Methods for synthesis of prodrugs from 1-acyl-alkyl derivatives and compositions thereof

A 1-acyl-alkyl derivative comprising a compound of structural Formula (I):

• 20
• or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
• n is 0 or 1;
• q is 0 or 1;
• provided that n and q are 0 unless Y is —NRR′ or —OR;
• Y is —NRR′, —OR, —C(O)R, —P(O)(OR′)R or —P(O)(OR′)(OR), wherein:
• —NRR′ is derived from a drug containing a primary or secondary amino group, with the proviso that the drug is not norfloxacin, pamidronate or a 2-aminomethyl-3-methylthiazolo[3,2a]benzimidazole derivative;
• —OR is derived from a drug containing a hydroxyl group, with the proviso that the drug is not 1-hydroxymethyl 5-fluorouracil or a 1-aryl-6,7-dialkoxyisoquinolone phosphodiesterase inhibitor;
• —OC(O)R is derived from a drug containing a carboxylic acid or carboxylate group, with the proviso that the drug is not a 6-azauracil-5-carboxylic acid derivative;
• —OP(O)(OR′)R is derived from a drug containing a phosphonic acid or phosphonate group;
• —OP(O)(OR′)(OR) is derived from a drug containing a phosphoric acid or phosphate group, with the proviso that the drug is not cytarabine-5′-phosphate or a-tocopherol phosphate;
• R1 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or a C23 bile acid moiety or optionally, R1 and either R2 or R3, together with the atoms to which R1 and R2 or R3 are attached, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring, which is optionally fused to an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;
• R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R2 and R3 together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;
• R21 is independently hydrogen, alkyl or substituted alkyl;
• and
• R22 is independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alklysulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkylthio, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino, halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substituted heteroaryloxy or optionally, R22 together with the carbon atom to which it is attached, the adjacent nitrogen atom and R21 substituent form a cycloheteroalkyl or substituted cycloheteroalkyl ring.