New compounds for inhibiting differentiation of osteoclast and pharmaceutical composition comprising thereof

Abstract

New compounds and pharmaceutical compositions comprising active ingredients having inhibition effects on osteoclast differentiation are provided. The pharmaceutical compositions comprising the new compounds can be used as medicines for treating metabolic bone diseases such as bone metastatic cancer, solid cancer bone metastasis, musculoskeletal complication by solid cancer bone metastasis, hypercalcemia by malignant tumor, multiple myeloma, primary bone tumor, osteoporosis, rheumatoid arthritis, osteoarthritis, periodontal disease, inflammatory resorption of alveolar bone, inflammatory resorption of bone, and Paget's disease.

What is claimed is: 
     
         1 . A compound comprising the following formula I-a, formula I-b, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein, in Formula I-a or I-b, R 1  represents phenyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl, C 3-10 cycloalkyl or 5-10 membered heteroaryl including at least one selected from nitrogen atom, oxygen atom and sulfur atom in a ring; 
         wherein R 2  and R 3  each independently represent halogen, phenyl, hydroxy, C 6-10 aryl, C 6-10 arylC 1-6 alkyl, C 3-10 cycloalkyl or 5-membered heteroaryl including at least one selected from nitrogen atom, oxygen atom and sulfur atom in a ring; 
         wherein X and Y each independently represent hydrogen, oxo, hydroxy, S or CH 2 ; 
         wherein Z represents hydrogen, aminoC 1-6 alkyloraminoC 1-6 alkyl which is mono-, di- or tri-substituted by C 1-6 alkyl; and 
         wherein said C 6-10 aryl, C 3-10 cycloalkyl and 5-10 membered heteroaryl including at least one selected from nitrogen atom, oxygen atom and sulfur atom in a ring can be substituted by at least one substituent selected from the groups consisting of halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, alkoxy, amide and carboxy. 
       
     
     
         2 . The compound according to  claim 1 ,
 wherein:   R 1  represents phenyl, C 6-13 aryl, C 6-13 arylC 1-6 alkyl, C 3-10 cycloalkyl or 5-10 membered heteroaryl including at least one selected from nitrogen atom, oxygen atom and sulfur atom in a ring;   R 2  and R 3  each independently represent halogen, phenyl, hydroxy, C 6-10 aryl, C 6-10 arylC 1-6 alkyl, C 3-10 cycloalkyl or 5-10 membered heteroaryl including at least one selected from nitrogen atom, oxygen atom and sulfur atom in a ring;   X and Y each independently represent hydrogen, oxo or hydroxy;   Z represents hydrogen or aminoC 1-6 alkyl which is mono-, di- or tri-substituted by C 1-6 alkyl; and the above C 6-10 aryl, C 3-10 cycloalkyl and 5-10 membered heteroaryl including at least one selected from nitrogen atom, oxygen atom and sulfur atom in a ring can be substituted by at least one substituent selected from the groups consisting of halogen, hydroxy, C 1-3 alkyl, halogenated C 1-3 alkyl, amide and carboxy.   
     
     
         3 . The compound according to  claim 1 ,
 wherein the compound of formula I-a or I-b is one of:   1-(2,6-diisopropylphenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1,3,4-triphenyl-1H-pyrrole-2,5-dione;   1-(2-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(3-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   3,4-diphenyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione;   1-cyclohexyl-3,4-diphenyl-1H-pyrrole-2,5-dione;   4-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic acid;   5-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic acid;   3-chloro-1,4-diphenyl-1H-pyrrole-2,5-dione;   3-chloro-1-(2-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   3-chloro-1-(3-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   3-chloro-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   1-(2-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(3-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(4-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-benzyl-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(2-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(3-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(4-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-phenethyl-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(2-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(3-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(4-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   3-(2-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   3-(3-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   1,3-bis(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   1-(4-chlorophenyl)-3-(2,6-dichlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   1-(4-chlorophenyl)-5-hydroxy-3,4-diphenyl-1H-pyrrol-2(5H)-one;   1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrol-2(5H)-one;   1-(4-chlorophenyl)-3-((dimethylamino)methyl)-3,4-diphenylpyrrolidin-2-one;   3-hydroxy-1,4-diphenyl-1H-pyrrole-2,5-dione;   1-(4-chlorophenyl)-3-phenyl-4-(thiophen-2-yl)-1H-pyrrole-2,5-dione;   4-chloro-5-hydroxy-1,3-diphenyl-1H-pyrrol-2(5H)-one;   1-(4-chlorophenyl)-3,4-diphenyl-2,5-dihydro-1H-pyrrole; or   1-(4-chlorophenyl)-3,4-diphenylpyrrolidine-2,5-dione.   
     
     
         4 . The compound according to  claim 1 ,
 wherein the compound of formula I-a or I-b is one of:   1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   4-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic acid;   5-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic acid;   3-chloro-1-(2-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   3-chloro-1-(3-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   1-(2-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(3-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(2-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(3-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(4-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(2-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(3-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(4-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   3-(2-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   3-(3-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   1-(4-chlorophenyl)-3-(2,6-dichlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   1-(4-chlorophenyl)-5-hydroxy-3,4-diphenyl-1H-pyrrol-2(5H)-one;   1-(4-chlorophenyl)-3-((dimethylamino)methyl)-3,4-diphenylpyrrolidin-2-one;   1-(4-chlorophenyl)-3-phenyl-4-(thiophen-2-yl)-1H-pyrrole-2,5-dione;   4-chloro-5-hydroxy-1,3-diphenyl-1H-pyrrol-2(5H)-one; or   1-(4-chlorophenyl)-3,4-diphenylpyrrolidine-2,5-dione.   
     
     
         5 . The compound according to  claim 1 ,
 wherein the compound of formula I-a or I-b is one of:   4-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic acid;   5-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic acid;   3-chloro-1-(2-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   3-chloro-1-(3-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   1-(2-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(3-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(2-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(3-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(4-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(2-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(3-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(4-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   3-(2-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   3-(3-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   1-(4-chlorophenyl)-3-(2,6-dichlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   1-(4-chlorophenyl)-5-hydroxy-3,4-diphenyl-1H-pyrrole-2(5H)-one;   1-(4-chlorophenyl)-3-((dimethylamino)methyl)-3,4-diphenylpyrrolidin-2-one;   1-(4-chlorophenyl)-3-phenyl-4-(thiophen-2-yl)-1H-pyrrole-2,5-dione;   4-chloro-5-hydroxy-1,3-diphenyl-1H-pyrrol-2(5H)-one; or   1-(4-chlorophenyl)-3,4-diphenylpyrrolidine-2,5-dione.   
     
     
         6 . A pharmaceutical composition for preventing or treating metabolic bone disease, the composition comprising a compound of the following formula I-a or I-b, or a pharmaceutically acceptable salt thereof as an active ingredient, 
       
         
           
           
               
               
           
         
         Wherein, in Formula I-a or I-b, R 1  represents phenyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl, C 3-10 cycloalkyl or 5-10 membered heteroaryl including at least one selected from nitrogen atom, oxygen atom and sulfur atom in a ring; 
         wherein R 2  and R 3  each independently represent halogen, phenyl, hydroxy, C 6-10 aryl, C 6-10 arylC 1-6 alkyl, C 3-10 cycloalkyl or 5-membered heteroaryl including at least one selected from nitrogen atom, oxygen atom and sulfur atom in a ring; 
         wherein X and Y each independently represent hydrogen, oxo, hydroxy, S or CH 2 ; 
         wherein Z represents hydrogen, aminoC 1-6 alkyl or aminoC 1-6 alkyl which is mono-, di- or tri-substituted by C 1-6 alkyl; and 
         wherein said C 6-10 aryl, C 3-10 cycloalkyl and 5-10 membered heteroaryl including at least one selected from nitrogen atom, oxygen atom and sulfur atom in a ring can be substituted by at least one substituent selected from the groups consisting of halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, alkoxy, amide and carboxy. 
       
     
     
         7 . The pharmaceutical composition for preventing or treating metabolic bone disease according to  claim 6 ,
 wherein:   R 1  represents phenyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl, C 3-10 cycloalkyl or 5-10 membered heteroaryl including at least one selected from nitrogen atom, oxygen atom and sulfur atom in a ring;   R 2  and R 3  each independently represent halogen, phenyl, hydroxy, C 6-10 aryl, C 6-10 arylC 1-6 alkyl, C 3-10 cycloalkyl or 5-10 membered heteroaryl including at least one selected from nitrogen atom, oxygen atom and sulfur atom in a ring;   X and Y each independently represent hydrogen, oxo or hydroxy;   Z represents hydrogen or aminoC 1-6 alkyl which is mono-, di- or tri-substituted by C 1-6 alkyl; and   said C 6-10 aryl, C 3-10 cycloalkyl and 5-10 membered heteroaryl including at least one selected from nitrogen atom, oxygen atom and sulfur atom in a ring can be substituted by at least one substituent selected from the groups consisting of halogen, hydroxy, C 1-3 alkyl, halogenated C 1-3 alkyl, amide and carboxy.   
     
     
         8 . The pharmaceutical composition for preventing or treating metabolic bone disease according to  claim 6 , wherein the compound is selected from the groups consisting of
 1-(2,6-diisopropylphenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1,3,4-triphenyl-1H-pyrrole-2,5-dione;   1-(2-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(3-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   3,4-diphenyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione;   1-cyclohexyl-3,4-diphenyl-1H-pyrrole-2,5-dione;   4-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic acid;   5-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic acid;   3-chloro-1,4-diphenyl-1H-pyrrole-2,5-dione;   3-chloro-1-(2-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   3-chloro-1-(3-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   3-chloro-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   1-(2-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(3-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(4-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-benzyl-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(2-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(3-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(4-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-phenethyl-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(2-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(3-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(4-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   3-(2-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   3-(3-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   1,3-bis(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   1-(4-chlorophenyl)-3-(2,6-dichlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   1-(4-chlorophenyl)-5-hydroxy-3,4-diphenyl-1H-pyrrol-2(5H)-one;   1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrol-2(5H)-one;   1-(4-chlorophenyl)-3-((dimethylamino)methyl)-3,4-diphenylpyrrolidin-2-one;   3-hydroxy-1,4-diphenyl-1H-pyrrole-2,5-dione;   1-(4-chlorophenyl)-3-phenyl-4-(thiophen-2-yl)-1H-pyrrole-2,5-dione;   4-chloro-5-hydroxy-1,3-diphenyl-1H-pyrrol-2(5H)-one;   1-(4-chlorophenyl)-3,4-diphenyl-2,5-dihydro-1H-pyrrole; and   1-(4-chlorophenyl)-3,4-diphenylpyrrolidine-2,5-dione, or   
       pharmaceutically acceptable salts thereof as an active ingredient. 
     
     
         9 . The pharmaceutical composition for preventing or treating metabolic bone disease according to  claim 6 , wherein the compound is selected from the groups consisting of 1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
 4-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic acid;   5-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic acid;   3-chloro-1-(2-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   3-chloro-1-(3-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   1-(2-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(3-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(2-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(3-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(4-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(2-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(3-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   1-(4-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;   3-(2-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   3-(3-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   1-(4-chlorophenyl)-3-(2,6-dichlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;   1-(4-chlorophenyl)-5-hydroxy-3,4-diphenyl-1H-pyrrol-2(5H)-one;   1-(4-chlorophenyl)-3-((dimethylamino)methyl)-3,4-diphenylpyrrolidin-2-one;   1-(4-chlorophenyl)-3-phenyl-4-(thiophen-2-yl)-1H-pyrrole-2,5-dione;   4-chloro-5-hydroxy-1,3-diphenyl-1H-pyrrol-2(5H)-one; and   1-(4-chlorophenyl)-3,4-diphenylpyrrolidine-2,5-dione, or   
       pharmaceutically acceptable salts thereof as an active ingredient. 
     
     
         10 . The pharmaceutical composition for preventing or treating metabolic bone disease according to  claim 6 , comprising 1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione as an active ingredient. 
     
     
         11 . The pharmaceutical composition for preventing or treating metabolic bone disease according to  claim 6 ,
 wherein the metabolic bone disease is selected from the groups consisting of bone metastatic cancer, solid cancer bone metastasis, musculoskeletal complication by solid cancer bone metastasis, hypercalcemia by malignant tumor, multiple myeloma, primary bone tumor, osteoporosis, Rheumatoid Arthritis, Osteoarthritis, Periodontal Disease, inflammatoryresorption of alveolar bone, inflammatory resorption of boneand Paget's disease.   
     
     
         12 . The pharmaceutical composition for preventing or treating metabolic bone disease according to  claim 6 ,
 wherein the metabolic bone disease is selected from the groups consisting of bone metastatic cancer, solid cancer bone metastasis, musculoskeletal complication by solid cancer bone metastasis, hypercalcemia by malignant tumor and multiple myeloma.