Prodrugs of NH-Acidic Compounds: Ester, Carbonate, Carbamate and Phosphonate Derivatives

摘要

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.

主权项

1. A compound having the formula: or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof; wherein represents a single or double bond; X is —S— or —O—; R1 is selected from —C(O)OR20, —C(O)R20, —C(O)NR20R21, —PO3MY, —P(O)2(OR20)M and —P(O)(OR20)(OR21); wherein each R20 and R21 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; each X1, and X2 is independently selected from absent, —C(O)—, —C(OR10)(R11)—, —[C(R10)(R11)]v-, —C(R10)(R11)═C(R10)(R11)-; wherein v is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; each R10 and R11 is independently absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two R10 and R11 together with the atoms to which they are attached may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring; semicircle represents an optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl or aryl containing one, two or three rings; each F1 and F2 is independently selected from absent and R5-A-Cy1-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(R30)(R31)]u-, —S(O)[C(R30)(R31)]u-, —S(O)2[C(R30)(R31)]u-, —O[C(R30)(R31)]u-, —N(R30)—, —N(R30)[C(R31)(R32)]u-, —[C(R30)(R31)]u, —C(O)[C(R30)(R31)]u-;wherein each u is independently 1, 2, 3, 4, 5, 6 or 7;Cy1 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—, —NR33, —C(R34)(R35)-, —S—, —S(O)-, —S(O)2-, —C(O)-; each G1 and G2 is independently selected from —S—, —O—, —S(O)-, —S(O)2-, —SC(R40)(R41)—, —S(O) C(R40)(R41)-, —S(O)2C(R40)(R41)-, —C(O)-, —C(OR40)(R41)-, —OC(R40)(R41)—, —N(R40)-, —C(R40)═C(R41)-, —N(R40)—C(R41)(R42)-, —[C(R40)(R41)]U-; each R3, R4, R5, R30, R31, R32 R33, R34, R35, R40, R41, and R42 is independently selected from absent, hydrogen, halogen, —OR10, —SR10, —NR10R11—, —C(O)R10, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl; Alternatively, two R3 groups together or two R4 groups together or one R3 group with one R4 group together forms an optionally substituted ring; m and q are independently selected from 0, 1, and 2.