IP Library › Granted Patent US 7,321,050

Granted Patent B2

US 7,321,050 · App. 10/893,863 · Granted Jan 22, 2008

Anti-inflammatory and psoriasis treatment and protein kinase inhibition by hydroxy stilbenes and novel stilbene derivatives and analogues

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Quick Facts

Patent No.: US 7,321,050
App. No.: 10/893,863
Granted: Jan 22, 2008
Kind: B2

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Abstract

The present invention provides novel diphenyl ethene compounds and pharmaceutically-acceptable salts thereof. Also provided are methods for making the compounds of the invention as well as methods for the use thereof in the treatment of immune, inflammatory, and auto-immune diseases.

Claims (65)

1. A compound of the following formula, or a salt thereof

wherein

R 1 is selected from the group consisting of unsubstituted or substituted alkyl with carbon between 1 and 18; alkenyl with carbon between 2 and 18; alkynyl with carbon between 2 and 18; halo, and COR 9 ;

R 2 and R 3 are independently selected from the group consisting of H, unsubstituted or substituted alkyl with carbon between 1 and 18, and acyl with carbon between 1 and 18;

R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of H, unsubstituted or substituted alkyl with carbon between 1 and 18, alkenyl with carbon between 2 and 18, alkynyl with carbon between 2 and 18, aryl or aralkyl group, chloro, bromo, iodo, fluoro, nitro, CN, COR 9 , NR 10 R 11 , S(O) 2 NR 10 R 11 , SR 10 , SOR 10 , SO 2 R 10 , and OR 12 ; with the proviso that at least one of R 4 , R 5 , R 6 , R 7 , and R 8 is fluoro;

R 9 is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, or aralkyl, or NR 10 R 11 , or OR 10 ;

R 10 and R 11 are selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl and aralkyl;

R 12 is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl and acyl; and

wherein the configuration of the double bond of the compound of Formula I is E or Z.

2. The compound of claim 1 , wherein R 1 is isopropyl.

3. The compound of claim 2 , wherein R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of F, H, COOR 10 , and OR 12 , provided that one or more than one of R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is COOR 10 or OR 12 and at least one of R 4 , R 5 , R 6 , R 7 and R 8 is fluoro.

4. The compound of claim 2 , wherein R 2 and R 3 are independently selected from the group consisting of H, methyl and acetate.

5. A compound selected from the group consisting of:

2-(3,5-dimethoxy-4-i-propylphenyl)-1-(2-fluorophenyl)ethene;

1-(3,5-dimethoxy-4-i-propylphenyl)-2-(3-fluorophenyl)ethene;

1-(3,5-dimethoxy-4-i-propylphenyl)-2-(4-fluorophenyl)ethene;

2-(3,5-difluorophenyl)-1-(3,5-dimethoxy-4-i-propylphenyl)ethene;

1-(2,4-difluorophenyl)-2-(3,5-dimethoxy-4-i-propylphenyl)ethene;

1-(2,6-difluorophenyl)-2-(3,5-dimethoxy-4-i-propylphenyl)ethene;

1-(3,5-dimethoxy-4-i-propylphenyl)-2-(2,4,6-trifluorophenyl)ethene;

1-(3,5-dimethoxy-4-i-propylphenyl)-2-(2,3,4,5,6-pentafluorophenyl)ethene;

5-[2-(2-fluorophenyl)ethenyl]-2-i-propyl-1,3-benzenediol;

5-[2-(3-fluorophenyl)ethenyl]-2-i-propylphenyl-1,3-diol;

5-[2-(4-fluorophenyl)ethenyl]-2-i-propylphenyl-1,3-diol;

5-[2-(3,5-difluorophenyl)ethenyl]-2-i-propylphenyl-1,3-diol;

5-[2-(2,4-difluorophenyl)ethenyl]-2-i-propyl-1,3-benzenediol;

5-[2-(2,6-difluorophenyl)ethenyl]-2-i-propyl-1,3-benzenediol;

2-i-propyl-5-[2-(2,4,6-trifluorophenyl)ethenyl]-1,3-benzenediol, and 5-[2-(2,3,4,5,6-pentafluorophenyl)ethenyl]-2-i-propyl-1,3-benzenediol.

6. The compound of claim 1 , wherein the configuration of the double bond of the compound of Formula I is E.

7. The compound of claim 1 , wherein the configuration of the double bond of the compound of Formula I is Z.

8. A pharmaceutical composition comprising: a compound of the following formula or a pharmaceutically acceptable salt thereof:

wherein

R 1 is selected from the group consisting of unsubstituted or substituted alkyl with carbon between 1 and 18; unsubstituted or substituted cyclic alkyl with carbon between 3 and 18; alkenyl with carbon between 2 and 18; alkynyl with carbon between 2 and 18; halo, and COR 9 ;

R 2 and R 3 are independently selected from the group consisting of H, unsubstituted or substituted alkyl with carbon between 1 and 18, and acyl with carbon between 1 and 18;

R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of H, unsubstituted or substituted alkyl with carbon between 1 and 18, alkenyl with carbon between 2 and 18, alkynyl with carbon between 2 and 18, aryl or aralkyl group, chloro, bromo, iodo, fluoro, nitro, CN, COR 9 , NR 10 R 11 , S(O) 2 N NR 10 R 11 , SR 10 , SOR 10 , SO 2 R 10 , and OR 12 , with the proviso that at least one of R 4 , R 5 , R 6 , R 7 and R 8 is fluoro;

R 9 is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl, NR 10 R 11 , and OR 10 ;

R 10 and R 11 are selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl and aralkyl;

R 12 is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl and acyl; wherein the configuration of the double bond of the compound of Formula I is E or Z; and

a pharmaceutically acceptable diluent or carrier.

9. The pharmaceutical composition of claim 8 , wherein R 1 is unsubstituted or substituted alkyl with carbon between 1 and 18.

10. The pharmaceutical composition of claim 8 , wherein R 1 is halo group.

11. The pharmaceutical composition of claim 9 or claim 10 , wherein R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of F, H, COOR 10 , and OR 12 , with the proviso that at least one of R 4 , R 5 , R 6 , R 7 and R 8 is fluoro.

12. The pharmaceutical composition of claim 9 or claim 10 , wherein R 2 and R 3 are independently selected from the group consisting of H, methyl and acetate.

13. The pharmaceutical composition of claim 8 , wherein R 1 is isopropyl.

14. A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: