US 2009/0023791 A1 · PH-dependent NMDA receptor antagonists

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.

Claims26

Dependent claims

1-20. (canceled)

A compound selected from the group consisting of (R)- or (S)-enantiomers and racemic mixtures of a compound of the formula:

wherein one of R9, R10, R11, R12 and R18 is
where R13 is alkyl, aralkyl or aryl;
R17 is H or lower alkyl;
and the others of R9, R10, R11, R12 and R18 are H, F, Cl, Br, I or lower alkyl;
wherein either
I) A is selected from the group consisting of:
wherein R1, R4, and R5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
R3 is independently O, S, NH or N(lower alkyl);
R2 is N, and R16 is C-alkyl, C-aralkyl or C-aryl;
wherein R1 and R5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
R2 is independently O, S, NH or N(lower alkyl);
R3 is N;
and R16 is C-alkyl, C-aralkyl or C-aryl;
wherein R1 is independently O, S, NH or N(lower alkyl);
and R2 through R4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
or R2 and R3 taken together are O—CH2—O;
wherein R1,is selected from the group consisting of O, S, NH or N(lower alkyl);
and R2 and R3 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
or R2 and R3 taken together are O—CH2—O, and R4 is N;
wherein R2 selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
R3 is selected from the group consisting of O, S, NH or N(lower alkyl);
and R4 is N;
wherein R1 is selected from the group consisting of O, S, NH and N(lower alkyl);
R2 is N, and R3 and R4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
wherein R1 is selected from the group consisting of O, S, NH and N(lower alkyl);
R2 and R4 are N, and R3 is independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
wherein R1 is selected from the group consisting of O, S, NH and N(lower alkyl);
R2 is selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
and R3 and R4 are N;
wherein R1 is selected from the group consisting of O, S, NH and N(lower alkyl);
and R2, R3 and R4 are N;
wherein R1 and R3 are independently selected from the group consisting of O, S, NH and N(lower alkyl);
and R2, R2′ and R4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
and
wherein R1 and R2 are independently selected from the group consisting of O, S, NH and N(lower alkyl);
and R2′, and R3 and R4 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 R6 and R6′ are independently H or F;
and R7 is H, lower n-alkyl, CH2Ar, CH2CH2Ar, CH2CHFAr, or CH2CF2Ar;
and R8 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 R6 and R6′ are independently H or F;
R7 is CH2 and R8 is O;
wherein R5, R6 and R7 are independently CH2, CH(lower alkyl) or C(lower alkyl)2;
and R8 is OH, or O(lower alkyl);
wherein R6 and R7 are independently CH2, CH(lower alkyl) or C(lower alkyl)2;
and R8 is OH, or O(lower alkyl);
wherein R6 and R7 are independently CH2, CH(lower alkyl) or C(lower alkyl)2;
and R8 is OH, or O(lower alkyl);
and n=1-3;
or
II) A is
wherein R1 and R5 are independently H or F;
R2, R3 and R4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
or R2 and R3 taken together are O—CH2—O;
and B is selected from the group consisting of:
wherein R6 and R6′ are independently H or F;
and R7 is CH2Ar, CH2CH2Ar, CH2CHFAr, or CH2CF2Ar, where Ar is 2,3,4,5,6-pentafluorophenyl;
and R8 is OH, O(lower alkyl);
wherein R6 and R6′ are independently H or F;
R7 is CH2 and R8 is O;
wherein R6 and R7 are independently CH2, CH(lower alkyl) or C(lower alkyl)2;
and R8 is OH, or O(lower alkyl);
and
wherein R6 and R7 are independently CH2, CH(lower alkyl) or C(lower alkyl)2;
and R8 is OH, or O(lower alkyl);
and n=1-3;
or
III) A is selected from the group consisting of:
wherein R1 and R5 are independently H or F;
R2, R3 and R4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
or R2 and R3 taken together are O—CH2—O;
wherein R1, R4, and R5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
R3 is independently O, S, NH or NR, R2 is N, and R16 is C-alkyl, C-aralkyl or C-aryl;
wherein R1, R4, and R5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
R2 is independently O, S, NH or N(lower alkyl);
R3 is N;
and R16 is C-alkyl, C-aralkyl or C-aryl;
wherein R1 is independently O, S, NH or N(lower alkyl);
and R2 through R4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
or R2 and R3 taken together are O—CH2—O;
wherein R1, is selected from the group consisting of O, S, NH or N(lower alkyl);
and R2 and R3 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
or R2 and R3 taken together are O—CH2—O, and R4 is N;
wherein R2 selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
R3 is selected from the group consisting of O, S, NH or N(lower alkyl);
and R4 is N;
wherein R1 is selected from the group consisting of O, S, NH and N(lower alkyl);
R2 is N, and R3 and R4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
wherein R1 is selected from the group consisting of O, S, NH and N(lower alkyl);
R2 and R4 are N, and R3 is independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
wherein R1 is selected from the group consisting of O, S, NH and N(lower alkyl);
R2 is selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
and R3 and R4 are N;
wherein R1 is selected from the group consisting of O, S, NH and N(lower alkyl);
and R2, R3 and R4 are N;
wherein R1 and R3 are independently selected from the group consisting of O, S, NH and N(lower alkyl);
and R2, R2′ and R4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
and
wherein R1 and R2 are independently selected from the group consisting of O, S, NH and N(lower alkyl);
and R2′, and R3 and R4 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 R6 and R6′ are independently H or F;
and R7 is H, lower n-alkyl, CH2Ar, CH2CH2Ar, CH2CHFAr, or CH2CF2Ar;
Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl;
and R8 is F;
wherein R5, R6 and R7 are independently CH2, CH(lower alkyl) or C(lower alkyl)2;
and
R8 is F;
wherein R6 and R7 are independently CH2, CH(lower alkyl) or C(lower alkyl)2;
and R8 is F;
and
wherein R6 and R7 are independently CH2, CH(lower alkyl) or C(lower alkyl)2;
R8 is F;
and n=1-3;
and pharmaceutically acceptable salts, enantiomers, enantiomeric mixtures, and mixtures of the foregoing.

113 more elements

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 R9, R10, R11, R12 and R18 is
where R13 is alkyl, aralkyl or aryl;
R17 is H or lower alkyl;
and
the others of R9, R10, R11, R12 and R18 are H, F, Cl, Br, I or lower alkyl;
wherein either
I) A is selected from the group consisting of:
wherein R1, R4, and R5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
R3 is independently O, S, NH or N(lower alkyl);
R2 is N, and R16 is C-alkyl, C-aralkyl or C-aryl;
wherein R1 and R5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
R2 is independently O, S, NH or N(lower alkyl);
R3 is N;
and R16 is C-alkyl, C-aralkyl or C-aryl;
wherein R1 is independently O, S, NH or N(lower alkyl);
and R2 through R4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
or R2 and R3 taken together are O—CH2—O;
wherein R1, is selected from the group consisting of O, S, NH or N(lower alkyl);
and R2 and R3 are independently selected from the group consisting of H, F, Cl, Br, I and O (lower alkyl);
or R2 and R3 taken together are O—CH2—O, and R4 is N;
wherein R2 selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
R3 is selected from the group consisting of O, S, NH or N(lower alkyl);
and R4 is N;
wherein R1 is selected from the group consisting of O, S, NH and N(lower alkyl);
R2 is N, and R3 and R4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
wherein R1 is selected from the group consisting of O, S, NH and N(lower alkyl);
R2 and R4 are N, and R3 is independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
wherein R1 is selected from the group consisting of O, S, NH and N(lower alkyl);
R2 is selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
and R3 and R4 are N;
wherein R1 is selected from the group consisting of O, S, NH and N(lower alkyl);
and R2, R3 and R4 are N;
wherein R1 and R3 are independently selected from the group consisting of O, S, NH and N(lower alkyl);
and R2, R2′ and R4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
and
wherein R1 and R2 are independently selected from the group consisting of O, S, NH and N(lower alkyl);
and R2′, and R3 and R4 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 R6 and R6′ are independently H or F;
and R7 is H, lower n-alkyl, CH2Ar, CH2CH2Ar, CH2CHFAr, or CH2CF2Ar;
and R8 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 R6 and R6′ are independently H or F;
R7 is CH2 and R8 is O;
wherein R5, R6 and R7 are independently CH2, CH(lower alkyl) or C(lower alkyl)2;
and R8 is OH, or O(lower alkyl);
wherein R6 and R7 are independently CH2, CH(lower alkyl) or C(lower alkyl)2;
and R8 is OH, or O(lower alkyl);
wherein R6 and R7 are independently CH2, CH(lower alkyl) or C(lower alkyl)2;
and R8 is OH, or O(lower alkyl);
and n=1-3;
or
II) A is
wherein R1 and R5 are independently H or F;
R2, R3 and R4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
or R2 and R3 taken together are O—CH2—O;
and B is selected from the group consisting of:
wherein R6 and R6′ are independently H or F;
and R7 is CH2Ar, CH2CH2Ar, CH2CHFAr, or CH2CF2Ar, where Ar is 2,3,4,5,6-pentafluorophenyl;
and R8 is OH, O(lower alkyl);
wherein R6 and R6′ are independently H or F;
R7 is CH2 and R8 is O;
wherein R6 and R7 are independently CH2, CH(lower alkyl) or C(lower alkyl)2;
and R8 is OH, or O(lower alkyl);
and
wherein R6 and R7 are independently CH2, CH(lower alkyl) or C(lower alkyl)2;
and R8 is OH, or O(lower alkyl);
and n=1-3;
or
III) A is selected from the group consisting of:
wherein R1 and R5 are independently H or F;
R2, R3 and R4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
or R2 and R3 taken together are O—CH2—O;
wherein R1, R4, and R5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
R3 is independently O, S, NH or NR, R2 is N, and R16 is C-alkyl, C-aralkyl or C-aryl;
wherein R1, R4, and R5 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
R2 is independently O, S, NH or N(lower alkyl);
R3 is N;
and
R16 is C-alkyl, C-aralkyl or C-aryl;
wherein R1 is independently O, S, NH or N(lower alkyl);
and R2 through R4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
or
R2 and R3 taken together are O—CH2—O;
wherein R1, is selected from the group consisting of O, S, NH or N(lower alkyl);
and R2 and R3 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
or R2 and R3 taken together are O—CH2—O, and R4 is N;
wherein R2 selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
R3 is selected from the group consisting of O, S, NH or N(lower alkyl);
and R4 is N;
wherein R1 is selected from the group consisting of O, S, NH and N(lower alkyl);
R2 is N, and R3 and R4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
wherein R1 is selected from the group consisting of O, S, NH and N(lower alkyl);
R2 and R4 are N, and R3 is independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
wherein R1 is selected from the group consisting of O, S, NH and N(lower alkyl);
R2 is selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
and R3 and R4 are N;
wherein R1 is selected from the group consisting of O, S, NH and N(lower alkyl);
and R2, R3 and R4 are N;
wherein R1 and R3 are independently selected from the group consisting of O, S, NH and N(lower alkyl);
and R2, R2′ and R4 are independently selected from the group consisting of H, F, Cl, Br, I and O(lower alkyl);
and
wherein R1 and R2 are independently selected from the group consisting of O, S, NH and N(lower alkyl);
and R2′, and R3 and R4 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 R6 and R6′ are independently H or F;
and R7 is H, lower n-alkyl, CH2Ar, CH2CH2Ar, CH2CHFAr, or CH2CF2Ar;
Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl;
and R8 is F;
wherein R5, R6 and R7 are independently CH2, CH(lower alkyl) or C(lower alkyl)2;
and
R8 is F;
wherein R6 and R7 are independently CH2, CH(lower alkyl) or C(lower alkyl)2;
and R8 is F;
and
wherein R6 and R7 are independently CH2, CH(lower alkyl) or C(lower alkyl)2;
R8 is F;
and n=1-3;
and pharmaceutically acceptable salts, enantiomers, enantiomeric mixtures, and mixtures of the foregoing.

117 more elements

Dependencies are inferred from the claim text.

Facts

Application

12/151,633Filed 8 May 2008

Priority

8 Mar 2001

Published

22 Jan 2009

Term ends

Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07C 217/34
The six-membered aromatic ring or condensed ring system containing that ring being further substituted: by halogen atoms, by trihalomethyl, nitro…
A61P 7/00
Drugs for disorders of the blood or the extracellular fluid
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/02
Drugs for disorders of the nervous system: for peripheral neuropathies

Family

Application60/274,205Us provisional application · filed 8 Mar 2001

Application10/469,824Continuation · filed 25 Feb 2004

Application12/151,633Continuation

US 2004/0138502 A1Published application

US 7,375,136 B2Related patent

US 2009/0023791 A1This patent

From the US filing history. Foreign family members aren’t listed.

PH-dependent NMDA receptor antagonists

Life of this patent

PH-dependent NMDA receptor antagonists

Life of this patent

Abstract

Claims26