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 : A conjugate of formula (I)
   P-[L 1 ] m -[A 1 ] o -[L 2 ] p -[A 2 ] r -[L 3 ] q -S   (I)
   wherein P is an insulin or an insulinotropic peptide;   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 substituent;   S is a sugar moiety which binds to the insulin independent glucose transporter GluT1, wherein the sugar moiety S comprises a terminal pyranose S1 moiety which is attached via position 2, 4, or 6 to the conjugate of formula (I),   m, o, p, r, and q are independently 0 or 1, wherein at least one of r and o is 1, or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         2 : The conjugate of formula (I) of  claim 1 , wherein P is an insulin which is attached via the amino side chain of an insulin B29Lys residue or via the amino terminus of an insulin B1Phe residue. 
     
     
         3 : The conjugate of formula (I) of  claim 1 , wherein L 1 , L 2 , and L 3  are independently (C 1 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene, or (C 2 -C 20 ) alkynylene, wherein one or more C-atoms are optionally replaced by heteroatoms or heteroatom moieties selected from the group consisting of O, NH, N(C 1-4 ) alkyl, S, SO, SO 2 , O—SO 2 , O—SO 3 , O—PHO 2 , and O—PO 3 , and/or wherein one or more C-atoms may be is optionally modified with (C 1-4 ) alkyl, (C 1-4 ) alkyloxy, oxo, carboxyl, halogen, or a phosphorus-containing group. 
     
     
         4 : The conjugate of formula (I) of  claim 1 , wherein; (i) L 3  is (C 1 -C 6 ) alkylene, wherein one or two C-atoms may be replaced by heteroatoms or heteroatom moieties selected from the group consisting of O, NH, N(C 1-4 ) alkyl, S, SO, SO 2 , O—SO 2 , O—SO 3 , O—PHO 2 , and O—PO 3  and/or wherein one or more C-atoms is optionally modified with (C 1-4 ) alkyl, (C 1-4 ) alkyloxy, oxo, carboxyl, halogen, or a phosphorus-containing group;
 (ii) L 3  is C═O; or 
 (iii) L 2  is selected from the group consisting of —CO—(CH 2 ) 3 —, —(CH 2 ) 6 —NH—, —(CH 2 ) 2 —CO—(CH 2 —CH 2 —O) 2 —(CH 2 ) 2 -NH— and —CH 2 —O—(CH 2 —CH 2 —O) 3 —. 
 
     
     
         5 - 6 . (canceled) 
     
     
         7 : The conjugate of formula (I) of  claim 1 , wherein; (i) A 1  and A 2  are independently of each other a heterocyclic ring, wherein the ring may carry at least one substituent;
 (ii) A 1  and A 2  are independently a 5 to 6 membered monocyclic or a 9 to 12 membered bicyclic ring, wherein the ring is heterocyclic with 1 to 4 heteroatom(s) selected from the group consisting of N, O, and/or S, and wherein the ring is optionally modified with at least one substituent; or   (iii) A 1  and A 2  are independently a 5 to 6 membered monocyclic ring, wherein the ring is a heteroalkyl ring optionally modified with at least one substituent, or a 9 to 12 membered bicyclic ring wherein the ring is a heterocyclic ring with 1 to 4 heteroatom(s) selected from the group consisting of N, O, and S, and wherein the ring is optionally modified with at least one substituent.   
     
     
         8 - 9 . (canceled) 
     
     
         10 : The conjugate of formula (I) of  claim 1 , wherein: (i) A 1  and A 2  are independently 1,2,3-triazolyl;
 (ii) A 2  is 1,2,3-triazolyl; or   (iii) A 2  is piperazinyl.   
     
     
         11 - 12 . (canceled) 
     
     
         13 : The conjugate of formula (I) of  claim 1 , wherein: (i) r=1 and A 2  is present and o=0 and A 1  is absent; or
 (ii) r=1 and A 2  is present and o=1 and A 1  is present.   
     
     
         14 . (canceled) 
     
     
         15 : The conjugate of formula (I) of  claim 1 , wherein: (i) m=1, o=0, p=0, and q=0 or 1; or
 (ii) m=1, o=1, p=1, and q=0 or 1.   
     
     
         16 : The conjugate of formula (I) of  claim 1 , wherein: (i) A 2  is piperazinyl, L 2  is absent and A 1  is cyclohexanyl;
 (ii) A 2  is piperazinyl, L 2  is —CH 2 — and A 1  is cyclohexanyl;   (iii) A 2  is piperazinyl, L 2  is absent and A 1  is phenyl; or   (iv) A 2  is 1,2,3-triazolyl, L 2  is absent and A 1  is phenyl.   
     
     
         17 - 20 . (canceled) 
     
     
         21 : The conjugate of formula (I) of  claim 1 , wherein:
 L 3  is —CO—, A 1  is phenyl, L 2  is —O— and A 1  is phenyl, wherein the phenyl ring is unsubstituted or is modified with at least one substituent selected from the group consisting of 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, mono (C 1-4 ) alkyl carboxamide, and di (C 1-4 ) alkyl carboxamide.   
     
     
         22 : The conjugate of formula (I) of  claim 1 , wherein the group -A 2 -L 3 - is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         23 - 24 . (canceled) 
     
     
         25 : The conjugate of  claim 1 , wherein the terminal pyranose moiety S1 is of the Formula (IIIa) or (IIIb): 
       
         
           
           
               
               
           
         
         wherein:
 R1 and R2 form, together with the pyranose ring atoms to which they are bound, a cyclic group, R3 is H or a protecting group, and R4 is H, OR8, NHR8, or an attachment site in the conjugate of formula (I), wherein R8 is H or a protecting group; 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 form, together with the carbon atom to which they are bound, a carbonyl group, and R7 is OR8, NHR8, or an attachment site in the conjugate of formula (I), wherein R8 is H or a protecting group; and 
 
         wherein one of R2, R4, and R7 is the attachment site in the conjugate of formula (I). 
       
     
     
         26 - 27 . (canceled) 
     
     
         28 : The conjugate of formula (I) of  claim 25 , wherein position 6 of the pyranose moiety S1 is the attachment site in the conjugate of formula (I). 
     
     
         29 : The conjugate of formula (I) of  claim 25 , wherein the pyranose moiety S1 is of formula (IVa), (IVb), (IVc), (IVd), or (IVe): 
       
         
           
           
               
               
           
         
         wherein: 
         R1 and R2 form, together with the pyranose ring atoms to which they are bound, a cyclic group; 
         R3 is H or a protecting group; 
         R5 and R6 are H or form, together with the carbon atom to which they are bound, a carbonyl group; 
         R7 is OR8, NHR8, or an attachment site in the conjugate of formula (I), wherein R8 is H or a protecting group; 
         R4 is H, a protecting group, or an attachment site in the conjugate of formula (I); and 
         R4a is H or an attachment site in the conjugate of formula (I). 
       
     
     
         30 : The conjugate of formula (I) of  claim 25 , wherein the sugar moiety S is of Formula (V):
   —[X 2 -S2] s -X 1 -S1   (V)
   wherein X 1  is a bond or O;   X 2  is a bond, NH or O;   S2 is a mono- or disaccharide moiety; S1 is a terminal pyranose moiety having a backbone structure of Formula (IIIa) or (IIIb):   
       
         
           
           
               
               
           
         
         wherein:
 R1 and R2 form, together with the pyranose ring atoms to which they are bound, a cyclic group, R3 is H or a protecting group, and R4 is H, OR8, NHR8, or an attachment site in the conjugate of formula (I), wherein R8 is H or a protecting group; 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 form, together with the carbon atom to which they are bound, a carbonyl group, and R7 is OR8, NHR8, or an attachment site in the conjugate of formula (I), wherein R8 is H or a protecting group; and 
 
         wherein one of R2, R4, and R7 is the attachment site in the conjugate of formula (I); and 
         s is 0 or 1. 
       
     
     
         31 : The conjugate of formula (I) of  claim 30 , wherein: (i) the saccharide moiety S2 is a pyranose moiety, or
 (ii) the saccharide moiety S2 is of Formula (VIa), (VIb), (VIc), (VId), or (VIe):   
       
         
           
           
               
               
           
         
         
           wherein: 
           R11 and R12 are taken together with the ring atoms to which they are bound to form a cyclic 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, and R14a is H or an attachment site to X 2 ; or 
           R13 and R14 are taken together with the ring atoms to which they are bound to form a cyclic group, R11 is a bond to X 1 , and R12 is OR8, NHR8, or an attachment site to X 2 , wherein R8 is H or a protecting group; 
           R15 and R16 are each H or are taken together with the carbon atom to which they are bound to form a carbonyl group; and 
           R17 is OR8 or an attachment site to X 2 , wherein R8 is H or a protecting group; 
         
         wherein one of R12, R14, and R17 is an attachment site to X 2 . 
       
     
     
         32 . (canceled) 
     
     
         33 : The conjugate of formula (I) of  claim 1  wherein the conjugate has an affinity of 10-500 nM to the insulin independent glucose transporter GluT1. 
     
     
         34 : The conjugate of formula (I) of  claim 1  wherein the conjugate reversibly binds to the insulin independent glucose transporter GluT1 dependent upon the glucose concentration in the surrounding medium. 
     
     
         35 - 38 . (canceled) 
     
     
         39 : A pharmaceutical composition comprising the conjugate of formula (I) of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         40 : A method of treating a disorder caused by and/or accompanied by a dysregulated glucose metabolism that elevates glucose blood level, comprising administering the conjugate of formula (I) of  claim 1  to a subject in need. 
     
     
         41 . (canceled) 
     
     
         42 . A compound of formula (Ib)
   [L 1 ] m -[A 1 ] o -[L 2 ] p -[A 2 ] r -[L 3 ] q -S   (Ib)
   wherein L 1 , L 2 , L 3 , A 1 , A 2 , S, m, o, p, r, and q are defined as in  claim 1 , or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         43 : A method of treating diabetes type 2 or diabetes type 1, comprising administering the conjugate of formula (I) of  claim 1  to a subject in need thereof. 
     
     
         44 : A method of treating a disorder caused by and/or accompanied by a dysregulated glucose metabolism that elevates glucose blood level, comprising administering the composition of  claim 39  to a subject in need thereof. 
     
     
         45 : A method of treating diabetes type 2 or diabetes type 1, comprising administering the composition of  claim 39  to a subject in need thereof. 
     
     
         46 : The conjugate of formula (I) of  claim 25 , wherein R7 is the attachment site in the conjugate of formula (I).