Compounds and methods for activating the apoptotic arm of the unfolded protein response

Patent metadata

Field	Value
Publication number	US-9732067-B2
Application number	US-201314408736-A
Country	US
Kind code	B2
Filing date	Jun 18, 2013
Priority date	Jun 20, 2012
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

Abstract

N-substituted sulfonylphenyl-5-mitrofuranyl-2-carboxamide derived compounds, which selectively activate the apoptotic, but not the adaptive arm, of the Unfolded Protein Response are provided as is their use in the treatment of diseases such as diabetes, Alzheimer's, Parkinson's, hemophilia, lysosomal storage diseases and cancer.

First claim

What is claimed is:

1. A compound having the structure of Formula I, or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein
X is C;
R 1 is a hydrogen; and
R 2 is a substituted alkyl group.

2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula I, or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein
X is C, N or O; and
R 1 and R 2 are each independently a hydrogen, hydroxyl, halo, or a substituted or unsubstituted alkyl or alkoxy group; or
R 1 and R 2 together form a substituted or unsubstituted cycloalkyl group,
with the proviso that when X is O, R 1 and R 2 are absent.

3. The pharmaceutical composition of claim 2 , wherein said composition is formulated for intratumoral, intracerebral, intracerebroventricular, or intrathecal administration.

4. A method for synthesizing a compound of Formula I comprising:
(a) treating a 4-substituted piperidine with an aryl sulfonyl chloride to produce a sulfonamide;
(b) contacting the sulfonamide with a reducing agent to produce an aniline; and
(c) treating the aniline with 5-nitrofuran acyl chloride under microwave irradiation, thereby producing a compound of Formula I

wherein
X is C; and R 1 and R 2 are each independently a hydrogen, hydroxyl, halo, or a substituted or unsubstituted alkyl or alkoxy group; or R 1 and R 2 together form a substituted or unsubstituted cycloalkyl group.

5. A compound having the structure of Formula I, or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein
X is C;
R 1 is a hydrogen; and
R 2 is an alkyl group substituted with a —F, —Cl, —Br, —I, —CF 3 , —NO 2 , —CN, —NH 2 , —COOH, —OH, —OCH 3 , —OCF 3 , —CONH 2 , or alkoxy group.

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula I, or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein
X is C, N or O; and
R 1 and R 2 are each independently a hydrogen, hydroxyl, halo, a substituted or unsubstituted alkoxy group, an unsubstituted methyl group, or an alkyl group substituted with a —F, —Cl, —Br, —I, —CF 3 , —NO 2 , —CN, —NH 2 , —COOH, —OH, —OCH 3 , —OCF 3 , —CONH 2 , or alkoxy group; or
R 1 and R 2 together form a substituted or unsubstituted cycloalkyl group,
with the proviso that when X is O, R 1 and R 2 are absent.

7. The pharmaceutical composition of claim 6 , wherein said composition is formulated for intratumoral, intracerebral, intracerebroventricular, or intrathecal administration.

Assignees

• Univ Kansas
• Univ Michigan Regents
• Univ Wayne State
• Sanford-Burnham Medical Res Inst

Inventors

• Golden Jennifer E
• Aube Jeffrey
• Flaherty Daniel P
• Fribley Andrew M
• Kaufman Randal J
• Chung Thomas D Y
• Pinkerton Anthony B
• Hedrick Michael Pablo

Classifications

• A61K31/4525

  containing a five-membered ring with oxygen as a ring hetero atom · CPC title

• C07D405/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• C07D307/71

  attached in position 5 · CPC title