Tetra-substituted NDGA derivatives via ether bonds and carbamate bonds and their synthesis and pharmaceutical use

A nordihydroguaiaretic acid (NDGA) derivative compound having the following general structure (Formula IV), and its pharmaceutically acceptable salts:

• wherein X is selected from the group consisting of:
• -A-R;
• —(CH2)xHal, where x is an integer of 1 to 10, and Hal is a halogen atom, and
• —(CH2CH2O)yH, where y is an integer of 1 to 10;
• and
• a carbamate-bonded group selected from the group consisting of:
• where n is an integer of 1 to 6, Z1 is a saturated linear hydrocarbon chain of 2-6 carbons and optionally 1-3 halogen atoms, Z2 is a 5- to 7-member ring optionally containing 0-3 double bonds and optionally containing 1-3 atoms of any of O, N and S, and Z3 is methyl or ethyl;
• wherein when X is -A-R, R is an end group and A is a linear saturated hydrocarbon side chain bonded at one end to the respective hydroxy residue O groups of NDGA by an ether bond from NDGA or a carbamate bond and at the other end to a carbon or a heteroatom in the end group R;
• wherein the side chain A is selected from the group consisting of a C2-C16 linear saturated hydrocarbon chain optionally with 1-5 heteroatoms selected from the group consisting of O, N and S, bonded to the respective hydroxy residue O groups of NDGA through an ether bond from NDGA;
• and 1-5 units of a polyethylene glycol (PEG) chain;
• wherein R is selected from the group consisting of:
• a 5 to 7 member carbocyclic ring selected from the group consisting of a fully saturated ring with 1 to 3 N, O or S heteroatoms;
• a ring containing 1 to 3 double bonds with 1 to 3 N, O or S heteroatoms;
• a ring containing a carbamate bond, a urea bond, a carbonate bond or an amide bond;
• and a water soluble group selected from the group consisting of an alkali metal salt of sulfonic acid;
• an alkali metal salt of phosphonic acid;
• a pharmaceutically acceptable salt;
• a sugar and a polyhydroxy group;
• and
• wherein when X is
• a is an integer of 3 to 16 and b is an integer of 4 to 16.