METHODS AND COMBINATION THERAPIES FOR TREATING ALZHEIMER'S DISEASE

• US 20100152108A1
• Filed: 10/26/2007
• Published: 06/17/2010
• Est. Priority Date: 10/27/2006
• Status: Abandoned Application

• Current Assignee: Medivation Neurology, Inc.
• Original Assignee: Medivation Neurology, Inc.
• Inventors: Hung, David T., Protter, Andrew Asher
• Application Number:
  US12/447,448
• Publication Number:
  US 20100152108A1
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The invention provides methods and combination therapies for treating and/or preventing and/or slowing the onset and/or development of Alzheimer'"'"'s disease using a hydrogenated pyrido (4,3-b) indole (e.g., dimebon) in conjunction with another compound, pharmaceutically acceptable salt thereof or therapy for Alzheimer'"'"'s disease.

Claims

1. A method of treating Alzheimer'"'"'s disease in an individual in need thereof, the method comprising administering to an individual an effective amount of a combination of (i) a first therapy comprising a hydrogenated pyrido (4,3-b) indole of the formula:

5. The method of claim 1, wherein aralkyl is PhCH₂—

and substituted heteroaralkyl is 6-CH₃-3-Py-(CH₂)₂—

.

6. The method of claim 1, wherein

R¹ is selected from CH₃—

, CH₃CH₂—

, or PhCH₂—

;

R² is selected from H—

, PhCH₂—

, or 6-CH₃-3-Py-(CH₂)₂—

; and

R³ is selected from H—

, CH₃—

or Br—

.

7. The method of claim 1, wherein the hydrogenated pyrido (4,3-b) indole is selected from the group consisting of:

cis(±

) 2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole;

2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2,8-dimethyl-5-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-methyl-5-(2-methyl-3-pyridyl)ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-methyl-8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole,

or a pharmaceutically acceptable salt thereof.

8. The method of claim 7, wherein the hydrogenated pyrido (4,3-b) indole is 2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, or a pharmaceutically acceptable salt thereof.

10. The method of claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride acid salt.

11. The method of claim 1, wherein the hydrogenated pyrido (4,3-b) indole is 2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole dihydrochloride.

19. The method of claim 1, wherein the second therapy comprises a compound that increases the amount or activity of acetylcholine, a NMDA receptor antagonist, an inhibitor of amyloid Aβ

peptide or amyloid plaque, a PDE5 inhibitor, a PDE4 inhibitor, a monoamine oxidase inhibitor, a VEGF protein, a trophic growth factor, a HIF activator, a HIF prolyl 4-hydroxylases inhibitor, an anti-apoptotic compound, an ADNP agonist or analog, an ADNF agonist or analog, an activator of an AMPA-type glutamate receptor, a serotonin 5-HT1A receptor agonist, a serotonin 1A receptor antagonist, a nicotinic alpha-7 receptor agonist, a neuronal L-type calcium channel modulator, a 5-HT4 receptor agonist, an anti-inflammatory agent or pharmaceutically acceptable salt thereof.

20. The method of claim 19, wherein the compound that increases the amount or activity of acetylcholine is an acetylcholinesterase inhibitor or an acetylcholine receptor agonist.

21. The method of claim 20, wherein the acetylcholinesterase inhibitor is Aricept®

, Exelon®

or Razadyne®

.

22. The method of claim 19, wherein the NMDA receptor antagonist is Namenda®

.

23. The method of claim 1, wherein the second therapy comprises an acetylcholinesterase inhibitor and a NMDA receptor antagonist.

24. The method of claim 1, wherein the first and second therapies are administered sequentially.

25. The method of claim 1, wherein the first and second therapies are administered simultaneously.

151. The method of claim 1, wherein the hydrogenated pyrido (4,3-b) indole is 2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole dihydrochloride and the second therapy comprises Aricept®

.

2-4. -4. (canceled)

9. (canceled)

12-18. -18. (canceled)

26-90. -90. (canceled)

91. A kit comprising:

(a) first therapy comprising a hydrogenated pyrido (4,3-b) indole of the formula;

95. The kit of claim 91, wherein aralkyl is PhCH₂—

and substituted heteroaralkyl is 6-CH₃-3-Py-(CH₂)₂—

.

96. The kit of claim 91, wherein

R¹ is selected from CH₃—

, CH₃CH₂—

, or PhCH₂—

;

R² is selected from H—

, PhCH₂—

, or 6-CH₃-3-Py-(CH₂)₂—

; and

R³ is selected from H—

, CH₃—

or Br—

.

97. The kit of claim 91, wherein the hydrogenated pyrido (4,3-b) indole is selected from the group consisting of:

cis(±

) 2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole;

2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2,8-dimethyl-5-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-methyl-5-(2-methyl-3-pyridyl)ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-methyl-8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole,

or a pharmaceutically acceptable salt thereof.

98. The kit of claim 97, wherein the hydrogenated pyrido (4,3-b) indole is 2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, or a pharmaceutically acceptable salt thereof.

100. The kit of claim 91, wherein the pharmaceutically acceptable salt is a hydrochloride acid salt.

101. The kit of claim 91, wherein the hydrogenated pyrido (4,3-b) indole is 2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole dihydrochloride.

109. The kit of claim 91, wherein the second therapy comprises a compound that increases the amount or activity of acetylcholine, a NMDA receptor antagonist, an inhibitor of amyloid Aβ

peptide or amyloid plaque, a PDE5 inhibitor, a PDE4 inhibitor, a monoamine oxidase inhibitor, a VEGF protein, a trophic growth factor, a HIF activator, a HIF prolyl 4-hydroxylases inhibitor, an anti-apoptotic compound, an ADNP agonist or analog, an ADNF agonist or analog, an activator of an AMPA-type glutamate receptor, a serotonin 5-HT1A receptor agonist, a serotonin 1A receptor antagonist, a nicotinic alpha-7 receptor agonist, a neuronal L-type calcium channel modulator, a 5-HT4 receptor agonist, an anti-inflammatory agent or pharmaceutically acceptable salt thereof.

110. The kit of claim 109, wherein the compound that increases the amount or activity of acetylcholine is an acetylcholinesterase inhibitor, a butrylcholinesterase inhibitor or an acetylcholine receptor agonist.

111. The kit of claim 110, wherein the acetylcholinesterase inhibitor is Aricept®

, Exelon®

or Razadyne®

.

112. The kit of claim 109, wherein the NMDA receptor antagonist is Namenda®

.

113. The kit of claim 91, wherein the second therapy comprises an acetylcholinesterase inhibitor and a NMDA receptor antagonist.

116. The kit of claim 91, wherein the first and second therapies are contained in the same pharmaceutical composition.

117. The kit of claim 91, wherein the first and second therapies are contained in separate pharmaceutical compositions.

152. The kit of claim 91, wherein the hydrogenated pyrido (4,3-b) indole is 2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole dihydrochloride and the second therapy comprises Aricept®

.

92-94. -94. (canceled)

99. (canceled)

102-108. -108. (canceled)

114-115. -115. (canceled)

118-120. -120. (canceled)

121. A pharmaceutical composition comprising:

(a) first therapy comprising a hydrogenated pyrido (4,3-b) indole of the formula;

127. The pharmaceutical composition of claim 121, wherein the hydrogenated pyrido (4,3-b) indole is selected from the group consisting of:

cis(±

) 2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole;

2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2,8-dimethyl-5-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-methyl-5-(2-methyl-3-pyridyl)ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-methyl-8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole,

or a pharmaceutically acceptable salt thereof.

128. The pharmaceutical composition of claim 127, wherein the hydrogenated pyrido (4,3-b) indole is 2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, or a pharmaceutically acceptable salt thereof.

131. The pharmaceutical composition of claim 121, wherein the hydrogenated pyrido (4,3-b) indole is 2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole dihydrochloride.

139. The pharmaceutical composition of claim 121, wherein the second therapy comprises a compound that increases the amount or activity of acetylcholine, a NMDA receptor antagonist, an inhibitor of amyloid Aβ

peptide or amyloid plaque, a PDE5 inhibitor, a PDE4 inhibitor, a monoamine oxidase inhibitor, a VEGF protein, a trophic growth factor, a HIF activator, a HIF prolyl 4-hydroxylases inhibitor, an anti-apoptotic compound, an ADNP agonist or analog, an ADNF agonist or analog, an activator of an AMPA-type glutamate receptor, a serotonin 5-HT1A receptor agonist, a serotonin 1A receptor antagonist, a nicotinic alpha-7 receptor agonist, a neuronal L-type calcium channel modulator, a 5-HT4 receptor agonist, an anti-inflammatory agent or pharmaceutically acceptable salt thereof.

140. The pharmaceutical composition of claim 139, wherein the compound that increases the amount or activity of acetylcholine is an acetylcholinesterase inhibitor, a butrylcholinesterase inhibitor or an acetylcholine receptor agonist.

141. The pharmaceutical composition of claim 140, wherein the acetylcholinesterase inhibitor is Aricept®

, Exelon®

or Razadyne®

.

142. The pharmaceutical composition of claim 139, wherein the NMDA receptor antagonist is Namenda®

.

143. The pharmaceutical composition of claim 121, wherein the second therapy comprises an acetylcholinesterase inhibitor and a NMDA receptor antagonist.

146. The pharmaceutical composition of claim 121, wherein the first and second therapies are contained in the same pharmaceutical composition.

147. The pharmaceutical composition of claim 121, wherein the first and second therapies are contained in the separate pharmaceutical compositions.

153. The pharmaceutical composition of claim 121, wherein the hydrogenated pyrido (4,3-b) indole is 2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole dihydrochloride and the second therapy comprises Aricept®

.

122-124. -124. (canceled)

129. (canceled)

130. The pharmaceutical composition of claim 129, wherein the pharmaceutically acceptable salt is a hydrochloride acid salt.

132-138. -138. (canceled)

144-145. -145. (canceled)

148-150. -150. (canceled)