Prodrugs of NH-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives
View Patent ↗The invention provides a method of sustained delivery of a lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug by administering to a patient an effective amount of a prodrug compound of the invention wherein upon administration to the patient, release of the parent drug from the prodrug is sustained release. Prodrug compounds suitable for use in the methods of the invention are labile conjugates of parent drugs that are derivatized through carbonyl linked prodrug moieties. The prodrug compounds of the invention can be used to treat any condition for which the lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug is useful as a treatment.
1. A compound of Formula XVII, XVIII or XIX:
or a pharmaceutically acceptable salt thereof;
wherein R 1 is selected from —C(O)O—CH 2 —OC(O)R 21 or —C(O)NH-CH 2 —OC(O)R 21 , —C(O)O—CH 2 —OC(O)N(R 21 ) 2 , —PO 3 MY, —P(O) 2 (OR 20 )M and —P(O)(OR 20 )(OR 21 );
wherein each R 20 and R 21 is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation;
F 1 is R 5 -A-Cy 1 —B-D-;
wherein, A is selected from absent, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, —S—, —O—, —S(O)—, —S(O) 2 —, —S[C(R 30 )(R 31 )] u —, —S(O)[C(R 30 )(R 31 )] u—, —(O)[C(R 30 )(R 31 )] u —, —N(R 30 )—, —N(R 30 )[C(R 31 )(R 32 )] u —, —[C(R 30 )(R 31 )] u —C(O)[C(R 30 )(R 31 )] u —;
wherein each u is independently 1, 2, 3, 4, 5, 6 or 7;
Cy 1 is absent or an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
B is absent, or a linker;
D is selected from absent, —O—, —NR 33 , —C(R 34 )(R 35 )—, —S—S(O)—S(O) 2 —, —C(O)—;
each R 5 , R 30 , R 31 , R 32 R 33 , R 34 , and R 35 is independently selected from absent, hydrogen, halogen, —OR 10 , —SR 10 , —NR 10 R 11 —, —C(O)R 10 , optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;
wherein each R 10 and R 11 is independently absent, 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 additional optionally substituted, 3, 4, 5, 6 or 7 membered ring; and,
each u is independently 1, 2, 3, 4, 5, 6 or 7.
2. A compound having the formula XX, XXI or XXII, or a pharmaceutically acceptable salt thereof:
Wherein R 1 is selected from —C(O)OR 20 , —C(O)R 20 , —C(O)NR 20 R 21 , —PO 3 MY, —P(O) 2 (OR 20 )M and —P(O)(OR 20 )(OR 21 );
wherein each R 20 and R 21 is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation;
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—,—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; and,
wherein each R 10 and R 11 is independently absent, 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 additional optionally substituted, 3 , 4 , 5 , 6 or 7 membered ring.
3. A compound having the Formula XXIV, XXV or XXVI, or a pharmaceutically acceptable salt thereof:
wherein R 1 is selected from —C(O)RO 20 , —C(O)R 20 , —C(O)NR 20 R 21 , —PO 3 MY, —P(O) 2 (OR 20 )M and —P(O)(OR 20 )(OR 21 );
wherein each R 20 and R 21 is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation.
4. A compound of claim 3 , wherein R 1 is selected from
Table 1 , or a pharmaceutically acceptable salt thereof;
TABLE 1
5. A compound having the Formula XXVII, XXVIII or XXIX:
wherein R 1 is selected from —C(O)OR 20 , —C(O)R 20 , —C(O)NR 20 R 21 , —PO 3 MY, —P(O) 2 (OR 20 )M and —P(O)(OR 20 )(OR 21 ), or a pharmaceutically acceptable salt thereof.
6. A compound of claim 5 , wherein R 1 is selected from Table 1 , or a pharmaceutically acceptable salt thereof;
TABLE 1
7. A compound of claim 1 having the Formula XXX, XXXI or XXXII:
wherein R 1 is selected from —C(O)OR 20 , —C(O)R 20 , —C(O)NR 20 R 21 , —Po 3 MY, —P(O) 2 (OR 20 )M and —P(O)(OR 20 )(OR 21 ), or a pharmaceutically acceptable salt thereof.
8. A compound of claim 7 , wherein R 1 is selected from Table 1 , or a pharmaceutically acceptable salt thereof;
9. A compound of claim 1 , wherein said R 1 is —C(O)O—CH 2 —OC(O)R 21 ;
wherein each R 20 and R 21 is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl and substituted aryl.
10. A compound of claim 1 , wherein said R 1 is —C(O)NH—CH 2 —OC(O)R 21 ;
wherein each R 20 and R 21 is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl and substituted aryl.
11. A compound of claim 1 , wherein said R 1 is —C(O)O—CH 2 —OC(O)N(R 21 ) 2 ;
wherein each R 20 and R 21 is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl and substituted aryl.
12. A compound of Table H or a pharmaceutically acceptable salt thereof:
TABLE H
No.
Structure
1000.
1001.
1002.
1003.
1004.
1005.
1006.
1007.
1008.
1009.
1010.
1011.
1012.
1013.
1014.
1015.
1016.
1017.
1018.
1019.
1020.
1021.
1022.
1023.
1024.
1025.
1026.
1027.
1028.
1029.
1030.
1031.
1032.
1033.
1034.
1035.
1036.
1037.
1038.
1039.
1040.
1041.