HK1149711A - Use of bicyclic amide in preparing pharmaceuticals for treatment of respiratory - Google Patents

Description

Use of bicyclic amides for the preparation of a medicament for the treatment of respiratory depression

The application is a divisional application of Chinese patent application with the application number of 200880102533.3, 8.8.2008, entitled "bicyclic amide for enhancing glutamatergic synaptic responses".

Technical Field

The present invention relates to compounds, pharmaceutical compositions and methods for the prevention and treatment of cerebral insufficiency, including enhancement of receptor function at synapses in brain networks responsible for various behaviors. These brain networks participate in basic functions (e.g., respiration) to more complex functions such as memory and cognition. Imbalances in neuronal activity between different brain regions can lead to a variety of disorders including psychiatric and neurological disorders including memory impairment, Parkinson's disease, schizophrenia, attention deficit and affective or mood disorders, respiratory depression and disorders involving a deficiency in neurotrophic factors. In particular aspects, the invention relates to compounds useful for the treatment of the above-mentioned conditions, and methods of using these compounds for such treatment.

RELATED APPLICATIONS

This application claims priority from U.S. provisional patent application US 60/964,362, filed 8/10/2007 with the same title, the entire contents of which are incorporated herein by reference.

Background

In the mammalian forebrain, synaptic release of glutamate at multiple sites stimulates two postsynaptic ionotropic glutamate receptors. These two receptors are commonly referred to as the DL- α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and the N-methyl-D-aspartic acid (NMDA) receptor. AMPA receptors mediate a rapid excitatory postsynaptic current that is independent of potential (i.e., rapid EPSC: (a) (b))excitatorygpst-synaptic current)), while the NMDA receptor produces a potential-dependent slow excitatory current. Studies on slices of the hippocampus or cortex indicate that AMPA receptors that mediate rapid EPSCs are now essentially the predominant component in most glutamatergic synapses, and that activation of AMPA receptors is often a prerequisite for activation of NMDA receptors.

AMPA receptors are expressed throughout the central nervous system. For example, Monaghan et al in Brainresearch 324: the concentration of these receptors in the superficial neocortex, the respective major synaptic regions of the hippocampus and the striatal complex (striatal complex) was found to be high as reported in 160-164 (1984). Animal and human studies have shown that these structures organize complex perceptual-motor processes and provide the basis for higher-level behaviors. Thus, AMPA receptors mediate transmission in these brain networks responsible for many cognitive activities. In addition, AMPA receptors mediate expression in brain regions regulated by the inspiratory drive (inhalation drive) that controls respiration (Paarmann et al, Journal of Neurochemistry, 74: 1335-1345 (2000)).

For the reasons described above, drugs that modulate and thereby enhance AMPA receptor function may have significant beneficial effects on intellectual behavior and the reversal of respiratory depression induced by pharmaceutical formulations (e.g., opioids and opiates) or otherwise. Such drugs should also be beneficial in facilitating memory encoding (memory encoding). For example, by Arai and Lynch in Brain Research 598: 173-184(1992), experimental studies have shown that increasing the magnitude of AMPA receptor-mediated synaptic responses potentiates the induction of long-term potentiation (LTP). LTP is a steady increase in the strength of synaptic connections that occurs with repetitive physiological activities known to occur within the brain during learning.

Compounds that enhance the function of the AMPA subtype of glutamate receptors promote the induction of LTP and facilitate the acquisition of learning tasks as assessed by the multiple paradigm (paradigm). See, for example, Granger et al, Synapse 15: 326-329 (1993); staubli et al, PNAS (Proc. Natl. Acad. Sci. USA) 91: 777. quadrature. 781 (1994); arai et al, Brain Res, (Brain journal) 638: 343- "346 (1994); staubli et al, PNAS 91: 11158-11162 (1994); shors et al, neurosci. let. (neuroscience communication) 186: 153-156 (1995); larson et al, j. neurosci (journal of neuroscience) 15: 8023-8030 (1995); granger et al, Synapse 22: 332- & ltSUB & gt 337- & gt (1996); arai et al, JPET (journal of pharmacology and experimental therapeutics) 278: 627-638 (1996); lynch et al, Internal clin.psychromerm (international clinical psychopharmacology) 11: 13-19 (1996); lynch et al, exp. 89-92 (1997); ingvar et al, exp. 553-559 (1997); hampson et al, j.neurosci.18: 2748 + 2763 (1998); porrino et al, PLoS Biol (scientific public library biology) 3 (9): 1-14(2006) and Lynch and Rogers, U.S. Pat. No. 5,747,492. There is a large body of evidence that LTP is the basis for memory. For example, the model of Neuroscience (Neuroscience) 49 by del Cerro and Lynch: 1-6(1992), compounds that block LTP interfere with memory formation in animals and disrupt the stability of LTP to certain drugs learned by humans. Learning a simple task will produce LTP in the hippocampus, where LTP produced under high frequency stimulation is retained (Whitlock et al, Science 313: 1093-. A finding of great significance in the field of learning is that treatment with positive modulators of AMPA-type glutamate receptors in vivo can restore the stability of LTP in basal dendrites in middle-aged animals (Rex et al, J. neurophysisol. 96: 677-685 (2006)).

Drugs that enhance AMPA receptor function can effectively reverse opioid and barbiturate-induced respiratory depression without reversing the analgesic response (Ren et al, American Journal of respiratory and clinical Care Medicine (Journal of U.S. respiratory and intensive Care Medicine), 174: 138-. Thus, these drugs are effective in preventing or reversing opioid-induced respiratory depression, and can alleviate other forms of respiratory depression, including use of sedatives and sleep apnea. Excitatory synaptic transmission provides the primary pathway for the increase of neurotrophic factors in specific brain regions. Accordingly, it was found that enhancement of AMPA receptor function by modulators can increase the level of neurotrophic factors, particularly brain-derived neurotrophic factor or bdnf (brain derived neurotrophic factor). See, for example, Lauterborn et al, j.neurosci.20: 8-21 (2000); gall et al, U.S. patent 6,030,968; lauterborn et al, JPET 307: 297-305 (2003); and Mackowiak et al Neuropharmacology 43: 1-10(2002). Other studies have linked BDNF levels to a variety of neurological disorders, such as parkinson's disease, Attention Deficit Hyperactivity Disorder (ADHD), autism, Fragile-X Syndrome, Rett Syndrome (RTT). See, for example, O' Neill et al, eur.j. pharmacol. (european journal of pharmacology) 486: 163-174 (2004); kent et al, mol. psychiatry (molecular psychiatry) 10: 939-943 (2005); riikonen et al, j. child Neurol (journal of childhood neuroscience) 18: 693-697(2003) and Chang et al, Neuron 49: 341-348(2006). Thus, AMPA receptor potentiators can be effectively used to treat these and other neurological disorders resulting from glutamatergic imbalances or a deficiency in neurotrophic factors.

Ito et al have also reported in j.physiol. (journal of physiology) 424: 533-543(1990) have described prototypes of compounds which selectively promote the AMPA receptor. These authors found that the nootropic drug (nootropic drug) aniracetam (N-anisoyl-2-pyrrolidone) increased the current mediated by brain AMPA receptors expressed in xenopus oocytes without affecting the response produced by gamma-aminobutyric acid (GABA), Kainic Acid (KA) or NMDA receptors. The injection of aniracetam into slices of hippocampus has also been shown to significantly increase the magnitude of the rapid synaptic potential without altering the properties of the resting membrane. Aniracetam has been shown to enhance synaptic responses at multiple sites in the Hippocampus and to have no effect on NMDA receptor-mediated potentials (Staubli et al, Psychobiology 18: 377-381(1990) and Xiao et al, hipppocampus 1: 373-380 (1991).

It has been found that aniracetam can be very rapidly acting and washed out very rapidly without significant sustained effect and can be used repeatedly, which is a desirable feature of behaviorally relevant drugs. However, aniracetam does also suffer from a number of deficiencies. Peripheral nerve administration of aniracetam (peripheraladministration) may not work for brain receptors. The drug only functions at high concentrations (about 1000. mu.M) and after peripheral nerve administration to humans, about 80% of the drug is converted to anisoyl GABA (Guenzi and Zanetti, J.Chromatogr. (J.chromatographies) 530: 397-406 (1990)). The metabolite anisoyl-GABA was found to be less active than aniracetam. In addition to these problems, aniracetam is recognized to have effects on numerous other neurotransmitter and enzyme targets in the brain, which makes the mechanism of all claimed therapeutic effects uncertain. See, for example, Himori et al, Pharmacology Biochemistry and Behavior (pharmacogenomics, Biochemistry and Behavior) 47: 219, 225 (1994); pizzi et al, j. neurochem. (journal of neurochemistry) 61: 683-689 (1993); nakamura and Shirane, eur.j.pharmacol.380: 81-89 (1999); spignoli and Pepeu, pharmacol, biochem, behav.27: 491-; hall and VonVoigtlander, Neuropharmacology 26: 1573-1579 (1987); and Yoshimoto et al, j.pharmacobiodyn (journal of pharmacokinetics) 10: 730-735(1987).

Compounds that potentiate AMPA receptors have been described that do not exhibit the low potency and inherent instability characteristics of aniracetam (Lynch and Rogers, U.S. patent 5,747,492). These are known as "ampakines"may be a substituted benzamide, including, for example, 6- (piperidin-1-ylcarbonyl) quinoxaline (CX 516; Ampalex^R). Generally, they are chemically more stable than aniracetam and show improved bioavailability. CX516 is active in animal experiments for the detection of effective drugs for the treatment of memory disorders, schizophrenia and depression. CX516 has been shown to be effective in improving various forms of human memory in three separate clinical trials (Lynch et al, Internat. Clin. Psychopharm.11: 13-19 (1996); Lynch et al, exp. neurology 145: 89-92 (1997); Ingvar et al, exp. neurology 146: 553-559 (1997)).

Another ampakine, a benzoxazine, has been found to have very high activity in vitro and in vivo models for assessing the potential for producing cognitive enhancer (Rogers and Lynch; U.S. Pat. No. 5,736,543). Substituted benzoxazines are rigid benzamide analogs with different receptor modulating properties compared to the flexible benzamide CX 516.

It has been found that certain substituted 2, 1, 3 benzoxadiazole compounds (benzoxadiazoles) have significant and much higher potency in animal models of Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia and cognition as compared to the previously disclosed compounds in US2002/0055508 and US 2002/0099050. This novel and novel bicyclic amide (a) is described herein in very specific detail and exhibits its outstanding activity in enhancing AMPA-mediated glutamatergic synaptic responses.

Disclosure of Invention

Accordingly, one aspect of the present invention includes a compound as shown in structure a and other structures described in section II of the detailed description that follows. It has been found that administration of such compounds enhances AMPA-mediated glutamatergic synaptic responses and significantly improves rodent behavior in a behavioural test stimulated by d-amphetamine (d-amphetamine). This behavioral test has been shown to be effective against neuroleptic agents in the treatment of schizophrenia and ADHD. The compounds have unexpected potency in increasing glutamatergic synaptic responses in vivo and are much more potent than the previously described compounds. Converting this activity into a pharmaceutical compound and corresponding methods of use, including methods of treatment, utilize the compounds of the invention at much lower concentrations than prior art compositions. Furthermore, the compounds of the present invention show improved pharmacokinetic properties and have good oral bioavailability compared to the previously described compounds.

The ability of the compounds of the present invention to enhance AMPA receptor-mediated responses enables the compounds to be used for a variety of purposes. These include facilitating glutamate receptor dependent learning behavior, treating conditions in which AMPA receptors or synapses utilizing these receptors are reduced in number or potency, and enhancing excitatory synaptic activity to repair imbalances between brain subregions or to increase the levels of neurotrophic factors.

In another aspect, the invention includes a method for treating a mammalian subject having a glutamate hypofunction (hypoglutamatergic) disorder, or an insufficient number or strength of excitatory synapses, or an insufficient number of AMPA receptors, resulting in impaired memory or other cognitive function. This condition can also cause cortical/striatal imbalance, leading to schizophrenia or schizophreniform behavior.

In another aspect, the invention includes a method of reducing or inhibiting respiratory depression in a subject having respiratory depression, the method comprising administering to the subject an amount of a compound of the invention sufficient to reduce or inhibit respiratory depression. In one embodiment of the invention, the subject is a human. In another embodiment, the subject is a mammal. The invention also claims a method for reducing or inhibiting respiratory depression, the method comprising administering to a subject an amount of a compound of the invention in combination with an opioid analgesic (opioid analgesic); examples of such opiates include, but are not limited to, alfentanil (alfentanil) and fentanyl (fentanyl).

In another aspect, the invention includes a method for reducing or inhibiting a respiratory-related sleep disorder or sleep apnea in a subject having sleep apnea, the method comprising administering to the subject an amount of a compound of the invention sufficient to reduce or inhibit the respiratory-related sleep disorder.

According to the methods of the present invention, these subjects are treated with an effective amount of a compound (in a pharmaceutically acceptable carrier) represented by structure I and described in section II of the detailed description below. The above and other objects and features of the present invention will become more apparent from the following detailed description of the present invention when read in conjunction with the accompanying drawings.

Detailed Description

I. Definition of

Unless otherwise stated, the terms hereinafter have the following meanings. Other terms used to describe the present invention are defined the same as terms commonly used by those skilled in the art.

As used herein, "alkyl" refers to a fully saturated monovalent radical containing carbon and hydrogen, which may be straight-chain, branched-chain, or cyclic. Examples of alkyl groups are methyl, ethyl, n-butyl, n-heptyl, isopropyl, 2-methylpropyl.

The term "cycloalkyl" as used herein refers to a fully saturated monovalent radical containing up to 8 carbons and hydrogen in one ring. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "bicycloalkyl" as used herein refers to a fully saturated monovalent radical containing up to 10 carbons and hydrogens in one bicyclic ring. Examples of bicycloalkyl radicals are bicyclo [2.2.2] octyl, bicyclo [2.2.1] heptyl and bicyclo [2.2.3] nonyl and bicyclo [3.2.1] octyl.

The term "azabicycloalkyl" as used herein refers to a fully saturated monovalent group containing up to 10 carbons and hydrogens and 1 nitrogen atom on one bicyclic ring. Examples of azabicycloalkyl groups include 1-azabicyclo [2.2.2] octyl, 2-azabicyclo [2.2.2] octyl, 1-azabicyclo [2.2.1] heptyl, 2-azabicyclo [2.2.1] heptyl, and 1-azabicyclo [3.2.1] octyl.

The term "alkenyl" herein refers to a monovalent group containing carbon and hydrogen that contains one or two sites of unsaturation, which alkenyl may be linear, branched, or cyclic. Examples of alkenyl groups are vinyl, n-butenyl, n-heptenyl, isopropenyl, cyclopentenyl, cyclopentenylethyl and cyclohexenyl. "alkynyl" refers to monovalent radicals containing at least one triple bond among the above monovalent radicals containing carbon and hydrogen.

The term "substituted alkyl" refers to alkyl groups as described above containing one or more functional groups, e.g., lower alkyl groups containing 1-6 carbon atoms, aryl, substituted aryl, acyl, halogen (i.e., haloalkyl, e.g., CF)₃) Amide (amidio), thioamide (thioamido), cyano, nitro, alkynyl, azido, hydroxy, alkoxy, alkoxyalkyl, amino, alkylamino and dialkylamino (dialkyl-amidio), amido (acylamino), acyloxy, aryloxy, aryloxyalkyl, carboxyalkyl, carboxamide (carboxamido), thio (thio), thioether, saturated and unsaturated cyclic hydrocarbons, heterocycles and the like.

The term "aryl" refers to a substituted or unsubstituted monovalent aromatic group having one ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl). Other examples include: heterocyclic aromatic ring groups which include one or more nitrogen, oxygen or sulfur atoms in the ring, such as oxazolyl (oxazolyl), isoxazolyl, pyrazolyl (pyrazolyl), thiazolyl (thiazolyl), thiadiazolyl (thiadiazolyl), tetrazolyl (tetrazolyl), pyridazinyl (pyridazyl), pyrimidinyl (pyrimidyl), benzofuranyl (benzofuranyl), benzothienyl (benzothienyl), benzimidazolyl (benzimidazolyl), benzoxazolyl (benzoxazolyl), benzothiazolyl (benzothiazolyl), quinolinyl (quinolyl), isoquinolinyl, imidazolyl (imidazoyl), furanyl, pyrrolyl (pyrrolyl), pyridinyl (pyridyl), thienyl and indolyl.

As used herein, the term "substituted" in the term "substituted aryl (aryl), substituted aromatic (aromatic), substituted heteroaryl, or substituted heteroaromatic" means that one or more substituents may be present, which may be selected from atoms and groups, which when present do not affect the compound's function as a potentiator of AMPA receptor function. Examples of substituents that may be present on the substituted aromatic or heteroaromatic groups may include, but are not limited to, the following groups, for example: (C)₁-C₇) Alkyl, (C)₁-C₇) Acyl, aryl, heteroaryl, substituted aryl and heteroaryl, halogen, cyano, nitro, amido (optionally substituted by one or two C)₁-C₇Alkyl substituted), thioamido (optionally substituted with one or two C)₁-C₇Alkyl substituted), azido, alkynyl, (C)₁-C₇) Haloalkyl (e.g. CF)₃) Hydroxy, (C)₁-C₇) Alkoxy group, (C)₂-C₈) Alkoxyalkyl group ((C)₂-C₈) alkosylkyl), amino, (C)₁-C₇) Alkylamino and dialkylamino radicals, (C)₁-C₇) Amido, (C)₁-C₇) Acyloxy, aryloxy, (C)₁-C₇) Aryloxyalkyl radical, (C)₁-C₇) Carboxyalkyl, carboxamide, thio, (C)₁-C₇) Thioethers, saturated and unsaturated (C)₃-C₈) Cyclic hydrocarbon (C)₃-C₈) Heterocyclic rings and the like. It should be noted that each substituent disclosed herein may itself be substituted.

"heterocycle" or "heterocyclic" refers to a carbocyclic ring in which one or more carbon atoms are replaced by one or more heteroatoms (e.g., nitrogen, oxygen, or sulfur). Examples of heterocycles include, but are not limited to: piperidine, pyrrolidine, morpholine, thiomorpholine (thiomorpholine), piperazine, tetrahydrofuran, tetrahydropyran, 2-pyrrolidone, δ -valerolactam, δ -valerolactone and 2-piperazinone (2-ketopiperazine).

The term "substituted heterocycle" refers to the aforementioned heterocycles containing or substituted with one or more functional groups (as described elsewhere herein) such as lower alkyl, acyl, aryl, cyano, halogen, amido, thioamido, azido, hydroxy, alkoxy, alkoxyalkyl, amino, alkylamino, and dialkylamino, amido, acyloxy, aryloxy, aryloxyalkyl, carboxyalkyl, carboxamido, thio, thioether, saturated and unsaturated cyclic hydrocarbons, heterocycles, and the like, as described elsewhere herein.

The term "compound" as used herein refers to any particular chemical compound disclosed herein. In the context of this application, the term is generally intended to refer to a single stable compound, but in some cases it may also refer to stereoisomers and/or optical isomers of the disclosed compounds (including enantiomerically pure compounds, enantiomerically enriched compounds, and racemic mixtures).

The term "effective amount" refers to an amount of a selected compound of formula I that produces the desired effect, e.g., enhancement of glutamatergic synaptic responses by increasing AMPA receptor activity, in the context of the intended use. The exact amount may vary depending on the particular compound selected and its intended use, the age and weight of the subject, the route of administration, and the like, but can be readily determined by routine experimentation. In treating a disorder or disease state, an effective amount refers to an amount that is effective to treat the particular disorder or disease state.

The term "pharmaceutically acceptable carrier" refers to a carrier or excipient that does not produce unacceptable toxicity to the subject to which it is administered. Pharmaceutically acceptable excipients are described extensively by e.w. martin in Remington's Pharmaceutical Sciences.

"pharmaceutically acceptable salts" of amine compounds, such as those set forth herein, are ammonium salts having inorganic anions (e.g., chloride, bromide, iodide, sulfate, sulfite, nitrate, nitrite, phosphate, etc.) or organic anions (e.g., acetate, malonate, pyruvate, propionate, fumarate (fumarate), cinnamate (cinnamate), toluenesulfonate (tosylate), etc.) as counterions.

The term "patient" or "subject" is used throughout the specification to describe an animal, typically a mammal, including a human, treated with or using a compound or composition provided herein. For the treatment or application to those conditions or disease states which are characteristic of a particular animal (in particular, for example, a human subject or patient), the term patient or subject refers to that particular animal.

The term "sensorimotor problems" is used to describe problems resulting from the inability to integrate external information derived from five known sensory modalities in a patient or subject to direct appropriate physical responses, including movement and action.

The term "cognitive work" or "cognitive function" is used to describe an effort or process involving thinking or cognition in a patient or subject. The multiple functions of the association cortex (association centers) which account for about 75% of the overall human brain tissue are responsible for a large amount of information processing between sensory input and behavioral output. The multiple functions of the contact cortex are generally referred to as cognition, which literally means the process of understanding the world. Selective attention to specific stimuli, recognition and identification of the characteristics of these related stimuli, and planning and testing of responses is a cognition-related process or ability mediated by the human brain.

The term "brain network" is used to describe different anatomical regions of the brain that communicate with each other through synaptic activity of neuronal cells.

The term "AMPA receptor" refers to protein aggregates found in membranes that allow cations to pass through the membrane in response to the binding of glutamate or AMPA (DL- α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) but not NMDA.

The term "excitatory synapse" is used to describe a cell-cell junction where a chemical signal is released by one cell to cause depolarization of the outer membrane of another cell. Excitatory synapses describe post-synaptic neurons with a reversal potential (reversal potential) that is greater than a threshold potential (threshold potential), and therefore, in such synapses, neurotransmitters increase the likelihood of generating excitatory post-synaptic potentials (triggering neurons to generate action potentials). The inverse potential and the threshold potential determine postsynaptic excitation and inhibition. If the inverse potential of the post-synaptic potential ("PSP") is greater than the threshold value of the action potential, the action of the neurotransmitter is excitatory, and an excitatory post-synaptic potential ("EPSP") is generated and triggered by the neuron. If the reversal potential of the post-synaptic potential is less than the threshold of the action potential (more negative), the neurotransmitter is inhibitory and may produce an inhibitory post-synaptic potential (IPSP), thereby reducing the likelihood that the synapse will trigger the action potential. The general rule for post-synaptic action is: if the reversal potential is greater than the threshold, an excitatory result is produced; if the reverse potential is less than the threshold, a suppression result is produced. See, for example, NEUROSCIENCE (NEUROSCIENCE) chapter seventh, Sinauer Associates, Inc., Sunderland, MA 1997, edited by Dale Purves.

The term "motor task" is used to describe the effort a patient or subject makes in performing a movement or action.

The term "perceptual task" is used to describe the act of a patient or subject focusing on sensory input.

The term "synaptic response" is used to describe a biophysical response that occurs in one cell due to a chemical signal released by another cell in close contact with it.

The term "glutamate hypofunction condition" is used to describe a condition or disorder in which glutamate (or related excitatory amino acids) mediated transmission is reduced below normal levels. Transmission involves the release of glutamate, binding to postsynaptic receptors, and the opening of channels that integrate into these receptors. The end point of the conditions of the hypoglutamatergic symptoms is the reduction of excitatory postsynaptic currents. The excitatory postsynaptic current may be caused by any of the three delivery phases mentioned above. Conditions or disease states that are considered to be conditions of glutamate hypofunction and that may be treated with the compounds, compositions and methods according to the present invention include, for example: memory loss, dementia, depression, attention disorders, sexual dysfunction, movement disorders including parkinson's disease, schizophrenia or schizophreniform behavior, memory and learning disorders (including those caused by aging, trauma, stroke and neurodegenerative diseases, such as disorders associated with drug-induced states, neurotoxic agents, alzheimer's disease and aging, respiratory depression and sleep apnea). These conditions can be readily identified and diagnosed by one of ordinary skill in the art.

The term "cortical-striatal imbalance" is used to describe a deviation from the normal state of the balance of neuronal activity in the interconnected cortex (interconnected cortix) and underlying striatal complex (underlying striatal complex). "Activity" can be assessed by electrical recording (electrical recording) or molecular biology techniques. The imbalance can be determined by applying the above measurements to both structures or by functional (behavioral or physiological) criteria.

The term "affective disorder" or "mood disorder" describes a condition when sadness or happiness (elation) is excessively intense and the stress on life activities continues to exceed the expected effect or sadness or happiness is generated endogenously. The term "affective disorder" as used herein includes all types of mood Disorders, for example as described in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM IV), page 317-.

The term "schizophrenia" is used to describe the general type of psychotic disorder characterized by dysregulation of thought processes, such as delusions and hallucinations, as well as severe attentions to other people and individuals in the external world and focusing only on his or her own world. Schizophrenia is currently considered to be a group of psychotic disorders rather than a single individual, and differences between reactive schizophrenia and progressive schizophrenia are considered. The term schizophrenia or schizophreniform as used herein includes all types of schizophrenia, including flowable schizophrenia (ambuladestructor), catatonic schizophrenia (catatonic schizophrenia), hebephrenic schizophrenia (hebephrenia), occult schizophrenia (latent schizophrenia), progressive schizophrenia, pseudoneurotic schizophrenia (pseudoneurotic schizophrenia), reactive schizophrenia, simple schizophrenia, and schizophrenia-related psychotic disorders (such disorders are similar to schizophrenia but not necessarily diagnosed as schizophrenia in nature). Schizophrenia and other psychotic disorders can be diagnosed by guidance established, for example, in the Diagnostic and Statistical Manual of mental disorders, fourth edition (DSM IV), section 293.81, section 293.82, section 295.10, section 295.20, section 295.30, section 295.40, section 295.60, section 295.70, section 295.90, section 297.1, section 297.3, section 298.8.

The term "brain function" is used to describe the combined task of sensing, integrating, filtering, and responding to external stimuli and internal motivational processes.

The term "impaired" is used to describe a function that operates at a level below normal. The impaired function may be so strongly impacted that the function is hardly performed, practically non-existent, or operates in a significantly worse mode than normal. Impaired function may also be less optimal. The impairment of function varies with the severity of the different patients and the condition to be treated.

The term "respiratory depression" as used herein refers to a variety of conditions characterized by a reduction in respiratory rate and inspiration driving cranial and spinal motor neurons. Specifically, respiratory depression refers to the action of the spinal nervous system (neural network) associated with the activity of the production of respiratory rhythms that do not contribute to the accumulation of PCO in the blood₂Level (or reduced CO)₂Horizontal) and cannot subsequently stimulate motor neurons that control the pulmonary musculature.

The term "sleep apnea" as used herein refers to breathing-related sleep disorders, which fall into two categories: central sleep apnea and obstructive sleep apnea. Central sleep apnea is defined as a neurological condition that causes a pause in all breathing during sleep, usually accompanied by a decrease in blood oxygen saturation, with no breathing and no breathing if the brainstem center controlling breathing is turned off. The auto-breathing reflex may result in little sleep as it causes a person to wake up from sleep. Obstructive sleep apnea is characterized by: breathing is repeatedly suspended by obstruction and/or collapse (collapse) of the upper airway during sleep, followed by waking to breathe. During the apnea, respiration is still ongoing.

The term "pro-drug" as used herein refers to a metabolically labile derivative which is pharmaceutically inactive in the parent form but which is rapidly metabolised to a pharmacologically active form in human or animal plasma. Examples of prodrugs useful in the present invention include, but are not limited to: derivatives of esters containing hydroxyl moieties, such esters including, but not limited to, those formed from substituted or unsubstituted natural or unnatural amino acids.

Compounds of the invention

The present invention provides compounds having AMPA receptor enhancing properties. The compounds include a substance having the following structure a or a pharmaceutically acceptable salt, solvate or polymorph thereof:

wherein:

w is oxygen, sulfur or CH ═ CH;

x, Y and Z are independently selected from the group consisting of-N or-CR,

wherein:

r is H, -Br, -Cl, -F, -CN, -NO₂、-OR¹、-SR¹、-NR¹ ₂、-C₁-C₆Unsubstituted or substituted branched or unbranched alkyl,

wherein:

R¹is H, -C₁-C₆Unsubstituted or substituted branched or unbranched alkyl,

n-0-5 (thus 0-5 methylene groups are present)

m is 0-5 (so that there are 0-5 methylene groups)

p-0-5 (thus 0-5 methylene groups are present)

R²And R³Each independently selected from H, halogen (preferably F), -CN, -NO₂、-OR¹、-SR¹、-NR¹ ₂、CF₃、OH、C＝O、-C₁-C₆Unsubstituted or substituted branched or unbranched alkyl, -C₂-C₆Unsubstituted or substituted branched or unbranched alkenyl, -C₂-C₆Unsubstituted or substituted, branched or unbranched alkynyl, -C₃-C₇Unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted carboxyalkyl, unsubstituted or substituted carboxyaryl, unsubstituted or substituted carboxyheteroaryl, unsubstituted or substituted sulfonylalkyl, unsubstituted or substituted sulfonylaryl, or unsubstituted or substituted sulfonylheteroaryl,

e and F are each independently selected from CH₂m、CR²R³、A、CH₂A、CR²＝CR³Or absent (provided that E and F are not both absent);

g is CR²R³、A、CH₂A、CR²＝CR³、CH₂C＝O、CH₂CR²R³Or in the absence of, or in the presence of,

a is O, S, SO₂C ═ O or CR²R³。

In another aspect, the invention also provides compounds having AMPA receptor enhancing properties. The compounds include a substance having the following structure I or a pharmaceutically acceptable salt, solvate or polymorph thereof:

wherein the content of the first and second substances,

w is oxygen, sulfur or CH ═ CH;

x, Y and Z are independently selected from the group consisting of-N or-CR,

wherein:

r is H, -Br, -Cl, -F, -CN, -NO₂、-OR¹、-SR¹、-NR¹ ₂、-C₁-C₆Unsubstituted or substituted branched or unbranched alkyl,

wherein:

R¹is H, -C₁-C₆Unsubstituted or substituted branched or unbranched alkyl,

n-0-5 (thus 0-5 methylene groups are present)

m is 0-5 (so that there are 0-5 methylene groups)

p-0-5 (thus 0-5 methylene groups are present)

R²And R³Independently selected from H, halogen (preferably F), -CN, -NO₂、-OR¹、-SR¹、-NR¹ ₂、CF₃、OH、C＝O、-C₁-C₆Unsubstituted or substituted branched or unbranched alkyl, -C₂-C₆Unsubstituted or substituted branched or unbranched alkenyl, -C₂-C₆Unsubstituted or substituted, branched or unbranched alkynyl, -C₃-C₇Unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substitutedA substituted heterocycle, unsubstituted or substituted carboxyalkyl, unsubstituted or substituted carboxyaryl, unsubstituted or substituted carboxyheteroaryl, unsubstituted or substituted sulfonylalkyl, unsubstituted or substituted sulfonylaryl, or unsubstituted or substituted sulfonylheteroaryl.

The ring of the azabicyclo can also be an unsaturated azabicyclo ring, as shown in structure II below or a pharmaceutically acceptable salt, solvate, or polymorph thereof:

wherein:

w, X, Y and Z are as defined above for formula I;

n-0-5 (thus 0-5 methylene groups are present)

m is 0-5 (so that there are 0-5 methylene groups)

p-0-4 (thus 0-4 methylene groups are present)

And R is²And R³As defined in structural formula I above.

The ring of the azabicyclo can also be represented by the substance of structure III or a pharmaceutically acceptable salt, solvate, or polymorph thereof:

wherein:

w, X, Y and Z are as defined above for formula I;

a is O, S, SO₂C ═ O or CR²R³；

n-0-5 (thus 0-5 methylene groups are present)

m-1-5 (thus 0-5 methylene groups are present)

p-0-5 (thus 0-5 methylene groups are present)

And R is²And R³As defined in structural formula I above.

In another aspect of the invention, the ring of the azabicyclo includes a compound of structure IV or a pharmaceutically acceptable salt, solvate, or polymorph of the compound:

wherein:

w, X, Y and Z are as defined above for formula I;

a is O, S, SO₂C ═ O or CR²R³；

n-1-5 (so that 1-5 methylene groups are present)

m-1-5 (so that 1-5 methylene groups are present)

p-0-5 (thus 0-5 methylene groups are present)

And R is²And R³As defined in structural formula I above.

In another aspect, the present invention provides compounds having formula a and formula I through formula IV selected from the group consisting of:

8-Azabicyclo [3.2.1] oct-8-yl ([2.1.3] -benzoxadiazol-5-yl) methanone (8-Azabicyclo [3.2.1] oct-8-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone)

8- ([2.1.3] -Benzoxadiazol-5-ylcarbonyl) -8-azabicyclo [3.2.1] oct-3-one (8- ([2.1.3] -Benzoxadiazol-5-ylcarbanyl) -8-aza-bicyclo [3.2.1] octan-3-one)

[2, 1, 3] -Benzoxadiazol-5-yl (3, 3-difluoro-8-azabicyclo [3.2.1] oct-8-yl) methanone ([2, 1, 3] -Benzoxadiazol-5-yl (3, 3-difluoro-8-azabicyclo [3.2.1] oct-8-yl) methanone)

[2, 1, 3] -Benzoxadiazol-5-yl (3-fluoro-8-azabicyclo [3.2.1] oct-2-en-8-yl) methanone ([2, 1, 3] -Benzoxadiazol-5-yl (3-fluoro-8-azabicyclo [3.2.1] oct-2-en-8-yl) methanone)

Endo- [2, 1, 3] -Benzoxadiazol-5-yl (3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl) methanone (endo- [2, 1, 3] -Benzoxadiazol-5-yl (3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl) methanone)

Exo- [2, 1, 3] -Benzoxadiazol-5-yl (3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl) methanone (exo- [2, 1, 3] -Benzoxadiazol-5-yl (3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl) methanone)

2-Azabicyclo [2.2.1] hept-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone (2-Azabicyclo [2.2.1] hept-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone)

1-Azabicyclo [2.2.1] hept-1-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone (1-Azabicyclo [2.2.1] hept-1-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone)

2-Azabicyclo [2.2.2] oct-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone (2-Azabicyclo [2.2.2] oct-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone)

[2, 1, 3] -Benzoxadiazol-5-yl (2-oxa-5-azabicyclo [2.2.1] hept-5-yl) methanone ([2, 1, 3] -Benzoxadiazol-5-yl (2-oxa-5azabicyclo [2.2.1] hep-5-yl) methanone)

2-Azabicyclo [2.2.1] hept-5-en-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone (2-Azabicyclo [2.2.1] hept-5-en-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone)

[2, 1, 3] -Benzoxadiazol-5-yl (5, 6-dichloro-2-azabicyclo [2.2.1] hept-2-yl) methanone ([2, 1, 3] -Benzoxadiazol-5-yl (5, 6-dichoro-2-azabicyclo [2.2.1] hep-2-yl) methanone)

R-2-Azabicyclo [2.2.1] hept-5-en-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone (R-2-Azabicyclo [2.2.1] hep-5-en-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone)

S-2-azabicyclo [2.2.1] hept-5-en-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone.

Synthesis of

The compounds of the present invention are preferably synthesized by the following reaction formulae. Other synthetic methods, similar to those found in the prior art, may also be used. The compounds may be prepared using the described synthetic methods, following the chemistry set forth herein or by making minor changes to synthetic methods well known in the art. The synthesis is convenient and can be readily varied within the scope of the teachings of the present invention. Starting from 4-amino-3-nitrobenzoic acid 1, synthesis of acid chloride 4 was carried out by first oxidizing 4-amino-3-nitrobenzoic acid 1 with a bleaching agent to give intermediate 2, and then with triethyl phosphite (P (OEt)₃) Reduction is carried out to give benzofurazan carboxylic acid 3(benzofurazan carboxylic acid). Carboxylic acid 3 is converted to acid chloride 4 by refluxing with thionyl chloride and a catalytic amount of DMF (dimethylformamide) in toluene. Carboxylic acid 3 can be converted to the bicyclic amide by reacting carboxylic acid 3 with bicyclic amines (amides) in a suitable solvent using standard coupling conditions such as CDI, EDCI, HBTU. Alternatively, the acid chloride 4 can be converted to the bicyclic amide 5 with the bicyclic amine under standard coupling conditions in the presence of a base (e.g., triethylamine or aqueous sodium hydroxide, etc. in a suitable solvent such as dichloromethane). Prepared from commercially available benzothiadiazole acid chloride (benzothiadiazole acid chloride) in the presence of a base (e.g., triethylamine or aqueous sodium hydroxide in a suitable solvent such as dichloromethane) under standard coupling conditionsThiadiazole carboxamide 6. Quinoxaline-6-carboxylic acid chloride (quinoxaline-6-carboxylic acid chloride) is prepared by condensation of commercially available 3, 4-diaminobenzoic acid with glyoxal, followed by refluxing with thionyl chloride and catalytic amounts of DMF in toluene under standard procedures. The quinoxaline-6-acyl chloride is reacted with a bicyclic amine to give the desired quinoxaline bicyclic amide (7). Other azabicycles represented by structures II through IV can be prepared by coupling the appropriate azabicyclo with acid chloride 4 in a similar manner.

Reaction type

Methods of treatment

According to one aspect of the invention, there is provided a method of treatment of a mammalian subject suffering from a condition of glutamate hypofunction, or suffering from an insufficient number or strength of excitatory synapses or an insufficient number of AMPA receptors. In the subject, memory or other cognitive function may be impaired, or a cortical/striatal imbalance may occur, resulting in memory loss, dementia, depression, attention disorders, sexual dysfunction, movement disorders, schizophrenia or schizophreniform behavior. Memory disorders and learning disorders that may be treated according to the present invention include those disorders caused by, for example, aging, trauma, stroke, and neurodegenerative diseases. Examples of neurodegenerative diseases include, but are not limited to, diseases associated with drug-induced states, nerve agents, alzheimer's disease, and aging. One skilled in the art can readily identify and diagnose such conditions and administer an effective amount of one or more compounds according to the present invention to the patient.

In another aspect, the invention provides a method for reducing or inhibiting respiratory depression in a subject suffering from respiratory depression, the method comprising administering to the subject an amount of a compound of the invention sufficient to reduce or inhibit respiratory depression. In another aspect of the invention, there is provided a method of reducing or inhibiting respiratory depression, the method comprising administering to a subject an amount of a compound of the invention in combination with an opioid analgesic; examples of such opiates include, but are not limited to, alfentanil and fentanyl.

In another aspect, the invention provides a method for reducing or inhibiting a respiratory-related sleep disorder or sleep apnea in a subject having sleep apnea, the method comprising administering to the subject an amount of a compound of the invention sufficient to reduce or inhibit the respiratory-related sleep disorder.

In the present invention, the method of treatment comprises administering to a patient in need of treatment an effective amount of a compound in a pharmaceutically acceptable carrier, said compound being a substance having the structure shown in formula a below or a pharmaceutically acceptable salt, solvate or polymorph of said substance:

wherein:

w is oxygen, sulfur or CH ═ CH;

x, Y and Z are independently selected from the group consisting of-N or-CR,

wherein:

r is H, -Br, -Cl, -F, -CN, -NO₂、-OR¹、-SR¹、-NR¹ ₂、-C₁-C₆Unsubstituted or substituted branched or unbranched alkyl,

wherein:

R¹is H, -C₁-C₆Is unsubstituted or substitutedA branched or unbranched alkyl group of (a),

n-0-5 (thus 0-5 methylene groups are present)

m is 0-5 (so that there are 0-5 methylene groups)

p-0-5 (thus 0-5 methylene groups are present)

R²And R³Each independently selected from H, halogen (preferably F), -CN, -NO₂、-OR¹、-SR¹、-NR¹ ₂、CF₃、OH、C＝O、-C₁-C₆Unsubstituted or substituted branched or unbranched alkyl, -C₂-C₆Unsubstituted or substituted branched or unbranched alkenyl, -C₂-C₆Unsubstituted or substituted, branched or unbranched alkynyl, -C₃-C₇Unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted carboxyalkyl, unsubstituted or substituted carboxyaryl, unsubstituted or substituted carboxyheteroaryl, unsubstituted or substituted sulfonylalkyl, unsubstituted or substituted sulfonylaryl, or unsubstituted or substituted sulfonylheteroaryl,

e and F are each independently selected from CH₂m、CR²R³、A、CH₂A、CR²＝CR³Or absent (provided that E and F are not both absent);

g is CR²R³、A、CH₂A、CR²＝CR³、CH₂C＝O、CH₂CR²R³Or in the absence of, or in the presence of,

a is O, S, SO₂C ═ O or CR²R³。

In another aspect of the invention, a method of treatment comprises administering to a patient in need of treatment an effective amount of a compound in a pharmaceutically acceptable carrier, the compound being a substance having the structure shown in formula I below or a pharmaceutically acceptable salt, solvate or polymorph of the substance:

wherein the content of the first and second substances,

w is oxygen, sulfur or CH ═ CH;

x, Y and Z are independently selected from the group consisting of-N or-CR,

wherein:

r is H, -Br, -Cl, -F, -CN, -NO₂、-OR¹、-SR¹、-NR¹ ₂、-C₁-C₆Unsubstituted or substituted branched or unbranched alkyl,

wherein:

R¹is H, -C₁-C₆Unsubstituted or substituted branched or unbranched alkyl,

n-0-5 (thus 0-5 methylene groups are present)

m is 0-5 (so that there are 0-5 methylene groups)

p-0-5 (thus 0-5 methylene groups are present)

R²And R³Each independently selected from H, halogen (preferably F), -CN, -NO₂、-OR¹、-SR¹、-NR¹ ₂、CF₃、OH、C＝O、-C₁-C₆Unsubstituted or substituted branched or unbranched alkyl, -C₂-C₆Unsubstituted or substituted branched or unbranched alkenyl, -C₂-C₆Unsubstituted or substituted, branched or unbranched alkynyl, -C₃-C₇Unsubstituted or substituted cycloalkyl, unsubstituted or substituted arylAn unsubstituted or substituted heterocycle, an unsubstituted or substituted carboxyalkyl group, an unsubstituted or substituted carboxyaryl group, an unsubstituted or substituted carboxyheteroaryl group, an unsubstituted or substituted sulfonylalkyl group, an unsubstituted or substituted sulfonylaryl group, or an unsubstituted or substituted sulfonylheteroaryl group.

In another aspect of the invention, it is preferred to use an azabicyclic compound represented by structure II or a pharmaceutically acceptable salt, solvate, or polymorph of the azabicyclic compound in the process:

wherein:

w, X, Y and Z are as defined in Structure I;

n＝0-5

m＝0-5

p＝0-4

and R is²And R³As defined in structural formula I above.

In another aspect of the methods of the present invention, preferred embodiments include a compound represented by structure III, or a pharmaceutically acceptable salt, solvate, or polymorph of the compound:

wherein:

w, X, Y and Z are as defined in Structure I;

a is O, S, SO₂C ═ O or CR²R³；

n＝0-5

m＝1-5

p＝0-5

And R is²And R³As defined in structural formula I above.

In another aspect of the methods of the present invention, preferred embodiments include a compound represented by structure IV or a pharmaceutically acceptable salt, solvate, or polymorph of the compound:

wherein:

w, X, Y and Z are as defined above for formula I;

a is O, S, SO₂C ═ O or CR²R³；

n＝1-5

m＝1-5

p＝0-5

And R is²And R³As defined in structural formula I above.

The compounds according to the invention exhibit enhanced bioavailability in most cases, due at least in part to the enhanced pharmacokinetics exhibited by the compounds of the invention. Thus, the compounds of the present invention can be formulated in pharmaceutical compositions in different dosage forms, particularly oral dosage forms.

As indicated above, treatment of a subject according to the present invention is beneficial for enhancing AMPA receptor activity and can thus be used to promote learning behavior that is dependent on AMPA receptors and can be used to treat conditions such as impaired memory in which the number of AMPA receptors or synapses utilizing such receptors is reduced or the efficacy is reduced. The methods are also useful for enhancing excitatory synaptic activity to repair imbalances between brain subregions that manifest themselves in schizophrenia or schizophreniform behavior, or other behavior described above. As shown by the in vivo tests described below, the compounds of the invention administered according to the method were found to be more effective in enhancing AMPA receptor activity than the previously described compounds.

V. biological Activity

A. Enhancement of AMPA receptor function in vivo

According to the methods of the present invention, synaptic responses mediated by AMPA receptors may be enhanced by the use of the compounds described herein.

The electrophysiological effects of the compounds of the invention were tested in anesthetized animals according to the following procedure. Animals were kept under anesthesia with phenobarbital by a Hamilton syringe pump (Hamilton syringe pump). Stimulation and recording electrodes were inserted into the fenestrated fibers (perforant path) and hippocampal gyrus, respectively. Once the electrodes were implanted, monophasic pulses (pulse duration 100 microseconds) were delivered to the stimulation electrodes at a frequency of 3 times/min to detect a stable baseline resulting from evoked responses (evoked responses). The field excitatory postsynaptic potentials (fieldesps) are monitored until a stable baseline is obtained (about 20-30 minutes), then a solution of the test compound is injected intraperitoneally and evoked field potentials are recorded. Evoked potentials were recorded about 2 hours after administration or until the increase in field excitatory postsynaptic potential (amplitude) returned to baseline. In the latter case, administration by intravenous injection (ivadministration) is also typically carried out with the same test compound at an appropriate dose. The compounds of the invention were analyzed using the in vivo electrophysiological assay described above, and data for typical test compounds are presented in column 1 of table 1. After intraperitoneal injection, the compound of the invention has significantly higher activity than CX516(1- (quinoxaline-6-ylcarbonyl) piperidine) and US 5,773,434(US2002/0055508) in increasing the amplification of field EPSP by 9% by intraperitoneal injection at 50 mg/kg.

TABLE 1

Compound example number¹In vivo electrophysiology²Inhibition of dextroamphetamine-stimulated activity

1 22％ 69％

2 16％ 40％

3 8％ NT

4 25％ NT

7 20％3 NT

1. Percent increase in field EPSP amplification (%)

2. Percent inhibition (%)

3. Intravenous dose

NT ═ untested

B. And (3) behavior testing: inhibition of dextroamphetamine-stimulated activity (lococotion)

The inhibitory ability of the compounds of the present invention on voluntary activity (nocolor activity) stimulated by dextroamphetamine was analyzed according to the following procedures. Male CD1 mice weighing 25-30gm were placed in the laboratory and allowed to acclimate for at least 30 minutes. Each mouse was placed in a test pen (testing enclosure) with an array of infrared beams that automatically monitored animal activity. Mice were habituated in the test pens for 20 minutes and then returned to their home cages. Mice were administered test compound intraperitoneally in a suitable vehicle and 5 minutes later were injected with dextroamphetamine (2 mpk). The mice were tested for voluntary activity 10 minutes after the dextroamphetamine injection and for 15 minutes. Data were collected by computer and expressed as "random motion units". All data were analyzed by comparing the groups treated with the test compounds with the control group treated with vehicle. Data for the test compounds are presented in table 1, column 2. The data shown are the percent inhibition of hyperactivity induced in mice by acute administration of 2mg/kg dextroamphetamine to the mice. Statistically, the tested compounds have significant inhibitory effect on the activity stimulated by dextroamphetamine.

Administration, dosage and dosage form

As noted above, the compounds and methods of the present invention enhance glutamatergic synaptic responses mediated by AMPA receptors and can be used to treat conditions of glutamate hypofunction. The compounds and methods of the invention are also effective in treating conditions such as impaired memory or other cognitive functions caused by insufficient numbers or strengths of excitatory synapses or by insufficient numbers of AMPA receptors. The compounds and methods of the invention can also be used to treat schizophrenia or schizophreniform behavior due to cortical/striatal imbalance and to promote learning behaviors that are dependent on AMPA receptors.

In subjects treated with the compounds, pharmaceutical compositions and methods of the invention, memory or other cognitive function may be impaired, or a cortical/striatal imbalance may occur, resulting in memory loss, dementia, depression, attention disorders, sexual dysfunction, movement disorders, schizophrenia or schizophreniform behavior. Memory disorders and learning disorders that may be treated according to the present invention include those resulting from aging, trauma, stroke, and neurodegenerative diseases. Examples of neurodegenerative diseases include, but are not limited to, diseases associated with drug-induced states, nerve agents, alzheimer's disease, and aging. One of ordinary skill in the art can readily identify and diagnose such conditions and administer an effective amount of one or more compounds according to the present invention to a patient for treatment.

In general, the dosage and route of administration of the compounds can be determined based on the weight and condition of the subject and based on standard pharmaceutical practice. The dosage level employed may vary over a wide range and can be readily determined by one skilled in the art. Generally, the amounts used are of the order of milligrams to grams. Administration to a subject can be by various routes, for example, oral, transdermal, peripherical (perineurally) or parenteral, i.e., by intravenous, subcutaneous, intraperitoneal or intramuscular injection, including buccal, rectal and transdermal. Subjects contemplated for treatment with the methods according to the invention include humans, companion animals (companion animals), laboratory animals, and the like.

Formulations containing a compound according to the present invention may take the form of solid, semi-solid, lyophilized powder or liquid dosage forms, such as tablets, capsules, powders, sustained release formulations, solutions, suspensions, emulsions, suppositories, creams (creams), ointments, lotions (motions), aerosols, patches and the like, preferably in unit dosage forms suitable for single administration of a precise dose.

The pharmaceutical compositions according to the invention contain an effective amount of one or more compounds according to the invention and usually conventional pharmaceutical carriers or excipients, and may additionally contain other pharmaceutical agents, carriers, adjuvants, additives and the like. Preferably, the composition contains one or more compounds of the invention in an amount of about 0.5 to 75% by weight or more, with the remainder being primarily suitable pharmaceutical excipients. For oral administration, the excipients include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like. The compositions may also contain minor amounts of non-toxic adjuvants, such as wetting agents, emulsifying agents, or buffering agents, if desired.

Liquid compositions may be prepared by dissolving or dispersing the compound (about 0.5-20% by weight or more) and optional pharmaceutical adjuvants in a carrier, such as saline solution, aqueous glucose solution, glycerol or ethanol, to form a solution or suspension. For use in oral liquid formulations, the compositions may be prepared as solutions, suspensions, emulsions or syrups, provided in liquid form or in dry form suitable for hydration in water or normal physiological saline.

When the composition of the present invention is used in the form of a solid preparation for oral administration, the preparation may be tablets, granules, powders, capsules, etc. In tablet formulations, the compositions are typically formulated with additives such as excipients (e.g., sugar or cellulose preparations), binders (e.g., starch paste or methyl cellulose), fillers, disintegrants and other additives commonly used in the preparation of pharmaceutical formulations.

Injectable compositions for parenteral administration typically contain the compound in a solution suitable for intravenous injection (i.v.), for example, a sterile physiological saline solution. The composition may also be formulated as a suspension in a lipid or phospholipid, a liposome suspension, or an aqueous emulsion.

Methods of preparing the above dosage forms are known or will be apparent to those skilled in the art; for example, seeRemington′s Pharmaceutical Sciences(17 th edition, Mack pub. co., 1985).

The composition to be administered may contain a plurality of pharmaceutically effective amounts of the compound selected to be effective to increase AMPA receptor current in the subject.

The following examples illustrate the invention and are not intended to limit the invention in any way. All temperatures given are in degrees Celsius (. degree. C.) unless otherwise indicated. All NMR (nuclear magnetic resonance) spectra are meant unless otherwise indicatedIs that¹H NMR spectrum, obtained using deuterated chloroform (deuterochloroform) or deuterated DMSO (dimethyl sulfoxide) as solvent, and tetramethylsilane as internal standard. The nomenclature of all the compounds of the examples conforms to the IUPAC (International Union of theory and applied chemistry) systematic nomenclature, provided by the computer software ChemSketch of the ACD laboratory (ACD Labs).

I. Chemical process

Intermediate 1

2, 1, 3-benzoxadiazole-5-carboxylic acids

In a 3L reactor equipped with mechanical stirrer, reflux condenser, thermometer and nitrogen inlet, KOH (72.46g) was dissolved in ethanol (250ml) and water (250 ml). 4-amino-3-nitrobenzoic acid (100g) was added and the orange suspension was heated to 65-70 ℃ over 30 minutes. The resulting suspension was stirred at the same temperature for 45 minutes and cooled to 0 ℃. + -. 5 ℃ over 30 minutes. A solution of commercially available sodium hypochlorite (448.93g) (13% w/w) was added dropwise over 1.5 hours at a temperature of 0 ℃ ± 5 ℃. The reaction mixture was stirred at the same temperature for 2 hours and controlled by Thin Layer Chromatography (TLC) (CHCl)₃100/acetone 2/acetic acid 1). Water (350ml) was added over 15 minutes at a temperature of 0 ℃. + -. 5 ℃ to give a pure yellow suspension. The reaction mixture was then acidified with 6N HCl solution (239ml) until a pH of 0.5 < 1 was reached. NaCl (58.44g) was added and the resulting suspension was stirred under nitrogen at 0 ℃. + -. 5 ℃ for 1.5 hours. The solid obtained by filtration was collected, washed with 3X 400ml of water and dried (40 ℃, 30 mbar (mbars), 12 hours) to yield 83.6g (88.8% yield) of 2, 1, 3-benzoxadiazole-5-carboxylic acid N-oxide.

In a hopper equipped with a mechanical stirrer, thermometer and an addition funnel2, 1, 3-Benzooxadiazole-5-carboxylic acid N-oxide (80g) was dissolved in anhydrous ethanol (800ml) in a 2L reactor with a reflux condenser and nitrogen inlet. Triethyl phosphite (114.05g) was added to the solution at 70 ℃. + -. 2 ℃ over 10 minutes. The resulting mixture was heated and refluxed (76-78 ℃ C.), and held for 2 hours. Monitoring by TLC (CHCl)₃100/acetone 2/acetic acid 1) showed the reaction was complete. The solvent was removed under vacuum (30 mbar, 40 ℃) to give a black oil (180 g). Water (400ml) was added to the mixture, which was subjected to extraction with ethyl acetate (400 and 160 ml). The organic phase is extracted with 850ml of water (pH < 10; 9.5) containing NaOH. The aqueous phase was separated and extracted with ethyl acetate (3X 240 ml). The aqueous phase was acidified (78ml of 6N HCl) at 5 ℃. + -. 2 ℃ to 1 < pH < 2, resulting in the crystallization of the yellow product, filtered and dried (40 ℃, 30 mbar, 12 hours) to yield 65.56g (90% yield) of 2, 1, 3-benzoxadiazole-5-carboxylic acid: melting point (mp) 160-,¹H NMR(300MHz，DMSO)δ13.8(s，1H)；8.57(s，1H)；8.56(d，1H，J＝0.6Hz)；7.87ppm(d，1H，J＝0.6Hz)。

intermediate 2

2, 1, 3-benzoxadiazole-5-carbonyl chloride

2, 1, 3-benzoxadiazole-5-carboxylic acid (28g) is suspended in toluene (245ml) in a 500ml reactor equipped with mechanical stirrer, thermometer, addition funnel, reflux condenser and nitrogen inlet. To the suspension was added thionyl chloride (39.4g) and DMF (0.35 ml). The resulting mixture was heated to reflux and held for 3 hours. Short pass columns (short pass column) were installed and toluene was distilled off (atmospheric pressure, 124ml) to remove excess reagent. After cooling, the remaining toluene was distilled off to give a viscous oil. The oil was distilled (90 ℃, 2mm Hg) to remove impurities and the product crystallized on standing (79.8% yield): melting point: 55-58 ℃.

Example 1

8-azabicyclo [3.2.1] oct-8-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanones

To a solution of tropane (2.5g, 20mmol) in toluene (80ml) was added chloroformic acid- [2, 2] slowly]-trichloroethyl ([2, 2)]-trichloroethyl chloride) (20ml, 94.4mmol) and Na₂CO₃(1.5g, 14 mmol). The mixture was heated to 110 ℃ overnight. The mixture was cooled to room temperature, and ethyl acetate (150ml), water (100ml) and H were added₂SO₄(reach a pH of 2(→ pH 2)). The organic phase was dried over sodium sulfate and concentrated in vacuo to give 9.3g of a colorless oil. The aforementioned product (3.3g) was dissolved in THF (tetrahydrofuran) (50ml) and methanol (50ml), and freshly prepared Zn/Cu (15g) was added followed by formic acid (5 ml). The mixture was stirred at room temperature for 20 minutes, then the solid was filtered and the solvent was evaporated to leave about 10 ml. Concentrated sodium hydroxide solution was added until the pH reached 10, the mixture was extracted with chloroform (100ml) and the organic phase was dried over sodium sulfate. Triethylamine (2ml) was added followed by slow addition of [2, 1, 3]]A solution of benzoxadiazole-5-carbonyl chloride (0.5g, 2.73mmol) in chloroform (20 ml). After stirring the mixture for 20 minutes, water (100ml) and H were added₂SO₄To a pH of 2(→ pH 2), the aqueous phase was extracted with chloroform (100ml) and dried over magnesium sulphate and concentrated under vacuum to give an oil. The material was purified by chromatography on silica gel eluting with hexane/ethyl acetate (3: 2) and then crystallized from dichloromethane/MTBE (methyl tert-butyl ether) to give 133mg of a white solid: melting point of 128-⁺＝258；¹H NMR(300MHz，CDCl₃)δ7.92(s，1H)；7.90(d，1H，J＝6.3Hz)；7.52(d，1H，J＝6.3Hz)；4.84(s，1H)；4.06(s，1H)；2.06-1.50ppm(m，10H)。

Example 2

8- ([2, 1, 3] -benzoxadiazol-5-ylcarbonyl) -8-azabicyclo [3.2.1] oct-3-one

To a solution of tropinone (10g, 71.8mmol) in toluene (120ml) was added chloroformic acid- [2, 2] slowly]-trichloroethyl ester (40ml, 189mmol) and sodium carbonate (4.0g, 37.7 mmol). The mixture was heated to 110 ℃ for 42 hours, the solvent evaporated and water (100ml) and H added₂SO₄To a pH of 2(→ pH 2) and the mixture was extracted with ethyl acetate (3 × 100 ml). The organic phase was dried over sodium sulfate, concentrated in vacuo and the residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate (4: 1) to give an oil (12.9g) which solidified on standing. To a solution of this product (2.5g) in THF (40ml) and methanol (40ml) was added the freshly prepared Zn/Cu (12g) and the mixture was stirred at room temperature for 1 hour. Triethylamine (3ml) was added and the solid was filtered off and washed with methanol (10ml) and the solvent evaporated. The residue was dissolved in chloroform (80ml), triethylamine (3ml) was added, followed by slow addition of [2, 1, 3]]A solution of benzoxadiazole-5-carbonyl chloride (1.5g, 8.2mmol) in chloroform (20 ml). After stirring the mixture for 1 hour, water (100ml) and H were added₂SO₄To a pH of 2(→ pH 2) and the aqueous phase was extracted with chloroform (100 ml). The combined organics were washed with NaHCO₃The solution (100ml) was washed, dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate (1: 1) and then crystallized from dichloromethane/MTB to give a solid (1.04 g): melting point 164-⁺＝272；¹H NMR(300MHz，CDCl₃)δ8.02(s，1H)；7.97(d，1H，J＝9Hz)；7.57(d，1H，J＝9Hz)；5.09(sb，1H)；4.44(sb，1H)；3.05-1.80ppm(m，8H)。

Example 3 and example 4

[2, 1, 3] -benzoxadiazol-5-yl (3, 3-difluoro-8-azabicyclo [3.2.1] oct-8-yl) methanone, and

[2, 1, 3] -benzoxadiazol-5-yl (3-fluoro-8-azabicyclo [3.2.1] oct-2-en-8-yl) methanone

To 8- ([2, 1, 3)]-benzoxadiazol-5-ylcarbonyl) -8-azabicyclo [3.2.1]To a solution of oct-3-one (0.67g, 2.45mmol) in dichloromethane (25ml) was slowly added diethylaminosulfur trifluoride ("DAST") (5 g). The mixture was stirred at room temperature for 3 days, then NaHCO was slowly poured in₃Solution (100ml) and chloroform (100 ml). The aqueous phase was extracted with chloroform (100ml) and the combined organics were dried over sodium sulfate, concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with hexane/ethyl acetate (65: 35) and then crystallized with dichloromethane/MTBE to give [2, 1, 3]-Benzooxadiazol-5-yl (3, 3-difluoro-8-azabicyclo [ 3.2.1)]Oct-8-yl) methanone (0.37g), the less polar of 2 products, melting point 165-⁺＝294；¹H NMR(300MHz，CDCl₃)δ7.96-7.93(m，2H)；7.54-7.50(m，1H)；5.00(sb，1H)；4.26(sb，1H)；2.60-2.05ppm(m，8H)。

The other more polar product was identified as [2, 1, 3]]-Benzooxadiazol-5-yl (3-fluoro-8-azabicyclo [ 3.2.1)]Oct-2-en-8-yl) methanone and crystallization from dichloromethane/MTBE gave (0.06 g): melting point 133-⁺＝274；¹H NMR(300MHz，CDCl₃)δ8.00-7.87(m，2H)；7.53(d，1H，J＝8.7Hz)；5.70-5.45(m，1H)；5.05(sb，1H)；4.31(sb，1H)；3.23-1.45ppm(m，6H)。

Example 5

Endo- [2, 1, 3] -benzoxadiazol-5-yl (3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl) methanones

To a solution of tropine (4.0g, 28.3mmol) in toluene (50ml) was added chloroformic acid- [2, 2] slowly]-trichloroethyl ester (16ml, 75.5mmol) and Na₂CO₃(4.0g, 37.7 mmol). The mixture was heated to 110 ℃ for 42H, toluene removed under vacuum, water (150ml) and H were added₂SO₄To a pH of 2(→ pH 2) and the mixture was extracted with ethyl acetate (2 × 100 ml). The combined organics were dried over sodium sulfate, concentrated in vacuo and the residue was purified by silica gel chromatography with hexane/ethyl acetate (70: 30) → (40: 60) to give a white solid (6.0 g). Freshly prepared Zn/Cu (15g) was added to a solution of the above product (2.5g, 8.26mmol) in TMF (50ml) and methanol (50ml) and the mixture stirred at room temperature for 18 hours. The solid was filtered off, the solvent was evaporated and the residue was dissolved in DMF (60ml) and DMAP (dimethylaminopyridine) (0.98g, 8mmol), HOBT (1-hydroxybenzotriazole) (0.54g, 4mmol), triethylamine (2ml), [2, 1, 3]-benzoxadiazole-5-carboxylic acid (1.31g, 8mmol) and EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) (3g, 15.6mmol), and the mixture was stirred at room temperature for 2 days. DMF was evaporated and water (100ml) and H were added₂SO₄To a pH of 2(→ pH 2). The mixture was extracted with chloroform (2X 100ml) and NaHCO₃The combined organics were washed with solution (100ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with THF/chloroform (15: 85 → 25: 75) and then crystallized from THF/chloroform/MTBE to give a white solid (1.25 g): melting point of 169 ℃ and 171 ℃, LC-MS, MH⁺＝274；¹H NMR(300MHz，CDCl₃)δ7.94-7.88(m，2H)；7.54-7.47(m，1H)；4.83(sb，1H)；4.25(sb，1H)；4.09(sb，1H)；2.40-1.80ppm(m，8H)。

Example 6

Exo- [2, 1, 3] -benzoxadiazol-5-yl (3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl) methanones

Inward-8- ([2, 1, 3)]-benzoxadiazol-5-ylcarbonyl) -8-azabicyclo [3.2.1]Octan-3-ol (endo-8- ([2, 1, 3)]-benzoxadiazol-5-ylcarbonyl)-8-azabicyclo[3.2.1]To a solution of octan-3-ol) (0.27g, 0.98mmol) in dry THF (10ml) was added a solution of 4-nitrobenzoic acid (0.33g, 2mmol), triphenylphosphine (0.52g, 2mmol) and diisopropyl azodicarboxylate (0.4g) in THF (1 ml). The mixture was stirred at room temperature overnight and NaHCO was added₃The solution (50ml) was extracted with ethyl acetate (2X 100 ml). The organics were dried over sodium sulfate, concentrated in vacuo and the residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (1: 1) to give a white solid (0.45 g). The previous product was suspended in dry methanol (70ml), a solution of sodium (0.2g) in dry methanol (50ml) was added, the mixture was stirred at room temperature for 0.75 h before adding concentrated HCl (0.5ml) to pH 3(→ pH 3), and the solvent was evaporated off in vacuo. The crude product was purified by chromatography on silica gel eluting with THF/chloroform (30: 70) followed by crystallization from chloroform/MTBE to give exo- [2, 1, 3]-Benzooxadiazol-5-yl (3-hydroxy-8-azabicyclo [ 3.2.1)]Oct-8-yl) methanone (0.11 g): melting point 176-⁺＝274；¹H NMR(300MHz，CDCl₃) δ 7.94-7.90(m, 2H); 7.21(dd, 1H, J ═ 9.3 and 1.2 Hz); 4.88(sb, 1H); 4.30-4.10(m, 2H); 4.09(sb, 1H); 2.20-1.50ppm (m, 8H).

Example 7

2-azabicyclo [2.2.1] hept-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanones

To 2-azabicyclo [2.2.1]To a solution of hept-5-en-3-one in THF (30ml) and dichloromethane (30ml) was added 10% Pd/C (0.25g), and the mixture was hydrogenated at room temperature for 18 hours. The solid was filtered off, the solvent was evaporated off in vacuo, the residue was dissolved in THF (60ml) and lithium aluminium hydride (2g) was added slowly. The mixture was refluxed for 1 hour and cooled to +5 ℃ before addition of hexane (60ml) and concentrated sodium hydroxide solution (4 ml). Celite (2g) was added and the mixture was stirred for 1 hour before filtering the solid and washing with THF (10 ml). Triethylamine (3ml) and [2, 1, 3] were added to the mixture]A solution of benzoxadiazole-5-carbonyl chloride (2g, 11.0mmol) in dichloromethane (10ml) and the mixture was stirred overnight. Water (100ml) was added, acidified to pH 2 with sulphuric acid and extracted with ethyl acetate (2X 100 ml). The combined organics were washed with saturated sodium bicarbonate solution (100ml) and with NaSO₄Drying, evaporation on silica gel (5g) and purification of the residue by column chromatography on silica gel with ethyl acetate/hexane (1: 1) → (3: 1) → (1: 0), followed by crystallisation from MTBE/hexane gave the desired product as white crystals (0.28 g): melting point 92-93 deg.C, LC-MS, MH⁺＝244；¹H NMR(300MHz，CDCl₃Rotamers) δ 7.93-7.87(m, 2H), 7.59-7.54(m, 1H), 4.79 and 4.17(s, total 1H), 3.61 and 3.48(m, total 1H), 3.28 and 3.08(dd, J ═ 9.3 and 1.5Hz, total 1H), 2.74 and 2.64(s, total 1H), 1.90-1.47ppm (m, 6H).

Example 8

1-azabicyclo [2.2.1] hept-1-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanones

Synthesis of 1-azabicyclo [2.2.1] ring by the method described in example 7]Heptane (org. Lett (organic Communication), 2001, 3(9), 1371-]-benzoxadiazole-5-carbonyl chloride to prepare the title compound. The compound was isolated as a white crystalline solid: melting point 143-⁺＝244；¹H NMR(300MHz，CDCl₃) δ 8.00(dd, J ═ 1.2 and 1.2Hz, 1H), 7.90(dd, J ═ 9.3 and 1.2Hz, 1H), 7.59(dd, J ═ 1.2 and 9.3Hz, 1H), 4.80(br s, 1H), 4.16(br s, 1H), 2.08-1.80(m, 4H), 1.64-1.50ppm (m, 4H).

Example 9

2-azabicyclo [2.2.2] oct-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanones

Cis-4-Aminocyclohexanecarboxylic acid (Cis-4-aminoheterocyclic carboxylic acid) (2.0g, 13.96mmol) in the flask was heated for 15 minutes with an air heating gun. After cooling to room temperature, THF (70ml) and lithium aluminium hydride (4g) were added slowly and in portions, and the mixture was heated at 65 ℃ for 1 hour. The mixture was cooled and hexane (70ml) and sodium hydroxide solution (5ml) were added with rapid stirring. Diatomaceous earth (5g) was added to the mixture and stirred overnight. The solid was removed by filtration and washed with THF (10 ml). Triethylamine (4ml) was added followed by [2, 1, 3]]A solution of benzoxadiazole-5-carbonyl chloride (2.0g, 10.95mmol) in dichloromethane (15ml) and the mixture was stirred at room temperature for 0.3 hours. After addition of water (100ml) and acidification to pH 2 with sulfuric acid, extraction was carried out with ethyl acetate (2X 100 ml). The combined organics were washed with saturated sodium bicarbonate solution (100ml) and dried (NaSO)₄) And evaporated under vacuum. The residue was purified by chromatography on silica gel, washing with ethyl acetate/dichloromethane/hexane (40: 10: 50)To obtain the desired product as a white solid (2.14 g): melting point 138-⁺＝258；¹HNMR(300MHz，CDCl₃Rotamers) δ 7.91(dd, J ═ 1.2 and 9.3Hz, 1H), 7.90 and 7.83(dd, J ═ 1.2 and 1.2Hz, total 1H), 7.51 and 7.46(dd, J ═ 1.2 and 9.3Hz, total 1H), 4.58 and 3.42(br s, total 1H), 3.68-2.64(m, 2H), 2.12-1.61ppm (m, 9H).

Example 10

[2, 1, 3] -benzoxadiazol-5-yl (2-oxa-5-azabicyclo [2.2.1] hept-5-yl) methanone

By the method described in example 7, starting from 2-aza-5-oxabicyclo [2.2.1]Heptane (2-aza-5-oxabicylo [2.2.1]]heptane) and [2, 1, 3]-benzoxadiazole-5-carbonyl chloride to prepare the title compound: melting point 102-⁺＝246；¹H NMR(300MHz，CDCl₃) δ 7.98-7.90(m, 2H), 7.58(dd, J ═ 1.2 and 9.3Hz, 1H), 5.08 and 4.78(s, total 1H), 4.66 and 4.47(s, total 1H), 4.05(m, 1H), 3.89(m, 1H), 3.73-3.63(m, 1H), 3.52(s, 1H), 2.06-1.95ppm (m, 2H).

Example 11

2-azabicyclo [2.2.1] hept-5-en-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanones

From 2-azabicyclo [2.2.1]Hept-5-en-3-one prepared by reacting with LiAlH₄Reduction is carried out and the 2-azabicyclo [2.2.1] obtained is subsequently]Hept-5-ene the procedure described in example 7 was followed with [2, 1, 3]]Coupling of-benzoxadiazole-5-carbonyl chloride. The title product was isolated as a white solid after crystallization from MTBE/hexane: melting point 106 ℃ and 108 ℃, LC-MS, MH⁺＝242.25；¹H NMR(300MHz，CDCl₃Rotamers) δ 7.98-7.86(m, 2H), 7.58-7.53(m, 1H), 6.60-6.50(m, 1H), 6.36-6.32(m, 1H), 5.25 and 4.57(s, total 1H), 3.67-3.62(m, 1H), 3.39 and 3.32(s, total 1H), 3.03 and 2.70 (both d, J ═ 10.2 and 8.7Hz, respectively, total 1H), 1.75ppm (s, 2H).

Example 12 and example 13

R-2-azabicyclo [2.2.1] hept-5-en-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone, and

s-2-azabicyclo [2.2.1] hept-5-en-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanones

The title compound was prepared from (R) -2-azabicyclo [2.2.1] hept-5-en-3-one and (S) -2-azabicyclo [2.2.1] hept-5-en-3-one using the procedure described in example 11.

R-2-azabicyclo [2.2.1] hept-5-en-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone: melting point 104-;

s-2-azabicyclo [2.2.1] hept-5-en-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone: melting point 104-.

Example 14

[2, 1, 3] -benzoxadiazol-5-yl (5, 6-dichloro-2-azabicyclo [2.2.1] hept-2-yl) methanone

At room temperatureConcentrated HCl (3ml) was added to a rapidly stirred mixture of bleach (20ml) in dichloromethane. The mixture is added to a stirred 2-azabicyclo [2.2.1] ring]Hept-5-en-2-yl ([2, 1, 3)]-benzoxadiazol-5-yl) (0.5g, 2.07mmol) in dichloromethane (50 ml). The mixture was evaporated and the residue was purified by silica gel chromatography, eluting with ethyl acetate/hexane (2: 3) and then crystallized from dichloromethane/MTBE to give the title compound as a white solid: melting point of 156-⁺＝312.16；¹H NMR(300MHz，CDCl₃Rotamers) delta 8.02-7.95(m, 2H), 7.52(dd, J ═ 1.1 and 9.2Hz, 1H), 4.89 and 4.29(s, total 1H), 4.24-4.15(m, 2H), 3.72-2.404.57 ppm (m, 5H).

Biological methods

Example 15

In vivo electrophysiology

The electrophysiological effects of the compounds of the invention were tested in anesthetized animals according to the following procedures.

Animals were kept anesthetized with phenobarbital via a hamilton syringe pump. Stimulation and recording electrodes were inserted into the fenestrated fibers and the hippocampal dentate gyrus, respectively. Once the electrodes were implanted, monophasic pulses (pulse duration 100 microseconds) were delivered to the stimulation electrodes at a frequency of 3 times/min to detect a stable baseline resulting from the evoked response. The field EPSP was monitored until a stable baseline was obtained (about 20-30 minutes), then a solution of the test compound was injected intraperitoneally and evoked field potentials were recorded. Evoked potentials were recorded continuously for about 2 hours after dosing or until the field EPSP amplitude returned to baseline. In the latter case, it is also usual to administer the same test compound by intravenous injection at a suitable dose.

Example 2

Inhibition of dextroamphetamine-stimulated activity

Male CD1 mice, weighing 25-30gm, were placed in the laboratory and allowed to acclimate for at least 30 minutes. Each mouse was placed in a test pen with an array of infrared beams that automatically monitored animal activity. Mice were habituated in the test pens for 20 minutes and then placed back in their home cages. Mice were given intraperitoneally test compound in a suitable vehicle and 5 minutes later injected with dextroamphetamine. The mice were tested for voluntary activity 10 minutes after the injection of dextroamphetamine for a total of 15 minutes. Data were collected by computer and expressed as "random motion units". All data were analyzed by comparing the groups treated with the test compound with the control group with vehicle. Data analysis was performed by analysis of variance (ANOVA) followed by the dunnett test (Dunnet's t-test), where significant differences were considered to exist when P was less than 0.05.

While the invention has been described with reference to specific methods and embodiments, it will be appreciated that various changes can be made without departing from the spirit of the invention.

Claims (15)

1. Use of a compound for the manufacture of a medicament for treating respiratory depression in a patient in need of treatment, wherein the compound is a substance having a chemical structure according to formula a:

wherein:

w is oxygen, sulfur or CH ═ CH;

x, Y and Z are independently selected from the group consisting of-N or-CR,

wherein:

r is H, -Br, -Cl, -F, -CN, -NO₂、-OR¹、-SR¹、-NR¹ ₂、-C₁-C₆Unsubstituted or substituted branched or unbranched alkyl,

wherein:

R¹is H, -C₁-C₆Unsubstituted or substituted branched or unbranched alkyl,

n is 0, 1, 2, 3,4, 5;

m is 0, 1, 2, 3,4, 5;

p is 0, 1, 2, 3,4, 5;

R²and R³Each independently selected from H, halogen (preferably F), -CN, -NO₂、-OR¹、-SR¹、-NR¹ ₂、CF₃、OH、C＝O、-C₁-C₆Unsubstituted or substituted branched or unbranched alkyl, -C₂-C₆Unsubstituted or substituted branched or unbranched alkenyl, -C₂-C₆Unsubstituted or substituted, branched or unbranched alkynyl, -C₃-C₇Unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted carboxyalkyl, unsubstituted or substituted carboxyaryl, unsubstituted or substituted carboxyheteroaryl, unsubstituted or substituted sulfonylalkyl, unsubstituted or substituted sulfonylaryl, or unsubstituted or substituted sulfonylheteroaryl;

e and F are each independently selected from CH₂m、CR²R³、A、CH₂A、CR²＝CR³Or absent, provided that E and F are not both absent;

g is CR²R³、A、CH₂A、CR²＝CR³、CH₂C＝O、CH₂CR²R³Or is absent;

a is O, S, SO₂C ═ O or CR²R³。

2. The use of claim 1, wherein the compound is a substance having a chemical structure according to formula I or a pharmaceutically acceptable salt, solvate or polymorph thereof:

wherein the content of the first and second substances,

w is oxygen, sulfur or CH ═ CH;

x, Y and Z are independently selected from the group consisting of-N or-CR,

wherein:

r is H, -Br, -Cl, -F, -CN, -NO₂、-OR¹、-SR¹、-NR¹ ₂、-C₁-C₆Unsubstituted or substituted branched or unbranched alkyl,

wherein:

R¹is H, -C₁-C₆Unsubstituted or substituted branched or unbranched alkyl,

n is a number of 0 to 5,

m is 0 to 5, and m is,

p is 0 to 5, and the compound has the structure of,

R²and R³Each independently selected from H, halogen (preferably F), -CN, -NO₂、-OR¹、-SR¹、-NR¹ ₂、CF₃、OH、C＝O、-C₁-C₆Unsubstituted or substituted branched or unbranched alkyl, -C₂-C₆Unsubstituted or substituted branched or unbranched alkenyl, -C₂-C₆Unsubstituted or substituted, branched or unbranched alkynyl, -C₃-C₇Unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted carboxyalkyl, unsubstituted or substituted carboxyarylSubstituted or substituted carboxyheteroaryl, unsubstituted or substituted sulfonylalkyl, unsubstituted or substituted sulfonylaryl, or unsubstituted or substituted sulfonylheteroaryl.

3. The use of claim 1, wherein the compound is a substance having a chemical structure represented by formula II or a pharmaceutically acceptable salt, solvate or polymorph thereof:

wherein:

w, X, Y and Z are as defined in formula I of claim 1;

n is a number of 0 to 5,

m is 0 to 5, and m is,

p is a number of 0 to 4,

and R is²And R³As defined in formula a.

4. The use of claim 1, wherein the compound is a substance having a chemical structure according to formula III:

wherein:

w, X, Y and Z are as defined in formula I;

a is O, S, SO₂C ═ O or CR²R³；

n is a number of 0 to 5,

m is 1 to 5, and m is,

p is 0 to 5, and the compound has the structure of,

and R is²And R³The same as defined in formula a of claim 1.

5. The use of claim 1, wherein the compound is a substance having a chemical structure according to formula IV:

wherein:

w, X, Y and Z are as defined in formula I;

a is O, S, SO₂C ═ O or CR²R³；

n is 1 to 5, and n is a hydrogen atom,

m is 1 to 5, and m is,

p is 0 to 5, and the compound has the structure of,

and R is²And R³As defined in formula a.

6. The use according to claim 1, wherein,

w is O;

x, Y and Z is CR;

r is H, F, Br, Cl, CN or NO₂；

E is CH₂m or CH₂A；

F is CH₂m or CR²R³；

R²And R³Is H;

g is CH₂A；

A is O;

m is 1;

n is 0; and

p is 1.

7. The use according to claim 1, wherein,

w is O;

x, Y and Z is CR;

r is H;

e and F are CH₂m；

G is CH₂A；

A is O;

m is 1;

n is 0; and

p is 1.

8. The use according to claim 1, wherein,

w is O;

x, Y and Z is CR;

r is H;

e is CH₂A；

F is CH₂m；

G is CH₂A；

A is O;

m is 1;

n is 0; and

p is 1.

9. Use according to claim 1, wherein

W is O;

x, Y and Z is CR;

r is H;

e is CH₂m；

F is CR²R³；

R²And R³Is H;

g is CH₂A；

A is O;

m is 2;

n is 0; and

p is 1.

10. Use according to claim 1, wherein the compound is:

8-azabicyclo [3.2.1] oct-8-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone,

8- ([2, 1, 3] -benzoxadiazol-5-ylcarbonyl) -8-azabicyclo [3.2.1] oct-3-one,

[2, 1, 3] -benzoxadiazol-5-yl (3, 3-difluoro-8-azabicyclo [3.2.1] oct-8-yl) methanone,

endo- [2, 1, 3] -benzoxadiazol-5-yl (3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl) methanone,

exo- [2, 1, 3] -benzoxadiazol-5-yl (3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl) methanone,

2-azabicyclo [2.2.1] hept-2-yl ([2, 1, 3-benzoxadiazol-5-yl) methanone,

1-azabicyclo [2.2.1] hept-1-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone,

2-azabicyclo [2.2.2] oct-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone, or

[2, 1, 3] -benzoxadiazol-5-yl (5, 6-dichloro-2-azabicyclo [2.2.1] hept-2-yl) methanone.

11. Use according to claim 1, wherein the compound is:

[2, 1, 3] -benzoxadiazol-5-yl (3-fluoro-8-azabicyclo [3.2.1] oct-2-en-8-yl) methanone,

2-azabicyclo [2.2.1] hept-5-en-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone,

r-2-azabicyclo [2.2.1] hept-5-en-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone, or

S-2-azabicyclo [2.2.1] hept-5-en-2-yl ([2, 1, 3] -benzoxadiazol-5-yl) methanone.

12. Use according to claim 1, wherein the compound is:

[2, 1, 3] -benzoxadiazol-5-yl (2-oxa-5-azabicyclo [2.2.1] hept-5-yl) methanone.

13. The use of any one of claims 1 to 12 wherein the compound is used in combination with an opiate or opioid analgesic.

14. The use of any one of claims 1-12, wherein the compound is used in combination with an anesthetic.

15. The use of claim 14, wherein the anesthetic is propofol or barbiturate.