6-Hydroxyequilenins as estrogenic agents

A method of treating or inhibiting prostatic hypertrophy, uterine leiomyomas, breast cancer, endometriosis, endometrial cancer, polycystic ovary syndrome, endometrial polyps, benign breast disease, adenomyosis, ovarian cancer, melanoma, prostrate cancer, colon cancer, glioma or astioblastomia in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound of formula 1, having the structure

• 9
• wherein,
• R1 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;
• X is
• 10
• R2 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;
• R3 is hydrogen, alkyl of 1-6 carbon atoms, hydroxy, or alkoxy of 1-6 carbon atoms;
• a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a sulfate ester of the hydrdoxyl group at the 3- or 17-position when R1 or R2 is hydrogen, or a glucuronide of the hydrdoxyl group at the 3- or 17-position when R1 or R2 is hydrogen.

A method of lowering cholesterol, triglycerides, Lp(a), or LDL levels;

• inhibiting or treating hypercholesteremia;
• hyperlipidemia;
• cardiovascular disease;
• atherosclerosis;
• peripheral vascular disease;
• restenosis, or vasospasm;
• or inhibiting vascular wall damage from cellular events leading toward immune mediated vascular damage in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound of formula I, having the structure
• 11
• wherein,
• R1 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;
• X is
• 12
• R2 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;
• R3 is hydrogen, alkyl of 1-6 carbon atoms, hydroxy, or alkoxy of 1-6 carbon atoms;
• a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a sulfate ester of the hydrdoxyl group at the 3- or 17-position when R1 or R2 is hydrogen, or a glucuronide of the hydrdoxyl group at the 3- or 17-position when R1 or R2 is hydrogen.

A method of providing cognition enhancement or neuroprotection;

• or treating or inhibiting senile dementias, Alzheimer's disease, cognitive decline, stroke, anxiety, or neurodegenerative disorders in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound of formula 1, having the structure
• 13
• wherein,
• R1 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;
• X is
• 14
• R2 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;
• R3 is hydrogen, alkyl of 1-6 carbon atoms, hydroxy, or alkoxy of 1-6 carbon atoms;
• a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a sulfate ester of the hydrdoxyl group at the 3- or 17-position when R1 or R2 is hydrogen, or a glucuronide of the hydrdoxyl group at the 3- or 17-position when R1 or R2 is hydrogen.

A method of treating or inhibiting free radical induced disease states in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound of formula 1, having the structure

• 15
• wherein,
• R1 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;
• X is
• 16
• R2 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;
• R3 is hydrogen, alkyl of 1-6 carbon atoms, hydroxy, or alkoxy of 1-6 carbon atoms;
• a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a sulfate ester of the hydrdoxyl group at the 3- or 17-position when R1 or R2 is hydrogen, or a glucuronide of the hydrdoxyl group at the 3- or 17-position when R1 or R2 is hydrogen.

A method of inhibiting conception in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound of formula 1, having the structure

• 17
• wherein,
• R1 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;
• X is
• 18
• R2 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;
• R3 is hydrogen, alkyl of 1-6 carbon atoms, hydroxy, or alkoxy of 1-6 carbon atoms;
• a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a sulfate ester of the hydrdoxyl group at the 3- or 17-position when R1 or R2 is hydrogen, or a glucuronide of the hydrdoxyl group at the 3- or 17-position when R1 or R2 is hydrogen.

A method of treating or inhibiting arthritis in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound of formula 1, having the structure

• 19
• wherein,
• R1 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;
• X is
• 20
• R2 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;
• R3 is hydrogen, alkyl of 1-6 carbon atoms, hydroxy, or alkoxy of 1-6 carbon atoms;
• a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a sulfate ester of the hydrdoxyl group at the 3- or 17-position when R1 or R2 is hydrogen, or a glucuronide of the hydrdoxyl group at the 3- or 17-position when R1 or R2 is hydrogen.

A method of treating or inhibiting joint swelling or erosion;

• or treating or inhibiting joint damage secondary to arthroscopic or surgical procedures in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound of formula 1, having the structure
• 21
• wherein,
• R1 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;
• X is
• 22
• R2 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;
• R3 is hydrogen, alkyl of 1-6 carbon atoms, hydroxy, or alkoxy of 1-6 carbon atoms;
• a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a sulfate ester of the hydrdoxyl group at the 3- or 17-position when R1 or R2 is hydrogen, or a glucuronide of the hydrdoxyl group at the 3- or 17-position when R1 or R2 is hydrogen.

A method of treating or inhibiting infertility in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound of formula 1, having the structure

• 23
• wherein,
• R1 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;
• X is
• 24
• R2 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;
• R3 is hydrogen, alkyl of 1-6 carbon atoms, hydroxy, or alkoxy of 1-6 carbon atoms;
• a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a sulfate ester of the hydrdoxyl group at the 3- or 17-position when R1 or R2 is hydrogen, or a glucuronide of the hydrdoxyl group at the 3- or 17-position when R1 or R2 is hydrogen.

A method of treating or inhibiting ischemia, reperfusion injury, asthma, pleurisy, multiple sclerosis, systemic lupus erythematosis, uveitis, sepsis, hemmorhagic shock, or type II diabetes in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound of formula I, having the structure

• 25
• wherein,
• R1 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;
• X is
• 26
• R2 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;
• R3 is hydrogen, alkyl of 1-6 carbon atoms, hydroxy, or alkoxy of 1-6 carbon atoms;
• a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a sulfate ester of the hydrdoxyl group at the 3- or 17-position when R1 or R2 is hydrogen, or a glucuronide of the hydrdoxyl group at the 3- or 17-position when R1 or R2 is hydrogen.