ALPHA2DELTA LIGANDS FOR THE TREATMENT OF FIBROMYALGIA AND OTHER DISORDERS

LIGANDS ALPHA2DELTA POUR LE TRAITEMENT DE LA FIBROMYALGIE ET D'AUTRES TROUBLES

English Abstract

The invention relates to a method of treating fibromyalgia and other
disorders in a mammal by administering a compound compound of
Formula I
<IMG>
R1 is straight or branched unsubstituted alkyl of from 1 to 5 carbon
atoms, unsubstituted phenyl, or unsubstituted cycloalkyl of from 3 to
6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl, or a pharmaceutically
acceptable salt thereof.

Claims

-29-
CLAIMS:
1. A pharmaceutical composition for treating
fibromyalgia in a mammal in need of such treatment
comprising:
(a) a therapeutically effective amount of a compound of the
formula I
<IMG>
or a pharmaceutically acceptable salt thereof, wherein:
R1 is a straight or branched unsubstituted alkyl of from 1
to 5 carbon atoms, unsubstituted phenyl, or unsubstituted
cycloalkyl of from 3 to 6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl, and
(b) a pharmaceutically acceptable carrier.
2. A pharmaceutical composition for treating a sleep
disorder in a mammal in need of such treatment comprising:
(a) a therapeutically effective amount of a compound of the
formula I
<IMG>
or a pharmaceutically acceptable salt thereof, wherein:

-30-
R1 is a straight or branched unsubstituted alkyl of from 1
to 6 carbon atoms, unsubstituted phenyl, or unsubstituted
cycloalkyl of from 3 to 6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl, and
(b) a pharmaceutically acceptable carrier.
3. The pharmaceutical composition of claim 2, wherein
the sleep disorder is insomnia, somnambulism, sleep
deprivation, an REM sleep disorder, sleep apnea,
hypersomnia, a parasomnia, a sleep-wake cycle disorder, jet
lag, narcolepsy, a sleep disorder associated with shift work
or irregular work schedules or deficient sleep quality due
to a decrease in slow wave sleep caused by medications or
other sources.
4. The pharmaceutical composition of claim 3, wherein
the insomnia is primary insomnia, secondary insomnia or
transient insomnia.
5. The pharmaceutical composition of claim 4, wherein
the primary insomnia is psychopysiological or idiopathic
insomnia.
6. The pharmaceutical composition of claim 4, wherein
the secondary insomnia is insomnia secondary to restless
legs syndrome, Parkinson's disease or another chronic
disorder.
7. A pharmaceutically composition for increasing slow
wave sleep in a human subject in need of such treatment
comprising:
(a) an amount of a compound of the formula I

- 31 -
<IMG>
or a pharmaceutical acceptable salt thereof, wherein:
R1 is a straight or branched unsubstituted alkyl of from 1
to 5 carbon atoms, unsubstituted phenyl, or unsubstituted
cycloalkyl of from 3 to 6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl;
that is effective in increasing slow wave sleep, and
(b) a pharmaceutically acceptable carrier.
8. A pharmaceutical composition for increasing
secretion of a human growth hormone in a human subject in
need of such treatment comprising:
(a) an amount of a compound of the formula I
<IMG>
or a pharmaceutically acceptable salt thereof, wherein:
R1 is a straight or branched unsubstituted alkyl of from 1
to 5 carbon atoms, unsubstituted phenyl, or unsubstituted
cycloalkyl of from 3 to 6 carbon atoms;

- 32 -
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl;
that is effective in increasing secretion of a human growth
hormone, and
(b) a pharmaceutically acceptable carrier.
9. A pharmaceutical composition for treating
irritable bowel syndrome in a mammal in need of such
treatment comprising:
(a) a therapeutically effective amount of a compound of the
formula I
<IMG>
or a pharmaceutically acceptable salt thereof, wherein:
R1 is a straight or branched unsubstituted alkyl of from 1
to 5 carbon atoms, unsubstituted phenyl, or unsubstituted
cycloalkyl of from 3 to 6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl, and
(b) a pharmaceutically acceptable carrier.
10. The pharmaceutical composition of claim 9, wherein
the mammal is a human.
11. A pharmaceutical composition for treating panic
disorder with or without agoraphobia, agoraphobia without
history of panic disorder, a specific phobia, social anxiety

- 33 -
disorder, social phobia, obsessive-compulsive disorder, or a
stress disorder in a mammal in need of such treatment
comprising:
(a) a therapeutically effective amount of a compound of the
formula I
<IMG>
or a pharmaceutically acceptable salt thereof, wherein:
R1 is a straight or branched unsubstituted alkyl of from 1
to 5 carbon atoms, unsubstituted phenyl, or unsubstituted
cycloalkyl of from 3 to 6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl, and
(b) a pharmaceutically acceptable carrier.
12. The pharmaceutical composition of claim 11,
wherein the stress disorder is post-traumatic stress
disorder or acute stress disorder.
13. A pharmaceutical composition for treating panic
disorder with or without agoraphobia, agoraphobia without
history of panic disorder, a specific phobia, social anxiety
disorder, social phobia, obsessive-compulsive disorder, or a
stress disorder in a mammal in need of such treatment
comprising:
(a) an amount of a compound of the formula I

- 34 -
<IMG>
or a pharmaceutically acceptable salt thereof, wherein:
R1 is a straight or branched unsubstituted alkyl of from 1
to 5 carbon atoms, unsubstituted phenyl, or unsubstituted
cycloalkyl of from 3 to 6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl, compound of the
formula I, or a pharmaceutically acceptable salt thereof;
and
(b) an amount of another compound that is an antidepressant
or an antianxiety agent, or a pharmaceutically acceptable
salt thereof;
wherein the amounts of the compounds "a" and "b" are chosen
so as to render the combination therapeutically effective.
14. The pharmaceutical composition of claim 13,
wherein the stress disorder is post-traumatic stress
disorder, or acute stress disorder.
15. The pharmaceutical composition of claim 13 for
treating social phobia or social anxiety disorder.
16. The pharmaceutical composition of claim 13, 14
or 15 further comprising a pharmaceutically acceptable
carrier.

- 35 -
17. A pharmaceutical composition for treating two or
more disorders or conditions, each of which is independently
selected from the group consisting of irritable bowel
syndrome, fibromyalgia, neuropathic pain, a sleep disorder,
panic disorder with or without agoraphobia, agoraphobia
without history of panic disorder, a specific phobia, social
anxiety disorder, social phobia, obsessive-compulsive
disorder, and a stress disorder in a mammal in need of such
treatment comprising:
(a) a therapeutically effective amount of a compound of the
formula I
<IMG>
or a pharmaceutically acceptable salt thereof, wherein:
R1 is a straight or branched unsubstituted alkyl of from 1
to 5 carbon atoms, unsubstituted phenyl, or unsubstituted
cycloalkyl of from 3 to 6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl, and
(b) a pharmaceutically acceptable carrier.
18. The pharmaceutical composition of claim 17,
wherein the sleep disorder is insomnia, somnambulism, sleep
deprivation, an REM sleep disorder, sleep apnea,
hypersomnia, a parasomnia, a sleep-wake cycle disorder, jet
lag, narcolepsy, a sleep disorder associated with shift work
or irregular work schedules, or deficient sleep quality due

- 36 -
to a decrease in slow wave sleep caused by medications or
other sources.
19. The pharmaceutical composition of claim 18,
wherein the insomnia is primary insomnia, secondary insomnia
or transient insomnia.
20. The pharmaceutical composition of claim 19,
wherein the primary insomnia is psychopysiological or
idiopathic insomnia.
21. The pharmaceutical composition of claim 19,
wherein the secondary insomnia is insomnia secondary to
restless legs syndrome, Parkinson's disease or another
chronic disorder.
22. The pharmaceutical composition of claim 17,
wherein the stress disorder is post-traumatic stress
disorder or acute stress disorder.
23. The pharmaceutical composition according to
claim 1 for the concomitant treatment of panic disorder,
irritable bowel syndrome, functional abdominal pain,
neuropathic pain, major depressive disorder or dysthymia.
24. The pharmaceutical composition according to
claim 1 for the concomitant treatment of a somatoform
disorder.
25. The pharmaceutical composition of claim 24,
wherein the somatoform disorder is somatization disorder,
conversion disorder, body dysmorphic disorder,
hypochondriasis, somatoform pain disorder or
undifferentiated somatoform disorder.
26. A pharmaceutical composition for increasing slow
wave sleep in a human subject being treated with an active

- 37 -
pharmaceutical agent that decreases slow wave sleep
comprising a therapeutically effective amount of a compound
of the formula I as defined in claim 1 or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
carrier.
27. A pharmaceutical composition for increasing slow
wave sleep in a human subject in need of such treatment
comprising:
(a) a compound of the formula I as defined in claim 1 or a
pharmaceutically acceptable salt thereof; and
(b) a compound that is a human growth hormone or human
growth hormone secretagogue, or a pharmaceutical acceptable
salt thereof;
wherein the amounts of the compounds "a" and "b" are chosen
so as to render the combination effective in increasing slow
wave sleep.
28. The pharmaceutical composition of claim 27 further
comprising a pharmaceutically acceptable carrier.
29. A pharmaceutical composition for increasing slow
wave sleep in a human subject being treated with an active
pharmaceutical agent that decreases slow wave sleep
comprising:
(a) a compound of the formula I as defined in claim 1 or a
pharmaceutically acceptable salt thereof; and
(b) a compound that is a human growth hormone or human
growth hormone secretagogue, or a pharmaceutically
acceptable salt thereof;

- 38 -
wherein the amounts of the compounds "a" and "b" are chosen
so as to render the combination effective in increasing slow
wave sleep.
30. The pharmaceutical composition of claim 29 further
comprising a pharmaceutically acceptable carrier.
31. The pharmaceutical composition according to any
one of claims 1 to 30, wherein the compound of formula I is
pregabalin.
32. A commercial package comprising the pharmaceutical
composition of any one of claims 1 to 31, and instructions
for the therapeutic use thereof.
33. A commercial package comprising:
(a) a compound of the formula I as defined in claim l, or a
pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier in a first unit dosage
form;
(b) another compound that is an antidepressant or an
antianxiety agent, or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier in a
second unit dosage form; and
(c) instructions for the use of the first and second unit
dosage forms for treating panic disorder with or without
agoraphobia, agoraphobia without history of panic disorder,
a specific phobia, social anxiety disorder, social phobia,
obsessive-compulsive disorder, or a stress disorder in a
mammal in need of such treatment.
34. The commercial package of claim 33, wherein the
stress disorder is post-traumatic stress disorder, or acute
stress disorder.

- 39 -
35. The commercial package of claim 33, wherein the
instructions describe use of the first and second unit
dosage forms for treating social phobia or social anxiety
disorder.
36. A commercial package comprising:
(a) a compound of the formula I as defined in claim 1, or a
pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier in a first unit dosage
form;
(b) a compound that is a human growth hormone or human
growth hormone secretagogue, or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
carrier on a second unit dosage form; and
(c) instructions for the use of the first and second unit
dosage forms for increasing slow wave sleep in a human
subject in need of such treatment.
37. Use of a compound of the formula I as defined in
claim l, or a pharmaceutically acceptable salt thereof, for
the treatment of fibromyalgia in a mammal in need of such
treatment.
38. Use of a compound of formula I as defined in
claim 1, or a pharmaceutically acceptable salt thereof, for
the manufacture of a medicament for the treatment of
fibromyalgia in a mammal in need of such treatment.
39. Use of a compound of the formula I as defined in
claim 1, or a pharmaceutically acceptable salt thereof, for
the treatment of a sleep disorder in a mammal in need of
such treatment.

- 40 -
40. Use of a compound of formula I as defined in
claim 1, or a pharmaceutically acceptable salt thereof, for
the manufacture of a medicament for the treatment of a sleep
disorder in a mammal in need of such treatment.
41. The use of claim 39 or 40, wherein the sleep
disorder is insomnia, somnambulism, sleep deprivation, an
REM sleep disorder, sleep apnea, hypersomnia, a parasomnia,
a sleep-wake cycle disorder, jet lag, narcolepsy, a sleep
disorder associated with shift work or irregular work
schedules or deficient sleep quality due to a decrease in
slow wave sleep caused by medications or other sources.
42. The use of claim 41, wherein the insomnia is
primary insomnia, secondary insomnia or transient insomnia.
43. The use of claim 42, wherein the primary insomnia
is psychopysiological or idiopathic insomnia.
44. The use of claim 42, wherein the secondary
insomnia is insomnia secondary to restless legs syndrome,
Parkinson's disease or another chronic disorder.
45. Use of a compound of the formula I as defined in
claim 1, or a pharmaceutically acceptable salt thereof, for
increasing slow wave sleep in a human object in need of such
treatment.
46. Use of a compound of formula I as defined in
claim 1, or a pharmaceutically acceptable salt thereof, for
the manufacture of a medicament for increasing slow wave
sleep in a human subject in need of such treatment.
47. Use of a compound of the formula I as defined in
claim 1, or a pharmaceutically acceptable salt thereof, for
increasing secretion of growth hormone in a human subject in
need of such treatment.

-41-
48. Use of a compound of formula I as defined in
claim 1, or a pharmaceutically acceptable salt thereof, for
the manufacture of a medicament for increasing secretion of
growth hormone in a human subject in need of such treatment.
49. Use of a compound of formula I as defined in
claim 1, or a pharmaceutically acceptable salt thereof, for
the treatment of irritable bowel syndrome in a mammal in
need of such treatment.
50. Use of a compound of formula I as defined in
claim 1, or a pharmaceutically acceptable salt thereof, for
the manufacture of a medicament for the treatment of
irritable bowel syndrome in a mammal in need of such
treatment.
51. Use of a compound of the formula I as defined in
claim 1, or a pharmaceutically acceptable salt thereof, for
the treatment of panic disorder with or without agoraphobia,
agoraphobia without history of panic disorder, a specific
phobia, social anxiety disorder, social phobia, obsessive-
compulsive disorder, or a stress disorder in a mammal in
need for such treatment.
52. Use of a compound of formula I as defined in
claim 1, or a pharmaceutically acceptable salt thereof, for
the manufacture of a medicament for the treatment of panic
disorder with or without agoraphobia, agoraphobia without
history of panic disorder, a specific phobia, social anxiety
disorder, social phobia, obsessive-compulsive disorder, or a
stress disorder in a mammal in need of such treatment.
53. The use of claim 51 or 52 further comprising use
of another compound that is an antidepressant or an
antianxiety agent, or a pharmaceutically acceptable salt
thereof.

-42-
54. The use of claim 51, 52, or 53, wherein the stress
disorder is post-traumatic stress disorder or acute stress
disorder.
55. The use of claim 53 for treating social phobia or
social anxiety disorder.
56. Use of a compound of the formula I as defined in
claim 1, or a pharmaceutically acceptable salt thereof, for
the treatment of two or more disorders or conditions, each
of which is independently selected from the group consisting
of irritable bowel syndrome, fibromyalgia, neuropathic pain,
a sleep disorder, panic disorder with or without
agoraphobia, agoraphobia without history of panic disorder,
a specific phobia, social anxiety disorder, social phobia,
obsessive-compulsive disorder, and a stress disorder in a
mammal in need of such treatment.
57. Use of a compound of formula I as defined in
claim 1, or a pharmaceutically acceptable salt thereof, for
the manufacture of a medicament for the treatment of two or
more disorders or conditions, each of which is independently
selected from the group consisting of irritable bowel
syndrome, fibromyalgia, neuropathic pain, a sleep disorder,
panic disorder with or without agoraphobia, agoraphobia
without history of panic disorder, a specific phobia, social
anxiety disorder, social phobia, obsessive-compulsive
disorder, and a stress disorder in a mammal in need of such
treatment.
58. The use of claim 56 or 57, wherein the sleep
disorder is insomnia, somnambulism, sleep deprivation, an
REM sleep disorder, sleep apnea, hypersomnia, a parasomnia,
a sleep-wake cycle disorder, jet lag, narcolepsy, a sleep
disorder associated with shift work or irregular work

-43-
schedules or deficient sleep quality due to a decrease in
slow wave sleep caused by medications or other sources.
59. The use of claim 58, wherein the insomnia is
primary insomnia, secondary insomnia or transient insomnia.
60. The use of claim 59, wherein the primary insomnia
is psychopysiological or idiopathic insomnia.
61. The use of claim 59, wherein the secondary
insomnia is insomnia secondary to restless legs syndrome,
Parkinson's disease or another chronic disorder.
62. The use of claim 56 or 57, wherein the stress
disorder is post-traumatic stress disorder or acute stress
disorder.
63. The use of claim 37 or 38 for the concomitant
treatment of panic disorder, irritable bowel syndrome,
functional abdominal pain, neuropathic pain, major
depressive disorder or dysthymia.
64. The use of claim 37 or 38 for the concomitant
treatment of a somatoform disorder.
65. The use of claim 64, wherein the somatoform
disorder is somatization disorder, conversion disorder, body
dysmorphic disorder, hypochondriasis, somatoform pain
disorder or undifferentiated somatoform disorder.
66. Use of a compound of the formula I as defined in
claim 1, or a pharmaceutically acceptable salt thereof, for
increasing slow wave sleep in a human subject being treated
with an active pharmaceutical agent that decreases slow wave
sleep.
67. Use of a compound of formula I as defined in
claim 1, or a pharmaceutically acceptable salt thereof, for

-44-
the manufacture of a medicament for increasing slow wave
sleep in a human subject being treated with an active
pharmaceutical agent that decreases slow wave sleep.
68. The use of claim 45, 46, 66 or 67 further
comprising use of a human growth hormone or human growth
hormone secretagogue, or a pharmaceutically acceptable salt
thereof.
69. The use of any one of claims 37 to 68, wherein the
compound of formula I is pregabalin.

Description

CA 02451268 2003-11-27
PC25677A
_t_
ALPHA2DELTA LIGANDS FOR THE TREATMENT OF FiBROMYALGIA
AND OTHER DISORDERS
This invention relates to methods of treating various central
nervous system and other disorders by administering certain compounds
that exhibit activity as calcium channel alpha2delta iigands ("oc28 ligands"
or "alpha2delta iigands"). Such compounds have affinity for the oc2S
subunit of a calcium channel. Such compounds have also been referred
to in the literature as gamma-aminobutyric acid (GABA) analogs.
Background Of The Invention
Several alpha2deita ligands are known. Gabapentin, a cyclic
alpha2delta ligand, is now commercially available (Neurontin~, Warner-
Lambert Company) and extensively used clinically for treatment of
epilepsy and neuropathic pain. Such cyclic alpha2delta ligands are
described in US Patent No. 4,024,175, which issued on May 17,
1977, and US Patent No. 4,087,544, which issued on May 2, 1978. Other
series of alpha2delta ligands are described in US Patent No. 5,563,175,
which issued on October 8, 1996, US Patent No. 6,316,638, which issued
on November 13, 2001, US Provisional Patent Application 60/353,632,
which was filed on January 31, 2002, US Provisional Patent Application
60/248,630, which was filed on November 2, 2002, US Provisional Patent
Application 60/421,868, which was filed on October 28, 2002, US
Provisional Patent Application 60/421,867, which was filed on October 28,
2002, US Provisional Patent Application 601413,856, which was filed on
September 25, 2002, US Provisional Patent Application 60/411,493, which
was filed on September 16, 2002, US Provisional Patent Application
60/421,866, which was filed on October 28, 2002, US Provisional Patent
Application 60/441,825, which was filed on January 22, 2003, US
Provisional Patent Application 601452,871, which was filed on March 7,
2003, European Patent Application EP 1112253, which was published on
July 4, 2001, PCT Patent Application WO 99/08671, which Was published
on February 25, 1999, and PCT Patent Application WO 99/61424, which

CA 02451268 2004-06-30
50190-34
- 2 -
was published on December 2, 1999.
Additional uses for alpha2delta ligands, including
compounds of the formula I, which are defined below, are
referred to in US Provisional Patent Application 60/433,491,
which was filed on December 13, 2002.
Summary Of The Invention
This invention relates to a method of treating
fibromyalgia in a mammal, preferably a human, comprising
administering to a mammal in need of such treatment a
therapeutically effective amount of an alpha2delta ligand of
the formula I
R3 R2
H2N CH C CH2 C02H I
R~
or a pharmaceutically acceptable salt thereof, wherein:
R1 is a straight or branched unsubstituted alkyl of
from 1 to 5 carbon atoms, unsubstituted phenyl or
unsubstituted cycloalkyl of from 3 to 6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl.
Fibromyalgia (FM) is a chronic syndrome
characterized mainly by widespread pain, unrefreshing sleep,
disturbed mood, and fatigue. Other syndromes commonly
comorbid with fibromyalgia include irritable bowel syndrome,
migraine headaches, depression and insomnia, among others.
Success of treating fibromyalgia with a single
pharmacological agent has been characterized as modest and

CA 02451268 2004-06-30
50190-34
- 2a -
results of clinical trials have been characterized as
disappointing. It is believed that based on current
understanding of the mechanisms and pathways involved in
fibromyalgia,

CA 02451268 2003-11-27
a
-3-
multiple agents wilt be required, aimed at the major symptoms of pain,
disturbed sleep, mood disturbances, and fatigue. Fibromyalgia patients
are often sensitive to side effects of medications, a characteristic perhaps
related to the pathophysiology of this disorder (Barkhuizen A, Rational
and Targeted pharmacologic treatment of fibromyalgia. Rheum Dis Ciin
N Am 2002; 28: 261-290; Leventhal LJ. Management of fibromyalgia.
Ann Intern Med 1999;131:850-8).
While fibromyalgia is a complex disorder with multiple facets, this
complexity can be well assessed (Yunus MB, A comprehensive medical
evaluation of patients with fibromyalgia syndrome, Rheum Dis N Am 2002;
28:201-217). The diagnosis of FM is usually based on the 1990
recommendations of the American College of Rheumatology classification
criteria (Bennett RM, The rational management of fibromyalgia patients.
Rheum Dis Clin N Am 2002; 28: 181-199; Wolfe F, Smythe HA, Yunus
MB, Bennett RM, Bombardier C, Goldenberg DL, et al. The American
College of Rheumatology 1990 criteria for the classification of
fibromyalgia: Report of the Multicenter Criteria Committee. Arthritis Rheum
1990; 33:160-72). Evaluation, management, and pharmacological
treatment of fibromyalgia have been reviewed (Barkhuizen A, Rational and
Targeted pharmacologic treatment of fibromyalgia. Rheum Dis Clin N Am
2002; Buskila D, Fibomyalgia, chronic fatigue syndrome and myofacial
pain syndrome. Current opinions in Rheumatology 2001; 13: 117-127;
Leventhal LJ. Management of fibromyalgia. Ann Intern Med 1999;131:850-
8; Bennett RM, The rational management of fibromyalgia patients.
Rheum Dis Clin N Am 2002; 28: 181-199; Yunus MB, A comprehensive
medical evaluation of patients with fibromyalgia syndrome, Rheum Dis N
Am 2002; 28:201-217 ).
A more specific method of this invention relates to the above method
of treating fibromyalgia wherein a compound of the formula I, or a
pharmaceutically acceptable salt thereof, is administered to a human for
the treatment of fibromyalgia that is accompanied by one or more somatic
symptoms selected from fatigue, headache, neck pain, back pain, limb
pain, joint pain, abdominal pain, abdominal distention, gurgling, diarrhea

CA 02451268 2003-11-27
x
-4-
nervousness, and the symptoms associated with generalized anxiety
disorder (e.g., excessive anxiety and worry (apprehensive expectation),
occurring more days than not for at least six months, about a number of
events and activities, difficulty controlling the worry, etc.) See Diagnostic
and Statistical manual of Mental Disorders, Fourth Edition (DSM-IV),
American Psychiatric Association, Washington, D.C., May 1194, pp. 435-
436 and 445-469.
This invention also relates to a method of treating a disorder or
condition selected from the group consisting of sleep disorders such as
insomnia (e.g., primary insomnia including psychophysiological and
idiopathic insomnia, secondary insomnia including insomnia secondary to
restless legs syndrome, Parkinson's disease or another chronic disorder,
and transient insomnia), somnambulism, sleep deprivation, REM sleep
disorders, sleep apnea, hypersomnia, parasomnias, sleep-wake cycle
disorders, jet lag, narcolepsy, sleep disorders associated with shift work or
irregular work schedules, deficient sleep quality due to a decrease in slow
wave sleep caused by medications or other sources, and other sleep
disorders in a mammal, comprising administering to a mammal in need of
such treatment a therapeutically effective amount of a compound of the
formula I, or a pharmaceutically acceptable salt thereof.
This invention also relates to a method of increasing slow wave
sleep in a human subject comprising administering to a human subject in
need of such treatment a therapeutically effective amount of a compound of
the formula I or a pharmaceutically acceptable salt thereof.
This invention also relates to a method of increasing growth hormone
secretion in a human subject comprising administering to a human subject
in need of such treatment a therapeutically effective amount of a compound
of the formula I or a pharmaceutically acceptable salt thereof.
This invention also relates to a method of increasing slow wave sleep
in a human subject comprising administering to a human subject in need of
such treatment:
(a) a compound of the formula I or a pharmaceutically acceptable
salt thereof; and

CA 02451268 2003-11-27
-5-
(b) a human growth hormone or a human growth hormone
secretagogue or a pharmaceutically acceptable salt thereof;
wherein the amounts of the active agents "a" and "b" are chosen so as to
render the combination effective in increasing slow wave sleep.
A more specific embodiment of this invention relates to the above
method wherein the human growth hormone secretagogue that is employed
is 2-amino-N-[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-
pyrazole[4,3-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-
proprionamide.
l0 This invention also relates to a method of increasing slow wave sleep
in a human subject being treated with an active pharmaceutical agent that
decreases slow wave sleep, such as morphine or another opioid analgesic
agent or a benzodiazepine, comprising administering to a human subject in
need of such treatment:
(a) a compound of the formula I or a pharmaceutically acceptable
salt thereof; and
(b) a human growth hormone or a human growth hormone
secretagogue or a pharmaceutically acceptable salt thereof;
wherein the amounts of the active agents "a" and "b" are chosen so as to
render the combination effective in increasing slow wave sleep.
A more specific embodiment of this invention relates to the above
method wherein the human growth hormone secretagogue that is employed
is 2-amino-N-[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-
pyrazole[4,3-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-
proprionamide.
This invention also relates to a method of increasing slow wave sleep
in a human subject being treated with an active pharmaceutical agent that
decreases slow wave sleep, such as morphine or another opioid analgesic
agent, comprising administering to such human subject an amount of a
compound of the formula (, as defined above, or a pharmaceutically
acceptable salt thereof, that is effective in increasing slow wave sleep.
This invention also relates to a method of treating irritable bowel
syndrome in a mammal, preferably a human, comprising administering to a

CA 02451268 2003-11-27
-6-
human subject in need of such treatment a therapeutically effective amount
of a compound of the formula t, or a pharmaceutically acceptable salt
thereof.
This invention also relates to a method of treating a disorder or
condition selected from the group consisting of panic disorder with or
without agoraphobia, agoraphobia without history of panic disorder,
specific phobias (e.g., specific animal phobias), social anxiety disorder,
social phobia, obsessive-compulsive disorder (OCD), and stress disorders
including post-traumatic stress disorder and acute stress disorder in a
mammal, comprising administering to a mammal in need of such
treatment a therapeutically effective amount of a compound of the formula
I, or a pharmaceutically acceptable salt thereof.
A more specific embodiment of this invention relates to the above
method wherein the disorder or condition being treated is post-traumatic
stress disorder.
Another more specific embodiment of this invention relates to the
above method wherein the disorder or condition being treated is social
phobia or social anxiety disorder.
Another more specific embodiment of this invention relates to the
above method wherein the disorder or condition being treated is OCD.
!t will be appreciated that for the treatment of panic disorder,
phobias, OCD and stress disorders, the compounds of formula I may be
used in conjunction with other antidepressant or anti-anxiety agents.
Suitable classes of anti-depressant agent include norepinephrine reuptake
inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine
oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase
(RIMAs}, serotonin and noradrenaline reuptake inhibitors (SNRis),
corticotropin releasing factor (CRF) antagonists, a-adrenoreceptor
antagonists and atypical antidepressants. Suitable norepinephrine
reuptake inhibitors include tertiary amine tricyclics and secondary amine
tricyclics. Suitable examples of tertiary amine tricyclics include
amitriptyline, clomipramine, doxepin, imipramine and trimipramine, and

CA 02451268 2003-11-27
pharmaceuticaNy acceptable salts thereof. Suitable examples of
secondary amine tricyclics include amoxapine, desipramine, maprotiline,
nortriptyline and protriptyline, and pharmaceutically acceptable salts
thereof. Suitable selective serotonin reuptake inhibitors include fiuoxetine,
fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptable
salts thereof. Suitable monoamine oxidase inhibitors include
isocarboxazid, phenelzine, tranylcypromine and selegiline, and
pharmaceutically acceptable salts thereof. Suitable reversible inhibitors of
monoamine oxidase include moclobemide, and pharmaceutically
acceptable salts thereof. Suitable serotonin and noradrenaline reuptake
inhibitors of use in the present invention include venlafaxine, and
pharmaceutically acceptable salts thereof. Suitable CRF antagonists
include those compounds described in International Patent Application
Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO
94/13677. Suitable atypical anti-depressants include bupropion, lithium,
nefazodone, trazodone and viloxazine, and pharmaceutically acceptable
salts thereof. Suitable classes of anti-anxiety agents include
benzodiazepines and 5-HT~A agonists or antagonists, especially 5-HTIA
partial agonists, and corticotropin releasing factor (CRF) antagonists.
Suitable benzodiazepines include alprazolam, chlordiazepoxide,
clonazepam, chlorazepate, diazepam, haiazepam, lorazepam, oxazepam,
and prazepam, and pharmaceutically acceptable salts thereof. Suitable 5-
HT,A receptor agonists or antagonists include, in particular, the 5-HT,A
receptor partial agonists buspirone, flesinoxan, gepirone and ipsapirone,
and pharmaceutically acceptable salts thereof.
This invention also relates to a method of treating a disorder or
condition selected from the group consisting of panic disorder with or
without agoraphobia, agoraphobia without history of panic disorder,
specific phobias (e.g., specific animal phobias), social anxiety disorder,
social phobia, obsessive-compulsive disorder, and stress disorders
including post-traumatic stress disorder and acute stress disorder in a
mammal, preferably a human, comprising administering to a mammal in
need of such treatment:

CA 02451268 2003-11-27
_$_
(a) a compound of the formula I, or a pharmaceutically acceptable
salt thereof; and
(b) another compound that is an antidepressant or an antianxiety
agent, or a pharmaceutically acceptable salt thereof;
wherein the amounts of the active agents "a" and "b" are chosen so
as to render the combination therapeutically effective.
A more specific embodiment of this invention relates to any of the
above methods wherein a therapeutic amount of a compound of the
formula I, or a pharmaceutically acceptable salt thereof, is administered to
l0 a human for the treatment of any two or more comorbid disorders or
conditions selected from those disorders and conditions the treatment of
which is referred to in any of the above methods. This method is hereinafter
also referred to as "the method for treating concomitant disorders"
Another more specific embodiment of this invention relates to the
above method of treating concomitant disorders wherein a compound of the
formula I, or a pharmaceutically acceptable salt thereof, is administered to
a human for the treatment of fibromyalgia and concomitant panic disorder.
Another more specific embodiment of this invention relates to the
above method of treating concomitant disorders wherein a compound of the
formula I, or a pharmaceutically acceptable salt thereof, is administered to
a human for the treatment of fibromyalgia and concomitant irritable bowel
syndrome.
Another more specific embodiment of this invention relates to the
above method of treating concomitant disorders wherein a compound of the
formula 1, or a pharmaceutically acceptable salt thereof, is administered to
a human for the treatment of fibromyalgia and concomitant functional
abdominal pain.
Another more specific embodiment of this invention relates to the
above method of treating concomitant disorders wherein a compound of the
formula l, or a pharmaceutically acceptable salt thereof, is administered to
a human for the treatment of fibromyalgia and concomitant neuropathic pain.
Neuropathic pain is defined as pain initiated or caused by a primary
lesion or dysfunction in the nervous system (international Association for

CA 02451268 2003-11-27
-9-
the Study of Pain). Nerve damage can be caused by trauma and disease
and thus the term 'neuropathic pain' encompasses many disorders with
diverse aetiologies. These include but are not limited to, diabetic
neuropathy, post herpetic neuralgia, back pain, cervical radiculopathy,
cancer neuropathy, chemotherapy-induced neuropathy, HIV neuropathy,
Phantom limb pain, Carpal Tunnel Syndrome, chronic alcoholism,
hypothyroidism, trigeminal neuralgia, uremia, trauma-induced neuropathy,
or vitamin deficiencies. Neuropathic pain is pathological as it has no
protective role. It is often present well after the original cause has
to dissipated, commonly lasting for years, significantly decreasing a patients
quality of life (Woolf and Mannion 1999 Lancet 353: 1959-1964). The
symptoms of neuropathic pain are difficult to treat, as they are often
heterogeneous even between patients with the same disease (Woolf &
Decosterd 1999 Pain Supp. 6: S141-S147; Woolf and Mannion 1999
Lancet 353: 1959-1964). They include spontaneous pain, which can be
continuous, or paroxysmal and abnormal evoked pain, such as
hyperalgesia (increased sensitivity to a noxious stimulus) and aliodynia
(sensitivity to a normally innocuous stimulus).
Another more specific embodiment of this invention relates to the
above method of treating concomitant disorders wherein a compound of the
formula t, or a pharmaceutically acceptable salt thereof, is.administered to
a human for the treatment of fibromyalgia and concomitant premenstrual
dysphoric disorder or premenstrual syndrome.
Another more specific embodiment of this invention relates to the
above method of treating concomitant disorders wherein a compound of the
formula I, or a pharmaceutically acceptable salt thereof, is administered to
a human for the treatment of fibromyalgia and concomitant major
depressive disorder.
Another more specific embodiment of this invention relates to the
above method of treating concomitant disorders wherein a compound of the
formula I, or a pharmaceutically acceptable salt thereof, is administered to a
human for the treatment of fibromyalgia and concomitant dysthymia.

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-10-
Another more specific embodiment of this invention relates to the
above method of treating concomitant disorders wherein a compound of the
formula I, or a pharmaceutically acceptable salt thereof, is administered to a
human for the treatment of fibromyalgia and a concomitant somatoform
disorder selected from somatization disorder, conversion disorder, body
dysmorphic disorder, hypochondriasis, somatoform pain disorder,
undifferentiated somatoform disorder and somatoform disorder not
otherwise specified. See Diagnostic and Statistical manual of Mental
Disortders, Fourth Edition (DSM-IV), American Psychiatric Association,
Washington, D.C., May 1194, pp. 435-436.
Another more specific embodiment of this invention relates to the
above method of treating fibromyalgia wherein a compound of the formula I,
or a pharmaceutically acceptable salt thereof, is administered to a human
for the treatment of fibromyalgia that is accompanied by one or more
somatic symptoms selected from loss of appetite, sleep disturbances (e.g.,
insomnia, interrupted sleep, early morning awakening, tired awakening), loss
of libido, restlessness, fatigue, constipation, dyspepsia, heart palpitations,
aches and pains (e.g., headache, neck pain, back pain, limb pain, joint pain,
abdominal pain), dizziness, nausea, heartburn, nervousness, tremors,
burning and tingling sensations, morning stiffness, abdominal symptoms
(e.g., abdominal pain, abdominal distention, gurgling, diarrhea), and the
symptoms associated with major depressive disorder (e.g., sadness,
fearfulness, loss of interest, ferafulness, helplessness, hopelessness,
fatigue, low self esteem, obsessive ruminations, suicidal thoughts, impaired
memory and concentration, loss of motivation, paralysis of will, reduced
appetite, increased appetite).
The foregoing methods are also referred to herein, collectively, as
the "inventive methods" or the "methods of this invention".
Preferred embodiments of the invention methods utilize a
compound of Formula J that is 3-aminomethyl-5-methyl-hexanoic acid or,
especially, (S)-3-(aminomethyl)-5-methylhexanoic acid, which is known
generically as pregabalin.

CA 02451268 2003-11-27
-11-
The term "alkyl", as used herein, unless otherwise indicated,
includes saturated monovalent hydrocarbon radicals having straight,
branched or cyclic moieties or combinations thereof. Examples of "alkyl"
groups include, but are not limited to, methyl, ethyl, propyl, isopropyl,
butyl, iso- sec- and tent-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl,
and the like.
The term "cycloalkyl", as used herein, refers to saturated
monovalent carbocyclic groups containing from 3 to 8 carbons and are
selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
and cyclooctyl, unless otherwise stated.
The term "treating", as used herein, refers to reversing, alleviating,
inhibiting the progress of, or preventing the disorder or condition to which
such term applies, or preventing one or more symptoms of such condition
or disorder. The term "treatment", as used herein, refers to the act of
treating, as "treating" is defined immediately above.
Compounds of the formula I may contain chiral centers and
therefore may exist in different enantiomeric and diastereomeric forms.
Individual isomers can be obtained by known methods, such as optical
resolution, optically selective reaction, or chromatographic separation in
the preparation of the final product or its intermediate. This invention
relates to all optical isomers and all stereoisomers of compounds of the
formula I, both as racemic mixtures and as individual enantiomers and
diastereoismers of such compounds, and mixtures thereof, and to all
pharmaceutical compositions and methods of treatment defined above
that contain or employ them, respectively. Individual enantiomers of the
compounds of formula I may have advantages, as compared with the
racemic mixtures of these compounds, in the treatment of various
disorders or conditions.
In so far as the compounds of formula I of this invention are basic
compounds, they are capable of forming a wide variety of different salts
with various inorganic and organic acids. Although such salts must be
pharmaceutically acceptable for administration to animals, it is often

CA 02451268 2003-11-27
-12-
desirable in practice to initially isolate the base compound from the
reaction mixture as a pharmaceutically unacceptable salt and then simply
convert to the free base compound by treatment with an alkaline reagent
and thereafter convert the free base to a pharmaceutically acceptable acid
addition salt. The free base form of the compound may be regenerated by
contacting the acid addition salt so formed with a base, and isolating the
free base form of the compound in the conventional manner. The free
base forms of compounds of the formula I prepared according to a
process of the present invention differ from their respective acid addition
salt forms somewhat in certain physical properties such as solubility,
crystal structure, hygroscopicity, and the like, but othenrvise such free base
forms of the compounds and their respective acid addition salt forms are
equivalent for purposes of the present invention.
Pharmaceutically acceptable acid addition salts of the basic
compounds useful in the method of the present invention include nontoxic
salts derived from inorganic acids such as hydrochloric, nitric, phosphoric,
sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like,
as well nontoxic salts derived from organic acids, such as aliphatic mono
and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy
alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic
sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate,
sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,
dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,
iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate,
oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate,
mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,
phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate,
lactate, malate, tartrate, methanesulfonate, and the like. Also
contemplated are salts of amino acids such as arginate and the like and
gluconate, galacturonate (see, for example, Berge S.M. et al.,
"Pharmaceutical Salts," J. of Pharma. Sci., 1977;66:1 ).
In so far as the compounds of formula I of this invention are acidic
compounds, they are capable of forming a wide variety of different salts

CA 02451268 2003-11-27
-13-
with various inorganic and organic bases. A base addition salt of an acidic
compound useful in the method of the present invention may be prepared
by contacting the free acid form of the compound with a sufficient amount
of a desired base to produce the salt in the conventional manner. A
pharmaceutically acceptable base addition salt of an acidic compound
useful in the above inventive methods be prepared by contacting the free
acid form of the compound with a nontoxic metal cation such as an alkali
or alkaline earth metal cation, or an amine, especially an organic amine.
Examples of suitable metal cations include sodium cation (Na+),
potassium cation (K+), magnesium cation (Mg2+), calcium cation (Ca2+),
and the like. Examples of suitable amines are
N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,
dicyclohexylamine, ethyfenediamine, N-methylglucamine, and procaine
(see, for example, Berge, supra., i 977). The free acid forms of the
compounds of formula I may be regenerated by contacting the base
addition salt forms so formed with an acid, and isolating the free acid of
the compound in the conventional manner. The free acid forms of the
compounds useful in the above inventive methods differ from their
respective salt forms somewhat in certain physical properties such as
solubility, crystal structure, hygroscopicity, and the like, but otherwise
they
are equivalent to their respective free acids for purposes of the present
invention.
Certain of the compounds useful in the methods of this invention
can exist in unsolvated forms as well as solvated forms, including
hydrated forms. In general, the solvated forms, including hydrated forms,
are equivalent to unsolvated forms and are intended to be encompassed
within the scope of the present invention.
Certain of the compounds useful in the methods of this invention
can exist as two or more tautomeric forms. Tautomeric forms of the
compounds may interchange, for example, via enolization/de-enolization
and the like. A method of the present invention may utilize any tautomeric

CA 02451268 2003-11-27
-14-
form of an alpha2delta ligand, or a pharmaceutically acceptable salt
thereof, as well as mixtures thereof.
The present invention also includes the above inventive methods
that employ isotopically IabePled compounds that are identical to those
recited in Formula I, but for the fact that one or more atoms are replaced
by an atom having an atomic mass or mass number different from the
atomic mass or mass number usually found in nature. Examples of
isotopes that can be incorporated into compounds of the present invention
include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,
sulfur, fluorine and chlorine, such as 2H, 3H, '3C, ~1C, 14C~ 15N~ X80, "O,
31 P~ 32P~ 355 lsF, and 36C1, respectively. Compounds of the present
invention, prodrugs thereof, and pharmaceutically acceptable salts of said
compounds or of said prodrugs which contain the aforementioned
isotopes and/or other isotopes of other atoms are within the scope of this
invention. Certain isotopically labelled compounds of the present
invention, for example those into which radioactive isotopes such as 3H
and 14C are incorporated, are useful in drug and/or substrate tissue
distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., '4C, isotopes
are particularly preferred for their ease of preparation and detectability.
Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can
afford certain therapeutic advantages resulting from greater metabolic
stability, for example increased in vivo half-life or reduced dosage
requirements and, hence, may be preferred in some circumstances.
The effectiveness of an orally administered drug is dependent upon
the drug's efficient transport across the mucosal epithelium and its stability
in entero-hepatic circulation. Drugs that are effective after parenteral
administration but less effective orally, or whose plasma half-life is
considered too short, may be chemically modified into a prodrug form.
A prodrug is a drug that has been chemically modified and may be
biologically inactive at its site of action, but which may be degraded or
modified by one or more enzymatic or other in vivo processes to the
parent bioactive form.

CA 02451268 2003-11-27
-15-
This chemically modified drug, or prodrug, should have a different
pharmacokinetic profile than the parent drug, enabling easier absorption
across the mucosal epithelium, better salt formulation and/or solubility,
improved systemic stability (for an increase in plasma half-life, for
example). These chemical modifications may be, for example:
1 ) ester or amide derivatives which may be cleaved by, for example,
esterases or lipases. For ester derivatives, the ester is derived from
the carboxylic acid moiety of the drug molecule by known means.
For amide derivatives, the amide may be derived from the
carboxylic acid moiety or the amine moiety of the drug molecule by
known means;
2) peptides which may be recognized by specific or nonspecific
proteinases (A peptide may be coupled to the drug molecule via
amide bond formation with the amine or carboxylic acid moiety of
the drug molecule by known means);
3) derivatives that accumulate at a site of action through membrane
selection of a prodrug form or modified prodrug form; or
4) any combination of 1 to 3.
Current research in animal experiments has shown that the oral
absorption of certain drugs may be increased by the preparation of "soft"
quaternary salts. The quaternary salt is termed a "soft" quaternary salt
since, unlike normal quaternary salts, e.g., R-N+(CHg)g, it can release the
active drug upon hydrolysis.
"Soft" quaternary salts have useful physical properties compared
with the basic drug or its salts. Water solubility may be increased
compared with other salts, such as the hydrochloride, but more important
there may be an increased absorption of the drug from the intestine.
Increased absorption is probably due to the fact that the "soft" quaternary
salt has surfactant properties and is capable of forming micelles and
unionized ion pairs with bile acids, etc., which are able to penetrate the

CA 02451268 2004-06-30
50190-34
- 16 -
intestinal epithelium more effectively. The prodrug, after
absorbtion, is rapidly hydrolyzed with release of the active
parent drug.
The above inventive methods that employ prodrugs
of compounds of formula I are included within the scope of
this invention. Prodrugs and soft drugs are known in the
art (Palomino E., Drugs of the Future, 1990;15(4):361-368).
Detailed Description Of The Invention
Alpha2delta ligands having the formula I,
and the synthesis of such compounds are described in
US Patent 5,563,175 and US Patent 6,197,819.
All that is required to practice the methods of
this invention is to administer a compound of the formula I,
or a pharmaceutically acceptable salt thereof, in an amount
that is therapeutically effective to treat one or more of
the disorders or conditions referred to above. Such
therapeutically effective amount will generally be from
about 1 to about 300 mg/kg body weight of the patient
being treated. Typical doses will be from about 10 to
about 5000 mg/day for an adult patient of normal weight.
In a clinical setting, regulatory agencies such as, for
example, the Food and Drug Administration ("FDA") in the
U.S. may require a particular therapeutically effective
amount.
In determining what constitutes an effective
amount or a therapeutically effective amount of a compound
of the formula I, or a pharmaceutically acceptable salt
thereof, for treating one or more of the disorders or
conditions referred to above according to the invention
method, a number of factors will generally be considered by

CA 02451268 2004-06-30
50190-34
- 16a -
the medical practitioner or veterinarian in view of the
mammal's age, sex, weight and general condition, as well as
the type and extent of the disorder or condition being
treated, and the use of other medications, if any, by the
mammal receiving the treatment. As such, the administered
dose may fall within the ranges or concentrations recited
above, or may vary outside,

CA 02451268 2003-11-27
i.e., either below or above, those ranges depending upon the
requirements of the individual subject, the severity of the condition being
treated, and the particular therapeutic formulation being employed.
Determination of a proper dose for a particular situation is within the skill
of the medical or veterinary arts. Generally, treatment may be initiated
using smaller dosages of the active compound or compounds that are less
than optimum for a particular subject. Thereafter, the dosage can be
increased by small increments until the optimum effect under the
circumstance is reached. For convenience, the total daily dosage may be
divided and administered in portions during the day, if desired.
The compounds of formula I and their pharmaceutically acceptable
salts can be administered to mammals via either the oral, parenteral (such
as subcutaneous, intravenous, intramuscular, intrasternal and infusion
techniques), rectal, buccal, topical or intranasal routes. Preferred routes of
administration are oral and parenteral. Preferably, administration is in unit
dosage form. A unit dosage form of a compound of formula I, or a
pharmaceutically acceptable salt thereof, to be used in the methods of this
invention may also comprise other compounds useful in the therapy of the
disorder or condition for which the compound of formula I or
pharmaceutically acceptable salt thereof is being administered or a
disorder or condition that is secondary to the disorder condition for which
the compound of formula I or pharmaceutically acceptable salt thereof is
being administered.
Pharmaceutical compositions containing a compound of the
formula I, or a pharmaceutically acceptable salt thereof, are produced by
formulating the active compound in unit dosage form with a
pharmaceutical carrier. Some examples of unit dosage forms are tablets,
capsules, pills, powders, cachets, lozenges, creams, aqueous and
nonaqueous oral solutions and suspensions, and parenteral solutions
packaged in containers containing either one or some larger number of
dosage units and capable of being subdivided into individual doses.

CA 02451268 2004-06-30
50190-34
- 17a -
Pharmaceutical compositions of the invention may be
contained in a commercial package, together with
instructions for the therapeutic use thereof.

CA 02451268 2003-11-27
-1 g-
Some examples of suitable pharmaceutical carriers, including
pharmaceutical diluents, are gelatin capsules; sugars such as lactose and
sucrose; starches such as corn starch and potato starch; cellulose
derivatives such as sodium carboxymethyl cellulose, ethyl cellulose,
methyl cellulose, and cellulose acetate phthalate; gelatin; talc; stearic
acid;
magnesium stearate; vegetable oils such as peanut oil, cottonseed oil,
sesame oil, olive oil, corn oil, and oil of theobroma; propylene glycol,
glycerin; sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic
saline, and phosphate buffer solutions; as well as other compatible
substances normally used in pharmaceutical formulations.
The compositions to be employed in the methods of this invention
can also contain other components such as coloring agents, flavoring
agents, andlor preservatives. These materials, if present, are usually used
in relatively small amounts. The compositions can, if desired, also contain
other therapeutic agents commonly employed to treat the disorder or
condition being treated.
The percentage of the active ingredients in the foregoing
compositions can be varied within wide limits, but for practical purposes it
is preferably present in a concentration of at least 10% in a solid
composition and at least 2% in a primary liquid composition. The most
satisfactory compositions are those in which a much higher proportion of
the active ingredient is present, for example, up to about 95%.
In tablets, the active component is mixed with the carrier having the
necessary binding properties in suitable proportions and compacted in the
shape and size desired. Powders and tablets preferably contain from five
or ten to about seventy percent of the active compound. Suitable carriers
are magnesium carbonate, magnesium stearate, talc, sugar, lactose,
pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The
term "preparation" is intended to include the formulation of the active
compound with encapsulating material as a carrier, providing a capsule in

CA 02451268 2003-11-27
-19-
which the active component, with or without other carriers, is surrounded
by a carrier, which is thus in association with it.
For preparing suppositories, a low melting wax, such as a mixture
of fatty acid glycerides or cocoa butter, is first melted and the active
component is dispersed homogeneously therein, as by stirring. The
molten homogenous mixture is then poured into convenient sized molds,
allowed to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, and
emulsions, for example, water or water propylene glycol solutions. For
parenteral injection liquid preparations can be formulated in solution in
aqueous polyethylene glycol solution. Aqueous solutions suitable for oral
use can be prepared by dissolving the active component in water and
adding suitable colorants, flavors, stabilizing and thickening agents as
desired. Aqueous suspensions suitable for oral use can be made by
dispersing the finely divided active component in water with viscous
material, such as natural or synthetic gums, resins, methylcellulose,
sodium carboxymethylcellulose, and other well-known suspending agents.
Also included are solid form preparations that are intended to be
converted, shortly before use, to liquid form preparations for oral
administration. Such liquid farms include solutions, suspensions, and
emulsions. These preparations may contain, in addition to the active
component, colorants, flavors, stabilizers, buffers, artificial and natural
sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The degree of binding of compounds of the formula I and their
pharmaceutically acceptable salts to an a28 subunit of a calcium channel
can be determined using the radioligand binding assay using
[3H]gabapentin and the a28 subunit derived from porcine brain tissue, as
described by N. S. Gee et al., J. Biol. Chem., 1996, 271:5879-5776.
The efficacy of pregabaiin in treating fibromyalgia was
demonstrated in the following in vivo experiment, which is summarized
below.

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SUMMARY:
Sprague-Dawley male rats given an intramuscular (IM) injection of
100 ,uL sterile pyrogen-free saline, pH 4 in the gastrocnemius muscle on
Days 1 and 5, develop chronic mechanical allodynia (static allodynia)
approximately 1 week after the second injection. (Sluka KA, Kalra A,
Moore SA. Intramuscular injections of acidic saline produce a bilateral
long-lasting hyperalgesia. Muscle & Nerve 2001; 24:37-46.) Allodynia was
measured by applying von Frey filaments of varying bending forces (0.41
to 29 g) to the plantar surface of the injected hind limb to determine paw
withdrawal threshold (PWT). Evaluations were performed blinded, with the
animals and treatments randomized. PWL, 1 to 2 weeks after the second
acid saline injection was usually less than 5 g (reduced from 22 to 28 g
prior to acid saline injection), representing tactile allodynia. Allodynia was
sustained for 3 weeks. Rats injected with pH 7.2 saline showed no
allodynia. After acid saline injection, there was no evidence for dynamic
allodynia (measured by paw withdrawal to cotton swab stroking) or weight-
bearing preference between the hind limbs. Treatment with pregabalin, 10
or 30 mglkg by oral gavage (PO) 2 weeks after the last acid saline
injection; reversed mechanical allodynia. Analgesic-like action of
pregabalin was significantly greater than vehicle treatment at 2 to 3 hours
after therapy. Morphine, 3 and 10 mg/kg subcutaneously (SC) reduced
aliodynia, while amitryptiline, 6 mg/kg SC did not alter allodynia.
Fibromyalgia is classified by the Americal College of Rheumatology as
chronic generalized musculoskeletal pain with allodynia to pressure over a
majority of specified tender points. The results with acid saline-injected
rats indicate that pregabalin reduces allodynia in a rat model with some
similarities to the human disease of fibromyalgia.
METHODS:
Acidic Saline-Induced Allodynia: Male Sprague-Dawley rats
(Harlan) approximately 350 g were housed in plastic isolators with organic
cellulose bedding. Food and water were available ad libidum and animals
were maintained on a 12 hr/12 hr light/dark cycle, with testing during the

CA 02451268 2003-11-27
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light phase. On test days, rats were placed in a metal chamber on an
elevated metal mesh floor and allowed to acclimate for at least 20
minutes. On Day 1, a baseline von Frey filament withdrawal threshold with
the right hind paw was obtained. Later on Day 1, acidic saline, pH 4 (100
,uL) was injected in the right gastrocnemius muscle and a similar injection
was made again in the same location on Day 5. On subsequent days, pain
responses (von Frey filament withdrawal threshold, withdrawal in
response to light stroking with a cotton swab, and changes in weight
bearing between the 2 hind paws) were determined for both hind paws.
Experimental drug treatments were evaluated for inhibitory effects on
static allodynia and other pain endpoints. Rats with a paw withdrawal
threshold (PWT) of 6 g or less on the day of drug testing (Days 14 to 18)
were used. Rats were evaluated for PWTs at 1, 2, and 3 hours after
receiving either drug or vehicle treatments.
MEASUREMENT OF PAIN-RELATED BEHAVIORAL
RESPONSES
Static Allodynia: PWT was determined using von Frey filaments
with varying bending forces (0.41, 0.69, 1.2, 2.0, 3.6, 5.5, 8.5, 15.1, and
28.8 g, Stoelting Corp, Wood Dale, IL). Pressure was applied to the
plantar surface of a hind paw with a single slow application for up to 6
seconds to the plantar surface beginning with the 2.0-g filament. If no
withdrawal was obtained, the next higher bending force filament was
applied or, in the case of a withdrawal, the next lower force filament was
applied. This continued until at least 6 responses were obtained, including
at least 1 withdrawal. Withdrawal threshold at each time point (for each
rat) then was determined using the Dixon , 'Up-Down' method. (Dixon WJ.
Efficient analysis of experimental observations. Ann Rev Pharmacol
Toxicol 1980; 20:441-62.) If no withdrawal was obtained with the 28.8 g
filament, a withdrawal threshold of 29 g was assigned.
Dynamic Allodynia: The plantar surfaces of injected and
contralateral hind paws were gently stroked with a cotton swab, applied

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from underneath the wire mesh for up to 15 seconds. Withdrawal time
(mean of triplicate values) is reported, with a maximum value of 15
seconds recorded if no withdrawal was observed.
Spontaneous Pain: The rat was placed in a compact clear acrylic
plastic box with an elevated platform for the forepaws and a square
cutaway in the base for the hind paws. The box was designed to allow
contact of the hind paws to each of 2 force transducer plates of an
incapacitance tester (Linton Instruments, Norfolk, England), that measured
the force applied by each of the hind paws to the floor of the chamber. The
weight (in grams) applied to each paw was averaged by the device over a
4-second period and recorded. Reported values are the mean of triplicate
readings of the difference in weight applied to the 2 hind paws
(contralateral minus injected hind paw).
RESULTS
Characterization of the Model: Two repeated intramuscular
injections of acidic saline caused a sustained decrease in the von Frey
withdrawal threshold to the planter surface of the previously injected hind
limb. These results were similar to those published previously. (Sluka KA,
Kalra A, Moore SA. Intramuscular injections of acidic saline produce a
bilateral long-lasting hyperalgesia. Muscle & Nerve 2001; 24:37-46.)
However, in contrast to the previously published findings, little or no
change in withdrawal threshold was observed in the hind limb contralateral
to acidic saline injection except at the latest time point tested (Table 1 ).
No
changes were observed in withdrawal in response to the cotton swab
stimulus or weight bearing endpoints in either hind paw. A representative
experiment is shown in Table 2.
Pharmacological Evaluations of Pregabalin in the Acidic Saline
Induced Allodynia Model: Rats injected with acidic saline on Days 1 and 5
were evaluated for changes in pain responses on alternate days,
beginning at .Day 14, following the last acidic saline injection. On a given

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day, only rats showing allodynia (withdrawal in response to von Frey
filaments of 6 g or less) and naive to previous drug treatments were used
to evaluate test compounds. Pregabalin or vehicle (water) was given PO,
30 minutes after baseline paw withdrawal readings. Rats were evaluated
at 1, 2, and 3 hours after drug or vehicle treatment. Pregabafin at either 10
or 30 mg/kg PO inhibited static allodynia (measured by von Frey
filaments) when tested either 2 or 3 hours after drug treatment (Table 3).
Pregabalin treatment at 3 mg/kg PO was without effect on allodynia.
Morphine, 10 rng/kg SC, given 30 minutes after baseline
measurements, inhibited static allodynia at 1 and 2 hours after treatment
(Table 4). Similar treatment with morphine, 3 mg/kg, increased PWTs, but
only at 1 hour (not 2 or 3 hours) after treatment. Amitriptyline, 6 mg/kg SC,
did not alter PWTs at 1, 2, or 3 hours posttreatment (Table 5).
Prior repeated injection of pH 4 saline in the gastrocnemius induced
mechanical allodynia (measured with von Frey filaments) of several weeks
duration to the ipsilateral plantar surface of the hind paw. The same rats
did not have dynamic allodynia of the hind paw (in response to cotton
swab stroking) or spontaneous pain behavior (a weight bearing preference
between the hind paws). Pregabalin 10 and 30 mglkg PO reduced static
allodynia produced by prior acidic saline injectians. Morphine 3 and 10
mglkg SC, reduced static allodynia from prior acidic saline injections.
Amitriptyline, 6 mg/kg PO was without inhibitory effects on allodynia.
These results agree with previous published results for morphine. (Sluka,
ICA, Rohlwing JJ, Bussey RA, Eikenberry SA, Wilken JM. J Pharmacol.
Exp. Ther. 2002, 302:1146-50). Although amitriptyline was without effect
in this study, it is often prescribed for fibromyalgia pain, and clinical
studies has shown it to be effective. 5,6 It is possible that amitriptyline
would be effective in this animal model (with allodynia from repeated
acidic saline injections) if it were tested after repeated dosing for several
days. This possibility remains to be tested. Higer dosages of amitriptyline
were not studied because tachycardia was observed at the 6 mg/kg PO
dose and a 10 mglkg PO dose was lethal in a fraction of rats that were
injected.

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Static allodynia in the rat hind paw produced by prior repeated
injections of acidic saline into the gastrocnemius muscle may provide a
method to evaluate novel agents for treating chronic musculoskeletal pain.
This animal model may be of use to evaluate experimental analgesic
compounds for the treatment of chronic allodynia in syndromes such as
fibromyalgia.
Table 1. Rat Paw Withdrawal Threshold
(PWT) of the Plantar Hind Paw
Surface
of the Left (Ipsilateral) and Right and After
(Contralateral) Side, Before 2
Injections of 100 ~,L of Acidic , pH
Saline 4.2
on the
Left
Gastrocnemius
Muscle _
Hind Limb Day 1 Day 5 Day 12 Day Day 26
16
Before Post- Post- Post- Post-
Injection Initial Initial InitialInitial
Injection InjectionInjectionInjection
Ipsilateral PWT 27.47 28.84 13_1 7,86 10.93
g a,b a' b
SEM 1.11 0.00 3.64 2.07 2.80
Contralateral PWT 28.84 25.64 28.84 28.84 17.58
b
SEM 0.00 2.48 0.00 0.00 3.61
N = 9, Data are mean values in grams.
p <0.05, injected versus contralateral hindlimb, one-way ANOVA on ranks with
Tukey test.
p <0.05 versus baseline on Day 1, before first injection, one-way ANOVA on
ranks
with Tukey test.
Table 2. Paw Withdrawal Threshold (Ipsilateral), Paw Withdrawal Latency
(Ipsilateral),
and Weight Bearing Measurements at Different Times Before (Day 1 ) and
After (Days 5 and 8) 2 Acid Saline Injections to the Gastrocnemius Muscle
Day 1 Day 5 PostinitialDay 18 Post
Before Injection Injection initial Injection
Paw Withdrawal
Threshold
to von Frey
Filaments
(g)
pH 7.4 25.59 20.15 23.50
SEM 2.28 3.65 3.94
pH 4.2 27.47 12.42a 9.89a
SEM 1.11 3.175 2.48
Paw Withdrawal
Latency to
Cotton Swab
Stroking (sec)
pH 7.4 9.39 10.83 9.11
SEM 0.65 0.34 0.93
pH 4.2 9.i7 6.33 9.78
SEM 0.40 1.34 1.96
Weight Bearing: ilateral Force
Contralateral (g)
Force Minus
Ips
pH 7.4 -3.0 -2.0 -10.0
SEM 5.0 6.0 4.0
pH 4.2 7.0 5.0 -13.0
SEM 5.0 5.0 14.0
a p <0.05 verus Day 1 by one-way ANOVA on ranks and Tukey test, n = 6/group.
Data
are means values.

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Table 3. Rat Paw
Withdrawal
Threshold
Before
and After
Treatment
With
Pregabalin ior RepeatedAcid Saline
PO Following Injections
Pr to
the Gastrocnemius
Muscles
Day 1 Baseiinei hr 2 hr Post3 hr Post
Post Rx- Rx
Rx
Vehicle 27.75 3.52 9.87 7.07 12.13
SE 1.09 0.35 4.05 2.24 5.04
Pregabalin, 5.32 7.92 4.53 6.07
3 mg/kg
PO 27.37
SEM 1:08 0.51 2.99 1.16 1.13
N=6/group
Vehicle 18.65 4.72 i 1.70 4.17 3.74
SEM 2.50 0.90 5.78 0.70 1.42
Pregabaiin, 3.55 2.28 28.84 22.23
mg/kg b b
PO 24.90
SEM 3.94 0.14 0.68 0.00 6.62
N=4/group
Vehicle 28.84 4.57 12.95 3.61 5.05
SEM 0.00 0.73 4.47 0.62 2.19
Pregabalin, 30 mg/kg PO 26.07 4.74 18.15 25.11 b 23.74 b
SEM 1.81 0.75 4.20 2.65 4.67
N = 6/group
a Paw withdrawal threshold measured by von Frey filaments, all measurements in
grams; all drug treatments given 30 minutes after baseline measurements.
b Significantly different from vehicle group (p <0.05, 1-way ANOVA on ranks
then
Tukey Test, all pairwise comparison procedures). Data are mean values.

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Table 4. Rat
Static Ailodynia
Before and
After Treatment
With Morphine
SC a
Day Baseline1 hr 2 hr Post hr
1 Post Rx 3 Post
Rx
Vehicle 28.24 4.11 4,07 9.99 9.74
SEM (n = 11 0.60 0.39 0.65 3.32 2.70
)
Morphine, 3 24.27 2.89 20.52 9.93 7.09
mg/kg SC b
SEM (n =10) 1.54 0.41 3.33 3.23 2.25
Vehicle 28.84 3.33 4.56 5.47 4.67
SEM (n = 6) 0.00 0.41 0.91 1.98 0.75
Morphine, 10 mg/kg26.63 3.09 28.840 22.05 16.91
SC b b
SEM (n = 6) 2.2i 0.60 0.00 4.32 4.58
Paw withdrawal threshold measured by von Frey filaments, all measurements in
grams; all drug treatments given 30 minutes after baseline measurements.
p <0.05 versus baseline measurement, 1-way ANOVA on ranks, and Tukey test.
Data
are mean values.
Table 5. Rat Static Allodynia Before and After Treatment With Amitriptyline,
SC a
Day Baseline1 hr Post2 hr Post3 hr Post
1 Rx Rx Rx
Vehicle 28.84 3.06 8.64 8.64 11.50
S E M 0.00 0.28 4.27 2.02 5.52
Amitriptyline, 24.44 2.36 12.01 7.38 7.20
6 mg/kg
SEM 2.21 0.40 4.55 2.74 4.03
N = 6/group. There was no significant difference between groups (1 way ANOVA
on ranks and Tukey test.
Drug is given 30 minutes after the baseline measurement.
A clinical study of the effect of pregabalin on human patients with
fibromyalgia was also conducted. This study was conducted to assess
the efficacy of pregabalin (150, 300, and 450 mg/day) compared with
placebo for the relief of pain and improvement in functional status in
patients with fibromyalgia. Patients who participated in the study must
have met the American College of Rheumatology criteria for fibromyalgia
(widespread pain present for at least 3 months, and pain in at least 11 of
18 tender point sites).
METHODOLOGY
Following a 1-week baseline phase, qualified patients were
randomized to receive either 150, 300, or 450 mglday pregabalin or

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placebo according to an 8-week, double-blind, multicenter study design.
The intent-to-treat (ITT) population comprised a total of 529 patients: 132
patients received 450 mg/day, 134 received 300 mg/day, i 32 received
150 mg/day pregabalin, and 131 received placebo. The first phase of the
8-week double-blind phase consisted of a 1-week titration phase. Patients
randomized to the placebo, 150 and 300 mg/day pregabalin treatment
groups started out at their fixed dose at Day 1. Patients randomized to 450
mg/day pregabalin treatment group started at 300 mg/day and titrated to
the target dose of 450 mg/day on Day 4, and remained at the fixed dose
for the remainder of the double-blind period. Following Week 8 of the
double-blind phase, patients had the option of entering an open-label
follow-on study (Protocol 1008-033).
CRITERIA FOR EVALUATION
The primary efficacy measurements were derived from the daily,
self-assessed pain score from the patient diary. Secondary measures
were derived from the SF-MPQ, Manual Tender Point Survey, quality of
sleep score from the daily diary, Multidimensional Assessment of Fatigue
(MAF), Clinical Global Impression of Change (CGIC) and Patient Global
Impression of Change (PGIC), the SF-36 Health Survey (SF-36), Hospital
Anxiety and Depression Scale (HADS), and Medical Outcomes Study
(MOS) Sleep Scale.
RESULTS
All analyses were performed on the lTT population, defined as all
randomized patients who received at least one dose of study medication.
The primary efficacy measure, endpoint mean pain score, was
significantly better for 450 mg/day pregabalin compared to placebo. A
significant difference from placebo was seen in mean pain scores at Week
1 for the 450 mg/day pregabalin group and continued through Week 7.
Similar results were seen for the 450 mg/day pregabalin group in most
other secondary parameters including: Mean quality of sleep at each week
and at endpoint, SF-MPQ sensory, affective, and total scores at endpoint

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and VAS at endpoint, CGIC, PGfC, and the MAF Global Fatigue Index. A
significant difference favoring 450 mg/day pregabalin compared to
placebo was seen in the Social Functioning, Bodily Pain, Vitality, and
General Health Perception domains of the SF-36 Health Survey.
Responder status (defined as the number of patients reporting at least
50% reduction in pain at endpoint compared to baseline) was significantly
better for patients in the 450 mg/day pregabalin group compared to
placebo (28.9% and 13.2%, respectively; p=0.003). Patients in the 300
and 150 mg/day pregabalin groups were not significantly different from
placebo for the primary efficacy parameter. Both 300 and 150 mg/day
pregabalin showed significant differences in many of the secondary
parameters compared to placebo.
CONCLUSIONS
Pregabalin was found to be effective at a dose of 450 mglday in
reducing pain associated with fibromyalgia. There was no significant effect
on pain at the 150- and 300-mg/day doses. Both the 300 and 450 mg/day
pregabalin treatment arms were superior to placebo on improvement in
fatigue, clinician and patient global assessments of change, and
improvement of sleep quality.

Representative Drawing