6-substituted estradiol derivatives for use in remyelination of nerve axons

摘要

Disclosed is a method of remyelinating axons with 6-substituted estradiol compounds of the formula;;The methods can be used to treat a variety of demyelinating diseases.

主权项

1. A method of treating demyelination and/or enhancing remyelination of an axon of a nerve cell that is need of remyelination comprising
contacting one or more progenitor cells with an effective amount of a 6-substituted estradiol derivative of the formula: initiating transcription of RNA encoding genes involved in signaling pathways for differentiation of the one or more progenitor cells to one or more cells that form myelin; differentiating the one or more progenitor cells to the one or more cells that form myelin; and enhancing remyelination of the axon of the nerve cell from the one or more cells that form myelin, wherein the “a” ring is selected from the group consisting of R1, R2, R3 and R4 are independently selected from the group consisting of H, C1-C6 alkyl, halo, a sulfate, a glucuronide, —OH, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, —N(CH2)n, a phosphate group, and a phosphinate group; R11 is selected from the group consisting of H, C1-C6 alkyl, halogen, a sulfate, a glucoronide, —SO2NH2, —COOH, —CN, —CH2CN—, —NHCN—, —CHO, ═CHOCH3, —COO salt, —OSO2alkyl, —NH2, and —NHCO(CH2)n; X is selected from the group consisting of C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, halogen, a glucoronide, —NH2, —SO2NH2, —COOH, —CN, —CH2CN, —NHCN, —CHO, —COO salt, —OSO2alkyl, —SH, —SCH3, —CH[(CH2)nCH3]COOCH3, —(CH2)mCOOCH3, —(CH2)m—O—CH3, —(CH2)m—O—(CH2)nCH3, (CH2)m—S—CH3, —(CH2)m—S—(CH2)nCH3, —(CH2)m—NH—(CH2)nCH3, —C2-C8 alkenyl-O—(CH2)nCH3, —C2-C8 alkenyl-S—(CH2)nCH3, —C2-C8 alkenyl-N—(CH2)nCH3, —C2-C8 alkynyl-O—(CH2)nCH3, —C2-C8 alkynyl-S—(CH2)nCH3, —C2-C8 alkynyl-N—(CH2)nCH3, —(CH2)m—OH, —(CH2)m—NH2, —(CH2)m—O—NH2, —(CH2)m—S—NH2, —NH(CH2)mCH3, —NH(CH2)mOCH3, —NH(CH2)mCHOH—COOH, —N(CH3)2, —(CH2)m(NH)CH2OH, —NHCOOH, —(CH2)mNHCOOH, —NO2, —SCN, —SO2alkyl, —B(OH)2, —(CH2)m N(CH3)—SO2—NH3, —(CH2)m—NH—SO2—NH2, —NHC(═S)CH3, and —NHNH2; Y is selected from the group consisting of H, ═O, —OCO(C1-C20 alkyl) and —OH; Z is selected from the group consisting of H and methyl; m is an integer between 0-20; n is an integer between 0-8; each symbol independently represents either a single or a double bond capable of forming a keto group at position 3 or 17; and the symbol represents any type of bond regardless of the stereochemistry; and the respective enantiomers, other stereochemical isomers, tautomers and pharmaceutically acceptable salts of said compounds.