FORMES CRISTALLINES DE LA 4-[2-(4-METHYLPHENYLSULFANYL)-PHENYL] PIPERIDINE AVEC INHIBITION DE LA REABSORPTION DE LA SEROTONINE ET DE LA NOREPINEPHRINE EN COMBINAISON POUR LE TRAITEMENT DE LA DOULEUR NEUROPATHIQUE

CRYSTALLINE FORMS OF 4-[2-(4-METHYLPHENYLSULFANYL)-PHENYL]PIPERIDINE WITH COMBINED SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITION FOR THE TREATMENT OF NEUROPATHIC PAIN

Abrégé anglais

Crystalline forms of 4-[2-(4-methylphenylsulfanyl)-phenyl]piperidine and salts
thereof
are provided e.g. for the treatment of neuropathic pain.
(see formula I)

Revendications

37
Claims
1. A compound, which is 4-[2-(4-methylphenyl-sulfanyl)phenyl]piperidine
<IMG>
DL-lactic acid addition salt in a crystalline form.
2. The compound according to claim 1, which compound is characterised by
peaks in an XRPD at approximately 5.30, 8.18, 9.44 and 17.24°2.theta..
3. The compound according to claim 1, which compound is characterised by an
XRPD as depicted in figure 4.
4. A compound, which is 4-[2-(4-methylphenyl-sulfanyl)phenyl]piperidine
<IMG>
glutaric acid addition salt (1:1) in a crystalline form.
5. The compound according to claim 4, which compound is characterised by
peaks in an XRPD at approximately 9.39, 11.70, 14.05 and
14.58°2.theta..
6. The compound according to claim 4, which compound is characterised by an
XRPD as depicted in figure 8.
7. A compound, which is 4-[2-(4-methylphenyl-sulfanyl)phenyl]piperidine
<IMG>

38
malonic acid addition salt (1:1) in a crystalline form.
8. The compound according to claim 7, which compound is characterised by
peaks in an XRPD at 10.77°, 16.70°, 19.93° 2.theta..
9. The compound according to claim 7, which compound is characterised by
peaks in an XRPD at 6.08°, 10.11°, 18.25° and
20.26° 2.theta..
10. The compound according to claim 7, which compound is characterised by an
XRPD as depicted in figure 9 or 10.
11. A compound, which is 4-[2-(4-methylphenyl-sulfanyl)phenyl]piperidine
<IMG>
L-aspartic acid addition salt (1:1) or L-aspartic acid addition salt hydrate
(1:1)
in a crystalline form.
12. A compound, which is 4-[2-(4-methylphenyl-sulfanyl)phenyl]piperidine
<IMG>
glutamic acid addition salt (1:1) or glutamic acid addition salt monohydrate
in
a crystalline form.
13. A pharmaceutical composition comprising a compound according to any one
of claims 1-12 together with a pharmaceutically acceptable excipient.
14. A composition for treating chronic pain, the composition comprising a
compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.

39
15. The composition according to claim 14, wherein said chronic pain is
phantom
limb pain.
16. The composition according to claim 14, wherein said chronic pain is
neuropathic pain.
17. The composition according to claim 14, wherein said chronic pain is post-
herpetic neuralgia (PHN).
18. The composition according to claim 14, wherein said chronic pain is carpal
tunnel syndrome (CTS).
19. The composition according to claim 14, wherein said chronic pain is HIV
neuropathy.
20. The composition according to claim 14, wherein said chronic pain is
complex
regional pain syndrome (CRPS).
21. The composition according to claim 14, wherein said chronic pain is
trigeminal neuralgia.
22. The composition according to claim 14, wherein said chronic pain is due to
a
surgical intervention.
23. The composition according to claim 14, wherein said chronic pain is
diabetic
vasculopathy.
24. The composition according to claim 14, wherein said chronic pain is
capillary
resistance or diabetic symptoms associated with insulitis.
25. The composition according to claim 14, wherein said chronic pain is pain
associated with angina.
26. The composition according to claim 14, wherein said chronic pain is pain
associated with menstruation.
27. The composition according to claim 14, wherein said chronic pain is pain
associated with cancer.

40
28. The composition according to claim 14, wherein said chronic pain is dental
pain.
29. The composition according to claim 14, wherein said chronic pain is
headache.
30. The composition according to claim 14, wherein said chronic pain is
migraine.
31. The composition according to claim 14, wherein said chronic pain is
tension-
type headache.
32. The composition according to claim 14, wherein said chronic pain is
temporomandibular joint syndrome.
33. The composition according to claim 14, wherein said chronic pain is
myofascial pain muscular injury.
34. The composition according to claim 14, wherein said chronic pain is
fibromyalgia syndrome.
35. The composition according to claim 14, wherein said chronic pain is bone
and
joint pain.
36. The composition according to claim 14, wherein said chronic pain is
osteoarthritis.
37. The composition according to claim 14, wherein said chronic pain is
rheumatoid arthritis.
38. The composition according to claim 14, wherein said chronic pain is
rheumatoid arthritis and edema resulting from trauma associated with burns,
sprains or fracture.
39. The composition according to claim 14, wherein said chronic pain is bone
pain.
40. The composition according to claim 39, wherein said chronic pain is bone
pain
due to osteoarthritis, osteoporosis, or bone metastases.
41. The composition according to claim 14, wherein said chronic pain is gout.

41
42. The composition according to claim 14, wherein said chronic pain is
fibrositis.
43. The composition according to claim 14, wherein said chronic pain is
myofascial pain.
44. The composition according to claim 14, wherein said chronic pain is
thoracic
outlet syndromes.
45. The composition according to claim 14, wherein said chronic pain is upper
back pain.
46. The composition according to claim 14, wherein said chronic pain is lower
back pain.
47. The composition according to claim 45 or 46, wherein the back pain results
from systematic, regional, or primary spine disease.
48. The composition according to claim 14, wherein said chronic pain is
radiculopathy.
49. The composition according to claim 14, wherein said chronic pain is pelvic
pain.
50. The composition according to claim 14, wherein said chronic pain is
cardiac
chest pain.
51. The composition according to claim 14, wherein said chronic pain is non-
cardiac chest pain.
52. The composition according to claim 14, wherein said chronic pain is spinal
cord injury (SCI)-associated pain.
53. The composition according to claim 14, wherein said chronic pain is
central
post-stroke pain.
54. The composition according to claim 14, wherein said chronic pain is cancer
neuropathy.

42
55. The composition according to claim 14, wherein said chronic pain is AIDS
pain.
56. The composition according to claim 14, wherein said chronic pain is sickle
cell pain.
57. The composition according to claim 14, wherein said chronic pain is
geriatric
pain.
58. The composition according to claim 16, wherein said neuropathic pain is
hyperpathia.
59. The composition according to claim 16, wherein said neuropathic pain is
hyperalgesia.
60. The composition according to claim 16, wherein said neuropathic pain is
neuropathy.
61. The composition according to claim 16, wherein said neuropathic pain is
diabetic neuropathy.
62. The composition according to claim 16, wherein said neuropathic pain is
neuritis.
63. The composition according to claim 16, wherein said neuropathic pain is
neuralgia.
64. The composition according to claim 16, wherein said neuropathic pain is
hyperesthesia.
65. The composition according to claim 16, wherein said neuropathic pain is
causalgia.
66. The composition according to claim 16, wherein said neuropathic pain is
allodynia.
67. Use of a compound according to any one of claims 1-12 in the manufacture
of
a medicament for the treatment of chronic pain.

43
68. Use of a compound according to any one of claims 1-12 for treating chronic
pain.
69. The use according to claim 67 or 68, wherein said chronic pain is phantom
limb pain.
70. The use according to claim 67 or 68, wherein said chronic pain is
neuropathic
pain.
71. The use according to claim 67 or 68, wherein said chronic pain is post-
herpetic
neuralgia (PHN).
72. The use according to claim 67 or 68, wherein said chronic pain is carpal
tunnel
syndrome (CTS).
73. The use according to claim 67 or 68, wherein said chronic pain is HIV
neuropathy.
74. The use according to claim 67 or 68, wherein said chronic pain is complex
regional pain syndrome (CRPS).
75. The use according to claim 67 or 68, wherein said chronic pain is
trigeminal
neuralgia.
76. The use according to claim 67 or 68, wherein said chronic pain is pain due
to a
surgical intervention.
77. The use according to claim 67 or 68, wherein said chronic pain is diabetic
vasculopathy.
78. The use according to claim 67 or 68, wherein said chronic pain is
capillary
resistance or diabetic symptoms associated with insulitis.
79. The use according to claim 67 or 68, wherein said chronic pain is pain
associated with angina.
80. The use according to claim 67 or 68, wherein said chronic pain is pain
associated with menstruation.

44
81. The use according to claim 67 or 68, wherein said chronic pain is pain
associated with cancer.
82. The use according to claim 67 or 68, wherein said chronic pain is dental
pain.
83. The use according to claim 67 or 68, wherein said chronic pain is
headache.
84. The use according to claim 67 or 68, wherein said chronic pain is
migraine.
85. The use according to claim 67 or 68, wherein said chronic pain is tension-
type
headache.
86. The use according to claim 67 or 68, wherein said chronic pain is
temporomandibular joint syndrome.
87. The use according to claim 67 or 68, wherein said chronic pain is
myofascial
pain muscular injury.
88. The use according to claim 67 or 68, wherein said chronic pain is
fibromyalgia
syndrome.
89. The use according to claim 67 or 68, wherein said chronic pain is bone and
joint pain.
90. The use according to claim 67 or 68, wherein said chronic pain is
osteoarthritis.
91. The use according to claim 67 or 68, wherein said chronic pain is
rheumatoid
arthritis.
92. The use according to claim 67 or 68, wherein said chronic pain is
rheumatoid
arthritis and edema resulting from trauma associated with burns, sprains or
fracture.
93. The use according to claim 67 or 68, wherein said chronic pain is bone
pain.
94. The use according to claim 93, wherein said chronic pain is bone pain due
to
osteoarthritis, osteoporosis or bone metastases.

45
95. The use according to claim 67 or 68, wherein said chronic pain is gout.
96. The use according to claim 67 or 68, wherein said chronic pain is
fibrositis.
97. The use according to claim 67 or 68, wherein said chronic pain is
myofascial
pain.
98. The use according to claim 67 or 68, wherein said chronic pain is thoracic
outlet syndromes.
99. The use according to claim 67 or 68, wherein said chronic pain is upper
back
pain.
100. The use according to claim 67 or 68, wherein said chronic pain is lower
back
pain.
101. The use according to claim 99 or 100, wherein the back pain results from
systematic, regional, or primary spine disease.
102. The use according to claim 67 or 68, wherein said chronic pain is
radiculopathy.
103. The use according to claim 67 or 68, wherein said chronic pain is pelvic
pain.
104. The use according to claim 67 or 68, wherein said chronic pain is cardiac
chest
pain.
105. The use according to claim 67 or 68, wherein said chronic pain is non-
cardiac
chest pain.
106. The use according to claim 67 or 68, wherein said chronic pain is spinal
cord
injury (SCI)-associated pain.
107. The use according to claim 67 or 68, wherein said chronic pain is central
post-
stroke pain.
108. The use according to claim 67 or 68, wherein said chronic pain is cancer
neuropathy.

46
109. The use according to claim 67 or 68, wherein said chronic pain is AIDS
pain.
110. The use according to claim 67 or 68, wherein said chronic pain is sickle
cell
pain.
111. The use according to claim 67 or 68, wherein said chronic pain is
geriatric
pain.
112. The use according to claim 70, wherein said neuropathic pain is
hyperpathia.
113. The use according to claim 70, wherein said neuropathic pain is
hyperalgesia.
114. The use according to claim 70, wherein said neuropathic pain is
neuropathy,
115. The use according to claim 70, wherein said neuropathic pain is diabetic
neuropathy.
116. The use according to claim 70, wherein said neuropathic pain is neuritis.
117. The use according to claim 70, wherein said neuropathic pain is
neuralgia.
118. The use according to claim 70, wherein said neuropathic pain is
hyperesthesia.
119. The use according to claim 70, wherein said neuropathic pain is
causalgia.
120. The use according to claim 70, wherein said neuropathic pain is
allodynia.
121. A compound according to any one of claims 1-12 for use in the treatment
of
chronic pain.
122. The compound according to claim 121, wherein said chronic pain is phantom
limb pain.
123. The compound according to claim 121, wherein said chronic pain is
neuropathic pain.
124. The compound according to claim 121, wherein said chronic pain is post-
herpetic neuralgia (PHN).

47
125. The compound according to claim 121, wherein said chronic pain is carpal
tunnel syndrome (CTS).
126. The compound according to claim 121, wherein said chronic pain is HIV
neuropathy.
127. The compound according to claim 121, wherein said chronic pain is complex
regional pain syndrome (CRPS).
128. The compound according to claim 121, wherein said chronic pain is
trigeminal
neuralgia.
129. The compound according to claim 121, wherein said chronic pain is pain
due
to a surgical intervention.
130. The compound according to claim 121, wherein said chronic pain is
diabetic
vasculopathy.
131. The compound according to claim 121, wherein said chronic pain is
capillary
resistance or diabetic symptoms associated with insulitis.
132. The compound according to claim 121, wherein said chronic pain is pain
associated with angina.
133. The compound according to claim 121, wherein said chronic pain is pain
associated with menstruation.
134. The compound according to claim 121, wherein said chronic pain is pain
associated with cancer.
135. The compound according to claim 121, wherein said chronic pain is dental
pain.
136. The compound according to claim 121, wherein said chronic pain is
headache.
137. The compound according to claim 121, wherein said chronic pain is
migraine.
138. The compound according to claim 121, wherein said chronic pain is tension-
type headache.

48
139. The compound according to claim 121, wherein said chronic pain is
temporomandibular joint syndrome.
140. The compound according to claim 121, wherein said chronic pain is
myofascial pain muscular injury.
141. The compound according to claim 121, wherein said chronic pain is
fibromyalgia syndrome.
142. The compound according to claim 121, wherein said chronic pain is bone
and
joint pain.
143. The compound according to claim 121, wherein said chronic pain is
osteoarthritis.
144. The compound according to claim 121, wherein said chronic pain is
rheumatoid arthritis.
145. The compound according to claim 121, wherein said chronic pain is
rheumatoid arthritis and edema resulting from trauma associated with burns,
sprains or fracture.
146. The compound according to claim 121, wherein said chronic pain is bone
pain.
147. The compound according to claim 146, wherein said chronic pain is bone
pain
due to osteoarthritis, osteoporosis, bone metastases.
148. The compound according to claim 121, wherein said chronic pain is gout.
149. The compound according to claim 121, wherein said chronic pain is
fibrositis.
150. The compound according to claim 121, wherein said chronic pain is
myofascial pain.
151. The compound according to claim 121, wherein said chronic pain is
thoracic
outlet syndromes.
152. The compound according to claim 121, wherein said chronic pain is upper
back pain.

49
153. The compound according to claim 121, wherein said chronic pain is lower
back pain.
154. The compound according to claim 152 or 153, wherein the back pain results
from systematic, regional, or primary spine disease.
155. The compound according to claim 121, wherein said chronic pain is
radiculopathy.
156. The compound according to claim 121, wherein said chronic pain is pelvic
pain.
157. The compound according to claim 121, wherein said chronic pain is cardiac
chest pain.
158. The compound according to claim 121, wherein said chronic pain is non-
cardiac chest pain.
159. The compound according to claim 121, wherein said chronic pain is spinal
cord injury (SCI)-associated pain.
160. The compound according to claim 121, wherein said chronic pain is central
post-stroke pain.
161. The compound according to claim 121, wherein said chronic pain is cancer
neuropathy.
162. The compound according to claim 121, wherein said chronic pain is AIDS
pain.
163. The compound according to claim 121, wherein said chronic pain is sickle
cell
pain.
164. The compound according to claim 121, wherein said chronic pain is
geriatric
pain.
165. A compound according to claim 123, wherein said neuropathic pain is
hyperpathia.

50
166. A compound according to claim 123, wherein said neuropathic pain is
hyperalgesia.
167. A compound according to claim 123, wherein said neuropathic pain is
neuropathy.
168. A compound according to claim 123, wherein said neuropathic pain is
diabetic
neuropathy.
169. A compound according to claim 123, wherein said neuropathic pain is
neuritis.
170. A compound according to claim 123, wherein said neuropathic pain is
neuralgia.
171. A compound according to claim 123, wherein said neuropathic pain is
hyperesthesia.
172. A compound according to claim 123, wherein said neuropathic pain is
causalgia.
173. A compound according to claim 123, wherein said neuropathic pain is
allodynia.
174. A composition for treating depression in partial responders, the
composition
comprising a compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
175. A composition for treating treatment resistant depression, the
composition
comprising a compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
176. A composition for treating Alzheimer's disease, the composition
comprising a
compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
177. A composition for treating cognitive impairment, the composition
comprising
a compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.

51
178. A composition for treating attention deficit hyperactivity disorder
(ADHD),
the composition comprising a compound according to any one of claims 1-12
together with a pharmaceutically acceptable excipient.
179. A composition for treating melancholia, the composition comprising a
compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
180. A composition for treating posttraumatic stress disorder (PTSD), the
composition comprising a compound according to any one of claims 1-12
together with a pharmaceutically acceptable excipient.
181. A composition for treating hot flushes, the composition comprising a
compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
182. A composition for treating sleep apnea, the composition comprising a
compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
183. A composition for treating alcohol, nicotine or carbohydrate craving, the
composition comprising a compound according to any one of claims 1-12
together with a pharmaceutically acceptable excipient.
184. A composition for treating substance abuse, the composition comprising a
compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
185. A composition for treating alcohol or drug abuse, the composition
comprising
a compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
186. A composition for treating emesis, the composition comprising a compound
according to any one of claims 1-12 together with a pharmaceutically
acceptable excipient.

52
187. A composition for treating eating disorders, the composition comprising a
compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
188. A composition for treating irritable bowel syndrome (IBS), the
composition
comprising a compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
189. A composition for treating affective disorders, the composition
comprising a
compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
190. A composition for treating depression, the composition comprising a
compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
191. A composition for treating major depressive disorder, the composition
comprising a compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
192. A composition for treating postnatal depression, the composition
comprising a
compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
193. A composition for treating depression associated with bipolar disorder,
Alzheimer's disease, psychosis or Parkinson's disease, the composition
comprising a compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
194. A composition for treating anxiety, the composition comprising a compound
according to any one of claims 1-12 together with a pharmaceutically
acceptable excipient.
195. A composition for treating general anxiety disorder, the composition
comprising a compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.

53
196. A composition for treating social anxiety disorder, the composition
comprising
a compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
197. A composition for treating obsessive compulsive disorder, the composition
comprising a compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
198. A composition for treating panic disorder, the composition comprising a
compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
199. A composition for treating panic attacks, the composition comprising a
compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
200. A composition for treating phobia, the composition comprising a compound
according to any one of claims 1-12 together with a pharmaceutically
acceptable excipient.
201. A composition for treating social phobia, the composition comprising a
compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
202. A composition for treating agoraphobia, the composition comprising a
compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
203. A composition for treating stress urinary incontinence, the composition
comprising a compound according to any one of claims 1-12 together with a
pharmaceutically acceptable excipient.
204. Use of a compound according to any one of claims 1-12 for treating
depression in partial responders.
205. Use of a compound according to any one of claims 1-12 for treating
treatment
resistant depression.

54
206. Use of a compound according to any one of claims 1-12 for treating
Alzheimer's disease.
207. Use of a compound according to any one of claims 1-12 for treating
cognitive
impairment.
208. Use of a compound according to any one of claims 1-12 for treating
attention
deficit hyperactivity disorder (ADHD).
209. Use of a compound according to any one of claims 1-12 for treating
melancholia.
210. Use of a compound according to any one of claims 1-12 for treating
posttraumatic stress disorder (PTSD).
211. Use of a compound according to any one of claims 1-12 for treating hot
flushes.
212. Use of a compound according to any one of claims 1-12 for treating sleep
apnea.
213. Use of a compound according to any one of claims 1-12 for treating
alcohol,
nicotine or carbohydrate craving.
214. Use of a compound according to any one of claims 1-12 for treating
substance
abuse.
215. Use of a compound according to any one of claims 1-12 for treating
alcohol or
drug abuse.
216. Use of a compound according to any one of claims 1-12 for treating
emesis.
217. Use of a compound according to any one of claims 1-12 for treating eating
disorders.
218. Use of a compound according to any one of claims 1-12 for treating
irritable
bowel syndrome (IBS).

55
219. Use of a compound according to any one of claims 1-12 for treating
affective
disorders.
220. Use of a compound according to any one of claims 1-12 for treating
depression.
221. Use of a compound according to any one of claims 1-12 for treating major
depressive disorder.
222. Use of a compound according to any one of claims 1-12 for treating
postnatal
depression.
223. Use of a compound according to any one of claims 1-12 for treating
depression associated with bipolar disorder, Alzheimer's disease, psychosis or
Parkinson's disease.
224. Use of a compound according to any one of claims 1-12 for treating
anxiety.
225. Use of a compound according to any one of claims 1-12 for treating
general
anxiety disorder.
226. Use of a compound according to any one of claims 1-12 for treating social
anxiety disorder.
227. Use of a compound according to any one of claims 1-12 for treating
obsessive
compulsive disorder.
228. Use of a compound according to any one of claims 1-12 for treating panic
disorder.
229. Use of a compound according to any one of claims 1-12 for treating panic
attacks.
230. Use of a compound according to any one of claims 1-12 for treating
phobia.
231. Use of a compound according to any one of claims 1-12 for treating social
phobia.

56
232. Use of a compound according to any one of claims 1-12 for treating
agoraphobia.
233. Use of a compound according to any one of claims 1-12 for treating stress
urinary incontinence.
234. A compound according to any one of claims 1-12 for treating depression in
partial responders.
235. A compound according to any one of claims 1-12 for treating treatment
resistant depression.
236. A compound according to any one of claims 1-12 for treating Alzheimer's
disease.
237. A compound according to any one of claims 1-12 for treating cognitive
impairment.
238. A compound according to any one of claims 1-12 for treating attention
deficit
hyperactivity disorder (ADHD).
239. A compound according to any one of claims 1-12 for treating melancholia.
240. A compound according to any one of claims 1-12 for treating posttraumatic
stress disorder (PTSD).
241. A compound according to any one of claims 1-12 for treating hot flushes.
242. A compound according to any one of claims 1-12 for treating sleep apnea.
243. A compound according to any one of claims 1-12 for treating alcohol,
nicotine
or carbohydrate craving.
244. A compound according to any one of claims 1-12 for treating substance
abuse.
245. A compound according to any one of claims 1-12 for treating alcohol or
drug
abuse.
246. A compound according to any one of claims 1-12 for treating emesis.

57
247. A compound according to any one of claims 1-12 for treating eating
disorders.
248. A compound according to any one of claims 1-12 for treating irritable
bowel
syndrome (IBS).
249. A compound according to any one of claims 1-12 for treating affective
disorders.
250. A compound according to any one of claims 1-12 for treating depression.
251. A compound according to any one of claims 1-12 for treating major
depressive
disorder.
252. A compound according to any one of claims 1-12 for treating postnatal
depression.
253. A compound according to any one of claims 1-12 for treating depression
associated with bipolar disorder, Alzheimer's disease, psychosis or
Parkinson's disease.
254. A compound according to any one of claims 1-12 for treating anxiety.
255. A compound according to any one of claims 1-12 for treating general
anxiety
disorder.
256. A compound according to any one of claims 1-12 for treating social
anxiety
disorder.
257. A compound according to any one of claims 1-12 for treating obsessive
compulsive disorder.
258. A compound according to any one of claims 1-12 for treating panic
disorder.
259. A compound according to any one of claims 1-12 for treating panic
attacks.
260. A compound according to any one of claims 1-12 for treating phobia.
261. A compound according to any one of claims 1-12 for treating social
phobia.

58
262. A compound according to any one of claims 1-12 for treating agoraphobia.
263. A compound according to any one of claims 1-12 for treating stress
urinary
incontinence.

Description

CA 02784304 2012-07-24
WO 2007/144006 PCT/DK2007/050076
CRYSTALLINE FORMS OF 4-[2-(4-METHYLPHENYLSULFANYL)-PHENYL)PIPERIDINE WITH
COMBINED SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITION FOR THE TREATMENT OF
NEUROPATHIC PAIN
The perception of pain is more complicated than a direct transmission of
signals from
an injured part of the body to specific receptors in the brain, and wherein
the pain
perceived is proportional to the injury. Rather, damage to peripheral tissue
and injury
to nerves may cause alterations in the central neural structures involved in
pain
perception affecting subsequent pain sensitivity. This neuroplasticity may
bring about
a central sensitization in response to longer lasting noxious stimuli, which
may
manifest itself as e.g. chronic pain, i.e. that the perception of pain remains
even after
the noxious stimulus has stopped, or as hyperalgesia, i.e. an increased
response to a
stimulus, which is normally painful. On of the more mysterious and dramatic
examples of this is the "phantom limb syndrome", i.e. the persistence of pain
that
existed in a limb prior to its amputation. For a recent review of central
neuroplasticity
and pain see Melzack et al in Ann. N.Y Acad. Sci., 933, 157-174, 2001.
Chronic pain, such as neuropathic pain manifests itself differently than other
types of pain, e.g. somatic or visceral pain. The pain is often described as
shooting,
burning, pins and needles, numb or stabbing. Common causes of neuropathic pain
include alcoholism, amputation, back, leg and hip problems, chemotherapy,
diabetes,
HIV, multiple sclerosis, spine surgery, and herpes zoster virus infection.
The central component to chronic pain may explain why chronic pain, such as
e.g. neuropathic pain often responds poorly to classical analgesics, such as
non-steroid
anti-inflammatory drugs (NSAIDS) and opioid analgesics. Tricyclic
antidepressants
(TCA), typified by amitryline, have become standard for the treatment of
neuropatic
pain, and the effect is believed to be mediated by the combined inhibitory
effect on
the serotonin transporter and the norepinephrine transporter [ Clin Ther., 26,
951-979,
2004 ]. More recently, the so-called dual action antidepressants having an
inhibitory
effect on both the serotonin and the norepinephrine reuptake have been used
clinically
for the treatment of neuropatic pain [Human Psychopharm., 19, S21-S25, 2004].
Examples of dual acting antidepressants are venlafaxine and duloxetine, and
this class
of antidepressants is often referred to as SNRI.

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2
Data on the use of selective serotonine reuptake inhibitors (SSRI) for
neuropathic pain is scarce, but generally suggest a limited effect [Bas. Clin.
Pharmacol., 96, 399-409, 2005]. In fact, it has been hypothesised that SSRI's
are only
weakly antinociceptive in and of themselves but that inhibition of the
serotonin
transporter augments the antinociceptive effect of norepinephrine reuptake
inhibition.
This notion is supported by a review of 22 animal and five human studies
showing
that SNRI's have superior antinociceptive effect compared to norepinephrine
reuptake
inhibitors, which again are superior to SSRI [Pain Med. 4, 310-316, 2000].
Recent data on the 5-HT3 antagonist odansetron implies that 5-HT3 antagonists
may have an analgesic effect and thus be useful in the treatment of
neuropathic pain
[Anesth.Analg., 97, 1474-1478, 2003].
The use of tricyclic antidepressants is, however, associated with known,
anticholinergic side effects, such as e.g. drowsiness, anxiety, restlessness,
and
cognitive and memory difficulties. Hence, there is a need in the art to find
alternative
ways of treating neuropatic pain.
The international patent application published as WO 2003/029232 discloses
e.g. the compound 4-[2-(4-methylphenylsulfanyl)phenyl]piperidine as a free
base and
the corresponding HCl salt. The compound is reported to be an inhibitor of the
serotonin transporter and the serotonin receptor 2C (5-HT2c), and is said to
be useful
for the treatment of affective disorders, e.g. depression and anxiety.
Summary of the invention
The present inventors have surprisingly found that in addition to the already
known
pharmacological profile, 4-[2-(4-methylphenylsulfanyl)-phenyl]piperidine is a
potent
inhibitor of the serotonin reuptake and the norepinephrine reuptake, an
antagonist of
the serotonin receptor 3 (5-HT3), an antagonist of the serotonin receptor 2A
(5-HT2A),
and an inhibitor or the al adrenergic receptor, and the compound may as such
be
useful in treatment of e.g. chronic of pain. Accordingly, the invention
relates to
compound I, which is 4-[2-(4-methylphenyl-sulfanyl)phenyl]piperidine and
pharmaceutically acceptable salts thereof in a crystalline form provided said
compound is not 4-[2-(4-methylphenyl-sulfanyl)phenyl]-piperidine hydrochloride
addition salt.

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3
In one embodiment, the invention relates to compound I for use in therapy.
In one embodiment, the invention relates to a method of treatment comprising
the administration of a therapeutically effective amount of compound Ito a
patient in
need thereof.
In one embodiment, the invention relates to a pharmaceutical composition
comprising compound I.
In one embodiment, the invention relates to the use of compound I for the
manufacture of a medicament.
Figures
Figure 1: X-ray diffraction pattern of the HBr addition salt of compound I
Figure 2: X-ray diffraction pattern of the HBr addition salt solvate of
compound I
Figure 3: X-ray diffraction pattern of the palmitic acid addition salt of
compound I
Figure 4: X-ray diffraction pattern of the DL-lactic acid addition salt of
compound I
Figure 5: X-ray diffraction pattern of the adipic acid addition salt (1:1) of
compound I
((x+(3 form)
Figure 6: X-ray diffraction pattern of the adipic acid addition salt (2:1) of
compound I
Figure 7: X-ray diffraction pattern of the fumaric acid addition salt (1:1) of
compound
I
Figure 8: X-ray diffraction pattern of the glutaric acid addition salt (1:1)
of compound
I
Figure 9: X-ray diffraction pattern of the malonic acid addition salt (1:1) of
compound
I, a-form
Figure 10: X-ray diffraction pattern of the malonic acid addition salt of
compound 1,
f3-form
Figure 11: X-ray diffraction pattern of the oxalic acid addition salt (1:1) of
compound
I
Figure 12: X-ray diffraction pattern of the sebacoinic acid addition salt
(2:1) of
compound I
Figure 13: X-ray diffraction pattern of the succinic acid addition salt (2:1)
of
compound I

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4
Figure 14: X-ray diffraction pattern of the L-malic acid addition salt (1:1)
of
compound I, a-form
Figure 15: X-ray diffraction pattern of the L-malic acid addition salt (1:1)
of
compound I, (3-form
Figure 16: X-ray diffraction pattern of the D-tartaric acid addition salt
(1:1) of
compound I
Figure 17: X-ray diffraction pattern of the L-aspartic acid addition salt
(1:1) of
compound I in mixture with L-aspartic acid
Figure 18: X-ray diffraction pattern of the L-aspartic acid addition salt
hydrate (1:1)
of compound I in mixture with L-aspartic acid
Figure 19: X-ray diffraction pattern of the glutamic acid addition salt (1:1)
of
compound I in mixture with glutamic acid monohydrate
Figure 20: X-ray diffraction pattern of the citric acid addition salt (2:1) of
compound I
Figure 21: X-ray diffraction pattern of the HCl acid addition salt of compound
I
Figure 22: X-ray diffraction pattern of the phosphoric acid addition salt
(1:1) of
compound I
Figure 23: Dopamine levels in prefrontal cortex upon administration of
compounds of
the present invention.
Figure 24: Acetylcholine levels in prefrontal cortex upon administration of
compounds of the present invention.
Figure 25a+b: Acetylcholine levels in the prefrontal cortex and ventral
hippocampus
upon administration of compounds of the present invention.
Detailed description of the invention
The present invention relates to compound I, which is 4-[2-(4-
methylphenylsulfanyl)-
phenyl]piperidine and pharmaceutically acceptable salts thereof in a
crystalline form
provided said compound is not the hydrochloride addition salt. The structure
of 4-[2-
(4-methylphenylsulfanyl)-phenyl]piperidine is

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N
S
The pharmacological profile of the compounds of the present invention is
depicted in the examples, but can be summarised as follows. The compounds are
inhibitors of the serotonin and norepinephrine reuptake; they inhibit the
serotonin
5 receptors 2A, 2C and 3; and they inhibit the a-1 adrenergic receptor.
In one embodiment, said pharmaceutically acceptable salts are acid addition
salts of acids that are non-toxic. Said salts include salts made from organic
acids, such
as maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-
methylenesalicylic,
methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic,
citric,
gluconic, lactic, malic, malonic, mandelic, cinnamic, citraconic, aspartic,
stearic,
palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic,
theophylline
acetic acids, as well as the 8-halotheophyllines, for example 8-
bromotheophylline.
Said salts may also be made from inorganic salts, such as hydrobromic,
sulfuric,
sulfamic, phosphoric and nitric acids. Additional useful salts are listed in
the table in
example Id (table 1).
In one embodiment, the compound of the present invention, i.e. the compound
of formula I, is the HBr addition salt
In one embodiment, the compound of the present invention is the DL-lactic
acid addition salt, and in particular the 1:1 salt.
In one embodiment, the compound of the present invention is the L-aspartic
acid addition salt, and in particular the 1:1 salt.
In one embodiment, the compound of the present invention is the glutamic
acid addition salt, and in particular the 1:1 salt.
In one embodiment, the compound of the present invention is the glutaric acid
addition salt, and in particular the 1:1 salt.
In one embodiment, the compound of the present invention is the malonic acid
addition salt, and in particular the 1:1 salt that is found to exist in two
polymorphic

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6
modifications a and (3 of which the 0 form is believed to be the most stable
based on a
lower solubility.
In one embodiment, the compounds of the present invention is in a purified
form. The term "purified form" is intended to indicate that the compound is
essentially free of other compounds or other forms, i.e. polymorphs of said
compound, as the case may be.
Oral dosage forms, and in particular tablets and capsules, are often preferred
by the patients and the medical practitioner due to the ease of administration
and the
consequently better compliance. For tablets and capsules, it is preferable
that the
active ingredients are crystalline.
Crystals of the present invention may exist as solvates, i.e. crystals wherein
solvent molecules form part of the crystal structure. The solvate may be
formed from
water, in which case the solvates are often referred to as hydrates.
Alternatively, the
solvates may be formed from other solvents, such as e.g. ethanol, acetone, or
ethyl
acetate. The exact amount of solvate often depends on the conditions. For
instance,
hydrates will typically loose water as the temperature is increased or as the
relative
humidity is decreased. Compounds, which do not change or which change only
little
when conditions, such as e.g. humidity change are generally regarded as better
suited
for pharmaceutical formulations. It is noted that the HBr addition salt does
not form
hydrates when precipitated from water whereas compounds such as the succinate,
malate and tatrate acid addition salts do.
Some compounds are hygroscopic, i.e. they absorb water when exposed to
humidity. Hygroscopicity is generally regarded as an undesired property for
compounds, which are to be presented in a pharmaceutical formulation, in
particular
in a dry formulation, such as tablets or capsules. In one embodiment, the
invention
provides crystals with low hygroscopicity.
For oral dosage forms using crystalline active ingredients it is also
beneficial if
said crystals are well-defined. In the present context, the term "well-
defined" in
particular means that the stoichiometry is well-defined, i.e. that the ratio
between the
ions forming the salt is the ratio between small integers, such as 1:1, 1:2,
2:1, 1:1:1,
etc. In one embodiment, the compounds of the present invention are well-
defined
crystals.

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The solubility of an active ingredient is also of significance for the choice
of
dosage form as it may have a direct impact on bio-availability. For oral
dosage forms,
a higher solubility of the active ingredient is generally believed to be
beneficial as it
increases the bio-availability. Some patients, e.g. elderly patients may have
difficulties swallowing tablets, and oral drop solutions may be a suitable
alternative
avoiding the need for swallowing tablets. In order to limit the volume of an
oral drop
solution, it is necessary to have a high concentration of the active
ingredient in the
solution, which again requires a high solubility of the compound. As shown in
table 3,
DL-lactic acid, L-aspartic acid, glutamic acid, glutaric acid and malonic acid
addition
salts have exceptionally high solubility.
Crystal forms impact the filtration and processing properties of a compound.
Needle formed crystals tend to be more difficult to handle in a production
environment as filtration becomes more difficult and time consuming. The exact
crystal form of a given salt may depend e.g. on the conditions under which the
salt
was precipitated. The HBr acid addition salt of the present invention grows
needle-
shaped, solvated crystals when precipitated from ethanol, acetic acid and
propanol,
but crystals of a non-hydrated form, which are not needle-shaped, when HBr
addition
salt is precipitated from water, providing superior filtration properties.
Table 3 also depicts the Resulting pH, i.e. the pH in the saturated solution
of
the salt. This property is of importance because moisture can never be
completely
avoided during storage and the accumulation of moisture will give rise to a pH
decrease in or on a tablet comprising a low Resulting pH salt, which may
decrease
shell life. Moreover, a salt with a low resulting pH may give rise to
corrosion of
process equipment if tablets are made by wet granulation. The data in table 3
suggest
that the HBr, HCl and adipic acid addition salts may be superior in this
respect.
In one embodiment, the compound of the present invention is the HBr addition
salt in a crystalline form, in particular in a purified form. In a further
embodiment,
said HBr salt has peaks in an X-ray powder diffractogram (XRPD) at
approximately
6.08 , 14.81 , 19.26 and 25.38 20, and in particular said HBr salt has an
XRPD as
depicted in figure 1.
In one embodiment, the compound of the present invention is the DL-lactic
acid addition salt (1:1) in a crystalline form, in particular in a purified
form. In a
further embodiment, said DL-lactic acid addition salt has peaks in a XRPD at

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approximately 5.30 , 8.81', 9.44 and 17.24 20, and in particular said DL
lactic acid
addition salt has an XRPD as depicted in figure 4.
In one embodiment, the compound of the present invention is the L-aspartic
acid addition salt (1:1) in a crystalline form, in particular in a purified
form. In a
further embodiment, said L-aspartic acid addition salt is unsolvated and has
peaks in a
XRPD at approximately 11.05 , 20.16 , 20.60 , 25.00 20, and in particular said
L-
aspartic salt, when mixed with L-aspartic acid, has an XRPD as depicted in
figure 17.
In one embodiment, said L-aspartic acid addition salt is a hydrate, in
particular in a
purified form. In a further embodiment, said L-aspartic acid addition salt
hydrate has
peaks in a XRPD at approximately 7.80 , 13.80 , 14.10 , 19.63 20, and in
particular
said L-aspartic addition salt hydrate, when mixed with L-aspartic acid, has an
XRPD
as depicted in figure 18.
In one embodiment, the compound of the present invention is the glutamic
acid addition salt (1:1) in a crystalline form, in particular in a purified
form. In a
further embodiment, said glutamic acid addition salt has peaks in a XRPD at
approximately 7.71', 14.01 , 19.26 , 22.57 20, and in particular said
glutamic acid
salt, when mixed with glutamic acid monohydrate, has an XRPD as depicted in
figure
19.
In one embodiment, the compound of the present invention is the malonic acid
addition salt (1:1) in a crystalline form, in particular in a purified form.
In a further
embodiment, said malonic acid addition salt is the a-form and has peaks in a
XRPD at
approximately 10.77 , 16.70 , 19.93 , 24.01 20, or said malonic acid addition
salt is
the f3-form and has peaks in a XRPD at approximately 6.08 , 10.11 , 18.25 ,
20.26 20
and in particular said malonic acid addition salt has an XRPD as depicted in
figure 9
or 10.
In one embodiment, the compound of the present invention is the glutaric acid
addition salt (1:1) in a crystalline form, in particular in a purified form.
In a further
embodiment, said glutaric acid addition salt has peaks in a XRPD at
approximately
9.39 , 11.70 , 14.05 , and 14.58 20, and in particular said glutaric acid
addition salt
has an XRPD as depicted in figure 8.
As mentioned above, compounds of the present invention is particular well
suited for the treatment of chronic pain. Chronic pain includes indications
such as

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phantom limb pain, neuropathic pain, diabetic neuropathy, post-herpetic
neuralgia
(PHN), carpal tunnel syndrome (CTS), HIV neuropathy, complex regional pain
syndrome (CPRS), trigeminal neuralgia / trigeminus neuralgia / tic douloureux,
surgical intervention (e.g. post-operative analgesics), diabetic vasculopathy,
capillary
resistance or diabetic symptoms associated with insulitis, pain associated
with angina,
pain associated with menstruation, pain associated with cancer, dental pain,
headache,
migraine, tension-type headache, trigeminal neuralgia, temporomandibular joint
syndrome, myofascial pain muscular injury, fibromyalgia syndrome, bone and
joint
pain (osteoarthritis), rheumatoid arthritis, rheumatoid arthritis and edema
resulting
from trauma associated with burns, sprains or fracture bone pain due to
osteoarthritis,
osteoporosis, bone metastases or unknown reasons, gout, fibrositis, myofascial
pain,
thoracic outlet syndromes, upper back pain or lower back pain (wherein the
back pain
results from systematic, regional, or primary spine disease (radiculopathy),
pelvic
pain, cardiac chest pain, non-cardiac chest pain, spinal cord injury (SCI)-
associated
pain, central post-stroke pain, cancer neuropathy, AIDS pain, sickle cell pain
or
geriatric pain.
In particular, the compounds of the present invention are useful for the
treatment of mood disorders, such as depression associated with the above
listed
chronic pain indications.
Pain is defined by the International Association for the Study of Pain (IASP)
as "an unpleasant sensory and emotional experience associated with actual or
potential tissue damage, or described in terms of such damage (IASP
Classification of
chronic pain, 2"d Edition, IASP Press (2002), 210). Even though pain is always
subjective its causes or syndromes can be classified. "Neuropathic pain" as a
subtype
is defined by the IASP as "pain initiated or caused by a primary lesion or
dysfunction
in the nervous system".
Different subtypes of neuropatic pain are recognised by IASP, and examples
are
= Allodynia which is defined as "a pain due to a stimulus which does not
normally provoke pain".
= Causalgia which is defined as "a syndrome of sustained burning pain,
allodynia and hyperpathia after a traumatic nerve lesion, often combined with
vasomotor and sudomotor dysfunction and later trophic changes".

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= Hyperesthesia, which is defined as "increased sensitivity to stimulation,
excluding the senses".
= Neuralgia, which is defined as "Pain in the distribution of a nerve or
nerves".
= Neuritis, which is defined as "Inflammation of a nerve or nerves".
5 = Neuropathy, which is defined as "a disturbance of function or pathological
change in a nerve: in one nerve mononeuropathy, in several nerves
mononeuropthy multiplex, if diffuse and bilateral, polyneuropathy".
Neuropathy may be associated with e.g. diabetes in which case it is termed
diabetic neuropathy.
10 = Hyperalgesia, which is defined as "an increased response to a stimulus
which
is normally painful ".
= Hyperpathia, which is defined as "a painful syndrome characterized by an
abnormally painful reaction to a stimulus, especially a repetitive stimulus,
as
well as an increased threshold".
The stimuli evoking the neuropatic pain may be mechanical or thermal.
The unique pharmacological profile of the compounds of the present
inventions make them suitable for the treatment of other diseases, which are
not
directly related to chronic pain. 5-HT2c receptors are located e.g. on
dopaminergic
neurons where activation exerts a tonic inhibitory influence on the dopamine
release,
and 5-HT2C antagonists will effect an increase in the dopamine level. Data
presented
in example 2E show that compounds of the present invention do, in deed, bring
about
a dose dependent increase in the extra cellular dopamine levels in the brain.
On this
background it may be hypothesized that 5-HT2C antagonists are particular well-
suited
for the treatment of depression which is refractory to the treatment with
selective
serotonin reuptake inhibitors [Psychopharmacol. Bull., 39, 147-166, 2006].
This
hypothesis finds support in several clinical studies showing a combination of
mirtazipine and SSRI to be superior to SSRI alone for the treatment of
depressed
patients with an inadequate clinical response (treatment resistant depression,
TRD, or
refractory depression) [Psychother. Psychosom., 75, 139-153, 2006].
Mirtazapine is
also a 5-HT2 and a 5-HT3 antagonist, which indicate that compounds exerting
serotonin reuptake inhibition in combination with 5-HT2 and 5-HT3 antagonism,
such

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as compounds of the present invention, are useful for the treatment of TRD,
i.e. will
increase the remission rate for patients suffering from treatment resistant
depression.
Data presented in example 2F and 2G shows that the compounds of the present
invention bring about an increase in the extracellular level of acetylcholine
in the
prefrontal cortex and ventral hippocampus. There is longstanding clinical
evidence
that increasing the acetylcholine levels in the brain is a way to treat
Alzheimer's
disease and cognitive impairment in general, cf. the use of acetylcholine
esterase
inhibitors in the treatment of Alzheimer's disease. On this background,
compounds of
the present invention are believed to be useful in the treatment of
Alzheimer's disease
and cognitive impairment, and also mood disorders, such as depression
associated
with Alzheimer's disease and cognitive impairment.
A segment of depressed patients will respond to treatment with e.g. SSRI in
the sense that they will improve on clinically relevant depression scales,
such as
MADRD and HAMD, but where other symptoms, such as sleep disturbances and
cognitive impairment remain. In the present context, these patients are
referred to as
partial responders. Due to the above discussed effects on the acetylcholine
levels, the
compounds of the present invention are expected to be useful in the treatment
of the
cognitive impairment in addition to the depression. Clinical studies have
shown that
the compound prazosin, which is an a-1 adrenergic receptor antagonist reduces
sleep
disturbances [ Biol. Psychiatry, 61, 928-934, 2007], Moreover, the 5-HT2A and
5-
HT2c antagonism of the compounds of the present invention is also believed to
have a
sedative, sleep-improving effect [Neuropharmacol, 33, 467-471, 1994] wherefore
the
compounds of the present invention are useful for the treatment of partial
responders,
or rephrased that treatment of depressed patients with compounds of the
present
invention will reduce the fraction of partial responders.
Attention deficit hyperactivity disorder (ADHD) is one of the most common
neurobehavoioral disorders. ADHD is characterised by the presence of a triad
of
social and communicative impairments with restricted, repetitive or
stereotyped
behaviours. ADHD usually starts in childhood or adolescence, but symptoms may
continue into adulthood. Atomoxetine is currently the only nonstimulant
approved by
FDA for the treatment of ADHD [Drugs, 64, 205-222, 2004]. Atomoxetine is a
norepinephrine reuptake inhibitor, and this suggests that compounds of the
present
invention may be used in the treatment of ADHD. In addition, compounds of the

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present invention may have a sedative effect due to the a-1 adrenergic
receptor and 5-
HT2 antagonism discussed above, which is beneficial in the treatment of ADHD.
Melancholia is a particular subtype of depression often connected to severe
depression; this type of depression is also referred to as melancholic
depression.
Melancholia is associated with anxiety, dread of the future, insomnia, and
loss of
appetite. Compounds that inhibit both the serotonin and the norepinephrine
reuptake,
such as e.g. venlafaxine, have been shown to be particular effective in the
treatment of
patients with severe depression and melancholia [Depres. Anxiety, 12, 50-54,
2000].
As discussed above, compounds exerting 5-HT2c antagonism increase the dopamine
level, wherefore such compounds would be expected to be effective in the
treatment
of melancholia [Psychpharm. Bull., 39, 147-166, 2006]. Additionally, the a-1
adrenergic receptor and 5-HT2 antagonism of the compounds of the present
invention
is expected to help normalise sleep, wherefore said compounds are useful in
the
treatment of melancholia.
FDA has recently approved sertraline and paroxetine, two SSRI's, for the
treatment of post traumatic stress disorder (PTSD). Moreover, compounds having
5-
HT2A antagonistic activity are useful as they are expected to be able to
contain
agitation, insomnia and explosiveness in PTSD patients [Curr opinion Invest.
Drug, 4,
37-41, 2003]. Accordingly, the compounds of the present invention are expected
to be
useful in the treatment of PTSD.
Hot flushes is a symptom associated with the menopausal transition. Some
women may suffer from this to an extent where it interferes with sleep or
activities in
general, and where treatment is necessary. Hormone replacement therapy with
estrogen has been established practice for decades, however, recently concerns
have
been voiced on side effects, such as breast cancer and cardiac events.
Clinical trials
with SSRI and SNRI have shown that these compounds have an effect on hot
flushes,
albeit less than for estrogen [J.Am.Med.Ass., 295, 2057-2071, 2006]. Treatment
of hot
flushes with compounds inhibiting serotonin and/or norepinephrine reuptake,
e.g.
compounds of the present invention could, however, be an alternative treatment
for
women who can not or will not accept estrogen.
Sleep apnea or obstructive sleep apnea-hyponea syndrome or obstructive
sleep-disordered breathing is a disorder for which an effective
pharmacotherapy
remains to be identified. Several studies in animals, however, suggest that 5-
HT3

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13
antagonists, e.g. compounds of the present invention may be effective in a
therapeutic
intervention [Sleep, 21, 131-136, 1998; Sleep, 8, 871, 878, 2001].
The 5-HT3 antagonist odansetron has recently been shown effective in the
treatment of craving and alcohol and drug abuse [Drug Alc.Depend., 84, 256-
263,
2006; Pharmacol Therapeut., 111, 855-876, 2006]. This would seem to support
the
notion that 5-HT3 antagonists, e.g. compounds of the present invention may be
useful
in the treatment of craving, such as alcohol, nicotine or carbohydrate
craving; and
alcohol and drug abuse.
Other suggested uses of 5-HT3 antagonists include emesis, in particular chemo
therapy-induced emesis, eating disorders, such as bulimia, and irritable bowl
syndrome (IBS) [Exp. Opin. Ther. Targets, 11, 527-540, 2007].
The compounds of the present invention being endowed with a unique
pharmacological profile are additionally expected to be useful in the
treatment of
affective disorders, depression, major depressive disorder, postnatal
depression,
depression associated with bipolar disorder, Alzheimer's disease, psychosis or
Parkinson's disease, anxiety, general anxiety disorder, social anxiety
disorder,
obsessive compulsive disorder, panic disorder, panic attacks, phobia, social
phobia,
agoraphobia and stress urinary incontinence.
In one embodiment, the invention relates to a method of treating chronic pain,
depression in partial responders, treatment resistant depression, Alzheimer's
disease,
cognitive impairment, ADHD, melancholia, PTSD, hot flushes, sleep apnea,
alcohol,
nicotine or carbohydrate craving, substance abuse, alcohol or drug abuse,
emesis,
eating disorders, IBS, affective disorders, depression, major depressive
disorder,
postnatal depression, depression associated with bipolar disorder, Alzheimer's
disease, psychosis or Parkinson's disease, anxiety, general anxiety disorder,
social
anxiety disorder, obsessive compulsive disorder, panic disorder, panic
attacks, phobia,
social phobia, agoraphobia or stress urinary incontinence, the method
comprising
administering to a patient in need thereof a therapeutically effective amount
of
compound I. In one embodiment, said patient being treated for any of the above
listed
diseases has initially been diagnosed with said disease.
In one embodiment, the invention relates to a method for the treatment of
chronic pain, the method comprising administering to a patient in need thereof
a
therapeutically effective amount of compound I. In one embodiment, said
chronic

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pain is selected from phantom limb pain, neuropathic pain, diabetic
neuropathy, post-
herpetic neuralgia (PHN), carpal tunnel syndrome (CTS), HIV neuropathy,
complex
regional pain syndrome (CPRS), trigeminal neuralgia / trigeminus neuralgia /
tic
douloureux, surgical intervention (e.g. post-operative analgesics), diabetic
vasculopathy, capillary resistance or diabetic symptoms associated with
insulitis, pain
associated with angina, pain associated with menstruation, pain associated
with
cancer, dental pain, headache, migraine, tension-type headache, trigeminal
neuralgia,
temporomandibular joint syndrome, myofascial pain muscular injury,
fibromyalgia
syndrome, bone and joint pain (osteoarthritis), rheumatoid arthritis,
rheumatoid
arthritis and edema resulting from trauma associated with bums, sprains or
fracture
bone pain due to osteoarthritis, osteoporosis, bone metastases or unknown
reasons,
gout, fibrositis, myofascial pain, thoracic outlet syndromes, upper back pain
or lower
back pain (wherein the back pain results from systematic, regional, or primary
spine
disease (radiculopathy), pelvic pain, cardiac chest pain, non-cardiac chest
pain, spinal
cord injury (SCI)-associated pain, central post-stroke pain, cancer
neuropathy, AIDS
pain, sickle cell pain or geriatric pain.
In one embodiment, said chronic pain is neuropathic pain,
In one embodiment, said neuropatic pain is selected from hyperpathia,
hyperalgesia, neuropathy, diabetic neuropathy, neuritis, neuralgia,
hyperesthesia,
causalgia, and allodynia.
In an embodiment, the compound of the invention is administered in an
amount of about 0.001 to about 100 mg/kg body weight per day.
A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg
body weight per day, preferably from about 0.01 to about 50 mg/kg body weight
per
day, administered in one or more dosages such as 1 to 3 dosages. The exact
dosage
will depend upon the frequency and mode of administration, the sex, age,
weight and
general condition of the subject treated, the nature and severity of the
condition
treated and any concomitant diseases to be treated and other factors evident
to those
skilled in the art.
A typical oral dosage for adults is in the range of 1-100 mg/day of a compound
of the present invention, such as 1-30 mg/day, or 5-25 mg/day. This may
typically be
achieved by the administration of 0.1-50 mg, such as 1-25 mg, such as 1, 5,
10, 15, 20
or 25 mg of the compound of the present invention once or twice daily.

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A "therapeutically effective amount" of a compound as used herein means an
amount sufficient to cure, alleviate or partially arrest the clinical
manifestations of a
given disease and its complications in a therapeutic intervention comprising
the
administration of said compound. An amount adequate to accomplish this is
defined
5 as "therapeutically effective amount". The term also includes amounts
sufficient to
cure, alleviate or partially arrest the clinical manifestations of a given
disease and its
complications in a treatment comprising the administration of said compound.
Effective amounts for each purpose will depend on the severity of the disease
or
injury as well as the weight and general state of the subject. It will be
understood that
10 determining an appropriate dosage may be achieved using routine
experimentation, by
constructing a matrix of values and testing different points in the matrix,
which is all
within the ordinary skills of a trained physician.
The term "treatment" and "treating" as used herein means the management and
care of a patient for the purpose of combating a condition, such as a disease
or a
15 disorder. The term is intended to include the full spectrum of treatments
for a given
condition from which the patient is suffering, such as administration of the
active
compound to alleviate the symptoms or complications, to delay the progression
of the
disease, disorder or condition, to alleviate or relief the symptoms and
complications,
and/or to cure or eliminate the disease, disorder or condition as well as to
prevent the
condition, wherein prevention is to be understood as the management and care
of a
patient for the purpose of combating the disease, condition, or disorder and
includes
the administration of the active compounds to prevent the onset of the
symptoms or
complications. Nonetheless, prophylactic (preventive) and therapeutic
(curative)
treatment are two separate aspect of the invention. The patient to be treated
is
preferably a mammal, in particular a human being.
In one embodiment, the invention relates to the use of the present invention
in
the manufacture of a medicament for the treatment of chronic pain, depression
in
partial responders, treatment resistant depression, Alzheimer's disease,
cognitive
impairment, ADHD, melancholia, PTSD, hot flushes, sleep apnea, alcohol,
nicotine or
carbohydrate craving, substance abuse, alcohol or drug abuse, emesis, eating
disorders, IBS, affective disorders, depression, major depressive disorder,
postnatal
depression, depression associated with bipolar disorder, Alzheimer's disease,
psychosis or Parkinson's disease, anxiety, general anxiety disorder, social
anxiety

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16
disorder, obsessive compulsive disorder, panic disorder, panic attacks,
phobia, social
phobia, agoraphobia or stress urinary incontinence.
In one embodiment, the invention relates to the use of the present invention
in
the manufacture of a medicament for the treatment of chronic pain, such as
neuropathic pain.
In one embodiment, the invention relates to of the present invention for use
as
a medicament for the treatment of chronic pain, depression in partial
responders,
treatment resistant depression, Alzheimer's disease, cognitive impairment,
ADHD,
melancholia, PTSD, hot flushes, sleep apnea, alcohol, nicotine or carbohydrate
craving, substance abuse, alcohol or drug abuse, emesis, eating disorders,
IBS,
affective disorders, depression, major depressive disorder, postnatal
depression,
depression associated with bipolar disorder, Alzheimer's disease, psychosis or
Parkinson's disease, anxiety, general anxiety disorder, social anxiety
disorder,
obsessive compulsive disorder, panic disorder, panic attacks, phobia, social
phobia,
agoraphobia or stress urinary incontinence.
In one embodiment, the invention relates to compounds of the present for use
as a medicament for the treatment of chronic pain, such as neuropathic pain
The compounds of the present invention may be administered alone as a pure
compound or in combination with pharmaceutically acceptable carriers or
excipients,
in either single or multiple doses. The pharmaceutical compositions according
to the
invention may be formulated with pharmaceutically acceptable carriers or
diluents as
well as any other known adjuvants and excipients in accordance with
conventional
techniques such as those disclosed in Remington: The Science and Practice of
Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
The pharmaceutical compositions may be specifically formulated for
administration by any suitable route such as the oral, rectal, nasal,
pulmonary, topical
(including buccal and sublingual), transdermal, intracisternal,
intraperitoneal, vaginal
and parenteral (including subcutaneous, intramuscular, intrathecal,
intravenous and
intradermal) route, the oral route being preferred. It will be appreciated
that the
preferred route will depend on the general condition and age of the subject to
be
treated, the nature of the condition to be treated and the active ingredient
chosen.

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17
Pharmaceutical compositions for oral administration include solid dosage
forms such as capsules, tablets, dragees, pills, lozenges, powders and
granules. Where
appropriate, they can be prepared with coatings.
Liquid dosage forms for oral administration include solutions, emulsions,
suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile
aqueous and nonaqueous injectable solutions, dispersions, suspensions or
emulsions
as well as sterile powders to be reconstituted in sterile injectable solutions
or
dispersions prior to use.
Other suitable administration forms include suppositories, sprays, ointments,
cremes, gels, inhalants, dermal patches, implants, etc.
Conveniently, the compounds of the invention are administered in a unit
dosage form containing said compounds in an amount of about 0.1 to 50 mg, such
as
I mg, 5 mg 10 mg, 15 mg, 20 mg or 25 mg of a compound of the present
invention.
For parenteral routes such as intravenous, intrathecal, intramuscular and
similar administration, typically doses are in the order of about half the
dose
employed for oral administration.
For parenteral administration, solutions of the compound of the invention in
sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or
sesame or
peanut oil may be employed. Such aqueous solutions should be suitably buffered
if
necessary and the liquid diluent first rendered isotonic with sufficient
saline or
glucose. The aqueous solutions are particularly suitable for intravenous,
intramuscular, subcutaneous and intraperitoneal administration. The sterile
aqueous
media employed are all readily available by standard techniques known to those
skilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers,
sterile
aqueous solution and various organic solvents. Examples of solid carriers are
lactose,
terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia,
magnesium
stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid
carriers
are syrup, peanut oil, olive oil, phospho lipids, fatty acids, fatty acid
amines,
polyoxyethylene and water. The pharmaceutical compositions formed by combining
the compound of the invention and the pharmaceutical acceptable carriers are
then

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18
readily administered in a variety of dosage forms suitable for the disclosed
routes of
administration.
Formulations of the present invention suitable for oral administration may be
presented as discrete units such as capsules or tablets, each containing a
predetermined amount of the active ingredient, and which may include a
suitable
excipient. Furthermore, the orally available formulations may be in the form
of a
powder or granules, a solution or suspension in an aqueous or non-aqueous
liquid, or
an oil-in-water or water-in-oil liquid emulsion.
If a solid carrier is used for oral administration, the preparation may be
tablet,
e.g. placed in a hard gelatine capsule in powder or pellet form or in the form
of a
troche or lozenge. The amount of solid carrier may vary but will usually be
from
about 25 mg to about 1 g.
If a liquid carrier is used, the preparation may be in the form of a syrup,
emulsion, soft gelatine capsule or sterile injectable liquid such as an
aqueous or non-
aqueous liquid suspension or solution.
Tablets may be prepared by mixing the active ingredient with ordinary
adjuvants
and/or diluents followed by the compression of the mixture in a conventional
tabletting machine. Examples of adjuvants or diluents comprise: Corn starch,
potato
starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any
other
adjuvants or additives usually used for such purposes such as colourings,
flavourings,
preservatives etc. may be used provided that they are compatible with the
active
ingredients.
Capsules comprising a compound of the present invention may be prepared by
mixing a powder comprising said compound with microcrystalline cellulose and
magnesium stearate and place said powder in a hard gelatine capsule.
Optionally, said
capsule may be coloured by means of a suitable pigment. Typically, capsules
will
comprise 0.25-20% of a compound of the present invention, such as 0.5-1.0%,
3.0-
4.0%, 14.0-16.0% of a compound of the present invention. These strengths can
be
used to conveniently deliver 1, 5, 10, 15, 20 and 25 mg of a compound of the
present
invention in a unit dosage form.
Solutions for injections may be prepared by dissolving the active ingredient
and possible additives in a part of the solvent for injection, preferably
sterile water,
adjusting the solution to the desired volume, sterilising the solution and
filling it in

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19
suitable ampoules or vials. Any suitable additive conventionally used in the
art may
be added, such as tonicity agents, preservatives, antioxidants, etc.
Compound I may be prepared as outlined in WO 2003/029232. Salts of
compound I may by addition of an appropriate acid followed by precipitation.
Precipitation may be brought about by e.g. cooling, removal of solvent,
addition of
another solvent or a mixture thereof.
The use of the terms "a" and "an" and "the" and similar referents in the
context of describing the invention are to be construed to cover both the
singular and
the plural, unless otherwise indicated herein or clearly contradicted by
context. For
example, the phrase "the compound" is to be understood as referring to various
"compounds" of the invention or particular described aspect, unless otherwise
indicated.
Unless otherwise indicated, all exact values provided herein are
representative
of corresponding approximate values (e.g., all exact exemplary values provided
with
respect to a particular factor or measurement can be considered to also
provide a
corresponding approximate measurement, modified by "about," where
appropriate).
The description herein of any aspect or aspect of the invention using terms
such as "comprising", "having," "including," or "containing" with reference to
an
element or elements is intended to provide support for a similar aspect or
aspect of the
invention that "consists of', "consists essentially of', or "substantially
comprises" that
particular element or elements, unless otherwise stated or clearly
contradicted by
context (e.g., a composition described herein as comprising a particular
element
should be understood as also describing a composition consisting of that
element,
unless otherwise stated or clearly contradicted by context).

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Examples
Analytical methods
X-Ray powder diffractograms (XRPD) were measured on a PANalytical X'Pert PRO
X-Ray Diffractometer using CuKai radiation. The samples were measured in
5 reflection mode in the 20-range 5-40 using an X'celerator detector.
Elemental composition (CHN) was measured on an Elementar Vario EL instrument
from Elementar. About 4 mg of sample was used for each measurement, and the
results are given as mean values of two measurements.
10 Example 1 a HBr salt of compound I
To 442 grams of stored and slightly heated (approx. 45 C) 4-(2-p-
Tolylsulfanyl-
phenyl)-piperidine-l-carboxylic acid ethyl ester as an oil was added 545 ml of
33 wt-
% HBr in AcOH (5.7 M, 2.5 eqv). This mixing gives a 10 C exotherm. After
final
addition the reaction mixture is heated to 80 C and left for 18 hours. A
sample is
15 withdrawn and analysed by HPLC and if not completed more 33 wt-% HBr in
AcOH
must be added. Otherwise the mixture is cooled to 25 C making the product 4-
(2-p-
Tolylsulfanyl-phenyl)-piperidine hydrobromide to precipitate. After one hour
at 25 C
the thick suspension is added 800 ml diethylether. Stirring is continued for
another
hour before the product is isolated by filtration, washed with 400 ml
diethylether and
20 dried in vacuum at 40 C overnight. The hydrobromide of compound I was
isolated
as white solid.
Example lb HBr salt of compound I
2-(4-tolylsu4fanyl) phenyl bromide
In a stirred nitrogen covered reactor N-methyl-pyrrolidone, NMP (4.5L) was
flushed
with nitrogen for 20 minutes. 4-Methylbenzenethiol (900g, 7.25mo1) was added
and
then 1,2-dibromobenzene (1709g, 7.25mo1). Potassium tert-butoxide (813g,
7.25mol)
was finally added as the last reactant. The reaction was exothermic giving a
temperature rise of the reaction mixture to 70 C. The reaction mixture was
then
heated to 120 C for 2 - 3 hours. The reaction mixture was cooled to room
temperature. Ethyl acetate (4L) was added and aqueous sodium chloride solution
(15%, 2.5L). The mixture was stirred for 20 minutes. The aqueous phase was

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21
separated and extracted with another portion of ethyl acetate (2L). The
aqueous phase
was separated and the organic phases were combined and washed with sodium
chloride solution (15%, 2.5L) The organic phase was separated, dried with
sodium
sulphate and evaporated at reduced pressure to a red oil which contains 20 -
30%
NMP. The oil was diluted to twice the volume with methanol and the mixture was
refluxed. More methanol was added until a clear red solution was obtained. The
solution was cooled slowly to room temperature while seeded. The product
crystallises as off white crystals, they were isolated by filtration and
washed with
methanol and dried at 40 C in a vacuum oven until constant weight.
Ethyl 4-hydroxy-4-(2-(4-to lylsulfanyl)phenyl) piperidin-1-carboxylate
In a stirred reactor under nitrogen cover 2-(4-tolylsulfanyl)-phenyl bromide
(600g,
2.15mol) was suspended in heptane (4.5L). At room temperature IOM BuLi in
hexane
(235mL, 2.36mo1) was added over 10 minutes. Only a small exotherm was noticed.
The suspension was stirred for 1 hour at ambient temperature and then cooled
down to
-40 C. 1-Carbethoxy-4-piperidone (368g, 2.15 mol) dissolved in THE (1.5L) was
added at a rate not faster than the reaction temperature was kept below -40 C.
When
the reaction has gone to completion, it was warmed to 0 C and I M HCl (1 L)
was
added keeping the temperature below 10 C. The acid aqueous phase was separated
and extracted with ethyl acetate (1 L). The organic phases were combined and
extracted with sodium chloride solution (15%, 1L). The organic phase was dried
over
sodium sulphate and evaporated to a semi crystalline mass. It was slurried
with ethyl
ether (250 mL) and filtered off. Dried in an vacuum oven at 40 C until
constant
weight.
Ethyl 4-(2-(4-tolylsulfanyl)phenyt)-piperidin-l-carboxylate
Trifluoroacetic acid (2.8kg, 24.9mol) and triethylsilane (362g, 3.lmol) was
charged in
a reactor with an efficient stirrer. Ethyl 4-hydroxy-4-(2-(4-
tolylsulfanyl)phenyl)-
piperidin- I -carboxylate (462g, 1.24mo1) was added via a powder funnel in
portions.
The reaction was slightly exothermic. The temperature rose to 50 C. After the
addition was finalised the reaction mixture was warmed to 60 C for 18 hours.
The
reaction mixture was cooled down to room temperature. Toluene (750mL) and
water

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22
(750mL) was added. The organic phase was isolated and the aqueous phase was
extracted with another portion of toluene (750mL). The organic phases were
combined and washed with sodium chloride solution (15%, 500mL) and dried over
sodium sulphate . The sodium sulphate was filtered off, the filtrate
evaporated at
reduced pressure to a red oil which was processed further in the next step.
4-(2-(4-tolylsulfanyl)phenyl)-piperidin hydrobromide
The crude ethyl 4-(2-(4-tolylsulfanyl)phenyl)-piperidin-l-carboxylate as a red
oil from example 3 was mixed in a stirred reactor with hydrobromic acid in
acetic acid
(40%, 545mL, 3.11 mol). The mixture was heated at 80 C for 18 hours. The
reaction
mixture was cooled down to room temperature. During the cooling the product
crystallises out. After 1 hour at room temperature ethyl ether (800mL) was
added to
the reaction mixture, and the mixture was stirred for another hour. The
product was
filtered off, washed with ethyl ether and dried in a vacuum oven at 50 C until
constant
weight.
Example 1 c Recrystallisation of the HBr salt of compound I
A mixture of 10.0 grams of the HBr salt of compound I, e.g. prepared as above,
was
heated to reflux in 100 ml H2O. The mixture became clear and fully dissolved
at 80-
90 C. To the clear solution was added 1 gram of charcoal and reflux was
continued
for 15 minutes before filtered and left to cool spontaneously to room
temperature.
During the cooling precipitation of white solid took place and the suspension
was
stirred for 1 hour at room temperature. Filtration and drying in vacuum at 40
C
overnight produced 6.9 grams (69 %) of the HBr acid addition salt of compound
I.
See Figure 1 for XRPD. Elemental analysis: 3.92%N, 59.36%C, 6.16%H (theory:
3.85%N, 59.34%C, 6.09%H)
Example I d Preparation of stock-solutions of free base
A mixture of 500 ml ethyl acetate and 200 ml H2O was added 50 grams of the HBr
salt of compound I producing a two-phased slurry. To this slurry was added
approximately 25 ml conc. NaOH that caused formation of a clear two-phased
solution (pH was measured to 13-14). The solution was stirred vigorously for
15
minutes and the organic phase was separated. The organic phase was washed with
200

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23
ml H2O, dried over Na2SO4, filtered and evaporated in vacuum at 60 C
producing the
free base in 38 grams yield (99 %) as an almost colourless oil.
Dissolving 10 grams of the oil and adjusting the volume to 150 ml using ethyl
acetate produced a 0.235 M stock-solution in ethyl acetate from which aliquots
of 1.5
ml (100 mg of the free base) was used.
Dissolving 10 grams of the oil and adjusting the volume to 100 ml using 96-
vol% EtOH produced a 0.353 M stock-solution in EtOH from which aliquots of 1.0
ml (100 mg of the free base) was used.
Example le Formation of salts using stock-solutions of the free base
The given aliquots were placed in test tubes and while stirred the appropriate
amount
of acid was added as indicated in Table 1. If the acid was a liquid it was
added neat
otherwise it was dissolved in the given solvent prior to addition. After
mixing and
precipitation stirring was continued overnight and the precipitate collected
by
filtration. Before drying in vacuum at 30 C a small reference sample was
withdrawn
and dried at room temperature without vacuum. This procedure was included in
order
to test for solvates. Some results are presented in Table 1. XRPD
diffractograms are
shown in figures 1-22, and selected peak positions are tabulated in Table 2.
Table 3
shows the solubilities of compounds of the present invention in water together
with
pH in the resulting saturated solution. The column "Precipitate" shows whether
the
precipitate isolated after the solubility determination is identical to the
compound
dissolved, which is indicative of the formation of hydrates.
Table 1
Acid (Base:Acid) MW Amount Solvent CHN (exp.) CHN (theory)
(glmol) of Acid
(mg or l)
Palmitic acid, hexadecanoic 256.42 90.5 EtOAc 75.36 9.77 2.46 75.64 9.9 2.6
acid 1:1
DL-Lactic acid, DL-2- 90.1 31.8 EtOAc 66.88 7.26 3.52 67.53 7.29 3.75
hydroxypropionic acid 1:1
Adipicacid, 1,6-hexanedioic 146.14 51.6 EtOAc 66.08 7.23 2.98 67.1 7.27 3.26
acid 1:1
Adipicacid, 1,6-hexanedioic 146.14 25.8 EtOAc 70.66 7.32 3.82 70.75 7.35 3.93
acid 2:1
Fumaric acid 1:1 116.01 40.9 EtOH 65.71 6.41 3.35 66.14 6.31 3.51

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24
Acid (Base:Acid) MW Amount Solvent CHN (exp.) CHN (theory)
(g/mol) of Acid
(mg or l)
Glutaric acid, 1,5- 132.12 46.6 EtOAc 66.09 6.97 3.2 66.48 7.03 3.37
pentanedioic acid 1:1
Malonic acid 1:1 104.1 36.7 EtOAc 65.04 6.53 3.54 65.09 6.5 3.62
Oxalic acid 1:1 90.1 31.8 EtOH 64.28 6.41 3.61 64.32 6.21 3.75
Sebacoinic acid, 1,8- 202.02 35.6 EtOAc 71.79 7.86 3.58 71.83 7.86 3.64
octanedioic acid 2:1
Succinic acid, 1,4- 118.1 20.8 EtOAc 65.65 6.86 3.4 65.80 6.78 3.49
butanedioic acid, 2:1 (1:1 salt formed)
L-malic acid, L-2-hydroxy 134.1 47.3 EtOAc 62.87 6.20 3.22 63.29 6.52 3.36
butanedioic acid 1: 1, a
L-malic acid, L-2-hydroxy 134.1 47.3 EtOH 62.99 6.66 3.13 63.29 6.52 3.36
butanedioic acid 1:1,(3
D-tartaric acid, D-2,3- 150.1 53.0 EtOH 60.67 6.4 3.07 60.95 6.28 3.23
dihydroxy butanedioic acid
1:1
L-aspartic acid 1:1 133.1 47.0 EtOH 59.31 6.7 7.1 63.43 6.78 6.73
(contains excess of
acid)
Glutamic acid 1:1 165.15 58.3 EtOH 56.38 6.88 7.35 56.46 6.94 7.06
(contains excess of (for 1:1-salt and acid-
acid) monohydrate 1:1)
Citric acid 2:1 192.13 33.9 EtOAc 65.93 6.72 3.44 66.46 6.64 3.69
HCl/Et2O 1:1 2M 176.4 EtOH
Phosphoric acid ] :1 14.7 M 24.0 EtOAc 55.79 6.47 3.43 56.68 6.34 3.67
Table 2: Selected X-ray peak positions ( 20), 2:1 means 2 bases to I acid. All
values +-0.1
Palmitate 7.00 16.34 22.73 28.21
Stearate 6.70 15.52 21.81 28.91
Lactate 5.30 8.18 9.44 17.24
Lactate hydrate 1 1.67 16.70 18.25 21.76
hydroxyl-isobutyrate 5.09 16.60 20.38 27.37
Sebacoin acid salt 7.18 12.53 21.11 24.19
Adipinic acid salt 2:1 8.03 13.52 17.90 24.60
Adipinic acid salt 1:1 a 9.33 14.01 18.72 20.63
Adipinic acid salt 1:1 15.69 21.53 25.81 31.18
Glutarate 1:1 9.39 11.70 14.05 14.58
Succinate 1:1 11.74 14.33 17.75 26.84
Fumarate 1:1 8.90 11.47 19.25 22.33
Fumarate 2:1 8.49 12.48 17.78 23.97
Maleate 1:1 12.11 15.51 17.48 22.53
Maleate 1:1 hydrate 12.81 18.76 20.53 27.31

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Malonate a 10.77 16.70 19.93 24.01
Malonate 6.08 10.11 18.25 20.26
Aspartate 11.05 20.1 20.60 25.00
Aspartate hydrate 7.80 13.80 14.10 19.63
Glutamate 7.71 14.01 19.26 22.57
Oxalate 14.68 17.45 19.50 23.90
Malate 1:1 a 8.30 12.04 17.23 20.67
Malate 1:1 R 10.91 12.87 14.14 26.16
Malate hydrate 12.30 15.56 19.56 23.30
D-tartrate (from EtOH) 5.08 17.18 19.42 22.10
Hydrochloride 12.44 16.72 19.45 25.02
Hydrobromide 6.08 14.81 19.26 25.38
Hydrobromide 1-PrOH solvate 6.57 13.12 19.07 24.77
Table 3
Acid (Base:Acid) Solubility Resulting pH Precipitate
(mg/ml)
Palmitic acid, hexadecanoic 0.4 8.6 =start
acid 1:1
DL-Lactic acid, DL-2- >150 6.1 =start (after
hydroxypropionic acid 1:] evaporation)
Adipicacid, 1,6-hexanedioic 2.5 4.0 Partly 2:1 salt
acid 1:1
Adipicacid, 1,6-hexanedioic 1.0 7.8 =start
acid 2:1
Fumaric acid 1:1 0.2 3.3 =start
Glutaric acid, 1,5- 13 4.6 =start
pentanedioic acid 1:1
Malonic acid 1:1 (a) 5.2 4.0 =new form ((3)
Oxalic acid 1 :1 1.1 2.7 =Start
Sebacoinic acid, 1,8- 0.7 5.5 =Start
octanedioic acid 2:1
Succinic acid, 1,4- 2.0 4.0 Hydrate
butanedioic acid, 2:1
L-malic acid, L-2-hydroxy 2.8 4.0 Hydrate
butanedioic acid I : ] , (3
D-tartaric acid, D-2,3- 1.8 3.5 Hydrate
dihydroxy butanedioic acid
1:1
L-aspartic acid 1:1 39 4.3 Hydrate
Glutamic acid 1:1 >35 4.6 -
Citric acid 2:1 0.5 4.7 =Start
Phosphoric acid 1:1 6.0 2.0 ?
HCI 4.5 6.8 =Start
HBr 2.4 7.0 =Start

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26
Example 2A Serotonin (5-HT) and norepinephrine (NE) reuptake inhibition
Aliquots of test compound and rat cortical synaptosome preparation were pre-
incubated for 10 min/37 C, and then added [3H]NE or [3H]5-HT (final
concentration
10 nM). Non-specific uptake was determined in the presence of 10 M talsupram
or
citalopram and the total uptake was determined in the presence of buffer.
Aliquots
were incubated for 15 minutes at 37 C. After the incubation [3H]NE or [3H]5-
HT
taken up by synaptosomes was separated by filtration through Unifilter GF/C,
presoaked in 0.1 % PEI for 30 minutes, using a Tomtec Cell Harvester program.
Filters were washed and counted in a Wallac MicroBeta counter.
At NET compounds of the present invention display an IC50 value of 23 nM.
At SERT compounds of the present invention display an IC50 value of 8 nM.
Example 2B 5-HTZA antagonism
Compounds of the present invention were tested for affinities towards
serotonin
receptors and was found to exhibit an antagonistic profile with affinity at 5-
HT2A
receptors (K; 54 nM). The affinity is calculated from Y = 100/(1+ I0(x-
!091c5o)) where
Y denotes % binding and X denotes the concentration of compound. 5
concentrations
of compound (1, 10, 30, 100, 1000 nM) were used to calculate the IC50 value.
Ki was
calculated from the Cheng Prusoff equation Ki = (IC5o/(1+ ([L]/Kd)) Affitiny
was
determined at MDL Pharmaservices catalogue number 271650.
In mammalian cells expressing human 5-HT2A receptors compounds of the
present invention display competitive antagonistic properties. The compounds
bind to
5-HT2A receptors with a Ki of < 100 nM and in a functional assay the compounds
antagonise 5-HT evoked release of CaZ+ from intracellular stores with a Kb of
67 nM.
A schild analysis revealed competitive antagonism with a Kb of 100 nM.
The experiment was carried out as follows. 2 or 3 days before the experiment
CHO cells expressing 250 fmol/mg human 5-HT2A receptors are plated at a
density
sufficient to yield a mono-confluent layer on the day of the experiment. The
cells are
dye loaded (CaZ+-kit from Molecular Devices) for 60 minutes at 37 C in a 5%
CO2
incubator at 95% humidity. Basal fluorescence was monitored in a fluorometric
imaging plate reader or FLIPR384 from Molecular Devices (Sunnyvale, CA) with
an
excitation wavelength of 488 nm and an emission range of 500 to 560 nm. Lacer

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27
intensity was set to a suitable level to obtain basal values of approximately
8000-
10000 fluorescence units. The variation in basal fluorescence should be less
than
10%. EC50 values are assessed using increasing concentrations of test compound
covering at least 3 decades. pA2 values are assessed challenging full dose
response
curves of 5-HT with four different concentrations of compound (150, 400 1500
and
4000 nM). Kb values were also assessed challenging 2 decades of concentrations
of
test substances with EC85 of 5-HT. Test substances are added to the cells 5
minutes
before the 5-HT. K; values are calculated using Cheng-Prusoff equation.
Example 2C 5-HT3A receptor antagonism
In oocytes expressing human-homomeric 5-HT3A receptors 5-HT activates currents
with an EC50 of 2600 nM. This current can be antagonised with classical 5-HT3
antagonists such as ondansetron. Ondansetron displays a Ki value below 1 nM in
this
system. Compounds of the present invention exhibit potent antagonism in low
concentrations (0.1 nM - 100 nM) (IC50 - 10 nM/ Kb - 2 nM) and agonistic
properties when applied in higher concentrations (100 - 100000 nM) (EC50- 2600
nM) reaching a maximal current of approximately 70-80 % of the maximal current
elicited by 5-HT itself. In oocytes expressing rat-homomeric 5-HT3A receptors
5-HT
activates currents with an EC50 of 3.3 M. The experiments were carried out as
follows. Oocytes were surgically removed from mature female Xenepus laevis
anaesthetized in 0.4 % MS-222 for 10 - 15 min. The oocytes were then digested
at
room temperature for 2-3 hours with 0.5 mg/ml collagenase (type IA Sigma-
Aldrich)
in OR2 buffer (82.5 mN NaCl, 2.0 mM KCI, 1.0 mM MgCl2 and 5.0 mM HEPES, pH
7.6). Oocytes avoid of the follicle layer were selected and incubated for 24
hours in
Modified Barth's Saline buffer [88 mM NaCl, 1 mM KC1, 15 mM HEPES, 2.4 mM
NaHCO3, 0.41 mM CaC12, 0.82 mM MgSO4, 0.3 mM Ca(N03)2] supplemented with 2
mM sodium pyruvate, 0.1 U/l penicillin and 0.1 g/l streptomycin. Stage IV-IV
oocytes were identified and injected with 12-48 nl of nuclease free water
containing
14 - 50 pg of cRNA coding for human 5-HT3A receptors receptors and incubated
at
18 C until they were used for electrophysio logical recordings (1 - 7 days
after
injection). Oocytes with expression of human 5-HT3 receptors were placed in a
1 ml
bath and perfused with Ringer buffer (115 mM NaCl, 2.5 mM KC1, 10 mM HEPES,
1.8 mM CaCl2, 0.1 mM MgCl2, pH 7.5). Cells were impaled with agar plugged 0.5-
1

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28
MS2 electrodes containing 3 M KCI and voltage clamped at -90 mV by a GeneClamp
500B amplifier. The oocytes were continuously perfused with Ringer buffer and
the
drugs were applied in the perfusate. 5-HT agonist-solutions were applied for
10 - 30
sec. The potencies of 5-HT3 receptor antagonists were examined by measuring
concentration-response against 10 M 5-HT stimulation.
Example 2D aIA receptor antagonism
Compounds of the present invention were tested for affinities towards the a,A
receptor and was found to exhibit an antagonistic profile with medium affinity
for a,A
receptors (Ki = 34 nM).
On the day of the experiments membranes (see below for description of
membrane preparation) are thawed and homogenized in buffer using an ultra
turrax
and diluted to the desired concentration (5 g / well.., 5 g / 900 l, store
on ice until
use).
The experiment is initiated by mixing of 50 l test compound, 50 1 [3H]-
Prazosin and 900 l membranes, and the mixture is incubated for 20 minutes at
25 C.
Non-specific binding is determined in the presence of 10 M WB-4101 and the
total
binding is determined in the presence of buffer. After the incubation, bound
ligand is
separated from unbound by filtration through Unifilter GF/B, presoaked in 0.1
% PEI
for 30 minutes, using a Tomtec Cell Harvester program (D4.2..4). 96 well.
Filters are
washed 3 times with 1 ml ice-cold buffer, dried at 50 C and 35 l
scintillation
liquid/well is added to the filters. Bound radioactivity is counted in a
Wallac OY 1450
MicroBeta. The affinity is calculated from Y = 100/(1+ I0(x-'0g1C50)) where Y
denotes
% binding and X denotes the concentration of compound. Concentrations of
compound covering 2 decades were used to calculate the IC50 value. Ki was
calculated from the Cheng Prusoff equation Ki = (IC50/(1+ ([L]/Kd))
In a functional assay compounds of the present invention antagonises
adrenaline evoked release of Caz+ from intracellular stores and a functional
assay
revealed that compounds were antagonists.
These experiments were carried out essentially as described below.

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All cells were cultured in DMEM medium supplemented with 10% BCS, 4
mM L-glutamine (or 2 mM in the case of COS-7), and 100 units/ml penicillin
plus
100 g/ml streptomycin, at 37 oC, in 5% C02.
Twenty-four hours prior to assays, CHO cells expressing the human alpha] A_7
receptors were seeded into 384-well black wall microtiter plates coated with
poly-D-
lysine. Culture medium was aspirated and cells were dye-loaded with 1.5 M
Fluo-4
in assay buffer composed of Hank's Balanced Salt Solution (138 mM NaCl, 5 mM
KC1, 1.3 mM CaC12, 0.5 mM MgCl2, 0.4 mM MgSO4, 0.3 mM KH2PO4, 0.3 mM
Na2HPO4, 5.6 mM glucose) plus 20 mM HEPES pH 7.4, 0.05% BSA and 2.5 mM
probenicid (50 Wwell) for 1 hour in 5% CO2 at 37 T. After excess dye was
discarded, cells were washed in assay buffer and layered with a final volume
equal to
45 l/well (or 30 ul/well for antagonist assay). In the case of antagonist
evaluation,
antagonist or vehicle was added at this point as a 15 l aliquot in 4% DMSO-
containing buffer at 4x the final concentration (final DMSO = 1%), followed by
a 20
min incubation. Basal fluorescence was monitored in a fluorometric imaging
plate
reader or FLIPRTM from Molecular Devices (Sunnyvale, CA) with an excitation
wavelength of 488 nm and an emission range of 500 to 560 rim. Laser excitation
energy was adjusted so that basal fluorescence readings were approximately
8,000
relative fluorescent units (RFU). Cells were then stimulated at room
temperature with
agonists diluted in assay buffer (15 l), and RFU were measured at 1.5 second
intervals over a period of 2.5 min. Maximum change in fluorescence was
calculated
for each well. Concentration-response curves derived from the maximum change
in
fluorescence were analyzed by nonlinear regression (Hill equation). For
antagonistic
determinations, after 20 min of compound incubation (as above), fixed
concentrations
of standard agonist serotonin were added.
Example 2E Increase in dopamine
A single injection of compounds of the present invention dose-dependently
increased
extracellular DA levels in the rat frontal cortex. The compound of the present
invention at 8.9mg/kg and 18mg/kg s.c., enhanced the DA levels by
approximately
100% and 150%, respectively, above baseline levels as depicted in figure 23.
Amounts are calculated as the free base.

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Method.
Male Sprague-Dawley rats, initially weighing 275-300 g, were used. The animals
were housed under a 12-hr light/dark cycle under controlled conditions for
regular in-
door temperature (21 2 C) and humidity (55+5%) with food and tap water
available
5 ad libitum. For the three-day treatment experiments osmotic minipumps
(Alzet,
2ML1) were used. The pumps were filled under aseptic conditions and implanted
subcutaneously under sevoflurance anaesthesia. The experiments were carried
out
with the minipumps on board. Blood samples for measuring plasma levels of the
test
compound after 3 days of treatment were collected at the end of the
experiments.
Surgery and microdialysis experiments.
Animals were anaesthetised with hypnorm/dormicum (2 ml/kg) and intracerebral
guide cannulas (CMA/12) were stereotaxically implanted into the hippocampus,
positioning the dialysis probe tip in the ventral hippocampus (co-ordinates:
5,6 mm
anterior to bregma, lateral -5,0 mm, 7,0 mm ventral to dura or in the frontal
cortex
(co-ordinates: 3,2 mm anterior to bregma; lateral, 3.0 mm; 4,0 mm ventral to
dura).
Anchor screws and acrylic cement were sued for fixation of the guide cannulas.
The
body temperature of the animals was monitored by rectal probe and maintained
at
37 C. The rats were allowed to recover from surgery for 2 days, housed singly
in
cages. On the day of the experiment a microdialysis probe (CMA/12, 0,5 mm
diameter, 3 mm length) was inserted through the guide cannula. The probes were
connected via a dual channel swivel to a microinjection pump. Perfusion of the
microdialysis probe with filtered Ringer solution (145 mm NaCl, 3 mm KCI, 1 mM
MgCl2, 1,2 mM CaCl2) was begun shortly before insertion of the probe into the
brain
and continued for the duration of the experiment at a constant flow rate of 1
(1,3)
L/min. After 180 min of stabilisation, the experiments were initiated.
Dialysates
were collected every 20 (30) min.
After the experiments the rats were sacrificed by decapitation, their brains
removed,
frozen and sliced for probe placement verification.
Analysis of dialysates.
Concentration of dopamine in the dialysates was analysed by means of HPLC with
electrochemical detection. The monoamines were separated by reverse phase
liquid

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31
chromatography (ODS 150 x 3 mm, 3 M). Dopamine: Mobile phase consisting of 90
mM NaH2PO4, 50 mM sodium citrate, 367 mg/l sodium 1-octanesulfonic acid, 50 M
EDTA and 8% acetonitrile (pH 4.0) at a flow rate of 0.5 ml/min.
Electrochemical
detection was accomplished using a coulometric detector; potential set at 250
mV
(guard cell at 350 mV) (Coulochem II, ESA).
Example 2F Increase in acetylcholin
The experiment was designed to evaluate the effects of compounds of the
present
invention on extracellular levels of acetylcholine in the prefrontal cortex of
freely-
moving rats.
Male Wistar rats (280-350 g; Harlan, Zeist, The Netherlands) were used for the
experiments. Rats were individually housed in plastic cages (30 x 30 x 40 cm)
and
had ad libitum access to food and water.
Rats were anesthetized using isoflurane (2%, 400 mL/min N20, 400 ml/min 02).
Lidocain (10 % m/v) was used for local anesthesia. Each animal was placed into
a
stereotaxic frame (Kopf instruments, USA), and home-made I-shaped probes
(Hospal
AN 69 membrane, 4 mm exposed surface) were inserted into the medial prefrontal
cortex (mPFC) using the rat brain atlas of Paxinos and Watson (1982).
Coordinates
for the tip of the probe was mPFC [AP = 3.4 mm, L = -0.8 mm, V = 5.0 mm].The
probe was then fixed to the skull with dental cement and a srew. Flunixin (1
mg/kg
s.c.) was administered as post-operative analgesic.
Experiments were carried out 24-48 hours after surgery. On the day of the
experiment, rats were connected with flexible PEEK tubing to microperfusion
pumps
(CMA 102), and the dialysis probes were perfused with a Ringer buffer
containing
147 mM NaCl, 3.0 mM KCI, 1.2 mM CaCl2, and 1.2 mM MgC12, at a flow rate of 1.5
L/min. Microdialysis samples were collected at 30 min intervals into mini-
vials
containing 55 L 0.02 M formic acid for determination of acetylcholine.
Samples
were collected by an automated fraction collector (CMA 142), and stored at -80
C
until analyzed. After completion of the experiments the rats were sacrificed.
The
brains were removed and cured in paraformaldehyde solution (4% m/v). The
positioning of each probe was verified histologically according to Paxinos and
Watson (1982), by making coronal sections of the brain.

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The test compound was dissolved in 10 % 2-OH-propyl-beta-cyclodextrin and
administration occurred by subcutaneous injections of 5 mL/kg volumes in
different
doses.
Concentrations of acetylcholine were determined by HPLC with tandem mass
spectrometry (MS/MS) detection.
Aliquots (25 .tL) were injected onto the HPLC column by an automated
sample injector (PerkinElmer Instruments, series 200). Chromatographic
separation
was performed on a reverse-phase 150 x 2.00 mm (4 m) analytical column
(Phenomenex Synergy MAX-RP, Bester) protected by a 4 x 2.0 mm guard column
(Phenomenex Synergy MAX-RP AJO-6073, Bester), both held at a temperature of 30
C. The mobile phase (isocratic) consisted of ultrapurified water (UP),
acetonitrile
(ACN), and trifluoroacetic acid (TFA) (UP:ACN:TFA = 95.0:0.5:0.1 v/v/v%).
Mobile
phase was run through the system at a flow rate of 0.300 mL/min by an HPLC
pump
(PerkinElmer Instruments, series 200 micro pump).
The LC/MS analyses were performed using a API 4000 MS/MS system
consisting of a API 4000 MS/MS detector and a Turbo Ion Spray interface (both
from
Applied Biosystems, the Netherlands). The acquisitions were performed in
positive
ionization mode, with ion spray voltage set at 5.5 kV, the nebulizer gas
pressure at 50
psig (on a SCIEX scale 0-90) with a probe temperature of 600 C. The instrument
was
operated in multiple-reaction-monitoring (MRM) mode for detection of
acetylcholine
(precursor 146.1 Da, product 86.8 Da). The collision energy was 21.0 eV, and
the
collision gas (nitrogen) pressure was held at 7 (on a SCIEX scale of 0-12).
Data were
calibrated and quantitated using the Analysttm data system (Applied Biosystem,
version 1.2).
Two consecutive microdialysis samples with less then 50 % variation were
taken as baseline levels and set at 100 %. Changes in acetylcholine
concentration
were expressed as percent of baseline within the same subject.
The data are shown in Figure 24
Example 2G Increase in acetylcholine
The experiment was designed to evaluate the effects of compounds of the
present
invention on extracellular levels of acetylcholine in the prefrontal cortex
and ventral
hippocampus of freely-moving rats.

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Male Sprague-Dawley rats, initially weighing 275-300 g, were used. The animals
were housed under a 12-hr light/dark cycle under controlled conditions for
regular in-
door temperature (21 2 C) and humidity (55 5%) with food and tap water
available
ad libitum.
Surgery and microdialysis experiments
Rats were anaesthetised with hypnorm/dormicum (2 ml/kg) and intracerebral
guide
cannulas (CMA/12) were stereotaxically implanted into the hippocampus, aiming
to
position the dialysis probe tip in the ventral hippocampus (co-ordinates: 5,6
mm
posterior to bregma, lateral -5,0 mm, 7,0 mm ventral to dura or in the frontal
cortex
(co-ordinates: 3,2 mm anterior to bregma; lateral, 0,8 mm; 4,0 mm ventral to
dura).
Anchor screws and acrylic cement were used for fixation of the guide cannulas.
The
body temperature of the animals was monitored by rectal probe and maintained
at
37 C. The rats were allowed to recover from surgery for 2 days, housed singly
in
cages. On the day of the experiment a microdialysis probe (CMA/12, 0,5 mm
diameter, 3 mm length) was inserted through the guide cannula.
The probes were connected via a dual channel swivel to a microinjection
pump. Perfusion of the microdialysis probe with filtered Ringer solution (145
mm
NaCl, 3 mM KC1, 1 MM MgC12, 1,2 mM CaC12 containing 0.5 M neostigmine) was
begun shortly before insertion of the probe into the brain and continued for
the
duration of the experiment at a constant flow rate of 1 l/min. After 180 min
of
stabilisation, the experiments were initiated. Dialysates were collected every
20 min.
After the experiments the animals were sacrificed, their brains removed,
frozen and
sliced for probe placement verification.
Analysis of dialysate acetylcholine
Concentration of acetylcholine (ACh) in the dialysates was analysed by means
of
HPLC with electrochemical detection using a mobile phase consisting of 100 mM
disodium hydrogenphosphate, 2.0 mM octane sulfonic acid, 0,5 mM tetramethyl-
ammonium chloride and 0.005% MB (ESA), pH 8Ø A pre-column enzyme reactor
(ESA) containing immobilised choline oxidase eliminated choline from the
injected
sample (10 l) prior to separation of ACh on the analytical column (ESA ACH-
250);

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flow rate 0.35 ml/min, temperature: 35 C. After the analytical column the
sample
passed through a post-column solid phase reactor (ESA) containing immobilised
acetylcholineesterase and choline oxidase. The latter reactor converted ACh to
choline
and subsequently choline to betaine and H202. The latter was detected
electrochemical by using a platinum electrode (Analytical cell: ESA, model
5040).
Data presentation
In single injection experiments the mean value of 3 consecutive ACh samples
immediately preceding compound administration served as the basal level for
each
experiment and data were converted to percentage of basal (mean basal pre-
injection
values normalized to 100%). The data are presented in Figure 25a and 25b.
The data presented in Figure 24 show unexpected drops in the acetycholine
levels (see
e.g. 8 mg/kg) which are difficult to explain and which are ascribed to
experimental
uncertainty. Overall, both data sets from example 2F and 2G show the same,
i.e. a
dose dependent increase in the extra-cellular acetylcholine levels in the
brain. This
pre-clinical finding is expected to translate into an improvement in cognition
in a
clinical setting useful e.g. in the treatment of diseases characterised by a
cognitive
impairment, such as e.g. Alzheimer's patients, partial responders, cognitive
impairment etc.
Example 3 Effect on neuropatic pain
To demonstrate an efficacy against neuropathic pain, the compound of the
present
invention was tested in the formalin model of neuropathic pain [Neuropharm.,
48,
252-263, 2005; Pain, 51, 5-17, 1992]. In this model, mice receive an injection
of
formalin (4.5 %, 20 l) into the plantar surface of the left hind paw and
afterwards are
placed into individual glass beakers (2 1 capacity) for observation. The
irritation
caused by the formalin injection elicits a characteristic biphasic behavioural
response,
as quantified by the amount of time spent licking the injured paw. The first
phase (-0-
10 minutes) represents direct chemical irritation and nociception, whereas the
second
(-20-30 minutes) is thought to represent pain of neuropathic origin. The two
phases
are separated by a quiescent period in which behaviour returns to normal.
Measuring

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the amount of time spent licking the injured paw in the two phases assesses
the
effectiveness of test compounds to reduce the painful stimuli.
Eight C57/B6 mice (ca. 25g) were tested per group. Table 4 below show the
amount of time spent licking the injured paw in the two phases, i.e. 0-5
minutes and
5 20-30 minutes post formalin injection. The amount of compound administered
is
calculated as the free base.
Table 4
Vehicle 1.0 mg/kg 2.5 mg/kg 10 mg/kg
0-5 minutes 42 37 30 37
(sec)
20-30 minutes 41 43 26 6
(sec)
The data in table 4 shows that the compound of the present invention has
little
10 effect in the first phase representing direct chemical irritation and
nociception. More
notably, the data also show a clear and dose dependent decrease in the time
spent
licking paws in the second phase indicating an effect of the compound of the
present
invention in the treatment of neuropathic pain.
15 Example 4 capsules
4- [2-(4-methylphenylsulfanyl) -phenyl]p iperi dine hydrobromide was mixed
with
microcrystalline cellulose in a first step. In a second step magnesium
stearate was
mixed in. Capsules with four strengths were prepared - the active ingredient
is stated
as the free base

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36
1 mg 5 mg 25 mg
Active 12.85 g 64.25 g 321.25 g
ingredient
Micro crystalline 2026.55 g 2034.55 g 1846.85 g
cellulose
Magnesium 20.6 g 21.2 g 21.9 g
stearate
Weight of 206 mg 212 mg 219 mg
capsule content
10.000 capsules were prepared from each batch.

Dessin représentatif