NMDA receptor antagonists for neuroprotection
Inventors
Liotta, Dennis C. • Snyder, James P. • Traynelis, Stephen F. • Wilson, Lawrence • Mosley, Cara • Dingledine, Raymond J. • Myers, Scott • Tahirovic, Yesim Altas
Assignees
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Publication Number
US-9079852-B2
Publication Date
2015-07-14
Expiration Date
Abstract
Provided are compounds, pharmaceutical compositions and methods of treatment or prophylaxis of disorders associated with NMDA receptor activity, including neuropathic pain, stroke, traumatic brain injury, epilepsy, and related neurologic events or neurodegeneration. Compounds are of the general Formula I, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof are provided: wherein: each (L)k-Ar1 is a substituted or unsubstituted, mono or bicyclic aryl or heteroaryl; W is a bond, alkyl, or alkenyl; X is a bond, NR1 or O and each R1 and R2 is independently H, alkyl, alkenyl or aralkyl or R1 and R2 taken together form a 5-8 membered ring; R3−-R6 are selected from certain specific substituents or a carbonyl; Y is a bond, O, S, SO, SO2, CH2, NH, N(alkyl), or NHC(═O); and Z is OH, NR6R7, NR8SO2(alkyl), NR8C(O)NR6R7, NR8C(O)O(alkyl), NR8-dihydrothiazole, or NR8-dihydroimidazole or wherein Z can fuse with Ar2 to form selected heterocycles.
Core Innovation
The invention relates to a method of treatment or reducing the symptoms of neuropathic pain, stroke, traumatic brain injury, epilepsy, and other neurologic events or neurodegeneration resulting from NMDA receptor activation by administering to a host in need thereof an effective amount of a compound of Formula I or Formula V, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof. Formula I and Formula V are defined by multiple structural variables and permitted ring-forming or substituent options, including variable aryl, cycloalkyl, heteroatom, and stereochemical features.
Formula I is defined by variable groups including L, Ar1, Ar2, W, X, R1-R6, Y, Z, n, and p, with explicit options for substituted and unsubstituted alkyl, alkoxy, haloalkyl, hydroxy, halogen, nitro, cyano, and related substituents. The definitions include ring formation in which two L groups may be taken together with Ar1 to form a dioxolane ring or a cyclobutane ring, together with further constraints on Y, Z, and linked substituent groups.
Formula V is defined by an arrangement of Ar'—W'—B'—W''—Y'—Ar''—Z' with selections for B', W', W'', Y', Ar', Ar'', and Z'. The structure includes options for substituted or unsubstituted aromatic or nonaromatic cycloalkyl groups optionally containing heteroatoms, Z' as NRC(O)NR2, and embodiments in which Ar' and Z' are taken together, with representative compounds shown in the provided structures/images.
Claims Coverage
The consolidated claim coverage includes two independent method-of-treatment claim families, one using Formula I and one using Formula V. Across the provided items, the claims center on administering effective amounts of the defined compounds for NMDA receptor activation-related neurologic indications, with dependent claims narrowing structural variables, stereochemical form, and selected compound sets.
NMDA receptor activation-related treatment using Formula I compounds
Administering to a host in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof, for treatment or reducing the symptoms of neuropathic pain, stroke, traumatic brain injury, epilepsy, and other neurologic events or neurodegeneration resulting from NMDA receptor activation.
Formula I structural constraints
Formula I is defined by selections for L, Ar1, Ar2, W, X, R1-R6, Y, Z, n, and p, including Y as O in some embodiments, X as NR1 in some embodiments, and a compound substantially present as a single enantiomer in some embodiments.
NMDA receptor activation-related treatment using Formula V compounds
Administering to a host in need thereof an effective amount of a compound of Formula V, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof, for treatment or reducing the symptoms of neuropathic pain, stroke, traumatic brain injury, epilepsy, and other neurologic events or neurodegeneration resulting from NMDA receptor activation.
Formula V structural constraints
Formula V is defined by Ar'—W'—B'—W''—Y'—Ar''—Z' with B', W', W'', Y', Ar', Ar'', and Z' selected from specified groups, including W' as a bond or C1-C4 alkyl, W'' as C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, or C(=O)—C1-C4 alkyl, Y' as a bond, O, S, CH2, or N, and Z' as NRC(O)NR2 with R independently H, C1-C6 alkyl, or C6-C12 aralkyl.
Enumerated compound selection
The administered compound is selected from the group consisting of the compounds shown in the provided chemical structures/images.
Overall, the claims are directed to administering effective amounts of Formula I or Formula V compounds to treat or reduce symptoms of NMDA receptor activation-related neurologic events or neurodegeneration. The claim scope is primarily defined by the Formula I and Formula V variable selections, with dependent refinements for specific structural choices, single-enantiomer embodiments, and enumerated compound selections.
Stated Advantages
Reduces the symptoms of neuropathic pain, stroke, traumatic brain injury, epilepsy, and other neurologic events or neurodegeneration resulting from NMDA receptor activation.
Provides a method of treatment for neurologic events or neurodegeneration resulting from NMDA receptor activation.
Reduces neuronal injury in a host with stroke or traumatic brain injury.
pH-dependent potency and reduced off-target activity are described for example compounds.
In vivo pharmacokinetic and brain-penetration data are reported for specific compounds.
Documented Applications
Treatment or symptom reduction for neuropathic pain, stroke, traumatic brain injury, epilepsy, and other neurologic events or neurodegeneration resulting from NMDA receptor activation.
Treatment or symptom reduction for Parkinson's disease, Alzheimer's disease, Huntington's chorea, Amyotrophic Lateral Sclerosis, ischemic injury, hypoxia, pre-eclampsia, spinal cord trauma, status epilepticus, inflammatory pain, chronic pain, vascular dementia, glioma tumors, acidification of brain or spinal cord tissue, and head trauma.
Reducing neuronal injury in stroke or traumatic brain injury.
In vitro assay evaluation of example compounds, including IC50 measurements at pH 6.9 and pH 7.6.
In vivo pharmacokinetic and brain-penetration evaluation of specific compound structures.
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