VACUOLAR-TYPE (H+)-ATPase-INHIBITING COMPOUNDS, COMPOSITIONS, AND USES THEREOF

Abstract

The present invention provides vacuolar-type (H+)-ATPase-inhibiting compounds, compositions thereof, and methods of using them to treat or prevent a condition treatable by the inhibition of a vacuolar-type (H+)-ATPase. The composition of the present invention comprises a compound of the present invention and a carrier. The method of the present invention includes administering a vacuolar-type (H+)-ATPase inhibiting-effective amount of a compound of the present invention. The compound of the present invention has the formula: wherein R 1 and R 2 are H, saturated or unsaturated alkyl, aryl, R 6 CH 2 —, R 6 CO—, or R 6 SO 2 —, wherein R 6 is H, saturated or unsaturated alkyl, or aryl; R 3 is H, alkyl, aryl, an oxime, or an oxime methyl ether; the aromatic ring is unsubstituted or substituted; and Z is a contiguous linker comprising a chain of 0 - 10 atoms which, together with the five atoms beginning with the carbon of the aromatic ring in meta-relationship with OR 1 and ending with the carbon directly attached to the alkyl oxygen of the lactone, integrally form a 5 - 17 membered ring; or a pharmaceutically acceptable salt, an ester, or a prodrug thereof.

1 . A method of treating or preventing a condition treatable by the inhibition of vacuolar-type (H+)-ATPase, said method comprising administering to a patient a vacuolar-type (H+)-ATPase inhibiting-effective amount of at least one compound of the formula: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are the same or different and each is H, a straight-chain or branched saturated or unsaturated alkyl, an aryl, R 6 CH 2 —, R 6 CO—, or R 6 SO 2 —, wherein R 6  is H, a straight-chain or branched saturated or unsaturated alkyl, or an aryl; R 3  is H, a straight-chain or branched saturated or unsaturated alkyl, an aryl, an oxime, or an oxime methyl ether; the aromatic ring is unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a nitro, an amino, a hydroxyl, a thio, an acyl, an alkyl, and a cyano; the saturated alkyl, unsaturated alkyl and aryl substituents defined in R 1 -R 3  and R 6  are unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a nitro, an amino, a hydroxyl, a thio, an acyl, an alkyl, and a cyano; and Z is a contiguous linker comprising a chain of 0-12 atoms which, together with the five atoms beginning with the carbon of the aromatic ring in meta-relationship with OR 1  and ending with the carbon directly attached to the alkyl oxygen of the lactone, said carbons being covalently bonded to either end of linker Z, integrally form a 5-17 membered ring; or a pharmaceutically acceptable salt, an ester, or a prodrug thereof. 
       
     
     
         2 . The method of  claim 1 , wherein Z is a contiguous linker comprising a chain of 7-12 atoms which, together with the five atoms beginning with the carbon of the aromatic ring in meta-relationship with OR 1  and ending with the carbon directly attached to the alkyl oxygen of the lactone, said carbons being covalently bonded to either end of linker Z, integrally form a 12-17 membered ring. 
     
     
         3 . The method of  claim 1 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are the same or different and each is H, a straight-chain or branched saturated or unsaturated alkyl, an aryl, R 6 CH 2 —, R 6 CO—, or R 6 SO 2 —, wherein R 6  is H, a straight-chain or branched saturated or unsaturated alkyl, or an aryl; R 3  is H, a straight-chain or branched saturated or unsaturated alkyl, an aryl, an oxime, or an oxime methyl ether; R 4  is H, an alkyl, or R 7 CH 2 —, wherein R 7  is R 60 —, R 6 CO 2 —, or R 6 SO 3 —; 
         R 5  and R 5′  are the same or different and each is H, a straight-chain or branched saturated or unsaturated alkyl, an aryl, a glycoside, R 6 CH 2 —, R 6 CO—, or R 6 SO 2 —; the saturated alkyl, unsaturated alkyl and aryl defined in R 1 -R 3 , R 5 , R 5′  and R 6 , and the alkyl defined in R 4 , are unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a nitro, an amino, a hydroxyl, a thio, an acyl, an alkyl, and a cyano; and the aromatic ring is unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a nitro, an amino, a hydroxyl, a thio, an acyl, an alkyl, and a cyano; or a pharmaceutically acceptable salt, an ester, or a prodrug thereof. 
       
     
     
         4 . The method of  claim 3 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, an ester, or a prodrug thereof. 
       
     
     
         5 . The method of  claim 1 , wherein Z is a contiguous linker comprising a chain of 0-6 atoms which, together with the five atoms beginning with the carbon of the aromatic ring in meta-relationship with OR 1  and ending with the carbon directly attached to the alkyl oxygen of the lactone, said carbons being covalently bonded to either end of linker Z, integrally form a 5-11 membered ring. 
     
     
         6 . The method of  claim 1 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 1 -R 3  are as defined in  claim 1 ; R 5″  is H, a straight-chain or branched saturated or unsaturated alkyl, an aryl, a glycoside, R 6 CH 2 —, R 6 CO—, or R 6 SO 2 —, wherein R 6  is as defined in  claim 1 ; the saturated alkyl, unsaturated alkyl and aryl defined in R 5  are unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a nitro, an amino, a hydroxyl, a thio, an acyl, an alkyl, and a cyano; A is a covalent bond or a C 1 -C 6  straight-chain saturated or unsaturated alkyl linker which is unsubstituted or is substituted with a one or more substituents selected from the group consisting of a halogen, a nitro, an amino, a hydroxyl, a thio, an acyl, an alkyl, and a cyano; X is a covalent bond or a C 1 -C 5  straight-chain saturated or unsaturated alkyl linker which is unsubstituted or is substituted with a one or more substituents selected from the group consisting of a halogen, a nitro, an amino, hydroxyl, thio, acyl, C 1 -C 6  alkyl, and cyano; and W is O, S, C(O), C(S), S(O) n  or N—R 4 , wherein R 4  is H, C 1 -C 6  straight-chain or branched saturated or unsaturated alkyl, aryl, R 6 CH 2 —, R 6 CO—, or R 6 SO 2 —, R 6  is as defined in  claim 1 , and n is an integer from 0-2. 
       
     
     
         7 . The method of  claim 6 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 5″  is N-acetyl-β-D-glucosamine. 
       
     
     
         8 . The method of  claim 1 , which further comprises co-administering to a patient in need thereof a therapeutically effective amount of at least one additional compound other than a compound defined in  claim 1 . 
     
     
         9 . The method of  claim 8 , wherein said additional compound is selected from the group consisting of bafilomycins and concanamycins. 
     
     
         10 . The method of  claim 9 , wherein said additional compound is concanamycin A. 
     
     
         11 . The method of  claim 9 , wherein said additional compound is bafilomycin A 1 . 
     
     
         12 . The method of  claim 1 , wherein said vacuolar-type (H+)-ATPase inhibiting-effective amount is effective to inhibit intra-organellar acidification of intracellular organelles. 
     
     
         13 . The method of  claim 1 , wherein said vacuolar-type (H+)-ATPase inhibiting-effective amount is effective to inhibit urinary acidification. 
     
     
         14 . The method of  claim 1 , wherein said vacuolar-type (H+)-ATPase inhibiting-effective amount is effective to inhibit bone resorption. 
     
     
         15 . The method of  claim 14 , wherein said vacuolar-type (H+)-ATPase inhibiting-effective amount is effective to treat osteoporosis. 
     
     
         16 . The method  claim 1 , wherein said vacuolar-type (H+)-ATPase inhibiting-effective amount is effective to inhibit fertility. 
     
     
         17 . The method of  claim 1 , wherein said vacuolar-type (H+)-ATPase inhibiting-effective amount is effective to inhibit the development of drug-resistance of tumor cells. 
     
     
         18 . The method of  claim 1 , wherein said vacuolar-type (H+)-ATPase inhibiting-effective amount is effective to inhibit angiogenesis, cellular invasiveness, or metastasis. 
     
     
         19 . A composition comprising a vacuolar-type (H+)-ATPase inhibiting-effective amount of at least one compound of the formula: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are the same or different and each is H, a straight-chain or branched saturated or unsaturated alkyl, an aryl, R 6 CH 2 —, R 6 CO—, or R 6 SO 2 —, wherein R 6  is H, a straight-chain or branched saturated or unsaturated alkyl, or an aryl; R 3  is H, a straight-chain or branched saturated or unsaturated alkyl, an aryl, an oxime, or an oxime methyl ether; the saturated alkyl, unsaturated alkyl and aryl substituents defined in R 1 -R 3  and R 6  are unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a nitro, an amino, a hydroxyl, a thio, an acyl, an alkyl, and a cyano; the aromatic ring is unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a nitro, an amino, a hydroxyl, a thio, an acyl, an alkyl, and a cyano; and Z is a contiguous linker comprising a chain of 0-12 atoms which, together with the five atoms beginning with the carbon of the aromatic ring in meta-relationship with OR 1  and ending with the carbon directly attached to the alkyl oxygen of the lactone, said carbons being covalently bonded to either end of linker Z, integrally form a 5-17 membered ring; or a pharmaceutically acceptable salt, an ester, or a prodrug thereof; and a pharmaceutically acceptable carrier. 
       
     
     
         20 . The composition of  claim 19 , wherein Z is a contiguous linker comprising a chain of 7-12 atoms which, together with the five atoms beginning with the carbon of the aromatic ring in meta-relationship with OR 1 , and ending with the carbon directly attached to the alkyl oxygen of the lactone, said carbons being covalently bonded to either end of linker Z, integrally form a 12-17 membered ring. 
     
     
         21 . The composition of  claim 19 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are the same or different and each is H, a straight-chain or branched saturated or unsaturated alkyl, an aryl, R 6 CH 2 —, R 6 CO—, or R 6 SO 2 —, wherein R 6  is H, a straight-chain or branched saturated or unsaturated alkyl, an aryl; R 3  is H, a straight-chain or branched saturated or unsaturated alkyl, an aryl, an oxime, or an oxime methyl ether; R 4  is H, an alkyl, or R 7 CH 2 —, wherein R 7  is R 60 —, 
         R 6 CO 2 —, or R 6 SO 3 —; R 5  and R 5′  are the same or different and each is H, a straight-chain or branched saturated or unsaturated alkyl, an aryl, a glycoside, R 6 CH 2 —, R 6 CO—, or R 6 SO 2 —; the saturated alkyl, unsaturated alkyl and aryl defined in R 1 -R 3 , R 5 , R 5′  and R 6 , and the alkyl defined in R 4 , are unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a nitro, an amino, a hydroxyl, a thio, an acyl, an alkyl, and a cyano; and the aromatic ring is unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a nitro, an amino, a hydroxyl, a thio, an acyl, an alkyl, and a cyano; or a pharmaceutically acceptable salt, an ester, or a prodrug thereof. 
       
     
     
         22 . The composition of  claim 21 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, an ester, or a prodrug thereof. 
       
     
     
         23 . The composition of  claim 19 , wherein Z is a contiguous linker comprising a chain of 0-6 atoms which, together with the five atoms beginning with the carbon of the aromatic ring in meta-relationship with OR 1  and ending with the carbon directly attached to the alkyl oxygen of the lactone, said carbons being covalently bonded to either end of linker Z, integrally form a 5-11 membered ring. 
     
     
         24 . The composition of  claim 19 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 1 -R 3  are as defined in  claim 19 ; R 5″  is H, a straight-chain or branched saturated or unsaturated alkyl, an aryl, a glycoside, R 6 CH 2 —, R 6 CO—, or R 6 SO 2 —, wherein R 6  is as defined in  claim 19 ; the saturated alkyl, unsaturated alkyl and aryl defined in R 5″  are unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a nitro, an amino, a hydroxyl, a thio, an acyl, an alkyl, and a cyano; A is a covalent bond or a C 1 -C 6  straight-chain saturated or unsaturated alkyl linker which is unsubstituted or is substituted with a one or more substituents selected from the group consisting of a halogen, a nitro, an amino, a hydroxyl, a thio, an acyl, an alkyl, and a cyano; X is a covalent bond or a C 1 -C 5  straight-chain saturated or unsaturated alkyl linker which is unsubstituted or is substituted with a one or more substituents selected from the group consisting of a halogen, a nitro, an amino, a hydroxyl, a thio, an acyl, an alkyl, and a cyano; and W is O, S, C(O), C(S), S(O) n  or N—R 4 , wherein R 4  is H, a straight-chain or branched saturated or unsaturated alkyl, an aryl, R 6 CH 2 —, R 6 CO—, or R 6 SO 2 —, wherein R 6  is as defined in  claim 19  and n is an integer from 0-2. 
       
     
     
         25 . The composition of  claim 24 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 5″  is N-acetyl-β-D-glucosamine. 
       
     
     
         26 . The composition of  claim 19 , which further comprises a vacuolar-type (H+)-ATPase inhibiting effective amount of at least one additional compound other than a compound defined in  claim 19 . 
     
     
         27 . The composition of  claim 26 , wherein said additional compound is selected from the group consisting of bafilomycins and concanamycins. 
     
     
         28 . The composition of  claim 26 , wherein said additional compound is concanamycin A. 
     
     
         29 . The composition of  claim 26 , wherein said additional compound is bafilomycin A 1 . 
     
     
         30 . The composition of  claim 19 , wherein said vacuolar-type (H+)-ATPase inhibiting-effective amount is effective to inhibit intra-organellar acidification of intracellular organelles. 
     
     
         31 . The composition of  claim 19 , wherein said vacuolar-type (H+)-ATPase inhibiting-effective amount is effective to inhibit urinary acidification. 
     
     
         32 . The composition of  claim 19 , wherein said vacuolar-type (H+)-ATPase inhibiting-effective amount is effective to inhibit bone resorption. 
     
     
         33 . The composition of  claim 32 , wherein said vacuolar-type (H+)-ATPase inhibiting-effective amount is effective to treat osteoporosis. 
     
     
         34 . The composition of  claim 19 , wherein said vacuolar-type (H+)-ATPase inhibiting-effective amount is effective to inhibit fertility. 
     
     
         35 . The composition of  claim 19 , wherein said vacuolar-type (H+)-ATPase inhibiting-effective amount is effective to inhibit the development of drug-resistance of tumor cells. 
     
     
         36 . The composition of  claim 19 , wherein said vacuolar-type (H+)-ATPase inhibiting-effective amount is effective to inhibit angiogenesis, cellular invasiveness, or metastasis.