Deacetylase inhibitors

Details Deacetylase inhibitors Deacetylase inhibitors

2002-11-19

2004-12-21

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S507000

Reexamination Certificate

active

06833384

ABSTRACT:

The present invention relates to hydroxamate compounds which are inhibitors of histone deacetylase. The inventive compounds are useful as pharmaceuticals for the treatment of proliferative diseases.
BACKGROUND
Reversible acetylation of histones is a major regulator of gene expression that acts by altering accessibility of transcription factors to DNA. In normal cells, histone deacetylase (HDA) and histone acetyltrasferase together control the level of acetylation of histones to maintain a balance. Inhibition of HDA results in the accumulation of hyperacetylated histones, which results in a variety of cellular responses.
Inhibitors of HDA have been studied for their therapeutic effects on cancer cells. For example, butyric acid and its derivatives, including sodium phenylbutyrate, have been reported to induce apoptosis in vitro in human colon carcinoma, leukemia and retinoblastoma cell lines. However, butyric acid and its derivatives are not useful pharmacological agents because they tend to be metabolized rapidly and have a very short half-life in vivo. Other inhibitors of HDA that have been widely studied for their anti-cancer activities are trichostatin A and trapoxin. Trichostatin A is an antifungal and antibiotic and is a reversible inhibitor of mammalian HDA. Trapoxin is a cyclic tetrapeptide, which is an irreversible inhibitor of mammalian HDA. Although trichostatin and trapoxin have been studied for their anti-cancer activities, the in vivo instability of the compounds makes them less suitable as anti-cancer drugs. There remains a need for an active compound that is suitable for treating tumors, including cancerous tumors, that is highly efficacious and stable.
SUMMARY
The present invention provides efficacious deacetylase inhibitor compounds that are useful as pharmaceutical agents having the formula (I):
wherein
R
1
is H, halo, or a straight chain C
1
-C
6
alkyl (especially methyl, ethyl or n-propyl, which methyl, ethyl and n-propyl substituents are unsubstituted or substituted by one or more substituents described below for alkyl substituents);
R
2
is selected from H, C
1
-C
10
alkyl, (e.g. methyl, ethyl or —CH
2
CH
2
—OH), C
4
-C
9
cycloalkyl, C
4
-C
9
heterocycloalkyl, C
4
-C
9
heterocycloalkylalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), aryl, heteroaryl, arylalkyl (e.g. benzyl), heteroarylalkyl (e.g. pyridylmethyl), —(CH
2
)
n
C(O)R
6
, —(CH
2
)
n
OC(O)R
6
, amino acyl, HON—C(O)—CH═C(R
1
)-aryl-alkyl- and —(CH
2
)
n
R
7
;
R
3
and R
4
are the same or different and independently H, C
1
-C
6
alkyl, acyl or acylamino, or R
3
and R
4
together with the carbon to which they are bound represent C═O, C═S, or C═NR
8
, or R
2
together with the nitrogen to which it is bound and R
3
together with the carbon to which it is bound can form a C
4
-C
9
heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromatic polyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring;
R
5
is selected from H, C
1
-C
6
alkyl, C
4
-C
9
cycloalkyl, C
4
-C
9
heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl (e.g. benzyl), heteroarylalkyl (e.g. pyridylmethyl), aromatic polycycles, non-aromatic polycycles, mixed aryl and non-aryl polycycles, polyheteroaryl, non-aromatic polyheterocycles, and mixed aryl and non-aryl polyheterocycles;
n, n
1
, n
2
and n
3
are the same or different and independently selected from 0-6, when n
1
is 1-6, each carbon atom can be optionally and independently substituted with R
3
and/or R
4
;
X and Y are the same or different and independently selected from H, halo, C
1
-C
4
alkyl, such as CH
3
and CF
3
, NO
2
, C(O)R
1
, OR
9
, SR
9
, CN, and NR
10
R
11
;
R
6
is selected from H, C
1
-C
6
alkyl, C
4
-C
9
cycloalkyl, C
4
-C
9
heterocycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), aryl, heteroaryl, arylalkyl (e.g., benzyl, 2-phenylethenyl), heteroarylalkyl (e.g., pyridylmethyl), OR
12
, and NR
13
R
14
;
R
7
is selected from OR
15
, SR
15
, S(O)R
16
, SO
2
R
17
, NR
13
R
14
, and NR
12
SO
2
R
6
;
R
8
is selected from H, OR
15
, NR
13
R
14
, C
1
-C
6
alkyl, C
4
-C
9
cycloalkyl, C
4
-C
9
heterocycloalkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), and heteroarylalkyl (e.g., pyridylmethyl);
R
9
is selected from C
1
-C
4
alkyl, for example, CH
3
and CF
3
, C(O)-alkyl, for example C(O)CH
3
, and C(O)CF
3
;
R
10
and R
11
are the same or different and independently selected from H, C
1
-C
4
alkyl, and —C(O)-alkyl;
R
12
is selected from H, C
1
-C
6
alkyl, C
4
-C
9
cycloalkyl, C
4
-C
9
heterocycloalkyl, C
4
-C
9
heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl (e.g., benzyl), and heteroarylalkyl (e.g., pyridylmethyl);
R
13
and R
14
are the same or different and independently selected from H, C
1
-C
6
alkyl, C
4
-C
9
cycloalkyl, C
4
-C
9
heterocycloalkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), heteroarylalkyl (e.g., pyridylmethyl), amino acyl, or R
13
and R
14
together with the nitrogen to which they are bound are C
4
-C
9
heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle;
R
15
is selected from H, C
1
-C
6
alkyl, C
4
-C
9
cycloalkyl, C
4
-C
9
heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH
2
)
m
ZR
12
;
R
16
is selected from C
1
-C
6
alkyl, C
4
-C
9
cycloalkyl, C
4
-C
9
heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH
2
)
m
ZR
12
;
R
17
is selected from C
1
-C
6
alkyl, C
4
-C
9
cycloalkyl, C
4
-C
9
heterocycloalkyl, aryl, aromatic polycycles, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR
13
R
14
;
m is an integer selected from 0 to 6; and
Z is selected from O, NR
13
, S and S(O),
or a pharmaceutically acceptable salt thereof.
The compounds of the present invention are suitable as active agents in pharmaceutical compositions that are efficacious particularly for treating cellular proliferative ailments. The pharmaceutical composition has a pharmaceutically effective amount of the present active agent along with other pharmaceutically acceptable exicipients, carriers, fillers, diluents and the like. The term pharmaceutically effective amount as used herein indicates an amount necessary to administer to a host to achieve a therapeutic result, especially an anti-tumor effect, e.g., inhibition of proliferation of malignant cancer cells, benign tumor cells or other proliferative cells.


REFERENCES:
patent: 5569668 (1996-10-01), Webster et al.
patent: 6552065 (2003-04-01), Remiszewski et al.

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