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(12) Patent Application Publication (10) Pub. No.: US 2004/0122090 A1 Lipton (43) Pub US 2004O122090A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0122090 A1 Lipton (43) Pub. Date: Jun. 24, 2004 (54) METHODS FOR TREATING Related U.S. Application Data NEUROPSYCHIATRIC DSORDERS WITH NMDA RECEPTOR ANTAGONSTS (60) Provisional application No. 60/254,007, filed on Dec. 7, 2000. (76) Inventor: Stuart A. Lipton, Rancho Santa Fe, CA (US) Publication Classification Correspondence Address: (51) Int. Cl. ................................................. A61K 31/21 MINTZ, LEVIN, COHN, FERRIS, GLOWSKY (52) U.S. Cl. .............................................................. 514/510 AND POPEO, PC. (57) ABSTRACT ONE FINANCIAL CENTER The present invention relates to compositions and methods BOSTON, MA 02111 (US) for treating a human patient afflicted with a neuropsychiatric disorder. Specifically, the invention provides for composi tions and methods of modulating or antagonizing the activity (21) Appl. No.: 10/250,786 of neuronal NMDA receptors, wherein Such antagonistic activity is capable of modulating the glutamate induced (22) PCT Fed: Dec. 7, 2001 excitatory response of the neurons, thereby inhibiting an excitotoxic effect, promoting a neurotrophic effect, and thereby providing a therapeutic effect that treats the neurop (86) PCT No.: PCT/US01/48516 Sychiatric disorder. NHCOCH Br NHCOCH 1. H2SO4 HC CH HC CHs --2. CHCN H3C CH ONO 8 2 1. H2SO4 2. HO tno, ACO (BOC).O NaOH HC CH HC CH --- HC CH OH OH OH 5 4 3 NHBOC NHHCI HNO | ACO HCl ( EtOAC -- -o-be ONO2 ONO2 Patent Application Publication Jun. 24 US 2004/O122090 A1 Patent Application Publication Jun. 24 US 2004/O122090 A1 Patent Application Publication Jun. 24, 2004 Sheet 4 of 9 US 2004/0122090 A1 Patent Application Publication Jun. 24, 2004 Sheet 5 of 9 US 2004/O122090 A1 2 30 O OY D U Z 2 20 5Cl O C SS 10 NMDA- NMDA + NMDA + 25uM7 50 LM 7 100 LM 7 Fig. 5 100 E g 75 f 9. O S. Y 5 25 MEMANTINE COMPOUND7 Fig. 6 Patent Application Publication Jun. 24, 2004 Sheet 6 of 9 US 2004/0122090 A1 COMPOUND 8(M) BASELNE Fig. 7A ETHANOL tul) 2 7 2. 7 l u Fig. 7B COMPOUNDMETHYLENE BLUE 8(M) (105M), 7 - -5 FLUSH Fig. 7C HEMOGLOBIN (106 M), -9 -8 -7 -6 i COMPOUND 8(M) Patent Application Publication Jun. 24, 2004 Sheet 7 of 9 US 2004/O122090 A1 COMPOUND 9 (M) EtOH (ul) BASELNE N -- - - FLUSH BASELINE -N- Fig. 8B COMPOUNDO (M) EtOH (ul) -- -5 2070 FLUSH FLUSH 2 7 BASELINE Fig. 8C Patent Application Publication Jun. 24, 2004 Sheet 8 of 9 US 2004/0122090 A1 Study Study Design/N Dosel Efficacy Adverse Events Duration study disease Fischer et al. 1977 |012 IV,40mgin2 + motor drive and rigor Dizziness, fatigue, lack of hours single dose coordination sense of well being at 6 hours post-infusion Rabey et al. 1992 O/12 P0, 10-30 + Parkinson's syndrome in Nausea, abdominal pain, mg/day X 5/10 confusion 4 wks and dizziness, psychomotor agitation Riedereretal. Ol4 PO, 10-30 1 memantinept had mild Psychosis in 2 patients 1991 mg/day X improve- (concomitant 6 wks mentin motor symptoms Meds included L-dopa, amantadine) Schneideretal. R, DB, Significant improvement in 90% tolerated well 1984 P-Cl67 fine motor ability in memantine group Merello et al. 1999 R, DB, CO, PO,30 Improvementin Parkinsonian Mild transient drowsiness and PC/12 mg/day X Symptoms SCa 2Wks Dementia Fleishchhackeret R, SB, P-CI20 IV, 20-30 5 Memantine and 4 PBOpts Delusions of guilt, delirium, al., 1986 mg/day X improved enough for mild 5 wks discharge hypotonia Ditzler 1991 R, DB, P-C/66 PO, 10-30 Memantine) PBO Agitation, increased motor Ing?day X activity, 6wks Insomnia, restlessness Görtelmeyer and R, DB, P-Cl88 PO, 10-20 Memantine > PBO Akathisia, increased motor Erbler 1992 mg/day X activity, 6 wks Insomnia, headache Pantevetal. 1993 R, DB, P-C/60 PO, 10-30 Memantinex PBO Restlessness, akathisia, vertigo mg/day X 4 wks Rieke and Glaser 01420 PO, 13-26 Memantine end) baseline Restlessness, nausea, fatigue 1996 mg/day Neurogenic bladder Grossman and O/18 PO, 20-70 Improvement in bladder Agitation, giddiness, impaired Schitz 1982 mg/day X function Concentration and sleep 2wks Fig. 9A Patent Application Publication Jun. 24, 2004 Sheet 9 of 9 US 2004/0122090 A1 Spasticity Mundinger and O?37 PO, 30-60 Improvementin neurological 78% tolerated well; some Milios 1985 mg/day X Symptoms patients giddiness, nausea, 8wks stupor Rohde 1982 O/30 Improvementin spasticity Fatigue, increased 17.30 transaminases, GGT Bayerland Gruia Single blindl P0, 20-30 61% improved Mood elevation, increase in 1985 Cross-overl30 mg/day X drive 6wks Leskow 1987 O226 PO, 10-30 Improvement infine motor Dizziness, tiredness, headaches mg/day X movement, muscle tone 6wks Craniacerebral trauma Miltner 1982 Ol45 Improvement in levelof Well-tolerated COSCOSESS Disease Ambrozi and DB, P-C/30 D0SeX Memantine > PBO Euphoria, Vertigo Danielczyk 1988 6 weeks Niss senetal. R, DB, C-0, P-C PO,5-20 Memantine + PBO Nausea, headache, skin rash Fig. 9B US 2004/O122090 A1 Jun. 24, 2004 METHODS FOR TREATING NEUROPSYCHIATRIC Johnson et al, Annu. Rev. Pharmacol. Toxicol., 30: 707-750 DSORDERS WITH NMDA RECEPTOR (1990) incorporated herein by reference). Further, NMDA ANTAGONSTS receptors have also been implicated in certain types of spatial learning, (see, Bliss et al., Nature, 361: 31 (1993), FIELD OF THE INVENTION incorporated herein by reference). Interestingly, both the 0001. The present invention relates to compositions and spatial and temporal distribution of NMDA receptors in methods for treating a human patient having an affliction mammalian nervous Systems have been found to vary. Thus, comprising a neuropsychiatric disorder. Specifically, the cells may produce NMDA receptors at different times in invention provides for compositions and methods of modu their life cycles and not all neural cells may utilize the lating or antagonizing the activity of neuronal ionotropic NMDA receptor. glutamate receptors, Such as NMDA receptors, wherein Such 0004. Due to its broad-spectrum of neurological involve antagonistic activity is capable of modulating the excitatory ment, yet non-universal distribution, investigators have been response of the neurons, inhibiting an excitotoxic effect, and interested in the identification and development of drugs promoting a neurotrophic effect, thereby providing a thera capable of acting on the NMDA receptor. Drugs that can peutic effect that treats the neuropsychiatric disorder. modulate the NMDA receptor are expected to have enor mous therapeutic potential. For instance, U.S. Pat. No. BACKGROUND OF THE INVENTION 4,904,681, issued to Cordi et al., and incorporated herein by 0002 Receptors to the neuroexcitatory amino acid, reference, describes the use of D-cycloSerine, which was glutamate, particularly the N-methyl-D-aspartate (NMDA) known to modulate the NMDA receptor, to improve and Subtype of these receptors, play critical roles in the devel enhance memory and to treat cognitive deficits linked to a opment, function and death of neurons (see, McDonald JW neurological disorder. D-cycloSerine is described as a gly et al., Brain Research Reviews, 15: 41-70 (1990) and Choi cine agonist which binds to the Strychnine-insensitive gly W, Neuron, 1: 623-34 (1988) incorporated herein by refer cine receptor. ence). The N-methyl-D-aspartate (NMDA) receptor is a 0005 U.S. Pat. No. 5,061,721, issued to Cordi et al., and postsynaptic, ionotropic receptor which is responsive to, incorporated herein by reference, describes the use of a inter alia, the excitatory amino acids glutamate and glycine combination of D-cycloSerine and D-alanine to treat Alzhe and the synthetic compound NMDA, hence the receptor imer's disease, age-associated memory impairment, learning name. The NMDA receptor controls the flow of both diva deficits, and psychotic disorders, as well as to improve lent (Cat") and monovalent (Na" and K") ions into the memory or learning in healthy individuals. D-alanine is postsynaptic neural cell through a receptor associated chan administered in combination with D-cycloSerine to reduce nel (see, Foster et al., Nature, 329: 395-396 (1987); Mayer the side effects observed in clinical trials of D-cycloserine, et al., Trends in Pharmacol. Sci., 11:254-260 (1990) incor mainly those due to its growth-inhibiting effect on bacteria porated herein by reference). resulting in depletion of natural intestinal flora. D-Alanine 0003) The NMDA receptor has been implicated during reverses the growth-inhibiting effect of D-cycloSerine on development in Specifying neuronal architecture and Synap bacteria. It is also reported that D-cycloSerine actually has tic connectivity, and may be involved in experience depen partial agonist character. dent synaptic modifications. In addition, NMDA receptors 0006 U.S. Pat. No. 5,086,072, issued to Trullas et al., and are also thought to be involved in long term potentiation, incorporated herein by reference, describes the use of 1-ami central nervous System (CNS) plasticity, cognitive pro nocyclopropanecarboxylic acid (ACPC), which was known cesses, memory acquisition, retention, and learning. Further to modulate the NMDA receptor as a partial agonist of the more, the NMDA receptor has also drawn particular interest Strychnine-insensitive glycine binding site, to treat mood since it appears to be involved in a broad spectrum of CNS disorders including major depression, bipolar disorder, dyS disorders. For instance, during brain ischemia caused by thymia and Seasonal effective disorder. It is also therein Stroke or traumatic injury, excessive amounts of the excita described that ACPC mimics the actions of clinically effec tory amino acid glutamate are released from damaged or tive antidepressants in animal models. In addition, a copend oxygen deprived neurons. This excess glutamate binds to the ing U.S. patent application is cited that describes that ACPC NMDA receptor which opens the ligand-gated ion channel and its derivatives may be used to treat neuropharmacologi thereby allowing Cat" influx producing a high level of cal disorders resulting from excessive activation of the intracellular Ca" which activates biochemical cascades NMDA receptor.
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