Treatment of sleeping disorders using CNS sleep target modulators
First Claim
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1. A method of treating a serotonin receptor associated disorder, comprising administering to a subject an effective amount of a therapeutic compound, such that the disorder is treated, wherein the therapeutic compound comprises the formula:
- [EG]r-(SP2)q-[SR]-(SP1)n-[MR]wherein SR is a serotonin receptor antagonist, MR is a metabolite reducing moiety that reduces the formation of wake promoting metabolites, EG is an ester group that modifies the half-life of the therapeutic compound, SP1 and SP2 are spacer molecules, n, q, and r are independently 0 or 1, and r and q are 0 when MR is the ester group.
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Abstract
The invention is directed to compositions used for treating sleep disorders. In addition, the invention provides convenient methods of treatment of a sleep 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 ester derivatized trazodone compounds for the treatment of sleep disorders.
22 Citations
127 Claims
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1. A method of treating a serotonin receptor associated disorder, comprising administering to a subject an effective amount of a therapeutic compound, such that the disorder is treated, wherein the therapeutic compound comprises the formula:
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[EG]r-(SP2)q-[SR]-(SP1)n-[MR] wherein SR is a serotonin receptor antagonist, MR is a metabolite reducing moiety that reduces the formation of wake promoting metabolites, EG is an ester group that modifies the half-life of the therapeutic compound, SP1 and SP2 are spacer molecules, n, q, and r are independently 0 or 1, and r and q are 0 when MR is the ester group. - View Dependent Claims (127)
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2. A method of treating a serotonin receptor associated disorder, comprising administering to a subject an effective amount of a therapeutic compound, such that the disorder is treated, wherein the therapeutic compound comprises the formula:
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[SR]-(SP)n-[EG] wherein SR is a serotonin receptor antagonist, 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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3. 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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[EG]r-(SP2)q-[TZ]-(SP1)n-[MR] wherein TZ is a trazodone compound, MR is a metabolite reducing moiety that reduces the formation of wake promoting metabolites, EG is an ester group that modifies the half-life of the therapeutic compound, SP1 and SP2 are spacer molecules, n, q, and r are independently 0 or 1, and r and q are 0 when MR is the ester group. - View Dependent Claims (9, 10, 11, 12, 47, 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)
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59. The sleep disorder target modulator of claim 58, wherein said spacer molecule is (CH2)m, where m is an integer number selected from 1 to 20.
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60. The method of claim 58, wherein the MR is one or more moieties that are attached at one or more positions along the dotted line.
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61. The method of claim 60, wherein the MR is a single moiety that is attached at multiple positions.
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62. The method of claim 60, wherein the MR comprises more than one moiety that are attached at multiple positions.
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63. The method of claim 58, wherein the MR is an alkyl group.
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64. The method of claim 58, wherein the MR is selected from the compounds listed in Table 2.
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65. The method of claim 3, wherein said therapeutic compound is selected from the group consisting of:
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66. The method of claim 3, wherein said therapeutic compound is selected from the group consisting of:
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67. The method of claim 66, wherein a=0 or 1.
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68. The method of claim 66, wherein b=0 or 1.
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69. The method of claim 66, wherein c=0 or 1.
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70. The method of claim 66, wherein R is selected from the group consisting of hydrocarbons and perfluorocarbons.
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71. The method of claim 70, wherein the hydrocarbons are selected from the group consisting of linear, branched, cyclic, aromatic, and a combination of saturated or unsaturated 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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72. The method of claim 70, wherein the hydrocarbons posses 1 to 20 carbons.
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73. The method of claim 66, 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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74. The method of claim 73, wherein R is a cyclohexyl group.
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75. The method of claim 73, wherein R is a cyclopentyl group.
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76. The method of claim 73, wherein R is a cycloheptyl group.
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77. The method of claim 73, wherein R is a cyclopropyl group.
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78. The method of claim 73, wherein R is an isobutyl group.
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79. The method of claim 73, wherein R is an ethyl group.
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80. The method of claim 73, wherein R is a methyl group.
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81. The method of claim 79 or 80, wherein the formulation of said therapeutic compound is formulated to sufficiently treat a sleep disorder.
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82. The method of claim 73, 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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83. The method of claim 73, wherein R is an n-propyl group.
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84. The method of claim 73, wherein R is an isopropyl group.
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85. The method of claim 73, wherein R is a t-butyl group.
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86. The method of claim 73, wherein R is a benzyl group.
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87. The method of claim 73, wherein R is a bulky ester.
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88. The method of claim 87, wherein the bulky ester is selected from the esters in Table 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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[TZ]-(SP)n-[EG] wherein TZ is a trazodone compound, 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. - View Dependent Claims (5, 6, 7, 48)
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- 8. A method of treating a sleep disorder, comprising administering to a subject an effective amount of trazodone compound, such that the sleep disorder is treated, wherein the trazodone compound has a favorable biological property (FBP).
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89. A method of modulating a serotonin receptor associated disorder target comprising administering to a subject an effective amount of a therapeutic compound, such that the disorder target is modulated, wherein the therapeutic compound comprises the formula:
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[EG]r-(SP2)q-[SR]-(SP1)n-[MR] wherein SR is a serotonin receptor antagonist, MR is a metabolite reducing moiety that reduces the formation of wake promoting metabolites, EG is an ester group that modifies the half-life of the therapeutic compound, SP1 and SP2 are spacer molecules, n, q, and r are independently 0 or 1, and r and q are 0 when MR is the ester group.
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90. A method of modulating a serotonin receptor associated disorder target comprising administering to a subject an effective amount of a therapeutic compound, such that the disorder target is modulated, wherein the therapeutic compound comprises the formula:
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[SR]-(SP)n-[EG] wherein SR is a serotonin receptor antagonist, 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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91. A method of modulating a sleep disorder target comprising administering to a subject an effective amount of a therapeutic compound, such that the sleep disorder target is modulated, wherein the therapeutic compound comprises the formula:
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[EG]r-(SP2)q-[TZ]-(SP1)n-[MR] wherein TZ is a trazodone compound, MR is a metabolite reducing moiety that reduces the formation of wake promoting metabolites, EG is an ester group that modifies the half-life of the therapeutic compound, SP1 and SP2 are spacer molecules, n, q, and r are independently 0 or 1, and r and q are 0 when MR is the ester group.
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92. A method of modulating a sleep disorder target comprising administering to a subject an effective amount of a therapeutic compound, such that the sleep disorder target is modulated, wherein the therapeutic compound comprises the formula:
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[TZ]-(SP)n-[EG] wherein TZ is a trazodone compound, 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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93. A compound comprising the formula:
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[EG]r-(SP2)q-[SR]-(SP1)n-[MR] wherein SR is a serotonin receptor antagonist, MR is a metabolite reducing moiety that reduces the formation of wake promoting metabolites, EG is an ester group that modifies the half-life of the therapeutic compound, SP1 and SP2 are spacer molecules, n, q, and r are independently 0 or 1, and r and q are 0 when MR is the ester group.
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94. A compound comprising the formula:
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[EG]r-(SP2)q-[TZ]-(SP1)n-[MR] wherein TZ is a trazodone compound, MR is a metabolite reducing moiety that reduces the formation of wake promoting metabolites, EG is an ester group that modifies the half-life of the therapeutic compound, SP1 and SP2 are spacer molecules, n, q, and r are independently 0 or 1, and r and q are 0 when MR is the ester group. - View Dependent Claims (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)
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97. The compound of claim 96, wherein said spacer molecule is (CH2)m, where m is an integer number selected from 1 to 20.
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98. The compound of claim 96, wherein the MR is one or more moieties that are attached at one or more positions along the dotted line.
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99. The compound of claim 98, wherein the MR is a single moiety that is attached at multiple positions.
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100. The compound of claim 98, wherein the MR comprises more than one moiety that are attached at multiple positions.
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101. The compound of claim 96, wherein the MR is an alkyl group.
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102. The compound of claim 96, wherein the MR is selected from the compounds listed in Table 2.
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103. The compound of claim 94 selected from the group consisting of:
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104. The compound of claim 94 selected from the group consisting of:
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105. The compound of claim 104, wherein a=0 or 1.
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106. The compound of claim 104, wherein b=0 or 1.
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107. The compound of claim 104, wherein c=0 or 1.
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108. The compound of claim 104, wherein R is selected from the group consisting of hydrocarbons and perfluorocarbons.
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109. The compound of claim 108, wherein the hydrocarbons are selected from the group consisting of linear, branched, cyclic, aromatic, and a combination of saturated or unsaturated 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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110. The compound of claim 108, wherein the hydrocarbons posses 1 to 20 carbons.
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111. The compound of claim 104, wherein R is selected from the group consisting of an n-propyl, an isopropyl, a t-butyl, a cyclopentyl, a cyclohexyl, a cycloheptyl, and a benzyl group.
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112. The compound of claim 111, wherein R is a cyclohexyl group.
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113. The compound of claim 111, wherein R is a cyclopentyl group.
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114. The compound of claim 111, wherein R is a cycloheptyl group.
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115. The compound of claim 111, wherein R is a cyclopropyl group.
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116. The compound of claim 111, wherein R is an isobutyl group.
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117. The compound of claim 111, wherein R is an n-propyl group.
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118. The compound of claim 111, wherein R is an isopropyl group.
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119. The compound of claim 111, wherein R is a t-butyl group.
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120. The compound of claim 111, wherein R is a benzyl group.
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121. The compound of claim 111, 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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122. A compound comprising the formula:
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[SR]-(SP)n-[EG] wherein SR is a serotonin receptor antagonist, 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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123. A compound comprising the formula:
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[TZ]-(SP)n-[EG] wherein TZ is a trazodone compound, 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. - View Dependent Claims (124, 125, 126)
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Specification