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 carbon skeleton selected from the group consisting of: —CH 2 —, —CY 1 Y 2 —, —CH 2 CH 2 —, —CH═CH—, —CY 1 Y 2 CY 3 Y 4 —, —CH 2 CH 2 CH 2 —, —CH═CHCH 2 —, —CH═CHCY 1 Y 2 —, and —CY 1 Y 2 CY 3 Y 4 CY 5 Y 6 —; where Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6  are independently selected from the group consisting of: H, F, Br, Cl, I, OH, OR′, and SH; or any one group of Y 1 /Y 2 , Y 3 /Y 4 , and Y 5 /Y 6  may be ═O; or Y 1 /Y 3  may form an epoxide; and, at least one of Y 1 , Y 2 , Y 3 , Y 4 , Y 5  and Y 6  when present, is not H;  
 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 or any one of the group of structures consisting of:  
                     
 
     
     
         2 . The compound of  claim 1 , wherein Y 1 -Y 6  are independently selected from H, F, Br, Cl and I.  
     
     
         3 . The compound of  claim 1 , wherein Q is —CH 2 —, —CH 2 CH 2 —, —CH═CH—, —CH 2 —CH 2 CH 2 —, or —CH═CHCH 2 —.  
     
     
         4 . The compound of  claim 1 , wherein the carbon skeleton of Q is saturated.  
     
     
         5 . The compound of  claim 1 , wherein the carbon skeleton of Q consists of one or two carbon atoms.  
     
     
         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 8 , wherein R′ is limited to methyl or ethyl.  
     
     
         11 . The compound of  claim 1 , wherein X 1  is H, OH, R, OR, —CONH 2 , —CONHR′, or —COR′ 2 .  
     
     
         12 . The compound of  claim 1 , wherein X 2  is H, OH, R, OR, —CONH 2 , —CONHR′, or —COR′ 2 .  
     
     
         13 . The compound of  claim 1 , wherein X 3  is H, OH, R, OR, —CONH 2 , —CONHR′, or —COR′ 2 .  
     
     
         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 1 , wherein X 2  is H, OH, or OCH 3 .  
     
     
         17 . The compound of  claim 1 , wherein X 2  is H, OCH 3 , or —NHOCH 3 .  
     
     
         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 1 , wherein R and R′ in X 4  are limited to methyl, ethyl, propyl or butyl.  
     
     
         21 . The compound of  claim 1 , wherein X 4  is H, R, OH, OCH 3 , —CO 2 H or —CO 2 CH 3 .  
     
     
         22 . The compound of  claim 1 , selected from: homopelorol, dimethoxypelorol, PNSR-4A, PNSR-15A, PNSR-16A, PNSR-17A 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 . The compound of  claim 1 , for use as a modulator of SHIP 1 activity.  
     
     
         26 . The compound of  claim 25 , wherein the compound is an agonist of SHIP 1 activity.  
     
     
         27 . (Canceled)  
     
     
         28 . A method of making a compound of Formula IA in which R 1 -R 4 , X 1 , X 3  and X 4  are as defined in  claim 1 ,  
       
         
           
           
               
               
           
         
       
       wherein, L′ is a C 1 -C 4  saturated or unsaturated alkyl linking group; and A is an activating group; comprising reacting a compound of Formula IIA or IIB:  
       
         
           
           
               
               
           
         
       
       in which L is absent or is a C 1 -C 3  saturated or unsaturated alkyl linking group and E and E′ are electrophilic reactive groups; with a compound of Formula III  
       
         
           
           
               
               
           
         
       
       in which Nu is a group that renders the compound of Formula III nucleophilic at Nu, followed by optional reduction and by hydrolysis, to produce a compound of Formula IV  
       
         
           
           
               
               
           
         
       
       and condensing the compound of Formula IV to produce a compound of Formula IA.  
     
     
         29 . The method of  claim 28 , wherein the compounds of Formula IIA and IIB have the structures:  
       
         
           
           
               
               
           
         
       
     
     
         30 . The method of  claim 29 , wherein the compounds of Formula IIA and IIB have the structures  
       
         
           
           
               
               
           
         
       
     
     
         31 . The method of  claim 28 , wherein the compound of Formula IIA or IIB is sclareolide or is derived from sclareolide.  
     
     
         32 . The method of  claim 28 , wherein Nu is lithium.  
     
     
         33 . The method of  claim 28 , wherein A is OCH 3  or —NHOCH 3 .  
     
     
         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 carbon skeleton selected from the group consisting of: —CH 2 —, —CY 1 Y 2 —, —CH 2 CH 2 —, —CH═CH—, —CY 1 Y 2 CY 3 Y 4 —, —CH 2 CH 2 CH 2 —, —CH═CHCH 2 —, —CH═CHCY 1 Y 2 —, and —CY 1 Y 2 CY 3 Y 4 CY 5 Y 6 —; where Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6  are independently selected from the group consisting of: H, F, Br, Cl, I, OH, OR′, and SH; or any one group of Y 1 /Y 2 , Y 3 /Y 4 , and Y 5 /Y 6  may be ═O; or Y 1 /Y 3  may form an epoxide; and, at least one of Y 1 , Y 2 , Y 3 , Y 4 , Y 5  and Y 6  when present, is not H;  
 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 the one or more compounds of Formula I is not solely pelorol.  
     
     
         36 . The pharmaceutical composition of  claim 34 , comprising pelorol.  
     
     
         37 . The pharmaceutical composition of  claim 34 , comprising a compound according to  claim 1 .  
     
     
         38 . A method of prophylaxis or treatment of an immune, hematopoietic, inflammatory or neoplastic disorder or condition comprising administering to a patient in need of said prophylaxsis or treatment, an effective amount of a pharmaceutical composition according to  claim 34.