Compositions of polyhydroxylated benzophenones and methods of treatment of neurodegenerative disorders

Patent metadata

Field	Value
Publication number	US-11639325-B2
Application number	US-202017116427-A
Country	US
Kind code	B2
Filing date	Dec 9, 2020
Priority date	Dec 17, 2015
Publication date	May 2, 2023
Grant date	May 2, 2023

Abstract

The present invention relates to polyhydroxylated benzophenone compounds useful in the treatment of neurodegenerative, neurological, psychiatric, and cognitive diseases, in particular those associated with a deficiency in HDAC1 deacetylase activity.

First claim

The invention claimed is:

1. A prodrug of a compound of formula I:

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof, wherein:
R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently H, PO(OR x ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, aryl, heteroaryl, CO(C 1 -C 6 alkyl), CO(C 2 -C 6 alkenyl), CO(C 2 -C 6 alkynyl), CO(C 3 -C 8 cycloalkyl), CO(3 to 8-membered heterocyclyl), CO(aryl), CO(heteroaryl), CON(R y ) 2 , COO(C 1 -C 6 alkyl), COO(C 2 -C 6 alkenyl), COO(C 2 -C 6 alkynyl), COO(C 3 -C 8 cycloalkyl), COO(3 to 8-membered heterocyclyl), or COO(aryl), COO(heteroaryl) wherein each PO(OR x ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, aryl, heteroaryl, CO(C 1 -C 6 alkyl), CO(C 2 -C 6 alkenyl), CO(C 2 -C 6 alkynyl), CO(C 3 -C 8 cycloalkyl), CO(3 to 8-membered heterocyclyl), CO(aryl), CO(heteroaryl), CON(R y ) 2 , COO(C 1 -C 6 alkyl), COO(C 2 -C 6 alkenyl), COO(C 2 -C 6 alkynyl), COO(C 3 -C 8 cycloalkyl), COO(3 to 8-membered heterocyclyl), COO(aryl) or COO(heteroaryl) is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, aryl, heteroaryl and C 1 -C 6 alkoxy;
R x is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, aryl, heteroaryl, CO(C 1 -C 6 alkyl), CO(C 2 -C 6 alkenyl), CO(C 2 -C 6 alkynyl), CO(C 3 -C 8 cycloalkyl), CO(3 to 8-membered heterocyclyl), CO(aryl), or CO(heteroaryl) wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, aryl, heteroaryl, CO(C 1 -C 6 alkyl), CO(C 2 -C 6 alkenyl), CO(C 2 -C 6 alkynyl), CO(C 3 -C 8 cycloalkyl), CO(3 to 8-membered heterocyclyl), CO(aryl), or CO(heteroaryl) is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, aryl, heteroaryl and C 1 -C 6 alkoxy;
R y is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, aryl, heteroaryl, CO(C 1 -C 6 alkyl), CO(C 2 -C 6 alkenyl), CO(C 2 -C 6 alkynyl), CO(C 3 -C 8 cycloalkyl), CO(3 to 8-membered heterocyclyl), CO(aryl), or CO(heteroaryl) wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, aryl, heteroaryl, CO(C 1 -C 6 alkyl), CO(C 2 -C 6 alkenyl), CO(C 2 -C 6 alkynyl), CO(C 3 -C 8 cycloalkyl), CO(3 to 8-membered heterocyclyl), CO(aryl), or CO(heteroaryl) is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, aryl, heteroaryl and C 1 -C 6 alkoxy
provided that the prodrug is not:

2. The prodrug of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof, wherein the compound has the formula Ia:

wherein:
R 1 is PO(OR x ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, aryl, heteroaryl, CO(C 1 -C 6 alkyl), CO(C 2 -C 6 alkenyl), CO(C 2 -C 6 alkynyl), CO(C 3 -C 8 cycloalkyl), CO(3 to 8-membered heterocyclyl), CO(aryl), CO(heteroaryl), CON(R y ) 2 , COO(C 1 -C 6 alkyl), COO(C 2 -C 6 alkenyl), COO(C 2 -C 6 alkynyl), COO(C 3 -C 8 cycloalkyl), COO(3 to 8-membered heterocyclyl), COO(aryl), or COO(heteroaryl), wherein each PO(OR x ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, aryl, heteroaryl, CO(C 1 -C 6 alkyl), CO(C 2 -C 6 alkenyl), CO(C 2 -C 6 alkynyl), CO(C 3 -C 8 cycloalkyl), CO(3 to 8-membered heterocyclyl), CO(aryl), CO(heteroaryl), CON(R y ) 2 , COO(C 1 -C 6 alkyl), COO(C 2 -C 6 alkenyl), COO(C 2 -C 6 alkynyl), COO(C 3 -C 8 cycloalkyl), COO(3 to 8-membered heterocyclyl), COO(aryl) or COO(heteroaryl) is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, aryl, heteroaryl and C 1 -C 6 alkoxy;
R 2 , R 3 , R 4 , R 5 and R 6 are each independently H, PO(OR x ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, aryl, heteroaryl, CO(C 1 -C 6 alkyl), CO(C 2 -C 6 alkenyl), CO(C 2 -C 6 alkynyl), CO(C 3 -C 8 cycloalkyl), CO(3 to 8-membered heterocyclyl), CO(aryl), CO(heteroaryl), CON(R y ) 2 , COO(C 1 -C 6 alkyl), COO(C 2 -C 6 alkenyl), COO(C 2 -C 6 alkynyl), COO(C 3 -C 8 cycloalkyl), COO(3 to 8-membered heterocyclyl), COO(aryl), COO(heteroaryl) wherein each PO(OR x ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, aryl, heteroaryl, CO(C 1 -C 6 alkyl), CO(C 2 -C 6 alkenyl), CO(C 2 -C 6 alkynyl), CO(C 3 -C 8 cycloalkyl), CO(3 to 8-membered heterocyclyl), CO(aryl), CO(heteroaryl), CON(R y ) 2 , COO(C 1 -C 6 alkyl), COO(C 2 -C 6 alkenyl), COO(C 2 -C 6 alkynyl), COO(C 3 -C 8 cycloalkyl), COO(3 to 8-membered heterocyclyl), COO(aryl) or COO(heteroaryl) is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, aryl, heteroaryl and C 1 -C 6 alkoxy.

3. The prodrug of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof, wherein the compound has the formula Ib:

wherein:
R 1 is H, PO(OR x ) 2 , C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, aryl, heteroaryl, CO(C 1 -C 6 alkyl), CO(C 2 -C 6 alkenyl), CO(C 2 -C 6 alkynyl), CO(C 3 -C 8 cycloalkyl), CO(3 to 8-membered heterocyclyl), CO(aryl), CO(heteroaryl), CON(R y ) 2 , COO(C 1 -C 6 alkyl), COO(C 2 -C 6 alkenyl), COO(C 2 -C 6 alkynyl), COO(C 3 -C 8 cycloalkyl), COO(3 to 8-membered heterocyclyl), COO(aryl), or COO(heteroaryl), wherein each PO(OR x ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, aryl, heteroaryl, CO(C 1 -C 6 alkyl), CO(C 2 -C 6 alkenyl), CO(C 2 -C 6 alkynyl), CO(C 3 -C 8 cycloalkyl), CO(3 to 8-membered heterocyclyl), CO(aryl), CO(heteroaryl), CON(R y ) 2 , COO(C 1 -C 6 alkyl), COO(C 2 -C 6 alkenyl), COO(C 2 -C 6 alkynyl), COO(C 3 -C 8 cycloalkyl), COO(3 to 8-membered heterocyclyl), COO(aryl) or COO(heteroaryl) is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, aryl, heteroaryl and C 1 -C 6 alkoxy;
R 2 , R 3 , R 4 , R 5 and R 6 are each independently H, PO(OR x ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, aryl, heteroaryl, CO(C 1 -C 6 alkyl), CO(C 2 -C 6 alkenyl), CO(C 2 -C 6 alkynyl), CO(C 3 -C 8 cycloalkyl), CO(3 to 8-membered heterocyclyl), CO(aryl), CO(heteroaryl), CON(R y ) 2 , COO(C 1 -C 6 alkyl), COO(C 2 -C 6 alkenyl), COO(C 2 -C 6 alkynyl), COO(C 3 -C 8 cycloalkyl), COO(3 to 8-membered heterocyclyl), COO(aryl), or COO(heteroaryl), wherein each PO(OR x ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl

Assignees

• Massachusetts Inst Technology
• Massachusetts Gen Hospital

Inventors

• Tsai Li-Huei
• Haggarty Stephen J
• Patnaik Debasis
• Pao Ping-Chieh

Classifications

• C07C69/017

  Esters of hydroxy compounds having the esterified hydroxy group bound to a carbon atom of a six-membered aromatic ring · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · 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

• C07C49/825 Primary

  all hydroxy groups bound to the ring · CPC title