U.S. patent application number 12/408537 was filed with the patent office on 2009-07-16 for compounds useful for treating neurological disorders.
This patent application is currently assigned to Yissum Research Development Company of The Hebrew University of Jerusalem. Invention is credited to Meir BIALER, Marshall DEVOR, IIan WINKLER, Boris YAGEN.
Application Number | 20090182048 12/408537 |
Document ID | / |
Family ID | 36952578 |
Filed Date | 2009-07-16 |
United States Patent
Application |
20090182048 |
Kind Code |
A1 |
BIALER; Meir ; et
al. |
July 16, 2009 |
Compounds Useful For Treating Neurological Disorders
Abstract
The invention relates to the use of compounds for the
preparation of a medicament for treating neuropathic pain,
migraine, psychiatric disorder and/or neuronal degeneration. The
invention additionally relates to a pharmaceutical composition
comprising compounds for treating neuropathic pain, migraine,
psychiatric disorder and/or neuronal degeneration. A method for
treating neuropathic pain, migraine, psychiatric disorder and/or
neuronal degeneration is also provided.
Inventors: |
BIALER; Meir; (Jerusalem,
IL) ; YAGEN; Boris; (Jerusalem, IL) ; WINKLER;
IIan; (Bat Yam, IL) ; DEVOR; Marshall;
(Jerusalem, IL) |
Correspondence
Address: |
BROWDY AND NEIMARK, P.L.L.C.;624 NINTH STREET, NW
SUITE 300
WASHINGTON
DC
20001-5303
US
|
Assignee: |
Yissum Research Development Company
of The Hebrew University of Jerusalem
Jerusalem
IL
|
Family ID: |
36952578 |
Appl. No.: |
12/408537 |
Filed: |
March 20, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11153894 |
Jun 16, 2005 |
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12408537 |
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PCT/IL2004/000689 |
Jul 28, 2004 |
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11153894 |
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60490273 |
Jul 28, 2003 |
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Current U.S.
Class: |
514/557 ;
514/624; 514/625 |
Current CPC
Class: |
A61P 25/06 20180101;
A61P 25/00 20180101; A61K 31/16 20130101; A61K 31/19 20130101; A61P
25/18 20180101 |
Class at
Publication: |
514/557 ;
514/624; 514/625 |
International
Class: |
A61K 31/19 20060101
A61K031/19; A61P 25/00 20060101 A61P025/00; A61K 31/164 20060101
A61K031/164 |
Claims
1. A method for treating a disease or condition selected from:
neuropathic pain, migraine, and neuronal degeneration, in a mammal
comprising administering to the mammal, a therapeutically effective
amount of a compound of formula [A]: ##STR00018## as racemic
mixtures or as individual stereoisomers or mixtures of racemic and
stereoisomers, wherein (i) X is selected from OH and
NR.sup.1R.sup.2; (ii) R.sup.1, R.sup.2 are independently selected
from H and C.sub.1-C.sub.6 alkyl; (iii) n is 0 or 1; and (iv) (a)
R.sup.3, R.sup.4 are independently selected from H and
C.sub.1-C.sub.6 alkyl; R.sup.1, R.sup.6 are independently selected
from H and C.sub.1-C.sub.6 alkyl; or (b) one of R.sup.3 and
R.sup.4, together with one of R.sup.5 and R.sup.6, form a
cyclopropyl ring, and the other of R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 is selected from H and C.sub.1-C.sub.6 alkyl, including
pharmaceutically acceptable salts, hydrates and solvates of the
compound of formula [A], with the exclusion of the following
compounds in racemic and stereoisomeric forms for treating
migraine: propylisopropyl acetic acid, propylisopropyl acetamide,
valnoctamide, valnoctic acid, diisopropyl acetamide and diisopropyl
acetic acid.
2. A method for treating a psychiatric disorder in a mammal
comprising administering to the mammal, a therapeutically effective
amount of a compound of formula [A] as defined in claim 1, with the
exclusion of compounds of formula II: ##STR00019## wherein R.sup.1
and R.sup.2 are independently selected from H and C.sub.1-C.sub.6
alkyl.
3. A method according to claim 1 for treating a disease or
condition selected from: neuropathic pain, migraine, and neuronal
degeneration, in a mammal comprising administering to said mammal,
a therapeutically effective amount of a compound of formula I
##STR00020## as racemic mixtures or as individual stereoisomers or
mixtures of racemic and stereoisomers, wherein (i) X is selected
from OH and NR.sup.1R.sup.2; (ii) R.sup.1, R.sup.2 are
independently selected from H and C.sub.1-C.sub.6 alkyl; and (iii)
(a) R.sup.3, R.sup.4 are independently selected from H and
C.sub.1-C.sub.6 alkyl; R.sup.5, R.sup.6 are independently selected
from H and C.sub.1-C.sub.6 alkyl; or (b) one of R.sup.3 and
R.sup.4, together with one of R.sup.5 and R.sup.6, form a
cyclopropyl ring, and the other of R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 is selected from H and C.sub.1-C.sub.6 alkyl, including
pharmaceutically acceptable salts, hydrates and solvates of the
compound of formula [I], with the exclusion of the following
compounds in racemic and stereoisomeric forms for treating
migraine: valnoctamide, valnoctic acid, diisopropyl acetamide and
diisopropyl acetic acid.
4. The method according to claim 1 wherein said C.sub.1-C.sub.6
alkyl group is a straight or a branched alkyl group.
5. The method according to claim 3 wherein the total number of
carbon atoms of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 in a compound
of formula I is two.
6. The method according to claim 3 wherein (i) X is selected from
OH and NR.sup.1R.sup.2; (ii) R.sup.1, R.sup.2 are independently
selected from H and C.sub.1-C.sub.6 alkyl; and (iii) (a) R.sup.3,
R.sup.4 are independently selected from H, methyl and ethyl;
R.sup.5, R.sup.6 are independently selected from H, methyl and
ethyl; or (b) one of R.sup.3 and R.sup.4, together with one of
R.sup.5 and R.sup.6, form a cyclopropyl ring, and the other of
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is selected from H, methyl
and ethyl.
7. The method according to claim 3 wherein X is selected from OH
and NR.sup.1R.sup.2; R.sup.1, R.sup.2 are independently selected
from H and C.sub.1-C.sub.6 alkyl; and one of R.sup.3 and R.sup.4,
together with one of R.sup.5 and R.sup.6, form a cyclopropyl ring
and the other of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is a
methyl.
8. The method according to claim 7 having the structural formula II
##STR00021## wherein R.sup.1 and R.sup.2 are independently selected
from H and C.sub.1-C.sub.6 alkyl.
9. The method according to claim 7 wherein at least one of R.sup.1
and R.sup.2 is H and the other of R.sup.1 and R.sup.2 is a
C.sub.1-C.sub.6 alkyl.
10. The method according to claim 7 wherein said C.sub.1-C.sub.6
alkyl is a methyl.
11. The method according to claim 7 wherein said compound is
N-Methyl-2,2,3,3-tetramethylcyclopropanecarboxamide.
12. The method according to claim 7 wherein said compound is
2,2,3,3-tetramethylcyclopropanecarboxamide.
13. The method according to claim 3 wherein said compound is
2-ethyl-3-methyl-pentanoic acid amide, as racemic mixture or as
individual stereoisomers or mixtures of racemic and stereoisomers,
including pharmaceutically acceptable salts, hydrates and solvates
thereof, for the treatment of neuropathic pain and neuronal
degeneration.
14. The method according to claim 3 wherein said compound is
2-ethyl-3-methyl-pentanoic acid, as racemic mixture or as
individual stereoisomers or mixtures of racemic and stereoisomers,
including pharmaceutically acceptable salts, hydrates and solvates
thereof, for the treatment of neuropathic pain and neuronal
degeneration.
15. The method according to claim 7 wherein said compound is
2,2,3,3-tetramethylcyclopropanecarboxylic acid.
16. The method according to claim 1 for treating neuropathic pain
or neuronal degeneration, wherein said compound is propyl
isopropylacetamide (PID) as racemic mixture or as individual 2R and
2S stereoisomers or mixtures of racemic and stereoisomers,
including pharmaceutically acceptable salts, hydrates and solvates
thereof.
17. The method according to claim 1 wherein said compound is
diisopropylacetamide (DID).
18. The method according to claim 1 wherein said compound is
diisopropylacetic acid (DIA).
19. The method according to claim 1 wherein said disease or
condition is a neuropathic pain.
20. The method according to claim 1 wherein the route of
administration of said compound is selected from oral, parenteral,
topical, transdermal, mucosal, rectal and buccal
administration.
21. The method according to claim 1 wherein the route of
administration of said compound is selected from oral and
parenteral administration.
22. The method according to claim 21 wherein said parenteral route
of administration is selected from intravenous, intramuscular,
intraperitoneal and subcutaneous administration.
23. The method of claim 1 wherein said mammal is a human.
Description
FIELD OF THE INVENTION
[0001] The invention relates to compounds for the treatment of
neurological disorders preferably neuropathic pain, migraine,
psychiatric disorders and/or neuronal degeneration.
BACKGROUND OF THE INVENTION
[0002] Neuropathic pain is an intractable pain initiated or caused
by a primary lesion or dysfunction in the peripheral or central
nervous system. Neuropathic pain is part of the neurological
disease spectrum and may be an expression of severe medical
pathology [Hansson P. European J. of Pain 2002; 6; 45]. Neuropathic
pain manifests itself due to neurological disorders accompanying
various causes such as wound, infection, cancer, ischemia and
metabolic disorders including diabetes mellitus. Though there are
many unclear points on the mechanism of neuropathic pain, it is
considered that abnormal continuous firing of sensory nerve and the
like are the cause. Typical symptoms of neuropathic pain include
allodinia, hyperalgesia, hyperesthesia and the like. Their symptoms
include characteristic pains expressed as "like burning", "like
stinging", "like electrical shock" and the like. Unfortunately, and
unlike other types of pain, neuropathic-pain tends to respond
poorly to analgesic medication.
[0003] It is known that analgesics, particularly narcotic
analgesics and the like, which are effective for general
nociceptive pains are hardly effective for neuropathic pain. For
example, it is known that morphine has a strong analgesic effect on
nociceptive pains but does not show a sufficient effect on
neuropathic pain.
[0004] Patients with neuropathic pain do not respond to
non-steroidal anti-inflammatory drugs and resistance or
insensitivity to opiates is common. Patients are usually treated
empirically with tricyclic or serotonin and norepinephrine uptake
inhibitors, and anticonvulsants that all have limited efficacy and
undesirable side effects. Neurosurgical lesions have a negligible
role and functional neurosurgery, including dorsal column or brain
stimulation, is controversial, although transcutaneous nerve
stimulation may provide some relief. Local anaesthetic blocks
targeted at trigger points, peripheral nerves, plexi, dorsal roots,
and the sympathetic nervous system have useful but short lived
effects; longer lasting blocks by phenol injection or cryotherapy
risk irreversible functional impairment and have not been tested in
placebo-controlled trials. Chronic epidural administration of drugs
such as clonidine, steroids, opiates, or midazolam is invasive, has
side effects and the efficacy of these drugs has not been
adequately assessed [Woolf J. et al. Lancet 1999; 353;
1959-64].
[0005] Valproic acid (VPA), is one of the major antiepileptic drugs
used today, having a wide use in both generalized and partial
epilepsies. VPA has not been well studied for effect on neuropathic
pain and the role of VPA in the treatment of neuropathic pain has
not been determined by clinical trials. In one double-blind
placebo-controlled trial of VPA reported on so far for the
treatment of neuropathic pain due to spinal cord injury there was
no difference between VPA and placebo in relieving pain [Backonja
M. M. The Clinical Journal of Pain, 16, S67-S72, 2000].
[0006] Additionally, the use of Valproic acid (VPA), is limited by
its considerable adverse effects including hepatotoxicity and
teratogenicity and thus cannot be given to women of childbearing
age and children [Baille, T. A. et al. In Antiepileptic Drugs, eds.
R. H. Levy et al. Raven Press, New York. Pp. 641-651 (1989)].
[0007] Since a safe and effective therapeutic method has not been
established, concern has been directed toward the development of a
therapy effective for neuropathic pain.
[0008] There is thus a widely recognized need for, and it would be
highly advantageous to have, new agents for treating neuropathic
pain devoid of the above limitations.
[0009] Valnoctamide (VCD), an amide analogue of VPA having
anti-convulsant activity was found to be distinctly less
teratogenic than VPA [Radatz M et al. Epilepsy Res.
1998:30(1):41-8]. M. Roeder et al [M. Roeder et al, Tetrahedron:
Asymmetry 1999: 10: 841-853] and U.S. Pat. No. 6,417,399 relate to
stereoisomers of valnoctamide (VCD), synthesis thereof, a method
for stereoselective separation thereof as well as uses thereof.
[0010] U.S. Pat. No. 5,880,157 and M. Bialer et al. [M. Bialer et
al. Pharm Res. 13:284-289 (1996)] disclose derivatives of 2,2,3,3
tetramethylcyclopropane carboxylic acid for treating epilepsy.
Isoherranen N. et al 2002, studied the anticonvulsant activity of
N-methyl-tetramethylcyclopropyl carboxamide (M-TMCD) and its
metabolite in various animal (rodent) models of human epilepsy, and
evaluated their ability to induce neural tube defects (NTDs) and
neurotoxicity. [Isoherranen N. et al. Epilepsia 2002; 43:115-126].
M-TMCD (a cyclopropyl analog of VPA) was found to be advantageous
compared to VPA because of its better potency as an anticonvulsant
drug, its wider safety of margin, its lack of teratogenicity and
its potential lack of hepatotoxicity.
[0011] Thus, there is a widely recognized need and it will be
highly advantageous to have compounds which are effective in
treating neuropathic pain with minimal side effects. Additionally,
it would be highly advantageous to have compounds effective against
migraine, psychiatric disorders and/or neurodegenerative
diseases.
SUMMARY OF THE INVENTION
[0012] According one aspect of the present invention there is
provided use of a compound of formula [A]:
##STR00001##
as racemic mixtures or as individual stereoisomers or mixtures of
racemic and stereoisomers, wherein (i) X is selected from OH and
NR.sup.1R.sup.2; (ii) R.sup.1, R.sup.2 are independently selected
from H and C.sub.1-C.sub.6 alkyl; (iii) n is 0 or 1; and (iv) (a)
R.sup.3, R.sup.4 are independently selected from H and
C.sub.1-C.sub.6 alkyl; [0013] R.sup.5, R.sup.6 are independently
selected from H and C.sub.1-C.sub.6 alkyl; or [0014] (b) one of
R.sup.3 and R.sup.4, together with one of R.sup.5 and R.sup.6, form
a cyclopropyl ring, and the other of R.sup.3. R.sup.4, R.sup.5 and
R.sup.6 is selected from H and C.sub.1-C.sub.6 alkyl, [0015]
including pharmaceutically acceptable salts, hydrates and solvates
of the compound of formula [A], for the preparation of a medicament
for treating a disease or condition selected from: neuropathic
pain, migraine and neuronal degeneration; with the proviso that
where the use is for the treatment of migraine, compounds disclosed
in WO 99/54282, incorporated herein by reference in its entirety,
are excluded. Among the excluded compounds are: propylisopropyl
acetic acid, propylisopropyl acetamide, valnoctamide, valnoctic
acid, diisopropyl acetamide and diisopropyl acetic acid, in racemic
and stereoisomeric forms.
[0016] In a preferred embodiment, there is provided use of a
compound of formula I
##STR00002##
as racemic mixtures or as individual stereoisomers or mixtures of
racemic and stereo isomers, wherein (i) X is selected from OH and
NR.sup.1R.sup.2; (ii) R.sup.1, R.sup.2 are independently selected
from H and C.sub.1-C.sub.6 alkyl; and (iii) (a) R.sup.3, R.sup.4
are independently selected from H and C.sub.1-C.sub.6 alkyl; [0017]
R.sup.5, R.sup.6 are independently selected from H and
C.sub.1-C.sub.6 alkyl; or [0018] (b) one of R.sup.3 and R.sup.4,
together with one of R.sup.5 and R.sup.6, form a cyclopropyl ring,
and the other of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is selected
from H and C.sub.1-C.sub.6 alkyl; [0019] including pharmaceutically
acceptable salts, hydrates and solvates of the compound of formula
[I], for the preparation of a medicament for treating a disease or
condition selected from: neuropathic pain, migraine and neuronal
degeneration.
[0020] According to another aspect of the present invention there
is provided use of a compound of formula [A] or [I] as defined
above, for the preparation of a medicament for treating a
psychiatric disorder, especially a bipolar disorder. In the case of
medicaments for treating psychiatric disorders, excluded are
compounds of formula II:
##STR00003##
wherein R.sup.1 and R.sup.2 are independently selected from H and
C.sub.1-C.sub.6 alkyl.
[0021] According to another aspect of the present invention there
is provided a pharmaceutical composition for treating a disease or
condition selected from: neuropathic pain, migraine, and neuronal
degeneration comprising a pharmaceutically acceptable carrier and
as an active ingredient a therapeutically effective amount of a
compound of formula [A]:
##STR00004##
as racemic mixtures or as individual stereoisomers or mixtures of
racemic and stereoisomers, wherein (i) X is selected from OH and
NR.sup.1R.sup.2; (ii) R.sup.1, R.sup.2 are independently selected
from H and C.sub.1-C.sub.6 alkyl; (iii) n is 0 or 1; and (iv) (a)
R.sup.3, R.sup.4 are independently selected from H and
C.sub.1-C.sub.6 alkyl; [0022] R.sup.5, R.sup.6 are independently
selected from H and C.sub.1-C.sub.6 alkyl; or [0023] (b) one of
R.sup.3 and R.sup.4, together with one of R.sup.5 and R.sup.6, form
a cyclopropyl ring, and the other of R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 is selected from H and C.sub.1-C.sub.6 alkyl, including
pharmaceutically acceptable salts, hydrates and solvates of the
compound of formula [A], with the proviso that where the use is for
the treatment of migraine, compounds disclosed in WO 99/54282,
incorporated herein by reference in its entirety, are excluded.
Among the excluded compounds are: propylisopropyl acetic acid,
propylisopropyl acetamide, valnoctamide, valnoctic acid,
diisopropyl acetamide and diisopropyl acetic acid, in racemic and
stereoisomeric forms.
[0024] In a preferred embodiment, there is provided a
pharmaceutical composition for treating a disease or condition
selected from: neuropathic pain, migraine and neuronal degeneration
comprising a pharmaceutically acceptable carrier and as an active
ingredient a therapeutically effective amount of a compound of
formula [I]:
##STR00005##
as racemic mixtures or as individual stereoisomers or mixtures of
racemic and stereoisomers wherein (i) X is selected from OH and
NR.sup.1R.sup.2; (ii) R.sup.1, R.sup.2 are independently selected
from H and C.sub.1-C.sub.6 alkyl; and (iii) (a) R.sup.3, R.sup.4
are independently selected from H and C.sub.1-C.sub.6 alkyl; [0025]
R.sup.5, R.sup.6 are independently selected from H and
C.sub.1-C.sub.6 alkyl; or [0026] (b) one of R.sup.3 and R.sup.4,
together with one of R.sup.5 and R.sup.6, form a cyclopropyl ring,
and the other of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is selected
from H and C.sub.1-C.sub.6 alkyl, [0027] including pharmaceutically
acceptable salts, hydrates and solvates of the compound of formula
[I].
[0028] According to another aspect of the present invention there
is provided a pharmaceutical composition for treating a psychiatric
disorder, comprising a pharmaceutically acceptable carrier and as
an active ingredient a therapeutically effective amount of a
compound of formula [A] or [I] as defined above. Excluded from the
above formulae are compounds of formula II:
##STR00006##
wherein R.sup.1 and R.sup.2 are independently selected from H and
C.sub.1-C.sub.6 alkyl.
[0029] According to yet another aspect of the present invention
there is provided a method for treating a disease or condition
selected from: neuropathic pain, migraine and neuronal
degeneration, in a mammal comprising administering to the mammal, a
therapeutically effective amount of a compound of formula [A]:
##STR00007##
as racemic mixtures or as individual stereoisomers or mixtures of
racemic and stereoisomers, wherein (i) X is selected from OH and
NR.sup.1R.sup.2; (ii) R.sup.1, R.sup.2 are independently selected
from H and C.sub.1-C.sub.6 alkyl; (iii) n is 0 or 1; and (iv) (a)
R.sup.3, R.sup.4 are independently selected from H and
C.sub.1-C.sub.6 alkyl; [0030] R.sup.5, R.sup.6 are independently
selected from H and C.sub.1-C.sub.6 alkyl; or [0031] (b) one of
R.sup.3 and R.sup.4, together with one of R.sup.5 and R.sup.6, form
a cyclopropyl ring, and the other of R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 is selected from H and C.sub.1-C.sub.6 alkyl including
pharmaceutically acceptable salts, hydrates and solvates of the
compound of formula [A], with the proviso that where the method is
for the treatment of migraine, compounds disclosed in WO 99/54282,
incorporated herein by reference in its entirety, are excluded.
Among the excluded compounds are: propylisopropyl acetic acid,
propylisopropyl acetamide, valnoctamide, valnoctic acid,
diisopropyl acetamide and diisopropyl acetic acid, in racemic and
stereoisomeric forms.
[0032] In a preferred embodiment, there is provided a method for
treating a disease or condition selected from: neuropathic pain,
migraine and neuronal degeneration, in a mammal comprising
administering to the mammal, a therapeutically effective amount of
a compound of formula [I]:
##STR00008##
as racemic mixtures or as individual stereoisomers or mixtures of
racemic and stereoisomers wherein (i) X is selected from OH and
NR.sup.1R.sup.2; (ii) R.sup.1, R.sup.2 are independently selected
from H and C.sub.1-C.sub.6 alkyl; and (iii) (a) R.sup.3, R.sup.4
are independently selected from H and C.sub.1-C.sub.6 alkyl; [0033]
R.sup.5, R.sup.6 are independently selected from H and
C.sub.1-C.sub.6 alkyl; or [0034] (b) one of R.sup.3 and R.sup.4,
together with one of R.sup.5 and R.sup.6, form a cyclopropyl ring,
and the other of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is selected
from H and C.sub.1-C.sub.6 alkyl, [0035] including pharmaceutically
acceptable salts, hydrates and solvates of the compound of formula
[I].
[0036] According to yet another aspect of the present invention
there is provided a method for treating a psychiatric disorder in a
mammal comprising administering to the mammal a therapeutically
effective amount of a compound of formula [A] or [I] as defined
above. Excluded from the above formulae are compounds of formula
II:
##STR00009##
wherein R.sup.1 and R.sup.2 are independently selected from H and
C.sub.1-C.sub.6 alkyl.
DETAILED DESCRIPTION OF THE INVENTION
[0037] The present invention relates to the use of a compound of
formula I
##STR00010##
as racemic mixtures or as individual stereoisomers or mixtures of
racemic and stereoisomers, wherein (i) X is selected from OH and
NR.sup.1R.sup.2; (ii) R.sup.1, R.sup.2 are independently selected
from H and C.sub.1-C.sub.6 alkyl and (iii) (a) R.sup.3, R.sup.4 are
independently selected from H and C.sub.1-C.sub.6 alkyl; [0038]
R.sup.5, R.sup.6 are independently selected from H and
C.sub.1-C.sub.6 alkyl; or [0039] (b) one of R.sup.3 and R.sup.4,
together with one of R.sup.5 and R.sup.6, form a cyclopropyl ring,
and the other of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is selected
from H and C.sub.1-C.sub.6 alkyl; [0040] including pharmaceutically
acceptable salts, hydrates and solvates of the compound of formula
[I], for the preparation of a medicament for treating a disease or
condition selected from: neuropathic pain, migraine and neuronal
degeneration, with the proviso that where the use is for the
treatment migraine, compounds disclosed in WO 99/54282,
incorporated herein by reference in its entirety, are excluded.
Among the excluded compounds are: valnoctamide, valnoctic acid,
diisopropyl acetamide and diisopropyl acetic acid, in racemic and
stereoisomeric forms.
[0041] The present invention additionally relates to the use of a
compound of formula [A]:
##STR00011##
as racemic mixtures or as individual stereoisomers or mixtures of
racemic and stereo isomers, wherein (i) X is selected from OH and
NR.sup.1R.sup.2; (ii) R.sup.1, R.sup.2 are independently selected
from H and C.sub.1-C.sub.6 alyl; (iii) n is 0 or 1; and (iv) (a)
R.sup.3, R.sup.4 are independently selected from H and
C.sub.1-C.sub.6 alkyl; [0042] R.sup.5, R.sup.6 are independently
selected from H and C.sub.1-C.sub.6 alkyl; or [0043] (b) one of
R.sup.3 and R.sup.4, together with one of R.sup.5 and R.sup.6, form
a cyclopropyl ring, and the other of R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 is selected from H and C.sub.1-C.sub.6 alkyl, [0044]
including pharmaceutically acceptable salts, hydrates and solvates
of the compound of formula [A], for the preparation of a medicament
for treating a disease or condition selected from: neuropathic
pain, migraine and neuronal degeneration, with the proviso that
where the use is for the treatment migraine, compounds disclosed in
WO 99/54282, incorporated herein by reference in its entirety, are
excluded. Among the excluded compounds are: propylisopropyl acetic
acid, propylisopropyl acetamide, valnoctamide, valnoctic acid,
diisopropyl acetamide and diisopropyl acetic acid, in racemic and
stereoisomeric forms.
[0045] The present invention additionally relates to a method for
treating a disease or condition selected from: neuropathic pain,
migraine and neuronal degeneration, in a mammal comprising
administering to the mammal, a therapeutically effective amount of
a compound of formula I
##STR00012##
as racemic mixtures or as individual stereoisomers or mixtures of
racemic and stereoisomers, wherein (i) X is selected from OH and
NR.sup.1R.sup.2; (ii) R.sup.1, R.sup.2 are independently selected
from H and C.sub.1-C.sub.6 alkyl; and (iii) (a) R.sup.3, R.sup.4
are independently selected from H and C.sub.1-C.sub.6 alkyl; [0046]
R.sup.5, R.sup.6 are independently selected from H and
C.sub.1-C.sub.6 alkyl; or [0047] (b) one of R.sup.3 and R.sup.4,
together with one of R.sup.5 and R.sup.6, form a cyclopropyl ring,
and the other of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is selected
from H and C.sub.1-C.sub.6 alkyl, including pharmaceutically
acceptable salts, hydrates and solvates of the compound of formula
[I], with the proviso that where the method is for the treatment
migraine, compounds disclosed in WO 99/54282, incorporated herein
by reference in its entirety, are excluded. Among the excluded
compounds are: valnoctamide, valnoctic acid, diisopropyl acetamide
and diisopropyl acetic acid, in racemic and stereoisomeric
forms.
[0048] The present invention additionally relates to a method for
treating a disease or condition selected from: neuropathic pain,
migraine and neuronal degeneration, in a mammal comprising
administering to the mammal, a therapeutically effective amount of
a compound of formula [A]:
##STR00013##
as racemic mixtures or as individual stereoisomers or mixtures of
racemic and stereoisomers, wherein (i) X is selected from OH and
NR.sup.1R.sup.2; (ii) R.sup.1, R.sup.2 are independently selected
from H and C.sub.1-C.sub.6 alkyl; (iii) n is 0 or 1; and (iv) (a)
R.sup.3, R.sup.4 are independently selected from H and
C.sub.1-C.sub.6 alkyl; [0049] R.sup.5, R.sup.6 are independently
selected from H and C.sub.1-C.sub.6 alkyl; or [0050] (b) one of
R.sup.3 and R.sup.4, together with one of R.sup.5 and R.sup.6, form
a cyclopropyl ring, and the other of R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 is selected from H and C.sub.1-C.sub.6 alkyl, including
pharmaceutically acceptable salts, hydrates and solvates of the
compound of formula [A], with the proviso that where the method is
for the treatment migraine, compounds disclosed in WO 99/54282,
incorporated herein by reference in its entirety, are excluded.
Among the excluded compounds are: propylisopropyl acetic acid,
propylisopropyl acetamide, valnoctamide, valnoctic acid,
diisopropyl acetamide and diisopropyl acetic acid, in racemic and
stereoisomeric forms.
[0051] The present invention also relates to a method for treating
a psychiatric disorder in a mammal comprising administering to the
mammal a therapeutically effective amount of a compound of formula
[A] or [I] as defined above. Excluded from the above formulae are
compounds of formula II:
##STR00014##
[0052] It should be noted that the present invention also excludes
the compound valproic acid for all the indications mentioned
above.
[0053] As used herein the term "the other of R.sup.3, R.sup.4,
R.sup.5 and R.sup.6" refers to the two groups of R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 which do not form a cyclopropyl ring. For
example, when R.sup.4 and R.sup.5 form together a cyclopropyl ring
"the other . . . " is R.sup.4 and R.sup.6. When R.sup.4 and R.sup.5
form together a cyclopropyl ring "the other . . . " is R.sup.3 and
R.sup.6, etc.
[0054] As used herein the term "treating" includes prophylactic
and/or therapeutic uses and refers to abrogating, preventing,
alleviating, slowing or reversing the progression of a disease or
condition, or substantially preventing the appearance of clinical
symptoms of a disease or condition.
[0055] As used herein the term "neuropathic pain" refers to any
pain which initial cause was due to damage, or injury to the neural
tissue. The predominant mechanism is aberrant somatosensory
processing.
[0056] As used herein the term "neuronal degeneration" refers to a
condition of neuronal death or decrease in neuronal function (such
as decrease in neurotransmitter release). The degeneration may be
due to a neurodegenerative disease (such as Alzheimer's disease.
Parkinson, Huntignton Chorea etc.), due to trauma such as that
following head injury or operation, due to lack ischemia or hypoxia
following trauma, stroke or a disease process, or due to natural
degenerative processes caused by old age.
[0057] As used herein the term "migraine" refers to an often
familial symptom complex of periodic attacks of vascular headache,
usually temporal and unilateral in onset, commonly associated with
irritability, nausea, vomiting, constipation or diarrhea and often
photophobia, attacks are preceded by constriction of the cranial
arteries, usually with resultant prodromal sensory (especially
ocular) symptoms and commence with the vasodilation that
follows.
[0058] As used herein the term "psychiatric disorder" refers
especially to bi-polar disorder or manic-depressive illness,
affective disorder and generalized anxiety disorder (GAD).
[0059] The medicaments of the present invention may be useful as
anxiolytic and/or mood stabilizers.
[0060] As used herein the term "therapeutically effective amount"
refers to an amount of a compound sufficient to prevent, inhibit,
reduce, or eliminate one or more causes, symptoms, or complications
of neuropathic pain, migraine, psychiatric disorder and/or neuronal
degeneration.
[0061] The term "therapeutically effective amount" also refers to
an amount of a compound sufficient to bring about at least one of
the effects defined under the term treating.
[0062] Preferably the C.sub.1-C.sub.6 alkyl of R.sup.1 and R.sup.2
consists of 1-3 carbon atoms and most preferably the alkyl is a
methyl.
[0063] Preferably the C.sub.1-C.sub.6 alkyl of R.sup.3, R.sup.4,
R.sup.5 and R.sup.6-consists of 1-3 carbon atoms, more preferably
1-2 carbon atoms and most preferably the alkyl is a methyl.
[0064] As used herein the term "C.sub.1-C.sub.6alkyl" refers to a
saturated aliphatic hydrocarbon of 1 to 6 carbon atoms. In case the
alkyl includes 2-6 carbon atoms, the alkyl may have one or more
carbon-carbon double bonds (termed also alkenyl). Thus, R.sup.3,
R.sup.4, R.sup.5 and R.sup.6 may also be an alkenyl (an unsaturated
straight or branched aliphatic hydrocarbon, having one or more
carbon-carbon double bonds) including 2 to 6 carbon atoms. Examples
of alkenyl groups include, without limitation, ethenyl, n-propenyl,
isopropenyl etc.
[0065] Whenever a numerical range e.g. "1-6" is stated herein, it
means that the group in this case the alkyl group, may contain 1
carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and
including 6 carbon atoms. The C.sub.1-C.sub.6alkyl group may be for
example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary
butyl, sec-butyl, amyl, pentyl, isopentyl, or hexyl.
[0066] The C.sub.1-C.sub.6 alkyl group may be a straight or a
branched alkyl group.
[0067] Preferably the total number of carbon atoms of R.sup.3,
R.sup.4, R.sup.5 and R.sup.6 in a compound of formula I is two. The
term "the total number of carbon atoms of R.sup.3, R.sup.4, R.sup.5
and R.sup.6" means the sum of carbon atoms of R.sup.3, R.sup.4,
R.sup.5 and R.sup.6.
[0068] Preferably the total number of carbon atoms in a compound of
formula I (or of formula A) excluding the carbon atoms of R.sup.1
and R.sup.2 is eight.
[0069] According to a preferred embodiment of the present
invention,
(i) X is OH; and
[0070] (ii) (a) R.sup.3, R.sup.4 are independently selected from H
and C.sub.1-C.sub.6 alkyl; [0071] R.sup.5, R.sup.6 are
independently selected from H and C.sub.1-C.sub.6 alkyl; or [0072]
(b) one of R.sup.3 and R.sup.4, together with one of R.sup.5 and
R.sup.6, form a cyclopropyl ring, and the other of R.sup.3,
R.sup.4, R.sup.5 and R.sup.6 is selected from H and C.sub.1-C.sub.6
alkyl.
[0073] According to another preferred embodiment of the present
invention,
(i) X is NR.sup.1R.sup.2;
[0074] (ii) R.sup.1, R.sup.2 are independently selected from H and
C.sub.1-C.sub.6 alkyl; and (iii) (a) R.sup.3, R.sup.4 are
independently selected from H and C.sub.1-C.sub.6 alkyl; [0075]
R.sup.5, R.sup.6 are independently selected from H and
C.sub.1-C.sub.6 alkyl; or [0076] (b) one of R.sup.3 and R.sup.4,
together with one of R.sup.5 and R.sup.6, form a cyclopropyl ring,
and the other of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is selected
from H and C.sub.1-C.sub.6 alkyl.
[0077] Additionally according to a preferred embodiment of the
present invention,
(i) X is selected from OH and NR.sup.1R.sup.2; (ii) R.sup.1,
R.sup.2 are independently selected from H and C.sub.1-C.sub.6
alkyl; and (iii) (a) R.sup.3, R.sup.4 are independently selected
from H, methyl and ethyl; [0078] R.sup.5, R.sup.6 are independently
selected from H, methyl and ethyl; or [0079] (b) one of R.sup.3 and
R.sup.4, together with one of R.sup.5 and R.sup.6, form a
cyclopropyl ring, and the other of R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 is selected from H, methyl and ethyl.
[0080] Moreover according to a more preferred embodiment of the
present invention,
[0081] X is selected from OH and NR.sup.1R.sup.2; R.sup.1, R.sup.2
are independently selected from H and C.sub.1-C.sub.6 alkyl; and
one of R.sup.3 and R.sup.4, together with one of R.sup.5 and
R.sup.6, form a cyclopropyl ring, and the other of R.sup.3,
R.sup.4, R.sup.5 and R.sup.6 is a methyl.
[0082] Further according to a more preferred embodiment the
compound of formula I or [A] is of structural formula II
##STR00015##
wherein R.sup.1 and R.sup.2 are independently selected from H and
C.sub.1-C.sub.6 alkyl.
[0083] According to this preferred embodiment and with relation to
formula [I], X is NR.sup.1R.sup.2; R.sup.1, R.sup.2 are
independently selected from H and C.sub.1-C.sub.6 alkyl; and one of
R.sup.3 and R.sup.4, together with one of R.sup.5 and R.sup.6, form
a cyclopropyl ring, and the other of R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 is a methyl.
[0084] Preferably the C.sub.1-C.sub.6 alkyl is a C.sub.1-C.sub.3
alkyl and most preferably a methyl.
[0085] Preferably at least one of R.sup.1 and R.sup.2 is H and the
other of R.sup.1 and R.sup.2 is a C.sub.1-C.sub.6 alkyl.
[0086] As used herein the term "the other of R.sup.1 and R.sup.2"
refers to the non-hydrogen group. For example, if R.sup.1 is H,
then R.sup.2 is C.sub.1-C.sub.6 alkyl and vice versa.
[0087] Preferably the C.sub.1-C.sub.6 alkyl of R.sup.1 and R.sup.2
is a C.sub.1-C.sub.3 alkyl and most preferably a methyl.
[0088] According to a preferred embodiment of the present invention
one of R.sup.1 and R.sup.2 is H and the other of R.sup.1 and
R.sup.2 is C.sub.1-C.sub.6 alkyl, more preferably C.sub.1-C.sub.3
alkyl and most preferably methyl.
[0089] According to another preferred embodiment of the present
invention R.sup.1 and R.sup.2 are H.
[0090] Preferred compounds are the following: [0091]
N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide
(M-TMCD)--compound III; [0092]
2,2,3,3-tetramethylcyclopropanecarboxamide (TMCD)--compound IV;
[0093] 2-ethyl-3-methyl-pentanoic acid amide
(Valnoctamide)--compound V, for treating neuropathic pain and
neuronal degeneration; [0094] propyl isopropylacetamide
(PID)--compound VI, for treating neuropathic pain and neuronal
degeneration; [0095] diisopropylacetamide (DID)--compound VII, for
treating neuropathic pain and neuronal degeneration; and [0096]
diisopropylacetic acid (DIA)--compound VIII, for treating
neuropathic pain and neuronal degeneration, where applicable as
racemic mixtures or as individual stereoisomers (i.e. where the
compound contains at least one asymmetric carbon atom) and when
applicable, including pharmaceutically acceptable salts, hydrates
and solvates of each compound (I.e. if the chemical structure
affords the formation of salts, hydrates or solvates) from the list
of compounds below.
[0097] More preferred compounds are
N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide (M-TMCD),
diisopropylacetamide (DID), propyl isopropylacetamide (PID) in
racemic form or 2R and 2S stereoisomeric form and
2-ethyl-3-methyl-pentanoic acid amide (Valnoctamide) in racemic or
stereoisomeric form and most preferred compound is
N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide (M-TMCD).
List of Compounds:
##STR00016##
[0099] For purposes of this specification, the term VCD refers to
2-ethyl-3-methyl-pentanoic acid amide (Valnoctamide).
[0100] Additional preferred compounds are: [0101]
2-ethyl-3-methyl-pentanoic acid (valnoctic acid (VCA)), for
treating neuropathic pain and neuronal degeneration; and [0102]
2,2,3,3-tetramethylcyclopropanecarboxylic acid (TMCA).
[0103] When X is OH; and one of R.sup.3 and R.sup.4, together with
one of R.sup.5 and R.sup.6, form a cyclopropyl ring, and the other
of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is a methyl, the compound
is TMCA.
[0104] The compound may also be propylisopropyl acetic acid (PIA),
for treating neuropathic pain and neuronal degeneration.
[0105] According to a preferred embodiment of the present invention
the disease or condition is a neuropathic pain.
[0106] Preferably the psychiatric disorder is a bipolar
disorder.
[0107] Preferably the psychiatric disorder is a bipolar disorder
and the compound is selected from PID, PIA, VCD, VCA, DID, and
DIA.
[0108] Preferably the compound is administered as a pharmaceutical
composition comprising a compound of formula I or [A] and a
pharmaceutical acceptable carrier.
[0109] According to a preferred embodiment of the present invention
the route of administration of the medicament is selected from
oral, parenteral, topical, transdermal, mucosal, rectal and buccal
administration.
[0110] According to a preferred embodiment of the present invention
the route of administration of the compound is selected from oral,
parenteral, topical, transdermal, mucosal, rectal and buccal
administration.
[0111] More preferably the route of administration of the
medicament is selected from oral and parenteral administration and
most preferably oral administration.
[0112] More preferably the route of administration of the compound
is selected from oral and parenteral administration and most
preferably oral administration.
[0113] Preferably the parenteral route of administration is
selected from intravenous, intramuscular, intraperitoneal and
subcutaneous administration.
[0114] Preferably the mammal is a human.
[0115] The invention further relates to a pharmaceutical
composition for treating a disease or condition selected from:
neuropathic pain, migraine, and neuronal degeneration comprising a
pharmaceutically acceptable carrier and as an active ingredient a
therapeutically effective amount of a compound of formula [A] as
defined above.
[0116] Preferably, the invention relates to a pharmaceutical
composition for treating a disease or condition selected from:
neuropathic pain, migraine, and neuronal degeneration comprising a
pharmaceutically acceptable carrier and as an active ingredient a
therapeutically effective amount of a compound of formula [I]:
##STR00017##
as racemic mixtures or as individual stereoisomers or mixtures of
racemic and stereoisomers, wherein (i) X is selected from OH and
NR.sup.1R.sup.2; (ii) R.sup.1, R.sup.2 are independently selected
from H and C.sub.1-C.sub.6 alkyl and (iii) (a) R.sup.3, R.sup.4 are
independently selected from H and C.sub.1-C.sub.6 alkyl; [0117]
R.sup.5, R.sup.6 are independently selected from H and
C.sub.1-C.sub.6 alkyl; or [0118] (b) one of R.sup.3 and R.sup.4,
together with one of R.sup.5 and R.sup.6, form a cyclopropyl ring,
and the other of R.sup.3, R.sup.5 and R.sup.6 is selected from H
and C.sub.1-C.sub.6 alkyl, [0119] including pharmaceutically
acceptable salts, hydrates and solvates of the compound of formula
[I].
[0120] The invention also relates to a pharmaceutical composition
for treating a psychiatric disorder, with the exclusion of
compounds of formula [II] as defined above.
[0121] The pharmaceutical compositions of the present invention
comprises as an active ingredient a therapeutically effective
amount of at least one compound as described in the present
invention and a pharmaceutically acceptable carrier.
[0122] As used herein a "pharmaceutical composition" refers to a
preparation of one or more compounds described herein, with other
inert chemical components such as suitable pharmaceutically
acceptable carriers. The purpose of a pharmaceutical composition is
to facilitate administration of a compound to a subject
(mammal).
[0123] As used herein the term "pharmaceutically acceptable
carrier" refers to an inert non-toxic carrier or diluent that does
not cause significant irritation to a subject (mammal) and does not
abrogate the biological activity and properties of the administered
compound.
[0124] Examples without limitation of carriers are lactose,
sucrose, water, organic solvents and polyethyleneglycol.
[0125] The carriers may include additional excipients such as
binders, disintegrants, lubricants, surface active agents,
preservatives and favoring agents.
[0126] The treatment may be prophylactic, for preventing the
disease from occurring such as for preventing neuropathic pain
following surgery by administration of the compound of the
invention prior to surgery. Alternatively the administration may be
performed after the disease or condition were already established
so as to eliminate or decrease at least one of the manifestations
of the disease or condition.
[0127] Preferably the disease is neuropathic pain, and the compound
may be administered to prevent the occurrence of the pain (for
example before amputation surgery, to a diabetic patient likely to
develop diabetic neuropathy) or may be administered after the
neuropathic pain is already established so as to eliminate or
reduce the intensity of the pain as compared to the non-treated
condition.
Modes of Administration and Amounts
[0128] The method of administration of the compounds above may be
oral, parenteral, topical, transdermal, mucosal or buccal. The
pharmaceutical composition may also be administered rectally for
example through the use of an enema or suppository. The term
"mucosal" refers to a tissue comprising a mucous membranes, such as
the nasal mucosa, pulmonary mucosa, oral mucosa (such as sublingual
or buccal) or rectal mucosa. Compositions for administration
through the mucosal route include for example nasal spray or nasal
drops or aerosol for inhalation.
[0129] In the practice of the invention the amount of the compound
incorporated in the pharmaceutical composition and the dosage may
vary widely. Factors considered when determining the precise dosage
are well known to those skilled in the art. Examples of such
factors include, but are not limited to, age, sex and weight of the
subject being treated, intended medical use of the compounds,
severity of the disease, patient's general condition, the dosage
form, route of administration being employed and the frequency with
which the composition is to be administered.
[0130] Most preferably, the pharmaceutical composition is in the
form of an oral preparation.
[0131] Because of their ease of administration, tablets and
capsules are preferred and represent the most advantageous oral
dosage unit form, in which case solid pharmaceutical excipients are
employed. If desired, tablets may be coated by standard aqueous or
non-aqueous techniques.
[0132] Preferably, the oral pharmaceutical compositions of the
present invention may be administered in single or divided doses,
from one to four times a day. The oral dosage-forms may be
conveniently presented in unit dosage forms and prepared by any
methods well known manner the art of pharmacy. Preferably, the
therapeutically or prophylactically effective amount of an active
ingredient ranges from about 20 mg to about 1000 mg daily
(preferably administered orally), more preferably from about 50 mg
to about 500 mg daily, and most preferably from about 100 mg to
about 400 mg daily (preferably administered orally). The daily dose
may be administered either singly or in multiple dosage over
24-hour period. For oral administration, the therapeutically
effective amount of the active ingredient may be several times
greater than that for, parenteral administration. The amount of the
orally administered active ingredient may range from about five to
ten times greater than that for intravenous or subcutaneous
administration.
Pharmaceutical Compositions and Dosage Forms Useful in the
Invention
[0133] Pharmaceutical compositions and dosage forms which may be
used in the invention comprise one or more of the active
ingredients disclosed herein. Pharmaceutical compositions and
dosage forms of the invention typically also comprise one or more
pharmaceutically acceptable excipients or diluents (pharmaceutical
acceptable carrier).
[0134] Single unit dosage forms of the invention are suitable for
example for oral, mucosal (e.g., nasal, sublingual, buccal,
pulmonary, or rectal mucosa), parenteral (e.g., subcutaneous,
intravenous, bolus injection, intramuscular, intraarterial,
intraperitoneal or subcutaneous), or transdermal administration to
a patient.
[0135] Examples of dosage forms include, but are not limited to:
tablets; caplets; capsules, such as soft elastic gelatin capsules;
cachets; troches; lozenges; dispersions; suppositories ointments;
cataplasms (poultices); pastes; powders; dressings; creams;
plasters; solutions; patches; aerosols (e.g., nasal sprays or
inhalers); gels; liquid dosage forms suitable for oral or mucosal
administration to a patient, including suspensions (e.g., aqueous
or non-aqueous liquid suspensions), emulsions (e.g., oil-in-water
emulsions, or a water-in-oil liquid emulsions), solutions, and
elixirs; liquid dosage forms suitable for parenteral administration
to a patient; and sterile solids (e.g., crystalline or amorphous
solids) that can be reconstituted to provide liquid dosage forms
suitable for parenteral administration to a patient.
Oral Dosage Forms Pharmaceutical Compositions
[0136] Oral dosage forms of the present invention suitable for oral
administration may be presented as discrete pharmaceutical unit
dosage forms, such as capsules, soft elastic gelatin capsules,
tablets, caplets, cachets, or aerosols sprays, each containing a
predetermined amount of the active ingredients, as a powder or
granules, or as a solution or a suspension in an aqueous liquid, a
non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil
liquid emulsion. Dosage forms such as oil-in-water emulsions
typically comprise surfactants such as an anionic surfactant, for
example anionic phosphate ester or lauryl sulfates, but other types
of surfactants such as cationic or nonionic surfactants may be used
in the compositions of the present invention. See generally,
Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing,
Easton Pa. (1990).
[0137] Pharmaceutical compositions of the present invention
suitable for oral administration may be formulated as a
pharmaceutical composition in a soft elastic gelatin capsule unit
dosage form by using conventional methods well known in the art.
See, e.g., Ebert, Pharm. Tech, 1(5):44-50 (1977). Pharmaceutical
compositions in the form of capsules or tablets coated by an
entero-soluble gastroresistant film and which contains a
lyophilisate consisting of glycosaminoglyean, a thickening agent,
and a surfactant have been previously described in U.S. Pat. No.
5,252,339, which is incorporated herein by reference in its
entirety. Soft elastic gelatin capsules have a soft, globular
gelatin shell somewhat thicker than that of hard gelatin capsules,
wherein a gelatin is plasticized by the addition of plasticizing
agent, e.g., glycerin, sorbitol, or a similar polyol. The hardness
of the capsule shell may be changed by varying the type of gelatin
used and the amounts of plasticizer and water.
[0138] Typical oral dosage forms of the invention are prepared by
combining the active ingredient(s) in an intimate admixture with at
least one excipient according to conventional pharmaceutical
compounding techniques. Excipients can take a wide variety of forms
depending on the form of preparation desired for administration.
For example, excipients suitable for use in liquid or aerosol
dosage forms include, but are not limited to, water, glycols, oils,
alcohols, flavoring agents, preservatives, and coloring agents.
Examples of excipients suitable for use in solid oral dosage forms
(e.g., powders, tablets, capsules, and caplets) include, but are
not limited to, starches, sugars, micro-crystalline cellulose,
diluents, granulating agents, lubricants, binders, and
disintegrating agents.
[0139] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit forms, in
which case solid excipients are employed. If desired, tablets can
be coated by standard aqueous or non-aqueous techniques. Such
dosage forms can be prepared by any of the methods of pharmacy. In
general, pharmaceutical compositions and dosage forms are prepared
by uniformly and intimately admixing the active ingredients with
liquid carriers, finely divided solid carriers, or both, and then
shaping the product into the desired presentation if necessary.
[0140] For example, a tablet can be prepared by compression or
molding. Compressed tablets can be prepared by compressing in a
suitable machine the active ingredients in a free-flowing form such
as powder or granules, optionally mixed with an excipient. Molded
tablets can be made by molding in a suitable machine a mixture of
the powdered compound moistened with an inert liquid diluent.
[0141] Examples of excipients that can be used in oral dosage forms
of the invention include, but are not limited to, binders, fillers,
disintegrants, and lubricants. Binders suitable for use in
pharmaceutical compositions and dosage forms include, but are not
limited to, corn starch, potato starch, or other starches, gelatin,
natural and synthetic gums such as acacia, sodium alginate, alginic
acid, other alginates, powdered tragacanth, guar gum, cellulose and
its derivatives (e.g., ethyl cellulose, cellulose acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),
polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,
hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910),
microcrystalline cellulose, and mixtures thereof.
Preparation of the Compounds
[0142] The compounds of the present invention can be prepared
according to the methods disclosed in Sterling et al (U.S. Pat. No.
5,880,157), M. Bialer et al, Pharm Res. 13:284-289 (1996) and
Freifelder et al. J. Org. Chem. 26:203 (1961) or a modification
thereof which will be apparent to those skilled in the art. The
disclosures of these references are incorporated herein by
reference in their entirety.
[0143] M-TMCD and TMCD were prepared according to the method
disclosed in Sterling et al (U.S. Pat. No. 5,880,157).
[0144] Valnoctamide (VCD, powder) was given as a gift from Sanofi,
France. VCD can also be obtained from ClinMeddy (Italy). VCD
stereoisomers can be synthesized as disclosed in U.S. Pat. No.
6,417,399.
[0145] PID, DID and DIA were prepared as disclosed in HAJ-YEHIA,
A., & BIALER, M. (1989). Structure-pharmacokinetic relationship
in series of valpromide isomers with entiepileptic activity. Pharm.
Res., 6, 683-689, HAJ-YEHIA, A., & BIALER, M (1990).
Structure-pharmacokinetic relationship in series of short fatty
acid amides that possess anticonvulsant activity. J. Pharm. Sci.,
79, 719-724.
[0146] PID stereoisomers can be prepared as disclosed in
SPIEGELSTEIN O. et al (1999) Enantioselective synthesis and
teratogenicity of propylisopropyl acetamide, a CNS active chiral
amide analogue of valproic acid. Chirality, 1, 645-650.
[0147] TMCD can be prepared as disclosed in BIALER M. et al. (1996)
Pharmacokinetic analysis and antiepileptic activity of
Tetra-Methylcyclopropane analogeous of valpromide. Pharm. Res. 13,
284-289.
[0148] The disclosures of the above references are incorporated
herein by reference in their entirety.
[0149] 2,2,3,3-tetramethylcyclopropanecarboxylic acid (TMCA) can be
obtained from Sigma Aldrich.
BRIEF DESCRIPTION OF THE DRAWING
[0150] FIG. 1. Shows the threshold of mechanical sensitivity of the
rat foot as a function of time after administration of M-TMCD, for
five different concentrations of the drug (20, 40, 60, 80, 100
mg/kg) and for methyl cellulose control (4 ml/kg). The term "B.
line" refers to baseline.
[0151] FIG. 2. Shows the threshold of mechanical sensitivity of the
rat foot as a function of time after administration of VCD, for
five different concentrations of the drug (20, 40, 60, 80, 100
mg/kg) and for methylcellulose control (4 ml/kg). The term "B.
line" refers to baseline.
[0152] FIG. 3. Shows the threshold of mechanical sensitivity of the
rat foot as a function of time after administration of TMCD, for
four different concentrations of the drug (40, 80, 100, 150 mg/kg)
and for methylcellulose control (4 ml/kg). The term "B. line"
refers to baseline.
[0153] FIG. 4. Shows the threshold of mechanical sensitivity of the
rat foot as a function of time after administration of VPA, for
four different concentrations of the drug (200, 250, 300, 400
mg/kg) and for methylcellulose control (4 ml/kg). The term "B.
line" refers to baseline.
[0154] FIG. 5. Shows the effect of i.p. administration of PID (40
and 80 mg/kg) and vehicle (MC) on tactile allodynia in rats with
SNL neuropathy. Paw withdrawal thresholds to von Frey filaments
were determined on both ipsilateral and contralateral paw prior to
(O) and up to 4 h after dosing, using blinded regimen. (A) Data
show withdrawal threshold of individual rats for the ipsilateral
paw. (B) Data show withdrawal threshold as mean value for the
ipsilateral paw.
[0155] FIG. 6. Shows the effect of i.p. administration of DIA and
DID on tactile allodynia in rats with SNL neuropathy. Paw
withdrawal thresholds to von Frey filaments were determined on both
ipsilateral and contralateral paw prior to (Pre-) and up to 4 h
after dosing, using a blinded regimen. Data show withdrawal
threshold as mean values for the ipsilateral paw. None of the drugs
affected contralateral withdrawal thresholds. *P<0.05 compared
to vehicle (MC) by nonparametric Wilcoxon one tailed test of area
under the response curve 30-240 mm after dosing (dose of drug
tested vs. vehicle). For clarity SD errors bars are not
presented.
[0156] FIG. 7. Shows PK-PD relationship. Time course of plasma
concentration and antiallodynic effect following i.p.
administration of DID (40 mgkg.sup.-1).
[0157] FIG. 8. Plot of antiallodynic activity (SNL-ED.sub.50) and
anticonvulsant activity (MES-ED.sub.50) in rats. The abbreviations
for the various compounds are given in Table 4.
[0158] In FIGS. 1-8: *, **, *** represent the statistical
significance of the dose of the compound versus methylcellulose of
the same experiment. `*` represent p<0.05, `**` represent
p<0.01 and `***` represent p<0.001. MC refers to
methylcellulose.
EXAMPLES
1. Experimental Procedures
A. Neuropathic Pain Model
[0159] Male Sprague-Dawley rats (Harlan laboratories, Jerusalem,
Israel) weighing 200-225 g were used throughout the study. The
mechanical sensitivity (tactile allodynia) of the foot was
quantified by the occurrence of foot withdrawal in response to
normally innocuous mechanical stimuli using nine different von Frey
filaments (VFF) ranging from 0.6 to 26 g. Rats that did not
withdraw the foot to mechanical stimulus (von Frey filaments) of 15
g for 2 consecutive days (-2 and -1) before surgery were included
in the study. At day 0, under xylazine-ketamine anesthesia, the L5
and L6 spinal nerves of one side of the rat were tightly ligated
and cut in order to induce the development of neuropathic pain
syndrome as disclosed in detail in Sheen, K. and Chung, J. M.,
Signs of neuropathic pain depend on signals from injured nerve
fibers in a rat model, Brain Research 610: 62-68 (1993),
incorporated herein by reference in its entirety. The effect on
neuropathic pain (tactile allodynia) was measured 5-6 days
following operation as disclosed above. Rats responding to
mechanical stimuli of 10 g or less (in the operated leg) were
eligible for the study and were included in the drug administration
regime.
B. Surgical Procedure
[0160] The procedure of legating and cutting of the spinal nerves
was performed as previously described by Sheen, K. and Chung, J.
M., Signs of neuropathic pain depend on signals from injured nerve
fibers in a rat model, Brain Research 610: 62-68 (1993),
incorporated herein by reference in its entirety. Briefly, under
ketamine-xylazine anesthesia the rat was placed in a prone position
and the left paraspinal muscles were separated from spinous
processes at the L4-S2 level. Part of the L6 transverse process was
removed and the L4-L6 spinal nerves were identified. The L5-L6
spinal nerves were isolated and tightly ligated and cut, distal to
the dorsal root ganglion and proximal to the formation of the
sciatic nerve. Following complete homeostasis the wound was
sutured.
C. Drug Testing Protocol
[0161] For all the studies, appropriate amounts of compounds were
suspended in a solution of 0.5% (w/v) methylcellulose in double
distilled water. The 0.5% w/v methyl cellulose vehicle was prepared
by dissolving 1.25 g of methyl cellulose (viscosity of 2%, 4000
centipoises, Sigma) in 250 ml of double distilled water (DDW).
[0162] A volume of 4 ml/kg (volume of injected suspension/rat body
weight) was then injected to the rats. The three drugs used were,
M-TMCD and VCD at concentrations of 20, 40, 60, 80 and 100 mg/kg
body weight, TMCD at concentrations of 40, 80, 100 and 150 mg/kg
body weight, VPA at concentrations of 200, 250, 300, 400 mg/kg and
methylcellulose was used as a control at 4 ml/kg (MC, vehicle). The
three drugs and the control vehicle were administered i.p.
(intraperitoneally) to rats at postoperative days 7, 14 and 21 in a
double blind randomized crossover manner. Tactile allodynia
(response to mechanical stimulus) was challenged using VFFs of
0.6-26 g at 30 min pre-dosing (Baseline (B. line)) and at 30, 60,
120, 180 and 240 min post-dosing. Rat that obtained threshold of at
least 15 g, (back to pre-operation baseline threshold), was
regarded as being free of tactile allodynia. This threshold was set
for the purpose of ED.sub.5(O) determination as the inclusion
criteria to this study was 15 g (considered as the minimum
non-allodynic threshold).
D. Foot Withdrawal Measurements
[0163] Measurements of the foot withdrawal to normally innocuous
mechanical stimuli were applied with set of 9 VFFs ranging from 0.6
g to 26 g. The rat was placed on a metal mesh floor covered with a
transparent plastic dome, a period of acclimatization was allowed
prior to testing. VFFs were applied from underneath the mesh floor
to the plantar surface of the foot. Each trial consisted of
repeated applications of each of the VFFs in an ascending order for
5 times, each for a period of 1 second. testing between two
consecutive ascending VFFs was separated by period of 2 min. If the
rat withdrew the foot at least 3 times out of 5 at a specific VFF
no further ascending filaments were tested and this filament was
considered as a withdrawal threshold (response). Mechanical
stimulus trials with the series of ascending VFF were repeated 2
times for a given time point. The repeated measurements were
averaged and taken as the paw withdrawal threshold on a given time
point.
E. Statistical Analysis
[0164] The absolute threshold and the difference in the allodynic
threshold (time point minus baseline) values were tested using
Mann-Whitney Test and Kruskal-Wallis Nonparametric test (two
tailed) followed by Dunn's Multiple comparison test. The ED.sub.50
(median effective dose) was calculated by using Probit analysis
method.
Example 1
Decrease in Neuropathic Pain Following Administration of M-TMCD
[0165] Male Sprague-Dawley rats (Harlan laboratories, Jerusalem,
Israel) weighing 200-225 g were used. The rats chosen feature
initial lack of foot withdrawal in response to mechanical stimuli,
as described in experimental A (neuropathic pain model) above. The
rats underwent surgery by legating and cutting of the L5-L6 nerves,
as disclosed in Experimental B (surgical procedure) above, to
produce neuropathic pain as verified by tactile allodynia. Rats
were divided to 3 groups including 8-10 rats per study. Each group
received 2 different doses of M-TMCD i.p (selected from 20, 40, 60,
80 and 100 mg/kg) and 4 ml/kg of methyl cellulose was used as
control. The doses of M-TMCD were 20, 40, 60, 80 and 100 mg/kg.
[0166] Tactile allodynia threshold was measured as base line and
30, 60, 120, 180 and 240 minutes after administration of the drug,
as described in the Experimental above, the threshold being the
foot withdrawal in response to mechanical stimulus trials with the
series of ascending VFF.
[0167] The results are shown in FIG. 1. As can be seen, M-TMCD
increased the threshold of tactile allodynia (proportional to the
neuropathic pain) in a dose dependent manner, maximal increase in
threshold, indicating maximal decrease in neuropathic pain was
evident 60 min after administration of the drug with an ED.sub.50
of 41 mg/kg.
Example 2
Decrease in Neuropathic Pain Following Administration of VCD
[0168] The same experiment described in Example 1 was repeated with
VCD, and the results are shown in FIG. 2.
[0169] As can be seen the rats responded in a dose dependent manner
to varying dosages of VCD, with maximal effect evident 60 min after
administration of the drug with an ED.sub.50 of 52.3 mg/kg.
Example 3
Decrease in Neuropathic Pain Following Administration of TMCD
[0170] The same experiment described in Example 1 was repeated with
TMCD, and the results are shown in FIG. 3.
[0171] As can be seen the rats responded in a dose dependent manner
to varying dosages of TMCD, with maximal effect evident 60 min
after administration of the drug with an ED.sub.50 of 84.5
mg/kg.
Example 4
Decrease in Neuropathic Pain Following Administration of Valproic
Acid
[0172] The same experiment described in Example 1 was repeated with
VPA (used as reference for comparison), and the results are shown
in FIG. 4. As can be seen the rats responded in a dose dependent
manner to varying dosages of VPA, with maximal effect evident 60
min after administration of the drug with an ED.sub.50 of 269
mg/kg.
Example 5
Decrease in Neuropathic Pain Following Administration of PID
[0173] The experimental procedures are as described in Example
6.
[0174] The thresholds are shown in Table 1 and FIG. 5. Table 2
presents the number of rats protected at each time interval after
PID (i.p.) administration.
TABLE-US-00001 TABLE 1 Activity of PID as antiallodynic agents at
doses of 40 and 80 mg/kg Dose (mg/kg) Time 40 80 MC 0 1.7 .+-. 1.3
2.6 .+-. 1.8 2.3 .+-. 1.6 30 min 3.9 .+-. 5.1 13.6 .+-. 12 2.5 .+-.
1.5 60 min 4.8 .+-. 6.3 14.0 .+-. 7.3 2.4 .+-. 1.7 120 min 6.5 .+-.
5.7 10.4 .+-. 4.8 3.1 .+-. 2.3 180 min 7.0 .+-. 8.0 13.2 .+-. 8.0
2.5 .+-. 1.3 240 min 4.0 .+-. 4.4 6.2 .+-. 3.8 1.8 .+-. 0.8 Data
presented as mean .+-. SD withdrawal threshold (g)
TABLE-US-00002 TABLE 2 Number of rats protected at each time
interval after PID (i.p.) administration Dose 30 min 60 min 120 min
180 min 240 min MC 0/9 0/9 0/9 0/9 0/9 40 mg/kg 1/9 1/9 2/9 2/9 0/9
80 mg/kg 3/9 4/9 2/9 5/9 0/9
Example 6
The Effect of DID and DIA on Neuropathic Pain
Experimental Procedures
1. Materials and Methods
1.1. Animals and Surgical Procedure
[0175] Experiments were performed on male Sprague-Dawley rats
(Harlan Laboratories, Jerusalem) weighing 175-200 g. The procedure
for inducing tactile allodynia in the spinal nerve ligation (SNL)
model was as described by Kim & Chung (1992) (KIM, S., &
CHUNG, J. M. (1992). An experimental model for peripheral
neuropathy produced by segmental spinal nerve ligation in the rat.
Pain 50, 355-363). Briefly, under ketamine-xylazine anesthesia (85
mg kg.sup.-1, i.p and 13 mg kg.sup.-1, i.p, respectively) rats were
placed in a prone position and paraspinal muscles on the left were
separated from the L4-S2 spinous processes. Part of the L6
transverse process was removed and the underlying L4-L6 spinal
nerves were identified. The L5 and L6 spinal nerves were isolated,
tightly ligated with 5-0 silk, and cut just distal to the ligature.
The ligature was approximately 8 mm distal to the corresponding
dorsal root ganglion (DRG). Following complete homeostasis the
wound was sutured in layers, the skin closed with Michel clips,
topical bacteriostatic power was applied, and 20000 units of
duplo-penicillin was injected intramuscularly (i.m.). After
uneventful recovery, the animals were returned to the vivarium
where they were maintained in groups of 2-3 in solid-bottomed
42.times.26 cm transparent plastic shoebox cages, bedded with pine
shavings. Rat dry food pellets (Kofholk, Petah Tikva, Israel,
product #19510) and water were available ad libitum. The day:night
cycle was 12 h:12 h (lights on at 6 AM).
1.2. Sensory Testing
[0176] We used a set of 9 nylon von Frey monofilaments (VFF,
Semmes-Weinstein monofilaments, Stoelting, Wood Dale, Ill., USA) to
quantify foot withdrawal in response to normally innocuous tactile
stimuli. Initial bending force of the filaments (in mN) was: 5.8,
13.4, 18.7, 37.9, 57.3, 77.5, 97.4, 145.9, and 254.1 (equivalent to
mass of: 0.6, 1.4, 1.9, 3.9, 5.9, 7.9, 9.9, 14.9 and 25.9 g).
Forces were calibrated by lowering filaments onto the pan of an
electronic balance until they just bent. Standard deviation (SD) on
repeated measurements was about .+-.0.2 g Filaments were cut flush,
and although they did not all have the same diameter, the same set
was used for all rats.
[0177] Rats were placed on a raised wire mesh screen (gaps 4
mm.times.4 mm), which allowed access to the plantar surface of the
hindpaw from below. They were covered with a transparent plastic
dome, 13 cm high, which prevented rearing on the hindlimbs. A
period of 20 min was allowed for acclimation prior to sensory
testing. The mid-plantar hindpaw skin just caudal to the footpads,
half way between medial and lateral edges of the foot, was
subjected to a series of 5 brief probes, spaced at about 1 s. Each
such stimulus was sufficient to just bend the filament. Testing
began with the filament with the weakest initial bending force (0.6
g). If the animal failed to respond with at least a momentary foot
twitch/withdrawal to .gtoreq.3 of the 5 probes the next stiffest
filament was tried, and so forth, using an ascending staircase
protocol. Response threshold was the bending force of the first
monofilament in the series that evoked a criterion .gtoreq.3/5
responses. This procedure was repeated twice on each foot,
alternating from side to side, with .gtoreq.5 min rest between
trials in a given animal. "Threshold" for each paw on a given test
day was the average of the two force determinations just sufficient
to evoke a criterion response. If there was no response to the
stiffest filament, threshold was recorded as 26 g. Rats were
included in the study only if they failed of respond to the 15 g
monofilament (or weaker) on two consecutive days, two and one day
before surgery.
[0178] The first postoperative tests were carried out 5 and 6 days
following surgery. We set an arbitrary response criterion for
demonstrating tactile allodynia on the operated side at .ltoreq.10
g. Only animals that passed this screening tests were used for drug
testing. About 15% of animals operated were excluded on these
grounds.
1.3. Pharmacological Treatments
[0179] Anesthetic reagents: ketamine (Fort Dodge, Fort Dodge, Iowa,
USA) and xylazine (VMD, Arendonk, Belgium). Antibiotic:
duplo-penicillin (Biochimie GmbH, Kundl, Austria). Drugs: Valproic
acid (VPA), valpromide (VPD), valnoctic acid (VCA), valnoctamide
(VCD), diisopropylacetic acid (DIA), diisopropylacetamide (DID),
N-methyl-valpromide (MVPD), and gabapentin (GBP) were tested. VPD,
VCD were gifts from Sanofi Labaz (France) VPA, and GBP were a gift
from Teva Pharmaceuticals (Netanya, Israel). VCA, DIA, diisopropyl
acetamide (DID) and MVPD were synthesized according to previously
published procedures (Haj-Yebia and Bialer, 1989 & 1990:
HAJ-YEHIA, A., & BIALER, M. (1989). Structure-pharmacokinetic
relationship in series of valpromide isomers with entiepileptic
activity. Pharm. Res., 6, 683-689.
[0180] HAJ-YEHIA, A., & BIALER, M. (1990).
Structure-pharmacokinetic relationship in series of short fatty
acid amides that possess anticonvulsant activity. J. Pharm. Sci.,
79, 719-724.). The products were identified and their structure was
proved by nuclear magnetic resonance spectra and by elemental
microanalysis. Each compound was suspended in 0.5% methylcellulose
in double distilled water (MC, vehicle) and administered
intraperitoneally (i.p.) in the doses noted below, in a uniform
volume of 4 ml/kg body weight. The following doses were tested: VPA
200, 250, 300 and 400 mg kg.sup.-1; VPD 20, 60, 80 and 100 mg
kg.sup.-1; VCA 100, 200 and 300 mg kg.sup.-1; VCD 20, 40, 60, 80
and 100 mg kg.sup.-1; DIA 200 and 300 mg kg.sup.-1; DID 20, 40, 80
and 90 mg kg.sup.-1; MVPD 60, 120 mg kg.sup.-1; and GBP 10, 30, 100
and 300 mg kg.sup.-1. In addition, vehicle control injections were
carried out using 4 ml kg-1 MC.
[0181] Drug tests were conducted at 7, 14 and 21 days postoperative
(dpo). In each rat two different doses of a particular drug and MC
were assessed in a blind randomized crossover manner. Response to
VFF probing was tested before for baseline (pre-) and then 30, 60,
120, 180 and 240 min after dosing. The individual who made the
behavioral assessment was unaware of the drug/dose given. The first
two doses of a drug were based on its potency (ED50) as an AED in
the maximal electroshock (MES) test (Table 4). I.e., one dose was
just below and the second was just above the MES ED50. Based on the
results of the first experiment the next dosages were chosen in
order to establish a scale of protection. VPAs first stage was 300
vs. 400 mg kg-1 vs. MC (n=8 rats tested per dose) and the second
stage was 200 vs. 250 mg kg-1 vs. MC (n=8). VPD: 20 vs. 60 mg
kg.sup.-1 vs. MC (n=8); 100 vs. 150 mg kg.sup.-1 vs. MC (n=8); VPD
80 mg kg.sup.-1 vs. VCA 300 mg kg.sup.-1 vs. MC (n=9). VCA: 100 vs.
200 mg kg.sup.-1 vs. MC (n=8). VCD: 40 vs. 80 mg kg.sup.-1 vs. MC
(n=9); 20 vs. 60 mg kg.sup.-1 vs. MC (n=8); 100 mg kg.sup.-1 vs. MC
(n=8). DIA: 200 vs. 300 mg kg.sup.-1 vs. MC (n=8). DID 40 vs. 80 mg
kg.sup.-1 vs. MC (n=7); 20 vs. 90 mg kg.sup.-1 vs. MC (n=8). MVPD
60 vs. 120 mg kg.sup.-1 vs. MC (n=9). GBP: 10 vs. 30 mg kg.sup.-1
vs. MC (n=8); 100 vs. 300 mg kg.sup.-1 vs. MC (n=9). A one-week
washout period was used after each drug treatment. Five days after
each drug administration the allodynic baseline threshold was
re-evaluated, and 2 days later drugs effect were tested again.
1.5. Determination of the Median Effective Dose (ED.sub.50)
[0182] To determine median effective dose (ED.sub.50) as an
estimate of the compounds' potency, we plotted a dose-response
curve 60 min. post injection except for DID (and GBP) which were
plotted at 120 min. These were the time points at which the largest
fraction of rats tested first reached their maximal antiallodynic
effect. Response was plotted as the percentage of animals tested at
that time point that failed to respond to the 15 g VFF. Maximum
possible response (100%) means that none of the rats tested
responded to the 15 g VFF. ED.sub.50 was the dose that yielded 50%
of the maximum possible response. This value was linearly
interpolated between the dose just above and just below the
ED.sub.50 value. These data were then subjected to probit analysis
(Finney, 1971: FINNEY, D. J. (1971). Probit analysis. 3.sup.rd ed.
Cambridge, UK: Cambridge University Press). 95% confidence
intervals (CI) of ED.sub.50 were calculated. efficacy of a drug was
defined as the percentage of animals tested that failed to respond
to the 15 g VFF at the highest dose used, at which ED.sub.50 was
determined (60 or 120 min).
1.6. Analysis of Plasma Drug Concentration
[0183] For each of the drugs VPA and DID nine rats (320-350 g)
underwent SNL surgery, and 28 days later were randomly divided into
3 groups of 3 rats per group. VPA (300 mg kg-1), and DID (40 mg
kg-1) were administered in 4 ml kg-1 i.p. 0.5% MC, and 400 .mu.l of
blood were collected from the amputated tail tip at each of three
time points after injection. Blood was withdrawn for group 1 at 15,
60 and 180 min after dosing; for group 2 at 30, 90 and 240 min
after dosing and for group 3 at 45, 120 and 360 min after dosing.
Plasma was immediately separated by centrifugation at 3000 g for 15
min and stored at -20.degree. C. until analyzed.
[0184] Plasma levels of VPA and DID were determined by gas
chromatography (GC). An HP5890 series II GC equipped with FID
detector, HP7673 autosampler, for DID HP-5 capillary column (0.25
.mu.m x15 m.times.0.25 mm) was used. The temperature program was as
follows: injector temperature 250.degree. C.; initial temperature,
60.degree. C. for 3 min; gradient of 15.degree. C. min-1 until
180.degree. C.; hold 5 min. For each drug, plasma levels obtained
from 3 rats at each time point were averaged. 25 .mu.l of internal
standard solution (50 mg L.sup.-1 of VPD for the DID assay) and 200
.mu.l of 0.1M NaOH were added to 50 .mu.l of plasma. The mixture
was vortexed, and 1 ml of chloroform was added. The phases were
separated, and the chloroform was evaporated. The dry residue was
redissolved in 50 .mu.l of chloroform, and 1 .mu.l was injected
into the gas chromatograph. Calibration curves were prepared
separately by spiking naive rat plasma samples with 1.56, 2.5,
3.12, 6.25, 12.5, 25.0, 37.5, 50.0, 75.0 and 100.0 mg L.sup.-1 of
DID. The limit of quantification (LOQ) of the method was 1.56
.mu.g/ml, and the coefficient of variation (CV %) was <15% at
all analyzed concentrations including LOQ.
[0185] For VPA determination a HP-FFAP capillary column (0.3
.mu.m.times.25 m.times.0.2 mm) was used. The temperature program
was as follows: injector temperature 280.degree. C.; oven
temperature, 135.degree. C. 30 .mu.l of internal standard solution
(250 mg L-1 of 1-methyl-1cyclohexane carboxylic acid, MCCA, in
MeOH) and 125 .mu.l of 5N Hydrochloric acid (HCl) were added to 250
.mu.l of plasma. The mixture was vortexed, and 2 ml of chloroform
was added. The phases were separated, and the 1 ml of NaOH was
added. 200 .mu.l of HCl 5N and 2 ml of chloroform were added to the
aqueous phase. The organic layer was evaporated and dry residue was
redissolved in 50 .mu.l of chloroform, and 30 .mu.l was injected
into the gas chromatograph. Calibration curves were prepared
separately by spiking naive rat plasma samples with 25.0, 50.0,
75.0, 100.0, 200.0, 300.0, 400.0, 500.0 and 600.0 mg L-1 of VPA.
LOQ of the method was 25 mg L-1, and the coefficient of variation
(CV %) was <15% at all analyzed concentrations including
LOQ.
1.7. Pharmacokinetics (PK)
[0186] PK parameters were determined by non-compartmental analysis
using the pharmacokinetic software package WinNonlin, version 4.0.1
(SCI Software, Lexington, Ky., U.S.A.; Yamaoka, et al., 1978
(YAMAOKA, K., NAKAGAWA, T., & UNO, T. (1978). Statistical
moments in pharmacokinetics. J Pharmacokinet. Biopharm., 6,
547-558.); Gibaldi & Perrier, 1982 (GIBALDI, M., & PERRIER,
D. (1982). Pharmacokinetics (2nd ed.). pp. 199-219 Marcel Dekker:
New York.); Rowland & Tozer, 1995 (ROWLAND, M., & TOZER, T.
(1995). Pharmacological Response. In: Clinical Pharamcokinetics.
pp. 340-365,) Baltimore: Williams & Wilkins.)). The terminal
half-life (t1/2) was calculated as 0.693/P, where P is the linear
terminal slope of the concentration (C)-versus-time curve. The area
under the C-versus-time curve (AUC) was calculated by trapezoidal
rule with extrapolation to infinity. The mean residence time (MRT)
was calculated from the quotient AUMC/AUC, where AUMC is the area
under the concentration-time product versus time curve from zero to
infinity. Total (apparent) clearance (CL/F) was calculated from the
quotient of FDose/AUCm with F being the absolute bioavailablity
following i.p. administration. The apparent volume of distribution
(V.beta./F) was calculated from the quotient of CL and P. The peak
plasma concentration (Cmax) and the time to reach Cmax (tmax) were
determined empirically by visual inspection.
1.8. Neurological Motor Dysfunction Tests
[0187] We confirmed that for VPA, VPD, VCD and DID the highest drug
dose tested was not sufficient to cause neurological motor
dysfunction or sedation as this might lead to false positive
results in behavioral tests of sensory response (Yanez et al, 1990
(YANEZ, A., SABBE, M. B., STEVENS, C. W., & YAKSH, T. L.
(1990). Interaction of midazolam and morphine in the spinal cord of
the rat. Neuropharmacology 29, 359-364.); Jourdan et al., 1997
(JOURDAN, D., ARDID, D., BARDIN, M., NEUZERET, D., LANPHOUTHACOUL,
L., & ESCHALIER, A. (1997). A new automated method of pain
scoring in the formalin test in rats. Pain 71, 265-270.)). In n=6
normal rats, without nerve injury (body weight 250-350 g), changes
in motor performance after VPA, VPD, VCD and DID administration
were measured using an accelerating rotarod (Columbus Instruments,
Columbus, Ohio, USA). The rotarod speed was increased from 10 to 30
rpm over a 120 sec. period, with the maximum time spent on the rod
set at 120 s. For acclimation rats received two training trials
(separated by 34 h) on two separate days prior to drug testing. On
the day of testing, a baseline response was obtained, and rats were
subsequently administered drug or vehicle. Motor performance (the
time (sec.) to fall off the rotarod) was tested at the time (after
dosing) when the ED.sub.50 was determined i.e., 60 min (VPA, VPD,
VCD) or 120 min (DID). In addition, we examined our rats
individually for signs of motor dysfunction and sedation as
assessed by posture and gate during spontaneous and induced
movement, grooming, chewing, stepping reflex, and startle reflex
evoked by tapping on the cage.
1.9. Statistical Analysis
[0188] Results are presented as the ED50 and 95% confidence
interval (CI). For each drug and dose, attenuation of tactile
allodynia (threshold measured in g) was measured. The average
response of all time points after administration (30, 60, 120, 180
and 240 min), area under the response curve, was calculated and the
pretreatment value was subtracted, per rat. These areas under the
response curve values for every group of rats per dose were
evaluated against vehicle treatment using the nonparametric
Wilcoxon one tailed test (dose of drug tested vs. vehicle on the
same treatment). The results for rotarod test (mean.+-.standard
deviation) were evaluated by the same statistical test (highest
dose of drug tested vs. vehicle). A p value <0.05 was considered
statistically significant.
Results
Pharmacodynamics (PD): Effect of Drugs on Tactile Allodynia
[0189] The drugs tested (shown in FIG. 6) showed significant,
dose-dependent attenuation of tactile allodynia during the first
few hours after i.p. injection. At the highest doses used, this
antiallodynic drug effect was near maximal 30 min after injection
with the exception of DID in which the degree of antiallodynia
continued to increase after 30 min. The antiallodynic effect of the
drugs began to decline 1-3 h post injection. For VPA and DID the
maximal dose used was less than that required to produce signs of
neurological motor deficits or sedation.
DIA
[0190] DIA was effective at a dose of 300 mg kg.sup.-1, i.p. (FIG.
6), 25% of rats were regarded as protected at the highest dose.
DID
[0191] The lowest dose needed to significantly increase the
allodynic threshold, when compared to vehicle, was 20 mg kg.sup.-1,
i.p. (FIG. 6) The response became larger in a dose-dependent manner
at time points between 30 min and 120 min. The mean effective dose
(ED.sub.50) at 120 min after dosing was 58 mg kg.sup.-1 with a 95%
CI of 18-97 mg kg.sup.-1. There was no response to 15 g or above
VFF for 63% of rats at the highest dose tested.
VPA
[0192] VPA (used as reference, Figure not shown) decreased tactile
allodynia in a dose-dependent manner. The lowest effective (i.p.)
dose was 300 mg kg.sup.-1. ED.sub.50 60 min after dosing was 269 mg
kg.sup.-1 (95% CI of 227-310 mg kg.sup.-1). At the highest dose
tested (400 mg kg.sup.-1, i.p.) 88% (7/8) of rats were relieved
from tactile allodynia.
Pharmacokinetic (PK) Analysis
[0193] The pharmacokinetics of VPA and DID was evaluated at low
effective antiallodynic doses as found in the PD study, 300 and 40
mg kg.sup.-1, respectively. The PK parameters was calculated using
a non-compartmental approach (Yamaoka et al., 1978 (YAMAOKA, K.,
NAKAGAWA, T., & UNO, T. (1978). Statistical moments in
pharmacokinetics. J Pharmacokinet. Biopharm., 6, 547-558.), Gibaldi
and Perrier, 1982 (GIBALDI, M., & PERRIER, D. (1982).
Pharmacokinetics (2.sup.nd ed.). pp. 199-219 Marcel Dekker New
York.) and are presented in Table 3. The antiallodynic effect of
DID at this dose was associated with a minimal plasma
concentrations of 7 mg L.sup.-1, (FIG. 7). The antiallodynic effect
of VPA at this dose was associated with a minimal plasma
concentrations of 125 mg L.sup.-1.
Rotarod Test
[0194] VPA, and DID, had no significant effect (p>0.05, n=6) on
motor performance (rotarod test) at the highest doses tested (400,
and 90 mg kg.sup.-1, i.p., respectively), at 60 or 120 min after
dosing when compared to vehicle treatment (96.8.+-.23.7 and
103.8.+-.22.3 seconds, vs. 118.0.+-.2.3 respectively).
TABLE-US-00003 TABLE 3 Pharmacokinetic (PK) parameters of VPA and
DID in the plasma after i.p. administration to SNL operated rats at
doses of 300 and 40 mg kg.sup.-1, respectively PK parameters VPA
DID CL/F (L h.sup.-1 kg.sup.-1) 0.2 0.5 V.beta./F (L kg.sup.-1) 1.2
1.2 t.sub.1/2 (h) 4.6 1.5 MRT (h) 5.8 2.4 Cmax (mg L.sup.-1) 515 28
tmax (min) 30 15 F-Absolute bioavailability; CL/F-Clearance
normalized by F; V.beta./F-Volume of distribution normalized by F;
t.sub.1/2-Half-life; MRT-Mean residence time; Cmax-Peak plasma
concentration; tmax-Time to reach Cmax.
Discussion
[0195] DID showed dose-related antiallodynic activity at doses that
did not produce neurological motor deficit or sedation. Moreover,
this compound proved to have much better antiallodynic potency than
VPA.
[0196] The peak plasma concentration (Cmax) for VPA (Figure not
shown), was obtained 30 min after dosing and its maximal
antiallodynic effects were observed shortly afterwards, with a
reasonable parallel between plasma concentration and antiallodynic
activity also at subsequent time points. DID was exceptional in
that its Cmax was obtained 15 min after dosing whilst its maximal
antiallodynic effect was observed 120 min after dosing (FIG.
7).
Antiallodynic Vs. Anticonvulsant Activity
[0197] The proven analgesic activity of some AEDs in animal models
of neuropathic pain, and in placebo controlled clinical trials,
naturally raises the suggestion that epilepsy and neuropathic pain
share underlying neural mechanisms (McQuay et al., 1995 (MCQUAY,
H., CARROLL, D., JADAD, A. R., WIFFEN, P. & MOORE, R. A.,
(1995). Anticonvulsant drugs for management of pain: a systematic
review, Brit. Med. J. 311, 1047-1052.); Zakrzewska et al., 1997
(ZAKRZEWSKA, J. M., CHAUDHRY, Z., NURMIKKO, T. J, et al. (1997).
Lamotrigine (Lamictal) in refractory trigeminal neuralgia: results
from a double-blind placebo controlled crossover trial. Pain 73,
223-230.); Blom, 1962 (BLOM, S. (1962). Trigeminal neuralgia: its
treatment with a new anticonvulsant drug. Lancet; 1, 839-840.);
Rogawski & Loscher, 2004b (ROGAWSKI, M. A., & LOSCHER, W.
(2004b). The neurobiology of antiepileptic drugs for the treatment
of nonepileptic conditions. Nat. Med., 10, 685-692.)). The
availability of ED50 data for a series of new anticonvulsant
isomers and analogues of VPD (valpromide) provides an opportunity
for testing this hypothesis. In fact, plotting the ED50 values for
these and other AEDs for which corresponding data are available
(carbamazepine-CBZ, felbamate-FBM, lamotrigine-LTG) and our series
of VPA analogues did not yield a significant overall positive
correlation (Table 4, FIG. 8). The rat-MES ED50 data presented in
Table 4 were taken from previous studies and were obtained
following oral administration (Bialer et al., 1994 (BIALER, M.,
HAJ-YEHIA, A., BADIR, K. & HADAD, S. (1994). Can we develop
improved derivatives of valproic acid. Pharm. World Sci. 16,
2-6.)), in collaboration with the NIH anticonvulsant screening
program (White et al., 2002 (WHITE. H. S., WOOHHEAD J. H., WILCOX,
K. S., STABLES, J. P., KUPFERBERG, H. J. & WOLF, H. H. (2002).
Discovery and preclinical development of antiepileptic drugs. in:
Antiepileptic drugs. 5.sup.th edit. Levy, R. H., Mattson, R. H.,
Meldrum, B. S., & Perucca, E, eds., pp. 36-48. Philadelphia:
Lippincott Williams & Wilkins.)).
TABLE-US-00004 TABLE 4 Activity of AEDs as anticonvulsants (MES
test) and agents that suppress tactile allodynia in the SNL model
of neuropathic pain in the rat. Relative brain access
(blood-to-brain ratio) is also provided. MES-ED.sub.50
SNL-ED.sub.50 ED.sub.50 Brain-to- Drug (mg kg.sup.-1, p.o.) (mg
kg-1, i.p.) MES/SNL plasma ratio VPA 485.sup.a 269 1.8 0.16.sup.c
VPD 32.sup.b 61 0.5 0.84.sup.c VCA NT >300 -- NT VCD 29.sup.c 52
0.6 1.0.sup.c DIA NT >300 -- NT DID 51 58 0.9 NT MVPD 65 >120
<0.54 NT GBP 14.8.sup.a 34.sup.d 0.43 0.85.sup.e FBM 25.3a
>600.sup.d <0.04 0.64.sup.f LTG 1.3.sup.a >100.sup.d
<0.01 0.4.sup.h CBZ 5.4.sup.a >30.sup.c <0.18 1.0.sup.i
.sup.aData from White et al., 2002 .sup.bData from Bialer et al., ,
1994 .sup.cData from Blotnik et al., 1996 .sup.dData from Hunter et
al., 1997 .sup.eData from Vajda, 2002 .sup.fData from Pellock et
al., 2002 .sup.hData from Walker et al., 2000 .sup.iData from
Spina, 2002
[0198] WHITE. H. S., WOOHHEAD J. H., WILCOX, K. S., STABLES, J. P.,
KUPFERBERG, H. J. & WOLF, H. H. (2002). Discovery and
preclinical development of antiepileptic drugs. in: Antiepileptic
drugs. 5.sup.th edit. Levy, R. H., Mattson, R. H., Meldrum, B. S.,
& Perucca, E, eds., pp. 36-48. Philadelphia: Lippincott
Williams & Wilkins. [0199] BIALER, M., HAJ-YEHIA, A., BADIR, K.
& HADAD, S. (1994). Can we develop improved derivatives of
valproic acid. Pharm. World Sci. 16, 2-6. [0200] BLOTNIK, S.,
BERGMAN, F., & BIALER, M., (1996). Disposition of valpromide,
valproic acid and valnoctamide in the brain, liver, plasma and
urine of rats. Drug Metab. Disposit., 24, 560-564. [0201] HUNTER,
J. C., GOGAS, K. R., HEDLEY, L. R., JACOBSON, L. O., KASSOTAKIS,
L., TOMPSON, J., & FONTANA, D. J. (1997). The effect of novel
anti-epileptic drugs in rat experimental models of acute and
chronic pain. Eur. J. Pharmacol., 324, 153-160. [0202] VAJDA, F. J.
E. (2002). Gabapentin-Chemistry, biotarnsoformation,
pharmacokinetics and interactions. in: Antiepileptic drugs.
5.sup.th edit. Levy, R. H., Mattson, R. H., Meldrum, B. S., &
Perucca, E., eds., pp. 335-339. Philadelphia: Lippincott Williams
& Wilkins. [0203] PELLOCK, J. M., PERHACH, J. L., & SOFIA,
R. D. (2002). Felbamate. in: Antiepileptic drugs. 5.sup.th edit.
Levy, R. H., Mattson, R. H., Meldrum, B. S., & Perucca, E.,
eds. pp. 301-18 Philadelphia: Lippincott Williams & Wilkins.
[0204] WALKER, M. C., TONG, X., PERRY, H., ALAVIJEH, M. S., &
PATSALOS, P. N. (2000). Comparison of serum, cerebrospinal fluid
and brain extracellular fluid pharmacokinetics of lamotrigine. Br.
J. Pharmacol. 130, 242-248. [0205] SPINA E. (2002).
Carbamazepine-Chemistry, biotransoformation, pharmacokinetics and
interactions. in: Antiepileptic drugs. 5.sup.th edit. Levy, R. H.,
Mattson, R. H., Meldrum, B. S., & Perucca, E., eds., pp.
232-246. Philadelphia: Lippincott Williams & Wilkins. MES,
maximal electro-shock; ED.sub.50, median effective dose; SNL,
spinal nerve ligation; NE, no effect; NT, not tested; CBZ,
carbamazepine; FBM, felbamate; LTG, lamotrigine.
[0206] In a different study several CNS-active
tetramethylcylcopropyl amide analogues of VPA have been assessed
for their antiallodynic activity, utilizing the SNL model (data not
shown). All tested compounds showed dose-related reversal of
tactile allodynia. 2,2,3,3-tetramethylcyclopropanecarboxylic acid
(TMCA) and its primary amide
2,2,3,3-tetramethylcyclopropanecarboxamide (TMCD) were the only
agents to exhibit antiallodynic effect without any anticonvulsant
activity in the rat-MES test.
[0207] The results show that the compounds (TMCD, M-TMCD, VCD, DID,
DIA, PID) are effective for treating neuropathic pain. The
compounds were highly effective compared to valproic acid as
evident by the lower ED.sub.50 values (compared to valproic acid).
The results show that M-TMCD and VCD are more preferred
compounds.
[0208] While this invention has been shown and described with
reference to preferred embodiments thereof, it will be understood
by those skilled in the art that many alternatives, modifications
and variations may be made thereto without departing from the
spirit and scope of the invention. Accordingly, it is intended to
embrace all such alternatives, modifications and variations that
fall within the spirit and broad scope of the appended claims.
[0209] All publications, patents and patent applications mentioned
in this specification are herein incorporated in their entirety by
reference into the specification, to the same extent as if each
individual publication, patent or patent application was
specifically and individually indicated to be incorporated herein
by reference.
* * * * *