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    • 专利摘要:
    NMDA RECEPTOR MODULATORS WITH STABILIZED SECONDARY STRUCTURE AND USES OF THE SAME.The present invention relates to compounds having enhanced potency in modulating NMDA receptor activity. Such compounds are considered for use in the treatment of diseases and disorders such as learning, cognitive activities and analgesia, particularly in relieving and / or reducing neuropathic pain.
    公开号:BR112012020142A2
    申请号:R112012020142-5
    申请日:2011-02-11
    公开日:2020-08-18
    发明作者:Joseph Moskal；Amin Khan
    申请人:Northwestern University；
    IPC主号:
    专利说明:

    . , 1/46 'Invention Patent Description Report for "MODULE- NMDA RECEIVER PAIN WITH SECONDARY STRUCTURE - STABILIZED AND USES OF THE SAME ".
    REMISSIVE REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application 61 / 303,472, filed on February 11, 2010, hereby incorporated by reference in its entirety.
    BACKGROUND An N-methyl-d-aspartate (NMDA) receptor is a postsynaptic ionotropic receptor that is responsive, inter alia, to the excitatory amino acids glutamate and glycine and to the synthetic NMDA compound. The NMDA TO receptor controls the flow of divalent and monovalent ions in the postsynaptic neural cell through a channel associated with the receptor (Foster et al., Nature '1987, 329: 395-396; Mayer et al, Trends in Pharmacol. Sci. 1990, 11: 254- 260). The NMDA receptor was involved, during development, in specifying neuronal architecture and synaptic connectivity and may be involved in experience-dependent synaptic modifications. In addition, NMDA receptors are also believed to be involved in long-term potentiation and central nervous system disorders.
    The NMDA receptor plays a major role in the synaptic plasticity that underlies many higher cognitive functions, such as memory acquisition, retention and learning, as well as certain cognitive pathways and pain perception (Collingridge et al, The NMDA Receiver, Oxford University Press, 1994). In addition, certain properties of NMDA receptors suggest that they may be involved in the processing of information in the brain that underlies consciousness itself.
    The NMDA receptor has attracted particular interest since it appears to be involved in a wide spectrum of CNS disorders. For example, during cerebral ischemia caused by stroke or traumatic injury, excessive amounts of the excitatory amino acid glutamate are released from damaged or oxygen-deprived neurons. That | Excess glutamate binds to NMDA receptors, which open
    . '2/46. its ligand-activated ion channels; in turn, the influx of calcium produces a high level of intracellular calcium, which activates a biochemical cascade, resulting in protein degradation and cell death. It is also believed that this phenomenon, known as excitotoxicity, is responsible for heart attack to epilepsy. In addition, there are many reports indicating similar involvement in chronic neurodegeneration of ma! Huntington's, Parkinson's and Alzheimer's. It has been shown that NMDA receptor activation is responsible for post-stroke seizures and, in certain models of epilepsy, it has been shown that NMDA receptor activation is necessary for attack attack. Neuropsychiatric involvement of the NUDA receptor has also been recognized, since blocking the Ca ** channel of NMDA receptor 7 by the animal anesthetic PCP (Phencyclidine) produces a psychotic state in humans similar to schizophrenia (reviewed in Johnson, K and 'Jones, S., 1990). In addition, NMDA receptors were also involved in certain types of spatial learning.
    The NDMA receptor is believed to consist of several protein chains embedded in the postsynaptic membrane. The first two types of subunits discovered to date form a large extracellular region which probably contains most allosteric binding sites, several transmembrane regions in a loop and duplicated to form a pore or channel, which is permeable to Ca ** and a terminal carbon region. The opening and closing of the channel are regulated by the binding of various ligands to domains (allosteric sites) of the protein that resides on the extracellular surface. It is believed that the binding of the ligands makes a conformational change in the overall structure of the protein which, finally, is reflected in the opening, partial opening, partial closing or closing of the channel.
    NMDA receptor compounds can have a double effect (agonist / antagonist) on the NMDA receptor through allosteric sites. These compounds are typically called "partial agonists”. In the presence of the main site ligand, a partial agonist will shift some of the ligand and thus decrease the Ca ** flow through the receptor.
    . + 3/46 R absence of or decreased level of the main site ligand, the partial agonist acts to increase the Ca ** flow through the receptor channel. - There remains a need in the art for new and more specific / potent compounds that are capable of binding to or modulating the glycine binding site of NMDA receptors, for example, the NR1 ligand binding nucleus of the NMDA receptor with, for example, significant specificity and / or potency, especially in vivo, to confer pharmaceutical benefits. In addition, there remains a need in the medical art for forms capable of oral delivery of such compounds.
    SUMMARY Here, at least in part, compounds are provided which are NMDA modulators, for example, partial NMDA agonists. For example, compounds are provided here that can mimic a beta-gyre structure that is capable of selectively interacting with the glycine-binding region of the NMDA NR1 receptor, for example, SEQ ID NO: 1. Disclosed peptide mimetics, for example, they have a beta-spin motif when binding to SEQ ID NO: 1. In some embodiments, peptide mimetics are disclosed that substantially maintain a beta-spin motif in vivo or in an aqueous solution. In some embodiments, a peptide mimetic capable of binding to or association with the NDMA ligand binding nucleus of SEQ ID NO: 1 is provided, in which said peptide mimetic has at least two alpha carbons around 6 to about 14 À away, for example, about 6 to about 8 À away. For example, common mimetics may include a cyclic amide core, for example, a spiro-beta-lactam. In another embodiment, a disclosed peptide mimetic may be a peptide having two or three amino acids replaced by a portion having a carboxyl group and an amino group. In one embodiment, a peptide mimetic is disclosed according to any one of claims 1-6, wherein said peptide mimetic is capable of forming a hydrogen bond in at least one, two, three or four of the next-
    . , 4/46. amino acids of SEQ ID NO: 1: PRO124, THR126, GLU178 and SER180 or may be capable of forming a hydrogen bond with all - four amino acids.
    For example, a peptide mimetic capable of binding to the NMDA ligand-binding nucleus of SEQ ID NO: 1 is provided here, wherein said peptide mimetic has two alpha carbons around 6 to about 14 A apart (for example, example, about 6 to about 10 Å in distance) and a beta-gyro motif comprising a bicyclic amide nucleus (eg, a spiro-beta-lactam) so that when the mimetic peptide binds to said SEQ ID NO: 1, the bicyclic amide core substantially retains the configuration.
    Such a peptide mimetic may include a nucleus represented by: O —Example peptide mimetics! can substantially maintain the beta-gyrus motif in vivo or in a | aqueous solution and may be able to form a hydro-! genius with the following amino acids of SEQ ID NO: 1: PRO124, THR126, | GLU178 and SER1I80. In some embodiments, the beta-gyrus nucleus can be conjugated to one or two amino acids.
    Methods of treating or preventing an NMDA receptor-mediated disorder in a patient are also considered to include administering, to a patient who needs it, an acceptable agonistic or antagonistic amount of the NMDA receptor ligand-binding nucleus, of a cyclic peptidomimetic beta-gyrus compound that mimics glycine having a portion of cyclic amide, for example, a portion of beta-lactam.
    Also provided here is a method of modulating the activity of SEQ ID NO: 1, in which the modulation originates from a favorable conformation adopted by a compound and in which said modulation originates from a hydrogen bonded interaction between the compound and one, two, three or four of the following amino acids of SEQ ID NO: 1: PRO124, THR126, GLU178eSER180.
    . . 5/46. In another embodiment, a method of identifying a compound capable of binding to SEQ ID NO: 1 is provided comprising: a) - providing a molecular model comprising one or more target regions of SEQ ID NO: 1 derived from at least a portion of: SEQ ID NO: 1, atomic coordinates by means of molecular modeling of SEQ ID NO: 1 or atomic coordinates deposited in the Protein Data Bank under accession number 1PBQ; b) use of the molecular model to identify a compound that can bind to one or more target regions in the molecular model; and c) compost production.
    In some embodiments, such a method may further comprise the additional step of determining whether the compound modulates SEQ ID NO: 1. Also provided herein are pharmaceutically acceptable compositions comprising a disclosed compound and a pharmaceutically acceptable excipient.
    For example, such compositions can be suitable for oral administration to a patient.
    A method for treating a cognitive disorder, such as a disorder associated with memory loss or impaired learning, including administration, to a patient who needs it, one. - effective amount of a disclosed compound.
    For example, methods for treating or alleviating memory loss or impaired learning are provided here for a patient who needs it.
    In one embodiment, methods for treating neuropathic pain in a patient who needs it comprising administering an effective amount of a disclosed compound are provided.
    Also disclosed here are methods for treating depression, obsessive-compulsive disorder or schizophrenia in a patient | which needs the same comprising administering an effective amount of a disclosed compound.
    In another modality, methods for working | treatment of post-traumatic stress disorder, an alcohol addiction disorder or an addiction to an addictive drug in a patient who needs it | thereof comprising administration of an effective amount of a | disclosed compound are provided. |
    . '6/46: DESCRIPTION OF FIGURES
    Figures 1A-1D indicate that a disclosed compound (AK52) - biphasically changes excitatory postsynaptic currents mediated by the postsynaptic NMDA receptor (epscs) in Schaffer-CA1i collateral synapses and selectively enhances LTP induction . 1A: Time course of AK52 marked reduction (1 µM; solid bar) of the collateral stimulated NMDA component of e.p.s.c.s! of Schaffer in pyramidal neurons CA1. (Each point is the mean + SEM of the amplitude of e.p.s.c. in peNRX of 5 cells). 1B: Time course of intensification of a ten-fold lower concentration of AK52 (100 NM; gray bar) of the NMDA component of e.p.s.c.s stimulated by Schaffer collateral in CAT1 pyramidal neurons. Í (Each point is the mean + SEM of the e.p.s.c. amplitude in peNRX of 5 cells). 1C: LTD time course induced by a series of low frequency stimuli (2 Hz / 10 min; starting at the arrow) in Schaffer-CA1 collateral synapses in sections pre-treated with NRX-10,052 at 1 uM (full circles; n = 10) and 100 nM (full diamonds; n = 6) compared to untreated control sections (open circles; n = 8). (Each point is the mean + SEM of the EPSP decline in a n-section normalized extracellular field). 1D: Experiment time course comparing LTP induced by a series of high frequency stimuli (3 x 100 Hz2 / 500 ms; arrow) in Schaffer-CA1 collateral synapses in sections pre-treated with NRX-10,052 at 1 µM (circles full; n = 10 or 100 nM (full diamonds; n = 8) compared to untreated control sections (open circles; n = 15). (Each point is the mean + SEM of the epscs decline in the normalized field of n if -
    tions)
    Figures 2A-2E indicate that a low concentration of a disclosed B compound markedly intensifies pharmacologically isolated postsynaptic NMDA receptor-mediated excitatory currents (e.p.s.c.s) in Schaffer-CA1 collateral synapses and potentiates LTP,
    whereas a 20-fold higher concentration reduces NMDA e.p.s.c.s. 2A: Time course of marked intensification by Compound B (50 nM; solid bar) of pharmacologically isolated stimulated NMDA e.p.s.c.s
    . , 7/46
    : by a single Schaffer collateral shock recorded in pyramidal neurons CA1. 2B: Time course of intensification by Compound B (50 nM; - solid bar) of e.p.s.c.s of NMDA stimulated by explosion (4 pulses / 100 Hz). 2C: Time course of marked reduction by Compound B (1 µM; solid bar) of NMDA e.p.s.c.s stimulated by a single Schaffer collateral shock recorded in CA1 pyramidal neurons. 2D: Time course of reduction by Compound B (1 µM; solid bar) of NMDA e.p.s.c.s stimulated by a Schaffer collateral explosion (4 pulses, 100 Hz) recorded in CA1 pyramidal neurons. 2E: LTP intensification evoked by Schaffer collateral stimulus (100 HZ / 500 ms x3; solid arrow) in CA1 pyramidal neuron synapses at 50 nM Compound B (full circles) compared to 'untreated control sections (open circles). (Each point is the average +
    SEM of the e.p.s.c. in peNRX over n cells). Figures 3A-3C demonstrate that concentrations of 100 nM and 1 µ4M of a disclosed compound (AK51) enhance the pharmacologically isolated postsynaptic NMDA receptor-mediated (e.p.s.c.s.) in Schaffer-CA1 collateral synapse and potentiate LTP. 3A: Time course of accentuated NRX-10,051 intensification (100 nM; solid bar) of pharmacologically isolated NMDA e.p.s.c.s stimulated by a single Schaffer collateral shock recorded in CA1 pyramidal neurons (n = x). 3B: Time course of AKS1 intensification (1 µM; solid bar) of pharmacologically isolated NMDA e.p.s.c.s stimulated by a single Schaffer collateral shock recorded in CA1 pyramidal neurons (n = y). 3C: LTP intensification evoked by high-frequency Schaffer collateral stimulus (100 Hz2 / 500 ms x3; solid arrow) at synapses over CA1 pyramidal neurons by AK1I51 at 100 nM () and 1 uM (full circles) compared with sections untreated control groups (open circles). 3D: LTD time course induced by a series of low frequency stimuli (2 Hz / 10 min; starting with the arrow) in collateral synapses of Schaffer-CA1 in sections pretreated with NRX-10,051 at 1 JM (full circles; n = 10) or 100 nM (full diamonds; n = 6) compared to untreated control sections (open circles; n = 8). Each point is the mean + SEM of the e.p.s.c.
    '. 8/46 'by the n-cell peNRX). Figure 4 indicates that a disclosed compound enhances NMDA current and LTP.
    A: Time course of the effect of applying a 20 min bath of AK51 at 100 nM (solid bar) on the current activated by pharmacologically isolated NMDA receptor normalized in CA1 pyramidal neurons under registration with whole cells (mean + SEM , n = 5). B: Time course of the effect of applying a 20 min bath of AK51 to 1 UM (solid bar) on the current activated by pharmacologically isolated NMDA receptor normalized in CA1 pyramidal neurons under record with whole cells (mean + SEM , n = 6). C: Time course of the effect of applying a bath of AK51 at 100 nM (solid bar, filled circles, n = í 8) compared with untreated control sections (open circles, n = 6) on the magnitude of potentiation at long term (Long Term Potentiation: - LTP) of decline in extracellular excitatory postsynaptic potential (mean + SEM, fEPSP) induced by high frequency Schaffer collateral stimulation (arrow, 2 x 100H2 / 500 msec). D: Time course of the effect of applying an AKS1 bath at 1 µM (solid bar, filled circles, n = 8) compared to untreated control sections (open circles, n = 6) on the magnitude LTP of fEPSP decline (mean + SEM) induced by high frequency Schaffer collateral stimulation (arrow, 2 x 100Hz / 500 msec). E: Time course of the effect of applying a 1 µM AK51 bath (solid bar, filled circles, n = 10) compared to untreated control sections (open circles, n = 8) on the long-term depression magnitude fEPSP decline period (mean + SEM) induced by Schaffer collateral stimulation at low frequency (arrow, 2 Hz2 / 10 min). Figure 5 represents the results of a T-labyrinth test using a disclosed compound.
    Figure 6 represents the results of a formalin neuropathic pain assay in rats.
    Figure 7 indicates that an isomer of a disseminated AK-55-A compound potentially enhances NMDA current and LTP, while AK-55-B does not.
    . , 9/46 'Figure 8 represents the quantification by GC / MS and shows the area under the curve for AK-51 and the internal standard [2H7] proline and was analyzed - with GC / MS by means of selective ion monitoring after derivatization by TBDMS based on methods adapted from Wood et al., Journal of Chromatography B, 831, 313-9 (2005). The quantitative assay range for this compound was 0.312 pmol to 10 pmol / column. The ions used for SIM were 241.2 (present compound) and 350.3 (deuterated proline). R2 = 0.9999 (quadratic non-linear regression). Figure 9 represents the NMDA NR1 receptor sequence and various compounds that associate, via hydrogen bonding, to specific amino acids. Figure 10 represents the crystal structure of compound X (GLYX-13) with the NMDA NR1 receptor. i Figure 11 represents a model peptide (GLYX-13) that has a distance of 12,171 Å between alpha carbons.
    Figure 12 represents * H NMR spectra of a compound disclosed herein.
    Figure 13 represents' H NMR spectra of a compound disclosed herein.
    “DETAILED DESCRIPTION The present disclosure is, in general, directed to compounds that are capable of modulating NMDA, for example, partial NMDA antagonists or agonists and compositions and / or methods of using the disclosed compounds.
    The following definitions are used throughout the description of this disclosure.
    The term "alkenyl", as used here, refers to a straight or branched unsaturated hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-12, 2-10 or 2-6 carbon atoms, referred to herein as C2-C12 alkenyl, C2-C19 alkenyl and C2-Cs alkenyl, respectively. Exemplary alkenyl groups in- | include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, |
    . , 10/46 'butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4- (2-methyl-3-butene) -pentenyl, etc. - The term "alkoxy", as used here, refers to an alkyl group attached to an oxygen (-O-alkyl). Exemplary alkoxy groups including, but not limited to, groups with an alkyl group of 1-12, 1-8 or 1-6 carbon atoms, referred to herein as C1-C12 alkoxy, C1-Cg alkoxy and C1- C alkoxy , respectively. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, etc. Similarly, exemplary "alkenoxy" groups include, but are not limited to, vinyloxy, allyoxy, butenoxy, etc. The term "alkyl", as used herein, refers to a straight or branched saturated hydrocarbon. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1- butyl, 2-methyl-3-butyl, 2,2-dimethyl-: 1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2 - pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl , t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.
    Alkyl, alkenyl and alkynyl groups can optionally be substituted, if not otherwise indicated, by one or more selected groups of alkoxy, alkyl, cycloalkyl, amino, halogen and -C (O) alkyl. In certain embodiments, the alkyl, alkenyl and alkynyl groups are not substituted, that is, they are unsubstituted.
    The term "alkynyl", as used herein, refers to a straight or branched unsaturated hydrocarbon having at least one triple bond - carbon-carbon. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl and butynyl.
    The term "amide" or "starch", as used here, refers to a radical! in the form -RC (O) N (Rs) -, -Ra.C (O) N (RYRc- or -C (O) NRYRe, where Ra, R, and Rc. are each independently selected from alkoxy , - alkyl, algenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxy, ketone and nitro.Amide can be attached to another group
    . ”11/46. through carbon, nitrogen, R., Rc or Ra.
    The amide can also be cyclic, for example, Ry and R., Rae Ry or Ra and Rc can be joined to form a 3 to 12 element ring, such as a 3 to 10 element ring or a 5 to 6 elements.
    The term "carboxamido" refers to the - C structure (ONRR.
    The term "amine" or "amino", as used here, refers to a radical of the form -NRJRe, where Rag and Re are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl , heteroaryl and heterocyclyl.
    The amino can also be cyclic, for example, Rg and Re are joined together with the N atom to form a ring of 3 to 12 elements, for example, morpholino or piperidinyl.
    The term amino | ”Also includes the corresponding quaternary ammonium salt of any group | amino po, for example, - [N (Ri) (Re) (R)]. "Exemplary amino groups include aminoalkyl groups, where at least one of Ra, Re or R; is an alkyl group.
    In certain modalities, Rg and R. are hydrogen or al- | quila.
    The terms "halo" or "halogen" or "Hal", as used here, refer to F, Cl, Br or | The term "haloalkyl", as used here, refers to an alkyl group substituted by one or more halogen atoms.
    The terms "heterocyclyl" or "heterocyclic group" are recognized in the art and refer to saturated or partially unsaturated ring structures of 3 to 10 elements, alternatively rings of 3 to 7 elements, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen and sulfur.
    Heterocycles can also be ring systems - mono-, bi- or other multi-cyclic.
    A heterocycle can be fused to one or more saturated or partially unsaturated aryl rings.
    Heterocyclyl groups include, for example, biotinyl, chromenyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, homopiperidinyl, imidazolidinyl, isoquinolyl, isothiazolidinyl, pyridine, pyridine, pyridine, pyridine , pyrazolinite, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrotinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, thiazolidinyl, thiol-
    -, 12/46. nila, thiomorpholinyl, thiopyranil, xanthenyl, lactones, lactams, such as azetinimines and pyrrolidinones, sultames, suitones and the like. The heterocyclic ring can be substituted, in one or more positions, by substituents such as alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, starch, amidino, amino,. aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkite, heteroaryl, heterocyclic, hydroxyl, imino, ketone, nitro, phosphate, phosphonate, phosphonate, sulfate, sulfide, suifonamido sulfonyl and thiocarbonyl. In certain embodiments, the heterocyclic group is not substituted, that is, the heterocyclic group is unsubstituted. The term "heterocycloalkyl" is recognized in the art and refer to it. to a saturated heterocyclyl group, as defined above. The term "he-" terocyclylalkoxy ", as used here, refers to a heterocyclyl attached to an alkoxy group. The term" heterocyclyloxyalkyl "refers to a heterocyclyl attached to an oxygen (-O-), which is trapped to an alkyl group. The terms "hydroxy" and "hydroxyl", as used herein, refer to the radical -OH.
    "Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce an adverse, allergic or other unwanted reaction when administered to an animal or human, as appropriate. For administration to humans, preparations must meet sterility, pyrogenicity, general safety and purity standards, as required by the FDA Office of Biologies standards.
    As used in the present disclosure, the term "NMDA parialdoreceptor agonist" is defined as a compound that is capable of binding to an NMDA receptor glycine binding site; at low concentrations, an NMDA receptor agonist acts substantially as an agonist and, at high concentrations, it acts substantially as an antagonist. These concentrations are experimentally determined for each and every partial agonist.
    As used herein, "pharmaceutically acceptable carrier" or "excipient" includes any and all solvents, dispersion media, coatings
    . , 13/46. antibacterial and antifungal agents, absorption delay and isotonic agents and the like that are physiologically compatible. - In one embodiment, the vehicle is suitable for parenteral administration.
    Alternatively, the vehicle may be suitable for intravenous, intraperitoneal, intramuscular, sublingual or oral administration.
    Pharmaceutically acceptable vehicles include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
    The use of such means and agents for pharmaceutically active substances is well known in the art.
    Except to the extent that any conventional medium or agent is incompatible with the active compound, use of them in the pharmaceutical compositions of the invention is considered.
    Supplementary active compounds can also be incorporated into the
    'tions. :
    The term "pharmaceutically acceptable salt (s)", as used herein, refers to salts of acidic or basic groups that may be present in compounds used in the present compositions.
    Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various organic and inorganic acids.
    Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, that is, salts containing pharmacologically acceptable anions including, but not limited to, malate salts, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate , glucaronate, saccharate, format, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzene sulfonate, p-toluene sulfonate and pamoate (ie 1,1'-methylene-bis- (2-hydroxy-3- naphttoate)). Compounds included in the present compositions that include an amino moiety can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
    Compounds included in the present compositions that are acidic in nature are capable of forming base salts
    . 14/46. with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, - calcium, magnesium, sodium, lithium, zinc, potassium and iron salts.
    The compounds of the disclosure can contain one or more chiral centers and / or double bonds and therefore exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term "stereoisomers", when used here, consists of all geometric isomers, enantiomers or diastereomers. These compounds can be designated by the symbols "R" or "S", depending on the configuration of substitutes around the stereogenic carbon atom. The present invention encompasses several stereoisomers of these compounds and mixtures thereof.
    'Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers can be designated by the nomenclature "(+)", but those versed in the field will recognize that a structure can implicitly note a chiral center. i Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers | or by preparing racemic mixtures, followed by methods of | 20 decomposition well known to those skilled in the field. These decomposition methods are exemplified by (1) fixing a mixture | from enantiomers to a chiral auxiliary, separation of the mixture resulting from diastereomers by means of recrystallization or chromatography and release of the optically pure product from the auxiliary, (2) formation of salt using a | 25 optically active decomposition agent or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Mistu- | | stereoisomeric strips can also be decomposed into their stereo- | component sums by well-known methods such as chro- | gas matography in chiral phase, high performance liquid chromatography | 30 in chiral phase, crystallization of the compound as a salt complex | chiral or crystallization of the compound in a chiral solvent. Stereoisomers can also be obtained from intermediates, reagents and catalysts
    . . 15/46. stereomerically pure paints through well-known asymmetric synthesis methods. . Geometric isomers can also exist in the compounds of the present invention.
    The === symbol denotes a connection that can be simple, double or triple, as described here.
    The present invention encompasses the various geometric isomers and mixtures thereof that result from the configuration of substituents around a carbon-carbon double bond or configuration of substituents around a carbocyclic ring.
    Substituents around a carbon-carbon double bond are designated here as being in the "Z" or "E" configuration, where the terms "Z" and "E" are used in accordance with IUPAC standards.
    Unless otherwise specified, structures representing double bonds comprise - - "Z'e '" E "osisomers, Substituents around a carbon-carbon double bond may alternatively be referred to as" cis "or" trans " ", where" cis "represents substituents on the same side of the double bond and" trans "represents substituents on opposite sides of the double bond.
    The configuration of substituents around a carbocyclic ring is referred to as "cis" "or" trans ". The term "cis" represents substituents on the same side of the ring plane the term "trans" represents substituents on opposite sides of the ring plane.
    Mixtures of compounds in which the substituents are arranged on it and opposite sides of the ring plane are called "cis / trans". The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents, such as water, ethanol and the like, and the invention is intended to encompass both solvated and unsolvated forms.
    In one embodiment, the compound is amorphous.
    In one embodiment, the compound is a polymorph.
    In another embodiment, the compound is in a crystalline form.
    The invention also encompasses isotopically labeled compounds of the invention, which are identical to those mentioned here, except that one or more atoms are replaced by an atom having a mass
    . , 16/46. atomic or mass number other than the atomic mass or mass number usually found in nature.
    Examples of isotopes that can | - can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as H, 5th HC, Mc, * N, NO, 70.5P, ºP, * s, ** F and PC1, respectively.
    Certain isotopically labeled compounds disclosed (for example, those labeled with H and "* C) are useful in compound and / or substrate tissue distribution assays.
    Tritiated (i.e., * H) and carbon-14 (i.e., * C) isotopes are particularly preferred for their ease of preparation and detectability.
    In addition, substitution with heavier isotopes, such as deuterium (i.e., H) can confer certain therapeutic advantages resulting from increased metabolic stability (eg, increased in vivo half-life or reduced dosage requirements) and, consequently, - you may be preferred in some circumstances.
    Isotopically labeled compounds of the invention can, in general, be prepared following procedures analogous to those disclosed in the Examples here by replacing an isotopically labeled reagent with a non-isotopically labeled reagent.
    As used in the present disclosure, "NMDA" is defined as N-methyl-d-aspartate.
    In this specification, the term "therapeutically effective amount" means the amount of the present compound that will stimulate the biological or medical response of a tissue, system, animal or human being being considered by the researcher, veterinarian, doctor or other clinician .
    The compounds of the invention are administered in amounts therapeutically effective to treat a disease.
    Alternatively, a therapeutically effective amount of a compound is the amount required to achieve a desired therapeutic and / or prophylactic effect, such as an amount which is defined as necessary to provide maximum intensification of a behavior (eg, learning ), physiological response (for example, LPT induction) or inhibition of neuropathic pain.
    . , 17/46. As used here, "beta-gyrus motif" or "beta-gyrus" refers to a chemical structure having C * (alpha carbon) atoms (a carbon atom next to a carbonyl carbon) substantially close, for example, example, having a hydrogen bond between a donor residue and an acceptor, where the donor and acceptor residues are separated by a distance that corresponds to the distance of two or three peptide bonds. A disclosed chemical structure has, for example, a beta-spin motif when the structure includes bicyclic rings (for example, bicyclic spiro-lactame) that have restricted rotation, for example, which can be evidenced by nOe spectra ( Nuclear Overhauser Effect - Weak effect, for example, between atoms H3 and H5.
    Compounds Compounds, for example, peptide mimetics disclosed herein, i in some embodiments, are capable of binding to the NMDA ligand binding nucleus of SEQ ID NO: 1. For example, a disclosed peptide mimetic may have, for example, two alpha carbons that can be about 6 to about 14 Å or about 9 to about 14 Å or about 10 to about 13 Å apart. In some embodiments, a peptide mimetic considered may be internally restricted or conformationally restricted, so that it can, for example, mimic a biologically active conformation of a peptide. For example, a disclosed peptide mimetic may include a cyclic amide core, for example, a cyclic beta-lactam. For example, a disclosed peptide mimetic can be a disclosed compound having two modular units (for example, a bicyclic beta-lactam nucleus), where each unit can be replaced by a naturally occurring amino acid. For example, a disclosed compound can having a cute motif that is stable when administered to a patient, for example, is substantially stable in vivo or in an aqueous solution. In some embodiments, a disclosed compound may be capable of forming a hydrogen bond or may be capable of bonding to at least one, two, three or four amino acids of SEQ ID NO: 1, for example, selected from the
    . . 18/46. group consisting of PRO124, THR126, GLU178 and SER180. : A disclosed peptide mimetic may include a conformationally restricted (ie, non-peptidyl) synthetic component (eg, a portion of spiro-lactam) which may, for example, contribute to partial agonist activity at the site glycine content of the compounds. For example, disclosed compounds include those represented by the Formula: -Be tr) and Koer al
    TO Ro I and pharmaceutically acceptable salts, stereoisomers and N-oxides of the same; where T is, independently for each occurrence, CREATE and right O,. 1.20uU3; A is optionally present and is selected from phenyl or pyridine, where À is optionally substituted by one or more substituents selected from R1; Ri, is selected from the group consisting of H, hydroxyl, Dx - O S $ c (o) 1 4 alkyl; -SO7 ;, C1-C, 4 alkyl, C2-Ca alkenyl, phenyl, R; or Re where C1,4 alkyl, Ca, alkenyl or phenyl is optionally substituted by one or more substituents selected from Ra; XéCHouNn; R3 and R3 are independently selected from the group consisting of H, halogen, hydroxyl, phenyl, C14 alkyl, starch, amine or C> 2.4 alkenyl, where C; .4 alkyl, Ca, alkenyl and phenyl are optionally substituted by one or more substituents selected from R ,; Ra and R are independently selected from the group consisting of H, halogen, hydroxyl, phenyl, C14 alkyl, starch, amine, C14 alkoxy or C24 alkenyl, where C; 4 alkyl, Ca, alkenyl, C1.4 alkoxy and phenyl are optionally substituted by one or more substituents selected from Ra;
    . '19/46 Í: R, is selected from the group consisting of H, R ;, -S (O) z, S (O)> - C1-Ca alkyl, C14 alkyl, hydroxyl or phenyl where C14 alkyl, Ca, alkyl- and phenyl are optionally substituted by one or more substituents selected from R1;
    R; and R5 are each independently selected from the group consisting of H, halogen, C14 alkyl, Cia alkoxy, Ca, 4 alkenyl, cyano, amino, phenyl and hydroxyl, where C14 alkyl, Co4 alkenia and phenyl are optionally replaced by one or more substituents selected from Ra;
    R7 is selected from the group consisting of -C (O) -Rs, -C (0) -O-R. or -C (O) -NR-Ro; Rg is selected from the group consisting of H, C14 alkyl, phenyl 7 or heterocyclic, where C14 alkyl, phenyl or heterocyclic is optionally substituted by 1, 2 or 3 substituents selected from R1; Rs is selected from the group consisting of H, -C (O) -C14 alkyl or C (0) -O-Ci alkyl, where C1.4 alkyl is optionally substituted by 1, 2 or 3 substituents selected from Ra; R, is selected, independently for each occurrence, from carboxy, hydroxyl, halogen, amino, phenyl, C14 alkyl and Cy4 alkoxy; Ry is selected, independently for each occurrence, from the group consisting of carboxy, hydroxyl, halogen, amino, phenyl, C14 alkyl, C14 alkoxy and -NH-R .; R. is selected, independently for each occurrence, from the group consisting of: -C (0) -O-C; 4 alkyl; and -C (O) -C14 alkyl; e 'Ra is selected, independently for each occurrence, from HeC 1, alkyl; and pharmaceutically acceptable salts, N-oxides or stereoisomers thereof.
    For example, disclosed compounds may include those represented by:
    . . 20/46 Rãx Aa Ry 'RS T. NR i “Nx 2 RO Ja where R; is C (O) -C24 alkyl, where C2,4 alkyl is substituted, on a carbon, by NH, or -N-carbobenzyloxy and, on a different carbon, by hydroxy. For example, R ;, can be C (0) -O-C14 alkyl (for example, methyl, ethyl, propyl, where Ci, aliquyl is replaced by phenyl and Ra, Ray, R; and Ra are provided above In another embodiment, R, and R; of the formula la can each be independently selected from an amino acid, for example, an L- or .D-isomer of an amino acid, for example, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, iso- leucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and / or valine, for example, R; and R2 can each be independently | -Thr or L-Ser, for example, compounds such as: Ss OO j N DP & Ne. We te no. AN So qa de x Mor e ”Mon su o
    EN É> x% ke)
    NS HANS rr * where R'is selected from the group consisting of H or C1.4 alkyl. In one embodiment, R1 can be carbobenzyloxy or can be represented by;
    . . 21/46 Re, so ': & where X can be N; R5: can be H; and Rg can be -C (O0) -C7.4 alkyd (for example, ethyl, propyl, n-butyl or t-butyl), where C2.4 alkyl is replaced, on a carbon, by NH> or -N -carbobenzyloxy and, in a different carbon, S porhydroxy.
    In certain embodiments, R3 may be phenyl (optionally substituted as above) or may be H. R> may, in some embodiments, be a -C (O) -C> .4 alkyl, (for example, ethyl, propyl , n-butyl or t-butyl), optionally substituted, on a carbon, by NH; and, in another “10 carbon, per hydroxyl. For any R group considered to include Ci alkyl (for example, R1, R3, Rs), the alkyl may be selected from the group consisting of methyl, ethyl, propyl, n-butyl or t-butyl and wherein said C, 4 alkyl is optionally substituted by one, two or three substituents selected from the group consisting of F, Cl or Br. Such compounds may have different isomerizations and, in some embodiments, may be represented by: Rs "x YR; Rs EN R> Ri O Ta or Ri O Tb. Where Ri, R2, R3, Rg and R; can be as described above In another embodiment, compounds represented by the formula | are considered: BR Pa Ry RR O Di and salts, stereoisomers and pharmaceutically acceptable N-oxides of the same, where: R1 is selected from the group consisting of H, hydroxyl, -S (O) 2-C1.
    . . 22/46 R3 + Hao) Ú 4 alkyl; -SO2, C14 alkyl; R; or Ro;
    XéCHouN,
    R; 3 and R3 are each independently selected from the group. po consisting of H, halogen, hydroxyl, phenyl, Cy4 alkyl, starch, amine or Cr, alkenyl, where Ci, alkyl, Ca, alkenyl and phenyl are optionally substituted by one or more substituents selected from R, a;
    R2 is selected from the group consisting of H, R7, -S (O), S (O) 2- C14 alkyd, C14 alkyl, hydroxyl or phenyl, where C1.4 alkyl, Ca, 4 alkenyl and phenyl are optionally substituted by one or more substituents selected
    i 10 cionadosdeR,;,
    . - Rs is selected from the group consisting of H, halogen, Ci, alkyl, C14 alkoxy, Ca, alkenyl, cyano, amino, phenyl and hydroxyl, where Ci. Alkyl, Cx, alkenyl and phenyl are optionally substituted by one or more substituents selected from R ,;
    Rs is selected from the group consisting of H, halogen, Ci, alkyl, C14 alkoxy, Cr, alkenyl, cyano, amino, phenyl and hydroxyl, where C14 alkyl, Co, alkenyl and phenyl are optionally substituted by 1, 2 or 3 selected substituents of Ra;
    R; is selected from the group consisting of -C (O) -Ra, -C (0) -O-R.a or -C (O) -NRg-Ro;
    Rs is selected from the group consisting of H, C14 alkyl, phenyl or heterocyclic, where C1.4 alkyl, phenyl or heterocyclic is optionally substituted by 1, 2 or 3 substituents selected from Ryv; or
    Ri eRs, tongadas along with the formula Il, form:
    R N NR; o N o R; ;
    | | | . . 23/46 Í. R; 3 is selected from the group consisting of H, -C (O) -C14 alkyl or C (0) -O-C14 alkyl, where C14 alkyl is optionally substituted by. 1, 2 or 3 substituents selected from Ra; Ra is selected, independently for each occurrence, from carboxy, hydroxyl, halogen, amino, phenyl, C14 alkyl and Cy, alkoxy; ! R, is selected, independently for each occurrence, from the group consisting of carboxy, hydroxyl, halogen, amino, phenyl, C; 4 alchemy, C14 alkoxy and -NH-R .; . R-. is selected, independently for each occurrence, - C (0) -O-Ci4 alquita; and -C (O) -C1.4 alkyl; and Ra is H or C14 alkyl. 'In an exemplary embodiment, the R portion of the formula |, II, la or Ib can be selected from the group consisting of:. O Os, AX O o; CWN OH, HN OH. H oO, E => nho O n PR z SS Os no O ço e 2 Õ q Exemplary compounds include: H
    N is S nO o (Compound B), A O Ho and “O x à O (AK5e (AK-52). Compound selected from the group consisting of
    Eee ogr steels the SESE EAD
    ASS Su:
    . . 25/46: o> "“> ”A, QxXom om and EX EP Om oo o. O [oe o bro, FPF (CH wH k NH
    N NON Ho. O
    N Axo 'HNÃTO (where ne 0, 1, 20u 3) and dd or pharmaceutically acceptable salts, stereoisomers or N-oxides of the same.
    The compounds of the present disclosure and formulations thereof are intended to include a D-isomeric form, an L-isomeric form or a racemic mixture (D- and L-isomeric forms) of any one or more of the compounds. In addition, compound formulations are intended to include any combination or ratio of L-isomeric forms to D-isomeric forms of one or more of the analogs described herein. These and other formulations of the disclosed compounds comprising a greater proportion of the D- and / or L-isomeric analog may have enhanced therapeutic characteristics with respect to racemic formulations of a disclosed compound or mixtures of compounds. For example, disclosed compounds can be enantiomers, for example: PDS P or NA AH
    EN SN N v N
    H H o HAN; oO Ho.
    . . 26/46 | | . Disclosed compounds can provide efficient cation channel opening at the NMDA receptor, for example, they can bind or as-. associate with the glutamate site of the NMDA receptor to assist in opening the cation channel. The disclosed compounds can be used to regulate (activate or deactivate) the NMDA receptor through action as an agonist.
    Other compounds considered herein include those having a cyclic amide core. Other exemplary compounds can be, in one embodiment, peptides or, in another embodiment, peptide mimetics.
    Compounds considered include those represented by: o -. R6 o o RI ua 'R5 E Re where: R1 is H or benzyl group; Ra is H or benzyl group; o No, | the NH: | The, Fr3 Rs is or the “R2. H o NH,, AN o Rg is either: | R> is H or CH;
    "1 |
    Í | . : 27/46: R3 is H or CHz; | and stereoisomers or pharmaceutically acceptable salts or N-oxides! - stable from them. Exemplary compounds include: and OH À O finger Y and 22 ES 10077) o; O ;
    H o md Id e LIA, OH: “ow DNH CIA É 9 dao 'NH NH N / fo Not Ho H OH. nO Jd. ACE tdo Ao & SS o o o NH; 1 Ss X Ni S 9 x Di no "and NH; i: ed DS a“ or iou. The compounds as described here can be partial NMDA receptor agonists at the glycine site. A partial agonist, as used herein context, it should be understood as meaning that, in a low concentration, the analogue acts as an agonist and, in a high concentration, the analogue acts as an antagonist.Glycine binding is not inhibited by glutamate or competitive glutamate inhibitors and also does not bind to the same site as glutamate on the NMDA receptor. A second and distinct glycine binding site exists on the NMDA receptor. The ligand-activated ion channel of the NMDA receptor is thus under the control of at least minus these two distinct allosteric sites. Disclosed compounds may be capable of binding or associating with the NMDA receptor glycine binding site. In some embodiments, the disclosed compounds may have a potency that is 10 times or greater
    . . 28/46 - than the activity of partial agonists of the glycine site of the existing NMDA receptor.
    For example, the disclosed compounds may have - a potency 10 times to 20 times enhanced compared to GLYX-13. GLYX-13 is represented by: À À KT oH “N TZ AO UNHA or For example, compounds are provided here that can be at least about 20 times more potent when compared to GLYX-13, as measured by conductance from a single Explosion-activated NMDA receptor-activated neuron (Ilnmuoa) in a culture of hippocampal CA1 pyramidal neurons at a concentration of 50 nM.
    In another embodiment, a compound provided may be capable of generating a single neuron conductance activated by a NMDA receptor stimulated by a single shock (Inmoa) in hypocaloric CA1 pyramidal neurons in concentrations of 100 nM to 1 µM.
    The disclosed compounds - 15 may have enhanced potency when compared to GLYX-13, as measured by the magnitude of long-term potentiation (LTP) in Schaffer-CA1 collateral synapses in in vitro hippocampal sections.
    Preparation of Compounds In some embodiments, a disclosed compound, for example, a peptide mimetic, having a beta-gyre motif capable of binding to the NMDA ligand-binding nucleus of SEQ ID NO: 1, can be formed incorporating one or more dehydro-amino acids within a peptide.
    For example, peptides containing dehydrophenylalanine and / or dehydroleucine — and alpha-aminobisobutyric acid can be incorporated to produce a peptide mimetic having a beta-spin motif.
    In another embodiment, a disclosed compound can be formed using bicyclic beta-turn Dipeptide motifs | restricted.
    This approach is based on the substitution of the dipep-
    . : 29/46 'tidic by incorporating a carboxyl and an amino group in positions geometrically suitable for peptide coupling (see figure. Below) for gyration induction. need assisted cata. Saes css jota va pi eniraiaêr ini 2 nina “4 do NE: dd dO OE no SoM | of QN and Vl Í. Typical beta-turn for Motif Bor a. For example, a dipeptide component, such as one or more azobicyclononans, can be incorporated to produce a structure having a beta-spin motif. In another example, a disclosed peptide mimetic may include a central structure as exemplified below, for example, instead of two, three or four amino acids: 227
    A LN HN uv o CO Me In some modalities, an azacycloalkane can mimic a beta-gyro mimetic, for example: 4 2 caught TT, al O PAN o SE) RA E 2. e 'o os | 2 & Os õv CO | x P Bo Com i The following schemes are representative synthetic routes that. can be used to prepare the disclosed compounds and intermediates therefrom.
    . . 30/46 BR Scheme 1: Lo - Cano LN o Paco o N CH, ON N ACOE N | d 9 Chz OQ bz O o 3 4 5 o QoBn oBn x PC Buli, THF Ho »“ o NHCbz NHCbz 6 7 o oH o oH | PS A NO AO] NHCbz | NHCbz ': Cbr O; Cbr O 9 Interest Va PAO o “oH o oH H NH2 H NH o 16 o "n Scheme 2) º NE cost º N o ta 2, Cc H SN. o Ceric ammonium nitrate or" CAN "is the chemical compound with the formula (NHa) -Ce (NO; 3) s.
    This orange-red water-soluble salt is widely used as an oxidizing agent in organic synthesis.
    This compound is used as a standard oxidant in quantitative analysis.
    PMP refers to p-methoxybenzylidene; Cbz refers to an OQ radical. 20 carbobenzyloxy that can be represented as: PF.
    . . 31/46 - Compositions: In other aspects, formulations and compositions comprising. the disclosed compounds and optionally a pharmaceutically acceptable excipient are provided. In some embodiments, a formulation considered comprises a racemic mixture of one or more of the disclosed compounds.
    Formulations considered can be prepared in any of a variety of forms for use. By way of example and not limitation, the compounds can be prepared in a formulation suitable for oral administration, subcutaneous injection or other methods for administering an active agent to an animal known in the pharmaceutical art. : Amounts of a disclosed compound described here in a formulation may vary according to factors such as the individual's sickness, age, sex and weight. Dosage regimens can be adjusted to provide the optimal therapeutic response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased,. as indicated by the requirements of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in the form of a dosage unit for ease of administration and uniformity of dosage. Dosage unit form, as used here, refers to physically distinct units suitable as unitary dosages for the mammal to be treated; each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
    The specification as to the dosage unit forms of the invention is guided by and directly dependent on (a) the unique characteristics of the selected compound and the particular therapeutic effect to be obtained and (b) the limitations inherent in the composition technique, such as a active compound for the treatment of sensitivity in individuals.
    As used herein, "pharmaceutically acceptable carrier" or o | . . 32/46: "excipient" includes any and all Therapeutic compositions should typically be sterile and. stable under manufacturing and storage conditions. The composition can be formulated as a solution, microemulsion, liposome or other ordered structure suitable for the high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid glycol polyethylene and the like) and suitable mixtures thereof. The proper fluidity can be maintained, for example, by using a coating, such as lecithin, maintaining the required particle size in the case of dispersion and by using surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols, such as mannitol, sorbite! or sodium chloride in the composition. Prolonged absorption of injectable compositions can be maintained by including, in the composition, an agent which delays absorption, for example, monostearate salts and gelatin.
    The compounds can be administered in a release formulation over time, for example, in a composition which includes a slow release polymer. The compounds can be prepared with vehicles that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, poly-polyesters, polylactic acid and poly-lactide-polyglycolide (PLG) copolymers. Many methods for preparing such formulations are generally known to those skilled in the field.
    Sterile injectable solutions can be prepared by incorporating the compound in the required amount in an appropriate solvent with one or a combination of ingredients listed above, as required, followed by filtered sterilization. In general, dispersions are prepared by incorporating the active compound in a sterile vehicle which contains a basic dispersion medium and the other required ingredients from those listed above. In the case of sterile powders for the preparation of injectable solutions'
    . In sterile 33/46 BR, the preferred methods of preparation are vacuum drying and lyophilization, which provide a powder of the active ingredient plus any additional desired ingredient from a previously filtered sterile solution of the same.
    According to an alternative aspect of the invention, a compound can be formulated with one or more additional compounds that are intensi | show the solubility of the compound. | Methods Methods for treating cognitive disorders and intensifying learning are provided. Such methods include administration. a pharmaceutically acceptable formulation of one or more of the compounds disclosed to a patient who needs it. Also considered are methods of treating patients who are suffering from 'memory deficits associated with aging, schizophrenia, special learning disorders, seizures, post-stroke seizures, cerebral ischemia, hypoglycemia, heart attack, epilepsy, migraine, as well as Huntington's disease, Parkinson's and Alzheimer's. Other methods considered here include the treatment of cerebral ischemia, stroke, brain trauma, brain tumors, acute neuropathic pain, chronic neuropathic pain, sleep disorders, drug addiction, depression, certain vision disorders, withdrawal from ethanol, anxiety and memory and learning disabilities. In yet another aspect, a method for enhancing pain relief and providing analgesia to an animal is provided.
    EXAMPLES The following examples are provided for illustrative purposes only and are not intended to limit the scope of the disclosure. Example 1 - Synthesis of B-spiro lactam derivatives derived from pyrrolidine The following reaction sequence was used (Scheme A) to synthesize spiro-lactam. Hexahidrol, 3,5-triazines, Cbz-1-proline acid chloride and N- (Cbz) O- (benzyl ether) -L-threonine acid chloride are used with
    . , 34/46: mo initiation materials. Scheme A
    PMP - | N
    It is N, NO 9 PH A pve N — PMP Y o Y FuN, BF; .O0Et, CH, CI !; H Eb UN. BF ;, OEL, CH, C); be É 1 3 N — PMP CEAN wo | PACO NH Y ces v Acoft N && O Ch O o. 3 Fi 5 o OBn o oBn. PCI Wi DIF Ho ——the NHCbz NHCbz 6 7 o oH o oH
    N N | NHCbz | NHCbz bz O; Che O Interest ur o OH o oH Os Os
    H NH H NH '9 x Sm THE
    . . 35/46. Table 1 - Quality already by HPLC | (M'H) | 20 mg 93 261 YES o ee [| SS
    CUBZ O pe o N (purity o> 95%) AA 17 mg 73 es TS) Example 2 - Synthesis of Compounds and Intermediates Spiro Lactame 3. The synthesis of spiro-lactam 3 C4 substituted. a Staudinger reaction of methyleneimine derived from triazine 2 was conducted. The [2 + 2] -cycloaddition reaction between cetene derived from Cbz-1-proline acid chloride and methyleneimine was performed as follows: ketene | was generated by dehydrochlorination of the acid chloride with triethylamine at - 40 ºC for 45 min and then a solution in triazine dichloromethane 2 and boron trifluoride etherate (which depolymerizes the triazine) was added After 12 hours, the corresponding lactame 3 spiro was obtained as a | mixture of enantiomers, with a yield of 30 to 50%. The oxy- | of the PMP group from the spiro lactame 3 in the presence of CAN pro | portioned the N-unsubstituted derivative lactame 4 which, when | treatment with Pd (OH) 2 / C, provided the intermediates of lacta- | corresponding me5.
    Spiro lactame 4 was obtained in 93% purity (HPLC)! after purification by chromatography on silica gel. Spiro lactam 5 was obtained with purities> 90% (through NMR) after chromatography on silica gel using gradient elution from 20% to 70% ethyl acetate / cyclohexane in a 50% yield. Example 3 - Synthetic Pathways to Triazine Intermediate Compounds 2. To a solution of p-anisidine (24.69, 200 mmol.) In a mixture (500 mL) of ethyl acetate / water (1: 1), cooled to 0ºC , an
    . '36/46' aqueous solution (17 mL) of formaldehyde (37%) was added. The reaction mixture was stirred for 3 hours at 0ºC, then 1 hour at room temperature and the organic layer was separated, washed with water (50 ml) and dried over Na7; SO ,. The solvent was removed in vacuo and a white solid was obtained. This solid was washed once with diethyl ether to provide 26.3 g (the solid was dried at 40 ° C overnight) of pure triazine 2 in a 97% yield. Spirame lactam intermediates 3. To a stirred solution of N-benzyloxycarbonyl L-proline acid chloride (5 g, 18.7 mmol.) In dry dichloromethane (65 mL) cooled to -40 ° C was added dropwise dry triethylamine (10.4 mL, 74.7 mmol.). The solution turned yellow to confirm that the ketene was formed.
    After 45 min at 40ºC, a purple solution of triazine 2 (2.52 9, 6.16 mmol.) And BF; OEt, (2.37 mL, 18.7 mmol.), Previously mixed in CHCI (35 mL) , was added dropwise. The mixture was allowed to warm slowly to room temperature and then dissipated with saturated aqueous NaHCO3. The aqueous layer was extracted twice with CH3 Cl, (20 ml); the combined organic layers were washed with brine (20 ml) and dried over anhydrous NazSO. The solution was then concentrated and purified by column chromatography on silica gel using gradient elution at 100% cyclohexane / cyclohexane to 20% ethyl acetate / cyclohexane to provide 7.01 g of pure product at a yield of 37%. Spiro lactam 4 intermediates. To a stirred solution of spirolactam 3 (2.4 g, 86.55 mmol.) In acetonitrile (49 mL) at -10 ° C was added dropwise over 1 hour, CAN (10, 8 g, 19.6 mmol.), Previously dissolved in H, zO (30 ml). After the addition was complete, the mixture was stirred. —That lasts 45 min (TLC did not show remaining starting material). The reaction mixture was diluted with ethyl acetate (100 mL) and NaHCO; saturated (5OmL). To the organic layer, water (100 ml) and solid sodium bisulfite (20 eq) were added. The organic layer was washed with brine and dried over anhydrous Na-SO. The solution was then concentrated and centrifuged by
    . '37/46' column chromatography medium over silica gel using elution in a gradient of 100% cyclohexane / cyclohexane to 50% ethyl acetate / cyclo] hexane to provide 0.87 g of pure product in a 50% yield. Spiral lactam 5 intermediates (AK-51). 0.5 g of 4 were dissolved in 20 ml of ethyl acetate and transferred, via cannula, to a vial under H, (1 atm) containing 50 mg of 10% PA (OH) -C catalyst. The mixture was stirred overnight under H; at 50 Psi and then the catalyst was filtered through celite. The organic layer was concentrated and purified by chromatography on silica gel to provide 120 mg of product in a 50% yield. 7 N- (Cbz) -O- (benzyl ether) -1-threonine acid chloride 7. To a stirred solution of N- (Cbz) -O- (benzyl ether) -1-threonine (0.95 g, 2.7 mmol.) in dry ether (27 mL) PCI was added; (0.61 g, 2.9 mmol.) And the mixture was stirred for 3 hours at room temperature. Then, the solvent was removed with high vacuum at room temperature. Toluene was added and removed as above. The crude white solid was used without any purification for the coupling reaction.
    Spiro lactam intermediates 8 and 9. To a stirred solution of spirolactam 4 (200 mg, 0.76 mmol.) In dry THF (4 mL) at -78 ° C was added BuLi (0.32 mL, 0.80 mmol. In hexane) drop by drop. After the addition was complete, the mixture was stirred at -78 ° C for 1 hour. N- (Cbz) -O- (benzyl ether) -1-threonine acid chloride 7 in THF (4 mL) was added at -78 ° C. The mixture was stirred overnight at -78 ° C to room temperature.
    The reaction mixture was dissipated with NH, saturated CI (10 ml) and ethyl acetate (10 ml) was added. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried with MgSO, and concentrated to provide 0.44 g of crude product. The crude product was eluted through silica gel with a gradient of CHCI, 100% to MEOH / CHCI; to 2%, providing fractions that fluctuated, in terms of purity, from 44% to 73%. This reaction was repeated on 0.28 g of spiro
    . õ 38/46 BR lactame 4 and provided, after chromatography, fractions with purities ranging from 50% to 73%. - Example 4 - NMDA Receptor Binding Assay Tissue Preparation Crude synaptic membranes were prepared from rat brain or rat hippocampus (male Sprague-Dawley rats) and washed extensively to remove endogenous amino acids, as previously described by Ransom and Stec (1988). Briefly, the crude synaptic membranes were resuspended in 20 volumes of 5 mM Tris-HCl buffer, pH 7.4 (for use in PHITCP binding experiments) or in 20 volumes of 5 Tris-acetate buffer mM, pH 7.4 '(for use in [ºH] glycine binding studies) and homogenized using a Polytron (Virtis Shear; Virtis, NY, USA). The membranes were then pelleted by centrifugation at 48,000 g for 20 min.
    This step was repeated twice and the homogenate was stored at -70º C in the same buffer.
    Before each use, the homogenates were thawed at room temperature, pelleted and washed four more times.
    For the experiment with [* H] glycine, the pellet was first incubated for 30 min at | 25ºC in 5 mM Tris-acetate buffer containing 0.04% Triton X-100 and then washed four times by means of homogenization and centrifugation.
    The final washed membranes were resuspended in concentrations of 2-3 mg / ml in 5 mM Tris-HCl buffer or 5 mM Tris-acetate buffer.
    TCP Binding Assays: [Specific HITCP binding measurements were performed as previously described (Haring et al., 1986, 1987; Kloog ef a /., 1988a). The final reaction mixtures consisted of 50-100 µg of membrane protein in 200 µl of 5 mM Tris-HCI buffer: and contained [PHJTCP or [ºHJTCP and the appropriate concentration of NMDA receptor ligands or mAbs.
    The reactions were initiated by adding the membranes to the reaction mixtures.
    Unless otherwise indicated, binding tests were performed under unbalanced conditions at 25 ° C for 1 h.
    Non-specific binding was determined in parallel samples containing 100 µM of unlabeled PCP.
    Binding reactions were
    . . 39/46 'terminated by filtration over Whatman GF / B glass filters that had been pretreated with 0.1% polyethyleneimine for 1 h. - The dissociation of [ºPH] JTCP from its membrane binding site was measured after equilibrating the receptors with [PHITCP at 20 nM for 120 min.
    Dissociation reaction was initiated by adding 100 µM unlabeled PCP in the presence and absence of NMDA or mAb receptor ligands.
    The reactions were terminated immediately (time zero) and after incubation for the additional time periods indicated.
    The effects of the three compounds were examined on 1) the conductance of a single neuron activated by the NMDA receptor (lnmoDa) on hippocampal CA1 pyramidal neurons and 2) the magnitude of long-term potentiation (LTP) and long-term depression (LTD) in collapsed synapses | of Schaffer-CA1 in hippocampal sections in vitro.
    It was reported that | GLYX-13 exhibits a low concentration (1-10 uM) intensification of Inv. Pa activated by explosion and LTP, while simultaneously reducing | LTP is stimulated by a single pulse.
    A concentration | one hundred times greater than 100 µM GLYX-13 converted to LTP reduction] and Inmoa explosion and no longer affected LTP. | Compound B showed a 20-fold intensification in power compared to GLYX-13, 50 nM of that compound intensely intensified Ivmoa stimulated by a single shock (1A) and by explosion (1B), as well as doubling the magnitude of LTP ( 15). In contrast, NRX-10,050 at 1 µM significantly reduced IlnvDa stimulated by a single shock | (1C) and explosion (1D), remaining GLYX-13 at 100 µM (see Figure 2). AK-51 exhibited less potency than compound B, but a broader concentration range in its stimulatory actions (Figure 3). NRX-10,051 at 100 nM (24) and 1 µM intensified Inwoa stimulated by a single shock, while NRX-10,051 at 1 µM doubled the magnitude of LTP (2D), while not changing the LTD (2E) . AK-52 produced only a mild intensification of INnmoa stimulated by a single shock at a low concentration (100 nM; 3A), which converted to a significant reduction in lnvDa EM at a concentration
    . . 40/46. 1 CU (3B). AK-52 at 100 nM produced an intensification of similar LTP, in terms of magnitude, to compound B and AK-51, but this was converted to - a slight but significant reduction in LTP at a concentration of 1 uM, without altering LTD.
    These three compounds showed an increase of about 20 times in potency compared to GLYX-13. Compound B is the most potent intensifier of Inmoa in low concentrations (50 nM). Although the: intensification of Invoa by AK-51 was of lesser magnitude, this effect remained when the AK-51 was increased 10 times (100 nM to 1 µM).
    The AK-52 was weaker intensifier of Invoa and this effect reverted more quickly to a frank reduction in InvDa. 'These compounds enhanced the magnitude of LTP to similar degrees, approximately to a doubling. GLYX-13 was the only compound that could simultaneously increase LTP and reduce LTD: AK-52 does not affect LTD, even in a concentration that reduced InvuDa. GLYX-13 can selectively enhance InvDa mediated by NMDA receptors containing NR2A / B subunits and these receptors are located in extrasynaptic foci and are more strongly activated by neuronal explosions that induce LTP. Although all compounds tested have potent effects on LTP and Invmna, the lesser effects on LTD suggest that they have increased selectivity for NR2A / B containing NMDA receptor glycine sites than GLYX-13. Example 5 - T-Maze Learning Model 3-month old male rats from Fisher 344 X Brown Norway F1 (FBNF1) were used for this study. The T-maze was constructed with arms (45 cm long x 10 cm wide x 10 cm high) made of black Plexi-glia surrounding the maze. Two plastic bottle caps, covered with wire mesh, were attached to the end of each target arm in which the food as a reward (Cheerios, 100 mg / piece) was placed. Before training began, the animals were gradually deprived of food to approximately 85% of their weight without food. In the three successive days before the start of training
    : '41/46. the animals were accustomed to the T-maze with food located through the maze.
    On the first day of training, the animals were rewarded for choosing the right arm and were trained to a criterion of 9 out of 10 consecutive correct choices.
    On the second day of training, the animals were rewarded for choosing the left arm for a criterion of 9 out of 10 consecutive correct choices.
    On the subsequent testing day, the animals were given injections of AKS1 (0.3, 1, 3, 10, 30 mg / kg po) or DMSO vehicle (1 mg / ml; Sigma, Saint Louis MO) in a blind manner via forced gastric ingestion (4 ", 16-ga; Braintree Scientific, Braintree MA) 60 min before the start of testing (n = 8-9 per group). In the first testing trial, both arms were with food bait and, for the 20 subsequent trials, only alternate choices (opposed to the previous animal choice) were rewarded (inter-experiment interval of 30 sec) .The number of experiments until criterion (5 consecutive correct choices) was calculated for each animal.
    The data were analyzed using ANOVA, followed by Fisher's PLSD post hoc tests that compare individual doses of drug with vehicle (o. = 0.05). Figure 5 represents experiments (mean + SEM) according to the criterion in the alternating T-maze task (20 experiments) in 3-month-old rats deprived of food.
    Animals were injected p.o. with 0, 0.3, 1, 3, 10 or 30 mg / kg of AKO5S1 in DMSO vehicle (n = 8-9 per group) 60 min before starting testing. *** P <0.001, ** P <0.01, Fisher's PLSD post hoc vs. vehicle.
    Example 6 - Formalin Test for Neuropathic Pain The experiments were conducted as previously described (Abbott et al!., Pain, 60, 91-102, 1995; Wood et al., Neuroreport, 19, 1059-1061 2008). Male 3-month-old rats from F1 Fisher 344 X Brown Norway (FBNF1) were used for this study.
    Before the start of testing, the animals were used to the testing chamber (opaque Plexiglass 30 x 30 x 60 cm) for 10 min per day for 2 consecutive days.
    On the testing day, the animals were given injections of AKS1 (0.3, 1, 3, 10, 30 mg / kg p.o.) or DMSO vehicle (1 mg / ml; Sigma, Saint
    . . 42/46 Louis MO) in a blind manner via forced gastric ingestion (4 ", 16-ga; Braintree Scientific, Braintree MA) 60 min before formalin injections - (n = 8-9 per group). The animals were placed in the testing chamber 10 min before formalin injection.
    For the injection of formalin, the rats were manually safe and a subcutaneous injection of 1.5% formalin (50 ul with a 26-ga needle; Sigma, Saint Louis MO) was provided in the pad of the lateral paw on the plantar surface of the left hind leg.
    The animals were recorded from below with the aid of an angled mirror for 50 min post formalin injection.
    The total time consuming licking the injected part and the total number of indentations of the injected paw during the posterior phase (30-50 min post formalin injection) were quantified 7 in a blinded manner by an experimenter trained with high reliability (r> 0.9) inter- and intra-classification for both measures.
    All animals were sacrificed with CO2 immediately after testing.
    Data were analyzed using ANOVA, followed by Fisher's PLSD post hoc tests that compare individual doses of drug with vehicle (a = 0.05). Figure 6 represents the% analgesia (mean + SEM) defined as a% reduction in the setbacks in the response at a later stage (30-50 min) after intraplantar injection of formalin (50 µL of 1.5% formalin). Example7 - Oral Formulations that Enhance Learning and Memory An oral preparation of AK-51 was made in dimethyl sulfoxide (DMSO). All doses were administered in a volume of 300 µl.
    The animals were then fed p.o. through forced oral ingestion (forced feeding through the mouth with a feeding needle inserted) of a volume calculated to deliver a defined dose based on body weight to the animal, as follows: 0.0 mg / kg in DMSO at 300 uL ( vehicle); 0.3 mg / kg in DMSO at 300 µl; 1.0 mg / kg in DMSO at 300 µl; 3.0 mg / kg in DMSO at 300 µl; 10.0 mg / kg in DMSO at 300 µL; 30.0 mg / kg in DMSO at 300 µl.
    The animals were injected 60 minutes before the start of testing with one of the dose quantities mentioned above.
    Then, a task in the alternating T-labyrinth (20 experiments) was used to assess the
    . . 43/46. learning behavior in animals.
    This protocol is described in Example 5. Briefly, the T-maze is a task of choice.
    The mouse . in question was placed at the base of the "T". After a short delay, he was allowed to explore the maze and choose to enter the right or left arms.
    The choice is classified according to a variety of criteria, including spontaneous alternation, reward with evidence or indicating a preference.
    Based on the criteria used in this study, the T-maze was used to test learning and memory.
    Food placed at one end of the labyrinth was used as the positive reinforcement for each animal test.
    Animals given a dose of 1.0 mg / kg through the mouth of AK-51 demonstrated a statistically significant increase in learning behavior in the T-maze test (P <0.001). Animals given a dose of 3.0 mg / kg through the mouth of the non-peptide analog NRX-10,051 also demonstrated a statistically significant enhancement of learning behavior in the T-maze test (P <0.07). Example 8: Isomers The two different isomers of AK-55 were used in an NDMA binding test, as in Example 4. One isomer of AK-55 potentially intensifies NMDA, while the other is not.
    Figure 7A indicates the time course of the effect of applying a 15 min bath of AJ-55 at 1 µM (solid bar) on the current activated by pharmacologically isolated NMDA receptor normalized in CA1 pyramidal neurons under whole cell recording ( mean + SEM, n = 6). B: time course of effect | All application of a 15 min bath of AK55 at 1 µM (solid bar) over the current activated by a pharmacologically isolated NMDA receptor standardized on CA1 pyramidal neurons under record with whole cells (mean + SEM, n = 7). C: time course of application of an AK6 bath | at 1 uM (solid bar, filled circles, n = 8) compared to treated con- trol sections (open circles, n = 8) on the magnitude of long-term potentiation (LTP) of the postsynaptic potential decline extracellular excitatory (mean + SEM, fEPSP) induced by collateral stimulation of
    . 44/46. High frequency schaffer (2 x 100 Hz / 500 msec). Example 9: Biochemical Assays: Table B represents the results of binding assays against several targets with AKS51: TableB | Guameto AmPR | to | om | ss [NMDA Ginamate Gina - | straight | om | = | - [NDA Phenthamid Cevenso | mo | tom | | | Glmamate NDA Pofamia | straight | tom | 6 [even náossemo - | and | om | o [Ghana Sense aesmenna - | straight | ow | the [| cansidepalssoneRG - [momano | tom | 3 Example 10: Identification of B-gyrus in spiro compound Experiments with 1-D proton, 'H, * C, DEPT, 2-D homo-nuclear experiments (DQF-COZY, TOCSY, NOESY) and HSQC and HMBC hetero-nuclear experiments in DMSO-D; at 30 degrees Celsius are conducted to confirm the exact chemical carbon shifts and chemical proton shifts of the compound spiro: no H.
    TSNH 6 Y | H 8 H | Chemical deviations are observed as follows: 1H, DMSO-ds,! 600 MHz, 8 in ppm, TMS at 0.00 ppm: 8.72 (bs, 1H), 3.47 (dd, 2H), 3.37 (t, | 2H) 2.21 (m, 2H), 2.02 (m, 1H), 1.89 (m, 1H) (see Figure 12); | CL, DMSO-ds, 150 MHz, 8 in ppm, reference DMSO at 39.5 | ppm: 169.6, 68.7, 45.6, 40.7, 32.9, 22.4. | The chemical shift of the amide proton was located at 8.72
    . . 45/46. ppm as a broad singlet and cross peaks were observed between 8.72 and 3.37. This discovery established the chemical shift from H-3 to 3, A7 ppm. - nOe weak between 3.37 and 2.21 ppm indicates populations of H-5 at 2.21 ppm. Total correlation was found from 3.37 to 2.21 ppm to 2.02 and 1.89 ppm; correlation nOe was observed between 2.21, 2.02, 1.89 and 3.37 ppm. This discovery was incomprehensible, since the resonances H-6 and H-7 are: H-6 (2.02 | and 1.89 ppm), H-7 (3.37 ppm). The 2-D heteronuclear experiments (HSQC i and HMBC) also confirmed the chemical deviations of protons and carbon. | | The chemical shifts of individual protons and carbons were ob- | served as follows: | 8.72 (bs, H-2, 1H), 3.47 (dd, H-3, 2H), 3.37 (t, H-7, 2H), 2.21 (m,! 'H-5 , 2H), 2.02 (m, H-6, 1H), 1.89 (m, H-6'1H) 169.6 (C-1), 68.7 (CH), 45.6 (C -7), 40.7 (0-3), 32.9 (0-5), 22.4 (C-6) 'A weak number between H-3 and H-5 is suggestive of restricted rotation of rings one with respect to the other. The absence of hydrogen bonds in which the donor and acceptor residues i (i + 3) and also the absence of long-range nOe (C atoms <7Aº) between two rings indicates that there is no significant secondary duplication. Example 11: Experiments with 1-D proton, 'H, "* C, DEPT, 2-D homo-nuclear experiments (DQF-COZY, TOCSY, NOESY) and HSQC and HMBC hetero-nuclear experiments in DMSO-Ds at 30 degrees Celsius are conducted to confirm the exact chemical carbon shifts and chemical proton shifts of the compound spiro: CX N TO
    HNO Q, O * H NMR in DMSO is shown in Figure 13. A 600 MHz N15-HSQC experiment can be performed to confirm chemical amide shifts. :
    . . 46/46. EQUIVALENTS Those skilled in the field will recognize or be able to. determine, using no more than routine experimentation, many equivalents to the specific modalities of the invention described here. Equivalent amounts are intended to be covered by the following claims.
    INCORPORATION BY REFERENCE The entire contents of all patents, published patent applications, websites and other references cited here are expressly incorporated in full by reference, including the following incorporated by reference: Abbott FV, Franklin KB, Westbrook RF, The formalin test: scoring 'properties of the first and second phases of the pain response in rats. Pain, 80 (1995) 91-102; Bennett GJ, Xie YK., A peripheral mononeuropathy in rat that 'produces disorders of pain sensation like ose seen in man. Pain, 33 (1988) 87-107; U.S. Patent No. 7,273,889; U.S. Patent No. 6,821,985; U.S. Patent No. 6,667,317, U.S. Patent No. 6,635,270; U.S. Patent No.
    6,521,414; U.S. Patent No. 6,197,820; U.S. Patent No. 6,147,230; U.S. Patent No. 6,007,841; U.S. Patent No. 5,952,389; U.S. Patent No.
    5,902,815; US patent. No. 5,741,778; U.S. Patent No. 5,605,911; US patent. No. 5,523,323; U.S. Patent No. 4,959,493; Moskal et al. (2005), Neuropharmacology, 49 (7): 1077-87; Narahshi, Toshio and a /. (2004) Biol. Pharm. Bull., 27 (1): 1701-1706; Lynch, Gari and a /. (2006), Aging Research Reviews, 5: 255-280; Rajashankar et al. J. Am. Chem. Soc. (1992), 114, 9225; Rajashankar et al. J. Am. Chem. Soc. (1995), 117, 10129; A. Karle et al, Biochemistry (1990), 29, 6747; Regan et a /., Science (1998), 241, 976; Kaumaya et al., Biochemistry (1990), 29, 13; Hanessian et a., Tetraahedron (1997), 53, 12789; Zhang et al., Org. Lett. (2003), 53115; Xuyuan et al., Org. Lett. (2004), 6, 3285; Halab et al., J. Med. Chem. (2002), 45,
    5353. |
    Í |
    权利要求:
    Claims (9)
    [1]
    1. Compound characterized by being represented by the formula: Rº
    LE N RºOHN, Ré Rº where: RéH; R 'is benzyl; o Di Rºé Rº or, RÁ om Aus Ré o; R is H or CHs, Rº is H or CH; and stereoisomers, N-oxides or pharmaceutically acceptable salts thereof.
    [2]
    2. Compound according to claim 1, characterized by the fact that R and Rº are CHs.
    [3]
    3. Composed according to claim 1, characterized by the fact that Rº is CHge Rº is H.
    [4]
    4. Compound characterized by being represented by the formula: Ri
    OLE NRÍOHN, Rô R where: RéH R'éH
    O and 3 Re Rº om '
    RÁ our s Re O; Ré CH; eRéH; or D He Rº is CHs; and stereoisomers, N-oxides or pharmaceutically acceptable salts thereof.
    [5]
    5. Compound characterized by being represented by the formula: Q q T g T and from ISA to Ro LO LE Z ss NE "OH or oH.
    [6]
    6. Use of a compound as defined in any of claims 1-5, characterized in that it is for the preparation of a pharmaceutical composition for the treatment of a cognitive disorder associated with poor memory or poor learning.
    [7]
    Pharmaceutically acceptable composition characterized in that it comprises a compound as defined in any one of claims 1-5, and a pharmaceutically acceptable excipient.
    [8]
    Use of a compound as defined in any one of claims 1-5, characterized in that it is for the preparation of a pharmaceutical composition for treating neuropathic pain.
    [9]
    Use of a compound as defined in any one of claims 1-5, characterized in that it is for the preparation of a pharmaceutical composition for treating depression, obsessive-compulsive disorder or schizophrenia.
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    法律状态:
    2020-09-01| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-11-17| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2020-12-29| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2021-03-16| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-08-24| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    2021-12-14| B11B| Dismissal acc. art. 36, par 1 of ipl - no reply within 90 days to fullfil the necessary requirements|
    优先权:
    申请号 | 申请日 | 专利标题
    US30347210P| true| 2010-02-11|2010-02-11|
    US61303472|2010-02-11|
    PCT/US2011/024583|WO2011100585A1|2010-02-11|2011-02-11|Secondary structure stabilized nmda receptor modulators and uses thereof|
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