| 摘要 |
The novel positively charged pro-drugs of retinoids and retinoid-like com pounds in the general formula (31) 'Structure 31' were designed and synthesi zed. The compounds of the general formula (31) 'Structure 31' indicated abov e can be prepared from retinoic acids and related compounds, by reaction wit h suitable alcohols, thiols, or amines and coupling reagents, such as N, N'- Dicyclohexylcarbodiimide, N,N'-Diisopropylcarbodiimide, O- (Benzotriazol-1-y l)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O- (Benzotriazol-1-yl)-N, N,N',N'-tetramethyluronium hexafluorophosphate, Benzotriazol- 1-yl-oxy-tris( dimethylamino)phosphonium hexafluorophosphate, et al. The positively charged amino groups of these pro-drugs not only largely increases the solubility o f the drugs in water, but also bonds to the negative charge on the phosphate head group of membranes. This bonding will disturb the membrane a little bi t and may make some room for the lipophilic portion of the prodrug. When the molecules of membrane move, the membrane may 'crack' a little bit due to th e bonding of the prodrug. This will let the prodrug insert into the membrane . At pH 7.4, only about 99% of amino group is protonated. When the amino gro up is not protonated, the bonding between the amino group of the prodrug and the phosphate head group of membrane will disassociate, and the prodrug wil l enter the membrane completely. When the amino group of the prodrug flips t o the other side of the membrane and thus become protonated, then the prodru g is pulled into the cytosol, a semi-liquid concentrated aqueous solution or suspension. The results suggest that the pro-drugs diffuse through human sk in -350 times faster than do retinoids and retinoid-like compounds. In plasm a, more than 90% of these pro-drugs can change back to the parent drugs in a few minutes. The prodrugs can be used medicinally in treating any retinoids and retinoid-like compounds-treatable conditions in humans or animals. The prodrugs can be administered transdermally for any kind of medical treatment s and avoid most of the side effects of retinoids and retinoid-like compound s. Controlled transdermal administration systems of the prodrug enables reti noids and retinoid-like compounds to reach constantly optimal therapeutic bl ood levels to increase effectiveness and reduce the side effects of retinoid s and retinoid-like compounds. Another great benefit of transdermal administ ration of these pro-drugs is that administering medication, especially to ch ildren, will be much easier. |
