Methods of promoting osteogenesis

Abstract

The invention is directed to methods of bone healing by administering a p38 MAP kinase inhibitor. The invention is directed to methods of treating bone fractures, bone diseases, bone grafting, especially enhancing bone healing following facial reconstruction, maxillary reconstruction, mandibular reconstruction or tooth extraction, enhancing long bone extension, enhancing prosthetic ingrowth, and increasing bone synostosis by administering a p38 MAP kinase inhibitor.

1 . A method of promoting osteogenesis in a patient, said method comprising administering to a patient in need of osteogenesis a pharmaceutically effective amount of a p38 mitogen activated protein (MAP) kinase inhibitor of the formula (1):  
       
         
           
           
               
               
           
         
         and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, wherein  
           represents a single or double bond;  
         one Z 2  is CA or CR 8 A and the other is CR 1 , CR 1   2 , NR 6  or N wherein each R 1 , R 6  and R 8  is independently hydrogen or noninterfering substituent;  
         A is —CO(X) j Y wherein Y is COR 2  or an isostere thereof and R 2  is hydrogen or a noninterfering substituent, X is a spacer of preferably 2-6 Å, and j is 0 or 1;  
         Z 3  is NR 7  or O;  
         each R 3  is independently a noninterfering substituent;  
         n is 0-3;  
         each of L 1  and L 2  is a linker;  
         each R 4  is independently a noninterfering substituent;  
         m is 0-4;  
         Z 1  is CR 5  or N wherein R 5  is hydrogen or a noninterfering substituent;  
         each of 1 and k is an integer from 0-2 wherein the sum of 1 and k is 0-3;  
         Ar is an aryl group substituted with 0-5 noninterfering substituents, wherein two noninterfering substituents can form a fused ring; and  
         the distance between the atom of Ar linked to L and the center of the α ring is preferably 4.5-24 Å.  
       
     
     
         2 . The method of  claim 1 , wherein said patient is in need of treatment of bone fracture.  
     
     
         3 . The method of  claim 2 , wherein said patient has a traumatic bone fracture or a long-term bone fracture.  
     
     
         4 . The method of  claim 1 , wherein said patient is in need of enhanced bone grafting.  
     
     
         5 . The method of  claim 1 , wherein said patient is in need of treatment of a bone disease.  
     
     
         6 . The method of  claim 5 , wherein the bone disease is selected from the group consisting of arthritis, osteoarthritis, and osteoporosis.  
     
     
         7 . The method of  claim 1 , wherein said patient is in need of decreased bone resorption.  
     
     
         8 . The method of  claim 1 , wherein said patient is a human.  
     
     
         9 . The method of  claim 1 , wherein administration of said p38 MAP kinase inhibitor decreases osteoclast numbers.  
     
     
         10 . A method of enhancing bone healing following facial reconstruction, maxillary reconstruction, mandibular reconstruction, periodontal disease or tooth extraction, enhancing long bone extension, enhancing prosthetic ingrowth or increasing bone synostosis in a patient, said method comprising administering a therapeutically effective amount of a p38 mitogen activated protein (MAP) kinase inhibitor to a patient in need of the same.  
     
     
         11 . The method of  claim 14 , wherein said patient is a human.  
     
     
         12 . A method of increasing bone mass in a mammal, said method comprising administering a therapeutically effective amount of a p38 mitogen activated protein (MAP) kinase inhibitor to a mammal in need of increased bone mass.  
     
     
         13 . A method of increasing chondrocyte differentiation in a mammal, said method comprising administering a therapeutically effective amount of a p38 mitogen activated protein (MAP) kinase inhibitor to a mammal in need of increased chondrocyte differentiation.  
     
     
         14 . A method of accelerating cartilage formation in a mammal, said method comprising administering a therapeutically effective amount of a p38 mitogen activated protein (MAP) kinase inhibitor to a mammal in need of accelerated cartilage formation.