Acetylenic cyanoenones as therapeutics for inflammation and carcinogenesis

Patent metadata

Field	Value
Publication number	US-10233146-B2
Application number	US-201615565846-A
Country	US
Kind code	B2
Filing date	Apr 14, 2016
Priority date	Apr 16, 2015
Publication date	Mar 19, 2019
Grant date	Mar 19, 2019

Abstract

The present invention provides a compound having the structure:

wherein
X is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, cyano, aryl, heteroaryl, alkylaryl, alkylheteroaryl, alkenylaryl, alkenylheteroaryl, alkynylaryl, alkynylheteroaryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, acyl, alkylhydroxy, alkylamino, alkenylamino, alkynylamino, amido, carboxyl, or carboxyl ester, or forms an unsubstituted or substituted cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indane or tetralin with Y, Y is H or forms an unsubstituted or substituted cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indane or tetralin with X, or forms an unsubstituted or substituted monocycle with Z; and Z is H or forms an unsubstituted or substituted monocycle with Y;
wherein when X and Y are both H, then X is C 2 alkenyl or C 2 alkynyl, and when Y is H forms a substituted cyclohexyl, cycloheptyl with X, the cyclohexyl is other than a trisubstituted cyclohexyl bearing CH 3 , i-Pr and (CH 2 ) 2 CO 2 CH 3 groups or CH 3 , i-Pr and (CH 2 ) 3 NH 2 ,

or a salt or ester thereof.

First claim

What is claimed is:

1. A compound having the structure:

wherein
X is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, cyano, aryl, heteroaryl, alkylaryl, alkylheteroaryl, alkenylaryl, alkenylheteroaryl, alkynylaryl, alkynylheteroaryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, acyl, alkylhydroxy, alkylamino, alkenylamino, alkynylamino, amido, carboxyl, or carboxyl ester, or forms an unsubstituted or substituted indane or tetralin with Y,
Y is H or forms an unsubstituted or substituted indane or tetralin with X, or forms an unsubstituted or substituted monocycle with Z; and
Z is H or forms an unsubstituted or substituted monocycle with Y,
wherein when Z and Y are both H, then X is C 2 alkenyl or C 2 alkynyl,

or a salt or ester thereof.

2. The compound of claim 1 , wherein
X is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, cyano, aryl, heteroaryl, alkylaryl, alkylheteroaryl, alkenylaryl, alkenylheteroaryl, alkynylaryl, alkynylheteroaryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, acyl, alkylhydroxy, alkylamino, alkenylamino, alkynylamino, amido, carboxyl, or carboxyl ester, or forms an unsubstituted or substituted indane or tetralin with Y,
Y is H or forms an unsubstituted or substituted indane or tetralin with X; and
Z is H
wherein when Z and Y are both H, then X is C 2 alkenyl or C 2 alkynyl,

or a salt or ester thereof.

3. The compound of claim 1 , wherein
X is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, cyano, aryl, heteroaryl, alkylaryl, alkylheteroaryl, alkenylaryl, alkenylheteroaryl, alkynylaryl, alkynylheteroaryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, acyl, alkylhydroxy, alkylamino, alkenylamino, alkynylamino, amido, carboxyl, or carboxyl ester,
Y is H or forms an unsubstituted or substituted monocycle with Z; and
Z is H or forms an unsubstituted or substituted monocycle with Y,
wherein when Z and Y are both H, then X is C 2 alkenyl or C 2 alkynyl,

or a salt or ester thereof.

4. The compound of claim 1 , wherein
X is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, cyano, aryl, heteroaryl, alkylaryl, alkylheteroaryl, alkenylaryl, alkenylheteroaryl, alkynylaryl, alkynylheteroaryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, acyl, alkylhydroxy, alkylamino, alkenylamino, alkynylamino, amido, carboxyl, or carboxyl ester,
Y forms an unsubstituted or substituted monocycle with Z; and
Z forms an unsubstituted or substituted monocycle with Y,
or a salt or ester thereof.

5. The compound of claim 1 having the structure:

wherein X is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, cyano, aryl, heteroaryl, alkylaryl, alkylheteroaryl, alkenylaryl, alkenylheteroaryl, alkynylaryl, alkynylheteroaryl, alkoxy, alkenyloxy, alkenyloxy, aryloxy, heteroaryloxy, acyl, alkylhydroxy, alkylamino, alkenylamino, alkynylamino, amido, carboxyl, or carboxyl ester,

or a salt or ester thereof.

6. The compound of claim 5 ,
wherein X is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl.

7. The compound of claim 1 having the structure:

wherein R 1 , R 2 , R 3 and R 4 are each independently, —H, halogen, —CN, —CF 3 , —OCF 3 , —(C 1 -C 12 alkyl), —(C 2 -C 12 alkenyl), —(C 2 -C 12 alkynyl), -(aryl), -(heteroaryl), —(C 1 -C 12 alkyl)-(aryl), —(C 2 -C 12 alkenyl)-(aryl), —(C 2 -C 12 alkynyl)-(aryl), —(C 1 -C 12 alkyl)-(heteroaryl), —(C 2 -C 12 alkenyl)-(heteroaryl), —(C 2 -C 12 alkynyl)-(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —CO 2 H, —CO 2 -(alkyl), —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), C(O)—NH 2 , C(O)—NH-(alkyl), C(O)—NH-(aryl) or C(O)—NH-(heteroaryl),
or a salt or ester thereof.

8. The compound of claim 7 ,
wherein R 1 , R 2 , R 3 and R 4 are each independently, —H, halogen or —(C 1 -C 12 alkyl).

9. The compound of claim 1 having the structure:

wherein R 5 , R 6 , R 7 and R 8 are each independently, —H, halogen, —CN, —CF 3 , —OCF 3 , —(C 1 -C 12 alkyl), —(C 2 -C 12 alkenyl), —(C 2 -C 12 alkynyl), -(aryl), -(heteroaryl), —(C 1 -C 12 alkyl)-(aryl), —(C 2 -C 12 alkenyl)-(aryl), —(C 2 -C 12 alkynyl)-(aryl), —(C 1 -C 12 alkyl)-(heteroaryl), —(C 2 -C 12 alkenyl)-(heteroaryl), —(C 2 -C 12 alkynyl)-(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —CO 2 H, —CO 2 -(alkyl), —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), C(O)—NH 2 , C(O)—NH-(alkyl), C(O)—NH-(aryl) or C(O)—NH-(heteroaryl),
or a salt or ester thereof.

10. The compound of claim 9 ,
wherein R 5 , R 6 , R 7 and R 8 are each independently, —H, halogen or —(C 1 -C 12 alkyl).

11. The compound of claim 1 having the structure:

wherein X is C 2 alkenyl or C 2 alkynyl.

12. A compound having the structure:

R 9 , R 10 , R 11 and R 12 are each independently, —H, halogen, —CN, —CF 3 , —OCF 3 , —(C 1 -C 12 alkyl), —(C 2 -C 12 alkenyl), —(C 2 -C 12 alkynyl), -(aryl), -(heteroaryl), —(C 1 -C 12 alkyl)-(aryl), —(C 2 -C 12 alkenyl)-(aryl), —(C 2 -C 12 alkynyl)-(aryl), —(C 1 -C 12 alkyl)-(heteroaryl), —(C 2 -C 12 alkenyl)-(heteroaryl), —(C 2 -C 12 alkynyl)-(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —CO 2 H, —CO 2 -(alkyl), —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), C(O)—NH 2 , C(O)—NH-(alkyl), C(O)—NH-(aryl) or C(O)—NH-(heteroaryl); and
each occurrence of R 13 and R 14 is each independently, —H, halogen, —CN, —CF 3 , —OCF 3 , —(C 1 -C 12 alkyl), —(C 2 -C 12 alkenyl), —(C 2 -C 12 alkynyl), -(aryl), -(heteroaryl), —(C 1 -C 12 alkyl)-(aryl), —(C 2 -C 12 alkenyl)-(aryl), —(C 2 -C 12 alkynyl)-(aryl), —(C 1 -C 12 alkyl)-(heteroaryl), —(C 2 -C 12 alkenyl)-(heteroaryl), —(C 2 -C 12 alkynyl)-(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-NH 2 , —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —CO 2 H, —CO 2 -(alkyl), —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), C(O)—NH 2 , C(O)—NH-(alkyl), C(O)—NH-(aryl) or C(O)—NH-(heteroaryl),
wherein when n=2, the cyclohexyl is other than a trisubstituted cyclohexyl bearing CH 3 , i-Pr and (CH 2 ) 2 CO 2 CH 3 groups or CH 3 , i-Pr and (CH 2 ) 3 NH 2 groups,
or a salt or ester thereof.

13. The compound of claim 12 , wherein n=1, or a salt or ester thereof.

14. The compound of claim 12 , wherein n=1 and each occurrence of R n and R 14 is —H; or wherein n=2 and each occurrence of R 13 and R 14 is —H; or wherein n=3 and each occurrence of R n and R 14 is —H, or a salt or ester thereof.

15. The compound of claim 12 having the structure:

Assignees

• Honda Tadashi
• Li Wei
• Zheng Suqing
• Dinkova Kostova Albena
• Univ New York State Res Found
• Univ Dundee

Inventors

• Honda Tadashi
• Li Wei
• Zheng Suqing
• Dinkova-Kostova Albena

Classifications

• C07C2603/18

  Fluorenes; Hydrogenated fluorenes · CPC title

• A61K31/277

  having a ring, e.g. verapamil · 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

• C07C2601/16

  the ring being unsaturated · CPC title

• A61P35/00

  Antineoplastic agents · CPC title