EP2391621A2 - Bicyclic amide derivatives for enhancing glutamatergic synaptic responses - Google Patents
Bicyclic amide derivatives for enhancing glutamatergic synaptic responsesInfo
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- EP2391621A2 EP2391621A2 EP10736150A EP10736150A EP2391621A2 EP 2391621 A2 EP2391621 A2 EP 2391621A2 EP 10736150 A EP10736150 A EP 10736150A EP 10736150 A EP10736150 A EP 10736150A EP 2391621 A2 EP2391621 A2 EP 2391621A2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/535—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
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/535—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
- A61K31/537—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 spiro-condensed or forming part of bridged ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/535—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
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/16—Central respiratory analeptics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
Definitions
- This invention relates to compounds, pharmaceutical compositions and methods for use in the prevention and treatment of cerebral insufficiency, including enhancement of receptor functioning in synapses in brain networks responsible for various behaviors. Imbalances in neuronal activities between different brain regions may lead to a number of disorders, including psychiatric and neurological disorders, including memory impairment, Parkinson's disease, schizophrenia, attention deficit and affective or mood disorders, and in disorders wherein a deficiency in neurotrophic factors is implicated.
- the invention relates to compounds useful for treatment of such conditions, and methods of using these compounds for such treatment.
- AMPA neuropeptide kinase kinase
- NMDA N-methyl-D-aspartic acid
- AMPA receptors mediate a voltage independent fast excitatory p_ost-synaptic current (the fast EPSC), whereas NMDA receptors generate a voltage-dependent, slow excitatory current.
- fast EPSC voltage independent fast excitatory p_ost-synaptic current
- NMDA receptors generate a voltage-dependent, slow excitatory current.
- AMPA receptors are expressed throughout the central nervous system. These receptors are found in high concentrations in the superficial layers of neocortex, in each of the major synaptic zones of hippocampus, and in the striatal complex, as reported by Monaghan et al., in Brain Research 324:160-164 (1984). Studies in animals and humans indicate that these structures organize complex perceptual-motor processes and provide the substrates for higher-order behaviors. Thus, AMPA receptors mediate transmission in those brain networks responsible for a host of cognitive activities. For the reasons set forth above, drugs that modulate and thereby enhance the functioning of AMPA receptors could have significant benefits for intellectual performance and such drugs should also facilitate memory encoding.
- LTP long-term potentiation
- Excitatory synaptic transmission provides a major pathway by which neurotrophic factors are increased within specific brain regions.
- potentiation of AMPA receptor function by modulators has been found to increase levels of neurotrophins, particularly brain derived neurotrophic factor, or BDNF.
- BDNF brain derived neurotrophic factor
- AMPA receptor potentiators may be useful for the treatment of these, as well as other, neurological diseases that are the result of a glutamatergic imbalance or a deficit in neurotrophic factors.
- aniracetam enhances synaptic responses at several sites in hippocampus, and that it has no effect on NMDA-receptor mediated potentials (Staubli et al., Psychobiology 18:377-381 (1990) and Xiao et al, Hip- pocampus 1:373-380 (1991 )).
- Aniracetam has been found to have an extremely rapid onset and washout, and can be applied repeatedly with no apparent lasting effects, which are desirable features for behaviorally-relevant drugs. Aniracetam does present several disadvantages, however.
- the peripheral administration of aniracetam is not likely to influence brain receptors.
- the drug works only at high concentrations (approx. lOOO ⁇ M), and about 80% of the drug is converted to anisoyl-GABA following peripheral administration in humans (Guenzi and Zanetti, J. Chromatogr. 530:397-406 (1990)).
- the metabolite, anisoyl-GABA has been found to have less activity than aniracetam.
- aniracetam has putative effects on a plethora of other neurotransmitter and enzymatic targets in the brain, which makes uncertain the mechanism of any claimed therapeutic drug effect. See, for example, Himori, et al., Pharmacology Biochemistry and Behavior 47:219-225 (1994); Pizzi et al., J. Neurochem. 61 :683-689 (1993); Nakamura and Shirane, Eur. J. Pharmacol. 380: 81-89 (1999); Spignoli and Pepeu, Pharmacol. Biochem. Behav. 27:491-495 (1987); Hall and Von Voigtlander, Neuropharmacology 26: 1573- 1579(1987); and Yoshimoto et al., J. Pharmacobiodyn. 10:730-735(1987).
- the present invention therefore, includes, in one aspect, a compound as shown by structure A and other structures and described in Section II of the Detailed Description, which follows.
- Administration of compounds of this class has been found to enhance AMPA mediated glutaniatergic synaptic responses and significantly improve the behavior of rodents in the d- amphetamine stimulated locomotion assay.
- This behavioral assay has proven useful in assessing the efficacy of neuroleptic drugs for the treatment of schizophrenia and ADHD.
- the compounds are significantly and surprisingly more potent than previously described compounds in increasing glutaniatergic synaptic responses in vivo. This activity translates into pharmaceutical compounds and corresponding methods of use, including treatment methods, which utilize significantly lower concentrations of the present compounds compared to prior art compositions.
- compounds within the present invention demonstrate improved pharmacokinetic properties compared with previously described compounds and have good oral bioavailability.
- the ability of the compounds of the invention to increase AMPA receptor-mediated responses makes the compounds useful for a variety of purposes. These include facilitating the learning of behaviors dependent upon glutamate receptors, treating conditions in which AMPA receptors, or synapses utilizing these receptors, are reduced in numbers or efficiency, and enhancing excitatory synaptic activity in order to restore an imbalance between brain sub- regions or increase the levels of neurotrophic factors.
- the invention includes a method for the treatment of a mammalian subject suffering from a hypoglutamatergic condition, or from a deficiency in the number or strength of excitatory synapses, or in the number of AMPA receptors, such that memory or other cognitive functions are impaired.
- a mammalian subject suffering from a hypoglutamatergic condition, or from a deficiency in the number or strength of excitatory synapses, or in the number of AMPA receptors, such that memory or other cognitive functions are impaired.
- Such conditions may also cause a cortical/striatal imbalance, leading to schizophrenia or schizophreniform behavior.
- a subject is treated with an effective amount of a compound as shown by structure A, and described in Section II of the Detailed Description, following, in a pharmaceutically acceptable carrier.
- compound is used herein to refer to any specific chemical compound disclosed herein. Within its use in context, the term generally refers to a single stable compound, but in certain instances may also refer to stereoisomers and/or optical isomers (including enantiopure compounds, enantiomerically enriched compounds and racemic mixtures) of disclosed compounds.
- an effective amount refers to the amount of a selected compound of formula I that is used within the context of its intended use to effect an intended result, for example, to enhance glutamatergic synaptic response by increasing AMPA receptor activity.
- the precise amount used will vary depending upon the particular compound selected and its intended use, the age and weight of the subject, route of administration, and so forth, but may be easily determined by routine experimentation.
- an effective amount is that amount which is used to effectively treat the particular condition or disease state.
- a “pharmaceutically acceptable salt” of an amine compound such as those contemplated in the current invention, is an ammonium salt having as counter ion an inorganic anion such as chloride, bromide, iodide, sulfate, sulfite, nitrate, nitrite, phosphate, and the like, or an organic anion such as acetate, malonate, pyruvate, propionate, fumarate, cinnamate, tosylate, and the like.
- patient or “subject” is used throughout the specification to describe an animal, generally a mammalian animal, including a human, to whom treatment or use with the compounds or compositions according to the present invention is provided.
- an animal generally a mammalian animal, including a human, to whom treatment or use with the compounds or compositions according to the present invention is provided.
- treatment or use with/or of those conditions or disease states which are specific for a specific animal are specific for treatment or use with/or of those conditions or disease states which are specific for a specific animal
- patient or subject refers to that particular animal.
- sensor motor problems is used to describe a problem which arises in a patient or subject from the inability to integrate external information derived from the five known senses in such a way as to direct appropriate physical responses involving movement and action.
- cognition is used to describe an endeavor or process by a patient or subject that involves thought or knowing.
- the diverse functions of the association cortices of the parietal, temporal and frontal lobes, which account for approximately 75% of all human brain tissue, are responsible for much of the information processing that goes on between sensory input and motor output.
- the diverse functions of the association cortices are often referred to as cognition, which literally means the process by which we come to know the world.
- Selectively attending to a particular stimulus, recognizing and identifying these relevant stimulus features and planning and experiencing the response are some of the processes or abilities mediated by the human brain which are related to cognition.
- brain network is used to describe different anatomical regions of the brain that communicate with one another via the synaptic activity of neuronal cells.
- AMPA receptor refers to an aggregate of proteins found in some membranes, which allows positive ions to cross the membrane in response to the binding of glutamate or AMPA (DL- ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), but not NMDA.
- excitatory synapse is used to describe a cell-cell junction at which release of a chemical messenger by one cell causes depolarization of the external membrane of the other cell.
- An excitatory synapse describes a postsynaptic neuron which has a reversal potential that is more positive than the threshold potential and consequently, in such a synapse, a neurotransmitter increases the probability that an excitatory post synaptic potential will result (a neuron will fire producing an action potential).
- Reversal potentials and threshold potentials determine postsynaptic excitation and inhibition.
- the reversal potential for a post synaptic potential is more positive than the action potential threshold, the effect of a transmitter is excitatory and produces an excitatory post synaptic potential (“EPSP”) and the firing of an action potential by the neuron.
- the reversal potential for a post synaptic potential is more negative than the action potential threshold, the transmitter is inhibitory and may generate inhibitory post synaptic potentials (IPSP), thus reducing the likelihood that a synapse will fire an action potential.
- the general rule for postsynaptic action is: if the reversal potential is more positive than threshold, excitation results; inhibition occurs if the reversal potential is more negative than threshold. See, for example, Chapter 7, NEUROS CIENCE, edited by Dale Purves, Sinauer Associates, Inc., Sunderland, MA 1997.
- motor task is used to describe an endeavor taken by a patient or subject that involves movement or action.
- perceptual task is used to describe an act by a patient or subject of devoting attention to sensory inputs.
- synaptic response is used to describe biophysical reactions in one cell as a consequence of the release of chemical messengers by another cell with which it is in close contact.
- hypoglutamatergic condition is used to describe a state or condition in which transmission mediated by glutamate (or related excitatory amino acids) is reduced to below normal levels. Transmission consists of the release of glutamate, binding to post synaptic receptors, and the opening of channels integral to those receptors. The end point of the hypoglutamatergic condition is reduced excitatory post synaptic current. It can arise from any of the three above noted phases of transmission.
- Conditions or disease states which are considered hypoglutamatergic conditions and which can be treated using the compounds, compositions and methods according to the present invention include, for example, loss of memory, dementia, depression, attention disorders, sexual dysfunction, movement disorders, including Parkinson's disease, schizophrenia or schizophreniform behavior, memory and learning disorders, including those disorders which result from aging, trauma, stroke and neurodegenerative disorders, such as those associated with drug-induced states, neurotoxic agents, Alzheimer's disease and aging, and sleep apnea. These conditions are readily recognized and diagnosed by those of ordinary skill in the art.
- cortico-striatal imbalance is used to describe a state in which the balance of neuronal activities in the interconnected cortex and underlying striatal complex deviates from that normally found. 'Activity' can be assessed by electrical recording or molecular biological techniques. Imbalance can be established by applying these measures to the two structures or by functional (behavioral or physiological) criteria.
- cognitivos or “mood disorder” describes the condition when sadness or elation is overly intense and continues beyond the expected impact of a stressful life event, or arises endogenously.
- effective disorder embraces all types of mood disorders as described in, for example, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV), pages 317-391.
- Schizophrenia is used to describe a condition which is a common type of psychosis, characterized by a disorder in the thinking processes, such as delusions and hallucinations, and extensive withdrawal of the individual's interest from other people and the outside world, and the investment of it in his or her own. Schizophrenia is now considered a group of mental disorders rather than a single entity, and distinction is made between reactive and process schizophrenias.
- schizophrenia or "schizophreniform” embraces all types of schizophrenia, including ambulatory schizophrenia, catatonic schizophrenia, hebephrenic schizophrenia, latent schizophrenia, process schizophrenia, pseudoneurotic schizophrenia, reactive schizophrenia, simple schizophrenia, and related psychotic disorders which are similar to schizophrenia, but which are not necessarily diagnosed as schizophrenia per se. Schizophrenia and other psychotic disorders may be diagnosed using guidelines established in, for example, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV) Sections 293.81 , 293.82, 295.10, 295.20, 295.30, 295.40, 295.60, 295.70, 295.90, 297.1 , 297.3, 298.8.
- DSM IV Diagnostic and Statistical Manual of Mental Disorders
- brain function is used to describe the combined tasks of perceiving, integrating, filtering and responding to external stimuli and internal motivational processes.
- Impaired is used to describe a function working at a level that is less than normal. Impaired functions can be significantly impacted such that a function is barely being carried out, is virtually non-existent or is working in a fashion that is significantly less than normal. Impaired functions may also be sub-optimal. The impairment of function will vary in severity from patient to patient and the condition to be treated.
- sleep apnea refers to breathing-related sleep disorders of which there are two types: central and obstructive.
- Central Sleep Apnea is defined as a neurological condition causing cessation of all respiratory effort during sleep, usually with decreases in blood oxygen saturation, if the brainstem center controlling breathing shuts down there's no respiratory effort and no breathing. The person is aroused from sleep by an automatic breathing reflex, so may end up getting very little sleep at all.
- Obstructive sleep apnea is characterized by repetitive pauses in breathing during sleep due to the obstruction and/or collapse of the upper airway and followed by an awakening to breathe. Respiratory effort continues during the episodes of apnea.
- pro-drug refers to a metabolically labile derivative that is pharmacologically inactive in the parent form but that is rapidly metabolized in human or animal plasma to a pharmacologically active form.
- pro-drugs include but in no way are limited to ester derivatives of hydroxyl containing moieties, such esters include but are not limited to those formed from substituted or un-substituted natural or un-natural amino acids.
- the present invention is directed to compounds having the property of enhancing AMPA receptor function. These include compounds having the structure A, below:
- a preferred embodiment includes a compound of formula B, below:
- a further preferred embodiment includes compounds of formula C, below:
- X O, or CH 2 , or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
- the present invention provides compounds of Formula A selected from: [2,l,3]-benzoxadiazol-5-yl(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methanone, [2,l,3]-Benzoxadiazol-5-yl(3-oxa-9-azabicyclo[3.3.1]non-9-yl)methanone and [2,l,3]-Benzoxadiazol-5-yl(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)methanone
- the carboxylic acid 3 was transformed to the acid chloride 4 by refluxing with thionyl chloride and a catalytic amount of DMF in toluene.
- the carboxylic acid 3 can be transformed into bicyclic amides A by reaction with the appropriate aminobicycles using standard coupling conditions like CDI, EDCI, HBTU in a suitable solvent.
- acid chloride 4 can be transformed into bicyclic amides A under standard coupling conditions with bicyclic amines in the presence of a base for example triethylamine or aqueous sodium hydroxide, among others in a suitable solvent, for example dichloromethane.
- a method for treating a mammalian subject suffering from a hypoglutamatergic condition, or from deficiencies in the number or strength of excitatory synapses or in the number of AMPA receptors, hi such a subject, memory or other cognitive functions may be impaired, or cortical/striatal imbalance may occur, leading to loss of memory, dementia, depression, attention disorders, sexual dysfunction, movement disorders, schizophrenia or schizophreniform behavior.
- Memory disorders and learning disorders which are treatable according to the present invention include those disorders that result from aging, trauma, stroke and neurodegenerative disorders. Examples of neurodegenerative disorders include, but are not limited to, those associated with drug-induced states, neurotoxic agents, Alzheimer's disease, and aging. These conditions are readily recognized and diagnosed by those of ordinary skill in the art and treated by administering to the patient an effective amount of one or more compounds according to the present invention.
- the invention provides a method for reducing or inhibiting breathing- related sleep disorders or sleep apnea in a subject having sleep apnea, comprising administering to the subject an amount of a compound of the invention, the amount being sufficient to reduce or inhibit the breathing related sleep disorder.
- the method of treatment comprises administering to the subject in need of treatment, in a pharmaceutically acceptable carrier, an effective amount of a compound having the Formula A below:
- Compounds according to the present invention exhibit enhanced bioavailability in most instances due, at least in part, to enhanced metabolic stability by the present compounds. Accordingly, the present compounds may be favorably formulated into pharmaceutical compositions in a variety of dosage forms, and in particular, oral dosage forms.
- treatment of a subject according to the method of the invention is useful for enhancing AMPA receptor activity, and thus may be used to facilitate the learning of behaviors dependent upon AMPA receptors, and to treat conditions, such as memory impairment, in which AMPA receptors, or synapses utilizing these receptors, are reduced in numbers or efficiency.
- the method is also useful for enhancing excitatory synaptic activity in order to restore an imbalance between brain sub-regions, which may manifest itself in schizophrenia or schizophreniform behavior, or other behavior as described above.
- the compounds administered in accordance with the method have been found to be more effective than previously described compounds in enhancing AMPA receptor activity, as shown in the in vivo tests described below.
- Synaptic responses mediated by AtMPA receptors are increased according to the method of the invention, using the compounds described herein.
- the electrophysiological effects of the invention compounds were tested in vivo in anesthetized animals according to the following procedures. Animals are maintained under anesthesia by phenobarbital administered using a Hamilton syringe pump. Stimulating and recording electrodes are inserted into the perforant path and dentate gyrus of the hippocampus, respectively. Once electrodes are implanted, a stable baseline of evoked responses are elicited using single monophasic pulses (100 ⁇ s pulse duration) delivered at 3/min to the stimulating electrode.
- Field EPSPs are monitored until a stable baseline is achieved (about 20-30 min), after which a solution of test compound is injected intraperitoneally and evoked field potentials are recorded. Evoked potentials were recorded for approximately 2 h following drug administration or until the amplitude of the field EPSP returns to baseline. In the latter instance, it is common that an iv administration is also carried out with an appropriate dose of the same test compound.
- Invention compounds were assayed in the in vivo electrophysiology assay described above and data for representative test compounds is shown in the Table. Compounds of the invention are significantly more active in increasing the amplitude of the field EPSP in the rat dentate gyrus following i.p.
- CX516 l-(quinoxalin-6-ylcarbonyl)piperidine; US patent 5,773,434, US2002/0055508
- CX516 l-(quinoxalin-6-ylcarbonyl)piperidine; US patent 5,773,434, US2002/0055508
- the compounds and method of the invention increase glutamatergic synaptic responses mediated by AMPA receptors, and are useful for the treatment of hypoglutamatergic conditions. They are also useful for treatment of conditions such as impairment of memory or other cognitive functions, brought on by a deficiency in the number or strength of excitatory synapses, or in the number of AMPA receptors. They may also be used in the treatment of schizophrenia or schizophreniform behavior resulting from a cortical/striatal imbalance, and in facilitation of learning of behaviorsdependent upon AMPA receptors.
- memory or other cognitive functions may be impaired or cortical/striatal imbalance may occur, leading to loss of memory, dementia, depression, attention disorders, sexual dysfunction, movement disorders, schizophrenia or schizophreniform behavior.
- Memory disorders and learning disorders which are treatable according to the present invention, include those disorders that result from aging, trauma, stroke and neurodegenerative disorders.
- Examples of neurodegenerative disorders include, but are not limited to, those associated with drug-induced states, neurotoxic agents, Alzheimer's disease, and aging. These conditions are readily recognized and diagnosed by those of ordinary skill in the art and treated by administering to the patient an effective amount of one or more compounds according to the present invention.
- dosages and routes of administration of the compound will be determined according to the size and condition of the subject, according to standard pharmaceutical practices. Dose levels employed can vary widely, and can readily be determined by those of skill in the art. Typically, amounts in the milligram up to gram quantities are employed.
- the composition may be administered to a subject by various routes, e.g. orally, transdermally, perineurally or parenterally, that is, by intravenous, subcutaneous, intraperitoneal, or intramuscular injection, among others, including buccal, rectal and transdermal administration.
- Subjects contemplated for treatment according to the method of the invention include humans, companion animals, laboratory animals, and the like.
- Formulations containing the compounds according to the present invention may take the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, capsules, powders, sustained-release formulations, solutions, suspensions, emulsions, suppositories, creams, ointments, lotions, aerosols, patches or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
- compositions according to the present invention comprise an effective amount of one or more compounds according to the present invention and typically include a conventional pharmaceutical carrier or excipient and may additionally include other medicinal agents, earners, adjuvants, additives and the like.
- the composition will be about 0.5 to 75% by weight or more of a compound or compounds of the invention, with the remainder consisting essentially of suitable pharmaceutical excipients.
- excipients include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
- the composition may also contain minor amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, or buffers.
- Liquid compositions can be prepared by dissolving or dispersing the compounds (about 0.5% to about 20% by weight or more), and optional pharmaceutical adjuvants, in a carrier, such as, for example, aqueous saline, aqueous dextrose, glycerol, or ethanol, to form a solution or suspension.
- a carrier such as, for example, aqueous saline, aqueous dextrose, glycerol, or ethanol
- the composition may be prepared as a solution, suspension, emulsion, or syrup, being supplied either in liquid form or a dried form suitable for hydration in water or normal saline.
- the preparations may be tablets, granules, powders, capsules or the like.
- the composition is typically formulated with additives, e.g. an excipient such as a saccharide or cellulose preparation, a binder such as starch paste or methyl cellulose, a filler, a disintegrator, and other additives typically used in the manufacture of medical preparations.
- additives e.g. an excipient such as a saccharide or cellulose preparation, a binder such as starch paste or methyl cellulose, a filler, a disintegrator, and other additives typically used in the manufacture of medical preparations.
- An injectable composition for parenteral administration will typically contain the compound in a suitable i.v. solution, such as sterile physiological salt solution.
- a suitable i.v. solution such as sterile physiological salt solution.
- the composition may also be formulated as a suspension in a lipid or phospholipid, in a liposomal suspension, or in an aqueous emulsion.
- composition to be administered will contain a quantity of the selected compound in a pharmaceutically effective amount for effecting increased AMPA receptor currents in a subject.
- KOH 72.46g
- ethanol 250 ml
- water 250 ml
- 4-Amino-3- nitrobenzoic acid 10Og
- the resulting suspension was stirred at the same temperature for 45 minutes and cooled to 0°C +5 ° C within 30 minutes.
- a commercially available (13% w/w) solution of sodium hypochlorite (448.93g) was added drop wise within 1.5 hours at 0°C +5°C.
- reaction mixture was stirred at the same temperature for 2 hours and controlled by TLC (CHCl 3 100/ acetone 2/ acetic acid 1). Water (350 ml) was added within 15 minutes at 0°C +5°C to give a fine yellow suspension. The reaction mixture was then acidified with a 6N HCl solution (239 ml) until 0.5 ⁇ pH ⁇ 1 was reached. NaCl (58.44g) was added and the resulting suspension was stirred at 0°C +5 ° C for 1.5 hours under nitrogen.
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- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
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- Epidemiology (AREA)
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- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Pulmonology (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
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Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US20664209P | 2009-02-02 | 2009-02-02 | |
PCT/US2010/000255 WO2010087981A2 (en) | 2009-02-02 | 2010-01-29 | Bicyclic amide derivatives for enhancing glutamatergic synaptic responses |
Publications (2)
Publication Number | Publication Date |
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EP2391621A2 true EP2391621A2 (en) | 2011-12-07 |
EP2391621A4 EP2391621A4 (en) | 2012-07-25 |
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ID=42396261
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Application Number | Title | Priority Date | Filing Date |
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EP10736150A Withdrawn EP2391621A4 (en) | 2009-02-02 | 2010-01-29 | Bicyclic amide derivatives for enhancing glutamatergic synaptic responses |
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EP (1) | EP2391621A4 (en) |
JP (1) | JP2012516845A (en) |
KR (1) | KR20110115139A (en) |
CN (1) | CN102369201A (en) |
AU (1) | AU2010208646A1 (en) |
BR (1) | BRPI1005316A2 (en) |
CA (1) | CA2751285A1 (en) |
EA (1) | EA018994B1 (en) |
IL (1) | IL214392A0 (en) |
MX (1) | MX2011008060A (en) |
SG (1) | SG173168A1 (en) |
WO (2) | WO2010087981A2 (en) |
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NZ255097A (en) * | 1992-07-24 | 2001-04-27 | Univ California | Heterocyclic derivatives (such as 1-(1,4-bgenzodioxan-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine) and medicaments that enhance synaptic responses |
US20020099050A1 (en) * | 1993-07-23 | 2002-07-25 | Lynch Gary S. | Drugs that enhance synaptic responses mediated by AMPA receptors |
US6110935A (en) * | 1997-02-13 | 2000-08-29 | The Regents Of The University Of California | Benzofurazan compounds for enhancing glutamatergic synaptic responses |
CN1281335A (en) * | 1997-10-27 | 2001-01-24 | 科泰克斯药物股份有限公司 | Treatment of schizophrenia with ampakines and neuroleptics |
KR101599661B1 (en) * | 2007-05-17 | 2016-03-03 | 코텍스 파마슈티칼스, 인크. | Di-substituted amides for enhancing glutamatergic synaptic responses |
BRPI0823262A2 (en) * | 2007-08-10 | 2013-09-24 | Cortex Pharma Inc | Respiratory depression treatment method and use of a compound in the manufacture of a medicament for the treatment of respiratory depression |
-
2010
- 2010-01-29 CA CA2751285A patent/CA2751285A1/en not_active Abandoned
- 2010-01-29 AU AU2010208646A patent/AU2010208646A1/en not_active Abandoned
- 2010-01-29 MX MX2011008060A patent/MX2011008060A/en active IP Right Grant
- 2010-01-29 BR BRPI1005316A patent/BRPI1005316A2/en not_active IP Right Cessation
- 2010-01-29 CN CN2010800154033A patent/CN102369201A/en active Pending
- 2010-01-29 WO PCT/US2010/000255 patent/WO2010087981A2/en active Application Filing
- 2010-01-29 KR KR1020117019461A patent/KR20110115139A/en not_active Application Discontinuation
- 2010-01-29 SG SG2011054376A patent/SG173168A1/en unknown
- 2010-01-29 JP JP2011547981A patent/JP2012516845A/en active Pending
- 2010-01-29 EA EA201101162A patent/EA018994B1/en not_active IP Right Cessation
- 2010-01-29 WO PCT/US2010/000254 patent/WO2010087980A2/en active Application Filing
- 2010-01-29 EP EP10736150A patent/EP2391621A4/en not_active Withdrawn
-
2011
- 2011-08-01 IL IL214392A patent/IL214392A0/en unknown
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See also references of WO2010087981A2 * |
Also Published As
Publication number | Publication date |
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SG173168A1 (en) | 2011-08-29 |
CA2751285A1 (en) | 2010-08-05 |
EA018994B1 (en) | 2013-12-30 |
KR20110115139A (en) | 2011-10-20 |
JP2012516845A (en) | 2012-07-26 |
AU2010208646A1 (en) | 2011-09-01 |
BRPI1005316A2 (en) | 2019-09-24 |
EA201101162A1 (en) | 2012-01-30 |
EP2391621A4 (en) | 2012-07-25 |
MX2011008060A (en) | 2011-09-09 |
WO2010087981A3 (en) | 2011-03-24 |
IL214392A0 (en) | 2011-09-27 |
WO2010087980A2 (en) | 2010-08-05 |
WO2010087980A3 (en) | 2011-02-24 |
WO2010087981A2 (en) | 2010-08-05 |
CN102369201A (en) | 2012-03-07 |
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