Ship 1 Modulators

Abstract

The present invention includes the use of pelorol, related compounds and pharmaceutical compositions thereof as modulators of SHIP 1 activity. This invention also provides novel terpene compounds capable of modulating SHIP 1 activity and methods of synthesis thereof.

1 . A compound of Formula I or a salt thereof,  
       
         
           
           
               
               
           
         
         wherein; 
 R 1  and R 2  are independently selected from the group consisting of: —CH 3 , —CH 2 CH 3 , —CH 2 OH, —CH 2 OR′, —CHO, —CO 2 H, and —CO 2 R′;  
 R 3  and R 4  are independently selected from the group consisting of: H, —CH 3 , —CH 2 CH 3 , —CH 2 OH, —CH 2 OR′, —CHO, —CO 2 H, and —CO 2 R′;  
 Q is a —CH 2 —;  
 X 1 , X 2 , X 3 , and X 4  are independently selected from the group consisting of: H, R, OH, —OR, —CO 2 H, —CO 2 R′, F, Br, Cl, I, —CN, —SO 3 H, —OSO 3 H, NO 2 , NH 2 , —NHR, and —NR 2 ; where R is a linear, branched, or cyclic, saturated or unsaturated one to ten carbon alkyl group that is unsubstituted or is substituted with one or more of: OH, ═O, SH, F, Br, Cl, I, NH 2 , —NHR′, —NR′ 2 , NO 2 , —CO 2 H, —CO 2 R′, and epoxide;  
 and R′ is a linear, branched, or cyclic, saturated or unsaturated one to ten carbon alkyl group that is unsubstituted or substituted with one or more of: OH, ═O, SH, F, Br, Cl, I, NH 2 , —NHR″, —NR″ 2 , NO 2  and —CO 2 H where R″ is a linear, branched, or cyclic, saturated or unsaturated one to ten carbon alkyl group;  
 providing that the compound does not have the precise structure of pelorol  
 
       
     
     
         2 - 5 . (canceled)  
     
     
         6 . The compound of  claim 1 , wherein R 1  is methyl, ethyl, —CH 2 OH, or —CH 2 OR′.  
     
     
         7 . The compound of  claim 1 , wherein R 2  is methyl, ethyl, —CH 2 OH, or —CH 2 OR′.  
     
     
         8 . The compound of  claim 1 , wherein R′ in R 1  is limited to methyl, ethyl, propyl or butyl.  
     
     
         9 . The compound of  claim 1 , wherein R′ in R 2  is limited to methyl, ethyl, propyl or butyl.  
     
     
         10 . The compound of  claim 1 , wherein R 1 , R 2 , R 3  and R 4  are methyl.  
     
     
         11 . The compound of  claim 1 , wherein X 1  is H, OH, R, OR, —CONH 2 , —CONHR′, or —COR′.  
     
     
         12 . The compound of  claim 1 , wherein X 2  is H, OH, R, OR, —CONH 2 , —CONHR′, or —COR′.  
     
     
         13 . The compound of  claim 1 , wherein X 3  is H, OH, R, OR, —CONH 2 , —CONHR′, or —COR′.  
     
     
         14 . The compound of  claim 1 , wherein R and R′ in one or more of X 1 , X 2 , and X 3  are limited to methyl, ethyl, propyl and butyl.  
     
     
         15 . The compound of  claim 1 , wherein X 1  is H, OH, or —OCH 3 .  
     
     
         16 . The compound of  claim 15 , wherein X 2  is H, OH, or OCH 3 .  
     
     
         17 . The compound of  claim 10 , wherein X 1  and X 2  are independently selected from H and OH.  
     
     
         18 . The compound of  claim 1 , wherein X 3  is H, OH, or OCH 3 .  
     
     
         19 . The compound of  claim 1 , wherein X 4  is H, R, OH, OR, CO 2 H or CO 2 R′.  
     
     
         20 . The compound of  claim 17 , wherein X 3  and X 4  are independently selected from H, methyl, ethyl, propyl and butyl.  
     
     
         21 . The compound of  claim 17 , wherein X 3  is H and X 4  is methyl.  
     
     
         22 . The compound of  claim 1 , selected from: PNSR-16A and PNSR-18A.  
     
     
         23 . The compound of  claim 1 , having the configuration S, R, R, S at C-5, C-8, C-9 and C-10 respectively.  
     
     
         24 . The compound of  claim 1 , having the configuration R, S, S, R at C-5, C-8, C-9 and C-10 respectively.  
     
     
         25 - 33 . (canceled)  
     
     
         34 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds of Formula I or pharmaceutically acceptable salts thereof,  
       
         
           
           
               
               
           
         
         wherein; 
 R 1  and R 2  are independently selected from the group consisting of: —CH 3 , —CH 2 CH 3 , —CH 2 OH, —CH 2 OR′, —CHO, —CO 2 H, and —CO 2 R′;  
 R 3  and R 4  are independently selected from the group consisting of: H, —CH 3 , —CH 2 CH 3 , —CH 2 OH, —CH 2 OR′, —CHO, —CO 2 H, and —CO 2 R′;  
 Q is a —CH 2 —;  
 X 1 , X 2 , X 3 , and X 4  are independently selected from the group consisting of: H, R, OH, —OR, —CO 2 H, —CO 2 R′, F, Br, Cl, I, —CN, —SO 3 H, —OSO 3 H, NO 2 , NH 2 , —NHR, and —NR 2 ; where R is a linear, branched, or cyclic, saturated or unsaturated one to ten carbon alkyl group that is unsubstituted or is substituted with one or more of: OH, ═O, SH, F, Br, Cl, I, NH 2 , —NHR′, —NR′ 2 , NO 2 , —CO 2 H, —CO 2 R′, and epoxide;  
 and R′ is a linear, branched, or cyclic, saturated or unsaturated one to ten carbon alkyl group that is unsubstituted or substituted with one or more of: OH, ═O, SH, F, Br, Cl, I, NH 2 , —NHR″, —NR″ 2 , NO 2  and —CO 2 H where R″ is a linear, branched, or cyclic, saturated or unsaturated one to ten carbon alkyl group.  
 
       
     
     
         35 . The pharmaceutical composition of  claim 34 , wherein R 1 , R 2 , R 3  and R 4  are methyl.  
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein X 1  and X 2  are independently selected from H and OH.  
     
     
         37 . The pharmaceutical composition of  claim 36 , wherein X 3  is hydrogen and X 4  is methyl.  
     
     
         38 . (canceled)