Derivatives of sobetirome

Patent metadata

Field	Value
Publication number	US-2016244418-A1
Application number	US-201615048672-A
Country	US
Kind code	A1
Filing date	Feb 19, 2016
Priority date	Feb 20, 2015
Publication date	Aug 25, 2016
Grant date	—

Abstract

Ester derivatives of sobetirome with enhanced CNS distribution are disclosed.

First claim

1 . A compound with the structure:

or any pharmaceutically acceptable salt thereof, where R 1 is alkyl or aryl.

2 . The compound of claim 1 where R 1 is unsubstituted alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, substituted aryl, heteroaryl, substituted heteroaryl.

3 . The compound of claim 2 where R 1 is ethyl, lysinyl, valinyl, phenylalaninyl, glucosyl, or 1-methylethanol.

4 . The compound of claim 2 where R 1 is alkylamino.

5 . The compound of claim 4 where R 1 is substituted alkylamino, cycloalkylamino, or substituted cycloalkylamino.

6 . The compound of claim 4 wherein R 1 is ethylamino, ethyl(N,N,N)-trimethylamino, ethylmorpholinyl, ethyl(N,N)-dimethylamino, 3-(N-methyl)azetidinyl, 4-pyrrolidinyl, 3-pyrrolidinyl, 2,2-dimethylethylamino, 3-(3-trifluoromethyl)azetidinyl, 2-pyrrolidinyl, 2-methylethylamino, 2-trifluoromethylamino, N-methyl-ethylamino, 1-methyl-(N,N)-dimethylethylamino, 1-methyl-2-imazodinylethylamino; 1-methyl-2-keto-ethylamino, 1-isopropyl-ethylamino, and 1-isopropyl-N-methyl-ethylamino.

7 . The compound of claim 6 wherein R 1 is 2-methylethylamino further comprising R and S enantiomers.

8 . The compound of claim 1 wherein the compound is 2-(dimethylamino)ethyl 2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate; 1-methylazetidin-3-yl 2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate; pyrrolidin-2-ylmethyl 2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate; 3-methyazetidin-3-yl 2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate; piperidin-4-yl 2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate; piperidin-4-yl 2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate; 1-amino-2-methlpropan-2-yl 2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate; 3-(trifluoromethyl)azetidin-3-yl 2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate; 2-((2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetoxy)methyl)piperidin-1-ium chloride; (R)-1-aminopropan-2-yl 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate; (S)-1-aminopropan-2-yl 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate; 2-(methylamino)ethyl 2-(4-(4-hydroxy-3-methylbenzyl)-3,5-dimethylphenoxy)acetate hydrochloride; 1-aminopropan-2-yl 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate; 1-(dimethylamino)propan-2-yl 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate; 1-(1H-imidazol-1-yl)propan-2-yl 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate; 1-amino-1-oxopropan-2-yl 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate; 1-hydroxypropan-2-yl 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate; 3-methyl-1-(methylamino)butan-2-yl 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate; or 1-amino-3-methylbutan-2-yl 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate.

9 . The compound of claim 6 with the structure:

10 . The compound of claim 9 wherein the compound is a halide salt.

11 . The compound of claim 6 with a structure selected from:

12 . A pharmaceutical composition comprising an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

13 . A method of treating a neurodegenerative disorder in a subject, the method comprising: administering the pharmaceutical composition of claim 12 to the subject, thereby treating the neurodegenerative disorder.

14 . The method of claim 13 wherein the neurodegenerative disorder comprises a demyelinating disease.

15 . The method of claim 14 wherein the neurodegenerative disorder is X-linked adrenoleukodystrophy or multiple sclerosis.

Assignees

• Scanlan Thomas S
• Placzek Andrew
• Banerji Tapasree
• Ferrara Sky
• Meinig James Matthew
• Univ Oregon Health & Science

Inventors

• Scanlan Thomas S
• Placzek Andrew
• Banerji Tapasree
• Ferrara Sky
• Meinig James Matthew

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07C2601/04

  with a four-membered ring · CPC title

• C07D207/08

  with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms · CPC title

• C07D205/04

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

• C07C235/06

  having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title