Methods for controlling gram negative bacteria in mammals

Abstract

Methods for controlling growth of gram negative bacteria, such as Helicobacter pylori, which are agents associated with disorders of the gastrointestinal tract of a mammal are described. They include administering a therapeutically effective amount of a polyether ionophore antibiotic to a mammal, such that growth of gram negative bacteria which are agents associated with disorders of the gastrointestinal tract of a mammal is controlled. Packaged pharmaceutical compositions for controlling gram negative bacteria are also described. The packaged compositions include a container holding a therapeutically effective amount of a pharmaceutical composition for controlling gram negative bacteria which are agents associated with disorders of the gastrointestinal tract of a mammal and instructions for using the pharmaceutical composition for control of the gram negative bacteria, such that growth of gram negative bacteria which are agents associated with disorders of the gastrointestinal tract of a mammal is controlled. The pharmaceutical composition includes at least one polyether ionophore antibiotic or a bicyclic spiroether.

What is claimed is:  
     
         1 . A method for controlling gram negative bacteria in a mammal, comprising administering to a mammal a therapeutically effective amount of a polyether ionophore antibiotic, such that gram negative bacteria in the mammal is controlled.  
     
     
         2 . The method of    claim 1   , wherein said mammal is a human.  
     
     
         3 . The method of    claim 1   , wherein said polyether ionophore antibiotic is selected from the group consisting of monensin, nigericin and calcimycin and pharmaceutically acceptable salts or esters thereof.  
     
     
         4 . The method of    claim 3   , wherein said ester is an acetomethoxy ester.  
     
     
         5 . The method of    claim 1   , wherein said polyether ionophore antibiotic has the formula  
       
         
           
           
               
               
           
         
         wherein, R is either phenyl, pyridyl or aminoethyl-Fmoc and pharmaceutically acceptable salts or esters thereof.  
       
     
     
         6 . The method of    claim 1   , wherein said therapeutically effective amount is between about 1 mg/kg/day and about 100 mg/kg/day.  
     
     
         7 . The method of    claim 1   , wherein said polyether ionophore antibiotic is administered orally.  
     
     
         8 . The method of    claim 1   , wherein said gram negative bacteria is an agent associated with disorders of the gastrointestinal tract.  
     
     
         9 . The method of    claim 8   , wherein said gram negative bacteria is  Helicobacter pylori.    
     
     
         10 . The method of    claim 1   , further comprising administering a proton pump inhibitor, an acid agonist or blocker, a bismuth salt or combinations thereof in combination with said polyether ionophore antibiotic.  
     
     
         11 . A method for controlling gram negative bacteria in a mammal, comprising administering to a mammal a therapeutically effective amount of a bicyclo spiroether compound having at least one heterocyclic moiety attached to at least one of the ether rings, such that gram negative bacteria in the mammal is controlled.  
     
     
         12 . The method of    claim 11   , wherein both ether rings are six membered rings.  
     
     
         13 . The method of    claim 11   , wherein one ether ring is a six membered ring and one ether ring is five membered.  
     
     
         14 . The method of    claim 11   , wherein at least one heterocyclic moiety is directly attached to one of the ether rings.  
     
     
         15 . The method of    claim 14   , wherein said heterocyclic moiety is a tetrahydrofuranyl group.  
     
     
         16 . The method of    claim 11   , wherein at least one heterocyclic moiety is attached to one of the ether rings via a substituted or unsubstituted alkylene diradical.  
     
     
         17 . The method of    claim 16   , wherein said heterocyclic moiety is a tetrahydrofuranyl group.  
     
     
         18 . The method of    claim 11   , wherein said gram negative bacteria is an agent associated with disorders of the gastrointestinal tract.  
     
     
         19 . The method of    claim 18   , wherein said gram negative bacteria is  Helicobacter pylori.    
     
     
         20 . The method of    claim 11   , further comprising administering a proton pump inhibitor, an acid agonist or blocker, a bismuth salt or combinations thereof in combination with said polyether ionophore antibiotic.  
     
     
         21 . A method for controlling gram negative bacteria in a mammal, comprising administering to a mammal a therapeutically effective amount of a compound having the formula:  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 1  is a hydrogen atom or a substituted or unsubstituted alkyl group;  
 A is either a covalent bond connecting the cyclic ring to B or a substituted or unsubstituted alkylene diradical connecting the cyclic ring to B;  
 B is a heterocyclic group;  
 D is a substituted or unsubstituted alkyl group;  
 the methylene carbon atoms of the cyclic rings are each independently substituted at one or more positions with one or two substitutents selected from hydrogen atoms, hydroxyl groups or substituted or unsubstituted alkyl groups; and  
 the methine carbon atoms are each independently substituted with hydrogen atoms or substituted or unsubstituted alkyl groups, such that gram negative bacteria in the mammal is controlled.  
 
     
     
         22 . The method of    claim 21   , wherein said heterocyclic group is a tetrahydrofuranyl group.  
     
     
         23 . The method of    claim 21   , wherein said gram negative bacteria is an agent associated with disorders of the gastrointestinal tract.  
     
     
         24 . The method of    claim 23   , wherein said gram negative bacteria is  Helicobacter pylori.    
     
     
         25 . The method of    claim 21   , further comprising administering a proton pump inhibitor, an acid agonist or blocker, a bismuth salt or combinations thereof in combination with said polyether ionophore antibiotic.  
     
     
         26 . A method treating a state characterized by the presence of gram negative bacteria in a mammal, comprising administering to a mammal a therapeutically effective amount of a polyether ionophore antibiotic, such that a state characterized by the presence of gram negative bacteria in a mammal is treated.  
     
     
         27 . The method of    claim 26   , wherein said mammal is a human.  
     
     
         28 . The method of    claim 26   , wherein said polyether ionophore antibiotic is selected from the group consisting of monensin, nigericin and calcimycin and pharmaceutically acceptable salts or esters thereof.  
     
     
         29 . The method of    claim 28   , wherein said ester is an acetomethoxy ester.  
     
     
         30 . The method of    claim 26   , wherein said polyether ionophore antibiotic has the formula  
       
         
           
           
               
               
           
         
         wherein, R is either phenyl, pyridyl or aminoethyl-Fmoc and pharmaceutically acceptable salts or esters thereof.  
       
     
     
         31 . The method of    claim 26   , wherein said therapeutically effective amount is between about 1 mg/kg/day and about 100 mg/kg/day.  
     
     
         32 . The method of    claim 26   , wherein said polyether ionophore antibiotic is administered orally.  
     
     
         33 . The method of    claim 26   , wherein said gram negative bacteria is an agent associated with disorders of the gastrointestinal tract.  
     
     
         34 . The method of    claim 33   , wherein said gram negative bacteria is  Helicobacter pylori.    
     
     
         35 . The method of    claim 26   , further comprising administering a proton pump inhibitor, an acid agonist or blocker, a bismuth salt or combinations thereof in combination with said polyether ionophore antibiotic.  
     
     
         36 . A method for treating a state characterized by the presence of gram negative bacteria in a mammal, comprising administering to a mammal a therapeutically effective amount of a bicyclo spiroether compound having at least one heterocyclic moiety attached to at least one of the ether rings, such that a state characterized by the presence of gram negative bacteria in the mammal is treated.  
     
     
         37 . The method of    claim 36   , wherein both ether rings are six membered rings.  
     
     
         38 . The method of    claim 36   , wherein one ether ring is a six membered ring and one ether ring is five membered.  
     
     
         39 . The method of    claim 36   , wherein at least one heterocyclic moiety is directly attached to one of the ether rings.  
     
     
         40 . The method of    claim 39   , wherein said heterocyclic moiety is a tetrahydrofuranyl group.  
     
     
         41 . The method of    claim 36   , wherein at least one heterocyclic moiety is attached to one of the ether rings via a substituted or unsubstituted alkylene diradical.  
     
     
         42 . The method of    claim 41   , wherein said heterocyclic moiety is a tetrahydrofuranyl group.  
     
     
         43 . The method of    claim 36   , wherein the gram negative bacteria is an agent associated with disorders of the gastrointestinal tract.  
     
     
         44 . The method of    claim 36   , wherein said gram negative bacteria is  Helicobacter pylori.    
     
     
         45 . The method of    claim 36   , further comprising administering a proton pump inhibitor, an acid agonist or blocker, a bismuth salt or combinations thereof in combination with said polyether ionophore antibiotic.  
     
     
         46 . A method for treating a state characterized by the presence of gram negative bacteria in a mammal, comprising administering to a mammal a therapeutically effective amount of compound having the formula:  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 1  is a hydrogen atom or a substituted or unsubstituted alkyl group;  
 A is either a covalent bond connecting the cyclic ring to B or a substituted or unsubstituted alkylene diradical connecting the cyclic ring to B;  
 B is a heterocyclic group;  
 D is a substituted or unsubstituted alkyl group;  
 the methylene carbon atoms of the cyclic rings are each independently substituted at one or more positions with one or two substitutents selected from hydrogen atoms, hydroxyl groups or substituted or unsubstituted alkyl groups; and  
 the methine carbon atoms are each independently substituted with hydrogen atoms or substituted or unsubstituted alkyl groups, such that a state characterized by the presence of gram negative bacteria in a mammal is treated.  
 
     
     
         47 . The method of    claim 46   , wherein said heterocyclic group is a tetrahydrofuranyl group.  
     
     
         48 . The method of    claim 46   , wherein the gram negative bacteria is an agent associated with disorders of the gastrointestinal tract.  
     
     
         49 . The method of    claim 48   , wherein said gram negative bacteria is  Helicobacter pylori.    
     
     
         50 . The method of    claim 49   , further comprising administering a proton pump inhibitor, an acid agonist or blocker, a bismuth salt or combinations thereof in combination with said polyether ionophore antibiotic.  
     
     
         51 . A method for controlling  Helicobacter pylori  in a mammal, comprising administering to a mammal a therapeutically effective amount of a polyether ionophore antibiotic, such that  Helicobacter pylori  in the mammal is controlled.  
     
     
         52 . The method of    claim 51   , wherein said polyether ionophore antibiotic is selected from the group consisting of monensin, nigericin, calcimycin,  
       
         
           
           
               
               
           
         
         wherein, R is either phenyl, pyridyl or aminoethyl-Fmoc and pharmaceutically acceptable salts or esters thereof.  
       
     
     
         53 . A method for controlling  Helicobacter pylori  in a mammal, comprising administering to a mammal a therapeutically effective amount of a bicyclo spiroether compound having at least one heterocyclic moiety attached to at least one of the ether rings, such that  Helicobacter pylori  in the mammal is controlled.  
     
     
         54 . A method for controlling  Helicobacter pylori  in a mammal, comprising administering to a mammal a therapeutically effective amount of a compound having the formula:  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 1  is a hydrogen atom or a substituted or unsubstituted alkyl group;  
 A is either a covalent bond connecting the cyclic ring to B or a substituted or unsubstituted alkylene diradical connecting the cyclic ring to B;  
 B is a heterocyclic group;  
 D is a substituted or unsubstituted alkyl group;  
 the methylene carbon atoms of the cyclic rings are each independently substituted at one or more positions with one or two substitutents selected from hydrogen atoms, hydroxyl groups or substituted or unsubstituted alkyl groups; and  
 the methine carbon atoms are each independently substituted with hydrogen atoms or substituted or unsubstituted alkyl groups, such that  Helicobacter pylori  in the mammal is controlled.  
 
     
     
         55 . A method for treating a gastrointestinal disorder in a mammal characterized by having  Helicobacter pylori  as a causative agent, comprising administering to a mammal a therapeutically effective amount of a polyether ionophore antibiotic, such that a gastrointestinal disorder characterized by having  Helicobacter pylori  as a causative agent is treated.  
     
     
         56 . The method of    claim 55   , wherein said polyether ionophore antibiotic is selected from the group consisting of monensin, nigericin, calcimycin,  
       
         
           
           
               
               
           
         
         wherein, R is either phenyl, pyridyl or aminoethyl-Fmoc and pharmaceutically acceptable salts or esters thereof.  
       
     
     
         57 . The method of    claim 55   , further comprising administering a proton pump inhibitor, an acid agonist or blocker, a bismuth salt or combinations thereof in combination with said polyether ionophore antibiotic.  
     
     
         58 . A method for treating a gastrointestinal disorder in a mammal characterized by having  Helicobacter pylori  as a causative agent, comprising administering to a mammal a therapeutically effective amount of a bicyclo spiroether compound having at least one heterocyclic moiety attached to at least one of the ether rings, such that a gastrointestinal disorder characterized by having  Helicobacter pylori  as a causative agent is treated.  
     
     
         59 . A method for treating a gastrointestinal disorder in a mammal characterized by having  Helicobacter pylori  as a causative agent, comprising administering to a mammal a therapeutically effective amount of a compound having the formula:  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 1  is a hydrogen atom or a substituted or unsubstituted alkyl group;  
 A is either a covalent bond connecting the cyclic ring to B or a substituted or unsubstituted alkylene diradical connecting the cyclic ring to B;  
 B is a heterocyclic group;  
 D is a substituted or unsubstituted alkyl group;  
 the methylene carbon atoms of the cyclic rings are each independently substituted at one or more positions with one or two substitutents selected from hydrogen atoms, hydroxyl groups or substituted or unsubstituted alkyl groups; and  
 the methine carbon atoms are each independently substituted with hydrogen atoms or substituted or unsubstituted alkyl groups, such that a gastrointestinal disorder characterized by having  Helicobacter pylori  as a causative agent is treated.  
 
     
     
         60 . A method for treating an ulcer in the gastrointestinal tract of a mammal, comprising administering to a mammal a therapeutically effective amount of a polyether ionophore antibiotic, such that an ulcer of the gastrointestinal tract of the mammal is treated.  
     
     
         61 . The method of    claim 60   , wherein said polyether ionophore antibiotic is selected from the group consisting of monensin, nigericin, calcimycin,  
       
         
           
           
               
               
           
         
         wherein, R is either phenyl, pyridyl or aminoethyl-Fmoc and pharmaceutically acceptable salts or esters thereof.  
       
     
     
         62 . The method of    claim 60   , further comprising administering a proton pump inhibitor, an acid agonist or blocker, a bismuth salt or combinations thereof in combination with said polyether ionophore antibiotic.  
     
     
         63 . A method for treating an ulcer associated with  Helicobacter pylori  in a mammal, comprising administering to a mammal a therapeutically effective amount of a polyether ionophore antibiotic, such that an ulcer associated with  Helicobacter pylori  in the mammal is treated.  
     
     
         64 . The method of    claim 63   , wherein said polyether ionophore antibiotic is selected from the group consisting of monensin, nigericin, calcimycin,  
       
         
           
           
               
               
           
         
         wherein, R is either phenyl, pyridyl or aminoethyl-Fmoc and pharmaceutically acceptable salts or esters thereof.  
       
     
     
         65 . The method of    claim 63   , further comprising administering a proton pump inhibitor, an acid agonist or blocker, a bismuth salt or combinations thereof in combination with said polyether ionophore antibiotic.  
     
     
         66 . A method for treating an ulcer associated with  Helicobacter pylori  in a mammal, comprising administering to a mammal a therapeutically effective amount of a bicyclo spiroether compound having at least one heterocyclic moiety attached to at least one of the ether rings, such that an ulcer associated with  Helicobacter pylori  in the mammal is treated.  
     
     
         67 . A method for treating an ulcer associated with  Helicobacter pylori  in a mammal, comprising administering to a mammal a therapeutically effective amount of a compound having the formula:  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 1  is a hydrogen atom or a substituted or unsubstituted alkyl group;  
 A is either a covalent bond connecting the cyclic ring to B or a substituted or unsubstituted alkylene diradical connecting the cyclic ring to B;  
 B is a heterocyclic group;  
 D is a substituted or unsubstituted alkyl group;  
 the methylene carbon atoms of the cyclic rings are each independently substituted at one or more positions with one or two substitutents selected from hydrogen atoms, hydroxyl groups or substituted or unsubstituted alkyl groups; and  
 the methine carbon atoms are each independently substituted with hydrogen atoms or substituted or unsubstituted alkyl groups, such that an ulcer associated with  Helicobacter pylori  in the mammal is treated.  
 
     
     
         68 . A packaged pharmaceutical composition for controlling gram negative bacteria in a mammal, comprising: 
 a container holding a therapeutically effective amount of a pharmaceutical composition for treating gram negative bacteria in a mammal, said pharmaceutical composition comprising at least one polyether ionophore antibiotic; and    instructions for using said pharmaceutical composition for control of said gram negative bacteria, such that gram negative bacteria in the mammal is controlled.    
     
     
         69 . The packaged pharmaceutical of    claim 68   , wherein said polyether ionophore antibiotic is selected from the group consisting of monensin, nigericin and calcimycin and pharmaceutically acceptable salts or esters thereof.  
     
     
         70 . The packaged pharmaceutical of    claim 69   , wherein said ester is an acetomethoxy ester thereof.  
     
     
         71 . The packaged pharmaceutical of    claim 68   , wherein said polyether ionophore antibiotic has the formula  
       
         
           
           
               
               
           
         
         wherein, R is either phenyl, pyridyl or aminoethyl-Fmoc.  
       
     
     
         72 . The packaged pharmaceutical of    claim 68   , wherein said therapeutically effective amount is between about 1 mg/kg/day and about 100 mg/kg/day.  
     
     
         73 . The packaged pharmaceutical of    claim 68   , wherein the pharmaceutical composition is administered orally.  
     
     
         74 . The packaged pharmaceutical of    claim 68   , said package further comprising a proton pump inhibitor, an acid agonist or blocker, a bismuth salt or combinations thereof.