Inhibitors of histone deacetylase

Details Inhibitors of histone deacetylase Inhibitors of histone deacetylase

2000-11-22

2003-04-01

McGarry, Sean (Department: 1635)

Organic compounds -- part of the class 532-570 series

Organic compounds

Persulfonate esters

C560S004000, C560S019000, C560S024000, C560S319000, C514S001000

Reexamination Certificate

active

06541661

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the inhibition of histone deacetylase. More particularly, the invention relates to compounds and methods for inhibiting histone deacetylase enzymatic activity.
2. Summary of the Related Art
In eukaryotic cells, nuclear DNA associates with histones to form a compact complex called chromatin. The histones constitute a family of basic proteins which are generally highly conserved across eukaryotic species. The core histones, termed H2A, H2B, H3, and H4, associate to form a protein core. DNA winds around this protein core, with the basic amino acids of the histones interacting with the negatively charged phosphate groups of the DNA. Approximately 146 base pairs of DNA wrap around a histone core to make up a nucleosome particle, the repeating structural motif of chromatin.
Csordas,
Biochem. J
., 286: 23-38 (1990) teaches that histones are subject to posttranslational acetylation of the &egr;-amino groups of N-terminal lysine residues, a reaction that is catalyzed by histone acetyl transferase (HAT1). Acetylation neutralizes the positive charge of the lysine side chain, and is thought to impact chromatin structure. Indeed, Taunton et al.,
Science
, 272: 408-411 (1996), teaches that access of transcription factors to chromatin templates is enhanced by histone hyperacetylation. Taunton et al. further teaches that an enrichment in underacetylated histone H4 has been found in transcriptionally silent regions of the genome.
Histone acetylation is a reversible modification, with deacetylation being catalyzed by a family of enzymes termed histone deacetylases (HDACs). Grozinger et al.,
Proc. Natl. Acad. Sci. USA
, 96: 4868-4873 (1999), teaches that HDACs may be divided into two classes, the first represented by yeast Rpd3-like proteins, and the second represented by yeast Hda1-like proteins. Grozinger et al. also teaches that the human HDAC1, HDAC2, and HDAC3 proteins are members of the first class of HDACs, and discloses new proteins, named HDAC4, HDAC5, and HDAC6, which are members of the second class of HDACs. Kao et al.,
Genes
&
Dev
., 14: 55-66 (2000), discloses HDAC7, a new member of the second class of HDACs. Van den Wyngaert,
FEBS
, 478: 77-83 (2000) discloses HDAC8, a new member of the first class of HDACs.
Richon et al.,
Proc. Natl. Acad. Sci. USA
, 95: 3003-3007 (1998), discloses that HDAC activity is inhibited by trichostatin A (TSA), a natural product isolated from
Streptomyces hygroscopicus
, and by a synthetic compound, suberoylanilide hydroxamic acid (SAHA). Yoshida and Beppu,
Exper. Cell Res
., 177: 122-131 (1988), teaches that TSA causes arrest of rat fibroblasts at the G
1
and G
2
phases of the cell cycle, implicating HDAC in cell cycle regulation. Indeed, Finnin et al.,
Nature
, 401: 188-193 (1999), teaches that TSA and SAHA inhibit cell growth, induce terminal differentiation, and prevent the formation of tumors in mice.
These findings suggest that inhibition of HDAC activity represents a novel approach for intervening in cell cycle regulation and that HDAC inhibitors have great therapeutic potential in the treatment of cell proliferative diseases or conditions. To date, only a few inhibitors of histone deacetylase are known in the art. There is thus a need to identify additional HDAC inhibitors and to identify the structural features required for potent HDAC inhibitory activity.
BRIEF SUMMARY OF THE INVENTION
The invention provides compounds and methods for treating cell proliferative diseases. In particular, the invention provides new inhibitors of histone deacetylase enzymatic activity.
In a first aspect, therefore, the invention provides novel inhibitors of histone deacetylase. In one embodiment, the novel inhibitors of histone deacetylase are represented by formula (1):
Cy—L
1
—Ar—Y
1
—C(O)—NH—Z  (1)
wherein
Cy is cycloalkyl, aryl, heteroaryl, or heterocyclyl, any of which may be optionally substituted;
L
1
is —(CH
2
)
m
—W—, where m is 0, 1, 2, 3, or 4, and W is selected from the group consisting of —C(O)NH—, —S(O)
2
NH—, —NHC(O)—, —NHS(O)
2
—, and —NH—C(O)—NH—;
Ar is arylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted;
Y
1
is a chemical bond or a straight- or branched-chain saturated alkylene, wherein said alkylene may be optionally substituted; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being H or a pharmaceutically acceptable cation;
provided that when L
1
is —C(O)NH—, Y
1
is —(CH
2
)
n
—, n being 1, 2, or 3, and Z is —O—M, then Cy is not aminophenyl, dimethylaminophenyl, or hydroxyphenyl; and further provided that when L
1
is —C(O)NH— and Z is pyridyl, then Cy is not substituted indolinyl.
In a second embodiment, the novel inhibitors of histone deacetylase are represented by formula (2):
Cy—L
2
—Ar—Y
2
—C(O)NH—Z  (2)
wherein
Cy is cycloalkyl, aryl, heteroaryl, or heterocyclyl, any of which may be optionally substituted, provided that Cy is not a (spirocycloalkyl)heterocyclyl;
L
2
is C
1
-C
6
saturated alkylene or C
2
-C
6
alkenylene, wherein the alkylene or alkenylene optionally may be substituted, provided that L
2
is not —C(O)—, and wherein one of the carbon atoms of the alkylene optionally may be replaced by a heteroatom moiety selected from the group consisting of O; NR′, R′ being alkyl, acyl, or hydrogen; S; S(O); or S(O)
2
;
Ar is arylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and
Y
2
is a chemical bond or a straight- or branched-chain saturated alkylene, which may be optionally substituted, provided that the alkylene is not substituted with a substituent of the formula —C(O)R wherein R comprises an &agr;-amino acyl moiety; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being H or a pharmaceutically acceptable cation;
provided that when the carbon atom to which Cy is attached is oxo substituted, then Cy and Z are not both pyridyl.
In a third embodiment, the novel inhibitors of histone deacetylase are represented by formula (3):
Cy—L
3
—Ar—Y
3
—C(O)NH—Z  (3)
wherein
Cy is cycloalkyl, aryl, heteroaryl, or heterocyclyl, any of which may be optionally substituted, provided that Cy is not a (spirocycloalkyl)heterocyclyl;
L
3
is selected from the group consisting of
(a) —(CH
2
)
m
—W—, where m is 0, 1, 2, 3, or 4, and W is selected from the group consisting of —C(O)NH—, —S(O)
2
NH—, —NHC(O)—, —NHS(O)
2
—, and —NH—C(O)—NH—; and
(b) C
1
-C
6
alkylene or C
2
-C
6
alkenylene, wherein the alkylene or alkenylene optionally may be substituted, provided that L
3
is not —C(O)—, and wherein one of the carbon atoms of the alkylene optionally may be replaced by O; NR′, R′ being alkyl, acyl, or hydrogen; S; S(O); or S(O)
2
;
Ar is arylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and
Y
3
is C
2
alkenylene or C
2
alkynylene, wherein one or both carbon atoms of the alkenylene optionally may be substituted with alkyl, aryl, alkaryl, or aralkyl; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being H or a pharmaceutically acceptable cation;
provided that when Cy is unsubstituted phenyl, Ar is not phenyl wherein L
3
and Y
3
are oriented ortho or meta to each other.
In a fourth embodiment, the novel histone deacetylase inhibitor is selected from the group represented by formulae (4)-(6):
In a second aspect, the invention provides a pharmaceutical composition comprising an inhibitor o

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