U.S. patent application number 13/944320 was filed with the patent office on 2014-07-31 for histone deacetylase inhibitors.
The applicant listed for this patent is James Elliot Bradner, Ralph Mazitschek. Invention is credited to James Elliot Bradner, Ralph Mazitschek.
Application Number | 20140213620 13/944320 |
Document ID | / |
Family ID | 38372243 |
Filed Date | 2014-07-31 |
United States Patent
Application |
20140213620 |
Kind Code |
A1 |
Bradner; James Elliot ; et
al. |
July 31, 2014 |
HISTONE DEACETYLASE INHIBITORS
Abstract
In recognition of the need to develop novel therapeutic agents,
the present invention provides novel histone deacetylase
inhibitors. These compounds include an ester bond making them
sensitive to deactivation by esterases. Therefore, these compounds
are particularly useful in the treatment of skin disorders. When
the compounds reaches the bloodstream, an esterase or an enzyme
with esterase activity cleaves the compound into biologically
inactive fragments or fragments with greatly reduced activity
Ideally these degradation products exhibit a short serum and/or
systemic half-life and are eliminated rapidly. These compounds and
pharmaceutical compositions thereof are particularly useful in
treating cutaneous T-cell lymphoma, neurofibromatosis, psoriasis,
hair loss, skin pigmentation, and dermatitis, for example. The
present invention also provides methods for preparing compounds of
the invention and intermediates thereto.
Inventors: |
Bradner; James Elliot;
(Cambridge, MA) ; Mazitschek; Ralph; (Arlington,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bradner; James Elliot
Mazitschek; Ralph |
Cambridge
Arlington |
MA
MA |
US
US |
|
|
Family ID: |
38372243 |
Appl. No.: |
13/944320 |
Filed: |
July 17, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13678983 |
Nov 16, 2012 |
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13944320 |
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12279398 |
Oct 19, 2009 |
8383855 |
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PCT/US2007/062152 |
Feb 14, 2007 |
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13678983 |
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60773172 |
Feb 14, 2006 |
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Current U.S.
Class: |
514/376 ;
435/184; 435/375; 514/538; 514/551; 548/229; 549/369; 560/170;
560/39 |
Current CPC
Class: |
A61P 29/00 20180101;
C07D 413/12 20130101; A61P 17/00 20180101; A61K 31/165 20130101;
A61K 9/0014 20130101; C07C 259/06 20130101; A61P 17/14 20180101;
C07C 235/78 20130101; A61K 31/231 20130101; A61P 17/06 20180101;
C07D 319/06 20130101; A61K 31/337 20130101; A61P 43/00 20180101;
A61P 35/00 20180101 |
Class at
Publication: |
514/376 ;
435/184; 435/375; 514/538; 514/551; 548/229; 549/369; 560/39;
560/170 |
International
Class: |
C07D 413/12 20060101
C07D413/12; C07C 235/78 20060101 C07C235/78; C07D 319/06 20060101
C07D319/06 |
Claims
1. A compound of the formula (I), ##STR00122## wherein A comprises
a functional group that inhibits histone deacetylase; L is a linker
moiety; and Ar is a substituted or unsubstituted aryl or heteroaryl
moiety; substituted or unsustituted, branched or unbranched
arylaliphatic or heteroarylaliphatic moiety; a substituted or
unsubstituted cyclic or heterocyclic moiety; substituted or
unsustituted, branched or unbranched cyclicaliphatic or
heterocyclicaliphatic moiety; and pharmaceutically acceptable salts
thereof.
2. The compound of claim 1, wherein A is a functional group that
chelates Zn.sup.2+.
3. The compound of claim 1, wherein A is selected from the group
consisting of: ##STR00123##
4. The compound of claim 1, wherein A comprises ##STR00124##
5. The compound of claim 1, wherein A comprises ##STR00125##
6. The compound of claim 1, wherein A comprises ##STR00126##
7. The compound of any one of claims 1-6, wherein Ar is
arylaliphatic.
8. The compound of any one of claims 1-6, wherein Ar is
heteroarylaliphatic.
9. The compound of any one of claims 1-6, wherein Ar is substituted
or unsubstituted aryl.
10. The compound of any one of claims 1-6, wherein Ar is a
substituted phenyl moiety.
11. The compound of any one of claims 1-6, wherein Ar is chosen
from one of the following: ##STR00127##
12. The compound of any one of claims 1-6, wherein Ar is a
substituted or unsubstituted heteroaryl moiety.
13. The compound of any one of claims 1-6, wherein Ar is chosen
from one of the following: ##STR00128##
14. The compound of any one of claims 1-13, wherein L is a
substituted or unsubstituted, cyclic or acyclic, branched or
unbranched aliphatic moiety; a substituted or unsubstituted, cyclic
or acyclic, branched or unbranched heteroaliphatic moiety; a
substituted or unsubstituted aryl moiety; a substituted or
unsubstituted heteroaryl moiety.
15. The compound of any one of claims 1-13, wherein L is a
substituted or unsubstituted, cyclic or acyclic, branched or
unbranched aliphatic moiety.
16. The compound of any one of claims 1-13, wherein L is a
substituted or unsubstituted, cyclic or acyclic, branched or
unbranched heteroaliphatic moiety.
17. The compound of any one of claims 1-13, wherein L is
C.sub.1-C.sub.15 alkylidene.
18. The compound of any one of claims 1-13, wherein L is
C.sub.1-C.sub.10 alkylidene.
19. The compound of any one of claims 1-13, wherein L is
C.sub.2-C.sub.6 alkylidene.
20. The compound of any one of claims 1-13, wherein L is an
unbranched, unsubstituted, acyclic alkyl chain.
21. The compound of any one of claims 1-13, wherein L is selected
from one of the following: ##STR00129##
22. The compound of any one of claims 1-13, wherein L is selected
from one of the following: ##STR00130##
23. The compound of any one of claims 1-13, wherein L is
##STR00131##
24. The compound of any one of claims 1-13 of the formula (Ia):
##STR00132## wherein n is an integer between 0 and 15.
25. The compound of any one of claims 1-13 of the formula (Ib):
##STR00133## wherein n is an integer between 0 and 15, inclusive; m
is an integer between 1 and 5, inclusive; and R.sub.1 is hydrogen;
halogen; cyclic or acyclic, substituted or unsubstituted, branched
or unbranched aliphatic; cyclic or acyclic, substituted or
unsubstituted, branched or unbranched heteroaliphatic; substituted
or unsubstituted, branched or unbranched acyl; substituted or
unsubstitued, branched or unbranched aryl; substituted or
unsubstituted, branched or unbranched heteroaryl; --OR.sub.A;
--C(.dbd.O)R.sub.A; --CO.sub.2R.sub.A; --CN; --SCN; --SR.sub.A;
--SOR.sub.A; --SO.sub.2R.sub.A; --NO.sub.2; --N(R.sub.A).sub.2;
--NHC(O)R.sub.A; or --C(R.sub.A).sub.3; wherein each occurrence of
R.sub.A is independently a hydrogen, a protecting group, an
aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl
moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio
moiety.
26. The compound of claim 25, wherein n is an integer between 1 and
8, inclusive.
27. The compound of claim 25, wherein n is 5, 6 or 7.
28. The compound of claim 25, wherein n is 6.
29. The compound of any one of claims 25-28, wherein m is 1.
30. The compound of any one of claims 25-28, wherein m is 2.
31. The compound of any one of claims 25-28, wherein m is 3.
32. The compound of any one of claims 25-31, wherein R.sub.1
comprises a substituted or unsubstituted 1,3-dioxane ring.
33. The compound of any one of claims 25-31, wherein R.sub.1 is
halogen.
34. The compound of any one of claim 25-31, wherein R.sub.1 is
--OR.sub.A.
35. The compound of any one of claims 25-31, wherein R.sub.1 is
--N(R.sub.A).sub.2.
36. The compound of any one of claims 25-31, wherein R.sub.1 is
--NHR.sub.A.
37. The compound of any one of claims 25-31, wherein R.sub.1 is
C.sub.1-C.sub.6 alkyl.
38. The compound of any one of claim 25-31, wherein R.sub.1 is
substituted or unsubstituted acyl.
39. The compound of any one of claims 25-31, wherein R.sub.1 is
--C(.dbd.O)OR.sub.A, wherein R.sub.A is hydrogen or C.sub.1-C.sub.6
alkyl.
40. The compound of any one of claims 25-31, wherein R.sub.1 is
--C(.dbd.O)N(R.sub.A).sub.2, wherein R.sub.A is hydrogen or
C.sub.1-C.sub.6 alkyl.
41. The compound of any one of claims 25-31, wherein R.sub.1 is
--C(.dbd.O)NH.sub.2.
42. The compound of any one of claims 25-31, wherein R.sub.1 is
--CHO.
43. The compound of any one of claims 25-31, wherein R.sub.1 is
--NHC(.dbd.O)R.sub.A, wherein R.sub.A is C.sub.1-C.sub.6 alkyl.
44. The compound of claim 1 of formula (Ic): ##STR00134## wherein n
is an integer between 0 and 15, inclusive; preferably, between 0
and 10, inclusive; more preferably, between 1 and 8, inclusive;
even more preferably, 4, 5, 6, 7, or 8; and R.sub.1 is hydrogen;
halogen; cyclic or acyclic, substituted or unsubstituted, branched
or unbranched aliphatic; cyclic or acyclic, substituted or
unsubstituted, branched or unbranched heteroaliphatic; substituted
or unsubstituted, branched or unbranched acyl; substituted or
unsubstitued, branched or unbranched aryl; substituted or
unsubstituted, branched or unbranched heteroaryl; --OR.sub.A;
--C(.dbd.O)R.sub.A; --CO.sub.2R.sub.A; --CN; --SCN; --SR.sub.A;
--SOR.sub.A; --SO.sub.2R.sub.A; --NO.sub.2; --N(R.sub.A).sub.2;
--NHC(O)R.sub.A; or --C(R.sub.A).sub.3; wherein each occurrence of
R.sub.A is independently a hydrogen, a protecting group, an
aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl
moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio
moiety.
45. The compound of claim 1 of formula: ##STR00135## wherein n is
an integer between 0 and 15, inclusive; preferably, between 0 and
10, inclusive; more preferably, between 1 and 8, inclusive; even
more preferably, 4, 5, 6, 7, or 8; and R.sub.1 is hydrogen;
halogen; cyclic or acyclic, substituted or unsubstituted, branched
or unbranched aliphatic; cyclic or acyclic, substituted or
unsubstituted, branched or unbranched heteroaliphatic; substituted
or unsubstituted, branched or unbranched acyl; substituted or
unsubstitued, branched or unbranched aryl; substituted or
unsubstituted, branched or unbranched heteroaryl; --OR.sub.A;
--C(.dbd.O)R.sub.A; --CO.sub.2R.sub.A; --CN; --SCN; --SR.sub.A;
--SOR.sub.A; --SO.sub.2R.sub.A; --NO.sub.2; --N(R.sub.A).sub.2;
--NHC(O)R.sub.A; or --C(R.sub.A).sub.3; wherein each occurrence of
R.sub.A is independently a hydrogen, a protecting group, an
aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl
moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio
moiety.
46. The compound of claim 1 of formula: ##STR00136## wherein n is
an integer between 0 and 15, inclusive; preferably, between 0 and
10, inclusive; more preferably, between 1 and 8, inclusive; even
more preferably, 4, 5, 6, 7, or 8; and R.sub.1 is hydrogen;
halogen; cyclic or acyclic, substituted or unsubstituted, branched
or unbranched aliphatic; cyclic or acyclic, substituted or
unsubstituted, branched or unbranched heteroaliphatic; substituted
or unsubstituted, branched or unbranched acyl; substituted or
unsubstitued, branched or unbranched aryl; substituted or
unsubstituted, branched or unbranched heteroaryl; --OR.sub.A;
--C(.dbd.O)R.sub.A; --CO.sub.2R.sub.A; --CN; --SCN; --SR.sub.A;
--SOR.sub.A; --SO.sub.2R.sub.A; --NO.sub.2; --N(R.sub.A).sub.2;
--NHC(O)R.sub.A; or --C(R.sub.A).sub.3; wherein each occurrence of
R.sub.A is independently a hydrogen, a protecting group, an
aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl
moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio
moiety.
47. The compound of claim 1 of formula: ##STR00137## wherein n is
an integer between 0 and 15, inclusive; preferably, between 0 and
10, inclusive; more preferably, between 1 and 8, inclusive; even
more preferably, 4, 5, 6, 7, or 8; and R.sub.1 is hydrogen;
halogen; cyclic or acyclic, substituted or unsubstituted, branched
or unbranched aliphatic; cyclic or acyclic, substituted or
unsubstituted, branched or unbranched heteroaliphatic; substituted
or unsubstituted, branched or unbranched acyl; substituted or
unsubstitued, branched or unbranched aryl; substituted or
unsubstituted, branched or unbranched heteroaryl; --OR.sub.A;
--C(.dbd.O)R.sub.A; --CO.sub.2R.sub.A; --CN; --SCN; --SR.sub.A;
--SOR.sub.A; --SO.sub.2R.sub.A; --NO.sub.2; --N(R.sub.A).sub.2;
--NHC(O)R.sub.A; or --C(R.sub.A).sub.3; wherein each occurrence of
R.sub.A is independently a hydrogen, a protecting group, an
aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl
moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio
moiety.
48. The compound of claim 44, 45, 46, or 47, wherein n is an
integer between 1 and 8, inclusive.
49. The compound of claim 44, 45, 46, or 47, wherein n is 5, 6 or
7.
50. The compound of claim 44, 45, 46, or 47, wherein n is 6.
51. The compound of claim 44, 45, 46, or 47, wherein R.sub.1
comprises a substituted or unsubstituted 1,3-dioxane ring.
52. The compound of claim 44, 45, 46, or 47, wherein R.sub.1 is
halogen.
53. The compound of claim 44, 45, 46, or 47, wherein R.sub.1 is
--OR.sub.A.
54. The compound of claim 44, 45, 46, or 47, wherein R.sub.1 is
--N(R.sub.A).sub.2.
55. The compound of claim 44, 45, 46, or 47, wherein R.sub.1 is
--NHR.sub.A.
56. The compound of claim 44, 45, 46, or 47, wherein R.sub.1 is
C.sub.1-C.sub.6 alkyl.
57. The compound of claim 44, 45, 46, or 47, wherein R.sub.1 is
substituted or unsubstituted acyl.
58. The compound of claim 44, 45, 46, or 47, wherein R.sub.1 is
--C(.dbd.O)OR.sub.A, wherein R.sub.A is hydrogen or C.sub.1-C.sub.6
alkyl.
59. The compound of claim 44, 45, 46, or 47, wherein R.sub.1 is
--C(.dbd.O)N(R.sub.A).sub.2, wherein R.sub.A is hydrogen or
C.sub.1-C.sub.6 alkyl.
60. The compound of claim 44, 45, 46, or 47, wherein R.sub.1 is
--C(.dbd.O)NH.sub.2.
61. The compound of claim 44, 45, 46, or 47, wherein R.sub.1 is
--CHO.
62. The compound of claim 44, 45, 46, or 47, wherein R.sub.1 is
--NHC(.dbd.O)R.sub.A, wherein R.sub.A is C.sub.1-C.sub.6 alkyl.
63. The compound of claim 1 of formula (If): ##STR00138## wherein n
is an integer between 1 and 6, inclusive.
64. The compound of claim 63, wherein Ar is substituted or
unsubstituted phenyl.
65. The compound of claim 1 of formula (Ig): ##STR00139## wherein
R.sub.2 is hydrogen; halogen; cyclic or acyclic, substituted or
unsubstituted, branched or unbranched aliphatic; cyclic or acyclic,
substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.B; --C(.dbd.O)R.sub.B;
--CO.sub.2R.sub.B; --CN; --SCN; --SR.sub.B; --SOR.sub.B;
--SO.sub.2R.sub.B; --NO.sub.2; --N(R.sub.B).sub.2; --NHC(O)R.sub.B;
or --C(R.sub.B).sub.3; wherein each occurrence of R.sub.B is
independently a hydrogen, a protecting group, an aliphatic moiety,
a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a
heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino,
alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;
and R.sub.3 is hydrogen; halogen; cyclic or acyclic, substituted or
unsubstituted, branched or unbranched aliphatic; cyclic or acyclic,
substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.C; --C(.dbd.O)R.sub.C;
--CO.sub.2R.sub.C; --CN; --SCN; --SR.sub.C; --SOR.sub.C;
--SO.sub.2R.sub.C; --NO.sub.2; --N(R.sub.C).sub.2; --NHC(O)R.sub.C;
or --C(R.sub.C).sub.3; wherein each occurrence of R.sub.C is
independently a hydrogen, a protecting group, an aliphatic moiety,
a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a
heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino,
alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio
moiety.
66. The compound of claim 65, wherein R.sub.2 is
--CH.sub.2--X(R.sub.B).sub.n; wherein X is O, S, or N; and n is 1
or 2
67. The compound of claim 1 of formula (Ih): ##STR00140## wherein n
is an integer between 1 and 6, inclusive; R.sub.2 is hydrogen;
halogen; cyclic or acyclic, substituted or unsubstituted, branched
or unbranched aliphatic; cyclic or acyclic, substituted or
unsubstituted, branched or unbranched heteroaliphatic; substituted
or unsubstituted, branched or unbranched acyl; substituted or
unsubstitued, branched or unbranched aryl; substituted or
unsubstituted, branched or unbranched heteroaryl; --OR.sub.B;
--C(.dbd.O)R.sub.B; --CO.sub.2R.sub.B; --CN; --SCN; --SR.sub.B;
--SOR.sub.B; --SO.sub.2R.sub.B; --NO.sub.2; --N(R.sub.B).sub.2;
--NHC(O)R.sub.B; or --C(R.sub.B).sub.3; wherein each occurrence of
R.sub.B is independently a hydrogen, a protecting group, an
aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl
moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio
moiety; and R.sub.3 is hydrogen; halogen; cyclic or acyclic,
substituted or unsubstituted, branched or unbranched aliphatic;
cyclic or acyclic, substituted or unsubstituted, branched or
unbranched heteroaliphatic; substituted or unsubstituted, branched
or unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.C; --C(.dbd.O)R.sub.C;
--CO.sub.2R.sub.C; --CN; --SCN; --SR.sub.C; --SOR.sub.C;
--SO.sub.2R.sub.C; --NO.sub.2; --N(R.sub.C).sub.2; --NHC(O)R.sub.C;
or --C(R.sub.C).sub.3; wherein each occurrence of R.sub.C is
independently a hydrogen, a protecting group, an aliphatic moiety,
a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a
heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino,
alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio
moiety.
68. The compound of claim 1 of formula (Ii): ##STR00141## wherein
R.sub.2 is hydrogen; halogen; cyclic or acyclic, substituted or
unsubstituted, branched or unbranched aliphatic; cyclic or acyclic,
substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.B; --C(.dbd.O)R.sub.B;
--CO.sub.2R.sub.B; --CN; --SCN; --SR.sub.B; --SOR.sub.B;
--SO.sub.2R.sub.B; --NO.sub.2; --N(R.sub.B).sub.2; --NHC(O)R.sub.B;
or --C(R.sub.B).sub.3; wherein each occurrence of R.sub.B is
independently a hydrogen, a protecting group, an aliphatic moiety,
a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a
heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino,
alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;
and R.sub.3 is hydrogen; halogen; cyclic or acyclic, substituted or
unsubstituted, branched or unbranched aliphatic; cyclic or acyclic,
substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.C; --C(.dbd.O)R.sub.C;
--CO.sub.2R.sub.C; --CN; --SCN; --SR.sub.C; --SOR.sub.C;
--SO.sub.2R.sub.C; --NO.sub.2; --N(R.sub.C).sub.2; --NHC(O)R.sub.C;
or --C(R.sub.C).sub.3; wherein each occurrence of R.sub.C is
independently a hydrogen, a protecting group, an aliphatic moiety,
a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a
heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino,
alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio
moiety.
69. The compound of claim 1 of formula (Ij): ##STR00142## wherein
R.sub.2 is hydrogen; halogen; cyclic or acyclic, substituted or
unsubstituted, branched or unbranched aliphatic; cyclic or acyclic,
substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.B; --C(.dbd.O)R.sub.B;
--CO.sub.2R.sub.B; --CN; --SCN; --SR.sub.B; --SOR.sub.B;
--SO.sub.2R.sub.B; --NO.sub.2; --N(R.sub.B).sub.2; --NHC(O)R.sub.B;
or --C(R.sub.B).sub.3; wherein each occurrence of R.sub.B is
independently a hydrogen, a protecting group, an aliphatic moiety,
a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a
heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino,
alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;
and R.sub.3 is hydrogen; halogen; cyclic or acyclic, substituted or
unsubstituted, branched or unbranched aliphatic; cyclic or acyclic,
substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.C; --C(.dbd.O)R.sub.C;
--CO.sub.2R.sub.C; --CN; --SCN; --SR.sub.C; --SOR.sub.C;
--SO.sub.2R.sub.C; --NO.sub.2; --N(R.sub.C).sub.2; --NHC(O)R.sub.C;
or --C(R.sub.C).sub.3; wherein each occurrence of R.sub.C is
independently a hydrogen, a protecting group, an aliphatic moiety,
a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a
heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino,
alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio
moiety.
70. The compound of any one of claim 65, 66, 67, 68, or 69, wherein
R.sub.2 is ##STR00143##
71. The compound of claim 68 of formula (Il): ##STR00144## wherein
n is an integer between 0 and 5, inclusive; and Z is hydrogen,
--(CH.sub.2).sub.qOR.sup.Z, --(CH.sub.2).sub.qSR.sup.Z,
--(CH.sub.2).sub.qN(R.sup.Z).sub.2, --C(.dbd.O)R.sup.Z,
--C(.dbd.O)N(R.sup.Z).sub.2, or an alkyl, heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl,
or -(heteroalkyl)heteroaryl moiety, wherein q is 0-4, and wherein
each occurrence of R.sup.Z is independently hydrogen, a protecting
group, a solid support unit, or an alkyl, cycloalkyl, heteroalkyl,
heterocyclic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl,
-(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety.
72. The compound of claim 71 of formula: ##STR00145##
73. A compound of claim 1 of formula: ##STR00146## ##STR00147##
74. A pharmaceutical composition comprising a compound of one of
the claims 1-73 and a pharmaceutically acceptable excipient.
75. A method of inhibiting histone deacetylase, the method
comprising steps of: contacting a histone deacetylase with a
compound of one of the claims 1-34.
76. The method of claim 75, wherein the histone deacetylase is
purified.
77. The method of claim 75, wherein the histone deacetylase is in a
cell.
78. The method of claim 75, 76, or 77, wherein the histone
deacetylase is HDAC6.
79. A method of treating a subject with a proliferative disorder,
the method comprising steps of: administering a therapeutically
effective amount of a compound of one of claims 1-34 to a
subject.
80. The method of claim 79, wherein the subject is a mammal.
81. The method of claim 79, wherein the subject is human.
82. The method of claim 79, 80, or 81, wherein the proliferative
disorder is cancer.
83. The method of claim 79, 80, or 81, wherein the proliferative
disorder is an inflammatory disease.
84. The method of claim 79, 80, or 81, wherein the proliferative
disorder is a proliferative disorder associated with the skin.
85. The method of claim 79, 80, or 81, wherein the proliferative
disorder is cutaneous T-cell lymphoma.
86. The method of claim 79, 80, or 81, wherein the proliferative
disorder is a skin cancer.
87. The method of claim 79, 80, or 81, wherein the proliferative
disorder is a benign skin growth.
88. The method of claim 79, 80, or 81, wherein the proliferative
disorder is psoriasis.
89. The method of claim 79, 80, or 81, wherein the proliferative
disorder is a dermatitis.
90. The method of claim 79, 80, or 81, wherein the proliferative
disorder is neurofibromatosis.
91. The method of any one of claims 79-90, wherein the step of
administering comprises administering the compound topically.
92. The method of any one of claims 79-90, wherein the compound is
cleaved by an esterase in vivo.
93. The method of claim 92, wherein the compound is cleaved by an
esterase found in the bloodstream.
94. The method of any one of claims 79-90, wherein the compound is
inactivated by an esterase in vivo.
95. The method of claim 94, wherein the compound is inactivated by
an esterase found in the bloodstream.
96. A method of treating a subject with hair loss, the method
comprising steps of: administering a therapeutically effective
amount of a compound of any one of claims 1-73 to a subject.
97. A method of treating a subject suffering from skin
hyperpigmentation, the method comprising steps of: administering a
therapeutically effective amount of a compound of any one of claims
1-73 to a subject.
98. A method of administering a compound of any one of claims 1-73,
the method comprising: administering topically a compound of any
one of claims 1-72 to a subject.
99. The method of claim 98, wherein the step of administering
comprises administering the compound to the subject's skin.
100. The method of claim 98, wherein the step of administering
comprises administering the compound to the subject's hair.
101. A method for synthesizing a compound of formula (III.sup.A),
the method comprising steps of: providing an epoxy alcohol having
the structure: ##STR00148## reacting the epoxy alcohol with a
reagent having the structure R.sup.2XH under suitable conditions to
generate a diol having the core structure: ##STR00149## reacting
the diol with a reagent having the structure R.sup.3CH(OMe).sub.2
under suitable conditions to generate a compound of formula
(III.sup.A): ##STR00150## wherein R.sup.1 is hydrogen, or an
aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or
heteroaromatic moiety; R.sup.2 is hydrogen, a protecting group, or
an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or
heteroaromatic moiety; X is --O--, --C(R.sup.2A).sub.2--, --S--, or
--NR.sup.2A--, wherein R.sup.2A is hydrogen, a protecting group, or
an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or
heteroaromatic moiety; or wherein two or more occurrences of
R.sup.2 and R.sup.2A, taken together, form an alicyclic or
heterocyclic moiety, or an aryl or heteroaryl moiety; R.sup.3 is an
aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or
heteroaromatic moiety; and R.sup.Z is an aliphatic, alicyclic,
heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety
and is optionally attached to a solid support.
102. A method of synthesizing a compound of formula: ##STR00151##
the method comprising steps of: providing an epoxy alcohol having
the structure: ##STR00152## reacting the epoxy alcohol with a
reagent having the structure R.sup.2XH under suitable conditions to
generate a diol having the core structure: ##STR00153## subjecting
the diol to a reagent having the structure: ##STR00154## wherein
R.sup.4C is a nitrogen protecting group, under suitable conditions
to generate an amine having the structure: ##STR00155## reacting
the amine with a reagent having the structure: ##STR00156## under
suitable conditions to generate a scaffold having the core
structure: ##STR00157## wherein R.sup.1 is hydrogen, or an
aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or
heteroaromatic moiety; R.sup.2 is hydrogen, a protecting group, or
an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or
heteroaromatic moiety; X is --O--, --C(R.sup.2A).sub.2--, --S--, or
--NR.sup.2A--, wherein R.sup.2A is hydrogen, a protecting group, or
an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or
heteroaromatic moiety; or wherein two or more occurrences of
R.sup.2 and R.sup.2A, taken together, form an alicyclic or
heterocyclic moiety, or an aryl or heteroaryl moiety; r is 0 or 1;
s is an integer from 2-5; w is an integer from 0-4; R.sup.4A
comprises a metal chelator; each occurrence of R.sup.4D is
independently hydrogen, alkyl, heteroalkyl, cycloalkyl,
heterocyclic, alkenyl, alkynyl, aryl, heteroaryl, halogen, CN,
NO.sub.2, or WR.sup.W1 wherein W is O, S, NR.sup.W2, --C(.dbd.O),
--S(.dbd.O), --SO.sub.2, --C(.dbd.O)O--, --OC(.dbd.O),
--C(.dbd.O)NR.sup.W2, --NR.sup.W2C(.dbd.O); wherein each occurrence
of R.sup.W1 and R.sup.W2 is independently hydrogen, a protecting
group, a prodrug moiety or an alkyl, cycloalkyl, heteroalkyl,
heterocyclic, aryl or heteroaryl moiety, or, when W is NR.sup.W2,
R.sup.W1 and R.sup.W2, taken together with the nitrogen atom to
which they are attached, form a heterocyclic or heteroaryl moiety;
or any two adjacent occurrences of R.sup.2B, taken together with
the atoms to which they are attached, form a substituted or
unsubstituted, saturated or unsaturated alicyclic or heterocyclic
moiety, or a substituted or unsubstituted aryl or heteroaryl
moiety; and R.sup.Z is an aliphatic, alicyclic, heteroaliphatic,
heterocyclic, aromatic or heteroaromatic moiety and is optionally
attached to a solid support.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 12/279,398, filed on Oct. 19, 2009 which is a
national phase application under 35 U.S.C. .sctn.371 of PCT
International Application No. PCT/US2007/062152, filed on Feb. 14,
2007, which claims priority under 35 U.S.C. .sctn.119(e) to U.S.
provisional patent application, U.S. Ser. No. 60/773,172, filed
Feb. 14, 2006. Each of these prior applications is incorporated
herein by reference.
BACKGROUND OF THE INVENTION
[0002] The identification of small organic molecules that affect
specific biological functions is an endeavor that impacts both
biology and medicine. Such molecules are useful as therapeutic
agents and as probes of biological function. In but one example
from the emerging field of chemical genetics, in which small
molecules can be used to alter the function of biological molecules
to which they bind, these molecules have been useful at elucidating
signal transduction pathways by acting as chemical protein
knockouts, thereby causing a loss of protein function (Schreiber et
al., J. Am. Chem. Soc., 1990, 112, 5583; Mitchison, Chem. and
Biol., 1994, 1, 3). Additionally, due to the interaction of these
small molecules with particular biological targets and their
ability to affect specific biological function, they may also serve
as candidates for the development of therapeutics. One important
class of small molecules, natural products, which are small
molecules obtained from nature, clearly have played an important
role in the development of biology and medicine, serving as
pharmaceutical leads, drugs (Newman et al., Nat. Prod. Rep. 2000,
17, 215-234), and powerful reagents for studying cell biology
(Schreiber, S. L. Chem. and Eng. News 1992 (October 26),
22-32).
[0003] Because it is difficult to predict which small molecules
will interact with a biological target, and it is oftent difficult
to obtain and synthesize efficiently small molecules found in
nature, intense efforts have been directed towards the generation
of large numbers, or libraries, of small organic compounds, often
"natural product-like" libraries. These libraries can then be
linked to sensitive screens for a particular biological target of
interest to identify the active molecules.
[0004] One biological target of recent interest is histone
deacetylase (see, for example, a discussion of the use of
inhibitors of histone deacetylases for the treatment of cancer:
Marks et al. Nature Reviews Cancer 2001, 1, 194; Johnstone et al.
Nature Reviews Drug Discovery 2002, 1, 287). Post-translational
modification of proteins through acetylation and deacetylation of
lysine residues has a critical role in regulating their cellular
functions. HDACs are zinc hydrolases that modulate gene expression
through deacetylation of the N-acetyl-lysine residues of histone
proteins and other transcriptional regulators (Hassig et al. Curr.
Opin. Chem. Biol. 1997, 1, 300-308). HDACs participate in cellular
pathways that control cell shape and differentiation, and an HDAC
inhibitor has been shown effective in treating an otherwise
recalcitrant cancer (Warrell et al. J. Natl. Cancer Inst. 1998, 90,
1621-1625). Eleven human HDACs, which use Zn as a cofactor, have
been characterized (Taunton et al. Science 1996, 272, 408-411; Yang
et al. J. Biol. Chem. 1997, 272, 28001-28007; Grozinger et al.
Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 4868-4873; Kao et al. Genes
Dev. 2000, 14, 55-66; Hu et al. J. Biol. Chem. 2000, 275,
15254-15264; Zhou et al. Proc. Natl. Acad. Sci. U.S.A. 2001, 98,
10572-10577; Venter et al. Science 2001, 291, 1304-1351). These
members fall into three related classes (class I, II, and III). An
additional seven HDACs have been identified which use NAD as a
confactor. To date, no small molecules are known that selectively
target either the two classes or individual members of this family
((for example ortholog-selective HDAC inhibitors have been
reported: (a) Meinke et al. J. Med. Chem. 2000, 14, 4919-4922; (b)
Meinke, et al. Curr. Med. Chem. 2001, 8, 211-235).
SUMMARY OF THE INVENTION
[0005] The present invention provides novel histone deacetylase
inhibitors and methods of preparing and using these compounds. The
inventive HDAC inhibitors comprise an esterase-sensitive ester
linakge, thereby when the compound is exposed to an esterase such
as in the bloodstream the compound is inactivated. The compounds
are particularly useful in the treatment of skin disorders such as
cutaneous T-cell lymphoma, neurofibromatosis, psoriasis, hair loss,
dermatitis, baldness, and skin pigmentation. The inventive compound
is adminitered topically to the skin of the patient where it is
clinically active. Once the compound is absorbed into the body, it
is quickly inactivated by esterases which cleave the compound into
two or more biologically inactive fragments. Thus, allowing for
high local concentrations (e.g., in the skin) and reduced systemic
toxicity. In certain embodiments, the compound is fully cleaved
upon exposure to serum in less than 5 min., preferably less than 1
min.
[0006] The present invention provides novel compounds of general
formula (I),
##STR00001##
and pharmaceutical compositions thereof, as described generally and
in subclasses herein, which compounds are useful as inhibitors of
histone deacetylases or other deacetylases, and thus are useful for
the treatment of proliferative diseases. The inventive compounds
are additionally useful as tools to probe biological function. In
certain embodiments, the compounds of the ivention are particularly
useful in the treatment of skin disorders. The ester linkage is
susceptible to esterase cleavage, particularly esterases found in
the blood. Therefore, these compounds may be administered topically
to treat skin disorders, such as cutaneous T-cell lymphoma,
psoriasis, hair loss, dermatitis, etc., without the risk of
systemic effects. Once the compound enters the bloodstream it is
quickly degraded by serum esterases. Preferably, the compound is
degraded into non-toxic, biologically inactive by-products.
[0007] In another aspect, the present invention provides methods
for inhibiting histone deacetylase activity or other deacetylase
activity in a patient or a biological sample, comprising
administering to said patient, or contacting said biological sample
with an effective inhibitory amount of a compound of the invention.
In certain embodiments, the compounds specifically inhibit a
particular HDAC (e.g., HDAC1, HDAC2, HDAC3, HDAC4, HDAC4, HDAC5,
HDAC6, HDAC7, HDAC8, HDAC9, HDAC10, HDAC11) or class of HDACs
(e.g., Class I, II, or III). In certain embodiments, the compounds
specifically inhibit HDAC6. In still another aspect, the present
invention provides methods for treating skin disorders involving
histone deacetylase activity, comprising administering to a subject
in need thereof a therapeutically effective amount of a compound of
the invention. The compounds may be administered by any method
known in the art. In certain embodiments, the compounds are
administered topically (e.g., in a cream, lotion, ointment, spray,
gel, powder, etc.). In certain embodiments, the compound is
administered to skin. In other certain embodiments, the compound is
administered to hair. The compounds may also be administered
intravenously or orally. The invention also provides pharmaceutical
compositions of the compounds wherein the compound is combined with
a pharmaceutically acceptable excipient.
[0008] In yet another aspect, the present invention provides
methods for preparing compounds of the invention and intermediates
thereof.
DEFINITIONS
[0009] Certain compounds of the present invention, and definitions
of specific functional groups are also described in more detail
below. For purposes of this invention, the chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed.,
inside cover, and specific functional groups are generally defined
as described therein. Additionally, general principles of organic
chemistry, as well as specific functional moieties and reactivity,
are described in Organic Chemistry, Thomas Sorrell, University
Science Books, Sausalito: 1999, the entire contents of which are
incorporated herein by reference. Furthermore, it will be
appreciated by one of ordinary skill in the art that the synthetic
methods, as described herein, utilize a variety of protecting
groups. By the term "protecting group," has used herein, it is
meant that a particular functional moiety, e.g., C, O, S, or N, is
temporarily blocked so that a reaction can be carried out
selectively at another reactive site in a multifunctional compound.
In preferred embodiments, a protecting group reacts selectively in
good yield to give a protected substrate that is stable to the
projected reactions; the protecting group must be selectively
removed in good yield by readily available, preferably nontoxic
reagents that do not attack the other functional groups; the
protecting group forms an easily separable derivative (more
preferably without the generation of new stereogenic centers); and
the protecting group has a minimum of additional functionality to
avoid further sites of reaction. As detailed herein, oxygen,
sulfur, nitrogen and carbon protecting groups may be utilized.
Exemplary protecting groups are detailed herein, however, it will
be appreciated that the present invention is not intended to be
limited to these protecting groups; rather, a variety of additional
equivalent protecting groups can be readily identified using the
above criteria and utilized in the method of the present invention.
Additionally, a variety of protecting groups are described in
Protective Groups in Organic Synthesis, Third Ed. Greene, T. W. and
Wuts, P.G., Eds., John Wiley & Sons, New York: 1999, the entire
contents of which are hereby incorporated by reference.
Furthermore, a variety of carbon protecting groups are described in
Myers, A.; Kung, D. W.; Zhong, B.; Movassaghi, M.; Kwon, S. J. Am.
Chem. Soc. 1999, 121, 8401-8402, the entire contents of which are
hereby incorporated by reference.
[0010] It will be appreciated that the compounds, as described
herein, may be substituted with any number of substituents or
functional moieties. In general, the term "substituted" whether
preceded by the term "optionally" or not, and substituents
contained in formulas of this invention, refer to the replacement
of hydrogen radicals in a given structure with the radical of a
specified substituent. When more than one position in any given
structure may be substituted with more than one substituent
selected from a specified group, the substituent may be either the
same or different at every position. As used herein, the term
"substituted" is contemplated to include all permissible
substituents of organic compounds. In a broad aspect, the
permissible substituents include acyclic and cyclic, branched and
unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic
substituents of organic compounds. For purposes of this invention,
heteroatoms such as nitrogen may have hydrogen substituents and/or
any permissible substituents of organic compounds described herein
which satisfy the valencies of the heteroatoms. Furthermore, this
invention is not intended to be limited in any manner by the
permissible substituents of organic compounds. Combinations of
substituents and variables envisioned by this invention are
preferably those that result in the formation of stable compounds
useful in the treatment, for example of proliferative disorders,
including, but not limited to cancer. The term "stable", as used
herein, preferably refers to compounds which possess stability
sufficient to allow manufacture and which maintain the integrity of
the compound for a sufficient period of time to be detected and
preferably for a sufficient period of time to be useful for the
purposes detailed herein.
[0011] The term "acyl", as used herein, refers to a
carbonyl-containing functionality, e.g., --C(.dbd.O)R' wherein R'
is an aliphatic, alycyclic, heteroaliphatic, heterocyclic, aryl,
heteroaryl, (aliphatic)aryl, (heteroaliphatic)aryl,
heteroaliphatic(aryl) or heteroaliphatic(heteroaryl) moiety,
whereby each of the aliphatic, heteroaliphatic, aryl, or heteroaryl
moieties is substituted or unsubstituted, or is a substituted
(e.g., hydrogen or aliphatic, heteroaliphatic, aryl, or heteroaryl
moieties) oxygen or nitrogen containing functionality (e.g.,
forming a carboxylic acid, ester, or amide functionality).
[0012] The term "aliphatic", as used herein, includes both
saturated and unsaturated, straight chain (i.e., unbranched) or
branched aliphatic hydrocarbons, which are optionally substituted
with one or more functional groups. As will be appreciated by one
of ordinary skill in the art, "aliphatic" is intended herein to
include, but is not limited to, alkyl, alkenyl, alkynyl moieties.
Thus, as used herein, the term "alkyl" includes straight and
branched alkyl groups. An analogous convention applies to other
generic terms such as "alkenyl", "alkynyl" and the like.
Furthermore, as used herein, the terms "alkyl", "alkenyl",
"alkynyl" and the like encompass both substituted and unsubstituted
groups. In certain embodiments, as used herein, "lower alkyl" is
used to indicate those alkyl groups (substituted, unsubstituted,
branched or unbranched) having 1-6 carbon atoms.
[0013] In certain embodiments, the alkyl, alkenyl and alkynyl
groups employed in the invention contain 1-20 aliphatic carbon
atoms. In certain other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the invention contain 1-10 aliphatic
carbon atoms. In yet other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the invention contain 1-8 aliphatic
carbon atoms. In still other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the invention contain 1-6 aliphatic
carbon atoms. In yet other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the invention contain 1-4 carbon atoms.
Illustrative aliphatic groups thus include, but are not limited to,
for example, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl,
sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl,
tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which
again, may bear one or more substituents. Alkenyl groups include,
but are not limited to, for example, ethenyl, propenyl, butenyl,
1-methyl-2-buten-1-yl, and the like. Representative alkynyl groups
include, but are not limited to, ethynyl, 2-propynyl (propargy1),
1-propynyl and the like.
[0014] The term "alicyclic", as used herein, refers to compounds
which combine the properties of aliphatic and cyclic compounds and
include but are not limited to cyclic, or polycyclic aliphatic
hydrocarbons and bridged cycloalkyl compounds, which are optionally
substituted with one or more functional groups. As will be
appreciated by one of ordinary skill in the art, "alicyclic" is
intended herein to include, but is not limited to, cycloalkyl,
cycloalkenyl, and cycloalkynyl moieties, which are optionally
substituted with one or more functional groups. Illustrative
alicyclic groups thus include, but are not limited to, for example,
cyclopropyl, --CH.sub.2-cyclopropyl, cyclobutyl,
--CH.sub.2-cyclobutyl, cyclopentyl, --CH.sub.2-cyclopentyl-n,
cyclohexyl, --CH.sub.2-cyclohexyl, cyclohexenylethyl,
cyclohexanylethyl, norborbyl moieties and the like, which again,
may bear one or more substituents.
[0015] The term "alkoxy" (or "alkyloxy"), or "thioalkyl" as used
herein refers to an alkyl group, as previously defined, attached to
the parent molecular moiety through an oxygen atom or through a
sulfur atom. In certain embodiments, the alkyl group contains 1-20
aliphatic carbon atoms. In certain other embodiments, the alkyl
group contains 1-10 aliphatic carbon atoms. In yet other
embodiments, the alkyl, alkenyl, and alkynyl groups employed in the
invention contain 1-8 aliphatic carbon atoms. In still other
embodiments, the alkyl group contains 1-6 aliphatic carbon atoms.
In yet other embodiments, the alkyl group contains 1-4 aliphatic
carbon atoms. Examples of alkoxy, include but are not limited to,
methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy,
neopentoxy and n-hexoxy. Examples of thioalkyl include, but are not
limited to, methylthio, ethylthio, propylthio, isopropylthio,
n-butylthio, and the like.
[0016] The term "alkylamino" refers to a group having the structure
--NHR' wherein R' is alkyl, as defined herein. The term
"aminoalkyl" refers to a group having the structure NH.sub.2R'--,
wherein R' is alkyl, as defined herein. In certain embodiments, the
alkyl group contains 1-20 aliphatic carbon atoms. In certain other
embodiments, the alkyl group contains 1-10 aliphatic carbon atoms.
In yet other embodiments, the alkyl, alkenyl, and alkynyl groups
employed in the invention contain 1-8 aliphatic carbon atoms. In
still other embodiments, the alkyl group contains 1-6 aliphatic
carbon atoms. In yet other embodiments, the alkyl group contains
1-4 aliphatic carbon atoms. Examples of alkylamino include, but are
not limited to, methylamino, ethylamino, iso-propylamino and the
like.
[0017] Some examples of substituents of the above-described
aliphatic (and other) moieties of compounds of the invention
include, but are not limited to aliphatic; heteroaliphatic; aryl;
heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy;
heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio;
heteroarylthio; F; Cl; Br; I; --OH; --NO.sub.2; --CN; --CF.sub.3;
--CH.sub.2CF.sub.3; --CHCl.sub.2; --CH.sub.2OH;
--CH.sub.2CH.sub.2OH; --CH.sub.2NH.sub.2;
--CH.sub.2SO.sub.2CH.sub.3; --C(O)R.sub.x; --CO.sub.2(R.sub.x);
--CON(R.sub.x).sub.2; --OC(O)R.sub.x; --OCO.sub.2R.sub.x;
--OCON(R.sub.x).sub.2; --N(R.sub.x).sub.2; --S(O).sub.2R.sub.x;
--NR.sub.x(CO)R.sub.x wherein each occurrence of R.sub.x
independently includes, but is not limited to, aliphatic,
alycyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl,
alkylaryl, or alkylheteroaryl, wherein any of the aliphatic,
heteroaliphatic, alkylaryl, or alkylheteroaryl substituents
described above and herein may be substituted or unsubstituted,
branched or unbranched, cyclic or acyclic, and wherein any of the
aryl or heteroaryl substituents described above and herein may be
substituted or unsubstituted. Additional examples of generally
applicable substituents are illustrated by the specific embodiments
shown in the Examples that are described herein.
[0018] In general, the term "aromatic moiety", as used herein,
refers to a stable mono- or polycyclic, unsaturated moiety having
preferably 3-14 carbon atoms, each of which may be substituted or
unsubstituted. In certain embodiments, the term "aromatic moiety"
refers to a planar ring having p-orbitals perpendicular to the
plane of the ring at each ring atom and satisfying the Huckel rule
where the number of pi electrons in the ring is (4n+2) wherein n is
an integer. A mono- or polycyclic, unsaturated moiety that does not
satisfy one or all of these criteria for aromaticity is defined
herein as "non-aromatic", and is encompassed by the term
"alicyclic".
[0019] In general, the term "heteroaromatic moiety", as used
herein, refers to a stable mono- or polycyclic, unsaturated moiety
having preferably 3-14 carbon atoms, each of which may be
substituted or unsubstituted; and comprising at least one
heteroatom selected from O, S and N within the ring (i.e., in place
of a ring carbon atom). In certain embodiments, the term
"heteroaromatic moiety" refers to a planar ring comprising at least
on heteroatom, having p-orbitals perpendicular to the plane of the
ring at each ring atom, and satisfying the Huckel rule where the
number of pi electrons in the ring is (4n+2) wherein n is an
integer.
[0020] It will also be appreciated that aromatic and heteroaromatic
moieties, as defined herein may be attached via an alkyl or
heteroalkyl moiety and thus also include -(alkyl)aromatic,
-(heteroalkyl)aromatic, -(heteroalkyl)heteroaromatic, and
-(heteroalkyl)heteroaromatic moieties. Thus, as used herein, the
phrases "aromatic or heteroaromatic moieties" and "aromatic,
heteroaromatic, -(alkyl)aromatic, -(heteroalkyl)aromatic,
-(heteroalkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic" are
interchangeable. Substituents include, but are not limited to, any
of the previously mentioned substituents, i.e., the substituents
recited for aliphatic moieties, or for other moieties as disclosed
herein, resulting in the formation of a stable compound.
[0021] The term "aryl", as used herein, does not differ
significantly from the common meaning of the term in the art, and
refers to an unsaturated cyclic moiety comprising at least one
aromatic ring. In certain embodiments, "aryl" refers to a mono- or
bicyclic carbocyclic ring system having one or two aromatic rings
including, but not limited to, phenyl, naphthyl,
tetrahydronaphthyl, indanyl, indenyl and the like.
[0022] The term "heteroaryl", as used herein, does not differ
significantly from the common meaning of the term in the art, and
refers to a cyclic aromatic radical having from five to ten ring
atoms of which one ring atom is selected from S, O and N; zero, one
or two ring atoms are additional heteroatoms independently selected
from S, O and N; and the remaining ring atoms are carbon, the
radical being joined to the rest of the molecule via any of the
ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl,
pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,
thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,
isoquinolinyl, and the like.
[0023] It will be appreciated that aryl and heteroaryl groups
(including bicyclic aryl groups) can be unsubstituted or
substituted, wherein substitution includes replacement of one or
more of the hydrogen atoms thereon independently with any one or
more of the following moieties including, but not limited to:
aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic;
heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl;
alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy;
heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio;
heteroarylthio; F; Cl; Br; I; --OH; --NO.sub.2; --CN; --CF.sub.3;
--CH.sub.2CF.sub.3; --CHCl.sub.2; --CH.sub.2OH;
--CH.sub.2CH.sub.2OH; --CH.sub.2NH.sub.2;
--CH.sub.2SO.sub.2CH.sub.3; --C(O)R.sub.x; --CO.sub.2(R.sub.x);
--CON(R.sub.x).sub.2; --OC(O)R.sub.x; --OCO.sub.2R.sub.x;
--OCON(R.sub.x).sub.2; --N(R.sub.x).sub.2; --S(O)R.sub.x;
--S(O).sub.2R.sub.x; --NR.sub.x(CO)R.sub.x wherein each occurrence
of R.sub.x independently includes, but is not limited to,
aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic,
heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl,
heteroalkylaryl or heteroalkylheteroaryl, wherein any of the
aliphatic, alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or
alkylheteroaryl substituents described above and herein may be
substituted or unsubstituted, branched or unbranched, saturated or
unsaturated, and wherein any of the aromatic, heteroaromatic, aryl,
heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl substituents
described above and herein may be substituted or unsubstituted.
Additionally, it will be appreciated, that any two adjacent groups
taken together may represent a 4, 5, 6, or 7-membered substituted
or unsubstituted alicyclic or heterocyclic moiety. Additional
examples of generally applicable substituents are illustrated by
the specific embodiments shown in the Examples that are described
herein.
[0024] The term "cycloalkyl", as used herein, refers specifically
to groups having three to seven, preferably three to ten carbon
atoms. Suitable cycloalkyls include, but are not limited to
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
the like, which, as in the case of aliphatic, alicyclic,
heteroaliphatic or heterocyclic moieties, may optionally be
substituted with substituents including, but not limited to
aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic;
heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl;
alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy;
heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio;
heteroarylthio; F; Cl; Br; I; --OH; --NO.sub.2; --CN; --CF.sub.3;
--CH.sub.2CF.sub.3; --CHCl.sub.2; --CH.sub.2OH;
--CH.sub.2CH.sub.2OH; --CH.sub.2NH.sub.2;
--CH.sub.2SO.sub.2CH.sub.3; --C(O)R.sub.x; --CO.sub.2(R.sub.x);
--CON(R.sub.x).sub.2; --OC(O)R.sub.x; --OCO.sub.2R.sub.x;
--OCON(R.sub.x).sub.2; --N(R.sub.x).sub.2; --S(O).sub.2R.sub.x;
--NR.sub.x(CO)R.sub.x wherein each occurrence of R.sub.x
independently includes, but is not limited to, aliphatic,
alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic,
aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or
heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic,
heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl
substituents described above and herein may be substituted or
unsubstituted, branched or unbranched, saturated or usaturated, and
wherein any of the aromatic, heteroaromatic, aryl or heteroaryl
substituents described above and herein may be substituted or
unsubstituted. Additional examples of generally applicable
substituents are illustrated by the specific embodiments shown in
the Examples that are described herein.
[0025] The term "heteroaliphatic", as used herein, refers to
aliphatic moieties in which one or more carbon atoms in the main
chain have been substituted with a heteroatom. Thus, a
heteroaliphatic group refers to an aliphatic chain which contains
one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms,
e.g., in place of carbon atoms. Heteroaliphatic moieties may be
linear or branched, and saturated o runsaturated. In certain
embodiments, heteroaliphatic moieties are substituted by
independent replacement of one or more of the hydrogen atoms
thereon with one or more moieties including, but not limited to
aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic;
heteroaromatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl;
alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio;
heteroalkylthio; heteroarylthio; F; Cl; Br; I; --OH; --NO.sub.2;
--CN; --CF.sub.3; --CH.sub.2CF.sub.3; --CHCl.sub.2; --CH.sub.2OH;
--CH.sub.2CH.sub.2OH; --CH.sub.2NH.sub.2;
--CH.sub.2SO.sub.2CH.sub.3; --C(O)R.sub.x; --CO.sub.2(R.sub.x);
--CON(R.sub.x).sub.2; --OC(O)R.sub.x; --OCO.sub.2R.sub.x;
--OCON(R.sub.x).sub.2; --N(R.sub.x).sub.2; --S(O).sub.2R.sub.x;
--NR.sub.x(CO)R.sub.x wherein each occurrence of R.sub.x
independently includes, but is not limited to, aliphatic,
alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic,
aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or
heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic,
heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl
substituents described above and herein may be substituted or
unsubstituted, branched or unbranched, saturated or unsaturated,
and wherein any of the aromatic, heteroaromatic, aryl or heteroaryl
substituents described above and herein may be substituted or
unsubstituted. Additional examples of generally applicable
substituents are illustrated by the specific embodiments shown in
the Examples that are described herein.
[0026] The term "heterocycloalkyl", "heterocycle" or
"heterocyclic", as used herein, refers to compounds which combine
the properties of heteroaliphatic and cyclic compounds and include,
but are not limited to, saturated and unsaturated mono- or
polycyclic cyclic ring systems having 5-16 atoms wherein at least
one ring atom is a heteroatom selected from O, S and N (wherein the
nitrogen and sulfur heteroatoms may be optionally be oxidized),
wherein the ring systems are optionally substituted with one or
more functional groups, as defined herein. In certain embodiments,
the term "heterocycloalkyl", "heterocycle" or "heterocyclic" refers
to a non-aromatic 5-, 6-, or 7-membered ring or a polycyclic group
wherein at least one ring atom is a heteroatom selected from O, S
and N (wherein the nitrogen and sulfur heteroatoms may be
optionally be oxidized), including, but not limited to, a bi- or
tri-cyclic group, comprising fused six-membered rings having
between one and three heteroatoms independently selected from
oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0
to 2 double bonds, each 6-membered ring has 0 to 2 double bonds and
each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and
sulfur heteroatoms may be optionally be oxidized, (iii) the
nitrogen heteroatom may optionally be quaternized, and (iv) any of
the above heterocyclic rings may be fused to an aryl or heteroaryl
ring. Representative heterocycles include, but are not limited to,
heterocycles such as furanyl, thiofuranyl, pyranyl, pyrrolyl,
thienyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,
imidazolidinyl, piperidinyl, piperazinyl, oxazolyl, oxazolidinyl,
isooxazolyl, isoxazolidinyl, dioxazolyl, thiadiazolyl, oxadiazolyl,
tetrazolyl, triazolyl, thiatriazolyl, oxatriazolyl, thiadiazolyl,
oxadiazolyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,
isothiazolidinyl, dithiazolyl, dithiazolidinyl, tetrahydrofuryl,
and benzofused derivatives thereof. In certain embodiments, a
"substituted heterocycle, or heterocycloalkyl or heterocyclic"
group is utilized and as used herein, refers to a heterocycle, or
heterocycloalkyl or heterocyclic group, as defined above,
substituted by the independent replacement of one, two or three of
the hydrogen atoms thereon with but are not limited to aliphatic;
alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic;
aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl;
heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy;
heteroaryloxy; alkylthio; arylthio; heteroalkylthio;
heteroarylthio; F; Cl; Br; I; --OH; --NO.sub.2; --CN; --CF.sub.3;
--CH.sub.2CF.sub.3; --CHCl.sub.2; --CH.sub.2OH;
--CH.sub.2CH.sub.2OH; --CH.sub.2NH.sub.2;
--CH.sub.2SO.sub.2CH.sub.3; --C(O)R.sub.x; --CO.sub.2(R.sub.x);
--CON(R.sub.x).sub.2; --OC(O)R.sub.x; --OCO.sub.2R.sub.x;
--OCON(R.sub.x).sub.2; --N(R.sub.x).sub.2; --S(O).sub.2R.sub.x;
--NR.sub.x(CO)R.sub.x wherein each occurrence of R.sub.x
independently includes, but is not limited to, aliphatic,
alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic,
aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or
heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic,
heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl
substituents described above and herein may be substituted or
unsubstituted, branched or unbranched, saturated or unsaturated,
and wherein any of the aromatic, heteroaromatic, aryl or heteroaryl
substitutents described above and herein may be substituted or
unsubstituted. Additional examples or generally applicable
substituents are illustrated by the specific embodiments shown in
the Examples, which are described herein.
[0027] Additionally, it will be appreciated that any of the
alicyclic or heterocyclic moieties described above and herein may
comprise an aryl or heteroaryl moiety fused thereto. Additional
examples of generally applicable substituents are illustrated by
the specific embodiments shown in the Examples that are described
herein. The terms "halo" and "halogen" as used herein refer to an
atom selected from fluorine, chlorine, bromine and iodine.
[0028] The terms "halo" and "halogen" as used herein refer to an
atom selected from fluorine, chlorine, bromine, and iodine.
[0029] The term "haloalkyl" denotes an alkyl group, as defined
above, having one, two, or three halogen atoms attached thereto and
is exemplified by such groups as chloromethyl, bromoethyl,
trifluoromethyl, and the like.
[0030] The term "amino", as used herein, refers to a primary
(--NH.sub.2), secondary (--NHR.sub.x), tertiary (--NR.sub.xR.sub.y)
or quaternary (--N.sup.+R.sub.xR.sub.yR.sub.z) amine, where
R.sub.x, R.sub.y and R.sub.z are independently an aliphatic,
alicyclic, heteroaliphatic, heterocyclic, aromatic or
heteroaromatic moiety, as defined herein. Examples of amino groups
include, but are not limited to, methylamino, dimethylamino,
ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino,
iso-propylamino, piperidino, trimethylamino, and propylamino.
[0031] The term "alkylidene", as used herein, refers to a
substituted or unsubstituted, linear or branched saturated divalent
radical consisting solely of carbon and hydrogen atoms, having from
one to n carbon atoms, having a free valence "-" at both ends of
the radical.
[0032] The term "alkenylidene", as used herein, refers to a
substituted or unsubstituted, linear or branched unsaturated
divalent radical consisting solely of carbon and hydrogen atoms,
having from two to n carbon atoms, having a free valence "-" at
both ends of the radical, and wherein the unsaturation is present
only as double bonds and wherein a double bond can exist between
the first carbon of the chain and the rest of the molecule.
[0033] The term "alkynylidene", as used herein, refers to a
substituted or unsubstituted, linear or branched unsaturated
divalent radical consisting solely of carbon and hydrogen atoms,
having from two to n carbon atoms, having a free valence "-" at
both ends of the radical, and wherein the unsaturation is present
only as triple bonds and wherein a triple bond can exist between
the first carbon of the chain and the rest of the molecule.
[0034] Unless otherwise indicated, as used herein, the terms
"alkyl", "alkenyl", "alkynyl", "heteroalkyl", "heteroalkenyl",
"heteroalkynyl", "alkylidene", alkenylidene", -(alkyl)aryl,
-(heteroalkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)heteroaryl,
and the like encompass substituted and unsubstituted, and linear
and branched groups. Similarly, the terms "aliphatic",
"heteroaliphatic", and the like encompass substituted and
unsubstituted, saturated and unsaturated, and linear and branched
groups. Similarly, the terms "cycloalkyl", "heterocycle",
"heterocyclic", and the like encompass substituted and
unsubstituted, and saturated and unsaturated groups. Additionally,
the terms "cycloalkenyl", "cycloalkynyl", "heterocycloalkenyl",
"heterocycloalkynyl", "aromatic", "heteroaromatic, "aryl",
"heteroaryl" and the like encompass both substituted and
unsubstituted groups.
[0035] The phrase, "pharmaceutically acceptable derivative", as
used herein, denotes any pharmaceutically acceptable salt, ester,
or salt of such ester, of such compound, or any other adduct or
derivative which, upon administration to a patient, is capable of
providing (directly or indirectly) a compound as otherwise
described herein, or a metabolite or residue thereof.
Pharmaceutically acceptable derivatives thus include among others
pro-drugs. A pro-drug is a derivative of a compound, usually with
significantly reduced pharmacological activity, which contains an
additional moiety, which is susceptible to removal in vivo yielding
the parent molecule as the pharmacologically active species. An
example of a pro-drug is an ester, which is cleaved in vivo to
yield a compound of interest. Pro-drugs of a variety of compounds,
and materials and methods for derivatizing the parent compounds to
create the pro-drugs, are known and may be adapted to the present
invention. Pharmaceutically acceptable derivatives also include
"reverse pro-drugs." Reverse pro-drugs, rather than being
activated, are inactivated upon absorption. For example, as
discussed herein, many of the ester-containing compounds of the
invention are biologically active but are inactivated upon exposure
to certain physiological environments such as a blood, lymph,
serum, extracellular fluid, etc. which contain esterase activity.
The biological activity of reverse pro-drugs and pro-drugs may also
be altered by appending a functionality onto the compound, which
may be catalyzed by an enzyme. Also, included are oxidation and
reduction reactions, including enzyme-catalyzed oxidation and
reduction reactions. Certain exemplary pharmaceutical compositions
and pharmaceutically acceptable derivatives will be discussed in
more detail herein below.
[0036] The term "linker," as used herein, refers to a chemical
moiety utilized to attach one part of a compound of interest to
another part of the compound. Exemplary linkers are described
herein.
[0037] Unless indicated otherwise, the terms defined below have the
following meanings:
[0038] "Compound": The term "compound" or "chemical compound" as
used herein can include organometallic compounds, organic
compounds, metals, transitional metal complexes, and small
molecules. In certain preferred embodiments, polynucleotides are
excluded from the definition of compounds. In other preferred
embodiments, polynucleotides and peptides are excluded from the
definition of compounds. In a particularly preferred embodiment,
the term compounds refers to small molecules (e.g., preferably,
non-peptidic and non-oligomeric) and excludes peptides,
polynucleotides, transition metal complexes, metals, and
organometallic compounds.
[0039] "Small Molecule": As used herein, the term "small molecule"
refers to a non-peptidic, non-oligomeric organic compound either
synthesized in the laboratory or found in nature. Small molecules,
as used herein, can refer to compounds that are "natural
product-like", however, the term "small molecule" is not limited to
"natural product-like" compounds. Rather, a small molecule is
typically characterized in that it contains several carbon-carbon
bonds, and has a molecular weight of less than 2000 g/mol,
preferably less than 1500 g/mol, although this characterization is
not intended to be limiting for the purposes of the present
invention. Examples of "small molecules" that occur in nature
include, but are not limited to, taxol, dynemicin, and rapamycin.
Examples of "small molecules" that are synthesized in the
laboratory include, but are not limited to, compounds described in
Tan et al., ("Stereoselective Synthesis of over Two Million
Compounds Having Structural Features Both Reminiscent of Natural
Products and Compatible with Miniaturized Cell-Based Assays" J. Am.
Chem. Soc. 120:8565, 1998; incorporated herein by reference). In
certain other preferred embodiments, natural-product-like small
molecules are utilized.
[0040] "Natural Product-Like Compound": As used herein, the term
"natural product-like compound" refers to compounds that are
similar to complex natural products which nature has selected
through evolution. Typically, these compounds contain one or more
stereocenters, a high density and diversity of functionality, and a
diverse selection of atoms within one structure. In this context,
diversity of functionality can be defined as varying the topology,
charge, size, hydrophilicity, hydrophobicity, and reactivity to
name a few, of the functional groups present in the compounds. The
term, "high density of functionality", as used herein, can
preferably be used to define any molecule that contains preferably
three or more latent or active diversifiable functional moieties.
These structural characteristics may additionally render the
inventive compounds functionally reminiscent of complex natural
products, in that they may interact specifically with a particular
biological receptor, and thus may also be functionally natural
product-like.
[0041] "Metal chelator": As used herein, the term "metal chelator"
refers to any molecule or moiety that is capable of forming a
complex (i.e., "chelates") with a metal ion. In certain exemplary
embodiments, a metal chelator refers to to any molecule or moiety
that "binds" to a metal ion, in solution, making it unavailable for
use in chemical/enzymatic reactions. In certain embodiments, the
solution comprises aqueous environments under physiological
conditions. Examples of metal ions include, but are not limited to,
Ca.sup.2+, Fe.sup.3+, Zn.sup.2+, Na.sup.+, etc. In certain
embodiments, the metal chelator binds Zn.sup.2+. In certain
embodiments, molecules of moieties that precipitate metal ions are
not considered to be metal chelators.
[0042] As used herein the term "biological sample" includes,
without limitation, cell cultures or extracts thereof; biopsied
material obtained from an animal (e.g., mammal) or extracts
thereof; and blood, saliva, urine, feces, semen, tears, or other
body fluids or extracts thereof. For example, the term "biological
sample" refers to any solid or fluid sample obtained from, excreted
by or secreted by any living organism, including single-celled
micro-organisms (such as bacteria and yeasts) and multicellular
organisms (such as plants and animals, for instance a vertebrate or
a mammal, and in particular a healthy or apparently healthy human
subject or a human patient affected by a condition or disease to be
diagnosed or investigated). The biological sample can be in any
form, including a solid material such as a tissue, cells, a cell
pellet, a cell extract, cell homogenates, or cell fractions; or a
biopsy, or a biological fluid. The biological fluid may be obtained
from any site (e.g., blood, saliva (or a mouth wash containing
buccal cells), tears, plasma, serum, urine, bile, cerebrospinal
fluid, amniotic fluid, peritoneal fluid, and pleural fluid, or
cells therefrom, aqueous or vitreous humor, or any bodily
secretion), a transudate, an exudate (e.g. fluid obtained from an
abscess or any other site of infection or inflammation), or fluid
obtained from a joint (e.g. a normal joint or a joint affected by
disease such as rheumatoid arthritis, osteoarthritis, gout or
septic arthritis). The biological sample can be obtained from any
organ or tissue (including a biopsy or autopsy specimen) or may
comprise cells (whether primary cells or cultured cells) or medium
conditioned by any cell, tissue or organ. Biological samples may
also include sections of tissues such as frozen sections taken for
histological purposes. Biological samples also include mixtures of
biological molecules including proteins, lipids, carbohydrates and
nucleic acids generated by partial or complete fractionation of
cell or tissue homogenates. Although the sample is preferably taken
from a human subject, biological samples may be from any animal,
plant, bacteria, virus, yeast, etc. The term animal, as used
herein, refers to humans as well as non-human animals, at any stage
of development, including, for example, mammals, birds, reptiles,
amphibians, fish, worms and single cells. Cell cultures and live
tissue samples are considered to be pluralities of animals. In
certain exemplary embodiments, the non-human animal is a mammal
(e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat,
a sheep, cattle, a primate, or a pig). An animal may be a
transgenic animal or a human clone. If desired, the biological
sample may be subjected to preliminary processing, including
preliminary separation techniques.
BRIEF DESCRIPTION OF THE DRAWING
[0043] FIG. 1 includes a table of esterases found in human and
mouse plasma.
[0044] FIG. 2 shows the design of a reverse pro-drug version of
SAHA-SAHP.
[0045] FIG. 3 illustrates the stability of SAHA (with an amide) in
PBS.
[0046] FIG. 4 illustrates the stability of SAHA in serum.
[0047] FIG. 5 shows the stability of SAHP (ester instead of amdie)
in PBS.
[0048] FIG. 6 shows the degradation of SAHP in serum. In less than
15 minutes, SAHP is completely degraded.
[0049] FIG. 7 shows a more detailed study of the degradation of
SAHP in serum. In less than 2 minutes, SAHP is completely degraded
into phenol and the corresponding carboxylic acid.
[0050] FIG. 8 shows the degradation of SAHP by human serum under
various conditions.
[0051] FIG. 9 shows the degradation of SAHP by recombinant
paraoxonase.
[0052] FIG. 10 shows the degradation of SAHP in RPMI media with 10%
FBS.
[0053] FIG. 11 shows the effect of SAHA v. SAHP on lysine
acetylation.
[0054] FIG. 12 shows the stability of SAHP in an olive oil/acetone
formulation for murine model.
[0055] FIG. 13 is an exemplary synthetic scheme for preparing
SAHP.
[0056] FIG. 14. Interleukin-7 is a growth factor for T-cell
development, in particular the gamma-delta subset. Transgenic mice
overexpressing IL-7 in keratinocytes were developed by the
laboratories of Thomas Kupper and Benjamin Rich, using a
tissue-specific keratin-14 promoter element. These mice have been
reported to develop a characteristic lymphoproliferative skin
disease grossly and histologically similar to human cutaneous
T-cell lymphoma (CTCL). Transformed lymphocytes derived from
involved skin were passaged ex vivo and injected into syngeneic
(non-transgenic) mice. After fourteen days, these mice develop a
homogeneous lymphoproliferative disease. Two cohorts of five mice
were included in a prospective study of topical, daily suberoyl
hydroxamic acid phenyl ester (SAHP, also known as SHAPE) versus
vehicle control. After fourteen days of therapy, mice were
sacrificed and the treated region was dissected for histopathologic
examination. In SHAPE-treated mice, hematoxylin-eosin staining
demonstrates a marked reduction in lymphomatous infiltration within
the treated window. Vehicle control mice failed to demonstrate a
cytotoxic response.
[0057] FIG. 15 shows the pharmacodynamic effect of SAHP treatment
as assessed using immunohistochemical staining for acetylated
histones compared to vehicle treated controls. In SAHP-treated
mice, AcH3K18 staining demonstrates hyperacetylated histone
staining at the margin of compound treatment, with absent nuclear
staining in the region of drug response. Vehicle control mice
failed to demonstrate an increase in histone hyperacetylation.
DETAILED DESCRIPTION OF THE INVENTION
[0058] As discussed above, there remains a need for the development
of novel histone deacetylase inhibitors. The present invention
provides novel compounds of general formula (I), and methods for
the synthesis thereof, which compounds are useful as inhibitors of
histone deacetylases, and thus are useful for the treatment of
proliferative diseases, particularly proliferative or other
disorders associated with the skin and/or hair. In particular, the
inventive compounds comprise an ester linkage. The ester linkage is
preferably sensitive to esterase cleavage; therefore, when the
compound is contacted with an esterase it is deactivated.
Compounds of the Invention
[0059] As discussed above, the present invention provides a novel
class of compounds useful for the treatment of cancer and other
proliferative conditions related thereto. In certain embodiments,
the compounds of the present invention are useful as inhibitors of
histone deacetylases and thus are useful as anticancer agents, and
thus may be useful in the treatment of cancer, by effecting tumor
cell death or inhibiting the growth of tumor cells. In certain
exemplary embodiments, the inventive anticancer agents are useful
in the treatment of cancers and other proliferative disorders,
including, but not limited to breast cancer, cervical cancer, colon
and rectal cancer, leukemia, lung cancer, melanoma, multiple
myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer,
prostate cancer, and gastric cancer, to name a few. In certain
embodiments, the inventive anticancer agents are active against
leukemia cells and melanoma cells, and thus are useful for the
treatment of leukemias (e.g., myeloid, lymphocytic, myelocytic and
lymphoblastic leukemias) and malignant melanomas. In certain
embodiments, the inventive compounds are active against cutaneous
T-cell lymphoma. Additionally, as described above and in the
exemplification, the inventive compounds may also be useful in the
treatment of protozoal infections. In certain exemplary
embodiments, the compounds of the invention are useful for
disorders resulting from histone deacetylation activity. In certain
embodiments, the compounds are useful for skin disorders. Examplary
skin disorders that may be treated using the inventive compounds
include cutaneous T-cell lymphoma (CTCL), skin cancers (e.g.,
squamous cell carcinoma, basal cell carcinoma, malignant melanoma,
etc.), psoriasis, hair loss, dermatitis, neurofibromatosis,
disorders asscoiated with skin hyperpigmentation, etc.
[0060] Compounds of this invention comprise those, as set forth
above and described herein, and are illustrated in part by the
various classes, subgenera and species disclosed elsewhere
herein.
[0061] In general, the present invention provides compounds having
the general structure (I):
##STR00002##
and pharmaceutically acceptable salts and derivatives thereof;
wherein
[0062] A comprises a functional group that inhibits histone
deacetylase;
[0063] L is a linker moiety; and
[0064] Ar is a substituted or unsubstituted aryl or heteroaryl
moiety; substituted or unsustituted, branched or unbranched
arylaliphatic or heteroarylaliphatic moiety; a substituted or
unsubstituted cyclic or heterocyclic moiety; substituted or
unsustituted, branched or unbranched cyclicaliphatic or
heterocyclicaliphatic moiety.
[0065] In certain embodiments, A comprises a metal chelating
functional group. For example, A comprises a Zn.sup.2+ chelating
group. In certain embodiments, A comprises a functional group
selected group consisting of:
##STR00003##
In certain embodiments, A comprises hydroxamic acid
##STR00004##
or a salt thereof. In other embodiments, A comprises the
formula:
##STR00005##
In certain particular embodiments, A comprises the formula:
##STR00006##
In other embodiments, A comprises a carboxylic acid (--CO.sub.2H).
In other embodiments, A comprises an o-aminoanilide
##STR00007##
In other embodiments, A comprises an o-hydroxyanilide
##STR00008##
In yet other embodiments, A comprises a thiol (--SH).
[0066] In certain embodiments, Ar is arylaliphatic. In other
embodiments, Ar is heteroarylaliphatic. In certain embodiments, Ar
is a substituted or unsubstituted aryl moiety. In certain
embodiments, Ar is a monocylic, substituted or unsubstituted aryl
moiety, preferably a five- or six-membered aryl moiety. In other
embodiments, Ar is a bicyclic, substituted or unsubstituted aryl
moiety. In still other embodiments, Ar is a tricyclic, substituted
or unsubstituted aryl moiety. In certain embodiments, Ar is a
susbstituted or unsubstituted phenyl moiety. In certain
embodiments, Ar is an unsubstituted phenyl moiety. In other
embodiments, Ar is a substituted phenyl moiety. In certain
embodiments, Ar is a monosubstituted phenyl moiety. In certain
particular embodiments, Ar is an ortho-substituted Ar moiety. In
certain particular embodiments, Ar is an meta-substituted Ar
moiety. In certain particular embodiments, Ar is an
para-substituted Ar moiety. In certain embodiments, Ar is a
disubstituted phenyl moiety. In certain embodiments, Ar is a
trisubstituted phenyl moiety. In certain embodiments, Ar is a
tetrasubstituted phenyl moiety. In certain embodiments, Ar is a
substituted or unsubstituted cyclic or heterocyclic.
[0067] In certain embodiments, Ar is a substituted or unsubstituted
heteroaryl moiety. In certain embodiments, Ar is a monocylic,
substituted or unsubstituted heteroaryl moiety, preferably a five-
or six-membered heteroaryl moiety. In other embodiments, Ar is a
bicyclic, substituted or unsubstituted heteroaryl moiety. In still
other embodiments, Ar is a tricyclic, substituted or unsubstituted
heteroaryl moiety. In certain embodiments, Ar comprises N, S, or O.
In certain embodiments, Ar comprises at least one N. In certain
embodiments, Ar comprises at least two N.
[0068] In certain embodiments, Ar is:
##STR00009##
wherein
[0069] n is an integer between 1 and 5, inclusive; preferably,
between 1 and 3, inclusive; more preferably, 1 or 2;
[0070] R.sub.1 is hydrogen; halogen; cyclic or acyclic, substituted
or unsubstituted, branched or unbranched aliphatic; cyclic or
acyclic, substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.A; --C(.dbd.O)R.sub.A;
--CO.sub.2R.sub.A; --CN; --SCN; --SR.sub.A; --SOR.sub.A;
--SO.sub.2R.sub.A; --NO.sub.2; --N(R.sub.A).sub.2;; --NHR.sub.A;
--NHC(O)R.sub.A; or --C(R.sub.A).sub.3; wherein each occurrence of
R.sub.A is independently a hydrogen, a protecting group, an
aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl
moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio
moiety. In certain embodiments, Ar is
##STR00010##
In other embodiments, Ar is
##STR00011##
In yet other embodiments, Ar is
##STR00012##
In certain embodiments, R.sub.1 is --N(R.sub.A).sub.2, wherein
R.sub.A is hydrogen or C.sub.1-C.sub.6 alkyl. In certain
embodiments, R.sub.1 is --OR.sub.A, wherein R.sub.A is hydrogen or
C.sub.1-C.sub.6 alkyl. In certain particular embodiments, R.sub.1
is --OMe. In certain embodiments, R.sub.1 is branched or unbranched
acyl. In certain embodiments, R.sub.1 is --O(.dbd.O)OR.sub.A. In
certain embodiments, R.sub.1 is --C(.dbd.O)OR.sub.A, wherein
R.sub.A is hydrogen or C.sub.1-C.sub.6 alkyl. In certain
embodiments, R.sub.1 is --C(.dbd.O)NH.sub.2. In certain
embodiments, R.sub.1 is --NHC(.dbd.O)R.sub.A. In certain
embodiments, R.sub.1 is --NHC(.dbd.O)R.sub.A, wherein R.sub.A is
hydrogen or C.sub.1-C.sub.6 alkyl. In certain embodiments, R.sub.1
is halogen. In certain embodiments, R.sub.1 is C.sub.1-C.sub.6
alkyl.
[0071] In certain particular embodiments, Ar is a substituted
phenyl moiety of formula:
##STR00013##
[0072] In certain embodiments, Ar is chosen from one of the
following:
##STR00014##
wherein
[0073] n is an integer between 1 and 4, inclusive; preferably,
between 1 and 3, inclusive; more preferably, 1 or 2;
[0074] R.sub.1 is hydrogen; halogen; cyclic or acyclic, substituted
or unsubstituted, branched or unbranched aliphatic; cyclic or
acyclic, substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.A; --C(.dbd.O)R.sub.A;
--CO.sub.2R.sub.A; --CN; --SCN; --SR.sub.A; --SOR.sub.A;
--SO.sub.2R.sub.A; --NO.sub.2; --N(R.sub.A).sub.2;; --NHR.sub.A;
--NHC(O)R.sub.A; or --C(R.sub.A).sub.3; wherein each occurrence of
R.sub.A is independently a hydrogen, a protecting group, an
aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl
moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio
moiety.
[0075] In certain embodiments, Ar is chosen from one of the
following:
##STR00015##
Any of the above bicyclic ring system may be substituted with up to
seven R.sub.1 susbstituents as defined above.
[0076] In certain embodiments, L is a substituted or unsubstituted,
cyclic or acyclic, branched or unbranched aliphatic moiety; a
substituted or unsubstituted, cyclic or acyclic, branched or
unbranched heteroaliphatic moiety; a substituted or unsubstituted
aryl moiety; a substituted or unsubstituted heteroaryl moiety. In
certain embodiments, L is a substituted or unsubstituted, cyclic or
acyclic, branched or unbranched aliphatic moiety. In certain
embodiments, L is C.sub.1-C.sub.20 alkylidene, preferably C.sub.1
to C.sub.12 alkylidene, more preferably C.sub.4-C.sub.7 alkylidene.
In certain embodiments, L is C.sub.1-C.sub.20 alkenylidene,
preferably C.sub.1 to C.sub.12 alkenylidene, more preferably
C.sub.4-C.sub.7 alkenylidene. In certain embodiments, L is
C.sub.1-C.sub.20 alkynylidene, preferably C.sub.1 to C.sub.12
alkynylidene, more preferably C.sub.4-C.sub.7 alkynylidene. In
certain embodiments, L is a a substituted or unsubstituted, cyclic
or acyclic, branched or unbranched heteroaliphatic moiety. In
certain embodiments, L comprises a cyclic ring system, wherein the
rings may be aryl, heteroaryl, non-aromatic carbocyclic, or
non-aromatic heterocyclic. In still other embodiments, L comprises
a substituted or unsubstituted heteroaryl moiety. In certain
particular embodiments, L comprises a phenyl ring. In certain
embodiments, L comprises multiple phenyl rings (e.g., one, two,
three, or four phenyl rings).
[0077] In certain embodiments, L is
##STR00016##
wherein n is an integer between 1 and 4, inclusive; preferably,
between 1 and 3, inclusive; more preferably, 1 or 2; and R.sub.1 is
is hydrogen; halogen; cyclic or acyclic, substituted or
unsubstituted, branched or unbranched aliphatic; cyclic or acyclic,
substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.A; --C(.dbd.O)R.sub.A;
--CO.sub.2R.sub.A; --CN; --SCN; --SR.sub.A; --SOR.sub.A;
--SO.sub.2R.sub.A; --NO.sub.2; --N(R.sub.A).sub.2;; --NHR.sub.A;
--NHC(O)R.sub.A; or --C(R.sub.A).sub.3; wherein each occurrence of
R.sub.A is independently a hydrogen, a protecting group, an
aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl
moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio
moiety. In certain embodiments, L is
##STR00017##
[0078] In certain embodiments, L is
##STR00018##
[0079] In certain embodiments, L is an unbranched, unsubstituted,
acyclic alkyl chain. In certain embodiments, L is
##STR00019##
In other embodiments, L is
##STR00020##
In certain other embodiments, L is
##STR00021##
In other embodiments, L is
##STR00022##
In yet other embodiments, L is
##STR00023##
[0080] In certain embodiments, L is a substituted, acyclic
aliphatic chain. In certain embodiments, L is
##STR00024##
[0081] In certain embodiments, L is an unbranched, unsubstituted,
acyclic heteroaliphatic chain. In certain particular embodiments, L
is
##STR00025##
wherein n is an integer between 0 and 10, inclusive; preferably,
between 0 and 5, inclusive; and m is an integer between 0 and 10,
inclusive; preferably, between 0 and 5, inclusive. In certain
particular embodiments, L is
##STR00026##
wherein n is an integer between 0 and 10, inclusive; preferably,
between 0 and 5, inclusive; and m is an integer between 0 and 10,
inclusive; preferably, between 0 and 5, inclusive. In certain
particular embodiments, L is
##STR00027##
wherein n is an integer between 0 and 10, inclusive; preferably,
between 0 and 5, inclusive; m is an integer between 0 and 10,
inclusive; preferably, between 0 and 5, inclusive; and R' is
hydrogen, C.sub.1-C.sub.6 aliphatic, heteroaliphatic, aryl,
heteroaryl, or acyl. In certain particular embodiments, L is
##STR00028##
wherein n is an integer between 0 and 10, inclusive; preferably,
between 0 and 5, inclusive; and m is an integer between 0 and 10,
inclusive; preferably, between 0 and 5, inclusive.
[0082] In certain embodiments of the invention, compounds of
formula (I) have the following structure as shown in formula
(Ia):
##STR00029##
wherein
[0083] n is an integer between 0 and 15, inclusive; preferably,
between 0 and 10, inclusive; more preferably, between 1 and 8,
inclusive; even more preferably, 4, 5, 6, 7, or 8; and
[0084] Ar is defined as above. In certain embodiments, n is 5. In
other embodiments, n is 6. In still other embodiments, n is 7.
[0085] In certain embodiments of the invention, compounds of
formula (I) have the following structure as shown in formula
(Ib):
##STR00030##
wherein
[0086] n is an integer between 0 and 15, inclusive; preferably,
between 0 and 10, inclusive; more preferably, between 1 and 8,
inclusive; even more preferably, 4, 5, 6, 7, or 8;
[0087] m is an integer between 1 and 5, inclusive; preferably, m is
1, 2, or 3; and
[0088] R.sub.1 is hydrogen; halogen; cyclic or acyclic, substituted
or unsubstituted, branched or unbranched aliphatic; cyclic or
acyclic, substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.A; --C(.dbd.O)R.sub.A;
--CO.sub.2R.sub.A; --CN; --SCN; --SR.sub.A; --SOR.sub.A;
--SO.sub.2R.sub.A; --NO.sub.2; --N(R.sub.A).sub.2; --NHC(O)R.sub.A;
or --C(R.sub.A).sub.3; wherein each occurrence of R.sub.A is
independently a hydrogen, a protecting group, an aliphatic moiety,
a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a
heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino,
alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
In certain embodiments, R.sub.1 is hydrogen, halogen, hydroxy,
amino, alkylamino, dialkylamino, nitroso, acyl, or C.sub.1-C.sub.6
alkyl. In certain embodiments, R.sub.1 is aryl. In certain
embodiments, R.sub.1 is a multicyclic aryl moiety. In other
embodiments, R.sub.1 is heteroaryl. In certain embodiments, R.sub.1
is carbocyclic. In other embodiments, R.sub.1 is heterocyclic. In
certain embodiments R.sub.1 comprises a 1,3-dioxane ring optionally
substituted. In certain embodiments, n is 5. In other embodiments,
n is 6. In still other embodiments, n is 7. In certain embodiments,
m is 0. In other embodiments, m is 1. In still other embodiments, m
is 2.
[0089] In certain embodiments of the invention, compounds of
formula (I) are of the formula (Ic):
##STR00031##
wherein
[0090] n is an integer between 0 and 15, inclusive; preferably,
between 0 and 10, inclusive; more preferably, between 1 and 8,
inclusive; even more preferably, 4, 5, 6, 7, or 8; and
[0091] R.sub.1 is hydrogen; halogen; cyclic or acyclic, substituted
or unsubstituted, branched or unbranched aliphatic; cyclic or
acyclic, substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.A; --C(.dbd.O)R.sub.A;
--CO.sub.2R.sub.A; --CN; --SCN; --SR.sub.A; --SOR.sub.A;
--SO.sub.2R.sub.A; --NO.sub.2; --N(R.sub.A).sub.2; --NHC(O)R.sub.A;
or --C(R.sub.A).sub.3; wherein each occurrence of R.sub.A is
independently a hydrogen, a protecting group, an aliphatic moiety,
a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a
heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino,
alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
In certain embodiments, R.sub.1 is hydrogen, halogen, hydroxy,
amino, alkylamino, dialkylamino, nitroso, acyl, or C.sub.1-C.sub.6
alkyl. In certain embodiments, R.sub.1 is aryl. In other
embodiments, R.sub.1 is heteroaryl. In certain embodiments, R.sub.1
is carbocyclic. In other embodiments, R.sub.1 is heterocyclic. In
certain embodiments, n is 5. In other embodiments, n is 6. In still
other embodiments, n is 7.
[0092] In certain embodiments of the invention, compounds of
formula (I) are of the formula (Id):
##STR00032##
wherein
[0093] n is an integer between 1 and 5, inclusive; preferably,
between 1 and 3; more preferably, 1 or 2; and
[0094] R.sub.1 is hydrogen; halogen; cyclic or acyclic, substituted
or unsubstituted, branched or unbranched aliphatic; cyclic or
acyclic, substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.A; --C(.dbd.O)R.sub.A;
--CO.sub.2R.sub.A; --CN; --SCN; --SR.sub.A; --SOR.sub.A;
--SO.sub.2R.sub.A; --NO.sub.2; --N(R.sub.A).sub.2; --NHC(O)R.sub.A;
or --C(R.sub.A).sub.3; wherein each occurrence of R.sub.A is
independently a hydrogen, a protecting group, an aliphatic moiety,
a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a
heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino,
alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
In certain embodiments, R.sub.1 is hydrogen, halogen, hydroxy,
amino, alkylamino, dialkylamino, nitroso, acyl, or C.sub.1-C.sub.6
alkyl. In certain embodiments, R.sub.1 is aryl. In other
embodiments, R.sub.1 is heteroaryl. In certain embodiments, R.sub.1
is carbocyclic. In other embodiments, R.sub.1 is heterocyclic. In
certain embodiments, n is 1. In other embodiments, n is 2.
[0095] In certain embodiments of the invention, compounds of
formula (I) are of the formula (Ie):
##STR00033##
wherein R1 is defined as above.
[0096] In certain embodiments of the invention, compounds of
formula (I) have the following stereochemistry and structure as
shown in formula (If):
##STR00034##
wherein A, L and Ar are defined as above; and
[0097] n is an integer between 0 and 10, inclusive; preferably,
between 0 and 5, inclusive; even more preferably, 0, 1, 2, or 3. In
certain embodiments, Ar is phenyl.
[0098] In certain embodiments, compounds of formula (I) are of the
formula (Ig):
##STR00035##
wherein
[0099] A and L are defined as above;
[0100] R.sub.2 is hydrogen; halogen; cyclic or acyclic, substituted
or unsubstituted, branched or unbranched aliphatic; cyclic or
acyclic, substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.B; --C(.dbd.O)R.sub.B;
--CO.sub.2R.sub.B; --CN; --SCN; --SR.sub.B; --SOR.sub.B;
--SO.sub.2R.sub.B; --NO.sub.2; --N(R.sub.B).sub.2; --NHC(O)R.sub.B;
or --C(R.sub.B).sub.3; wherein each occurrence of R.sub.B is
independently a hydrogen, a protecting group, an aliphatic moiety,
a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a
heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino,
alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;
and
[0101] R.sub.3 is hydrogen; halogen; cyclic or acyclic, substituted
or unsubstituted, branched or unbranched aliphatic; cyclic or
acyclic, substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.C; --C(.dbd.O)R.sub.C;
--CO.sub.2R.sub.C; --CN; --SCN; --SR.sub.C; --SOR.sub.C;
--SO.sub.2R.sub.C; --NO.sub.2; --N(R.sub.C).sub.2; --NHC(O)R.sub.C;
or --C(R.sub.C).sub.3; wherein each occurrence of R.sub.C is
independently a hydrogen, a protecting group, an aliphatic moiety,
a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a
heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino,
alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio
moiety.
[0102] In certain embodiments, R.sub.2 is hydrogen. In other
embodiments, R.sub.2 is hydroxyl or a protected hydroxyl group. In
certain embodiments, R.sub.2 is alkoxy. In yet other embodiments,
R.sub.2 is a lower alkyl, alkenyl, or alkynyl group. In certain
embodiments, R.sub.2 is --CH.sub.2--X(R.sub.B).sub.n, wherein X is
O, S, N, or C, preferably O, S, or N; and n is 1, 2, or 3. In
certain embodiments, R.sub.2 is --CH.sub.2--OR.sub.B. In other
embodiments, R.sub.2 is --CH.sub.2--SR.sub.B. In yet other
embodiments, R.sub.2 is --CH.sub.2--R.sub.B. In other embodiments,
R.sub.2 is --CH.sub.2--N(R.sub.B).sub.2. In still other
embodiments, R.sub.2 is --CH.sub.2--NHR.sub.B. In certain
embodiments of the invention, R.sub.B is one of:
##STR00036## ##STR00037## ##STR00038## ##STR00039##
[0103] wherein m and p are each independently integers from 0 to 3;
q.sub.1 is an integer from 1 to 6; R.sup.2C is hydrogen, lower
alkyl or a nitrogen protecting group; and each occurrence of
R.sup.2B is independently hydrogen, halogen, --CN, or WR.sup.W1
wherein W is O, S, NR.sup.W2, --C(.dbd.O), --S(.dbd.O), --SO.sub.2,
--C(.dbd.O)O--, --OC(.dbd.O), --C(.dbd.O)NR.sup.W2,
--NR.sup.W2C(.dbd.O); wherein each occurrence of R.sup.W1 and
R.sup.W2 is independently hydrogen, a protecting group, a prodrug
moiety or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or
heteroaryl moiety, or, when W is NR.sup.W2, R.sup.W1 and R.sup.W2,
taken together with the nitrogen atom to which they are attached,
form a heterocyclic or heteroaryl moiety; or any two adjacent
occurrences of R.sup.2B, taken together with the atoms to which
they are attached, form a substituted or unsubstituted, saturated
or unsaturated alicyclic or heterocyclic moiety, or a substituted
or unsubstituted aryl or heteroaryl moiety. In certain embodiments
of the invention, R.sub.B is one of the structures:
##STR00040##
wherein m is an integer from 1 to 4; R.sup.2C is hydrogen, lower
alkyl or a nitrogen protecting group; and each occurrence of
R.sup.2B is independently hydrogen, halogen, --CN, or WR.sup.W1
wherein W is O, S, NR.sup.W2, --C(.dbd.O), --S(.dbd.O), --SO.sub.2,
--C(.dbd.O)O--, --OC(.dbd.O), --C(.dbd.O)NR.sup.W2,
--NR.sup.W2C(.dbd.O); wherein each occurrence of R.sup.W1 and
R.sup.W2 is independently hydrogen, a protecting group, a prodrug
moiety or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or
heteroaryl moiety, or, when W is NR.sup.W2, R.sup.W1 and R.sup.W2,
taken together with the nitrogen atom to which they are attached,
form a heterocyclic or heteroaryl moiety; or any two adjacent
occurrences of R.sup.2B, taken together with the atoms to which
they are attached, form a substituted or unsubstituted, saturated
or unsaturated alicyclic or heterocyclic moiety, or a substituted
or unsubstituted aryl or heteroaryl moiety.
[0104] In certain embodiments, --X(R.sub.B).sub.n has one of the
structures:
##STR00041## ##STR00042## ##STR00043##
[0105] In certain embodiments, R.sub.2 is
##STR00044##
wherein X is N and Y is NH, S, or O. In other embodiments, R.sub.2
is
##STR00045##
[0106] In certain embodiments, R.sub.3 is substituted or
unsubstituted aryl. In certain embodiments, R.sub.3 is substituted
or unsubstituted phenyl. In certain particular embodiments, R.sub.3
is monosubstituted phenyl. In certain embodiments, R.sub.3 is
para-substituted phenyl. In certain embodiments, R.sub.3 is
##STR00046##
wherein R.sub.3' is hydrogen, a protecting group, a solid support
unit, an alkyl, acyl, cycloalkyl, heteroalkyl, heterocyclic, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl,
or -(heteroalkyl)heteroaryl moiety. In certain embodiments, R.sub.3
is
##STR00047##
In other embodiments, R.sub.3 is substituted or unsubstituted
heteroaryl.
[0107] In certain embodiments, the stereochemistry of formula (Ig)
is defined as follows:
##STR00048##
[0108] In certain embodiments of the invention, compounds of
formula (I) are of the formula (Ih):
##STR00049##
wherein
[0109] A and L are defined as above;
[0110] n is an integer between 0 and 10, inclusive; preferably,
between 1 and 6, inclusive; more preferably, between 1 and 3,
inclusive; and even more preferably, 0, 1, 2, or 3;
[0111] R.sub.2 is hydrogen; halogen; cyclic or acyclic, substituted
or unsubstituted, branched or unbranched aliphatic; cyclic or
acyclic, substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.B; --C(.dbd.O)R.sub.B;
--CO.sub.2R.sub.B; --CN; --SCN; --SR.sub.B; --SOR.sub.B;
--SO.sub.2R.sub.B; --NO.sub.2; --N(R.sub.B).sub.2; --NHC(O)R.sub.B;
or --C(R.sub.B).sub.3; wherein each occurrence of R.sub.B is
independently a hydrogen, a protecting group, an aliphatic moiety,
a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a
heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino,
alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;
and
[0112] R.sub.3 is hydrogen; halogen; cyclic or acyclic, substituted
or unsubstituted, branched or unbranched aliphatic; cyclic or
acyclic, substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.C; --C(.dbd.O)R.sub.C;
--CO.sub.2R.sub.C; --CN; --SCN; --SR.sub.C; --SOR.sub.C;
--SO.sub.2R.sub.C; --NO.sub.2; --N(R.sub.C).sub.2; --NHC(O)R.sub.C;
or --C(R.sub.C).sub.3; wherein each occurrence of R.sub.C is
independently a hydrogen, a protecting group, an aliphatic moiety,
a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a
heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino,
alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio
moiety.
[0113] In certain embodiments, R.sub.2 is hydrogen. In other
embodiments, R.sub.2 is hydroxyl or a protected hydroxyl group. In
certain embodiments, R.sub.2 is alkoxy. In yet other embodiments,
R.sub.2 is a lower alkyl, alkenyl, or alkynyl group. In certain
embodiments, R.sub.2 is --CH.sub.2--X(R.sub.B).sub.n, wherein X is
O, S, N, or C, preferably O, S, or N; and n is 1, 2, or 3. In
certain embodiments, R.sub.2 is --CH.sub.2--OR.sub.B. In other
embodiments, R.sub.2 is --CH.sub.2--SR.sub.B. In yet other
embodiments, R.sub.2 is --CH.sub.2--R.sub.B. In other embodiments,
R.sub.2 is --CH.sub.2--N(R.sub.B).sub.2. In still other
embodiments, R.sub.2 is --CH.sub.2--NHR.sub.B. In certain
embodiments of the invention, R.sub.B is one of:
##STR00050## ##STR00051## ##STR00052## ##STR00053##
[0114] wherein m and p are each independently integers from 0 to 3;
q.sub.1 is an integer from 1 to 6; R.sup.2C is hydrogen, lower
alkyl or a nitrogen protecting group; and each occurrence of
R.sup.2B is independently hydrogen, halogen, --CN, or WR.sup.W1
wherein W is O, S, NR.sup.W2, --C(.dbd.O), --S(.dbd.O), --SO.sub.2,
--C(.dbd.O)O--, --OC(.dbd.O), --C(.dbd.O)NR.sup.W2,
--NR.sup.W2C(.dbd.O); wherein each occurrence of R.sup.W1 and
R.sup.W2 is independently hydrogen, a protecting group, a prodrug
moiety or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or
heteroaryl moiety, or, when W is NR.sup.W2, R.sup.W1 and R.sup.W2,
taken together with the nitrogen atom to which they are attached,
form a heterocyclic or heteroaryl moiety; or any two adjacent
occurrences of R.sup.2B, taken together with the atoms to which
they are attached, form a substituted or unsubstituted, saturated
or unsaturated alicyclic or heterocyclic moiety, or a substituted
or unsubstituted aryl or heteroaryl moiety. In certain embodiments
of the invention, R.sub.B is one of the structures:
##STR00054##
wherein m is an integer from 1 to 4; R.sup.2C is hydrogen, lower
alkyl or a nitrogen protecting group; and each occurrence of
R.sup.2B is independently hydrogen, halogen, --CN, or WR.sup.W1
wherein W is O, S, NR.sup.W2, --C(.dbd.O), --S(.dbd.O), --SO.sub.2,
--C(.dbd.O)O--, --OC(.dbd.O), --C(.dbd.O)NR.sup.W2,
--NR.sup.W2C(.dbd.O); wherein each occurrence of R.sup.W1 and
R.sup.W2 is independently hydrogen, a protecting group, a prodrug
moiety or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or
heteroaryl moiety, or, when W is NR.sup.W2, R.sup.W1 and R.sup.W2,
taken together with the nitrogen atom to which they are attached,
form a heterocyclic or heteroaryl moiety; or any two adjacent
occurrences of R.sup.2B, taken together with the atoms to which
they are attached, form a substituted or unsubstituted, saturated
or unsaturated alicyclic or heterocyclic moiety, or a substituted
or unsubstituted aryl or heteroaryl moiety.
[0115] In certain embodiments, --X(R.sub.B).sub.n has one of the
structures:
##STR00055## ##STR00056## ##STR00057##
[0116] In certain embodiments, R.sub.2 is
##STR00058##
wherein X is N and Y is NH, S, or O. In other embodiments, R.sub.2
is
##STR00059##
[0117] In certain embodiments, R.sub.3 is substituted or
unsubstituted aryl. In certain embodiments, R.sub.3 is substituted
or unsubstituted phenyl. In certain particular embodiments, R.sub.3
is monosubstituted phenyl. In certain embodiments, R.sub.3 is
para-substituted phenyl. In certain embodiments, R.sub.3 is
##STR00060##
wherein R.sub.3' is hydrogen, a protecting group, a solid support
unit, an alkyl, acyl, cycloalkyl, heteroalkyl, heterocyclic, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl,
or -(heteroalkyl)heteroaryl moiety. In certain embodiments, R.sub.3
is
##STR00061##
[0118] In other embodiments, R.sub.3 is substituted or
unsubstituted heteroaryl.
[0119] In certain embodiments, the stereochemistry of formula (Ih)
is defined as follows:
##STR00062##
[0120] In certain embodiments of the invention, compounds of
formula (I) have structure as shown in formula (Ii):
##STR00063##
wherein
[0121] A and L are defined as above;
[0122] R.sub.2 is hydrogen; halogen; cyclic or acyclic, substituted
or unsubstituted, branched or unbranched aliphatic; cyclic or
acyclic, substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.B; --C(.dbd.O)R.sub.B;
--CO.sub.2R.sub.B; --CN; --SCN; --SR.sub.B; --SOR.sub.B;
--SO.sub.2R.sub.B; --NO.sub.2; --N(R.sub.B).sub.2; --NHC(O)R.sub.B;
or --C(R.sub.B).sub.3; wherein each occurrence of R.sub.B is
independently a hydrogen, a protecting group, an aliphatic moiety,
a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a
heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino,
alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;
and
[0123] R.sub.3 is hydrogen; halogen; cyclic or acyclic, substituted
or unsubstituted, branched or unbranched aliphatic; cyclic or
acyclic, substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.C; --C(.dbd.O)R.sub.C;
--CO.sub.2R.sub.C; --CN; --SCN; --SR.sub.C; --SOR.sub.C;
--SO.sub.2R.sub.C; --NO.sub.2; --N(R.sub.C).sub.2; --NHC(O)R.sub.C;
or --C(R.sub.C).sub.3; wherein each occurrence of R.sub.C is
independently a hydrogen, a protecting group, an aliphatic moiety,
a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a
heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino,
alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio
moiety.
[0124] In certain embodiments, R.sub.2 is hydrogen. In other
embodiments, R.sub.2 is hydroxyl or a protected hydroxyl group. In
certain embodiments, R.sub.2 is alkoxy. In yet other embodiments,
R.sub.2 is a lower alkyl, alkenyl, or alkynyl group. In certain
embodiments, R.sub.2 is --CH.sub.2--X(R.sub.B).sub.n, wherein X is
O, S, N, or C, preferably O, S, or N; and n is 1, 2, or 3. In
certain embodiments, R.sub.2 is --CH.sub.2--OR.sub.B. In other
embodiments, R.sub.2 is --CH.sub.2--SR.sub.B. In yet other
embodiments, R.sub.2 is --CH.sub.2--R.sub.B. In other embodiments,
R.sub.2 is --CH.sub.2--N(R.sub.B).sub.2. In still other
embodiments, R.sub.2 is --CH.sub.2--NHR.sub.B. In certain
embodiments of the invention, R.sub.B is one of:
##STR00064## ##STR00065## ##STR00066## ##STR00067##
[0125] wherein m and p are each independently integers from 0 to 3;
q.sub.1 is an integer from 1 to 6; R.sup.2C is hydrogen, lower
alkyl or a nitrogen protecting group; and each occurrence of
R.sup.2B is independently hydrogen, halogen, --CN, or WR.sup.W1
wherein W is O, S, NR.sup.W2, --C(.dbd.O), --S(.dbd.O), --SO.sub.2,
--C(.dbd.O)O--, --OC(.dbd.O), --C(.dbd.O)NR.sup.W2,
--NR.sup.W2C(.dbd.O); wherein each occurrence of R.sup.W1 and
R.sup.W2 is independently hydrogen, a protecting group, a prodrug
moiety or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or
heteroaryl moiety, or, when W is NR.sup.W2, R.sup.W1 and R.sup.W2,
taken together with the nitrogen atom to which they are attached,
form a heterocyclic or heteroaryl moiety; or any two adjacent
occurrences of R.sup.2B, taken together with the atoms to which
they are attached, form a substituted or unsubstituted, saturated
or unsaturated alicyclic or heterocyclic moiety, or a substituted
or unsubstituted aryl or heteroaryl moiety. In certain embodiments
of the invention, R.sub.B is one of the structures:
##STR00068##
wherein m is an integer from 1 to 4; R.sup.2C is hydrogen, lower
alkyl or a nitrogen protecting group; and each occurrence of
R.sup.2B is independently hydrogen, halogen, --CN, or WR.sup.W1
wherein W is O, S, NR.sup.W2, --C(.dbd.O), --S(.dbd.O), --SO.sub.2,
--C(.dbd.O)O--, --OC(.dbd.O), --C(.dbd.O)NR.sup.W2,
--NR.sup.W2C(.dbd.O); wherein each occurrence of R.sup.W1 and
R.sup.W2 is independently hydrogen, a protecting group, a prodrug
moiety or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or
heteroaryl moiety, or, when W is NR.sup.W2, R.sup.W1 and R.sup.W2,
taken together with the nitrogen atom to which they are attached,
form a heterocyclic or heteroaryl moiety; or any two adjacent
occurrences of R.sup.2B, taken together with the atoms to which
they are attached, form a substituted or unsubstituted, saturated
or unsaturated alicyclic or heterocyclic moiety, or a substituted
or unsubstituted aryl or heteroaryl moiety.
[0126] In certain embodiments, --X(R.sub.B).sub.n has one of the
structures:
##STR00069## ##STR00070## ##STR00071##
[0127] In certain embodiments, R.sub.2 is
##STR00072##
wherein X is N and Y is NH, S, or O. In other embodiments, R.sub.2
is
##STR00073##
[0128] In certain embodiments, R.sub.3 is substituted or
unsubstituted aryl. In certain embodiments, R.sub.3 is substituted
or unsubstituted phenyl. In certain particular embodiments, R.sub.3
is monosubstituted phenyl. In certain embodiments, R.sub.3 is
para-substituted phenyl. In certain embodiments, R.sub.3 is
##STR00074##
wherein R.sub.3' is hydrogen, a protecting group, a solid support
unit, an alkyl, acyl, cycloalkyl, heteroalkyl, heterocyclic, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl,
or -(heteroalkyl)heteroaryl moiety. In certain embodiments, R.sub.3
is
##STR00075##
In other embodiments, R.sub.3 is substituted or unsubstituted
heteroaryl.
[0129] In certain embodiments, the stereochemistry of formula (II)
is defined as follows:
##STR00076##
[0130] In certain embodiments of the invention, compounds of
formula (I) have the following stereochemistry and structure as
shown in formula (Ij):
##STR00077##
wherein
[0131] R.sub.2 is hydrogen; halogen; cyclic or acyclic, substituted
or unsubstituted, branched or unbranched aliphatic; cyclic or
acyclic, substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.B; --C(.dbd.O)R.sub.B;
--CO.sub.2R.sub.B; --CN; --SCN; --SR.sub.B; --SOR.sub.B;
--SO.sub.2R.sub.B; --NO.sub.2; --N(R.sub.B).sub.2; --NHC(O)R.sub.B;
or --C(R.sub.B).sub.3; wherein each occurrence of R.sub.B is
independently a hydrogen, a protecting group, an aliphatic moiety,
a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a
heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino,
alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;
and
[0132] R.sub.3 is hydrogen; halogen; cyclic or acyclic, substituted
or unsubstituted, branched or unbranched aliphatic; cyclic or
acyclic, substituted or unsubstituted, branched or unbranched
heteroaliphatic; substituted or unsubstituted, branched or
unbranched acyl; substituted or unsubstitued, branched or
unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; --OR.sub.C; --C(.dbd.O)R.sub.C;
--CO.sub.2R.sub.C; --CN; --SCN; --SR.sub.C; --SOR.sub.C;
--SO.sub.2R.sub.C; --NO.sub.2; --N(R.sub.C).sub.2; --NHC(O)R.sub.C;
or --C(R.sub.C).sub.3; wherein each occurrence of R.sub.C is
independently a hydrogen, a protecting group, an aliphatic moiety,
a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a
heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino,
alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio
moiety.
[0133] In certain embodiments, R.sub.2 is hydrogen. In other
embodiments, R.sub.2 is hydroxyl or a protected hydroxyl group. In
certain embodiments, R.sub.2 is alkoxy. In yet other embodiments,
R.sub.2 is a lower alkyl, alkenyl, or alkynyl group. In certain
embodiments, R.sub.2 is --CH.sub.2--X(R.sub.B).sub.n, wherein X is
O, S, N, or C, preferably O, S, or N; and n is 1, 2, or 3. In
certain embodiments, R.sub.2 is --CH.sub.2--OR.sub.B. In other
embodiments, R.sub.2 is --CH.sub.2--SR.sub.B. In yet other
embodiments, R.sub.2 is --CH.sub.2--R.sub.B. In other embodiments,
R.sub.2 is --CH.sub.2--N(R.sub.B).sub.2. In still other
embodiments, R.sub.2 is --CH.sub.2--NHR.sub.B. In certain
embodiments of the invention, R.sub.B is one of:
##STR00078## ##STR00079## ##STR00080## ##STR00081##
[0134] wherein m and p are each independently integers from 0 to 3;
q.sub.1 is an integer from 1 to 6; R.sup.2C is hydrogen, lower
alkyl or a nitrogen protecting group; and each occurrence of
R.sup.2B is independently hydrogen, halogen, --CN, or WR.sup.W1
wherein W is O, S, NR.sup.W2, --C(.dbd.O), --S(.dbd.O), --SO.sub.2,
--C(.dbd.O)O--, --OC(.dbd.O), --C(.dbd.O)NR.sup.W2,
--NR.sup.W2C(.dbd.O); wherein each occurrence of R.sup.W1 and
R.sup.W2 is independently hydrogen, a protecting group, a prodrug
moiety or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or
heteroaryl moiety, or, when W is NR.sup.W2, R.sup.W1 and R.sup.W2,
taken together with the nitrogen atom to which they are attached,
form a heterocyclic or heteroaryl moiety; or any two adjacent
occurrences of R.sup.2B, taken together with the atoms to which
they are attached, form a substituted or unsubstituted, saturated
or unsaturated alicyclic or heterocyclic moiety, or a substituted
or unsubstituted aryl or heteroaryl moiety. In certain embodiments
of the invention, R.sub.B is one of the structures:
##STR00082##
wherein m is an integer from 1 to 4; R.sup.2C is hydrogen, lower
alkyl or a nitrogen protecting group; and each occurrence of
R.sup.2B is independently hydrogen, halogen, --CN, or WR.sup.W1
wherein W is O, S, NR.sup.W2, --C(.dbd.O), --S(.dbd.O), --SO.sub.2,
--C(.dbd.O)O--, --OC(.dbd.O), --C(.dbd.O)NR.sup.W2,
--NR.sup.W2C(.dbd.O); wherein each occurrence of R.sup.W1 and
R.sup.W2 is independently hydrogen, a protecting group, a prodrug
moiety or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or
heteroaryl moiety, or, when W is NR.sup.W2, R.sup.W1 and R.sup.W2,
taken together with the nitrogen atom to which they are attached,
form a heterocyclic or heteroaryl moiety; or any two adjacent
occurrences of R.sup.2B, taken together with the atoms to which
they are attached, form a substituted or unsubstituted, saturated
or unsaturated alicyclic or heterocyclic moiety, or a substituted
or unsubstituted aryl or heteroaryl moiety.
[0135] In certain embodiments, --X(R.sub.B).sub.n has one of the
structures:
##STR00083## ##STR00084## ##STR00085##
[0136] In certain embodiments, R.sub.2 is
##STR00086##
wherein X is N and Y is NH, S, or O. In other embodiments, R.sub.2
is
##STR00087##
[0137] In certain embodiments, R.sub.3 is substituted or
unsubstituted aryl. In certain embodiments, R.sub.3 is substituted
or unsubstituted phenyl. In certain particular embodiments, R.sub.3
is monosubstituted phenyl. In certain embodiments, R.sub.3 is
para-substituted phenyl. In certain embodiments, R.sub.3 is
##STR00088##
wherein R.sub.3' is hydrogen, a protecting group, a solid support
unit, an alkyl, acyl, cycloalkyl, heteroalkyl, heterocyclic, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl,
or -(heteroalkyl)heteroaryl moiety. In certain embodiments, R.sub.3
is
##STR00089##
In other embodiments, R.sub.3 is substituted or unsubstituted
heteroaryl.
[0138] Another class of compounds of special interest includes
those compounds of the invention as described above and in certain
subclasses herein, wherein R.sub.3 is a substituted phenyl moiety
and the compounds have the formula (Il):
##STR00090##
wherein
[0139] L, A, X, and R.sub.B are defined as above;
[0140] n is an integer between 0 and 5, inclusive; preferably,
between, 1 and 3; more preferably, 2; and
[0141] Z is hydrogen, --(CH.sub.2).sub.qOR.sup.Z,
--(CH.sub.2).sub.qSR.sup.Z, --(CH.sub.2).sub.qN(R.sup.Z).sub.2,
--C(.dbd.O)R.sup.Z, --C(.dbd.O)N(R.sup.Z).sub.2, or an alkyl,
heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl,
-(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety, wherein q
is 0-4, and wherein each occurrence of R.sup.Z is independently
hydrogen, a protecting group, a solid support unit, or an alkyl,
acyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl,
-(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or
-(heteroalkyl)heteroaryl moiety. In certain embodiments, R.sup.Z is
hydrogen. In other embodiments, R.sup.Z is C.sub.1-C.sub.6 alkyl.
In certain embodiments, R.sup.Z is an oxygen-protecting group.
[0142] Another class of compounds includes those compounds of
formula (II), wherein Z is --CH.sub.2OR.sup.Z, and the compounds
have the general structure (Im):
##STR00091##
wherein
[0143] R.sub.B, R.sup.Z, X, L, n, and A are defined generally above
and in classes and subclasses herein. In certain embodiments, X is
S. In other embodiments, X is O.
[0144] Yet another class of compounds of particular interest
includes those compounds of formula (Ii), wherein X is S and the
compounds have the general structure (In):
##STR00092##
wherein
[0145] R.sub.B, X, L, n, and A are defined as above; and
[0146] R.sup.Z is as defined generally above and in classes and
subclasses herein.
[0147] Yet another class of compounds of special interest includes
those compounds of formula (Ii), wherein X is --NR.sup.2A and the
compounds have the general structure (Io):
##STR00093##
wherein
[0148] R.sub.B, R.sup.Z, X, L, n, and A are defined generally above
and in classes and subclasses herein.
[0149] Yet another class of compounds of special interest includes
those compounds of formula (Ii), wherein X is O and the compounds
have the general structure (Ip):
##STR00094##
wherein
[0150] R.sub.B, R.sup.Z, X, L, n, and A are defined generally above
and in classes and subclasses herein.
[0151] Exemplary compounds of the invention are shown:
##STR00095##
[0152] Some of the foregoing compounds can comprise one or more
asymmetric centers, and thus can exist in various isomeric forms,
e.g., stereoisomers and/or diastereomers. Thus, inventive compounds
and pharmaceutical compositions thereof may be in the form of an
individual enantiomer, diastereomer or geometric isomer, or may be
in the form of a mixture of stereoisomers. In certain embodiments,
the compounds of the invention are enantiopure compounds. In
certain other embodiments, mixtures of stereoisomers or
diastereomers are provided.
[0153] Furthermore, certain compounds, as described herein may have
one or more double bonds that can exist as either the Z or E
isomer, unless otherwise indicated. The invention additionally
encompasses the compounds as individual isomers substantially free
of other isomers and alternatively, as mixtures of various isomers,
e.g., racemic mixtures of stereoisomers. In addition to the
above-mentioned compounds per se, this invention also encompasses
pharmaceutically acceptable derivatives of these compounds and
compositions comprising one or more compounds of the invention and
one or more pharmaceutically acceptable excipients or
additives.
[0154] Compounds of the invention may be prepared by
crystallization of the compound under different conditions and may
exist as one or a combination of polymorphs of the compound forming
part of this invention. For example, different polymorphs may be
identified and/or prepared using different solvents, or different
mixtures of solvents for recrystallization; by performing
crystallizations at different temperatures; or by using various
modes of cooling, ranging from very fast to very slow cooling
during crystallizations. Polymorphs may also be obtained by heating
or melting the compound followed by gradual or fast cooling. The
presence of polymorphs may be determined by solid probe NMR
spectroscopy, IR spectroscopy, differential scanning calorimetry,
powder X-ray diffractogram and/or other techniques. Thus, the
present invention encompasses inventive compounds, their
derivatives, their tautomeric forms, their stereoisomers, their
polymorphs, their pharmaceutically acceptable salts their
pharmaceutically acceptable solvates and pharmaceutically
acceptable compositions containing them.
Synthetic Overview
[0155] The synthesis of the various monomeric compounds used to
prepare the dimeric, multimeric, and polymeric compounds of the
invention are known in the art. These published syntheses may be
utilized to prepare the compounds of the invention. Exemplary
synthesic methods for preparing compounds of the invention are
described in U.S. Pat. No. 6,960,685; U.S. Pat. No. 6,897,220; U.S.
Pat. No. 6,541,661; U.S. Pat. No. 6,512,123; U.S. Pat. No.
6,495,719; US 2006/0020131; US 2004/087631; US 2004/127522; US
2004/0072849; US 2003/0187027; WO 2005/018578; WO 2005/007091; WO
2005/007091; WO 2005/018578; WO 2004/046104; WO 2002/89782; each of
which is incorporated herein by reference. In many cases, an amide
moiety is changed to an ester moiety to prepare the inventive
compounds.
[0156] An exemplary synthetic scheme for preparing SAHP is showin
in FIG. 13. Those of skill in the art will realize that based on
this teaching and those in the art as referenced above one could
prepare any of the esterase-sensitive compounds of the
invention.
[0157] In yet another aspect of the invention, methods for
producing intermediates useful for the preparation of certain
compounds of the invention are provided.
[0158] In one aspect of the invention, a method for the synthesis
of the core structure of certain compounds is provided, one method
comprising steps of:
[0159] providing an epoxy alcohol having the structure:
##STR00096##
[0160] reacting the epoxy alcohol with a reagent having the
structure R.sup.2XH under suitable conditions to generate a diol
having the core structure:
##STR00097##
[0161] reacting the diol with a reagent having the structure
R.sup.3CH(OMe).sub.2 under suitable conditions to generate a
scaffold having the core structure:
##STR00098##
[0162] wherein R.sup.1 is hydrogen, or an aliphatic, alicyclic,
heteroaliphatic, heterocyclic, aromatic or heteroaromatic
moiety;
[0163] R.sup.2 is hydrogen, a protecting group, or an aliphatic,
alicyclic, heteroaliphatic, heterocyclic, aromatic or
heteroaromatic moiety;
[0164] X is --O--, --C(R.sup.2A).sub.2--, --S--, or --NR.sup.2A--,
wherein R.sup.2A is hydrogen, a protecting group, or an aliphatic,
alicyclic, heteroaliphatic, heterocyclic, aromatic or
heteroaromatic moiety;
[0165] or wherein two or more occurrences of R.sup.2 and R.sup.2A,
taken together, form an alicyclic or heterocyclic moiety, or an
aryl or heteroaryl moiety;
[0166] R.sup.3 is an aliphatic, alicyclic, heteroaliphatic,
heterocyclic, aromatic or heteroaromatic moiety; and
[0167] R.sup.Z is an aliphatic, alicyclic, heteroaliphatic,
heterocyclic, aromatic or heteroaromatic moiety and is optionally
attached to a solid support.
[0168] In certain exemplary embodiments, the epoxy alcohol has the
structure:
##STR00099##
[0169] the diol has the structure:
##STR00100##
[0170] and the core scaffold has the structure:
##STR00101##
[0171] In certain other exemplary embodiments, the epoxy alcohol
has the structure:
##STR00102##
[0172] the diol has the structure:
##STR00103##
[0173] and the core scaffold has the structure:
##STR00104##
[0174] In certain embodiments, R.sup.3 has the following
structure:
##STR00105## [0175] and the method described above generates the
structure:
##STR00106##
[0176] In another aspect of the invention, a method for the
synthesis of the core structure of certain compounds of the
invention is provided, one method comprising steps of:
[0177] providing an epoxy alcohol having the structure:
##STR00107##
[0178] reacting the epoxy alcohol with a reagent having the
structure R.sup.2XH under suitable conditions to generate a diol
having the core structure:
##STR00108##
[0179] subjecting the diol to a reagent having the structure:
##STR00109##
wherein R.sup.4C is a nitrogen protecting group; to suitable
conditions to generate an amine having the structure:
##STR00110##
[0180] reacting the amine with a reagent having the structure:
##STR00111##
under suitable conditions to generate a scaffold having the core
structure:
##STR00112##
[0181] wherein R.sup.1 is hydrogen, or an aliphatic, alicyclic,
heteroaliphatic, heterocyclic, aromatic or heteroaromatic
moiety;
[0182] R.sup.2 is hydrogen, a protecting group, or an aliphatic,
alicyclic, heteroaliphatic, heterocyclic, aromatic or
heteroaromatic moiety;
[0183] X is --O--, --C(R.sup.2A).sub.2--, --S--, or --NR.sup.2A--,
wherein R.sup.2A is hydrogen, a protecting group, or an aliphatic,
alicyclic, heteroaliphatic, heterocyclic, aromatic or
heteroaromatic moiety;
[0184] or wherein two or more occurrences of R.sup.2 and R.sup.2A,
taken together, form an alicyclic or heterocyclic moiety, or an
aryl or heteroaryl moiety;
[0185] r is 0 or 1;
[0186] s is an integer from 2-5;
[0187] w is an integer from 0-4;
[0188] R.sup.4A comprises a metal chelator;
[0189] each occurrence of R.sup.4D is independently hydrogen,
alkyl, heteroalkyl, cycloalkyl, heterocyclic, alkenyl, alkynyl,
aryl, heteroaryl, halogen, CN, NO.sub.2, or WR.sup.W1 wherein W is
O, S, NR.sup.W2, --C(.dbd.O), --S(.dbd.O), --SO.sub.2,
--C(.dbd.O)O--, --OC(.dbd.O), --C(.dbd.O)NR.sup.W2,
--NR.sup.W2C(.dbd.O); wherein each occurrence of R.sup.W1 and
R.sup.W2 is independently hydrogen, a protecting group, a prodrug
moiety or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or
heteroaryl moiety, or, when W is NR.sup.W2, R.sup.W1 and R.sup.W2,
taken together with the nitrogen atom to which they are attached,
form a heterocyclic or heteroaryl moiety; or any two adjacent
occurrences of R.sup.2B, taken together with the atoms to which
they are attached, form a substituted or unsubstituted, saturated
or unsaturated alicyclic or heterocyclic moiety, or a substituted
or unsubstituted aryl or heteroaryl moiety; and
[0190] R.sup.Z is an aliphatic, alicyclic, heteroaliphatic,
heterocyclic, aromatic or heteroaromatic moiety and is optionally
attached to a solid support.
[0191] In certain exemplary embodiments, the epoxy alcohol has the
structure:
##STR00113##
[0192] the diol has the structure:
##STR00114##
[0193] the amine has the structure:
##STR00115##
[0194] and the core scaffold has the structure:
##STR00116##
[0195] In certain exemplary embodiments, the epoxy alcohol has the
structure:
##STR00117##
[0196] the diol has the structure:
##STR00118##
[0197] the amine has the structure:
##STR00119##
[0198] and the core scaffold has the structure:
##STR00120##
[0199] In certain embodiments, the methods described above are
carried out in solution phase. In certain other embodiments, the
methods described above are carried out on a solid phase. In
certain embodiments, the synthetic method is amenable to
high-throughput techniques or to techniques commonly used in
combinatorial chemistry.
Pharmaceutical Compositions
[0200] As discussed above, the present invention provides novel
compounds having antitumor and antiproliferative activity, and thus
the inventive compounds are useful for the treatment of cancer
(e.g., cutaneous T-cell lymphoma). Benign proliferative diseases
may also be treated using the inventive compounds. The compounds
are also useful in the treatment of other diseases or condition
that benefit from inhibtion of deacetylation activity (e.g. HDAC
inhibition). In certain embodiments, the compounds are useful in
the treatment of baldness based on the discovery that HDAC
inhibition (particularly, HDAC6 inhibition) blocks androgen
signaling vis hsp90. HDAC inhibition has also been shown to inhibit
estrogen signaling. In certain embodiments, the compounds are
useful in blocking the hyperpigmentation of skin by HDAC
inhibition.
[0201] Accordingly, in another aspect of the present invention,
pharmaceutical compositions are provided, which comprise any one of
the compounds described herein (or a prodrug, pharmaceutically
acceptable salt or other pharmaceutically acceptable derivative
thereof), and optionally comprise a pharmaceutically acceptable
carrier. In certain embodiments, these compositions optionally
further comprise one or more additional therapeutic agents.
Alternatively, a compound of this invention may be administered to
a patient in need thereof in combination with the administration of
one or more other therapeutic agents. For example, additional
therapeutic agents for conjoint administration or inclusion in a
pharmaceutical composition with a compound of this invention may be
an approved chemotherapeutic agent, or it may be any one of a
number of agents undergoing approval in the Food and Drug
Administration that ultimately obtain approval for the treatment of
hair loss, skin hyperpigmentation, protozoal infections, and/or any
disorder associated with cellular hyperproliferation. In certain
other embodiments, the additional therapeutic agent is an
anticancer agent, as discussed in more detail herein. In certain
other embodiments, the compositions of the invention are useful for
the treatment of protozoal infections.
[0202] It will also be appreciated that certain of the compounds of
present invention can exist in free form for treatment, or where
appropriate, as a pharmaceutically acceptable derivative thereof.
According to the present invention, a pharmaceutically acceptable
derivative includes, but is not limited to, pharmaceutically
acceptable salts, esters, salts of such esters, or a pro-drug or
other adduct or derivative of a compound of this invention which
upon administration to a patient in need is capable of providing,
directly or indirectly, a compound as otherwise described herein,
or a metabolite or residue thereof.
[0203] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. Pharmaceutically acceptable salts of amines,
carboxylic acids, and other types of compounds, are well known in
the art. For example, S. M. Berge, et al. describe pharmaceutically
acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19
(1977), incorporated herein by reference. The salts can be prepared
in situ during the final isolation and purification of the
compounds of the invention, or separately by reacting a free base
or free acid function with a suitable reagent, as described
generally below. For example, a free base function can be reacted
with a suitable acid. Furthermore, where the compounds of the
invention carry an acidic moiety, suitable pharmaceutically
acceptable salts thereof may, include metal salts such as alkali
metal salts, e.g. sodium or potassium salts; and alkaline earth
metal salts, e.g. calcium or magnesium salts. Examples of
pharmaceutically acceptable, nontoxic acid addition salts are salts
of an amino group formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, phosphoric acid, sulfuric acid and
perchloric acid or with organic acids such as acetic acid, oxalic
acid, maleic acid, tartaric acid, citric acid, succinic acid or
malonic acid or by using other methods used in the art such as ion
exchange. Other pharmaceutically acceptable salts include adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like. Further
pharmaceutically acceptable salts include, when appropriate,
nontoxic ammonium, quaternary ammonium, and amine cations formed
using counterions such as halide, hydroxide, carboxylate, sulfate,
phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
[0204] Additionally, as used herein, the term "pharmaceutically
acceptable ester" refers to esters that hydrolyze in vivo and
include those that break down readily in the human body to leave
the parent compound or a salt thereof. Suitable ester groups
include, for example, those derived from pharmaceutically
acceptable aliphatic carboxylic acids, particularly alkanoic,
alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl
or alkenyl moeity advantageously has not more than 6 carbon atoms.
Examples of particular esters include formates, acetates,
propionates, butyrates, acrylates and ethylsuccinates.
[0205] Furthermore, the term "pharmaceutically acceptable prodrugs"
as used herein refers to those prodrugs of the compounds of the
present invention which are, within the scope of sound medical
judgment, suitable for use in contact with the issues of humans and
lower animals with undue toxicity, irritation, allergic response,
and the like, commensurate with a reasonable benefit/risk ratio,
and effective for their intended use, as well as the zwitterionic
forms, where possible, of the compounds of the invention. The term
"prodrug" refers to compounds that are rapidly transformed in vivo
to yield the parent compound of the above formula, for example by
hydrolysis in blood. A thorough discussion is provided in T.
Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14
of the A.C.S. Symposium Series, and in Edward B. Roche, ed.,
Bioreversible Carriers in Drug Design, American Pharmaceutical
Association and Pergamon Press, 1987, both of which are
incorporated herein by reference.
[0206] As described above, the pharmaceutical compositions of the
present invention additionally comprise a pharmaceutically
acceptable carrier, which, as used herein, includes any and all
solvents, diluents, or other liquid vehicle, dispersion or
suspension aids, surface active agents, isotonic agents, thickening
or emulsifying agents, preservatives, solid binders, lubricants and
the like, as suited to the particular dosage form desired.
Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W.
Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various
carriers used in formulating pharmaceutical compositions and known
techniques for the preparation thereof. Except insofar as any
conventional carrier medium is incompatible with the compounds of
the invention, such as by producing any undesirable biological
effect or otherwise interacting in a deleterious manner with any
other component(s) of the pharmaceutical composition, its use is
contemplated to be within the scope of this invention. Some
examples of materials which can serve as pharmaceutically
acceptable carriers include, but are not limited to, sugars such as
lactose, glucose and sucrose; starches such as corn starch and
potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatine; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil, sesame oil; olive oil; corn oil and soybean
oil; glycols; such as propylene glycol; esters such as ethyl oleate
and ethyl laurate; agar; buffering agents such as magnesium
hydroxide and aluminum hydroxide; alginic acid; pyrogenfree water;
isotonic saline; Ringer's solution; ethyl alcohol, and phosphate
buffer solutions, as well as other non-toxic compatible lubricants
such as sodium lauryl sulfate and magnesium stearate, as well as
coloring agents, releasing agents, coating agents, sweetening,
flavoring and perfuming agents, preservatives and antioxidants can
also be present in the composition, according to the judgment of
the formulator.
[0207] Liquid dosage forms for oral administration include, but are
not limited to, pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active compounds, the liquid dosage forms may
contain inert diluents commonly used in the art such as, for
example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
[0208] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0209] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0210] In order to prolong the effect of a drug, it is often
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This may be accomplished by the use of a
liquid suspension or crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution that, in turn, may depend upon crystal
size and crystalline form. Alternatively, delayed absorption of a
parenterally administered drug form is accomplished by dissolving
or suspending the drug in an oil vehicle. Injectable depot forms
are made by forming microencapsule matrices of the drug in
biodegradable polymers such as polylactide-polyglycolide. Depending
upon the ratio of drug to polymer and the nature of the particular
polymer employed, the rate of drug release can be controlled.
Examples of other biodegradable polymers include (poly(orthoesters)
and poly(anhydrides). Depot injectable formulations are also
prepared by entrapping the drug in liposomes or microemulsions
which are compatible with body tissues.
[0211] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0212] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar--agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0213] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
that can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polethylene
glycols and the like.
[0214] The active compounds can also be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose and starch. Such dosage forms may also
comprise, as in normal practice, additional substances other than
inert diluents, e.g., tableting lubricants and other tableting aids
such as magnesium stearate and microcrystalline cellulose. In the
case of capsules, tablets and pills, the dosage forms may also
comprise buffering agents. They may optionally contain opacifying
agents and can also be of a composition that they release the
active ingredient(s) only, or preferentially, in a certain part of
the intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions which can be used include polymeric
substances and waxes.
[0215] The present invention encompasses pharmaceutically
acceptable topical formulations of inventive compounds. The term
"pharmaceutically acceptable topical formulation", as used herein,
means any formulation which is pharmaceutically acceptable for
intradermal administration of a compound of the invention by
application of the formulation to the epidermis. In certain
embodiments of the invention, the topical formulation comprises a
carrier system. Pharmaceutically effective carriers include, but
are not limited to, solvents (e.g., alcohols, poly alcohols,
water), creams, lotions, ointments, oils, plasters, liposomes,
powders, emulsions, microemulsions, and buffered solutions (e.g.,
hypotonic or buffered saline) or any other carrier known in the art
for topically administering pharmaceuticals. A more complete
listing of art-known carriers is provided by reference texts that
are standard in the art, for example, Remington's Pharmaceutical
Sciences, 16th Edition, 1980 and 17th Edition, 1985, both published
by Mack Publishing Company, Easton, Pa., the disclosures of which
are incorporated herein by reference in their entireties. In
certain other embodiments, the topical formulations of the
invention may comprise excipients. Any pharmaceutically acceptable
excipient known in the art may be used to prepare the inventive
pharmaceutically acceptable topical formulations. Examples of
excipients that can be included in the topical formulations of the
invention include, but are not limited to, preservatives,
antioxidants, moisturizers, emollients, buffering agents,
solubilizing agents, other penetration agents, skin protectants,
surfactants, and propellants, and/or additional therapeutic agents
used in combination to the inventive compound. Suitable
preservatives include, but are not limited to, alcohols, quaternary
amines, organic acids, parabens, and phenols. Suitable antioxidants
include, but are not limited to, ascorbic acid and its esters,
sodium bisulfite, butylated hydroxytoluene, butylated
hydroxyanisole, tocopherols, and chelating agents like EDTA and
citric acid. Suitable moisturizers include, but are not limited to,
glycerine, sorbitol, polyethylene glycols, urea, and propylene
glycol. Suitable buffering agents for use with the invention
include, but are not limited to, citric, hydrochloric, and lactic
acid buffers. Suitable solubilizing agents include, but are not
limited to, quaternary ammonium chlorides, cyclodextrins, benzyl
benzoate, lecithin, and polysorbates. Suitable skin protectants
that can be used in the topical formulations of the invention
include, but are not limited to, vitamin E oil, allatoin,
dimethicone, glycerin, petrolatum, and zinc oxide.
[0216] In certain embodiments, the pharmaceutically acceptable
topical formulations of the invention comprise at least a compound
of the invention and a penetration enhancing agent. The choice of
topical formulation will depend or several factors, including the
condition to be treated, the physicochemical characteristics of the
inventive compound and other excipients present, their stability in
the formulation, available manufacturing equipment, and costs
constraints. As used herein the term "penetration enhancing agent"
means an agent capable of transporting a pharmacologically active
compound through the stratum corneum and into the epidermis or
dermis, preferably, with little or no systemic absorption. A wide
variety of compounds have been evaluated as to their effectiveness
in enhancing the rate of penetration of drugs through the skin.
See, for example, Percutaneous Penetration Enhancers, Maibach H. I.
and Smith H. E. (eds.), CRC Press, Inc., Boca Raton, Fla. (1995),
which surveys the use and testing of various skin penetration
enhancers, and Buyuktimkin et al., Chemical Means of Transdermal
Drug Permeation Enhancement in Transdermal and Topical Drug
Delivery Systems, Gosh T. K., Pfister W. R., Yum S. I. (Eds.),
Interpharm Press Inc., Buffalo Grove, Ill. (1997). In certain
exemplary embodiments, penetration agents for use with the
invention include, but are not limited to, triglycerides (e.g.,
soybean oil), aloe compositions (e.g., aloe-vera gel), ethyl
alcohol, isopropyl alcohol, octolyphenylpolyethylene glycol, oleic
acid, polyethylene glycol 400, propylene glycol,
N-decylmethylsulfoxide, fatty acid esters (e.g., isopropyl
myristate, methyl laurate, glycerol monooleate, and propylene
glycol monooleate), and N-methylpyrrolidone.
[0217] In certain embodiments, the compositions may be in the form
of ointments, pastes, creams, lotions, gels, powders, solutions,
sprays, inhalants or patches. In certain exemplary embodiments,
formulations of the compositions according to the invention are
creams, which may further contain saturated or unsaturated fatty
acids such as stearic acid, palmitic acid, oleic acid,
palmito-oleic acid, cetyl or oleyl alcohols, stearic acid being
particularly preferred. Creams of the invention may also contain a
non-ionic surfactant, for example, polyoxy-40-stearate. In certain
embodiments, the active component is admixed under sterile
conditions with a pharmaceutically acceptable carrier and any
needed preservatives or buffers as may be required. Ophthalmic
formulation, eardrops, and eye drops are also contemplated as being
within the scope of this invention. Additionally, the present
invention contemplates the use of transdermal patches, which have
the added advantage of providing controlled delivery of a compound
to the body. Such dosage forms are made by dissolving or dispensing
the compound in the proper medium. As discussed above, penetration
enhancing agents can also be used to increase the flux of the
compound across the skin. The rate can be controlled by either
providing a rate controlling membrane or by dispersing the compound
in a polymer matrix or gel.
[0218] It will also be appreciated that the compounds and
pharmaceutical compositions of the present invention can be
formulated and employed in combination therapies, that is, the
compounds and pharmaceutical compositions can be formulated with or
administered concurrently with, prior to, or subsequent to, one or
more other desired therapeutics or medical procedures. The
particular combination of therapies (therapeutics or procedures) to
employ in a combination regimen will take into account
compatibility of the desired therapeutics and/or procedures and the
desired therapeutic effect to be achieved. It will also be
appreciated that the therapies employed may achieve a desired
effect for the same disorder (for example, an inventive compound
may be administered concurrently with another immunomodulatory
agent, anticancer agent or agent useful for the treatment of
psoriasis), or they may achieve different effects (e.g., control of
any adverse effects).
[0219] For example, other therapies or anticancer agents that may
be used in combination with the inventive compounds of the present
invention include surgery, radiotherapy (in but a few examples,
.gamma.-radiation, neutron beam radiotherapy, electron beam
radiotherapy, proton therapy, brachytherapy, and systemic
radioactive isotopes, to name a few), endocrine therapy, biologic
response modifiers (interferons, interleukins, and tumor necrosis
factor (TNF) to name a few), hyperthermia and cryotherapy, agents
to attenuate any adverse effects (e.g., antiemetics), and other
approved chemotherapeutic drugs, including, but not limited to,
alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide,
Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine
antagonists and pyrimidine antagonists (6-Mercaptopurine,
5-Fluorouracil, Cytarabile, Gemcitabine), spindle poisons
(Vinblastine, Vincristine, Vinorelbine, Paclitaxel),
podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics
(Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine,
Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes
(Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, and
Megestrol), to name a few. For a more comprehensive discussion of
updated cancer therapies see, The Merck Manual, Seventeenth Ed.
1999, the entire contents of which are hereby incorporated by
reference. See also the National Cancer Institute (CNI) website
(www.nci.nih.gov) and the Food and Drug Administration (FDA)
website for a list of the FDA approved oncology drugs
(www.fda.gov/cder/cancer/druglistframe).
[0220] In certain embodiments, the pharmaceutical compositions of
the present invention further comprise one or more additional
therapeutically active ingredients (e.g., chemotherapeutic and/or
palliative). For purposes of the invention, the term "palliative"
refers to treatment that is focused on the relief of symptoms of a
disease and/or side effects of a therapeutic regimen, but is not
curative. For example, palliative treatment encompasses
painkillers, antinausea medications and anti-sickness drugs. In
addition, chemotherapy, radiotherapy and surgery can all be used
palliatively (that is, to reduce symptoms without going for cure;
e.g., for shrinking tumors and reducing pressure, bleeding, pain
and other symptoms of cancer).
[0221] Additionally, the present invention provides
pharmaceutically acceptable derivatives of the inventive compounds,
and methods of treating a subject using these compounds,
pharmaceutical compositions thereof, or either of these in
combination with one or more additional therapeutic agents.
[0222] It will also be appreciated that certain of the compounds of
present invention can exist in free form for treatment, or where
appropriate, as a pharmaceutically acceptable derivative thereof.
According to the present invention, a pharmaceutically acceptable
derivative includes, but is not limited to, pharmaceutically
acceptable salts, esters, salts of such esters, or a prodrug or
other adduct or derivative of a compound of this invention which
upon administration to a patient in need is capable of providing,
directly or indirectly, a compound as otherwise described herein,
or a metabolite or residue thereof.
Research Uses, Pharmaceutical Uses and Methods of Treatment
Research Uses
[0223] According to the present invention, the inventive compounds
may be assayed in any of the available assays known in the art for
identifying compounds having antiprotozoal, HDAC inhibitory, hair
growth, androgen signalling inhibitory, estogen singaling
inhibitory, and/or antiproliferative activity. For example, the
assay may be cellular or non-cellular, in vivo or in vitro, high-
or low-throughput format, etc.
[0224] Thus, in one aspect, compounds of this invention which are
of particular interest include those which: [0225] exhibit
HDAC-inhibitory activity; [0226] exhibit HDAC Class I inhbitiory
activity (e.g., HDAC1, HDAC2, HDAC3, HDAC8); [0227] exhibit HDAC
Class II inhibitory activity (e.g., HDAC4, HDAC5, HDAC6, HDAC7,
HDAC9a, HDAC9b, HDRP/HDAC9c, HDAC10); [0228] exhibit the ability to
inhibit HDAC1 (Genbank Accession No. NP.sub.--004955, incorporated
herein by reference); [0229] exhibit the ability to inhibit HDAC2
(Genbank Accession No. NP.sub.--001518, incorporated herein by
reference); [0230] exhibit the ability to inhibit HDAC3 (Genbank
Accession No. O15739, incorporated herein by reference); [0231]
exhibit the ability to inhibit HDAC4 (Genbank Accession No.
AAD29046, incorporated herein by reference); [0232] exhibit the
ability to inhibit HDAC5 (Genbank Accession No. NP.sub.--005465,
incorporated herein by reference); [0233] exhibit the ability to
inhibit HDAC6 (Genbank Accession No. NP.sub.--006035, incorporated
herein by reference); [0234] exhibit the ability to inhibit HDAC7
(Genbank Accession No. AAP63491, incorporated herein by reference);
[0235] exhibit the ability to inhibit HDAC8 (Genbank Accession No.
AAF73428, NM.sub.--018486, AF245664, AF230097, each of which is
incorporated herein by reference); [0236] exhibit the ability to
inhibit HDAC9 (Genbank Accession No. NM.sub.--178425,
NM.sub.--178423, NM.sub.--058176, NM.sub.--014707, BC111735,
NM.sub.--058177, each of which is incorporated herein by reference)
[0237] exhibit the ability to inhibit HDAC10 (Genbank Accession No.
NM.sub.--032019, incorporated herein by reference) [0238] exhibit
the ability to inhibit HDAC11 (Genbank Accession No. BC009676,
incorporated herein by reference); [0239] exhibit the ability to
inhibit tubulin deactetylation (TDAC); [0240] exhibit the ability
to modulate the glucose-sensitive subset of genes downstream of
Ure2p; [0241] exhibit cytotoxic or growth inhibitory effect on
cancer cell lines maintained in vitro or in animal studies using a
scientifically acceptable cancer cell xenograft model; and/or
[0242] exhibit a therapeutic profile (e.g., optimum safety and
curative effect) that is superior to existing chemotherapeutic
agents.
[0243] As detailed in the exemplification herein, in assays to
determine the ability of compounds to inhibit cancer cell growth
certain inventive compounds may exhibit IC.sub.50 values
.ltoreq.100 .mu.M. In certain other embodiments, inventive
compounds exhibit IC.sub.50 values .ltoreq.50 .mu.M. In certain
other embodiments, inventive compounds exhibit IC.sub.50 values
.ltoreq.40 .mu.M. In certain other embodiments, inventive compounds
exhibit IC.sub.50 values .ltoreq.30 .mu.M. In certain other
embodiments, inventive compounds exhibit IC.sub.50 values
.ltoreq.20 .mu.M. In certain other embodiments, inventive compounds
exhibit IC.sub.50 values .ltoreq.10 .mu.M. In certain other
embodiments, inventive compounds exhibit IC.sub.50 values
.ltoreq.7.5 .mu.M. In certain embodiments, inventive compounds
exhibit IC.sub.50 values .ltoreq.5 .mu.M. In certain other
embodiments, inventive compounds exhibit IC.sub.50 values
.ltoreq.2.5 .mu.M. In certain embodiments, inventive compounds
exhibit IC.sub.50 values .ltoreq.1 .mu.M. In certain embodiments,
inventive compounds exhibit IC.sub.50 values .ltoreq.0.75 .mu.M. In
certain embodiments, inventive compounds exhibit IC.sub.50 values
.ltoreq.0.5 .mu.M. In certain embodiments, inventive compounds
exhibit IC.sub.50 values .ltoreq.0.25 .mu.M. In certain
embodiments, inventive compounds exhibit IC.sub.50 values
.ltoreq.0.1 .mu.M. In certain other embodiments, inventive
compounds exhibit IC.sub.50 values .ltoreq.75 nM. In certain other
embodiments, inventive compounds exhibit IC.sub.50 values
.ltoreq.50 nM. In certain other embodiments, inventive compounds
exhibit IC.sub.50 values .ltoreq.25 nM. In certain other
embodiments, inventive compounds exhibit IC.sub.50 values
.ltoreq.10 nM. In other embodiments, exemplary compounds exhibited
IC.sub.50 values .ltoreq.7.5 nM. In other embodiments, exemplary
compounds exhibited IC.sub.50 values .ltoreq.5 nM.
Pharmaceutical Uses and Methods of Treatment
[0244] In general, methods of using the compounds of the present
invention comprise administering to a subject in need thereof a
therapeutically effective amount of a compound of the present
invention. The compounds of the invention are generally inhibitors
of deacetyalse activity. As discussed above, the compounds of the
invention are typically inhibitors of histone deacetylases and, as
such, are useful in the treatment of disorders modulated by histone
deacetylases. Other deacetylase such as tubulin deacetylases may
also be inhibited by the inventive compounds.
[0245] In certain embodiments, compounds of the invention are
useful in the treatment of proliferative diseases (e.g., cancer,
benign neoplasms, inflammatory disease, autoimmune diseases). In
certain embodiments, given the esterase sensitive ester linkage in
the compounds of the invention, they are particularly useful in
treating skin disorders modulated by histone deacetyalses where
systemic effects of the drug are to be avoided or at least
minimized. This feature of the inventive compounds may allow the
use of compounds normally too toxic for administration to a subject
systemically. In certain embodiments, these skin disorders are
proliferative disorders. For example, the inventive compounds are
particularly useful in the treatment of skin cancer and benign skin
tumors. In certain embodiments, the compounds are useful in the
treatment of cutaneous T-cell lymphoma. In certain embodiments, the
compounds are useful in the treatment of neurofibromatosis.
Accordingly, in yet another aspect, according to the methods of
treatment of the present invention, tumor cells are killed, or
their growth is inhibited by contacting said tumor cells with an
inventive compound or composition, as described herein. In other
embodiments, the compounds are useful in treating inflammatory
diseases of the skin such as psoriasis or dermatitis. In other
embodiments, the compounds are useful in the treatment or
prevention of hair loss. In certain embodiments, the compounds are
useful in the treatment of diseases associated with skin
pigmentation. For example, the compounds may be used to prevent the
hyperpigmentation of skin.
[0246] Thus, in another aspect of the invention, methods for the
treatment of cancer are provided comprising administering a
therapeutically effective amount of an inventive compound, as
described herein, to a subject in need thereof. In certain
embodiments, a method for the treatment of cancer is provided
comprising administering a therapeutically effective amount of an
inventive compound, or a pharmaceutical composition comprising an
inventive compound to a subject in need thereof, in such amounts
and for such time as is necessary to achieve the desired result.
Preferably, the inventive compounds is administered topically. In
certain embodiments of the present invention a "therapeutically
effective amount" of the inventive compound or pharmaceutical
composition is that amount effective for killing or inhibiting the
growth of tumor cells. The compounds and compositions, according to
the method of the present invention, may be administered using any
amount and any route of administration effective for killing or
inhibiting the growth of tumor cells. Thus, the expression "amount
effective to kill or inhibit the growth of tumor cells," as used
herein, refers to a sufficient amount of agent to kill or inhibit
the growth of tumor cells. The exact amount required will vary from
subject to subject, depending on the species, age, and general
condition of the subject, the severity of the infection, the
particular anticancer agent, its mode of administration, and the
like. In certain embodiments of the present invention a
"therapeutically effective amount" of the inventive compound or
pharmaceutical composition is that amount effective for inhibiting
deacetylase activity (in particular, HDAC activity) in skin cells.
In certain embodiments of the present invention a "therapeutically
effective amount" of the inventive compound or pharmaceutical
composition is that amount effective to kill or inhibit the growth
of skin cells.
[0247] In certain embodiments, the method involves the
administration of a therapeutically effective amount of the
compound or a pharmaceutically acceptable derivative thereof to a
subject (including, but not limited to a human or animal) in need
of it. In certain embodiments, the inventive compounds as useful
for the treatment of cancer (including, but not limited to,
glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon
and rectal cancer, leukemia, lymphoma, lung cancer (including, but
not limited to small cell lung cancer), melanoma and/or skin
cancer, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer,
pancreatic cancer, prostate cancer and gastric cancer, bladder
cancer, uterine cancer, kidney cancer, testicular cancer, stomach
cancer, brain cancer, liver cancer, or esophageal cancer).
[0248] In certain embodiments, the inventive anticancer agents are
useful in the treatment of cancers and other proliferative
disorders, including, but not limited to breast cancer, cervical
cancer, colon and rectal cancer, leukemia, lung cancer, melanoma,
multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer,
pancreatic cancer, prostate cancer, and gastric cancer, to name a
few. In certain embodiments, the inventive anticancer agents are
active against leukemia cells and melanoma cells, and thus are
useful for the treatment of leukemias (e.g., myeloid, lymphocytic,
myelocytic and lymphoblastic leukemias) and malignant melanomas. In
still other embodiments, the inventive anticancer agents are active
against solid tumors.
[0249] In certain embodiments, the inventive compounds also find
use in the prevention of restenosis of blood vessels subject to
traumas such as angioplasty and stenting. For example, it is
contemplated that the compounds of the invention will be useful as
a coating for implanted medical devices, such as tubings, shunts,
catheters, artificial implants, pins, electrical implants such as
pacemakers, and especially for arterial or venous stents, including
balloon-expandable stents. In certain embodiments inventive
compounds may be bound to an implantable medical device, or
alternatively, may be passively adsorbed to the surface of the
implantable device. In certain other embodiments, the inventive
compounds may be formulated to be contained within, or, adapted to
release by a surgical or medical device or implant, such as, for
example, stents, sutures, indwelling catheters, prosthesis, and the
like. For example, drugs having antiproliferative and
anti-inflammatory activities have been evaluated as stent coatings,
and have shown promise in preventing retenosis (See, for example,
Presbitero P. et al., "Drug eluting stents do they make the
difference?", Minerva Cardioangiol, 2002, 50(5):431-442; Ruygrok P.
N. et al., "Rapamycin in cardiovascular medicine", Intern. Med. J.,
2003, 33(3):103-109; and Marx S. O. et al., "Bench to bedside: the
development of rapamycin and its application to stent restenosis",
Circulation, 2001, 104(8):852-855, each of these references is
incorporated herein by reference in its entirety). Accordingly,
without wishing to be bound to any particular theory, Applicant
proposes that inventive compounds having antiproliferative effects
can be used as stent coatings and/or in stent drug delivery
devices, inter alia for the prevention of restenosis or reduction
of restenosis rate. Suitable coatings and the general preparation
of coated implantable devices are described in U.S. Pat. Nos.
6,099,562; 5,886,026; and 5,304,121. The coatings are typically
biocompatible polymeric materials such as a hydrogel polymer,
polymethyldisiloxane, polycaprolactone, polyethylene glycol,
polylactic acid, ethylene vinyl acetate, and mixtures thereof. The
coatings may optionally be further covered by a suitable topcoat of
fluorosilicone, polysaccarides, polyethylene glycol, phospholipids
or combinations thereof to impart controlled release
characteristics in the composition. A variety of compositions and
methods related to stent coating and/or local stent drug delivery
for preventing restenosis are known in the art (see, for example,
U.S. Pat. Nos. 6,517,889; 6,273,913; 6,258,121; 6,251,136;
6,248,127; 6,231,600; 6,203,551; 6,153,252; 6,071,305; 5,891,507;
5,837,313 and published U.S. patent application No.:
US2001/0027340, each of which is incorporated herein by reference
in its entirety). For example, stents may be coated with
polymer-drug conjugates by dipping the stent in polymer-drug
solution or spraying the stent with such a solution. In certain
embodiment, suitable materials for the implantable device include
biocompatible and nontoxic materials, and may be chosen from the
metals such as nickel-titanium alloys, steel, or biocompatible
polymers, hydrogels, polyurethanes, polyethylenes, ethylenevinyl
acetate copolymers, etc. In certain embodiments, the inventive
compound is coated onto a stent for insertion into an artery or
vein following balloon angioplasty.
[0250] The compounds of this invention or pharmaceutically
acceptable compositions thereof may also be incorporated into
compositions for coating implantable medical devices, such as
prostheses, artificial valves, vascular grafts, stents and
catheters. Accordingly, the present invention, in another aspect,
includes a composition for coating an implantable device comprising
a compound of the present invention as described generally above,
and in classes and subclasses herein, and a carrier suitable for
coating said implantable device. In still another aspect, the
present invention includes an implantable device coated with a
composition comprising a compound of the present invention as
described generally above, and in classes and subclasses herein,
and a carrier suitable for coating said implantable device.
[0251] Within other aspects of the present invention, methods are
provided for expanding the lumen of a body passageway, comprising
inserting a stent into the passageway, the stent having a generally
tubular structure, the surface of the structure being coated with
(or otherwise adapted to release) an inventive compound or
composition, such that the passageway is expanded. In certain
embodiments, the lumen of a body passageway is expanded in order to
eliminate a biliary, gastrointestinal, esophageal,
tracheal/bronchial, urethral and/or vascular obstruction.
[0252] Methods for eliminating biliary, gastrointestinal,
esophageal, tracheal/bronchial, urethral and/or vascular
obstructions using stents are known in the art. The skilled
practitioner will know how to adapt these methods in practicing the
present invention. For example, guidance can be found in U.S.
Patent Application Publication No.: 2003/0004209 in paragraphs
[0146]-[0155], which paragraphs are hereby incorporated herein by
reference.
[0253] Another aspect of the invention relates to a method for
inhibiting the growth of multidrug resistant cells in a biological
sample or a patient, which method comprises administering to the
patient, or contacting said biological sample with a compound of
formula I or a composition comprising said compound.
[0254] Additionally, the present invention provides
pharmaceutically acceptable derivatives of the inventive compounds,
and methods of treating a subject using these compounds,
pharmaceutical compositions thereof, or either of these in
combination with one or more additional therapeutic agents.
[0255] Another aspect of the invention relates to a method of
treating or lessening the severity of a disease or condition
associated with a proliferation disorder in a patient, said method
comprising a step of administering to said patient, a compound of
formula I or a composition comprising said compound.
[0256] It will be appreciated that the compounds and compositions,
according to the method of the present invention, may be
administered using any amount and any route of administration
effective for the treatment of cancer and/or disorders associated
with cell hyperproliferation. For example, when using the inventive
compounds for the treatment of cancer, the expression "effective
amount" as used herein, refers to a sufficient amount of agent to
inhibit cell proliferation, or refers to a sufficient amount to
reduce the effects of cancer. The exact amount required will vary
from subject to subject, depending on the species, age, and general
condition of the subject, the severity of the diseases, the
particular anticancer agent, its mode of administration, and the
like.
[0257] The compounds of the invention are preferably formulated in
dosage unit form for ease of administration and uniformity of
dosage. The expression "dosage unit form" as used herein refers to
a physically discrete unit of therapeutic agent appropriate for the
patient to be treated. It will be understood, however, that the
total daily usage of the compounds and compositions of the present
invention will be decided by the attending physician within the
scope of sound medical judgment. The specific therapeutically
effective dose level for any particular patient or organism will
depend upon a variety of factors including the disorder being
treated and the severity of the disorder; the activity of the
specific compound employed; the specific composition employed; the
age, body weight, general health, sex and diet of the patient; the
time of administration, route of administration, and rate of
excretion of the specific compound employed; the duration of the
treatment; drugs used in combination or coincidental with the
specific compound employed; and like factors well known in the
medical arts (see, for example, Goodman and Gilman's, "The
Pharmacological Basis of Therapeutics", Tenth Edition, A. Gilman,
J. Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001,
which is incorporated herein by reference in its entirety).
[0258] Another aspect of the invention relates to a method for
inhibiting histone deacetylase activity in a biological sample or a
patient, which method comprises administering to the patient, or
contacting said biological sample with an inventive compound or a
composition comprising said compound.
[0259] Furthermore, after formulation with an appropriate
pharmaceutically acceptable carrier in a desired dosage, the
pharmaceutical compositions of this invention can be administered
to humans and other animals orally, rectally, parenterally,
intracisternally, intravaginally, intraperitoneally, topically (as
by powders, ointments, creams or drops), bucally, as an oral or
nasal spray, or the like, depending on the severity of the
infection being treated. In certain embodiments, the compounds of
the invention may be administered at dosage levels of about 0.001
mg/kg to about 50 mg/kg, from about 0.01 mg/kg to about 25 mg/kg,
or from about 0.1 mg/kg to about 10 mg/kg of subject body weight
per day, one or more times a day, to obtain the desired therapeutic
effect. It will also be appreciated that dosages smaller than 0.001
mg/kg or greater than 50 mg/kg (for example 50-100 mg/kg) can be
administered to a subject. In certain embodiments, compounds are
administered orally or parenterally.
Treatment Kit
[0260] In other embodiments, the present invention relates to a kit
for conveniently and effectively carrying out the methods in
accordance with the present invention. In general, the
pharmaceutical pack or kit comprises one or more containers filled
with one or more of the ingredients of the pharmaceutical
compositions of the invention. Such kits are especially suited for
the topical delivery of the inventive compounds. Optionally
associated with such container(s) can be a notice in the form
prescribed by a governmental agency regulating the manufacture, use
or sale of pharmaceutical products, which notice reflects approval
by the agency of manufacture, use or sale for human
administration.
EQUIVALENTS
[0261] The representative examples which follow are intended to
help illustrate the invention, and are not intended to, nor should
they be construed to, limit the scope of the invention. Indeed,
various modifications of the invention and many further embodiments
thereof, in addition to those shown and described herein, will
become apparent to those skilled in the art from the full contents
of this document, including the examples which follow and the
references to the scientific and patent literature cited herein. It
should further be appreciated that, unless otherwise indicated, the
entire contents of each of the references cited herein are
incorporated herein by reference to help illustrate the state of
the art. The following examples contain important additional
information, exemplification and guidance which can be adapted to
the practice of this invention in its various embodiments and the
equivalents thereof.
[0262] These and other aspects of the present invention will be
further appreciated upon consideration of the following Examples,
which are intended to illustrate certain particular embodiments of
the invention but are not intended to limit its scope, as defined
by the claims.
EXAMPLES
[0263] The compounds of this invention and their preparation can be
understood further by the examples that illustrate some of the
processes by which these compounds are prepared or used. It will be
appreciated, however, that these examples do not limit the
invention. Variations of the invention, now known or further
developed, are considered to fall within the scope of the present
invention as described herein and as hereinafter claimed.
General Description of Synthetic Methods
[0264] The various references cited herein provide helpful
background information on preparing compounds similar to the
inventive compounds described herein or relevant intermediates, as
well as information on formulation, uses, and administration of
such compounds which may be of interest.
[0265] Moreover, the practitioner is directed to the specific
guidance and examples provided in this document relating to various
exemplary compounds and intermediates thereof.
[0266] The compounds of this invention and their preparation can be
understood further by the examples that illustrate some of the
processes by which these compounds are prepared or used. It will be
appreciated, however, that these examples do not limit the
invention. Variations of the invention, now known or further
developed, are considered to fall within the scope of the present
invention as described herein and as hereinafter claimed.
[0267] According to the present invention, any available techniques
can be used to make or prepare the inventive compounds or
compositions including them. For example, a variety of a variety
combinatorial techniques, parallel synthesis and/or solid phase
synthetic methods such as those discussed in detail below may be
used. Alternatively or additionally, the inventive compounds may be
prepared using any of a variety of solution phase synthetic methods
known in the art.
[0268] It will be appreciated as described below, that a variety of
inventive compounds can be synthesized according to the methods
described herein. The starting materials and reagents used in
preparing these compounds are either available from commercial
suppliers such as Aldrich Chemical Company (Milwaukee, Wis.),
Bachem (Torrance, Calif.), Sigma (St. Louis, Mo.), or are prepared
by methods well known to a person of ordinary skill in the art
following procedures described in such references as Fieser and
Fieser 1991, "Reagents for Organic Synthesis", vols 1-17, John
Wiley and Sons, New York, N.Y., 1991; Rodd 1989 "Chemistry of
Carbon Compounds", vols. 1-5 and supps, Elsevier Science
Publishers, 1989; "Organic Reactions", vols 1-40, John Wiley and
Sons, New York, N.Y., 1991; March 2001, "Advanced Organic
Chemistry", 5th ed. John Wiley and Sons, New York, N.Y.; and Larock
1990, "Comprehensive Organic Transformations: A Guide to Functional
Group Preparations", 2.sup.nd ed. VCH Publishers. These schemes are
merely illustrative of some methods by which the compounds of this
invention can be synthesized, and various modifications to these
schemes can be made and will be suggested to a person of ordinary
skill in the art having regard to this disclosure.
[0269] The starting materials, intermediates, and compounds of this
invention may be isolated and purified using conventional
techniques, including filtration, distillation, crystallization,
chromatography, and the like. They may be characterized using
conventional methods, including physical constants and spectral
data.
Synthesis of Exemplary Compounds
[0270] Unless otherwise indicated, starting materials are either
commercially available or readily accessibly through laboratory
synthesis by anyone reasonably familiar with the art. Described
generally below, are procedures and general guidance for the
synthesis of compounds as described generally and in subclasses and
species herein.
Example 1
Synthesis of SAHP for Use as HDAC Inhibitors
##STR00121##
[0272] Described below is the synthesis of a SAHP, an
ester-containing analog of SAHA (as shown in FIG. 12).
[0273] 3.86 g (24.2 mmol) O-benzylhydroxylamine hydrochloride and
13 mL (75 mmol) diisopropylethylamine were dissolved in 100 mL
methylene chloride and cooled to 0.degree. C. 5.00 g (24.2 mmol)
methyl 8-chloro-8-oxooctanoate were dissolved in 10 mL methylene
chloride and slowly added to the reaction mixture. The reaction
mixture was stirred for 1 h at 0.degree. C. and warmed to room
temperature. After stirring for additional 12 h, 300 mL 0.5N HCl
were added. The organic layer was separated and washed with brine
and sat. bicarb. After drying over sodium sulfate, the organic
solvent was removed under reduced pressure and the crude product
was purified on silica (methylene chloride/methanol 12:1, rf=0.7)
to yield the desired compound 1 as white solid (6.3 g, 89%).
[0274] 6.3 g (21.5 mmol) methyl ester 1 were dissolved in 200 mL
methanol, followed by the addition of 50 mL 2N LiOH. The reaction
mixture was heated to reflux for 1 h and cooled to room
temperature. After addition of 100 mL 1N HCl and 200 mL water, the
reaction mixture was extracted three times with 150 mL ethyl
acetate. The combined organic layers were dried over sodium sulfate
and the solvent was removed under reduced pressure to afford the
carboxylic acid 2 pure and in quantitative yields as white
solid
[0275] 140 mg carboxylic acid 2 (5 mmol), 56.5 mg phenol (6 mmol)
and 113 mg dicyclohexylcarbodiimide (5.5 mmol) are mixed followed
by the addition of 10 mL methylene chloride and 30 mg
4-Dimethylaminopyridine. The reaction mixture was stirred for 2 h
and applied crude on a silica column followed by elution with
haxanes/ethyl acetate (10-100% ethyl acetate). The desired phenol
ester 3 was obtained as a white solid in 87% yield (155 mg).
[0276] 80 mg phenol ester 3 (0.225 mmol) are dissolved in methanol.
A catalytical amount of palladium on charcoal (10%) was as added
and hydrogen was bubbled through the reaction mixture. After 1 h
hour no starting material was detectable by TLC. The reaction
mixture was filtered through Celite and the solvent was removed
under reduced pressure to yield the free hydroxamte SAHP as
brownish solid in quantitative yields (59 mg). The crude product
did not show any impurities as judged by LCMS and NMR.
Example 2
Biological Assay Procedures
[0277] Cell Culture and Transfections.
[0278] TAg-Jurkat cells were transfected by electroporation with 5
.mu.g of FLAG-epitope-tagged pBJ5 constructs for expression of
recombinant proteins. Cells were harvested 48 h
posttransfection.
[0279] HDAC Assays.
[0280] [.sup.3H]Acetate-incorporated histones were isolated from
butyrate-treated HeLa cells by hydroxyapatite chromatography (as
described in Tong, et al. Nature 1997, 395, 917-921.)
Immunoprecipitates were incubated with 1.4 .mu.g (10,000 dpm)
histones for 3 h at 37.degree. C. HDAC activity was determined by
scintillation counting of the ethyl acetate-soluble [.sup.3H]acetic
acid (as described in Taunton, et al., Science 1996, 272, 408-411).
Compounds were added in DMSO such that final assay concentrations
were 1% DMSO. IC50s were calculated using Prism 3.0 software. Curve
fitting was done without constraints using the program's
Sigmoidal-Dose Response parameters. All data points were acquired
in duplicate and IC50s are calculated from the composite results of
at least two separate experiments.
Example 3
In Vivo Activity
[0281] Although a variety of methods can be utilized, one exemplary
method by which the in vivo activity of the inventive compounds is
determined is by subcutaneously transplanting a desired tumor mass
in mice. Drug treatment is then initiated when tumor mass reaches
approximately 100 mm.sup.3 after transplantation of the tumor mass.
A suitable composition, as described in more detail above, is then
administered to the mice, preferably in saline and also preferably
administered once a day at doses of 5, 10 and 25 mg/kg, although it
will be appreciated that other doses can also be administered. Body
weight and tumor size are then measured daily and changes in
percent ratio to initial values are plotted. In cases where the
transplanted tumor ulcerates, the weight loss exceeds 25-30% of
control weight loss, the tumor weight reaches 10% of the body
weight of the cancer-bearing mouse, or the cancer-bearing mouse is
dying, the animal is sacrificed in accordance with guidelines for
animal welfare.
Example 4
Assays to Identify Potential Antiprotozoal Compounds by Inhibition
of Histone Deacetylase
[0282] As detailed in U.S. Pat. No. 6,068,987, inhibitors of
histone deacetylases may also be useful as antiprotozoal agents.
Described therein are assays for histone deacetylase activity and
inhibition and describe a variety of known protozoal diseases. The
entire contents of U.S. Pat. No. 6,068,987 are hereby incorporated
by reference.
* * * * *