Methods for using synthetic triterpenoids in the treatment of bone or cartilage diseases or conditions

Abstract

The present invention features the use of a synthetic triterpenoid to induce gene expression and differentiation of stem or progenitor cells in the treatment of bone/cartilage diseases or conditions.

What is claimed is: 
     
         1 . A method for producing a stem or progenitor cell with induced gene expression comprising contacting a stem or progenitor cell with an effective amount of a synthetic triterpenoid to induce the expression of one or more of SOX9 (Sex determining region Y-box 9), COL2A1 (Type II Collagen (alpha1)), TGF (Transforming Growth Factor)-β1, TGF-β2, TGF-β3, BMP (Bone Morphogenic Protein) 2, BMP4, BMPRII (Bone Morphogenic Protein Receptor II), SMAD (Small Mothers Against Decapentaplegic) 3, SMAD4, SMAD6, SMAD7, TIMP (Tissue Inhibitor of Metalloproteinase)-1 or TIMP-2 in the stem or progenitor cell, wherein the stem or progenitor cell is a mesenchymal stem cell, adipose tissue-derived mesenchymal stem cell, embryonic stem cell, stem cell from exfoliated deciduous teeth, periosteum cell, osteoprogenitor cell, or growth plate progenitor cell. 
     
     
         2 . The method of  claim 1 , wherein the synthetic triterpenoid has the structure of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein,
 X′ and X 2  are independently hydrogen, OR a , NR a R b , or SR a , wherein
 R a  is a hydrogen, cyano, —CF 3 , nitro, amino, or substituted or unsubstituted heteroaryl group; 
 R b  is hydrogen, hydroxyl, alkyl, aryl, aralkyl, acyl, alkoxy, aryloxy, acyloxy, alkylamino, arylamino, amido, or a substituted version of any of these groups; 
 or a substituent convertible in vivo to hydrogen; 
 provided that R a  is absent when the atom to which it is bound is part of a double bond, further provided that when R a  is absent the atom to which it is bound is part of a double bond; 
 
 Y is CH 2  or CH 2 —CH 2 ; 
 Z is a covalent bond, —C(═O)—, alkanediyl, alkenediyl, alkynediyl, or a substituted version of any of these groups; 
 the dashed bonds can be independently present or absent; 
 R 1 , R 2 , R 3  and R 4  are each independently a hydrogen, hydroxyl, alkyl, substituted alkyl, alkoxy or substituted alkoxy group; 
 R 5 , R 6 , R 7 , R 8 , R 9  and R 10  are independently hydrogen, hydroxyl, halo, cyano, —C═CR a , —CO 2 R a , —COR a , alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, alkoxy, aryloxy, acyloxy, alkylamino, arylamino, nitro, amino, amido, —C(O)R c  or a substituted version of any of these groups, wherein
 R c  is hydrogen, hydroxy, halo, amino, hydroxyamino, azido or mercapto; or C 1 -C 15 -alkyl, C 2 -C 15 -alkenyl, C 2 -C 15 -alkynyl, C 6 -C 15 -aryl, C 7 -C 15 -aralkyl, C 1 -C 15 -heteroaryl, C 2 -C 15 -heteroaralkyl, C 1 -C 15 -acyl, C 1 -C 15 -alkoxy, C 2 -C 15 -alkenyloxy, C 2 -C 15 -alkynyloxy, C 6 -C 15 -aryloxy, C 7 -C 15 -aralkyloxy, C 1 -C 15 -heteroaryloxy, C 2 -C 15 -heteroaralkyloxy, C 1 -C 15 -acyloxy, C 1 -C 15 -alkylamino, C 2 -C 15 -dialkylamino, C 1 -C 15 -alkoxyamino, C 2 -C 15 -alkenylamino, C 2 -C 15 -alkynylamino, C 6 -C 15 -arylamino, C 7 -C 15 -aralkylamino, C 1 -C 15 -heteroarylamino, C 2 -C 15 -heteroaralkylamino, C 1 -C 15 -alkylsulfonylamino, C 1 -C 15 -amido, C 1 -C 15 -alkylsilyloxy, or substituted versions of any of these groups; 
 
 R 5  and R 6 , R 7  and R 8 , or R 9  and R 10  are independently taken together as ═O; 
 R 11  and R 12  are each independently hydrogen, hydroxyl, halo, alkyl , alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, alkoxy, aryloxy, aralkoxy, heteroaryloxy, hetero-aralkoxy, acyloxy, alkylamino, dialkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, amido, or a substituted version of any of these groups, or 
 R 11  and R 12  are taken together and are alkanediyl, alkenediyl, arenediyl, alkoxydiyl, alkenyloxydiyl, alkylaminodiyl, alkenylaminodiyl, or alkenylaminooxydiyl; 
 R 13  is hydrogen, hydroxy or oxo; 
 R 14  is hydrogen or hydroxyl; and 
 R 15  is
 a hydrogen, hydroxyl, —NR d R e , cyano, halo, azido, phosphate, 1,3-dioxoisoindolin-2-yl, mercapto, silyl or —COOH group, 
 substituted or unsubstituted versions of C 1 -C 15 -alkyl, C 2 -C 15 -alkenyl, C 2 -C 15 -alkynyl, C 6 -C 15 -aryl, C 7 -C 15 -aralkyl, C 1 -C 15 -heteroaryl, C 2 -C 15 -heteroaralkyl, C 1 -C 15 -acyl, C 1 -C 15 -alkoxy, C 2 -C 15 -alkenyloxy, C 2 -C 15 -alkynyloxy, C 6 -C 15 -aryloxy, C 7 -C 15 -aralkyloxy, C 1 -C 15 -heteroaryloxy, C 2 -C 15 -heteroaralkyloxy, C 1 -C 15 -acyloxy, C 1 -C 15 -alkylamino, C 2 -C 15 -alkenylamino, C 2 -C 15 -alkynylamino, C 6 -C 15 -arylamino, C 7 -C 15 -aralkylamino, C 1 -C 15 -heteroarylamino, C 2 -C 15 -heteroaralkylamino, C 1 -C 15 -amido, C 1 -C 15 -alkylthio, C 2 -C 15 -alkenylthio, C 2 -C 15 -alkynylthio, C 6 -C 15 -arylthio, C 7 -C 15 -aralkylthio, C 1 -C 15 -heteroarylthio, C 2 -C 15 -heteroaralkylthio, C 1 -C 15 -acylthio, C 1 -C 12 -thioacyl, C 1 -C 12 -alkylsulfonyl, C 2 -C 12 -alkenylsulfonyl, C 2 -C 12 -alkynylsulfonyl, C 6 -C 12 -arylsulfonyl, C 7 -C 12 -aralkylsulfonyl, C 1 -C 12 -heteroarylsulfonyl, C 1 -C 12 -heteroaralkylsulfonyl, C 1 -C 12 -alkylsulfinyl, C 2 -C 12 -alkenylsulfinyl, C 2 -C 12 -alkynylsulfinyl, C 6 -C 12 -aryl sulfinyl, C 7 -C 12 -aralkylsulfinyl, C 1 -C 12 -heteroarylsulfinyl, C 1 -C 12 -heteroaralkylsulfinyl, C 1 -C 12 -alkylphosphonyl, C 1 -C 12 -alkylphosphate, C 2 -C 12 -dialkylphosphate, C 1 -C 12 -alkylammonium, C 1 -C 12 -alkylsulfonium, C 1 -C 15 -alkylsilyl, or a substituted version of any of these groups, 
 
 a —CO 2 Me, carbonyl imidazole, —CO—D-Glu(OAc) 4 , —CONH 2 , —CONHNH 2 , —CONHCH 2 CF 3 , or —C(═O)-heteroaryl group, or
 Z and R 15  form a three to seven-membered ring, such that Z and R 15  are further connected to one another through one or more of —O— and alkanediyl, further wherein Z is —CH— and R 15  is —CH 2 — or Z, R 15 , and carbon numbers 13, 17 and 18 form a ring such that R 15  is bound to carbon 13, wherein Y is methanediyl or substituted methanediyl and R 15  is —O—, wherein 
 R d  and R e  are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, thioacyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, aralkylsulfonyl, heteroarylsulfonyl, or heteroaralkylsulfonyl, or a substituted version of any of these groups. 
 
 
     
     
         3 . The method of  claim 1 , wherein the stem or progenitor cell is multipotent. 
     
     
         4 . A stem or progenitor cell produced by the method of  claim 1 . 
     
     
         5 . A method for treating a degenerative disease or injury comprising transplanting into a patient suffering from a degenerative disease or injury a stem or progenitor cell of  claim 4  thereby treating the patient's degenerative disease or injury, wherein the degenerative disease or injury is bone injury, cartilage injury, joint injury, dental disease, osteoarthritis, rheumatoid arthritis, degenerative disc disease, kyphosis, or osteopenia. 
     
     
         6 . A method for treating a congenital disorder comprising transplanting into a patient suffering from a congenital disorder a stem or progenitor cell of  claim 4  thereby treating the patient's congenital disorder, wherein the congenital disorder is scoliosis or a skeletal disorder. 
     
     
         7 . A method for treating a degenerative disease or injury comprising administering to a patient suffering from a degenerative disease or injury an effective amount of a synthetic triterpenoid thereby treating the patient's degenerative disease or injury, wherein the degenerative disease or injury is bone injury, cartilage injury, joint injury, degenerative disc disease, dental disease, osteoarthritis, rheumatoid arthritis, kyphosis, or osteopenia. 
     
     
         8 . A method for treating a congenital disorder comprising administering to a patient suffering from a congenital disorder an effective amount of a synthetic triterpenoid thereby treating the patient's congenital disorder, wherein the congenital disorder is scoliosis or a skeletal disorder.