Byrostatin analogues, synthetic methods and uses

Abstract

Biologically active compounds related to the bryostatin family of compounds, having simplified spacer domains and/or improved recognition domains are disclosed, including methods of preparing and utilizing the same.

1 . A compound having the structure represented by a formula of the group:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: 
 R 3  is H, OH or a protecting group;  
 R 6  is H, H or ═O;  
 R 8  is H, OH, ═O, R′, —(CH 2 ) n O(O)CR′ or (CH 2 ) n CO 2 -haloalkyl where n is 0, 1, 2, 3, 4 or 5, provided that R 6  and R 8  are not both ═O;  
 R 9  is H, OH or is absent;  
 R 20  is H, OH, or -T-U—V—R′ where: 
 T is —O—, —S—, —N(H)— or —N(Me)—;  
 U is absent or is —C(O)—, —C(S)—, —S(O)— or —S(O) 2 —; and  
 V is absent or is —O—, —S—, —N(H)— or —N(Me)—, provided that V is absent when U is absent;  
 
 R 21  is ═CR a R b  or R 21  represents independent moieties R c  and R d  where: 
 R a  and R b  are independently H, CO 2 R′, CONR c R d  or R′;  
 R c  and R d  are independently H, alkyl, alkenyl, alkynyl or (CH 2 ) p CO 2 R′ where p is 1, 2 or 3;  
 
 R′ is independently selected from: H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl and heteroaralkyl;  
 R″ is OH, OTBS or OBn; and  
 X is —CH 2 —, —O—, —S— or —N(R e )— where R′ is COH, CO 2 R′ or SO 2 R′,  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       2 . A compound of  claim 1  having one or more of the stereochemical configurations represented by the corresponding formula of the group:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       3 . The compound or salt of any of  claims 1  to  3  where: 
 R 8  is H, alkyl, aralkyl, or —O 2 C-lower alkyl, provided that for Formula C26 des-methyl 705 R 8  is other than —O 2 C-t-butyl;    R 9  is H;    R 20  is H, OH, —O 2 C-lower alkyl or —O 2 C-alkenyl;    R 21  is ═C—CO 2 -lower alkyl; and    X is —CH 2 — or —O—.    
   
   
       4 . The compound or salt of  claim 3  where: 
 R 3  is OH;    R 8  is H, t-butyl, —O 2 C—CH 3 , —O 2 C—C(CH 3 ) 3  or —O 2 C—CH 2 —CH 2 —CH 3 ; and    R 20  is H, OH, —O 2 C—CH 3 , —O 2 C—CH 2 —CH 2 —CH 3  or —O 2 C—CH═CH—CH═CH—CH 2 —CH 2 —CH 3 .    
   
   
       5 . A compound having the structure represented by a formula of the group:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: 
 R 7  is absent or represents from 1 to 4 substituents on the ring to which it is attached, independently selected from: lower alkyl, hydroxyl, amino, alkoxyl, alkylamino, ═O, acylamino and acyloxy;  
 R 20  is H, OH, or -T-U—V—R′ where: 
 T is —O—, —S—, —N(H)— or —N(Me)—;  
 U is absent or is —C(O)—, —C(S)—, —S(O)— or —S(O) 2 —; and  
 V is absent or is —O—, —S—, —N(H)— or —N(Me)—, provided that V is absent when U is absent;  
 
 R 26  is H, OH or R′;  
 R′ is independently selected from: H, alkyl alkenyl, alkynyl, aryl, heteroaryl, aralkyl and heteroaralkyl;  
 R* is independently selected from: H and lower alkyl;  
 q is 0 or 1;  
 E is an aldehyde, hydroxymethyl, carboxyl, or a protected form thereof;  
 P is H or a protecting group; and  
 G is absent or represents P,  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       6 . A compound of  claim 5  having one or more of the stereochemical configurations represented by the corresponding formula of the group:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       7 . The compound of any of claims  5  or  6  wherein: 
 R* is independently selected from: H, methyl and ethyl;    E is an aldehyde, hydroxymethyl, carboxyl, CHO, CH 2 OP, CH(OP) 2  or CO 2 P; and    P is independently H or a protecting group selected from: allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyl, and protecting groups wherein two occurrences of P, taken together with the atoms through which they are connected, form a ring having 5-7 members.    
   
   
       8 . The compound or salt of  claim 7  where: 
 R 20  is H, OH, —O 2 C-lower alkyl or —O 2 C-alkenyl;    R 26  is H or CH 3 ;    R′ is independently selected from: H and methyl;    q is 1;    E is OPMB, TBSO—CH 2 — or —C(O)H; and/or    P is H, benzyl, OPMB or TBSO.    
   
   
       9 . The compound or salt of  claim 8  where: 
 R 20  is H, OH, —O 2 C—CH 3 , —O 2 C—CH 2 —CH 2 —CH 3  or —O 2 C—CH═CH—CH═CH—CH 2 —CH 2 —CH 3 .    
   
   
       10 . The compound of salt of  claim 7  where: 
 R 7  is absent;    R 26  is H or C 1 -C 6  alky; and    q is zero in Formula 15 F.    
   
   
       11 . The compound or salt of  claim 7  where R 26  is H.  
   
   
       12 . A compound having the structure represented by a formula of the group:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: 
 R 3  is H, OH or a protecting group;  
 R 6  is H, H or ═O;  
 R 7  is absent or represents from 1 to 4 substituents on the ring to which it is attached, independently selected from: lower alkyl, hydroxyl, amino, alkoxyl, alkylamino, ═O, acylamino and acyloxy;  
 R 8  is H, OH, ═O, R′, —(CH 2 ) n O(O)CR′ or (CH 2 ) n CO 2 -haloalkyl, 
 provided that R 6  and R 8  are not both ═O;  
 
 R 9  is H, OH or is absent;  
 R 12  and R 12a  are independently H, OH, lower alkyl, lower alkoxyl, or lower acyloxy, or R 12  and R 12a  taken together represent ═O;  
 R 20  is H, OH, or -T-U—V—R′ where: 
 T is —O—, —S—, —N(H)— or —N(Me)—;  
 U is absent or is —C(O)—, —C(S)—, —S(O)— or —S(O) 2 —; and  
 V is absent or is —O—, —S—, —N(H)— or —N(Me)—, provided that V is absent when U is absent;  
 
 R 21  is ═CR a R b  or R 21  represents independent moieties R c  and R d  where: 
 R a  and R b  are independently H, CO 2 R′, CONR c R d  or R′;  
 R c  and R d  are independently H, alkyl, alkenyl, alkynyl or (CH 2 ) p CO 2 R′;  
 
 R 26  is H, OH or R′;  
 R′ is independently selected from: H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl and heteroaralkyl;  
 L is a straight or branched linear, cyclic or polycyclic moiety, containing a continuous chain of preferably from 6 to 14 chain atoms, which substantially maintains the relative distance d of about 2.5 to 5.0 angstroms between the C1 and C17 atoms and the directionality, represented by the bold arrows, of the C1C2 and C16C17 bonds of naturally-occurring bryostatin;  
 X is —CH 2 —, —O—, —S— or —N(R e )— where R′ is COH, CO 2 R′ or SO 2 R′,  
 Y is CH 2 , —O— or —N(H)—;  
 Z is —O— or —N(H)—;  
 n is 0, 1, 2, 3, 4 or 5; and  
 p is 1, 2 or 3,  
 or a pharmaceutically acceptable salt thereof,  
 excluding the compounds of Formula 1998a where R 3  is H or OH and where R 20  is —O—C(O)—CH 3  or —O—C(O)—(CH 2 ) 6 —CH 3 , and the compounds of Formula 1998b where R 8  is H or t-Bu:  
                     
 
   
   
       13 . A compound of  claim 12  having one or more of the stereochemical configurations represented by the corresponding formula of the group:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       14 . A compound of  claim 12  having the stereochemical configurations represented by the corresponding formula of the group:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       15 . The compound or salt of any of  claims 12  to  14  where: 
 R 7  is absent;    R 8  is H, alkyl, aralkyl or —O 2 C-lower alkyl;    R 20  is H, OH, —O 2 C-lower alkyl or —O 2 C-alkenyl;    R 21  is ═C—CO 2 -lower alkyl;    R 26  is H or C 1 -C 6  alky; and    X is —CH 2 — or —O—.    
   
   
       16 . The compound or salt of  claim 15  where: 
 R 3  is OH;    R 8  is H, t-butyl, —O 2 C—CH 3 , —O 2 C—C(CH 3 ) 3  or —O 2 C—CH 2 —CH 2 —CH 3 ; and    R 20  is H, OH, —O 2 C—CH 3 , —O 2 C—CH 2 —CH 2 —CH 3  or —O 2 C—CH═CH—CH═CH—CH 2 —CH 2 —CH 3 .    
   
   
       17 . The compound or salt of  claim 16  where R 26  is H.  
   
   
       18 . A method for preparing a bryostatin analog, comprising a step selected from the group:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: 
 R 7  is absent or represents from 1 to 4 substituents on the ring to which it is attached, independently selected from: lower alkyl, hydroxyl, amino, alkoxyl, alkylamino, ═O, acylamino and acyloxy;  
 R 20  is H, OH, or -T-U—V—R′ where: 
 T is —O—, —S—, —N(H)— or —N(Me)—;  
 U is absent or is —C(O)—, —C(S)—, —S(O)— or —S(O) 2 —; and  
 V is absent or is —O—, —S—, —N(H)— or —N(Me)—, provided that V is absent when U is absent;  
 
 R 26  is H, OH or R′;  
 R′ is independently selected from: H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl and heteroaralkyl;  
 R* is independently selected from: H and lower alkyl;  
 q is 0 or 1;  
 E is an aldehyde, hydroxymethyl, carboxyl, or a protected form thereof; and  
 P is H or a protecting group.  
 
   
   
       19 . The method of  claim 18  comprising a stereospecific synthesis wherein the starting material for Step 13a, 14a, 15c, 15d or 16d has one or more of the stereochemical configurations represented by formulae 12F, 12F, 15C, 15D or 16D, respectively:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       20 . The method of any of claims  18  or  19  wherein: 
 Step 13a takes place under reaction conditions including the presence of an acid;    Step 14a takes place under reaction conditions including the presence of an acid and an alcohol of the formula R*—OH, where R* is lower alkyl;    Step 15c takes place under reaction conditions including the presence of an acid;    Step 15d takes place under reaction conditions including the presence of an alkyl glutarate ester; and/or    Step 16d takes place under reaction conditions including the presence of a dienolate of an ester of acetoacetate.    
   
   
       21 . The method of  claim 20  wherein: 
 R 7  is absent;    R 20  is R 20  is H, OH, —O 2 C-lower alkyl or —O 2 C-alkenyl;    R 26  is H or OH;    R′ is independently selected from: H and methyl;    R* is independently selected from: H, methyl and ethyl;    q is 1;    E is OPMB, TBSO—CH 2 — or —C(O)H; and/or    P is H, benzyl, OPMB or TBSO.