U.S. patent application number 09/971007 was filed with the patent office on 2002-03-28 for sodium channel blocker compositions and the use thereof.
Invention is credited to Lan, Nancy C..
Application Number | 20020037926 09/971007 |
Document ID | / |
Family ID | 22435837 |
Filed Date | 2002-03-28 |
United States Patent
Application |
20020037926 |
Kind Code |
A1 |
Lan, Nancy C. |
March 28, 2002 |
Sodium channel blocker compositions and the use thereof
Abstract
Methods of treating or preventing chronic pain or convulsion are
disclosed by administering to an animal a sodium channel blocker
and at least one of gabapentin and pregabalin. Also disclosed are
pharmaceutical compositions and kits for the treatment or
prevention of chronic pain or convulsion.
Inventors: |
Lan, Nancy C.; (Altadena,
CA) |
Correspondence
Address: |
STERNE, KESSLER, GOLDSTEIN & FOX PLLC
1100 NEW YORK AVENUE, N.W., SUITE 600
WASHINGTON
DC
20005-3934
US
|
Family ID: |
22435837 |
Appl. No.: |
09/971007 |
Filed: |
October 5, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09971007 |
Oct 5, 2001 |
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PCT/US00/09387 |
Apr 10, 2000 |
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60128543 |
Apr 9, 1999 |
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Current U.S.
Class: |
514/561 ;
514/217 |
Current CPC
Class: |
A61K 31/195 20130101;
A61K 31/53 20130101; A61P 25/00 20180101; A61K 31/195 20130101;
A61K 45/06 20130101; A61P 9/10 20180101; A61K 31/197 20130101; A61K
31/55 20130101; A61K 31/196 20130101; A61P 9/06 20180101; A61K
31/55 20130101; A61K 31/53 20130101; A61K 31/53 20130101; A61K
31/196 20130101; A61P 21/04 20180101; A61K 31/195 20130101; A61K
31/197 20130101; A61K 2300/00 20130101; A61K 31/195 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 31/175 20130101; A61K 31/195 20130101; A61K 2300/00 20130101;
A61K 31/195 20130101; A61K 2300/00 20130101; A61K 31/55 20130101;
A61K 31/40 20130101; A61K 31/195 20130101; A61K 31/40 20130101;
A61K 31/40 20130101; A61K 45/06 20130101; A61P 43/00 20180101; A61P
29/00 20180101 |
Class at
Publication: |
514/561 ;
514/217 |
International
Class: |
A61K 031/55; A61K
031/195 |
Claims
What is claimed is:
1. A pharmaceutical composition, comprising a first agent which is
a sodium channel blocker, and a second agent selected from the
group consisting of gabapentin, pregabalin, salts thereof and
combinations thereof; wherein the total amount of said first agent
and said second agent is effective to treat, prevent or ameliorate
chronic pain or convulsions.
2. A pharmaceutical composition, comprising at least one sodium
channel blocker and at least one of gabapentin or pregabalin,
wherein said sodium channel blocker and at least one of gabapentin
or pregabalin are present in amounts effective to treat or prevent
chronic pain or convulsions.
3. The pharmaceutical composition of claim 1, wherein said
composition further comprises a pharmaceutically acceptable
carrier.
4. The pharmaceutical composition of claim 1, wherein said second
agent is gabapentin.
5. The pharmaceutical composition of claim 1, wherein said second
agent is pregabalin.
6. The pharmaceutical composition of claim 1, wherein said first
agent is carbamazepine.
7. The pharmaceutical composition of claim 1, wherein said first
agent is lamotrigine.
8. The pharmaceutical composition of claim 1, wherein said first
agent is 4-(4'-fluorophenoxy)benzaldehyde semicarbazone.
9. A method of treating, preventing or ameliorating chronic pain or
convulsions, comprising administering to a patient in need thereof
a first agent which is a sodium channel blocker, and a second agent
selected from the group consisting of gabapentin, pregabalin, salts
thereof and combinations thereof; wherein the total amount of said
first agent and said second agent is effective to treat, prevent or
ameliorate chronic pain or convulsions.
10. A method of treating, preventing or ameliorating chronic pain
or convulsions, comprising administering substantially
simultaneously to a patient in need thereof a sodium channel
blocker and at least one of gabapentin and pregabalin, wherein said
sodium channel blocker and at least one of gabapentin and
pregabalin are administered in amounts effective to treat or
prevent chronic pain or convulsions.
11. The method of claim 9, wherein said method is treating,
preventing or ameliorating chronic pain.
12. The method of claim 11, wherein said chronic pain is due to
trigeminal neuralgia.
13. The method of claim 11, wherein said chronic pain is due to
diabetic neuropathy.
14. The method of claim 11, wherein said chronic pain is due to
cancer pain.
15. The method of claim 8, wherein said first agent and said second
agent are administered separately.
16. The method of claim 8, wherein said first agent and said second
agent are administered as part of a single pharmaceutical
composition.
17. A kit for the treatment of chronic pain or convulsions
comprising a carrier containing one or more containers one of which
comprises a sodium channel blocker and another of which comprises
at least one of gabapentin and pregabalin.
Description
[0001] The present application is a continuation of International
Application PCT/US00/09387, published under PCT Article 21(2) in
English as WO 00/61188 on Oct. 19, 2000, having an International
filing date of Apr. 10, 2000, and which claims priority under 35
U.S.C. .sctn. 119(e) to U.S. Provisional Application No.
60/128,543, filed Apr. 9, 1999. The full disclosure of each of
these applications is herein incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention is in the field of medicinal chemistry. In
particular, the invention relates to compositions comprising
blockers of sodium (Na.sup.+) channels and at least one of
gabapentin or pregabalin. The invention also relates to methods for
the treatment of chronic pain or convulsions comprising
coadministering a sodium channel blocker and at least one of
gabapentin or pregabalin.
[0004] 2. Related Background Art
[0005] Several classes of therapeutically useful drugs, including
local anesthetics such as lidocaine and bupivacaine,
antiarrhythmics such as propafenone and amioclarone, and
anticonvulsants such as lamotrigine, phenytoin and carbamazepine,
have been shown to share a common mechanism of action by blocking
or modulating Na.sup.+ channel activity (Catterall, W. A., Trends
Pharmacol. Sci. 8:57-65 (1987)). Each of these agents is believed
to act by interfering with the rapid influx of Na.sup.+ ions.
Recently, other Na.sup.+ channel blockers such as BW619C89 and
lifarizine have been shown to be neuroprotective in animal models
of global and focal ischemia and are presently in clinical trials
(Graham et al., J Pharmacol. Exp. Ther. 269:854-859 (1994); Brown
et al., British J. Pharmacol. 115:1425-1432 (1995); SCRIP 1870:8
(1993); SCRIP 1773:14 (1992)).
[0006] The neuroprotective activity of Na.sup.+ channel blockers is
due to their effectiveness in decreasing extracellular glutamate
concentration during ischemia by inhibiting the release of this
excitotoxic amino acid neurotransmitter. Studies have shown that
unlike glutamate receptor antagonists, Na.sup.+ channel blockers
prevent hypoxic damage to mammalian white matter (Stys et al., J.
Neurosci. 12:430-439 (1992)). Thus, they may offer advantages for
treating certain types of strokes or neuronal trauma where damage
to white matter tracts is prominent.
[0007] Another example of clinical use of a Na.sup.+ channel
blocker is riluzole. This drug has been shown to prolong survival
in a subset of patients with ALS (Bensimm et al., New Engl. J. Med.
330:585-591 (1994)) and has subsequently been approved by the FDA
for the treatment of ALS. In addition to the above-mentioned
clinical uses, carbamazepine, lidocaine and phenytoin are
occasionally used to treat neuropathic pain, such as from
trigeminal neurologia, diabetic neuropathy and other forms of nerve
damage (Taylor and Meldrum, Trends Pharmacol. Sci. 16:309-316
(1995)), and carbamazepine and lamotrigine have been used for the
treatment of manic depression (Denicott et al., J. Clin. Psychiatry
55: 70-76 (1994)).
[0008] It has been established that there are at least five to six
sites on the voltage-sensitive Na.sup.+ channels which bind
neurotoxins specifically (Catterall, W. A., Science 242:50-61
(1988)). Studies have further revealed that therapeutic
antiarrhythmics, anticonvulsants and local anesthetics whose
actions are mediated by Na.sup.+ channels, exert their action by
interacting with the intracellular side of the Na.sup.+ channel and
allosterically inhibiting interaction with neurotoxin receptor site
2 (Catterall, W. A., Ann. Rev. Pharmacol. Toxicol. 10:15-43
(1980)).
[0009] Chronic pain or neuropathic pain is a heterogenous disease
state with an unclear etiology. In chronic pain, the pain can be
mediated by multiple mechanisms. This type of pain generally arises
from injury to the peripheral or central nervous tissue. The
syndromes include pain associated with spinal cord injury, multiple
sclerosis, post-herpetic neuralgia, trigeminal neuralgia, phantom
pain, causalgia and reflex sympathetic dystrophy and lower back
pain. The chronic pain is different from acute pain in that
patients suffer the abnormal pain sensations that can be described
as spontaneous pain, continuous superficial burning and/or a deep
aching pain. The pain can be evoked by heat-, cold- and
mechano-hyperalgesia or by heat-, cold- and mechano-allodynia
(International association for the study of pain: The
classification of chronic pain (1995); Bennett G. J. Molecular
Neurobiology of Pain, Progress in Pain Research and Management Vol.
9, pp. 109-113, edited by D. Borsook, 1997). In most cases, chronic
neuropathic pain responds poorly to treatment with opiates or
nonsteroidal anti-inflammatory analgesia.
[0010] Carbamazepine (Tegretol.TM.), a sodium channel blocker
anticonvulsant, has been shown to be effective in trigeminal
neuralgia. However, one third of patients cannot tolerate the drug
in the dose required to alleviate the pain (Victor et al.,
Harrison's Principles of Internal Medicine. 11.sup.thed. New York:
McGraw-Hill 1987; 2035-40). In addition, carbamazepine may cause
aplastic anemia, agranulocytosis, and hypersensitivity reaction
(Canavero et al., Pain 60:229-31 (1995)). These serious side
effects are dose related. Carbamazepine is the only drug approved
by the FDA for this indication.
[0011] There are no other drugs thus far that have been approved
for chronic pain. Lamotrigine (Lamictal) is a sodium channel
blocker that has been approved by the FDA for treating convulsions.
This drug has also been shown to be effective for treating chronic
pain (Lundardi et al., Neurology 48: 1714 (1997)). However, the
doses required for the treatment of chronic pain are relatively
high and result in side effects. The major side effect of this drug
is severe, potentially life-threatening rashes (Dichter and Brodie,
New Engl. J. Med. 334: 1583 (1996)).
[0012] Gabapentin (Neurontin.TM.), an anticonvulsant with unknown
mechanism of action has been shown recently to be efficacious for
treating chronic pain (Rowbotham et al., JAMA 280: 1837-1842 (1998)
and Backonja et al., JAMA 280: 1831-1836 (1998)). However, higher
doses are necessary to treat chronic pain. Side effects such as
exacerbated absence seizures and nausea are associated with these
high doses in addition to being fetotoxic. In addition, in clinical
trials, gabapentin showed limited efficacy (i.e., less than 50% of
patient population showed effectiveness, whereas 15-20% of patients
treated with placebo showed effectiveness).
[0013] Pregabalin is a potent follow-up compound to gabapentin. The
compound has similar activity to gabapentin and is currently under
clinical trials for neuropathic pain (SCRIP 2330:8 (1998)).
[0014] Thus, a need exists for treatments of chronic pain and
convulsions that avoid the side effects exhibited by lamotrigine,
carbamazepine and gabapentin. The present invention provides
compositions and methods which reduces such side effects and
improves the response rate of patients.
SUMMARY OF THE INVENTION
[0015] The present invention relates to pharmaceutical
compositions, comprising a first agent which is a sodium channel
blocker, and a second agent selected from the group consisting of
gabapentin, pregabalin, salts thereof and combinations thereof,
wherein the total amount of said first agent and said second agent
is effective to treat, prevent or ameliorate chronic pain or
convulsions. Preferably, said first agent and said second agent are
present in synergistic amounts, that is the sodium channel blocker
and at least one of gabapentin or pregabalin or their salts are
present in amounts lower than those used to treat or prevent
chronic pain or convulsions when used alone. The invention further
relates to such compositions that further comprise a
pharmaceutically acceptable carrier, and optionally include
pharmaceutically acceptable excipients.
[0016] The invention also relates to a method of treating,
preventing or ameliorating chronic pain or convulsions, comprising
administering to a patient in need thereof a first agent which is a
sodium channel blocker, and a second agent selected from the group
consisting of gabapentin, pregabalin, salts thereof and
combinations thereof, wherein the total amount of said first agent
and said second agent is effective to treat, prevent or ameliorate
chronic pain or convulsions. Preferably, said sodium channel
blocker and at least one of gabapentin and pregabalin are
administered in synergistic amounts. Preferably, the two agents are
administered substantially simultaneously as defined herein. The
sodium channel blocker and at least one of gabapentin and
pregabalin may be administered separately or as part of a single
pharmaceutical composition.
[0017] The invention also relates to a kit for the treatment of
chronic pain or convulsions comprising a carrier containing one or
more containers one of which comprises a sodium channel blocker and
another of which comprises an agent selected from the group
consisting of gabapentin, pregabalin, salts thereof and
combinations thereof.
DESCRIPTION OF THE FIGURE
[0018] FIG. 1 depicts a graph showing the synergistic antiallodynic
effect of gabapentin and the sodium channel blocker
4-(4'-fluoro-phenoxy)benzald- ehyde semicarbazone (Co 102862) in
the Chung model of neuropathic pain in rats (Kim and Chung, Pain
50: 355-363 (1992)).
DETAILED DESCRIPTION OF THE INVENTION
[0019] The present invention arises out of the discovery that
administration of a sodium channel blocker with gabapentin,
pregabalin, salts thereof or combinations thereof, is effective for
the treatment, prevention and/or amelioration of chronic pain and
convulsions. The present invention also arises out of the discovery
that it is possible to treat, prevent and/or ameliorate chronic
pain and convulsions with synergistic amounts of at least one
sodium channel blocker together with gabapentin, pregabalin or
salts thereof or combinations thereof.
[0020] Useful first agents and second agents are described in the
sections below. The first agent can be a single sodium channel
blocker, or can two or more sodium channel blockers. Likewise, the
second agent can be a single compound or can be a mixture of two or
more compounds.
[0021] The present invention relates to pharmaceutical
compositions, comprising a first agent which is a sodium channel
blocker, and a second agent selected from the group consisting of
gabapentin, pregabalin, salts thereof and combinations thereof;
wherein the total amount of said first agent and said second agent
is effective to treat, prevent or ameliorate chronic pain or
convulsions. Preferably, said first agent and said second agent act
in synergy to treat, prevent or ameliorate chronic pain or
convulsions. The invention further relates to such compositions
that further comprise a pharmaceutically acceptable carrier, and
optionally include pharmaceutically acceptable excipients.
[0022] The invention also relates to a method of treating,
preventing or ameliorating chronic pain or convulsions, comprising
administering to a patient in need thereof a first agent which is a
sodium channel blocker, and a second agent selected from the group
consisting of gabapentin, pregabalin, salts thereof and
combinations thereof; wherein the total amount of said first agent
and said second agent is effective to treat, prevent or ameliorate
chronic pain or convulsions. Preferably, said sodium channel
blocker and at least one of gabapentin and pregabalin are
administered in synergistic amounts. Preferably the agents are
administered substantially simultaneously. The sodium channel
blocker and at least one of gabapentin and pregabalin may be
administered separately or as part of a single pharmaceutical
composition in the treatment of pain, especially for treatment of
chronic pain disorders. Such disorders include, but are not limited
to, inflammatory pain, postoperative pain, osteoarthritis pain
associated with metastatic cancer, trigeminal neuralgia, acute
herpetic and postherpetic neuralgia, diabetic neuropathy,
causalgia, brachial plexus avulsion, occipital neuralgia, reflex
sympathetic dystrophy, fibromyalgia, gout, phantom limb pain, bum
pain, and other forms of neuralgic, neuropathic, and idiopathic
pain syndromes.
[0023] Thus, one aspect of the present invention is a method for
the treatment of pain as listed above. Pain such as inflammatory
pain, neuropathic pain, cancer pain, postoperative pain, and
idiopathic pain which is pain of unknown origin, for example,
phantom limb pain are included especially. Neuropathic pain is
caused by injury or infection of peripheral sensory nerves. It
includes, but is not limited to pain from peripheral nerve trauma,
herpes virus infection, diabetes mellitus, causalgia, plexus
avulsion, neuroma, limb amputation, and vasculitis. Neuropathic
pain is also caused by nerve damage from chronic alcoholism, human
immunodeficiency virus infection, hypothyroidism, uremia, or
vitamin deficiencies. Neuropathic pain includes, but is not limited
to pain caused by nerve injury such as, for example, the pain from
which diabetics suffer.
[0024] Another aspect of the invention is directed to a method for
treating convulsions as described above.
[0025] Gabapentin and Pregabalin
[0026] One agent employed in the composition and methods of the
present invention (referred to as the second agent) is a derivative
of GABA (4-aminobutanoic acid). Gabapentin is a generic term used
to identify the compound 1-(aminomethyl)cyclohexaneacetic acid. The
compound can also exist as a hydrate, and the compound can exist in
an amorphous or crystalline form. For example, U.S. Pat. No.
4,894,476 discloses crystalline gabapentin monohydrate and a method
for making it. PCT Published Application No. W099/61408 discloses a
non-hydrated gabapentin polymorph. PCT Published Application No.
98/28255 discloses alternate crystal forms of gabapentin (form II
and form III) and methods for making these forms. Gabapentin is
useful in the present invention in all of its forms. Preferred
forms include those forms described in U.S. Pat. Nos. 4,024,175,
4,087,544 and 4,894,476. Gabapentin can also form salts, for
example a hydrochloride salt. Salts of gabapentin are included
within the scope of the invention.
[0027] Pregabalin is a generic term used to identify the compound
3-(aminomethyl)-5-methylhexanoic acid. This compound has a
stereocenter and the 3S-enantiomer,
(3S)-3-(aminomethyl)-5-methylhexanoic acid is the more active
stereoisomer. Racemic mixtures or mixtures having an enantiomeric
excess of the 3S stereoisomer are preferred for the present
invention. The compound is useful in the present invention in all
of its forms, whether amorphous or crystalline, anhydrous or
hydrated. Pregabalin can also exist in salt forms, which are
included within the scope of the invention.
[0028] Gabapentin and pregabalin can be formulated to provide
greater stability to the compound. Useful excipients for inclusion
with gabapentin and pregabalin include neutral amino acids, such as
glycine and L-valine; and humectants, such as ethylene glycol,
propylene glycol and glycerine. The active compounds may also be
coated as agglomerated powders with a polymer such as polyvinyl
pyrrolidone to provide better stability and processing
characteristics.
[0029] Sodium Channel Blockers
[0030] The first agent in the compositions and methods of the
present invention is a sodium channel blocker.
[0031] Compounds can be tested for their Na.sup.+ channel blocking
activity by the electrophysiological and binding assays which are
described herein. Preferred sodium channel blocking properties
exhibit an Ki of about 100 .mu.M or less in the
electrophysiological assay. Preferably, the sodium channel blockers
exhibit an Ki of 10 .mu.M or less. Most preferably, the sodium
channel blockers exhibit an Ki of about 1.0 .mu.M or less.
[0032] Sodium channel blockers that may be used in the practice of
the invention include any of the known sodium channel blockers as
described herein, including compounds disclosed in the following
documents.
[0033] PCT International Published Application W096/40628 discloses
semicarbazones represented by Formula I: 1
[0034] where R.sub.1-R.sub.4 are independently hydrogen, halogen,
C.sub.1-9 alkyl, C.sub.3-9 cycloalkyl, cyano, C.sub.1-9 alkoxy, or
C.sub.6-10 aryloxy; R.sub.5 is hydrogen, C.sub.1-9 alkyl, C.sub.3-9
cycloalkyl, or C.sub.6-10 aryl; and X is oxygen or sulfur. The
compounds are disclosed to be useful as anticonvulsants.
[0035] PCT International Published Application W098/47869 discloses
the compounds claimed in WO 96/40628 act as sodium channel
blockers. In addition, it discloses sodium channel blocking
semicarbazones and thiosemicarbazones represented by Formula II:
2
[0036] or a pharmaceutically acceptable salt or prodrug thereof,
wherein:
[0037] Y is oxygen or sulfur;
[0038] R.sub.1 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,
haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or
carboxyalkyl;
[0039] R.sub.21, R.sub.22 and R.sub.23 are independently hydrogen,
alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl,
hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R.sub.21, is defined
as above, and R.sub.22 and R.sub.23 together with the nitrogen atom
to which they are attached form a heterocycle, including
piperidine, piperazine, or morpholine;
[0040] A.sub.1 and A.sub.2 are independently aryl, heteroaryl,
saturated or partially unsaturated carbocycle or saturated or
partially unsaturated heterocycle, any of which is optionally
substituted;
[0041] X is one or O, S, NR.sub.24, CR.sub.25R.sub.26, C(O),
NR.sub.24C(O), C(O)NR.sub.24, SO, SO.sub.2 or a covalent bond;
where
[0042] R.sub.24 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,
haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or
carboxyalkyl; and
[0043] R.sub.25 and R.sub.26 are independently hydrogen, alkyl,
cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl,
hydroxyalkyl, alkoxyalkyl or carboxyalkyl.
[0044] **PCT International Published Application WO99/26614 (Appl.
No. PCT/US98/24965, filed Nov. 20, 1998), discloses sodium channel
blockers represented by Formula III: 3
[0045] or a pharmaceutically acceptable salt or prodrug thereof,
wherein:
[0046] R.sub.1 R.sub.2, R.sub.3 and R4 are independently hydrogen,
alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl,
hydroxyalkyl, alkoxyalkyl or carboxyalkyl;
[0047] R.sub.5, R.sub.6 and R.sub.7 are independently hydrogen,
alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl,
hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R.sub.5, is defined
as above, and R.sub.6 and R.sub.7 together with the nitrogen atom
to which they are attached form a heterocycle;
[0048] A.sub.1 and A.sub.2 are independently aryl, heteroaryl,
saturated or partially unsaturated carbocycle or saturated or
partially unsaturated heterocycle, any of which is optionally
substituted;
[0049] X is one or O, S, NR.sub.8, CH.sub.2, C(O), NR.sub.8C(O),
C(O)NR8, SO, SO.sub.2 or a covalent bond; where
[0050] R.sub.8 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,
haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or
carboxyalkyl;
[0051] n is 0, 1, 2or 3.
[0052] **PCT International Published Application WO 99/39712 (Appl.
No. PCT/US99/02419, filed Feb. 4, 1999), discloses sodium channel
blockers represented by Formula IV: 4
[0053] or a pharmaceutically acceptable salt or prodrug thereof,
wherein:
[0054] R.sub.1 and R.sub.2 are independently hydrogen, alkyl,
cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl,
hydroxyalkyl, alkoxyalkyl or carboxyalkyl;
[0055] R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are independently
hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl,
aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R.sub.3
and R.sub.4 is defined as above, and R.sub.5 and R.sub.6 together
with the nitrogen atom to which they are attached form a
heterocycle, including piperidine, piperazine, morpholine;
[0056] A.sub.1 and A.sub.2 are independently aryl, heteroaryl,
saturated or partially unsaturated carbocycle or saturated or
partially unsaturated heterocycle, any of which is optionally
substituted;
[0057] X is one of O, S, NR.sub.7, CH.sub.2, C(O), NR.sub.7C(O),
C(O)NR.sub.7, SO, SO.sub.2 or a covalent bond; where
[0058] R.sub.7 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,
haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or
carboxyalkyl;
[0059] n is 0, 1, 2 or 3.
[0060] m is 0, 1, 2, or 3.
[0061] PCT International Published Application WO98/08842 discloses
sodium channel blockers having the Formula V: 5
[0062] wherein R.sup.1 and R.sup.2 each represents hydrogen, lower
alkyl which may be substituted or acyl; R.sup.3, R.sup.4 and
R.sup.5 each represents lower alkyl which may be substituted or
lower alkoxy which may be substituted or R.sup.4 or R.sup.5 taken
together represent a 5- or 6-membered carbocyclic group; R.sup.6
represents lower alkyl; Ar represents an aromatic group which may
be substituted; ring A represents a 5- to 8-membered
nitrogen-containing heterocyclic ring which may be substituted; X
represents lower alkylene which may be substituted; Y represents
carbon or nitrogen; Za represents CH.sub.2, COCH.sub.2, OCH.sub.2,
SCH.sub.2, NHCH.sub.2, etc.; Zb represents a bond or a divalent
aliphatic hydrocarbon group which may be substituted and may
contain O, N or S; and m represents an integer of 1 to 3, or a salt
thereof.
[0063] U.S. Pat. No. 5,449,692 discloses compounds having Formula
VI: 6
[0064] wherein n is an integer of 1 to 4; each of R and R.sub.1,
which may be the same or different, is hydrogen, halogen,
trifluoromethyl or C.sub.1-C.sub.4 alkoxy; R.sub.2 is hydrogen or
C.sub.1-C.sub.4 alkyl; and a pharmaceutically acceptable salts
thereof; and wherein when, at the same time, R is hydrogen, R.sub.1
is hydrogen or halogen and n is one, then R.sub.2 is other than
hydrogen or methyl; and of Formula VIa: 7
[0065] wherein R.sub.3 is halogen, and a pharmaceutical acceptable
salt thereof.
[0066] Other sodium channel blocker compounds useful in the
practice of the invention include compounds disclosed in PCT
International Published Application WO 97/05102 having Formula VII:
8
[0067] wherein n is zero, 1, 2 or 3; X is --O--, --S--,
--CH.sub.2-- or --NH--; each of R and R.sub.1 independently is
hydrogen, C.sub.1-C.sub.6 alkyl, halogen, hydroxy, C.sub.1-C.sub.4
alkoxy or trifluoromethyl; each of R.sub.2, R.sub.3 and R4
independently is hydrogen, C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.7
cycloalkyl; and the pharmaceutically acceptable salts thereof.
[0068] Other sodium channel blocker compounds useful in the
practice of the invention, include compounds disclosed in U.S. Pat.
No. 5,446,066 having Formula VIII: 9
[0069] wherein n is zero or an integer of 1 to 3; each of R and
R.sub.1, which may be the same or different, is hydrogen, halogen,
trifluoromethyl or C.sub.1-C.sub.4 alkoxy; R.sub.2 is hydrogen or
C.sub.1-C.sub.4 alkyl optionally substituted by hydroxy; each of
R.sub.3 and R.sub.4 independently is hydrogen or C.sub.1-C.sub.4
alkyl; or a pharmaceutically acceptable salt thereof; and of
Formula VIIIa: 10
[0070] wherein R.sub.5 is hydrogen, halogen, trifluoromethyl or
C.sub.1-C.sub.4 alkoxy, or a pharmaceutically acceptable salt
thereof.
[0071] Other sodium channel blocker compounds useful in the
practice of the invention include compounds disclosed in U.S. Pat.
No. 5,236,957 having Formula IX: 11
[0072] wherein R is C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8
cycloalkyl, furyl, thienyl, pyridyl or unsubstituted or substituted
phenyl; A is a --(CH.sub.2).sub.m-- or
--(CH.sub.2).sub.p--X--(CH.sub.2).sub.q--group wherein X is --O--,
--S-- or --NR.sub.4--; R.sub.1, R.sub.2, R.sub.3, and R'.sub.3 are
hydrogen or C.sub.1-C.sub.6 alkyl, n, m, p, and q are zero or an
integer from 1 to 3; and each of R.sub.5 and R.sub.6 is
independently hydrogen or C.sub.1-C.sub.6 alkyl, and the
pharmaceutical acceptable salts thereof.
[0073] Other sodium channel blocker compounds useful in the
practice of the invention include compounds disclosed in PCT
International Published Application WO 98/43964 having Formula X:
12
[0074] wherein n is zero, or an integer of 1 to 3; X is O, S or NH;
each of R and R.sub.1, which are the same or different, is
hydrogen, C.sub.1-C.sub.6 alkyl, halogen, hydroxy, C.sub.1-C.sub.4
alkoxy or trifluoromethyl; each of R.sub.2, R.sub.5 and R.sub.6,
which are the same or different, is hydrogen or C.sub.1-C.sub.6
alkyl; each of R.sub.3 and R.sub.4, which are the same or
different, is hydrogen or C.sub.1-C.sub.6 alkyl or R.sub.3 or
R.sub.4 taken together with the adjacent carbon atom form a
C.sub.3-C.sub.7 cycloalkyl ring; and their pharmaceutically
acceptable salts.
[0075] Other sodium channel blocker compounds may be used in the
practice of the invention, including compounds disclosed in U.S.
patent application Ser. No. 60/126,553 having Formula XI and XII:
13
[0076] or a pharmaceutically acceptable salt, prodrug or solvate
thereof, wherein:
[0077] R.sub.1 and R.sub.4 are independently selected from the
group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl,
C(O)R.sub.16, S(O)R.sub.16, SO.sub.2R.sub.16 all of which may be
optionally substituted;
[0078] R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are independently
selected from the group consisting of hydrogen, alkyl, cycloalkyl,
alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl,
alkoxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl or
carboxyalkyl, or taken together with the carbon atoms to which they
are attached to form a carbocycle or heterocycle. Examples of
bridges formed by R.sub.2 and R.sub.3 or R.sub.5 and R.sub.6 taken
together are --OCH.sub.2O--, --OCF.sub.2O--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, --OCH.sub.2CH.sub.2O--,
--CH.sub.2N(R.sub.17)CH.sub.2--,
--CH.sub.2CH.sub.2N(R.sub.17)CH.sub.2--,
--CH.sub.2N(R.sub.17)CH.sub.2CH.- sub.2-- and
--CH.dbd.CH--CH.dbd.CH--; where R.sub.17 is hydrogen, alkyl,
cycloalkyl;
[0079] R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12,
R.sub.13, R.sub.14, and R.sub.15 are independently selected from
the group consisting of hydrogen, halo, haloalkyl, aryl,
cycloalkyl, saturated or partially unsaturated heterocycle,
heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl,
arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl,
cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl,
carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamido,
hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or
alkylthiol; or R.sub.11 and R.sub.12 or R.sub.12 and R.sub.13 are
taken together with the carbon atoms to which they are attached to
form a carbocycle or heterocycle. Examples of bridges formed by
R.sub.11 and R.sub.12 or R.sub.12 and R.sub.13 taken together are
--OCH.sub.2O--, --OCF.sub.2O--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, --OCH.sub.2CH.sub.2O--,
--CH.sub.2N(R.sub.17)CH.sub.2--,
--CH.sub.2CH.sub.2N(R.sub.17)CH.sub.2--,
--CH.sub.2N(R.sub.17)CH.sub.2CH.- sub.2-- and
--CH.dbd.CH--CH.dbd.CH--; where R.sub.17 is defined as above;
[0080] R.sub.16 is selected from the group consisting of amino,
alkyl, cycloalkyl, aralkyl, aryl, or heteroaryl;
[0081] X is one of O, S, NR.sub.17, CH.sub.2, C(O), NR.sub.17C(O),
C(O)NR.sub.17, SO, SO.sub.2, or a covalent bond where R.sub.17 is
defined as above.
[0082] Exemplary compounds that may be employed as blockers of
sodium channels in the compositions and methods of the present
invention include, without limitation:
[0083] Lidocaine;
[0084] Tetracaine;
[0085] Phenytoin;
[0086] Carbamazepine;
[0087] Lamotrigine;
[0088] 5-(2,3,5-trichlorophenyl)-2,4-diamino-pyrimidine
(BW1003C87);
[0089]
4-amino-2-(4-methylpiperazine-1-yl)-5-(2,3,5-trichlorophenyl)pyrimi-
dine (BW619C89);
[0090] Zonisamide;
[0091] Riluzole;
[0092] Lifarizine;
[0093]
(.dbd.)-cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-
-benzamide (U54494A);
[0094]
N-[3-(2,6-dimethyl-1-piperidinyl)]-.alpha.-phenylbenzeneacetamide
(PD85639);
[0095] Ralitoline;
[0096] N-(2-chloro-6-methylphenyl)-N-4-pyridinyl urea (CI953);
[0097] Fluarizine;
[0098] Verapamil;
[0099] Carvedilol;
[0100] N-acenaphth-5-yl-N'-4-methoxynaphthyl guanidine CNS1237;
[0101] Mexiletine;
[0102] Amitriptyline;
[0103] 1-(4-(4-fluorophenoxy)benzyl)semicarbazide;
[0104]
5-methylthio-3-(4-phenoxyphenyl)-1H-pyrazole-1-carboxamide;
[0105]
5-methylsulfinyl-3-(4-phenoxyphenyl)-1H-pyrazole-1-carboxamide;
[0106] 3-[4-(4-fluorophenoxy)phenyl]-1H-pyrazole-1-carboxamide;
[0107] 3-[4-(4-nitrophenoxy)phenyl]-1H-pyrazole-1-carboxamide;
[0108]
3-[4-(4-methoxyphenoxy)phenyl]-1H-pyrazole-1-carboxamide;
[0109]
3-[4-(3-chloro-2-cyanophenoxy)phenyl]-1H-pyrazole-1-carboxamide;
[0110]
3-[4-(2,4-difluorophenoxy)phenyl]-1H-pyrazole-1-carboxamide;
[0111]
3-[4-(2-chloro-4-fluorophenoxy)phenyl]-1H-pyrazole-1-carboxamide;
[0112] 1-[3-[4-(4-nitrophenoxy)phenyl]-1H-pyrazole]ethanone;
[0113] 2-methyl-1-[3-(4-phenoxyphenyl)-1H-pyrazole]propanone;
[0114] 3-[4-(4-fluorophenoxy)phenyl]-2H-pyrazole-2-carboxamide;
[0115] 1-methanesulfonyl-3-(4-phenoxy)phenyl-1H-pyrazole;
[0116] 1-(4-phenoxybenzyl)semicarbazide;
[0117] 1-(4-(4-fluorophenoxy)benzyl)semicarbazide;
[0118] 1-(4-(4-chlorophenoxy)benzyl)semicarbazide;
[0119] 1-(4-(4-bromophenoxy)benzy)lsemicarbazide;
[0120] 1-(4-(4-methoxyphenoxy)benzyl)semicarbazide;
[0121] 1-(4-(4-trifluoromethylphenoxy)benzyl)semicarbazide;
[0122] 1-(4-(4-methylphenoxy)benzyl)semicarbazide;
[0123] 1-(4-(3,4-difluorophenoxy)benzyl)semicarbazide;
[0124] 1-(4-(4-chloro-2-fluorophenoxy)benzy)semicarbazide;
[0125] 1-(4-(4-nitrophenoxy)benzyl)semicarbazide;
[0126] 1-(4-(3-methylphenoxy)benzyl)semicarbazide;
[0127] 1-(4-(4-t-butylphenoxy)benzyl)semicarbazide;
[0128] 1-(4-(4-propylphenoxy)benzyl)semicarbazide;
[0129] 1-(4-(4-s-butylphenoxy)benzyl)semicarbazide;
[0130] 1-(4-(3,4-methylenedioxyphenoxy)benzyl)semicarbazide;
[0131] 1-(4-cyclohexyloxybenzyl)semicarbazide;
[0132] 1-(4-cycloheptyloxybenzyl)semicarbazide;
[0133] 1-(4-(5-indanyloxy)benzyl)semicarbazide;
[0134] 1-(4-(6-quinolinyloxy)benzyl)semicarbazide;
[0135] 2-(4-(4-fluorophenoxy)-3-fluorobenzyl)semicarbazide;
[0136] 1-(4-(tetrahydropyranyloxy)benzyl)semicarbazide;
[0137] 1-(4-(4-fluorophenoxy)benzyl-4-methylsemicarbazide;
[0138] 1-(4-(4-fluorophenoxy)benzyl)-2-methylsemicarbazide;
[0139]
2-(4-(2-fluorobenzyloxy)benzylamino)-2-methyl-propanamide;
[0140] 2-(4-(4-fluorophenoxy)benzylamino)-2-methyl-propanamide;
[0141]
2-(4-(3,4-methylenedioxyphenoxy)benzylamino)-2-methyl-propanamide;
[0142]
2-(4-(3,4-methylenedioxybenzyloxy)benzylamino)-2-methyl-propanamide-
;
[0143] 2-(4-cyclohexyloxybenzylamino)-2-methyl-propanamide;
[0144]
2-(4-(5,6,7,8-tetrahydro-2-naphthoxy)benzylamino)-2-methyl-propanam-
ide;
[0145] 2-(4-(2-adamantanoxy)benzylamino)-2-methyl- propanamide;
[0146]
2-(4-(4-Chloro-2-fluorophenoxy)benzylamino)-2-methyl-propanamide;
[0147]
2-(4-(2,4-difluorophenoxy)benzylamino)-2-methyl-propanamide;
[0148]
2-(4-(3,4-difluorophenoxy)benzylamino)-2-methyl-propanamide;
[0149]
2-(4-(6-bromo-4-fluorophenoxy)benzylamino)-2-methyl-propanamide;
[0150]
2-(4-(2,4-difluorophenoxy)benzylamino)-2-methyl-propanamide;
[0151] 2-(4-(4-nitrophenoxy)benzylamino)-2-methyl-propanamide;
[0152]
2-(4-(4-tetrahydropyranoxy)benzylamino)-2-methyl-propanamide;
[0153]
2-(4-(3,5-difluorophenoxy)benzylamino)-2-methyl-propanamide;
[0154] 2-(4-(4-chlorophenoxy)benzylamino)-2-methyl-propanamide;
[0155] 2-(4-(4-methylphenoxy)benzylamino)-2-methyl-propanamide;
[0156]
2-(4-(2-chloro-4-fluorophenoxy)benzylamino)-2-methyl-propanamide;
[0157] 2-(4-(5-indanoxy)benzylamino)-2-methyl-propanamide;
[0158] 2-(4-cycloheptoxybenzylamino)-2-methyl-propanamide;
[0159]
2-(4-(1-methyl-4-piperidinoxy)benzylamino)-2-methyl-propanamide;
[0160] 2-(4-(exo-2-norbornoxy)
benzylamino)-2-methyl-propanamide;
[0161]
2-(4-(4-fluorophenoxy)-5-pyridylmetylamino)-2-methyl-propanamide;
[0162] 2-(4-(4-pyridinoxy) benzylamino)-2-methyl-propanamide;
[0163] 2-(3
-fluoro-4-(4-fluorophenyl)benzylamino)-2-methyl-propanamide;
[0164] 2-(4-(2-pyrimidinoxy)benzylamino)-2-methyl-propanamide;
[0165] 2-(4-(6-quinolinoxy)benzylamino)-2-methyl-propanamide;
[0166]
2-(4-(N,N-diphenylamino)benzylamino)-2-methyl-propanamide;
[0167] 2-(4-diphenylmethoxy)benzylamino-2-methyl-propanamide;
and
[0168] 2-(4-triphenylmethoxy)benzylamino-2-methyl-propanamide;
[0169] or pharmaceutically acceptable salts, hydrates or esters
thereof.
[0170] Certain of the sodium channel blockers, gabapentin and
pregabalin may exist as optical isomers and the invention includes
both the racemic mixtures of such optical isomers as well as the
individual enantiomers that may be separated according to methods
that are well know to those of ordinary skill in the art.
[0171] The invention disclosed herein is meant to encompass all
pharmaceutically acceptable salts thereof of the disclosed
compounds. The pharmaceutically acceptable salts include, but are
not limited to, metal salts such as sodium salt, potassium salt,
cesium salt and the like; alkaline earth metals such as calcium
salt, magnesium salt and the like; organic amine salts such as
triethylamine salt, pyridine salt, picoline salt, ethanolamine
salt, triethanolamine salt, dicyclohexylamine salt,
N,N'-dibenzylethylenediamine salt and the like; inorganic acid
salts such as hydrochloride, hydrobromide, sulfate, phosphate and
the like; organic acid salts such as formate, acetate,
trifluoroacetate, maleate, tartrate and the like; sulfonates such
as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the
like; amino acid salts such as arginate, asparginate, glutamate and
the like.
[0172] The invention disclosed herein is also meant to encompass
prodrugs of the disclosed compounds. Prodrugs are considered to be
any covalently bonded carriers which release the active parent drug
in vivo. Examples of prodrugs include esters or amides of compounds
having hydroxyalkyl or aminoalkyl substituents, and these may be
prepared by reacting such compounds with anhydrides such as
succinic anhydride.
[0173] Some of the compounds disclosed herein may contain one or
more asymmetric centers and may thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms. The present
invention is also meant to encompass racemic mixtures, resolved
forms mixtures thereof, as well as the individual enantiomers that
may be separated according to methods that are well know to those
of ordinary skill in the art. When the compounds described herein
contain olefinic double bonds or other centers of geometric
asymmetry, and unless specified otherwise, it is intended to
include both E and Z geometric isomers. All tautomers are intended
to be encompassed by the present invention as well.
[0174] As used herein, the term "stereoisomers" is a general term
for all isomers of individual molecules that differ only in the
orientation of their atoms in space. It includes enantiomers and
isomers of compounds with more than one chiral center that are not
mirror images of one another (diastereomers).
[0175] The term "chiral center" refers to a carbon atom to which
four different groups are attached.
[0176] The term "enantiomer" or "enantiomeric" refers to a molecule
that is nonsuperimposeable on its mirror image and hence optically
active wherein the enantiomer rotates the plane of polarized light
in one direction and its mirror image rotates the plane of
polarized light in the opposite direction.
[0177] The term "racemic" refers to a mixture of equal parts of
enantiomers and which is optically inactive.
[0178] The term "resolution" refers to the separation or
concentration or depletion of one of the two enantiomeric forms of
a molecule. The phrase "enantiomeric excess" refers to a mixture
wherein one enantiomer is present is a greater concentration than
its mirror image molecule.
[0179] The sodium channel blockers, gabapentin and pregabalin may
be prepared using methods known to those skilled in the art.
[0180] Compositions within the scope of this invention include all
compositions wherein the sodium channel blockers, gabapentin and/or
pregabalin are contained in an amount which is effective to achieve
its intended purpose. The amount of sodium channel blockers,
gabapentin and/or pregabalin is preferably less than the amount
needed when each compound is used alone as a single agent. While
individual needs vary, determination of optimal ranges of effective
amounts of each component is within the skill of the art.
Typically, the sodium channel blockers may be administered to
mammals, e.g. humans, orally at a dose of 0.1 to 10 mg/kg, or an
equivalent amount of the pharmaceutically acceptable salt thereof,
per day of the body weight of the mammal being treated. Gabapentin
and/or pregabalin may be administered orally at a dose of about 50
to about 3200 mg/kg per day, preferably about 150 to about 2400
mg/kg per day, and more preferably 300 to 1800 mg/kg, or an
equivalent amount of the pharmaceutically acceptable salt thereof,
per day of the body weight of the mammal being treated. For
intramuscular injection, the dose is generally about one-half of
the oral dose. Typically, pregabalin can be administered at lower
doses than gabapentin.
[0181] With respect to the first agent, exemplary unit oral doses
comprise: For carbamazepine, from about 50 to about 1500 mg/day,
preferably about 100 to about 800 mg/day, more preferably about 100
to about 600 mg/day, and most preferably about 100 to about 400
mg/day; or For lamotrigine, from about 50 to about 1200 mg/day,
preferably 100 to about 600 mg/day, more preferably about 100 to
about 450 mg/day, and most preferably about 100 to about 300
mg/day; or For Co 102862, from about 50 to about 1200 mg/day,
preferably from about 200 to about 900 mg/day, more preferably from
about 200 to about 750 mg/day, and most preferably from about 200
to about 600 mg/day Co 102862.
[0182] Additional useful unit oral doses for the first agent
include: from about 400 to about 800 mg/day carbamazepine, from
about 200 to about 600 mg/day lamotrigine from about 350 to about
900 mg/day Co 102862.
[0183] With respect to the second agent, exemplary unit oral doses
comprise: from about 100 to about 3200 mg/day gabapentin,
preferably about 100 to about 1800 mg/day gabapentin, and more
preferably from about 150 to about 900 mg/day gabapentin; or from
about 75 to about 900 mg/kg pregabalin, preferably 75 to about 450
mg/day of pregabalin.
[0184] Another useful range is from about 300 to about 1800 mg/day
of gabapentin. Another useful range is from about 150 to about 900
mg/day pregabalin.
[0185] The unit dose may be administered one or more times daily as
one or more tablets.
[0186] In addition to administering the sodium channel blockers,
gabapentin and pregabalin as a raw chemical, the compounds may be
administered as part of a pharmaceutical preparation containing
suitable pharmaceutically acceptable carriers comprising excipients
and auxiliaries which facilitate processing of the compounds into
preparations which can be used pharmaceutically. Preferably, the
preparations, particularly those preparations which can be
administered orally and which can be used for the preferred type of
administration, such as tablets, dragees, and capsules, and also
preparations which can be administered rectally, such as
suppositories, as well as suitable solutions for administration by
injection or orally, contain from about 0.01 to 99 percent,
preferably from about 0.25 to 75 percent of active compound(s),
together with the excipient.
[0187] Also included within the scope of the present invention are
the non-toxic pharmaceutically acceptable salts of the sodium
channel blockers, gabapentin and pregabalin. Acid addition salts
are formed by mixing a solution of the particular compound with a
solution of a pharmaceutically acceptable non-toxic acid such as
hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic
acid, citric acid, tartaric acid, carbonic acid, phosphoric acid,
oxalic acid, dichloroacetic acid, and the like. Basic salts are
formed by mixing a solution of the particular compound with a
solution of a pharmaceutically acceptable non-toxic base such as
sodium hydroxide, potassium hydroxide, choline hydroxide, sodium
carbonate and the like.
[0188] The pharmaceutical compositions of the invention may be
administered to any animal which may experience the beneficial
effects of the compounds of the invention. Foremost among such
animals are mammals, e.g., humans, although the invention is not
intended to be so limited.
[0189] The pharmaceutical compositions of the present invention may
be administered by any means that achieve their intended purpose.
For example, administration may be by parenteral, subcutaneous,
intravenous, intramuscular, intraperitoneal, transdermal, or buccal
routes. Alternatively, or concurrently, administration may be by
the oral route. The dosage administered will be dependent upon the
age, health, and weight of the recipient, kind of concurrent
treatment, if any, frequency of treatment, and the nature of the
effect desired.
[0190] In the practice of the present invention, the sodium channel
blockers, gabapentin and pregabalin are preferably administered
substantially simultaneously. By "substantially simultaneously" is
intended to mean that the sodium channel blockers, gabapentin
and/or pregabalin are administered in sequence or at the same time
so long as effective blood levels of the sodium channel blockers,
gabapentin and pregabalin are achieved at the same time. The first
agent or the second agent can be administered first if sequential
administration is chosen. It is preferred that the sodium channel
blockers, gabapentin and pregabalin are administered as part of a
single dosage form.
[0191] The pharmaceutical preparations of the present invention are
manufactured in a manner which is itself known, for example, by
means of conventional mixing, granulating, dragee-making,
dissolving, or lyophilizing processes. Thus, pharmaceutical
preparations for oral use can be obtained by combining the active
compounds with solid excipients, optionally grinding the resulting
mixture and processing the mixture of granules, after adding
suitable auxiliaries, if desired or necessary, to obtain tablets or
dragee cores.
[0192] Suitable excipients are, in particular, fillers such as
saccharides, for example lactose or sucrose, mannitol or sorbitol,
cellulose preparations and/or calcium phosphates, for example
tricalcium phosphate or calcium hydrogen phosphate, as well as
binders such as starch paste, using, for example, maize starch,
wheat starch, rice starch, potato starch, gelatin, tragacanth,
methyl cellulose, hydroxypropylmethylcellulose, sodium
carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,
disintegrating agents may be added such as the above-mentioned
starches and also carboxymethyl-starch, cross-linked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof, such as
sodium alginate. Auxiliaries are, above all, flow-regulating agents
and lubricants, for example, silica, talc, stearic acid or salts
thereof, such as magnesium stearate or calcium stearate, and/or
polyethylene glycol. Dragee cores are provided with suitable
coatings which, if desired, are resistant to gastric juices. For
this purpose, concentrated saccharide solutions may be used, which
may optionally contain gum arabic, talc, polyvinyl pyrrolidone,
polyethylene glycol and/or titanium dioxide, lacquer solutions and
suitable organic solvents or solvent mixtures. In order to produce
coatings resistant to gastric juices, solutions of suitable
cellulose preparations such as acetyl-cellulose phthalate or
hydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or
pigments may be added to the tablets or dragee coatings, for
example, for identification or in order to characterize
combinations of active compound doses.
[0193] Other pharmaceutical preparations which can be used orally
include push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer such as glycerol or
sorbitol. The push-fit capsules can contain the active compounds in
the form of granules which may be mixed with fillers such as
lactose, binders such as starches, and/or lubricants such as talc
or magnesium stearate and, optionally, stabilizers. In soft
capsules, the active compounds are preferably dissolved or
suspended in suitable liquids, such as fatty oils, or liquid
paraffin. In addition, stabilizers may be added.
[0194] Possible pharmaceutical preparations which can be used
rectally include, for example, suppositories, which consist of a
combination of one or more of the active compounds with a
suppository base. Suitable suppository bases are, for example,
natural or synthetic triglycerides, or paraffin hydrocarbons. In
addition, it is also possible to use gelatin rectal capsules which
consist of a combination of the active compounds with a base.
Possible base materials include, for example, liquid triglycerides,
polyethylene glycols, or paraffin hydrocarbons.
[0195] Suitable formulations for parenteral administration include
aqueous solutions of the active compounds in water-soluble form,
for example, water-soluble salts and alkaline solutions. In
addition, suspensions of the active compounds as appropriate oily
injection suspensions may be administered. Suitable lipophilic
solvents or vehicles include fatty oils, for example, sesame oil,
or synthetic fatty acid esters, for example, ethyl oleate or
triglycerides or polyethylene glycol-400 (the compounds are soluble
in PEG-400). Aqueous injection suspensions may contain substances
which increase the viscosity of the suspension include, for
example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
Optionally, the suspension may also contain stabilizers.
[0196] Preferred sodium channel blocking properties exhibit an Ki
of about 100 .mu.M or less in the electrophysiological assay.
Preferably, the sodium channel blockers exhibit an Ki of 10 .mu.M
or less. Most preferably, the sodium channel blockers exhibit an Ki
of about 1.0 .mu.M or less. The sodium channel blockers may be
tested for their Na.sup.+ channel blocking activity by the
following electrophysiological and binding assays.
[0197] First Electrophysiological Assay
[0198] Cell preparation. HEK-293 cells stably expressing the hSkM1
isoform of Na.sup.+ channels (generous gift from Dr. A. L. George,
Vanderbilt University Medical School) were cultured using standard
techniques, as described previously (Verdoorn, T. A, el al., Neuron
4:919-928 (1990)). For electrophysiology, cells were plated onto 35
mm Petri dishes (pre-coated with poly-D-lysine) at a density of
1:40 on the day of re-seeding from confluent cultures. Cells are
suitable for recordings for 2-3 days after plating.
[0199] Patch-clamp recordings of voltage-sensitive Na.sup.+
currents: Whole-cell voltage-clamp recordings were made using
conventional patch-clamp techniques (Hamill et al., Pfluegers Arch.
391:85-100 (1981)) with an Axopatch 200A amplifier (Axon
Instruments, Foster City, Calif.). Recordings were made within 2-3
hours after neuron dissociation. The recording chamber was
continuously superfused with the external solution (150 mM NaCl,
5.4 mM KCl, 1.8 mM CaCl.sub.2, 1 mM MgCl.sub.2, 10 mM HEPES, 10 mM
glucose, pH 7.4 (NaOH)) at a speed of about 1 ml/min. Recording
pipettes were pulled from thick-walled capillaries (WPI, Sarasota,
Fla.) and fire-polished. The pipette resistances ranged from 1 to 3
M.OMEGA. when the pipettes were filled with internal solution
containing (in mM): 110 CsF, 10 NaCl, 5 MgCl.sub.2, 11 EGTA, 10
HEPES, pH adjusted to 7.4 with CsOH. Osmolality was set with a
difference of 15-20 mmol/kg between external and internal solutions
(lower inside the cell). Drugs and intervening wash-outs were
applied through a linear array of flow pipes (Drummond Microcaps,
2-.mu.l, 64-mm length). Compounds are dissolved in
dimethylsulfoxide (DMSO) to make a 30 mM stock solution, which was
subsequently diluted into the external solution to give final
concentrations of 0.1-100 .mu.M. At the highest (1%) concentration,
DMSO inhibited the size of Na.sup.+ current only slightly. Currents
were recorded at room temperature (22-25.degree. C.), filtered at 5
kHz with an active 8-pole Bessel filter (Frequency Devices,
Haverhill, Mass.), digitized at 10-50 .mu.s intervals, and stored
using Digidata 1200 analog/digital interface with Pclamp6/Clampex
software (Axon Instruments). Series resistance was cancelled
typically by .about.75% when necessary. The inhibitory potency of
drugs was assessed by measuring reductions in the peak amplitude of
Na.sup.+ currents induced by increasing concentrations of compounds
tested. Na.sup.+ currents were elicited by stepping membrane
voltage from holding potentials over the range -100 mV to -50 mV,
to a pulse potential of -10 mV. The test pulse duration was 5-10
msec, repeated at a frequency .ltoreq.1 Hz.
Concentration-inhibition curves were fitted with equation 1:
I/I.sub.control=1/(1+([compound]/IC.sub.50)) Eq. 1
[0200] where I.sub.control is the maximal Na.sup.+ current in the
absence of antagonist, [compound] is the drug concentration, and
IC.sub.50 is the concentration of compound that produces half
maximal inhibition.
[0201] Alternate Electrophysiological Assay
[0202] Cell preparation. HEK-293 (NaIIA-B2) cell line stably
expressing the rBIIA isoform of Na.sup.+ channels is established
in-house. The cells are cultured using standard techniques, as
described previously (Verdoorn, T. A, et al., Neuron 4:919-928
(1990)). For electrophysiology, cells are plated onto poly-D-lysine
pre-coated Cellware 35 mm Petri dishes (BIOCOAT, Becton Dickinson)
at a density of .about.104 cells/dish on the day of re-seeding from
confluent cultures. Our experience has been that cells are suitable
for recordings for 2-3 days after plating.
[0203] Patch-clamp recordings of voltage-sensitive Na.sup.+
currents. Whole-cell voltage-clamp recordings are made using
conventional patch-clamp techniques (Hamill et al., Pfluegers Arch.
391:85-100 (1981)) with an Axopatch 200A amplifier (Axon
Instruments, Foster City, Calif.). The recording chamber is
continuously superfused with the external solution (150 mM NaCl,
5.4 mM KCl, 1.8 mM CaCl.sub.2, 1 mM MgCl.sub.2, 10 mM HEPES, 10 mM
glucose, pH 7.4 adjusted with NaOH, osmolality 320 mmol/kg) at a
speed of about 1 mL/min. Recording pipettes were pulled from the
thick-walled capillaries (WPI, Sarasota, Fla.) and fire-polished.
The pipette resistances range from 1 to 3 M.OMEGA. when the
pipettes are filled with internal solution containing (in mM): 130
CsF, 20 NaCl, 2 MgCl.sub.2, 10 EGTA, 10 HEPES, pH adjusted to 7.4
with CsOH, osmolality .about.310 mmol/kg. Drugs and intervening
wash-outs are applied through a linear array of flow pipes
(Drummond Microcaps, 2 .mu.L, 64-mm length). Compounds are
dissolved in dimethylsulfoxide (DMSO) to make a 30 mM stock
solution, which is subsequently diluted into the external solution
to give final concentrations of 0.1-100 .mu.M. At the highest (1%)
concentration, DMSO inhibits the size of Na current only slightly.
Currents are recorded at room temperature (22-25 .degree. C.),
filtered at 3 kHz with an active 8-pole Bessel filter (Frequency
Devices, Haverhill, Mass.), digitized at 10-50 .mu.s intervals, and
stored using Digidata 1200 analog/digital interface with
Pclamp6/Clampex software (Axon Instruments). Series resistance is
cancelled typically by .about.75% when necessary.
[0204] The following voltage pulse protocols are used to assess the
potency and kinetics of inhibition of the Na.sup.+ channels by the
compounds (FIG. 1). 14
[0205] Current-voltage relationship (IV-curve), protocol A, is used
to report the voltage at which the maximal inward Na.sup.+ current
is achieved. This voltage is used throughout the experiment as
testing voltage, V.sub.t. The steady-state inactivation (or,
availability) curve, protocol C, is used to get the voltage at
which almost complete (.gtoreq.95%) inactivation of Na.sup.+
channels occurs; it serves as voltage for conditioning prepulse,
V.sub.c, throughout the experiment. Protocol B reports how fast the
channels recover from inactivation at hyperpolarized voltages. This
permits us to set up the duration of the hyperpolarization gap
which is used in measurement of the kinetics of binding of
compounds to inactivated Na.sup.+ channels (protocol D). Channel
repriming under control conditions is fast (.gtoreq.90% recovery
during first 5-10 ms). If a drug substantially retards the
repriming process, then it becomes possible (protocol D) to
accurately measure the kinetics of binding of the inhibitor to
inactivated channels as well as the steady-state affinity (k.sub.+
and K.sub.1). To estimate k.sub.+ values, the reduction in peak
currents in successive trials with varying pre-pulse duration is
plotted as a function of pre-pulse duration and the time constant
(.tau.) measured by mono-exponential fit. A plot of 1/.tau. as a
function of antagonist concentration then allows calculating of the
macroscopic binding rates of the antagonists. To determine K.sub.i
values the partial inhibition curves measured by fractional
responses in steady-state are fitted with the logistic
equation:
I/I.sub.control=1/(1+([antagonist]/K.sub.i).sup.P), Eq. 2
[0206] where I.sub.control is the maximal Na.sup.+ current in the
absence of antagonist, [antagonist] is the drug concentration,
K.sub.i is the concentration of antagonist that produces half
maximal inhibition, and p is the slope factor.
[0207] Binding Assay
[0208] The ability of sodium channel blockers to modulate either
site 1 or site 2 of the Na.sup.+ channel may be determined
following the procedures fully described in Yasushi, J. Biol. Chem.
261:6149-6152 (1986) and Creveling, Mol. Pharmacol. 23:350-358
(1983), respectively. Rat forebrain membranes were used as sources
of Na.sup.+ channel proteins. The binding assays are conducted in
130 .mu.M choline chloride at 37.degree. C. for 60-minute
incubation with [.sup.3H] saxitoxin and [.sup.3H] batrachotoxin as
radioligands for site 1 and site 2, respectively.
[0209] In vivo Pharmacology
[0210] The compounds of the present invention may be tested for in
vivo anticonvulsant activity after i.v., p.o. or i.p. injection
using a number of anticonvulsant tests in mice, including the
maximum electroshock seizure test (MES). Maximum electroshock
seizures were induced in male NSA mice weighing between 15-20 g and
male Sprague-Dawley rats weighing between 200-225 g by application
of current (50 mA, 60 pulses/sec, 0.8 msec pulse width, 1 sec
duration, D.C., mice; 99 mA, 125 pulses/sec, 0.8 msec pulse width,
2 sec duration, D.C., rats) using a Ugo Basile ECT device (Model
7801). Mice were restrained by gripping the loose skin on their
dorsal surface and saline-coated corneal electrodes were held
lightly against the two corneae. Rats were allowed free movement on
the bench top and ear-clip electrodes were used. Current was
applied and animals were observed for a period of up to 30 sec for
the occurrence of a tonic hindlimb extensor response. A tonic
seizure was defined as a hindlimb extension in excess of 90 degrees
from the plane of the body. Results were treated in a quantal
manner.
[0211] The compounds may be tested for their antinociceptive
activity in the formalin model as described in Hunskaar, S., B.
Fasmer, and K. Hole, J. Neurosci. Methods 14. 69-76 (1985). Male
Swiss Webster NIH mice (20-30 g; Harlan, San Diego, Calif.) were
used in all experiments. Food was withdrawn on the day of
experiment. Mice were placed in Plexiglass jars for at least 1 h to
accommodate to the environment. Following the accommodation period
mice were weighed and given either the compound of interest
administered i.p. or p.o., or the appropriate volume of vehicle
(10% Tween-80). Fifteen minutes after the i.p. dosing, and 30 min
after the p.o. dosing mice were injected with formalin (20 .mu.L of
5% formaldehyde solution in saline) into the dorsal surface of the
right hind paw. Mice were transferred to the Plexiglass jars and
monitored for the amount of time spent licking or biting the
injected paw. Periods of licking and biting were recorded in 5 min
intervals for 1 hr after the formalin injection. All experiments
were done in a blinded manner during the light cycle. The early
phase of the formalin response was measured as licking/biting
between 0-5 min, and the late phase was measured from 15-50 min.
Differences between vehicle and drug treated groups were analyzed
by one-way analysis of variance (ANOVA). A P value .ltoreq.0.05 was
considered significant. Having activity in blocking the acute and
second phase of formalin-induced paw-licking activity, the
compounds are considered to be efficacious for acute and chronic
pain.
[0212] The compounds may be tested for their potential for the
treatment of chronic pain (antiallodynic and antihyperalgesic
activities) in the Chung model of peripheral neuropathy. Male
Sprague-Dawley rats weighing between 200-225 g were anesthetized
with halothane (1-3% in a mixture of 70% air and 30% oxygen) and
their body temperature controlled during anesthesia through use of
a homeothermic blanket. A 2-cm dorsal midline incision was then
made at the L5 and L6 level and the para-vertibral muscle groups
retracted bilaterally. L5 and L6 spinal nerves were then be
exposed, isolated, and tightly ligated with 6-0 silk suture. A sham
operation was performed exposing the contralateral L5 and L6 spinal
nerves as a negative control. Tactile Allodynia. Rats were
transferred to an elevated testing cage with a wire mesh floor and
allowed to acclimate for five to ten minutes. A series of
Semmes-Weinstein monofilaments were applied to the plantar surface
of the hindpaw to determine the animal's withdrawal threshold. The
first filament used possessed a buckling weight of 9.1 gms (0.96
log value) and was applied up to five times to see if it elicited a
withdrawal response. If the animal had a withdrawal response then
the next lightest filament in the series would be applied up to
five times to determine if it could elicit a response. This
procedure was repeated with subsequent lesser filaments until there
was no response and the lightest filament that elicited a response
was recorded. If the animal did not have a withdrawal response from
the initial 9.1 gm filament then subsequent filaments of increased
weight were applied until a filament elicited a response and this
filament was then recorded. For each animal, three measurements
were made at every time point to produce an average withdrawal
threshold determination. Tests were performed prior to and at 1, 2,
and 24 hrs post drug administration. Tactile allodynia and
mechanical hyperalgesia tests were conducted concurrently.
[0213] Mechanical Hyperalgesia: Rats were transferred to an
elevated testing cage with a wire mesh floor and allowed to
acclimate for five to ten minutes. A slightly blunted needle was
touched to the plantar surface of the hindpaw causing a dimpling of
the skin without penetrating the skin. Administration of the needle
to control paws typically produced a quick flinching reaction, too
short to be timed with a stopwatch and arbitrarily given a
withdrawal time of 0.5 sec. The operated side paw of neuropathic
animals exhibited an exaggerated withdrawal response to the blunted
needle. A maximum withdrawal time of ten seconds was used as a
cutoff time. Withdrawal times for both paws of the animals were
measured three times at each time point with a five-minute recovery
period between applications. The three measures were used to
generate an average withdrawal time for each time point. Tactile
allodynia and mechanical hyperalgesia tests were conducted
concurrently.
[0214] The compounds may be tested for their neuroprotective
activity after focal and global ischemia produced in rats or
gerbils according to the procedures described in Buchan et al.
(Stroke, Suppl. 148-152 (1993)) and Sheardown et al. (Eur. J.
Pharmacol. 236:347-353 (1993)) and Graham et al. (J. Pharmacol.
Exp. Therap. 276:1-4 (1996)).
[0215] The compounds may be tested for their neuroprotective
activity after traumatic spinal cord injury according to the
procedures described in Wrathall et. al. (Exp. Neurology
137:119-126 (1996)) and Iwasaki et. al. (J. Neuro Sci. 134:21-25
(1995)).
[0216] The invention also relates to a kit for the treatment of
chronic pain or convulsions comprising a carrier containing one or
more containers one of which comprises a sodium channel blocker and
another of which comprises at least one of gabapentin and
pregabalin. Examples of such carriers include boxes, tubes and the
like that are used to package pharmaceuticals. Examples of
containers include bottles, jars, tubes and the like.
[0217] The following examples are illustrative, but not limiting,
of the method and compositions of the present invention. Other
suitable modifications and adaptations of the variety of conditions
and parameters normally encountered in clinical therapy and which
are obvious to those skilled in the art are within the spirit and
scope of the invention.
EXAMPLE 1
Coadministration of Co 102862 and Gabapentin
[0218] The tactile antiallodynia effect of Co 102862 and gabapentin
was tested alone or in combination in the Chung model of
neuropathic rats. As shown in FIG. 1, rats that received 1.25 mg/kg
Co 102862 p.o. showed moderate antiallodynia effect whereas 25
mg/kg gabapentin s.c. exhibited minimum or no effect when given
alone. However, when both compounds were given together, a much
greater withdrawal threshold was observed than if one were to add
the effect of Co 102862 and gabapentin given individually. Thus,
the combination of the two drugs has a synergistic effect. See FIG.
1.
[0219] Having now fully described this invention, it will be
understood by those of ordinary skill in the art that the same can
be performed within a wide and equivalent range of conditions,
formulations and other parameters without affecting the scope of
the invention or any embodiment thereof. All patents, patent
applications and publications cited herein are fully incorporated
by reference herein in their entirety.
* * * * *