COMBINATION OF MORPHINAN COMPOUNDS AND ANTIDEPRESSANT FOR THE TREATMENT OF PSEUDOBULBAR AFFECT, NEUROLGICAL DISEASES, INTRACTABLE AND CHRONIC PAIN AND BRAIN INJURY

• US 20160143902A1
• Filed: 11/30/2015
• Published: 05/26/2016
• Est. Priority Date: 10/30/2008
• Status: Abandoned Application

• Current Assignee: Concert Pharmaceuticals Inc.
• Original Assignee: Concert Pharmaceuticals Inc.
• Inventors: Thomas, Amanda
• Application Number:
  US14/954,605
• Publication Number:
  US 20160143902A1
• Time in Patent Office: Days
• 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 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/15 Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
• CPC Class Codes: A61K 31/343 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• CPC Class Codes: A61K 31/4525 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids

Abstract

Provided herein are compositions comprising a dextromethorphan analog according to Formula I or Formula II or a pharmaceutically acceptable salt thereof of either of the foregoing, and a co-agent, e.g., an antidepressant such as a serotonin norepinephrine reuptake inhibitor; a serotonin noradrenaline dopamine reuptake inhibitor; a norepinephrine dopamine reuptake inhibitor; a monoamine oxidase inhibitor; a selective serotonin reuptake inhibitor; and a tricyclic antidepressant or a pharmaceutically acceptable salt of any of the foregoing. The compositions are useful in the the treatment of pseudobulbar affect, neuropathic pain, neurodegenerative diseases, brain injuries, and the like.

Claims

1-90. -90. (canceled)

91. A method of treating pseudobulbar affect in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of a co-agent which is norepinephrine-dopamine reuptake inhibitor (NDRI), or a pharmaceutically acceptable salt thereof;

and a compound of Formula II;

92. The method of claim 91, wherein R⁴ is selected from —

CH₃, —

CHD₂, or —

CD₃.

93. The method of claim 92, wherein R³ is selected from —

OCF₃, —

OCD₃, or —

OCHF₂.

94. The method of claim 91, wherein said co-agent is an inhibitor of a cytochrome p450 2D6 enzyme.

95. The method of claim 91, wherein said co-agent is bupropion, or a pharmaceutically acceptable salt thereof.

96. The method of claim 91, wherein a co-agent is administered with a therapeutically effective amount of a compound selected from the group consisting of:

97. The method of claim 91, wherein a co-agent is administered with a therapeutically effective amount of a compound selected from the group consisting of:

98. The method of claim 91, wherein a co-agent is administered with a therapeutically effective amount of a compound of formula:

99. A method of treating pseudobulbar affect in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of bupropion or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound selected from the group consisting of:

100. The method of claim 99, wherein bupropion or a pharmaceutically acceptable salt thereof is administered with a therapeutically effective amount of a compound selected from the group consisting of:

101. The method of claim 99, wherein bupropion or a pharmaceutically acceptable salt thereof is administered with a therapeutically effective amount of a compound of formula:

102. A method of treating chronic or intractable pain in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of a co-agent which is norepinephrine-dopamine reuptake inhibitor (NDRI), or a pharmaceutically acceptable salt thereof;

and a compound of Formula II;

103. The method of claim 102, wherein said chronic or intractable pain is a neuropathic pain.

104. The method of claim 102, wherein said chronic or intractable pain is diabetic neuropathic pain.

105. The method of claim 102, wherein R⁴ is selected from —

CH₃, —

CHD₂, or —

CD₃.

106. The method of claim 105, wherein R³ is selected from —

OCF₃, —

OCD₃, or —

OCHF₂.

107. The method of claim 102, wherein said co-agent is an inhibitor of a cytochrome p450 2D6 enzyme.

108. The method of claim 102, wherein said co-agent is bupropion, or a pharmaceutically acceptable salt thereof.

109. The method of claim 102, wherein a co-agent is administered with a therapeutically effective amount of a compound selected from the group consisting of:

110. The method of claim 102, wherein a co-agent is administered with a therapeutically effective amount of a compound selected from the group consisting of:

111. The method of claim 102, wherein a co-agent is administered with a therapeutically effective amount of a compound of formula:

112. A method of treating chronic or intractable pain in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of bupropion or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound selected from the group consisting of:

113. The method of claim 112, wherein said chronic or intractable pain is a neuropathic pain.

114. The method of claim 112, wherein said chronic or intractable pain is diabetic neuropathic pain.

115. The method of claim 112, wherein bupropion or a pharmaceutically acceptable salt thereof is administered with a therapeutically effective amount of a compound selected from the group consisting of:

116. The method of claim 112, wherein bupropion or a pharmaceutically acceptable salt thereof is administered with a therapeutically effective amount of a compound of formula:

117. A method of treating a neurological disorder selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson'"'"'s disease, Alzheimer'"'"'s disease, and Huntington'"'"'s disease in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of a co-agent which is norepinephrine-dopamine reuptake inhibitor (NDRI), or a pharmaceutically acceptable salt thereof;

and a compound of Formula II;

118. The method of claim 117, wherein R⁴ is selected from —

CH₃, —

CHD₂, or —

CD₃.

119. The method of claim 118, wherein R³ is selected from —

OCF₃, —

OCD₃, or —

OCHF₂.

120. The method of claim 117, wherein said co-agent is an inhibitor of a cytochrome p450 2D6 enzyme.

121. The method of claim 117, wherein said co-agent is bupropion, or a pharmaceutically acceptable salt thereof.

122. The method of claim 117, wherein a co-agent is administered with a therapeutically effective amount of a compound selected from the group consisting of:

123. The method of claim 117 wherein a co-agent is administered with a therapeutically effective amount of a compound selected from the group consisting of:

124. The method of claim 117, wherein a co-agent is administered with a therapeutically effective amount of a compound of formula:

125. A method of treating a neurological disorder selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson'"'"'s disease, Alzheimer'"'"'s disease, and Huntington'"'"'s disease in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of bupropion or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound selected from the group consisting of:

126. The method of claim 125, wherein bupropion or a pharmaceutically acceptable salt thereof is administered with a therapeutically effective amount of a compound selected from the group consisting of:

127. The method of claim 125, wherein bupropion or a pharmaceutically acceptable salt thereof is administered with a therapeutically effective amount of a compound of formula:

128. A method of treating a brain injury that is the result of stroke, traumatic brain injury, ischemia, hypoglycemia, hypoxia, or neuronal death in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of a co-agent which is norepinephrine-dopamine reuptake inhibitor (NDRI), or a pharmaceutically acceptable salt thereof;

and a compound of Formula II;

129. The method of claim 128, wherein R⁴ is selected from —

CH₃, —

CHD₂, or —

CD₃.

130. The method of claim 129, wherein R³ is selected from —

OCF₃, —

OCD₃, or —

OCHF₂.

131. The method of claim 128, wherein said co-agent is an inhibitor of a cytochrome p450 2D6 enzyme.

132. The method of claim 128, wherein said co-agent is bupropion, or a pharmaceutically acceptable salt thereof.

133. The method of claim 128, wherein a co-agent is administered with a therapeutically effective amount of a compound selected from the group consisting of:

134. The method of claim 128, wherein a co-agent is administered with a therapeutically effective amount of a compound selected from the group consisting of:

135. The method of claim 128, wherein a co-agent is administered with a therapeutically effective amount of a compound of formula:

136. A method of treating a brain injury that is the result of stroke, traumatic brain injury, ischemia, hypoglycemia, hypoxia, or neuronal death in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of bupropion or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound selected from the group consisting of:

137. The method of claim 136, wherein bupropion or a pharmaceutically acceptable salt thereof is administered with a therapeutically effective amount of a compound selected from the group consisting of:

138. The method of claim 136, wherein bupropion or a pharmaceutically acceptable salt thereof is administered with a therapeutically effective amount of a compound of formula: