Inhibitors of histone deacetylase

• US 20060058298A1
• Filed: 03/15/2005
• Published: 03/16/2006
• Est. Priority Date: 09/14/2001
• Status: Active Grant

• Current Assignee: 92229129 Quebec Inc.
• Original Assignee: MethylGene, Inc.
• Inventors: Vaisburg, Arkadii, Frechette, Sylvie, Raeppel, Stephane, Leit, Silvana, Delorme, Daniel, Bouchain, Giliane, Woo, Soon Hyung, Moradei, Oscar
• Granted Patent: US 7,838,520 B2
• Time in Patent Office: Days
• US Class Current: 514/237.500
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/537 spiro-condensed or forming part of bridged ring systems
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07C 233/44 having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
• CPC Class Codes: C07C 233/80 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/38 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/42 having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
• CPC Class Codes: C07C 235/56 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/84 with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 237/20 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 237/22 : having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C07C 237/40 : having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 237/42 : having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• CPC Class Codes: C07C 255/58 : containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
• CPC Class Codes: C07C 255/59 : the carbon skeleton being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 275/34 : having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 275/36 : with at least one of the oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. N-aryloxyphenylureas
• CPC Class Codes: C07C 311/42 : to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 323/32 : having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
• CPC Class Codes: C07C 323/36 : the sulfur atom of the sulfide group being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 323/44 : X or Y being nitrogen atoms
• CPC Class Codes: C07C 323/60 : with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• CPC Class Codes: C07C 381/00 : Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
• CPC Class Codes: C07D 213/30 : Oxygen atoms
• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 233/64 : with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 239/91 : with aryl or aralkyl radicals attached in position 2 or 3
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 251/18 : with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
• CPC Class Codes: C07D 251/52 : with an oxygen or sulfur atom attached to the third ring carbon atom
• CPC Class Codes: C07D 251/54 : Three nitrogen atoms
• CPC Class Codes: C07D 263/14 : with radicals substituted by oxygen atoms
• CPC Class Codes: C07D 263/24 : with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
• CPC Class Codes: C07D 265/36 : condensed with one six-membered ring
• CPC Class Codes: C07D 271/06 : 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• CPC Class Codes: C07D 277/42 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 277/74 : Sulfur atoms substituted by carbon atoms
• CPC Class Codes: C07D 277/82 : Nitrogen atoms
• CPC Class Codes: C07D 295/155 : with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 307/12 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 307/28 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 311/56 : without hydrogen atoms in position 3
• CPC Class Codes: C07D 311/58 : other than with oxygen or sulphur atoms in position 2 or 4
• CPC Class Codes: C07D 333/36 : Nitrogen atoms
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 473/40 : with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems
• CPC Class Codes: C07F 7/081 : comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
• CPC Class Codes: C07F 7/0812 : comprising a heterocyclic ring

Abstract

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.

Claims

1-93. -93. (canceled)

94. A histone deacetylase inhibitor of formula (3):

95. The compound according to claim 94 wherein Ar³ has the structure:

96. The compound according to claim 94 wherein X² is selected from the group consisting of L³, W¹-L³, L³-W¹, W¹-L³-W¹, and L³-W¹-L³.

97. The compound according to claim 94 wherein when X² is a chemical bond, then Ar³ is not

98. The compound according to claim 95 wherein Q at each occurrence is C(R⁸), where R⁸ is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkoxy, amino, nitro, halo, haloalkyl, and haloalkoxy.

99. The compound according to claim 95 wherein from one to about three Q are nitrogen.

100. The compound according to claim 94 wherein Ar³ is selected from the group consisting of phenylene, pyridylene, thiazolylene, and quinolylene.

101. The compound according to claim 94 wherein X² is a chemical bond.

102. The compound according to claim 94 wherein X² is a non-cyclic hydrocarbyl.

103. The compound according to claim 94 wherein X² is alkylene.

104. The compound according to claim 94 wherein X² methylene or ethylene.

105. The compound according to claim 94 wherein X² alkenylene or alkynylene.

106. The compound according to claim 102 wherein one carbon in the hydrocarbyl chain is replaced with —

NH—

or —

S—

.

107. The compound according to claim 94 wherein X² is W¹-L³-W¹ and W¹ is —

NH—

or —

N(CH₃)—

.

108. The compound according to claim 94 wherein Cy³ is cycloalkyl.

109. The compound according to claim 94 wherein Cy³ is cyclohexyl.

110. The compound according to claim 94 wherein Cy³ is aryl or heteroaryl, each of which is optionally substituted and is optionally fused to one or two aryl rings.

111. The compound according to claim 94 wherein Cy³ is phenyl, pyridyl, pyrimidyl, imidazolyl, thiazolyl, oxadiazolyl, quinolyl, or fluorenyl, each of which is optionally substituted and is optionally fused to one or two aryl rings.

112. The compound according to claim 94 wherein the cyclic moiety of Cy³ is fused to a benzene ring.

113. The compound according to claim 94 wherein Cy³ has from one to three substituents independently selected from the group consisting of alkyl, alkoxy, aryl, aralkyl, amino, halo, haloalkyl, and hydroxyalkyl.

114. The compound according to claim 113 wherein the substituents are selected from methyl, methoxy, fluoro, trifluoromethyl, amino, nitro, aminomethyl, hydroxymethyl, and phenyl.

115. The compound according to claim 94 wherein Cy³ has from one to three substituents of the formula -K¹-N(H)(R¹⁰), wherein

K¹ is a chemical bond or C₁-C₄ alkylene;

R¹⁰ is selected from the group consisting of Z′ and

-Ak²-Z′

, wherein

Ak² is C₁-C₄ alkylene; and

Z′

is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted, and each of which is optionally fused to one or two aryl or heteroaryl rings, or to one or two saturated or partially unsaturated cycloalkyl or heterocyclic rings.

116. The compound according to claim 115 wherein the substituent is selected from

117. The compound according to claim 94 wherein Cy³ is heterocyclyl, each of which is optionally substituted and is optionally fused to one or two aryl rings.

118. The compound according to claim 94 wherein Cy³ is selected from

119. The compound according to claim 117 wherein the heterocycle of Cy³ is fused to a benzene ring.

120. The compound of claim 94 wherein when Ar⁴ is quinoxalinylene, then X³ is not —

CH(OH)—

.

121. The compound of claim 94 wherein Ar³ is

122. The compound of claim 94 wherein Ar³ is

132. A composition comprising a compound according to claim 94 and a pharmaceutically acceptable carrier.

133. A method of inhibiting histone deacetylase in a cell, the method comprising contacting a cell with a compound according to claim 94.

123. A compound of formula

124. The compound according to claim 123 wherein Cy²-X¹—

is collectively selected from the group consisting of

a) A₁-L₁-B₁-, wherein A₁ is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein L₁ is —

(CH₂)_0-1NH(CH₂)_0-1—

, —

NHC(O)—

, or —

NHCH₂—

; and

wherein B₁ is phenyl or a covalent bond;

b) A₂-L₂-B₂-, wherein A₂ is CH₃(C═

CH₂)—

, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted aryl;

wherein L₂ is —

C≡

C—

; and

wherein B₂ is a covalent bond;

c) A₃-L₃-B₃, wherein A₃ is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein L₃ is a covalent bond; and

wherein B₃ is —

CH₂NH—

;

d) A₄-L₄-B₄-, wherein A₄ is an optionally substituted aryl;

wherein L₄ is —

NHCH₂—

; and

wherein B₄ is a thienyl group;

e) A₅-L₅-B₅-, wherein A₅ is an optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein L₅ is a covalent bond; and

wherein B₅ is —

SCH₂—

;

f) morpholinyl-CH₂—

g) optionally substituted aryl;

h) A₆-L₆-B₆-, wherein A₆ is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein L₆ is a covalent bond; and

wherein B₆ is —

NHCH₂—

;

i) A₇-L₇-B₇-, wherein A₇ is an optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein L₇ is a covalent bond; and

wherein B₇ is —

CH₂—

;

j) aptionally substituted heteroaryl or optionally substituted heterocyclyl;

k) A₈-L₈-B₈-, wherein A₈ is optionally substituted phenyl;

wherein L₈ is a covalent bond; and

wherein B₈ is —

O—

;

l) A₉-L₉-B₉-, wherein A₉ is an optionally substituted aryl;

wherein L₉ is a covalent bond; and

wherein B₉ is a furan group;

m) A₁₀-L₁₀-B₁₀-, wherein A₁₀ is an optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein L₁₀ is —

CH(CH₂CH₃)—

; and

wherein B₁₀ is —

NHCH₂—

;

n) A₁₁-L₁₁-B₁₁-, wherein A₁₁ is an optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein L₁₁ is a covalent bond; and

wherein B₁₁ is —

OCH₂—

;

o) A₁₂-L₁₂-B₁₂-, wherein A₁₂ is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein L₁₂ is —

NHC(O)—

; and

wherein B₁₂ is —

N (optionally substituted aryl)CH₂—

;

p) A₁₃-L₁₃-B₁₃-, wherein A₁₂ is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein L₁₃ is a covalent bond; and

wherein B₁₃ is —

NHC(O)—

;

q) A₁₄-L₁₄-B₁₄-, wherein A₁₄ is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein L₁₄ is —

NHC(O) (optionally substituted heteroaryl); and

wherein B₁₄ is —

S—

S—

;

r) F₃CC(O)NH—

;

s) A₁₅-L₁₅-B₁₅-, wherein A₁₅ is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein L₁₅ is —

(CH₂)_0-1NH (optionally substituted heteroaryl)-; and

wherein B₁₅ is —

NHCH₂—

;

t) A₁₆-L₁₆-B₁₆-, wherein A₁₆ is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein L₁₆ is a covalent bond; and

wherein B₁₆ is —

N(optionally substituted alkyl)CH₂—

; and

u) A₁₆-L₁₆-B₁₆-, wherein A₁₆ is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein L₁₆ is a covalent bond; and

wherein B₁₆ is -(optionally substituted aryl-CH₂)₂—

N—

.

125. The compound according to claim 123 wherein Cy²-X¹- is collectively selected from the group consisting of

a) D₁-E₁-F₁-, wherein D₁ is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein E₁ is —

CH₂—

or a covalent bond; and

wherein B₁ is a covalent bond;

b) D₂-E₂-F₂-, wherein D₂ is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein E₂ is —

NH(CH₂)_0-2—

; and

wherein F₂ is a covalent bond;

c) D3-E₃-F₃-, wherein D₃ is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein E₃ is —

(CH₂)_0-2NH—

; and

wherein F₃ is a covalent bond;

d) D₄-E₄-F₄-, wherein D₄ is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein E₄ is —

S(CH₂)_0-2—

; and

wherein F₄ is a covalent bond;

e) D₅-E₅-F₅-, wherein D₅ is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein E₅ is —

(CH₂)_0-2S—

; and

wherein F₅ is a covalent bond; and

f) D₆-E₆-F₆-, wherein D₆ is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

wherein E₆ is —

NH(CH₂)_0-2NH—

; and

wherein F₆ is a covalent bond.

134. A composition comprising a compound according to claim 123 and a pharmaceutically acceptable carrier.

135. A method of inhibiting histone deacetylase in a cell, the method comprising contacting a cell with a compound according to claim 123.

126-129. -129. (canceled)

131. A histone deacetylase inhibitor selected from the compounds listed in Tables 2a-b, 3a-d, 4a-c, and 5a-5f, or a pharmaceutically acceptable salt thereof.