Tetra-o-substituted butane-bridge modified ndga derivatives, their synthesis and pharmaecutical use

Abstract

The present invention relates to nordihydroguaiaretic acid derivative compounds, namely, butane bridge modified nordihydroguaiaretic acid (NDGA) compounds and butane bridge modified tetra-O-substituted NDGA compounds, pharmaceutical compositions containing them, methods of making them, and methods of using them and kits including them for the treatment of diseases and disorders, in particular, diseases resulting from or associated with a virus infection, such as HIV infection, HPV infection, or HSV infection, an inflammatory disease, such as various types of arthritis and inflammatory bowel diseases, metabolic diseases, such as diabetes and hypertension, or a proliferative disease, such as diverse types of cancers.

We claim: 
     
         1 . 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, R is an end group and A is a linear saturated hydrocarbon side chain with optional heteroatoms that is bonded at one end to the respective hydroxy residue O groups by an ether bond or a carbamate bond and at the other end to a carbon or a heteroatom in the end group R; an alkali metal salt of phosphonic acid; a sugar and a polyhydroxy group or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A composition comprising the BB-Sb4N compound of  claim 1  and a pharmaceutically acceptable carrier, optionally with other pharmaceutically acceptable excipients. 
     
     
         3 . A method of administering to a subject an amount of the BB-Sb4N compound of  claim 1  alone or as part of a pharmaceutical composition effective prophylactically or for treating a viral infection. 
     
     
         4 . A method of administering to a subject an amount of the BB-Sb4N compound of  claim 1  alone or as part of a pharmaceutical composition effective prophylactically or for treating a proliferative disease. 
     
     
         5 . A method of administering to a subject an amount of the BB-Sb4N compound of  claim 1  alone or as part of a pharmaceutical composition effective prophylactically or for treating an inflammatory disease. 
     
     
         6 . A method of administering to a subject an amount of the BB-Sb4N compound of  claim 1  alone or as part of a pharmaceutical composition effective prophylactically or for treating a metabolic disease. 
     
     
         7 . A method of administering to a subject an amount of the BB-Sb4N compound of  claim 1  alone or as part of a pharmaceutical composition effective prophylactically or for treating a vascular disease. 
     
     
         8 . A kit comprising a pharmaceutical composition comprising the BB-Sb4N compound of  claim 1  and instructions for its use. 
     
     
         9 . The kit of  claim 8  wherein the instructions are to administer the compound for the purpose of relieving, alleviating or ameliorating proliferative a cancer. 
     
     
         10 . The kit of  claim 9  wherein the cancer is selected from relieving, alleviating or ameliorating refractory malignant and solid tumors, leukemia, glioma, cervical intraepithelial neoplasia, refractory head and neck cancer, colon cancer, breast cancer, ovarian cancer, renal cancer, CNS cancer, and prostate cancer. 
     
     
         11 . The pharmaceutically acceptable salt of  claim 1  which is selected from the following acids HCl, HBr, HNO3, MeSO3H, H2SO4, aspartic acid, citric acid, benzenesulfonic acid, camphoric acid, camphorsulfonic acid, ethanesulfonic acid, ethansulfonic acid, formic acid, fumaric acid, galactaric acid, D-gluconic acid, glycolic acid, hippuric acid, L-lactic acid, maleic acid, malic acid, malonic acid, nicotinic acid, palmitic acid, pamoic acid, phosphoric acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid. 
     
     
         12 . The pharmaceutically acceptable salt of  claim 11  which is selected from the following acids HCl, HBr, HNO3, MeSO3H, H2SO4, aspartic acid, citric acid, benzenesulfonic acid, camphoric acid, camphorsulfonic acid, ethanesulfonic acid, ethansulfonic acid, formic acid, fumaric acid, galactaric acid, D-gluconic acid, glycolic acid, hippuric acid, L-lactic acid, maleic acid, malic acid, malonic acid, nicotinic acid, palmitic acid, pamoic acid, phosphoric acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid.