Glycomimetic inhibitors of the pa-il lectin, pa-iil lectin or both the lectins from pseudomonas

Abstract

Compositions and methods are provided related to Pseudomonas bacteria. The compositions and methods may be used for diagnosis and therapy of medical conditions involving infection with Pseudomonas bacteria. Such infections include Pseudomonas aeruginosa in the lungs of patients with cystic fibrosis. A compound useful in the present methods may be used in combination with a therapeutic agent or may be linked to a therapeutic agent. Pseudomonas bacteria may be inhibited by blocking colonization, inhibiting virulence factors, arresting growth or killing the bacteria.

1 . A compound or physiologically acceptable salt thereof, having the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 where —O— separating the two rings in the formula is in an alpha or beta 1-3 linkage; 
 R 1 =independently selected from OH, NHAc, 6′ sulfated GlcNAc, 6′ carboxylated GlcNAc, GalNAc, galactose linked by an O glycosidic bond, a C glycosidic bond or an S glycosidic bond, thiodigalactoside, 6′ sulfated galactose and 6′ carboxylated galactose, with the proviso that three of the four R 1  are independently selected from OH and NHAc and one R 1  is not OH or NHAc; 
 R 2 =H, a fucose, a galactose, an arabinose, a fructose, a mannose, cyclohexane, substituted cyclohexane, tetrahydropyran, substituted tetrahydropyran, piperidine, substituted piperidine, a polyol or substituted polyol; 
 R 3 =(CH 2 ) p , NH 2 , —CH 2 —OH, —CH 2 NH q X or 
 
       
         
           
           
               
               
           
         
       
       where m, n and q are independently selected from 0-1, p is 1-20, Z is N, O or S, and X is NH—C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, substituted C 3 -C 8  cycloalkyl, C 1 -C 8  alkyl, C 6 -C 14  aryl, substituted C 6 -C 14  aryl, C 1 -C 14  heteroaryl, substituted C 1 -C 14  heteroaryl, non-aryl C 1 -C 14  heterocycle or substituted non-aryl C 1 -C 14  heterocycle, NHCH 2 Ph, N(CH 2 Ph) 2 , NHSO 3 Na, NHCO—C 6 H 4 —COOH (ortho), NHCOPh, NHCO—C 6 H 4 —Cl (para), NHCO—C 6 H 4 —OMe (para), NHCO—C 6 H 4 —NO 2  (para), NHCO—C 6 H 4 -Ph (para), NHCO—C 6 H 3 (OMe) 2  (meta, para), NHCO(2-naphthyl), NHCO—C 6 H 4 —OCH 2 Ph (para), N(CH 2 Ph)COPh, NHCOCH 2 CH 2 Ph, NHCOCHPh 2 , NHCOMe, NHCO(cyclo-C 6 H 11 ), NHSO 2 —C 6 H 4 -Me (para), NHCONHEt, NHCONHPh, NHCOOCH 2 —C 6 H 4 —NO 2  (para), NHCOOCH 2 (2-naphthyl), or NHCOOCH 2 Ph;
 R 4 =H, NHAc, —O-Lactose, substituted —O-Lactose, —O-Lactosamine, substituted —O-Lactosamine, NHAc substituted with N-glycolyl, polyethylene glycol or substituted polyethylene glycol; and 
 R 5 =H, NHAc, or NHAc substituted with N-glycolyl. 
 
     
     
         2 . The compound or salt thereof according to  claim 1  wherein R 1a  is not OH or NHAc. 
     
     
         3 . The compound or salt thereof according to  claim 1  wherein R 1b  is not OH or NHAc. 
     
     
         4 . The compound or salt thereof according to  claim 1  wherein R 1c  is not OH or NHAc. 
     
     
         5 . The compound or salt thereof according to  claim 1  wherein R 1d  is not OH or NHAc. 
     
     
         6 . The compound or salt thereof according to  claim 1  wherein R 1a , R 1b , R 1c  or R 1d  is 6′ sulfated GlcNAc or 6′ carboxylated GlcNAc. 
     
     
         7 . The compound or salt thereof according to  claim 1  wherein R 1a , R 1b , R 1c  or R 1d  is galactose. 
     
     
         8 . The compound or salt thereof according to  claim 1  wherein R 1a , R 1b , R 1c  or R 1d  is 6′ sulfated galactose or 6′ carboxylated galactose. 
     
     
         9 . The compound or salt thereof according to  claim 1  wherein R 1a , R 1b , R 1c  or R 1d  is thiodigalactoside. 
     
     
         10 . The compound or salt thereof according to  claim 1 , where —O—separating the two rings in the formula is in a beta 1-3 linkage. 
     
     
         11 . The compound or salt thereof according to  claim 1  wherein R 2  is fucose. 
     
     
         12 . The compound or salt thereof according to  claim 1  wherein R 3  is —CH 2 —OH. 
     
     
         13 . The compound or salt thereof according to  claim 1  wherein R 3   
       
         
           
           
               
               
           
         
       
       is where X is defined according to R 3  of  claim 1 . 
     
     
         14 . The compound or salt thereof according to  claim 13  wherein X is 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound or salt thereof according to  claim 1  wherein at least one of R 4  and R 5  is H. 
     
     
         16 . The compound or salt thereof according to  claim 1  wherein at least one of R 4  and R 3  is NHAc. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . The compound or salt thereof according to  claim 1  wherein the compound or salt thereof is in combination with a pharmaceutically acceptable carrier or diluent. 
     
     
         20 . A conjugate comprising a therapeutic agent linked to a compound according to  claim 1 . 
     
     
         21 . The conjugate of  claim 20  wherein the conjugate is in combination with a pharmaceutically acceptable carrier or diluent. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . A conjugate comprising a therapeutic agent linked to a compound or salt thereof wherein the compound is with the formula: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The conjugate of  claim 24  wherein the conjugate is in combination with a pharmaceutically acceptable carrier or diluent. 
     
     
         26 . A method of inhibiting  Pseudomonas  bacteria infection in a warm-blooded animal comprising administering to the animal in an amount effective to inhibit one or more lectins of the bacteria a compound comprising a compound according to  claim 1 . 
     
     
         27 . The method of  claim 26  wherein the compound is linked to a therapeutic agent. 
     
     
         28 . The method of  claim 26  or  claim 27  wherein the compound is in combination with a pharmaceutically acceptable carrier or diluent. 
     
     
         29 . The method of  claim 26  or  claim 27  wherein the compound is in combination with another anti-bacterial compound. 
     
     
         30 . The method of  claim 26  wherein the bacteria are  Pseudomonas aeruginosa.    
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled)