CHONDROPSIN-CLASS ANTITUMOR V-ATPase INHIBITOR COMPOUNDS, COMPOSITIONS AND METHODS OF USE THEREOF

Abstract

A composition comprising a substantially purified compound of the formula: in combination with at least one additional therapeutic agent, and methods of preventing or treating cancer and a condition treatable by the inhibition of vacuolar-type (H+)-ATPase.

1 .- 11 . (canceled) 
     
     
         12 . A method of preventing or treating a patient for a condition treatable by the inhibition of vacuolar-type (H+)-ATPase, said method comprising administering to the patient a vacuolar-type (H+)-ATPase-inhibiting effective amount of at least one substantially purified compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H, a straight-chain or branched C 1-30  saturated alkyl, a straight-chain or branched C 2-30  unsaturated alkyl, or an aryl comprising 6-10 carbon atoms in the ring skeleton thereof, wherein R 1  is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of a halogen, an oxo, OR 1a , CO 2 R 1a , and OC(O)R 1a , wherein R 1a  is H, a straight-chain or branched C 1-30  saturated alkyl, a straight-chain or branched C 2-30  unsaturated alkyl, or an aryl comprising 6-10 carbon atoms in the ring skeleton thereof; 
 R 2 -R 8  are the same or different and each is R 10 , C(O)R 10 , SO 3 R 10 , or SO 2 R 10 , wherein R 10  is H, a straight-chain or branched C 1-30  saturated alkyl, a straight-chain or branched C 2-30  unsaturated alkyl, or an aryl comprising 6-10 carbon atoms in the ring skeleton thereof, wherein R 10  is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of a halogen, an oxo, OR 10a , CO 2 R 10a  and OC(O)R 10a , wherein R 10a  is H, a straight-chain or branched C 1-30  saturated alkyl, a straight-chain or branched C 2-30  unsaturated alkyl, or an aryl comprising 6-10 carbon atoms in the ring skeleton thereof; and 
 R 9  is a substituent of the formula: 
 
       
         
           
           
               
               
           
         
         wherein the R 9a  substituents are the same or different and each is R 11 , C(O)R 11 , or SO 2 R 11 , wherein R 11  is H, a straight-chain or branched C 1-30  saturated alkyl, a straight-chain or branched C 2-30  unsaturated alkyl, or an aryl comprising 6-10 carbon atoms in the ring skeleton thereof, wherein R 11  is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of a halogen, an oxo, OR 11a , CO 2 R 11a  and OC(O)R 11a , wherein R 11a  is H, a straight-chain or branched C 1-30  saturated alkyl, a straight-chain or branched C 2-30  unsaturated alkyl, or an aryl comprising 6-10 carbon atoms in the ring skeleton thereof; 
         wherein R 1a , R 10a  and R 11a  are unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen, an oxo, and a hydroxyl; or a pharmaceutically acceptable salt thereof, 
         whereupon the patient is treated for the condition. 
       
     
     
         13 . The method of  claim 12 , wherein said condition is selected from the group consisting of osteoporosis, Alzheimer's disease, glaucoma, fertility, abnormal urinary acidification, abnormal secretion of degradative enzymes, fungal infection and cancer. 
     
     
         14 . The method of  claim 12 , wherein the method further comprises administering a vacuolar-type (H+)-ATPase inhibiting-effective amount of at least one additional compound other than a compound of formula (I), which inhibits vacuolar-type (H+)-ATPase. 
     
     
         15 . The method of  claim 14 , wherein the at least one additional compound is a salicylihalamide. 
     
     
         16 . A method of preventing or treating a patient for cancer, which method comprises administering to the patient an anticancer effective amount of at least one substantially purified compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H, a straight-chain or branched C 1-30  saturated alkyl, a straight-chain or branched C 2-30  unsaturated alkyl, or an aryl comprising 6-10 carbon atoms in the ring skeleton thereof, wherein R 1  is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of a halogen, an oxo, OR 1a , CO 2 R 1a , and OC(O)R 1a , wherein R 1a  is H, a straight-chain or branched C 1-30  saturated alkyl, a straight-chain or branched C 2-30  unsaturated alkyl, or an aryl comprising 6-10 carbon atoms in the ring skeleton thereof; 
 R 2 -R 8  are the same or different and each is R 10 , C(O)R 10 , SO 3 R 10 , or SO 2 R 10 , wherein R 10  is H, a straight-chain or branched C 1-30  saturated alkyl, a straight-chain or branched C 2-30  unsaturated alkyl, or an aryl comprising 6-10 carbon atoms in the ring skeleton thereof, wherein R 10  is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of a halogen, an oxo, OR 10a , CO 2 R 10a  and OC(O)R 10a , wherein R 10a  is H, a straight-chain or branched C 1-30  saturated alkyl, a straight-chain or branched C 2-30  unsaturated alkyl, or an aryl comprising 6-10 carbon atoms in the ring skeleton thereof; and 
 R 9  is a substituent of the formula: 
 
       
         
           
           
               
               
           
         
       
       wherein the R 9a  substituents are the same or different and each is R 11 , C(O)R 11 , or SO 2 R 11 , wherein R 11  is H, a straight-chain or branched C 1-30  saturated alkyl, a straight-chain or branched C 2-30  unsaturated alkyl, or an aryl comprising 6-10 carbon atoms in the ring skeleton thereof, wherein R 11  is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of a halogen, an oxo, OR 11a , CO 2 R 11a  and OC(O)R 11a , wherein R 11a  is H, a straight-chain or branched C 1-30  saturated alkyl, a straight-chain or branched C 2-30  unsaturated alkyl, or an aryl comprising 6-10 carbon atoms in the ring skeleton thereof;
 wherein R 1a , R 10a  and R 11a  are unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen, an oxo, and a hydroxyl; or a pharmaceutically acceptable salt thereof, 
 whereupon the patient is treated for cancer. 
 
     
     
         17 . The method of  claim 16 , wherein the method further comprises administering an anticancer effective amount of at least one additional compound other than a compound of formula (I), which is an anti-cancer compound. 
     
     
         18 . The method of  claim 17 , wherein the at least one additional compound is a salicylihalamide. 
     
     
         19 . The method of  claim 16 , wherein the cancer is selected from the group consisting of human leukemias, lymphomas, melanomas and solid tumors. 
     
     
         20 . The method of  claim 19 , wherein the solid tumor is selected from the group consisting of lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, head and neck cancer, testicular cancer, germ-line cancers, endocrine tumors, uterine cancer, breast cancer, sarcomas, gastric cancer, hepatic cancer, esophageal cancer and pancreatic cancer. 
     
     
         21 . The method of  claim 16 , wherein the cancer is selected from the group consisting of colon cancer, melanoma, breast cancer, ovarian cancer and non-small lung cancer. 
     
     
         22 . The method of  claim 12 , wherein said vacuolar-type (H+)-ATPase inhibiting-effective amount is effective to inhibit one or more conditions selected from the group consisting of Alzheimer's disease, intra-organellar acidification of intracellular organelles, urinary acidification, bone resorption, fertility, drug-resistance of tumor cells, tumor cell proliferation, cellular invasiveness, angiogenesis, and metastasis.