U.S. patent application number 10/425375 was filed with the patent office on 2003-11-13 for use of derivatives of valproic acid and 2-valproenic acid amides for the treatment of mania in bipolar disorder.
This patent application is currently assigned to Yissum Research Development Company of the Hebrew University of Jerusalem. Invention is credited to Bialer, Meir, Shirvan, Mitchell.
Application Number | 20030212142 10/425375 |
Document ID | / |
Family ID | 22822065 |
Filed Date | 2003-11-13 |
United States Patent
Application |
20030212142 |
Kind Code |
A1 |
Shirvan, Mitchell ; et
al. |
November 13, 2003 |
Use of derivatives of valproic acid and 2-valproenic acid amides
for the treatment of mania in bipolar disorder
Abstract
A method for the treatment of mania in bipolar disorder using
derivatives of valproic acid and 2-valproenic acid amides having
the following structures: 1 wherein R.sub.1, R.sub.2, and R.sub.3
are independently the same or different and are hydrogen, a
C.sub.1-C.sub.6 alkyl group, an aralkyl group, or an aryl group,
and n is an integer which is greater than or equal to 0 and less
than or equal to 3, or a compound containing a valproic or a
2-valproenic moiety, as well as pharmaceutical compositions
comprising these derivatives or compounds.
Inventors: |
Shirvan, Mitchell;
(Hertzleya, IL) ; Bialer, Meir; (Jerusalem,
IL) |
Correspondence
Address: |
John P. White
Cooper & Dunham LLP
1185 Avenue of the Americas
New York
NY
10036
US
|
Assignee: |
Yissum Research Development Company
of the Hebrew University of Jerusalem
Teva Pharmaceutical Industries, Ltd.
|
Family ID: |
22822065 |
Appl. No.: |
10/425375 |
Filed: |
April 28, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10425375 |
Apr 28, 2003 |
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09910543 |
Jul 20, 2001 |
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6555585 |
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60220102 |
Jul 21, 2000 |
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Current U.S.
Class: |
514/616 |
Current CPC
Class: |
A61K 31/16 20130101;
A61K 31/19 20130101; A61P 25/24 20180101; A61K 31/45 20130101; A61P
25/00 20180101; A61P 25/18 20180101 |
Class at
Publication: |
514/616 |
International
Class: |
A61K 031/16 |
Claims
What is claimed:
1. A method of treating bipolar disorder in a subject comprising
administering to the subject a therapeutically effective amount of
a derivative of a valproic acid amide or a 2-valproenic acid amide
having one of the following structures: 6wherein R.sub.1, R.sub.2,
and R.sub.3 are independently the same or different and are
hydrogen, a C.sub.1-C.sub.6 alkyl group, an aralkyl group, or an
aryl group, and n is an integer which is greater than or equal to 0
and less than or equal to 3, to thereby treat the bipolar
disorder.
2. The method of claim 1, wherein the derivative has the structure:
7
3. The method of claim 1, wherein the derivative is in a
pharmaceutical composition with a pharmaceutically acceptable
carrier.
4. The method of claim 1, wherein the derivative is in the form of
a pharmaceutically acceptable salt.
5. The method of claim 1, wherein the bipolar disorder is
mania.
6. The method of claim 1, wherein the subject is human.
7. The method of claim 1, wherein the route of administration is
selected from the group consisting of oral, parenteral,
intraperitoneal, intravenous, intramuscular, transdermal,
subcutaneous, topical and rectal administration.
8. The method of claim 1, wherein the effective amount is an amount
from about 10 mg to 1,000 mg.
9. The method of claim 8, wherein the effective amount is an amount
from about 50 mg to 500 mg.
10. The method of claim 1, wherein the derivative has structure I
and the C.sub.1-C.sub.6 alkyl group is a linear chain alkyl
group.
11. The method of claim 1, wherein the derivative has structure I
and the C.sub.1-C.sub.6 alkyl group is a branched chain alkyl
group.
12. The method of claim 1, wherein the derivative has structure I
and the aralkyl group is selected from the group consisting of a
benzyl, alkylbenzyl, hydroxybenzyl, alkoxycarbonylbenzyl,
aryloxycarbonylbenzyl, carboxybenzyl, nitrobenzyl, cyanobenzyl, and
halobenzyl group.
13. The method of claim 1, wherein the derivative has structure I
and the aryl group is selected from the group consisting of a
phenyl, naphthyl, anthracenyl, pyridinyl, indolyl, furanyl,
alkylphenyl, hydroxyphenyl, alkoxycarbonylphenyl,
aryloxycarbonylphenyl, nitrophenyl, cyanophenyl, halophenyl group,
mercaptophenyl, and aminophenyl group.
14. The method of claim 1, wherein the derivative has structure II
and the C.sub.1-C.sub.6 alkyl group is a linear chain alkyl
group.
15. The method of claim 1, wherein the derivative has structure II
and the C.sub.1-C.sub.6 alkyl group is a branched chain alkyl
group.
16. The method of claim 1, wherein the derivative has structure II
and the aralkyl group is selected from the group consisting of a
benzyl, alkylbenzyl, hydroxybenzyl, alkoxycarbonylbenzyl,
aryloxycarbonylbenzyl, carboxybenzyl, nitrobenzyl, cyanobenzyl, and
halobenzyl group.
17. The method of claim 1, wherein the derivative has structure II
and the aryl group is selected from the group consisting of a
phenyl, naphthyl, anthracenyl, pyridinyl, indolyl, furanyl,
alkylphenyl, hydroxyphenyl, alkoxycarbonylphenyl,
aryloxycarbonylphenyl, nitrophenyl, cyanophenyl, halophenyl group,
mercaptophenyl, and aminophenyl group.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/220,102, filed Jul. 21, 2000.
[0002] Throughout this application, various references are
referenced by short citations within parenthesis. Full citations
for these references may be found at the end of the specification,
immediately preceding the claims. These references, in their
entireties, are hereby incorporated by reference to more fully
describe the state of the art to which this invention pertains.
FIELD OF THE INVENTION
[0003] Disclosed is a method for the treatment of mania in bipolar
disorder using derivatives of valproic acid and 2-valproenic acid
amides.
BACKGROUND OF THE INVENTION
[0004] Affective disorders refer mainly to changes in mood rather
than thought disturbances (Rang, H. P., M. M. Dale and J. M.
Ritter). Depression is the most common manifestation, although it
also includes mania. In many respects the symptoms of mania are
opposite to those of depression. Whereas the symptoms of depression
include a feeling of misery, apathy, and low self-esteem, those of
mania include excessive exuberance, enthusiasm and self-confidence.
There are two basic types of depressive syndrome: bipolar and
unipolar (Rang, H. P., M. M. Dale and J. M. Ritter). Patients with
a history of both depression and mania are considered to have a
bipolar disorder (BPD). Those patients which suffer from depression
are considered to be unipolar. Bipolar disorder is further
subdivided into different segments. In bipolar I patients have at
least one manic episode with or without depression. In bipolar II
patients have at least one hypomanic episode with depression.
Patients with BPD have the highest rate of suicide among patients
with psychiatric illnesses.
[0005] Anti-depresants are the standard treatment for unipolar
depression, but are not effective for mania. To treat mania in
bipolar depression lithium (Li.sup.+) has classically been used,
and more recently the anti-epileptic drug (AED) valproate has been
demonstrated to be effective (Bowden et al.; Calabrese, J. R. et
al.) Other AEDs, such as carbamazepine, are also considered to be
useful for mania. However phenobarbital, although clearly an
effective AED, is not useful as a drug to treat mania (Belmaker, R.
H. and Y. Yaroslavsky), or affective disorders. Today, many
patients with mania are not controlled by current treatments
(Calabresse, J. R. et al.). Therefore, there is a need for new
treatments.
[0006] In order to discover new drugs in this area, rodent models
relevant to the manic phase are used. One commonly used model is
the amphetamine-induced hyperactivity model (Lyon, M.). This model
focuses on an induced increase in the activity level of the animal
(hyperactivity) as a parallel to the hyperactivity of the manic
patient. The reversal of the induced hyperactivity in rodents, by
pretreatment with a drug indicates the possible efficacy of this
drug in the treatment of human mania. The most consistent finding
with Li.sup.+ (the standard drug for mania) in untreated animals,
is the reduction in rearing (Johnson, F. N.). Rearing is followed
in the models by observing the vertical activity of the
animals.
[0007] Bialer et al. describe a series of derivatives of valproic
acid amides and 2-valproenic acid for the effective treatment of
epilepsy and other neurological disorders (U.S. Pat. No.
5,585,358).
SUMMARY OF THE INVENTION
[0008] It has been surprisingly observed that the valproic acid
amide of Bialer et al. (U.S. Pat. No. 5,585,358), Compound 1 below,
decreases amphetamine-induced hyperactivity. The subject invention
provides a method for the treatment of mania in bipolar disorder
using derivatives of valproic acid amides and 2-valproenic acid
amides.
[0009] The subject invention provides a method of treating mania in
bipolar disorders in a subject. The invention comprises the
administration of a therapeutically effective amount of a
derivative of a valproic acid amide or a 2-valproenic acid amide
having one of the following structures: 2
[0010] wherein R.sub.1, R.sub.2, and R.sub.3 are independently the
same or different and are hydrogen, a C.sub.1-C.sub.6 alkyl group,
an aralkyl group, or an aryl group, and n is an integer which is
greater than or equal to 0 and less than or equal to 3,
[0011] or a compound containing a valproic or a 2-valproenic
moiety, as well as pharmaceutical compositions comprising these
derivatives or compounds.
DETAILED DESCRIPTION OF THE INVENTION
[0012] Disclosed is a method of treating bipolar disorder in a
subject comprising administering to the subject a therapeutically
effective amount of a derivative of a valproic acid amide or a
2-valproenic acid amide having one of the following structures:
3
[0013] wherein R.sub.1, R.sub.2, and R.sub.3 are independently the
same or different and are hydrogen, a C.sub.1-C.sub.6 alkyl group,
an aralkyl group, or an aryl group, and n is an integer which is
greater than or equal to 0 and less than or equal to 3, to thereby
treat the bipolar disorder.
[0014] The derivative may have the structure: 4
[0015] The derivative used in the method may be in the form of a
pharmaceutical composition with a pharmaceutically acceptable
carrier. The derivative may also be in the form of a
pharmaceutically acceptable salt.
[0016] The bipolar disorder may be mania.
[0017] The subject may be human.
[0018] In one embodiment, the invention provides the derivative of
formula I hereinabove shown wherein the C.sub.1-C.sub.6 alkyl group
is a linear chain alkyl group. In another embodiment, the invention
provides the derivative of formula I hereinabove shown wherein the
C.sub.1-C.sub.6 alkyl group is a branched chain alkyl group. In yet
another embodiment, the invention provides the derivative of
formula I hereinabove shown wherein the aralkyl group is a benzyl,
alkylbenzyl, hydroxybenzyl, alkoxycarbonylbenzyl,
aryloxycarbonylbenzyl, carboxybenzyl, nitrobenzyl, cyanobenzyl, or
halobenzyl group. In still another embodiment, the invention
provides the derivative of formula I wherein the aryl group is a
phenyl, naphthyl, anthracenyl, pyridinyl, indolyl, furanyl,
alkylphenyl, hydroxyphenyl, alkoxycarbonylphenyl,
aryloxycarbonylphenyl, nitrophenyl, cyanophenyl, halophenyl group,
mercaptophenyl, or aminophenyl group.
[0019] In one embodiment, the invention provides the derivative of
formula II hereinabove shown wherein the C.sub.1-C.sub.6 alkyl
group is a linear chain alkyl group. In another embodiment, the
invention provides the derivative of formula II hereinabove shown
wherein the C.sub.1-C.sub.6 alkyl group is a branched chain alkyl
group. In still another embodiment, the invention provides the
derivative of formula II hereinabove shown wherein the aralkyl
group is a benzyl, alkylbenzyl, hydroxybenzyl,
alkoxycarbonylbenzyl, aryloxycarbonylbenzyl, carboxybenzyl,
nitrobenzyl, cyanobenzyl, or halobenzyl group. In yet another
embodiment, the invention provides the derivative of formula II
hereinabove shown wherein the aryl group is a phenyl, naphthyl,
anthracenyl, pyridinyl, indolyl, furanyl, alkylphenyl,
hydroxyphenyl, alkoxycarbonylphenyl, aryloxycarbonylphenyl,
nitrophenyl, cyanophenyl, halophenyl group, mercaptophenyl, or
aminophenyl group.
[0020] Some of the derivatives used in this invention possess
chiral centers. It is a further embodiment of this invention that
these derivatives may comprise substantially pure D or L
enantiomers or racemic mixtures. It is to be understood that
derivatives of the general formula II may be of the E-(trans) or
Z-(cis) geometric configuration, or a mixture thereof.
[0021] In the practice of the invention, the amount of the
derivative incorporated in the pharmaceutical composition may vary
widely. Factors considered when determining the precise amount are
well known to those skilled in the art. Examples of such factors
include, but are not limited to, the subject being treated, the
specific pharmaceutical carrier, and route of administration being
employed and the frequency with which the composition is to be
administered.
[0022] In one embodiment, the effective amount of derivatives of
valproic acid amides and 2-valproenic acid amides for the treatment
of mania in bipolar disorder comprises an amount from about 10 to
about 1,000 mg. The effective amount may also be an amount from
about 10 mg to about 500 mg. Additionally, the effective amount may
comprise an amount from about 50 mg to about 500. The effective
amount may additionally comprise an amount from about 100 mg to
about 250 mg. Also, the effective amount may comprise an amount
from about 150 mg to about 200 mg.
[0023] In a preferred embodiment, the derivative is administered in
a pharmaceutical composition which comprises the derivative and a
pharmaceutically acceptable carrier. As used herein, the term
"pharmaceutically acceptable carrier" encompasses any of the
standard pharmaceutically accepted carriers, such as a
phosphate-buffered saline solution, water, emulsions such as an
oil/water emulsion or a triglyceride emulsion, various types of
wetting agents, tablets, coated tablets, and capsules. An example
of an acceptable triglyceride emulsion useful in the intravenous
and intraperitoneal administration of the derivatives is the
triglyceride emulsion commercially known as Intralipid.RTM..
[0024] Typically, such carriers contain excipients such as starch,
milk, sugar, certain types of clay, gelatin, stearic acid, talc,
vegetable fats or oils, gums, glycols, or other known excipients.
Such carriers may also include flavor and color additives or other
ingredients.
[0025] In the practice of the invention, the administration of the
pharmaceutical composition may be effected by any of the well known
methods including, but not limited to, rectal, oral, intravenous,
intraperitoneal, parenteral, intramuscular, transmdermal,
subcutaneous or topical administration. Topical administration can
be effected by any method commonly known to those skilled in the
art and include, but are not limited to, incorporation of the
pharmaceutical composition into creams, ointments, or transdermal
patches.
[0026] The invention further provides a pharmaceutical composition
which comprises any derivative of Formula I or II in a amount which
is therapeutically effective to treat mania in bipolar disorder and
a pharmaceutically acceptable carrier. The invention encompasses a
pharmaceutical composition as hereinabove described wherein the
carrier is a solid and the composition is a tablet. The invention
also encompasses a pharmaceutical composition as hereinabove
described wherein the carrier is a gel and the composition is a
suppository. The invention further encompasses a pharmaceutical
composition as hereinabove described wherein the carrier is a
liquid and the composition is a solution.
[0027] The following Experimental Details are set forth to aid in
an understanding of the invention, and are not intended, and should
not be construed, to limit in any way the invention set forth in
the claims which follow thereafter.
EXPERIMENTAL DETAILS
I. Synthesis of Compound 1
Compound 1
[0028] 5
[0029] Compound 1 was prepared as disclosed by Bialer et al. (U.S.
Pat. No. 5,585,358).
II. Experimental Details
[0030] Evaluation of possible anti-bipolar effects of Compound 1
was followed in the amphetamine-induced hyperactivity model of
mania in rats. Activities of rats were followed in an activity
meter (Elvicom, Israel) based on 2 levels laser beams and equipped
with a computerized system that can count the vertical movements of
rats (rearing). Activities were recorded for -30 min for each
session, and the resultant appropriate movement reported per 30
min. Rats were housed under a 12 hr light/dark cycle and the
behavioral testing was conducted in the light phase.
[0031] The activities of rats following treatment with Compound 1,
Li.sup.+ (the standard drug for mania), and a control group were
followed before and after being challenged with amphetamine. The
statistical analyses were conducted using a two way ANOVA for the
effects of drugs, amphetamine (repeated measure) and the
drug-amphetamine interaction.
[0032] In these experiments 30 male Sprague Dawley (weighing
200-250 g) rats were equally divided into 3 treatment groups:
control, Li.sup.+ (6 mg/kg by gavage)), and Compound 1 (200 mg/kg
by gavage) (Drugs were suspended in 5% methyl cellulose). Half of
the rats in each group were challenged (administered) amphetamine
(0.5 mg/kg subsutaneously (s.c.)) and the other half was given
saline (s.c.). Ten minutes later all rats were placed in the
activity meter. One week later the procedure was repeated, except
that the order of treatment was reversed; those rats which received
saline on the first day were given amphetamine and those given
amphetamine the first day were administered saline.
III. Results
[0033] The results of the experiment employing Compound 1 are shown
in Table 1. Hyperactivity in the rats was induced after the
amphetamine challenge, as indicated by the increase in rearing
(vertical movements) compared to saline challenged animals in the
control group.
[0034] Treatment with Compound 1 reduced the rearing when animal
were challenged with amphetamine compared to control animals
challenged with atmphetamine (p=0.06) (Table 1). This effect is in
a similar direction to that observed with Li.sup.+.
1TABLE 1 Activities of rats on Compound 1 or Li.sup.+after a
challenge with saline or amphetamine. Saline Mean Amphetamine
Challenge activity SD Mean Activity SD Vertical Activity (Rearing)
Treatments Control 102.9 83.7 181.4 138.3 Li 59.8 45 126.7 173.1
Compound 1 34.1 26 71.3 49.4 SD, standard deviation
Discussion
[0035] The effects of Compound 1 in rats have been evaluated in
comparison with that of Li.sup.+, a well established drug for the
treatment of bipolar disease. Compound 1 was tested in the
amphetamine-induced hyperactivity model, that is well accepted as a
model of bipolar disease (mania phase). The end point criteria was
reduction in vertical movements (rearing). Compound 1 decreased the
induced rearing in a similar manner as Li.sup.+, indicating that
Compound 1 and the claimed valproic acid amides and 2-valproenic
acid amides are effective for the treatment of mania in bipolar
disorder.
References
[0036] U.S. Pat. No. 5,585,358, Bialer et al., issued Dec. 6,
1996.
[0037] Belmaker, R. H. and Y. Yaroslavsky, Basic Mechanism and
Therapeutic Implications of BP disorder, Marcel Dekker, Inc., Ed.
S. Gershon and J. Soares, 2000.
[0038] Bowden et al., Efficacy of divalproex vs. lithium and
placebo in the treatment of mania, JAMA 1994: 271:918-924.
[0039] Calabrese, J. R. et al., Lithium and the anticonvulsants in
the treatment of bipolar disorder, in: Psyqhopharmacology: The
fourth generation of progress, eds. R. Bloom and D. Kupfer, Raven
Press, Ltd., 1995.
[0040] Lyon, M., Animal model mania and schizophrenia in: Willner,
P. Behavior Model in Psychopharmacology, Cambrige University Press,
NY, 1991, pp. 253-310.
[0041] Johnson, F. N., Association of vertical and horizontal
components of activity in rats treated with lithium chloride,
Experientia, 1972, 28: 533-535.
[0042] Rang, H. P., M. M. Dale and J. M. Ritter, Pharmacology
3.sup.rd Ed., Churchill Livingstone, p. 576.
* * * * *