Prodrugs of NH-acidic compounds
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 XV and pharmaceutically acceptable salts and solvates thereof:
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 , and R 54 together with the atoms to which they are attached form an optionally substituted ring;
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;
wherein the term “substituted” refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, heteroaryl, and aliphatic;
R 1 is selected from:
2. A compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, selected from:
or a pharmaceutically acceptable salt thereof.
3. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from:
4. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from:
5. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from:
6. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from:
7. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from:
8. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from: