Low calcemic, highly antiproliferative, analogs of calcitriol
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 thereof, wherein:
m is an integer from 0 to 1;
R 1 is selected from the group consisting of
and
each n is independently an integer from 0 to 2.
2. The compound of claim 1 , wherein the compound of formula I has formula IV:
or a pharmaceutically acceptable salt thereof.
3. A method of treating a disorder characterized by abnormal cell-proliferation and/or cell-differentiation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I of claim 1 , wherein the disorder is selected from the group consisting of leukemia, myelofibrosis and psoriasis.
4. A method of treating secondary hyperparathyroidism, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I of claim 1 .
5. 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.
6. The method of claim 5 , wherein the base is an alkali metal hydride or organolithium compound; and the protecting group is a silyl protecting group.