Modulators of the eIF2alpha pathway

Patent metadata

Field	Value
Publication number	US-9708247-B2
Application number	US-201514849428-A
Country	US
Kind code	B2
Filing date	Sep 9, 2015
Priority date	Mar 15, 2013
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

Provided herein, inter alia, are compounds and methods useful for modulating the translational effects of eIF2α phosphorylation, the Integrated Stress Response (ISR), and the unfolded protein response (UPR); for treating diseases; for increasing protein production, and for improving long-term memory.

First claim

What is claimed is:

1. A method of treating traumatic brain injury in a patient in need of such treatment, said method comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, to said patient, wherein said compound has the formula:

wherein
L 2 is —OCH 2 or —SCH 2 ;
L 4 is a bond, (CH 2 ) 1-2 O, ethylene, —CH 2 NH—, or —SCH 2 —;
R 1 , R 3 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, —OCH 3 , —OCH 2 Ph, —C(O)Ph, —CH 3 , —CF 3 , —CCl 3 , —CN, —S(O)CH 3 , —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —C(O)CH 3 , —CH(CH 3 ) 2 , —CCSi(CH3) 3 , —CCH, —CH2CCH, —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCH 3 , —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 2 and R 4 are independently ═NR 7 or ═O;
z5 and z6 are independently an integer from 0 to 5;
R 8 and R 9 are independently hydrogen, halogen, —OCH 3 , —OCH 3 , —OCH 2 Ph, —C(O)Ph, —CH 3 , —CF 3 , —CCl 3 , —CN, —S(O)CH 3 , —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —C(O)CH 3 , —CH(CH 3 ) 2 , —CCSi(CH 3 ) 3 , —CCH, —CH 2 CCH, —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
and b and d are independently 0 or 1.

2. The method of claim 1 , wherein the compound has the formula:

wherein
R 5.1 and R 6.1 are independently hydrogen, halogen, —CF 3 , —CN, —N 3 , substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted 5 to 6 membered heteroaryl,

R 5.2 and R 6.2 are independently hydrogen, halogen, —CCSi(CH 3 ) 3 , —CF 3 , —NO 2 , —CN, —N 3 , substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted 5 to 6 membered heteroaryl,

3. The method of claim 2 , wherein
R 5.1 and R 6.1 are independently —Cl, —I, —CF 3 , —CH 3 , or —CCH; and
R 5.2 and R 6.2 are independently hydrogen, —Cl, —F, —I, —CCSi(CH 3 ) 3 , —CF 3 , —NO 2 , —CH 3 , or CCH.

4. The method of claim 1 , wherein the compound is

5. The method of claim 1 , wherein the compound is

6. The method of claim 1 , wherein the method comprises improving long term memory, increasing spatial learning, improving cognitive function after surgery, or improving cognitive function after a traumatic brain injury.

Assignees

• Univ California

Inventors

• Walter Peter
• Sidrauski Carmela
• Acosta Alvear Diego
• Arkin Michelle R
• Wilson Christopher G
• Ang Kean Hooi
• Hearn Brian R
• Vedantham Punitha
• Renslo Adam R
• Maze Mervyn
• Vacas Susana

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title