Treatment of CNS disorders using CNS target modulators
First Claim
1. A method of treating a Central Nervous System (CNS) disorder, comprising administering to a subject an effective amount of a therapeutic compound, such that the therapeutic compound penetrates into the CNS and modulates the CNS target, thereby treating the CNS disorder, wherein the therapeutic compound comprises the formula:
- [CA]-(SP)n-[DA]wherein CA is a moiety that modulates an active CNS target receptor or a collection of active CNS target receptors, DA is a drug activity modulating moiety that provides the ability to modulate the activity of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
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Accused Products
Abstract
The invention is directed to compositions used for treating Central Nervous System (CNS) disorders. In addition, the invention provides convenient methods of treatment of a CNS disorder. Furthermore, the invention provides methods of treating sleep disorders using compositions that remain active for a discrete period of time to reduce side effects. More specifically, the invention is directed to the compositions and use of derivatized, e.g., ester or carboxylic acid derivatized, antihistamine antagonists for the treatment of sleep disorders.
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Citations
169 Claims
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1. A method of treating a Central Nervous System (CNS) disorder, comprising administering to a subject an effective amount of a therapeutic compound, such that the therapeutic compound penetrates into the CNS and modulates the CNS target, thereby treating the CNS disorder, wherein the therapeutic compound comprises the formula:
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[CA]-(SP)n-[DA] wherein CA is a moiety that modulates an active CNS target receptor or a collection of active CNS target receptors, DA is a drug activity modulating moiety that provides the ability to modulate the activity of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1. - View Dependent Claims (2, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 167, 168, 169)
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79. The method of claim 1, wherein said therapeutic compound is:
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80. The method of claim 1, wherein said therapeutic compound is:
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81. The method of claim 1, wherein said therapeutic compound is:
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82. The method of claim 81, wherein the (CH2)n spacer molecule to the carboxylic acid group, is substituted with one or more substituents.
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83. The method of claim 82, wherein the spacer molecule is disubstituted.
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84. The method of claim 82, wherein the spacer molecule is geminally-dialkylated.
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85. The method of claim 84, wherein the spacer molecule is gem-dimethylated.
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86. The method of claim 82, wherein the spacer molecule is singly substituted with a substituent other than a noncyclic alkyl group.
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87. The method of claim 86, wherein the spacer molecule is substituted with a heteroatom or a cyclic substituent.
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88. The method of claim 86, wherein the cyclic substituent is a cyclic alkyl or a cyclic ether.
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89. The method of claim 78, wherein a=0 or 1.
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90. The method of claim 78, wherein b=0 or 1.
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91. The method of claim 79, wherein d=0 or 1.
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92. The method of claim 79, wherein e=0 or 1.
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93. The method of claim 80, wherein f=0 or 1.
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94. The method of any one of claims 78, 79, and 80, wherein R is selected from the group consisting of hydrocarbons and perfluorocarbons.
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95. The method of claim 94, wherein the hydrocarbons are selected from the group consisting of linear, branched, cyclic, aromatic, and a combination of aliphatic and aromatic, which are optionally substituted with O, N, S, or halogens and may additionally include a center of chirality.
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96. The method of claim 94, wherein the hydrocarbons posses 1 to 20 carbons.
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97. The method of any one of claims 78, 79, and 80, wherein R is selected from the group consisting of a methyl, an ethyl, an n-propyl, an isopropyl, a cyclopropyl, a t-butyl, an isobutyl, a cyclopentyl, a cyclohexyl, a cycloheptyl, and a benzyl group.
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98. The method of claim 97, wherein R is a cyclohexyl group.
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99. The method of claim 97, wherein R is a cyclopentyl group.
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100. The method of claim 97, wherein R is a cycloheptyl group.
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101. The method of claim 97, wherein R is a cyclopropyl group.
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102. The method of claim 97, wherein R is an isobutyl group.
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103. The method of claim 97, wherein R is an ethyl group.
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104. The method of claim 97, wherein R is a methyl group.
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105. The method of claim 97, wherein the formulation of said therapeutic compound is used to provide controlled in vivo adsorption of the therapeutic compound over a discrete period of time.
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106. The method of claim 97, wherein R is an n-propyl group.
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107. The method of claim 97, wherein R is an isopropyl group.
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108. The method of claim 97, wherein R is a t-butyl group.
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109. The method of claim 97, wherein R is a benzyl group.
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110. The method of claim 1, wherein said therapeutic compound is:
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111. The method of claim 110, wherein c=0 or 1.
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112. The method of claim 110, wherein R is selected from the group consisting of hydrocarbons and perfluorocarbons.
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113. The method of claim 112, wherein the hydrocarbons are selected from the group consisting of linear, branched, cyclic, aromatic, and a combination of aliphatic and aromatic, which are optionally substituted with O, N, S, and/or halogens and may additionally include a center of chirality.
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114. The method of claim 112, wherein the hydrocarbons posses 1 to 20 carbons.
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115. The method of claim 110, wherein R is selected from the group consisting of a methyl, an ethyl, an n-propyl, an isopropyl, a t-butyl, a cyclopentyl, a cyclohexyl, a cycloheptyl, and a benzyl group.
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116. The method of claim 115, wherein R is a cyclohexyl group.
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117. The method of claim 115, wherein R is a cyclopentyl group.
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118. The method of claim 115, wherein R is a cycloheptyl group.
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119. The method of claim 115, wherein R is a cyclopropyl group.
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120. The method of claim 115, wherein R is an isobutyl group.
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121. The method of claim 115, wherein R is an ethyl group.
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122. The method of claim 115, wherein R is a methyl group.
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123. The method of claim 115, wherein the formulation of said therapeutic compound is used to provide controlled in vivo adsorption of the therapeutic compound over a discrete period of time.
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124. The method of claim 115, wherein R is an n-propyl group.
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125. The method of claim 115, wherein R is an isopropyl group.
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126. The method of claim 115, wherein R is a t-butyl group.
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127. The method of claim 115, wherein R is a benzyl group.
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167. The method of any one of claims 78, 79, 80, 81, and 112, wherein R is selected from the group consisting of the alkyl groups in Table 1.
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168. The method of claim 1, wherein the therapeutic compound is selected from the group consisting of the compounds in Table 2.
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169. The method of claim 1, wherein the therapeutic compound is selected from the group consisting of the compounds in Table 3.
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3. A method of treating a Central Nervous System (CNS) disorder, comprising administering to a subject an effective amount of a therapeutic compound, such that the therapeutic compound penetrates into the CNS and modulates the CNS target, thereby treating the CNS disorder, wherein the therapeutic compound comprises the formula:
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[CA]-(SP)n-[EG] wherein CA is a moiety that modulates an active CNS target receptor or a collection of active CNS target receptors, EG is an ester group that modifies the half-life of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
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4. A method of treating a sleep disorder, comprising administering to a subject an effective amount of a therapeutic compound, such that the sleep disorder is treated, wherein the therapeutic compound comprises the formula:
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[CA]-(SP)n-[EG] wherein CA is a moiety that modulates an active CNS target receptor or a collection of active CNS target receptors, EG is an ester group that modifies the half-life of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
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5. A method of treating a sleep disorder, comprising administering to a subject an effective amount of a therapeutic compound, such that the sleep disorder is treated, wherein the therapeutic compound comprises the formula:
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[AD]-(SP)n-[EG] wherein AD is a moiety that agonizes an adenosine receptor or a collection of adenosine receptors, EG is an ester group that modifies the half-life of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
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6. A method of treating a sleep disorder target, comprising administering to a subject an effective amount of a therapeutic compound, such that the sleep disorder is treated, wherein the therapeutic compound comprises the formula:
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[AH]-(SP)n-[DA] wherein AH is a moiety that antagonizes a histamine receptor or a collection of histamine receptors, DA is a drug activity modulating moiety that provides the ability to modulate the activity of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1. - View Dependent Claims (7, 8, 9)
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10. A method of treating a sleep disorder, comprising administering to a subject an effective amount of an antihistamine compound, such that the sleep disorder is treated, wherein the antihistamine compound has a favorable biological property (FBP).
- 128. A compound having a formula selected from the group consisting of:
- 129. A compound of Formula IV:
- 130. A compound of Formula V:
- 131. A compound of Formula VI:
- 155. A compound having a formula:
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164. A sleep disorder target modulator comprising the formula:
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[AH]-(SP)n-[DA] wherein AH is a moiety that antagonizes a histamine receptor, DA is a drug activity modulating moiety that provides the ability to modulate the activity of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1. - View Dependent Claims (165, 166)
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Specification