NMDA receptor antagonists for neuroprotection
Inventors
Liotta, Dennis C. • Snyder, James P. • Traynelis, Stephen F. • Wilson, Lawrence • Mosley, Cara • Dingledine, Raymond J. • Tahirovic, Yesim Altas • Myers, Scott J.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-8420680-B2
Publication Date
2013-04-16
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 provides compounds defined by Formula I and Formula V, each having defined aromatic or heteroaromatic substituents and specified linkage and residue variables. In Formula I, each L is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C(=O)-(C1-C6)-alkyl, C1-C6 haloalkyl, alkaryl, hydroxy, O-alkyl, O-aryl, -SH, -S-alkyl, -S-aryl, fluoro, chloro, bromo, iodo, nitro, or cyano, with two L groups optionally forming a dioxolane ring or a cyclobutane ring with Ar1. The compounds also define Ar1 and Ar2 as aryl or heteroaryl and include variable W and X as bond- or alkyl/alkenyl-type linkages.
Formula I further defines additional residue and functional-group selections through variables R1-R6 and Y and Z. The substituent set includes combinations where X is a bond or NR1 or O, and Y is selected from a bond, O, S, SO, SO2, CH2, NH, N(C1-C6 alkyl), or NHC(=O), while Z is selected from OH and multiple NR6R7/NR8-linked carbonyl- and heterocycle-containing groups such as NR8SO2(C1-C6 alkyl), NR8C(=O)NR6R7, NR8C(S)NR6R7, NR8C(=O)O(C1-C6 alkyl), NR8-dihydrothiazole, or NR8-dihydroimidazole. Constraints are provided for allowed substituent sizes via H, C1-C6 alkyl, C2-C6 alkenyl, and C6-C12 aralkyl, including ring formation where R1 and R2 are taken together to form a 5-8 membered ring.
The invention additionally provides compounds defined by Formula V, using a scaffold of Ar′-W′-B′-W3′-Y′-Ar3′-Z′ with defined ranges for B′, W′, W3′, Y′, Ar′, Ar3′, and Z′. B′ is selected so that the scaffold includes bond or C1-C4 alkyl-type options, and W3′ is constrained to C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, or C(=O)-C1-C4 alkyl. Z′ is defined as NRC(=O)NR2, with R independently selected from H, C1-C6 alkyl, or C6-C12 aralkyl, and Ar′/Ar3′ are specified as substituted or unsubstituted aromatic or nonaromatic cycloalkyl groups optionally including 0-3 heteroatoms.
Claims Coverage
The provided claim set includes two independent claims: a compound defined by Formula I and a compound defined by Formula V. Across these independent claims, the coverage is structured around extensive structural variability in ring-forming linkages, aromatic/heteroaromatic substitution (Ar1/Ar2), residue substituent options (L, R1-R6), and functional-group choices (Y and Z, and Z′ = NRC(=O)NR2).
Formula I compound with extensive substituent and linkage definition
A compound of Formula I wherein each L is independently C1-C6 alkyl, C1-C6 alkoxy, C(=O)-(C1-C6)-alkyl, C1-C6 haloalkyl, alkaryl, hydroxy, -O-alkyl, -O-aryl, -SH, -S-alkyl, -S-aryl, fluoro, chloro, bromo, iodo, nitro, or cyano; or two L groups may be taken together with Ar1 to form a dioxolane ring or a cyclobutane ring; k is 0, 1, 2, 3, 4 or 5; each Ar1 and Ar2 is independently aryl or heteroaryl; W is a bond, C1-C4 alkyl, or C2-C4 alkenyl; X is a bond, NR1 or O; each R1 and R2 is independently H, C1-C6 alkyl, C2-C6 alkenyl or C6-C12 aralkyl, or R1 and R2 can be taken together to form a 5-8 membered ring; each R3 and R4 is independently H, C1-C6 alkyl, C1-C6 alkoxy, C(=O)-(C1-C6)-alkyl, C1-C6 haloalkyl, hydroxy, fluoro, chloro, bromo, iodo, nitro, or cyano, or CR3R4 is C(=O); n is 1, 2, 3 or 4; p is 2, 3 or 4; each R5 and R6 is independently H, C1-C6 alkyl, C1-C6 alkoxy, C(=O)-(C1-C6)-alkyl, C1-C6 haloalkyl, hydroxy, fluoro, chloro, bromo, iodo, nitro, or cyano, or CR5R6 is C(=O) or C(=CH2); Y is a bond, O, S, SO, SO2, CH2, NH, N(C1-C6 alkyl), or NHC(=O); and Z is OH, NR6R7, NR8SO2(C1-C6 alkyl), NR8C(O)NR6R7, NR8C(S)NR6R7, NR8C(O)O(C1-C6 alkyl), NR8-dihydrothiazole, or NR8-dihydroimidazole, wherein each R6, R7 and R8 is independently H, C1-C6 alkyl or C6-C12 aralkyl, and wherein Ar2-Z is further defined by R9 and R10 being each independently H, C1-C6 alkyl, or aralkyl with conditional exclusions depending on X; or a pharmaceutically acceptable salt or ester thereof.
Formula V compound with selected scaffold substituents and NRC(=O)NR2 Z′ group
A compound of Formula V wherein W′ is a bond or C1-C4 alkyl; W3′ is C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl or C(=O)-C1-C4 alkyl; Y′ is selected from a bond, O, S, CH2 and N; Ar′ is a substituted or unsubstituted aromatic or nonaromatic cycloalkyl which optionally may include 0-3 heteroatoms; Ar3′ is an aromatic or nonaromatic cycloalkyl which optionally may include 0-3 heteroatoms; Z′ is NRC(=O)NR2; wherein each R is independently selected from H, C1-C6 alkyl or C6-C12 aralkyl; or Ar3′-Z′ are taken together and selected from the group consisting of the recited alternatives, or a pharmaceutically acceptable salt or ester thereof.
Overall, claim coverage centers on two compound families: Formula I compounds with broadly permitted substituent classes L, Ar1/Ar2, and residue options R1-R6, together with defined Y and Z functional possibilities and conditional restrictions; and Formula V compounds with a defined Ar′-W′-B′-W3′-Y′-Ar3′-Z′ scaffold and constrained choices for B′/W′/W3′/Y′/Ar′/Z′, including Z′ as NRC(=O)NR2 and optional Ar3′-Z′ combination selections.
Stated Advantages
Enhanced potency in brain tissue at reduced pH conditions.
Reduced infarct volume.
A stated safety improvement by reducing hERG binding.
A stated safety improvement by reducing β1 adrenergic receptor activation.
Associated with an activity-related potency threshold of IC50 ≤ 400 nM.
Associated with an activity-related potency threshold of IC50 ≤ 600 nM, including at pH 6.9 and ischemic pH.
Associated with a pH boost threshold, including pH boost ≥ 5.
Modulation of hERG binding and alpha-1 adrenergic receptor binding with corresponding potency improvements linked to structural changes.
Documented Applications
Therapeutic use for neuropathic pain, stroke, traumatic brain injury, epilepsy, and neurodegeneration from NMDA receptor activation.
Interested in licensing this patent?