Novel 16-member triamilide derivatives and uses thereof

Abstract

The invention discloses 20,23-modified novel derivatives of 16-membered demycarosyltylonolide antibiotics, which are useful against bacterial and mycoplasmic pathogens in humans and animals. Also claimed are pharmaceutical compositions of such derivatives and their use in treating bacterial and mycoplasmic infections in humans and animals.

1 . A compound having Formula II, its enantiomers, diastereoisomers, tautomers or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         Wherein: 
         R 1  is optionally substituted C 1-6  alkyl or C 3-8  cycloalkyl, where the substituent is selected from the group consisting of aryl and hydroxyl; 
         R 2  is hydrogen, optionally substituted C 1-6  alkyl or C 3-8  cycloalkyl, where the substituent is selected from the group consisting of aryl and hydroxyl; 
         Or R 1  and R 2  are bonded covalently so that R 1 —N—R 2  forms an optionally substituted 3-5 membered or 7-9 membered heterocyclic ring, where the substituent is selected from C 1-3  alkyl or hydroxyl. 
       
     
     
         2 . A compound or pharmaceutically acceptable salt thereof according to  claim 1  wherein:
 R 1  is optionally substituted C 1-4  alkyl or C 3-8  cycloalkyl, where the substituent is selected from the group consisting of benzene, pyridine and hydroxyl; 
 R 2  is hydrogen or an optionally substituted C 1-4  alkyl group, where the substituent is selected from the group consisting of benzene, pyridine and hydroxyl. 
 
     
     
         3 . A compound or pharmaceutically acceptable salt thereof according to  claim 2  wherein:
 R 1  is ethyl, n-propyl, isopropyl, butyl, benzyl, 2-hydroxyethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, or cyclohexyl; 
 R 2  is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl or 2-hydroxyethyl. 
 
     
     
         4 . A compound or pharmaceutically acceptable salt thereof according to  claim 1  wherein:
 R 1  and R 2  are bonded covalently so that R 1 —N—R 2  forms an optionally substituted 5-membered or 9-membered heterocyclic ring, where the substituent is selected from methyl, ethyl, n-propyl, isopropyl or hydroxyl. 
 
     
     
         5 . A compound or pharmaceutically acceptable salt thereof according to  claim 4  wherein:
 R 1  and R 2  are bonded covalently so that R 1 —N—R 2  forms an optionally substituted 5-membered or 9-membered heterocyclic ring comprising pyrrolidinyl, 3-hydroxy-pyrrolidinyl, 3,5-dimethyl-piperidinyl or isoindolinyl group. 
 
     
     
         6 . (canceled) 
     
     
         7 . A compound or pharmaceutically acceptable salt thereof according to  claim 1  selected from the group consisting of:
 (4R,5S,6S,7R,9R,11E,13E,15R,16R)-15-((benzyl(methyl)amino)methyl)-6-(((2R,3R,4S,5S,6R)-4-(dimethylamino)-3,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-16-ethyl-4-hydroxy-7-(2-(isoindolin-2-yl)ethyl)-5,9,13-trimethyloxacyclohexadeca-11,13-diene-2,10-dione; 
 (4R,5S,6S,7R,9R,11E,13E,15R,16R)-6-(((2R,3R,4S,5S,6R)-4-(dimethylamino)-3,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-16-ethyl-4-hydroxy-7-(2-(isoindolin-2-yl)ethyl)-5,9,13-trimethyl-15-(piperidin-1-ylmethyl)oxacyclohexadeca-11,13-diene-2,10-dione; 
 (4R,5S,6S,7R,9R,11E,13E,15R,16R)-15-((diethylamino)methyl)-6-(((2R,3R,4S,5S,6R)-4-(dimethylamino)-3,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-16-ethyl-4-hydroxy-7-(2-(isoindolin-2-yl)ethyl)-5,9,13-trimethyloxacyclohexadeca-11,13-diene-2,10-dione; and 
 (4R,5S,6S,7R,9R,11E,13E,15R,16R)-6-(((2R,3R,4S,5S,6R)-4-(dimethylamino)-3,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-15-((3,5-dimethylpiperidin-1-yl)methyl)-16-ethyl-4-hydroxy-7-(2-(isoindolin-2-yl)ethyl)-5,9,13-trimethyloxacyclohexadeca-11,13-diene-2,10-dione. 
 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to  claim 1  and a pharmaceutically acceptable adjuvant, diluents or carrier. 
     
     
         11 . A pharmaceutical composition according to  claim 10  wherein the compound is selected from the group consisting of:
 (4R,5S,6S,7R,9R,11E,13E,15R,16R)-15-((benzyl(methyl)amino)methyl)-6-(((2R,3R,4S,5S,6R)-4-(dimethylamino)-3,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-16-ethyl-4-hydroxy-7-(2-(isoindolin-2-yl)ethyl)-5,9,13-trimethyloxacyclohexadeca-11,13-diene-2,10-dione; 
 (4R,5S,6S,7R,9R,11E,13E,15R,16R)-6-(((2R,3R,4S,5S,6R)-4-(dimethylamino)-3,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-16-ethyl-4-hydroxy-7-(2-(isoindolin-2-yl)ethyl)-5,9,13-trimethyl-15-(piperidin-1-ylmethyl)oxacyclohexadeca-11,13-diene-2,10-dione; 
 (4R,5S,6S,7R,9R,11E,13E,15R,16R)-15-((diethylamino)methyl)-6-(((2R,3R,4S,5S,6R)-4-(dimethylamino)-3,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-16-ethyl-4-hydroxy-7-(2-(isoindolin-2-yl)ethyl)-5,9,13-trimethyloxacyclohexadeca-11,13-diene-2,10-dione; and 
 (4R,5S,6S,7R,9R,11E,13E,15R,16R)-6-(((2R,3R,4S,5S,6R)-4-(dimethylamino)-3,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-15-((3,5-dimethylpiperidin-1-yl)methyl)-16-ethyl-4-hydroxy-7-(2-(isoindolin-2-yl)ethyl)-5,9,13-trimethyloxacyclohexadeca-11,13-diene-2,10-dione. 
 
     
     
         12 . (canceled)