Hydroxy-Biphenyl-Carbaldehyde Oxime Derivatives and Their Use As Estrogenic Agents

Abstract

This invention provides estrogen receptor modulators having the structure: wherein R 1 to R 6 and R 8 are as defined in the specification; or a pharmaceutically acceptable salt thereof.

1 . A compound of the formula  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is OH or lower alkoxy; and  
 R 5 , R 6 , and R 7  are each, independently, H, OH, halogen, CN, phenyl, lower alkyl, lower alkoxy, said phenyl, lower alkyl, and lower alkoxy being optionally substituted; or a pharmaceutically acceptable salt thereof or a prodrug thereof.  
 
   
   
       2 . The compound of  claim 1  wherein R 5 , R 6 , and R 7  are each, independently, H, Me, Cl, F, or methoxy.  
   
   
       3 . The compound of  claim 1  where the compound is 4′-Hydroxy-3-methoxy-1,1′-biphenyl-4-carbaldehyde oxime.  
   
   
       4 . A pharmaceutical composition comprising:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is OH or lower alkoxy; and  
 R 5 , R 6 , and R 7  are each, independently, H, OH, halogen, CN, phenyl, lower alkyl, lower alkoxy, said phenyl, lower alkyl, and lower alkoxy being optionally substituted; or a pharmaceutically acceptable salt thereof or a prodrug thereof, and  
 a pharmaceutical carrier.  
 
   
   
       5 . 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 
 R 1  and R 2 , are each, independently, H, halogen, CN, phenyl, or lower alkyl;  
 R 3 , R 4 , R 5  and R 6 , are each independently, H, OH, halogen, CN, phenyl, lower alkyl, or lower alkoxy;  
 R 8  are each, independently, H, —C(O)R 9 , or lower alkyl; and  
 R 9  is lower alkyl;  
 or a pharmaceutically acceptable salt thereof or a prodrug thereof.  
 
   
   
       6 . 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 
 R 1  and R 2 , are each, independently, H, halogen, CN, phenyl, or lower alkyl;  
 R 3 , R 4 , R 5  and R 6 , are each independently, H, OH, halogen, CN, phenyl, lower alkyl, or lower alkoxy;  
 R 8  are each, independently, H, —C(O)R 9 , or lower alkyl; and  
 R 9  is lower alkyl;  
 or a pharmaceutically acceptable salt thereof or a prodrug thereof.  
 
   
   
       7 . The method of  claim 6  wherein the abnormal tissue growth is prostatic hypertrophy, uterine leiomyomas, breast cancer, endometriosis, endometrial cancer, polycystic ovary syndrome, endometrial polyps, benign breast disease, adenomyosis, ovarian cancer, melanoma, prostrate cancer, cancers of the colon, or CNS cancers.  
   
   
       8 . 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 
 R 1  and R 2 , are each, independently, H, halogen, CN, phenyl, or lower alkyl;  
 R 3 , R 4 , R 5  and R 6 , are each independently, H, OH, halogen, CN, phenyl, lower alkyl, or lower alkoxy;  
 R 8  are each, independently, H, —C(O)R 9 , or lower alkyl; and  
 R 9  is lower alkyl;  
 or a pharmaceutically acceptable salt thereof or a prodrug thereof.  
 
   
   
       9 . 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 
 R 1  and R 2 , are each, independently, H, halogen, CN, phenyl, or lower alkyl;  
 R 3 , R 4 , R 5  and R 6 , are each independently, H, OH, halogen, CN, phenyl, lower alkyl, or lower alkoxy;  
 R 8  are each, independently, H, —C(O)R 9 , or lower alkyl; and  
 R 9  is lower alkyl;  
 or a pharmaceutically acceptable salt thereof or a prodrug thereof.  
 
   
   
       10 . A method of providing cognition enhancement or neuroprotection; or treating or inhibiting senile dementias, Alzheimer's disease, cognitive 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 
 R 1  and R 2 , are each, independently, H, halogen, CN, phenyl, or lower alkyl;  
 R 3 , R 4 , R 5  and R 6 , are each independently, H, OH, halogen, CN, phenyl, lower alkyl, or lower alkoxy;  
 R 8  are each, independently, H, —C(O)R 9 , or lower alkyl; and  
 R 9  is lower alkyl;  
 or a pharmaceutically acceptable salt thereof or a prodrug thereof.  
 
   
   
       11 . 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 
 R 1  and R 2 , are each, independently, H, halogen, CN, phenyl, or lower alkyl;  
 R 3 , R 4 , R 5  and R 6 , are each independently, H, OH, halogen, CN, phenyl, lower alkyl, or lower alkoxy;  
 R 8  are each, independently, H, —C(O)R 9 , or lower alkyl; and  
 R 9  is lower alkyl;  
 or a pharmaceutically acceptable salt thereof or a prodrug thereof.  
 
   
   
       12 . 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 
 R 1  and R 2 , are each, independently, H, halogen, CN, phenyl, or lower alkyl;  
 R 3 , R 4 , R 5  and R 6 , are each independently, H, OH, halogen, CN, phenyl, lower alkyl, or lower alkoxy;  
 R 8  are each, independently, H, —C(O)R 9 , or lower alkyl; and  
 R 9  is lower alkyl;  
 or a pharmaceutically acceptable salt thereof or a prodrug thereof.