Mammalian and Bacterial Nitric Oxide Synthase Inhibitors

Abstract

Disclosed are compounds that are shown to inhibit the biological activity of nitric oxide synthases (NOSs). Also disclosed are pharmaceutical compositions comprising the compounds, and methods of using the compounds and pharmaceutical compositions for treating a subject in need thereof. Because the disclosed compounds are shown to inhibit the activity of nitric oxide synthases (NOSs), the disclosed compounds and pharmaceutical compositions may be utilized in methods for treating a subject having or at risk for developing a disease or disorder that is associated with NOS activity.

1 . A compound of a formula 
       
         
           
           
               
               
           
         
         or a salt or solvate thereof, wherein R 1  is selected from H, alkyl and amino moieties; L 1  is a divalent linker moiety selected from a covalent bond, alkylene and substituted alkylene moieties, said alkylene substituents selected from hydroxy, amino, aminoalkyl, aza (—NH—), alkyl (R) substituted aza (—NR—) and combinations thereof; R 3  is selected from H, alkyl, halo, haloalkyl, cyano and amino moieties and combinations thereof; X is selected from CH, CR 3  and N; L 2  is selected from alkylene and substituted alkylene moieties, said alkylene substituents selected from aza (—NH—) and substituted aza (—NR—) substituents where R is selected from alkyl and cycloalkyl moieties; R 2  is selected from hydrogen, alkyl, alkoxy, amino, alkyl-substituted amino and optionally-substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl moieties, said substituents selected from amino, halo, alkyl, cycloalkyl and heterocycloalkyl substituents and divalent alkylene and heteroatom-substituted alkylene substituents; provided that if L 2  is alkylene then R 2  is amino or alkyl-substituted amino. 
       
     
     
         2 . The compound of  claim 1  of a formula 
       
         
           
           
               
               
           
         
         wherein n is 1-3. 
       
     
     
         3 . The compound of  claim 2  wherein n is 2, L 2  is selected from —(CH 2 ) m —, —NH(CH 2 ) m — and —N(R)(CH 2 ) m — moieties, where m is 0-4; R is selected from alkyl and cycloalkyl moieties; and R2 is selected from amine, alkyl- and cycloalkyl-substituted amine moieties and optionally-substituted aryl and heteroaryl moieties. 
     
     
         4 . The compound of  claim 1  wherein L 1  is a covalent bond and R 3  is H, said compound of a formula 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 4  of a formula 
       
         
           
           
               
               
           
         
         wherein L 2  is an aza-substituted alkylene moiety, said substituent selected from —NH— and —NR— where R is alkyl; and R 2  is selected from halo-substituted phenyl and alkyl-substituted amino moieties. 
       
     
     
         6 . The compound of  claim 5  wherein said aza-substituted alkylene moiety is selected from —CH 2 NH(CH 2 ) 2 —, —CH 2 N(CH 3 )(CH 2 ) 2 —, —CH 2 NH(CH 2 ) 3 —, —CH 2 NHCH 2 —, and —N(CH 3 )(CH 2 ) 2 — moieties. 
     
     
         7 . The compound of  claim 1  wherein L 1  is selected from alkylene moieties; X is N; L 2  is selected from alkylene and aza-substituted alkylene moieties; and R 2  is selected from alkyl-substituted amino moieties. 
     
     
         8 . The compound of  claim 7  wherein said aza-substituted alkylene moiety is selected from —CH 2 NH(CH 2 ) 2 —, —CH 2 N(CH 3 )(CH 2 ) 2 —, —CH 2 NH(CH 2 ) 3 —, —CH 2 N(CH 3 )(CH 2 ) 3 —, —CH 2 NHCH 2 —, and —N(CH 3 )(CH 2 ) 2 — moieties. 
     
     
         9 . A compound of a formula: 
       
         
           
           
               
               
           
         
         or a salt or solvate thereof, wherein R 1  is selected from H and methyl moieties; X and Y are independently selected from CH, CR 3  and N, providing both X and Y are not N; Z is selected from N, NH, N(R) where R is alkyl or cycloalkyl, CH, and CH 2 ; W is selected from N, NH, and O; m is an integer selected from 0-3; and R 4  is selected from H, alkyl, cycloalkyl and divalent alkylene moieties; and R 5  and R 6  are independently selected from H, alkyl, cycloalkyl, optionally substituted aryl and heteroaryl moieties and divalent alkylene moieties, providing where m is 0, R 6  is selected from H and alkyl and R 4  and R 5  are independently selected from divalent alkylene moieties to provide together with W and Z a heterocycloalkyl moiety. 
       
     
     
         10 . The compound of  claim 9  wherein Z is selected from N and NH; m is 0; and R 4  and R 5  are independently divalent alkylene moieties to provide the said heterocycloalkyl moiety. 
     
     
         11 . The compound of  claim 10  wherein Z is N and said heterocycloalkyl moiety is a piperazinyl moiety. 
     
     
         12 . The compound of  claim 10  wherein Z is NH and said heterocycloalkyl moiety is a piperidinyl moiety. 
     
     
         13 . The compound of  claim 9  wherein one of X and Y is N; R 3  is H; Z is N; R 4  is selected from H, alkyl and cycloalkyl; m is 2-3; R 5  and R 6  are independently selected from H, alkyl and cycloalkyl moieties. 
     
     
         14 . The compound of  claim 9  wherein X is CH and Y is CR 3 , where R 3  is selected from fluoro, trifluoromethyl and cyano substituents; R 4  is selected from H and alkyl; m is 2-3; R 5  and R 6  are independently selected from H, alkyl and cycloalkyl moieties. 
     
     
         15 . The compound of  claim 4  wherein n is 2; L 2  is —NH(CH 2 ) m —, where m is selected from 1 and 2; and R 2  is selected from pyridinyl and substituted phenyl moieties. 
     
     
         16 . A compound of a formula 
       
         
           
           
               
               
           
         
         or a salt or solvate thereof, wherein R 1  is selected from H, alkyl and amino moieties; L 1  is an amino-substituted alkylene moiety or an alkylamino-substituted alkylene moiety; R 3  is selected from H, alkyl, halo, haloalkyl, cyano and amino moieties and combinations thereof; X is selected from CH, CR 3  and N; L 2  is a divalent linker moiety selected from alkylene and substituted alkylene moieties, said alkylene substituents selected from aza (—NH—), alkyl, cycloalkyl, and substituted aza (—NR—) substituents where R is selected from alkyl and cycloalkyl moieties; and R 2  is selected from hydrogen, amino, substituted amino and optionally-substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl moieties, said substituents selected from amino, halo, alkyl, cycloalkyl and heterocycloalkyl substituents and divalent alkylene and heteroatom-substituted alkylene substituents, or a salt thereof. 
       
     
     
         17 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         18 . A method of treating a disease or disorder associated with nitric oxide synthase in a subject in need thereof, the method comprising administering the composition of  claim 17  to the subject. 
     
     
         19 . A method of treating a bacterial infection in a subject in need thereof, the method comprising administering the composition of  claim 17  to the subject. 
     
     
         20 . The method of  claim 19 , further comprising administering an antibiotic to the subject concurrently with the composition.