NAPHTHYL COMPOUNDS, INTERMEDIATES, PROCESSES, COMPOSITIONS, AND METHODS

摘要

THE PRESENT INVENTION PROVIDES A COMPOUND OF FORMULA I(FORMULA 1)WHEREIN@R1 IS -H, -OH, -O(C1-C4 ALKYL), -OCOC6H5, -OCO (C1-C6 ALKYL), OR -OSO2 (C4-C6 ALKYL);@R2 IS -H, -OH, -O(C1-C4 ALKYL), -OCOC6H5, -OCO(C1-C6 ALKYL OR OSO2 (C4-C6 ALKYL); @N IS 2 OR 3; AND@R3 IS 1-PIPERIDINYL, 1-PYRROLIDINYL, METHYL-1-PYRROLIDINYL, DIMETHYL-1-PYRROLIDINYL, 4-MORPHOLINO, DIMETHYLAMINO, DIETHYLAMINO, OR 1-HEXAMETHYLENEIMINO; OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF.@ALSO PROVIDED ARE INTERMEDIATE COMPOUNDS OF FORMULA IV(FORMULA 2)WHEREIN@R1A IS -H, -OH, OR -O(C1-C4 ALKYL);@R2A IS -H, -OH, OR -O(C1-C4 ALKYL);@R3 IS 1-PIPERIDINYL, 1-PYRROLIDINYL, DIMETHYLAMINO, DIETHYLAMINO, OR 1-HEXAMETHYLENEIMINO; AND@N IS 2 OR 3; OR A @OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF.@THE PRESENT INVENTION FURTHER PROVIDES PHARMACEUTICAL COMPOSITIONS CONTAINING COMPOUNDS OF FORMULA I, OPTIONALLY CONTAINING ESTROGEN OR PROGESTIN, AND THE USE OF SUCH COMPOUNDS ALONE, OR IN COMBINATION WITH ESTROGEN OR PROGESTIN, FOR ALLEVIATING THE SYMPTOMS OF POST-MENOPAUSAL SYNDROME, PARTICULARLY OSTEOPOROSIS, CARDIOVASCULAR RELATED PATHOLOGICAL CONDITIONS, AND ESTROGEN-DEPENDENT CANCER. AS USED HEREIN, THE TERM "PROGESTIN" INCLUDES COMPOUNDS HAVING PROGESTATIONAL ACTIVITY SUCH AS, FOR EXAMPLE, PROGESTERONE, NORETHYLNODREL, NONGESTREL, MEGESTROL ACETATE, NORETHINDRONE, AND THE LIKE.@THE COMPOUNDS OF THE PRESENT INVENTION ALSO ARE USEFUL FOR INHIBITING UTERINE FIBROID DISEASE AND ENDOMETRIOSIS IN WOMEN AND AORTAL SMOOTH MUSCLE CELL PROLIFERATION, PARTICULARLY RESTENOSIS, IN HUMANS.@FURTHERMORE, THE PRESENT INVENTION PROVIDES A NOVEL PROCESS FOR PREPARING COMPOUNDS OF FORMULA IA(FORMULA 3)WHEREIN@R1A IS -H, -OH, OR -O(C1-C4 ALKYL);@R2A IS -H, -OH, OR -O(C1-C4 ALKYL);@R3 IS 1-PIPERIDINYL, 1-PYRROLIDINYL, DIMETHYLAMINO, DIETHYLAMINO, OR 1-HEXAMETHYLENEIMINO; AND @N IS 2 OR 3;@OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, WHICH COMPRISES@A) REACTING A COMPOUND OF FORMULA IIID@R3 -(CH2)N-O(FORMULA 4)WHEREIN@R1B IS -H, OR -O(C1-C4 ALKYL);@R2B IS -H, OR -O(C1-C4 ALKYL); AND@R3 AND N ARE AS DEFINED ABOVE, 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;B) WHEN R1B AND/OR R2B IS -O(C1-C4 ALKYL, OPTIONALLY REMOVING THE R1B AND/OR R2B HYDROXY PROTECTING GROUPS; ANDC) OPTIONALLY SALIFYING THE REACTION PRODUCT FROM STEP A) OR B).