Benzamide compounds and related methods of use

Patent metadata

Field	Value
Publication number	US-9890117-B2
Application number	US-201615187163-A
Country	US
Kind code	B2
Filing date	Jun 20, 2016
Priority date	Dec 21, 2012
Publication date	Feb 13, 2018
Grant date	Feb 13, 2018

Abstract

Benzamide compounds and derivatives thereof, as can be used for selective inhibition of the SIRT2 enzyme and/or therapeutic use in the treatment of Huntington's disease.

First claim

We claim:

1. A pharmaceutical composition comprising a suitable carrier and a compound selected from compounds of the following formula or salts thereof:

wherein
each of R 1 and R 2 is independently selected from phenyl, benzyl, heteroaryl, and heteroarylalkyl moieties;
each of E 1 and E 2 is independently selected from CH and N, provided at least one of E 1 and E 2 is CH;
A is a divalent moiety selected from carbonyl, amino, carboxamido (—C(O)NH—), imidocarbyl (—C(NH)—) and a tautomer thereof (—N═C(NH 2 )—) with X;
X is a divalent moiety selected from methylene, carbonyl, amino, and aza-substituted ethylene (—NHCH 2 —) moieties;
Y is a divalent moiety selected from oxy, amino, alkylene, and aza-substituted alkylene moieties; and
Z is a divalent moiety selected from sulfonyl, sulfinyl, thio, oxy, amino, and methylene moieties, providing where A is carbonyl, Z is sulfonyl and R 1 and R 2 are selected from phenyl and substituted phenyl, X is not amino or methylamino and Y is not amino, alkylamino, allylamino or benzylamino, and
wherein
each of R 1 , R 2 , A, X, Y and Z is optionally substituted with 1-10 substituents independently selected from halo, cyano, nitro, hydroxy, amino, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, alkoxy, alkenyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkylene, alkylsulfonyl, haloalkylsulfonyl, haloalkylsulfinyl, alkylamido, alkylsulfonamido, alkylthio, alkylcarbonyl, alkoxycarbonyl and combinations of such substituents; R 3 is selected from said substituents and combinations thereof; and n is an integer from 0-4.

2. The pharmaceutical composition of claim 1 , wherein A is carbonyl and E 2 is CH, said compound of a formula

3. The pharmaceutical composition of claim 2 , wherein X is selected from amino and alkylamino moieties, and Z is methylene, said compound of a formula

4. The pharmaceutical composition of claim 3 , wherein Y is selected from oxy, alkylene, alkyl-substituted alkylene, amino and substituted amino moieties.

5. The pharmaceutical composition of claim 4 , wherein R 2 is a substituted benzyl moiety, said substituents selected from 1-3 halo and cyano substituents and combinations thereof.

6. The pharmaceutical composition of claim 4 , wherein Y is a substituted amino moiety and R 2 is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl moieties.

7. The pharmaceutical composition of claim 6 , wherein Y is an alkyl-substituted amino moiety or a cycloalkyl-substituted amino moiety.

8. A method of treating a subject having a disease or disorder associated with sirtuin 2 (SIRT2) activity, the method comprising administering the pharmaceutical composition of claim 1 to the subject.

9. The method of claim 8 , wherein the disease or disorder is a neurodegenerative disorder associated with SIRT2 activity.

10. The method of claim 9 , wherein the neurodegenerative disorder associated with SIRT2 activity is Huntington's disease.

11. The method of claim 9 , wherein the neurodegenerative disorder associated with SIRT2 activity is Parkinson's disease.

12. A pharmaceutical composition comprising a suitable carrier and a compound selected from compounds of the following formula or salts thereof:

wherein
R 1 is selected from phenyl, benzyl and heteroaryl moieties;
each of E 1 and E 2 is independently selected from CH and N; and
wherein
each of R 1 is optionally substituted with 1-5 substituents independently selected from but not limited to halo, cyano, nitro, hydroxy, amino, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, alkoxy, alkenyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkylsulfonyl, alkylsulfinyl, haloalkylsulfonyl, haloalkylsulfinyl, alkylamido, alkylsulfonamido, alkylthio, alkylcarbonyl, alkoxycarbonyl and combinations of such substituents;
each of R 3 and R 4 is independently selected from said substituents and combinations thereof; and
each of n and m is an integer independently selected from 0-4, providing where R 1 is a benzothiazolyl moiety, E 1 and E 2 are CH, n is 1 and m is 0, then R 3 is not a phenyl substituent at E 2 .

13. The pharmaceutical composition of claim 12 , wherein wherein m is 1-2.

14. The pharmaceutical composition of claim 13 , wherein R 1 is selected from phenyl, mono-substituted phenyl, and di-substituted phenyl moieties.

15. The pharmaceutical composition of claim 14 , wherein E 2 is CH, and E 1 is selected from CH and N.

16. The pharmaceutical composition of claim 14 , wherein n is 0.

17. A method of treating a subject having a disease or disorder associated with sirtuin 2 (SIRT2) activity, the method comprising administering the pharmaceutical composition of claim 12 to the subject.

18. The method of claim 17 , wherein the disease or disorder is a neurodegenerative disorder associated with SIRT2 activity.

19. The method of claim 18 , wherein the neurodegenerative disorder associated with SIRT2 activity is Huntington's disease.

20. The method of claim 18 , wherein the neurodegenerative disorder associated with SIRT2 activity is Parkinson's disease.

Assignees

• Univ Northwestern
• Massachusetts Gen Hospital

Inventors

• Silverman Richard B
• Wang Hua
• Khanfar Mohammad
• Kazantsev Aleksey G

Classifications

• C07D277/46

  by carboxylic acids, or sulfur or nitrogen analogues thereof · CPC title

• C07C235/60

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

• C07D213/82

  in position 3 · CPC title

• C07D417/12

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

• C07D213/80

  in position 3 · CPC title