IP Library › Granted Patent US 8,796,276

Granted Patent B2

US 8,796,276 · App. 13/607,066 · Granted Aug 5, 2014

Heterocyclic compounds for the treatment of neurological and psychological disorders

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Quick Facts

Patent No.: US 8,796,276
App. No.: 13/607,066
Granted: Aug 5, 2014
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

Lactam compounds of Formula I and their use for the treatment of neurological and psychiatric disorders including schizophrenia, bipolar disorder, anxiety disorder and insomnia is disclosed.

Claims (385)

1. A method of treating schizophrenia, mania, bipolar disorder, anxiety or depression by administering a compound of Formula III or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates to a patient in need thereof:

wherein represents a single or double bond;

A is selected from absent, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkenyl;

R 1 is selected from absent, hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;

R 2 is selected from absent, hydrogen, halogen, —OR 10 , —SR 10 , —N(R 10 )(R 11 ), —S(O)R 10 , —S(O) 2 R 10 , optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;

R 3 is selected from absent, hydrogen, halogen, —OR 10 , —SR 10 , —N(R 10 )(R 11 ), —S(O)R 10 , —S(O) 2 R 10 , optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;

R 4 is selected from absent, hydrogen, halogen, —OR 10 , —SR 10 , —N(R 10 )(R 11 ), —S(O)R 10 , —S(O) 2 R 10 , optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;

R 10 is absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

R 11 is absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

D is selected from absent, —O—, —NR 10 , —C(R 10 )(R 11 )— and —S—, —S(O)—, —S(O) 2 —, —C(O)—;

m and q are independently selected from 0, 1, and 2;

p is 0, 1, 2, 3 or 4;

r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; and,

R 5 is selected from Table 1;

TABLE 1

Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation.

2. A method of treating schizophrenia, mania, bipolar disorder, anxiety or depression by administering a compound selected from Table A or B or the geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof to a patient in need thereof:

TABLE A

Structure

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

TABLE B

Structure

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

3. A method of treating schizophrenia, mania, bipolar disorder, anxiety or depression by administering a compound of Formula III or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates to a patient in need thereof:

wherein represents a single or double bond;

A is selected from absent, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkenyl;

R 1 is selected from absent, hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;

R 10 is absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

R 11 is absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

D is selected from absent, —O—, —NR 10 , —C(R 10 )(R 11 )— and —S—, —S(O)—, —S(O) 2 —, —C(O)—;

m and q are independently selected from 0, 1, and 2;

p is 0, 1, 2, 3 or 4;

r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; and,

wherein R 5 is selected from:

wherein R 105 , R 106 and R 107 are independently selected from hydrogen, halogen, optionally substituted C 1 -C 24 alkyl, optionally substituted C 2 -C 24 alkenyl, optionally substituted C 2 -C 24 alkynyl, optionally substituted C 3 -C 24 cycloalkyl, optionally substituted C 1 -C 24 alkoxy, optionally substituted C 1 -C 24 alkylamino and optionally substituted C 1 -C 24 aryl; and,

Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation.

4. A method of treating schizophrenia, mania, bipolar disorder, anxiety or depression by administering a compound of Formula III or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates to a patient in need thereof:

wherein represents a single or double bond;

A is selected from absent, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkenyl;

R 1 is independently selected from absent, hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;

R 10 is absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

R 11 is absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

D is selected from absent, —O—, —NR 10 , —C(R 10 )(R 11 )— and —S—, —S(O)—, —S(O) 2 —, —C(O)—;

m and q are independently selected from 0, 1, and 2;

p is 0, 1, 2, 3 or 4;

r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; and,

wherein R 5 is selected from:

wherein, each x and y is independently an integer between 0 and 30, and

Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation.

5. A method of treating schizophrenia, mania, bipolar disorder, anxiety or depression by administering a compound of Formula III or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates to a patient in need thereof:

wherein represents a single or double bond;

A is selected from absent, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkenyl;

R 1 is selected from absent, hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;

R 10 is absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

R 11 is absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

D is selected from absent, —O—, —NR 10 , —C(R 10 )(R 11 )— and —S—, —S(O)—, —S(O) 2 —, —C(O)—;

m and q are independently selected from 0, 1, and 2;

p is 0, 1, 2, 3 or 4;

r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; and,

wherein R 5 is selected from:

6. A method of treating schizophrenia, mania, anxiety or bipolar disease by administering a compound selected from Compounds 5-10 or a pharmaceutically acceptable salt thereof to a patient in need thereof:

7. A method of treating schizophrenia, mania, bipolar disorder, anxiety or depression by administering a compound of Formula III or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates to a patient in need thereof:

wherein represents a single or double bond;

A is selected from absent, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkenyl;

R 1 is selected from absent, hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;

R 10 is absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

R 11 is absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

D is selected from absent, —O—, —NR 10 , —C(R 10 )(R 11 )— and —S—, —S(O)—, —S(O) 2 —, —C(O)—;

m and q are independently selected from 0, 1, and 2;

p is 0, 1, 2, 3 or 4;

r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; and,

wherein R 5 is selected from Table 2:

TABLE 2

8. A method of treating schizophrenia, mania, bipolar disorder, anxiety or depression by administering a compound of Formula III or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates to a patient in need thereof:

wherein represents a single or double bond;

A is selected from absent, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkenyl;

R 1 is selected from absent, hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;

R 10 is absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

R 11 is absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

D is selected from absent, —O—, —NR 10 , —C(R 10 )(R 11 )— and —S—, —S(O)—, —S(O) 2 —, —C(O)—;

m and q are independently selected from 0, 1, and 2;

p is 0, 1, 2, 3 or 4;

r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; and,

wherein R 5 is selected from Table 3:

TABLE 3

9. A method of treating schizophrenia, mania, bipolar disorder, anxiety or depression by administering a compound of Formula III or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates to a patient in need thereof:

wherein represents a single or double bond;

A is selected from absent, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkenyl;

R 1 is selected from absent, hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;

R 10 is absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

R 11 is absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

D is selected from absent, —O—, —NR 10 , —C(R 10 )(R 11 )— and —S—, —S(O)—, —S(O) 2 —, —C(O)—;

m and q are independently selected from 0, 1, and 2;

p is 0, 1, 2, 3 or 4;

r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; and,

wherein R 5 is selected from Table 4:

TABLE 4

10. A method of treating schizophrenia, mania, anxiety or bipolar disease by administering a compound of Formula V or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates to a patient in need thereof:

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof:

wherein represents a single or double bond;

R 5 is selected from —CH(R 10 )—OR 20 , —CH(R 10 )—OC(O)OR 20 , —CH(R 10 )—OC(O)R 20 , —CH(R 10 )—OC(O)NR 20 R 21 , —(CH(R 10 ))—OPO 3 MY, —(CH(R 10 ))—OP(O)(OR 20 )(OR 21 ), —[CH(R 10 )O] z —R 20 , —[CH(R 10 )O]—C(O)OR 20 , —[CH(R 10 )O] z —C(O)R 20 , —[CH(R 10 )O] z —C(O)NR 20 R 21 , —[CH(R 10 )O]z-OPO 3 MY, —[CH(R 10 )O] z —P(O) 2 (OR 20 )M and —[CH(R 10 )O] z —P(O)(OR 20 )(OR 21 );

wherein z is 1, 2, 3, 4, 5, 6, or 7;

each R 20 and R 21 is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl; Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation;

R 10 is absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; and,

w is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11.

11. A method of treating schizophrenia, mania, anxiety or bipolar disease by administering a compound of formula:

or a pharmaceutically acceptable salt thereof to a patient in need thereof.

12. A method of treating schizophrenia, mania, anxiety or bipolar disease by administering a compound of formula:

or a pharmaceutically acceptable salt thereof to a patient in need thereof.

13. A method of treating schizophrenia, mania, anxiety or bipolar disease by administering a compound of formula:

or a pharmaceutically acceptable salt thereof to a patient in need thereof.

14. A method of treating schizophrenia, mania, bipolar disorder, anxiety or depression by administering a compound of Formula III or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates to a patient in need thereof:

wherein represents a single or double bond;

wherein A is selected from absent, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkenyl;

R 5 is selected from —CH(R 10 )—OR 20 , —CH(R 10 )—OC(O)OR 20 , —CH(R 10 )—OC(O)R 20 , —CH(R 10 )—OC(O)NR 20 R 21 , —(CH(R 10 ))—OPO 3 MY, —(CH(R 10 ))—OP(O)(OR 20 )(OR 21 ), —[CH(R 10 )O] z —R 20 , —[CH(R 10 )O] z —C(O)OR 20 , —[CH(R 10 )O] z —C(O)R 20 , —[CH(R 10 )O] z —C(O)NR 20 R 21 , —[CH(R 10 )O]z-OPO 3 MY, —[CH(R 10 )O] z —P(O) 2 (OR 20 )M and —[CH(R 10 )O] z —P(O)(OR 20 )(OR 21 );

wherein z is 1, 2, 3, 4, 5, 6, or 7;

each R 20 and R 71 is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation;

R 10 is absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

R 11 is absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

D is selected from absent, —O—, —NR 10 , —C(R 10 )(R 11 )— and —S—, —S(O)—, —S(O) 2 —, —C(O)—;

m and q are independently selected from 0, 1, and 2;

p is 0, 1, 2, 3 or 4;

r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; and,

wherein R 1 is selected from:

wherein R 100 R 101 , and R 103 are independently selected from hydrogen, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino and optionally substituted C 1 -C 8 aryl.

15. The method according to claim 14 , wherein R 1 is selected from:

Assignments (3)

SECURITY INTEREST Recorded Feb 13, 2026

From: ALKERMES PHARMA IRELAND LIMITED

To: JPMORGAN CHASE BANK, N.A. AS ADMINISTRATIVE AGENT

Reel/Frame 074858/0405 →

RELEASE OF SECURITY INTEREST IN PATENTS PREVIOUSLY RECORDED AT REEL/FRAME (073213/0302) Recorded Feb 13, 2026

From: JPMORGAN CHASE BANK, N.A., AS ADMINISTRATIVE AGENT

To: ALKERMES PHARMA IRELAND LIMITED

Reel/Frame 074858/0429 →

SECURITY INTEREST Recorded Oct 23, 2025

From: ALKERMES PHARMA IRELAND LIMITED

To: JPMORGAN CHASE BANK, N.A. AS ADMINISTRATIVE AGENT

Reel/Frame 073213/0302 →