Lactone formulations and method of use

Abstract

Compounds of Formulae Ia and Ic having a lactone structure and an methylene group at the alpha-position of the lactone structure and methods for using and making the compounds have been disclosed. The lactone compounds can be reacted with an neucleaphilic agent to open the lactone ring to a compound of Formula Ib. The lactone of Formula Ia and its functional derivatives have been isolated from Securidaca virgata . These compounds are referred to as LMSV-6 or Securolide™. The purified compounds have demonstrated activity in assays for anti-bacterial and anti-fungal activities, and for treating proliferation disorders such as cancer. Based on the in vitro assays, the lactones are useful for treating proliferation disorders including, for example, breast cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, lung cancer, liver cancer, ovarian cancer, esophageal cancer, and leukemia. They are also effective for treatment of bacterial and fungal infections, including treatment of peptic ulcer disease, gingivitis and periodontitis. The lactone and its derivatives has the following chemical structure: wherein R 1 -R 9 and Y 1 -Y 3 taken independently are preferably a hydrogen atom, a halogen atom, a hydroxyl group, or any other organic groups or groupings which optionally include a heteroatom such as oxygen, sulfur, or nitrogen groupings in linear, branched, or cyclic structural formats; Z and X are independently and preferably a heteroatom such as oxygen, sulfur, or nitrogen groupings in linear, branched, or cyclic structural formats; and Z′ may a hydrogen atom, a halogen atom, a hydroxyl group, or any other organic groups or groupings which optionally include a heteroatom such as oxygen, sulfur, or nitrogen groupings in linear, branched, or cyclic structural formats.

1 . An isolated compound defined by one of the following structures:  
       
         
           
           
               
               
           
         
       
       wherein R 1 -R 7  taken independently or R 3 -R 6  taken together are a hydrogen atom or a group or grouping selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substituted C1-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, and polypeptide groups; 
 Z is a heteratom selected from the group consisting of oxygen, sulfur, and nitrogen groupings in linear, branched, or cyclic structural formats;  
 Z′ is a hydrogen atom, a halogen atom, a hydroxyl group, or an organic group having 1-8 carbon atoms which includes a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen groupings in linear, branched, or cyclic structural formats; and  
 X is a heteratom selected from the group consisting of oxygen, sulfur, and nitrogen groupings in linear, branched, or cyclic structural formats, or  
 an isolated lactone defined by the following structure:  
                     
 wherein  
 R 1 -R 9  taken independently or R 5  and R 6  taken together may be a hydrogen atom or any other groups or groupings selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substituted C1-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, and polypeptide groups;  
 Y 1 , Y 2 , and Y 3  taken independently or Y 1  and Y 2  taken together may be a hydrogen or any other groups or groupings selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substituted C1-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, and polypeptide groups;  
 Z is a heteratom selected from the group consisting of oxygen, sulfur, and nitrogen groupings in linear, branched, or cyclic structural formats; and  
 X is a heteratom selected from the group consisting of oxygen, sulfur, and nitrogen groupings in linear, branched, or cyclic structural formats.  
 
     
     
         2 . The compound of  claim 1  defined by Formula Ia.  
     
     
         3 . The compound of  claim 2  wherein the X is an oxygen.  
     
     
         4 . The compound of  claim 2  wherein R 5  is an exocyclicc methylene.  
     
     
         5 . The compound of  claim 1  defined by Formula Ib.  
     
     
         6 . The compound of  claim 1  which has one of the following structure.  
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1  of Formula Ia wherein the lactone is isolated from a  Securidaca virgata.    
     
     
         8 . The compound of  claim 1  of Formula Ia further comprising a pharmaceutically acceptable carrier for parenteral, enteral, or topical administration.  
     
     
         9 . A method of treating a patient in need thereof, comprising administering an effective amount of the compound defined by one of the following structures:  
       
         
           
           
               
               
           
         
       
       wherein R 1 -R 7  taken independently or R 3 -R 6  taken together are a hydrogen atom or a group or grouping selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substituted C1-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, and polypeptide groups; 
 Z is a heteratom selected from the group consisting of oxygen, sulfur, and nitrogen groupings in linear; branched, or cyclic structural formats;  
 Z′ is a hydrogen atom, a halogen atom, a hydroxyl group, or an organic group having 1-8 carbon atoms which includes a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen groupings in linear, branched, or cyclic structural formats; and  
 X is a heteratom selected from the group consisting of oxygen, sulfur, and nitrogen groupings in linear, branched, or cyclic structural formats, or  
 an isolated lactone defined by the following structure:  
                     
 wherein  
 R 1 -R 9  taken independently or R 5  and R 6  taken together may be a hydrogen atom or any other groups or groupings selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substituted C1-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, and polypeptide groups;  
 Y 1 , Y 2 , and Y 3  taken independently or Y 1  and Y 2  taken together may be a hydrogen or any other groups or groupings selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substituted C1-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, and polypeptide groups;  
 Z is a heteratom selected from the group consisting of oxygen, sulfur, and nitrogen groupings in linear, branched, or cyclic structural formats; and  
 X is a heteratom selected from the group consisting of oxygen, sulfur, and nitrogen groupings in linear, branched, or cyclic structural formats.  
 
     
     
         10 . The method of  claim 9  wherein X is oxygen.  
     
     
         11 . The method of  claim 9  wherein R 5  is an exocyclicc methylene.  
     
     
         12 . The method of  claim 9  wherein the compound has one of following structures:  
       
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 8  wherein the compound of Formula Ia is administered orally, parenterally, topically, or transdermally.  
     
     
         14 . The method of  claim 9  wherein the patient has a proliferation disorder.  
     
     
         15 . The method of  claim 14  wherein the proliferation disorder is cancer.  
     
     
         16 . The method of  claim 9  wherein the patient has an infection.  
     
     
         17 . The method of  claim 16  wherein the infection is bacterial.  
     
     
         18 . The method of  claim 16  wherein the infection is fungal.  
     
     
         19 . The method of  claim 9  wherein the patient has peptic ulcer disease.  
     
     
         20 . The method of  claim 19  wherein the peptic ulcer disease is linked to the presence of  Helicobacter pylori.    
     
     
         21 . The method of  claim 9  wherein the patient is in pain.  
     
     
         22 . The method of  claim 9  further comprising administering the compound of Formula Ia in a pharmaceutically acceptable carrier.  
     
     
         23 . The method of  claim 22  wherein the carrier for oral administration is a mouthwash, lozenge, tablet, capsule, solution, suspension, granule, or any combination thereof.  
     
     
         24 . The method of  claim 22  wherein the carrier for topical administration is a suppository, ointment, cream, gel, paste, collodion, glycerogelatin, liniment, lotion, paste, plaster, powder, tape, patch, aerosol, solution, tincture, or any combination thereof.  
     
     
         25 . A process of isolating a lactone from a plant, the lactone being defined by the following structure:  
       
         
           
           
               
               
           
         
       
       wherein R 1 -R 7  taken independently or R 3 -R 6  taken together are a hydrogen atom or a group or grouping selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substituted C1-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, and polypeptide groups; 
 Z is a heteratom selected from the group consisting of oxygen, sulfur, and nitrogen groupings in linear, branched, or cyclic structural formats; and  
 X is a heteratom selected from the group consisting of oxygen, sulfur, and nitrogen groupings in linear, branched, or cyclic structural formats, comprising extracting the lactone from plant material.  
 
     
     
         26 . The process of  claim 25  wherein the plant is  Securidaca virgata.    
     
     
         27 . The process of  claim 25  wherein the method of isolation is extraction followed by chromatography.  
     
     
         28 . A synthetic compound defined by one of the following structures:  
       
         
           
           
               
               
           
         
       
       Wherein R 1 -R 7  taken independently or R 3 -R 6  taken together are a hydrogen atom or a group or grouping selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substituted C1-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, and polypeptide groups; 
 Z is a heteratom selected from the group consisting of oxygen, sulfur, and nitrogen groupings in linear, branched, or cyclic structural formats;  
 Z′ is a hydrogen atom, a halogen atom, a hydroxyl group, or an organic group having 1-8 carbon atoms which includes a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen groupings in linear, branched, or cyclic structural formats; and  
 X is a heteratom selected from the group consisting of oxygen, sulfur, and nitrogen groupings in linear, branched, or cyclic structural formats, or  
 an isolated lactone defined by the following structure:  
                     
 wherein  
 R 1 -R 9  taken independently or R 5  and R 6  taken together may be a hydrogen atom or any other groups or groupings selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C1-20 cyclic, substituted C1-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, and polypeptide groups;  
 Y 1 , Y 2 , and Y 3  taken independently or Y 1  and Y 2  taken together may be a hydrogen or any other groups or groupings selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substituted C1-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, and polypeptide groups;  
 Z is a heteratom selected from the group consisting of oxygen, sulfur, and nitrogen groupings in linear, branched, or cyclic structural formats; and  
 X is a heteratom selected from the group consisting of oxygen, sulfur, and nitrogen groupings in linear, branched, or cyclic structural formats.  
 
     
     
         29 . The compound of  claim 28  defined by any of the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         30 . A method of making a compound of Formulae Ia and Ic comprising: 
 a) providing a precursor having a lactone structure, and    b) reacting the precursor with one or more chemical reagents to provide a product having a methylene group at the α-position of the lactone structure.    
     
     
         31 . A method of making a compound of Formula Ib comprising: 
 a) providing a precursor having a lactone structure,    b) reacting the precursor with one or more chemical reagents to provide a product having a methylene group at the α-position of the lactone structure, and    c) reacting the product with a neucleaphile.