WO1997039750A1 - Treatment of mood/affective disorders by glutamatergic upmodulators - Google Patents

Treatment of mood/affective disorders by glutamatergic upmodulators Download PDF

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WO1997039750A1
WO1997039750A1 PCT/US1997/003121 US9703121W WO9739750A1 WO 1997039750 A1 WO1997039750 A1 WO 1997039750A1 US 9703121 W US9703121 W US 9703121W WO 9739750 A1 WO9739750 A1 WO 9739750A1
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Jose Ambros-Ingerson
Gary Lynch
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The Regents Of The University Of California
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Publication of WO1997039750A1 publication Critical patent/WO1997039750A1/en

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    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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Definitions

  • This invention resides in the field of affective or mood disorders, and the pharmacological treatment of such disorders.
  • Sadness and normal depression are a universal human response to defeat, 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 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 characteristic of certain neurotic and other related psychiatric disorders.
  • heterocyclic antidepressants are the largest class of 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 to cause fine tremor, stomach irritation and diarrhea.
  • REM sleep Those reported to cause less than 50% depression of REM sleep are the amine precursors L-dopa and L-tryptophane; the antiepileptic phenytoin; the antihistamines diphenhydramine and promethazine; the antipsychotics chlorpromazine, haloperidol, pimozide and thioridazine; the benzodiazepines adinazolam, diazepam, flurazepam, lorazepam, midazolam, temazepam and triazolam; the cholinergic agonists arecholine and pilocarpine; the cholinergic antagonist physostigmine; the muscarinic antagonist atropine; the noradrenergic alpha agonist ⁇ -methil dopa; the noradrenergic alpha blocker yohimbine; the noradren
  • 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.
  • Lower doses (in a typical therapeutic range) of alprazolam and scopolamine did not result in a large depression of REM sleep.
  • 28 are reported in the literature as having no more than small effects on REM sleep. Of the remaining three, two were found to depress REM sleep at high dosages, but not at lower, therapeutic, dosages.
  • REM sleep reduction is a persuasive indicator of antidepressant activity. Accordingly, REM sleep is used as an indicator in the present invention.
  • a rat model is used, in accordance with literature indicating an effective correlation between REM sleep in rats and other animals and REM sleep in humans.
  • the present invention resides in the discovery that mental depression in human patients can be reduced by enhancement of glutamatergic transmission. It is known that glutamate is released by input axons onto ⁇ -amino-3-hydroxy- 5-mefhylisoxazole-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 by the present invention is the discovery that these drugs are beneficial in the treatment of depression by pharmacologically amplifying the effects of the natural stimulators of AMPA receptors. This effect is allosteric in its nature.
  • AMPA ⁇ -amino-3-hydroxy- 5-mefhylisoxazole-4-propionic acid
  • any of the variety of compounds that meet this description are suitable for this invention.
  • a preferred group of compounds are certain compounds having a phenyl ketone structure.
  • aniracetam Keratz et al , U.S. Patent No. 4,369, 139, January 18, 1993, to Hoffman LaRoche
  • the discovery of efficacy against affective disorders has arisen from experimental data showing significant depression of rapid-eye-movement (REM) sleep, in conjunction with the known correlation between reduction in REM sleep and antidepressant activity.
  • REM rapid-eye-movement
  • the compounds of the present invention primarily act, not by directly stimulating neural activation, but by up-modulating ("allosteric modulation") neural activation and transmission in neurons that contain glutamatergic receptors. These compounds bind to the glutamate receptor at a site other than the glutamate binding site, but such binding does not by itself give rise to ion fluxes. However, when a glutamate molecule binds to a glutamate receptor that has bound to it a glutamatergic 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 glutamate than postsynaptic neurons that do not contain bound compounds.
  • AMPA ⁇ -Amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid
  • AMPA glutamatergic receptors
  • 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.
  • central nervous system or “CNS” comprises the brain and the spinal cord.
  • peripheral nervous system or “PNS” comprises all parts of the nervous system that are not part of the CNS, including cranial and spinal nerves and the autonomic nervous system.
  • phrases "effective amount” means a dosage sufficient to produce a desired result.
  • the desired result is a subjective or objective improvement in behavior, as measured by the techniques described below.
  • the phrase "affective disorder” encompasses a variety of medical conditions as described in the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association, which assigns code numbers to the conditions as follows: i. Depressive Disorders:
  • mood episodes which are periods of time when a subject feels abnormally happy or sad.
  • mood episodes 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, 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 simultaneously, although for a shorter period of time.
  • a “hypomanic episode” is similar to a manic episode, although briefer and less severe.
  • 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 episodes. 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 “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 episodes. 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
  • 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 enough to be called major depressive episodes or manic episodes.
  • 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 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 difficulties and sadness, by a trained professional.
  • Compounds useful in the practice of this invention are generally those which amplify (up-modulate) the activity of the natural stimulators of AMPA receptors, particularly by amplifying excitatory synaptic responses.
  • a wide variety of diverse compounds suitable for use in the invention are disclosed herein. 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.
  • EBP excitatory postsynaptic potential
  • 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
  • NMDA glutamatergic
  • GABA in the opposite (hyperpolarizing) direction as the glutamatergic (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.
  • agents that block the unwanted components so that the detectable responses are essentially only AMPA responses.
  • an NMDA receptor blocker for example, AP-5 or other NMDA blockers known in the art
  • a GAB A blocker for example, picrotoxin or other GAB A blockers known in the art
  • AMPA upmodulators useful in the present invention are substances that cause an increased ion flux through the AMPA receptor complex channels in response to glutamatergic stimulation.
  • Increased ion flux is typically measured as one or more of the following non-limiting parameters: at least a 10% increase in decay 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 preparations 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 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. Glutamate 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 currents will not 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 quantitation 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 amplifying excitatory synaptic response as defined above. They are quite varied in structure and so long as they embrace the above physiological properties they will 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 1 is N or CH. m is 0 or 1.
  • R 2 is (CR 3 2 ) n - m or C n . m R 2 ( n - m )- 2 » m which n is 4, 5, or 6, and the R 3 's in any single compound are the same or different.
  • Each R 3 is H or C r C 6 alkyl, or one R 3 is combined with R 4 to form a single bond linking the no. 6 and no. 3' ring vertices or to form a single divalent linking moiety linking the no. 6 and no. 3' ring vertices, any remaining R 3 's being H or C r C 6 alkyl, or one R 3 is combined with R 5 to form a single bond linking the no. 2 and no.
  • R 3' ring vertices or to form a single divalent linking moiety linking the no. 2 and no. 3' ring vertices, any remaining R 3 's being H or C r C 6 alkyl.
  • the "linking moiety" in the R 3 definitions is CH 2 , O, NH or N(C r C 6 alkyl).
  • R 4 when not combined with any R 3 is H, C,-C 6 alkyl, or C,-C 6 alkoxy.
  • R 5 when not combined with any R 3 is H, C r C 6 alkyl, or C,-C 6 alkoxy.
  • R 6 is H, OH, C,-C ⁇ alkyl, C,-C 6 alkoxy, hydroxy-(C,-C 6 alkyl), or C r C 6 alkoxy-(C,-C 6 alkyl), or is combined with R 7 .
  • R 7 is H, OH, C r C 6 alkyl, C r C 6 alkoxy, hydroxy-(C r C 6 alkyl), C,-C 6 alkoxy-(C r C 6 alkyl), amino, mono(C,-C 6 alkyl)amino, or di(C,-C ( , alkyl)amino, or is combined with R 6 .
  • R 6 and R 7 when combined form one of the following
  • R 8 is O, NH or N(C,-C 6 alkyl).
  • R 9 is O, NH or N(C,-C 6 alkyl).
  • the R 10 's in any single compound are the same or different, and each R l ⁇ is H or C,-C 6 alkyl.
  • p is 1, 2, or 3.
  • q is 1 or 2.
  • R 2 is preferably (CHR 3 ) n . m or C n . m HR 3 2(n . m) . 3 , and more preferably either C n . m H 2(n . m) .,R 3 or C n . m H 2 ⁇ n m) . 3 R 3 .
  • Particularly preferred groups are C 5 H 9 R 3 and C 5 H g .
  • 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 preferably 0.
  • R 3 of an R 2 group When one R 3 of an R 2 group is combined with R 4 , the preferred combination is either a methylene (CH 2 ) group, an O atom, or a N atom, and most preferably an O atom.
  • R 5 When one R 3 is combined with R 5 , the preferred combination is similarly either a methylene (CH 2 ) group, an O atom, or a N atom, and most preferably an O atom.
  • preferred groups for R 3 are a H atom and a methyl group, with a H atom preferred.
  • R 3 's that are not combined with either R 4 or R 5 are generally preferred.
  • R 1 is preferably N.
  • R 4 and R 5 when not combined with any R 3 , are each preferably an H atom or a C r C(, 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 R 4 and R 5 is methoxy.
  • R 6 and R 7 it is preferred that one of these groups is other than H.
  • R ⁇ and R 7 are preferably chosen such that one is H and the other is OH,
  • preferred members are C r C 3 alkyl, C r C 3 alkoxy, hydroxy-(C r C 3 alkyl), C,-C 3 alkoxy-(C,-C 3 alkyl), amino, mono(C r C 3 alkyl)amino, or di(C r C 3 alkyl)amino.
  • R 6 and R 7 are combined to form one of the four divalent groups whose formulas are shown above, preferred among the four are the last two divalent groups, with the last divalent group particularly preferred. It is noted that the last divalent group forms an aromatic ring with two N atoms, fused to the phenyl ring shown in the generic formula.
  • R 8 is preferably an O atom.
  • R 9 is preferably an O atom.
  • the R 10 's are preferably either H or methyl, independently, although in the most preferred compounds, all R 10 's are H atoms.
  • p is preferably 1
  • q is preferably 1 as well.
  • alkyl and “alkoxy” are used herein to include branched-chain groups when containing three or more carbon atoms.
  • Some of the compunds can be prepared from an appropriately substituted benzoic acid by contacting the acid under conditions suitable to activate 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 benzoyl chloride. The activated acid is then contacted with a nitrogen-containing heterocyclic compound under conditions suitable for producing the desired imide or amide.
  • the substituted benzoic acid can be ionized by contact with at least two equivalents of base such as triethylamine in an inert solvent such as methylene chloride or alcohol-free chloroform, and the ionized benzoic acid can then be reacted with pivaloyl chloride or a reactive 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 contact the appropriately selected 3,4-(alkylenedihetero)- benzaldehyde with ammonia to form an imine, then contacting the imine with benzoyloxycarbonyl chloride to form the benzoyloxycarbonyl imine.
  • Suitable 3,4- (alkylenedihetero)-benzaldehydes include 3, 4-(methylenedioxy)-benzaldehyde, 3,4- (ethylenedioxy)-benzaldehyde, 3,4-(propylenedioxy)-benzaldehyde, 3,4- (ethylidenedioxy)-benzaldehyde, 3,4-(propylenedithio)-benzaldehyde, 3,4- (ethylidenedithio)-benzaldehyde, 5-benzimidazolecarboxaldehyde, and 6- quinoxalinecarboxaldehyde.
  • the benzoyloxycarbonyl imine is then contacted with a simple conjugated diene such as butadiene under cycloaddition reaction conditions, and then with a Lewis acid under conditions suitable for a Friedel- Crafts acylation.
  • a simple conjugated diene such as butadiene under cycloaddition reaction conditions
  • a Lewis acid under conditions suitable for a Friedel- Crafts acylation.
  • suitable conjugated dienes include butadiene, 1 ,3- pentadiene, and isoprene
  • suitable Lewis acids include A1C1 3 and ZnCl 2 .
  • Still further compounds within the generic formula are prepared from 2,3- 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 permanganate to produce 4,5-ethylenedioxyphthaldehydic acid.
  • the latter is contacted with anhydrous ammonia to form an imine, which is then treated with a suitable carbonyl-activating agent such as dicyclohexylcarbodiimide under cyclization 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 formula can be prepared by contacting an ⁇ -halotoluic acid with at least two equivalents of an alkali salt of a lower alcohol according to the Williamson ether synthesis to produce an ether linkage.
  • the resulting alkoxymethylbenzoic acid is activated with carbonyldiimidazole, thionyl chloride, dicyclohexylcarbodiimide, or any other suitable activating agent, and reacted with a suitable amine to achieve a carboxamide linkage.
  • 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.
  • a tertiary amine for example, triethyl amine
  • an acid chloride for example, pivaloyl chloride
  • 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, thionyl bromide, mineral acids such as hydrochloric, hydrobromic or hydroiodic acids, or the combined action of a tertiary amine plus either a suitable sulfonic anhydride or sulfonyl halide.
  • 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 resulting 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 R 4 or R 5 and one of the R 3 's of the formula are combined as a single linking group can be synthesized in the following manner.
  • the carboxyl group of an appropriately substituted salicylic acid is activated with carbonyldiimidazole in dichloromethane, chloroform, tetrahydrofuran, or other anhydrous solvent.
  • An aminoalkylacetal such as H 2 N(CH 2 ) 3 CH(OCH 2 CH 3 ) 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 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.
  • a solvent of low basicity such as chloroform or dichloromethane
  • the above described genus and species of compounds represent two large groups of the diverse glutamatergic compounds that may be used to treat affective disorders according to the present invention.
  • the treatments provided by present invention are not limited to the compounds described above.
  • the present invention further encompasses administering other compounds that enhance the stimulation of ⁇ -amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid ("AMPA") receptors in a subject, said enhancement being sufficient to treat affective disorder.
  • AMPA ⁇ -amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid
  • Examples of other such AMPA-selective compounds include 7-chloro-3-methy 1-3-4- dihydro-2H-l,2,4-benzothiadiazine S,S-dioxide, as described in Zivkovic et al , 1995, J. Pharmacol Exp. Therap.
  • AMPA potentiating drugs are expected to be developed.
  • excised patches and excitatory synaptic responses are measured in the presence of different concentrations of test compounds, and the 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 synaptic responses) tests.
  • the relative physiological potency was an accurate measure of their behavioral potency.
  • 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.
  • a preferred means is to measure the physiological potency of a given compound that is a candidate for administration by methods detailed in Staubli, U. , et al , 1994a, Proc. Nat. Acad. Sci., USA, 9i:777-781 and Arai, A., et al , 1994, Brain Res., 658:343-346. Briefly, currents 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 currents) and behavioral effects (various learning 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.
  • the compounds of this invention can be incorporated into a variety of formulations for therapeutic administration. Examples are capsules, tablets, syrups, suppositories, and various injectable forms. Administration of the compounds can be achieved in various ways, including oral, bucal, rectal, parenteral, intraperitoneal, intradermal, transdermal administration.
  • Preferred formulations of the compounds are oral preparations, particularly capsules or tablets containing each from about 10 milligrams up to about 1000 milligrams of active ingredient.
  • the compounds are formulated in a variety of physiologically compatible matrixes or solvents suitable for ingestion or injection. Saline is used in Example 1.
  • compositions are administered at a dosage that suppresses depressive behavior in subjects suffering from affective disorder while minimizing any side-effects. It is contemplated that the composition will be obtained and used under the guidance of a physician.
  • Typical dosages for systemic administration range from 0.1 to 10 milligrams per kg weight of subject per administration.
  • a typical dosage may be one 10-50 mg tablet taken once a day, or one time-release capsule or tablet taken once a day and containing 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 stimulate glutamatergic receptors are 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. The skilled practitioner is directed to section D where compound potency is evaluated using excised tissue.
  • Preferred glutamatergic compounds for suppression of mood disorders may have a half-life measured from less than 30 minutes to more than 5 hours.
  • kits with unit doses of AMPA up-modulating drugs either in oral or injectable doses In addition to the containers containing 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. The following example is offered for illustrative purposes only.
  • 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 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.
  • test drug l-(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.
  • vehicle consisting of a 33% (weight/ volume) 2-hydroxypropyl- ⁇ -cyclodextrin solution in 50% physiological saline/50% water.
  • vehicle consisting of a 33% (weight/ volume) 2-hydroxypropyl- ⁇ -cyclodextrin solution in 50% physiological saline/50% water.
  • vehicle consisting of a 33% (weight/ volume) 2-hydroxypropyl- ⁇ -cyclodextrin solution in 50% physiological saline/50% water.
  • test compound l-(quinoxalin-6-ylcarbonyl)piperidine
  • zimelidine rats: Reyes, R.B. , et al , "Effects of acute doses of zime l id i ne on REM s leep i n rats , " Psychopharmacology 80:214-216 (1983) humans: 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) Accordingly, the test results herein establish the utility of this invention on humans.

Abstract

Affective disorders in humans are treated by enhancing glutamatergic transmission. This is achieved in various ways, one of which is by the administration of a class of therapeutic agents having a phenyl ketone-containing molecular structure and similar to the structure of aniracetam. This discovery is based on tests using REM sleep reduction in an animal model as an indicator.

Description

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 No. N00014-89-J1255, awarded by the Office of Naval Research. The Government has certain rights in this invention.
BACKGROUND OF THE INVENTION
Sadness and normal depression are a universal human response to defeat, 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 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 characteristic of certain neurotic and other related psychiatric disorders.
Pharmaceutical therapy for mood disorders has been achieved by administration 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 administration have been developed to maximize their effectiveness with minimal risk, each still poses potential hazards. Heterocyclic antidepressants are the largest class of 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 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 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 protriptyline. The two that do not show the correlation are iprindole and trimipramine. For second-generation antidepressants, the 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 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 precursors L-dopa and L-tryptophane; the antiepileptic phenytoin; the antihistamines diphenhydramine and promethazine; the antipsychotics chlorpromazine, haloperidol, pimozide and thioridazine; the benzodiazepines adinazolam, diazepam, flurazepam, lorazepam, midazolam, temazepam and triazolam; the cholinergic agonists arecholine and pilocarpine; the cholinergic antagonist physostigmine; the muscarinic antagonist atropine; the noradrenergic alpha agonist α-methil dopa; the noradrenergic alpha blocker yohimbine; the noradrenergic beta blockers 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. 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 remaining three, two were found to depress REM sleep at high dosages, but not at lower, therapeutic, dosages.
On the other hand, endogenous depression in humans 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 subjects 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 accordance with literature indicating an effective correlation between REM sleep in rats and other animals and REM sleep in humans.
SUMMARY OF THE INVENTION
The present invention resides in the discovery that mental depression in human patients can be reduced by enhancement of glutamatergic transmission. It is known that glutamate is released by input axons onto α-amino-3-hydroxy- 5-mefhylisoxazole-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 by the present invention is the discovery that these drugs are beneficial in the 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 having a phenyl ketone structure. Among these preferred 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 experimental data showing significant depression of rapid-eye-movement (REM) sleep, in conjunction with the known 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 succeeding sections of this specification.
DETAILED DESCRIPTION OF THE INVENTION
AND PREFERRED EMBODIMENTS
Most excitatory neurotransmission in the forebrain structures occurs via glutamate. The majority of CNS glutamatergic receptors are of the AMPA class. The remaining receptors are of the NMDA class. See, Jonas, P. , 1993, Exs, 66:61-76; Zorumsky et al. , 1993, Pharmacology and Therapeutics, 59: 145-162; and Orrego et al , 1993, Neuroscience, 56:539-555.
Facilitation of central (brain) glutamatergic transmission via up-modulation of "AMPA-type" glutamate receptors has larger effects on complex, poly synaptic circuitries than on simple circuits (Sirvio et al , "Effects of pharmacologically facilitating glutamatergic transmission 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 behaviors affected by up-modulations of AMPA-type receptors are mood disorders. The compounds of the present invention primarily act, not by directly stimulating neural activation, but by up-modulating ("allosteric modulation") neural activation and transmission in neurons that contain glutamatergic receptors. These compounds bind to the glutamate receptor at a site other than the glutamate binding site, but such binding does not by itself give rise to ion fluxes. However, when a glutamate molecule binds to a glutamate receptor that has bound to it a glutamatergic 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 glutamate than postsynaptic neurons that do not contain bound compounds.
A. Definitions
Unless defined otherwise, all technical and scientific terms used herein have the same meaning 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. α-Amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid ("AMPA") or glutamatergic receptors are molecules or complexes of molecules present in cells, particularly neurons, usually at their surface membrane, that recognize and bind glutamate or AMPA. The binding of AMPA or glutamate 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 spinal nerves 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. The phrase "affective disorder" encompasses a variety of medical conditions as described in the Diagnostic and Statistical Manual of Mental Disorders of the American 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 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, 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 simultaneously, although for a shorter period of time. A "hypomanic episode" is similar to a manic episode, although briefer and less severe. 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 episodes. 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. "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 enough 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 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 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 stimulators of AMPA receptors, particularly by amplifying excitatory synaptic responses. A wide variety of diverse compounds suitable for use in the invention are disclosed herein. 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 mammal such as rat are prepared and maintained in an interface chamber using conventional methods. Field EPSPs are recorded in the stratum radiatum of region CAlb and elicited by single stimulation pulses delivered once per 20 seconds to a bipolar electrode positioned in the Schaffer-commissural projections (see Granger, R. et al , 1993, Synapse, i5:326-329; Staubli, U. et al , 1994a, Proc. Nat. Acad. Sci. , 97:777-781; and Staubli, V. etal , 1994b, Proc. Nat. Acad. Sci. , 91: 11158-11162; Arai, A. et al , 1994, Brain Res. , 658:343-346; 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 glutamatergic (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 receptor blocker (for example, AP-5 or other NMDA blockers known in the art) and/or a GAB A blocker (for example, picrotoxin or other GAB A 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 glutamatergic stimulation. Increased ion flux is typically measured as one or more of the following non-limiting parameters: at least a 10% increase in decay 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 preparations 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. Glutamate 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 currents will not 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 quantitation 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 amplifying excitatory synaptic response as defined above. They are quite varied in structure and so long as they embrace the above physiological properties they will 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
Figure imgf000012_0001
In this formula:
R1 is N or CH. m is 0 or 1.
R2 is (CR 3 2)n-m or Cn.mR 2(n-m)-2» m 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 CrC6 alkyl, or one R3 is combined with R4 to form a single bond linking the no. 6 and no. 3' ring vertices or to form a single divalent linking moiety linking the no. 6 and no. 3' ring vertices, any remaining R3's being H or CrC6 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 remaining R3's being H or CrC6 alkyl. The "linking moiety" in the R3 definitions is CH2, O, NH or N(CrC6 alkyl). R4 when not combined with any R3 is H, C,-C6 alkyl, or C,-C6 alkoxy. R5 when not combined with any R3 is H, CrC6 alkyl, or C,-C6 alkoxy. R6 is H, OH, C,-Cή alkyl, C,-C6 alkoxy, hydroxy-(C,-C6 alkyl), or CrC6 alkoxy-(C,-C6 alkyl), or is combined with R7. R7 is H, OH, CrC6 alkyl, CrC6 alkoxy, hydroxy-(CrC6 alkyl), C,-C6 alkoxy-(CrC6 alkyl), amino, mono(C,-C6 alkyl)amino, or di(C,-C(, alkyl)amino, or is combined with R6. R6 and R7 when combined form one of the following
Figure imgf000013_0001
In these formulas:
R8 is O, NH or N(C,-C6 alkyl). R9 is O, NH or N(C,-C6 alkyl). The R10's in any single compound are the same or different, and each Rlϋ is H or C,-C6 alkyl. p is 1, 2, or 3. q is 1 or 2. Certain subclasses within the generic formula are preferred. For example, R2 is preferably (CHR3)n.m or Cn.mHR3 2(n.m).3, and more preferably either Cn.mH2(n.m).,R3 or Cn.mH2{n m).3R3. Particularly preferred groups are C5H9R3 and C5Hg. 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 preferably 0.
When one R3 of an R2 group is combined with R4, the preferred 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 R5, the preferred combination is similarly either a methylene (CH2) 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, 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 R5 are generally preferred.
R1 is preferably N.
R4 and R5, when not combined with any R3, are each preferably an H atom or a CrC(, 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 R5 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 above, Rή and R7 are preferably chosen such that one is H and the other is OH,
C,-C6 alkyl, C,-C6 alkoxy, hydroxy-(CrC6 alkyl), CrC6 alkoxy-(CrC6 alkyl), amino, mono(C,-C6 alkyl)amino, or di(C,-C6 alkyl)amino. Among the latter list, preferred members are CrC3 alkyl, CrC3 alkoxy, hydroxy-(CrC3 alkyl), C,-C3 alkoxy-(C,-C3 alkyl), amino, mono(CrC3 alkyl)amino, or di(CrC3 alkyl)amino. Most preferred 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, preferred among the four are the last two divalent groups, with the last divalent group particularly preferred. It is noted that the last divalent 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 R10's are preferably either H or methyl, independently, although in the most preferred compounds, all R10's are H atoms. Finally, p is preferably 1 , and q is preferably 1 as well.
The terms "alkyl" and "alkoxy" are used herein to include branched-chain groups when containing three or more carbon atoms.
Compounds 1 through 24 below are examples of compounds within the scope of the generic formula and these definitions:
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000015_0003
11 12 13 14 15
Figure imgf000016_0001
CHgOC
Figure imgf000016_0002
CHgOCHg
Figure imgf000016_0003
Figure imgf000016_0004
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 appropriately substituted benzoic acid by contacting the acid under conditions suitable to activate 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 benzoyl chloride. The activated acid is then contacted with a nitrogen-containing heterocyclic compound 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 as methylene chloride or alcohol-free chloroform, and the ionized benzoic acid can then be reacted with pivaloyl chloride or a reactive 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 contact the appropriately selected 3,4-(alkylenedihetero)- benzaldehyde with ammonia to form an imine, then contacting the imine with benzoyloxycarbonyl chloride to form the benzoyloxycarbonyl imine. Suitable 3,4- (alkylenedihetero)-benzaldehydes include 3, 4-(methylenedioxy)-benzaldehyde, 3,4- (ethylenedioxy)-benzaldehyde, 3,4-(propylenedioxy)-benzaldehyde, 3,4- (ethylidenedioxy)-benzaldehyde, 3,4-(propylenedithio)-benzaldehyde, 3,4- (ethylidenedithio)-benzaldehyde, 5-benzimidazolecarboxaldehyde, and 6- quinoxalinecarboxaldehyde. The benzoyloxycarbonyl imine is then contacted with a simple conjugated diene such as butadiene under cycloaddition reaction conditions, and then with a Lewis acid under conditions suitable for a Friedel- Crafts acylation. Examples of suitable conjugated dienes include butadiene, 1 ,3- pentadiene, and isoprene, and examples of suitable Lewis acids include A1C13 and ZnCl2.
Still further compounds within the generic formula are prepared from 2,3- 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 permanganate to produce 4,5-ethylenedioxyphthaldehydic acid. The latter is contacted with anhydrous ammonia to form an imine, which is then treated with a suitable carbonyl-activating agent such as dicyclohexylcarbodiimide under cyclization 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 formula can be prepared by contacting an α-halotoluic acid with at least two equivalents of an alkali salt of a lower alcohol according to the Williamson ether synthesis to produce an ether linkage. The resulting alkoxymethylbenzoic acid is activated with carbonyldiimidazole, 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, thionyl bromide, mineral acids such as hydrochloric, hydrobromic or hydroiodic acids, or the 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 resulting 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 R5 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 appropriately 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 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 glutamatergic compounds that may be used to treat affective disorders according to the present invention. The treatments provided by present invention are not limited to the compounds described above. The present invention further encompasses administering other compounds that enhance the stimulation of α-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-methy 1-3-4- dihydro-2H-l,2,4-benzothiadiazine 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. , et al , J. Neurosc. 13:3904- 3915 (1993). Other AMPA potentiating drugs are expected to be developed.
D. Testing compounds for relative AMPA up-modulation. 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 those of 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 candidate for administration, by the method of Davis et al. , "A profile of the behavioral changes produced by the facilitation of AMPA-type glutamate receptors, " submitted to Behavioral Neuroscience (1996). Briefly, excised patches and excitatory synaptic responses are measured in the presence of different concentrations of test compounds, and the 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 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 stimulate glutamatergic receptors are 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 preferred means is to measure the physiological potency of a given compound that is a candidate for administration by methods detailed in Staubli, U. , et al , 1994a, Proc. Nat. Acad. Sci., USA, 9i:777-781 and Arai, A., et al , 1994, Brain Res., 658:343-346. Briefly, currents 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 currents) and behavioral effects (various learning 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 administration. Examples are capsules, tablets, syrups, suppositories, and various injectable forms. Administration of the compounds can be achieved in various ways, including oral, bucal, rectal, parenteral, intraperitoneal, intradermal, transdermal administration.
Preferred formulations of the compounds are oral preparations, particularly capsules or tablets containing each from about 10 milligrams up to about 1000 milligrams of active ingredient. The compounds are formulated in a variety of 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 administered at a dosage that suppresses depressive behavior in subjects suffering from affective disorder while minimizing any side-effects. It is contemplated that the composition will be obtained and used under the guidance of a physician.
Typical dosages for systemic administration range from 0.1 to 10 milligrams per kg weight of subject per administration. A typical dosage may be one 10-50 mg tablet taken once a day, or one time-release capsule or tablet taken once a day and containing 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 stimulate glutamatergic receptors are 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. The skilled practitioner is directed to section D where compound potency is evaluated using excised tissue.
Preferred glutamatergic 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 drugs either in oral or injectable doses. In addition to the containers containing 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. The following example is offered for illustrative purposes only.
EXAMPLE
Male Sprague-Dawley rats aged 2 to 4 months, maintained on a 12-hour light/ 12-hour dark sleeping cycle, were used as test animals. 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 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, l-(quinoxalin-6-ylcarbonyl)piperidine (Compound No. 14 above), was dissolved in a vehicle consisting of a 33% (weight/ volume) 2-hydroxypropyl-β-cyclodextrin solution in 50% physiological saline/50% water. On selected days, each rat received an intraperitoneal 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 administration, relative to the same animal's sleep time on days on which only the vehicle was administered. It was also observed that REM sleep time as a percent of total sleep time was reduced from 13 to 7.5% . After allowing for an elimination 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 animals, particularly in rats, do so in humans as well. Reports of REM sleep reduction for both humans and animals due to the administration 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 Pharmacol. 53: 104-112 (1975) humans: 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) humans: 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 monoamine oxidase inhibitors on the sleep-wakefulness cycle of the cat, " Neurosci. Behav. Physiol. 18:301-306 (1988) humans: Wyatt, R.J. , et al , "Longitudinal studies of the effect of monoamine oxidase inhibitors on sleep in man, " Psychopharmacologia 15:236-244 (1969) fluoxetine: rats: Tsai, L.L. , et al. , "Changes in sleep patterns by intralaminar thalamic 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) 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) humans: Brezinova, V. , "Effect of butriptyline on subjective feelings and sleep, " Br. J. Clin. Pharmacol 4:243-245
(1977) zimelidine: rats: Reyes, R.B. , et al , "Effects of acute doses of zime l id i ne on REM s leep i n rats , " Psychopharmacology 80:214-216 (1983) humans: 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) Accordingly, the test results herein establish the utility of this invention on humans.
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 administration, and other parameters of the invention as described herein may be further modified or substituted in various ways without departing from the spirit and scope of the invention.

Claims

WE CLAIM:
1. A method for treating depression in a human patient suffering from a mental disorder, said method comprising the selective potentiation of α-amino- 3-hydroxy-5-methylisoxazole-4-propionic acid ("AMPA") brain receptors of said patient to natural ligands thereof, said selective potentiation being sufficient to amplify the effects of the natural ligands in an amount adequate to improve said depression.
2. A method in accordance with claim 1 comprising administering to said patient an effective amount of a compound having the following formula, with ring vertices numbered as shown:
Figure imgf000025_0001
in which:
R1 is a member selected from the group consisting of N and CH; m is 0 or 1;
R2 is a member selected from the group consisting of (CR3 2)n m and Cn-m R3 2(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 being a member selected from the group consisting of H and C,-C6 alkyl, or one R3 being combined with R4 to form a single bond linking the no. 6 and no. 3' ring vertices or to form a single divalent linking moiety linking the no. 6 and no. 3' ring vertices, any remaining R3's being members selected from the group consisting of H and C,-C6 alkyl, or one R3 being 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 remaining R3's being members selected from the group consisting of H and C,-C6 alkyl, said linking moiety being a member selected from the group consisting of CH2, O, NH and N(CrC6 alkyl);
R4, when not combined with any R3, is a member selected from the group consisting of H, C,-C6 alkyl, and CrC6 alkoxy; R5, when not combined with any R3, is a member selected from the group consisting of H, CrC6 alkyl, and C,-C6 alkoxy; R6 is a member selected from the group consisting of H, OH, CrC6 alkyl, CrC6 alkoxy, hydroxy-^! -C6 alkyl), and C,-C6 alkoxy-(C,-C6 alkyl), and R7 is a member selected from the group consisting of H, OH, CrC6 alkyl, C,-C6 alkoxy, hydroxy-(C,-C6 alkyl), CrC6 alkoxy-(C,-C6 alkyl), amino, mono(CrC6 alkyl)amino, and di(CrC6 alkyl)amino, or R6 and R7 together form a member selected from the group consisting of
0
Figure imgf000026_0001
in which:
R8 is a member selected from the group consisting of O, NH and
N(C,-C6 alkyl);
R9 is a member selected from the group consisting of O, NH and
N(C,-C6 alkyl); the R10's in any single compound are the same or different, each R10 being a member selected from the group consisting of H and C,-C6 alkyl; p is 1 , 2, or 3; and q is 1 or 2.
3. A method in accordance with claim 2 in which R2 is a member selected from the group consisting of (CHR3)„.m and Cn.mHR3 2(n.m)_3, and R5 is a member selected from the group consisting of H, C,-C6 alkyl, and CrC6 alkoxy.
4. A method in accordance with claim 2 in which m is 0, R2 is a member selected from the group consisting of (CHR3)n and CnHR3 2n_3, and R5 is a member selected from the group consisting of H, CrC6 alkyl, and C,-C6 alkoxy.
5. A method in accordance with claim 2 in which R1 is N, R2 is a member selected from the group consisting of (CHR3)n.m and Cπ.mHR3 2(n.m).3, and R5 is a member selected from the group consisting of H, C,-C6 alkyl, and CrC6 alkoxy.
6. A method in accordance with claim 2 in which m is 0, R1 is N, R2 is a member selected from the group consisting of (CHR3)n and CnH2n.2, and R5 is a member selected from the group consisting of H and C,-C6 alkyl.
7. A method in accordance with claim 2 in which R1 is N, R2 is a member selected from the group consisting of (CHR3)n.m and Cn.mH2(n.m)_2, R4 is a member selected from the group consisting of H and CrC6 alkyl and R5 is a member selected from the group consisting of H and CrC6 alkyl.
8. A method in accordance with claim 2 in which R1 is N.
9. A method in accordance with claim 2 in which m is 0, R1 is N, R2 is a member selected from the group consisting of (CHR3)„ and CnH2n_2, R4 is a member selected from the group consisting of H and CrC6 alkyl, and R5 is a member selected from the group consisting of H and C,-C6 alkyl.
10. A method in accordance with claim 2 in which m is 0, Rl is N, and R2 is a member selected from the group consisting of C5HQR3 and C5Hg.
11. A method in accordance with claim 2 in which m is 0, R1 is N, R2 is a member selected from the group consisting of CnH2n.,R3 and CnH2n.2, R4 is a member selected from the group consisting of H and methyl, and R5 is a member selected from the group consisting of H and methyl.
12. A method in accordance with claim 2 in which m is 0, R1 is N, R2 is a member selected from the group consisting of CnH2n.,R3 and CnH2ll.2, R4 is H, and R5 is H.
13. A method in accordance with claim 2 in which R6 and R7 are combined to form a member selected from the group consisting of
Figure imgf000028_0001
14. A method in accordance with claim 13 in which R10 is a member selected from the group consisting of H and CH3.
15. A method in accordance with claim 2 in which R6 and R7 are combined to form a member selected from the group consisting of
o
Figure imgf000028_0002
in which R10 is a member selected from the group consisting of H and CH3.
16. A method in accordance with claim 2 in which R6 and R7 are combined to form 0
Figure imgf000029_0001
in which R10 is a member selected from the group consisting of H and CH3.
17. A method in accordance with claim 2 in which R6 and R7 are combined to form
Figure imgf000029_0002
in which R10 is H.
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