Prodrugs of Nh-acidic compounds
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 having the formula XIJ or formula XIIJ:
wherein,
X is —S— or —O—;
R 1 is selected from —C(R A )(R B )—OR 20 , —C(R A )(R B )—OC(O)OR 20 , —C(R A )(R B )—OC(O)R 20 , —C(R A )(R B )—OC(O)NR 20 R 21 , —(C(R A )(R B ))—OPO 3 MY, —(C(R A )(R B ))—OP(O)(OR 20 )(OR 21 ), —[C(R A )(R B )O] z —R 20 , —[C(R A )(R B )O] z —C(O)OR 20 , —[C(R A )(R B )O] z —C(O)R 20 , —[C(R A )(R B )O] z —C(O)NR 20 R 21 , —[C(R A )(R B )O] z —OPO 3 MY, —[C(R A )(R B )O] z —P(O) 2 (OR 20 )M, and —[C(R A )(R B )] z —P(O)(OR 20 )(OR 21 );
R 2 is selected from the group consisting of absent, hydrogen, halogen, —OR 10 , —SR 10 , —NR 10 R 11 —, aliphatic, aryl, and heterocyclyl;
each R 10 and R 11 is independently selected from the group consisting of absent, hydrogen, halogen, aliphatic, and aryl;
alternatively, two R 10 and R 11 together with the atoms to which they are attached and any intervening atoms may form an additional 3, 4, 5, 6 or 7 membered ring;
A is selected from the group consisting of absent, alkyl, alkenyl, alkynyl, —S—, —O—, —S(O)—, —S(O) 2 —, —S[C(R 30 )(R 31 )] u —, —S(O)[C(R 30 )(R 31 )] u —, —S(O) 2 [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 —;
each R 3 , R 4 , R 5 , R 30 , R 31 , and R 32 is independently selected from the group consisting of absent, hydrogen, halogen, —OR 10 , —SR 10 , —NR 10 R 11 —, —C(O)R 10 , aliphatic, aryl and heterocyclyl;
alternatively, two R 3 groups together or two R 4 groups together or one R 3 group with one R 4 group together forms a ring;
each R A and R B is independently selected from the group consisting of hydrogen, halogen, aliphatic, and aryl;
each R 20 and R 21 is independently selected from the group consisting of hydrogen, aliphatic, and aryl;
Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation;
r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;
m and q are independently 0, 1, or 2;
p is 0, 1, 2 or 3;
z is 2 or 3; and
u is independently 1, 2, 3, 4, 5, 6 or 7.
2. The compound of claim 1 , wherein the compound of Formula XIJ or Formula XIIJ is a compound of Formula XIK or Formula XIIK:
3. The compound of claim 1 , wherein R 5 is selected from the group consisting of
wherein
R 100 and R 101, each represent 1 to 4 substituents independently selected from the group consisting of hydrogen, halogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, and C 6 -C 8 aryl.
4. The compound of claim 1 , wherein the compound of Formula XIJ or Formula XIIJ is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.