Treatment of CNS disorders using CNS target modulators

• US 20030187021A1
• Filed: 10/16/2002
• Published: 10/02/2003
• Est. Priority Date: 10/16/2001
• Status: Active Grant

• Current Assignee: Hypnion, Inc.
• Original Assignee: Hypnion, Inc.
• Inventors: Hangauer, David G., Leighton, Harry Jefferson, Edgar, Dale M., Mignot, Emmanuel J.M.
• Granted Patent: US 7,189,757 B2
• Time in Patent Office: Days
• US Class Current: 514/317
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: C07D 211/14 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/46 having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 211/70 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/55 Acids; Esters
• CPC Class Codes: C07D 313/12 [b,e]-condensed
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings

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.

Claims

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.

2. The method of claim 1, wherein the CNS disorder is a sleep disorder.

11. The method of claim 1, wherein the therapeutic compound has at least one favorable biological property (FBP).

12. The method of claim 11, wherein the FBP is selected from the group consisting of penetration through the blood brain barrier into the CNS, sequestration of the compound in the CNS as a result of in vivo hydrolysis of an ester by esterases, modification of the half-life of the therapeutic compound, and any combination thereof.

13. The method of claim 11, wherein the CA is AH and the favorable biological property is selected from the group consisting of alteration of charge, pharmacology-kinetics, log P by a value of 1 or more, and any combination thereof.

14. The method of claim 11, wherein the CA is AH and the favorable biological property is selected from the group consisting of increased receptor selectivity, reduced peripheral half-life, the ability to increase dosage, increased peripheral elimination, decreased anti-muscarinic activity, decreased anti-cholinergic, or any combination thereof, relative to the original AH compound.

15. The method of claim 11, wherein the FBP is the discrete period of time that the therapeutic compound remains active.

16. The method of claim 11, wherein the FBP is the induction of a discrete sleep or hypnotic state.

17. The method of claim 15, wherein the FBP is the reduced ability of the subject to form a tolerance to the therapeutic compound.

18. The method of claim 11, wherein the FBP is penetration through the blood brain barrier into the CNS.

19. The method of claim 18, wherein the FBP is penetration through the blood brain barrier into the CNS due to the lipophilicity of substituents or conformational lipophilicity.

20. The method of claim 19, wherein the conformational lipophilicity is a result of an internal salt formation between a carboxylate anion and a protonated amine.

21. The method of claim 12, wherein the FBP is modulation of the half-life of the therapeutic compound.

22. The method of claim 12, wherein the FBP is the in vivo hydrolysis of an ester by esterases that allows sequestration of the therapeutic compound in the CNS.

23. The method of claim 13, wherein the favorable biological property of said AH compound is an alteration of charge.

24. The method of claim 13, wherein the favorable biological property of said AH compound is an alteration of pharmacology-kinetics.

25. The method of claim 13, wherein the favorable biological property of said AH compound is an alteration of log P by a value of 1 or more.

26. The method of claim 14, wherein the favorable biological property of said AH compound is increased receptor selectivity relative to the original AH compound.

27. The method of claim 14, wherein the favorable biological property of said AH compound is reduced peripheral half-life relative to the original AH compound.

28. The method of claim 14, wherein the favorable biological property of said AH compound is the ability to increase dosage relative to the original AH compound.

29. The method of claim 14, wherein the favorable biological property of said AH compound is increased peripheral elimination relative to the original AH compound.

30. The method of claim 14, wherein the favorable biological property of said AH compound is decreased anti-muscarinic activity relative to the original AH compound.

31. The method of claim 14, wherein the favorable biological property of said AH compound is decreased anti-cholinergic relative to the original AH compound.

32. The method of claim 15, wherein the therapeutic compound has an FBP that includes increased concentration within the CNS for a discrete period of time as a result of the existence of an ionic bond that includes the carboxylate ion of the corresponding carboxylic acid.

33. The method of claim 15, wherein the therapeutic compound has an FBP that includes increased concentration within the CNS for a discrete period of time as a result of a slower rate of conversion to the corresponding carboxylic acid by in vivo esterase activity within the CNS as compared with the periphery.

34. The method of claim 33, wherein said acid is not a therapeutically active agent for treating disorders.

35. The method of claim 33, wherein said compound containing said EG or DA is more active as a therapeutic agent for treating disorders than said acid.

36. The method of claim 16, wherein the therapeutic compound induces a discrete sleep or hypnotic state by penetration into the Central Nervous System (CNS).

37. The method of claim 11 wherein the CNS disorder is selected from the group consisting of sleep disorders, depression, anxiety, schizophrenia, attention-deficit hyperactivity disorder (ADHD)/cognition, Alzheimer'"'"'s, Parkinson'"'"'s, dementia, pain, epilepsy, drug abuse, stroke, multiple sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS).

38. The method of claim 37, wherein the CNS disorder is depression.

39. The method of claim 37, wherein the CNS disorder is anxiety.

40. The method of claim 37, wherein the CNS disorder is schizophrenia.

41. The method of claim 37, wherein the CNS disorder is ADHD/cognition.

42. The method of claim 37, wherein the CNS disorder is Alzheimer'"'"'s.

43. The method of claim 37, wherein the CNS disorder is Parkinson'"'"'s.

44. The method of claim 37, wherein the CNS disorder is dementia.

45. The method of claim 37, wherein the CNS disorder is pain.

46. The method of claim 37, wherein the CNS disorder is epilepsy.

47. The method of claim 37, wherein the CNS disorder is drug abuse.

48. The method of claim 37, wherein the CNS disorder is stroke.

49. The method of claim 37, wherein the CNS disorder is MS.

50. The method of claim 37, wherein the CNS disorder is ALS.

51. The method of claim 37, wherein the sleep disorder is selected from the group consisting of insomnia, hypersomnia, narcolepsy, sleep apnea syndromes, parasomnia, restless leg syndrome, and circadian rhythm abnormality.

52. The method of claim 51, wherein the sleep disorder is insomnia.

53. The method of claim 51, wherein the sleep disorder is hypersomnia.

54. The method of claim 51, wherein the sleep disorder is narcolepsy.

55. The method of claim 51, wherein the sleep disorder is sleep apnea syndrome.

56. The method of claim 51, wherein the sleep disorder is parasomnia.

57. The method of claim 51, wherein the sleep disorder is restless leg syndrome.

58. The method of claim 51, wherein the sleep disorder is circadian rhythm abnormality.

59. The method of claim 51, wherein the circadian rhythm abnormality is selected from the group consisting of jet lag, shift-work disorders, and delayed or advanced sleep phase syndrome.

60. The method of claim 1, wherein said spacer molecule is (CH₂)_m, where m is an integer number selected from 1 to 20.

61. The method of claim 60, wherein the (CH₂)_n spacer molecule is substituted with one or more substituents.

62. The method of claim 61, wherein the spacer molecule is disubstituted.

63. The method of claim 62, wherein the spacer molecule is geminally-dialkylated.

64. The method of claim 63, wherein the spacer molecule is gem-dimethylated.

65. The method of claim 61, wherein the spacer molecule is singly substituted with a substituent other than a noncyclic alkyl group.

66. The method of claim 61, wherein the spacer molecule is substituted with a heteroatom or a cyclic substituent.

67. The method of claim 66, wherein the cyclic substituent is a cyclic alkyl or a cyclic ether.

68. The method of claim 1, wherein the DA group is positioned in the therapeutic compound such that said therapeutic compound sufficiently treats said disorder target.

69. The method of claim 1, wherein the therapeutic compound is administered by any means that sufficiently treats said disorder.

70. The method of claim 69, wherein the therapeutic compound is administered orally.

71. The method of claim 1, further comprising administering the therapeutic compound in a pharmaceutically acceptable vehicle.

72. The method of claim 1, wherein the subject is under the influence of an additional modulating factor (AMF).

73. The method of claim 72, wherein the AMF is an additional therapeutic treatment.

74. The method of claim 72, wherein the AMF is a chemical imbalance.

75. The method of claim 72, wherein the effective amount of the therapeutic compound acts to enhance the activity of the AMF.

76. The method of claim 72, wherein the effective amount of the therapeutic compound acts to reduce the activity of the AMF.

77. The method of claim 72, wherein the effective amount of the therapeutic compound acts independently from the AMF.

78. The method of claim 1, wherein said therapeutic compound is selected from the group consisting of:

79. The method of claim 1, wherein said therapeutic compound is:

80. The method of claim 1, wherein said therapeutic compound is:

81. The method of claim 1, wherein said therapeutic compound is:

82. The method of claim 81, wherein the (CH₂)_n spacer molecule to the carboxylic acid group, is substituted with one or more substituents.

83. The method of claim 82, wherein the spacer molecule is disubstituted.

84. The method of claim 82, wherein the spacer molecule is geminally-dialkylated.

85. The method of claim 84, wherein the spacer molecule is gem-dimethylated.

86. The method of claim 82, wherein the spacer molecule is singly substituted with a substituent other than a noncyclic alkyl group.

87. The method of claim 86, wherein the spacer molecule is substituted with a heteroatom or a cyclic substituent.

88. The method of claim 86, wherein the cyclic substituent is a cyclic alkyl or a cyclic ether.

89. The method of claim 78, wherein a=0 or 1.

90. The method of claim 78, wherein b=0 or 1.

91. The method of claim 79, wherein d=0 or 1.

92. The method of claim 79, wherein e=0 or 1.

93. The method of claim 80, wherein f=0 or 1.

94. The method of any one of claims 78, 79, and 80, wherein R is selected from the group consisting of hydrocarbons and perfluorocarbons.

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.

96. The method of claim 94, wherein the hydrocarbons posses 1 to 20 carbons.

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.

98. The method of claim 97, wherein R is a cyclohexyl group.

99. The method of claim 97, wherein R is a cyclopentyl group.

100. The method of claim 97, wherein R is a cycloheptyl group.

101. The method of claim 97, wherein R is a cyclopropyl group.

102. The method of claim 97, wherein R is an isobutyl group.

103. The method of claim 97, wherein R is an ethyl group.

104. The method of claim 97, wherein R is a methyl group.

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.

106. The method of claim 97, wherein R is an n-propyl group.

107. The method of claim 97, wherein R is an isopropyl group.

108. The method of claim 97, wherein R is a t-butyl group.

109. The method of claim 97, wherein R is a benzyl group.

110. The method of claim 1, wherein said therapeutic compound is:

111. The method of claim 110, wherein c=0 or 1.

112. The method of claim 110, wherein R is selected from the group consisting of hydrocarbons and perfluorocarbons.

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.

114. The method of claim 112, wherein the hydrocarbons posses 1 to 20 carbons.

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.

116. The method of claim 115, wherein R is a cyclohexyl group.

117. The method of claim 115, wherein R is a cyclopentyl group.

118. The method of claim 115, wherein R is a cycloheptyl group.

119. The method of claim 115, wherein R is a cyclopropyl group.

120. The method of claim 115, wherein R is an isobutyl group.

121. The method of claim 115, wherein R is an ethyl group.

122. The method of claim 115, wherein R is a methyl group.

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.

124. The method of claim 115, wherein R is an n-propyl group.

125. The method of claim 115, wherein R is an isopropyl group.

126. The method of claim 115, wherein R is a t-butyl group.

127. The method of claim 115, wherein R is a benzyl group.

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.

168. The method of claim 1, wherein the therapeutic compound is selected from the group consisting of the compounds in Table 2.

169. The method of claim 1, wherein the therapeutic compound is selected from the group consisting of the compounds in Table 3.

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:

[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.

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:

[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.

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:

[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.

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:

[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.

7. The method of claim 6, wherein the DA does not substantially effect the biological activity of said AH compound.

8. The method of claim 6, wherein the DA significantly effects the biological activity of said AH compound.

9. The method of claim 8, wherein the DA improves the biological activity of said AH compound.

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:

145. The compound of anyone of claims 128, 129, 130, and 131, wherein R is a bulky alkyl group.

146. The compound of any one of claims 145, wherein the bulky alkyl group is a Type B alkyl of Table 1.

147. The compound of any one of claims 145, wherein the bulky alkyl group is a Type A alkyl of Table 1.

148. The compound of any one of claims 145, wherein R is a bulky alkyl selected from the group consisting of the bulky alkyls in Table 1.

149. The compound of claim 128, wherein the therapeutic compound is selected from 15d-oxalate, 15e-oxalate, 15f-oxalate, 15g-oxalate, 15h-oxalate, 15i-oxalate, 11d-oxalate, 11e-oxalate, 11e-HCl, 11f-oxalate, 11g-oxalate, 11h-oxalate, and 11i-oxalate in Table 3.

150. The compound of claim 128, wherein a=0 or 1.

151. The compound of claim 128, wherein b=0 or 1.

129. A compound of Formula IV:

152. The compound of claim 129, wherein d=0 or 1.

153. The compound of claim 129, wherein e=0 or 1.

130. A compound of Formula V:

154. The compound of claim 130, wherein f=0 or 1.

131. A compound of Formula VI:

132. The compound of claim 131, wherein the (CH₂)_n spacer molecule to the carboxylic acid group, is substituted with one or more substituents.

133. The compound of claim 132, wherein the spacer molecule is disubstituted.

134. The compound of claim 132, wherein the spacer molecule is geminally-dialkylated.

135. The compound of claim 134, wherein the spacer molecule is gem-dimethylated.

136. The compound of claim 132, wherein the spacer molecule is singly substituted with a substituent other than a noncyclic alkyl group.

137. The compound of claim 132, wherein the spacer molecule is substituted with a heteroatom or a cyclic substituent.

138. The compound of claim 132, wherein the cyclic substituent is a cyclic alkyl or a cyclic ether.

139. The compound of claim 131, wherein R₁ and R₂ are both H, the alkyl spacer molecule to the carboxylic acid is singly or doubly substituted with alkyl.

140. The compound of claim 139, wherein the alkyl spacer molecule to the carboxylic acid is gem-dialkylated.

141. The compound of claim 139, wherein the alkyl spacer molecule to the carboxylic acid is gem-dimethylated.

142. The compound of claim 131, R₁ and R₂ are not both H when the alkylene spacer molecule is unsubstituted.

143. The compound of claim 131, with the proviso that the compound is not a compound. of Formula VI when the alkylene spacer molecule is unsubstituted, and R₁ and R₂ are selected from the group consisting of H, halogen CF₃, OH, C_1-6 alkyl, C_1-6 alkoxy.

144. The compound of claim 131, n is not 2 or 3 when the spacer molecule is unsubstituted.

155. A compound having a formula:

156. The compound of claim 155, wherein R is a bulky alkyl group.

157. The compound of claim 156, wherein the bulky alkyl is a Type B alkyl of Table 1.

158. The compound of claim 155, wherein R is a bulky alkyl group, with the proviso that the bulky alkyl is not an n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl group.

159. The compound of claim 155, wherein R is an alkyl group, with the proviso that the alkyl is not a C-1 to C-4 alkyl and/or a C-3 to C-4 bulky alkyl.

160. The compound of claim 155, wherein R is a bulky alkyl group selected from the group consisting of the bulky alkyls in Table 1.

161. The compound of claim 155, wherein R is a bulky alkyl group selected from the group consisting of the bulky alkyls in Table 1, with the proviso that the bulky alkyl is not isopropyl or isobutyl.

162. The compound of claim 155, wherein the therapeutic compound is selected from 6d-oxalate, 6e-oxalate, 6f-oxalate, 6g-oxalate, 6h-oxalate, and 6i-oxalate in Table 3.

163. The compound of claim 155, wherein c=0 or 1.

164. A sleep disorder target modulator comprising the formula:

[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.

165. The compound of claim 164, wherein R is a bulky alkyl group.

166. The compound of claim 164, wherein R is a bulky alkyl group selected from the group consisting of the bulky alkyls in Table 1.