Tetra-O-substituted butane-bridge modified NDGA derivatives, their synthesis and pharmaceutical use

A butane bridge modified tetra-O-substituted nordihydroguaiaretic acid derivative compound (BB-Sb4N), having the following general structure (Formula VI), and its pharmaceutically acceptable salts:

• wherein each Z is selected from the group consisting of H, —CHO, —CN, —CH2CH3, —CH2Cl, —CH2Br and —CH2F;
• wherein Y 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, namely any of chlorine, fluorine, bromine or iodine;
• —(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, T1 is a saturated linear hydrocarbon chain of 2-6 carbons and optionally 1-3 halogen atoms, T2 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 T3 is methyl or ethyl;
• wherein when Y is -A-R, the side chain A is selected from the group consisting of a C2-C6 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 NGDA through an ether bond;
• and 1-5 units of a polyethylene glycol (PEG) chain;
• the end group 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 for a 6- or 7-member ring and 1 to 2 double bonds for a 5-member ring, with 1 to 3 N, O or S heteroatoms for the 5 to 7 member ring;
• 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 sugar and a polyhydroxy group or a pharmaceutically acceptable salt thereof.