharmaceutical composition thereof is administered to a human
adult. In yet other embodiments, a Sulfonamide-Based Compound or
pharmaceutical composition thereof is administered to an elderly
human.
[0260] In certain embodiments, a Sulfonamide-Based Compound or
pharmaceutical composition thereof is administered a subject in an
immunocompromised state or immunosuppressed state or at risk for
becoming immunocompromised or immunosuppressed. In certain
embodiments, a Sulfonamide-Based Compound or pharmaceutical
composition thereof is administered to a subject receiving or
recovering from immunosuppressive therapy.
[0261] In some embodiments, a Sulfonamide-Based Compound or
pharmaceutical composition thereof is administered to a patient who
is susceptible to adverse reactions to conventional
anti-.gamma.-secretase therapies. In some embodiments, a
.gamma.-secretase inhibitor or pharmaceutical composition thereof
is administered to a patient who has proven refractory to
anti-.gamma.-secretase therapies other than .gamma.-secretase
inhibitors, but are no longer on these therapies. Among these
patients are refractory patients, and patients who are too young
for conventional therapies.
[0262] In some embodiments, the subject being administered a
Sulfonamide-Based Compound or pharmaceutical composition thereof
has not received therapy prior to the administration of the
Sulfonamide-Based Compound or pharmaceutical composition
thereof.
VI. Kits Comprising a Sulfonamide-Based Compound
[0263] The invention provides kits that can simplify the
administration of a Sulfonamide-Based Compound to a subject.
[0264] A typical kit of the invention comprises a unit dosage form
of a Sulfonamide-Based Compound. In one embodiment, the unit dosage
form is a container, which can be sterile, containing an effective
amount of a Sulfonamide-Based Compound and a pharmaceutically
acceptable carrier, diluent, excipient, or vehicle. The kit can
further comprise a label or printed instructions instructing the
use of the Sulfonamide-Based Compound to treat or prevent a
neurodegenerative disease. The kit can also further comprise a unit
dosage form of another prophylactic or therapeutic agent, for
example, a container containing an effective amount of the other
prophylactic or therapeutic agent. In one embodiment, the kit
comprises a container containing an effective amount of a
Sulfonamide-Based Compound and an effective amount of another
prophylactic or therapeutic agent. Examples of other prophylactic
or therapeutic agents include, but are not limited to, those listed
above.
[0265] The invention is further defined by reference to the
following examples.
EXAMPLES
Example 1
Synthesis of endo-5-chloro-thiophene-2-sulfonic acid
(tricyclo[8.2.1.0]trideca-3(8),4,6-trien-13-yl)-amide
Step A: Synthesis of
11-oxo-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene
##STR00032##
[0267] Ethyl diisopropylamine (10.3 g, 13.9 mL, 79.8 mmol) and a
solution of 1-pyrrolidino-1-cyclopentene (5.2 g, 5.5 mL, 37.8 mmol)
in acetonitrile (75 mL) were added successively to a vigorously
stirred solution of .alpha.,.alpha.'-dibromo-o-xylene (10.0 g, 38.0
mmol) in acetonitrile (75 mL) and the resultant mixture was heated
to reflux under nitrogen for 18 hours. Water (75 mL) was added and
the mixture was heated for an addition 1 hour. Then the solution
was cooled and 10% hydrochloric acid (38 mL) was added. Most of the
volatiles were removed in vacuo, and the resultant residue was
extracted with ether (4.times.100 mL). The combined ethereal
extracts were washed successively with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The concentrate was
purified using flash column chromatography ("FCC") to provide
11-oxo-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene (5.1 g,
72%).
Step B: Synthesis of tricyclo[8.2.1.0]trideca-3(8),4,6-trien-13-one
oxime
##STR00033##
[0269] 11-oxo-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene
(2.3 g, 12.4 mmol) was suspended in EtOH (16.5 mL) and H.sub.2O
(8.3 mL) and stirred. Hydroxylamine hydrochloride (2.6 g, 37.1
mmol) was added to the suspension, resulting in the dissolution of
the 11-oxo-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene.
Sodium acetate trihydrate (4.6 g, 33.8 mmol) was then added to the
resultant solution. After a few minutes, a thick white precipitate
formed. The resultant mixture was heated to reflux until a clear
solution was obtained, and then allowed to cool to room
temperature. The product
tricyclo[8.2.1.0]trideca-3(8),4,6-trien-13-one oxime crystallized
from the solution and the crystals were collected by filtration.
The crystals were then washed with water and dried to provide
tricyclo[8.2.1.0]trideca-3(8),4,6-trien-13-one oxime 2.4 g (99%) as
a pure white crystalline solid.
Step C: Synthesis of
endo-tricyclo[8.2.1.0]trideca-3(8),4,6-trien-13-ylamine
##STR00034##
[0271] Tricyclo[8.2.1.0]trideca-3(8),4,6-trien-13-one oxime (250
mg, 1.2 mmol) was dissolved in acetic acid (2 mL). PtO.sub.2 (1.5
mg) was added to the solution, and the resultant mixture was
hydrogenated for 18 hours. The mixture was filtered through
Celite.RTM., washing with acetic acid, and the filtrate was
concentrated to provide
endo-tricyclo[8.2.1.0]trideca-3(8),4,6-trien-13-ylamine as a white
solid, which was used in Step D without further purification.
Step D: Synthesis of endo-5-chloro-thiophene-2-sulfonic acid
(tricyclo[8.2.1.0]trideca-3(8),4,6-trien-13-yl)-amide
##STR00035##
[0273] The endo-tricyclo[8.2.1.0]trideca-3(8),4,6-trien-13-ylamine
from Step D was dissolved in CH.sub.2Cl.sub.2 (7 mL) and treated
with ethyl diisopropylamine (384.4 mg, 2.9 mmol, 0.5 mL) and
2-thiophenesulfonyl chloride (270 mg, 1.5 mmol). The resultant
mixture was stirred for 16 hours, and then concentrated in vacuo.
The concentrate was purified using FCC to provide
endo-5-chloro-thiophene-2-sulfonic acid
(tricyclo[8.2.1.0]trideca-3(8),4,6-trien-13-yl)-amide (107.7 mg,
26% from
endo-tricyclo[8.2.1.0]trideca-3(8),4,6-trien-13-ylamine).
Example 2
In Vitro Inhibition of .gamma.-Secretase Activity
[0274] Without being bound by theory, it is believed that
inhibiting .gamma.-secretase activity, including that which
generates A.beta.40, is desirable for the treatment or prevention
of a neurodegenerative disease, particularly Alzheimer's
disease.
[0275] Several of the above-described Sulfonamide-Based Compounds
show in vitro inhibition of .gamma.-secretase activity that
generates A.beta.40. IC.sub.50 values for inhibition of the
generation of A.beta.40 were measured. The results of these studies
are summarized below in Table 3.
[0276] The assay protocol employed was a modified version of that
described in Li et al., 2000, Proc. Nat'l Acad. Sci. USA
97:6183-643, incorporated herein by reference. Briefly, recombinant
peptide substrate was incubated with .gamma.-secretase (40
.mu.g/ml) in the presence or absence of test compound. The reaction
mixture contained 0.25% CHAPSO, 0.1 .mu.g/nl BSA, protease
inhibitor, 50 mM PIPES, pH 7.0, 5 mM MgCl.sub.2, 5 mM CaCl.sub.2
and 150 mM KCl. The reaction was incubated for 2.5 hr at 37.degree.
C. and stopped by adding RIPA buffer (150 mM NaCl, 1.0% NP-40, 0.5%
sodium deoxycholate, 0.1% SDS, 50 mM Tris HCl, pH 8.0). The
products were detected with various antibody combinations using
electrochemiluminescence (ECL) technology as previously described
in Li et al., 2000, Proc. Nat'l Acad. Sci. USA 97:6183-643; Lai et
al., 2003, J. Biol. Chem. 278: 22475-22481; and Yin et al., 2007,
J. Biol. Chem. 282:23639-23644. The amount of product was
determined using synthetic peptide or recombinant standards.
TABLE-US-00005 TABLE 3 In vitro inhibition of .gamma.-secretase
activity for Sulfonamide-Based Compounds Compound Chemical
Structure IC.sub.50 (M) 5 ##STR00036## 1 11 ##STR00037## 0.8 19
##STR00038## 630 25 ##STR00039## 20 (trans)-31 ##STR00040## 84
(trans) 35 ##STR00041## 200 165 ##STR00042## 800
* * * * *