COMBINAISONS D'ANALOGUES D'ACIDE GLUTAMIQUE ET D'ACIDE GAMMA-AMINOBUTYRIQUE (GABA) ET DE COMPOSES TRICYCLIQUES PERMETTANT DE TRAITER LA DEPRESSION

COMBINATIONS OF GABA ANALOGS AND TRICYCLIC COMPOUNDS TO TREAT DEPRESSION

Abrégé français

L'invention concerne une technique utilisant certains analogues d'acide glutamique et d'acide gamma-aminobutyrique associés à des composés tricycliques, afin de traiter la dépression.

Abrégé anglais

The instant invention is a method of using certain analogs of glutamic acid
and gamma-aminobutyric acid in combination with tricyclic compounds to relieve
depression.

Revendications

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What is claimed is:
1. A method for treating a patient having depression comprising
administering a pharmaceutical composition comprising:
(a) a therapeutically effective amount of a GABA analog; and
(b) a therapeutically effective amount of a tricyclic compounds.
2. The method according to claim 1, wherein the GABA analog is the
compound according to Formula I:
<IMG>
wherein R1 is hydrogen or lower alkyl and n is an integer of from 4 to 6, and
the
pharmaceutically acceptable salts thereof.
3. The method according to claim 2, wherein Formula I comprises
gabapentin.
4. The method according to claim 2, comprising from about 10 mg to
about 400 mg of Formula I.
5. The method according to claim 3, comprising from about 10 mg to
about 400 mg of gabapentin.

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6. The method according to claim 3, comprising from about 10 mg to
about 400 mg of gabapentin and from about 25 mg to about 350 mg of tricyclic
antidepressant.
7. The method according to claim 1, wherein the GABA analog is a
compound according to Formula II:
<IMG>
or a pharmaceutically acceptable salt thereof wherein
R1 is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or
cycloalkyl of from 3 to 6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl.
8. The method according to claim 7, wherein Formula II comprises
pregabalin.
9. The method according to claim 7, comprising from about .15 mg to
about 65 mg of Formula II.
10. The method according to claim 8, comprising from about .15 mg to
about 65 mg of pregabalin.
11. A composition for treating depression in a human comprising:
(a) a therapeutically effective amount of a GABA analog; and
(b) a therapeutically effective amount of a tricyclic compounds.
12. The composition according to claim 11, wherein the GABA analog

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the compound according to Formula I:
<IMG>
wherein R1 is hydrogen or lower alkyl and n is an integer of from 4 to 6, and
the
pharmaceutically acceptable salts thereof.
13. The composition method according to claim 12, wherein Formula I
comprises gabapentin.
14. The composition according to claim 12, comprising from about 10
mg to about 400 mg of Formula I.
15. The composition according to claim 13, comprising from about 10
mg to about 400 mg of gabapentin.
16. The composition according to claim 11, wherein the GABA analog
is a compound according to Formula II:
<IMG>
or a pharmaceutically acceptable salt thereof wherein
R1 is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or
cycloalkyl of from 3 to 6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl.

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17. The composition according to claim 16, wherein Formula II
comprises pregabalin.
18. The composition according to claim 16, comprising from about .15
mg to about 65 mg of Formula II.
19. The composition according to claim 18, comprising from about .15
mg to about 65 mg of pregabalin.

Description

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COMBINATIONS OF GABA ANALOGS AND TRICYCLIC COMPOUNDS TO TREAT DEPRESSION
BACKGROUND OF THE INVENTION
1. Field Of The Invention
The present invention relates to the use of analogs of glutamic acid and
gamma-aminobutyric acid (GABA) in combination with tricyclic compounds for
the treatment of depression.
2. Description of Related Art
The GABA analogs of the present invention are known agents useful in
antiseizure therapy for central nervous system disorders such as epilepsy,
Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive
dyskinesia,
and spasticity. It has also been suggested that the compounds can be used as
antidepressants, anxiolytics, and antipsychotics. See WO 92/09560 (United
States
Serial Number 618,692 filed November 27, 1990) and WP 93/23383 (United
States Serial Number 886,080 filed May 20, 1992).
WO 97/33858 teaches that compounds related to gabapentin are useful or
treating epilespy, faintness attacks, hypokinesia, cranial disorders,
neurodegenerative disorders, depression, anxiety, panic, pain, and
neuropathological disorders. WO 97/33858 does not specify what forms of pain
are treated.

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Additionally, the compounds of the invention are known for treatment of
neuropathic pain. For example, see Rosner H; Rubin L; Kestenbaum A.,
Gabapentin adjunctive therapy in neuropathic pain states. Clin 7 Pain, 1996
Mar,
S 12:1, 56-8; Segal AZ; Rordorf G., Gabapentin as a novel treatment for
postherpetic neuralgia. Neurology, 1996 Apr, 46:4, 1175-6; Wetzel CH; Connelly
JF., Use of gabapentin in pain management. Ana Pharmacother, 1997 Sep, 31:9,
1082-3; Zapp JJ., Postpoliomyelitis pain treated with gabapentin [letter]. Am
Fam
Physician, 1996 Jun, 53:8, 2442, 2445; Cheville A, et al., Neuropathic pain in
radiation myelopathy:a case report. Program book, American Pain Society ( 14th
Annual Scientific Meeting). Abstract #95823, p. A-115; Sist T; Filadora V;
Miner M; Lema M., Gabapentin for idiopathic trigeminal neuralgia: report of
two
cases. Neurology, 1997 May, 48:5, 1467; Waldman SD, Tutorial 28: Evaluation
and Treatment of Trigeminal Neuralgia. Pain Digest (1'997) 7:21-24; Mellick
LB;
Mellick GA., Successful treatment of reflex sympathetic dystrophy with
gabapentin [letter]. Am J Emerg Med, 1995 Jan, 13:1, 96; Mellick GA; Seng ML,
The use of gabapentin in the treatment of reflex sympathetic dystrophy and a
phobic disorder. Am J Pain Manage 1995; 5:7-9; Mellick GA; Mellicy LB;
Mellick LB., Gabapentin in the management of reflex sympathetic dystrophy
[letter]. J Pain Symptom Manage, 1995 May, 10:4, 265-6; Mellick GA; Mellick
LB., Reflex sympathetic dystrophy treated with gabapentin. Arch Phys Med
Rehabil, 1997 Jan, 78:1, 98-105 and Mackin GA., Medical and pharmacologic
management of upper extremity neuropathic pain syndromes. J Hand Ther, 1997

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Tricyclic antidepressants are prescribed for endogenous depression, a
condition thought to be caused by a defect in the uptake of amine
neurotransmitters at the presvnaptic junctions. The tricyclic antidepressants
benefit from a controlled delivery formulation for a number of reasons.
Depressed
patients are at a higher risk for suicide, and thus more likely to hoard the
drug and
then attempt to take an overdose. Furthermore, tricyclic antidepressants have
a
long induction period, sometimes taking several w=eeks before patients obtain
relief from the drug. As a result of the long induction period. patients often
stop
using the medication after a short period of time because they think it is not
working. A controlled delivery form of the drug solves these problems by
providing continuous release of the drug for the time period necessary to
provide
relief.
Additionally, many patients who respond to tricyclic antidepressants are
much more likely to avoid a relapse if they are maintained on the drug.
However,
patient compliance to long-term drug regimens is generally very poor. This
problem is also eliminated with controlled release drug formulations.

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Representative e~camples of tricyclic antidepressants are shown below.
~ C /
n
R
R = CH(CH~N(CH3~
amitriptyliae
R
R = (CH~~1(CH3~
itaipramine
R = (CH~3NHCH3
d~sipramine
R = CHICH(CH;~HZN(CH3~
trimipi~amiae
i i
R
R = (CH~3NHCH3
ptouiptytine

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Tricyclic antidepressant drugs such as imipramine. 2 -chloroimipramine
and amitriptyline; penfluridol; haloperidol; pimozide; clozapine;
calmidazolin;
and, mixtures and pharmaceutically acceptable salts of any of the foregoing
are
useful in the present invention
SL;~N1MARY OF THE INVENTION
The invention related to methods and compositions for treating patients
suffering from depression. In methods according to the invention, compositions
comprising a gabs analog and a tricyclic antidepressant in a pharmaceutically-
acceptable vehicle are administered to a patient suffering from depression.
Compositions according to the invention comprise at least one gabs analog and
at
least one tricyclic antidepressant both in amounts effective to alleviate
symptoms
of depression.
This invention provides a method for treating depression comprising
administering to a subject suffering from depression an effective amount of a
GABA analog in combination with an effective amount of a tricyclic compounds.
A preferred embodiment utilizes a cyclic amino acid compound of Formula I
H2N- CH2-C-CH2C02R1
C ~ I
(CH2)n

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wherein R1 is hydrogen or lower alkyl and n is an integer of from 4 to 6, and
the
pharmaceutically acceptable salts thereof. An especially preferred embodiment
utilizes a compound of Formula I where Rl is hydrogen and n is 4, which
compound is 1-(aminomethyl)-cyclohexane acetic acid, known generically as
gabapentin.
In another embodiment, the invention includes treating depression with a
compound of Formula II.
Formula II
R3 RZ
H2NCHCCH2COOH II
R1
or a pharmaceutically acceptable salt thereof wherein
Rl is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or
cycloalkyl of from 3 to 6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl; and tricyclic compounds.
Preferred compounds of the invention are those wherein R3 and R2 are
hydrogen, and Rl is -(CH2)0-2-i C4H9 as an (R), (S), or (R,S) isomer.

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The more preferred compounds of Formula II invention are (S)-3-
(aminomethyl)-5-methylhexanoic acid and 3-aminomethyl-S-methyl-hexanoic
acid, now known generically as pregabalin.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The method of this invention utilizes any GABA analog. A GABA analog
is any compound derived from or based upon gamma-aminobutyric acid. The
compounds are readily available, either commercially, or by synthetic
methodology well-known to those skilled in the art of organic chemistry. The
preferred GABA analogs to be utilized in the method of this invention are
cyclic
amino acids of Formula I. These are described in U.S. Patent 4,024,175, which
is
incorporated herein by reference. Another preferred method utilizes the GABA
analogs of Formula II, and these are described in U.S. Patent 5,563,175, which
is
incorporated herein by reference.
All that is required to practice the method of this invention is to administer
a GABA analog in combination with tricyclic compounds. The amount of GABA
analog in the composition will generally be from about 1 to about 300 mg per
kg
of subject body weight. Typical doses will be from about 10 to about 5000 mg
per
day for an adult subject of non~al weight. It is expected that common doses
that
might be administered could be from 100 mg three times a day up to 600 mg four
times a day. Commercially available capsules of 100 mg, 300 mg, and 400 mg of
gabapentin can be administered. Alternate forms include liquids and filin-
coated

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_g_
tablets.
If a compound of Formula II , such as pregabalin is used, the dosage level
is one sixth that of gabapentin. The dosage range for pregabalin is from about
0.15 mg to about 50 mg per kg per day of subject body weight. Typical dosages
for pregabalin will be from about 1.6 mg to about 840 mg per day with
individual
dosages ranging from abut 0.1 S mg to about 65 mg per dose.
The dosage range for the tricyclic antidepressant can be determined by one
skilled in the art. Amitriptyline is available in 10, 2~, 50, 75 and 150 mg
tablets.
Daily dosages can range from between 75 to 350 mg.
A benefit of the claimed compositions is to lessen the chance of overdose.
Overdoses of antidepressants are common reports to poison control centers. As
a
result, physicians and pharmacists are encouraged to provide small
prescriptions
(2 to 4 weeks) at a time to avoid providing a potential suicide victim with
the tools
to do it. Antidepressant are therefore potential lethal as the dose is
increased and
patients have to be titrated up to an effective dose.
This invention would allow for a synergistic improvement in mood with
lower doses (therefore) safer and potentially faster. The different mechanism
of
action of the two drugs would offer greater benefit to patients.
The compounds of the present invention may form pharmaceutically
acceptable salts with both organic and inorganic acids or bases. For example,
the

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acid addition salts of the basic compounds are prepared either by dissolving
the
free base in aqueous or aqueous alcohol solution or other suitable solvents
containing the appropriate acid and isolating the salt by evaporating the
solution.
Examples of pharmaceutically acceptable salts are hydrochlorides,
hydrobromides,
hydrosulfates, etc. as well as sodium, potassium, and magnesium, etc. salts.
The compounds of the Formula II can contain one or several asymmetric
carbon atoms. The invention includes the individual diastereomers or
enantiomers,
and the mixtures thereof. The individual diastereomers or enantiomers may be
prepared or isolated by methods already well-known in the art.
Formulating the active compound in dosage unit form with a
pharmaceutical carrier produces pharmaceutical compositions of the compound of
the present invention or its salts. Some examples of dosage unit forms are
tablets,
capsules, pills, powders, aqueous and nonaqueous oral solutions and
suspensions,
and parenteral solutions packaged in containers containing either one or some
larger number of dosage units and capable of being subdivided into individual
doses.
Some examples of suitable pharmaceutical carriers, including
pharmaceutical diluents, are gelatin capsules; sugars such as lactose and
sucrose;
starches such as com starch and potato starch, cellulose derivatives such as
sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and
cellulose

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acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable
oils
such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil
of
theobroma; propylene glycol, glycerin; sorbitol; polyethylene glycol; water;
agar;
alginic acid; isotonic saline, and phosphate buffer solutions; as well as
other
compatible substances normally used in pharmaceutical formulations. The
compositions of the invention can also contain other components such as
coloring
agents, flavoring agents, and/or preservatives. ~ These materials, if present,
are
usually used in relatively small amounts. The compositions can, if desired;
also
contain other therapeutic agents.
The percentage of the active ingredients in the foregoing compositions can
be varied within wide limits, but for practical purposes it is preferably
present in a
concentration of at least 10% in a solid composition and at least 2% in a
primary
liquid composition. The most satisfactory compositions are those in which a
much higher proportion of the active ingredient is present.
Routes of administration of the subject compound or its salts are oral or
parenteral. For example, a useful intravenous dose is between 5 and SO mg and
a
useful oral dosage is between 20 and 800 mg. The dosage is within the dosing
range used in treatment of pain or as would be with the needs of the patient
as
described by the physician.
The advantages of using the compounds of Formula I and II, especially

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gabapentin and pregabalin, in the instant invention include the relatively
nontoxic
nature of the compounds, the ease of preparation, the fact that the compounds
are
well-tolerated, and the ease of IV administration of the drugs. Gabapentin has
few
interactions with major classes of drugs since it is not metabolized in the
liver, but
rather excreted unchanged from the body. Further, the drugs are not
metabolized
in the body. The subjects treated with the method of the present invention are
mammals, including humans.
While the invention has been described in detail and with reference to
specific examples thereof, it will be apparent to one skilled in the art that
various
changes and modifications can be made therein without departing from the
spirit
and scope thereof.