Inhibitors of Histone Deacetylase
The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.
1 . An inhibitor of histone deacetylase represented by formula (1):
Cy-X-Y 1 -W (1)
wherein
Cy is cycloalkyl, aryl, or a radical of a heterocyclic moiety, any of which may be optionally substituted;
X is selected from the group consisting of C═O, C═CH 2 , CH(OH), CH(OR 1 ), C═N(OH), and C═N(OR 1 ), where R 1 is alkyl, aryl, aralkyl, or acyl;
Y 1 is a C 3 -C 7 alkylene, wherein said alkylene may be optionally substituted, and wherein one or two carbon atoms in the linear chain connecting X and W may be replaced with O, NR 3 , or S(O) n , where R 3 is hydrogen, alkyl, aryl, aralkyl, sulfonyl, acyl, alkoxycarbonyl, or carbamoyl, and n is 0, 1, or 2, provided that the atoms in Y 1 that are attached to X and to W are carbon atoms, and further provided that Y 1 does not comprise an ester or amide linkage in the linear chain connecting X and W; and
W is selected from the group consisting of —C(O)—CH 2 —SR 2 , —C(O)—NH-OM, —NH—C(O)—NH-Z, and —C(O)—NH-Z, where
R 2 is alkyl, aryl, aralkyl, or acyl, wherein the aryl portion of any such groups may be optionally substituted;
M is hydrogen or a pharmaceutically acceptable cation;
Z is selected from the group consisting of anilinyl, pyridyl, thiazolyl, hydroxyphenyl, thiadiazolyl, anilinylmethyl, or pyridylmethyl, any of which groups optionally may be substituted with halo, hydroxy, amino, nitro, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
provided that X is C═CH 2 , CH(OR 1 ), C═N(OH), or C═N(OR 1 ) when W is —C(O)—NH-OM and Cy is unsubstituted phenyl, dimethylaminophenyl, or methoxyphenyl; and
further provided that when W is —C(O)—CH 2 —SR 2 , the carbon atom in Y 1 that is attached to W is unsubstituted or is substituted with other than amino, acylamino, alkoxycarbonyl, or carbamoyl.
2 . The inhibitor of claim 1 , wherein Cy is C 6 -C 10 aryl or is a radical of a heterocyclic moiety selected from the group consisting of thiophene, benzothiophene, furan, benzofuran, pyridine, quinoline, indole, isoquinoline, thiazole, morpholine, piperidine, and piperazine, any of which groups may be optionally substituted.
3 . The inhibitor of claim 2 , wherein the aryl or heterocyclic moiety is substituted by one or two substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 6 -C 10 aryl, heteroaryl, heterocyclyl, (C 6 -C 10 )ar(C 1 -C 6 )alkyl, halo, nitro, hydroxy, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy, heteroaryloxy, C 1 -C 6 alkoxycarbonyl, C 6 -C 10 aryloxycarbonyl, heteroaryloxycarbonyl, carboxy, and amino.
4 . The inhibitor of claim 1 , wherein Cy has the formula -Cy 1 -Cy 2 or -Cy 1 -G-Cy 2 , wherein Cy 1 and Cy 2 are independently C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, or a radical of a heterocyclic moiety, which groups optionally may be substituted, and G is O, NR 3 , or S(O) n , where R 3 is hydrogen, alkyl, aryl, aralkyl, sulfonyl, acyl, alkoxycarbonyl, or carbamoyl, and n is 0, 1, or 2.
5 . The inhibitor of claim 4 , wherein Cy 1 and Cy 2 are independently selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperidinyl, piperazinyl, which groups optionally may be substituted.
6 . The inhibitor of claim 1 , wherein X is selected from the group consisting of CH(OR 1 ), C═N(OH), and C═N(OR 1 ), where R 1 is C 1 -C 6 alkyl, C 6 -C 10 aryl, or (C 6 -C 10 )ar(C 1 -C 6 )alkyl.
7 . The inhibitor of claim 1 , wherein one to about three carbon atoms of the alkylene are independently substituted with halo, oxo, oximino, nitro, haloalkyl, alkyl, aralkyl, alkoxy, aryloxy, alkoxycarbonyl, carboxy, hydroxyalkyl, acyl, acyloxy, or cyano.
8 . The inhibitor of claim 1 , wherein Y 1 comprises an all-carbon linear chain connecting X and W.
9 . The inhibitor of claim 8 , wherein the linear chain connecting X and W comprises a dienyl moiety, wherein the dienyl moiety is attached to W.
10 . The inhibitor of claim 9 , wherein Y 1 is selected from the group consisting of
11 . The inhibitor of claim 8 , wherein Y 1 is —(CH 2 ) m , where m is 5, 6, or 7.
12 . The inhibitor of claim 1 , wherein one carbon atom in the linear chain connecting X and W is replaced with O, NR 3 , or S(O) n .
13 . The inhibitor of claim 12 , wherein Y 1 is —(CH 2 )—S(O) n —(CH 2 ) p , where n is 0, 1, or 2, and p is 3, 4, or 5.
14 . The inhibitor of claim 1 , wherein W is —C(O)—NH-OM, M being selected from the group consisting of hydrogen, sodium, potassium, magnesium, and calcium.
15 . The inhibitor of claim 1 , wherein W is —C(O)—NH-Z or —NH—C(O)—NH-Z, Z being unsubstituted 2-anilinyl or unsubstituted 2-pyridyl.
16 . The inhibitor of claim 1 , wherein W is —C(O)—CH 2 —SR 2 , R 2 being selected from the group consisting of C 1 -C 6 alkyl, C 6 -C 10 aryl, (C 6 -C 10 )ar(C 1 -C 6 )alkyl, (C 1 -C 6 alkyl)carbonyl, (C 6 -C 10 aryl)carbonyl, and ((C 6 -C 10 )ar(C 1 -C 6 )alkyl)carbonyl, wherein the aryl portion of any such groups may be optionally substituted.
17 . The inhibitor of claim 16 , wherein R 2 is selected from the group consisting of methyl, phenyl, benzyl, benzoyl, and acetyl.
18 . An inhibitor of histone deacetylase represented by formula (2):
Cy-Y 2 -W (2)
wherein
Cy is cycloalkyl, aryl, or a radical of a heterocyclic moiety, any of which may be optionally substituted;
Y 2 is C 5 -C 7 alkylene, wherein said alkylene may be optionally substituted, and wherein one or two carbon atoms in the linear chain connecting Cy and W may be replaced with O, NR 3 , or S(O) n , where R 3 is hydrogen, alkyl, aryl, aralkyl, sulfonyl, acyl, alkoxycarbonyl, or carbamoyl, and n is 0, 1, or 2, provided that Y 2 does not comprise an ester or amide linkage in the linear chain connecting Cy and W; and
W is selected from the group consisting of —C(O)—CH 2 —SR 2 , —NH—C(O)—NH-Z, and —C(O)—NH-Z, where
R 2 is alkyl, aryl, aralkyl, or acyl, wherein the aryl portion of any such groups may be optionally substituted; and
Z is selected from the group consisting of anilinyl, pyridyl, thiazolyl, hydroxyphenyl, thiadiazolyl, anilinylmethyl, or pyridylmethyl, any of which groups optionally may be substituted with halo, hydroxy, amino, nitro, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
provided that when W is —C(O)—CH 2 —SR 2 , the carbon atom in Y 2 that is attached to W is unsubstituted or is substituted with other than amino, acylamino, alkoxycarbonyl, or carbamoyl.
19 . The inhibitor of claim 18 , wherein Cy is C 6 -C 10 aryl or is a radical of a heterocyclic moiety selected from the group consisting of thiophene, benzothiophene, furan, benzofuran, pyridine, quinoline, indole, isoquinoline, thiazole, morpholine, piperidine, piperazine, quinazolinone, benzotriazinone, phthalimide, and dioxobenzoisoquinoline, any of which groups may be optionally substituted.
20 . The inhibitor of claim 18 , wherein the aryl or heterocyclic moiety is substituted by one or two substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 6 -C 10 aryl, heteroaryl, heterocyclyl, (C 6 -C 10 )ar(C 1 -C 6 )alkyl, halo, nitro, hydroxy, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy, heteroaryloxy, C 1 -C 6 alkoxycarbonyl, C 6 -C 10 aryloxycarbonyl, heteroaryloxycarbonyl, carboxy, and amino.
21 . The inhibitor of claim 20 , wherein Cy has the formula -Cy 1 -Cy 2 or -Cy 1 -G-Cy 2 , wherein Cy 1 and Cy 2 are independently C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, or a radical of a heterocyclic moiety, which groups optionally may be substituted, and G is O, NR 3 , or S(O) n , where R 3 is hydrogen, alkyl, aryl, aralkyl, sulfonyl, acyl, alkoxycarbonyl, or carbamoyl, and n is 0, 1, or 2.
22 . The inhibitor of claim 21 , wherein Cy 1 and Cy 2 are independently selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperidinyl, piperazinyl, which groups optionally may be substituted.
23 . The inhibitor of claim 18 , wherein one to about four carbon atoms of the alkylene are independently substituted with halo, oxo, oximino, nitro, haloalkyl, alkyl, aralkyl, alkoxy, aryloxy, alkoxycarbonyl, carboxy, hydroxyalkyl, acyl, acyloxy, or cyano.
24 . The inhibitor of claim 18 , wherein one carbon atom in the linear chain connecting Cy and W is replaced with O, NR 3 , or S(O) n .
25 . The inhibitor of claim 19 , wherein one carbon atom in the linear chain connecting Cy and W is replaced with NR 3 , where R 3 is selected from the group consisting of C 1 -C 6 alkyl, C 6 -C 10 aryl, (C 6 -C 10 )ar(C 1 -C 6 )alkyl, (C 1 -C 6 alkyl)oxycarbonyl, (C 6 -C 10 aryl)oxycarbonyl, ((C 6 -C 10 )ar(C 1 -C 6 )alkyl)oxycarbonyl, (C 1 -C 6 alkyl)carbonyl, (C 6 -C 10 aryl)carbonyl, and ((C 6 -C 10 )ar(C 1 -C 6 )alkyl)carbonyl.
26 . The inhibitor of claim 18 , wherein one or two carbon atoms in the linear chain connecting Cy and W are replaced by O.
27 . The inhibitor of claim 18 , wherein W is —C(O)—NH-Z or —NH—C(O)—NH-Z, Z being unsubstituted 2-anilinyl or unsubstituted 2-pyridyl.
28 . The inhibitor of claim 18 , wherein W is —C(O)—CH 2 —SR 2 , R 2 being selected from the group consisting of C 1 -C 6 alkyl, C 6 -C 10 aryl, (C 6 -C 10 )ar(C 1 -C 6 )alkyl, (C 1 -C 6 alkyl)carbonyl, (C 6 -C 10 aryl)carbonyl, and ((C 6 -C 10 )ar(C 1 -C 6 )alkyl)carbonyl, wherein the aryl portion of any such groups may be optionally substituted.
29 . The inhibitor of claim 28 , wherein R 2 is selected from the group consisting of methyl, phenyl, benzyl, benzoyl, and acetyl.
30 . An inhibitor of histone deacetylase represented by formula (3):
Cy-S(O) 2 —NH—Y 3 -W (3)
wherein
Cy is cycloalkyl, aryl, or a radical of a heterocyclic moiety, any of which may be optionally substituted, provided that Cy is other than dimethylaminonaphthyl when Y 3 is —(CH 2 ) 3 —;
Y 3 is C 2 -C 6 alkylene, wherein said alkylene may be optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, nitro, haloalkyl, alkyl, aralkyl, alkoxy, aryloxy, carboxy, hydroxyalkyl, acyl, acyloxy, and cyano; and
W is selected from the group consisting of —C(O)—CH 2 —SR 2 , —C(O)—NH-OM, —NH—C(O)—NH-Z, and —C(O)—NH-Z, where
R 2 is alkyl, aryl, aralkyl, or acyl, wherein the aryl portion of any such groups may be optionally substituted;
M is hydrogen or a pharmaceutically acceptable cation; and
Z is selected from the group consisting of anilinyl, pyridyl, thiazolyl, hydroxyphenyl, thiadiazolyl, anilinylmethyl, or pyridylmethyl, any of which groups optionally may be substituted with halo, hydroxy, amino, nitro, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
provided that Z does not have the formula —(C 5 H 3 N)—NHC(O)—Y 3 —NH—S(O) 2 -Cy.
31 . The inhibitor of claim 30 , wherein Cy is C 6 -C 10 aryl or is a radical of a heterocyclic moiety selected from the group consisting of thiophene, benzothiophene, furan, benzofuran, pyridine, quinoline, indole, isoquinoline, thiazole, morpholine, piperidine, and piperazine, any of which groups may be optionally substituted.
32 . The inhibitor of claim 31 , wherein the aryl or heterocyclic moiety is substituted by one or two substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 6 -C 10 aryl, heteroaryl, heterocyclyl, (C 6 -C 10 )ar(C 1 -C 6 )alkyl, halo, nitro, hydroxy, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy, heteroaryloxy, C 1 -C 6 alkoxycarbonyl, C 6 -C 10 aryloxycarbonyl, heteroaryloxycarbonyl, carboxy, and amino.
33 . The inhibitor of claim 30 , wherein Cy has the formula -Cy 1 -Cy 2 or -Cy 1 -G-Cy 2 , wherein Cy 1 and Cy 2 are independently C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, or a radical of a heterocyclic moiety, which groups optionally may be substituted, and G is O, NR 3 , or S(O) n , where R 3 is hydrogen, alkyl, aryl, aralkyl, sulfonyl, acyl, alkoxycarbonyl, or carbamoyl, and n is 0, 1, or 2.
34 . The inhibitor of claim 33 , wherein Cy 1 and Cy 2 are independently selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperidinyl, piperazinyl, which groups optionally may be substituted.
35 . The inhibitor of claim 30 , wherein Y 3 is a C 2 -C 6 alkylene optionally substituted with one or two non-hydrogen substituents independently selected from the group consisting of halo, hydroxy, oxo, nitro, (halo) 1-5 (C 1 -C 3 )alkyl, C 1 -C 6 alkyl, (C 6 -C 10 )ar(C 1 -C 6 )alkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy, carboxy, hydroxy(C 1 -C 6 )alkyl, C 1 -C 6 alkylcarbonyl, C 6 -C 10 arylcarbonyl, C 1 -C 6 alkylcarbonyloxy, C 6 -C 10 arylcarbonyloxy, and cyano.
36 . The inhibitor of claim 33 , wherein Y 3 is an optionally substituted saturated C 4 -C 5 alkylene.
37 . The inhibitor of claim 30 , wherein W is —C(O)—NH-OM, M being selected from the group consisting of hydrogen, sodium, potassium, magnesium, and calcium.
38 . The inhibitor of claim 30 , wherein W is —C(O)—NH-Z or —NH—C(O)—NH-Z, Z being unsubstituted 2-anilinyl or unsubstituted 2-pyridyl.
39 . The inhibitor of claim 30 , wherein W is —C(O)—CH 2 —SR 2 , R 2 being selected from the group consisting of C 1 -C 6 alkyl, C 6 -C 10 aryl, (C 6 -C 10 )ar(C 1 -C 6 )alkyl, (C 1 -C 6 alkyl)carbonyl, (C 6 -C 10 aryl)carbonyl, and ((C 6 -C 10 )ar(C 1 -C 6 )alkyl)carbonyl, wherein the aryl portion of any such groups may be optionally substituted.
40 . An inhibitor of histone deacetylase represented by one of formulae (4)-(5):
41 . An inhibitor of histone deacetylase represented by one of formulae (6)-(7):
42 . A pharmaceutical composition comprising an inhibitor of histone deacetylase represented by formula (1):
Cy-X-Y 1 -W (1)
wherein
Cy is cycloalkyl, aryl, or a radical of a heterocyclic moiety, any of which may be optionally substituted;
X is selected from the group consisting of C═O, C═CH 2 , CH(OH), CH(OR 1 ), C═N(OH), and C═N(OR 1 ), where R 1 is alkyl, aryl, aralkyl, or acyl;
Y 1 is a C 3 -C 7 alkylene, wherein said alkylene may be optionally substituted, and wherein one or two carbon atoms in the linear chain connecting X and W may be replaced with O, NR 3 , or S(O) n , where R 3 is hydrogen, alkyl, aryl, aralkyl, sulfonyl, acyl, alkoxycarbonyl, or carbamoyl, and n is 0, 1, or 2, provided that the atoms in Y 1 that are attached to X and to W are carbon atoms, and further provided that Y 1 does not comprise an ester or amide linkage in the linear chain connecting X and W; and
W is selected from the group consisting of —C(O)—CH 2 —SR 2 , —C(O)—NH-OM, —NH—C(O)—NH-Z, and —C(O)—NH-Z, where
R 2 is alkyl, aryl, aralkyl, or acyl, wherein the aryl portion of any such groups may be optionally substituted;
M is hydrogen or a pharmaceutically acceptable cation;
Z is selected from the group consisting of anilinyl, pyridyl, thiazolyl, hydroxyphenyl, thiadiazolyl, anilinylmethyl, or pyridylmethyl, any of which groups optionally may be substituted with halo, hydroxy, amino, nitro, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; and
a pharmaceutically acceptable carrier, excipient, or diluent;
provided that X is C═CH 2 , CH(OR 1 ), C═N(OH), or C═N(OR 1 ) when W is —C(O)—NH-OM and Cy is unsubstituted phenyl, dimethylaminophenyl, or methoxyphenyl; and
further provided that when W is —C(O)—CH 2 —SR 2 , the carbon atom in Y 1 that is attached to W is unsubstituted or is substituted with other than amino, acylamino, alkoxycarbonyl, or carbamoyl.
43 . A pharmaceutical composition comprising an inhibitor of histone deacetylase represented by formula (2):
Cy-Y 2 -W (2)
wherein
Cy is cycloalkyl, aryl, or a radical of a heterocyclic moiety, any of which may be optionally substituted;
Y 2 is C 5 -C 7 alkylene, wherein said alkylene may be optionally substituted, and wherein one or two carbon atoms in the linear chain connecting Cy and W may be replaced with O, NR 3 , or S(O) n , where R 3 is hydrogen, alkyl, aryl, aralkyl, sulfonyl, acyl, alkoxycarbonyl, or carbamoyl, and n is 0, 1, or 2, provided that Y 2 does not comprise an ester or amide linkage in the linear chain connecting Cy and W; and
W is selected from the group consisting of —C(O)—CH 2 —SR 2 , —NH—C(O)—NH-Z, and —C(O)—NH-Z, where
R 2 is alkyl, aryl, aralkyl, or acyl, wherein the aryl portion of any such groups may be optionally substituted; and
Z is selected from the group consisting of anilinyl, pyridyl, thiazolyl, hydroxyphenyl, thiadiazolyl, anilinylmethyl, or pyridylmethyl, any of which groups optionally may be substituted with halo, hydroxy, amino, nitro, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; and
a pharmaceutically acceptable carrier, excipient, or diluent;
provided that when W is —C(O)—CH 2 —SR 2 , the carbon atom in Y 2 that is attached to W is unsubstituted or is substituted with other than amino, acylamino, alkoxycarbonyl, or carbamoyl.
44 . A pharmaceutical composition comprising an inhibitor of histone deacetylase represented by formula (3):
Cy-S(O) 2 —NH—Y 3 -W (3)
wherein
Cy is cycloalkyl, aryl, or a radical of a heterocyclic moiety, any of which may be optionally substituted, provided that Cy is other than dimethylaminonaphthyl when Y 3 is —(CH 2 ) 3 —;
Y 3 is C 2 -C 6 alkylene, wherein said alkylene may be optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, nitro, haloalkyl, alkyl, aralkyl, alkoxy, aryloxy, carboxy, hydroxyalkyl, acyl, acyloxy, and cyano; and
W is selected from the group consisting of —C(O)—CH 2 —SR 2 , —C(O)—NH-OM, —NH—C(O)—NH-Z, and —C(O)—NH-Z, where
R 2 is alkyl, aryl, aralkyl, or acyl, wherein the aryl portion of any such groups may be optionally substituted;
M is hydrogen or a pharmaceutically acceptable cation; and
Z is selected from the group consisting of anilinyl, pyridyl, thiazolyl, hydroxyphenyl, thiadiazolyl, anilinylmethyl, or pyridylmethyl, any of which groups optionally may be substituted with halo, hydroxy, amino, nitro, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; and
a pharmaceutically acceptable carrier, excipient, or diluent.
provided that Z does not have the formula —(C 5 H 3 N)—NHC(O)—Y 3 —NH—S(O) 2 -Cy.
45 . A pharmaceutical composition comprising an inhibitor of histone deacetylase represented by one of formulae (4)-(5):
and a pharmaceutically acceptable carrier, excipient, or diluent.
46 . A pharmaceutical composition comprising an inhibitor of histone deacetylase represented by one of formulae (6)-(7):
and a pharmaceutically acceptable carrier, excipient, or diluent.
47 . A method of inhibiting histone deacetylase in a cell, comprising contacting a cell in which inhibition of histone deacetylase is desired with an inhibitor of histone deacetylase represented by formula (1):
Cy-X-Y 1 -W (1)
wherein
Cy is cycloalkyl, aryl, or a radical of a heterocyclic moiety, any of which may be optionally substituted;
X is selected from the group consisting of C═O, C═CH 2 , CH(OH), CH(OR 1 ), C═N(OH), and C═N(OR 1 ), where R 1 is alkyl, aryl, aralkyl, or acyl;
Y 1 is a C 3 -C 7 alkylene, wherein said alkylene may be optionally substituted, and wherein one or two carbon atoms in the linear chain connecting X and W may be replaced with O, NR 3 , or S(O) n , where R 3 is hydrogen, alkyl, aryl, aralkyl, sulfonyl, acyl, alkoxycarbonyl, or carbamoyl, and n is 0, 1, or 2, provided that the atoms in Y 1 that are attached to X and to W are carbon atoms, and further provided that Y 1 does not comprise an ester or amide linkage in the linear chain connecting X and W; and
W is selected from the group consisting of —C(O)—CH 2 —SR 2 , —C(O)—NH-OM, —NH—C(O)—NH-Z, and —C(O)—NH-Z, where
R 2 is alkyl, aryl, aralkyl, or acyl, wherein the aryl portion of any such groups may be optionally substituted;
M is hydrogen or a pharmaceutically acceptable cation;
Z is selected from the group consisting of anilinyl, pyridyl, thiazolyl, hydroxyphenyl, thiadiazolyl, anilinylmethyl, or pyridylmethyl, any of which groups optionally may be substituted with halo, hydroxy, amino, nitro, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
provided that X is C═CH 2 , CH(OR 1 ), C═N(OH), or C═N(OR 1 ) when W is —C(O)—NH-OM and Cy is unsubstituted phenyl, dimethylaminophenyl, or methoxyphenyl; and
further provided that when W is —C(O)—CH 2 —SR 2 , the carbon atom in Y 1 that is attached to W is unsubstituted or is substituted with other than amino, acylamino, alkoxycarbonyl, or carbamoyl.
48 . A method of inhibiting histone deacetylase in a cell, comprising contacting a cell in which inhibition of histone deacetylase is desired with an inhibitor of histone deacetylase represented by formula (2):
Cy-Y 2 -W (2)
wherein
Cy is cycloalkyl, aryl, or a radical of a heterocyclic moiety, any of which may be optionally substituted;
Y 2 is C 5 -C 7 alkylene, wherein said alkylene may be optionally substituted, and wherein one or two carbon atoms in the linear chain connecting Cy and W may be replaced with O, NR 3 , or S(O) n , where R 3 is hydrogen, alkyl, aryl, aralkyl, sulfonyl, acyl, alkoxycarbonyl, or carbamoyl, and n is 0, 1, or 2, provided that Y 2 does not comprise an ester or amide linkage in the linear chain connecting Cy and W; and
W is selected from the group consisting of —C(O)—CH 2 —SR 2 , —NH—C(O)—NH-Z, and —C(O)—NH-Z, where
R 2 is alkyl, aryl, aralkyl, or acyl, wherein the aryl portion of any such groups may be optionally substituted; and
Z is selected from the group consisting of anilinyl, pyridyl, thiazolyl, hydroxyphenyl, thiadiazolyl, anilinylmethyl, or pyridylmethyl, any of which groups optionally may be substituted with halo, hydroxy, amino, nitro, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
provided that when W is —C(O)—CH 2 —SR 2 , the carbon atom in Y 2 that is attached to W is unsubstituted or is substituted with other than amino, acylamino, alkoxycarbonyl, or carbamoyl.
49 . A method of inhibiting histone deacetylase in a cell, comprising contacting a cell in which inhibition of histone deacetylase is desired with an inhibitor of histone deacetylase represented by formula (3):
Cy-S(O) 2 —NH—Y 3 -W (3)
wherein
Cy is cycloalkyl, aryl, or a radical of a heterocyclic moiety, any of which may be optionally substituted, provided that Cy is other than dimethylaminonaphthyl when Y 3 is —(CH 2 ) 3 —;
Y 3 is C 2 -C 6 alkylene, wherein said alkylene may be optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, nitro, haloalkyl, alkyl, aralkyl, alkoxy, aryloxy, carboxy, hydroxyalkyl, acyl, acyloxy, and cyano; and
W is selected from the group consisting of —C(O)—CH 2 —SR 2 , —C(O)—NH-OM, —NH—C(O)—NH-Z, and —C(O)—NH-Z, where
R 2 is alkyl, aryl, aralkyl, or acyl, wherein the aryl portion of any such groups may be optionally substituted;
M is hydrogen or a pharmaceutically acceptable cation; and
Z is selected from the group consisting of anilinyl, pyridyl, thiazolyl, hydroxyphenyl, thiadiazolyl, anilinylmethyl, or pyridylmethyl, any of which groups optionally may be substituted with halo, hydroxy, amino, nitro, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
provided that Z does not have the formula —(C 5 H 3 N)—NHC(O)—Y 3 —NH—S(O) 2 -Cy.
50 . A method of inhibiting histone deacetylase in a cell, comprising contacting a cell in which inhibition of histone deacetylase is desired with an inhibitor of histone deacetylase represented by one of formulae (4)-(5):
51 . A method of inhibiting histone deacetylase in a cell, comprising contacting a cell in which inhibition of histone deacetylase is desired with an inhibitor of histone deacetylase represented by one of formulae (6)-(7):
52 . The method of any one of claims 47 - 51 , wherein cell proliferation is inhibited in the contacted cell.
53 . The method of any one of claims 47 - 51 , wherein the cell is a neoplastic cell.
54 . The method of claim 53 , wherein the neoplastic cell is in an animal.
55 . The method of claim 54 , wherein the neoplastic cell is in a neoplastic growth.
56 . The method of any one of claims 47 - 51 , further comprising contacting the cell with an antisense oligonucleotide that inhibits the expression of a histone deacetylase.