Low calcemic, highly antiproliferative, analogs of calcitriol

Abstract

The disclosure provides compounds, compositions and methods using these compounds and compositions to stimulate the differentiation of cells and inhibit excessive cell proliferation of certain cells, including cancer cells and skin cells, which may be useful in the treatment of diseases characterized by abnormal cell proliferation and/or cell differentiation such as leukemia, myelofibrosis and psoriasis without the well known effect on calcium metabolism, which gives rise to hypercalcemia.

1 . A compound having formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
    is a single bond; 
 X is O; 
 L 1  is a direct bond; 
 L 2  is a direct bond; 
 R 1  is an optionally substituted alkyl group; 
 R 2  is H, alkyl, or perfluoroalkyl; 
 R 3  is independently H, F, Cl, Br, I, OH, CN, NO 2 , substituted or unsubstituted alkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —(CH 2 ) j OR 4 , —(CH 2 ) j C(O)R 4 , —(CH 2 ) j C(NR 7 )R 4 , —(CH 2 ) j C(NNR 7 )R 4 , —(CH 2 ) j C(O)OR 4 , —(CH 2 ) j NR 5 R 6 , —(CH 2 ) j C(O)NR 5 R 6 , —(CH 2 ) j OC(O)NR 5 R 6 , —(CH 2 ) j NR 7 C(O)R 4 , —(CH 2 ) j NR 7 C(O)OR 4 , —(CH 2 ) j NR 7 C(O)NR 5 R 6 , —(CH 2 ) j S(O) m R 8 , —(CH 2 ) j NR 7 S(O) 2 R 8 , or —(CH 2 ) j S(O) 2 NR 5 R 6 , wherein each j is independently an integer from 0 to 6, wherein m is independently an integer from 0 to 2, and wherein alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are each optionally independently substituted with 1 to 3 R 9  groups; 
 R 4  is independently H, substituted or unsubstituted alkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl, wherein R 4  is optionally independently substituted with 1 to 3 R 9  groups; 
 R 5 , R 6 , R 7  and R 8  are each independently a direct bond, H, OH, —(CH 2 ) j OR 9 , substituted or unsubstituted alkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl, wherein R 5 , R 6 , R 7 , and R 8  are each optionally independently substituted with 1 to 3 R 9  groups, or 
 R 7  and R 8  are as described above, and R 5  and R 6 , together with the N atom to which they are attached, form substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl, wherein R 5  and R 6  are each optionally independently substituted with 1 to 3 R 9  groups; and 
 R 9  is H, F, Cl, Br, I, OH, CN, NO 2 , alkyl, perfluoroalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —(CH 2 ) j OR 10 , —(CH 2 ) j C(O)R 10 , —(CH 2 ) j C(NR 13 )R 4 , —(CH 2 ) j C(O)OR 10 , —(CH 2 ) j NR 11 R 12 , —(CH 2 ) j C(O)NR 11 R 12 , —(CH 2 ) j OC(O)NR 11 R 12 , —(CH 2 ) j NR 13 C(O)R 14 , —(CH 2 ) j NR 13 C(O)OR 10 , —(CH 2 ) j NR 13 C(O)NR 11 R 12 , —(CH 2 ) j S(O) m R 15 , —(CH 2 ) j NR 13 S(O) 2 R 15 , or —(CH 2 ) j S(O) 2 NR 11 R 12 ; wherein each j is independently an integer from 0 to 6, wherein m is independently an integer from 0 to 2; and 
 R 10 , R 11 , R 12 , R 13 , R 14  and R 15  are each independently H, F, Cl, Br, I, OH, CN, NO 2 , alkyl, perfluoroalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl. 
 
     
     
         2 - 9 . (canceled) 
     
     
         10 . A pharmaceutical composition, comprising an effective amount of one or more of the compounds of formula I of  claim 1 , together with one or more pharmaceutically acceptable carriers, optionally in topical, oral or injectable form. 
     
     
         11 . The compound of formula I of  claim 1  or the pharmaceutical composition of  claim 10  for use in treating patients suffering from disorders characterized by abnormal cell-proliferation and/or cell-differentiation. 
     
     
         12 . The compound of formula I of  claim 1  or the pharmaceutical composition of  claim 10  for use in treating patients suffering from secondary hyperparathyroidism. 
     
     
         13 . A method of preparing the compound of formula I of  claim 1 , comprising: 
       
         
           
           
               
               
           
         
         a) reacting the compound of formula XI with base to form the corresponding anion; 
         b) coupling the anion with the compound of formula XII, wherein PG is a protecting group; and 
         c) removing the protecting groups to provide the compound of formula I. 
       
     
     
         14 . The method of  claim 13 , wherein the base is an alkali metal or organolithium compound; and the protecting group is a silyl protecting group. 
     
     
         15 . The method of  claim 14 , wherein the alkali metal is sodium hydride or lithium hydride; the organolithium compound is n-butyl lithium, sec-butyl lithium or tert-butyl lithium, and the silyl protecting group is tert-butyldimethylsilane.