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 . A prodrug conjugate of Formula I, IA or IB: 
       
         
           
           
               
               
           
         
         wherein a is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16; 
         e is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16; 
         f is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, wherein the sum of e and f is at least two; 
         each R 1  and R 2  is independently selected from hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , —N(R 20 )C(O)R 21 , —CF 3 , —CN, —NO 2 , —N 3 , acyl, optionally substituted alkoxy, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted alkylthio, optionally substituted alkylsulfonyl, optionally substituted aliphatic, optionally substituted aryl and optionally substituted heterocyclyl;
 wherein each R 20  and R 21  is independently selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl and substituted aryl; 
 
         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; 
         C1 is a carrier; 
         each API is independently a biologically active moiety. 
       
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The prodrug conjugate of  claim 1  having the formula: 
       
         
           
           
               
               
           
         
         wherein each X 1  is independently selected from S or O; 
         each X 2  is selected from absent, O, S or NR 20  wherein R 20  is selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; 
         API-1 is a biologically active moiety; 
         API-2 is a biologically active moiety. 
       
     
     
         5 . (canceled) 
     
     
         6 . The prodrug conjugate of  claim 4  having the formula: 
       
         
           
           
               
               
           
         
         wherein n is an integer between 1 and 50; 
         each R 10  and R 11  is independently selected from absent, hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , —N(R 20 )C(O)R 21 , —CF 3 , —CN, —NO 2 , —N 3 , acyl, optionally substituted alkoxy, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted alkylthio, optionally substituted alkylsulfonyl, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;
 wherein each R 20  and R 21  is independently selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; 
 
         alternatively two R 10  and R 11  together with the atoms to which they are attached may form an optionally substituted 3, 4, 5, 6 or 7 membered ring. 
       
     
     
         7 . A prodrug conjugate of  claim 6  having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         8 . A prodrug conjugate of  claim 7 , wherein API-1 is selected from Tables 1-13. 
     
     
         9 . A prodrug conjugate of  claim 7 , wherein API-2 is selected from Tables 1-13. 
     
     
         10 . A prodrug conjugate of  claim 6  having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         11 . A prodrug conjugate of  claim 10 , wherein API-1 is selected from Tables 1-13. 
     
     
         12 . A prodrug conjugate of  claim 10 , wherein API-2 is selected from Tables 1-13. 
     
     
         13 . A prodrug conjugate of  claim 6  having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         14 . A prodrug conjugate of  claim 13 , wherein API-1 is selected from Tables 1-13. 
     
     
         15 . A prodrug conjugate of  claim 13 , wherein API-2 is selected from Tables 1-13. 
     
     
         16 . A prodrug conjugate of  claim 4  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 3 or 4; and, 
         X 100  is —CH— or —N—. 
       
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . The prodrug conjugate of  claim 4  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 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . The prodrug of  claim 19 , wherein A 1 , B 1  and E 1  together with the nitrogen forms a parent drug selected from amisulpride, aripiprazole, asenapine, cariprazine, citalopram, dehydroaripiprazole, escitalopram, galantamine, iloperidone, latrepirdine, lurasidone, olanzapine, paliperidone, perospirone, risperidone, or ziprasidone. 
     
     
         23 . The prodrug of  claim 19 , wherein A 2 , B 2  and E 2  together with the nitrogen forms a parent drug selected from amisulpride, aripiprazole, asenapine, cariprazine, citalopram, dehydroaripiprazole, escitalopram, galantamine, iloperidone, latrepirdine, lurasidone, olanzapine, paliperidone, perospirone, risperidone, or ziprasidone. 
     
     
         24 . The prodrug conjugate of  claim 4  having the formula: 
       
         
           
           
               
               
           
         
         wherein A and B together with the nitrogen they are attached to form first biologically active molecule; 
         A 2 , B 2  and C 2  together with the nitrogen they are attached to form a tertiary amine containing second biologically active molecule; 
         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, 
         X— is a pharmaceutically acceptable counterion; and 
         C1 represents a carrier group. 
       
     
     
         25 . The prodrug conjugate of  claim 4  having the formula: 
       
         
           
           
               
               
           
         
         wherein D together with the oxygen it is attached to form a first biologically active molecule; D 2  together with the oxygen it is attached to form a second biologically active molecule; 
         each X 1  is independently selected from S or O; 
         each X 2  is selected from absent, O, S or NR 20  wherein R 20  is selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; and, 
         C1 is as defined above. 
       
     
     
         26 . The prodrug conjugate of  claim 4 , wherein said API-1 or API-2 is selected from Tables 1-13. 
     
     
         27 . The prodrug conjugate of  claim 1 , wherein at least one of said API from Formula I, Formula IA or Formula IB is selected from Tables 1-13. 
     
     
         28 . The prodrug conjugate of  claim 1  having the formula: 
       
         
           
           
               
               
           
         
         wherein API-1 and API-2 are as defined above; and API-3 is a biologically active moiety and is the same or different from API-1 and API-2. 
       
     
     
         29 . A compound of  claim 1  wherein C1 is selected from: 
       
         
           
           
               
               
           
         
         wherein 
         c is selected from 0, 1, 2, 3 and 4; 
         g is an integer between about 1 and about 1,000; 
         each b and d is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13; 
         s and t is independently selected from 0, 1, 2, 3, 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; 
         each R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16  is independently selected from absent, hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , —N(R 20 )C(O)R 21 , —CF 3 , —CN, —NO 2 , —N 3 , acyl, optionally substituted alkoxy, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted alkylthio, optionally substituted alkylsulfonyl, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl; 
         wherein each R 20  and R 21  is selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; 
         alternatively two R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16  together with the atoms to which they are attached form an optionally substituted 3, 4, 5, 6 or 7 membered ring. 
       
     
     
         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 - 80 . (canceled)