US 2009006 1024A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0061024 A1 Eppler et al. (43) Pub. Date: Mar. 5, 2009 (54) COMPOSITIONS AND METHODS (22) Filed: Aug. 26, 2008 EMPLOYING NMDA ANTAGONSTS FOR ACHIEVING AN ANESTHETC-SPARING Related U.S. Application Data EFFECT (60) Provisional application No. 60/968,236, filed on Aug. 27, 2007. (75) Inventors: Cecil Mark Eppler, Langhome, PA (US); David Robert Hustead, Publication Classification Overland Park, KS (US); Thomas (51) Int. Cl. Gerard Cullen, Milltown, NJ (US); A633/00 (2006.01) Raphael Johannes Zwijnenberg, A63/675 (2006.01) Lambertville, NJ (US); William W. A6IP 23/00 (2006.01) Muir, III, Columbus, OH (US) (52) U.S. Cl. ........................................... 424/718; 514/79 Correspondence Address: (57) ABSTRACT WYETH PATENT LAW GROUP Provided herein are compositions, combinations, and meth 5 GRALDA FARMS ods comprising NMDA antagonists including, but not limited MADISON, NJ 07940 (US) to, NMDA glutamate receptor antagonists such as 2-(8.9- dioxo-2,6-diazabicyclo5.2.0non-1-(7)-en-2-yl)alkylphos (73) Assignee: Wyeth, Madison, NJ (US) phonic acid and derivatives thereof, which are effective in reducing the amount of anesthetic required to maintain anes (21) Appl. No.: 12/198,489 thesia (i.e. to achieve an anesthetic-sparing effect). US 2009/006 1024 A1 Mar. 5, 2009 COMPOSITIONS AND METHODS 14:46-50 (1991)), reaching the approximately 50% level only EMPLOYING NMDA ANTAGONSTS FOR at distinctly non-clinical doses (Hall et al., Anesthesiology ACHIEVING AN ANESTHETC-SPARING 68:862-866 (1988)) where side effects such as respiratory EFFECT depression and reduced analgesic efficacy of concurrently used opioids may occur (Gear et al., Pain 71:25-29 (1997) and CROSS-REFERENCE TO RELATED Daghero et al., Anesthesiology 66:944-947 (1987)). APPLICATIONS 0007 Glutamate and aspartate play dual roles in the cen tral nervous system (CNS) as essential amino acids and as the 0001. This application claims the benefit under 35 U.S.C. principal excitatory neurotransmitters. There are at least four S119(e) to U.S. provisional application no. 60/968,236, filed classes of excitatory amino acid receptors: NMDA (N-me Aug. 27, 2007, each of which is hereby incorporated by thyl-D-aspartate), AMPA (2-amino-3-(methyl-3-hydroxy reference in its entirety. isoxazol-4-yl)propanoic acid), kainate, and metabotropic receptors. These excitatory amino acid receptors regulate a BACKGROUND OF THE DISCLOSURE wide range of signaling events that impact physiological 0002 1. Technical Field of the Disclosure brain functions. For example, activation of the NMDA recep 0003. The present disclosure relates generally to the field tor has been shown to be the central event that leads to exci of medicine, including veterinary medicine. More specifi totoxicity and neuronal death in many disease states, as well cally, the present disclosure provides compositions, combi as a result of hypoxia and ischemia following head trauma, nations, kits and methods comprising NMDA glutamate stroke, and following cardiac arrest. It is also known that the receptor antagonists including, but not limited to, the com NMDA receptor plays a major role in the synaptic plasticity pound: 2-(8,9-dioxo-2,6-diazabicyclo5.2.0 non-1-(7)-en that underlies many higher cognitive functions, such as 2-yl)ethylphosphonic acid and derivatives thereof, which memory and learning, certain nociceptive pathways, and in compounds, compositions, combinations kits and methods the perception of pain. In addition, certain properties of are effective for achieving an anesthetic-sparing effect. NMDA receptors suggest that they may be involved in the 0004 2. Description of the Related Art information-processing in the brain that underlies conscious 0005 Anesthetic-sparing effects have been noted for sev ness itself (above information. (Reviewed in Petrenko et al., eral classes of drugs used to complement the beneficial Anesth. Analg.97:1108-1116 (2003)). effects, and/or mitigate undesirable side effects, of anesthet 0008 NMDA glutamate receptors (or “NMDA recep ics. These so-called “anesthetic adjuvant” drugs include C-2 tors') are localized throughout the CNS and in nerves pro adrenergic agonists (Soares et al., American Journal of Vet jecting from the CNS to peripheral tissues. NMDA receptors erinary Research 96:854-859 (2004) and Muir and Lerch, are ligand-gated cation channels that modulate Sodium, Am. J. Vet. Res.67:782-789 (2006)), benzodiazepines (Hallet potassium, and calcium ion flux when they are activated by al., Anesthesiology 68:862-866 (1988)); and opioids glutamate in combination with glycine (reviewed by Childers (Machado et al., Veterinary Anesthesia and Analgesia 33:70 and Baudy, Journal of Medicinal Chemistry 50:2557-2562 77 (2006) and Muir et al., Am. J. Vet. Res. 64:1-6 (2003)). (2007)). Functional NMDA receptors are heterotetramers, Anesthetic sparing can also be achieved by blocking NMDA consisting of 1-3 NR1 subunits and 1-3 NR2 subunits (gen glutamate receptors. Ketamine, a non-competitive NMDA erally depicted as 2 NR1+2 NR2). This heterogeneity is glutamate receptor antagonist, is commonly used as a hyp greatly augmented by the existence of at least 8 NR1 splice notic/dissociative/analgesic adjuvant for anesthetics. The variants and 4 NR2 subunits (NR2A-NR2D). NR1 subunits, anesthetic-sparing effects of 10-20% provided by ketamine at which can constitute ion channels when expressed alone, doses typically used clinically are rather modest (Muir et al., contain the glycine-binding site. NR2 subunits, which are Am. J. Vet. Res. 64:1-6 (2003)), but are still considered one of necessary for full ion conductance, contain the glutamate the benefits of ketamine as an anesthetic adjuvant. binding site and also allosteric modulatory sites for 0006. The anesthetic-sparing effects attainable through polyamines and Zn". The NMDA receptor also contains a currently used anesthetic adjuvant drugs are limited by unde Mg" binding site located inside the pore of the ion channel, sirable side effects, however. For example, the dissociative which blocks ion flow through the channel when occupied by and other dysphoric effects of ketamine referenced above can Mg". persist into the post-Surgical setting, where they are consid 0009 Activation of NMDA receptors plays a major role in ered undesirable side-effects. Ketamine is often administered the induction of pain associated with peripheral tissue and by IV infusion at relatively low doses rather than by a bolus nerve injury (Sindrup et al., Pain 83:389-400 (1999) and IV injection (which would be more convenient) to avoid these Salter, Cur. Topics in Med. Chem. 5:557-567 (2005)). Under side effects. Use-limiting side effects of otheranesthetic adju conditions of normal (nociceptive) pain, the excitatory signal vant drugs include bradycardia for both C-2 adrenergicago received from afferent neurons in the spinal cord dorsal horn nists (Salmenperra et al., Anesthesiology 80:837-846 (1994)) is mediated primarily by the fast-inactivating kainate and and opioids (Ilkiw et al., Canadian Journal of Veterinary AMPA subtypes of the glutamate receptor. Painful stimuli of Research 58:248-253 (1994)) and respiratory depression for greater duration and intensity result in accumulating, pro opioids (van den Berget al., British Journal of Clinical Phar longed, slowly depolarizing synaptic potentials that relieve macology38:533-543 (1994); Willette et al., Journal of Phar the NMDA subtype of the glutamate receptor from its tonic macology and Experimental Therapeutics 240:352-358 block by Mg" ions. Activation of NMDA receptors accentu (1987)). Although benzodiazepines can provide significant ates the Sustained depolarization and contributes to an anesthetic-sparing effects, they tend to be rather modest (typi increase in the discharge of dorsal horn nociceptive neurons cally less than 25%) at doses used clinically (Tranquilliet al., in a process called “wind-up.” Prolonged activation of American J. of Vet. Res. 52:662-664 (1991); Muir et al., NMDA receptors can lead to modifications in cellular signal Journal of Veterinary Pharmacology and Therapeutics ing pathways that enhance the responsiveness of the nocice US 2009/006 1024 A1 Mar. 5, 2009 ptive neuron to activation in a collection of processes referred 48: 1212-1218 (1997) and Sang et al... Anesthesiology to as “central sensitization.” The elements of central sensiti 96:1053-1061 (2002)) and, with mixed success, for postop Zation, Such as reversible post-translational modification of erative pain as an adjunct to opioids (Duedahl et al., Acta proteins, may act over both the short term and longer term. Anesthesiol. Scand. 50: 1-13 (2006)). Amantadine has been Central sensitization includes both short-term, reversible used to treat postSurgical neuropathic pain in cancer patients components (such as post-translational modification of pro (Pud et al., Pain 75:349-354 (1998)) and phantom limb pain teins) and long-term elements. One Such long-term element (Wiech et al., Anesth. Analg. 98:408-413 (2004)). thought to be associated with neuropathic pain is an enhanced 0013 Clinical usefulness of the noncompetitive channel response of the NMDA receptor itself to excitatory input blocking NMDA antagonists has, however, been limited by through up-regulation of the modulatory tyrosine kinase Src. adverse effects Such as auditory and visual disturbances and Yu and Salter, Proc. Natl. Acad. Sci. U.S.A. 96:7697-7704 hallucinations, feelings of unreality, feelings of detachment (1999). from the body, dizziness, sedation, nausea, and Vomiting 0010 Earlier demonstrations that NMDA receptor (Chizh and Hedley, Curr: Pharm. Design 11:2977-2994 antagonists could inhibit the “wind-up' response had pro (2005); Kohrs and Durieux, Anesth. Analg. 87:1186-1193 vided the initial evidence for involvement of NMDA recep (1998); and Max et al., Clin. Neuropharm. 18:360-368 tors in central sensitization and supported further efforts to (1995)). Some of these effects are similar to those of phen develop novel analgesics targeting this mechanism.