EP1351670A1 - Methodes de traitement de troubles neuropsychiatriques avec des antagonistes des recepteurs de nmda - Google Patents

Methodes de traitement de troubles neuropsychiatriques avec des antagonistes des recepteurs de nmda

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Publication number
EP1351670A1
EP1351670A1 EP01990191A EP01990191A EP1351670A1 EP 1351670 A1 EP1351670 A1 EP 1351670A1 EP 01990191 A EP01990191 A EP 01990191A EP 01990191 A EP01990191 A EP 01990191A EP 1351670 A1 EP1351670 A1 EP 1351670A1
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Prior art keywords
nmda receptor
receptor antagonist
day
antagonist compound
human patient
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EP01990191A
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German (de)
English (en)
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EP1351670A4 (fr
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Stuart Lipton, M.D.
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Adamas Pharmaceuticals Inc
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Neuromolecular Inc
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Priority to EP07000173A priority Critical patent/EP1852113A3/fr
Publication of EP1351670A1 publication Critical patent/EP1351670A1/fr
Publication of EP1351670A4 publication Critical patent/EP1351670A4/fr
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to compositions and methods for treating a human patient having an affliction comprising a neuropsychiatric disorder.
  • the invention provides for compositions and methods of modulating or antagonizing the activity of neuronal ionotropic glutamate receptors, such as NMDA receptors, wherein such antagonistic activity is capable of modulating the excitatory response of the neurons, inhibiting an excitotoxic effect, and promoting a neurotrophic effect, thereby providing a therapeutic effect that treats the neuropsychiatric disorder.
  • N-methyl- D-aspartate (NMDA) subtype of these receptors play critical roles in the development, function and death of neurons (see, Mc Donald J W et al, Brain Research Reviews, 15: 41-70 (1990) and Choi W, Neuron, 1: 623-34 (1988) incorporated herein by reference).
  • the N-methyl-D-aspartate (NMDA) receptor is a postsynaptic, ionotropic receptor which is responsive to, inter alia, the excitatory amino acids glutamate and glycine and the synthetic compound NMDA, hence the receptor name.
  • the NMDA receptor controls the flow of both divalent (Ca 2+ ) and monovalent (Na + and K + ) ions into the postsynaptic neural cell through a receptor associated channel (see, Foster et al, Nature, 329: 395-396 (1987); Mayer et al, Trends in Pharmacol. Sci., 11 : 254-260 (1990) incorporated herein by reference).
  • NMDA receptor has been implicated during development in specifying neuronal architecture and synaptic connectivity, and may be involved in experience dependent synaptic modifications.
  • NMDA receptors are also thought to be involved in long term potentiation, central nervous system (CNS) plasticity, cognitive processes, memory acquisition, retention, and learning.
  • CNS central nervous system
  • the NMDA receptor has also drawn particular interest since it appears to be involved in a broad spectrum of CNS disorders. For instance, during brain ischemia caused by stroke or traumatic injury, excessive amounts of the excitatory amino acid glutamate are released from damaged or oxygen deprived neurons.
  • NMDA receptor Activation of the NMDA receptor has been shown to be responsible for post-stroke convulsions, and, in certain models of epilepsy, activation of the NMDA receptor has been shown to be necessary for the generation of seizures.
  • Blockage of the NMDA receptor Ca 2+ channel by the animal anesthetic PCP (phencyclidine) produces a psychotic state in humans similar to schizophrenia (reviewed in Johnson et al, Annu. Rev. Pharmacol. Toxicol., 30: 707-750 (1990) incorporated herein by reference).
  • NMDA receptors have also been implicated in certain types of spatial learning, (see, Bliss et al, Nature, 361: 31 (1993), incorporated herein by reference).
  • both the spatial and temporal distribution of NMDA receptors in mammalian nervous systems have been found, to vary. Thus, cells may produce NMDA receptors at different times in their life cycles and not all neural cells may utilize the NMDA receptor.
  • D-cycloserine which was known to modulate the NMDA receptor, to improve and enhance memory and to treat cognitive deficits linked to a neurological disorder.
  • D-cycloserine is described as a glycine agonist which binds to the strychnine-insensitive glycine receptor.
  • D-cycloserine is administered in combination with D-cycloserine to reduce the side effects observed in clinical trials of D-cycloserine, mainly those due to its growth-inhibiting effect on bacteria resulting in depletion of natural intestinal flora.
  • D-Alanine reverses the growth-inhibiting effect of D-cycloserine on bacteria. It is also reported that D-cycloserine actually has partial agonist character.
  • NMDA receptor Although desirous, has been hindered because the structure of the NMDA receptor has not yet been completely elucidated. It is believed to consist of several protein chains (subunits) embedded in the postsynaptic membrane. The first two subunits determined so far form a large extracellular region which probably contains most of the allosteric binding sites, several transmembrane regions looped and folded to form a pore or channel which is permeable to Ca 2+ and a carboxyl terminal region with an as yet unknown function. The opening and closing of the channel is regulated by the binding of various ligands to domains of the protein residing on the extracellular surface and separate from the channel.
  • these ligands are all known as allosteric ligands.
  • the binding of two co-agonist ligands (glycine and glutamate) is thought to effect a conformational change in the overall structure of the protein which is ultimately reflected in the channel opening, partially open, partially closed, or closed.
  • the binding of other allosteric ligands modulates the conformational change caused or effected by glutamate and glycine. It is believed that the channel is in constant motion, alternating between a cation passing (open) and a cation blocking (closed) state. It is not known at present whether the allosteric modulators actually increase the time during which the channel is open to the flow of ions, or whether the modulators increase the frequency of opening.
  • Channel blockers such as MK-801 and antagonists are known to protect cells from excitotoxic death but, in their case, the cure may be as undesirable as the death since they block any flux of Ca 2+ thereby eliminating any chance of resumed normal activity.
  • Channel blockers and glutamate site antagonists are known to cause hallucinations, high blood pressure, loss of coordination, vacuolation in the brain, learning disability and memory loss.
  • PCP a typical channel blocker, produces a well characterized schizophrenic state in man.
  • Mg 2+ and Zn 2+ can modulate the NMDA receptor.
  • the exact location of the divalent cation binding site(s) is still unclear.
  • Zn 2+ appears to be antagonistic to channel opening and appears to bind to an extracellular domain.
  • Mg 2+ shows a biphasic activation curve - at low concentrations it is an agonist for NMDA receptor function, and at high concentrations it is a receptor antagonist. It appears to be absolutely necessary for proper receptor functioning and appears to bind at two sites - a voltage dependant binding site for Mg 2+ within the channel and another non-voltage dependent binding site on the extracellular domain.
  • These compounds can modulate the NMDA receptor but are not appropriate for long term therapy. There is a need in the art for a safe and effective compound for treating neuropsychiatric disorders.
  • the present invention provides a method for treating neuropsychiatric disorders comprising administering to a human patient suffering from a neuropsychiatric disorder, an effective amount of an NMDA receptor antagonist compound, wherein the compound modulates glutamatergic neurotransmission by the receptor, thereby treating or alleviating the neuropsychiatric disorder and thereby providing a therapeutic effect.
  • the compound provides robust neurotrophic effects via direct intracellular mechanisms.
  • excessive glutamatergic transmission is modulated, thereby mediating the excitotoxic effect of glutamate on neurons and thereby providing a neuroprotective effect.
  • the NMDA receptor antagonist compound modulates glutamatergic activation of the cortico-striatal or subthallamicopalladial pathways.
  • the neuropsychiatric disorder is major depressive disorder. In another embodiment, the neuropsychiatric disorder is bipolar disorder. In yet another embodiment, the neuropsychiatric disorder is anxiety. In still another embodiment, the neuropsychiatric disorder is a drug-related disorder such as drug addiction, drug dependency, drug withdrawal, or drug tolerance.
  • the invention provides for uses of NMDA receptor antagonists to treat patients with major depression without psychotic features according to the DSM-IN criteria, as well as methods of improving overall depressive symptomatology, by administering to the patient a therapeutically effective dosage of the compound, hi one embodiment, the compound is memantine. In another embodiment, the compound is a nitromemantine derivative.
  • the invention also provides for methods of assessing the neurotrophic effects of ⁇ MDA receptor antagonist compounds in the treatment of patients with neuropsychiatric disorders and methods of determining whether compound-induced alterations in brain glutamate (Glu) levels are associated with responsiveness to the compound's therapeutic effects.
  • the invention likewise provides for methods of assessing the effects of memantine or nitromemantine derivatives on glucose metabolism in unipolar depression.
  • the present invention provides for the use of NMDA receptor antagonist compounds that are formulated into medicaments used in the treatment of patients suffering from neuropsychiatric disorders.
  • the NMDA receptor antagonist compounds are of the following formula or pharmaceutically acceptable salts thereof:
  • R ls R 2 , R 3 , R 4 and R 5 of the formula are independently defined.
  • Rj is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)O R 6 or C(O)R 6 .
  • R 2 is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR 6 or C(O)R 6 .
  • R 3 is H, alkyl, heteroalkyl, aryl or heteroaryl.
  • Rj is H, alkyl, heteroalkyl, aryl or heteroaryl.
  • R 5 is OR , alkyl-OR 7 or heteroalkyl — OR .
  • Re is alkyl, heteroalkyl, aryl or heteroaryl.
  • R 7 is NO 2 , C(O)R 6 , C(O)alkyl— ONO 2 or C(O)heteroalkyl — ONO 2 .
  • the following substituents are preferred: Ri and R 2 are H; R 3 and 4 are H or alkyl; and, R 7 is NO 2 or C(O)alkyl-ONO 2 .
  • compositions that can be used to treat a neurological disorder.
  • the compositions include a pharmaceutically acceptable carrier and one or more compounds of the following formula or pharmaceutically acceptable salts thereof:
  • R is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR 6 or C(O)R 6 .
  • R 2 is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR 6 or C(O)R 6 .
  • R 3 is H, alkyl, heteroalkyl, aryl or heteroaryl.
  • 1 ⁇ is H, alkyl, heteroalkyl, aryl or heteroaryl.
  • R 5 is OR 7 , alkyl — OR7 or heteroalkyl — OR 7 .
  • R is alkyl, heteroalkyl, aryl or heteroaryl.
  • R 7 is NO 2 , C(O)R 6 , C(O)alkyl— ONO 2 or C(O)heteroalkyl — ONO 2 .
  • the following substituents are preferred: R ⁇ and R 2 are H; R 3 and t are H or alkyl; and, R 7 is NO 2 or C(O)alkyl— ONO 2 .
  • the present invention also provides methods of treating a neurological disorder.
  • the methods include administering to a patient a pharmaceutically acceptable carrier and one or more compounds of the following formula, or pharmaceutically acceptable salts thereof:
  • Ri is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR 6 or C(O)R 6 .
  • R 2 is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR 6 or C(O)R 6 .
  • R 3 is H, alkyl, heteroalkyl, aryl or heteroaryl.
  • R-t is H, alkyl, heteroalkyl, aryl or heteroaryl.
  • R 5 is OR 7 , alkyl — OR or heteroalkyl — OR .
  • Re is alkyl, heteroalkyl, aryl or heteroaryl.
  • R 7 is NO 2 , C(O)R 6 , C(O)alkyl— ONO 2 or
  • Ri and R 2 are H; R 3 and R-t are H or alicyl; and, R 7 is NO 2 or C(O)alkyl— ONO 2 .
  • the present invention further provides methods of making medicaments comprising NMDA receptor antagonist compounds of the following formula or pharmaceutically acceptable salts thereof:
  • Ri is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR 6 or C(O)R 6 .
  • R 2 is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR 6 or C(O)R 6 .
  • R 3 is H, alkyl, heteroalkyl, aryl or heteroaryl.
  • R is H, alkyl, heteroalkyl, aryl or heteroaryl.
  • R5 is OR 7 , allcyl — OR 7 or heteroalkyl — OR 7 .
  • Re is alkyl, heteroalkyl, aryl or heteroaryl.
  • R 7 is NO 2 , C(O)R 6 , C(O)alkyl— ONO 2 or C(O)heteroalkyl — ONO 2 .
  • the following substituents are preferred: i and R 2 are H; R 3 and R4 are H or alkyl; and, R 7 is NO 2 or C(O)alkyl— ONO 2 .
  • the methods involve oxidizing a compound of the following formula:
  • the methods further involve nitrating a compound of the formula:
  • the compound is treated with H 2 SO and water in the oxidation step.
  • the nitration step preferably includes treatment with HNO 3 and Ac 2 O.
  • FIG. 1 shows the synthesis of an adamantane nitrate derivative.
  • FIG. 2 shows the synthesis of an adamantane ester derivative.
  • FIG. 3 shows the synthesis of halo and nitrate substituted adamantane ester derivatives.
  • FIG. 4 shows the synthesis of an alkyl — ONO 2 derivative of adamantane.
  • FIG. 6 shows that administration of compound 7 decreases cerebral damage after stroke in a murine cerebral ischemia model as compared to both a control and memantine (see Example 20).
  • FIG. 7 shows that administration of compound 8 relaxes a precontracted aortic vessel in a dose-dependent fashion (see Example 21).
  • FIG. 7a shows that relaxations were seen at 10 "6 M and complete relaxation was achieved at 10.6 M.
  • FIG. 7b shows the effect of solvent.
  • FIG. 7c shows that relaxations were attenuated by methylene blue.
  • FIG. 7d shows that relaxations were attenuated by hemoglobin.
  • FIG. 8 shows that the action of aminoadamantane derivatives are specific.
  • Compound 9 (a) and 10 (c) produced either no effect or slight blood vessel contractions that were comparable to those produced by solvent (EtOH) alone.
  • Compound 7 (b) produced modest relaxation at a 10 ⁇ M concentration.
  • FIG. 9 illustrates studies with memantine, indicative of its activating or antidepressant properties.
  • the present invention provides for compositions and methods of treating neuropsychiatric disorders by modulating the activity of NMDA subtype glutamate receptors in patients afflicted with one or more neuropsychiatric disorders.
  • the compounds used in the present invention modulate glutamatergic neurotransmission and provide or exert robust neurotrophic effects via direct intracellular mechanisms, thereby treating or alleviating the neuropsychiatric disorder.
  • neuropsychiatric disorder refers to acute and subacute disorders with both neurological and psychiatric features.
  • Examples of common neuropsychiatric disorders that are treatable by the present invention comprise major depressive disorder
  • MMD bipolar disorder
  • BPD menic-depressive illness
  • anxiety and drug addiction including dependence, withdrawal, and drug tolerance
  • disorders arising from trauma, ischemic or hypoxic conditions including stroke, hypoglycemia, cerebral ischemia, cardiac arrest, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest and hypoglycemic neuronal damage, epilepsy, Alzheimer's disease, Huntington's disease, Parkinsonism, amyotrophic lateral sclerosis, convulsion, pain, schizophrenia, muscle spasms, migraine headaches, urinary incontinence, emesis, brain edema, tardive dyskinesia, AIDS -induced dementia, ocular damage, retinopathy, cognitive disorders, and neuronal injury associated with HIN-infection such as dysfunction in cognition, movement and sensation.
  • Neuropsychiatric disorders are described in Diagnostic and Statistical Manual of Mental Disorders, 4 th Ed., American Psychiatric Press, (1994) incorporated herein by reference.
  • an "NMDA receptor antagonist compound” refers to aminoadamantane derivatives such as memantine, nitromemantine compounds, and related memantine and nitromemantine derivatives which use memantine as a NMDAR channel blocker and a nitric oxide species to regulate the redox modulatory site on the NMDA receptor.
  • NMDA receptor antagonist compounds are specified in U.S. patent nos. 6,071,876, 5,801,203, 5,747,545, 5,614,560, 5,506,231, and PCT application 01/62706, all to Lipton, S.A., et al., and incorporated herein by reference.
  • Alkyl refers to unsubstituted or substituted linear, branched or cyclic alkyl carbon chains of up to 15 carbon atoms.
  • Linear alkyl groups include, for example, methyl, ethyl, N-propyl, N-butyl, N-pentyl, N-hexyl, N-heptyl and N-octyl.
  • Branched alkyl groups include, for example, iso-propyl, sec-butyl, iso-butyl, tert- butyl and neopentyl.
  • Cyclic alkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Alkyl groups can be substituted with one or more substituents. Nonlimiting examples of such substituents include NO 2 , ONO 2 , F, CI, Br, I, OH, OCR , CO 2 H, C0 2 CH , CN, aryl and heteroaryl. Where "alkyl" is used in a context such as
  • alkyl — ONO 2 it refers to an alkyl group that is substituted with a ONO 2 moiety.
  • alkyl is used in a context such as “C(O)alkyl — ONO 2 ,” it refers to an alkyl group that is connected to a carbonyl group at one position and that is substituted with a ONO 2 moiety.
  • Heteroalkyl refers to unsubstituted or substituted linear, branched or cyclic chains of up to carbon atoms that contain at least one heteroatom (e.g., nitrogen, oxygen or sulfur) in the chain.
  • Linear heteroalkyl groups include, for example, CH 2 CH 2 OCH 3 , CH 2 CH 2 N(CH 3 )2 and CH 2 CH 2 SCH 3 .
  • Branched groups include, for example, CH 2 CH(OCH 3 )CH 3 , CH 2 CH(N(CH 3 ) 2 )CH 3 and CH 2 CH(OCH 3 )CH 3 .
  • Cyclic heteroalkyl groups include, for example, CH(CH 2 CH 2 ) 2 O, H(CH 2 CH 2 ) 2 NCH 3 and CH(CH CH 2 ) 2 S.
  • Heteroalkyl groups can be substituted with one or more substituents.
  • substituents include NO 2 , ONO 2 , F, CI, Br, I, OH, OCR 3 , CO 2 H, CO CH 3 , CN, aryl and heteroaryl.
  • heteroalkyl is used in a context such as “heteroalkyl — ONO 2 ,” it refers to a heteroalkyl group that is substituted with an ONO 2 moiety.
  • heteroalkyl is used in a context such as “C(O)heteroalkyl — NO 2 ,” it refers to an alkyl group that is connected to a carbonyl group at one position and that is substituted with a ONO 2 moiety.
  • Halo refers to F, CI, Br or 1.
  • Aryl refers to an unsubstituted or substituted aromatic, carbocyclic group. Aryl groups are either single ring or multiple condensed ring compounds. A phenyl group, for example, is a single ring, aryl group. An aryl group with multiple condensed rings is exemplified by a naphthyl group. Aryl groups can be substituted with one or more, substituents. Nonlimiting examples of such substituents include NO 2 , ONO 2 , F, CI, Br, I, OH, OCR 3 , CO 2 H, CO 2 CH 3 , CN, aryl and heteroaryl.
  • Heteroaryl refers an unsubstituted or substituted aromatic group having at least one heteroatom (e.g., nitrogen, oxygen or sulfur) in the aromatic ring. Heteroaryl groups are either single ring or multiple condensed ring compounds. Single ring heteroaryl groups having at least one nitrogen include, for example, tetrazoyl, pyrrolyl, pyridyl, pyridazinyl, indolyl, quinolyl, imidazolyl, isoquinolyl, pyrazolyl, pyrazinyl, pyrimidinyl and pyridazinonyl.
  • a furyl group for example is a single ring heteroaryl group containing one oxygen atom.
  • a condensed ring heteroaryl group containing one oxygen atom is exemplified by a benzofuranyl group.
  • Thienyl for example, is a single ring heteroaryl group containing one sulfur atom.
  • a condensed ring heteroaryl group containing one sulfur atom is exemplified by benzothienyl heteroaryl groups containing more than one kind of heteroatom in the same ring. Examples of such groups include furazanyl, oxazolyl, isoxazolyl, thiazolyl and phenothiazinyl.
  • Heteroaryl groups can be substituted with one or more substituents.
  • Nonlimiting examples of such substituents include NO 2 , ONO 2 , F, CI, Br, I, OH, OCH 3 , CO 2 H, CO 2 CH 3 , CN, aryl and heteroaryl.
  • a "therapeutic effect" refers to an observable improvement over the baseline clinically observable signs and symptoms of a neuropsychiatric disorder, as measured by the techniques disclosed herein.
  • pharmaceutically acceptable refers to a lack of unacceptable toxicity in a compound, such as a salt or excipient.
  • Pharmaceutically acceptable salts include inorganic anions such as chloride, bromide, iodide, sulfate, sulfite, nitrate, nitrite, phosphate, and the like, and organic anions such as acetate, malonate, pyruvate, propionate, cinnarnate, tosylate, citrate, and the like.
  • Pharmaceutically acceptable excipients are described at length by E. W. Martin, in Remington's Pharmaceutical Sciences (Mack Pub. Co.).
  • direct intracellular mechanisms refer to effects on intracellular signaling pathways that either promote neuroprotection or block cell death (apoptotic) and injury pathways.
  • glutamatergic neurotransmission refers to synaptic transmission between nerve cells in the brain whereby glutamate is released from the presynaptic cell onto the postsynaptic cell to bind to glutamate receptors, thereby triggering an electrical current in the postsynaptic cell. This process effects information transfer between the nerve cells.
  • glutamate receptor on the postsynaptic cell that is most implicated in the pathophysiology of the neuropsychiatric manifestations is the NMDA subtype of glutamate receptor.
  • providing a neurotrophic effect refers to the upregulation of intracellular signaling pathways in response to NMDA receptor antagonists, that enhance neuronal survival and are generally regulated by neurotrophic factors such as brain-derived neurotrophic factor (BDNF).
  • BDNF brain-derived neurotrophic factor
  • decreasing the pathophysiology of depressive disorders refers to a decrease in an underlying event for depression that consists of overstimulation of glutamate receptors, especially of the NMDA receptor subtype.
  • excessive glutamate-induced currents refers to overstimulation of glutamate receptors, leading to excessive Ca influx, free radical formation and other biochemical events that contribute to nerve cell toxicity, damage, and even cell death (due to either necrosis or apoptosis).
  • substantially without dopamine or norepinephrine refers to concentrations of these neurotransmitters insufficient to trigger and propagate an action potential in the postsynaptic cell.
  • Neuropsychiatric mood disorders such as major depressive disorder (MDD) and bipolar disorder (manic-depressive illness, BPD) are common, severe, chronic and often life-threatening illnesses.
  • MDD major depressive disorder
  • BPD bipolar disorder
  • Suicide is estimated to be the cause of death in up to approximately 15 percent of individuals afflicted with MDD, and in addition to suicide, many other deleterious health-related effects are increasingly being recognized (see, Mussehnan et al, 1998; Schulz et al, 2000, incorporated herein by reference).
  • MDD ulcerative colitis
  • cardiovascular disease a major risk factor for both the development of cardiovascular disease, as well as for death after an index myocardial infarction.
  • the cumulative effects of recurring bouts of affective episodes lead to an increased rate of marital and family breakdown, unemployment, impaired career progress and consequent financial difficulties.
  • Morphometric neuroimaging studies have demonstrated that, in toto, patients with both BPD and MDD display morphometric changes suggestive of cell loss and/or atrophy (Drevets et al, 1997; Drevets, 1999; Sheline et al, 1996; 1999, incorporated herein by reference).
  • Volumetric neuroimaging studies show an enlargement of third and lateral ventricles, as well as reduced gray matter volumes in the orbital and medial prefrontal cortex (PFC), the ventral striatum, and the mesiotemporal cortex in patients with mood disorders (Drevets, 1999; Sheline et al, 1996; 1999).
  • NAAA brain N-acetyl aspartate
  • Baumann and associates (1999) reported reduced volumes of the left nucleus accumbens, the right putamen and bilateral pallidum externum in postmortem brain samples obtained from patients with unipolar MDD or BPD.
  • Several recent postmortem stereological studies of the PFC also have demonstrated reduced regional volume, cell numbers and/or sizes.
  • Morphometric analysis of the density and size of cortical neurons in the DLPFC and orbitofrontal cortices has revealed significant reductions in mood disorders patients as compared to control subjects (Rajkowska et al, 1999; 2000).
  • Factors involved in neuronal atrophy and survival are targets of antidepressant treatments in the present invention.
  • Important pathways involved in cell survival and plasticity that contribute to providing a neurotrophic effect include, for example, the cAMP- CREB cascade, as well as a CREB target, brain derived neurotrophic factor (BDNF). These can be up-regulated by antidepressant treatment (Duman et al, 2000, incorporated herein by reference).
  • Upregulation of CREB and BDNF occurs in response to several different classes of antidepressant treatments, including norepinephrine (NE) and SSRIs and electroconvulsive seizure, indicating that the cAMP-CREB cascade and BDNF are common post-receptor targets of therapeutic compounds (Nibuya et al, 1995, 1996).
  • NE norepinephrine
  • SSRIs electroconvulsive seizure
  • Antidepressant treatments produce neurotrophic-like effects, such as a greater regeneration of catecholamine axon terminals in the cerebral cortex (Nakamura, 1990).
  • Use of NMDA receptor antagonist compounds to modulate the excess activity of the glutamatergic system provides a neurotrophic effect to the patient thereby decreasing the pathophysiology of this neuropsychiatric disorder.
  • NMDA receptor antagonists such as MK-801 and AP-7, have demonstrated antidepressant effects in animal models of depression, including the application of inescapable stressors, forced-swim, and tail suspension-induced immobility tests, in learned helplessness models of depression, and in animals exposed to a chronic mild stress procedure (Hauang, 1997; Paul, 1997).
  • antidepressant administration has been shown to affect NMDA receptor function (Nowak et al, 1993, 1995) and receptor binding profiles (Paul et al, 1994).
  • NMDA antagonists produce neurochemical alterations in the brain similar to antidepressant drugs and that they show an antidepressant-like behavioral profile in some animal models of depression.
  • a growing body of preclinical evidence suggests that existing antidepressants, upon chronic administration, exert significant dampening (albeit complex) effects on the glutamatergic system.
  • many stress paradigms are believed to exert many of their deleterious effects on hippocampal structures via enhancement of glutamatergic neurotransmission.
  • modulation of the excess activity of the glutamatergic system provides a method of treating the pathophysiology of neuropsychiatric disorders. More specifically, compositions and methods that dampen glutamatergic activity provide a method of administering a therapeutic antidepressant effect to a patient afflicted with or suffering from a depressive disorder.
  • NMDA receptor antagonist compounds Ketamine has been studied in depression but is associated with an increased risk of developing psychosis. Also, psychomimetic effects were reported to occur with other NMDA antagonists.
  • Lainotrigine in a double-blind, placebo-controlled study was reported to be effective in acute bipolar depression (Calabrese et al., 1999). In unipolar depression, lamotrigine was found to be superior to placebo in last observation carried forward HAMD item 1 and CGI severity change but not in total score HAMD and MADRS (Laurenza et al, 1999).
  • NMDA receptor antagonist memantine which unlike other glutamate receptor antagonists, appears to spare nonnal neurotransmission and blocks only excessive glutamate-induced currents, as demonstrated in patch-clamp electrophysiological recordings correlated to behavioral studies (see, Chen et al., 1992, 1988, Chen and Lipton, 1997, Lipton, 1993, Lipton and Rosenberg 1994, incorporated herein by reference).
  • Memantine (Akatinol Memantine®, (Merz & Co., GmbH) CAS Registry No. 41100-52-1), is an uncompetitive N-methyl-D-aspartate ( ⁇ MDA) antagonist currently used for the treatment of dementia syndrome, spinal spasticity and Parkinson's disease. Chemically, memantine is l-amino-3,5-dimethyladamantane of the adamantine class. Compared to the other ⁇ MDA antagonists, memantine has been reported to have the greatest effective potency for binding at the PCP and MK-801 receptor sites in human brain tissue ( Komhuber et al, 1991).
  • Memantine binds to the PCP and MK-801 binding sites of the ⁇ MDA receptor in postmortem human frontal cortex at therapeutic concentrations (Komhuber et al, 1989), and reduces membrane currents (Bormann, 1989). Memantine is well tolerated, and despite its wide use in Germany, only a few isolated cases of psychosis and cognitive deficits have been reported with its use. Compared to other ⁇ MDA antagonists, memantine appears to have a more favorable pharmacological profile and is less likely to induce psychosis and cognitive deficits.
  • memantine is less likely to induce cognitive deficits and psychosis may be due its negligible effects on the hypothalamic-pituitary axis (HP A) compared to other ⁇ MDA antagonists such as ketamine.
  • HP A hypothalamic-pituitary axis
  • ⁇ MDA receptors have been reported to be involved in the physiologic pulsatile regulation of hormone release from the HPA axis (Bhat et al, 1995) resulting in hypercortisolemia.
  • Psychotic symptoms and cognitive deficits in depression has been linked to an increased dopamine activity secondary to this HPA overactivity (Walder et al, 2000).
  • memantine has no active metabolites that possess NMDA antagonizing properties (Ziemann et al, 1996). Furthermore, memantine serum levels are available for measurement. Memantine is one of the few NMDA antagonists available for use in humans and is ideal for treating major depression as it and its precursors amantadine, have been in clinical use for many years with minimal sideeffects (Komhuber et al, 1994).
  • Memantine Rarely has memantine been associated with significant the side-effects of agitation, confusion, and psychosis (Rabey et al, 1992; Riederer et al, 1991) as seen with other -MMDA antagonists, such as phencyclidine and ketamine. Memantine is well tolerated in the geriatric populations for which it is typically prescribed in Europe (Gortelmeyer et al, 1992). Memantine has significant neurotrophic and activating properties, and it can be used to modulate glutamatergic neurotransmission, while also providing for robust neurotrophic effects via direct intracellular mechanisms. Memantine displays potent non-competitive voltage-dependent NMDA antagonist properties with effects comparable to MK-801 (see, Bormann, 1989, incorporated herein by reference).
  • Memantine also demonstrates anticonvulsant and neuroprotective properties and dopaminergic effects in vitro (see, Maj, 1982, incorporated herein by reference). Memantine has been used since 1978 and is approved in Germany for the treatment of mild and moderate cerebral performance disorders with the following cardinal symptoms: concentration and memory disorders, loss of interest and drive, premature fatigue, and dementia syndrome, as well as in diseases in which an increase of attention and alertness (vigilance) is required. Cerebral and spinal spasticity, Parkinson and Parkinson-like diseases are other indications. Memantine acts as a modulator of glutamatergic neurotransmission. In the states of a reduced glutamate release, after degeneration of neurons, memantine results in an improvement in signal transmission and activation of neurons.
  • memantine blocks NMDA receptors that mediate the excitotoxic action of glutamate on neurons. It is believed that its neuroprotective properties are due to NMDA receptor antagonism in pathologies with increased glutamate.
  • Memantine' s efficacy in Parkinson's Disease has been suggested to be a result of its ability to neutralize (or modulate) the increased activity of the glutamatergic cortico-striatal and subthalamicopallidal pathways (Klockgether and Turski, 1989, 1990, and Schmidt et al, 1990, incorporated herein by reference). This effect is independent of dopamine or norepinephrine release.
  • Memantine has been reported for many years to have positive effects on deficit symptoms or depressive symptoms commonly found in other neuropsychiatric disorders such as Parkinson's disease and dementia.
  • dementia dementia
  • Parkinson's disease dementia
  • the symptoms of depressed mood, anxiety, lack of drive, somatic disturbances, impairment in vigilance, short-term memory and concentration were significantly improved with memantine.
  • Some of these studies also reported the adverse events of hyperactivity, restlessness, and euphoria with memantine, suggesting that it may have activating or antidepressant properties.
  • Memantine is quickly and completely absorbed and is practically unbound to human albumin ( ⁇ 10%). Its elimination is biphasic. The average half-life of memantine is reported to be 4-9 hours for the first therapeutically relevant phase, and then 40-65 hours for the second phase. Elimination occurs primarily by the renal route in 75%-90%, and fecal excretion is only about 10%-25% (Weseman et al, 1980). Side effects of memantine are dose dependent and include dizziness, internal and motoric restlessness and agitation, fatigue, congestion in the head, and nausea.
  • the NMDA receptor antagonist compounds of the present invention comprise aminoadamantane derivatives that can be formulated into medicaments comprising pharmaceutically acceptable salts or in a pharmaceutical composition further comprising excipients.
  • Memantine and nitromemantine derivatives are administered to human patients across dosage ranges from 0.1 to 1000 mg/day.
  • the currently preferred therapeutic dose of memantine is approximately 5-35 mg/day, but memantine is well tolerated at doses of 100- 500 mg/day.
  • Dosages of nitromemantine compounds are commonly 1-100 mg/day, and are similarly tolerated.
  • the serum levels of memantine in humans have been reported to range between 0.25 and 0.529 ⁇ M at a dose between 5 and 30 mg/day.
  • the mean CSF/serum ratio was 0.52 (see, Komhuber and Quack, 1995, incorporated herein by reference).
  • memantine specifically interacts with the PCP or MK-108 binding site of the NMDA receptor (Komhuber et al, 1994; Komhuber and Quack, 1995), and is effective at modulating glutamatergic neurotransmission by the receptor.
  • NMDA receptor antagonist compounds that are administered in a pharmaceutical composition are mixed with a suitable carrier or excipient such that a therapeutically effective amount is present in the composition.
  • a therapeutically effective amount refers to an amount of the compound that is necessary to achieve a desired endpoint (e.g., decreasing neuronal damage as the result ofa stroke).
  • a therapeutic endpoint in a dosage regimen is recognized by the development of a therapeutic effect in the patient, as determined by the assessments and techniques disclosed herein. A medical professional can determine the appropriate dosage regimen for memantine, and adjust the patient's dose upward or downward as needed to provide a therapeutic effect and minimize adverse side effects.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • the NMDA receptor antagonist compound, its enantiomers or a pharmaceutically acceptable salt thereof may be administered orally, topically, parenterally, intranasally by inhalation or spray, or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • the amount of active compound that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • the invention provides a pharmaceutical formulation comprising a NMDA receptor antagonist compound and a pharmaceutically acceptable carrier.
  • the active compound may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
  • the pharmaceutical compositions containing the active compound may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more compounds selected from the group consisting of sweetening compounds, flavoring compounds, coloring compounds and preserving compounds in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active compound in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating compounds, for example, corn starch, or alginic acid; binding compounds, for example starch, gelatin or acacia, and lubricating compounds, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending compounds, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting compounds may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring compounds, one or more flavoring compounds, and one or more sweetening compounds, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening compound, for example beeswax, hard paraffin or acetyl alcohol. Sweetening compounds such as those set forth above, and flavoring compounds may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting compound, suspending compound and one or more preservatives.
  • Suitable dispersing or wetting compounds and suspending compounds are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring compounds, may also be present.
  • compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying compounds may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example sweetening, flavoring and coloring compounds, may also be present.
  • Syrups and elixirs may be formulated with sweetening compounds, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring compounds.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting compounds and suspending compounds which have been mentioned above.
  • the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the active compound may also be administered in the fo ⁇ n of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • the active compound may be administered parenterally in a sterile medium.
  • the drug depending on the vehicle and concentration used can either be suspended or dissolved in the vehicle.
  • adjuvants such as local anesthetics, preservatives and buffering compounds can be dissolved in the vehicle.
  • the compounds of the present invention are NMDA receptor antagonists comprising aminoadamantane derivatives such as memantine, nitromemantine, and the like.
  • the NMDA receptor antagonists are of the following formula:
  • Ri is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR 6 or C(O)R 6 .
  • R 2 is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR 6 or C(O)R 6 .
  • R 3 is H, alkyl, heteroalkyl, aryl or heteroaryl.
  • R_t is H, alkyl, heteroalkyl, aryl or heteroaryl.
  • R 5 is OR 7 , alkyl — OR7 or heteroalkyl — OR 7 .
  • Re is alkyl, heteroalkyl, aryl or heteroaryl.
  • R 7 is NO 2 , C(O)R 6 , C(O)alky]— ONO 2 or C(O)heteroalkyl — ONO 2 .
  • the following substituents are preferred: Ri and R 2 are H; R 3 and R 4 are H or alkyl; and, R 7 is NO 2 or C(O)alkyl— ONO 2 .
  • Ri is H and R 2 is H, C(O)O— alkyl or C(O)O— aryl.
  • R 2 is C(O)O — alkyl
  • the alkyl group is methyl, ethyl, N-propyl, iso-propyl, N-butyl, sec-butyl, tert-butyl or benzyl.
  • R 2 is C(O)O — aryl
  • Ri and R 2 are both H.
  • both R 3 and R4 are H or linear alkyl groups. Where R 3 and R 4 are both alkyl groups, it is preferred that the groups are methyl, ethyl, N-propyl, N-butyl, sec-butyl, tert-butyl or benzyl.
  • R 5 is ONO 2 , O— alkyl— ONO2 or OC(O)— allcyl— ONO 2 .
  • R 5 is O— allcyl— ONO 2 , it is prefe ⁇ ed that the alkyl group be CH 2 , CH 2 CH 2 or CH 2 CH 2 CH 2 .
  • R 5 is OC(O)— alkyl— ONO 2 , it is prefe ⁇ ed that the alkyl group be CH 2 , CH 2 CH 2 , CH2CH2CH2 or CH 2 CH 2 CH 2 CH 2 . More preferably, R 5 is ONO 2 .
  • the NMDA receptor antagonist compounds of the present invention are synthesized starting from a haloadamantane derivative.
  • the haloadamantane derivative is treated with acid and a nitrile to form an amidoadamantane derivative.
  • Treatment of the NMDA receptor antagonist compounds with an acid and second reagent provides a functionalized NMDA receptor antagonist compound.
  • the second reagent used to form the functionalized NMDA receptor antagonist compound is water.
  • the compound fo ⁇ ned in this case is an amido alcohol.
  • the amido alcohol is either nitrated to provide an amido nitrate derivative or hydrolyzed to provide an amino alcohol derivative.
  • NMDA receptor antagonist compounds including the following nonlimiting examples: 1) protection of the amine group, followed by nitration of the alcohol group and deprotection of the amine group to provide an amino nitrate derivative; 2) protection of the amine group, followed by esterification of the alcohol group and deprotection of the amine group to provide an amino ester derivative; and, 3) protection of the amine group, followed by esterification to with a halogenated acid chloride and nucleophilic displacement to provide an carbarnate nitrate-ester derivative.
  • the second reagent used to form the functionalized NMDA receptor antagonist compound is formic acid.
  • the compound formed in this case is an amido acid.
  • the amido acid is subjected to conditions that form an amido alkanol.
  • the amido alkanol is either nitrated to provide an amido alkane nitrate derivative or deprotected to provide an amino alkanol derivative.
  • the amine group is protected to form an amido alkanol derivative, which is subsequently nitrated to provide an amido alkane-nitrate derivative. Deprotection of the amido group affords an amino alkane- nitrate derivative.
  • FIG. 1 shows the synthesis of an amido nitrate derivative.
  • Compound 1 a dimethyl- bromo-adamantane, was treated with sulfuric acid and acetonitrile to afford the dimethyl amido compound 2.
  • Amide 2 was reacted with sulfuric acid and water, providing amido alcohol 3, which was nitrated using nitric acid and acetic anhydride to form compound 8.
  • FIG. 1 also shows the synthesis of an amino nitrate derivative.
  • Compound 3 was deprotected with sodium hydroxide, affording amino alcohol 4.
  • the amine group of compound 4 was protected with (BOC) 2 ⁇ to form the carbamate alcohol 5.
  • Carbamate 5 was nitrated using nitric acid and acetic anhydride, providing nitrate 6, which was deprotected upon treatment with hydrochloric acid to form amino nitrate hydrochloride salt 7.
  • FIG. 2 shows the synthesis of an amino ester derivative.
  • Amino alcohol 9 was alkylated with two equivalents of benzyl bromide to afford protected amino alcohol 10.
  • Compound 10 was acetylated, yielding ester 11. Ester 11 was subjected to hydrogenation and then acidified to provide the amino alcohol hydrochloride salt 12.
  • FIG. 3 shows the synthesis of a carbamate nitrate-ester derivative.
  • Amino alcohol 9 was protected upon treatment with (PhCH 2 OCO) 2 ⁇ , yielding carbamate 13.
  • Carbamate 13 was esterified using a haloalkyl acid chloride to provide compound 14, which was subjected to nucleophilic displacement with AgNO 3 , affording carbamate nitrate-ester 15.
  • FIG. 4 shows the synthesis of an amido alkyl-nitrate derivative.
  • Amide 2 was reacted with sulfuric acid and formic acid to form amido acid 16.
  • FIG. 4 also shows the synthesis of an amino alkyl-nitrate derivative. Amido alkanol
  • the compounds and compositions of the present invention can be used to manufacture medicaments to treat a number of neuropsychiatric disorders and disease states, such as disorders arising from trauma, ischemic or hypoxic conditions including stroke, hypoglycemia, cerebral ischemia, cardiac a ⁇ est, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest and hypoglycemic neuronal damage.
  • Neurodegenerative disorders such as epilepsy, Alzheimer's disease, Huntington's disease, Parkinsonism, and amyotrophic lateral sclerosis can also be treated.
  • neuropsychiatric diseases or disorders that can be ameliorated through admimstration of the compounds and compositions include, without limitation, the following: depression, bipolar disorder, anxiety, convulsion, pain, schizophrenia, muscle spasms, migraine headaches, urinary incontinence, nicotine withdrawal, opiate tolerance and withdrawal, emesis, brain edema, tardive dyskinesia, AIDS-induced dementia, ocular damage, retinopathy, cognitive disorders, and neuronal injury associated with HIV-infection such as dysfunction in cognition, movement and sensation.
  • assessments can be combined with other criteria, i.e., weight gain or loss, the ability to acquire or maintain employment, the ability to interact in social situations, as well as more subjective inventories, such as drug craving behavior, an increase or decrease of libido or energy, and generalized assessments of well-being, to give a more complete analysis of the patient's response to therapy.
  • a therapeutic effect from the compounds used to modulate NMDA receptor activity may be determined by assaying for a reduction of glutamate or glutamine levels in plasma and cerebral spinal fluid. Glutamate plasma levels are known to be higher in depressed patients compared with a population control group (see, Kim et al, 1982; Mathis et al,
  • memantine does not block glutamate release but only the effect of glutamate on its NMDA receptor, that is, glutamate levels may remain elevated but memantine may simply block the effects of the elevated glutamate. However, because memantine will block cell death and hence abnormal glutamate release in that manner, plasma and CSF glutamate levels often decrease in response to patient therapy.
  • Efficacy of therapy with NMDA receptor antagonists can also be determined by administering one or more of the inventories described below.
  • An improvement in patient score generally correlates with a reduced pathophysiological state and an improvement in the neuropsychiatric disease state.
  • the MADRS (Montgomery and Asberg, 1979, incorporated herein by reference) is a
  • HAMD 21 -item version of this scale
  • the 21 -item version of this scale (HAMD) is administered to assess the severity of depression and its improvement during the course of therapy. It assesses both the presence and severity of individual signs and symptoms characterizing depression without psychotic features.
  • the total score is the sum of 21 items, and it ranges from 0 to 65.
  • An improvement in patient score of greater than 5% after administration of the NMDA antagonist compound indicates a decrease in the pathophysiology of the neuropsychiatric disorder, while an improvement in patient score of 10% following a therapeutic regimen with the compound indicates the achievement of a therapeutic effect.
  • the CORE Assessment of Psychomotor Change (Parker and Hadzi-Pavlovic, 1996) is comprised of 18 signs (observable features), which are rated by the clinician at the end of the interview. Each sign is rated on a four-point scale (0-3). Summing subsets of the items produces scores on three dimensions found to underlie psychomotor change: non- interactiveness, retardation and agitation. A total score from the items can be used to assign patients to melancholic or non-melancholic subtypes.
  • the CORE Assessment of Psychomotor Change is not a diagnostic measure. It is a sub-type system to be used when a diagnosis of primary depression has been made and to divide melancholic versus non- melancholic type. A change in classification from a melancholic subtype to a non- melancholic subtype indicates a decrease in the pathophysiology of the disease state.
  • the Hamilton Psychiatric Rating Scale for Anxiety is a widely used observational rating measure of anxiety severity.
  • the scale consists of 14 items. Each item is rated on a scale of 0 to 4. This scale is administered to assess the severity of anxiety and its improvement during the course of therapy.
  • the HAM-A total score is the sum of the 14 items and the score ranges from 0 to 56.
  • An improvement in patient score of greater than 5% after administration of the NMDA antagonist compound indicates a decrease in the pathophysiology of the neuropsychiatric disorder, while an improvement in patient score of 10% following a therapeutic regimen with the compound indicates the achievement of a therapeutic effect in treating anxiety.
  • the YMRS (Young et al, 1978, incorporated herein by reference) consists of 11 items. Items 5, 6, 8, and 9 are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). Items 5, 6, 8, and 9 (irritability, speech, content and disraptive-aggressive behavior) are given twice the weight of the remaining 7 in order to compensate for the poor condition of severely ill patients.
  • the YMRS total score ranges from 0 to 60 and is the primary efficacy parameter.
  • the YMRS scale is obtained should hypomanic/manic symptoms develop during therapy. An improvement in patient score of greater than 5% after administration of the NMDA antagonist compound indicates a decrease in the pathophysiology of the neuropsychiatric disorder, while an improvement in patient score of 10% following a therapeutic regimen with the compound indicates the achievement of a therapeutic effect.
  • the PANSS ratings are derived from a formal, semi-stractured, 30- to 40-minute clinical interview and additional sources of information.
  • the PANSS rating provides a method of evaluating patients should psychotic symptoms develop during the course of therapy. Psychotic symptoms have been reported to occur with the use of NMDA antagonists, and any compound that modulates the glutamate neurotransmission pathway should be evaluated for its propensity to develop psychotic symptoms.
  • the CGI scale (National Institute of Mental Health, 1976, incorporated herein by reference) is a three-item scale that assesses treatment response in psychiatric patients. The administration time is 5 minutes. This scale consists of three items: Severity of Illness (item 1); Global Improvement (item 2); and Efficacy Index (item 3).
  • Item 3 is rated on a four-point scale (from none to outweighs therapeutic effect). Items 1 and 3 are assessed based on the previous week's experience. Item 2 is assessed from the period since the initiation of the current treatment. An improvement in patient score of greater than 5% after administration of the NMDA antagonist compound indicates a decrease in the pathophysiology of the neuropsychiatric disorder, while an improvement in patient score of 10% following a therapeutic regimen with the compound indicates the achievement of a therapeutic effect.
  • More empirical data on patient response to therapy can be obtained through magnetic resonance spectroscopy, and PET.
  • Neuronal injury is associated with, for example, decreased N-acetyl-aspartate (NAA) peaks on MR spectroscopy.
  • NAA N-acetyl-aspartate
  • a Stimulated Echo Acquisition Mode (STEAM) pulse sequence is used to acquire spectra using the following acquisition parameters and also includes unsuppressed water reference scans for metabolite quantitation: an echo time of 30 msec, a modulation time of 13.7 msec, a repetition time of 2 sec, 8 step phase cycle, 2048 points, a spectral width of 2500 Hz, and 128 averages for a total acquisition time of approximately 5 minutes.
  • STEAM Stimulated Echo Acquisition Mode
  • Spectra will be acquired from approximately 8cc regions of interest (ROIs) in the frontal, temporal, parietal, and occipital lobes.
  • Compounds identified in the short echo [ 1 H]-MRS human brain studies include the neuronal marker, N-acetyl-aspartate (NAA), glutamine/glutamate/GABA (Glx), creatine/phosphocreatine (Cr), choline compounds (Cho) and myo-Ihositol (ml).
  • NAA N-acetyl-aspartate
  • Glx glutamine/glutamate/GABA
  • Cr creatine/phosphocreatine
  • Cho choline compounds
  • myo-Ihositol myo-Ihositol
  • the area under each of the resonances is proportional to the concentration of the specific neurochemical compound.
  • a decrease in the pathophysiology of the neuropsychiatric disorder in response to memantine administration results in increases in, for example, the NAA
  • the user enters a priori information regarding the metabolite data in order to give the software starting values for its fitting process.
  • the a priori information given includes the expected chemical shifts for each of the major chemical compounds appearing in the typical proton brain spectrum as well as a starting linewidth determined by the co ⁇ esponding water linewidth.
  • the chemical shift values given to the program are based on literature values, which are 2.02 ppm for NAA, 2.3 ppm for the Glx complex, 3.03 ppm for Cr, 3.22 for Cho, and 3.56 for ml.
  • the software will then attempt to fit the metabolite spectrum and display its results both visually and in a file, which can be pasted into a spreadsheet analysis program.
  • Quantitative metabolite concentrations are reported in arbitrary units as (xl0 4 )/water. Water and metabolite relaxation effects are not corrected for with this technique because obtaining these values on each patient would be time prohibitive (measurement time would take an additional 2 hours in each subject). Acquisition parameters are utilized, which minimize the uncertainty in neurochemical concentration estimates due to relaxation effects. Specifically, a short echo time of 30 msec minimizes T2 signal decay and a standard repetition time of 2 sec minimizes TI e ⁇ or resulting from collecting spectra under less than fully relaxed conditions. This is a common trade-off in clinical situations .
  • the major depressive episode is associated with elevated glucose metabolism in limbic areas such as amygdala and ventral anterior, cingulate cortex, and cortical and subcortical areas which have extensive anatomical connections with these regions, such as the anterior insula, the orbital cortex, the posterior cingulate, the medial thalamus, and the ventral striatum (reviewed in Drevets, 2000).
  • limbic areas such as amygdala and ventral anterior, cingulate cortex, and cortical and subcortical areas which have extensive anatomical connections with these regions, such as the anterior insula, the orbital cortex, the posterior cingulate, the medial thalamus, and the ventral striatum (reviewed in Drevets, 2000).
  • Metabolism in the amygdala and anterior cingulate is abnormally elevated in MDD subgroups who were responsive to sleep deprivation.
  • Medicated, remitted MDD subjects who relapsed during serotonin depletion have typically higher baseline amygdala and orbital cortex metabolism than those who did not relapse.
  • Subject preparation consists of intravenous catheterization.
  • PET scans are acquired using a GE Advance (35 contiguous slices with 4.25 mm plane separation; 3D resolution 6 to 7 mm FWHM, 3D acquisition mode).
  • the initial emission scan is acquired over the heart, so the subjects are moved feet first into the whole body seamier.
  • a 2-min transmission scan using rotating rods of 68 Ge/ 68 Ga with electronic windowing around the rods to minimize scatter is obtained over the chest.
  • This scan is immediately reconstructed to guide repositioning of the seamier gantry so that it is centered over the heart.
  • an approximately 8 min transmission scan is acquired for attenuation co ⁇ ection of the cardiac emission scan during the tracer uptake period.
  • FDG fluorodeoxyglucose
  • the subject will get up off the scanner bed and the bed will be fitted with the head-holder.
  • the subject is positioned head first into the scanner and the head is immobilized using a thermoplastic mask, which constrains head position at multiple surfaces (e.g., forehead, temporal and occipital surfaces, mandible) to reduce the likelihood of movement.
  • the cerebral emission scan is acquired as subjects rest with eyes-closed.
  • a 2 minute transmission scan is acquired and immediately reconstructed so that the primary structures of interest are located approximately in the center of the field-of-view.
  • a second transmission scan (8 minutes) is acquired for attenuation co ⁇ ection of the emission data.
  • a 10-minute emission scan is initiated 45 min after FDG injection. Venous blood sampling at 5 minute intervals is initiated at 45 min post FDG injection. The radioactivity of the plasma and whole blood is counted. Three venous samples are also obtained to measure plasma glucose.
  • the post-treatment scan is acquired using identical methods. Subjects are repositioned in the scanner by aligning laser lines projected from the scanner gantry onto markings on the hardened thermoplastic mask worn during the initial scan so that the head position is approximately the same in all frames.
  • ventral striatum contains the nucleus accumbens.
  • the cells with connectional and histochemical features of the accumbens blend with those of the anteroventral putamen and ventromedial caudate, such that the nucleus accumbens lacks distinct microscopic and macroscopic borders (Heimer and Alheid, 1991, incorporated herein by reference).
  • This anteroventral portion of the striatum is innervated by the amygdala and the orbital and medial PFC areas implicated in reward- related and emotional processing, while the dorsal caudate and dorsal putamen primarily receives afferent connections from cortical areas involved in sensorimotor function (Everitt et al, 1989; Haber et al, 1995; Ong ⁇ r and Price, 2000; Selemon and Goldman-Rakic, 1985, incorporated herein by reference).
  • the volumetric resolution of a 1.25 mm point radioactivity source in a Siemens HR+ (similar to that of the GE Advance) has a measured FWHM resolution of 5.3 mm axial and 6.6 mm transverse, yielding a volumetric resolution of 0.23 mL. This volume is only 8.3 % of the mean AVS volume (2.77 ⁇ 0.722 mL) measured in MRI images from healthy humans.
  • the axial resolution of 5.3 mm FWHM implies that pixels located greater than 11 mm from the edge of the AVS will have virtually no effect on PET measures from the AVS.
  • Example 2 Synthesis of l-amino-3, 5-dimethyl-7-hydroxyadamantane hydrochloride (4) l-Acetamido-3, 5-dimethyl-7-hydroxyadamantane (0.4 g) and NaOH (1.1 g) were added to diethylene glycol (7 ml) and the reaction mixture was heated to 175°C for 15 h. After cooling to room temperature, ice (10 g) was added and the product was extracted with ether (10 mL x 4). The combined ether solution was washed with brine (10 mL) and water (10 mL). The solution was dried using sodium sulfate. The solvent was removed in vacuo and, after crystallization on standing, 250 mg of white product was obtained.
  • Example 4 Synthesis of l-tert-butylcarbamate-3, 5-dimethyI-7-nitrate- adamantane (6) A cooled (0°C) acetyl nitrate (0.08 mL, from a mixture of fuming HNO 3 and acetic anhydride (1: 1.5/v: v) was added to a dichloromethane (1 mL) solution of l-tert- butylcarbamate-3, 5-dimethyl-7-hydroxyadamantane (40 mg) at 0 °C under nitrogen and the reaction mixture was sti ⁇ ed at 0 °C for 15 minutes.
  • Example 7 Synthesis of 1, l-dibenzylamino-3, 5-dimethyl-7-hydroxy- adamantane (10) To a solution of l-amino-3, 5-dimethyl-7-hydroxyadamantane hydrochloride (100 mg) in DMF (2 mL) was added benzyl bromide (0.16 mL) and sodium carbonate (200 mg). The reaction mixture was sti ⁇ ed overnight. The product was extracted with dichloromethane (10 mL) and washed with water (20 mL x 2). The organic phase was dried using sodium sulfate and the solvent was removed in vacua.
  • Triethylamine (0.80 mL) and ethyl chloroformate (0.80 mL) were added sequentially into a suspension of l-acetamido-3, 5-dimethyl-7-carboxylic acid- adamantane (2.0 g) in THF at 0 °C.
  • the reaction mixture was sti ⁇ ed for 4 h at room temperature.
  • the white precipitate formed was then filtered and washed with THF.
  • NaBH 4 (2.40 g) was added to the filtrate. Water (2 mL) was added dropwise to the solution over a period of 1 h followed by addition of more water (50 mL).
  • Example 14 1 -Amino-3, 5-dimethyl-7-hydroxymethyIadamantane hydrochloride (18). l-Acetamido-3, 5-dimethyl-7-hydroxymethyladamantane (200 mg) and NaOH (540 mg) were added to diethylene glycol (4 mL) and the reaction mixture was heated to 175 °C under nitrogen for 15 h. After cooling to room temperature, ice (5 g) was added and the product was extracted with ethyl acetate (10 mL x 6). The combined extract was washed with water (10 mL) and brine (10 mL), and dried using sodium sulfate. Solvent was removed in vacua.
  • Example 16 l-(benzyloxycarbonyl)amino-3, 5-dimethyl-7-nitratemethyl- adamantane (20). To a solution of l-(benzyloxycarbonyl)amino-3,5-dimethyl-7- hydroxymethyladamantane (60 mg) in dichloromethane (3 mL) was added a cooled (0°C) 30 acetyl nitrate (1 mL, from a mixture of fuming HNO 3 and Ac 0 (2: 3/v: v). The reaction mixture was sti ⁇ ed at 0 °C for 15 minutes. A sodium bicarbonate solution (1 N, 5 mL) was added and the product was extracted with dichioromethane.
  • Example 17 l-Amino-3, 5-dimethyl-7-nitratemethyladamantane hydrobromide (21) l-(benzyloxycarbonyl)amino-3,5-dimethyl-7-nitratemethyl-adamantane (17 mg) was dissolved in HBr/acetic acid (1 mL) and the solution was sti ⁇ ed at room temperature for 2 h. The reaction mixture was concentrated in v ⁇ cuo to give a white solid which was washed with ether to afford the target product (10 mg).
  • Example 19 In vitro protection of neurons by compound 7.
  • Example 20 In vivo protection by compound 7 in a murine cerebral ischemia model.
  • the intraluminal suture technique was used to produce a 2 hr occlusion of the middle cerebral artery (MCA), following the same protocol for focal cerebral ischemial reperfusion as published previously (Chen, et al, Neuroscience (1998) 86: 1121). However, here C57B1/6 mice were used instead of rats.
  • the loading dose was 20 mg/kg i.p. with a maintenance dose of 1 mg/kg 12 hours, as this had been previously shown to produce parenchymal levels of 1-10 ⁇ M memantine in the brain, which was shown to be neuroprotective (Chen, et al, Neuroscience (1998) 86: 1121).
  • the loading dose was 100 mg/kg i.p.
  • Example 21 Vasodilation by compound 8 in a rabbit model.
  • New Zealand white female rabbits weighing 3-4 kilograms were anesthetized with sodium pentobarbital, 13 milligram per kilogram.
  • Descending thoracic aorta were isolated, the vessels were cleaned of adherent tissue and the endothelium was removed by a gentle rubbing with a cotton-tipped applicator inserted into the lumen.
  • the vessels were cut into 5 millimeter rings and mounted on stirrups connected to transducers by which changes in isometric tension were recorded (model TO3C, Grass Instruments, Quincy, Mass).
  • Vessel rings were suspended in 20 mL of oxygenated Krebs buffer at 37°C and sustained contractions were induced with 1 ⁇ M norepinephrine.
  • the vessels were then relaxed in a dose-dependent fashion (109 tlirough 10 " M compound 8).
  • vessels were pretreated with methylene blue or 30 hemoglobin to block relaxations.
  • FIG. 7 shows relaxation of the precontracted aortic vessel in a dose-dependent fashion using compound 8. Relaxations were seen at 10 "8 M and complete relaxation was achieved at i06 M (a). Relaxations were attenuated by methylene blue (c) and hemoglobin (d) indicating an NO-related effect, (b) is a control with solvent.
  • FIG. 8 shows site and specificity to derivatization of memantine. That is, compound 9 (a) and 10 (c) produced either no effect or slight contractions of blood vessels that were attributed to solvent (shown on right side). Compound 7 (b) produced modest relaxation at a 10 ⁇ M concentration. These results demonstrate that compound 7 has vasodilator activity, in addition to
  • Compound 7 thus acts through a unique mechanism of action that likely contributes to protective effects in models of stroke.
  • Auer DP Putz B, Kraft E, et al. Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study. Biol Psychiatry. 2000 Feb 15;47(4): 305-13. Baumann B, Danos P, Krell D, et al. Reduced volume of limbic system-affiliated basal ganglia in mood disorders: preliminary data from a post mortem study. J Neuropsych. Clin. Neurosci. 1999; 11 : ' 71 -78.
  • NMDA N-methyl-D-aspartate
  • Eisenberg E LaCross S, Strassman AM.
  • Eisenberg E Vos BP, Strassman AM.
  • the NMDA antagonist memantine blocks pain behavior in a rat model of formalin-induced facial pain. Pain 1993;54: 301-307.
  • N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission in the pathophysiology and therapeutics of psychiatric syndromes. Eur Neuropsychopharrnacol 1988;8: 141-152.
  • Klockgether T and Turski L Excitatory amino acids and the basal ganglia: implications for the therapy of Parkinson's disease. Trends Neurosci 1989;12: 285-286. Klockgether T and Turski L. NMDA antagonist potentiate antiparkinsonian actins of L- dopa in monoamine depleted rats. Ann Neurol 1990;28: 539-546.
  • Lipton SA Prospects for clinically-tolerated NMDA antagonists: open-channel blockers and alternative redox states of nitric oxide. Trends Neurosci 1993;16: 527-532. Lipton SA, Rosenberg RA. Mechanisms of disease: Excitatory amino acids as a final common pathway in neurologic disorders. N Engl J Med 1994;330: 613-622.
  • NMDA N-methyl-D-aspartate
  • CREB cAMP response element binding protein
  • Nierenberg AA Methodological problems in treatment resistant depression research. Psychopharmacol Ew//.1994; 190/26: 461-464.
  • Sheline YI Sanghavi M, Mintun MA, et al. Depression duration but not age predicts hippocampal volume loss in medically health women with recu ⁇ ent major depression. J Neurosci 1999;19: 5034-43. Sheline YI, Wang PW, Gado MH, et al. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA 1996;93: 3908-13. Skolnick P. Antidepressants for the new millennium. Eur J Pharmacol. 1999 Jun 30;375(1- 3): 31-40.

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Abstract

La présente invention concerne des compositions et des méthodes de traitement d'un patient humain atteint d'un trouble neuropsychiatrique. L'invention concerne plus particulièrement des compositions et des méthodes qui modulent ou antagonisent l'activité des récepteurs neuronaux de NMDA. Cette activité antagoniste peut moduler la réaction excitatrice des neurones induite par le glutamate, ce qui inhibe un effet excitotoxique, produit un effet neurotrophique, et induit un effet thérapeutique pouvant traiter le trouble neuropsychiatrique.
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Families Citing this family (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7674222B2 (en) 1999-08-09 2010-03-09 Cardiokinetix, Inc. Cardiac device and methods of use thereof
US8377114B2 (en) 1999-08-09 2013-02-19 Cardiokinetix, Inc. Sealing and filling ventricular partitioning devices to improve cardiac function
US10307147B2 (en) 1999-08-09 2019-06-04 Edwards Lifesciences Corporation System for improving cardiac function by sealing a partitioning membrane within a ventricle
US9694121B2 (en) 1999-08-09 2017-07-04 Cardiokinetix, Inc. Systems and methods for improving cardiac function
US8246671B2 (en) 1999-08-09 2012-08-21 Cardiokinetix, Inc. Retrievable cardiac devices
US8257428B2 (en) 1999-08-09 2012-09-04 Cardiokinetix, Inc. System for improving cardiac function
US8529430B2 (en) 2002-08-01 2013-09-10 Cardiokinetix, Inc. Therapeutic methods and devices following myocardial infarction
US6444702B1 (en) 2000-02-22 2002-09-03 Neuromolecular, Inc. Aminoadamantane derivatives as therapeutic agents
US9332992B2 (en) 2004-08-05 2016-05-10 Cardiokinetix, Inc. Method for making a laminar ventricular partitioning device
US10064696B2 (en) 2000-08-09 2018-09-04 Edwards Lifesciences Corporation Devices and methods for delivering an endocardial device
US9332993B2 (en) 2004-08-05 2016-05-10 Cardiokinetix, Inc. Devices and methods for delivering an endocardial device
US9078660B2 (en) 2000-08-09 2015-07-14 Cardiokinetix, Inc. Devices and methods for delivering an endocardial device
TW200403066A (en) * 2002-04-30 2004-03-01 Novartis Ag New uses of substituted aminoalkanephosphonic acids
AR046314A1 (es) * 2003-11-05 2005-11-30 Merz Pharma Gmbh & Co Kgaa Composiciones que comprenden ciclohexilaminas y aminoadamantanos
UY28650A1 (es) * 2003-12-05 2005-02-28 Forest Laboratories Memantina para la prevencion o disminucion de la conducta suicida y para el tratamiento de la depresion mayor asociada con esta conducta
TW200531680A (en) * 2004-03-03 2005-10-01 Merz Pharma Gmbh & Co Kgaa Therapy using 1-aminocyclohexane derivatives for the treatment of behavioral disorders associated with alzheimer's disease
BRPI0512177A (pt) 2004-06-17 2008-02-12 Forest Laboratories formulação de liberação modificada de memantina
CA2607600A1 (fr) * 2005-06-16 2006-12-28 Forest Laboratories, Inc. Formulation de gouttes de memantine a liberation modifiee et immediate
WO2007130724A2 (fr) 2006-02-06 2007-11-15 Northwind Ventures Systèmes et procédés de réduction de volume
CN101426484B (zh) * 2006-04-13 2013-05-22 纽若泰克制药株式会社 药物组合物在制备用于治疗或预防退行性和炎症性疾病的药物中的应用
IT1396556B1 (it) 2009-02-11 2012-12-14 Serra Uso di memantina per il trattamento di disturbi dell umore
CN102070463A (zh) * 2009-06-11 2011-05-25 辽宁利锋科技开发有限公司 具有金刚烷结构药物美金刚胺及其衍生物和类似物抗肿瘤新适应症的应用
AU2010315535A1 (en) 2009-10-26 2012-05-03 Cardiokinetix, Inc. Ventricular volume reduction
MX365650B (es) 2009-12-02 2019-06-10 Adamas Pharmaceuticals Inc Composiciones de amantadina y metodos para su uso.
JP5562716B2 (ja) * 2010-05-12 2014-07-30 花王株式会社 電位依存性カチオンチャネル抑制剤
US10154971B2 (en) 2013-06-17 2018-12-18 Adamas Pharma, Llc Methods of administering amantadine
SG10202102125SA (en) * 2014-04-30 2021-04-29 Yufeng Tseng Use of known compounds as d-amino acid oxidase inhibitors
CN105294450B (zh) * 2014-05-29 2024-05-17 广州喜鹊医药有限公司 具有神经保护作用的金刚烷胺硝酸酯化合物及其制备和医药应用
CA2962747C (fr) 2014-09-28 2023-02-28 Cardiokinetix, Inc. Appareils permettant de traiter un dysfonctionnement cardiaque
IL296380A (en) * 2015-05-22 2022-11-01 Vistagen Therapeutics Inc Medicinal uses for l–4–chlorokynurenine
US10898330B2 (en) 2017-03-28 2021-01-26 Edwards Lifesciences Corporation Positioning, deploying, and retrieving implantable devices
US11529319B2 (en) * 2017-08-01 2022-12-20 Stuart A. Lipton Methods and compositions for treating neurological conditions
US11447442B2 (en) * 2017-11-22 2022-09-20 Panorama Research, Inc. Aminoadamantyl nitrate compounds and their use to treat CNS disorders
CN109206317B (zh) * 2018-09-12 2021-07-09 青岛海蓝医药有限公司 一种金刚烷胺类硝酸酯衍生物的制备工艺
CN110938006A (zh) * 2019-12-04 2020-03-31 重庆植恩药业有限公司 盐酸美金刚杂质c的制备方法
CN114544826B (zh) * 2020-11-24 2023-12-08 重庆医科大学 检测血浆中组氨酸的试剂在制备抑郁症检测试剂盒中的用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994005275A1 (fr) * 1992-09-03 1994-03-17 The Children's Medical Center Corporation Procede de prevention contre les lesions neuronales dues au recepteur nmda
WO1994006428A1 (fr) * 1992-09-22 1994-03-31 The Children's Medical Center Corporation Procede de prevention de deteriorations neuronales induites par le complexe recepteur nmda
WO2001062706A1 (fr) * 2000-02-22 2001-08-30 Panorama Research, Inc. Derives d'aminoadamantane convenant comme agents therapeutiques

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS584718A (ja) * 1981-06-30 1983-01-11 Nippon Chibagaigii Kk 新規適応症に用うる医薬製剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994005275A1 (fr) * 1992-09-03 1994-03-17 The Children's Medical Center Corporation Procede de prevention contre les lesions neuronales dues au recepteur nmda
WO1994006428A1 (fr) * 1992-09-22 1994-03-31 The Children's Medical Center Corporation Procede de prevention de deteriorations neuronales induites par le complexe recepteur nmda
WO2001062706A1 (fr) * 2000-02-22 2001-08-30 Panorama Research, Inc. Derives d'aminoadamantane convenant comme agents therapeutiques

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PARSONS C G ET AL: "Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist - A review of preclinical data" NEUROPHARMACOLOGY, vol. 38, no. 6, June 1999 (1999-06), pages 735-767, XP002279262 ISSN: 0028-3908 *
See also references of WO0245710A1 *
YAMADA KAZUO ET AL: "Changes in symptoms and plasma homovanillic acid with amantadine hydrochloride in chronic schizophrenia" BIOLOGICAL PSYCHIATRY, vol. 41, no. 10, 1997, pages 1062-1064, XP002279263 ISSN: 0006-3223 *

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