2-(4-Hydroxyphenyl)benzothiophene compounds, compositions and methods for alleviating the symptoms of post-menopause syndrome

The present invention provides novel benzothiophene compounds of formula I wherein R is -H, -OH, -O(C -C alkyl), -O-CO-(C -C alkyl), -O-CO-Ar in which Ar is optionally substituted phenyl, or -O-SO -(C -C alkyl); R is -H, -OH, -O(C -C alkyl), -O-CO-(C -C alkyl), -O-CO-Ar in which Ar is optionally substituted phenyl, -O-SO -(C -C alkyl) chloro or bromo; R² is -H or -OH; n is 2 or 3; and R and R each are independently C -C alkyl, or combine to form 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-l-pyrrolidinyl, 4-morpholino, or 1-hexamethyleneimino; or a pharmaceutically acceptable salt thereof. Further provided are methods for alleviating the symptoms of post-menopausal syndrome, and inhibiting endometriosis, uterine fibrosis, and aortal smooth muscle cell proliferation. Also provided are pharmaceutical formulations with formula I compounds, optionally including estrogen or progestin. The present invention further provides a process for preparing a compound of formula Ic wherein Ra and R1a each are -OH or -OR ; R and R each are independently C -C alkyl, or combine to form 1-piperidinyl, 1-pyrrolidinyl, methoxy-1-pyrrolidinyl, dimethyl-l-pyrrolidinyl, 4-morpholino, or 1-hexamethyleneimino; and R is a hydroxy protecting group capable of resisting reduction by a strong reducing agent; or a pharmaceutically acceptable salt thereof, which comprises a) optionally removing the R hydroxy protecting groups of a compound of formula II wherein n, R , R , and R are as defined above, or a salt thereof; b) reacting said formula II compound with a reducing agent in the presence of a solvent having a boiling point in the range from about 150° C to about 200° C, and heating the mixture to reflux; and c) optionally salifying the reaction product from step b).