Heterocyclic compounds for the treatment of neurological and psychological disorders
View Patent ↗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.
1. A compound having the Formula:
wherein represents a single or double bond;
or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof:
wherein 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 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 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;
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;
each R 6 is independently selected from hydrogen, halogen, OR 10 , SR 10 , NR 10 R 11 , aliphatic, substituted aliphatic, aromatic, substituted aromatic, wherein each R 10 and R 11 are independently hydrogen, halogen, aliphatic, substituted aliphatic aryl or substituted aryl; or alternatively two adjacent R 6 groups form a second ring; and
t and s are independently selected from 0, 1, and 2.
2. A compound of claim 1 having the Formula:
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] 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 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;
R 11 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.
3. A compound having the Formula:
wherein represents a single or double bond;
or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof:
wherein,
A is selected from absent, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, —S—, —O—, —S(O)—, —S(O) 2 —, —S[C(R 10 )(R 11 )] u —, —S(O)[C(R 10 )(R 11 )] u —, —S(O) 2 [C(R 10 )(R 11 )] u —, —O[C(R 10 )(R 11 )] u —, —N(R 10 )—, —N(R 10 )—[C(R 10 )(R 11 )] u —, —[C(R 10 )(R 11 )] u ;
wherein each u is independently 1, 2, 3, 4, 5, 6 or 7;
wherein each R 10 and R 11 is independently absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
Each R 1 , R 2 , R 3 and R 4 is independently 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 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 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;
R 11 is absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
each G 3 and G 4 is independently selected from —N—, and —C(R 10 )—[C(R 10 )(R 11 )] a —, wherein a is 0, 1 or 2;
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,
X 2 is —S— or —O—.
4. A compound of claim 1 , wherein R 5 is selected from Table 1, 2, 3 or 4;
TABLE 1
TABLE 2
TABLE 3
TABLE 4
5. A compound having the Formula:
or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof:
wherein R 5 is selected from Table 1.
6. A compound having the Formula:
or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof:
wherein R 5 is selected from Table 1.
7. A compound selected from Table A, B, C, D or E and the geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof:
TABLE A
No
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
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
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
TABLE B
No
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
TABLE C
No.
Structure
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
TABLE D
No.
Structure
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
435
436
437
TABLE E
No.
Structure
501
502
503
504
505
506
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540