Histone deacetylase inhibitors

Details Histone deacetylase inhibitors Histone deacetylase inhibitors

2001-03-27

2002-12-17

Dentz, Bernard (Department: 1625)

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

Organic compounds

Hydroxamic acids, chalcogen analogs or salts thereof

C546S336000, C548S467000, C549S077000, C549S496000, C560S033000, C560S104000, C560S137000, C560S312000

Reexamination Certificate

active

06495719

ABSTRACT:

TECHNICAL FIELD
This invention relates to enzyme inhibitors, and more particularly to histone deacetylase inhibitors.
BACKGROUND
DNA in the nucleus of the cell exists as a hierarchy of compacted chromatin structures. The basic repeating unit in chromatin is the nucleosome. The nucleosome consists of a histone octomer of proteins in the nucleus of the cell around which DNA is twice wrapped. The orderly packaging of DNA in the nucleus plays an important role in the functional aspects of gene regulation. Covalent modifications of the histones have a key role in altering chromatin higher order structure and function and ultimately gene expression. The covalent modification of histones occurs by enzymatically mediated processes, such as acetylation.
Regulation of gene expression through the inhibition of the nuclear enzyme histone deacetylase (HDAC) is one of several possible regulatory mechanisms whereby chromatin activity can be affected. The dynamic homeostasis of the nuclear acetylation of histones can be regulated by the opposing activity of the enzymes histone acetyl transferase (HAT) and histone deacetylase (HDAC). Transcriptionally silent chromatin can be characterized by nucleosomes with low levels of acetylated histones. Acetylation of histones reduces its positive charge, thereby expanding the structure of the nucleosome and facilitating the interaction of transcription factors to the DNA. Removal the acetyl group restores the positive charge condensing the structure of the nucleosome. Acetylation of histone-DNA activates transcription of DNA's message, an enhancement of gene expression. Histone deacetylase can reverse the process and can serve to repress gene expression. See, for example, Grunstein,
Nature
389, 349-352 (1997); Pazin et al.,
Cell
89, 325-328 (1997); Wade et al.,
Trends Biochem. Sci.
22, 128-132 (1997); and Wolffe,
Science
272, 371-372 (1996).
SUMMARY
Histone deacetylase is a metallo-enzyme with zinc at the active site. Compounds having a zinc-binding moiety, such as, for example, a hydroxamic acid group, can inhibit histone deacetylase. Histone deacetylase inhibition can repress gene expression, including expression of genes related to tumor suppression. Accordingly, inhibition of histone deacetylase can provide an alternate route for treating cancer, hematological disorders, e.g., hemoglobinopathies, and genetic related metabolic disorders, e.g., cystic fibrosis and adrenoleukodystrophy.
In one aspect, hydroxamic acid-containing compounds have a structure of formula (I):
A is a cyclic moiety selected from the group consisting of C
3-14
cycloalkyl, 3-14 membered heterocycloalkyl, C
4-14
cycloalkenyl, 3-14 membered heterocycloalkenyl (e.g., C
3-8
cycloalkyl, 3-8 membered heterocycloalkyl, C
4-8
cycloalkenyl, 3-8 membered heterocycloalkenyl), monocyclic aryl, or monocyclic heteroaryl. Each of these cyclic moieties is optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminocarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl. Each of X
1
and X
2
, independently, is O or S. Y
1
is —CH
2
—, —O—, —S—, —N(R
a
)—, —N(R
a
)—C(O)—O—, —O—C(O)—N(R
a
)—, —N(R
a
)—C(O)—N(R
b
)—, —O—C(O)—, —C(O)—O—, —O—C(O)—O—, or a bond wherein each of R
a
and R
b
, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl. Y
2
is —CH
2
—, —O—, —S—, —N(R
c
)—, —N(R
c
)—C(O)—O—C(O)—N(R
c
)—, —N(R
c
)—C(O)—N(R
d
)—, —O—C(O)—, —C(O)—O—, or —O—C(O)—O— wherein each of R
c
and R
d
, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl. L is (1) a saturated straight C
1-12
hydrocarbon chain substituted with C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, C
1-4
alkoxy, halo, carboxyl, amino, nitro, cyano, C
3-6
cycloalkyl, 3-6 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C
1-4
alkylcarbonyloxy, C
1-4
alkyloxycarbonyl, C
1-4
alkylcarbonyl, formyl, C
1-4
alkylcarbonylamino, or C
1-4
aminocarbonyl, or at least two hydroxyl; and further optionally interrupted by —O—, —N(R
e
)—, —N(R
e
)—C(O)—O—, —O—C(O)—N(R
e
)—, —N(R
e
)—C(O)—N(R
f
)—, —O—C(O)—, —C(O)—O—, or —O—C(O)—O— wherein each of R
e
and R
f
, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; or L is (2) an unsaturated straight C
4-12
hydrocarbon chain containing at least two double bonds, at least one triple bond, or at least one double bond and one triple bond, where the unsaturated hydrocarbon chain is optionally substituted with C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, C
1-4
alkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano, C
3-6
cycloalkyl, 3-6 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C
1-4
alkylcarbonyloxy, C
1-4
alkyloxycarbonyl, C
1-4
alkylcarbonyl, formyl, C
1-4
alkylcarbonylamino, or C
1-4
aminocarbonyl; and further being optionally interrupted by —O—, —N(R
g
)—, —N(R
g
)—C(O)—O—, —O—C(O)—N(R
g
)—, —N(R
g
)—C(O)—N(R
h
)—, —O—C(O)—, —C(O)—O—, or —O—C(O)—O— wherein each of R
g
and R
h
, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl. R
1
is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, haloalkyl, or an amino protecting group; and R
2
is hydrogen, alkyl, hydroxylalkyl, haloalkyl, or a hydroxyl protecting group.
In another aspect, hydroxamic acid-containing compounds have a structure of formula (I), supra. A is a cyclic moiety selected from the group consisting of monocyclic aryl or monocyclic heteroaryl. Each of the cyclic moieties is optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, or amino. Each of X
1
and X
2
, independently, is O or S. Y
1
is —CH
2
—, —O—, —S—, —N(R
a
)—, —N(R
a
)—C(O)—O—, —O—C(O)—N(R
a
)—, —N(R
a
)—C(O)—N(R
b
)—, —O—C(O)—, —C(O)—O—, —O—C(O)—O—, or a bond, where each of R
a
and R
b
, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl. Y
2
is —CH
2
—, —O—, —S—, —N(R
c
)—, —N(R
c
)—C(O)—O—, —O—C(O)—N(R
c
)—, —N(R
c
)—C(O)—N(R
d
)—, —O—C(O)—, —C(O)—O—, or —O—C(O)—O—; each of R
c
and R
d
, independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl. L is (1) a saturated straight C
3-10
hydrocarbon chain substituted with C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, C
1-4
alkoxy, or amino, and further optionally interrupted by —O— or —N(R
e
)—, where R
e
is hydrogen, alkyl, hydroxylalkyl, or haloalkyl; or L is (2) an unsaturated straight C
4-10
hydrocarbon chain containing at least two double bonds, at least one triple bond, or at least one double bond and one triple bond; said unsaturated hydrocarbon chain being optionally substituted with C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, C
1-4
alkoxy, or amino, and further optionally interrupted by —O— or —N(R
f
)—, where R
f
is hydrogen, alkyl, hydroxylalkyl, or haloalkyl. Each of R
1
and R
2
, independently, is hydrogen, alkyl, hydroxylalkyl, or haloalkyl.
In certain embodiments, R
1
is hydrogen, R
2
is hydrogen, X
1
is O, X
2
is O, or Y
1
is —CH
2
—, —O—, —N(R
a
—, or a bond, and Y
2
is —CH
2
—, —O—, or —N(R
c
)—. L can be a saturated straight C
4-10
hydrocarbon chain, or C
5-8
hydrocarbon chain (e.g., a saturated straight C
5
hydrocarbon chain, a saturated straight C
6
hydrocarbon chain, or a saturated straight C
7
hydrocarbon chain), substituted with C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, C
1-4
alkoxy, or amino, and further optionally interrupted by —O— or —N(R
c
)—. In other embodiments, L is an unsaturated straight C
4-10
hydrocarbon chain, or an unsaturated straight C
4-8
hydrocarbon chain, containing 2-5 double bonds, or 1-2 double bonds and 1-2 triple bonds, optionally substituted with C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, or C
1-4
alkoxy, and further being optionally interrupted by —O— or —N(R
g
)—. In certain embodiments, L can be —(CH═CH)
m
— where m

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