| Autor: |
Akram N. Saab, Kenneth B. Sloan |
| Rok vydání: |
1989 |
| Předmět: |
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| Zdroj: |
International Journal of Pharmaceutics. 57:253-261 |
| ISSN: |
0378-5173 |
| DOI: |
10.1016/0378-5173(89)90215-9 |
| Popis: |
A series of aminomethyl (N-Mannich base) derivatives of S6-pivaloyloxymethyl-6-mercaptopurine (6-POM-6-MP) have been synthesized from the reaction of 6-POM-6-MP with formaldehyde and secondary amines. In contrast to the results from the aminomethylation of 6-mercaptopurine (6-MP), which gave 7-alkylation (7-AM-6-MP), the aminomethylation of 6-POM-6-MP gave 9-alkylation (9-AM-6-POM-6-MP). The 9-AM-6-POM-6-MP derivatives were much more soluble in isopropyl myristate (IPM) than 6-POM-6-MP itself or the corresponding 7-AM-6-MP derivatives. The 9-AM-6-POM-6-MP derivatives were all more effective (2.5–4 times) than 6-POM-6-MP and were more effective (1.5–15 times) than the corresponding 7-AM-6-MP derivatives in delivering 6-MP through hairless mouse skin, except for the 9-diethylaminomethyl-6-POM-6-MP derivative which was only 0.28 times as effective as 7-diethylaminomethyl-6-MP. In contrast to the 6-POM-6-MP derivative which delivered only 6-MP, the 9-AM-6-POM-6-MP derivatives also delivered comparable amounts of 6-POM-6-MP through hairless mouse skin from isopropyl myristate (IPM). There was a fairly good correlation between the log experimental permeability coefficients for the delivery of 6-MP (r = 0.87) or for the delivery of total 6-MP (r = 0.81) and the calculated solubility parameter values for the 9-AM-6-POM-6-MP prodrugs with the permeability coefficient generally decreasing as the calculated solubility parameter value for the prodrug approached that of the vehicle IPM. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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