Dioxanes and uses thereof

• US 20080269245A1
• Filed: 07/17/2007
• Published: 10/30/2008
• Est. Priority Date: 05/09/2001
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Schreiber, Stuart L., Haggarty, Stephen J., Sternson, Scott M., Wong, Jason C., Koeller, Kathryn M., Grozinger, Christina M.
• Granted Patent: US 8,178,579 B2
• Time in Patent Office: Days
• US Class Current: 514/254.1
• CPC Class Codes: C07D 319/06 not condensed with other rings
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 491/10 Spiro-condensed systems

Abstract

In recognition of the need to develop novel therapeutic agents and efficient methods for the synthesis thereof, the present invention provides novel compounds of general formula (I):

• • and pharmaceutically acceptable derivatives thereof, wherein R¹, R², R³, n, X and Y are as defined herein. The present invention also provides pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The present invention further provides compounds capable of inhibiting histone deacetylatase activity and methods for treating disorders regulated by histone deacetylase activity (e.g., cancer and protozoal infections) comprising administering a therapeutically effective amount of a compound of formula (I) to a subject in need thereof. The present invention additionally provides methods for modulating the glucose-sensitive subset of genes downstream of Ure2p. The present invention also provides methods for preparing compounds of the invention.

Claims

1-54. -54. (canceled)

55. A method for inhibiting histone deacetylase activity in a patient or a biological sample, comprising administering to said patient, or contacting said biological sample with an effective inhibitory amount of a compound of having the structure (I):

57. The method according to claim 55, wherein the histone deacetylase is HDAC1 or HDAC6.

66. The method according to claim 55, wherein:

R¹ is hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety;

R² is hydrogen, a protecting group, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety;

X is —

O—

, —

C(R^2A)₂—

, —

S—

, or —

NR^2A, wherein R^2A is hydrogen, a protecting group, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety;

or wherein two or more occurrences of R² and R^2A, taken together, form an alicyclic or heterocyclic moiety, or an aryl or heteroaryl moiety;

R³ is an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety; and

Y is an aryl, -(aliphatic)aryl, or -(heteroaliphatic)aryl moiety.

67. The method according to claim 55, wherein the compound has the structure as shown in formula (Ia):

68. The method according to claim 55, wherein the compound has the structure as shown in formula (Ib):

69. The method according to claim 55, wherein R³ represents a phenyl group substituted with a moiety having the structure —

P-Q, the following groups do not occur simultaneously as defined;

P is selected from the group consisting of substituted or unsubstituted C₄-C₈ alkylene, C₄-C₈ alkenylene, C₄-C₈ alkynylene, and —

R-T-U-, wherein R and U are independently absent or represent a C₂-C₇ alkylene, a C₂-C₇ alkenylene, or a C₂-C₇ alkynylene, and T represents O, S or NR^T, wherein R^T represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl or heterocyclyl; and

Q is selected from the group consisting of;

70. The method according to claim 55, wherein R³ represents a phenyl group substituted with a moiety having the structure —

P-Q, the following groups do not occur simultaneously as defined;

P is selected from the group consisting of;

71. The method according to claim 55, wherein Y is an aryl or heteroaryl moiety substituted with Z, wherein Z is hydrogen, —

(CH₂)_qOR^Z, —

(CH₂)_qSR^Z, —

(CH₂)_qN(R^Z)₂, —

C(═

O)R^Z, —

C(═

O)N(R^Z)₂, or an aliphatic, alycyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -heteroaliphatic)heteroaryl moiety, wherein q is 0-4, and wherein each occurrence of R^Z is independently hydrogen, a protecting group, a solid support unit, or an aliphatic, alycyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety.

72. The method according to claim 55, wherein Y is a substituted phenyl moiety and the compound has the structure (II):

73. The method according to claim 55, wherein Y is a substituted phenyl moiety and the compound has the structure (III):

74. The method according to claim 55, wherein Y is a substituted phenyl moiety and X is S and the compound has the structure (IV):

75. The method according to claim 55, wherein Y is a substituted phenyl moiety and X is —

NR^2A and the compound has the structure (V);

76. The method according to claim 55, wherein Y is a substituted phenyl moiety and X is —

O— and

the compound has the structure (VI);

77. The method according to claim 55, wherein Y is a substituted phenyl moiety and R³ is a phenyl moiety substituted with R⁴ and the compound has the structure (VII):

78. The method according to claim 77, wherein Z is —

CH₂OR^Z, and the compound has the structure (VIII);

79. The method according to claim 55, wherein R¹ is hydrogen, methyl, or phenyl.

80. The method according to claim 55, wherein X—

R² has one of the structures;

81. The method according to claim 55, wherein R³ is one of the following structures:

82. The method according to claim 81, wherein L is —

(CH₂)_rN(R^4C)Alk¹-, wherein r is or 1;

R^4C is hydrogen, a nitrogen protecting group, alkyl, acyl, heteroalkyl, aryl or heteroaryl; and

Alk¹ is a substituted or unsubstituted C_3-7alkylene or C_3-7alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by CO, CO₂, COCO, CONR^Z1, OCONR^Z1, NR^Z1NR^Z2, NR^Z1NR^Z2CO, NR^Z1CO, NR^Z1CO₂, NR^Z1CONR^Z2, SO, SO₂, NR^Z1SO₂, SO₂NR^Z1, NR^Z1SO₂NR^Z2, O, S, or NR^Z1;

wherein each occurrence of R^Z1 and R^Z2 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or acyl.

83. The method according to claim 81, wherein L is —

(CH₂)_rN(R^4C)C(═

O)Alk²-, wherein r is 0 or 1;

R^4C is hydrogen, a nitrogen protecting group, alkyl, acyl, heteroalkyl, aryl or heteroaryl; and

Alk² is a substituted or unsubstituted C_3-6alkylene or C_3-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by CO, CO₂, COCO, CONR^Z1, OCONR^Z1, NR^Z1NR^Z2, NR^Z1NR^Z2CO, NR^Z1CO, NR^Z1CO₂, NR^Z1CONR^Z2, SO, SO₂, NR^Z1SO₂, SO₂NR^Z1, NR^Z1SO₂NR^Z2, O, S, or NR^Z1;

wherein each occurrence of R^Z1 and R^Z2 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or acyl.

84. The method according to claim 81, wherein L is —

(CH₂)_rNHC(═

O)(CH₂)_t—

, wherein r is 0 or 1; and

t is 3, 4, 5 or 6.

85. The method according to any one of claims 81-84, wherein R^4A is —

C(═

O)OR^4B, —

C(═

O)NHOR^4B or a moiety having the structure;

86. The method according to claim 55, wherein the compound has the structure:

87. The method according to claim 86, wherein R¹ is hydrogen, phenyl or methyl, R^Z is hydrogen or a solid support unit;

R² is a substituted or unsubstituted alkyl or heteroalkyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; and

R⁴ is —

(CH₂)_rN(R^4A)₂, —

(CH₂)_rSR^4A, —

(CH₂)_rOR^4A, —

(CH₂)_rNR^4AC(═

O)R^4B, —

(CH₂)_rC(═

O)N(R^4A)₂, —

S(O)₂R^4A, or is an aliphatic, alycyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety, wherein each occurrence of R^4B is independently hydrogen, an aliphatic, alycyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety; and

each occurrence of R^4A is independently hydrogen, a protecting group, an aliphatic, alycyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety, or is —

C(═

O)CH(R^4C)NH(SO₂)R^4D, —

SO₂R^4C, —

C(═

O)R^4C, —

C(═

O)N(R^4C)₂, —

C(═

S)N(R^4C)₂, or —

C(═

O)(CH₂)_tC(═

O)NHR^4C, wherein each occurrence of R^4C and R^4D is independently hydrogen, a protecting group, hydroxyl, protected hydroxyl, or an aliphatic, alycyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety, wherein r and t are each independently 0-5.

88. The method according to claim 86, wherein R⁴ represents a moiety having the structure -L-R^4A and the compound has the structure:

89. The method according to claim 88, wherein L is a substituted or unsubstituted C_4-8alkylene or C_4-8alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by CO, CO₂, COCO, CONR^Z1, OCONR^Z1, NR^Z1NR^Z2, NR^Z1NR^Z2CO, NR^Z1CO, NR^Z1CO₂, NR^Z1CONR^Z2, SO, SO₂, NR^Z1SO₂, SO₂NR^Z1, NR^Z1SO₂NR^Z2, O, S, or NR^Z1;

wherein each occurrence of R^Z1 and R^Z2 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or acyl.

90. The method according to claim 89, wherein L is —

(CH₂)_rNHC(═

O)(CH₂)_t—

, wherein r is 0 or 1; and

t is 3, 4, 5 or 6.

91. The method according to claim 88, wherein R^4A is C(═

O)OR^4B, —

C(═

O)NHOR^4B or a moiety having the structure;

92. The method according to claim 88, wherein the compound has the structure:

93. The method according to claim 92, wherein Alk¹ is a moiety having the structure —

C(═

O)-Alk²- and the compound has the structure;

94. The method according to claim 93, wherein Alk² is a substituted or unsubstituted C_3-6alkylene chain.

95. The method according to claim 93, wherein R^4A is —

C(═

O)OR^4B, —

C(═

O)NHOR^4B or a moiety having the structure;

96. The method according to claim 92, wherein the compound has the structure:

97. The method according to claim 96, wherein R^4A is —

C(═

O)OR^4B, —

C(═

O)NHOR^4B or a moiety having the structure;

98. The method according to claim 55, wherein the compound has the structure:

99. The method according to claim 98, wherein R¹ is hydrogen, phenyl or methyl, R^Z is hydrogen or a solid support unit;

R² is a substituted or unsubstituted alkyl or heteroalkyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety;

either or both of R² and R^2A, or R² and R^2A taken together with the nitrogen atom to which they are attached, forms a substituted or unsubstituted cycloalkyl or heterocyclic moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; and

R⁴ is —

(CH₂)_rN(R^4A)₂—

(CH₂)_rSR^4A, —

(CH₂)_rOR^4A, —

(CH₂)_rNR^4AC(═

O)R^4B, —

(CH₂)_rC(═

O)N(R^4A)₂, —

S(O)₂R^4A, or is an aliphatic, alycyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety, wherein each occurrence of R^4B is independently hydrogen, an aliphatic, alycyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety; and

each occurrence of R^4A is independently hydrogen, a protecting group, an aliphatic, alycyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety, or is —

C(═

O)CH(R^4C)NH(SO₂)R^4D, —

SO₂R^4C, —

C(═

O)R^4C, —

C(═

O)N(R^4C)₂, —

C(═

S)N(R^4C)₂, or —

C(═

O)(CH₂)_tC(═

O)NHR^4C, wherein each occurrence of R^4C and R^4D is independently hydrogen, a protecting group, hydroxyl, protected hydroxyl, or an aliphatic, alycyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety, wherein r and t are each independently 0-5.

100. The method according to claim 98, wherein R⁴ represents a moiety having the structure -L-R^4A and the compound has the structure:

101. The method according to claim 100, wherein L is a substituted or unsubstituted C_4-8alkylene or C_4-8alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by CO, CO₂, COCO, CONR^Z1, OCONR^Z1, NR^Z1NR^Z2, NR^Z1NR^Z2CO, NR^Z1CO, NR^Z1CO₂, NR^Z1CONR^Z2, SO, SO₂, NR^Z1SO₂, SO₂NR^Z1, NR^Z1SO₂NR^Z2, O, S, or NR^Z1;

wherein each occurrence of R^Z1 and R^Z2 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or acyl.

102. The method according to claim 101, wherein L is —

(CH₂)_rNHC(═

O)(CH₂)_t—

, wherein r is 0 or 1; and

t is 3, 4, 5 or 6.

103. The method according to claim 100, wherein R^4A is —

C(═

O)OR^4B, —

C(═

O)NHOR^4B or a moiety having the structure;

104. The method according to claim 98, wherein the compound has the structure:

105. The method according to claim 104, wherein Alk¹ is a moiety having the structure —

C(═

O)-Alk²- and the compound has the structure;

106. The method according to claim 105, wherein Alk² is a substituted or unsubstituted C_3-6alkylene chain.

107. The method according to claim 105, wherein R^4A is —

C(═

O)OR^4B, —

C(═

O)NHOR^4B or a moiety having the structure;

108. The method according to claim 98, wherein the compound has the structure:

109. The method according to claim 108, wherein R^4A is —

C(═

O)OR^4B, —

C(═

O)NHOR^4B or a moiety having the structure;

110. The method according to any one of claims 55, 86, 96, 98, or 108, wherein R² is one of the following structures:

111. The method according to claim 98 or 108, wherein either or both of R², R^2A, or R² and R^2A, taken together with the nitrogen atom to which they are attached comprise

112. The method according to claims 98 or 108, wherein one or both of R² and R^2A is an aryl or heteroaryl moiety substituted with —

COOH, halogen, alkyl, heteroalkyl, aryl, heteroaryl, OH, SH, NO₂, NH₂, or —

NHC(═

O)alkyl.

113. The method according to claims 96 or 108, wherein R^4A is —

C(═

O)OH, —

C(═

O)NHOH or a moiety having the structure;

114. The method according to claims 96 or 108, wherein R^4A is —

C(═

O)NHOH.

115. The method according to claim 55, wherein the compound has the structure:

116. The method according to claim 55, wherein the compound has the structure:

117. The method according to any one of claims 55, 86, 96, 98, or 108, comprising further administering to said patient, or contacting said biological sample, an additional therapeutic agent.

118. The method according to any one of claims 55, 86, 96, 98, or 108, wherein the biological sample is a cell.

56. (canceled)

58-65. -65. (canceled)

119. A method for inhibiting histone deacetylase activity in a cell comprising contacting a cell with a compound having the structure (I):