U.S. patent application number 09/809470 was filed with the patent office on 2001-09-06 for treatment of depression.
This patent application is currently assigned to H. Lundbeck A/S. Invention is credited to Sanchez, Connie.
Application Number | 20010020027 09/809470 |
Document ID | / |
Family ID | 8101704 |
Filed Date | 2001-09-06 |
United States Patent
Application |
20010020027 |
Kind Code |
A1 |
Sanchez, Connie |
September 6, 2001 |
Treatment of depression
Abstract
The compound
1'-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl-spiro[isobe-
nzofuran-1(3H,4'-piperidine] is active in models predictive of
antidepressant effects and is useful for the preparation of a
medicament for the treatment of depression or diseases associated
with depressive symptoms.
Inventors: |
Sanchez, Connie; (Glostrup,
DK) |
Correspondence
Address: |
DARBY & DARBY P.C.
805 Third Avenue
New York
NY
10022
US
|
Assignee: |
H. Lundbeck A/S
Copenhagen
DK
|
Family ID: |
8101704 |
Appl. No.: |
09/809470 |
Filed: |
March 15, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09809470 |
Mar 15, 2001 |
|
|
|
PCT/DK99/00482 |
Sep 14, 1999 |
|
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Current U.S.
Class: |
514/278 |
Current CPC
Class: |
A61P 25/24 20180101;
A61K 31/454 20130101 |
Class at
Publication: |
514/278 |
International
Class: |
A61K 031/4747 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 15, 1998 |
DK |
PA 1998 01163 |
Claims
1. A method of treating depression, comprising administering the
compound 1'
-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl]-spiro[isobenzo-furan--
1(3H),4' -piperidine] or a pharmaceutically acceptable salt
thereof, to a person in need thereof.
2. The method of claim 1, wherein the compound is used in the form
of the base, the fumarate or the hydrochloride.
3. The method of claim 1, wherein the compound is administered as a
unit dose.
4. The method of claim 3, wherein the unit dose comprises the
compound in an amount from about 10 .mu.g/kg to 10 mg/kg body
weight.
5. The method of claim 4, wherein the unit dose comprises the
compound in an amount from 25 .mu.g/day/kg to 2.0 mg/day/kg body
weight.
6. The method of claim 4, wherein the unit dose comprises the
compound in an amount from 0.1 mg/day/kg to 2.0 mg/day/kg body
weight.
7. The method of claim 1, wherein the depression is selected from
the group consisting of major depression, dysthymic disorder,
depressive episodes of bipolar disorders, or depressive episodes
associated with other mood disorders.
Description
FIELD OF INVENTION
[0001] The present invention relates to the use of the compound
1'-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl]-spiro[isobenzofuran-1(-
3H),4'-piperidine] or a pharmaceutically acceptable salt thereof
for the preparation of medicaments for the treatment of
depression.
BACKGROUND OF THE INVENTION
[0002] International Patent Publication No. WO 92/22554 describes a
series of sigma receptor ligands considered useful for the
treatment of a range of psychic and neurological disorders. The
structure activity relationship of these compounds has been further
investigated by Perregaard, J. et al., J. Med. Chem., 1995, 38, 11,
p. 1998-2008.
[0003] Among numerous other compounds, said patent publication
discloses the compound
1'-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl]-spiro[iso-
benzofuran-1(3H)4'-piperidine] 1
[0004] which is the subject of the present invention. This compound
was shown in Perregaard, J. et al., J. Med. Chem., 1995, 38, 11, p.
1998-2008 to be a potent and selective sigma ligand, in particular
a sigma.sub.2 ligand. Furthermore, the anxiolytic potential of the
compound was tested in the black/white exploration test in rats,
which is an animal model predictive for effect in the treatment of
generalised anxiety disorder. It was found to be active over a
large dose range. Results of further tests in generalised anxiety
disorder models are reported in J. Pharmacol. Exp. Ther., 1997,
283, No. 2.
[0005] Co-pending Danish patent applications Nos. 1267/97, 0071/98
and 0501/98 relate to the hydrochloride of the compound, the effect
of the compound in the treatment of addiction to drugs and other
substances of abuse and the use of the compound in the treatment of
panic attacks, respectively.
[0006] Evidence has been presented from studies of the biology and
function of sigma receptors that sigma receptor ligands may be
useful in the treatment of a range of psychic and neurological
disorders, including psychosis and movement disorders, such as
dystonia and tardive dyskinesia, and motor disturbances associated
with Huntington's chorea or Tourette's syndrome and in Parkinson's
disease (Walker, J. M. et al, Pharmacological Reviews, 1990, 42,
355). The known sigma receptor ligand, rimcazole, clinically shows
effect in the treatment of psychosis (Snyder, S. H., Largent, B. L.
J. Neuropsychiatry, 1989, 1, 7) and a group of sigma receptor
ligands have been described to show antihallucinogenic activity in
animal models (International Patent Publication No. WO
9103243).
[0007] Sigma receptor ligands have also been reported to be
involved in modulation of NMDA receptor mediated events in the
brain and to act as anti-ischemic agents in in vivo tests (Rao, T.
S. et al, Molecular Pharmacology, 1990, 37, 978). In addition to
ischemia, the sigma receptor ligands may also be useful in the
treatment of other such NMDA receptor mediated events, e.g.
epilepsy and convulsion.
[0008] Also, some sigma receptor ligands have been found to show
anti-amnesic effects in an animal model (Early et al., Brain
Research, 1991, 546, 281-286). Sigma ligands have been shown to
influence central acetylcholine levels in animal models (Matsuno et
al, Brain Research, 1992, 575, 315-319; Junien et al, Eur. J.
Pharm., 1991, 200, 343-345) and may, therefore, have potential in
the treatment of senile dementia of the Alzheimer type.
[0009] Finally, some guanidine derivatives having sigma receptor
activity have been disclosed to be useful as anxiolytics
(International Patent Publication No. WO 9014067) and some sigma
receptor ligands have been found to bind to the cocaine binding
site on the dopamine transporter and others have been found to
inhibit dopamine uptake (Izenwasser, S., et al, Eur. J. Pharmacol.,
243, 201-205 and Woodward, J. J. and Harms, J., Eur. J. Pharmacol.,
210, 265-270.
[0010] Depression is now well recognised as an extremely damaging
and invalidating disorder and it has a very large prevalence. It is
often associated with suicidal behaviour and people afflicted have
a very low quality of life.
[0011] Selective serotonin re-uptake inhibitors are now first
choice treatments in depression disorders. However, they are only
effective after 3-4 weeks of treatment and they are not effective
in all patients.
[0012] Consequently, there is a need for alternative therapies
useful in the treatment of disorders associated with
depression.
[0013] It has now, surprisingly, been found that the compound of
the invention shows a beneficial effect in the treatment of
depression.
DESCRIPTION OF THE INVENTION
[0014] According to the present invention, a novel use of
1'-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]
-1-butyl]-spiro[isobenzo-furan-- 1(3H),4'-piperidine], namely for
the preparation of a medicament useful in the treatment depression
is provided.
[0015] The term depression contemplates all diseases and conditions
which are associated with depression including those classified in
the IDC-10 and DSM-IV rating scales. Such diseases or disorders
comprise major depression, dysthymic disorder, depressive episodes
of bipolar disorders and depressive episodes associated with other
mood disorders, including seasonal mood disorders and mood
disorders due to a general medical condition and substance induced
mood disorder.
[0016] The term "treatment of depression" covers relief of
symptoms, cure or prevention of the disease or condition.
[0017] According to the invention, the compound
1'-[4-[1-(4-fluorophenyl)--
1H-indole-3-yl]-1-butyl]-spiro[isobenzo-furan-1(3H),4'-piperidine]
may be used as the base of the compound or as a pharmaceutically
acceptable acid addition salt thereof or as an anhydrate or hydrate
of such salt. The salts of the compound used in the invention are
salts formed with non-toxic organic or inorganic acids. Exemplary
of such organic salts are those with maleic, fumaric benzoic,
ascorbic, succinic, oxalic, bis-methylenesalicylic,
methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric,
salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic,
citraconic, aspartic, stearic, palmitic, itaconic, glycolic,
p-amino-benzoic, glutamic, benzene sulfonic and theophylline acetic
acids, as well as the 8-halotheophyllines, for example
8-bromo-theophylline. Exemplary of such inorganic salts are those
with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and
nitric acids. Preferably, the compound is used as the base, the
hydrochloride or the fumarate.
[0018] Chronic administration of the compounds used in the method
of the invention has been found to cause a reversal of anhedonia
induced by chronic mild stress in rats in the chronic mild stress
(CMS) model. The CMS-model is a well recognised model of depression
(Willner, Paul, Psycopharmacology, 1997, 134, 319-329.)
[0019] According to the invention,
1'-[4-[1-(4-fluorophenyl)-1H-indole-3-y-
l]-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine], or a
pharmaceutically acceptable salt thereof, may be administered in
any suitable way such as orally or parenterally, and it may be
presented in any suitable form for such administration, for example
in the form of tablets, capsules, powders, syrups or solutions or
dispersions for injection. Preferably, and in accordance with the
purpose of the present invention, the compound of the invention is
administered in the form of a solid pharmaceutical entity, suitably
as a tablet or a capsule or in the form of a suspension, solution
or dispersion for injection.
[0020] Methods for the preparation of solid pharmaceutical
preparations are well known in the art. Tablets may thus be
prepared by mixing the active ingredients with ordinary adjuvants
and/or diluents and subsequently compressing the mixture in a
convenient tabletting machine. Examples of adjuvants or diluents
comprise: corn starch, lactose, talcum, magnesium stearate,
gelatine, lactose, gums, and the like. Any other adjuvant or
additive such as colourings, aroma, preservatives, etc. may also be
used provided that they are compatible with the active
ingredients.
[0021] The compound of the invention is most conveniently
administered orally in unit dosage forms such as tablets or
capsules, containing the active ingredient in an amount from about
10 .mu.g/kg to 10 mg/kg body weight, preferably 25 .mu.g/day/kg to
2.0 mg/day/kg, most preferably 0.1 mg/day/kg to 1.0 mg/day/kg body
weight.
[0022] The fumarate of
1'-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl]--
spiro[isobenzo-furan-1(3H),4'-piperidine] can be prepared as
described in Perregaard, J. et al., J. Med. Chem., 1995, 38, 11,
1998-2008 (compound 14f) and the base and other pharmaceutically
acceptable salts may be obtained therefrom by standard
procedures.
[0023] Thus the acid addition salts according to the invention may
be obtained by treatment of 1'
-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-but-
yl]-spiro[isobenzo-furan-1(3H),4' -piperidine] with the acid in an
inert solvent followed by precipitation, isolation and optionally
recrystallization by known methods and if desired micronisation of
the crystalline product by wet or dry milling or another convenient
process, or preparation of particles from a solvent-emulsification
process.
[0024] Precipitation of the salt is preferably carried out in an
inert solvent, e.g. an inert polar solvent such as an alcohol (e.g.
ethanol, 2-propanol and n-propanol).
[0025] Pharmacological Tests
[0026] The model of Chronic Mild Stress Induced Anhedonia in
Rats
[0027] The effect of the compound of the invention in the treatment
of depression was tested in the model of chronic mild stress
induced anhedonia in rats. This model is based on the observation
that chronic mild stress causes a gradual decrease in sensitivity
to rewards, for example consumption of sucrose, and that this
decrease is dose-dependently reversed by chronic treatment with
antidepressants. The method has previously been described and more
information with respect to the test appears from Willner, Paul,
Psycopharmacology, 1997, 134, 319-329.
[0028] Experimental Procedure
[0029] Male Wistar rats were trained to consume a 1% sucrose
solution by nine 1-hour baseline tests in which sucrose was
presented in the home cage following 14 h food and water
deprivation.
[0030] One group of animals was subjected to a chronic mild stress
procedure for a period of 9 consecutive weeks. Each week of the
stress regime consisted of two periods of food and water
deprivation, two periods of 45-degree cage tilt, two periods of
intermittent illumination (light on and off every 2 h), two periods
of soiled cage (250 ml water saw dust bedding), two periods of
paired housing, two periods of low stroboscobic illumination (150
flashes/min) and two periods of no stress. All stress periods were
of 12-14 hours duration and followed continuously, day and night.
Control animals were housed in separate rooms with food and water
freely available except for a 14-h period preceding each sucrose
test, and they had no contact with stressed animals.
[0031] Stressed animals as well as control animals were divided
into matched subgroups, and for subsequent five weeks they received
daily intraperitoneal injections (1 ml/kg body weight) of vehicle
(minimum amount of propylene glycol and methane sulfonic acid (1:1)
diluted with water) or test compound. Sucrose tests were carried
out 24 hours following to last drug treatment.
[0032] Results
[0033] In the final baseline test, all animals consumed about 16 g
sucrose solution. After three weeks the intake remained at 14 g in
the control group whereas it fell to about 9.5 g in stressed
animals. These levels persisted for the remainder of the 9-week
period resulting in a significant group effect.
[0034] The compound of the invention did not significantly affect
the consumption of sucrose in the control animals.
[0035] The compound of the invention was able to reverse the
chronic mild stress induced deficit in sucrose intake at a dose of
1.0 mg/kg. In stressed animals treated with 1.0 mg/kg intake was
significantly increased from initial scores after three, four and
five weeks and at the end of the treatment period the sucrose
intake did not significantly differ from that of vehicle treated
controls (p=0.130) and it was significantly higher than that of
vehicle treated stressed animals (p=0.003).
[0036] Citalopram, a well known serotonin re-uptake inhibitor, was
included in the tests for comparison purposes. Citalopram (10
mg/kg) did not significantly affect the consumption of sucrose in
the control animals whereas it was able to reverse the chronic mild
stress induced deficit in sucrose. The increase in intake in
stressed animals was significantly increased from initial scores
after two weeks and maintained thereafter. At the end of the
treatment period the sucrose intake did not significantly differ
from that of vehicle treated controls (p=0.177) and it was
significantly higher than that of vehicle treated stressed animals
(p=0.001).
* * * * *