Furoxan-based compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-2020339596-A1
Application number	US-201916960470-A
Country	US
Kind code	A1
Filing date	Jan 11, 2019
Priority date	Jan 11, 2018
Publication date	Oct 29, 2020
Grant date	—

Abstract

Described herein are compounds of the formula (I), as well as pharmaceutical compositions comprising such compounds, and methods for using such compounds/pharmaceutical compositions for treating neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis (MS).

First claim

1 . A compound of the general formula (I):

or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein:
the dashed line represents a single or a double bond;
R 1 is H or aryl;
R 2 is H or aryl; and
X 1 and X 2 are each, independently, N, N + —O − or CR 3 , wherein R 3 is H or alkyl and only one of X 1 and X 2 can be N + —O − ;
with the proviso that the compound of the formula (I) is not the compound of the formula:

2 . The compound of claim 1 , wherein the compound of formula (I) is a compound of the general formula (Ia) or (Ib):

or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the dashed line in the compounds of formula (Ia) and (Ib) represents a single or a double bond;
R 1 is H or aryl; and
R 2 is H or aryl;
with the proviso that the compound of the formula (Ia) is not the compound of the formula:

3 . The compound of claim 1 , wherein the formula (I) is a compound of the formula (Ic):

or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the dashed line represents a single or a double bond;
R 1 is H or aryl;
X 1 and X 2 are each, independently, N, N + —O − or CR 3 , wherein R 3 is H or alkyl and only one of X 1 and X 2 can be N + —O − ;
m is an integer from 1 to 3; and
each R 4 is, independently, H, halo, alkyl, alkoxy, nitro, N(R 5 ) 2 , COR 6 , or haloalkyl, wherein each R 5 is, independently, H, S(O) n R 7 or acyl, wherein R 7 can be alkyl or aryl and n is an integer from 1 to 2, and R 6 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl or N(R 8 ) 2 , wherein each R 8 is, independently, H, alkyl or aryl; or
two adjacent R 4 groups, together with the atoms to which they are attached, can form an aryl or a heteroaryl group;
with the proviso that the compound of the formula (Ic) is not the compound of the formula:

4 . The compound of claim 1 , wherein the compound of the formula (I) is a compound of the formula (Id):

or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the dashed line represents a single or a double bond;
R 1 is H or aryl;
X 1 and X 2 are each, independently, N, N + —O − or CR 3 , wherein R 3 is H or alkyl and only one of X 1 and X 2 can be N + —O − ;
m is an integer from 1 to 3; and
R 9 is H, alkyl, aryl, alkenyl, alkynyl, arylalkyl or heteroarylalkyl.

5 . The compound of claim 1 , wherein the compound of the formula (I) is a compound of the formula (Ie):

or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the dashed line represents a single or a double bond;
R 1 is H or aryl;
X 1 and X 2 are each, independently, N, N + —O − or CR 3 , wherein R 3 is H or alkyl and only one of X 1 and X 2 can be N + —O − ;
m is an integer from 1 to 3; and
R 10 is H, halo, alkyl, OH, alkoxy, aryl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, heterocyclyl, N(R) 2 or COR 6 , wherein each R 5 is, independently, H, S(O) n R 7 or acyl, wherein R 7 can be alkyl or aryl and n is an integer from 1 to 2, and R 6 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl or N(R 8 ) 2 , wherein each R 8 is, independently, H, alkyl or aryl; or
two adjacent R 10 groups, together with the atoms to which they are attached, can form a cycloalkyl, aryl or a heteroaryl group.

6 . The compound of claim 1 , wherein the compound of the formula (I) is a compound of the formula (If):

or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the dashed line represents a single or a double bond;
R 1 is H or aryl;
m is an integer from 1 to 3; and
R 10 is H, halo, alkyl, OH alkoxy, aryl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, heterocyclyl, N(R 5 ) 2 or COR 6 , wherein each R 5 is, independently, H, S(O) n R 7 or acyl, wherein R 7 can be alkyl or aryl and n is an integer from 1 to 2, and R 6 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl or N(R 8 ) 2 , wherein each R 8 is, independently, H, alkyl or aryl; or two adjacent R 10 groups, together with the atoms to which they are attached, can form a cycloalkyl, aryl or a heteroaryl group.

7 . The compound of claim 1 , wherein the compound of the formula (I) is a compound of the formula:

or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.

8 . A pharmaceutical composition comprising at least one compound of claim 1 and a pharmaceutically acceptable excipient.

9 . A method for treating a neurodegenerative disease, the method comprising administering a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.

10 . The method of claim 9 , wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease or multiple sclerosis (MS).

11 . A method for inhibiting caspase-6 with a compound that reacts with the sulfhydryl group (SH) on cysteine 246 of caspase-6, the method comprising contacting caspase-6 with an effective amount of said compound.

12 . A method for treating a neurodegenerative disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of the genera

Assignees

• Univ Massachusetts

Inventors

• Hardy Jeanne A
• Meka Penchala Narasimharao

Classifications

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title