Aryl-carbaldehyde oxime derivatives and their use as estrogenic agents

Abstract

This invention provides estrogen receptor modulators having the structure where R 1 —R 5 are defined in the specification; or a pharmaceutically acceptable salt thereof.

1 . 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: 
 R 1  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy;  
 R 2  and R 3 , together, form a fused aryl or heteroaryl ring;  
 R 4  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy;  
 R 5  is hydrogen, lower alkyl, or —C(O)R 6 ; and  
 R 6  is lower alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
   
   
       2 . 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  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy;  
 R 2  and R 3 , together, form a fused aryl or heteroaryl ring;  
 R 4  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy;  
 R 5  is hydrogen, lower alkyl, or —C(O)R 6 ; and  
 R 6  is lower alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
   
   
       3 . 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  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy;  
 R 2  and R 3 , together, form a fused aryl or heteroaryl ring;  
 R 4  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy;  
 R 5  is hydrogen, lower alkyl, or —C(O)R 6 ; and  
 R 6  is lower alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
   
   
       4 . The method of  claim 3  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.  
   
   
       5 . 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  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy;  
 R 2  and R 3 , together, form a fused aryl or heteroaryl ring;  
 R 4  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy;  
 R 5  is hydrogen, lower alkyl, or —C(O)R 6 ; and  
 R 6  is lower alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
   
   
       6 . 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  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy;  
 R 2  and R 3 , together, form a fused aryl or heteroaryl ring;  
 R 4  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy;  
 R 5  is hydrogen, lower alkyl, or —C(O)R 6 ; and  
 R 6  is lower alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
   
   
       7 . 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: 
 R 1  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy;  
 R 2  and R 3 , together, form a fused aryl or heteroaryl ring;  
 R 4  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy;  
 R 5  is hydrogen, lower alkyl, or —C(O)R 6 ; and  
 R 6  is lower alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
   
   
       8 . 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  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy;  
 R 2  and R 3 , together, form a fused aryl or heteroaryl ring;  
 R 4  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy;  
 R 5  is hydrogen, lower alkyl, or —C(O)R 6 ; and  
 R 6  is lower alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
   
   
       9 . 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  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy;  
 R 2  and R 3 , together, form a fused aryl or heteroaryl ring;  
 R 4  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy;  
 R 5  is hydrogen, lower alkyl, or —C(O)R 6 ; and  
 R 6  is lower alkyl;  
 or a pharmaceutically acceptable salt thereof.