Phenyl quinolines and their use as estrogenic agents

A method of inhibiting osteoporosis in a mammal in need thereof, comprising providing to said mammal an effective amount of a compound of the formula:

• wherein:
• A and A′ are each, independently, OH or OP;
• P is alkyl, alkenyl, benzyl, acyl, aroyl, alkoxycarbonyl, sulfonyl or phosphoryl;
• R1 and R2 are each, independently, H, halogen, C1-C6 alkyl, C2-C7 alkenyl, or C1-C6 alkoxy;
• R3 is H, halogen, or C1-C6 alkyl;
• R4, R5 and R6 are each, independently, H, halogen, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, C1-C6 alkoxy, —CN, —CHO, acyl, phenyl, aryl or heteroaryl;
• wherein the alkyl or alkenyl moieties of R4, R5 or R6 may be optionally substituted with halogen, OH, —CN, trifluroalkyl, trifluoroalkoxy, —NO2, or phenyl;
• wherein the alkynyl moiety of R4, R5 or R6 may be optionally substituted with halogen, —CN, —CHO, acyl, trifluroalkyl, trialkylsilyl, or optionally substituted phenyl;
• wherein the phenyl moiety of R4, R5 or R6 may be optionally mono-, di-, or tri-subsitituted with halogen, C1-C6 alkyl, C2-C7 alkenyl, OH, C—C6 alkoxy, —CN, —CHO, NO2, amino, C1-C6 alkylamino, di-(C1-C6)alkylamino, thiol, or C1-C6 alkylthio;
• or a N-oxide thereof or a pharmaceutically acceptable salt thereof or a prodrug thereof.

A method of inhibiting osteoarthritis, hypocalcemia, hypercalcemia, Paget's disease, osteomalacia, osteohalisteresis, multiple myeloma or other forms of cancer having deleterious effects on bone tissues in a mammal in need thereof, comprising providing to said mammal an effective amount of a compound of the formula:

• wherein:
• A and A′ are each, independently, OH or OP;
• P is alkyl, alkenyl, benzyl, acyl, aroyl, alkoxycarbonyl, sulfonyl or phosphoryl;
• R1 and R2 are each, independently, H, halogen, C1-C6 alkyl, C2-C7 alkenyl, or C1-C6 alkoxy;
• R3 is H, halogen, or C1-C6 alkyl;
• R4, R5 and R6 are each, independently, H, halogen, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, C1-C6 alkoxy, —CN, —CHO, acyl, phenyl, aryl or heteroaryl;
• wherein the alkyl or alkenyl moieties of R4, R5 or R6 may be optionally substituted with halogen, OH, —CN, trifluroalkyl, trifluoroalkoxy, —NO2, or phenyl;
• wherein the alkynyl moiety of R4, R5 or R6 may be optionally substituted with halogen, —CN, —CHO, acyl, trifluroalkyl, trialkylsilyl, or optionally substituted phenyl;
• wherein the phenyl moiety of R4, R5 or R6 may be optionally mono-, di-, or tri-subsitituted with halogen, C1-C6 alkyl, C2-C7 alkenyl, OH, C1-C6 alkoxy, —CN, —CHO, NO2, amino, C1-C6 alkylamino, di-(C1-C6)alkylamino, thiol, or C1-C6 alkylthio;
• or a N-oxide thereof or a pharmaceutically acceptable salt thereof or a prodrug thereof.

A method of inhibiting benign or malignant abnormal tissue growth in a mammal in need thereof, comprising providing to said mammal an effective amount of a compound of the formula:

• wherein:
• A and A′ are each, independently, OH or OP;
• P is alkyl, alkenyl, benzyl, acyl, aroyl, alkoxycarbonyl, sulfonyl or phosphoryl;
• R1 and R2 are each, independently, H, halogen, C1-C6 alkyl, C2-C7 alkenyl, or C1-C6 alkoxy;
• R3 is H, halogen, or C1-C6 alkyl;
• R4, R5 and R6 are each, independently, H, halogen, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, C1-C6 alkoxy, —CN, —CHO, acyl, phenyl, aryl or heteroaryl;
• wherein the alkyl or alkenyl moieties of R4, R5 or R6 may be optionally substituted with halogen, OH, —CN, trifluroalkyl, trifluoroalkoxy, —NO2, or phenyl;
• wherein the alkynyl moiety of R4, R5 or R6 may be optionally substituted with halogen, —CN, —CHO, acyl, trifluroalkyl, trialkylsilyl, or optionally substituted phenyl;
• wherein the phenyl moiety of R4, R5 or R6 may be optionally mono-, di-, or tri-subsitituted with halogen, C1-C6 alkyl, C2-C7 alkenyl, OH, C1-C6 alkoxy, —CN, —CHO, —NO2, amino, C1-C6 alkylamino, di-(C1-C6)alkylamino, thiol, or C1-C6 alkylthio;
• or a N-oxide thereof or a pharmaceutically acceptable salt thereof or a prodrug thereof.

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

• or inhibiting 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, comprising providing to said mammal an effective amount of a compound of the formula:
• wherein:
• A and A′ are each, independently, OH or OP;
• P is alkyl, alkenyl, benzyl, acyl, aroyl, alkoxycarbonyl, sulfonyl or phosphoryl;
• R1 and R2 are each, independently, H, halogen, C1-C6 alkyl, C2-C7 alkenyl, or C1-C6 alkoxy;
• R3 is H, halogen, or C1-C6 alkyl;
• R4, R5 and R6 are each, independently, H, halogen, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, C1-C6 alkoxy, —CN, —CHO, acyl, phenyl, aryl or heteroaryl;
• wherein the alkyl or alkenyl moieties of R4, R5 or R6 may be optionally substituted with halogen, OH, —CN, trifluroalkyl, trifluoroalkoxy, —NO2, or phenyl;
• wherein the alkynyl moiety of R4, R5 or R6 may be optionally substituted with halogen, —CN, —CHO, acyl, trifluroalkyl, trialkylsilyl, or optionally substituted phenyl;
• wherein the phenyl moiety of R4, R5 or R6 may be optionally mono-, di-, or tri-subsitituted with halogen, C1-C6 alkyl, C2-C7 alkenyl, OH, C1-C6 alkoxy, —CN, —CHO, NO2, amino, C1-C6 alkylamino, di-(C1-C6)alkylamino, thiol, or C1-C6 alkylthio;
• or a N-oxide thereof or a pharmaceutically acceptable salt thereof or a prodrug thereof.

A method of inhibiting free radical induced disease states in a mammal in need thereof, comprising providing to said mammal an effective amount of a compound of the formula:

• wherein:
• A and A′ are each, independently, OH or OP;
• P is alkyl, alkenyl, benzyl, acyl, aroyl, alkoxycarbonyl, sulfonyl or phosphoryl;
• R1 and R2 are each, independently, H, halogen, C1-C6 alkyl, C2-C7 alkenyl, or C1-C6 alkoxy;
• R3 is H, halogen, or C1-C6 alkyl;
• R4, R5 and R6 are each, independently, H, halogen, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, C1-C6 alkoxy, —CN, —CHO, acyl, phenyl, aryl or heteroaryl;
• wherein the alkyl or alkenyl moieties of R4, R5 or R6 may be optionally substituted with halogen, OH, —CN, trifluroalkyl, trifluoroalkoxy, —NO2, or phenyl;
• wherein the alkynyl moiety of R4, R5 or R6 may be optionally substituted with halogen, —CN, —CHO, acyl, trifluroalkyl, trialkylsilyl, or optionally substituted phenyl;
• wherein the phenyl moiety of R4, R5 or R6 may be optionally mono-, di-, or tri-subsitituted with halogen, C1-C6 alkyl, C2-C7 alkenyl, OH, C1-C6 alkoxy, —CN, —CHO, NO2, amino, C1-C6 alkylamino, di-(C1-C6)alkylamino, thiol, or C1-C6 alkylthio;
• or a N-oxide thereof or a pharmaceutically acceptable salt thereof or a prodrug thereof.

A method of providing cognition enhancement or neuroprotection;

• or treating or inhibiting senile dementias, Alzheimer's disease, congnitive decline, or neurodegenerative disorders in a mammal in need thereof, comprising providing to said mammal an effective amount of a compound of the formula:
• wherein:
• A and A′ are each, independently, OH or OP;
• P is alkyl, alkenyl, benzyl, acyl, aroyl, alkoxycarbonyl, sulfonyl or phosphoryl;
• R1 and R2 are each, independently, H, halogen, C1-C6 alkyl, C2-C7 alkenyl, or C1-C6 alkoxy;
• R3 is H, halogen, or C1-C6 alkyl;
• R4, R5 and R6 are each, independently, H, halogen, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, C1-C6 alkoxy, —CN, —CHO, acyl, phenyl, aryl or heteroaryl;
• wherein the alkyl or alkenyl moieties of R4, R5 or R6 may be optionally substituted with halogen, OH, —CN, trifluroalkyl, trifluoroalkoxy, —NO2, or phenyl;
• wherein the alkynyl moiety of R4, R5 or R6 may be optionally substituted with halogen, —CN, —CHO, acyl, trifluroalkyl, trialkylsilyl, or optionally substituted phenyl;
• wherein the phenyl moiety of R4, R5 or R6 may be optionally mono-, di-, or tri-subsitituted with halogen, C1-C6 alkyl, C2-C7 alkenyl, OH, C1-C6 alkoxy, —CN, —CHO, —NO2, amino, C1-C6 alkylamino, di-(C1-C6)alkylamino, thiol, or C1-C6 alkylthio;
• or a N-oxide thereof or a pharmaceutically acceptable salt thereof or a prodrug thereof.

A method of inhibiting inflammatory bowel disease, ulcerative proctitis, Crohn's disease, colitis, hot flashes, vaginal or vulvar atrophy, atrophic vaginitis, vaginal dryness, pruritus, dyspareunia, dysuria, frequent urination, urinary incontinence, urinary tract infections, vasomotor symptoms;

• male pattern baldness;
• skin atrophy;
• acne;
• type II diabetes;
• dysfunctional uterine bleeding;
• or infertility in a mammal in need thereof, comprising providing to said mammal an effective amount of a compound of the formula:
• wherein:
• A and A′ are each, independently, OH or OP;
• P is alkyl, alkenyl, benzyl, acyl, aroyl, alkoxycarbonyl, sulfonyl or phosphoryl;
• R1 and R2 are each, independently, H, halogen, C1-C6 alkyl, C2-C7 alkenyl, or C1-C6 alkoxy;
• R3 is H, halogen, or C1-C6 alkyl;
• R4, R5 and R6 are each, independently, H, halogen, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, C1-C6 alkoxy, —CN, —CHO, acyl, phenyl, aryl or heteroaryl;
• wherein the alkyl or alkenyl moieties of R4, R5 or R6 may be optionally substituted with halogen, OH, —CN, trifluroalkyl, trifluoroalkoxy, —NO2, or phenyl;
• wherein the alkynyl moiety of R4, R5 or R6 may be optionally substituted with halogen, —CN, —CHO, acyl, trifluroalkyl, trialkylsilyl, or optionally substituted phenyl;
• wherein the phenyl moiety of R4, R5 or R6 may be optionally mono-, di-, or tri-subsitituted with halogen, C1-C6 alkyl, C2-C7 alkenyl, OH, C1-C6 alkoxy, —CN, —CHO, NO2, amino, C1-C6 alkylamino, di-(C1-C6)alkylamino, thiol, or C1-C6 alkylthio;
• or a N-oxide thereof or a pharmaceutically acceptable salt thereof or a prodrug thereof.

A method of inhibiting leukemia, endometrial ablations, chronic renal or hepatic disease or coagulation diseases or disorders in a mammal in need thereof, comprising providing to said mammal an effective amount of a compound of the formula:

• wherein:
• A and A′ are each, independently, OH or OP;
• P is alkyl, alkenyl, benzyl, acyl, aroyl, alkoxycarbonyl, sulfonyl or phosphoryl;
• R1 and R2 are each, independently, H, halogen, C1-C6 alkyl, C2-C7 alkenyl, or C1-C6 alkoxy;
• R3 is H, halogen, or C1-C6 alkyl;
• R4, R5 and R6 are each, independently, H, halogen, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, C1-C6 alkoxy, —CN, —CHO, acyl, phenyl, aryl or heteroaryl;
• wherein the alkyl or alkenyl moieties of R4, R5 or R6 may be optionally substituted with halogen, OH, —CN, trifluroalkyl, trifluoroalkoxy, —NO2, or phenyl;
• wherein the alkynyl moiety of R4, R5 or R6 may be optionally substituted with halogen, —CN, —CHO, acyl, trifluroalkyl, trialkylsilyl, or optionally substituted phenyl;
• wherein the phenyl moiety of R4, R5 or R6 may be optionally mono-, di-, or tri-subsitituted with halogen, C1-C6 alkyl, C2-C7 alkenyl, OH, C1-C6 alkoxy, —CN, —CHO, NO2, amino, C1-C6 alkylamino, di-(C1-C6)alkylamino, thiol, or C1-C6 alkylthio;
• or a N-oxide thereof or a pharmaceutically acceptable salt thereof or a prodrug thereof.