Conjugates of a pharmaceutical agent and a moiety capable of binding to a glucose sensing protein

Abstract

The invention describes novel conjugates of formula (I) of a pharmaceutical agent and a moiety capable of binding to a glucose sensing protein allowing a reversible release of the pharmaceutical agent depending on the glucose concentration.

1 - 40 . (canceled) 
     
     
         41 . A compound of formula (Ia)
   R—(O═C)−[L 1 ] m −[A 1 ] o −[L 2 ] p −[A 2]   r −[L 3 ] q −S   (Ia)
   
       wherein
 L 1 , L 2 , and L 3  are independently a linker having a chain length of 1-20 atoms, 
 A 1  and A 2  are independently:
 a 5 to 6 membered monocyclic ring, 
 a 9 to 12 membered bicyclic ring, 
 two 5 to 6 membered monocyclic rings connected to each other, 
 two 9 to 12 membered bicyclic rings connected to each other, or 
 a 5 to 6 membered monocyclic ring and a 9 to 12 membered bicyclic ring connected to each other 
 wherein each ring is independently a saturated, unsaturated, or aromatic carbocyclic or heterocyclic ring and wherein each ring is optionally modified with at least one sub stituent, 
 
 S is a sugar moiety which binds to the insulin independent glucose transporter GluT1, and wherein the sugar moiety S comprises a terminal pyranose Si moiety which is attached via position 2, 4, or 6 to the compound of formula (Ia), 
 m, o, p, r, and q are independently of each other 0 or 1, and wherein at least one of r and o is 1, R is H, halogen, OH, O-alkyl-, an anhydride forming group, an active ester forming group, 4-nitrophenylester, succinate, or N-hydroxy benzotriazol, or a pharmaceutically acceptable salt or solvate thereof. 
 
     
     
         42 . (canceled) 
     
     
         43 . The compound of formula (Ia) of  claim 41 , wherein L 1 , L 2 , and L 3  are independently of each other (C 1 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene, or (C 2 -C 20 ) alkynylene, wherein one or more C-atoms may be replaced by heteroatoms or heteroatom moieties, particularly by O, NH, N(C 1-4 ) alkyl, S, SO, SO 2 , O—SO 2 , O—SO 3 , O—PHO 2 , or O—PO 3  and/or wherein one or more C-atoms may be substituted with (C 1-4 ) alkyl, (C 1-4 ) alkyloxy, oxo, carboxyl, halogen, F, Cl, Br, or I, or a phosphorus-containing group. 
     
     
         44 . The compound of formula (Ia) of  claim 41 , wherein L 3  is (C 1 -C 6 ) alkylene, or (C 1-4 ) alkylene, wherein one or two C-atoms may be replaced by heteroatoms or heteroatom moieties, particularly by O, NH, N(C 1-4 ) alkyl, S, SO, SO 2 , O—SO 2 , O—SO 3 , O—PHO 2 , or O—PO 3  and/or wherein one or more C-atoms may be substituted with (C 1-4 ) alkyl, (C 1-4 ) alkyloxy, oxo, carboxyl, halogen, e.g. F, Cl, Br, or I, or a phosphorus-containing group. 
     
     
         45 . The compound of formula (Ia) of  claim 41 , wherein L 3  is C═O. 
     
     
         46 . The compound of formula (Ia) of  claim 41 , wherein L 2  is selected from —CO—(CH 2 ) 3 —, —(CH 2 ) 6 —NH—, —(CH 2 ) 2 —CO—(CH 2 —CH 2 —O) 2 —(CH 2 ) 2 —NH— or —CH 2 —O—(CH 2 —CH 2 —O) 3 —. 
     
     
         47 . The compound of formula (Ia) of  claim 41 , wherein A 1  and A 2  are independently of each other a heterocyclic ring, wherein the ring may carry at least one sub stituent. 
     
     
         48 . The compound of formula (Ia) of  claim 41 , wherein A 1  and A 2  are independently of each other selected from a 5 to 6 membered monocyclic or a 9 to 12 membered bicyclic ring, wherein the ring is heterocyclic with 1 to 4 ring atoms being selected from N, O, and/or S, and wherein the ring may carry at least one substituent. 
     
     
         49 . The compound of formula (Ia) of  claim 41 , wherein A 1  and A 2  are independently of each other a 5 to 6 membered monocyclic ring, wherein the ring is a heteroalkyl ring, particularly selected from pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolidinyl, piperazinyl, piperidinyl, or morpholinyl, wherein the ring may carry at least one substituent, or a 9 to 12 membered bicyclic ring wherein the ring is a heteroalkyl ring with 1 to 4 ring atoms being selected from N, O, and/or S, and wherein the ring may carry at least one substituent. 
     
     
         50 . The compound of formula (Ia) of  claim 41 , wherein A 1  and A 2  are independently of each other 1,2,3-triazolyl. 
     
     
         51 . The compound of formula (Ia) of  claim 41 , wherein A 2  is 1,2,3-triazolyl. 
     
     
         52 . The compound of formula (Ia) of  claim 41 , wherein A 2  is piperazinyl. 
     
     
         53 . The compound of formula (Ia) of  claim 41 , wherein r=1 and A 2  is present and o=0 and A 1  is absent. 
     
     
         54 . The compound of formula (Ia) of  claim 41 , wherein r=1 and A 2  is present and o=1 and A 1  is present. 
     
     
         55 . The compound of formula (Ia) of  claim 41 , wherein 
       (i) m=1, o=0, p=0, and q=0 or 1, 
       or wherein 
       (ii) m=1, o=1, p=1, and q=0 or 1. 
     
     
         56 . The compound of formula (Ia) of  claim 41 , wherein A 2  is piperazinyl, L 2  is absent and A 1  is cyclohexanyl. 
     
     
         57 . The compound of formula (Ia) of  claim 41 , wherein A 2  is piperazinyl, L 2  is absent and A 1  is cyclohexanyl. 
     
     
         58 . The compound of formula (Ia) of  claim 41 , wherein A 2  is piperazinyl, L 2  is —CH 2 — and A 1  is cyclohexanyl. 
     
     
         59 . The compound of formula (Ia) of  claim 41 , wherein A 2  is piperazinyl, L 2  is absent and A 1  is phenyl. 
     
     
         60 . The compound of formula (Ia) of  claim 41 , wherein A 2  is1,2,3-triazolyl, L 2  is absent and A 1  is phenyl. 
     
     
         61 . The compound of formula (Ia) of  claim 41 , wherein
 L3 is —CO—, A 1  is phenyl, L 2  is —O— and A 1  is phenyl wherein each ring may be unsubstituted or carry at least one substituent, for example, 1 to 3 substituents selected from halogen, NO 2 , CN, (C 1-4 ) alkyl, (C 1-4 ) alkoxy, (C 1-4 )alkyl-(C 3-7 )cycloalkyl, (C 3-7 ) cycloalkyl, OH, benzyl, —O-benzyl, carboxyl, carboxyester, carboxamide, or mono (C 1-4 ) alkyl, or di (C 1-4 ) alkyl carboxamide.   
     
     
         62 . The compound of formula (Ia) of  claim 41 , wherein the group -A 2 -L 3 - is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         63 . The compound of formula (Ia) of  claim 41 , wherein the sugar moiety S comprises a terminal pyranose moiety S1 having a backbone structure of Formula (II) 
       
         
           
           
               
               
           
         
       
       wherein 1, 2, 3, 4, 5, and 6 denote the positions of the C-atoms in the pyranose moiety;
 wherein   is a single bond and   is a single or a double bond; and 
 R1 and R3 are H or a protecting group; 
 which is attached via position 2, 4, or 6 to the compound of formula (Ia). 
 
     
     
         64 . The compound of formula (Ia) of  claim 63 , wherein the terminal pyranose moiety Si is selected from glucose, galactose, 4-deoxyglucose, or 4,5-dehydroglucose derivatives, wherein the terminal pyranose moiety S1 is attached via position 2, 4, or 6 to the compound of formula (Ia); or
 S1 is mannose attached via position 6.   
     
     
         65 . The compound of formula (Ia) of  claim 63 , wherein the terminal pyranose moiety S1 is of the Formula (IIIa) or (IIIb): 
       
         
           
           
               
               
           
         
       
       wherein R1 is H or a protecting group,
 R2 is OR8, or NHR8 or an attachment site to the compound of formula (Ia), wherein R8 is H or a protecting group, 
 R3 is H or a protecting group, 
 R4 is H, OR8, or NHR8 or an attachment site to the compound of formula (Ia), wherein R8 is H or a protecting group, 
 or R1 and R2 and/or R3 and R4 form together with the pyranose ring atoms to which they are bound a cyclic group, 
 R5 and R6 are H or together with the carbon atom to which they are bound form a carbonyl group, 
 R7 is OR8, or NHR8 or an attachment site to the compound of formula (Ia), wherein R8 is H or a protecting group, and 
 wherein one of R2, R4, and R7 is the attachment site to the compound of formula (Ia). 
 
     
     
         66 . The compound of formula (Ia) of  claim 63 , wherein R1 and R3 are H. 
     
     
         67 . The compound of formula (Ia) of  claim 63 , wherein R2 is OR8 or an attachment site to the compound of formula (Ia),
 R4 is H, OR8, or an attachment site to the compound of formula (Ia), and   R7 is OR8 or an attachment site to the compound of formula (Ia),   
       and wherein R8 is H or a protecting group. 
     
     
         68 . The compound of formula (Ia) of  claim 63 , wherein position 6 of the pyranose moiety S1 and particularly R7 is the attachment site to the compound of formula (Ia). 
     
     
         69 . The compound of formula (Ia) of  claim 63 , wherein the pyranose moiety S1 is of formula (IVa), (IVb), (IVc), (IVd), or (IVe): 
       
         
           
           
               
               
           
         
         wherein R1, R2, R3, R5, R6, and R7 are defined as in any one of  claims 65 - 68  and wherein R4 is H, a protecting group, or an attachment site to the compound of formula (Ia), or R4a is H, or an attachment site to the compound of formula (Ia). 
       
     
     
         70 . The compound of formula (Ia) of  claim 41 , wherein the sugar moiety S is of Formula (V):
   —[X 2 —S 2 ] s —X 1 —S1   (V)
   
       wherein X 1  is a bond or O,
 X 2  is a bond, NH or O, 
 S 2  is a mono- or disaccharide moiety, particularly comprising at least one hexose or pentose moiety, more particularly at least one pyranose or furanose moiety and S1 is a terminal pyranose moiety as defined in any one of  claims 63 - 68 , and 
 s is 0 or 1. 
 
     
     
         71 . The compound of formula (Ia) of  claim 70 , wherein the saccharide moiety S2 is a pyranose moiety, particularly selected from glucose, galactose, 4-deoxyglucose and 4,5-dehydroglucose derivatives, or a furanose moiety, particularly selected from fructose derivatives. 
     
     
         72 . The compound of formula (Ia) of  claim 70 , wherein the saccharide moiety S2 is of Formula (VIa), (VIb), (VIc), (VId), or (VIe): 
       
         
           
           
               
               
           
         
       
       wherein R11 is a bond to X 1 ,
 R12 is OR8 or NHR8 or an attachment site to X 2 , wherein R8 is H or a protecting group, 
 R13 is H or a protecting group, 
 R14 is R8 or an attachment site to X 2 , wherein R8 is H or a protecting group, 
 R14a is H or an attachment site to X 2 , 
 R15 and R16 are H or together with the carbon atom to which they are bound form a carbonyl group, 
 R17 is OR8 or an attachment site to X 2 , wherein R8 is H or a protecting group, 
 or R11 and R12 and/or R13 and R14 form together with the ring atoms to which they are bound a cyclic group, 
 and wherein one of R12, R14, and R17 is an attachment site to X 2 . 
 
     
     
         73 . The compound of formula (Ia) of  claim 41 , wherein the sugar moiety S comprises a single terminal saccharide moiety.