Calcilytic compounds

Abstract

Novel calcilytic compounds and methods of using them are provided.

What is claimed is:  
     
         1 . A compound according to Formula (I) herein below:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is an aryl or fused aryl, dihydro or tetrahydro fused aryl, heteroaryl or fused heteroaryl, dihydro or tetrahydro fused heteroaryl, unsubstituted or substituted with any substituent being selected from the group consisting of OH, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 3-6  cycloalkyl, CF 3 , OCF 3 , CN, and NO 2 ;  
 X 1  and X 5  are independently selected from the group consisting of H, halogen, CN, and NO 2 , provided that either X 1  or X 5  is H;  
 X 2 , X 3  and X 4  are selected from the group consisting of H, halogen, O—C 1-4  alkyl, and J-K, wherein: 
 J is a covalent bond, alkylene, O-alkylene or alkenylene; and  
 K is selected from the group consisting of, CO 2 R 5 , CONR 4 R′ 4 , OH, NR 4 R′ 4  and CN;  
 
 R 4  and R′ 4  are independently H, alkyl, aryl or heteroaryl;  
 R 5  is H, alkyl, or alkyl-(O-alkyl) m -O-alkyl;  
 n is an integer from 0 to 4; and  
 m is an integer from 1-3;  
 or a pharmaceutically acceptable salt thereof of.  
 
     
     
         2 . A compound according to  claim 1  with a structure according to Formula (II) herein below:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is an aryl or fused aryl, dihydro or tetrahydro fused aryl, heteroaryl or fused heteroaryl, dihydro or tetrahydro fused heteroaryl, unsubstituted or substituted with any substituent being selected from the group consisting of halogen, C 1-4  alkyl, C 1-4  alkoxy, CF 3 , and OCF 3 ;  
 X 1  and X 5  are independently selected from the group consisting of H, halogen, CN, and NO 2 , provided that either X 1  or X 5  is H;  
 X 2 , X 3  and X 4  are selected from the group consisting of H, halogen, O—C 1-4  alkyl, and J-K, wherein: 
 J is a covalent bond, alkylene, O-alkylene or alkenylene; and  
 K is selected from the group consisting of, CO 2 R 5 , CONR 4 R′ 4 , and NR 4 R′ 4 ;  
 
 R 4  and R′ 4  are independently H, alkyl, aryl or heteroaryl;  
 R 5  is H, alkyl, or alkyl-(O-alkyl) m -O-alkyl;  
 n is an integer from 0 to 4; and  
 m is an integer from 1-3.  
 
     
     
         3 . A compound according to  claim 2  having a structure according to Formula (III) herein below:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is an aryl or fused aryl, dihydro or tetrahydro fused aryl, heteroaryl or fused heteroaryl, dihydro or tetrahydro fused heteroaryl, unsubstituted or substituted with any substituent being selected from the group consisting of halogen, C 1-4  alkoxy, CF 3 , and OCF 3 ;  
 X 1  and X 5  are independently selected from the group consisting of H, halogen and CN, provided that either X 1  or X 5  is H;  
 X 2 , X 3  and X 4  are selected from the group consisting of H, halogen, O—C 1-4  alkyl, and J-K, wherein: 
 J is a covalent bond, alkylene, O-alkylene or alkenylene; and  
 K is CO 2 R 5 ;  
 
 R 5  is H, or alkyl; and 
 n is an integer from 0 to 4.  
 
 
     
     
         4 . A compound according to  claim 1  selected from the group consisting of: 
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic ethyl ester;  
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid;  
 3-{4-Cyano-3-[(S)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic ethyl ester;  
 3-{4-Cyano-3-[(S)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid;  
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid octyl ester;  
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid 2-methoxy-ethyl ester;  
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid butyl ester;  
 3-{4-Cyano-3-[(R)-2-hydoxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxyl]-phenyl}-propionic acid isopropyl ester;  
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid pentyl ester;  
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid 2-ethoxy ethyl ester;  
 3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid 3-methyl-butyl ester;  
 3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid 1-ethyl-propyl ester;  
 3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid sec-butyl ester;  
 3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid 2-methoxy-1-methyl-ethyl ester;  
 2,2-Dimethyl-propionic acid 3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propanoyloxymethyl ester;  
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid (S)-2-amino-3-methyl-butyl ester;  
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid 5-amino-pentyl ester;  
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid methyl ester;  
 3-(4-Cyano-3-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid;  
 3-(4-Cyano-3-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid ethyl ester;  
 3-(3-Cyano-4-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid;  
 3-(3-Cyano-4-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid ethyl ester;  
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-5-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid;  
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-5-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionate ethyl ester;  
 3-{2-Chloro-4-cyano-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic ethyl ester;  
 3-{2-Chloro-4-cyano-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid;  
 3-{2-Fluoro-4-cyano-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic ethyl ester;  
 3-{2-Fluoro-4-cyano-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid;  
 3-{2-Cyano-3-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-hydroxy-propoxy]-phenyl}-propionic acid ethyl ester;  
 4-{2-Cyano-3-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric acid ethyl ester;  
 3-{2-Cyano-3-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-hydroxy-propoxy]-phenyl}-propionic acid;  
 4-{2-Cyano-3-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric acid;  
 4-{4-Cyano-3-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric acid ethyl ester;  
 4-{4-Cyano-3-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric acid;  
 4-{3-Cyano-4-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric acid ethyl ester;  
 4-{3-Cyano-4-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric acid;  
 3-{2-Cyano-3-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydroxy-propoxy]-phenyl}-propionic acid ethyl ester;  
 4-{2-Cyano-3-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric acid ethyl ester;  
 3-{2-Cyano-3-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydroxy-propoxy]-phenyl}-propionic acid;  
 4-{2-Cyano-3-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric acid;  
 4-{4-Cyano-3-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric acid ethyl ester;  
 4-{4-Cyano-3-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric acid;  
 4-{3-Cyano-4-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric acid ethyl ester;  
 4-{3-Cyano-4-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric acid;  
 (S)-2-Amino-3-{4-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-hydroxy-propoxy]-3-nitro-phenyl}-propionic acid ethyl ester;  
 (S)-2-Amino-3-{4-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-hydroxy-propoxy]-3-nitro-phenyl}-propionic acid;  
 (R)-2-Amino-5-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pentanoic acid ethyl ester;  
 (R)-2-Amino-5-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pentanoic acid;  
 5-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pentanoic acid ethyl ester;  
 5-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pentanoic acid;  
 (R)-2-Amino-5-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid ethyl ester;  
 (R)-2-Amino-5-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid;  
 (S)-2-Amino-5-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid ethyl ester; and  
 (S)-2-Amino-5-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         5 . A compound according to  claim 4  selected from the group consisting of: 
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic ethyl ester;  
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid;  
 3-{4-Cyano-3-[(R)-2-hydoxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxyl]-phenyl}-propionic acid isopropyl ester;  
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid 2-ethoxy ethyl ester;  
 3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid 2-methoxy-1-methyl-ethyl ester;  
 3-(4-Cyano-3-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid;  
 3-(4-Cyano-3-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid ethyl ester;  
 3-(3-Cyano-4-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid;  
 3-(3-Cyano-4-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid ethyl ester;  
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-5-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid; and  
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-5-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionate ethyl ester;  
 and pharmaceutically acceptable salts and complexes thereof.  
 
     
     
         6 . A compound according to  claim 5  selected from the group consisting of: 
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic ethyl ester; and  
 3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid;  
 and pharmaceutically acceptable salts and complexes thereof.  
 
     
     
         7 . A method of antagonizing a calcium receptor, which comprises administering to a subject in need thereof, an effective amount of a compound according to  claim 1 .  
     
     
         8 . A method of treating a disease or disorder characterized by an abnormal bone or mineral homeostasis, which comprises administering to a subject in need of treatment thereof an effective amount of a compound of  claim 1 .  
     
     
         9 . A method according to  claim 8  wherein the bone or mineral disease or disorder is selected from the group consisting of osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia, malignancy and osteoporosis.  
     
     
         10 . A method according to  claim 8  wherein the bone or mineral disease or disorder is osteoporosis.  
     
     
         11 . A method of increasing serum parathyroid levels which comprises administering to a subject in need of treatment an effective amount of a compound of  claim 1 .  
     
     
         12 . A method according to  claim 7  wherein the calcilytic compound is co-administered with an anti-resorptive agent.  
     
     
         13 . A method according to  claim 12  wherein the anti-resorptive agent is selected from the group consisting of estrogen, 1, 25 (OH) 2  vitamin D3, calcitonin, selective estrogen receptor modulators, vitronectin receptor antagonists, V-H+-ATPase inhibitors, src SH 2  antagonists, bisphosphonates and cathepsin K inhibitors.  
     
     
         14 . A compound selected from the group consisting of: 
 2-Indan-2-yl-1,1-dimethyl-ethylamine;    Indan-2-yl-acetic acid methyl ester;    1-Indan-2-yl-2-methyl-propan-2-ol;    N-(2-Indan-2-yl-1,1-dimethyl-ethyl)-acetamide;    Ethyl (R)-4-cyano-3-(oxiranylmethoxy)benzenepropionate;    Ethyl 4-formyl-3-hydroxybenzenepropionate;    Ethyl 3-hydroxy-4-[(hydroxyimino)methyl]benzenepropionate;    Ethyl 3-acetoxy-4-cyanobenzenepropionate; and    Ethyl 4-cyano-3-hydroxybenzenepropionate.