Note: Descriptions are shown in the official language in which they were submitted.
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TREATMENT OF MOOD/AFFECTIVE DISORDERS
BY GLUTAMATERGIC UPMODULATORS
This invention resides in the field of affective or mood disorders, and the
pharmacological treatment of such disorders.
GOVERNMENT RIGHTS
This invention was made with Government support under ONR Grant
10 No. N00014-89-J1255, awarded by the Office of Naval Research. The
Government has certain rights in this invention.
BACKGROUND OF THE INVENTION
Sa-ln~ss and normal depression are a universal human response to defeat,
15 disappointment, or other adverse situations. Similar types of depression occur in
such forms as holiday blues, anniversary reactions, premenstrual depressions, and
maternity blues. None of these conditions are psychopathologic. When sadness
or elation is overly intense and continues beyond the expected impact of a stressful
life event, however, or arises endogenously, i.e., in the absence of apparent life
20 stress, the condition is an affective or mood disorder. Affective disorders typically
take the form of discrete syndromal episodes fifteen days or more in duration with
a tendency for recurrence on a periodic or seasonal basis. Symptoms of these
disorders include various types of depression, such as mixed anxiety depression,anxious depression and atypical depression. These symptoms are also
25 characteristic of certain neurotic and other related psychiatric disorders.
Ph~rm~reutical therapy for mood disorders has been achieved by
~tlmini.ctration of three classes of therapeutic agents -- heterocyclic antidepressants,
monoamine oxidase inhibitors, and lithium salts. Although each of these three
classes has an extensive history of use, and methods of ~(lmini~tration have been
30 developed to maximize their effectiveness with minim~l risk, each still posespotential hazards. Heterocyclic antidepressants are the largest class of
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antidepressants, with such side effects as postural hypotension, cardiotoxicity, and
peripheral anticholinergic side effects. Monoamine oxidase inhibitors are suspected
to interact with normal dietary habits and common drugs to cause hypertension,
postural hypotension, erectile difficulties and insomnia. Lithium salts are known
S to cause fine tremor, stomach irritation and diarrhea.
As for the therapeutic effectiveness of these drugs, studies have shown that
an effective determinant of antidepressant activity is the inhibition of rapid-eye-
movement (REM) sleep. Published research (Vogel, G.W., et al., "Drug effects
on REM sleep and on endogenous depression," Neurosc. & Biobehav. Reviews
10 14:49-63 (1990)) indicates that of twelve first-generation antidepressant drugs
studied, ten are found to reduce REM sleep. These are amitriptyline,
clomipramine, clorgyline, desipramine, doxepin, imipramine, nortriptyline,
pargyline, phenelzine, and plotliptyline. The two that do not show the correlation
are iprindole and trimipramine. For second-generation antidepressants, the
15 literature reports that eleven out of thirteen studied are found to reduce REM sleep.
These eleven are amoxapine, butriptyline, fluoxetine, fluvoxamine, indalpine,
maproxiline, mianserin, nomifensime, oxaprotiline, viloxazine, and zimelidine.
The only two that did not reduce REM sleep were amineptine and trazadone.
Combining these figures, the result is that 21 out of 25 drugs known to exhibit
20 antidepressant activity at therapeutic dosages have been shown to also inhibit REM
sleep to a large degree at therapeutic dosages.
Conversely, very few nonaddictive centrally active drugs that are not
antidepressants have demonstrated a significant effect on REM sleep. Those
reported to cause less than 50% depression of REM sleep are the amine precursors25 L-dopa and L-tryptophane; the antiepileptic phenytoin; the antihistamines
diphenhydramine and prometh~7inP; the antipsychotics chlorpromazine,
haloperidol, pimozide and thloridazine; the benzodiazepines adinazolam, diazepam,
flurazepam, lorazepam, midazolam, temazepam and triazolam; the cholinergic
agonists arecholine and pilocarpine; the cholinergic antagonist physostigmine; the
30 muscarinic antagonist atropine; the noradrenergic alpha agonist ~-methil dopa; the
noradrenergic alpha blocker yohimbine; the noradrenergic beta blockers
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metoprolol, propanolol and timolol; the noradrenergic modulators guanethidine and
reserpine; and lithium. Centrally active non-antidepressant drugs that did reduce
REM sleep to a significant effect were the benzodiazepine alprazolam, the
muscarinic agonist scopolamine, and the noradrenergic alpha agonist clonodine.
5 Lower doses (in a typical therapeutic range) of alprazolam and scopolamine~
however, did not result in a large depression of REM sleep. Thus, of 31
nonaddictive centrally active comopunds, 28 are reported in the literature as having
no more than small effects on REM sleep. Of the rem~ining three, two were
found to depress REM sleep at high dosages, but not at lower, therapeutic,
10 dosages.
On the other hand, endogenous depression in hllm~n~ has been found to be
improved by non-pharmacological REM sleep deprivation (Vogel, G.W., et al.,
"REM sleep reductions effects on depression syndromes," Arch. Gen. Psych.
32:765-777 (1975)). In these studies, patients' sleep was monitored and subjects15 awakened during REM (experimental) or non-REM (control) periods in the absence
of drug treatment.
Taken as a whole, these studies indicate that REM sleep reduction is a
persuasive indicator of antidepressant activity. Accordingly, REM sleep is used
as an indicator in the present invention. In addition, a rat model is used, in
20 accordance with literature indicating an effective correlation between REM sleep
in rats and other animals and REM sleep in hllm~n~.
SUl\IMARY OF THE INVENTION
The present invention resides in the discovery that mental depression in
25 human patients can be reduced by enhancement of glut~m~tergic tr~n.~mi~ion. It
is known that glutamate is released by input axons onto lx-amino-3-hydroxy-
5-methylisoxazole-4-propionic acid ("AMPA") receptors, and that this release
mediates excitatory currents at many sites in the teleo-diencephalon. It is known
also that certain drugs are effective in increasing these currents. What is offered
30 by the present invention is the discovery that these drugs are beneficial in the
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treatment of depression by pharmacologically amplifying the effects of the natural
stimulators of AMPA receptors. This effect is allosteric in its nature.
Any of the variety of compounds that meet this description are suitable for
this invention. A preferred group of compounds however are certain compounds
5 having a phenyl ketone structure. Among these pler~l,ed compounds is aniracetam
(Kyburz et al., U.S. Patent No. 4,369,139, January 18, 1993, to Hoffman
LaRoche) as well as others related in structure. The discovery of efficacy against
affective disorders has arisen from experirnental data showing significant
depression of rapid-eye-movement (REM) sleep, in conjunction with the known
10 correlation between reduction in REM sleep and antidepressant activity. A detailed
description of the class of compounds discovered to be useful in this regard plus
specific examples and experimental findings supporting the discovery are provided
in the succee~ling sections of this specification.
15DETAILED DESCRIPIION OF THE INVENTION
AND PREFERRED EMBODIMENTS
Most excitatory neurotr~n~mi~sion in the forebrain structures occurs via
glut~m~te. The majority of CNS gl-lt~m~t~rgic receptors are of the AMPA class.
The rem~inin~ receptors are of the NMDA class. See, Jonas, P., 1993, Exs,
20 66:61-76; Zorumsky et al., 1993, Pharm~cology and Therapeutics, 59:145-162;
and Orrego et al., 1993, Neuroscience, 56:539-555.
Facilitation of central (brain) glut~m~tergic tr~n.~mi~ion via up-modulation
of "AMPA-type" glut~m:lte receptors has larger effects on complex, polysynaptic
circuitries than on simple circuits (Sirvio et al., "Effects of pharmacologically
25 facilit~tinE glutAm~tergic tr~n~ sion in the tri-synaptic intra-hippocampal circuit, "
Neuroscience in press, 1996), and hence is expected to produce greater facilitation
of the types of network functions found in neocortex than those located in the
lower brain. This invention is based upon the discovery that among the behaviorsaffected by up-modulations of AMPA-type receptors are mood disorders.
30The compounds of the present invention primarily act, not by directly
stim~ ting neural activation, but by up-modul~ting ("allosteric modulation") neural
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activation and tr:~n~mi.c~ion in neurons that contain glut~m~tergic receptors. These
compounds bind to the glut~m~te receptor at a site other than the glut~m~te binding
site, but such binding does not by itself give rise to ion fluxes. However, whena glut~m~te molecule binds to a glutamate receptor that has bound to it a
glut~m~tergic compound of the invention, the subsequent ion flux is increased.
Thus, in the presence of the compounds used herein, postsynaptic neurons are
activated by much lower concentrations of glut~m~te than postsynaptic neurons that
do not contain bound compounds.
A. Definitions
Unless defined otherwise, all technical and scientific terms used herein have
the same me~ning as commonly understood by one of ordinary skill in the art to
which this invention belongs. Although any methods and materials similar or
equivalent to those described herein can be used in the practice or testing of the
present invention, the preferred methods and materials are described. For purposes
of the present invention, the following terms are defined below.
c~-Amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid ("AMPA") or
glut~m~tergic receptors are molecules or complexes of molecules present in cells,
particularly neurons, usually at their surface membrane, that recognize and bindglutAm~te or AMPA. The binding of AMPA or gll~t~m~te to an AMPA receptor
normally gives rise to a series of molecular events or reactions that result in a
biological response. The biological response may be the activation or potentiation
of a nervous impulse, changes in cellular secretion or metabolism, or causing cells
to undergo differentiation or movement.
The term "central nervous system" or "CNS" comprises the brain and the
spinal cord. The term "peripheral nervous system" or "PNS" comprises all parts
of the nervous system that are not part of the CNS, including cranial and spinalnerves and the autonomic nervous system.
The phrase "effective amount" means a dosage sufficient to produce a
desired result. Generally, the desired result is a subjective or objective
improvement in behavior, as measured by the techniques described below.
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The phrase "affective disorder" encompasses a variety of medical conditions
as described in the Diagnostic and Statistical Manual of Mental Disorders of theAmerican Psychiatric Association, which assigns code numbers to the conditions
as follows:
i. Depressive Disorders:
296.XX Major Depressive Disorder
300.4 Dysthymic Disorder
311 Depressive Disorder Not Otherwise Specified
ii. BiPolar Disorders
0 296.XX Bipolar I Disorder
296.89 Bipolar II Disorder
301.13 Cyclothymic Disorder
296.80 Bipolar Disorder Not Otherwise Specified
iii. Other Mood Disorders
296.83 Mood Disorders Not Otherwise Specified
These disorders are defined in terms of mood episodes, which are periods
of time when a subject feels abnormally happy or sad. There are four types of
mood episodes:
A "major depressive episode" is characterized by a period of at least
two weeks during which time a subject feels depressed and has problems
with eating and sleeping, or suffers guilt feelings or loss of energy, has
trouble concentrating and has thoughts about death.
A "manic episode" is characterized by a period of at least one week
during which time the subject feels elated and may be grandiose, talkative,
2~ hyperactive, and distractible, with bad judgment leading to marked social
or work impairment.
A "mixed episode" is characterized by both symptoms of both a
major depressive episode and a manic episode sim-llt~neously, although for
a shorter period of time.
A "hypomanic episode" is similar to a manic episode, although
briefer and less severe.
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The mood disorders themselves are defined as follows:
"Depressive disorders" are of three types. One is the "major
depressive disorder," defined as a disorder suffered by patient who has had
no manic or hypomanic episodes but has had one or more major depressive
5episodes. The second is the "dysthymic disorder," defined as a type of
depression that lasts longer than a major depressive disorder but is not
severe enough to be a major depressive episode. The third is the
"depressive order not otherwise specified," which is defined as depressive
symptoms that do not meet the any of the criteria speficied above.
10"Bipolar disorders" are also of three types. A "bipolar disorder I"
is characterized by at least one manic episode, and often also a major
depressive episode. A "bipolar disorder II" requires at least one hypomanic
episode plus at least one major depressive episode. A "cyclothymic
disorder" is characterized by repeated mood swings but none that are severe
15enough to be called major depressive episodes or manic episodes.
Depressions that accompany many other mental disorders may also be treated by
the methods of this invention.
The severity of depression is assessed by various tests recognized in the
field of psychiatry. One such test is the Hamilton Depression Rating Scale, as
20 disclosed by Hamilton, M., "Rating scale for depression," J. Neurol. Neurosurg.
Psych. 23:56-62. Another is the Montgomery-Asberg Depression Rating Scale, as
disclosed by Montgomery, S., et al., "A new depression rating scale designed to
be sensitive to change, " Br. J. Psych. 134:382-389. Both of these tests consist of
grading the patient on a number of aspects such as suicidal thoughts, concentration
25 difficulties and sadness, by a trained professional.
B. Compounds used to treat mood/affective disorders.
Compounds useful in the practice of this invention are generally those
which amplify (up-modulate) the activity of the natural stim~ tors of AMPA
30 receptors, particularly by amplifying excitatory synaptic responses. A wide variety
of diverse compounds suitable for use in the invention are disclosed herein.
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Methods for identifying other compounds are routine. These methods involve a
variety of accepted tests to determine whether a given candidate compound is an
up-modulator of the AMPA receptor. The primary assay is measurement of
enlargement of the excitatory postsynaptic potential (EPSP) in in vitro brain slices,
such as rat hippocampal brain slices.
In experiments of this kind, slices of hippocampus from a m~mm~l such as
rat are prepared and m~int~inl~d in an interface chamber using conventional
methods. Field EPSPs are recorded in the stratum r~di~h-m of region CAlb and
elicited by single stimulation pulses delivered once per 20 seconds to a bipolarelectrode positioned in the Schaffer-commissural projections (see Granger, R. etal., 1993, Synapse, 15:326-329; Staubli, U. et al., 1994a, Proc. Nat. Acad. Sci.,
91:777-781; and Staubli, V. etal., 1994b, Proc. Nat. Acad. Sci., 91:11158-11162;Arai, A. et al., 1994, Brain Res., 638:343-346; Arai, A. et al., (submitted),
"Effects of a centrally active drug on AMPA receptor kinetics").
The wave form of a normal EPSP is composed of:
an AMPA component, which has a relatively rapid rise time in the
depolarizing direction (about 5-10 msec) and which decays within about 20
msec;
an NMDA component (slow rise time of about 30-40 msec and slow
decay of about 40-70 msec) -- the NMDA portion will not appear in normal
CSF media, due to the voltage requirement for NMDA receptor channel
activation, but in low magnesium media, an NMDA component may
appear; and
a GABA component in the opposite (hyperpolarizing) direction as
the glut~m~tergic (AMPA and NMDA) components, exhibiting a time
course with a rise time of about 10-20 msec and very slow decay (about 50-
100 msec or more).
The different components can be separately measured to assay the effect of
a putative AMPA receptor enhancing agent. This is accomplished by adding agents
that block the unwanted components, so that the detectable responses are essentially
only AMPA responses. For example, to measure AMPA responses, an NMDA
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receptor blocker (for example, AP-5 or other NMDA blockers known in the art)
and/or a GABA blocker (for example, picrotoxin or other GABA blockers known
in the art) are added to the slice. To prevent epileptiform activity in the GABA-
blocked slices, known agents such as tetrodotoxin may be used.
AMPA upmodulators useful in the present invention are substances that
cause an increased ion flux through the AMPA receptor complex channels in
response to ghlt~m~tergic stim~ tion. Increased ion flux is typically measured as
one or more of the following non-limitin~ parameters: at least a 10% increase indecay time, amplitude of the waveform and/or the area under the curve of the
waveform and/or a decrease of at least 10% in rise time of the waveform, for
example in pl~l,a,dtions treated to block NMDA and GABA components. The
increase or decrease is preferably at least 25-50%; most preferably it is at least
100~. How the increased ion flux is accomplished (for example, increased
amplitude or increased decay time) is of secondary importance; up-modulation is
reflective of increased ion fluxes through the AMPA channels, however achieved.
An additional and more detailed assay is that of excised patches, i.e.,
membrane patches excised from cultured hippocampal slices; methods are
described in Arai et al., 1994. Outside-out patches are obtained from pyramidal
hippocampal neurons and transferred to a recording chamber. Glut~m~te pulses
are applied and data are collected with a patch clamp amplifier and digitized (Arai
et al., 1994). Because no GABA is applied to the patch, GABAergic ~;ullenl~ willnot be elicited. Any NMDA currents can be blocked as above (for example, with
AP-5).
The central action of a drug can be verified by measurement of field EPSPs
in behaving animals (see Staubli et al., 1994a) and time course of biodistribution
can be ascertained via injection and subsequent qu~ntitation of drug levels in
various tissue samples. Quantitation can be accomplished by methods known to
those skilled in the art and will vary depending on the chemical nature of the drug.
Compounds useful in the practice of this invention are generally those that
amplify the activity of the natural stimulators of AMPA receptors, particularly by
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amplifying excitatory synaptic response as defined above. They are quite varied
in structure and so long as they embrace the above physiological properties theywill work in this invention. Preferred compounds include but are not limited to
the compounds defined by Formulae described above.
A class of preferred compounds useful in the practice of this invention are
those having the formula
()~ / R~ R2
R4~ " R5
5 ~R6
R7
In this formula:
R~ is N or CH.
m is 0 or 1.
R2 is (CR3~)n m or Cn.mR32(n m) 2, in which n is 4, 5, or 6, and the R3's in
any single compound are the same or different.
Each R3 is H or Cl-C6 alkyl, or
one R3 is combined with R4 to form a single bond linking the no.
6 and no. 3' ring vertices or to forrn a single divalent linking
moiety linking the no. 6 and no. 3' ring vertices, any
rem~ining R3's being H or Cl-C6 alkyl, or
one R3 is combined with R5 to form a single bond linking the no.
2 and no. 3' ring vertices or to form a single divalent linking
moiety linking the no. 2 and no. 3' ring vertices, any
rem~ining R3's being H or Cl-C6 alkyl.
The "linking moiety" in the R3 definitions is CH2, O, NH or
N(C,-C6 alkyl).
R4 when not combined with any R3 is H, Cl-C6 alkyl, or Cl-C6 alkoxy.
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Rs when not combined with any R3 is H, Cl-C6 alkyl, or C,-C6 alkoxy.
R6 is H, OH, C,-C6 alkyl, Cl-C6 alkoxy, hydroxy-(C,-C6 alkyl), or C,-C6
alkoxy-(Cl-C6 alkyl), or is combined with R7.
R7 is H, OH, C,-C6 alkyl, C,-C6 alkoxy, hydroxy-(C,-C6 alkyl), Cl-C6
S alkoxy-(Cl-C6 alkyl), amino, mono(C,-C6 alkyl)amino, or di(C,-C6
alkyl)amino, or is combined with R6.
R6 and R7 when combined form one of the following
R9 R9
R8 / N\
\ (CR10 ~ \ (cqRlo2q-l )
N
N\ C
~ ( C Rl ~ )// \ C/ \ Rl ~
In these formulas:
R8 is O, NH or N(C,-C6 alkyl).
R9 is O, NH or N(C,-C6 alkyl).
The Rl~'s in any single compound are the same or difrelellt, and
each R'~ is H or C,-C6 alkyl.
p is 1 , 2, or 3.
qis 1 or2.
Certain subclasses within the generic formula are preferred.
For example, R2 is preferably (CHR3)n m or Cn mHR32(n m) 3, and more
preferably either Cn mH2(n m) lR3 or Cn mH2(n.m) 3R3. Particularly preferred groups are
20 C5H9R3 and C5H~. Values of n equal to 4 or 5, and particularly 5, are preferred
for compounds in which m is 0, while values of n equal to 3 or 4, and particularly
3, are preferred for compounds in which m is 1. The index m itself is preferably0.
When one R3 of an R2 group is combined with R4, the preferred
25 combination is either a methylene (CH2) group, an O atom, or a N atom, and most
preferably an O atom. When one R3 is combined with Rs, the preferred
combination is similarly either a methylene (CH~) group, an O atom, or a N atom,and most preferably an O atom. When no R3's are combined with either R4 or R5,
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preferred groups for R3 are a H atom and a methyl group, with a H atom
preferred. R3's that are not combined with either R4 or Rs are generally preferred.
Rl is preferably N.
R4 and Rs, when not combined with any R3, are each preferably an H atom
5 or a C,-C6 alkyl group, and more preferably and H atom or a methyl group.
Among these, H and methyl are more preferred, and H is the most preferred. A
preferred alkoxy group for both R4 and Rs is methoxy.
For R6 and R7, it is preferred that one of these groups is other than H.
When not combined with each other to form one of the four divalent groups shown
10 above, R6 and R7 are preferably chosen such that one is H and the other is OH,
Cl-C6 alkyl, C,-C6 alkoxy, hydroxy-(C,-C6 alkyl), Cl-C6 alkoxy-(CI-C6 alkyl),
amino, mono(CI-C6 alkyl)amino, or di(CI-C6 alkyl)amino. Among the latter list,
preferred members are C,-C3 alkyl, C,-C3 alkoxy, hydroxy-(C,-C3 alkyl), C1-C3
alkoxy-(C,-C3 alkyl), amino, mono(C,-C3 alkyl)amino, or di(C,-C3 alkyl)amino.
15 Most pler~l,ed are methoxy, ethoxy, hydroxymethoxy, hydroxyethoxy,
methoxymethyl, ethoxymethyl, amino, methylamino, and dimethylamino. When
R6 and R7 are combined to form one of the four divalent groups whose formulas
are shown above, plef~l,ed among the four are the last two divalent groups, withthe last divalent group particularly preferred. It is noted that the last divalent
20 group forms an aromatic ring with two N atoms, fused to the phenyl ring shown in the generic formula.
For the divalent groups, R8 is preferably an O atom. Likewise, R9 is
preferably an O atom. The R'~'s are preferably either H or methyl, independently,
although in the most preferred compounds, all R'~'s are H atoms. Finally, p is
25 preferably 1, and q is preferably 1 as well.
The terms "alkyl" and "alkoxy" are used herein to include branched-chain
groups when cont~ining three or more carbon atoms.
Compounds 1 through 24 below are examples of compounds within the
scope of the generic formula and these definitions:
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~0 ~ 0
2 3 4 5
O N/3 o N~) O N~ ~ N~3 0
~$ O ~o C ~o ~ N ~ ,N
6 7 8 9 10
O N13 0 ,Nf3 ~ N~3 oN~ O N13
~i O ~ NH N~l N~l H C'l;'CH
2 13 14 15
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14
16 aniracetam 18 19
O N~ O N~
0~
CH30CH2~ ~20C2H5 CH20H
21 22
O N~
C 2~0CH3 CH30CH
23 24
Compounds within the scope of this invention can be prepared by
conventional methods known to those skilled in organic synthesis.
Some of the compunds, for example, can be prepared from an appro~liately
substituted benzoic acid by contacting the acid under conditions suitable to activate
5 the carboxy group for the formation of an amide. This is accomplished, for
example, by activating the acid with carbonyl diimidazole, or with a chlorinating
agent such as thionyl chloride or oxalyl chloride to obtain the corresponding
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benzoyl chloride. The aetivated acid is then contacted with a nitrogen-containing
heterocyclic eompound under conditions suitable for producing the desired imide
or amide. Alternatively, the substituted benzoic acid can be ionized by contact
with at least two equivalents of base such as triethylamine in an inert solvent such
5 as methylene chloride or alcohol-free chloroform, and the ionized benzoic acid can
then be reacted with pivaloyl chloride or a reaetive carboxylic acid anhydride such
as trifluoroacetic anhydride or trichloroacetic anhydride, to produce a mixed
anhydride. The mixed anhydride is then contacted with a nitrogen-containing
heterocyclic compound to produce the desired imide or amide.
A further alternative to these methods, suitable for some of the compounds
in Formula I, is to contaet the ap~lop,iately selected 3,4-(alkylen~clihetero)-
benzaldehyde with ammonia to form an imine, then cont~cting the imine with
benzoyloxycarbonyl chloride to form the ben_oyloxyearbonyl imine. Suitable 3,4-
(alkylenedihetero)-benzaldehydes include 3 ,4-(methylenedioxy)-benzaldehyde, 3,4-
15 (ethylenedioxy)-benzaldehyde, 3,4-(propylenedioxy)-benzaldehyde, 3,4-
(ethylidenedioxy)-benzaldehyde, 3,4-(propylenedithio)-benzaldehyde, 3,4-
(ethylidenedithio)-benzaldehyde, 5-ben7.imiAa7:olecarboxaldehyde, and 6-
quinoxalinPcarboxaldehyde. The benzoyloxycarbonyl imine is then contacted with
a simple conjugated diene such as butadiene under cyeloaddition reaetion
20 conditions, and then with a Lewis aeid under eonditions suitable for a Friedel-
Crafts aeylation. Examples of suitable eonjugated dienes include butadiene, 1,3-pentadiene, and isoprene, and examples of suitable Lewis acids include AlCl3 and
ZnCl2.
Still further compounds within the generic formula are prepared from 2,3-
25 dihydroxy naphthalene. This starting material is reacted with 1,2-dibromoethane
in the presence of base to produce an ethylenedioxy derivative of naphthalene,
which is then reacted with an oxidizing agent such as potassium perm~nganate to
produce 4,5-ethylenedioxyphthaldehydic acid. The latter is contacted with
anhydrous ammonia to form an imine, which is then treated with a suitable
30 carbonyl-activating agent such as dicyclohexylcarbodiimide under cyclization
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16
conditions to form an acyl imine. The acyl imine is then reacted with a simple
conjugated diene to achieve cycloaddition.
Still further compounds within the generic forrnula can be prepared by
contacting an ~-halotoluic acid with at least two equivalents of an alkali salt of a
5 lower alcohol according to the Williamson ether synthesis to produce an ether
linkage. The resulting alkoxymethylbenzoic acid is activatèd with
carbonyldiimi(l:~7ole, thionyl chloride, dicyclohexylcarbodiimide, or any other
suitable activating agent, and reacted with a suitable amine to achieve a
carboxamide linkage.
In an alternate to the scheme of the preceding paragraph, a formyl-
substituted aromatic carboxamide is prepared by activation of an appropriate
starting acid with a tertiary amine (for example, triethyl amine) plus an acid
chloride (for example, pivaloyl chloride) to produce a mixed anhydride for
coupling to a suitable amine. The formyl group is then reduced to an alcohol by
a suitable reducing agent such as sodium borohydride. The alcohol is then
converted to a leaving group which is replaceable by the alkali salt of an alcohol.
The leaving group can be generated by reagents such as thionyl chloride, thionylbromide, mineral acids such as hydrochloric, hydrobromic or hydroiodic acids, orthe combined action of a tertiary amine plus either a suitable sulfonic anhydride or
sulfonyl halide. Alternatively, the alcohol can be activated by removing the
proton. This is achieved by the action of a strong base such as sodium hydride in
an aprotic solvent such as dimethylformamide. The res~llting alkoxide is then
reacted with a suitable alkyl halide or other alkyl compound with a suitable leaving
group to produce the desired ether linkage.
Fused ring structures such as those in which R4 or Rs and one of the R3's
of the formula are combined as a single linking group can be synthesized in the
following manner. The carboxyl group of an applupliately substituted salicylic
acid is activated with carbonyldiimidazole in dichloromethane, chloroform,
tetrahydrofuran, or other anhydrous solvent. An aminoalkylacetal such as
H2N(CH2)3CH(OCH2CH3)2 is then added. The resulting amide is treated with an
aryl or alkyl sulfonic acid, trifluoroacetic acid, or other strong acid, in a solvent
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of low basicity such as chloroform or dichloromethane, to cleave the acetal and
cyclize the intermediate aldehyde with the amide nitrogen and the phenolic oxygen.
In all of these reaction schemes, the methods and reaction conditions for
each of the individual reactions are well within the routine skill of, and will be
readily apparent to, the synthesis chemist.
C. Other compounds.
The above described genus and species of compounds represent two large
groups of the diverse ghlt~m~tergic compounds that may be used to treat affective
disorders according to the present invention. The treatments provided by presentinvention are not limited to the compounds described above. The present invention
further encomp~cses ~Amini.~tering other compounds that enh~m~e the stim~ tion
of c~-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid ("AMPA") receptors
in a subject, said enhancement being sufficient to treat affective disorder.
Examples of other such AMPA-selective compounds include 7-chloro-3-methyl-3-4-
dihydro-2H-1,2,4-benzothi~ 7.in~ S,S-dioxide, as described in Zivkovic et al.,
1995, J. Pharmacol. Exp. Therap., 272:300-309; Thompson et al., 1995, Proc.
Nat. Acad. Sci. USA, 92:7667-7671; Yamada, K., etal., J. Neurosc. 13:3904-
3915 (1993). Other AMPA potentiating drugs are expected to be developed.
D. Testing compolmds for relative AMPA up-mo~ ion.
Dose levels can vary as a function of the specific compound, the severity
of the symptoms, and the susceptibility of the subject to side effects. Some of the
specific compounds that stimulate glutamatergic receptors are more potent than
others. Preferred dosages for a given compound are readily determinable by thoseof skill in the art by a variety of means. A preferred means is to measure the
physiological potency of a given compound that is a c~n~ te for ~mini~tration,
by the method of Davis et al., "A profile of the behavioral changes produced by
the facilitation of AMPA-type glut~m~te receptors," submitted to Behaviora/
Neuroscience (1996). Briefly, excised patches and excitatory synaptic responses
are measured in the presence of different concentrations of test compounds, and the
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18
differences in dosage response potency are recorded and compared. Davis et al.
found that one specific compound designated BDP-20 was about ten-fold more
potent than another designated BDP-12 in a variety of behavioral (exploratory
activity, speed of performance) and physical (excised patches and excitatory
5 synaptic responses) tests. The relative physiological potency was an accurate
measure of their behavioral potency. Thus, excised patches and excitatory synaptic
responses may be used to gauge the relative physiological (and behavioral) potency
of a given compound with regard to a known standard.
Some of the specific compounds that stim~ te gl~t~m~tergic receptors are
10 more potent than others. Preferred dosages for a given compound are readily
determinable by those of skill in the art by a variety of means. A ~ rell~d means
is to measure the physiological potency of a given compound that is a candidate for
~lmini.~tration by methods detailed in Staubli, U., et al., 1994a, Proc. Nat. Acad.
Sci., USA, 91:777-781 and Arai, A., et al., 1994, Brain Res., 638:343-346.
15 Briefly, ~;ull~.lls in excised patches or from excitatory synaptic responses in
hippocampal slice preparations are measured in the presence of different
concentrations of test compounds, and the concentrations to achieve a standard
response are determined and compared. A good correlation between physiological
potency (increased AMPA ~;u~ L~) and behavioral effects (various learning
20 paradigms) has been observed. Thus, AMPA current modulation in vitro may be
used to gauge the relative potency of a given compound for a biological response.
E. Administration of compounds
The compounds of this invention can be incorporated into a variety of
formulations for therapeutic ~(1mini~tration Examples are capsules, tablets,
25 syrups, suppositories, and various injectable forms. Administration of the
compounds can be achieved in various ways, including oral, bucal, rectal,
parenteral, intraperitoneal, intradermal, transdermal ~(lmini~tration.
Preferred formulations of the compounds are oral preparations, particularly
capsules or tablets cont~ining each from about 10 milligrams up to about 1000
30 milligrams of active ingredient. The compounds are form~ te~l in a variety of
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19
physiologically compatible matrixes or solvents suitable for ingestion or injection.
Saline is used in Example 1.
F. Dosage
The above described compounds and/or compositions are a-lmini.ctered at
5 a dosage that suppresses depressive behavior in subjects suffering from affective
disorder while minimi7.ing any side-effects. It is contemplated that the composition
will be obtained and used under the guidance of a physician.
Typical dosages for systemic ~mini~tration range from 0.1 to 10
milligrams per kg weight of subject per ~r~mini~tration. A typical dosage may be10 one 10-50 mg tablet taken once a day, or one time-release capsule or tablet taken
once a day and cont~ining a proportionally higher content of active ingredient. The
time-release effect may be obtained by capsule materials that dissolve at different
pH values, by capsules that release slowly by osmotic pressure, or by any other
known means of controlled release.
Dose levels can vary as a function of the specific compound, the severity
of the symptoms, and the susceptibility of the subject to side effects. Some of the
specific compounds that stimul~te glllt~m~tergic receptors are more potent than
others. Preferred dosages for a given compound are readily determinable by thoseof skill in the art by a variety of means. The skilled practitioner is directed to
20 section D where compound potency is evaluated using excised tissue.
Preferred glut~m~tergic compounds for suppression of mood disorders may
have a half-life measured from less than 30 minutes to more than 5 hours.
G. Kits
This invention provides for kits with unit doses of AMPA up-modulating
25 drugs either in oral or injectable doses. In addition to the containers cont~ining the
unit doses will be a informational package insert describing the use of the drugs
in controlling depressive behavior and its attendant benefits. Preferred compounds
and unit doses are those described herein above.
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WO 97/39750 PCT/US97/03121
The following example is offered for illustrative purposes only.
EXAMPLE
Male Sprague-Dawley rats aged 2 to 4 months, m~int~inf~d on a 12-hour
light/12-hour dark sleeping cycle, were used as test ~nim~lc. Electrodes were
implanted in the frontal and occipital cranium and in the musculature of each rat
and were connected to an automated system capable of classifying vigilance states
as awake, intermediate-eye-movement sleep, slow-eye-movement sleep and rapid-
eye-movement (REM) sleep. The automated system used is described by Chouvet,
G., et al., in "An automated sleet classifier for laboratory rodents," Waking and
0 Sleeping 4:9-31 (1980). Recordings were made by the automated system for
periods of seven hours during the sleep portion of the cycle while the rats were in
a sound attenuated chamber.
The test drug, 1-(quinoxalin-6-ylcarbonyl)piperidine (Compound No. 14
above), was dissolved in a vehicle consisting of a 33 % (weight/volume)
2-hydroxypropyl-~-cyclodextrin solution in 50~ physiological saline/50% water.
On selected days, each rat received an intMperitoneal injection of the test
compound and vehicle at varying dosages of the test compound. On other days the
same rats received an injection of the vehicle alone.
The recordings showed that at a dosage of 32 mg/kg of the test compound,
the percentage of time spent in the REM sleep was reduced from 9.7+2.5% to
3.4+1.3% (mean + standard error for 8 rats) during the first hour following
atlministration, relative to the same animal's sleep time on days on which only the
vehicle was ~(lministered. It was also observed that REM sleep time as a percentof total sleep time was reduced from 13 to 7.5%.
After allowing for an elimin~tion period based on a previously determined
half-life of approximately twenty minutes for this test compound, monitoring of the
the vigilance states revealed no significant changes in subsequent hours.
These test results are logically transferred to human subjects, since the
literature indicates that agents that inhibit REM sleep in ~nim~lc, particularly in
rats, do so in hllm~n.c as well. Reports of REM sleep reduction for both humans
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and ~nimal.~ due to the a(lmini~tration of various known antidepressants outside the
scope of this invention are as follows.
amitriptyline: rats: Jaramillo, J., et al., "Comparative
pharmacological studies on butriptyline and
some related standard tricyclic antidepressants, "
Can J. Physiol. Pharrnacol. 53:104-112 (1975)
hl]m~n.c: Hartmann, E., "Amitriptyline and imipramine: Effects
on human sleep," Psychophysiology 5:207 (1968)
clomipramine: rats: Hilakivi, L.A., et al., "Effects of neonatal treatment
with clomipramine on adult ethanol related behavior in
the rat," Brain Res. 317:129-132 (1984)
hllm~n~: Dunleavy, D.L., et al., "Changes during weeks in
effects of tricyclic drugs on the human sleeping brain,"
Br. J. Psychiatry 120:663-672 (1972)
phenelzine: cats: Oniani, T., et al., "Influence of some monoamin~
oxidase inhibitors on the sleep-wakefulness cycle of the
cat," Neuroscl. Behav. Physiol. 18:301-306 (1988)
hllm~n~: Wyatt, R.J., et al., "Lon~ lin:3l studies of the effect
of mono~min~ oxidase inhibitors on sleep in man,"
Psychopharmacologia 15:236-244 (1969)
fluoxetine: rats: Tsai, L.L., et al., "Changes in sleep patterns by
intral~min~r ~h~l~mic microinjection of fluoxetine in
rats," Proc. Nat. Sci. Council, Rep. of China B17: 15-
20 (1993)
hamsters: Gao, B., et al., "Fluoxetine decreases brain
temperature and REM sleep in Syrian hamsters,"
Psychopharmacology 106:321-329 (1992)
humans: Slater, I., et al., "Inhibition of REM sleep by
fluoxetine, a specific inhibitor of serotonin uptake,"
Neuropharmacology 17:383-389 (1978)
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WO 97t397S0 PCT/US97/03121
butriptyline: rats: Jaramillo, J., et al., "Comparative
pharmacological studies on butriptyline and
- some related standard tricyclic antidepressants, "
Can J. Physiol. Pharmacol. 53:104-112 (1975)
hllm~nc: Brezinova, V., "Effect of butriptyline on subjective
feelings and sleep," Br. J. Clin. Pharrnacol. 4:243-245
(1977)
zimelidine: rats: Reyes, R.B., et al., "Effects of acute doses of
zimelidine on REM sleep in rats,"
Psychopharmacology 80:214-216 (1983)
hum~n~: Shipley, J.E., et al., "Differential effects of
amitripyline and of zimelidine on the sleep
electroencephalogram of depressed patients," Clin.
Pharmacol. Ther. 36:251-259 (1984)
15 Accordingly, the test results herein establish the utility of this invention on
hum~n~.
The foregoing is offered primarily for purposes of illustration. It will be
readily apparent to those skilled in the art that the dosages, formulations, methods
of ~clmini~tration, and other parameters of the invention as described herein may
20 be further modified or substituted in various ways without departing from the spirit
and scope of the invention.
