Crystal forms of 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol

Abstract

The present invention is directed to monohydrate and anhydrate crystal forms of 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol, an estrogenic receptor modulator useful in the treatment of, for example, diseases related to abnormal levels of estrogen.

1 . A 2 (3 fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol monohydrate in a crystal form that has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at about 9.2° and about 12.2°. 
   
   
       2 - 13 . (canceled) 
   
   
       14 . A composition comprising the monohydrate of  claim 1 . 
   
   
       15 . The composition of  claim 14  wherein said monohydrate constitutes at least about 50% by weight of said composition. 
   
   
       16 . (canceled) 
   
   
       17 . The composition of  claim 14  wherein said monohydrate constitutes at least about 90% by weight of said composition. 
   
   
       18 . (canceled) 
   
   
       19 . The composition of  claim 14  wherein said monohydrate constitutes at least about 99% by weight of said composition. 
   
   
       20 . A composition comprising the monohydrate of  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       21 . A process for preparing the monohydrate of  claim 1  comprising precipitating said monohydrate from a solution comprising water. 
   
   
       22 . The process of  claim 21  wherein said solution further comprises an alcohol. 
   
   
       23 . The process of  claim 22  wherein said alcohol comprises ethanol. 
   
   
       24 . The process of  claim 22  wherein the weight ratio of alcohol to water is about 1:1 to about 3:1. 
   
   
       25 . (canceled) 
   
   
       26 . The process of  claim 21  wherein said precipitating is induced by cooling said solution, adding antisolvent to said solution, or changing pH of said solution. 
   
   
       27 . (canceled) 
   
   
       28 . A method of modulating an estrogen receptor comprising contacting said receptor with the monohydrate of  claim 1 ; or
 a method of treating prostatitis, interstitial cystitis, inflammatory bowel disease, Crohn's disease, ulcerative proctitis, colitis, prostatic hypertrophy, uterine leiomyomas, breast,' cancer, endometrial cancer, polycystic ovary syndrome, endometrial polyps, endometriosis, benign breast disease, adenomyosis, ovarian cancer, melanoma, prostrate cancer, colon cancer, glioma, astioblastomia, free radical induced disease states, vaginal or vulvar atrophy, atrophic vaginitis, vaginal dryness, pruritus, dyspareunia, dysuria, frequent urination, urinary incontinence, urinary tract infections, vasomotor symptoms, arthritis, joint swelling or erosion, joint damage secondary to arthroscopic or surgical procedures, psoriasis, dermatitis, 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 a therapeutically effective amount of the monohydrate of  claim 1 ; or   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 a therapeutically effective amount of the monohydrate of  claim 1 ; or   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 the monohydrate of  claim 1 ; or   a method of inhibiting conception in a mammal in need thereof, which comprises providing to said mammal an effective amount of the monohydrate of  claim 1 .   
   
   
       29 - 32 . (canceled) 
   
   
       33 . An anhydrous crystal form of 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol having an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at about 8.2°, about 10.3°, and about 14.6°. 
   
   
       34 . The crystal form of  claim 33  having an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at about 8.2°, about 10.3°, about 14.6°, about 15.1°, and about 16.3°. 
   
   
       35 . The crystal form of  claim 33  having an X-ray powder diffraction pattern comprising peaks, in terms of 28, at about 8.2°, about 10.3°, about 14.6°, about 15.1°, about 16.3°, about 22.3°, about 24.S0, and about 26.7°. 
   
   
       36 . (canceled) 
   
   
       37 . The crystal form of  claim 33  having a differential scanning calorimetry trace comprising a melting endotherm having an onset at about 250° C. 
   
   
       38 . (canceled) 
   
   
       39 . The crystal form of  claim 33  having a thermogravimetric analysis profile showing less than about 1% weight loss from about 60 to about 150° C. 
   
   
       40 . (canceled) 
   
   
       41 . A composition comprising the crystal form of  claim 33 . 
   
   
       42 . The composition of  claim 41  wherein said crystal form constitutes at least about 50% by weight of said composition. 
   
   
       43 . (canceled) 
   
   
       44 . The composition of  claim 41  wherein said crystal form constitutes at least about 90% by weight of said composition. 
   
   
       45 - 46 . (canceled) 
   
   
       47 . The composition of  claim 41  wherein said crystal form constitutes at least about 99% by weight of said composition. 
   
   
       48 - 52 . (canceled) 
   
   
       53 . A composition comprising the crystal form of  claim 33  and a pharmaceutically acceptable carrier. 
   
   
       54 . A process for preparing the crystal form of  claim 33  comprising precipitating said crystal form from an anhydrous solution. 
   
   
       55 . The process of  claim 54  wherein said anhydrous solution comprises ethyl acetate. 
   
   
       56 . The process of  claim 55  wherein said solution further comprises a hydrocarbon. 
   
   
       57 . The process of  claim 56  wherein said hydrocarbon is heptane. 
   
   
       58 . The process of  claim 54  wherein said precipitating is induced by cooling said solution or adding antisolvent to said solution. 
   
   
       59 . (canceled) 
   
   
       60 . A method of modulating an estrogen receptor comprising contacting said receptor with the crystal form of  claim 33 ; or
 a method of treating prostatitis, interstitial cystitis, inflammatory bowel disease, Crohn's disease, ulcerative proctitis, colitis, prostatic hypertrophy, uterine leiomyomas, breast cancer, endometrial cancer, polycystic ovary syndrome, endometrial polyps, endometriosis, benign breast disease, adenomyosis, ovarian cancer, melanoma, prostrate cancer, colon cancer, glioma, astioblastomia, free radical induced disease states, vaginal or vulvar atrophy, atrophic vaginitis, vaginal dryness, pruritus, dyspareunia, dysuria, frequent urination, urinary incontinence, urinary tract infections, vasomotor symptoms, arthritis, joint swelling or erosion, joint damage secondary to arthroscopic or surgical procedures, psoriasis, dermatitis, 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 a therapeutically effective amount of the crystal form of  claim 33 ; or   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 a therapeutically effective amount of the crystal form of  claim 33 ;   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 the crystal form of  claim 33 ; or   a method of inhibiting conception in a mammal in need thereof, which comprises providing to said mammal an effective amount of the crystal form of  claim 33 .   
   
   
       61 - 64 . (canceled)