Positively charged water-soluble prodrugs of prostaglandins and related compounds with very high skin penetration rates

Abstract

The novel positively charged pro-drugs of prostaglandins, prostacyclins and related compounds in the general formula (2) 'Structure 2' were designed and synthesized. The compounds of the general formula (2) 'Structure 2' indicated above can be prepared from protected prostaglandins, prostacyclins, and related compounds, by reaction with suitable alcohols, thiols, or amines and coupling reagents, such as N, N'-Dicyclohexylcarbodiimide, N, N'-Diisopropylcarbodiimide, O-(Benzotriazol-1-yl)-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 of the drugs in water, but also bonds to the negative charge on the phosphate head group of membranes and pushes the pro-drug into the cytosol. The results suggest that the pro-drugs diffuse through human skin 1000 times faster than do prostaglandins, prostacyclins, and related compounds. In plasma, 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 prostaglandins, prostacyclins, and related compounds-treatable conditions in humans or animals. The prodrugs can be administered transdermally for any kind of medical treatments and avoid most of the side effects of prostaglandins, prostacyclins, and related compounds. Controlled transdermal administration systems of the prodrug enable prostaglandins, prostacyclins, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of prostaglandins, prostacyclins, and related compounds. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.

Description

technical field [0001] The present invention relates to positively charged water-soluble prodrugs of prostaglandins, prostacyclins and related compounds and their use in the treatment of any prostaglandin, prostacyclin and related compounds treatable state in humans or animals. Specifically, the present invention is directed to the rapid penetration of the skin by prostaglandins, prostacyclins and related compounds. Background technique [0002] Natural prostaglandins and prostacyclins are eicosanoid-like compounds that are self-active substances derived from biomembrane phospholipids. They can be found almost anywhere on the body. The basic structure of prostaglandins is shown in structural formula 1. [0003] [0004] Structural Formula 1 [0005] All natural prostaglandins have a 15α-hydroxyl group and a C-13 trans double bond (William O. Foye, et al. Principles of Medicinal Chemistry, fourth edition, Williams & Wilkins, 1995, pg 538). Chains containing carboxyl gr...

AI Technical Summary

Problems solved by technology

Prostaglandins, when administered by injection, are painful and in many cases require frequent and expensive doctor visits to treat chronic disease states, and most prostaglandins, prostacyclins and related compounds do not reach their intended site of action Destroyed and inactivated in the blood and liver

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