Anti-inflammatory and protein kinase inhibitor compositions and related methods for downregulation of detrimental cellular responses and inhibition of cell death

Abstract

A novel class of pyridazine compositions and related methods of use.

1 . An N-heterocyclic composition having the structural formula  
       
         
           
           
               
               
           
         
       
       wherein 
 A is a pyridazinyl component; and R 3  is a component selected from the group consisting of hydrogen, alkyl and substituted alkyl moieties; arylalkyl and substituted arylalkyl moieties; phenyl and substituted phenyl moieties;  
 R 4  is a component selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, and amino; phenyl and substituted phenyl moieties, alkyl and substituted alkyl moieties, arylalkyl and substituted arylalkyl moieties, said moieties and substituted moieties providing a cyclic moiety with R 5 ;  
 R 5  is a component selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl; phenyl and substituted phenyl moieties, heterocyclic and substituted heterocyclic moieties, alkyl and substituted alkyl moieties, arylalkyl and substituted arylalkyl moieties, said moieties and substituted moieties providing a cyclic moiety with R 6 ;  
 R 6  is a component selected from the group consisting of hydrogen, halogen; alkyl and substituted alkyl moieties, phenyl and substituted phenyl moieties, heterocyclic and substituted heterocyclic moieties, arylalkyl and substituted arylalkyl moieties, said moieties and substituted moieties providing a cyclic moiety with R 5 ;  
 R 2  is a component selected from the group consisting of divalent alkyl, cycloalkyl, acyl, alkylacyl, amido, alkylamido moieties, and further including said moieties having at least one unsaturated carbon-carbon bond sequence; and monovalent hydrogen, halogen, alkyl, substituted alkyl, amino, phenyl and substituted phenyl moieties, and arylalkyl and substituted arylalkyl moieties.  
 G is a divalent component coupling divalent R 2  and B, said component selected from the group consisting of alkyl, cycloalkyl, acyl, alkylacyl, alkylamido, ureido, sulfonamido, thio, and primary, secondary and tertiary amine moieties; and  
 B is a component selected from the group consisting of hydroxy, amine, substituted amine, arylamine, heteroarylamine, arylalkylamine, hydrazinyl, substituted hydrazinyl, pyrimidinyl and substituted pyrimidinyl, pyridinyl and substituted pyridinyl, pyrazinyl and substituted pyrazinyl, thienyl and substituted thienyl, thiazolyl and substituted thiazolyl, pyrazolyl and substituted pyrazolyl, stilbenyl and substituted stilbenyl, imidazolyl and substituted imidazolyl, phthalazine and substituted phthalazine, piperazinyl and substituted piperazinyl moieties.  
 
     
     
         2 . The composition of  claim 1  wherein R 6  is selected from the group consisting of phenyl and substituted phenyl moieties.  
     
     
         3 . The composition of  claim 2  wherein R 2  is a (CH 2 ) n  alkyl moiety and n is about 4-12.  
     
     
         4 . The composition of  claim 3  wherein G is an acyl moiety.  
     
     
         5 . The composition of  claim 4  wherein said substituent is chlorine and said moiety is 4-chlorophenyl.  
     
     
         6 . The composition of  claim 1  wherein B is selected from the group consisting of piperazinyl and substituted piperazinyl moieties.  
     
     
         7 . The composition of  claim 6  wherein said substituent is a pyrimidinyl moiety.  
     
     
         8 . The composition of  claim 7  wherein R 6  is a substituted phenyl moiety.  
     
     
         9 . The composition of  claim 1  wherein R 6  is phenyl and R 5  is a (CH 2 ) n  alkyl moiety providing a carbocyclic moiety with R 6 .  
     
     
         10 . The composition of  claim 9  wherein R 2  is a (CH 2 ) n  alkyl moiety and n is about 4-12.  
     
     
         11 . The composition of  claim 10  wherein G is selected from the group consisting of amido and acyl moieties.  
     
     
         12 . The composition of  claim 11  wherein B is selected from the group consisting of pyrimidinyl, substituted pyrimidinyl, piperazinyl and substituted piperazinyl moieties.  
     
     
         13 . The composition of  claim 12  wherein G is an amido moiety and B is a substituted pyrimidinyl moiety.  
     
     
         14 . The composition of  claim 12  wherein G is an acyl moiety and B is a 4-substituted piperazinyl moiety, said substituent selected from the group consisting of methyl, phenyl, substituted phenyl and pyrimidin-2-yl moieties.  
     
     
         15 . An N-heterocyclic composition having the structural formula  
       
         
           
           
               
               
           
         
       
       wherein 
 A is a first pyridazinyl component; and R 3  is a component selected from the group consisting of hydrogen, alkyl and substituted alkyl, arylalkyl and substituted arylalkyl moieties;  
 R 4  is a component selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, amino, phenyl and substituted phenyl moieties, and alkyl and substituted alkyl, arylalkyl and substituted arylalkyl moieties, said moieties providing a cyclic moiety with R 5 ;  
 R 5  is a component selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, phenyl, substituted phenyl, heterocyclic and substituted heterocyclic moieties, arylalkyl and substituted arylalkyl moieties, alkyl and substituted alkyl moieties, said moieties and substituted moieties providing a cyclic moiety with R 6 ;  
 R 6  is a component selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, phenyl, substituted phenyl, heterocyclic and substituted heterocyclic moieties, arylalkyl and substituted arylalkyl moieties, said moieties and substituted moieties providing a cyclic moiety with R 5 ;  
 R 2  is a divalent component coupling A and G, said component is selected from the group consisting of alkyl, cycloalkyl, acyl, alkylacyl, amido, alkylamido moieties, and further including said moieties having at least one unsaturated carbon-carbon bond sequence;  
 G is a divalent component coupling R 2  and B, said component selected from the group consisting of cycloalkyl, acyl, alkylacyl, alkylamido, ureido, sulfonamido, thio, and primary, secondary and tertiary amine moieties; and  
 B is a second pyridazinyl component having the structural formula  
                     
 wherein  
 R 3 ′ is a component selected from the group consisting of hydrogen, alkyl and substituted alkyl moieties;  
 R 4 ′ is a component selected from the group consisting of hydrogen, halogen, amino, alkyl and substituted alkyl, phenyl and substituted phenyl moieties, arylalkyl and substituted arylalkyl moieties and alkyl and substituted alkyl moieties, said moieties and substituted moieties providing a cyclic moiety with R′ 5 ;  
 R 5 ′ is a component selected from the group consisting of hydrogen, halogen, amino, alkyl and substituted alkyl, phenyl and substituted phenyl, heterocyclic and substituted heterocyclic moieties, arylalkyl and substituted arylalkyl moieties and alkyl and substituted alkyl moieties, said moieties and substituted moieties providing a cyclic moiety with R′ 6 ; and  
 R 6 ′ is hydrogen, halogen, amine and substituted amine, alkyl and substituted alkyl, phenyl and substituted phenyl, hetercyclic and substituted heterocyclic moieties, arylalkyl and substituted arylalkyl moieties, said moieties and substituted moieties providing a cyclic moiety with R′ 5 ;  
 wherein said second pyridazinyl component is coupled with said G component at one of said 1-, 2-, 3-nitrogen and 4-positions thereof.  
 
     
     
         16 . The composition of  claim 15  wherein R 6 ′ is phenyl and R 5 ′ is a (CH 2 ) 2  alkyl moiety providing a carbocyclic moiety with R 6 ′, and component B is coupled with component G at the 3-amino position thereof.  
     
     
         17 . The composition of  claim 16  wherein said component G is selected from the group consisting of amido and acyl moieties.  
     
     
         18 . The composition of  claim 17  wherein said component B is coupled with said component G at the 2-position thereof.  
     
     
         19 . The composition of  claim 17  wherein R 6  of said component A is selected from the group consisting of hydrogen, halogen, alkyl, phenyl and substituted phenyl moieties.  
     
     
         20 . The composition of  claim 19  wherein R 6  is a chlorine moiety.  
     
     
         21 . The composition of  claim 19  wherein R 6  is phenyl and R 5  is a (CH 2 ) 2  alkyl moiety providing a carbocyclic moiety with R 6 .  
     
     
         22 . A method of modulating glial cell activation response, said method comprising: 
 providing a heterocyclic composition selected from the group of pyridazinyl compositions of  claim 1  and  claim 15  and combinations thereof; and    adminstering said composition to glial cells activated by disease-linked stimuli, said administration in an amount sufficient to inhibit neuroinflammation.    
     
     
         23 . The method of  claim 22  wherein said composition has an A component comprising a 3-amino-9,10-dihydro-3,4-diazaphenanthr-3-yl moiety; a G component comprising an acyl moiety; and a B component comprising a (4-pyrimidin-2-yl)piperazine moiety.  
     
     
         24 . The method of  claim 23  wherein said composition selectively inihibits calmodulin dependent kinase activity.  
     
     
         25 . The method of  claim 23  wherein said inhibition is dependent on concentration of said administered composition.  
     
     
         26 . A method of using a pyridazinyl composition to inhibit production of nitric oxide associated with glial cell activation, said method comprising: 
 providing a heterocyclic composition selected from the group of pyridazinyl compositions of  claim 1  and  claim 15  and combinations thereof; and    administering said composition to glial cells activated by a disease-linked stimuli, said administration in an amount sufficient to inhibit nitric oxide production.    
     
     
         27 . The method of  claim 26  wherein said composition has an A component comprising a 3-amino-9,10-dihydro-3,4-diazaphenanthr-3-yl moiety; and a B component comprising a (4-pyrimidin-2-yl)piperazine moiety.  
     
     
         28 . The method of  claim 27  wherein said composition is MW01-070C.  
     
     
         29 . The method of  claim 27  wherein said administration further inhibits proinflammatory cytokine production in activated glia cells, said administration selectively inhibiting nitric oxide and proinflammatory cytokine production.  
     
     
         30 . A method of inhibiting mammalian cellular injury and apoptosis, said method comprising: 
 providing a heterocyclic composition selected from the group of pyridazinyl compositions of  claim 1  and  claim 15  and combinations thereof;    providing a subject mammal with induced cellular apoptosis; and    administering said composition to said mammal in an amount sufficient to inhibit cellular injury.    
     
     
         31 . The method of  claim 30  wherein said composition selectively inhibits death associated protein kinase or other calmodulin regulated kinase activity.  
     
     
         32 . The method of  claim 31  wherein said composition has an A component comprising a 3-aminopyridazinyl moiety, and a G component comprising an acyl moiety.  
     
     
         33 . The method of  claim 32  wherein said A component comprises a 2-amino-9,10-dihydro-3,4-diazaphenanthryl moiety.  
     
     
         34 . The method of  claim 30  wherein said induction is hypoxia-ischemia, and said inhibition is expressed as reduction in tissue loss.  
     
     
         35 . A method of reducing acute lung injury, said method comprising: 
 providing a composition selected from the group of pyridazinyl composition of  claim 1 ,  claim 15  and combinations thereof;    administering said composition to a subject mammal in an amount sufficient to reduce lung injury;    and/or reducing endothelial cell dysfunction in said mammal.    
     
     
         36 . The method of  claim 35  wherein said composition has a component A comprising a substituted-3-aminopyridazine moiety, and a G component comprising an acyl moiety.  
     
     
         37 . The method of  claim 36  wherein R 6  of said A component is a chlorine moiety.  
     
     
         38 . The method of  claim 37  wherein said B component comprises a substituted piperazine moiety.  
     
     
         39 . The method of  claim 35  wherein said composition is administered before, during or after said induction.  
     
     
         40 . The method of  claim 35  wherein said composition selectively inhibits myosin light chain kinase activity.  
     
     
         41 . A pyridazinyl composition having a structural formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 3  is a component selected from the group consisting of alkyl and substituted alkyl moieties, arylalkyl and substituted arylalkyl, and phenyl and substituted phenyl moieties;  
 R 4  is a component selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, amino, phenyl and substituted phenyl moieties, and alkyl and substituted alkyl moieties, arylalkyl and substituted arylalkyl moieties, said moieties and substituted moieties providing a carbocyclic moiety with R 5 ;  
 R 5  is a component selected from the group consisting of hydrogen, halogen; alkyl and substituted alkyl, phenyl and substituted phenyl, arylalkyl and substituted arylalkyl, heterocyclic and substituted heterocyclic moieties, said moieties and substituted moieties providing a cyclic moiety with R 6 ; and  
 R 6  is a component selected from the group consisting of hydrogen, halogen; alkyl and substituted alkyl, phenyl and substituted phenyl, arylalkyl and substituted arylalkyl, heterocyclic and substituted heterocyclic moieties, said moieties and substituted moieties providing a cyclic moiety with R 5 .  
 
     
     
         42 . The composition of  claim 41  wherein R 3  is selected from the group consisting of alkylamine and alkylamide components.  
     
     
         43 . The composition of  claim 42  wherein R 3  is (CH 2 ) n NH 2  and n=1−˜14.  
     
     
         44 . The composition of  claim 43  wherein said alkylamine is further substituted with a heterocyclic component.  
     
     
         45 . The composition of  claim 44  wherein said heterocyclic component is selected from the group consisting of pyridazinyl and substituted pyridazinyl moieties, and pyrimidinyl and substituted pyrimidinyl moieties.  
     
     
         46 . The composition of  claim 41  further substituted at the 2-position, said substituent selected from the group of R 2 , G and B components of  claim 1 .  
     
     
         47 . The composition of  claim 41  further substituted at the 2-position, said substituent selected from the group of R 2 , G and B components of  claim 15 .  
     
     
         48 . A method of using a pyridazine composition to inhibit protein kinase activity, said method comprising: 
 providing a heterocyclic composition selected from the group of pyridazine compositions of  claim 1 ,  claim 15  and combinations thereof;    providing a subject mammal with induced kinase activity; and    administering said composition to said mammal in an amount sufficient to inhibit said kinase activity.    
     
     
         49 . The method of  claim 48  wherein said activity is selected from the group consisting of death associated protein kinase activity, calmodulin-regulated kinase activity and combinations of said activities, and said composition inhibiting said activity.  
     
     
         50 . The method of  claim 48  wherein said composition has an A component comprising a 3-aminopyridazinyl moiety, and a G component comprising an acyl moiety.  
     
     
         51 . The method of  claim 49  wherein at least one of said activities manifests a cancer disease state.  
     
     
         52 . The method of  claim 51  wherein said composition has an A component comprising a 3-aminopyridazinyl moiety, and a G component comprising an acyl moiety.  
     
     
         53 . The method of  claim 49  wherein said activity is at least one of the phosphorylation of myosin light chains and the modulation of phosphatase enzyme.  
     
     
         54 . The method of  claim 53  wherein said composition is MW01-022AZ.