Calcium receptor active compounds

Abstract

A novel calcium receptor active compound having the formula is provided: Ar 1 —[CR 1 R 2 ] p —X—[CR 3 R 4 ] q —[CR 5 R 6 ]—NR 7 —[CR 8 R 9 ]—Ar 2 wherein: Ar 1 is selected from the group consisting of aryl, heteroaryl, bis(arylmethyl)amino, bis(heteroarylmethyl)amino and arylmethyl(heteroarylmethyl) amino; X is selected from the group consisting of oxygen, sulfur, sulfinyl, sulfonyl, carbonyl and amino; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are, for example, hydrogen or alkyl; Ar 2 is selected from the group consisting of aryl and heteroaryl; p is an integer of from 0 to 6, inclusive; and, q is an integer of from 0 to 14, inclusive.

We claim:  
     
         1 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R′ and R″ are independently phenyl optionally substituted by one or more moieties independently selected from the group consisting of halogen, hydroxy, unsubstituted alkyl, lower alkyl substituted with one or more halogens, lower alkoxy optionally substituted with one or more halogens, nitro, phenyl, and a phenyl ring fused to R′ or R″ through two adjacent substituents;  
 or a pharmaceutically acceptable salt or hydrate of said compound.  
 
     
     
         2 . A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R′ and R″ are independently phenyl optionally substituted by one or more moieties independently selected from the group consisting of halogen, hydroxy, unsubstituted alkyl, lower alkyl substituted with one or more halogens, lower alkoxy optionally substituted with one or more halogens, nitro, phenyl, and a phenyl ring fused to R′ or R″ through two adjacent substituents.  
 
     
     
         3 . A method of treating a patient comprising administering to said patient a therapeutically effective amount of one or more of compounds, or a pharmaceutically acceptable salt or hydrate thereof, having the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R′ and R″ are independently phenyl optionally substituted by one or more moieties independently selected from the group consisting of halogen, hydroxy, unsubstituted alkyl, lower alkyl substituted with one or more halogens, lower alkoxy optionally substituted with one or more halogens, nitro, phenyl, and a phenyl ring fused to R′ or R″ through two adjacent substituents.  
 
     
     
         4 . The method of  claim 3  wherein said patient is suffering from a disease or disorder characterized by either or both of (1) abnormal calcium homeostasis and, (2) an abnormal amount of an intracellular or extracellular messenger whose production can be affected by calcium receptor activity.  
     
     
         5 . A method for modulating the PTH level in a patient comprising administering to said patient an effective amount of a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R′ and R″ are independently phenyl optionally substituted by one or more moieties independently selected from the group consisting of halogen, hydroxy, unsubstituted alkyl, lower alkyl substituted with one or more halogens, lower alkoxy optionally substituted with one or more halogens, nitro, phenyl, and a phenyl ring fused to R′ or R″ through two adjacent substituents.  
 
     
     
         6 . The method of  claim 5  wherein said effective amount of said compound reduces said PTH level in a patient.  
     
     
         7 . The method of  claim 6  wherein said patient has an abnormally high PTH level and effective amount of said compound reduces said PTH level in said patient to a degree sufficient to cause a decrease in plasma Ca 2+ .  
     
     
         8 . The method of  claim 7 , wherein administering said compound to said patient results in a PTH level in said patient equal to a level present in a normal individual.  
     
     
         9 . A method for modulating parathyroid hormone secretion in a patient comprising administering to said patient an effective amount of a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R′ and R″ are independently phenyl optionally substituted by one or more moieties independently selected from the group consisting of halogen, hydroxy, unsubstituted alkyl, lower alkyl substituted with one or more halogens, lower alkoxy optionally substituted with one or more halogens, nitro, phenyl, and a phenyl ring fused to R′ or R″ through two adjacent substituents.  
 
     
     
         10 . The method of  claim 9  wherein said effective amount of said compound reduces said parathyroid hormone secretion in said patient.  
     
     
         11 . The method of  claim 10  wherein said patient has an abnormally high parathyroid secretion and said therapeutically effective amount of said compound reduces said parathyroid hormone secretion in said patient to a degree sufficient to cause a decrease on plasma Ca 2+ .  
     
     
         12 . A method for modulating one or more Ca 2+  receptors activities in a cell comprising administration to said cell one or more compounds, or a pharmaceutically acceptable salt or hydrate thereof, having the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R′ and R″ are independently phenyl optionally substituted by one or more moieties independently selected from the group consisting of halogen, hydroxy, unsubstituted alkyl, lower alkyl substituted with one or more halogens, lower alkoxy optionally substituted with one or more halogens, nitro, phenyl, and a phenyl ring fused to R′ or R″ through two adjacent substituents.  
 
     
     
         13 . The method of  claim 12  wherein said cell is a parathyroid cell, a juxtaglomerular kidney cell, a proximal tubule kidney cell, a parafollicular thyroid cell, a bone osteoclast, a keratinocyte or a placental trophoblast.  
     
     
         14 . A method for treating or preventing a disorder selected from the group consisting of hyperparathyroidism, renal osteodystrophy, hypercalcemia malignancy, osteoporosis, Paget's disease and hypertension comprising administering to a patient suffering from said disorder a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the formula: wherein:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R′ and R″ are independently phenyl optionally substituted by one or more moieties independently selected from the group consisting of halogen, hydroxy, unsubstituted alkyl, lower alkyl substituted with one or more halogens, lower alkoxy optionally substituted with one or more halogens, nitro, phenyl, and a phenyl ring fused to R′ or R″ through two adjacent substituents.  
 
     
     
         15 . The method of  claim 14  wherein said hyperparathyroidism is primary hyperparathyroidism.  
     
     
         16 . The method of  claim 15  wherein said hyperparathyroidism is secondary hyperparathyroidism.  
     
     
         17 . A pharmaceutical composition for treatment of primary and secondary hyperparathyroidism comprising a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R′ and R″ are independently phenyl optionally substituted by one or more moieties independently selected from the group consisting of halogen, hydroxy, unsubstituted alkyl, lower alkyl substituted with one or more halogens, lower alkoxy optionally substituted with one or more halogens, nitro, phenyl, and a phenyl ring fused to R′ or R″ through two adjacent substituents.  
 
     
     
         18 . A pharmaceutical composition for treatment of renalosteodystrophy comprising a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R′ and R″ are independently phenyl optionally substituted by one or more moieties independently selected from the group consisting of halogen, hydroxy, unsubstituted alkyl, lower alkyl substituted with one or more halogens, lower alkoxy optionally substituted with one or more halogens, nitro, phenyl, and a phenyl ring fused to R′ or R″ through two adjacent substituents.  
 
     
     
         19 . A pharmaceutical composition for treatment of hypercalcemia comprising a compound, or, a pharmaceutically acceptable salt or hydrate thereof, having the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R′ and R″ are independently phenyl optionally substituted by one or more moieties independently selected from the group consisting of halogen, hydroxy, unsubstituted alkyl, lower alkyl substituted with one or more halogens, lower alkoxy optionally substituted with one or more halogens, nitro, phenyl, and a phenyl ring fused to R′ or R″ through two adjacent substituents.  
 
     
     
         20 . A pharmaceutical composition for treatment of hypercalcemia malignancy comprising a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R′ and R″ are independently phenyl optionally substituted by one or more moieties independently selected from the group consisting of halogen, hydroxy, unsubstituted alkyl, lower alkyl substituted with one or more halogens, lower alkoxy optionally substituted with one or more halogens, nitro, phenyl, and a phenyl ring fused to R′ or R″ through two adjacent substituents.  
 
     
     
         21 . A pharmaceutical composition for treatment of osteoporosis comprising a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the formula: wherein:  
       
         
           
           
               
               
           
         
       
       wherein  
       R′ and R″ are independently phenyl optionally substituted by one or more moieties independently selected from the group consisting of halogen, hydroxy, unsubstituted alkyl, lower alkyl substituted with one or more halogens, lower alkoxy optionally substituted with one or more halogens, nitro, phenyl, and a phenyl ring fused to R′ or R″ through two adjacent substituents.  
     
     
         22 . A compound selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or hydrate thereof.