Multi-API Loading Prodrugs

Abstract

The present invention accomplishes this by having multiple molecules of parent drugs attached to carrier moieties and by extending the period during which the parent drug is released and absorbed after administration to the patient and providing a longer duration of action per dose than the parent drug itself. Prodrug conjugates are suitable for sustained delivery of heteroaryl, lactam-amide-, imide-, sulfonamide-, carbamate-, urea-, benzamide-, acylaniline-, cyclic amide- and tertiary amine-containing parent drugs that are substituted at the amide nitrogen or oxygen atom with labile aldehyde-linked prodrug moieties. The carrier groups of the prodrugs can be hydrophobic to reduce the polarity and solubility of the parent drug under physiological conditions.

1 - 15 . (canceled) 
     
     
         16 . A prodrug conjugate, having the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each R 50 , R 51 , R 52 , R 53 , R 54  and R 55  is independently selected from hydrogen, halogen, —OR 10 , —SR 10 , —NR 10 R 11 —, optionally substituted aliphatic, optionally substituted aryl or aryl or optionally substituted heterocyclyl; 
         alternatively, two or more R 50 , R 51 , R 52 , R 53 , R 54  and R 55  together form an optionally substituted ring; 
         each R 100 , R 101 , R 102 , and R 103  are independently selected from absent, hydrogen, halogen, —OR 10 , —SR 10 , —NR 10 R 11 —, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl; alternatively, two R 100 , and R 101  together form an optionally substituted ring; 
         h is 3or 4; 
         X 100  is —CH— or —N—; 
         C1 is a carrier moiety; and, 
         X 2  is selected from direct bond, O, S or NR 20 . 
       
     
     
         17 . A prodrug conjugate of  claim 16 , having the formula: 
       
         
           
           
               
               
           
         
         wherein n is selected from 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30. 
       
     
     
         18 . A prodrug conjugate, having the formula: 
       
         
           
           
               
               
           
         
         wherein Cy 2  is an optionally substituted heterocyclic ring; and 
         X 5  is selected from absent, —S—, —O—, —S(O)—, —S(O) 2 —, —N(R 10 )—, —C(O)—, —C(OR 10 )(R 11 )—, —[C(R 10 )(R 11 )] v —, —O[C(R 10 )(R 11 )] v —, —O[C(R 10 )(R 11 )] v O—, —S[C(R 10 )(R 11 )] v O—, —NR 12 [C(R 10 )(R 11 )] v O—, —NR 12 [C(R 10 )(R 11 )] v S—, —S[C(R 10 )(R 11 )] v —, —C(O)[C(R 10 )(R 11 )] v —, and —C(R 10 )(R 11 )═C(R 10 )(R 11 )—; wherein v is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; 
         C1 is a carrier moiety; and, 
         X 2  is selected from direct bond, O, S or NR 20 . 
       
     
     
         19 . The prodrug conjugate, having the formula: 
       
         
           
           
               
               
           
         
         wherein A 1 , B 1  and E 1  together with the nitrogen they are attached to form a tertiary amine containing first biologically active molecule; 
         A 2 , B 2  and E 2  together with the nitrogen they are attached to form a tertiary amine containing second biologically active molecule; 
         X is a pharmaceutically acceptable counterion; 
         X 1  is selected from O or S; 
         X 2  is selected from direct bond, O, S or NR 20  wherein R 20  is selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; and 
         C1 represents a carrier group. 
       
     
     
         20 - 27 . (canceled) 
     
     
         28 . The prodrug conjugate, having the formula: 
       
         
           
           
               
               
           
         
         wherein API-1 is a biologically active moiety; and API-2 is a biologically active moiety and is the same or different from API-1; and API-3 is a biologically active moiety and is the same or different from API-1 and API-2. 
       
     
     
         29 . (canceled) 
     
     
         30 . A method for sustained delivery of a parent drug to a patient comprising administering a prodrug compound of claim  1 , wherein upon administration to the patient, release of the parent drug from the prodrug is sustained. 
     
     
         31 - 33 . (canceled) 
     
     
         34 . A method of synthesizing a compound of formula I, IA or IB comprising the steps of reacting a dicarboxylic acid containing compound with thionyl chloride followed by reacting with formaldehyde or trioxane to yield chloromethyl ester which is reacted with a biologically active compound to give said compound of formula I, IA, IB. 
     
     
         35 - 80 . (canceled)