US2007259842A1PendingUtilityA1

Triterpene quaternary salts as biologically active surfactants

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Assignee: UNIV MINNESOTAPriority: Jan 18, 2002Filed: Jun 19, 2007Published: Nov 8, 2007
Est. expiryJan 18, 2022(expired)· nominal 20-yr term from priority
Inventors:Pavel A. KrasutskyDmytro AvilovTatiana SergeevaDmytre KrasutskyyOksana Kolomitsyna
C07J 63/00A61P 31/10C07J 63/008C07J 53/00A61P 31/04
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Claims

Abstract

The invention provides novel compounds that are quaternary amine derivatives of betulin and other triterpenes. The compounds have antibacterial, antifungal, and surfactant properties.

Claims

exact text as granted — not AI-modified
1 - 188 . (canceled)  
     
     
         189 . A compound of formula (IV)  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , R 3 , and R 4  are together —O—CH 2 —;  
 R 5  is absent, oxy, thio, or imino;  
 R 6  is absent or alkylene;  
 R 7  is N + -containing heteroaryl, N + -containing heterocycle, or —N + R a R b R c ;  
 R a , R b , and R c  are each independently (C 1 -C 24 )alkyl, aryl, arylalkyl, heteroarylalkyl, heterocycle, or heterocylealkyl;  
 any heteroaryl, heterocycle, or R a , R b , or R c  of R 4  and R 7  can optionally be substituted on carbon with one or more alkyl, hydroxyalkyl, arylalkyl, heteroarylalkyl, aryl, heterocycle, heterocyclealkyl, oxo, hydroxy, halo, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , —NR d R d , or cycloalkylalkyl;  
 any cycloalkylalkyl can optionally be substituted on carbon with one or more hydroxyl, N + -containing heteroaryl, N + -containing heterocycle, —N + R a R b R c , N + -containing heteroarylalkyloxy, N + -containing heterocyclealkyloxy, or —NR a R b R c oxy;  
 R d  and R e  are each independently hydrogen or alkyl;  
 any alkyl or alkylene of R 3 , R 4 , R 6 , or R 7  can be optionally substituted on carbon with one or more oxo, hydroxy, halo, aryl, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , or —NR d R e , and optionally interrupted on carbon with one or more oxy, imino, or thio, and is optionally partially unsaturated;  
 or an acceptable salt thereof.  
 
     
     
         190 . The compound of  claim 189 , wherein R 5  is oxy.  
     
     
         191 . The compound of  claim 189 , wherein R 6  is acetyl.  
     
     
         192 . The compound of  claim 189 , wherein R 7  is N-diazabicyclo[2.2.2]octyl; N-pyridinium; or —N + (CH 3 ) 3 .  
     
     
         193 . The compound of  claim 192 , wherein 
 R 5  is oxy, thio, or imino;    R 6  is alkylene optionally substituted on carbon with one or more oxo, hydroxy, halo, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, or —NR d R e , and optionally interrupted on carbon with one or more oxy, imino, or thio, and is optionally partially unsaturated; and    R 7  is —N + R a R b R c  wherein R a  and R b  are each (C 6 -C 24 )alkyl optionally substituted on carbon with one or more oxo, hydroxy, halo, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , or —NR d R e , and optionally interrupted on carbon with one or more oxy, imino, or thio, and optionally partially unsaturated; wherein R d  and R e  are each independently hydrogen or alkyl.    
     
     
         194 . The compound of  claim 189 , wherein N + -containing heteroaryl is N-pyridinium, N-methyl-2-pyridinium, N-methyl-3-pyridinium, N-methyl-4-pyridinium, N-ethyl-2-pyridinium, N-ethyl-3-pyridinium, N-ethylpyridinium, 3,5-dimethylpyridinium, or 4-(dimethylamino)pyridinium; 
 wherein any heteroaryl can optionally be substituted on carbon with one or more alkyl, hydroxyalkyl, arylalkyl, heteroarylalkyl, aryl, heterocycle, heterocyclealkyl, oxo, hydroxy, halo, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , —NR d R d R e , or cycloalkylalkyl;    wherein R d  and R e  are each independently hydrogen or alkyl.    
     
     
         195 . The compound of  claim 189 , wherein N + -containing heterocycle is N-diazabicyclo[2.2.2]octyl; N-azabicyclo[2.2.2]octyl; N-methyl-N-piperidino; N,N-dimethyl-2-piperidino; N,N-dimethyl-3-piperidino; N,N-dimethyl-4-piperdino; N-methyl-N-morpholino; N,N-dimethyl-2-morpholino; or N,N-dimethyl-3-morpholino; 
 wherein any heterocycle can optionally be substituted on carbon with one or more alkyl, hydroxyalkyl, arylalkyl, heteroarylalkyl, aryl, heterocycle, heterocyclealkyl, oxo, hydroxy, halo, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , —NR d R e , or cycloalkylalkyl;    wherein R d  and R e  are each independently hydrogen or alkyl.    
     
     
         196 . The compound of  claim 189 , wherein —N + —R a R b R c  is N′-benzyl-N,N,N′,N′-tetramethylethylenediamine-N-yl; N,N,N′,N′-tetramethylethylenediamine-N-yl; octyldimethylammonium; tetradecyldimethylammonium; trimethylammonium; triethylammonium, or tri(hydroxymethyl)ammonium.  
     
     
         197 . The compound of  claim 189 , wherein R 6  is alkylene optionally substituted with one or more oxo  
     
     
         198 . The compound of  claim 189 , wherein R 7  is —N+—R a R b R c  wherein R a  and R b  are each (C 6 -C 24 )alkyl optionally substituted on carbon with one or more oxo, hydroxy, halo, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , or —NR d R e , and optionally interrupted on carbon with one or more oxy, imino, or thio, and optionally partially unsaturated.  
     
     
         199 . The compound of  claim 189 , wherein R 7  is —N + R a R b R c  wherein R a  and R b  are each (C 6 -C 24 )alkyl.  
     
     
         200 . The compound of  claim 189 , wherein R 7  is —N+—R a R b R c  wherein R a  and R b  are each (C 6 -C 24 )alkyl and R c  is (C 6 -C 24 )alkyl.  
     
     
         201 . The compound of  claim 189 , wherein R 7  is —N + —R a R b R c  wherein R a  and R b  are each (C 6 -C 24 )alkyl and R c  is (C 6 -C 24 )alkyl.  
     
     
         202 . A compound of formula (IV)  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , R 3  and R 4  are together —O—C(═X)—; wherein X is two hydrogens, oxo, or thioxo (═S);  
 R 5  is oxy;  
 R 6  is absent or alkylene;  
 R 7  is N + -containing heteroaryl, N + -containing heterocycle, or —N + R a R b R c ;  
 R a , R b , and R c  are each independently (C 1 -C 24 )alkyl, aryl, arylalkyl, heteroarylalkyl, heterocycle, or heterocylealkyl;  
 any heteroaryl, heterocycle, or R a , R b , or R c  of R 4  and R 7  can optionally be substituted on carbon with one or more alkyl, hydroxyalkyl, arylalkyl, heteroarylalkyl, aryl, heterocycle, heterocyclealkyl, oxo, hydroxy, halo, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , —NR d R e , or cycloalkylalkyl;  
 any cycloalkylalkyl can optionally be substituted on carbon with one or more hydroxyl, N + -containing heteroaryl, N + -containing heterocycle, —N + R a R b R c , N + -containing heteroarylalkyloxy, N + -containing heterocyclealkyloxy, or —N + R a R b R c oxy;  
 R d  and R e  are each independently hydrogen or alkyl;  
 any alkyl or alkylene of R 3 , R 4 , R 6 , or R 7  can be optionally substituted on carbon with one or more oxo, hydroxy, halo, aryl, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , or —NR d R e , and optionally interrupted on carbon with one or more oxy, imino, or thio, and is optionally partially unsaturated;  
 or an acceptable salt thereof.  
 
     
     
         203 . The compound of  claim 202 , wherein R 1 , R 2 , R 3 , and R 4  are together —O—CH 2 —.  
     
     
         204 . The compound of  claim 202 , wherein R 6  is acetyl.  
     
     
         205 . The compound of  claim 202 , wherein R 7  is N-diazabicyclo[2.2.2]octyl; N-pyridinium; or —N + (CH 3 ) 3 .  
     
     
         206 . The compound of  claim 202 , wherein N + -containing heteroaryl is N-pyridinium, N-methyl-2-pyridinium, N-methyl-3-pyridinium, N-methyl-4-pyridinium, N-ethyl-2-pyridinium, N-ethyl-3-pyridinium, N-ethyl-4-pyridinium, 3,5-dimethylpyridinium, or 4-(dimethylamino)pyridinium; 
 wherein any heteroaryl can optionally be substituted on carbon with one or more alkyl, hydroxyalkyl, arylalkyl, heteroarylalkyl, aryl, heterocycle, heterocyclealkyl, oxo, hydroxy, halo, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , —NR d R e , or cycloalkylalkyl;    wherein R d  and R e  are each independently hydrogen or alkyl.    
     
     
         207 . The compound of  claim 202 , wherein N + -containing heterocycle is N-diazabicyclo[2.2.2]octyl; N-azabicyclo[2.2.2]octyl; N-methyl-N-piperidino; N,N-dimethyl-2-piperidino; N,N-dimethyl-3-piperidino; N,N-dimethyl-4-piperdino; N-methyl-N-morpholino; N,N-dimethyl-2-morpholino; or N,N-dimethyl-3-morpholino; 
 wherein any heterocycle can optionally be substituted on carbon with one or more alkyl, hydroxyalkyl, arylalkyl, heteroarylalkyl, aryl, heterocycle, heterocyclealkyl, oxo, hydroxy, halo, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , —NR d R e , or cycloalkylalkyl;    wherein R d  and R e  are each independently hydrogen or alkyl.    
     
     
         208 . The compound of  claim 202 , wherein —N+—R a R b R c  is N′-benzyl-N,N,N′,N′-tetramethylethylenediamine-N-yl; N,N,N′,N′-tetramethylethylenediamine-N-yl; 
 octyldimethylammonium; tetradecyldimethylammonium; trimethylammonium;    triethylammonium, or tri(hydroxymethyl)ammonium.    
     
     
         209 . The compound of  claim 202 , wherein R 6  is alkylene optionally substituted with one or more oxo  
     
     
         210 . The compound of  claim 202 , wherein R 7  is —N + —R a R b R c  wherein R a  and R b  are each (C 6 -C 24 )alkyl optionally substituted on carbon with one or more oxo, hydroxy, halo, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , or —NR d R e , and optionally interrupted on carbon with one or more oxy, imino, or thio, and optionally partially unsaturated.  
     
     
         211 . The compound of  claim 202 , wherein R 7  is —N + —R a R b R c  wherein R a  and R b  are each (C 6 -C 24 )alkyl.  
     
     
         212 . The compound of  claim 202 , wherein R 7  is —N + —R a R b R c  wherein R a  and R b  are each (C 6 -C 24 )alkyl and R c  is (C 6 -C 24 )alkyl.  
     
     
         213 . The compound of  claim 202 , wherein R 7  is —N+—R a R b R c  wherein R a  and R b  are each (C 6 -C 24 )alkyl and R c  is (C 6 -C 24 )alkyl.  
     
     
         214 . A compound of formula (IV)  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , R 3  and R 4  are together O—C(═X)—; wherein X is two hydrogens, oxo, or thioxo (═S);  
 R 5  is absent, oxy, thio, or imino;  
 R 6  is acetyl;  
 R 7  is N + -containing heteroaryl, N + -containing heterocycle, or —N + R a R b R c ;  
 R a , R b , and R c  are each independently (C 1 -C 24 )alkyl, aryl, arylalkyl, heteroarylalkyl, heterocycle, or heterocylealkyl;  
 any heteroaryl, heterocycle, or R a , R b , or R c  of R 4  and R 7  can optionally be substituted on carbon with one or more alkyl, hydroxyalkyl, arylalkyl, heteroarylalkyl, aryl, heterocycle, heterocyclealkyl, oxo, hydroxy, halo, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , —NR d R e , or cycloalkylalkyl;  
 any cycloalkylalkyl can optionally be substituted on carbon with one or more hydroxyl, N + -containing heteroaryl, N + -containing heterocycle, —N + R a R b R c , N + -containing heteroarylalkyloxy, N + -containing heterocyclealkyloxy, or —NR a R b R c R c oxy; R d  and R e  are each independently hydrogen or alkyl;  
 any alkyl or alkylene of R 3 , R 4 , R 6 , or R 7  can be optionally substituted on carbon with one or more oxo, hydroxy, halo, aryl, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , or —NR d R e , and optionally interrupted on carbon with one or more oxy, imino, or thio, and is optionally partially unsaturated;  
 or an acceptable salt thereof.  
 
     
     
         215 . The compound of  claim 214 , wherein R 1 , R 2 , R 3 , and R 4  are together —O—CH 2 —.  
     
     
         216 . The compound of  claim 214 , wherein R 5  is oxy.  
     
     
         217 . The compound of  claim 214 , wherein R 7  is N-diazabicyclo[2.2.2]octyl; N-pyridinium; or —N + (CH 3 ) 3 .  
     
     
         218 . The compound of  claim 214 , wherein N + -containing heteroaryl is N-pyridinium, N-methyl-2-pyridinium, N-methyl-3-pyridinium, N-methylpyridinium, N-ethyl-2-pyridinium, N-ethyl-3-pyridinium, N-ethylpyridinium, 3,5-dimethylpyridinium, or 4-(dimethylamino)pyridinium; 
 wherein any heteroaryl can optionally be substituted on carbon with one or more alkyl, hydroxyalkyl, arylalkyl, heteroarylalkyl, aryl, heterocycle, heterocyclealkyl, oxo, hydroxy, halo, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , —NR d R e , or cycloalkylalkyl;    wherein R d  and R e  are each independently hydrogen or alkyl.    
     
     
         219 . The compound of  claim 214 , wherein N + -containing heterocycle is N-diazabicyclo[2.2.2]octyl; N-azabicyclo[2.2.2]octyl; N-methyl-N-piperidino; N,N-dimethyl-2-piperidino; N,N-dimethyl-3-piperidino; N,N-dimethyl-4-piperdino; N-methyl-N-morpholino; N,N-dimethyl-2-morpholino; or N,N-dimethyl-3-morpholino; 
 wherein any heterocycle can optionally be substituted on carbon with one or more alkyl, hydroxyalkyl, arylalkyl, heteroarylalkyl, aryl, heterocycle, heterocyclealkyl, oxo, hydroxy, halo, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , —NR d R e , or cycloalkylalkyl;    wherein R d  and R e  are each independently hydrogen or alkyl.    
     
     
         220 . The compound of  claim 214 , wherein —N + —R a R b R c  is N′-benzyl-N,N,N′,N′-tetramethylethylenediamine-N-yl; N,N,N′,N′-tetramethylethylenediamine-N-yl; octyldimethylammonium; tetradecyldimethylammonium; trimethylammonium; triethylammonium, or tri(hydroxymethyl)ammonium.  
     
     
         221 . The compound of  claim 214 , wherein R 7  is —N + —R a R b R c  wherein R a  and R b  are each (C 6 -C 24 )alkyl optionally substituted on carbon with one or more oxo, hydroxy, halo, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , or —NR d R e , and optionally interrupted on carbon with one or more oxy, imino, or thio, and optionally partially unsaturated.  
     
     
         222 . The compound of  claim 214 , wherein R 7  is —N + —R a R b R c  wherein R a  and R b  are each (C 6 -C 24 )alkyl.  
     
     
         223 . The compound of  claim 214 , wherein R 7  is —N + —R a R b R c  wherein R a  and R b  are each (C 6 -C 24 )alkyl and R c  is (C 6 -C 24 )alkyl.  
     
     
         224 . The compound of  claim 214 , wherein R 7  is —N + —R a R b R c  wherein R a  and R b  are each (C 6 -C 24 )alkyl and R c  is (C 6 -C 24 )alkyl.  
     
     
         225 . A compound of formula (IV)  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , R 3  and R 4  are together —O—C(═X)—; wherein X is two hydrogens, oxo, or thioxo (═S);  
 R 5  is absent, oxy, thio, or imino;  
 R 6  is alkylene optionally substituted with one or more oxo;  
 R 7  is N + -containing heteroaryl, N + -containing heterocycle, or —N + R a R b R c ;  
 R a , R b , and R c  are each independently (C 1 -C 24 )alkyl, aryl, arylalkyl, heteroarylalkyl, heterocycle, or heterocylealkyl;  
 any heteroaryl, heterocycle, or R a , R b , or R c  of R 4  and R 7  can optionally be substituted on carbon with one or more alkyl, hydroxyalkyl, arylalkyl, heteroarylalkyl, aryl, heterocycle, heterocyclealkyl, oxo, hydroxy, halo, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , —NR d R e , or cycloalkylalkyl;  
 any cycloalkylalkyl can optionally be substituted on carbon with one or more hydroxyl, N + -containing heteroaryl, N + -containing heterocycle, —N + R a R b R c , N + -containing heteroarylalkyloxy, N + -containing heterocyclealkyloxy, or —N + R a R b R c oxy;  
 R d  and R e  are each independently hydrogen or alkyl;  
 any alkyl or alkylene of R 3 , R 4 , R 6 , or R 7  can be optionally substituted on carbon with one or more oxo, hydroxy, halo, aryl, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , or —NR d R e , and optionally interrupted on carbon with one or more oxy, imino, or thio, and is optionally partially unsaturated;  
 or an acceptable salt thereof.  
 
     
     
         226 . The compound of  claim 225 , wherein R 1 , R 2 , R 3 , and R 4  are together —O—CH 2 —.  
     
     
         227 . The compound of  claim 225 , wherein R 5  is oxy.  
     
     
         228 . The compound of  claim 225 , wherein R 6  is acetyl.  
     
     
         229 . The compound of  claim 225 , wherein R 7  is N-diazabicyclo[2.2.2]octyl; N-pyridinium; or —N + (CH 3 ) 3 .  
     
     
         230 . The compound of  claim 225 , wherein N + -containing heteroaryl is N-pyridinium, N-methyl-2-pyridinium, N-methyl-3-pyridinium, N-methylpyridinium, N-ethyl-2-pyridinium, N-ethyl-3-pyridinium, N-ethyl-4-pyridinium, 3,5-dimethylpyridinium, or 4-(dimethylamino)pyridinium; 
 wherein any heteroaryl can optionally be substituted on carbon with one or more alkyl, hydroxyalkyl, arylalkyl, heteroarylalkyl, aryl, heterocycle, heterocyclealkyl, oxo, hydroxy, halo, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , —NR d R e , or cycloalkylalkyl;    wherein R d  and R e  are each independently hydrogen or alkyl.    
     
     
         231 . The compound of  claim 225 , wherein N + -containing heterocycle is N-diazabicyclo[2.2.2]octyl; N-azabicyclo[2.2.2]octyl; N-methyl-N-piperidino; N,N-dimethyl-2-piperidino; N,N-dimethyl-3-piperidino; N,N-dimethyl-4-piperidino; N-methyl-N-morpholino; N,N-dimethyl-2-morpholino; or N,N-dimethyl-3-morpholino; 
 wherein any heterocycle can optionally be substituted on carbon with one or more alkyl, hydroxyalkyl, arylalkyl, heteroarylalkyl, aryl, heterocycle, heterocyclealkyl, oxo, hydroxy, halo, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , —NR d R e , or cycloalkylalkyl;    wherein R d  and R e  are each independently hydrogen or alkyl.    
     
     
         232 . The compound of  claim 225 , wherein —N + R a R b R c  is N′-benzyl-N,N,N′,N′-tetramethylethylenediamine-N-yl; N,N,N′,N′-tetramethylethylenediamine-N-yl; octyldimethylammonium; tetradecyldimethylammonium; trimethylammonium; triethylammonium, or tri(hydroxymethyl)ammonium.  
     
     
         233 . The compound of  claim 225 , wherein R 7  is —N + —R a R b R c  wherein R a  and R b  are each (C 6 -C 24 )alkyl optionally substituted on carbon with one or more oxo, hydroxy, halo, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, —COOR d , or —NR d R e , and optionally interrupted on carbon with one or more oxy, imino, or thio, and optionally partially unsaturated.  
     
     
         234 . The compound of  claim 225 , wherein R 7  is —N + —R a R b R c  wherein R a  and R b  are each (C 6 -C 24 )alkyl.  
     
     
         235 . The compound of  claim 225 , wherein R 7  is —N + —R a R b R c  wherein R a  and R b  are each (C 6 -C 24 )alkyl and R c  is (C 6 -C 24 )alkyl.  
     
     
         236 . The compound of  claim 225 , wherein R 7  is —N + —R a R b R c  wherein R a  and R b  are each (C 6 -C 24 )alkyl and R c  is (C 6 -C 24 )alkyl.  
     
     
         237 . A pharmaceutical composition comprising a pharmaceutically effective diluent or carrier, and a compound of any one of claims  189 ,  202  and  225 .  
     
     
         238 . A method of killing or inhibiting a bacterium, the method comprising contacting the bacterium with an effective anti-bacterial amount of a compound of any one of claims  189 ,  202  and  225 .  
     
     
         239 . A method of killing or inhibiting a fungus, the method comprising contacting the fungus with an effective anti-fungal amount of a compound of any one of claims  189 ,  202  and  225 .

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