EP0918518A1 - Traitement des troubles de l'humeur et des troubles affectifs par des renfor ateurs glutamatergiques - Google Patents

Traitement des troubles de l'humeur et des troubles affectifs par des renfor ateurs glutamatergiques

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Publication number
EP0918518A1
EP0918518A1 EP97906793A EP97906793A EP0918518A1 EP 0918518 A1 EP0918518 A1 EP 0918518A1 EP 97906793 A EP97906793 A EP 97906793A EP 97906793 A EP97906793 A EP 97906793A EP 0918518 A1 EP0918518 A1 EP 0918518A1
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alkoxy
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EP0918518A4 (fr
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Jose Ambros-Ingerson
Gary Lynch
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University of California
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University of California
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
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    • A61K31/40—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
    • 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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    • A61K31/40—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
    • A61K31/4025—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 not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
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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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

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.

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Abstract

On traite les désordres affectifs chez l'homme en renforçant la transmission glutamatergique. Pour ce faire plusieurs méthodes sont possibles, notamment l'administration d'une classe d'agents thérapeutiques présentant une structure moléculaire contenant du phénylcétone, semblable à la structure de l'aniracétam. Cette découverte est fondée sur des essais portant sur la réduction du sommeil paradoxal chez un modèle animal servant d'indicateur.
EP97906793A 1996-04-19 1997-02-27 Traitement des troubles de l'humeur et des troubles affectifs par des renfor ateurs glutamatergiques Withdrawn EP0918518A4 (fr)

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US6329368B1 (en) 1997-05-09 2001-12-11 The Regents Of The University Of California Endocrine modulation with positive modulators of AMPA type glutamate receptors
PE20000942A1 (es) * 1998-07-31 2000-09-28 Lilly Co Eli Derivados de amida, carbamato y urea
US20040235957A1 (en) * 2001-10-12 2004-11-25 David Bleakman Use of sulfonamide derivatives as pharmaceuticals compounds
WO2006109085A1 (fr) 2005-04-13 2006-10-19 Astex Therapeutics Limited Derives d'hydroxybenzamide et leur utilisation comme inhibteurs de hsp90
US7754725B2 (en) 2006-03-01 2010-07-13 Astex Therapeutics Ltd. Dihydroxyphenyl isoindolymethanones
WO2008044045A1 (fr) 2006-10-12 2008-04-17 Astex Therapeutics Limited Combinaisons pharmaceutiques
JP5528806B2 (ja) 2006-10-12 2014-06-25 アステックス、セラピューティックス、リミテッド 複合薬剤
WO2008044054A2 (fr) 2006-10-12 2008-04-17 Astex Therapeutics Limited Composés pharmaceutiques
GB0620259D0 (en) 2006-10-12 2006-11-22 Astex Therapeutics Ltd Pharmaceutical compounds
JP5721949B2 (ja) 2006-10-12 2015-05-20 アステックス、セラピューティックス、リミテッドＡｓｔｅｘ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｌｉｍｉｔｅｄ 複合薬剤
US8779132B2 (en) 2006-10-12 2014-07-15 Astex Therapeutics Limited Pharmaceutical compounds
GB0806527D0 (en) 2008-04-11 2008-05-14 Astex Therapeutics Ltd Pharmaceutical compounds
WO2018145080A1 (fr) * 2017-02-06 2018-08-09 Case Western Reserve University Compositions et procédés de modulation de l'activité de la déshydrogénase à chaîne courte

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