MXPA06007536A - Benzo[d]isoxazol-3-ol daao inhibitors - Google Patents

Abstract

Methods for increasing D-Serine concentration and reducing concentration of the toxic products of D-Serine oxidation, for enhancing learning, memory and/or cognition, or for treating schizophrenia, Alzheimer's disease, ataxia, or neuropathic pain, or preventing loss in neuronal function characteristic of neurodegenerative diseases involve administering to a subject in need of treatment a therapeutic amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof:I wherein Z1 is N or CR3;Z2 is N or CR4;Z3 is O or S;A is hydrogen, alkyl or M+;M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof;R1, R2, R3 and R4 are independently selected from hydrogen, alkyl, hydroxy alkoxy, aryl, acyl, halo, cyano, haloalkyl, NHCOOR5 and SO2NH2;R5 is aryl, arylalkyl, heteroaryl or heteroarylalkyl;at least one of R1, R2, R3 and R4 is other than hydrogen;and at least one of Z1 and Z2 is other than N.

Description

INHIBITORS OF BENZO [D] lSOXAZOL-3 -OL D -AMINOACYL OXIDASE (DAAO) Background of the Invention The enzyme D-amino acid oxidase (DAAO) metabolizes D-amino acids, and in particular, metabolizes the D- In vitro serine at physiological pH DAAO is expressed in the mammalian brain and periphery The role of D-serine as a neurotransmitter is important in the activation of the selective subtype of N-methyl-D-aspartate (NMDA) ) of the glutamate receptor, an ion channel expressed in neurons, here denoted as an NMDA receptor Small organic molecules, which inhibit the enzymatic cycle of DAAO, can control D-serine levels, and thus influence receptor activity NMDA in the brain: NMDA receptor activity is important in a variety of disease states, such as schizophrenia, psychosis, ataxia, ischemia, various forms of pain including neuropathic pain, and memory deficits and coagulation. The small organic molecules that inhibit the enzymatic cycle of DAAO can also control the production of toxic metabolites of D-serine oxidation, such as hydrogen peroxide and ammonia. In this way, these molecules can influence the progression of cell loss in neurodegenerative disorders. Ref .: 174231 neurodegenerative diseases are diseases in which the neurons of the CNS and / or peripheral neurons suffer a progressive loss of function, usually accompanied by (and perhaps caused by) a physical deterioration of the structure of either the neuron by itself or its interference with other neurons. Such conditions include Parkinson's disease, Alzheimer's disease, Huntington's disease and neuropathic pain. N-methyl-D-aspartate (NMDA) glutamate receptors are expressed at excitation synapses throughout the central nervous system (CNS). These receptors mediate a wide range of brain processes, including synaptic plasticity, that are associated with certain types of memory formation and learning. NMDA glutamate receptors require binding of two agonists to effect neurotransmission. One of these agonists is the amino acid L-gutamate of excitation, while the second agonist, in the so-called "glycine site insensitive to estriquinin", is now through being D-serine. In animals, D-serine is synthesized from L-serine by serine racemase and degraded to its corresponding ketoacid by DAAO. Together, serine racemase and DAAO are thought to play a crucial role in modulating NMDA neurotransmission by regulating D-serine concentrations of the CNS. Alzheimer's disease manifests as a form of dementia that typically involves mental deterioration, reflected in memory loss, confusion and disorientation. In the context of the present invention, dementia is defined as a syndrome of progressive decline in multiple domains of cognitive function, which eventually leads to an inability to maintain social behavior and / or normal occupations. Early symptoms include memory lapses and mild but progressive deterioration of specific cognitive functions, such as language (aphasia), motor experiences (apraxia) and perception (agnosia). The earliest manifestation of the -Alzheimer's disease is often memory damage, which is required for a diagnosis of dementia in both the National Institute of Neurological and Communictive Disorders and Stroke-Alzheimer's Disease and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) (McKhann et al., 1984, Neurology 34: 939-944), which are specific for Alzheimer's disease, and criteria of The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), which are applicable for all forms of dementia. The cognitive function of a patient can also be evaluated by the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-cog); Rosen et al., 1984, Am. J. Psychiatry 141: 1356-1364). Alzheimer's disease is typically treated by acetylcholine esterase inhibitors such as tacrine hydrochloride or donepezil. Unfortunately, the few forms of treatment for loss of memory and damaged learning available so far are not considered effective in making any significant difference in a patient, and there is currently a lack of a standard notrópico drug for use in such treatment. Neuropsychiatric disorders include schizophrenia, autism and attention deficit disorder. Doctors recognize a distinction between such disorders, and there are many schemes to categorize them. The Diagnostic and Statistical Manual of Mental Disorders, Revised, Fourth Edition, (DSM-IV-R) published by the American Psychiatric Association, provides a standard diagnostic system upon which experienced persons rely, and is incorporated herein for reference . According to the DSM-IV work scheme, mental disorders of Axis I include: disorders diagnosed in childhood (such as Attention Deficit Disorder (ADD) and Attention Deficit Hyperactivity Disorder (ADHD) by its acronym in English)) and disorders diagnosed in adulthood. Disorders diagnosed in adulthood include (1) schizophrenia and psychotic disorders, (2) cognitive disorders; (3) mood disorders; (4) disorders related to anxiety (5) eating disorders; (6) disorders related to substances; (7) personality disorders; and (8) disorders not yet included in the scheme. The ADD and ADHD disorders that are most prevalent in childhood and are associated with increased motor activity and a decreased attention deficit. These disorders are commonly treated by administration of psychostimulants such as methylphenidate and dextroamphetamine sulfate. Schizophrenia represents a group of neuropsychiatric disorders characterized by dysfunctions of the thinking process, such as delusions, hallucinations, and withdrawal of the patient's interest from other people. Approximately one percent of the world population is afflicted with schizophrenia, and this disorder is accompanied by high proportions of morbidity and mortality. The so-called negative symptoms of schizophrenia include affecting the dull, anergy, alloy and social distraction, which can be measured using SANS (Andreasen, 1983, Scales for the Assessment of Negative Symtpoms (SANS), Iowa City, Iowa). Positive symptoms of schizophrenia include delusion and hallucination, which can be measured using PANSS (Positive and Negative Syndrome Scale) (Kay et al, 1987, Schizophrenia Bulletin 13: 261-276). Cognitive symptoms of schizophrenia include damage to obtain, organize and use intellectual knowledge which can be measured by the subscale of positive and negative syndrome scale (PANSS cognitive subscale) (Lindenmayer et al., 1994, J. Nerv. Ment Dis. 182: 631-638) or with cognitive tasks such as Wisconsin Card Sorting Test. Conventional antipsychotic drugs, which act on the dopamine D2 receptor, can be used to treat positive symptoms of schizophrenia, such as delusion and hallucination. In general, conventional antipsychotic drugs and atypical antipsychotic drugs, which act on the dopamine D2 receptor and serotonin 5HT2, are limited in their ability to treat cognitive deficits and negative symptoms such as blunting (ie, lack of facial expressions). , anergy and social distraction. Other conditions that are manifested as deficits in memory and learning include benign memory and closed brain damage. Benign poor memory refers to a slight tendency to be unable to retrieve or retain information that was once recorded, learned, and stored in memory (for example, an inability to remember where the keys were placed or where the car was parked). Benign poor memory typically affects individuals after 40 years of age and can be recognized by standard assessment instruments such as the Wechsler Memory Scale. Closed brain damage refers to a clinical condition after damage or brain trauma. Such a condition, which is characterized by cognitive and memory impairment, can be diagnosed as "amnestic disorder due to a general medical condition" according to DSM-IV. Known inhibitors of DAAO include benzoic acid, pyrrole-2-carboxylic acids, and indole-2-carboxylic acids, as described by Frisell, et al., J. Biol. Chem., 223: 75-83 (1956) and Parikh et al., JACS, 80: 953 (1958). Indole derivatives and particularly certain indole-2-carboxylates have been described in the literature for the treatment of neurodegenerative disease and neurotoxic damage. European Patent 396124 describes indole-2-carboxylates and derivatives for the treatment or management of neurotoxic damage resulting from a CNS disorder or traumatic event or in the treatment or management of a neurodegenerative disease. Several examples of traumatic events that can result in neurotoxic damage, including hypoxia, anoxia, ischemia, associated with perinatal asphyxia, cardiac arrest or infarction are given. Neurodegeneration is associated with CNS disorders such as seizures and epilepsy. Patents of the United States of North America NO. 5,373,018; 5,374,649; 5,686,461; 5,962,496 and 6,100,289 to Cugola, describe the treatment of neurotoxic damage and neurodegenerative disease using indole derivatives. None of the previous references mentioned improvement or increase of learning, memory or knowledge. The application WO 03/039540 discloses increased learning, memory and cognition and treatment of neurodegenerative disorders using DAAO inhibitors, including indole-2-carboxylic acids. However, there are still. a need for new drugs which are clinically effective in the treatment of memory defects, damaged learning and loss of consciousness, and other symptoms related to NMDA receptor activity, or lack of it. Summary of the Invention It has been unexpectedly discovered that certain benzo [d] isoxazol-3-ol derivatives exhibit more potent inhibition of DAAO activity than known inhibitors. Dramatically low concentrations of these compounds have been observed to inhibit DAAO in vitro, particularly in relation to known DAAO inhibitors such as benzoic acid, pyrrole-2-carboxylic acid and indole-2-carboxylic acid. Due to its ability to inhibit the activity of DAAO, certain benzisoxazole derivatives are useful for treating a variety of diseases and / or conditions wherein the levels of D-serine, and / or its oxidative products, are effective in ameliorating symptoms, along with a reduction in undesirable side effects. In particular, the compounds may be useful for increasing levels of D-serine and reducing levels of toxic products of D-serine oxidation; in this way, the compounds are useful for increasing, learning, memory and / or cognition, or for treating schizophrenia, for treating or preventing memory loss and / or cognition associated with Alzheimer's disease, for treating ataxia, or to prevent the loss of neuronal function characteristics of neurodegenerative diseases. Accordingly, in one aspect, the invention relates to methods for increasing D-serine and reducing toxic D-serine oxidation products, for increasing learning, memory and / or cognition, or for treating schizophrenia, for treating or prevent the loss of memory and / or cognition associated with Alzheimer's disease, to treat ataxia, or to prevent the loss of neuronal function characteristics of neurodegenerative diseases. The methods involve administering to a subject in need thereof a therapeutic amount of a compound of the formula I, or a pharmaceutically acceptable salt or solvate thereof. wherein Z1 is N or CR3; Z2 is N or CR4; Z3 is O or S; A is hydrogen, alkyl or M +; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, or a mixture thereof; R1, R2, R3 and R4 are independently selected from hydrogen, alkyl, hydroxy, alkoxy, aryl, acyl, halo, cyano, haloalkyl, NHCOOR5 and S02NH; R5 is aryl, arylalkyl, heteroaryl or heteroarylalkyl; and At least one of Z1 and Z2 is different from N. In a second aspect the invention relates to methods for treating autism, schizophrenia, Alzheimer's, ataxia and neurodegenerative diseases, which comprise administering a therapeutically effective amount of the above D-amino acid oxidase inhibitor (DAAO) of formula I to a subject in need of treatment for one or more of these conditions.

In preferred embodiments, the compounds of the formula I are benzo [d] isoxazole-3-ols, substituted, that is, at least one of R1, R2, R3 and R4 is different from hydrogen. Example compounds are: DETAILED DESCRIPTION OF THE INVENTION The present invention relates to methods to increase D-serine and reduce the toxic products of D-serine oxidation, to increase learning, memory and / or cognition, or to treat schizophrenia, to treat or prevent memory loss and / or cognition associated with Alzheimer's disease, to treat ataxia or to prevent the loss of neuronal function characteristics of neurodegenerative diseases. The methods include administering to a subject a therapeutic amount of a compound of formula I: Or a pharmaceutically acceptable salt or solvate thereof; wherein Z1 is N or CR3; Z2 is N or CR4; Z3 is 0 or S; A is hydrogen, alkyl or M +; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof; R1, R2, R3 and R4 are independently selected from hydrogen, alkyl, hydroxy, alkoxy, aryl, acyl, halo, cyano, haloalkyl, NHCOOR5 and S02NH2; R5 is aryl, arylalkyl, heteroaryl or heeroarylalkyl; and i at least one of Z1 and Z2 is different from N. Therapeutic treatment with a compound of formula I improves and / or increases memory, learning and cognition, particularly in individuals suffering from neurodegenerative diseases such as Alzheimer's diseases, Huntington or Parkison. The compounds also improve the cognitive dysfunctions associated with age and improve catatonic schizophrenia. The compounds of the formula I possess unique pharmacological characteristics with respect to the inhibition of DAAO, and they influence the activity of the NMDA receptor in the brain, particularly by controlling the levels of D-serine. Therefore, these compounds are effective in treating conditions and disorders, especially disorders related to the CNS, modulated by DAAQ, D-serine activity and / or NMDA receptor, with diminished side effects compared to the administration of current treatment standards. . These conditions and disorders include, but are not limited to, neuropsychiatric disorders, such as schizophrenia, autism, attention deficit disorder (ADD and ADHD) and childhood learning disorders, and neurodegenerative diseases and disorders, such as MLS - ( cerebellar ataxia), Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Down syndrome, neuropathic pain, multi-infarct dementia, status epilepticus, contusive damage (eg spinal cord damage and brain damage), neurodegeneration induced by viral infection (eg, AIDS, encephalopathies), epilepsy, benign memory and closed brain damage. Compounds of Formula I may also be useful for the treatment of neurotoxic damage which follows cerebral infarction, thromboembolic infarction, hemorrhagic infarction, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. The compounds of the formula I are typically more selective than the known DAAO inhibitors, including indole-2-carboxylates, and are shown to be selective for inhibition of DAAO relative to the linkage at the D-serine binding site of the NMDA receptor. The compounds also exhibit an advantageous profile of activity including good bioavailability. Accordingly, they offer advantages over many methods of the known art to treat disorders modulated by DAAO, D-serine or NMDA receptor activity. For example, unlike many conventional antipsychotic therapeutics, DAAO inhibitors can produce a desirable reduction in the cognitive symptoms of schizophrenia. Conventional antipsychotics often produce undesirable side effects, including tardive dyskinesia (irreversible involuntary movement disorders), extrapyramidal symptoms, and acanthesia, and these can be reduced or eliminated by administering compounds of the formula I. In another aspect, the present invention also relates to compounds of the formula la, or pharmaceutically acceptable salts or solvates and pharmaceutical compositions containing them: Where A is hydrogen, alkyl or M +; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, or a mixture thereof; Z is .0 or S; R1, and R2, are independently selected from hydrogen, alkyl, hydroxy, alkoxy, aryl, acyl, halo, cyano, haloalkyl, NHCOOR5 and S02NH2; R5 is aryl, arylalkyl, heteroaryl or heteroarylalkyl; and R3a and Ra are independently selected from alkyl, hydroxy, alkoxy, aryl, acyl, halo, cyano, haloalkyl, NCOOR5 and S02NH2. The compounds of the formula form a subgroup of the compounds of the formula I, and can therefore be used in the methods of the present invention. References herein to the compounds of the formula I are proposed to include compounds of the formula la. In preferred embodiments, the compounds of the formula I and the are benzo [d] isoxazole-3-ols, substituted at the 5-position and / or the 6-position. Preferred substituents for compounds of the formula I and the and for the benzo [ d] isoxal-3-oles 5-, 6- and 5,6-substituted are also halo, particularly chloro, hydroxy, alkyl, particularly higher alkyl (C6-C20) and alkoxy. D-amino acid oxidase inhibitors particularly preferred benzo [d] isoxazo-3-ols include: The invention includes compounds of formula I and II, as well as pharmaceutically acceptable salts and solvates of these compounds. The term "compound or pharmaceutically acceptable salt or solvate of a compound" proposes the meaning inclusive of "or", that a material which is both a salt and solvate is comprised. Pharmaceutically acceptable salts include, but are not limited to, inorganic salts of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, and organic salts of lysine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine and tromethamine. Subjects for treatment according to the present invention include humans (patients) and other mammals in need of therapy for the established condition. Patients who have a need for therapy to improve or increase learning and memory are those who exhibit symptoms of dementia or loss of learning and memory. Individuals with an amnesic disorder are damaged in their ability to learn new information or are unable to retrieve previously learned information or past events. Memory deficits are more apparent in tasks that require instant recovery and may also be evident when the examiner provides stimuli for the person to remember at a later time.

The memory disturbance must be severe enough to cause marked damage in social functioning or occupations and must represent a significant decline from a previous level of functioning. The memory deficit can be related to age or the result of illness or other cause. Dementia is characterized by multiple clinically significant cognitive deficits that represent a significant change from a previous level of functioning, including memory impairment that implies inability to learn new material or forget previously learned material. Memory can be formally tested by measuring the ability to record, retain, remember and recognize information. A diagnosis of dementia also requires at least one of the following cognitive disturbances: aphasia, apraxia, agnosia or a disturbance in executive functioning. These deficits in language, motor behavior, object recognition and abstract thinking, respectively, must be sufficiently severe, together with the memory deficit to cause damage in occupational or social functioning and must represent a decline from a previously higher level of functioning . Compounds of formula I and can also be used together with therapy involving administration of D-serine or an analog thereof, such as a D-serine salt, an D-serine ester, an alkylated D-serine, or a D-serine precursor, or may be used in conjunction with therapy involving administration of antipsychotics, antidepressants, psychostimulants, and / or Therapeutics of Alzheimer's disease. In animals several established patterns of learning and memory are available to examine the effects of beneficial cognitive enhancement and potential side effects related to treatment. The descriptions of tests that can be used to evaluate changes in cognition in non-human species are given in Sarter, Martín, Intern. J. Neuroscience, 32: 765-774 (1987). The tests include the Morris water maze (Stewart and Morris, Behavioral Neuroscience, R. Saghal, Ed. P. 107 (1993)), without delayed coupling to sample and social discrimination models. The Morris water labyrinth is one of the best validated models of learning and memory, and is sensitive to the effects of cognitive increase of a variety of pharmacological agents. The task performed in the maze is particularly sensitive to manipulations of the hippocampus in the brain, an area of the brain important for spatial learning in animals and memory consolidation in humans. On the other hand, the improvement in Morris water maze behavior is predictive of clinical efficacy of a compound as a cognitive enhancer. For example, treatment with cholinesterase inhibitors or selective muscarinic cholinergic agonists reverses the learning deficiencies in the Morris maze animal model of learning and memory, as well as in clinical populations with dementia. In addition, this animal paradigm accurately models the increased degree of damage with advanced age and the increased vulnerability of memory traces to delay or pretest interference which is a characteristic of amnestic patients. The test is a simple spatial learning task in which the animal is placed in a tank of warm water, which is opaque due to the addition of milk powder. The animals learn the location of a platform in relation to the visual inputs located inside the maze and the test room; this learning is referred to as a place of learning. Groups of animals receive control solution or a dose of the therapeutic agent, in the desired time interval before training or after training. Control animals typically reach the platform within five to ten seconds after three days of training. The measurement of the memory modulating effects of a therapeutic agent is a change of this period of time. In the second phase or test probe, the animals, which have previously learned the position of the platform are placed in the tank from which the platform has been removed. The animals that remember the position of the platform will spend more time in the square that has contained the platform and will make more crosses on the position previously occupied by the platform. Increases in memory or cognitive capacity are manifested by animals that spend more time in the correct square or make more crosses over the position previously occupied by the platform as compared to control animals. Declines in memory or cognitive ability are manifested by animals spending less time in the correct square or by making fewer crossings of the platform position than the control animals. A non-coupled test animal delayed to sample is presented with a stimulus (for example lever A). After a period of time, the animal is presented with two choices (example Lever A and lever B). The selection of the election that does not match the original stimulus (lever B) results in a reward. More than the random selection of the appropriate choice indicates that the original stimulus is remembered. As soon as the time between the stimulus and the response of choice is increased, the behavior decreases and reaches pure chance. The number of correct choices in a given time is related to cognitive stability. Deficiencies in knowledge or memory can be induced physically, biochemically or by the use of old animals. In the social interaction test, a foreign animal (animal B) is introduced into the housing of the test animal (animal A). Animal A will recognize the animal introduced as a stranger and will investigate it. If animal B is removed and reintroduced later, the test animal (animal A) will spend less time investigating the new cage mate since it remembers it from the previous introduction. As soon as the introduction time is increased, more time is spent investigating the new animal the second time since it is less remembered. The time spent researching the new cage partner during the second introduction is inversely related to cognitive ability. Deficits in cognition or memory can be introduced physically, biochemically or by the use of old animals. In humans, methods to improve learning and memory can be measured by such tests as the Wchsler Memory scale and the Minimental test. A standard clinical test to determine if the patient has learning and damaged memory is the Minimental Test for Learning and Memory (Folstein et al., J. Psychiatric Res. 12; 185, 1975), especially for those suffering from Korsakoff brain trauma, disease or trauma. The result of the test serves as a short-term working memory index, of the type that deteriorates rapidly in the early stages of dementia or amnestic disorders. Ten pairs of non-related words (eg table-articulated) are read to the subject.The subjects are then asked to remember the second word when the first word of each pair is given.The memory damage measurement is a number Reduced corrected associated words remembered in relation to a coupled control group Improvement in learning and memory constitutes either (a) a statistically significant difference between the behavior of treated patients as compared to members of a placebo group; b) a statistically significant change in behavior in the direction of normality in measurements relevant to the disease model.The animal models or clinical examples of symptoms exhibit disease which are by definition distinguishable from normal controls. effective pharmacotherapy will be a significant investment, but not necessarily complete, of symptoms. it can be facilitated in both the animal and human models of memory pathology by clinically effective "cognitive increase" drugs which serve to improve the behavior of a memory task. For example, cognitive enhancers which function as cholinomimetic replacement therapies in patients suffering from dementia and memory loss of the Alzheimer's type significantly improve short-term working memory in such paradigms as the task associated with pairs. Another potential application for therapeutic interventions against memory damage is suggested by age-related behavioral deficiencies that are effectively modeled by the longitudinal study of recent memory in old mice. The Wechsler memory scale is a widely used pencil and paper test of cognitive function and memory capacity. In the normal population, the standardized test produces an average of 100 and a standard deviation of 15, so that a mild amnesia can be detected with a reduction of 10-15 points in the classification, a more severe amnesia with a reduction of 20-30 points, and so on. During the clinical interview, a battery of tests, including, but not limited to, the Minimental test, the Wechsler memory scale, or associated learning in pairs are applied to sympathetic diagnostic memory loss. These tests provide general sensitivity to both general cognitive impairment and specific loss of learning / memory capacity (Squiare, 1987). Apart from the specific diagnosis of dementia or amnestic disorders, these clinical instruments also identify age-related cognitive decline which reflects an objective decrease in consequent mental function consequent to the aging process that is within normal limits given the age of the person ( DSM IV, 1994). As indicated above, "improvement" in learning and memory within the context of the present invention occurs when there is a statistically significant difference in the direction of normality in the test associated with pairs, for example, between the behavior of patients treated with agent therapeutic as compared to members of the placebo group or between subsequent tests given to the same patient. The pre-boost inhibition test can be used to identify compounds that are effective in treating schizophrenia. The test is based on observations that animals or humans that are exposed to a loud sound will exhibit a startle reflex and those animals or humans exposed to a series of lower intensity sounds prior to the higher intensity test sound will not exhibit more as intense of a startle reflex. - Patients diagnosed with schizophrenia exhibit defects in prepulsing inhibition, that is, lower intensity pre-pulses do not further inhibit the startle reflex to the intense test sound. Similar defects in pre-stimulation inhibition can be induced in animals by means of drug treatments (scopolamine, ketamine, PCP or MK801) or by subsequent offspring in isolation. These defects in pre-stimulation inhibition in animals can be "partially reversed by drugs known to be effective in patients with schizophrenia." It is intuited that animal pre-stimulation inhibition models have conflicting values to predict the efficacy of compounds in treatment of patients with schizophrenia. The spinal nerve ligation model (SNL) (Kim SH and Chung JM (1992) An experimental model for peripheral neuropathy produced by segmental spinal nerve ligand in the rat, Pain 50: 355-53.) May be used to determine the effect of therapeutic agents in chronic neuropathic pain.The animals are anesthetized with isoflurane, the left transverse process L5 is removed and the spinal nerves L5 and L6 are strongly ligated with a 6-0 silk suture. closed with internal sutures and external staples.The wound restraints are removed 10-11 days after surgery. The base, postdamage and post-treatment baselines are evaluated for a non-harmful mechanical sensitivity using 8 Semmes-Weinstein filaments (Stoetilting, Wood Dale, IL, USA) with several fixations (0.4, 0.7, 1.2, 2. 0, 3.6, 5.5, 8.5 and 15 g) according to the descending method (Chaplan SR, Bach FW, Pogrel JW, Chung JM and Yaksh TL (1994). Quantitative evaluation of tactile allodynia in the rat's paw. J Neurosci Methods 53: 55-63). The animals are placed on a perforated metal platform and allowed to acclimatise around them for a minimum of minutes before the test. The mean and standard error of the mean (SEM for its acronym in English) are determined for each animal in each treatment group. Since this stimulus is not normally considered painful, the increases induced by significant damage in response to this test are interpreted as a measure of mechanical allodynia. The mechanical hypersensitivity of the damaged leg is determined by comparing the contralateral or ipsilateral leg values within the vehicle group. The data is analyzed using the Mann-Whitney test. The stability of damaged leg values per vehicle group over time is tested using Friedman's two-way analysis of variance by rank. The effect of the drug is analyzed at each time point by carrying out an analysis of a Kruskal-Wallis form of variance by rank by Dunn post hoc test or Mann-Whitney signed rank test. If desired, compounds of formula I and can also be used in conjunction with therapy involving administration of D-serine or an analog thereof, such as a D-serine salt, a D-serine ester, D- alkylated serine, or a precursor of D-serine. The compounds can also be used together with therapy involving administration (to treat schizophrenia and other psychotic conditions), psychostimulants (to treat attention deficit disorder, depression or learning disorders), antidepressants, non-tropics (for example, piracetam, oxiracetam or aniracetam), acetylcholinesterase inhibitors (for example, compounds related to physostigmine, tacrine or donepezil) and / or therapeutics of Alzheimer's disease (to treat Alzheimer's disease). Such methods for combination therapies are included within the invention. The phrase "therapeutically effective amount" as used herein means that amount of a compound, material or composition comprising a compound of the present invention which is effective to produce any desired therapeutic effect by inhibiting DAAO in at least one subpopulation of cells in an animal and therefore blocking the biological consequences of that path in the treated cells, at a reasonable benefit / risk ratio applicable to any medical treatment.

The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metal salts made of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made of lysine, N, N'-dibencylethylenediamine, chloroprocaine, choline , diethanolamine, ethylenediamine, meglumine (N-methylglucamine) procaine and tromethamine. In general, the compounds of the present invention are commercially available or can be prepared by methods well known to persons skilled in the art. In addition, the methods described below, or modifications thereof, using readily available starting materials, reagents and conventional synthesis methods may be employed. In these reactions, it is also possible to make use of variants that are themselves known, but not mentioned herein. In the context of the present invention, alkyl is proposed to include linear, branched or cyclic hydrocarbon structures and combinations thereof, including lower alkyl and higher alkyl. Preferred alkyl groups are those of C20 or less. The lower alkyl refers to alkyl groups of 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, and n-, s-, and t-butyl. The "higher alkyl" refers to alkyl groups having seven or more carbon atoms, preferably 7-20 carbon atoms, and includes n-, s- and t-heptyl, octyl and dodecyl. Cycloalkyl is a subgroup of alkyl and includes cyclic hydrocarbon groups of 3 to 8 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and norbornyl. Aryl and heteroaryl means a 5 or 6 membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from nitrogen, oxygen or sulfur, a 9 or 10 membered bicyclic aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from nitrogen , oxygen or sulfur; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from nitrogen, oxygen or sulfur. Carbocyclic rings of 6 to 14 aromatic members include, for example, benzene, naphthalene, indane, tetralin and fluorene; and 5- to 10-membered aromatic heterocyclic rings include, for example, imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole. Arylalkyl means an alkyl residue attached to an aryl ring. The examples are benzyl and phenethyl. "Heteroarylalkyl" means an alkyl residue attached to a heteroaryl ring. Examples include pyridinylmethyl and pyrimidinylethyl. "Alkylaryl" means an aryl residue having one or more alkyl groups attached thereto. Examples are tolyl and mesityl. "Alkoxy" or "alkoxy" refers to groups of 1 to 8 carbon atoms of a linear, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy. "Lower alkoxy" refers to groups containing one to four carbons. Acyl refers to groups of 1 to 8 carbon atoms of a linear, branched, cyclic configuration, saturated, unsaturated and aromatic combinations thereof, linked to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue can be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains in the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, and benzyloxycarbonyl. Lower acyl refers to groups containing one to four carbons. "Heterocycle" means a cycloalkyl or aryl residue in which one to two of the carbons is replaced by a heteroatom such as oxygen, nitrogen or sulfur. Examples of heterocycles falling within the scope of the invention include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxole (commonly referred to as methylenedioxyphenyl, -when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine. , pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, and tetrahydrofuran. Substituted refers to residues, including, but not limited to, alkyl, alkylaryl, aryl, arylalkyl, and heteroaryl, wherein up to three H atoms of the residue are replaced with lower alkyl, substituted alkyl, substituted alkynyl, haloalkyl, alkoxy, carbonyl, carboxy, carboxalkoxy, carboxamido, acyloxy, amidino, nitro, halogen, hydroxy, OCH (COOH) 2, cyano, primary amino, secondary amino, acylamino, alkylthio, sulfoxide, sulfone, phenyl, benzyl, phenoxy, benzyloxy, heteroaryl or heteroaryloxy. Haloalkyl refers to an alkyl residue, wherein one or more H atoms are replaced by halogen atoms, the term "haloalkyl" includes perhaloalkyl. Examples of haloalkyl groups that fall within the scope of the invention include CHF2 and CF3. In the context of the present invention, compounds that are considered to possess activity as DAAO inhibitors are those that exhibit -50% inhibition of the enzymatic cycle of DAAO (IC50) a concentration of about < 100 μM, preferably, approximately 10 μM and more preferably and approximately < 1 μM. Many of the compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms which can be defined, in terms of absolute stereochemistry, as (R) - (S) . The present invention is understood to include all possible isomers, as well as their racemic and optically pure forms. Optically active isomers (R) - and (S) can be prepared using chiral or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and at least specified otherwise, it is proposed that the compounds include both geometric isomers E and Z. Similarly, all tautomeric forms are also proposed for be included While it may be possible for compounds of formula I and be administered as the unpurified chemical, it is preferable to present them as a pharmaceutical composition. According to a further aspect, the present invention provides a pharmaceutical composition which comprises a compound of the formula I and the pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutical carriers thereof and optionally one or more different therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. The formulations include those suitable for oral, parental (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The most appropriate route may depend on the condition and disorder of the receiver. The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the pharmacy art. All methods include the step of bringing into association a compound or pharmaceutically acceptable salt or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

Oral formulations are well known to those skilled in the art, and general methods for preparing them are found in any standard pharmacy school textbook, eg, Remington: The Science and Practice of Pharmacy, A. R. Gennaro, ed. (1995), the description of which is incorporated herein by reference. Formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be presented as a bolus, electuary or paste. A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient the active ingredient in a free fluid form, optionally mixed with a binder, lubricant, inert diluent, lubricant, surface active or dispersing agent. The molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or sorted and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein. Oral and parental sustained release drug delivery systems are well known to those skilled in the art, and general methods for achieving sustained release of orally or parenterally administered drugs are found, for example, in Remington: The Science and Practice of Pharmacy, pages 1660-1675 (1995). Formulations for parental administration include sterile aqueous and non-aqueous injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which lead to the formulation isotonic with the blood of the proposed recipient. Formulations for parental administration also include sterile aqueous and non-aqueous suspensions, which may include suspending agents and thickening agents. The formulations can be presented in a unit dose of multi-dose containers, for example sealed vials and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, saline solution buffered by phosphate (PBS) or similar, immediately before use. The extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the type described above. Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol. Formulations for topical administration in the mouth, for example, buccally or sublingually, include pellets comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth, and pellets comprising the active ingredient in a base such as gelatin and glycerin. or sucrose and acacia. Pharmaceutical compositions containing compounds of formula I and can be conveniently presented in a unit dosage form by any of the methods well known in the pharmacy art. Preferred unit dose formulations are those that contain an effective dose, or an appropriate fraction thereof, of the active ingredient, or a pharmaceutically acceptable salt thereof. The magnitude of a prophylactic or therapeutic dose typically varies with the nature and severity of the condition to be treated and the route of administration. The dose, and perhaps the frequency of the dose, will also vary according to the age, body weight and response of the individual patient. In general, the daily total dose ranges from about 1 mg per day to about 7000 mg per day, preferably and about 1 mg per day to about 100 mg per day, and more preferably, about 25 mg per day to about 50 mg per day. day, in simple and divided doses. In some embodiments, the daily daily dose may be in the range of about 50 mg to about 500 mg per day, and preferably, about 100 mg to about 500 mg per day. It is also recommended that children, patients over 65 years of age, and those with impaired renal or hepatic function, initially receive low doses and that the dose be titrated based on individual responses and blood levels. It may be necessary to use doses outside these ranges in some cases, as will be apparent to those in the art. Furthermore, it is indicated that the physician or means in treatment knows how and when to interrupt, adjust or terminate the therapy together with the response of the individual patient. It should be understood that in addition to the ingredients particularly mentioned above, the formulations of the invention may include other agents conventional in the art with respect to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

EXAMPLES Example 1: General procedure for the preparation of benzo [d] isoxazole-3-ols NH2OH Dioxane / H20 NH2OH dioxanß / HgO Ethyl ester of 2-hydroxy-4-methyl-benzoic acid.

A 50 ml robottom flask equipped with a stir bar r an atmosphere of dry nitrogen is charged with methylsalicyclic acid (1.5 g, 10.0 mmol, 1.0 equivalents) followed by dry MeOH (15 ml). The reaction mixture is cooled to 0 ° C in an ice bath and pure S0C1 is added (1.1 ml, 15.0 mmol, 1.5 equivalents) in drops. The reaction is allowed to warm to room temperature and then stirred refluxing for 5 hours. After that time, the excess MeoH is removed in vacuo, the residue is dissolved in EtOAc and extracted with saturated NaHCO3, the organic layer is dried with MgSO4 and filtered. Removal of the excess solvent from the filtrate in vacuo gives 1.20 g (72%) of the title compoas a clear oil. (XH CDC13, 400 MHz): d (s, ¡H), 7.70 (d, J = 8.1 Hz, ÍH), 6.75 (s, 1H), 6.69 (d, J = 8.1 Hz, 1H), 3.93 (s) , 3H), 2.34 (s, 3H). 2-N-dihydroxy-4-methyl-benzamide: a 250 ml robottom flask equipped with a stir bar loaded with hydroxylamine hydrochloride (3.5 g, 50.0 mmol, 25.0 equivalents) followed by H20 (35 ml) is charged. and by an aqueous NaOH solution (3.0 M / H20, 38 mL, 114 mmol, 57.0 equivalents). In a separate flask, the crude methyl ester of 2-hydroxy-4-methylbenzoic acid (332 mg, 2.0 mmol, 1.0 equivalents) is dissolved in dioxane and added dropwise to the above solution. The reaction mixture is stirred at room temperature for 20 hours, cooled to 0 ° C in an ice bath and neutralized to pH = 5 (pH paper strips) with concentrated aqueous HCl (10.0 M / H20). The reaction is allowed to warm to room temperature. EtOAc is added, the crude product is fractionated in a separating funnel (3xEtOAc), the organic layer is dried with MgSO and filtered. Removal of the excess solvent from the filtrate in vacuo gives 331 mg (99%) of the title compoas a cream colored solid. (^? DMSO-d6, 400 MHz) d 12.29 (s, 1H), 11.37 (s, ÍH), 9.26 (s, ÍH), 7.54 (d, J = 8.0 Hz, 1H), 6.70 (s, ÍH) , 6.648 (d, J = 8.1 Hz, ÍH), 2.24 (s, 3H). 6-methyl-benzo [d] isoxazole-3-ol: a 50 ml robottom flask equipped with a stir bar is charged r an atmosphere of dry nitrogen with 2-N-dihydroxy-4-methyl-benzamide (331 mg, 2.0 mmol, 1.0 equivalents) and carbonyldiimidazole (1.0 g, 6.0 mmol, 3.0 equivalents) ~ followed by dry THF (20 mL). The reaction mixture is stirred r reflux for 30 minutes and then pure TEA (415 μL, 3.0 mmol, 1.5 equivalents) is added. The reaction mixture is refluxed for an additional 20 hours, cooled to room temperature and the excess THF is removed in vacuo. The residue is dissolved in EtOAc, extracted with aqueous HCl (1.0 M / H20), the organic layer is dried with MgSO4, filtered and the excess solvent is removed from the filtrate in vacuo. Purification of the crude product by flash chromatography (silica gel, 0% > 405 gradient 2% AcOH /? TOAc in hexanes) provides 167 mg (56%) as a white solid. (XH DMSO-ds, 400 MHz) d 12.19 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.34 (s, ÍH), 7.12 (d, J = 8.1 Hz, ÍH), 2.07 ( s, 3H). (13C-DMSO-d6, 100 MHz) d 165.09, 163.59, 141.18, 124.588, 120.76, 112.08, 109.80, 21.33. 5-methyl-benzo [d] isoxazol-3-ol: The title compois prepared from commercially available 2-N-dihydroxy-5-methyl-benzamide as described above. (XH DMSO-ds, 400 MHz) d 12.19 (s, 1H), 7.48 (s, 1H), 7.42-7.40 (m, 2H), 2.38 (s, 3H); (13C-DMSO-d6, 100 MHz) d 165.01, 161.61, 132.22, 131.92, 120.38, 114.47, 109.64, 20.45. 5-chloro-benzo [d] isoxazol-3-ol: The title compois prepared from commercially available 2-N-dihydroxy-5-chloro-benzamide as described above. (- "" H DMSO-d6, 400 MHz) d 12.55 (s, ÍH), 7.78 (s, ÍH), 7.60 (m, 2H); (13C-DMSO-d6, 100 MHz) d 164.67, 161.65, 130.66, 127.17, 120.62, 115.90, 111.88. 5-methoxy-benzo [d] isoxazol-3-ol: The title compound is prepared from commercially available 2-hydroxy-5-methoxy-benzoic acid methyl ester as described above. ^ H DMSO-ds, 400 MHz) d 12.21 (s, ÍH), 7.45 (d, J = 9.0 Hz, ÍH), 7.18 (dd, J = 9.5 Hz, J = 11.5 Hz, 1H), 7.14 (d, J '= 11.5 Hz), 3.80 (d, J' = 11.5 Hz, 3H); (13C-DMSO-d6, 100 MHz) d 165.23, 158.26, 155.44, 120.50, 114.51, 110.90, 101.60, 55.67. 5-hydroxy-benzo [d] isoxazole-3-ol: The title compound is prepared from commercially available 2,5-dihydroxy-benzoic acid methyl ester as described above. ^ H DMSO-d6, 400 MHz) d 12.03 (s, ÍH), 9.55 (s, ÍH), 7.34 (d, J = 9.0 Hz, ÍH), 7.02 (dd, J = 9.4 Hz, J '= 2.4 Hz , ÍH), 6.94 (d, J = 2.4 Hz, 1H); (13C-DMSO-d6, 100 MHz) d 164.97, 157.41, 153.22, 120.14, 114.74, 110.52, 103.89. 6-Hydroxy-benzo [d] isoxazole-3-ol: The title compound is prepared from 2-, 4-dihydroxy-5-methoxy-benzoic acid methyl ester commercially available as described above. (XH DMS0-d6, 400 MHz) d 12.00 (s, 1H), 10.29 (s, 1H), 7.49 (d, J = 9.0 Hz, 1H), 6.75-6.73 (m, 2H); (13C-DMSO-d6, 100 MHz) d 165.17, 164.91, 160.57, 121.90, 113.13, 106.52, 95.10. -bromo-benzo [d] isoxazol-3-ol: The title compound is prepared from commercially available 5-bromo-2-hydroxy-benzoic acid as described above. (XH DMSO-ds, 400 MHz) d 12.55 (s, 1H), 7.93 (d, J = 1.8 Hz, ÍH), 7.73 (dd, J = 1.8 Hz, J '= 8.9 Hz), 7.56 (d , J '= 8.8 Hz); (13C-DMSO-ds, 100 MHz) d 164.48, 161.98, 133.26, 123.70, 116.52, 114.76, 112.29. 7-methoxy-benzo [d] isoxazole-3-ol: The title compound is prepared from commercially available 2-hydroxy-3-methoxy-benzoic acid methyl ester as described above. (^? DMSO-d6, 400 MHz) d 12.29 (s, 1H), 7. 26-7.13 (m, 3H), 3.92 (s, 3H); (13C-DMSO-d6, 100 MHz) d 165. 48, 153.07, 143.98, 124.17, 115.95, 112.41, 111.57, 55. 97. 4-Hydroxy-benzo [d] isoxazole-3-ol: The title compound is prepared from 2,6-dihydroxy-benzoic acid methyl ester commercially available as described above. (XH DMSO-d6, 400 MHz) d 11.90 (s, -1H), 10.49 (s, 1H), 7.30 (t, J = 8.0 Hz, J '= 8.2 Hz, 1H), 6.85 (d, J' = 8.3 Hz, ÍH), 6.55 (d, J = 7.9 Hz, ÍH); (13C-DMSO-d6, 100 MHz) d 165. 24, 164.89, 153.41, 132.00, 107.55, 103.44, 100.24. 6-Fluoro-benzo [d] isoxazol-3-ol: The title compound is prepared from commercially available 4-fluoro-2-hydroxy-benzoic acid methyl ester as described above. ^ H DMS0-d6, 400 MHz) d 12.47 (s, 1H), 7.77 (dd, J (H, F) = 5.4 Hz, J = 8.7 Hz. ÍH), 7.53 (dd, J '= l, 7 Hz , 3J (H, F) = 10.0 Hz, ÍH), 7.19 (dt, J "= 1.4 Hz, 3J (H, F) = 9.5 Hz, J = 9.0 Hz, ÍH); (13C-DMSO-d6, 100 MHz) d 165.02, 163.65 (d, 3J (C, F) = 14 Hz), 163.33 (d, 1J (C, F) = 247 Hz), 122.90 (d, 3J (C, F) = 11 Hz), 111.97 (d, 2J (C, F) = 26 Hz), 111.27, 97.70 (d, J (C, F) = 27 Hz) 4-fluoro-benzo [d] isoxazol-3-ol: The compound is prepared Title from methyl ester of 6-fluoro-2-hydroxy-benzoic acid commercially available as described above. (2H DMSO-d6, 400 MHz) d 12.69 (s, ÍH), 7.60 (dt, J (H, F) = 5.4 Hz, J = 8.2 Hz, J '= 8.2 Hz, ÍH), 7.40 (d, J = 8.5 Hz, ÍH), 7.19 (t, 3J (H, F) = 9.7 Hz, J = 8.1 Hz, ÍH); (13C- DMSO-de, 100 MHz) d 165.15, 163.45, 155.13 (d, 1J (C, F) = 254 Hz), 132.50 (d, 3J (C, F) = 18 Hz), 108.55 (d, 2J (C, F) = 18 Hz), 106.74, 106.78. 6-methoxy-benzo [d] isoxazole-3-ol: The title compound is prepared from commercially available 2-hydroxy-4-methoxy-benzoic acid methyl ester as described above. (^? DMSO-d6, 400 MHz) d 12.14 (s, ÍH), 7.56 (d, J = 8.6 Hz. ÍH), 7.09 (d, J '= 1.9 Hz, ÍH), 6.87 (dd, J = 8.7 Hz, J = 1.9 Hz, ÍH), 3.82 (s, 3H); (13C-DMSO-d6, 100 MHz) d 165. 08, 164.99, 162.23, 121.68, 113.21, 107.43, 93.34, 55.79. 4-methoxy-benzo [d] isoxazole-3-ol: The title compound is prepared from 2-hydroxy-6-methoxy-benzoic acid commercially available as described above. (XH CD3OD, 400 MHz) d 7.52 (t, J = J '"= 8.2 Hz. ÍH), 7.01 (d, J = 8.4 Hz, ÍH), 6.74 (d, J' = 8.0 Hz, ÍH), 3.95 (s, 3H); (13CD3OD, 100 MHz) d 165.83, 165.37, 155.89, 132.83, 104.28, 103.26, 102.25, 55.12 5-Fluoro-benzo [d] isoxazol-3-ol: The title compound is prepared from of 5-fluoro-2-hydroxy-benzoic acid commercially available as described above (aH CD3OD, 400 MHz) 12.48 (s, 1H), 7.61 (dd, J (H, F) = 5.3Hz, J = 9.0 Hz .IH), 7.53 (dd, J '= 2.2 Hz, 3J (H, F) = 7.7 Hz, ÍH), 7.49 (dt, J '= 2.2 Hz, 3J (H, F) = 9.0 Hz, J = 9.0 Hz, ÍH); (13C DMSO-d6, 100 MHz) d 165.31, 159.62, 158.02 (d, J (C, F) = 238 Hz), 119.0 (d, 2J (C, F) = 27 Hz, 111.61 (d, 3H (C, F) = 9 Hz), 106.47, 106.22. 6-bromo-benzo [d] isoxazol-3-ol: The title compound is prepared from 6-bromo-2-hydroxy-benzoic acid (J. Med. Che. (1992), 35, 739) as described above. (XH CD30D, 400 MHz) d 7.71 (s, ÍH), 7.61 (d, J = 8.3 Hz. ÍH), 7.45 (d, J = 8.3 Hz, ÍH); (13CD3OD, 100 MHz) d 166. 77, 165.43, 127.79, 126.08, 123.62, 115.27, 114.56. 7-Fluoro-benzo [d] isoxazol-3-ol: The title compound is prepared from commercially available 3-fluoro-2-hydroxy-benzoic acid as described above. (XH DMSO-d6, 400 MHz) 12.73 (s, ÍH), 7.57 (d, J = 7.9 Hz. ÍH), 7.53 (dd, 3J (H, F) = 11.3 Hz, J = 8.0 Hz, 1H), 7.31 (dt, 4J (H, F) = 4.0 Hz, J = 7.9 Hz, J '= 7.9 Hz); (13C CD3OD, 100 MHz) d 167.05 (d, J (C, F) = 3 Hz). , 152.49 (d, 2J (C, F) = 14 Hz), 147.88 (d, 1J (C, F) = 249 Hz), 125.22 (d, 3J (C, F) = 5 Hz), 119.92 (d, 4J (C, F) = 3Hz, 118.13 (d, 3J (C, F) = 5 Hz), 117.11 (d, 2J (C, F) = 14 Hz) 7-chloro-benzo [d] isoxazole-3 -ol: The title compound is prepared from commercially available 3-chloro-2-hydroxy-benzoic acid (XH DMSO-ds, 400 MHz) d 12.74 (s, 1H), 7.74 (s, 1H), 7.72 ( s, 1H), 7.33 (t, J = J '= 7.8 Hz.' 1H); (13C CD3OD, 100 MHz) d 167.18, 160.58, 131.51, 125.37, 121.18, 117.87, 116.71. 7-Hydroxy-benzo [d ] isoxazol-3-ol: The title compound is prepared from commercially available 2,3-dihydroxybenzoic acid (XH DMS0-d6, 400 MHz) d 12.17 (s, 1H), 10.37 (s, 1H), 7.11 (dd, J = 8.0 Hz, J "= 1.7 Hz, 1H), 7.07 (t, J = J '= 7.7 Hz, ÍH), 6.93 (dd, J = 8.0 Hz, J' = 1.7 Hz, 1H); (13C CD3OD, 100 MHz) d 167.29, 154.69, 143.12, 125.26, 117.58, 116.69, 112.51, 5-iodo-benzo [d] isoxazol-3-ol: The title compound is prepared from 5- iodine-2-hydroxy-benzoic commercially available. (^? DMS O-ds, 400 MHz) d 12.48 (s, ÍH), 8.08 (s, ÍH), 7.85 (d, J = 8.8 Hz, ÍH), 7.42 (d, J = 8.7 Hz, ÍH); (13C DMSO-d6, 100 MHz) d 164.11, 162.43, 138.62, 129.68, 117.15, 112.49, 86.28.

EXAMPLE 2: General procedure for bromination of benzo [d] isoxazole-3-ace -bromo-6-methyl-benzo [d] isoxazol-3-ol: A 25 ml high-pressure tube equipped with a stir bar and a screwed Teflon cap is loaded with 6-methyl-benzo [d] isoxazol-3-ol (745 mg, 5.0 mmol, 1.0 equivalents) and glacial acetic acid (5.0 ml). Pure Br2 drops are added (774 μl, 15.0 mmol, 3.0 equivalents). After shaking in 80 ° C for 20 hours, the reaction is allowed to cool slowly to room temperature. The resulting precipitate is collected by filtration and washed rapidly with 3x1.0 ml of glacial acetic acid. Crystallization of this crude product (624 mg) from 50 ml of MeCN yields 567 mg of the title compound (95% purity determined by RP-HPLC). Additional crystallization from 70 ml of toluene gives 519 mg (46%) as a white solid (98.1% purity determined by HPLC). (XH DMS0-d6, 400 MHz) d 12.45 (s, ÍH), 7.94 (s, 1H), 7.61 (s, 1H), 2.45 (s, 3H); (13C CD30D, 100 MHz) d 165.96, 164.50, 142.34, 125.39, 119.73, 115.78, 112.67, 24.10. 5,6-dibromo-benzo [d] isoxazol-3-ol: The title compound is prepared by bromination as described above. (XH DMSO-ds, 400 MHz) d 12.72 (s, 1H), 8.15 (s, ÍH), 8.12 (s, ÍH); (13C CD3OD, 100 MHz) d 165.90, 164.04, 117.33, 116.46, 128.08, 126.48, 119.30. 5-bromo-6-chloro-benzo [d] isoxazol-3-ol: The title compound is prepared by bromination as described above. (^? DMSO-d6, 400 MHz) d 12.71 (s, ÍH), 8.13 (s, 1H), 8.03 (s, ÍH); (13C CD3OD, 100 MHz) d 165.83, 164.03, 137. 92, 126.71, 117.19, 116.71, 113.14. EXAMPLE 3: General procedure for chlorination of benzo [d] isoxazole-3-ols -chloro-6-methyl-benzo [d] isoxazol-3-ol: A 25 ml round bottom flask equipped with a stir bar is charged with 6-methyl-benzo [d] isoxazol-3-ol (298 mg, 2.0 mmol, 1.0 equivalents) and TFA (2.0 ml) and cooled to 0 ° C in an ice bath. Pure N-chloromorpholine (242 μl, 2.0 mmol, 1.0 equivalent, Organic Syntheses, CV 8, 167) is added in drops and the reaction mixture is allowed to warm to room temperature over the period of 30 minutes. EtOAc is added, the product is fractionated in a separatory funnel (EtOAc / 1O M aqueous HCl), the organic layer is dried with MgSO 4 and the excess solvent is removed from the filtrate in vacuo.

Crystallization of the crude product (383 mg) from a mixture of 20 ml of toluene and 6 ml of EtOAc affords 206 mg (94% purity determined by HPLC) as a white solid. (XH DMSO-d6, 400 MHz) d 12.41 (s, ÍH), 7.77 (s, ÍH), 7.59 (s, ÍH), 2.43 (s, 3H); (13C DMSO-d6, 100 MHz) d 164.46, 161.87, 138.53, 128.08, 120.59, 113.78, 111.83, 20.49. 5,6-dichloro-benzo [d] isoxazol-3-ol: The title compound is prepared by chlorination as described above. ^ H DMSO-d6, 400 MHz) d 12.73 (s, ÍH), 8.03 (s, ÍH), 8.01 (s, ÍH); (13C DMSO-d6, 100 MHz) d 164.46, 161.39, 133. 60, 125.82, 122.27, 114.85, 112.40. 5-chloro-6-bromo-benzo [d] isoxazol-3-ol: The title compound is prepared by chlorination as described above. (aH DMSO-d6, 400 MHz) d 12.74 (s, ÍH), 8.16 (s, 1H), 7.99 (s, ÍH); (13C CD3OD, 100 MHz) d 166.11, 163.47, 130. 04, 126.00, 122.95, 116.87, 116.53. EXAMPLE 4: General procedure for iodination of benzo [d] isoxazole-3 -ols -iodo-6-methyl-benzo [d] isoxazol-3-ol: A 25 ml high-pressure tube equipped with a stir bar and a screwed Teflon cap is loaded with solid ICI (648 mg, 4.0 mmol , 2.0 equivalents) and AcOH (6.0 ml). 6-Methyl-benzo [d] isoxazol-3-ol (298 mg, 2.0 mmol, 1.0 equivalents) is added in one portion followed by water (15 ml). The heterogeneous reaction mixture is stirred at 80 ° C for 64 hours. The solid precipitate is removed by filtration, EtOAc is added to the filtrate, the unpurified product is fractionated in a separatory funnel (EtOAC / 1.0 M aqueous HCl), the organic layer is dried with MgSO and the excess solvent is removed. from filtering in vacuo. The double recrystallization of the combined precipitate and the unpurified product after aqueous development (471 mg) from 15 ml and 10 ml of toluene, respectively, yields 106 mg (19%) (92% purity determined by HPLC) as a solid white. (1H DMSO-d6, 400 MHz) d 12.35 (s, 1H), 8.16 (s, 1H), 7.60 (s, ÍH), 2.48 (s, overlap with DMS0-d6); (13C DMSO-ds, 100 MHz) d 163.76, 163.37, 142.88, 130.47, 114.87, 110.72, 93.42, 28.204. Example 4: In vitro measurements of DAAO activity: Purified pork DAAO, added to a buffered mixture of 50 mM D-serine, produces H202 in stoichiometric amounts for each molecule of oxidized D-serine. The production of H202 can be monitored with a commercially available Amplex Red dye, which in the presence of H202, is converted to the resorufin fluorescent product. To control the artifactual inhibition of the dye conversion, and to quantify the amount of H202 produced. In an alternative DAAO activity assay, purified DAAO from pig is added to a buffered mixture of 1 mM phenylglycine in the presence of compounds. The activity of DAAO is monitored spectrophotometrically by its enzymatic conversion of phenylglycine to benzoylmorphic acid with optical absorption at 252 nm. The inhibitors of the enzymatic cycle of DAAO are serially diluted to reduce the level of inhibition. The parameters of a non-linear equation are adjusted to be fixed to the resulting series of inhibition levels to extrapolate the concentration of the compound where 50% inhibition is achieved (IC50). These numbers are averaged for the number (n) of independent measurements (on separate days) of the inhibition.

TABLE 1 Compound Inhibition of Compound Inhibition of DAAO, IC50 DAAO, IC50 < lmM It can be seen from Table 1 that the IC 50 values of DAAO inhibitors previously reported are all greater than 1 μM compound by more than 50% inhibition of DAAO activity. The benzisoxazole derivatives of the present invention exhibit at least this more inhibitory activity, and several individual examples are 5 times or more active, requiring less than 200 nM of the compounds to inhibit 50% DAAO activity. Example 5: NMDA receptor affinity measurements To measure the affinity of the compounds reported herein for D-serine binding site at the NMDA receptor (also known as the "glycine site" or the "glycine site"). insensitive to estriquinin "), a radioligand binding assay is performed with membranes prepared from rat cerebral cortex. The radioactive ligand is [3H] MDL105, 519. The amount of radioactivity displaced by the compounds is evaluated by scintillation counting. No nonspecific binding is counted in the presence of 1 mM glycine. The affinities are calculated from the% inhibition values of [3 H] MDL105, 519 specific by the test compounds. The indole-2-carboxylic acid inhibits 77% specific binding of the radiolabelled compound when tested in 100 μM, while the following compound, exemplified by benzo [d] isoxazole-3-ol substituted, shows no affinity (less than 10). % inhibition of specific binding of [3H] MDL-509,519 when tested in 100 μM) for the D-serine binding site of the NMDA receptor: Example 6: Measurement of brain uptake of the rat Experiments evaluating the cerebral penetration of the rat of test compounds use an perfusion system where the left carotid artery is cannulated and the cerebral arteries are unlinked. The test compound plus internal controls are prefused for 30 seconds in the left hemisphere in phosphate buffered saline at pH 7.4. The internal controls are atenolol (with low brain uptake) and antipyrine (with high brain uptake). After a 30 second wash with perfusate, the brain is surgically removed. The left hemisphere is homogenized. The test compounds (plus left controls) are extracted from the brain homogenate, and analyzed using LC / MS / MS to determine the concentration of the test compound and internal controls in the brain. The proportions of brain uptake for selected compounds, expressed as pmoles / g brain / second + SD for N of 4 rats, are shown in Table 2.

Example 7: Measurement of cerebral D-serine levels Measurements of D-serine in mammalian brains indicate that the level of endogenous production is balanced by degradation of D-serine. D-serine is produced from 1-serine by the action of serine racemase, whereas D-serine is metabolized by the action of DAAO. D-serine administered exogenously produces short-term increases in the brain of D-serine due to the action of DAAO. Similarly, DAAO inhibitors are shown in this invention to increase the cerebral levels several times of D-serine. The clinical utility of exogenously administered D-serine has been demonstrated in schizophrenia; see Coyle, Joseph J., Ann. N.Y. Acad. Sci., 1003: 318-327 (2003) and U.S. Patent No. 6,227,875; 6,420,351 and 6,667,297. Therefore, measurements of cerebral D-serine levels in rats are useful to evaluate the potential therapeutic action of DAAO inhibitors in increments in D-serine for the treatment of schizophrenia. In vivo increase in cerebral D-serine. The compounds are suspended in phosphate-buffered saline (pH 7.4 with 2% Tween 80) and administered intraperitoneally in adult male Sprague Daly rats (40-60 days old)., Charles River Laboratories, Inc.) weighing 185-225 g at the time of the experiment. After several hours, the rats are sacrificed by decapitation and the cerebellum is rapidly removed and frozen at -80 ° C for further analysis. The rest of the brain is similarly removed and frozen. On the day of the analysis, the brain tissue is homogenized in 5 times its volume in 5% trichloroacetic acid cooled in ice. The homogenate is centrifuged in 18,000 times of gravity for 30 minutes. The granules are discarded. The supernatant is washed 3 times with saturated diethyl ether in water, the organic layer is discharged. After filtration of the aqueous layer through a 0.45 μm pore size filter membrane, the samples are ready for derivatization with o-phthaldialdehyde (OPA) and BOC L-Cys-OH according to to the methods of Hashimoto and colleagues (Hashimoto A, et al., J Chromatogr. 582 (l-2): 41-8 (1992)). Briefly, 50 mg of each derivatization reagent are dissolved in 5 ml of methanol. An aliquot of 200 μl of this to 100 μl of sample dissolved in 700 μl of borate buffer (0.4 M pH adjusted to 9.0 with sodium hydroxide). The D-serine levels are then detected fluorometrically (344 nm excitation wavelength, 443 emission wavelength) by injecting 10 μl aliquots into the high resolution liquid chromatography system. Exemplary compounds of those in this patent produce robust and significant increases in levels of D-serine in rat brain. In particular, a benzo [d] isoxazol-3-ol derivative administered in two separate doses (125 mg / kg followed by 75 mg / kg 3 hours later) produces a 2-fold increase in cerebellar D-serine levels 6 hours after the first dose. Example 8: Dosage Forms Dose form of lactose-free tablet Table 3 provides the ingredients for a lactose-free tablet dosage form of a compound of formula I and the: * Water evaporates during manufacture. The active ingredient is mixed with the cellulose until a uniform mixture is formed. The smallest amount of corn starch is mixed with an adequate amount of water to form a cornstarch paste. This is then mixed with the uniform mixture until a uniform moist mass is formed. The remaining corn starch is added to the resulting moist mass and mixed until uniform granules are obtained. The granules are then screened through a suitable grinding machine, using a% inch stainless steel (0.635 cm) screen. The ground granules are then poured into a drying oven until the desired moisture content is obtained. The dried xules are then ground through a suitable ground machine using a stainless steel screen of size (0.635 cm). The magnesium stearate is then mixed and the resulting mixture is compressed into tablets of desired thickness, hardness and disintegration. The openings are coated by standard aqueous or non-aqueous technique. Tablet dosage form Another tablet dosage formulation suitable for use with the active ingredients of the invention is provided in Table 4.

The active ingredient is sifted and mixed with cellulose, starch and pregelatinized corn starch. Suitable volumes of purified water are added and the powders are granulated. After drying, the granules are sieved and mixed with the magnesium stearate. The granules are then compressed into tablets using die cutters. Tablets of other strengths can be prepared by altering the ratio of the active ingredient to pharmaceutically acceptable carrier, the compression weight, or by using different die cutters. 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 (32)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound characterized in that the formula has a pharmaceutically acceptable salt or solvate thereof: IA wherein A is hydrogen, alkyl or M +; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, or a mixture thereof; Z is 0 or S; R1, and R2, are independently selected from hydrogen, alkyl, hydroxy, alkoxy, aryl, acyl, halo, cyano, haloalkyl, NHCOOR5 and S02NH2; R5 is aryl, arylalkyl, heteroaryl or heteroarylalkyl; R3a and R4a are independently selected from alkyl, hydroxy, alkoxy, aryl, acyl, halo, cyano, haloalkyl, NCOOR5 and S02NH2.
2. 2. The compound according to claim 1, characterized in that R3a and Ra are independently selected from alkyl, hydroxy, alkoxy and halo.
3. 3. The compound according to claim 1, characterized in that R3 and R4a are independently selected from alkyl, and halo.
4. 4. A method for increasing the concentration of D-serine and / or decreasing the concentration of toxic products of oxidation of D-serine by DAAO in a mammal, characterized in that it comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the formula I or a pharmaceutically acceptable salt or solvate thereof: wherein Z1 is N or CR3; Z2 is N or CR4; Z3 is O or S; A is hydrogen, alkyl or M +; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, or a mixture thereof; R1, R2, R3 and R4 are independently selected from hydrogen, alkyl, hydroxy, alkoxy, aryl, acyl, halo, cyano, haloalkyl, NHCOOR5 and S02NH2; R5 is aryl, arylalkyl, heteroaryl or heteroarylalkyl; and At least one of Z1 and Z2 is different from N.
5. 5. A method for treating schizophrenia, for treating or preventing memory loss and / or cognition associated with Alzheimer's disease, for treating ataxia, for treating neuropathic pain or to prevent loss of neuronal function characteristic of neurodegenerative diseases, characterized in that it comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the formula I or a pharmaceutically acceptable salt or solvate thereof: wherein Z1 is N or CR3; Z2 is N or CR4, 7X is O or S; A is hydrogen, alkyl or M +; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, or a mixture thereof; R1, R2, R3 and R4 are independently selected from hydrogen, alkyl, hydroxy, alkoxy, aryl, acyl, halo, cyano, haloalkyl, NHCOOR5 and S02NH2; R5 is aryl, arylalkyl, heteroaryl or heteroarylalkyl; and At least one of Z1 and Z2 is different from N.
6. 6. A method for increasing learning, memory and / or cognition characterized in that it comprises administering to a subject a therapeutically effective amount of a compound of the formula I, or a salt or pharmaceutically acceptable solvate thereof. wherein Z1 is N or CR3; Z2 is N or CR4, is O or S; A is hydrogen, alkyl or M +; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, or a mixture thereof; R1, R2, R3 and R4 are independently selected from hydrogen, alkyl, hydroxy, alkoxy, aryl, acyl, halo, cyano, haloalkyl, NHCOOR5 and S02NH2; R5 is aryl, arylalkyl, heteroaryl or heteroarylalkyl; and At least one of Z1 and Z2 is different from N.
7. 7. A method for treating neuropathic pain characterized in that it comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or an acceptable salt or solvate pharmaceutically thereof. wherein Z1 is N or CR3; Z2 is N or CR4, Z3 is O or S; A is hydrogen, alkyl or M +; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, or a mixture thereof; R1, R2, R3 and R4 are independently selected from hydrogen, alkyl, hydroxy, alkoxy, aryl, acyl, halo, cyano, haloalkyl, NHCOOR5 and S02NH2; R5 is aryl, arylalkyl, heteroaryl or heteroarylalkyl; and At least one of Z1 and Z2 is different from N.
8. 8. The method according to any of claims 4-7, characterized in that A is hydrogen.
9. The method according to any of claims 4-7 or 16, characterized in that Z3 is O.
10. 10. The method according to claim 8, characterized in that Z1 is CR3 or Z2 is CR.
11. 11. The method according to claim 8, characterized in that Z1 is CR3 and Z2 is CR4.
12. 12. The method in accordance with the claim 8, characterized in that two of R1, R2, R3 and R4 are hydrogen.
13. The method according to claim 8, characterized in that three of R1, R2, R3 and R4 are hydrogen.
14. 14. The method according to claim 8, characterized in that R1 and R2 are hydrogen.
15. 15. The method according to claim 8, characterized in that R1, R2 and one of R3 and R4 are hydrogen.
16. 16. The method according to claim 8, characterized in that one of R3 and R4 is chlorine.
17. 17. The method according to any of claims 4-7, characterized in that the compound is selected from
18. 18. The method according to any of claims 4-7, 8, characterized in that R1, R2, R3 and R4 are independently selected from hydrogen, Ce-C20 alkyl, hydroxy, alkoxy, aryl, acyl, halo, cyano, haloalkyl, NHCOOR5 and S02NH2.
19. 19. The method according to any of claims 4-7, characterized in that it additionally comprises co-administering D-serine or cycloserine.
20. 20. A pharmaceutical composition characterized in that it comprises a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier: wherein Z1 is N or CR3; 7X is N or CR; ZJ is 0 or S; A is hydrogen, alkyl or M +; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, or a mixture thereof; R1, R2, R3 and R4 are independently selected from hydrogen, alkyl, hydroxy, alkoxy, aryl, acyl, halo, cyano, haloalkyl, NHCOOR5 and S02NH2; R5 is aryl, arylalkyl, heteroaryl or heteroarylalkyl; and At least one of Z1 and Z2 is different from N.
21. 21. The pharmaceutical composition according to claim 20, characterized in that A is hydrogen.
22. 22. The pharmaceutical composition according to claim 21, characterized in that Z3 is O.
23. 23. The pharmaceutical composition according to claim 21, characterized in that Z1 is CR3 or Z2 is CR4.
24. 24. The pharmaceutical composition according to claim 21, characterized in that Z1 is CR3 and Z2 is CR4.
25. 25. The pharmaceutical composition according to claim 21, characterized in that two of R1, R2, R3 and R4 are hydrogen.
26. 26. The pharmaceutical composition according to claim 21, characterized in that three of R1, R2, R3 and R4 are hydrogen.
27. 27. The pharmaceutical composition according to claim 21, characterized in that R1 and R2 are hydrogen.
28. 28. The pharmaceutical composition according to claim 21, characterized in that R1, R2 and one of R3 and R4 are hydrogen.
29. 29. The pharmaceutical composition according to claim 21, characterized in that one of R3 and R4 is chloro.
30. 30. The pharmaceutical composition according to claim 20, characterized in that the compound is selected from
31. 31. The pharmaceutical composition according to claim 20, characterized in that R1, R2, R3 and R4 are independently selected from hydrogen, C3-C20 alkyl, hydroxy, alkoxy, aryl, acyl, halo, cyano, haloalkyl, NHCOOR5 and S02NH2.
32. 32. The pharmaceutical composition according to claim 20, characterized in that it additionally comprises D-serine or cycloserine.