US2009023791A1PendingUtilityA1
PH-dependent NMDA receptor antagonists
Est. expiryMar 8, 2021(expired)· nominal 20-yr term from priority
Inventors:Stephen F. TraynelisDennis C. LiottaJames P. SnyderYesim AltasDavid D. MottJames J. DohertyRaymond J. Dingledine
A61P 35/00A61P 43/00A61P 7/00A61P 25/02A61P 25/08C07C 311/21A61P 25/14C07D 263/24A61P 25/04A61P 29/00C07C 311/08A61P 25/28C07C 217/34A61P 25/00
52
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
NMDA receptor blockers, including pH-sensitive NMDA receptor blockers, are provided as neurprotective drugs that are useful in stroke, traumatic brain injury, epilepsy, and other neurologic events that involve acidification of brain or spinal cord tissue. Compositions and methods of this invention are used for treating neurodegeneration resulting from NMDA receptor activation. The compounds described herein have enhanced activity in brain tissue having lower than normal pH due to pathological conditions such as hypoxia resulting from stroke, traumatic brain injury, global ischemia that may occur during cardiac surgery, hypoxia that may occur following cessation of breathing, pre-eclampsia, spinal cord trauma, epilepsy, chrounic pain, vascular dementia and glioma rumors. Compounds described herein are also useful in preventing neurodegeneration in patients with Parkinson's Alzheimer's, Huntington's chorea, ALS, and other neurodegenerative conditions known to the art to be responsive to treatment using NMDA receptor blockers. Prefebably the compounds provided herein are allosteric NMDA inhibitors.
Claims
exact text as granted — not AI-modified1 - 20 . (canceled)
21 . A compound selected from the group consisting of (R)- or (S)-enantiomers and racemic mixtures of a compound of the formula:
wherein one of R 9 , R 10 , R 11 , R 12 and R 18 is
where R 13 is alkyl, aralkyl or aryl; R 17 is H or lower alkyl; and the others of R 9 , R 10 , R 11 , R 12 and R 18 are H, F, Cl, Br, I or lower alkyl;
wherein either
I) A is selected from the group consisting of:
wherein R 1 , R 4 , and R 5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 3 is independently O, S, NH or N(lower alkyl); R 2 is N, and R 16 is C-alkyl, C-aralkyl or C-aryl;
wherein R 1 and R 5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 2 is independently O, S, NH or N(lower alkyl); R 3 is N; and R 16 is C-alkyl, C-aralkyl or C-aryl;
wherein R 1 is independently O, S, NH or N(lower alkyl); and R 2 through R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O;
wherein R 1 ,is selected from the group consisting of O, S, NH or N(lower alkyl); and R 2 and R 3 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O, and R 4 is N;
wherein R 2 selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 3 is selected from the group consisting of O, S, NH or N(lower alkyl); and R 4 is N;
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 is N, and R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 and R 4 are N, and R 3 is independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 is selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); and R 3 and R 4 are N;
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); and R 2 , R 3 and R 4 are N;
wherein R 1 and R 3 are independently selected from the group consisting of O, S, NH and N(lower alkyl); and R 2 , R 2 ′ and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); and
wherein R 1 and R 2 are independently selected from the group consisting of O, S, NH and N(lower alkyl); and R 2 ′, and R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
and B is selected from the group consisting of:
wherein R 6 and R 6 ′ are independently H or F; and R 7 is H, lower n-alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr, or CH 2 CF 2 Ar; and R 8 is OH, O(lower alkyl); Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl;
wherein R 6 and R 6 ′ are independently H or F; R 7 is CH 2 and R 8 is O;
wherein R 5 , R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; and R 8 is OH, or O(lower alkyl);
wherein R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl)2; and R 8 is OH, or O(lower alkyl);
wherein R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; and R 8 is OH, or O(lower alkyl); and n=1-3;
or
II) A is
wherein R 1 and R 5 are independently H or F; R 2 , R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O;
and B is selected from the group consisting of:
wherein R 6 and R 6 ′ are independently H or F; and R 7 is CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr, or CH 2 CF 2 Ar, where Ar is 2,3,4,5,6-pentafluorophenyl; and R 8 is OH, O(lower alkyl);
wherein R 6 and R 6 ′ are independently H or F; R 7 is CH 2 and R 8 is O;
wherein R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; and R 8 is OH, or O(lower alkyl); and
wherein R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; and R 8 is OH, or O(lower alkyl); and n=1-3;
or
III) A is selected from the group consisting of:
wherein R 1 and R 5 are independently H or F; R 2 , R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O;
wherein R 1 , R 4 , and R 5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 3 is independently O, S, NH or NR, R 2 is N, and R 16 is C-alkyl, C-aralkyl or C-aryl;
wherein R 1 , R 4 , and R 5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 2 is independently O, S, NH or N(lower alkyl); R 3 is N; and R 16 is C-alkyl, C-aralkyl or C-aryl;
wherein R 1 is independently O, S, NH or N(lower alkyl); and R 2 through R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O;
wherein R 1 , is selected from the group consisting of O, S, NH or N(lower alkyl); and R 2 and R 3 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O, and R 4 is N;
wherein R 2 selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 3 is selected from the group consisting of O, S, NH or N(lower alkyl); and R 4 is N;
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 is N, and R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 and R 4 are N, and R 3 is independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 is selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); and R 3 and R 4 are N;
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); and R 2 , R 3 and R 4 are N;
wherein R 1 and R 3 are independently selected from the group consisting of O, S, NH and N(lower alkyl); and R 2 , R 2 ′ and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); and
wherein R 1 and R 2 are independently selected from the group consisting of O, S, NH and N(lower alkyl); and R 2 ′, and R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
and B is selected from the group consisting of:
wherein R 6 and R 6 ′ are independently H or F; and R 7 is H, lower n-alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr, or CH 2 CF 2 Ar; Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl;
and R 8 is F;
wherein R 5 , R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; and
R 8 is F;
wherein R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; and R 8 is F; and
wherein R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; R 8 is F;
and n=1-3;
and pharmaceutically acceptable salts, enantiomers, enantiomeric mixtures, and mixtures of the foregoing.
22 . The compound of claim 21 in combination with a suitable pharmaceutical carrier.
23 . The compound of claim 21 selected from (R)- and (S)-enantiomers and mixtures thereof of compounds selected from the group consisting of:
wherein R 1 and R 5 are independently H or F; and
R 2 , R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O; R 6 and R 6 ′ are independently H or F;
R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; and R 13 is alkyl, aralkyl or aryl; and
when R 1 and R 5 are H; R 7 is selected from the group consisting of CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr and CH 2 CF 2 Ar, where Ar is 2,3,4,5,6-pentafluorophenyl; R 8 is OH, O(lower alkyl) or F; and
when one of R 1 or R 5 is F and the other is H or F; R 7 is CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr, or CH 2 CF 2 Ar, where Ar is 2,3,4,5,6-pentafluorophenyl; R 8 is OH or F;
wherein R 1 and R 5 are independently H or F; R 2 is N; R 3 is O, S, NH or N(lower alkyl);
R 4 is selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 6 and R 6 ′ are independently H or F; R 7 is selected from the group consisting of H, lower n-alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr and CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R 8 is OH, O(lower alkyl) or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl; and R 16 is C-alkyl, C-aralkyl or C-aryl;
wherein R 1 and R 5 are independently H or F; R 2 is independently O, S, NH or N(lower alkyl); R 3 is N; R 4 is selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 6 and R 6 ′ are independently H or F; R 7 is selected from the group consisting of H, lower n-alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr and CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R 8 is OH, O(lower alkyl) or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl; and R 16 is C-alkyl, C-aralkyl, or C-aryl;
wherein R 1 through R 5 are independently selected from the group consisting of H, F, Cl, Br, I and OR 14 ; or R 2 and R 3 taken together are O—CH 2 —O; R 6 and R 6 ′ are independently H or F; R 7 is CH 2 , R 8 is O; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl; R 14 is C-alkyl, C-aralkyl or C-aryl;
wherein R 1 , R 4 and R 5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 2 is O, S, NH or N(lower alkyl); R 3 is N; R 6 and R 6 ′ are independently H or F; R 7 is CH 2 ; R 8 is O; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl;
and R 16 is C-alkyl, C-aralkyl or C-aryl;
wherein R 1 , R 4 and R 5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 2 is N; R 3 is O, S, NH or N(lower alkyl); R 6 and R 6 ′ are independently H or F; R 7 is CH 2 ; R 8 is O; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, R 13 is alkyl, aralkyl or aryl; and R 16 is C-alkyl, C-aralkyl or C-aryl;
wherein R 1 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR 14 ; R 2 and R 3 are independently selected from the group consisting of F, Cl, Br, I, and OR 14 , or R 2 and R 3 taken together are O—CH 2 —O; R 5 , R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; R 1 is F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I or lower alkyl; R 13 is alkyl, aralkyl or aryl; and R 14 is C-alkyl, C-aralkyl or C-aryl;
wherein R 1 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR 14 ; R 2 is selected from the group consisting of O, S, NH or N(lower alkyl); R 3 is N; R 5 , R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, R 13 is alkyl, aralkyl or aryl; R 14 is C-alkyl, C-aralkyl or C-aryl; and R 16 is C-alkyl, C-aralkyl, or C-aryl;
wherein R 1 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR 14 ; R 2 is N; R 3 is selected from the group consisting of O, S, NH and N(lower alkyl); R 5 , R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, R 13 is alkyl, aralkyl or aryl; R 14 is C-alkyl, C-aralkyl or C-aryl; and R 16 is C-alkyl, C-aralkyl, or C-aryl;
wherein R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of H, F, Cl, Br, I and OR 14 , or R 2 and R 3 taken together are O—CH 2 —O; R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, R 13 is alkyl, aralkyl or aryl; R 14 is C-alkyl, C-aralkyl or C-aryl; and
n=1-3;
wherein R 1 , R 4 and R 5 are independently selected form the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 2 is O, S, NH or N(lower alkyl); R 3 is N; R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, R 13 is alkyl, aralkyl or aryl; R 16 is C-alkyl, C-aralkyl or C-aryl; and
n=1-3;
wherein R 1 , R 4 and R 5 are independently selected form the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 2 is N; R 3 is O, S, NH or N(lower alkyl); R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl; R 16 is C-alkyl, C-aralkyl or C-aryl; and
n=1-3;
wherein R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group g of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O; R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I or lower alkyl; R 13 is alkyl, aralkyl or aryl; and n=1-3;
wherein R 1 , R 4 and R 5 are independently selected form the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 2 is O, S, NH or N(lower alkyl); R 3 is N; R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, R 13 is alkyl, aralkyl or aryl; R 16 is C-alkyl, C-aralkyl or C-aryl; R 16 is C-alkyl, C-aralkyl or C-aryl; and n=1-3;
wherein R 1 , R 4 and R 5 are independently selected form the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 2 is N; R 3 is O, S, NH or N(lower alkyl); R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, R 13 is alkyl, aralkyl or aryl; R 16 is C-alkyl, C-aralkyl or C-aryl, and n=1-3;
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 , R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 5 is H; R 6 and R 6 ′ are independently H or F; R 7 is H, lower alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl;
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 and R 3 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O; R 4, R 5 and R 6 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; R 7 is H, R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl;
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 and R 3 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O; R 4 is N; R 5 is H; R 6 and R 6 ′ are independently H or F; R 7 is H, lower alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl;
wherein R 1 and R 2 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 3 is selected from the group consisting of O, S, NH and N(lower alkyl); R 4 is N; R 5 is H; R 6 and R 6 ′ are independently H or F; R 7 is H, lower alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl;
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 is N; R 3 and R 4 are is selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 5 is H, R 6 and R 6 ′ are independently H or F; R 7 is H, lower alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl;
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 is N; R 3 is selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 4 , R 5 and R 6 are independently CH 2 , CH(lower alkyl) or C(lower alkyl); R 7 is H; R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I or lower alkyl; R 13 is alkyl, aralkyl or aryl;
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 3 is selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 2 and R 4 are N;
R 5 is H; R 6 and R 6 ′ are independently H or F; R 7 is H, lower alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl;
R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl;
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 is selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 3 and R 4 are N;
R 5 is H; R 6 and R 6 ′ are independently H or F; R 7 is H, lower alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl;
R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl;
wherein R 1 is selected from a group consisting of O, S, NH or N(lower alkyl); R 2 , R 3 and R 4 are N; R 5 is H, R 6 and R 6 ′ are independently H or F; R 7 is selected from the group consisting of H, lower alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl;
wherein R 1 and R 3 are independently selected from the group consisting of O, S, NH and N(lower alkyl); R 2 , R 2 ′ and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 5 is H; R 6 and R 6 ′ are independently H or F; R 7 is H, lower alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I or lower alkyl; R 13 is alkyl, aralkyl or aryl;
wherein R 1 and R 2 are independently selected from the group consisting of O, S, NH and N(lower alkyl); R 2 ′, R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 5 is H; R 6 and R 6 ′ are independently H or F; R 7 is H, lower alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R 8 is OH, O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl;
wherein R 1 and R 4 are independently selected from the group consisting of O, S, NH and N(lower alkyl); R 2 and R 3 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O; R 5 , R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl); R 8 is OH, or O(lower alkyl), or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl; and
wherein R 1 and R 2 are independently selected from the group consisting of O, S, NH and N(lower alkyl); R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl) or R 3 and R 4 taken together are O—CH 2 —O; R 5 , R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl); R 8 is OH or F; R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl.
24 . The compound of claim 21 selected from the group consisting of the (S) or (R) forms of:
1-(4-Methanesulphonamidophenoxy)-3-(N-(2,3,4,5,6-pentafluoro-benzyl)-3,4-di-chlorophenylethylamino)-2-propanol; mixtures thereof and pharmaceutically acceptable salts thereof.
25 . The compound of claim 21 wherein A is selected from the group consisting of:
wherein R 1 , R 4, and R 5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 3 is independently O, S, NH or N(lower alkyl); R 2 is N, and R 16 is C-alkyl, C-aralkyl or C-aryl;
wherein R 1 is independently O, S, NH or N(lower alkyl); and R 2 through R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O;
wherein R 1 , is selected from the group consisting of O, S, NH or N(lower alkyl); and R 2 and R 3 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O, and R 4 is N;
wherein R 2 selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 3 is selected from the group consisting of O, S, NH or N(lower alkyl); and R 4 is N;
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 is N, and R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 and R 4 are N, and R 3 is independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 is selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); and R 3 and R 4 are N;
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); and R 2 , R 3 and R 4 are N;
wherein R 1 and R 3 are independently selected from the group consisting of O, S, NH and N(lower alkyl); and R 2 , R 2 ′ and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); and
wherein R 1 and R 2 are independently selected from the group consisting of O, S, NH and N(lower alkyl); and R 2 ′, and R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
and wherein B is
wherein R 6 and R 6 ′ are independently H or F; and R 7 is H, lower n-alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr, or CH 2 CF 2 Ar; Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl;
and R 8 is OH, O(lower alkyl), or F.
26 . The compound of claim 27 wherein R 7 is lower-alkyl.
27 . The compound of claim 27 wherein R 7 is CH 2 Ar.
28 . The compound of claim 27 wherein R 8 is OH.
29 . The compound of claim 27 wherein R 8 is F.
30 . The compound of claim 21 wherein A is
wherein R 1 and R 5 are independently H or F; R 2 , R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O;
and B is
wherein R 6 and R 6 ′ are independently H or F; and R 7 is CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr, or CH 2 CF 2 Ar, where Ar is 2,3,4,5,6-pentafluorophenyl; and R 8 is OH, O(lower alkyl).
31 . The compound of claim 30 wherein R 7 is CH 2 Ar, where Ar is 2,3,4,5,6-pentafluorophenyl.
32 . The compound of claim 30 wherein R 8 is OH.
33 . The compound of claim 30 wherein R 8 is O(lower alkyl).
34 . The compound of claim 25 wherein A is
wherein R 1 and R 5 are independently H or F; R 2 , R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O;
and B is
wherein R 6 and R 6 ′ are independently H or F; R 7 is CH 2 and R 8 is O.
35 . The compound of claim 21 wherein A is
wherein R 1 and R 5 are independently H or F; R 2 , R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O;
and B is
wherein R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; and R 8 is OH, O(lower alkyl).
36 . A compound of claim 21 wherein A is selected from the group consisting of:
wherein R 1 and R 5 are independently H or F; R 2 , R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O;
and B is selected from the group consisting of:
wherein R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; R 8 is OH, O(lower alkyl); and n=1-3.
37 . The compound of claim 21 wherein A is
wherein R 1 and R 5 are independently H or F; R 2 , R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O;
and wherein B is
wherein R 6 and R 6 ′ are independently H or F; and R 7 is H, lower n-alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr, or CH 2 CF 2 Ar; Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl;
and R is F.
38 . The compound of claim 37 wherein R 7 is lower alkyl.
39 . The compound of claim 37 wherein R 7 is CH 2 Ar.
40 . The compound of claim 37 wherein R 3 and R 4 are Cl.
41 . The compound of claim 37 wherein R 3 and R 4 are O(lower alkyl).
42 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 21 optionally in a pharmaceutically acceptable carrier.
43 . The pharmaceutical composition of claim 42 suitable for oral administration.
44 . The pharmaceutical composition of claim 42 suitable for parenteral administration.
45 . A method of treating neurodegeneration associated with a pathological condition characterized by lowered brain-tissue pH, said method comprising
administering to a patient in need of such treatment a pharmaceutically effective amount of a compound having enhanced NMDA receptor blocking activity at said lowered brain-tissue pH over normal brain-tissue pH, said compound being selected from the group consisting of (R)- or (S)-enantiomers and racemic mixtures of a compound of the formula:
wherein one of R 9 , R 10 , R 11 , R 12 and R 18 is
where R 13 is alkyl, aralkyl or aryl; R 17 is H or lower alkyl; and
the others of R 9 , R 10 , R 11 , R 12 and R 18 are H, F, Cl, Br, I or lower alkyl;
wherein either
I) A is selected from the group consisting of:
wherein R 1 , R 4, and R 5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 3 is independently O, S, NH or N(lower alkyl); R 2 is N, and R 16 is C-alkyl, C-aralkyl or C-aryl;
wherein R 1 and R 5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 2 is independently O, S, NH or N(lower alkyl); R 3 is N; and R 16 is C-alkyl, C-aralkyl or C-aryl;
wherein R 1 is independently O, S, NH or N(lower alkyl); and R 2 through R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O;
wherein R 1 , is selected from the group consisting of O, S, NH or N(lower alkyl); and R 2 and R 3 are independently selected from the group consisting of H, F, Cl, Br, I and O (lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O, and R 4 is N;
wherein R 2 selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 3 is selected from the group consisting of O, S, NH or N(lower alkyl); and R 4 is N;
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 is N, and R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 and R 4 are N, and R 3 is independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 is selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); and R 3 and R 4 are N;
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); and R 2 , R 3 and R 4 are N;
wherein R 1 and R 3 are independently selected from the group consisting of O, S, NH and N(lower alkyl); and R 2 , R 2 ′ and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); and
wherein R 1 and R 2 are independently selected from the group consisting of O, S, NH and N(lower alkyl); and R 2 ′, and R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
and B is selected from the group consisting of:
wherein R 6 and R 6 ′ are independently H or F; and R 7 is H, lower n-alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr, or CH 2 CF 2 Ar; and R 8 is OH, O(lower alkyl); Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl;
wherein R 6 and R 6 ′ are independently H or F; R 7 is CH 2 and R 8 is O;
wherein R 5 , R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; and R 8 is OH, or O(lower alkyl);
wherein R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; and R 8 is OH, or O(lower alkyl);
wherein R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; and R 8 is OH, or O(lower alkyl); and n=1-3;
or
II) A is
wherein R 1 and R 5 are independently H or F; R 2 , R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O;
and B is selected from the group consisting of:
wherein R 6 and R 6 ′ are independently H or F; and R 7 is CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr, or CH 2 CF 2 Ar, where Ar is 2,3,4,5,6-pentafluorophenyl; and R 8 is OH, O(lower alkyl);
wherein R 6 and R 6 ′ are independently H or F; R 7 is CH 2 and R 8 is O;
wherein R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; and R 8 is OH, or O(lower alkyl); and
wherein R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; and R 8 is OH, or O(lower alkyl); and n=1-3;
or
III) A is selected from the group consisting of:
wherein R 1 and R 5 are independently H or F; R 2 , R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O;
wherein R 1 , R 4 , and R 5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 3 is independently O, S, NH or NR, R 2 is N, and R 16 is C-alkyl, C-aralkyl or C-aryl;
wherein R 1 , R 4 , and R 5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 2 is independently O, S, NH or N(lower alkyl); R 3 is N; and
R 16 is C-alkyl, C-aralkyl or C-aryl;
wherein R 1 is independently O, S, NH or N(lower alkyl); and R 2 through R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or
R 2 and R 3 taken together are O—CH 2 —O;
wherein R 1 , is selected from the group consisting of O, S, NH or N(lower alkyl); and R 2 and R 3 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R 2 and R 3 taken together are O—CH 2 —O, and R 4 is N;
wherein R 2 selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); R 3 is selected from the group consisting of O, S, NH or N(lower alkyl); and R 4 is N;
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 is N, and R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 and R 4 are N, and R 3 is independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); R 2 is selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); and R 3 and R 4 are N;
wherein R 1 is selected from the group consisting of O, S, NH and N(lower alkyl); and R 2 , R 3 and R 4 are N;
wherein R 1 and R 3 are independently selected from the group consisting of O, S, NH and N(lower alkyl); and R 2 , R 2 ′ and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl); and
wherein R 1 and R 2 are independently selected from the group consisting of O, S, NH and N(lower alkyl); and R 2 ′, and R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
and B is selected from the group consisting of:
wherein R 6 and R 6 ′ are independently H or F; and R 7 is H, lower n-alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr, or CH 2 CF 2 Ar; Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl;
and R 8 is F;
wherein R 5 , R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; and
R 8 is F;
wherein R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; and R 8 is F; and
wherein R 6 and R 7 are independently CH 2 , CH(lower alkyl) or C(lower alkyl) 2 ; R 8 is F;
and n=1-3;
and pharmaceutically acceptable salts, enantiomers, enantiomeric mixtures, and mixtures of the foregoing.Join the waitlist — get patent alerts
Track US2009023791A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.