Substituted 2-phenyl benzofurans as estrogenic agents

A compound which is

• a) 2-Hydroxy-3-iodo-5-methoxy-benzaldehyde;
• b) 5-Methoxy-2-(4-methoxy-phenyl)-benzofuran-7-carbaldehyde;
• c) [5-Methoxy-2-(4-methoxy-phenyl)-benzofuran-7-yl]-methanol;
• d) 7-Bromomethyl-2-(4-hydroxy-phenyl)-benzofuran-5-ol;
• e) 2-(4-Hydroxy-phenyl)-7-methoxymethyl-benzofuran-5-ol;
• f) 7-Ethoxymethyl-2-(4-hydroxy-phenyl)-benzofuran-5-ol;
• g) 2-(4-Hydroxy-phenyl)-7-isopropoxymethyl benzofuran-5-ol;
• h) 2-(4-Hydroxy-phenyl)-7-methyl-benzofuran-5-ol;
• i) 2-(4-Hydroxy-phenyl)-7-methylsulfanylmethyl-benzofuran-5-ol;
• j) 7-Ethylsulfanylmethyl-2-(4-hydroxy-phenyl)-benzofuran-5-ol;
• k) 2-(4-Hydroxy-phenyl)-7-phenylsulfanylmethyl-benzofuran-5-ol;
• l) 2-(4-Hydroxy-phenyl)-7-methanesulfinylmethyl-benzofuran-5-ol;
• m) 2-(4-Hydroxy-phenyl)-7-methanesulfonylmethyl-benzofuran-5-ol;
• n) 2-(4-Hydroxy-phenyl)-7-thiocyanatomethyl-benzofuran-5-ol;
• o) 2-(4-Hydroxy-phenyl)-7-imidazol-1-ylmethyl-benzofu ran-5-ol;
• p) 7-Bromomethyl-5-methoxy-2-(4-methoxy-phenyl)-benzofu ran;
• q) 5-Methoxy-2-(4-methoxy-phenyl)-benzofuran-7-carboxylic acid;
• r) 5-Hydroxy-2-(4-hydroxy-phenyl)-benzofuran-7-carboxylic acid;
• s) 7-Hydroxymethyl-2-(4-hydroxy-phenyl)-benzofuran-5-ol;
• t) 5-Methoxy-2-(4-methoxy-phenyl)-benzofuran-7-carbaldehyde oxime;
• u) 5-Methoxy-2-(4-methoxy-phenyl)-7-vinyl-benzofuran;
• v) 7-Ethyl-5-methoxy-2-(4-methoxy-phenyl)-benzofuran;
• w) 7-Ethyl-2-(4-hydroxy-phenyl)-benzofuran-5-ol;
• x) 7-(2,2-Dichloro-vinyl)-5-methoxy-2-(4-methoxy-phenyl)-benzofuran;
• y) 7-(2,2-Dichloro-vinyl)-5-hydroxy-2-(4-hydroxy-phenyl)-benzofuran-5-ol;
• Z) 5-Methoxy-2-(4-methoxy-phenyl)-7-propenyl-benzofuran;
• aa) 5-Methoxy-2-(4-methoxy-phenyl)-7-propyl-benzofuran;
• bb) 2-(4-Hydroxy-phenyl)-7-propyl-benzofuran-5-ol;
• cc) 5-Hydroxy-2-(4-hydroxy-phenyl)-benzofuran-7-carboxylic acid isopropyl ester;
• dd) 5-Hydroxy-2-(4-hydroxy-phenyl)-benzofuran-7-carboxylic acid propyl ester;
• ee) 5-Hydroxy-2-(4-hydroxy-phenyl)-benzofuran-7-carboxylic acid ethyl ester;
• ff) 2-(3-Fluoro-4-methoxy-phenyl)-5-methoxy-benzofuran-7-carboxylic acid methyl ester;
• gg) [2-(3-Fluoro-4-methoxy-phenyl)-5-methoxy-benzofuran-7-yl]-methanol;
• hh) 7-Bromomethyl-2-(3-fluoro-4-hydroxy-phenyl)-benzofuran-5-ol;
• ii) 2-(3-Fluoro-4-methoxy-phenyl)-5-methoxy-benzofuran-7-carboxylic acid;
• jj) 2-(3-Fluoro-4-methoxy-phenyl)-5-methoxy-benzofuran-7-carboxylic acid methoxy-methyl-amide;
• kk) 2-(3-Fluoro-4-methoxy-phenyl)-5-methoxy-benzofuran-7-carbaldehyde;
• ll) 2-(3-Fluoro-4-methoxy-phenyl)-5-methoxy-benzofuran-7-carbaldehyde oxime;
• mm) 2-(3-Fluoro-4-hydroxy-phenyl)-5-hydroxy-benzofuran-7-carbonitrile;
• nn) 2-(3-Fluoro-4-hydroxy-phenyl)-7-methyl-benzofuran-5-ol;
• oo) 3-Bromo-2-hydroxy-5-methoxy-benzaldehyde;
• pp) 3-Bromo-2,5-dimethoxy-benzaldehyde;
• qq) (3-Bromo-2,5-dimethoxy-phenyl)-methanol;
• rr) 1-Bromo-3-chloromethyl-2,5-dimethoxy-benzene;
• ss) (3-Bromo-2,5-dimethoxy-phenyl)-acetonitrile;
• tt) (3-Bromo-2,5-dimethoxy-phenyl)-acetic acid;
• uu) 2-(3-Bromo-2,5-dimethoxy-phenyl)-1-(4-methoxy-phenyl)-ethanone;
• vv) 7-Chloro-2-(4-hydroxy-phenyl)-benzofuran-5-ol;
• ww) 7-Bromo-2-(4-hydroxy-phenyl)-benzofuran-5-ol;
• xx) 3-[5-Hydroxy-2-(4-hydroxy-phenyl)benzofuran-7-yl]-acrylic acid methyl ester;
• yy) 3-[5-Hydroxy-2-(4-hydroxy-phenyl)-benzofuran-7-yl]-propionic acid methyl ester;
• zz) 3-[5-Hydroxy-2-(4-hydroxyphenyl)-benzofuran-7-yl]-acrylamide;
• aaa) 4,7-Dibromo-2-(4-hydroxy-phenyl)-benzofuran-5-ol;
• bbb) 3-[5-Hydroxy-2-(4-hydroxy-phenyl)-benzofuran-7-yl]-acrylonitrile;
• ccc) 7-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-2-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-benzofuran;
• ddd) 2-(4-Hydroxy-phenyl)-7-vinyl-benzofuran-5-ol;
• eee) 5-Hydroxy-2-(4-hydroxy-phenyl)-7-methoxy-benzofuran-4-carbaldehyde oxime;
• fff) 2-(2,5-Dimethoxy-phenyl)-1-(4-methoxy-phenyl)-ethanone;
• ggg) 2-(4-Hydroxy-phenyl)-benzofuran-5-ol;
• hhh) 2-(2,5-Dimethoxy-phenyl)-1-(2-fluoro-4-methoxy-phenyl)-ethanone;
• iii) 2-(2-Fluoro-4-hydroxy-phenyl)-benzofuran-5-ol;
• iii) 5-OMe-Benzofuran 2-boronic acid;
• kkk) 4-(5-Methoxy-benzofuran-2-yl)-3-methyl-phenol;
• lll) 2-(4-Hydroxy-2-methyl-phenyl)-benzofuran-5-ol;
• mmm) 5-Bromo-2-(4-methoxy-phenyl)-benzofuran;
• nnn) 5-Chloro-2-(4-methoxy-phenyl)-benzofuran;
• ooo) 5-Fluoro-2-(4-methoxy-phenyl)-benzofuran;
• ppp) 5-tert-Butyl-2-(4-methoxy-phenyl)-benzofuran;
• qqq) 5,7-Dichloro-2-(4-methoxy-phenyl)-benzofuran;
• rrr) 5,7-Difluoro-2-(4-methoxy-phenyl)-benzofuran;
• sss) 5,7-Dibromo-2-(4-methoxy-phenyl)-benzofuran;
• ttt) 2-(4-Methoxy-phenyl)-5-trifluoromethyl-benzofuran;
• uuu) 4-(5-Bromo-benzofuran-2-yl)-phenol;
• vvv) 4-(5-Chloro-benzofuran-2-yl)-phenol;
• www) 4-(5-Fluoro-benzofuran-2-yl)-phenol;
• xxx) 4-(5-tert-Butyl-benzofuran-2-yl)-phenol;
• yyy) 4-(5,7-Dichloro-benzofuran-2-yl)-phenol;
• zzz) 4-(5,7-Difluoro-benzofuran-2-yl)-phenol;
• aaaa) 4-(5,7-Dibromo-benzofuran-2-yl)-phenol;
• bbbb) 4-(5-Trifluoromethyl-benzofuran-2-yl)-phenol;
• cccc) 2-Iodo-4-methoxy-6-nitro-phenol;
• dddd) 5-Methoxy-2-(4-methoxy-phenyl)-7-nitro-benzofuran;
• eeee) 2-(4-Hydroxy-phenyl)-7-nitro-benzofuran-5-ol;
• ffff) 7-Amino-2-(4-hydroxy-phenyl)-benzofuran-5-ol;
• gggg) 1-(2-Bromo-4-methoxy-phenyl)-2-(2,5-dimethoxy-phenyl)-ethanone;
• hhhh) 2-(2-Bromo-4-hydroxy-phenyl)-benzofuran-5-ol;
• iiii) 2-(5-Hydroxy-biphenyl-2-yl)-benzofuran-5-ol;
• jjjj) 2-(4′-Benzyloxy-5-hydroxy-biphenyl-2-yl)-benzofuran-5-ol;
• kkkk) 6-(5-Hydroxy-benzofuran-2-yl)-biphenyl-3,4′-diol;
• llll) 2-[5-Hydroxy-4′-(2-pyrrolidin-1-yl-ethoxy)-biphenyl-2-yl]-benzofuran-5-ol;
• mmmm) 2,2-Dimethyl-propionic acid 2-[4-(2,2-dimethyl-propionyloxy)-phenyl]-benzofuran-5-yl ester;
• nnnn) 1-[5-Hydroxy-2-(4-hydroxy-phenyl)-benzofuran-3-yl]-ethanone;
• oooo) 1-[5-Hydroxy-2-(4-hydroxy-phenyl)-benzofuran-3-yl]-ethanone oxime;
• pppp) 3-(1-Hydroxy-ethyl)-2-(4-hydroxy-phenyl)-benzofuran-5-ol;
• qqqq) 2-[5-Methoxy-2-(4-methoxy-phenyl)-benzofuran-7-yl]-propan-2-ol;
• rrrr) 7-Isopropenyl-5-methoxy-2-(4-methoxy-phenyl)-benzofu ran;
• ssss) 7-Isopropyl-5-methoxy-2-(4-methoxy-phenyl)-benzofuran;
• tttt) 2-(4-Hydroxy-phenyl)-7-isopropyl-benzofuran-5-ol;
• uuuu) 5-Hydroxy-2-(4-hydroxy-phenyl)-benzofuran-7-carboxylic acid methoxy-methyl-amide;
• vvvv) 5-Hydroxy-2-(4-hydroxy-phenyl)-benzofuran-7-carbaldehyde;
• wwww) 5-Methoxy-2-(4-methoxy-phenyl)-benzofu ran-7-carboxylic acid methoxy-methyl-amide;
• xxxx) 1-[5-Methoxy-2-(4-methoxy-phenyl)-benzofuran-7-yl]-ethanone;
• yyyy) 1-[5-Hydroxy-2-(4-hydroxy-phenyl)-benzofuran-7-yl]-ethanone;
• zzzz) 1-[5-Hydroxy-2-(4-hydroxy-phenyl)-benzof uran-7-yl]-propan-1-one;
• aaaaa) 2-(2,5-Dimethoxy-phenyl)-1-(3-fluoro-4-methoxy-phenyl)-ethanone;
• bbbbb) 2-(3-Fluoro-4-hydroxy-phenyl)-benzofuran-5-ol;
• ccccc) 4-(5-Methoxy-benzofuran-2-yl)-benzoic acid methyl ester;
• ddddd) 4-(5-Hydroxy-benzofuran-2-yl)-benzoic acid;
• eeeee) 2-(4-Hydroxymethyl-phenyl)-benzofuran-5-ol;
• fffff) 4-Bromo-2-(4-hydroxy-phenyl)-benzofuran-5-ol;
• ggggg) 4-Chloro-2-(4-hydroxy-phenyl)-benzofuran-5-ol;
• hhhhh) 2-(4-Hydroxy-phenyl)-4-methoxy-benzofuran-5-ol;
• iiiii) 4-Bromo-5-methoxy-2-(4-methoxy-phenyl)-benzofuran;
• jjjjj) 5-Methoxy-2-(4-methoxy-phenyl)-benzofuran-4-carbonitrile;
• kkkkk) 5-Hydroxy-2-(4-hydroxy-phenyl)-benzofuran-4-carbonitrile;
• lllll) 5-Methoxy-2-(4-methoxy-phenyl)-4-methyl-benzofuran;
• mmmmm) 2-(4-Hydroxy-phenyl)-4-methyl-benzofuran-5-ol;
• nnnnn) 2-(4-Hydroxy-phenyl)-7-[1,3,4]oxadiazol-2-yl-benzofuran-5-ol;
• ooooo) 2,2,2-Trifluoro-1-[5-methoxy-2-(4-methoxy-phenyl)-benzofuran-7-yl]-ethanol;
• ppppp) 5-Methoxy-2-(4-methoxy-phenyl)-7-(2,2,2-trifluoro-ethyl)-benzofuran;
• qqqqq) 2-(4-Hydroxy-phenyl)-7-(2,2,2-trifluoro-ethyl)-benzofuran-5-ol;
• rrrrr) 2-(4-Methoxy-phenyl)-benzofuran-5-carboxylic acid methyl ester;
• sssss) 2-(4-Hydroxy-phenyl)-benzofuran-5-carboxylic acid;
• ttttt) 4-(5-Hydroxymethyl-benzofuran-2-yl)-phenol
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting prostatitis or interstitial cystitis 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
• P and P′ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or acyl of 2-7 carbon atoms;
• X is hydrogen or halogen;
• R is hydrogen, alkyl of 1-6 carbon atoms, halogen, —CN, or —CHO;
• R′ is alkoxy of 1-6 carbon atoms, or cyanoalkyl having 1-6 carbon atoms in the alkyl moiety;
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting inflammatory bowel disease, Crohn's disease, ulcerative proctitis, or colitis in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound of formula I, having the structure

• 26
• wherein
• P and P′ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or acyl of 2-7 carbon atoms;
• X is hydrogen or halogen;
• R is hydrogen, alkyl of 1-6 carbon atoms, halogen, —CN, or —CHO;
• R′ is alkoxy of 1-6 carbon atoms, or cyanoalkyl having 1-6 carbon atoms in the alkyl moiety;
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting prostatic hypertrophy, uterine leiomyomas, breast cancer, 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 I, having the structure

• 27
• wherein
• P and P′ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or acyl of 2-7 carbon atoms;
• X is hydrogen or halogen;
• R is hydrogen, alkyl of 1-6 carbon atoms, halogen, —CN, or —CHO;
• R′ is alkoxy of 1-6 carbon atoms, or cyanoalkyl having 1-6 carbon atoms in the alkyl moiety;
• or a pharmaceutically acceptable salt thereof.

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

• inhibiting or treating hypercholesteremia;
• hyperlipidemia;
• cardiovascular disease;
• atherosclerosis;
• hypertension;
• 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
• 28
• wherein
• P and P′ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or acyl of 2-7 carbon atoms;
• X is hydrogen or halogen;
• R is hydrogen, alkyl of 1-6 carbon atoms, halogen, —CN, or —CHO;
• R′ is alkoxy of 1-6 carbon atoms, or cyanoalkyl having 1-6 carbon atoms in the alkyl moiety;
• or a pharmaceutically acceptable salt thereof.

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 I, having the structure
• 29
• wherein
• P and P′ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or acyl of 2-7 carbon atoms;
• X is hydrogen or halogen;
• R is hydrogen, alkyl of 1-6 carbon atoms, halogen, —CN, or —CHO;
• R′ is alkoxy of 1-6 carbon atoms, or cyanoalkyl having 1-6 carbon atoms in the alkyl moiety;
• or a pharmaceutically acceptable salt thereof.

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 I, having the structure

• 30
• wherein
• P and P′ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or acyl of 2-7 carbon atoms;
• X is hydrogen or halogen;
• R is hydrogen, alkyl of 1-6 carbon atoms, halogen, —CN, or —CHO;
• R′ is alkoxy of 1-6 carbon atoms, or cyanoalkyl having 1-6 carbon atoms in the alkyl moiety;
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting vaginal or vulvar atrophy;

• atrophic vaginitis;
• vaginal dryness;
• pruritus;
• dyspareunia;
• dysuria;
• frequent urination;
• urinary incontinence;
• urinary tract infections in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound of formula I, having the structure
• 31
• wherein
• P and P′ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or acyl of 2-7 carbon atoms;
• X is hydrogen or halogen;
• R is hydrogen, alkyl of 1-6 carbon atoms, halogen, —CN, or —CHO;
• R′ is alkoxy of 1-6 carbon atoms, or cyanoalkyl having 1-6 carbon atoms in the alkyl moiety;
• or a pharmaceutically acceptable salt thereof.

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

• 32
• wherein
• P and P′ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or acyl of 2-7 carbon atoms;
• X is hydrogen or halogen;
• R is hydrogen, alkyl of 1-6 carbon atoms, halogen, —CN, or —CHO;
• R′ is alkoxy of 1-6 carbon atoms, or cyanoalkyl having 1-6 carbon atoms in the alkyl moiety;
• or a pharmaceutically acceptable salt thereof.

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 I, having the structure

• 33
• wherein
• P and P′ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or acyl of 2-7 carbon atoms;
• X is hydrogen or halogen;
• R is hydrogen, alkyl of 1-6 carbon atoms, halogen, —CN, or —CHO;
• R′ is alkoxy of 1-6 carbon atoms, or cyanoalkyl having 1-6 carbon atoms in the alkyl moiety;
• or a pharmaceutically acceptable salt thereof.

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 I, having the structure

• 34
• wherein
• P and P′ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or acyl of 2-7 carbon atoms;
• X is hydrogen or halogen;
• R is hydrogen, alkyl of 1-6 carbon atoms, halogen, —CN, or —CHO;
• R′ is alkoxy of 1-6 carbon atoms, or cyanoalkyl having 1-6 carbon atoms in the alkyl moiety;
• or a pharmaceutically acceptable salt thereof.

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 I, having the structure
• 35
• wherein
• P and P′ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or acyl of 2-7 carbon atoms;
• X is hydrogen or halogen;
• R is hydrogen, alkyl of 1-6 carbon atoms, halogen, —CN, or —CHO;
• R′ is alkoxy of 1-6 carbon atoms, or cyanoalkyl having 1-6 carbon atoms in the alkyl moiety;
• or a pharmaceutically acceptable salt thereof.

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

• 36
• wherein
• P and P′ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or acyl of 2-7 carbon atoms;
• X is hydrogen or halogen;
• R is hydrogen, alkyl of 1-6 carbon atoms, halogen, —CN, or —CHO;
• R′ is alkoxy of 1-6 carbon atoms, or cyanoalkyl having 1-6 carbon atoms in the alkyl moiety;
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting ischemia, reperfusion injury, asthma, pleurisy, multiple sclerosis, systemic lupus erythematosis, uveitis, sepsis, hemmorhagic shock, macular degeneration 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

• 37
• wherein
• P and P′ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or acyl of 2-7 carbon atoms;
• X is hydrogen or halogen;
• R is hydrogen, alkyl of 1-6 carbon atoms, halogen, —CN, or —CHO;
• R′ is alkoxy of 1-6 carbon atoms, or cyanoalkyl having 1-6 carbon atoms in the alkyl moiety;
• or a pharmaceutically acceptable salt thereof.

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

• 38
• wherein
• P and P′ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or acyl of 2-7 carbon atoms;
• X is hydrogen or halogen;
• R is hydrogen, alkyl of 1-6 carbon atoms, halogen, —CN, or —CHO;
• R′ is alkoxy of 1-6 carbon atoms, or cyanoalkyl having 1-6 carbon atoms in the alkyl moiety;
• or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition which comprises a compound of formula I, having the structure

• 39
• wherein
• P and P′ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or acyl of 2-7 carbon atoms;
• X is hydrogen or halogen;
• R is hydrogen, alkyl of 1-6 carbon atoms, halogen, —CN, or —CHO;
• R′ is alkoxy of 1-6 carbon atoms, or cyanoalkyl having 1-6 carbon atoms in the alkyl moiety;
• or a pharmaceutically acceptable salt thereof.