Multi-API loading prodrugs
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, having the formula:
wherein
h is 3 or 4;
X 1 is O or S;
R 20 is selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
C1 is a carrier moiety; and
X 2 is selected from direct bond, O, S or NR 20 .
2. A prodrug conjugate having the formula:
wherein n is selected from 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 and R 11 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 or optionally substituted heterocyclyl;
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 carbocyclic or heterocyclyl ring;
X 1 is O or S; and
X 2 is selected from direct bond, O, S or NR 20 ;
wherein each R 20 and R 21 is selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl.
3. A method for sustained delivery of a parent drug selected from aripiprazole and dehydroaripiprazole to a patient comprising administering to the patient a prodrug conjugate of claim 1 , wherein upon administration to the patient, release of the parent drug from the prodrug is sustained.
4. A method for sustained delivery of a parent drug selected from aripiprazole and dehydroaripiprazole to a patient comprising administering to the patient a prodrug conjugate of claim 2 , wherein upon administration to the patient, release of the parent drug from the prodrug is sustained.
5. A prodrug conjugate according to claim 1 , selected from the group consisting of:
6. A method for sustained delivery of a parent drug selected from aripiprazole and dehydroaripiprazole to a patient comprising administering to the patient a prodrug conjugate of claim 5 , wherein upon administration to the patient, release of the parent drug from the prodrug is sustained.