U.S. patent application number 11/407192 was filed with the patent office on 2006-08-24 for pharmaceutically active morpholinol.
This patent application is currently assigned to SmithKline Beecham Corporation. Invention is credited to Philip Frederick Morgan, David Lee Musso, John Joseph Partridge.
Application Number | 20060189612 11/407192 |
Document ID | / |
Family ID | 36959655 |
Filed Date | 2006-08-24 |
United States Patent
Application |
20060189612 |
Kind Code |
A1 |
Morgan; Philip Frederick ;
et al. |
August 24, 2006 |
Pharmaceutically active morpholinol
Abstract
Disclosed is the compound
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol and
pharmaceutically acceptable salts and solvates thereof,
pharmaceutical compositions comprising them, and processes for
their preparation and use; also disclosed is a method of treating
depression, attention deficit hyperactivity disorder (ADHD),
obesity, migraine, pain, sexual dysfunction, Parkinson's disease,
Alzheimer's disease, or addiction to cocaine or nicotine-containing
(especially tobacco) products using such compound, salts, solvates
or compositions.
Inventors: |
Morgan; Philip Frederick;
(Cary, NC) ; Musso; David Lee; (Durham, NC)
; Partridge; John Joseph; (Durham, NC) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
SmithKline Beecham
Corporation
Philadelphia
PA
19102
|
Family ID: |
36959655 |
Appl. No.: |
11/407192 |
Filed: |
April 20, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10150339 |
May 17, 2002 |
|
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|
11407192 |
Apr 20, 2006 |
|
|
|
09886391 |
Jun 22, 2001 |
6391875 |
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|
10150339 |
May 17, 2002 |
|
|
|
09233531 |
Jan 20, 1999 |
6274579 |
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09886391 |
Jun 22, 2001 |
|
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60072180 |
Jan 22, 1998 |
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Current U.S.
Class: |
514/237.5 |
Current CPC
Class: |
A61K 31/5375 20130101;
A61K 31/537 20130101 |
Class at
Publication: |
514/237.5 |
International
Class: |
A61K 31/537 20060101
A61K031/537 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 21, 1998 |
GB |
9801230 |
Claims
1. A method of treating pain in a mammal comprising the
administration to said mammal of an effective amount of
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol or
pharmaceutically acceptable salts and solvates thereof.
2. A method as claimed in claim 1 wherein the treatment is of
neuropathic pain.
3. A method as claimed in claim 1 comprising the administration of
the compound
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
hydrochloride.
4. A method as claimed in claim 2 wherein said compound has an
optical rotation [.alpha.].sup.20.sub.D at c=0.64 in 95% EtOH of
+31.9.degree..
5. A method of treating sexual dysfunction in a mammal comprising
the administration to said mammal of an effective amount of
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol or
pharmaceutically acceptable salts and solvates thereof.
6. A method as claimed in claim 5 wherein the sexual dysfunction is
psychosexual dysfunction.
7. A method as claimed in claim 6 wherein the psychosexual
dysfunction is HSDD or FSD.
8. A method as claimed in claim 5 wherein the sexual dysfunction is
a side-effect induced by treatment of the said mammal with an
SSRI-class antidepressant.
9. A method as claimed in claim 5 comprising the administration of
the compound
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
hydrochloride.
10. A method as claimed in claim 9 wherein said compound has an
optical rotation [.alpha.].sup.20.sub.D at c=0.64 in 95% EtOH of
+31.9.degree..
11. A method of treating Parkinson's disease in a mammal comprising
the administration to said mammal of an effective amount of
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol or
pharmaceutically acceptable salts and solvates thereof.
12. A method as claimed in claim 11 wherein the treatment is for
symptoms of locomotor deficit, motor disability, or both
symptoms.
13. A method as claimed claim 11 wherein comprising the
administration of the compound
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
hydrochloride.
14. A method as claimed in claim 13 wherein said compound has an
optical rotation [.alpha.].sup.20.sub.D at c=0.64 in 95% EtOH of
+31.9.degree..
15. A method of treating migraine in a mammal comprising the
administration to said mammal of an effective amount of
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol or
pharmaceutically acceptable salts and solvates thereof.
16. A method as claimed in claim 15 wherein the treatment is
prophylactic.
17. A method as claimed in claim 15 wherein comprising the
administration of the compound
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
hydrochloride.
18. A method as claimed in claim 17 wherein said compound has an
optical rotation [.alpha.].sup.20.sub.D at c=0.64 in 95% EtOH of
+31.9.degree..
19. A method of treating addiction to nicotine-containing products
comprising the administration to a mammal of an effective amount of
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol or
pharmaceutically acceptable salts and solvates thereof.
20. A method as claimed in claim 19 wherein comprising the
administration of the compound
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
hydrochloride.
21. A method as claimed in claim 20 wherein said compound has an
optical rotation [.alpha.].sup.20.sub.D at c=0.64 in 95% EtOH of
+31.9.degree..
Description
[0001] This application is a Divisional of co-pending application
Ser. No. 10/150,339, filed on May 17, 2002. application Ser. No.
10/150,339 is a continuation-in-part of U.S. Ser. No. 09/886,391,
filed Jun. 22, 2001, now U.S. Pat. No. 6,391,875, which is a
divisional application of U.S. Ser. No. 09/233,531, filed Jan. 20,
1999, now U.S. Pat. No. 6,274,579. This application also claims
priority to U.S. Provisional Application No. 60/072,180, filed Jan.
22, 1998 and GB Application No. 9801230, filed in Great Britain on
Jan. 21, 1998. The entire contents of each of these references are
hereby incorporated by reference and priority is claimed under 35
U.S.C. .sctn.119 and .sctn.120.
[0002] This invention relates to an optically pure morpholinol,
salts and solvates thereof, pharmaceutical formulations containing
them and processes for their preparation and use.
BACKGROUND OF THE INVENTION
[0003] Bupropion hydrochloride,
(.+-.)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)-amino]-1-propanone
hydrochloride, is the active ingredient of Wellbutrin.RTM. which is
marketed in the United States for the treatment of depression. It
is also the active ingredient of Zyban.RTM. which is marketed in
the United States as an aid to smoking cessation. Bupropion is a
relatively weak inhibitor of the neuronal uptake of noradrenaline
(NA), serotonin and dopamine (DA), and does not inhibit monoamine
oxidase. While the mechanism of action of bupropion, as with other
antidepressants, is unknown, it is presumed that this action is
mediated by noradrenergic and/or dopaminergic mechanisms. Available
evidence suggests that Wellbutrin.RTM. is a selective inhibitor of
noradrenaline (NA) at doses that are predictive of antidepressant
activity in animal models. See Ascher, J. A., et al., Bupropion: A
Review of its Mechanism of Antidepressant Activity. Journal of
Clinical Psychiatry, 56: p. 395-401, 1995. ##STR1##
[0004] Bupropion is extensively metabolized in man as well as
laboratory animals. Urinary and plasma metabolites include
biotransformation products formed via hydroxylation of the
tert-butyl group and/or reduction of the carbonyl group of
bupropion. Four basic metabolites have been identified. They are
the erythro- and threo-amino alcohols of bupropion, the
erythro-amino diol of bupropion, and a morpholinol metabolite.
These metabolites of bupropion are pharmacologically active, but
their potency and toxicity relative to bupropion have not been
fully characterized. Because the plasma concentrations of the
metabolites are higher than those of bupropion, they may be of
clinical importance.
[0005] The morpholinol metabolite
(+/-)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
hydrochloride is believed to be formed from hydroxylation of the
tert-butyl group of bupropion. ##STR2##
SUMMARY OF THE INVENTION
[0006] It has now surprisingly been discovered that despite the (-)
form of the morpholinol metabolite predominating significantly in
human plasma samples, it is the (+) enantiomer,
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol in
which the activity resides.
[0007] Thus the present invention provides, in one aspect, the
compound of formula (I),
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol or
pharmaceutically acceptable salts and solvates thereof.
##STR3##
[0008] Another aspect of the invention is pharmaceutical
compositions comprising a compound of formula (I) or
pharmaceutically acceptable salts and solvates thereof together
with one or more pharmaceutically acceptable carriers, diluents or
excipients.
[0009] A further aspect of the present invention is the use of a
compound of formula (I) or pharmaceutically acceptable salts and
solvates thereof in therapy.
[0010] Yet another aspect of the invention provides methods of
treating depression, attention deficit hyperactivity disorder
(ADHD), obesity, migraine, pain, sexual dysfunction, Parkinson's
disease, Alzheimer's disease, or addiction to cocaine or
nicotine-containing (especially tobacco) products in a mammal
(human or animal subject) comprising the administration to said
subject of an effective amount of a compound of formula (I) or
pharmaceutically acceptable salts and solvates thereof or
pharmaceutical compositions thereof.
[0011] Yet another aspect of the present invention is the use of
the compound of formula (I) or pharmaceutically acceptable salts
and solvates thereof or pharmaceutical compositions thereof in the
preparation of a medicament for the treatment of depression,
attention deficit hyperactivity disorder (ADHD), obesity, migraine,
pain, sexual dysfunction, Parkinson's disease, Alzheimer's disease,
addiction to cocaine or nicotine-containing (especially tobacco)
products.
DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1. Effect of Compounds at 25 mg/kg (ip) on TBZ-Induced
Depression.
[0013] FIG. 2. Dose Response of Compound of Formula I Against
TBZ-Induced Depression (Compounds administered 30 minutes prior to
TBZ, Male, CD-I Mice, i.p., n=6).
[0014] FIG. 3. Dose Response of Compound of Formula II Against
TBZ-Induced Depression (Compounds administered 30 minutes prior to
TBZ, Male, CD-I Mice, i.p., n=6).
[0015] FIG. 4. Effect of Compound of formula (I) on locomotor
deficits in MPTP-induced Parkinsonian marmosets.
[0016] FIG. 5. Effect of Compound of formula (I) on motor
disability in MPTP-induced Parkinsonian marmosets.
[0017] FIG. 6. Effect of Compound of formula (I) on CCI-induced
decrease in rat mechanical paw withdrawal threshold.
DETAILED DESCRIPTION OF THE INVENTION
[0018] It will be appreciated that references herein to "treatment"
extend to prophylaxis, prevention of recurrence and suppression or
amelioration of symptoms (whether mild, moderate or severe) as well
as the treatment of established conditions.
[0019] As used herein, the term "method of treating depression"
includes treatment of a major depressive disorder (MDD), bipolar
depression (type I and II), and depression with atypical features
(e.g. lethargy, over-eating/obesity, hypersomnia). In such
treatments, accompanying treatment (alleviation) of
depression-related anxiety symptoms is also contemplated. Treatment
of major (unipolar) depression is of particular interest. In the
treatment of depressive episodes in bipolar disorder, the extent or
severity of activation of mania/hypermania (switching) is expected
to be improved relative to known antidepressants, especially those
of the SSRI-class.
[0020] As used herein, the term "a method for treating obesity"
means both partial and complete alleviation of the condition. Thus,
as well as alleviation of obesity, this will also include reducing
the degree of severity of obesity. Included within this term is the
prevention of weight gain (avoiding weight gain and attenuating the
amount of weight gain in a susceptible subject), the production of
weight loss, or maintaining weight loss (preventing re-gain of
weight lost as a result of treatment with the compound of formula
(I) or as a result of diet or exercise in the absence of treatment
with a compound of formula (I)). The method may be employed even if
the subject being treated is not obese or overweight according to
clinical measures. The method may be employed pre-emptively in
those subjects at risk of obesity e.g. in individuals attempting to
quit smoking, diabetics, or those individuals being treated with
certain drugs (including antidiabetics and antidepressants) which
are known or suspected to promote weight gain.
[0021] As used herein the term "a method for treating pain"
encompasses in particular the treatment of neuropathic pain.
Neuropathic pain syndromes can develop following neuronal injury
and the resulting pain may persist for months or years, even after
the original injury has healed. Neuronal injury may occur in the
peripheral nerves, dorsal roots, spinal cord or certain regions in
the brain. Neuropathic pain syndromes are traditionally classified
according to the disease or event that precipitated them.
Neuropathic pain syndromes include: diabetic neuropathy; sciatica;
non-specific lower back pain; multiple sclerosis pain;
fibromyalgia; HIV-related neuropathy; neuralgia, such as
post-herpetic neuralgia and trigeminal neuralgia; and pain
resulting from physical trauma, amputation, cancer, toxins or
chronic inflammatory conditions. The symptoms of neuropathic pain
are incredibly heterogeneous and are often described as spontaneous
shooting and lancinating pain, or ongoing, burning pain. In
addition, there is pain associated with normally non-painful
sensations such as "pins and needles" (paraesthesias and
dysesthesias), increased sensitivity to touch (hyperesthesia),
painful sensation following innocuous stimulation (dynamic, static
or thermal allodynia), increased sensitivity to noxious stimuli
(thermal, cold, mechanical hyperalgesia), continuing pain sensation
after removal of the stimulation (hyperpathia) or an absence of or
deficit in selective sensory pathways (hypoalgesia).
[0022] As used herein, the term "method of treating sexual
dysfunction" encompasses prevention of, or treatment relief from,
sexual dysfunction or one or more symptoms of sexual dysfunction.
The term "sexual dysfunction" as used herein principally
encompasses psychosexual dysfunction. Examples of psychosexual
dysfunction include, but are not limited to, inhibited sexual
desire (low libido), inhibited sexual arousal or excitement, orgasm
dysfunction, inhibited female orgasm and inhibited male orgasm.
Particular examples of more specifically defined disorders include
hypoactive sexual desire disorder (HSDD) and female sexual desire
disorder (FSDD). Of particular note is the alleviation of sexual
dysfunction side-effects induced by treatment with antidepressants
of the SSRI-class.
[0023] As used herein, the term "method of treating Parkinson's
disease" means relief from the symptoms of Parkinson's disease
which include, but are not limited to, locomotor deficits and/or
motor disability, including slowly increasing disability in
purposeful movement, tremors, bradykinesia, hyperkinesia (moderate
and severe), akinesia, rigidity, disturbance of balance and
co-ordination, and a disturbance of posture.
[0024] As used herein, the term "treatment of addiction to
nicotine-containing products" includes both partial and complete
alleviation of addiction. Thus, in respect of tobacco products, as
well as the cessation of the activity, for example smoking, this
will also include reducing the level or frequency of such activity
e.g. reduction of the number of cigarettes smoked in a given
period. In respect of other nicotine-containing products, treatment
will also involve both cessation of, and a reduction in the level
of, usage of such products. The term "treatment of addiction to
cocaine products" has an analogous meaning.
Preparation
[0025] The compound of formula (I) or pharmaceutically acceptable
salts and solvates thereof may be prepared by first synthesizing
the racemate of the morpholinol metabolite of bupropion and
subsequently separating the (+) and (-) enantiomers of the racemate
via HPLC.
[0026] The racemate of the morpholinol metabolite of bupropion
hydrochloride
((+/-)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
hydrochloride) may be synthesized by the following process. To
3'-chloropropiophenone (10.0 g, 0.06 mol) in dioxane (50 mL) was
added a solution of dioxane dibromide (14.9 g, 0.06 mol) in dioxane
(50 mL). The reaction mixture was stirred for 2 h at ambient
temperature and poured into a mixture of ice and water (500 mL).
The mixture was extracted several times with methylene chloride.
The combined extracts were dried (Na.sub.2SO.sub.4) and
concentrated in vacuo to give 14.8 g (85%) of
2-bromo-3'-chloropropiophenone as a pale yellow oil. This was used
without further purification. NMR (300 Mhz, CDCl.sub.3); .delta.
7.99 (m, 1H), 7.90 (d, 1H), 7.57 (d, 1H), 7.44 (t, 1H), 5.22 (q,
1H), 1.91 (t, 3H).
[0027] To a solution of 2-bromo-3'-chloropropiophenone (19.3 g,
0.08 mol) in MeOH (100 mL) was added dropwise a solution of
2-amino-2-methyl-1-propanol (27.8 g, 0.31 mol) in methanol (200 mL)
at ambient temperature. The mixture was stirred for 18 h and
concentrated in vacuo. The residue was partitioned between water
and diethyl ether. The combined organic phase was extracted with
10% aqueous hydrogen chloride. The combined aqueous acid extracts
were chilled in an ice bath and made basic with 40% aqueous sodium
hydroxide. The mixture was extracted with diethyl ether, the
combined diethyl ether extracts were washed with water and
saturated sodium chloride solution, dried (K.sub.2CO.sub.3) and
concentrated in vacuo to give 15.0 g (75%) of
(+/-)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol as
an off-white solid.
[0028]
(+/-)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
may be converted to
(+/-)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
hydrochloride by the following process. A 6.0 g sample was
dissolved in diethyl ether, chilled in an ice bath and ethereal
hydrogen chloride added until the mixture was acidic. The resulting
solid was filtered and recrystallized from ethanol/diethyl
ether/ethereal hydrogen chloride mixtures to give 4.93 g of
(+/-)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
hydrochloride as a white solid: m.p. 202-203.degree. C. NMR (80
Mhz, DMSO-d.sub.6); .delta. 10.9 (br, 1H), 8.85 (br, 1H), 7.60-7.41
(m, 5H), 4.04 (d, 1H), 3.50 (d, 1H), 3.37 (br s, 1H), 1.58 (s, 3H),
1.34 (s, 3H), 1.03 (d, 3H). Anal. Calcd for
C.sub.13H.sub.19Cl.sub.2NO.sub.2: C, 53.43; H, 6.55; N, 4.79.
Found: C, 53.54; H, 6.58; N, 4.75.
[0029]
(+/-)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
hydrochloride may be converted back to its free base by the
following process. A 3.0 g sample of
(+/-)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
hydrochloride was dissolved in water (100 mL) and diethyl ether was
added (200 mL). The mixture was chilled in an ice bath and the pH
was adjusted to >10 with 1.0N aqueous sodium hydroxide. After
stirring for 30 min., the phases were separated and the aqueous
phase was extracted with diethyl ether. The combined diethyl ether
extracts were dried (Na.sub.2SO.sub.4) and concentrated in vacuo to
give 2.6 g of
(+/-)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol as
a white solid. This was used without further purification for the
chiral chromatography described below.
[0030] The (+) and (-) enantiomers of
(+/-)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
may be separated by the following process.
(+/-)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
(2.54 gms.) was dissolved in 250 ml of 2:8 Isopropyl alcohol:Hexane
(both HPLC grade). A Daicel Chiralcel OD column (2.times.25 cm.)
was equilibrated for one hour at 8 ml./min in the elution solvent,
1:9:0.2 Isopropanol:Hexane:Diethylamine. The solution of the
(+/-)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
was injected in 1 ml. aliquots by an automated Waters Prep LC 2000,
using a Waters 510 EF pump for injections. Each run was 15 minutes
in length, using the conditions listed before. The separated
optical isomers were collected by fraction collector (Waters) at a
2% above baseline threshold, based on 2 absorbance units full scale
at 240 nm (Waters 490E UV detector). Each optical isomer solution
was evaporated on a rotary evaporator at 40 degrees Centigrade and
aspirator vacuum. After drying for 6 hours under high vacuum at
room temperature, optical isomer 1 weighed 1.25 gm. and optical
isomer 2 weighed 1.26 gm.
[0031] The enantiomeric purity of each isomer was assayed by
analytical chiral HPLC on a Waters 860 HPLC with 996 Photodiode
Array detector, using a Daicel Chiralcel OD-H column (4.6.times.250
mm.) eluted with 1:9:0.2 Isopropyl alcohol:Hexane:Diethylamine at 1
ml/min. Optical isomer 1 was 100% pure (R.T. 6.117 min.). Optical
isomer 2 was 99.19% pure (R.T. 6.800 min.), containing 0.81%
optical isomer I (R.T. 6.133 min.).
[0032] Hydrochloride salts of the separated enantiomers were
obtained by the following processes. 1.25 g (0.005 mol) of optical
isomer 1 (retention time 6.117 min)
((-)-(2R,3R)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol) was
dissolved in diethyl ether. The solution was filtered and the
filtrate was chilled in an ice-bath adding ethereal hydrogen
chloride until the solution was acidic. After standing at ambient
temperature for 24 h, the resulting solid was filtered, washed with
diethyl ether and dried in a vacuum oven at 60.degree. C. for 18 h
to give 1.32 g (90%) of
(-)-(2R,3R)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
hydrochloride as a white solid: mp 208-209.degree. C. NMR (300 Mhz,
DMSO-d.sub.6); .delta. 9.72 (br, 1H), 8.76 (br, 1H), 7.54-7.41 (m,
5H), 3.98 (d, 1H), 3.52 (d, 1H), 3.37 (br s, 1H), 1.53 (s, 3H),
1.29 (s, 3H), 0.97 (d, 3H). Anal. Calcd for
C.sub.13H.sub.19Cl.sub.2NO.sub.2: C, 53.43; H, 6.55; N, 4.79.
Found: C, 53.35; H, 6.57; N, 4.71. [.alpha.].sub.D.sup.20.degree.
C.=-33.2.degree.(0.67, 95% EtOH)
[0033] 1.26 g (0.005 mol) of optical isomer 2 (retention time 6.800
min) (+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol)
was dissolved in diethyl ether. The solution was filtered and the
filtrate was chilled in an ice-bath adding ethereal hydrogen
chloride until the solution was acidic. After standing at ambient
temperature for 24 h, the resulting solid was filtered, washed with
diethyl ether and dried in a vacuum oven at 60.degree. C. for 18 h
to give 1.36 g (93%) of
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
hydrochloride as a white solid: mp 208-209.degree. C. NMR (300 Mhz,
DMSO-d.sub.6); .delta. 9.87 (br, 1H), 8.76 (br, 1H), 7.54-7.41 (m,
5H), 3.99 (d, 1H), 3.51 (d, 1H), 3.37 (br s, 1H), 1.54 (s, 3H),
1.30 (s, 3H), 0.98 (d, 3H). Anal. Calcd for
C.sub.13H.sub.19Cl.sub.2NO.sub.2: C, 53.43; H, 6.55; N, 4.79.
Found: C, 53.51; H, 6.58; N, 4.73. [.alpha.].sub.D.sup.20.degree.
C.=+31.9.degree. (0.64, 95% EtOH)
[0034] The absolute configuration of
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol was
determined by the following x-ray crystallographic method. Crystal
Data: C.sub.13H.sub.18Cl.sub.2NO.sub.2, M=291, Orthorhombic, space
group P2.sub.12.sub.12.sub.1, a=8.7348 (6), b=14.9824 (10),
c=23.1605 (15) .ANG., V=3031 (4) .ANG..sup.3, Z=8, Dc=1.276
Mgm.sup.-3, F(000)=1226.95. Of 12224 reflections measured. 3764
were unique and 2318 which had I>3.0.sigma.(I) were used in
subsequent calculations. Data was collected on a Siemens SMART
diffractometer using omega scans and monochromated MoK.alpha.
radiation (.lamda.=0.71073 .ANG.). The positions of all
non-hydrogen atoms were determined by direct methods and refined
anisotropically. The hydrogen positions were all located in
difference syntheses and included in subsequent refinement cycles
using a riding model and an idealized bond length of 0.96 .ANG..
The absolute configuration was determined by refinement of the
Rogers' parameter and confirmed by an analysis of the 185 best
Bijvoet intensity differences which indicated a probability of
0.006 that the model was in error. Least squares refinement
minimized .SIGMA.w(.DELTA.F).sub.2 with weights based on counter
statistics. The final agreement factors were R.sub.f=0.064 (0.108
for all data), R.sub.w=0.068 (0.081 for all data), and GoF=1.93.
References included E. J. Gabe, Y. Le Page, J.-P. Charland, F. L.
Lee and P. S. White, Journal of Applied Crystallography, 22,
384-387 (1989) and D. Rogers, Acta Crystallographica, A37, 734-741,
1981.
Dosage and Formulation
[0035] The amount of compound of formula (I) required to achieve
the desired therapeutic effect will, of course depend on a number
of factors, for example, the mode of administration, the recipient
and the condition being treated. In general, the daily dose will be
in the range of 0.02 to 5.0 mg/kg. More particular ranges include
0.02 to 2.5 mg/kg, 0.02 to 1.0 mg/kg, 0.02 to 0.25 mg/kg, 0.02 to
0.15 mg/kg and 0.02 to 0.07 mg/kg.
[0036] The compound of formula (I) may be employed in the treatment
of depression, attention deficit hyperactivity disorder (ADHD),
obesity, migraine, pain, sexual dysfunction, Parkinson's disease,
Alzheimer's disease, addiction to cocaine or nicotine-containing
(especially tobacco) products as the compound per se, but is
preferably presented with one or more pharmaceutically acceptable
carriers, diluents or excipients in the form of a pharmaceutical
formulation. The carriers, diluents and exipients must, of course,
be acceptable in the sense of being compatible with the other
ingredients of the formulation and must not be deleterious to the
recipient. The carrier may be a solid or a liquid, or both, and is
preferably formulated with the agent as a unit-dose formulation,
for example, a tablet.
[0037] The formulations include those suitable for oral, rectal,
topical, buccal (e.g. sub-lingual) and parenteral (e.g.
subcutaneous, intramuscular, intradermal or intravenous)
administration.
[0038] Formulations suitable for buccal (sub-lingual)
administration include lozenges comprising a compound of formula
(I) in a flavoured base, usually sucrose and acacia or tragacanth,
and pastilles comprising the agent in an inert base such as gelatin
and glycerin or sucrose and acacia.
[0039] Formulations of the present invention suitable for
parenteral administration conveniently comprise sterile aqueous
preparations of a compound of formula (I), preferably isotonic with
the blood of the intended recipient. These preparations are
preferably administered intravenously, although administration may
also be effected by means of subcutaneous, intramuscular, or
intradermal injection. Such preparations may conveniently be
prepared by admixing the agent with water and rendering the
resulting solution sterile and isotonic with the blood.
[0040] Formulations suitable for rectal administration are
preferably presented as unit-dose suppositories. These may be
prepared by admixing a compound of formula (I) with one or more
conventional solid carriers, for example, cocoa butter, and then
shaping the resulting mixture.
[0041] Formulations suitable for topical application to the skin
preferably take the form of an ointment, cream, lotion, paste, gel,
spray, transdermal patch, aerosol, or oil. Carriers which may be
used include vaseline, lanolin, polyethylene glycols, alcohols, and
combinations of two or more thereof.
[0042] It should be understood that in addition to the ingredients
particularly mentioned above, the formulations may include other
agents conventional in the art having regard to the type of
formulation in question.
Biological Activity
[0043] Biological activity of the compound of formula (I) was
demonstrated by in vitro uptake models, the tetrabenazine-induced
behavioural depression model, the MPTP-treatment Parkinson's
disease model, the chronic constriction injury mononeuropathy
model, and a mouse sexual behaviour model. The racemic morpholinol
metabolite,
(+/-)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol,
is referred to herein as "Racemate". The (-) form of the
morpholinol metabolite is (-)-(2R,
3R)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol or
pharmaceutically acceptable salts and solvates thereof and is
referred to herein as a compound of formula (II): ##STR4## In Vitro
Synaptosomal Uptake Experiments
[0044] In vitro uptake was determined, as reported previously,
using synaptosomes prepared from rat caudoputamen (for dopamine
uptake) and hypothalamus (for NA and serotonin uptake) using
[.sup.3H]-dopamine, [.sup.3H]-NA and [.sup.3H]-serotonin as
transport substrates, respectively. See Eckhardt, S. B., R. A.
Maxwell, and R. M. Ferris, A Structure-Activity Study of the
Transport Sites for the Hypothalamic and Striatal Catecholamine
Uptake Systems. Similarities and differences. Molecular
Pharmacology, 21: p. 374-9, 1982.
[0045] Synaptosomes for use in obtaining in vitro uptake data were
prepared from hypothalamus or striatum by gently homogenizing the
tissue in a 0.3 M sucrose/25 mM Tris pH 7.4 buffer containing
iproniazid phosphate to inhibit monoamine oxidase. The homogenate
was centrifuged at 1100.times.g at 4.degree. C. for 10 min and the
supernatant was used for uptake studies. The supernatant (.about.1
mg tissue protein) was incubated with Km concentrations of
[.sup.3H]-noradrenaline, [.sup.3H]-dopamine or [.sup.3H]-serotonin
at 37.degree. C. for 5 minutes in Modified Krebs-Henseleit buffer
(118 mM NaCl, 5 mM KCl, 25 mM NaHCO.sub.3, 1.2 mM
NaH.sub.2PO.sub.4, 1.2 mM MgSO.sub.4, 11 mM Dextrose, 2.5 mM
CaCl.sub.2) in the absence and presence of drug. Under these
conditions uptake was linear with respect to both for substrate and
tissue (with <5% total substrate transported). Non-specific
uptake was defined as uptake at 0.degree. C. [.sup.3H]-substrate,
which had been transported into synaptosomes, was separated from
free [.sup.3H]-substrate by filtration over GF/B filters and
washing with cold Krebs-Henseleit buffer. The filters were counted
for tritum in a liquid scintillation spectrometer.
[0046] The data for in vitro synaptosomal uptake are presented as
Table 1. Among the 2 enantiomers of the morpholinol metabolite of
bupropion, the (+) enantiomer, the compound of formula (I),
inhibited noradrenaline (NA) uptake with an IC.sub.50 of 2.2 .mu.M.
In contrast, the (-) enantiomer was ineffective at a concentration
of 30 .mu.M. On dopamine (DA) uptake, the compound of formula (I)
had an IC.sub.50 of .about.10 .mu.M while the (-) enantiomer was
inactive at 30 .mu.M. Neither compound inhibited serotonin uptake
at 30 mM.
[0047] For comparison, Wellbutrin.RTM. was equipotent for
inhibiting DA and noradrenaline uptake with IC.sub.50 values of 1.9
and 2.2 .mu.M, and did not inhibit serotonin uptake at 30 .mu.M.
Imipramine (a non-specific tricyclic antidepressant) inhibited NA
uptake and serotonin uptake with IC.sub.50 values of 0.072 and 0.24
.mu.M, respectively.
[0048] The compound of formula (I) was approximately twice as
potent as Wellbutrin.RTM. as an NA inhibitor but, unlike the
latter, was approximately 10-fold less potent as an inhibitor of
dopamine uptake. These data are consistent with the observed
noradrenergic actions of Wellbutrin.RTM. and the racemic
morpholinol metabolite of bupropion,
(+/-)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
hydrochloride, (306 U73) in vivo, at their respective anti-TBZ
doses (Cooper, B. R., et al, Neuropsychopharmacology, 11: p.
133-41, 1994). Behavioral and electrophysiological data suggest
that the effects of Wellbutrin.RTM. are mediated by a noradrenergic
mechanism (ibid).
Tetrabenazine-Induced Behavioural Depression Experiments
[0049] Tetrabenazine(TBZ)-induced behavioural depression was used
as an in vivo measure of antidepressant activity. The test has been
validated with a wide range of antidepressants, known to act
through noradrenergic mechanisms (Cooper B. R. et al, "Animal
models used in the prediction of antidepressant effects in man", J.
Clin. Psychiatry 44: 63-66, 1983). Moreover, the test was also used
to identify Wellbutrin.RTM. as an anti-depressant. Briefly, animals
were injected with the candidate agent (p.o. or i.p.) 30 minutes
before receiving an i.p. injection of tetrabenazine (35 mg/kg, as
the HCl salt--prepared fresh for each use). Assessments were
performed 30 minutes thereafter and included: locomotor activity
(1-4 scale); ptosis (1-4 scale) and body temperature as described
previously (Cooper, B. R., J. L. Howard, and F. E. Soroko, Animal
models used in prediction of antidepressant effects in man (Journal
of Clinical Psychiatry, 44: p. 63-6, 1983). In all studies, the
scientist performing the assessments was blind to the treatments.
All parameters were weighted equally to give a "lumped" score (X)
through the following algorithm: X=(1+Ptosis score)/(Activity
score[Temp,treated/Temp,control]
[0050] Results from the tetrabenazine-induced behavioural
depression model are as follows. Assessed in vivo at 25 mg/kg (ip)
the compound of formula (I), the racemate, Wellbutrin.RTM. and, for
comparison, amitryptyline all abolished the tetrabenazine-induced
behavioural depression. In contrast, the (-) enantiomer showed only
modest activity (FIG. 1).
[0051] In the TBZ model of behavioural depression, activity resided
in the compound of formula (I). When analysed in a dose-effect
study with TBZ, the activity showed a sharp increase in activity
between 3 mg/kg and 6 mg/kg (ip) (FIG. 2). The compound of formula
II, in comparison, did not possess dose-related activity and, at 50
mg/kg, appeared to worsen the animal's condition (FIG. 3). In FIGS.
2 and 3, AMIT (5) refers to amitryptiline dosed at 5 mg/kg and SHAM
refers to a control group of animals that have received no
medication at all.
[0052] Since the TBZ test has been predictive of anti-depressants
acting through noradrenergic mechanisms and the compound of formula
(I) is an inhibitor of noradrenaline uptake and Wellbutrin.RTM. is
metabolised to this morpholinol in vivo, the data suggest that the
anti-depressant activity of Wellbutrin.RTM. is likely to result
from the effects of the compound of formula (I). (Welch, R. M., A.
A. Lai, and D. H. Schroeder, Pharmacological significance of the
species differences in bupropion metabolism. Xenobiotica, 17: p.
287-98, 1987).
[0053] By extension, other activities of Wellbutrin.RTM. could be
attributed to the compound of formula (I). In particular, a
noradrenergic mechanism is common to agents used to treat ADHD
(e.g. methylphenidate and amphetamine). While the molecular
mechanism for Wellbutrin's effects on smoking cessation is less
well understood, a catecholaminergic pathway is thought to
participate in the behavioural reinforcing properties of nicotine.
Wellbutrin.RTM. (and, by extension, the compound of formula (I)),
by augmenting NA release into brain synapses, could mimic some of
the actions of nicotine and, thus, decrease the signs associated
with nicotine withdrawal. Additionally, amphetamines have been used
to treat obesity. The addictive properties of amphetamine, however,
preclude its use for most obese patients. Wellbutrin.RTM. causes
weight loss and, like amphetamine, acts through a noradrenergic
mechanism. (Zarrindast, M. R. and T. Hosseini-Nia, Anorectic and
behavioural effects of bupropion. General Pharmacology, 19: p.
201-4, 1988 and Harto-Truax, N., et al., Effects of Bupropion on
Body Weight. Journal of Clinical Psychiatry, 44: p. 183-6, 1983).
However, unlike amphetamine, Wellbutrin.RTM. is not addictive.
(Lamb, R. J. and R. R. Griffiths, Self-administration in Baboons
and the Discriminative Stimulus Effects in Rats of Bupropion,
Nomifensine, Diclofensine and Imipramine. Psychopharmacology, 102:
p. 183 90, 1990; Bergman, J., et al., Effects of Cocaine and
Related Drugs in Nonhuman Primates. III. Self-administration by
Squirrel Monkeys. Journal of Pharmacology & Experimental
Therapeutics, 251: p. 150-5, 1989 and Johanson, C. E.; and J. E.
Barrett, The Discriminative Stimulus Effects of Cocaine in Pigeons.
Journal of Pharmacology & Experimental Therapeutics, 267: p.
1-8, 1993). By extension, the compound of formula (I) would also be
expected to have efficacy in obesity and cocaine addiction.
[0054] Additional studies demonstrating the use of bupropion in the
treatment of the conditions referred to above have been published
as follows: bipolar depression (Journal of Affective Disorders,
56(2-3): p 237-243, December 1999; J. Clin. Psych., 55: p 391-393,
1994), sexual dysfunction (Journal of Sex and Marital Therapy,
13(4), p 239-252, 1987), HSDD (Journal of Sex and Marital Therapy,
27: p 303-316, 2001), obesity (Obesity Research, 9: p 544-551,
2001), treatment of SSRI-induced sexual dysfunction (J. Clin.
Psych., 62: p 185-190, 2001; J. Clin. Psych., 54: p 459-465, 1993;
J. Clin. Psych., 59: p 112-115, 1998; Ann. Clin. Psych., 9: p
241-245, 1997), neuropathic pain (Clin. J. Pain, 16(1): p 6-11,
March 2000; Neurology, 57, p 1583-1588, 2001).
MPTP-Treatment Parkinson's Disease Model
[0055] Locomotor deficits and motor disability were induced in
marmosets by the administration of MPTP 2 mg/kg sc on five
consecutive days. After the acute effects of MPTP administration
had been overcome, bradykinesia, rigidity and loss of vocalisation
remained. The compound of formula (I) (as its hydrochloride salt)
was administered once weekly by oral gavage, freshly dissolved in
10% sucrose solution with dosages calculated as the free base.
Assessment of locomotor activity was by use of automatic locomotor
cages (Smith et al., Movmt. Disord., 12: p 935-945, 1997) to
monitor climbing, floor and perch activity. Assessment of motor
disablities was by an observer through a one-way mirror: alertness,
checking movements, posture, balance/co-ordination, reaction,
vocalisation and motility were each scored. A score of zero
indicated a "normally" behaing animal, while a maximum total score
of 18 in the monitoring period indicated a severely disabled
animal. Administration of the compound of formula (I) reversed the
locomotor deficits and motor disability exhibited by MPTP-treated
marmosets as shown in FIGS. 4 and 5 respectively; data is given as
the mean.+-.sem of four animals versus treatment with vehicle
alone.
Chronic Constriction Injury Model of Mononeuropathy
[0056] Mononeuropathy was reproduced in male Random Hooded rats
(180-250 g) using the Chronic Constriction Injury (CCI) model as
described by Bennett and Xie (1988). Under Isoflurane anaesthesia,
the common left sciatic nerve of the rats was exposed at mid thigh
level. Four ligatures of Chromic gut (4.0) were tied loosely around
the nerve with a 1 mm spacing between each. The wound was then
closed and secured with suture staples. The surgical procedure was
identical for the sham operated animals except the sciatic nerve
was not ligated. The animals were allowed a period of 12 days to
recover from the surgery before any behavioural testing began.
[0057] The effect of the compound of formula (I) (administered as
the hydrochloride salt at 20 mgkg.sup.-1 t.i.d. p.o. chronically
for a period of 7 days) on CCI-induced decrease in mechanical paw
withdrawal threshold was measured using an algesymeter (Randall
& Selitto, 1957).
[0058] The data is shown in FIG. 6, expressed as mean.+-.sem
comparing the difference between the drug-treated group and
vehicle-treated groups. The CCI operated animals were showing the
characteristic decrease in paw withdrawal threshold, demonstrating
the onset of neuropathic hypersensitivity, prior to the start of
treatment. A single dose of the compound of formula (I) (20
mgkg.sup.-1) produced an immediate reversal of the fall in paw
withdrawal threshold back towards sham operated levels. This
reversal was maintained throughout the chronic dosing period,
falling back towards CCI-operated vehicle-treated levels on
cessation of treatment.
Mouse Sexual Behaviour Model
[0059] Male (10 weeks old) and female (8 weeks old) mice (C57BL/6
inbred strain, Charles River, Como (Italy) that had no reproductive
or copulatory experience were used in the study. Females were
brought into behavioral oestrus with s.c. injections of 0.03 mg
estradiol benzoate approximately 48 hr before testing and 0.1 mg
progesterone, in sesame oil, 4 hr before testing.
[0060] The compound of formula (I) (as its hydrochloride salt) was
dissolved in saline to provide a solution for intraperitoneal
injection at a dose of 3 mg/kg, with a dose volume of 10 ml/kg.
Dosing was performed one hour prior to the test.
[0061] Tests were conducted in Perspex arenas, 30 cm in diameter
and 50 cm high, which were placed in the cage in which males had
been placed individually one day prior to test. The sexual
behaviour was filmed remotely under red light for 30 min using a
video camera and recorder, the test starting immediately after
placing a female mouse into the male's cage. Behavior parameters
recorded were (i) the extent of male/female interaction, (ii) the
extent of genital sniffing, and (iii) the mount frequency (the
number of male mounts).
[0062] The results are set out in Tables 2 to 4 below. The compound
of formula (I) (as its hydrochloride salt) administered by
intraperitoneal injection caused a statistically significant
(unpaired t-test) increase in male/female interaction and genital
sniffing, and a trend towards increasing mount frequency.
Safety and Toxicity
[0063] Additional dose-ranging studies were performed to determine
the range of safe doses for the isomers and the racemate. Animals
were observed for the presence of serious adverse events (e.g.
seizures and deaths) following administration of the compounds of
formula I, formula II or the racemate by the oral and
intraperitoneal (i.p.) routes. The data are presented as Table
5.
[0064] Administered orally, at 100 mg/kg p.o., seizures were
observed with the compound of formula II and the racemate but not
with the compound of formula I. Seizures were observed in all of
the animals with all 3 compounds when dosed at 300 mg/kg.
Additionally, the 300 mg/kg oral dose resulted in 100 and 80%
lethality for the compound of formula II and the racemate while no
deaths were observed with the compound of formula I.
[0065] Administered i.p., all of the compounds produced seizures at
100 mg/kg. No deaths were observed with the compound of formula I,
whereas the compound of formula II and the racemate resulted in
lethality of 100% and 20%, respectively. At the 300 mg/kg oral dose
all of the lethality was observed for all of the compounds.
TABLE-US-00001 TABLE 1 Effects on Uptake In Vitro Compound IC50
(.mu.M) SEM [.sup.3H]-Dopamine Uptake Bupropion 1.9 0.15 Formula
(I) 9.3 0.41 Formula (II) >100 [.sup.3H]-Noradrenaline Uptake
Bupropion 2.2 0.7 Formula (I) 1.1 0.07 Formula (II) >30
Imipramine 0.072 0.020 [.sup.3H]-Serotonin Uptake Bupropion >30
Formula (I) >30 Formula (II) >100 Imipramine 0.24 0.03
[0066] TABLE-US-00002 TABLE 3 Male/Female interaction Treatment M/F
interaction (sec) Control 110.4 .+-. 8.8 Compound of formula (I)
*228.8 .+-. 30.3 *P < 0.05, unpaired t-test
[0067] TABLE-US-00003 TABLE 4 Genital sniffing Time spent in
genital sniffing Treatment (sec) Control 94.2 .+-. 10.8 Compound of
formula (I) *203.6 .+-. 30.1 *P < 0.05, unpaired t-test
[0068] TABLE-US-00004 TABLE 5 Mount frequency Treatment No. of
events .+-. SEM Control 2.1 .+-. 0.7 Compound of formula (I) 6.6
.+-. 1.7
[0069] TABLE-US-00005 TABLE 6 Adverse Events Associated with
Compounds of Formula I, Formula II and the Racemate. Dose Time to
Seizures Time to Death Compound Route mg/kg) Seizures (%) (min) %
Died (min) Formula I i.p. 100 100 3.93 0 n/a Formula I p.o. 100 0
n/a 0 n/a Formula I i.p. 300 100 3.95 100 6 Formula I p.o. 300 100
11.23 0 n/a Formula II i.p. 100 20 5 100 7 Formula II p.o. 100 100
7.2 0 n/a Formula II i.p. 300 100 1.1 100 6 Formula II p.o. 300 100
6.8 100 7 Racemate i.p. 100 100 3 20 14 Racemate p.o. 100 100 9.2 0
n/a Racemate i.p. 300 100 3 100 3 Racemate p.o. 300 100 6.8 80 7
N/a denotes that the effect was not observed and, therefore, no
percentage was given.
* * * * *