High penetration prodrug compositions of peptides and peptide-related compounds

摘要

The invention provides compositions of novel high penetration compositions (HPC) or high penetration prodrugs (HPP) of peptides and peptide-related compounds, which are capable of crossing biological barriers with higher penetration efficiency comparing to their parent drugs. The HPPs are capable of being converted to parent drugs or drug metabolites after crossing the biological barrier and thus can render treatments for the conditions that the parent drugs or metabolites can. Additionally, the HPPs/HPCs are capable of reaching areas that parent drugs may not be able to access or to render a sufficient concentration at the target areas and therefore render novel treatments. The HPPs/HPCs can be administered to a subject through various administration routes, e.g., locally delivered to an action site of a condition with a high concentration or systematically administered to a biological subject and enter the general circulation with a faster rate.

主权项

1. A compound comprising a structure selected from the group consisting of including stereoisomers and pharmaceutically acceptable salts thereof, wherein: R is selected from the group consisting of H, substituted alkyl, unsubstituted alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted heterocycloalkyl, unsubstituted heterocycloalkyl, substituted alkoxyl, unsubstituted alkoxyl, substituted alkylthio, unsubstituted alkylthio, substituted alkylamino, unsubstituted alkylamino, substituted aryl, unsubstituted aryl, substituted heteroaryl, and unsubstituted heteroaryl residues; X, X4, X5, X6, X7, X8, X9, X10, X21, X22, X23, X24, X25, X26, and X27 are independently selected from the group consisting of C═O, C═S, CSO, COO, CH2OCO, COOCH2OCO, COCH2OCO, CH2—O—CH(CH2OR4)2, CH2—O—CH(CH2OCOR4)2, SO2, PO(OR), NO, O, S, NR5, and a bond; R1, R2, R4, R5, R6, R7, R8, R9, R10, R21, R22, R23, R24, R25, R26, and R27 are independently selected from the group consisting of H, O, NO2, substituted alkyl, unsubstituted alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted heterocycloalkyl, unsubstituted heterocycloalkyl, substituted alkoxyl, unsubstituted alkoxyl, substituted alkylthio, unsubstituted alkylthio, substituted alkylamino, unsubstituted alkylamino, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, and unsubstituted heteroaryl residues; Ar is selected from the group consisting of phenyl, 2′-naphthyl, 4-iodophenyl, substituted aryl, unsubstituted aryl, and substituted heteroaryl, and unsubstituted heteroaryl residues; and HA is selected from the group consisting of, hydrochloride, hydrobromide, hydroiodide, nitric acid sulfic acid, bisulfic acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisinic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid and pamoic acid; and the compound has only one or two amino groups and does not have a functional group selected from the group consisting of carboxylic, hydroxyl, and thio groups.