Compounds and therapeutic uses thereof

Abstract

The invention relates to novel compounds with the ability to link an immune response to a defined therapeutic target, to the use of said compounds in treating cancer and a disease or disorder mediated and/or caused by an infective agent, to compositions containing said compounds, processes for their preparation and to novel intermediates used in said process.

1 .- 27 . (canceled) 
     
     
         28 . A method of treating cancer or a disease mediated by an infective agent which comprises administering to an individual in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein:
 L represents a binding moiety selected from a nucleic acid aptamer or biotin; 
 S 1  represents a spacer selected from a —(CH 2 ) a — or —(CH 2 ) b —(CH 2 —CH 2 —O) c —(CH 2 ) d — group, wherein one to five of said —CH 2 — groups may optionally be substituted by one or more groups selected from —O—, —C(O)NH—, —NHC(O)— and phenyl; 
 a represents an integer selected from 1 to 35; 
 b represents an integer selected from 0 to 5; 
 c represents an integer selected from 1 to 20; 
 d represents an integer selected from 1 to 20; 
 S 2  represents a spacer selected from a —(CH 2 ) e — or —(CH 2 ) f —(CH 2 —CH 2 —O) g —(CH 2 ) h -group, wherein one to three of said —CH 2 — groups may optionally be substituted by one or more groups selected from —N(H)—, —C(O)NH— and —NHC(O)—; 
 
         e represents an integer selected from 1 to 15; 
         f represents an integer selected from 1 to 10; 
         g represents an integer selected from 1 to 20; 
         h represents an integer selected from 1 to 5; 
         X 1  represents —O— or —NH—, such that when L represents a nucleic acid aptamer, X 1  represents —O— and when L represents biotin, X 1  represents —NH—; 
         Y 1  and Y 2  independently represent a bond, —O—, —S—, —NH—, —NHC(O)—, —C(O)NH—, —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—, —NHSO 2 —, —SONH— or —NHC(O)NH— group; 
         F represents a carbohydrate molecule capable of binding to a human anti-alpha-galactosyl antibody; 
         m represents an integer selected from 1 to 5; 
         Cy represents phenyl, biphenyl, triphenyl or a bicyclic heteroaromatic ring system, such that when Cy represents biphenyl or triphenyl, said —Y 1 —S 1 —X 1 -L group may be present on any of said phenyl rings and said [F—S 2 —Y 2 ] m — group or groups may be present on any of said phenyl rings; and 
         wherein L represents a therapeutic target binding moiety selected from a nucleic acid aptamer. 
       
     
     
         29 .- 30 . (canceled) 
     
     
         31 . The method of  claim 28 , wherein S 1  represents a spacer selected from:
 —(CH 2 ) a , wherein one to four of said —CH 2 — groups are optionally substituted by one or more groups selected from —C(O)NH— and —NHC(O)— (such as —(CH 2 ) 2 —, —CH 2 —CONH—(CH 2 ) 2 —, —CH 2 —NHCO—(CH 2 ) 4 —CONH—(CH 2 ) 2 —, —(CH 2 ) 6 —, —(CH 2 ) 5 —CONH—(CH 2 ) 5 —CONH—(CH 2 ) 6 — or —(CH 2 ) 5 —CONH—(CH 2 ) 5 —CONH—(CH 2 ) 5 —CONH—(CH 2 ) 5 —CONH— (CH 2 ) 6 —); or   —(CH 2 ) b —(CH 2 —CH 2 —O) c —(CH 2 ) d —, wherein one to five of said —CH 2 — groups are optionally substituted by one or more groups selected from —O—, —C(O)NH—, —NHC(O)— and phenyl (such as —(CH 2 ) 2 —NHCO—(CH 2 CH 2 O) 12 —(CH 2 ) 2 —, —(CH 2 ) 2 —NHCO—(CH 2 CH 2 O) 4 —(CH 2 ) 2 —NHCO—CH 2 —O-phenyl-CONH—(CH 2 ) 6 —, —(CH 2 ) 2 —NHCO—(CH 2 CH 2 O) 12 —(CH 2 ) 2 —NHCO—CH 2 —O-phenyl-CONH—(CH 2 ) 6 — or —(CH 2 CH 2 O) 4 —(CH 2 ) 2 —CONH—(CH 2 ) 2 —);   Or S 1  represents a spacer selected from:   —(CH 2 ) a , wherein two or four of said —CH 2 — groups are optionally substituted by—C(O)NH— (such as —(CH 2 ) 6 —, —(CH 2 ) 5 —CONH—(CH 2 ) 5 —CONH—(CH 2 ) 6 — or —(CH 2 ) 5 —CONH—(CH 2 ) 5 —CONH—(CH 2 ) 5 —CONH—(CH 2 ) 5 —CONH—(CH 2 ) 6 —); or   —(CH 2 ) b —(CH 2 —CH 2 —O) c —(CH 2 ) d —, wherein five of said —CH 2 — groups are optionally substituted by one or more groups selected from —O—, —C(O)NH—, —NHC(O)— and phenyl (such as —(CH 2 ) 2 —NHCO—(CH 2 CH 2 O) 4 —(CH 2 ) 2 —NHCO—CH 2 —O-phenyl-CONH—(CH 2 ) 6 — or —(CH 2 ) 2 —NHCO—(CH 2 CH 2 O) 2 —(CH 2 ) 2 —NHCO—CH 2 —O-phenyl-CONH—(CH 2 ) 6 —).   
     
     
         32 . The method of  claim 28 , wherein a represents an integer selected from: 1 to 30; or 2 to 30; or 2, 4, 6, 9, 18 or 30; or 6, 18 or 30. 
     
     
         33 . The method of  claim 28 , wherein b represents an integer selected from: 0 to 3; or 0 or 3; or 3. 
     
     
         34 . The method of  claim 28 , wherein c represents an integer selected from: 1 to 15; or 1 to 12; or 4 to 12; or 4 or 12; or 12. 
     
     
         35 . The method of  claim 28 , wherein d represents an integer selected from: 1 to 15; or 2 to 13; or 2, 5 or 13; or 13. 
     
     
         36 . The method of  claim 28 , wherein Y 1  represents a bond, —C(O)NH— or —O—; or Y 1  represents —C(O)NH—. 
     
     
         37 . The method of  claim 28 , wherein S 2  represents a spacer selected from:
 —(CH 2 ) e —, wherein one or two of said —CH 2 — groups are optionally substituted by one or two groups selected from —N(H)—, —C(O)NH— and —NHC(O)— (such as —(CH 2 ) 3 —NHCO—CH 2 —, —(CH 2 ) 3 —, —(CH 2 ) 3 —NHCO—(CH 2 ) 4 —CONH—CH 2 —, —(CH 2 ) 3 —NH—CH 2 — or —(CH 2 ) 3 —NHCO—(CH 2 ) 3 —NHCO—CH 2 —); or   —(CH 2 ) f —(CH 2 —CH 2 —O) g —(CH 2 ) h —, wherein one to three of said —CH 2 — groups are optionally substituted by one to three —NHC(O)— groups (such as —(CH 2 ) 3 —NHCO—(CH 2 CH 2 O) 4 —(CH 2 ) 2 —NHCO—CH 2 —, —(CH 2 ) 3 —NHCO—(CH 2 CH 2 O) 2 —(CH 2 ) 2 —NHCO—CH 2 — or —(CH 2 ) 3 —NHCO—(CH 2 ) 3 —NHCO—(CH 2 CH 2 O) 4 —(CH 2 ) 2 —NHCO—CH 2 —);   or S 2  represents a spacer selected from:   —(CH 2 ) e —, wherein one or two of said —CH 2 — groups are optionally substituted by one or two —NHC(O)— groups (such as —(CH 2 ) 3 —NHCO—CH 2 — or —(CH 2 ) 3 —NHCO—(CH 2 ) 3 —NHCO—CH 2 —); or   —(CH 2 ) f —(CH 2 —CH 2 —O) g —(CH 2 ) h —, wherein one to three of said —CH 2 — groups are optionally substituted by one to three —NHC(O)— groups (such as —(CH 2 ) 3 —NHCO—(CH 2 CH 2 O) 4 —(CH 2 ) 2 —NHCO—CH 2 —, —(CH 2 ) 3 —NHCO—(CH 2 CH 2 O) 2 —(CH 2 ) 2 —NHCO—CH 2 — or —(CH 2 ) 3 —NHCO—(CH 2 ) 3 —NHCO—(CH 2 CH 2 O) 4 —(CH 2 ) 2 —NHCO—CH 2 —).   
     
     
         38 . The method of  claim 28 , wherein e represents an integer selected from: 1 to 10; or 3 to 10; or 3, 5, 9 or 10; or 5 or 9. 
     
     
         39 . The method of  claim 28 , wherein f represents an integer selected from: 1 to 8; or 2 to 8; or 4 to 8; or 4 or 8. 
     
     
         40 . The method of  claim 28 , wherein g represents an integer selected from: 1 to 15; or 4 to 12; or 4 or 12; or 4. 
     
     
         41 . The method of  claim 28 , wherein h represents an integer selected from: 1 to 4; or 4. 
     
     
         42 . The method of  claim 28 , wherein: Y 2  represents a bond, —O— or —NHC(O)—; or Y 2  represents a bond or —O—; or Y 2  represents —O—. 
     
     
         43 . The method of  claim 28 , wherein m represents an integer selected from: 1 to 4; or 3 or 4; or 1 to 3; or 2 or 3; or 1 or 2; or 1. 
     
     
         44 . The method of  claim 28 , wherein Cy represents phenyl, biphenyl, triphenyl or quinolinyl; or Cy represents phenyl, biphenyl or triphenyl. 
     
     
         45 . The method of  claim 28 , wherein the compound is selected from any one of Examples 1-62. 
     
     
         46 . The method of  claim 28 , wherein F is selected from galactosyl-alpha-1,3-galactosyl-beta-1,4-N-acetylglucosamine, alpha1-3 galactobiose, alpha1-3-beta1-4-galactotriose or galilipentasaccharide. 
     
     
         47 . The method of  claim 28 , wherein the nucleic acid aptamer is: an EGFR nucleic acid aptamer; or the nucleic acid aptamer of SEQ ID NO: 1 and the compound is selected from any one of Examples 22-24 and 26-43. 
     
     
         48 . The method of  claim 28 , wherein the nucleic acid aptamer is: a group A  Streptococcus  (GAS) nucleic acid aptamer; or the nucleic acid aptamer of SEQ ID NO: 2 and the compound is selected from Example 25. 
     
     
         49 . The method of  claim 28 , wherein the nucleic acid aptamer is: a nucleic acid aptamer configured to bind to  Staphyococcus aureus  bacteria, such as protein A (SpA); or the nucleic acid aptamer of SEQ ID NO: 3 and the compound is selected from any one of Examples 44-47.