MXPA00009480A - Acylbenzoxazines for enhancing synaptic response(s) - Google Patents

Abstract

Compounds based on the benzoxazine ring system that are remarkably more potent than corresponding benzoyl piperidines for enhancing synaptic responses mediated by AMPA receptors are disclosed, as are methods for the preparation thereof, and methods for their use for treatment of subjects suffering from impaired nervous or intellectual functioning due to deficiencies in the number of excitatory synapses or in the number of AMPA receptors. The invention compounds can also be used for the treatment of non-impaired subjects for enhancing performance in sensory-motor and cognitive tasks which depend on brain networks utilizing AMPA receptors and for improving memory encoding.

Description

ACILBENZOXAZINAS TO IMPROVE THE SYNAPTIC RESPONSE OR FIELD OF THE INVENTION This invention relates to the prevention and treatment of cerebral insufficiency, including the improvement of receptor function in the synapses in the brain networks, responsible for the highest order behaviors. In a particular aspect, the invention relates to methods for the use of the compounds described herein, and methods for the preparation thereof.

BACKGROUND OF THE INVENTION The release of glutamate at the synapse in many sites in the mammal forebrain stimulates two classes of post-synaptic ionotropic receptors. These classes are usually referred to as AMPA / quisqualate and N-methyl-D-aspartic acid (NMDA) receptors. The AMPA / quisqualate receptors are mediators of a fast, excitatory post-synaptic current independent of the Fte_: 122984 voltage (the fast epsc), while the NMDA receivers generate a slow, voltage-dependent excitatory current. Studies carried out on slices of hippocampus or cortex indicate that the rapid epsc mediated by AMPA receptor is by far the dominant component in most glutamatergic synapses under most circumstances. AMPA receptors are not evenly distributed throughout the brain, but rather are largely restricted to the telencephalon and the cerebellum. These receptors are found in high concentrations in the superficial layers of the neocortex, in each of the major synaptic areas of the hippocampus, and in the striatum complex, as reported by Monaghan et al., In Brai n Res earch 324: 160-164 (1984) . Studies in animals and humans indicate that these structures organize complex perceptual-motor processes, and provide the substrates for the highest order behaviors. In this way, AMPA receptors are mediators of transmission in those brain networks responsible for the cognitive activities of a host.

For the reasons described above, drugs that improve the functioning of AMPA receptors could have significant benefits on cognitive functioning. Such drugs could also facilitate the coding of memory. Experimental studies, such as those reported by Arai and Lynch, Bra in Resea rch, 598: 173-184 (1992), indicate that the increase in the size of the or of the synaptic responses mediated by the AMPA receptor, improves induction of long-term empowerment (LTP). LTP is a stable increase in the strength of synaptic contacts that follows the repetitive physiological activity of a known type, which occurs in the brain during learning. Compounds that improve the functioning of the AMPA form of glutamate receptors facilitate the induction of LTP and the acquisition of learned tasks, as measured by a number of paradigms. Granger et al., Synapse 15: 326-329 (1993); Staubli et al., PNAS 91: 777-781 (1994); Arai et al., Bra i n Res, 638: 343-346 (1994); Staubli et al., PNAS 91: 11158-1162 (1994); Shors et al., Neuros ci. Le t. 186: 153-156 (1995); Larson et al., J. Neuros ci. 15: 8023-8030 (1995); Granger et al., Synapse 22: 332-337 (1996); Arai, et al., JPET 278: 627-638 (1996); 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); Hampson et al., J. Neurosci. , 18: 2740-2747 (1998); Hampson, et al., J. Neurosci. 18: 2748-2763 (1998) and International Patent Application Publication No. WO 94/02475 (PCT / US 93/06916) (Lynch and Rogers, Rectors of the University of California). There is a considerable body of evidence showing that LTP is the substrate of memory. For example, compounds that block LTP interfere with memory formation in animals, and certain drugs that interrupt learning in humans antagonize the stabilization of LTP as reported by del Cerro and Lynch, Neuroscience 49: 1-6 (1992). A possible prototype for a compound that selectively facilitates the AMPA receptor was described by Ito et al., J. Physiol. 24: 533-543 (1990). These authors found that the nootropic drug aniracetam (N-anisole-2-pyrrolidinone) increases currents mediated by cerebral AMPA receptors expressed in Xenopus oocytes without affecting the response by α-aminobutyric acid (GABA), kainic acid (KA) ), c NMDA receptors. The infusion of aniracetam into hippocampal slices was also shown to substantially increase the size of the fast synaptic potentials without altering the remaining membrane properties. It has been confirmed since then that aniracetam improves synaptic responses at several sites in the hippocampus, and that it has no effect on the potentials mediated by the NMDA receptor. See for example, Staubli et al., In Psych obi olgy 18: 377-381 (1990) and Xiao et al., Hippocampus 1: 373-380 (1991). It has also been found that aniracetam has an extremely rapid onset and wash and can be applied repeatedly without apparent lasting effects; there are valuable traits for behaviorally relevant drugs. Unfortunately, the peripheral administration of aniracetam is not likely to influence brain receptors. The drug works only at high concentrations (~ 1.0 mM) and Guenzi and Zenetti, J. Chroma t ogr. 530: 397-406 (1990) report that approximately 80% of the drug is hydrolyzed to anisole-GABA after peripheral administration in humans. The metabolite, anisole-GABA, has been found to have only weak effects similar to aniracetam. A class of compounds that does not show the low potency and inherent hydrolytic instability characteristic of aniracetam has been recently described. These compounds, referred to as "Ampacines", are described in International Patent Application Publication No. WO 94/02475 (PCT / US 93/06916) (Lynch and Rogers, Rectors of the University of California). Ampacines are generally substituted benzamides, are chemically more acceptable than aniracetam, and show improved bioavailability as judged by the experiments performed by Positron Emission Tomography (PET) [see for example, Staubli et al., In PNAS 91 : 11158-11162 (1994JJ) Additional ampacins in the form of benzoylpiperidms and pyrrolidines have also been discovered and are the subject of United States Patent Application No. 08 / 458,957, filed on June 2, 1995. A new The class of ampacins, the benzoxaxins, have recently been discovered as having unexpectedly high activity in in vi tro ein vi ve models to assess the likelihood of production of improved cognition [Rogers and Lynch "Benzoxázinas to Improve the Synaptic Responses", the U.S. Patent No. 5,736,543, issued April 7, 1998. The further development of structure-activity has discovered a series new compounds, acylbenzoxazines, which produce potent responses in assays of AMPA receptor activation, and show significantly improved biostability compared to isomeric benzoxazines. These compounds are described herein.

BRIEF DESCRIPTION OF THE INVENTION It has now been discovered that the synaptic responses mediated by AMPA receptors are increased by the administration of a novel class of derivatives of acylbenzoxazine. The ability of the novel compounds of the invention to increase the responses mediated by the AMPA receptor, makes the compounds useful in serving a variety of purposes, including facilitating the learning of the AMPA receptor dependent behaviors, and as therapeutic drugs under conditions in which AMPA receptors or synapses using these receptors are reduced in number or efficiency, or in those circumstances when the increased excitatory synaptic activity may be beneficial. It has been unexpectedly discovered that the compounds of the present invention demonstrate increased bioavailability and increased metabolic stability compared to the prior art compounds. In addition, the compounds of the present invention, which were originally thought to be completely inactive or show significantly reduced activity compared to the prior art compounds, unexpectedly showed increased activity compared to the prior art compounds. The following examples demonstrate that the compounds of the invention possess surprising biological activity, as evidenced by their ability to increase the function of the AMPA receptor in rat hippocampal slices, by being substantially more metabolically stable than ampacines. , structurally related, and promote improvement in relevant memory tasks, such as operating in an eight-armed radial labyrinth. These and other aspects and advantages of the invention will become apparent from the following description.

DETAILED DESCRIPTION OF THE INVENTION AND MODALITIES PREFERRED The compounds of the present invention are acylbenzoxazines having the following formula: wherein: R "and R" are either individual monovalent portions or linked together to form a simple divalent moiety. As monovalent portions, R * and R2 are either the same or different and are each hydrogen, CH OR ", or OR" with the proviso that at least one of R 'and R2 is not hydrogen, and in wherein R4 is either hydrogen, alkyl of 1 to 6 hydrogen atoms, fluoroalkyl of 1 to 6 carbon atoms, arylalkyl of 7 to 12 carbon atoms, or heteroarylalkyl of 3 to 10 carbon atoms, as a simple divalent moiety , R1 and Rr together form a group selected from wherein: R5 is (CR2) ^, CR? CR2, or CR = CR, R is hydrogen, halogen, cyano, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, arylalkyl of 7 to 12 carbon atoms, or heteroarylalkyl of 3 to 10 carbon atoms and is either the same or different in any R5; R ° is hydrogen, cyano, OH, alkyl of 1 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, arylalkyl of 7 to 12 carbon atoms, or heteroarylalkyl of 3 to 10 carbon atoms, heteroarylalkyl of 3 to 10 carbon atoms, or OR4, and R "is the same as described above: R ^ is hydrogen, alkyl of 1 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, arylalkyl of 7 to 12 carbon atoms carbon, or heteroarylalkyl of 3 to 10 carbon atoms, R is hydrogen, alkyl of 1 to 6 carbon atoms, or fluoroalkyl of 1 to 6 carbon atoms, Q is a substituted or unsubstituted lower alkylene, cycloalkyl, aryl, arylalkyl , or heteroarylalkyl, X and Y are both independently of hydrogen, or together form a covalent bond or (CH) n, which binds Q to the benzoxazine ring; m is 1 or 2; and n is 1 or 2.

The following terms will be used to describe the present invention. The term "alkyl" is used herein to include the straight chain, branched chain and cycloalkyl species. The term "fluoroalkyl" is used herein to include simple and multiple fluorine substitutions, with the 1 to 3 perfluorinated carbon portions being preferred. The term "aryl" includes the substituted and unsubstituted carbocyclic and heterocyclic aromatic species, such as phenyl, tolyl, pyridyl, imidazoyl, alkylenedioxyphenyl, etc. Thus, for those compounds in which R and R: are individual monovalent portions, the preferred compounds are those in which one of these two portions is hydrogen and the other is OR 4 wherein R 4 is either alkyl of 1 to β carbon or fluoroalkyl atoms of 1 to 3 carbon atoms, with R 4 being more preferably either alkyl of 1 to 3 carbon atoms or fluoroalkyl of 1 to 2 carbon atoms, still more preferably CH (CH 3) 2 or CF 3, and most preferably CH (CH.) 2. R3 is preferred to be hydrogen, and Q is preferred to be lower alkylene, and X and Y together form a covalent bond. The term "effective amount" or "therapeutically effective amount" is used throughout the present application to describe an amount or concentration of one or more of the compounds according to the present invention that are used to produce a desired effect or Treat a specific condition in a patient or subject. The compounds according to the present invention can be used to improve the functioning of a patient on sensory-motor problems to improve the functioning of the subjects by involving cognitive tasks dependent on brain networks using AMPA receptors, to improve the strength of the patient. memory coding or to improve brain functioning in subjects with deficiencies in the number of excitatory or AMPA receptor synapses. The present compounds can also be used in effective amounts to decrease the time necessary for a subject to learn a cognitive task., motor or perceptual, or to reduce the amount and / or severity of errors made by a subject in remembering a cognitive, motor or perceptual task. The present compounds are also useful for the treatment of human subjects to improve the synaptic response measured by AMPA receptors. In addition, the present compounds can be used to treat schizophrenia, schizophrenic behavior or depression in a patient or human subject. In each case, wherein the present compounds are used, they are used in effective amounts or concentrations to produce a desired effect or to treat a specific condition in a patient. The term "patient" or subject "is used throughout the specification to describe an animal, including a human, to whom the treatment or use of the compounds or compositions according to the present invention is provided. or use with / or conditions or disease states that are specific to a specific animal (especially, for example, a human subject or patient), the term patient or subject refers to that particular animal. or sensorimotor "is used to describe a problem that 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 the appropriate physical responses that involve movement and action The term "cognitive task" is used to describe an effort by a patient or subject, which involves thinking or knowing. Various ions of the parietal, temporal, and frontal lobe association cortexes, which account for approximately 75% of all human brain tissue, are responsible for much of the information processing that continues between sensory input and motor output. The various functions of association barks are often referred to as cognition, which literally means the process by which we acquire knowledge of the world. By selectively attending to a particular stimulus, the recognition and identification of these relevant stimulus characteristics and the planning and experimentation of the response are some of the processes or abilities mediated by the human brain that are related to cognition. The term "brain network" is used to describe the different anatomical regions of the brain that communicate with one another via the synaptic activity of neuronal cells. The term "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-α-amino-3-hydroxy-5-acid). methyl-4-isoxazolepropionic), but not NMDA. The term "excitatory synapse" is used to describe a cell-cell junction in which the release of a chemical messenger with one cell causes depolarization of the outer membrane of the other cell. An excitatory synapse is used to describe a post-synaptic neuron that has an inverse potential that is more positive than the threshold potential and consequently, at such a synapse, a neurotransmitter increases the likelihood that an excitatory post-synaptic potential will result (a neuron will ignite the production of an action potential). Inverse potentials and threshold potentials determine post-synaptic excitation and inhibition. If the inverse potential for a post-synaptic potential ("PSP") 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 ignition of an action potential by the neuron. If the inverse potential for a post-synaptic potential is more negative than the action potential threshold, the transmitter is inhibitory and can generate inhibitory post-synaptic potentials (IPSP), thereby reducing the likelihood that a synapse will ignite an action potential. The general rule for post-synaptic action is: If the inverse potential is more positive than the threshold, it results in excitation; inhibition occurs if the inverse potential is more negative than the threshold. See, for example, Chapter 7, NEUROSCIENCE, edited by Dale Purves, Sinauer Associates, Inc., Sunderland, MA 1997. The term "motor task" is used to describe an attempt that is taken by a patient or subject, involving movement. or action The term "perceptual task" is used to describe an act by a patient or subject, to pay attention to sensory stimuli. The term "synaptic response" is used to describe the biophysical reactions in a cell as a consequence of the release of chemical messengers by another cell with which it is in close contact. The term "schizophrenia" is used to describe a condition that is a common type of psychosis, characterized by a disorder in thought processes, such as delusions and hallucinations, and intense withdrawal of the individual's interest from other people and the outside world. , and the investment of this in itself. Schizophrenia is now considered a group of mental disorders instead of a simple entity, and the distinction is made between reactive and process schizophrenia. As used herein, the term schizophrenia or schizophrenia encompasses all types of schizophrenia, including ambulatory schizophrenia, catatonic schizophrenia, hebephrenic schizophrenia, latent schizophrenia, schizophrenia in process, pseudoneurotic schizophrenia, reactive schizophrenia, Simple schizophrenia, and related psychotic disorders that are similar to schizophrenia, but that are not necessarily diagnosed as schizophrenia per se. Schizophrenia and other psychotic disorders can be diagnosed using the guidelines established in, for example, Di agnos ti c and S ta ti sti l l Ma nual of Men t al Di sorders, 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. The term "brain function" is used to describe the combined tasks of perception, integration, filtering and response to external stimuli and internal motivational processes. The compounds of the present invention can be identified in a variety of ways, using conventional synthetic chemistry techniques. A method for the preparation of the compounds of the present invention comprises: the preparation of a benzylamine substituted with orthohydroxy, by contacting a phenol suitably substituted with hydroxymethylphthalimide in an inert solvent with a suitable catalyst such as an aryl or alkylsulfonic acid or other Lewis acid catalyst known to those skilled in the art. After the benzylic amine is released by treatment with hydrazine in ethanol, it is acylated by a suitably activated carboxylic acid to produce an amide. The ring closure to an acylbenzoxazine can be achieved by treatment with formaldehyde, or a suitably substituted higher aldehyde to give the structures of the type shown below: wherein each R1 and R2 is as defined above and may further be an aromatic, aromatic / benzylic heterocyclic carbocyclic group, any of which may have structurally diverse variable substituents. Yet another method for the preparation of the compounds of the present invention comprises contacting the benzylamine with an activated acid containing an incipient aldehyde or ketone in the form of an acetal or ketal or oxidizable alcohol. The aldehyde or ketone is generated and catalyzed by a strong acid in a low alkalinity solvent to cyclize with the amide nitrogen and phenol to give rotationally restricted structures of the type shown below: wherein each R1 and R2 is as defined above and may further be an aromatic carbocyclic, heterocyclic aromatic, or benzyl group, any of which may have structurally diverse variable substitutes. This application is related to U.S. Patent no. 5,736,543, issued April 7, 1998, and the patent application. Serial number PCT / US 93/06916, filed July 23, 1993, published as WO 94/02475 on February 3, 1994, the relevant teachings of which are incorporated by reference herein. The compounds described above can be incorporated into a variety of formulations (e.g., capsule, tablet, controlled release capsule, syrup, suppository, injectable form, transdermal patch, etc.), preferably in combination with a pharmaceutically carrier, excipient or additive. acceptable, for administration to a subject. Similarly, various modes of administration (eg, oral, buccal, rectal, parenteral, intraperitoneal, cutaneous, etc.) may be employed. The dose levels employed can vary widely, and can be readily determined by those of ordinary skill in the art. Typically, amounts in the order of milligrams up to decigrams are employed. Oral administration (one to four times a day) is clearly preferred. Due to the unexpectedly favorable bioavailability and stability of the compounds according to the present invention, they can be administered orally as little as twice or even once a day. Subjects contemplated for treatment with the compounds of the invention, include humans, domestic animals, laboratory animals, and the like. The compounds of the invention can be used, for example, as a research tool to study the biophysical and biochemical properties of the AMPA receptor and the consequences of selectively improving excitatory transmission on the operation of the neuronal circuitry. Because the compounds of the invention reach the central synapses, they will allow the testing of the behavioral effects of increasing the currents of the AMPA receptor. Stably stable compounds that are positive modulators of AMPA currents have many potential applications in humans. For example, increasing the strength of excitatory synapses could compensate for the losses of synapses or receptors associated with aging and brain disease (for example, Alzheimer's). The increase in AMPA receptors could cause faster processing by the mui-synaptic circuit assemblies found in higher brain regions, and thus could produce an increase in perceptual-cognitive functioning. As another example, because the increase in responses mediated by the AMPA receptor facilitates synaptic changes of the type that is believed to encode memory, it is expected that metabolically stable AMPA modulators are functional as memory enhancers.

Additional applications contemplated by the compounds of the present invention include the improvement of the functioning of subjects with brain-dependent sensory-motor problems using AMPA receptors.; the improvement of the functioning of the subjects, impaired in cognitive tasks dependent on the brain networks that use the AMPA receptors; the improvement of the functioning of the subjects with memory deficiencies; and similar, as previously described. Additional uses contemplated by the compounds of the present invention include correction of suboptimal communication at the level of systems between brain regions responsible for behaviors associated with psychiatric disorders such as schizophrenia. Accordingly, the compounds of the invention, in suitable formulations, can be employed to decrease the amount of time necessary to learn a cognitive, motor or perceptual task. Alternatively, the compounds of the invention, in suitable combinations, can be used to increase the time for which the cognitive, motor or perceptual tasks are conserved. As another alternative, the compounds of the invention, in suitable formulations, can be used to decrease the amount and / or severity of the errors made in remembering a cognitive, motor or perceptual task. Such treatment may prove to be especially advantageous in individuals who have suffered from damage to the nervous system, or who have endured the disease of the nervous system, especially damage or disease that affects the number of AMPA receptors in the nervous system. The compounds of the invention are administered to the affected individual, and thereafter, the individual is presented with a cognitive, motor or perceptual task. In each case, the compounds according to the present invention can be administered to a patient or a subject in need of therapy, of an effective amount of the compound. Having generally described the invention, reference is now made to the following examples, which are intended to illustrate certain preferred embodiments and comparisons. The examples included are not to be considered as limiting for the scope of this invention, as is more broadly described above and in the appended claims.

CHEMICAL SYNTHESIS Example 1 5a, 6, 7, 8-tetrahydro-l, 3-dioxolo [4, 5-g] pyrrolo [2, 1 -b] [1, 3] benzoxazin-8 (1 OH) -one P-Toluenesulfonic acid monohydrate (3.61 g, 19.0 mmol) was dehydrated by azeotropic distillation in a 100 ml solution of chloroform. The remaining solution (50 ml) was cooled, 9.14 g (66.2 mmol) of sesamol, 10.01 g (57 mmol) of N- (hydroxymethyl) -phthalimide, and 100 ml of chloroform were added, and the resulting green solution was heated to I reflux all night. The black reaction mixture was cooled to room temperature and diluted to 500 ml with chloroform, and washed three times with saturated sodium bicarbonate. The combined aqueous phases were extracted again with ethyl acetate, which was combined with the chloroform solution and dried over sodium sulfate. The residue that resulted from the evaporation of the solvents on a rotary evaporator was taken up in dichloromethane and filtered through a short column of silica gel. A dichloromethane rinse of the silica gel was combined with the eluent and evaporated to yield 9.3 g of N- (2-hydroxy-4,5-methylenedioxybenzyl) -phthalimide as a yellow solid (55%), which showed a spot on the silica gel. TLC (thin layer chromatography) (R = 0.6, dichloromethane). IR: 1768 and 1699 cm. "1 NMR 1E (200 MHz); d 7.81-7.90 (2H, m); 7.70-7.79 (2H, m); 7.76 (1H, s); 6.86 (1H, s); (1H, s), 5.88 (2H, s), and 4.73 ppm (2H, s) The N- (2-hydroxy-4, 5-ethylenedioxybenzyl) phthalimide (2.0 g, 6.7 mmol) was dissolved in 20 ml of tetrahydrofuran (THF) under argon atmosphere Sodium hydride (0.27 g, 6.78 mmol) was added in portions as a 60% dispersion in mineral oil to the stirred solution, and after 0.30 ml 0.65 ml (7.01 mmol) was added. of ethyl chloromethyl ether The mixture was allowed to stand overnight, after which additional equivalents of sodium hydride and chloromethyl ethyl ether were added and allowed to react for an additional 4 hours. in a rotary evaporator, and the residue was partitioned between water and dichloromethane.

The aqueous phase was further extracted with dichloromethane (three times) and the combined organic layers were combined and washed with 10% sodium hydroxide (three times) and with a saturated solution of brine before being dried over sodium sulfate. Evaporation of the solvent and dissolution of the resulting brown liquid in ethyl ether gave crystals, which were collected by filtration and washed with ethyl ether / petroleum ether (1: 1). The supernatant and the washing solutions were combined and additional product was isolated by chromatography on silica gel (10% -20% ethyl acetate / hexane) for a total yield of 1.70 g of N- (2-ethoxymethoxy-5). - ethylene-dioxybenzyl) phthalimide (71%). IR (thin film): 1770 and 1709 cm "1 XH NMR (200 MHz); 6 7.80-7.90 (2H, m); 7.67-7.77 (2H, m); 6.77 (2H, s); 5.88 (2H, s); 5.19 (2H, s), 4.86 (2H, s), 3.73 (2H, q, J = 7.04 Hz); and 1.21 ppm (3H, t, J = 7.15 Hz).

The N- (2-ethoxymethoxy-4,5-methylenedioxybenzyl) phthalimide (1.70 g, 4.77 mmol) was treated with 0.5 ml (16 mmol) of hydrazine in 90 ml of refluxing ethanol for three hours. The reaction mixture was cooled and the phthalhydrazide was removed by filtration and washed three times with ethyl ether. The organic solutions were combined and evaporated to dryness in a rotary evaporator to produce a residue which was taken up in dichloromethane. The organic solution was washed three times with 10% sodium hydroxide and the combined aqueous solutions were re-extracted with dichloromethane twice. The combined organic solutions were washed with brine and dried over sodium sulfate / potassium carbonate. Evaporation of the solvent gave the 2-ethoxymethoxy-, 5-methylenedioxybenziline as a slightly yellow liquid (0.98 g, 92% yield) which solidified after standing. IR: 3298 cm "1. NMR: H (200 MHz); d 6.77 (1H, s); 6.75 (1H, s); 5.91 (2H, s); 5.18 (2H, s); 3.74 (2H, q, J = 7.1 Hz); 3.73 (2H, s); 1.45 (2H, broad s); and 1.24 ppm (3H, t, J = 7.1 Hz). The 4,4-diethoxybutyric acid (716 mg, 4.06 mmol) was activated by addition to a solution of 613 mg (3.78 mmol) of carbonyldiimidazole in 10 ml of dichloromethane. The solution was stirred for 2 hours, after which a solution of 978 mg (4.35 mmol) of 2-ethoxymethoxy-, 5-methylenedioxybenzyl sheet in 15 ml of dichloromethane was added and allowed to stand for three days. The solution was washed with phosphate buffer (0.1 M, pH 6.8) three times and once with brine before being dried over sodium sulfate. Evaporation of the solvent gave 1.42 g (98% yield) of a yellow liquid. IR: 1644 cm ": NMR: H (200 MHz); d 6.78 (1H, s); 6.75 (1H, s); 5.95-6.08 (1H, broad t); 5.91 (2H, s); 5.17 (2H); , s), 4.49 (1H, t, J = 5.5 Hz), 4.34 (2H, d, J = 5.8 Hz), 3.78 - 3.89 (6H, m), 2.26 (2H, t, J = 5.8 Hz), 1.94 (2H, dt, J = 7.5 and 5.4 Hz), and 1.13-1.30 ppm (9H, t, J = 7.0 Hz) The amide / acetal (1.20 g, 3.12 mmol) from the previous step was combined with 4 ml of 2 -propanol and 200 μl of concentrated HCl in 20 ml of THF and allowed to stand at room temperature overnight The residue resulting from the evaporation of the solvents was divided between water and dichloromethane.The aqueous layer was extracted with dichloromethane three times and the combined organic fractions were washed twice with 10% hydrochloric acid, three times with 10% sodium hydroxide, and once with brine before being dried over sodium sulfate.The removal of the solvent gave an off-white solid which was purified over silica gel (20% ethyl acetate / hexane) and crystallized from dichloromethane or ethyl ether to produce 301 mg (41%) of acylbenzoxazine with m.p. = 163-164 ° C. IR: 1697 cm "1. NMR: H (200 MHz); d 6.51 (1H, s); 6.40 (1H, s); 5.91 (2H, s); 5.31 (1H, dd, J = 5.3 and 1.6 Hz);; 4.85 (1H, d, J = 16.5 Hz), 4.20 (1H, d, J = 16.4 Hz), and 2.14 - 2.69 ppm (4H,).

Example 2 6a, 7.8, -tetrahydro-l, 4-dioxin [2, 3-g] pyrrolo [2,1-b] [1, 3] benzoxazin-9 (11H) -one The N- (hydroxymethyl) phthalimide (97.46 g, 42.1 mmol), 3,4-ethylenedioxyphenol) (96.4 g, 42.1 mmol), and the p-toluenesulfonic monohydrate acid (0.87 g, 4.6 mmol) were dissolved in 80 ml of chloroform and the mixture was heated to reflux for three days under a Dean-Stark trap with occasional water removal. The brown solution was filtered through a pad of silica, the silica pad was washed with chloroform, and the combined organic solutions were evaporated to yield a yellow solid which was purified by flash chromatography with dichloromethane as eluent. The intermediate was obtained as a yellow solid (5.8 g) composed of a mixture of isomers, which was used without further purification. The solid from the previous step (1.4 g, 4.5 mmol) was dissolved in 15 ml of tetrahydrofuran and treated with 0.7 g (7.4 mmol) of chloromethyl ethyl ether and 0.3 g (7.5 mmol) of sodium hydride (as a 60% dispersion in mineral oil) under an argon atmosphere for one hour. Water was added and the separated aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed three times with 10% sodium hydroxide and once with brine before being dried over sodium sulfate. Evaporation of the solvent gave an oil which was dissolved in ethyl ether and crystallized to yield 0.63 g (38%) of white crystals. P.f. = 97-98.5 ° C. IR: 1771 and 1709 cm "1. 5H (200 MHz); d 7.6-7.9 (4H, m); 6.70 (1H, s); 6.69 (1H, s); 5.17 (2H, s); 4.82 (2H, s); 4.18 (4H, m); 3. 71 (2H, q, J = 7.2 Hz); and 1.2 ppm (3H, t, J = 7.1 Hz). The N- (2-ethoxymethoxy-4,5-ethylenedioxybenzyl) phthalimide (625 mg, 1.69 mmol) was mixed with 0.2 ml (6.4 mmol) of hydrazine in 30 ml of ethanol and heated to reflux for three hours. The reaction mixture was cooled, 30 ml of ethyl ether was added to the mixture, and a white precipitate was removed by filtration. The filter press cake was washed three times with diethyl ether and the combined organic solutions were evaporated to yield a residue which was partitioned between ethyl ether and 10% sodium hydroxide. The organic phase was washed three times with 10% sodium hydroxide, and the aqueous washings were combined and re-extracted twice with dichloromethane. The organic solutions were combined and washed with brine and dried with sodium sulfate / potassium carbonate. Subsequent evaporation of the solvent gave 2-ethoxymethoxy-4,5-ethylenedioxybenzylamine as a light yellow oil (346 g, 86% crude), which solidified on standing. IR: 3375 cm ": The acid 4,4-diethoxybutyrate (270 mg, 1.53 mmol) was activated by the addition to a solution of 213 mg (1.31 mmol) of carbonyldiimidazole in 5 ml of dichloromethane.The solution was stirred by 30 minutes, after which a solution of 347 mg (1.45 mmol) of 2-ethoxymethoxy-4,5-ethylenedioxybenzylamine in 1 ral of dichloromethane was added and left to stand overnight.The solution was washed with phosphate buffer ( 0.1 M, pH 6.8) three times and once with brine before being dried over sodium sulfate The solution was filtered through a small pad of silica gel and evaporated to yield 436 mg (84% crude) of an oil IR: 3293 and 1644 cm "1. The amide / acetal (436 mg, 1.1 mmol) from the previous step was combined with 2 ml of 2-propanol and 100 μl of concentrated hydrochloric acid in 10 ml of tetrahydrofuran and allowed to stand at room temperature overnight. The residue resulting from evaporation of the solvents was taken up in dichloromethane and washed three times with 10% hydrochloric acid, three times with 10% sodium hydroxide, and once with brine before being dried over sodium sulfate. Removal of the solvent gave a white solid which was crystallized from dichloromethane / ethyl ether and washed twice with ethyl ether / petroleum ether to yield 123 mg (45%) of acylbenzoxazine with p.f_ = 151-152 ° C. IR: 1703 and 1689 (sh) cm "1, NMR JH (200 MHz), 6 6.58 (1H, s), 6.41 (1H, s), 5.32 (1H, dd), 4.86 (1H, d, J = 16.7 Hz), 4.22 (4H, m), 4.20 (1H, d, J = 16.3 Hz), and 2.12-2.0 ppm (4H, m).

Example 3 6a, 7, 8, 9-tetrahydro-l, 4-dioxan [2, 3-g] pyrido [2, 1-b] [1,3] benzoxazin-10 (10H, 12H) -dione Trimethylaluminum as a 2 M solution in toluene (2.3 ml, 4.6 mmol) was added to a two-necked flask under an argon atmosphere cooled to -5 to -10 ° C. 2-Ethoxymethoxy-4,5-ethylenedioxybenzylamine (1.0 g, 4.18 mmol, as a mixture of isomers) in 5 ml of anhydrous chloroform was added to the flask and the resulting solution was kept at the same temperature for 20 minutes. After the solution was allowed to warm to room temperature, 0.81 g (4.6 mmol) of methyl 5,5-dimethoxyvalerate was added and the resulting solution was heated to reflux overnight. The reaction was quenched with methanol and with phosphate buffer (0.1 M, pH 6.8) and extracted three times with dichloromethane. The combined organic phases were washed with phosphate buffer three times, once with brine, and dried over sodium sulfate. The amide was purified to a light yellow oil on silica gel with dichloromethane / ethyl ether (4: 1) as eluent, and was tested (via NMR) which was a mixture of the free and protected phenolic compounds, which was used without additional purification. IR 3279 and 1632 cm "1. The oil from the previous step was dissolved in 10 ml of tetrahydrofuran, 2 ml of 2-propanol, and 100 μl of concentrated hydrochloric acid, and allowed to stand for 24 hours. The residue was taken up in dichloromethane, which was washed three times with 10% hydrochloric acid, three times with 10% sodium hydroxide, and once with brine before being dried over sodium sulfate. white solid which was crystallized from dichloromethane / ethyl ether to produce 141 mg of the desired quantity.As the crystals of the product were heated, a transformation occurred at 147 ° C to give a new form that melts at 163 ° C. C IR: 1647 and 1639 cm "1 (unresolved doublet) .NMR (200 MHz); d 6.58 (1H, s); 6.39 (1H, s); 5.31 (1H, d, J = 16 .. Hz); 1H, t, J = 3.4 Hz), 4.22 (4H, m), 4.12 (1H, d, J = 16.7 Hz), 2.30-2.60 (2H, m), 1.00-2.20 (3H, m), and 1.70- 1.90 ppm (1H, m).

Example 4 5a, 6,7,8-tetrahydro-l, 3-dioxolo [4,5-gjpirrolo [2, l 'b] [1,3] benzoxazin-8,10 (10H) -dione 4,5-Methienedioxysalicylamide (496 mg, 2.74 mmol) was dissolved in 10 ml of trifluoroacetic acid to which 491 mg (2.79 mmol) of 4,4-diethoxybutyl acid was added. After 24 hours the reaction solution was reduced to 5 ml in a rotary evaporator and the addition of an additional 526 mg of 4,4-diethoxybutyric acid caused a white precipitate to form. The trifluoroacetic acid was removed by evaporation and the solid was in turn collected by ethyl acetate and ethanol, and again isolated by evaporation of the solvent. Finally, the solid was subjected to high vacuum. IR: 1720, 1657, 1617, 1470, 1260, and 1177 cm ": H-NMR (200 MHz, d6DMSO / CDCl3) / d 8.32 (1H, broad), 7.17 (1H, s), 6.47 (1H, s) ), 6.02 (2H, s), 5.25 (1H, t, J = 4.5 Hz), 2.48-2.6 (2H, m), and 2.06-2.2 ppm (2H, m) The intermediate acid was added to a solution of 1.09 g (6.17 mmol) of carbonyldiimidazole in 20 ml of methylene dichloride After 24 hours a white milky suspension was observed.A thin-layer chromatography (TLC) analysis suggested that some of the initial material remained and therefore were added. 474 mg of additional CDI to the suspension No further reaction was observed and the white solid was isolated by filtration and washed with dichloromethane.The UV and IR spectra indicate that this intermediate (310 mg) is the acylimidazole and is therefore suspended in 10 ml of dichloromethane and treated with 105 mg of triethylamine for 4 days, during which time the reaction solution was homogeneous.The solution was washed with hydrochloric acid. ico to 10% (3 times) and once with brine, and finally dried over sodium sulfate. Solvent removal by evaporation yielded 205.6 mg of a white solid. The solid was dissolved in trifluoroacetic acid, but no change occurred (via TLC) in a period of days. The product was re-isolated and crystallized from chloroform / diethyl ether to produce the material with m.p. = 224-225 ° C. IR: 1750 (s), 1673 (m), and 1625 (m) cm "1. NMR: H (500 MHz); d 7.4 (1H, s); (1H, s); 6.05 (2H, s); 5.77 (1H, dd, J = 5.0 and 7.1 Hz); 2.69-2.78 (1H, m); 2.53-2.64 (2H, m); and 2.29-2.39 ppm (1H, m). FAB MS: m / z = 248 (P + l).

BIOLOGICAL DATA Example 5 Physiological Test In Vi tro The physiological effects of the compounds of the invention can be tested with slices of rat hippocampus, according to the following procedure. Excitatory responses (field EPSPs) are measured in hippocampal slices, which are maintained in a recording chamber continuously perfused with artificial cerebrospinal fluid (ACSF). During an interval of 15 to 30 minutes, the perfusion medium is changed to one containing various concentrations of the test compounds. The responses collected immediately before and at the end of the drug perfusion were superimposed in order to calculate the percentage increase in the EPSP amplitude and the percentage increase in the response width at half the peak height (half the width). ). To conduct these tests, the hippocampus was removed from anesthetized 2-month-old Sprague-Dawley rats and slices were prepared in vi tro (400 micrometers thick) and maintained in an interfacial chamber at 35 ° C using conventional techniques [ see for example, Dunwiddie and Lynch, J. Physi ol. 276: 353-367 (1978)]. The chamber was previously perfused at 0.5 ml / min with ACSF containing (in M): sodium chloride 124, potassium chloride 3, potassium diacid phosphate 1.25, magnesium sulfate 2.5, calcium chloride 3.4, sodium acid carbonate 26, glucose 10 and L-ascorbate 2. A bipolar nichrome stimulation electrode was placed in the dendritic layer (stratu radiatu) of the hippocampal subcap CAI near the edge of the CA3 subfield. Current pulses (0.1 msec) through the stimulating electrode stimulate a population of Schaffer-commissural (SC) fibers that arise from the neurons in subdivision CA3 and end in the • synapses on the dendrites of the CAI neurons. The activation of these synapses causes them to release the transmitter glutamate. Glutamate binds to post-synaptic AMPA receptors which then transiently open an associated ion channel and allow a sodium current to enter the post-synaptic cell This current results in a voltage in the extracellular space (the potential post field excitatory t-synaptic or field "EPSP") that is registered by a high impedance recording electrode placed in the intermediate part of the CATI radute stratu. For the experiments summarized in Table 1, the intensity of the stimulation current was adjusted to produce maximum average EPSPs (typically about 1.5-2.0 mV). Paired stimulation pulses were administered every 40 seconds with an interpulse interval of 200 msec (see below). The field EPSPs of the second response were digitized and analyzed to determine the amplitude, average width, and response area. If the responses were stable for 15-30 minutes (baseline), the test compounds were added to the perfusion lines for a period of approximately 15 minutes. The perfusion was then changed back to the regular ACSF. The paired pulse stimulation was used since the stimulation of the SC fibers, in part, activates the interneurons that generate an inhibitory post-synaptic potential (IPSP) in the pyramidal CAI cells. This forward power IPSP typically comes after the EPSP reaches its peak. This accelerates repolarization and shortens the decay phase of the EPSP, and thus could partially mask the effects of the test compounds. One of the relevant features of the front power IPSP is that it can not be reactivated for several hundred milliseconds after a stimulation pulse. This phenomenon can be used to take advantage of eliminating the IPSP by distributing paired pulses separated by 200 milliseconds and using the second response ("aprestada") for the data analysis. The field EPSP recorded in the CAI field after the stimulation of CA3 axons is known to be mediated by AMPA receptors: the receptors are present in the synapses [Kessler et al., Ba ri n Re s. 560: 337-341 (1991)] and drugs that selectively block the receptor selectively block the field EPSP [Muller et al., Sci in ce, s upra]. Aniracetam increases the mean opening time of the AMPA receptor channel and, as expected, increases the amplitude of the synaptic current and prolongs its duration [Tang et al., Sci ence, s upra]. These effects are reflected in the field EPSP, as reported in the literature [see, for example, Staubli et al., Psych obi ol ogy, s upra; Xiao et al., Hippocampus s upra; Staubli et al., Hippocampu s 2: 49-58 (1992)]. Similar results have been reported for the stable, previously described benzamide derivatives of aniracetam [International Patent Application Publication No. WO 94/02475 (PCT / US93 / 06916) (Lynch and Rogers, Rectors of the University of California )]. The compounds of the invention were tested in the physiological test system described above for the generation of data presented in Table 1 below. In addition, a compound lacking the rigidity of the benzoxazines of the present invention is also listed as the fifth entry. This serves as a comparison illustrating the significant increase in activity derived by the elimination of two degrees of rotational freedom inherent in the non-rigid benzylpyrrolidinone (compare 20% increase in response to 300 μM of compound 1, 20% to 2%). mM of benzylpyrrolidinone). It is also important to recognize that the structure of the imide of compound 4, which could be considered a rigid model of the aniracetam, is inactive in the slice model at 300 μM. Considering the biological activity that has been demonstrated for benzamides in which the single carbonyl portion is adjacent to the aromatic ring (Rogers et al., U.S. Patent No. 5,650,409), little or no activity could be expected from the acylbenzoxazines of the present invention. It is now apparent, however, that while the presence of two carbonyl groups in the rigid benzoxazine structure (to provide the imide) is not favorable for biological activity, a simple carbonyl moiety in any position is sufficient. In addition, it is unexpected that carbonyl in the alpha position to nitrogen and gamma to the aromatic ring (in contrast to the compounds described in U.S. Patent No. 5,650,409) produced significantly greater bioavailability and improved activity. The first two columns of data from the Table 1 show the half-life for plasma clearance (58 minutes) and bioavailability (100%) in the rat for the compound of Example 1. These data can be compared with those of the corresponding benzamide (Example 1 of U.S. Patent No. 5,736,543, issued April 7, 1998), which shows a half-life and a bioavailability of 31 minutes and 35%, respectively. The third column of data reports the magnitude of the increase in the amplitude of the EPSP at the lowest concentrations that produced a significant increase. The characteristic of a compound to produce an increase in EPSP response has been a reliable predictor of the ability to improve memory in the 8-arm radial maze task. The last column of Table 1 describes the threshold dose for the most potent compound to improve memory in rats that were tested in a learning paradigm using an 8-arm radial labyrinth as described in Staubli et al., PNAS 91 : 11158-1162 (1994).

Table 1 position m n R Life BiodisResponse MED median * ponibilidad * EPSP 'labyrinth' (min.) (%) (conc.) (mg / kg) 1 1 1 CH2 58 100 25 (300 μM) NT ° 2 2 1 CH2 NT NT 20 (30 μM) 0.1 3 2 2 CH2 NT NT 10 (30 μM) NT 4 1 1 C = 0 NT NT 0 (300 μM) NT Plasma clearance after intravenous administration in rats' AUC for oral administration as a percentage of AUC for intravenous administration Percent increase in the area of EPSP response: Minimum effective dose to improve the performance of rats in the radial labyrinth of eight arms aNT = not tested The invention has been described in detail with reference to the particular embodiments thereof. It will be understood, however, that variations and modifications may be made between the spirit and scope of the invention as defined by the following claims.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (22)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: A compound that has the structure characterized in that: X1 and X2 are independently selected from hydrogen, -NR22, -0R ?, and -CH2OR3; or X1 and X2 taken together are, -OCR420-, or = N-S-N =; each occurrence of R in the portion (CR2) is independently hydrogen, halogen, cyano, hydroxyl, alkoxy of 1 to 6 carbon atoms, fluoroalkoxy of 1 to 3 carbon atoms, thiol, alkyl of 1 to 6 carbon atoms, fluoroalkyl from 1 to 3 carbon atoms, alkoxyalkyl of 2 to 6 carbon atoms, aryl of 6 to 12 carbon atoms, heteroaryl of 3 to 12 carbon atoms, arylalkyl of 7 to 12 carbon atoms, heteroarylalkyl of 4 to 12 atoms carbon, aryloxy of 6 to 12 carbon atoms, aryloxyalkyl of 7 to 12 carbon atoms, arylalkoxy of 7 to 12 carbon atoms, heteroarylalkoxy of 4 to 12 carbon atoms, carboxyalkyl, or both groups R together are = 0; each occurrence of R 1 is independently hydrogen, alkyl of 1 to 6 carbon atoms, fluoroalkyl of 1 to 3 carbon atoms, arylc heteroaryl, arylalkyl, or heteroarylalkyl; each occurrence of R2 is independently hydrogen, alkyl of 1 to 6 carbon atoms, fluoroalkyl of 1 to 3 carbon atoms, aryl of 6 to 12 carbon atoms, heteroaryl of 3 to 12 carbon atoms, arylalkyl of 7 to 12 atoms of carbon, heteroarylalkyl of 4 to 12 carbon atoms, or both R 'groups together form a carboxylic ring including the nitrogen atom; each occurrence of R 3 is independently hydrogen, alkyl of 1 to 6 carbon atoms, fluoroalkyl of 1 to 3 carbon atoms, alkoxyalkyl of 2 to 6 carbon atoms, aryloxyalkyl of 7 to 12 carbon atoms, arylalkyl of 7 to 12 atoms carbon, or heteroarylalkyl of 4 to 12 carbon atoms; each occurrence of R 4 is independently hydrogen, halogen, cyano, carboxyalkyl, carboxaraid, alkyl of 1 to 6 carbon atoms, fluoroaikyl of 1 to 3 carbon atoms, alkoxyalkyl of 2 to 6 carbon atoms, aryloxyalkyl of 7 to 12 carbon atoms. carbon, arylalkyl of 7 to 12 carbon atoms, or heteroarylalkyl of 4 to 12 carbon atoms; each occurrence of R5 is independently hydrogen, cyano, hydroxyl, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, fluoroalkyl of 1 to 3 carbon atoms, alkoxyquinone of 2 to 6 carbon atoms, or arylalkyl of 7 to 12 carbon atoms, heteroaryl locha of 4 to 12 carbon atoms, aryloxy of 6 to 12 carbon atoms, aryloxyalkyl of 7 to 12 carbon atoms, arylalkoxy of 7 to 12 carbon atoms, or heteroarylalkoxy of 4 to 12 carbon atoms; each occurrence of R6 is independently hydrogen, alkyl of 1 to 6 carbon atoms, fluoroalkyl of 1 to 3 carbon atoms, arylalkyl of 7 to 12 carbon atoms or heteroarylalkyl of 4 to 12 carbon atoms; and n is 1, 2, 3, or 4.
2. 2. A compound according to claim 1, characterized in that X1 and X 'taken together are -OCR420-, -OC2R4 0-, -0C2R420-; and n is 2 or 3.
3. 3. A compound according to claim 1, characterized in that X1 and X2 taken together are -N = CR52CR52 = N-; and n is 2 or 34.
4. A compound according to claim 1, characterized in that X1 and X2 taken together are -OCR6 = N-; and n is 2 or 3.
5. 5. A compound according to claim 1, characterized in that X1 and X2 taken together are = N-0-N = or = N-S-N =; n is 2 or 3.
6. 6. A compound according to claim 1 or 5, characterized in that X1 and X2 taken together are = N-0-N =.
7. 7. A compound according to claim 1 or 2, characterized in that each appearance of R in the portion (CR2) is independently hydrogen, fluoro, cyano, hydroxyl, alkoxy of 1 to 6 carbon atoms, fluoroalkoxy of 1 to 3 carbon atoms , alkyl of 1 to 6 carbon atoms, fluoroalkyl of 1 to 3 carbon atoms, alkoxyalkyl of 2 to 6 carbon atoms, heteroaryl of 3 to 12 carbon atoms, arylalkyl of 7 to 12 carbon atoms, heteroarylalkyl of 4 to 12 carbon atoms, aryloxy of 6 to 12 carbon atoms, aryloxyalkyl of 7 to 12 carbon atoms, arylalkoxy of 7 to 12 carbon atoms, heteroarylalkoxy of 4 to 12 carbon atoms, or both R groups together are = 0; and each occurrence of R 'is independently hydrogen, arylalkyl, or heteroarylalkyl; and each occurrence of R4 is independently hydrogen, fluoro, cyano, carboxylalkyl, alkyl of 1 to 6 carbon atoms, fluoroaikyl of 1 to 3 carbon atoms, alkoxyalkyl of 2 to 6 carbon atoms, aryloxyalkyl of 7 to 12 carbon atoms , arylalkyl of 12 carbon atoms, or heteroarylalkyl of 4 to 12 carbon atoms.
8. 8. A compound according to claim 3, characterized in that each occurrence of R is independently hydrogen, fluoro, cyano, hydroxyl, alkoxy of 1 to 6 carbon atoms, fluoroalkoxy of 1 to 3 carbon atoms, alkyl of 1 to 6 carbon atoms. carbon, fluoroalkyl of 1 to 3 carbon atoms, alkoxyalkyl of 2 to 6 carbon atoms, heteroaryl of 3 to 12 carbon atoms, arylalkyl of 7 to 12 carbon atoms, heteroarylalkyl of 4 to 12 carbon atoms, aryloxy of 6 at 12 carbon atoms, aryloxyalkyl of 7 to 12 carbon atoms, arylalkoxy of 7 to 12 carbon atoms, heteroarylalkoxy of 4 to 12 carbon atoms, or both R groups together are = 0; and each occurrence of R "is independently hydrogen, arylalkyl, or heteroarylalkyl.
9. 9. A compound according to claim 4, characterized in that each occurrence of R is independently hydrogen, fluoro, cyano, hydroxyl, alkoxy of 1 to 6 carbon atoms, fluoroalkoxy of 1 to 3 carbon atoms, alkyl of 1 to 6 carbon atoms. carbon, fluoroalkyl of 1 to 3 carbon atoms, alkoxyalkyl of 2 to 6 carbon atoms, heteroaryl of 3 to 12 carbon atoms, arylalkyl of 7 to 12 carbon atoms, heteroarylalkyl of 4 to 12 carbon atoms, aryloxy of 6 at 12 carbon atoms, aryloxyalkyl of 7 to 12 carbon atoms, arylalkoxy of 7 to 12 carbon atoms, heteroarylalkoxy of 4 to 12 carbon atoms, or both R groups together are = 0; and each occurrence of R is independently hydrogen, arylalkyl, or heteroarylalkyl.
10. 10. A compound according to claim 6, characterized in that each occurrence of R is independently hydrogen, fluoro, cyano, hydroxyl, alkoxy of 1 to 6 carbon atoms, fluoroalkoxy of 1 to 3 carbon atoms, alkyl of 1 to 6 carbon atoms. carbon, fluoroalkyl of 1 to 3 carbon atoms, alkoxyalkyl of 2 to 6 carbon atoms, heteroaryl of 3 to 12 carbon atoms, arylalkyl of 7 to 12 carbon atoms, heteroarylalkyl of 4 to 12 carbon atoms, aryloxy of 6 at 12 carbon atoms, aryloxyalkyl of 7 to 12 carbon atoms, arylalkoxy of 7 to 12 carbon atoms, heteroarylalkoxy of 4 to 12 carbon atoms, or both R groups together are = 0; and each occurrence of R1 is independently hydrogen, arylalkyl, or heteroarylalkyl.
11. 11. The compound according to claim 1, characterized in that it is 5a, 6,7, 8-tetrahydro-1,3-dioxolo [4,5-g] pyrrolo [2, 1-b] [1,3] -benzoxazin- 8 (1 OH) -one.
12. 12. A compound according to claim 1, characterized in that it is 6a, 7,8, 9-tetra idro-1,4-dioxin [2, 3-g] pyrrolo [2, 1-b] [1,3] -benzoxazin -9 [11H] -one.
13. 13. A compound according to claim 1, characterized in that it is 6a, 7,8,9-tetrahydro-1,4-dioxan [2,3-g] pyrido [2, lb] [1,3] -benzoxazin-10 ( 10H, 12H) -dione.
14. 14. Use of a compound according to any of claims 1-13 for the manufacture of a medicament that is used to improve the functioning of a subject on sensory-motor problems or the cognitive tasks dependent on the brain networks that use the receptors of AMPA.
15. 15. Use of a compound according to any of claims 1-13 for the manufacture of a medicament for use in decreasing the amount of time necessary for a subject to learn a cognitive, motor or perceptual task, or to increase the time for which the subject retains cognitive, motor or perceptual tasks, or to reduce the amount or severity of errors made by a subject in remembering a cognitive motor or perceptual task.
16. 16. Use of a compound according to any of claims 1-13 for the manufacture of a medicament that is used in a method of treating a human subject to improve the synaptic response mediated by AMPA receptors.
17. 17. Use of a compound according to any of claims 1-13 for the manufacture of a medicament that is used in the treatment of schizophrenia, schizophreniform behavior or depression in a human subject in need of such treatment.
18. 18. A pharmaceutical composition, characterized in that it comprises an effective amount of at least one compound according to any of claims 1 to 13.
19. 19. The composition according to claim 18, characterized in that it further comprises a pharmaceutically acceptable carrier, excipient or additive.
20. 20. The composition according to claim 18 or 19, characterized in that it is adapted for oral or parenteral administration.
21. 21. The composition according to claim 18 or 19, characterized in that it is adapted for oral administration.
22. 22. The compound according to any of claims 1-13, for use as a medicament.