Claims
- 1. A compound of formula I, having the structure
- 2. The compound according to claim 1, wherein X is O.
- 3. The compound according to claim 2, wherein R1 is alkenyl of 2-3 carbon atoms, which is optionally substituted with hydroxyl, —CN, halogen, trifluoroalkyl, trifluoroalkoxy, —COR5, —CO2R5, —NO2, CONR5R6, NR5R6 or N(R5)COR6.
- 4. The compound according to claim 1, which is 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol or a pharmaceutically acceptable salt thereof.
- 5. The compound according to claim 1, which is 2-(2-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol or a pharmaceutically acceptable salt thereof.
- 6. The compound according to claim 1, which is 2-(2,3-difluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol or a pharmaceutically acceptable salt thereof.
- 7. The compound according to claim 1, which is 4-bromo-2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol or a pharmaceutically acceptable salt thereof.
- 8. The compound according to claim 1, which is 4,6-dibromo-2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol or a pharmaceutically acceptable salt thereof.
- 9. The compound according to claim 1, which is 7-(1-bromovinyl)-2-(2-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol or a pharmaceutically acceptable salt thereof.
- 10. The compound according to claim 1, which is 7-(1-bromovinyl)-2-(2,3-difluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol or a pharmaceutically acceptable salt thereof.
- 11. The compound according to claim 1, which is 7-allyl-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol or a pharmaceutically acceptable salt thereof.
- 12. The compound according to claim 1, which is 2-(3,5-difluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol or a pharmaceutically acceptable salt thereof.
- 13. The compound according to claim 1, which is 2-(3-fluoro-4-hydroxyphenyl)-7-(1-fluorovinyl)-1,3-benzoxazol-5-ol or a pharmaceutically acceptable salt thereof.
- 14. A compound which is,
a) 2-(5-hydroxy-1,3-benzoxazol-2-yl) benzene-1,4-diol; b) 3-(5-hydroxy-1,3-benzoxazol-2-yl)benzene-1,2-diol; c) 2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol; d) 2-(3-chloro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol; e) 2-(2-chloro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol; f) 2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-ol; g) 2-(3-tert-butyl-4-hydroxyphenyl)-1,3-benzoxazol-6-ol; h) 2-(6-hydroxy-1,3-benzoxazol-2-yl)benzene-1,4-diol; i) 3-(6-hydroxy-1,3-benzoxazol-2-yl)benzene-1,2-diol; j) 4-(6-hydroxy-1,3-benzoxazol-2-yl)benzene-1,2-diol; k) 2-(3-chloro-4-hydroxyphenyl)-1,3-benzoxazol-6-ol; l) 4-(5-hydroxy-1,3-benzoxazol-2-yl)benzene-1,3-diol; m) 4-(6-hydroxy-1,3-benzoxazol-2-yl)benzene-1,3-diol; n) 6-chloro-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol; o) 6-bromo-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol; p) 6-chloro-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol; q) 5-chloro-2-(4-hydroxyphenyl)-1,3-benzoxazol-6-ol; r) 7-bromo-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol; s) 7-bromo-2-(2-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol; t) 7-bromo-2-(2,3-difluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol; u) 2-(4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol.; v) 7-(1,2-dibromoethyl)-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol; w) 7-(1-bromovinyl)-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol; x) 7-ethynyl-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol; y) 2-(4-hydroxyphenyl)-7-propyl-1,3-benzoxazol-5-ol; z) 7-butyl-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol; aa) 7-cyclopentyl-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol; bb) ethyl 5-hydroxy-2-(4-hydroxyphenyl)-1,3-benzoxazole-7-carboxylate; cc) 2-(4-hydroxyphenyl)-7-phenyl-1,3-benzoxazol-5-ol; dd) 2-(4-hydroxyphenyl)-7-methoxy-1,3-benzoxazol-5-ol; ee) 7-ethyl-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol; ff) 7-ethyl-2-(2-ethyl-4-hydroxyphenyl)-1,3-benzoxazol-5-ol; gg) 5-hydroxy-2-(4-hydroxyphenyl)-1,3-benzoxazole-7-carbaldehyde; hh) 7-(hydroxymethyl)-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol; ii) 7-(bromomethyl)-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol; jj) [5-hydroxy-2-(4-hydroxyphenyl)-1,3-benzoxazol-7-yl]acetonitrile; kk) 7-(1-hydroxy-1-methylethyl)-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol]; ll) 2-(4-hydroxyphenyl)-7-isopropenyl-1,3-benzoxazol-5-ol mm) 2-(4-hydroxyphenyl)-7-isopropyl-1,3-benzoxazol-5-ol]; nn) 7-bromo-2-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3-benzoxazol-5-ol; oo) 7-(2-furyl)-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol; pp) 2-(3-fluoro-4-hydroxyphenyl)-7-(2-furyl)-1,3-benzoxazol-5-ol; qq) 2-(4-hydroxyphenyl)-7-thien-2-yl-1,3-benzoxazol-5-ol; rr) 2-(4-hydroxyphenyl)-7-(1,3-thiazol-2-yl)-1,3-benzoxazol-5-ol; ss) 2-(3-fluoro-4-hydroxyphenyl)-5-hydroxy-1,3-benzoxazole-7-carbonitrile; tt) 4-bromo-2-(4-hydroxyphenyl)-7-methoxy-1,3-benzoxazol-5-ol; uu) 4,6-bibromo-2-(4-hydroxyphenyl)-7-methoxy-1,3-benzoxazol-5-ol; vv) 7-bromo-2-(3,5-difluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol; or a pharmaceutically acceptable salt thereof.
- 15. 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
- 16. 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
- 17. 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
- 18. 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 1, having the structure
- 19. 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
- 20. 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
- 21. 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
- 22. 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
- 23. 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
- 24. 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
- 25. The method according to claim 24, wherein the arthritis is rheumatoid arthritis, osteoarthritis, or spondyloarthropathies.
- 26. 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
- 27. 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
- 28. 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
- 29. 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
- 30. A pharmaceutical composition which comprises a compound of formula I, having the structure
- 31. A method of treating or inhibiting inflammatory bowel disease in a mammal in need thereof, which comprises providing to said mammal an effective amount of an ER-β selective ligand, wherein the binding affinity of the ER-β selective ligand to ER-β is at least about 20 times greater than its binding affinity to ER-α.
- 32. The method according to claim 31, wherein the inflammatory bowel disease is Crohn's disease, ulcerative colitis, indeterminate colitis, infectious colitis, or ulcerative proctitis.
- 33. The method according to claim 32, wherein the binding affinity of the ER-β selective ligand to ER-β is at least about 50 times greater than its binding affinity to ER-α.
- 34. The method according to claim 33, wherein the ERβ selective ligand causes an increase in wet uterine weight which is less than about 10% of that observed for a maximally efficacious dose of 17β-estradiol in a standard pharmacological test procedure measuring uterotrophic activity, and the ERβ selective ligand causes an increase in casein kinase II mRNA which is less than about 10% of that observed for a maximally efficacious dose of 17β-estradiol in a standard pharmacological test procedure measuring mammotrophic activity.
- 35. The method according to claim 34, wherein the ER-β selective ligand does not significantly (p>0.05) increase wet uterine weight compared with a control that is devoid of uterotrophic activity, and does not significantly (p>0.05) increase casein kinase II mRNA compared with a control that is devoid of mammotrophic activity.
- 36. A method of treating or inhibiting arthritis in a mammal in need thereof, which comprises providing to said mammal an effective amount of a non-uterotropic, non-mammotrophic ERβ selective ligand, wherein the binding affinity of the ER-β selective ligand to ER-β is at least about 20 times greater than its binding affinity to ER-α.
- 37. The method according to claim 36, wherein the arthritis is rheumatoid arthritis, osteoarthritis, or spondyloarthropathies.
- 38. The method according to claim 37, wherein wherein the binding affinity of the ERβ selective ligand to ERβ is at least about 50 times greater than its binding affinity to ERα.
- 39. The method according to claim 38, wherein the ERβ0 selective ligand causes an increase in wet uterine weight which is less than about 10% of that observed for a maximally efficacious dose of 17β-estradiol in a standard pharmacological test procedure measuring uterotrophic activity, and the ERβ selective ligand causes an increase in casein kinase II mRNA which is less than about 10% of that observed for a maximally efficacious dose of 17β-estradiol in a standard pharmacological test procedure measuring mammotrophic activity.
- 40. The method according to claim 39, wherein the ERβ selective ligand does not significantly (p>0.05) increase wet uterine weight compared with a control that is devoid of uterotrophic activity, and does not significantly (p>0.05) increase casein kinase II mRNA compared with a control that is devoid of mammotrophic activity.
- 41. 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 non-uterotrophic, non-mammotrophic ERβ selective ligand, wherein the binding affinity of the ER-β selective ligand to ER-β is at least about 20 times greater than its binding affinity to ER-α.
- 42. The method according to claim 41, wherein wherein the binding affinity of the ERβ selective ligand to ERβ is at least about 50 times greater than its binding affinity to ERα.
- 43. A method of treating or inhibiting endometriosis in a mammal in need thereof, which comprises providing to said mammal an effective amount of an ER-β selective ligand, wherein the binding affinity of the ER-β selective ligand to ER-β is at least about 20 times greater than its binding affinity to ER-α.
- 44. The method according to claim 43, wherein the binding affinity of the ER-β selective ligand to ER-β is at least about 50 times greater than its binding affinity to ER-α.
- 45. The method according to claim 44, wherein the ERβ selective ligand causes an increase in wet uterine weight which is less than about 10% of that observed for a maximally efficacious dose of 17β-estradiol in a standard pharmacological test procedure measuring uterotrophic activity, and the ERβ selective ligand causes an increase in casein kinase II mRNA which is less than about 10% of that observed for a maximally efficacious dose of 17β-estradiol in a standard pharmacological test procedure measuring mammotrophic activity.
- 46. The method according to claim 45, wherein the ER-β selective ligand does not significantly (p >0.05) increase wet uterine weight compared with a control that is devoid of uterotrophic activity and does not significantly (p >0.05) increase casein kinase II mRNA compared with a control that is devoid of mammotrophic activity.
Parent Case Info
[0001] This application claims priority from copending provisional application Serial No. 60/336,663, filed Dec. 5, 2001, the entire disclosure of which is hereby incorporated by reference.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60336663 |
Dec 2001 |
US |