Compounds

Abstract

The present invention provides a compound which is a nystatin derivative having an additional double bond present between C28 and C29 and which is further modified relative to nystatin at one or more of positions C5, C7, C9, C10, C11, C16 or at the amino group of mycosamine.

1 .- 32 . (canceled) 
     
     
         33 . A compound which is a nystatin derivative having an additional double bond present between C28 and C29 and which is further modified relative to nystatin at C16 and optionally one or more of positions C5, C7, C9, C10, C11 or at the amino group of mycosamine, having the formula (I′) 
       
         
           
           
               
               
           
         
         preferably of formula (I), 
       
       
         
           
           
               
               
           
         
         wherein, 
         R 1  and R 2  each independently represent a hydrogen atom, a hydroxyl group, an alkoxy group, an acyloxy group or an alkyl group or together form a carbonyl group; 
         R 1′  and R 2′  each independently represent a hydrogen atom, a hydroxyl group, an alkoxy group, an acyloxy group or an alkyl group or together form a carbonyl group; 
         R 3  and R 4  each independently represent a hydrogen atom, a hydroxyl group, an alkoxy group, an acyloxy group or an alkyl group or together form a carbonyl group; 
         R 3′  and R 4′  each independently represent a hydrogen atom, a hydroxyl group, an alkoxy group, an acyloxy group or an alkyl group or together form a carbonyl group; 
         R 5  and R 6  each independently represent a hydrogen atom, a hydroxyl group, an alkoxy group, an acyloxy group or an alkyl group; 
         R 7  represents an alkyl group, carboxylic ester group or an amide group; 
         R 8  and R 9  each independently represent a hydrogen atom, an alkylamino group, a sugar group or an acyl group, 
         or a pharmaceutically acceptable salt thereof, 
       
     
     
         34 . A compound as claimed in  claim 33  which is modified at position C5 relative to nystatin. 
     
     
         35 . A compound as claimed in  claim 33  which is modified at C9 relative to nystatin. 
     
     
         36 . A compound as claimed in  claim 33  which is modified at C10 relative to nystatin. 
     
     
         37 . A compound as claimed in  claim 33  which is modified at the amino group of mycosamine. 
     
     
         38 . A compound as claimed in  claim 33  wherein R 1  represents a hydrogen atom, a hydroxyl group or an alkoxy group (e.g. a group —OC 1-6 ) and R 2  is a hydrogen atom or wherein R 1  and R 2  together form a carbonyl group. 
     
     
         39 . A compound as claimed in  claims 33 , wherein R 3  represents a hydrogen atom, a hydroxyl group or an alkoxy group (e.g. a group —OC 1-6 ) and R 4  is a hydrogen atom or wherein R 3  and R 4  together form a carbonyl group. 
     
     
         40 . A compound as claimed in  claim 33 , wherein R 5  represents a hydrogen atom, a hydroxyl group or an alkoxy group (e.g. a group —OC 1-6 ) and R 6  is a hydrogen atom 
     
     
         41 . A compound as claimed in  claim 33 , wherein R 8  represents a hydrogen atom, an alkylamino group, a sugar or an acyl group and R 9  is identical to R 8  or is a hydrogen atom, e.g. R 9  is a hydrogen atom. 
     
     
         42 . A compound as claimed in  claim 33 , wherein R 7  is an alkyl group (e.g. methyl) or is an amide group, e.g. an amide of formula III 
       
         
           
           
               
               
           
         
         wherein R 10  and R 11  each independently represent a hydrogen atom or a C 1-10  branched or unbranched C 1-10  alkyl group optionally substituted by hydroxy, acyloxy or amino groups and optionally interrupted by oxygen or nitrogen atoms or R 10  and R 11  together form a C 1-8  cyclic alkyl group, optionally substituted by hydroxy, acyloxy or amino groups and optionally interrupted by oxygen or nitrogen atoms. 
       
     
     
         43 . A compound as claimed in  claim 42  wherein R 7  is methyl, CONH(CH 2 ) n N(CH 3 ) 2  or CONH(CH 2 ) n OH where n is 2 or 3. 
     
     
         44 . A compound as claimed in  claim 33 , wherein R 8  is an alkylamino group of the formula —(CH 2 ) x NH 2  or —(CH 2 ) x N(C 1-6 alkyl) 2  wherein x is 2 to 6 or is a monosaccharide selected from glucose, galactose, glucopyranose, mannopyranose, galactopyranose, fructopyranose and tagotopyranose or is an oligosaccharide selected from lactose, melibiose, sucrose, maltose and cellobiose. 
     
     
         45 . A compound as claimed in  claim 33 , wherein R 1  and R 2  together form a carbonyl group, R 3 , R 4  and R 6  are hydrogen atoms and R 5  is a hydroxyl group. 
     
     
         46 . A compound as claimed in  claim 33 , wherein R 7  is C 1-6  alkyl (e.g. methyl) and at least one of R 8  and R 9  (e.g. both R 8  and R 9 ) are hydrogen atoms. 
     
     
         47 . A compound as claimed in  claim 33 , wherein R 7  is an amide group, preferably an amide group of formula III are hereinbefore defined and at least one of R 8  and R 9  (e.g. both R 8  and R 9 ) are hydrogen atoms. 
     
     
         48 . A compound as claimed in  claim 33 , wherein R 8  is a sugar group or an alkylamino group and R 9  is a hydrogen atom. 
     
     
         49 . A compound as claimed in  claim 33 , comprising the skeleton 
       
         
           
           
               
               
           
         
         in which any COOH at the 16-position is an amide as defined for R 7 . 
       
     
     
         50 . A compound as claimed in  claim 33  selected from: compound nos. 1, 9, 11, 12, 13, 14, 15, 16, 28, 29, 41, 48 and 51. 
     
     
         51 . A compound of formula: 
       
         
           
           
               
               
           
         
         or a glutamate salt thereof. 
       
     
     
         52 . A process for making a compound of  claim 33 , comprising:
 (i) modifying a gene cluster encoding the polyketide synthase system responsible for nystatin synthesis to produce a nystatin derivative having a double bond between C28 and C29; and   (ii) additionally modifying said gene cluster to produce nystatin derivative which is modified at C16 and optionally one or more of positions C5, C7, C9, C10, C11, or at the amino group of mycosamine,   OR   (iii) modifying the resulting derivative at C16 and optionally one or more of positions C5, C7, C9, C10, C11 or at the amino group of mycosamine by a chemical reaction.