3-(benzylamino)-4-(cyclohexylamino)-n-(2-(piperazin-1-yl)ethyl)benzenesulfonamide derivatives and related ferrostatin-1 analogues as cell death inhibitors for treating e.g. stroke

Patent metadata

Field	Value
Publication number	US-11339124-B2
Application number	US-201916967871-A
Country	US
Kind code	B2
Filing date	Feb 5, 2019
Priority date	Feb 7, 2018
Publication date	May 24, 2022
Grant date	May 24, 2022

Abstract

The present invention relates to 3-(benzylamino)-4-(cyclohexylamino)-N-(2-(piperazin-1-yl)ethyl)benzenesulfonamide derivatives and related ferrostatin-1 (Fer-1) analogues as cell death inhibitors by inhibition of ferroptosis and/or oxytosis for the treatment of stroke, myocardial infarction, diabetes, sepsis, the prevention of transplant rejection, neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, dementia with Lewy bodies and Friedreich's ataxia. The present invention further relates to pharmaceutical compositions of these compounds and discloses methods for making the compounds and the corresponding intermediate.

First claim

The invention claimed is:

1. A compound depicted in formula (I)

wherein
R1 is selected from the group consisting of H and aryl-substituted C1-C4-alkyl;
R2 is selected from the group consisting of H and aryl-substituted C1-C4-alkyl;
R3 is selected from the group consisting of a C3-C12-cycloalkyl optionally substituted with one of more halogens, optionally replacing one or more carbons by heteroatoms in the cycloalkyl ring structure;
R4 is selected from the group consisting of C1-C4-alkyl, wherein said C1-C4-alkyl is terminated with an R7 group wherein R7 is a C3-C10-heterocycle optionally substituted with one or more halogens;
R5 is selected from the group consisting of H or C3-C12-cycloalkyl optionally substituted with one of more halogens, optionally replacing one or more carbons by heteroatoms in the cycloalkyl ring structure; and
R6 is selected from the group consisting of H or a structure as defined in R4;

and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.

2. A compound according to claim 1 , wherein R1 or R2 is a pyridinyl-substituted C1-C4-alkyl.

3. A compound according to claim 1 , selected from the group consisting of 3-amino-4-(cyclohexylamino)-N-(2-(4-methylpiperazin-1-yl)ethyl)benzenesulfonamide, 3-amino-4-(cyclohexylamino)-N-(2-morpholino-ethyl)benzenesulfonamide, 3-amino-4-(cyclohexylamino)-N-(2-(piperazin-1-yl)ethyl)-benzenesulfonamide, 3-(benzylamino)-4-(cyclohexylamino)-N-(2-(4-methylpiperazin-1-yl)ethyl)benzenesulfonamide, 4-(cyclohexylamino)-N-(2-(4-methylpiperazin-1-yl)ethyl)-3-((pyridin-4-ylmethyl)amino)benzenesulfonamide, 4-(cyclohexylamino)-N-(2-morpholinoethyl)-3-((pyridin-4-ylmethyl)amino)benzenesulfonamide, 4-(cyclohexylamino)-N-(2-(piperazin-1-yl)ethyl)-3-((pyridin-4-ylmethyl)amino)benzenesulfonamide hydrochloride, 3-(benzylamino)-4-(cyclohexylamino)-N-(2-morpholinoethyl)benzenesulfonamide and 3-(benzylamino)-4-(cyclohexylamino)-N-(2-(piperazin-1-yl)ethyl)benzenesulfonamide hydrochloride.

4. A medicament comprising a compound of claim 1 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of the same in an amount sufficient to inhibit ferroptosis and/or oxytosis in a subject.

5. A pharmaceutical composition comprising a compound according to claim 1 , or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of the same; and a pharmaceutically acceptable carrier or diluent.

6. A method of inhibiting ferroptosis and/or oxytosis in a subject comprising administering to the subject the pharmaceutical composition according to claim 5 so as to inhibit ferroptosis and/or oxytosis in the subject.

7. A method of treating a subject for a disease where an excess of ferroptosis and/or oxytosis occurs, wherein the disease is selected from stroke, myocardial infarction, diabetes, sepsis, the prevention of transplant rejection, neurodegenerative diseases including Alzheimer's Disease, Parkinson's Disease, Amyotrophic lateral sclerosis, Huntington's Disease, Dementia with Lewy bodies, Friedreich's ataxia and multiple sclerosis, the method comprising administering to the subject the pharmaceutical composition according to claim 5 .

Assignees

• Vib Vzw
• Univ Antwerpen
• Univ Gent

Inventors

• Vandenabeele Peter
• Vanden Berghe Tom
• Augustyns Koen
• Hofmans Sam
• Van Der Veken Pieter
• Devisscher Lars

Classifications

• C07D295/14 Primary

  substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · 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

• C07C311/41

  to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups · CPC title

• C07D241/04

  having no double bonds between ring members or between ring members and non-ring members · CPC title

• C07D227/02

  with only hydrogen or carbon atoms directly attached to the ring nitrogen atom · CPC title