Carboxylesterase inhibitors

Abstract

This disclosure relates to amides, aryl sulphonamides, aryl ureas, and α,β-diketones derivatives useful as carboxylesterase esterase inhibitors. The disclosure is also directed to the use of these compounds as selective human intestinal carboxylesterase inhibitors and insect carboxylesterase inhibitors. The disclosure is also directed to pharmaceutical compositions and pesticide formulations containing these compounds, and to methods for treating or ameliorating the toxic effects following administration of drugs such as cancer therapy drugs, treating or ameliorating the effects of a drug overdose, and to the use of the compounds for increasing the effectiveness of insecticides and pesticides.

1 . A method of inhibiting an esterase in a patient in need thereof, which method comprises administering an esterase inhibiting amount of an esterase inhibitor selected from amides, aryl sulphonamides, aryl ureas, α,β-diketones, and mixtures thereof to the patient.  
     
     
         2 . The method of  claim 1 , wherein the amide is of Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  to R 12  are each independently selected from hydrogen, C 1 -C 6  linear alkyl, C 1 -C 6  branched alkyl, substituted alkyl, phenyl, substituted phenyl, hydroxy, halogen, and C 1 -C 6  alkoxy; and  
 optionally R 8  and R 9  are linked to form an optionally substituted aryl or heteroaryl ring system.  
 
     
     
         3 . The method of  claim 1 , wherein the amide is of Formula (II):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 11  to R 12  are each independently selected from hydrogen, C 1 -C 6  linear alkyl, C 1 -C 6  branched alkyl, substituted alkyl, phenyl, substituted phenyl, alkylphenyl, hydroxyl, halogen, and C 1 -C 6  alkoxy; and  
 Ar is optionally substituted phenyl or naphthyl.  
 
     
     
         4 . The method of  claim 1 , wherein the aryl sulphonamide is of Formula (III):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 13 , R 14 , R 16  and R 17  are each independently selected from hydrogen, halogen, and C 1 -C 6  linear or branched alkyl, or R 16  and R 17  are optionally linked to form an optionally substituted aryl or heteroaryl ring system;  
 R 15  is selected from hydrogen, C 1 -C 6  alkoxy, optionally substituted phenoxy, and NHSO 2 R 19 ; wherein R 19  is C 1 -C 6  linear or branched alkyl, phenyl, mono-, di- or tri-halosubstituted phenyl or S 2 C 6 H 5 NHSO 2 CH 3 ; and  
 R 18  is selected from hydrogen, C 1 -C 6  linear or branched alkyl, halogen, phenyl, halosubstituted phenyl and [C 6 H 2 (CH 3 ) 2 ]SO 2 NHC 6 H 5 .  
 
     
     
         5 . The method of  claim 1 , wherein the aryl urea is of Formula (IV):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 20  to R 29  are each independently selected from hydrogen, halogen, C 1 C 6  linear or branched alkyl and NO 2 .  
 
     
     
         6 . The method of  claim 1 , wherein the α,β-diketone is of Formula (V)  
       
         
           
           
               
               
           
         
       
       wherein R 31  and R 32  are each independently aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more hydrogen, halogen, hydroxy, C 1 -C 6  linear or branched alkyl, C 1 -C 6  linear or branched halo-alkyl, C 1 -C 6  alkoxy, NR 33 R 34 , COOH, or NO 2 ; or R 31  and R 32  may optionally be linked to form an optionally substituted polycyclic aryl or heteroaryl ring system; and R33 and R are independently hydrogen or C 1 -C 6  linear or branched alkyl.  
     
     
         7 . The method of  claim 1 , wherein the esterase is a carboxylesterase.  
     
     
         8 . The method of  claim 7 , wherein the carboxylesterase is human intestinal carboxylesterase.  
     
     
         9 . The method of  claim 8 , wherein the amide is selected from: 
 N-(5-chloro-2,4-dimethoxyphenyl)-3-hydroxy-2-naphthamide,    N-(4-chlorophenyl)-8-hydroxy-4aH-carbazole-7-carboxamide,    2-Benzoylamino-3-phenyl-propionic acid naphthalene-2-yl ester, and    2-naphthyl 2-(acetylamino)-4-methylpentanoate.    
     
     
         10 . The method of  claim 8 , wherein the aryl sulfonamide is selected from: 
 N-{2,3,5,6-tetrachloro-4-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide,    4-chloro-N-(4{[(4-chlorophenyl)sulfonyl]amino}-2,3,4,6-tetrafluorophenyl) benzenesulfonamide,    4-chloro-N-(4-{[(4-chlorophenyl)sulfonyl]amino}phenyl)benzenesulfonamide,    4-bromo-N-(4-phenoxyphenyl)benzenesulfonamide,    4-chloro-N-(4-{[(4-chlorophenyl)sulfonyl]amino}-1-naphthyl)benzenesulfonamide,    4,6-dimethyl-N,N′-diphenylbenzene-1,3-disulfonamide,    N-{2-methyl-4-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide,    N-[4-({4-[(methylsulfonyl)amino]phenyl}dithio)phenyl]methanesulfonamide,    N-{4-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide, and    4-chloro-N-(4-ethoxyphenyl)benzenesulfonamide.    
     
     
         11 . The method of  claim 8 , wherein the aryl urea is selected from: 
 N-(2-chloro-4-nitrophenyl)-N′-(4-chlorophenyl)urea,    N-(2,6-dimethylphenyl)-N′-(4-nitrophenyl)urea,    N-(3-fluorophenyl)-N′-(2-methyl-4-nitrophenyl)urea, and    N-(2-methyl-4-nitrophenyl)-N′-phenylurea.    
     
     
         12 . The method of  claim 7 , wherein the carboxylesterase is an insect carboxylesterase.  
     
     
         13 . A method of reducing the gastrointestinal toxicity following administration of a drug to a patient in need thereof, which method comprises administering an esterase inhibiting amount of an esterase inhibitor selected from amides, aryl sulphonamides, aryl ureas, α,β-diketones, and mixtures thereof to the patient.  
     
     
         14 . The method of  claim 13 , wherein the amide is of the Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein  
       R 1  to R 12  are each independently selected from hydrogen, C 1 -C 6  linear alkyl, C 1 -C 6  branched alkyl, substituted alkyl, phenyl, substituted phenyl, hydroxyl, halogen, and C 1 -C 6  alkoxy; and 
 optionally R 8  and R 9  are linked to form an optionally substituted aryl or heteroaryl ring system.  
 
     
     
         15 . The method of  claim 13 , wherein the amide is of the Formula (II):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 11  to R 12  are each independently selected from hydrogen, C 1 -C 6  linear alkyl, C 1 -C 6  branched alkyl, substituted alkyl, phenyl, substituted phenyl, alkylphenyl, hydroxyl, halogen, and C 1 -C 6  alkoxy; and  
 Ar is optionally substituted phenyl or naphthyl.  
 
     
     
         16 . The method of  claim 13  wherein the aryl sulphonamide is of the Formula (III):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 13 , R 14 , R 16  and R 17  are each independently selected from hydrogen, halogen, and C 1 -C 6  linear or branched alkyl, or R 16  and R 17  are linked to form an optionally substituted aryl or heteroaryl ring system;  
 R 15  is selected from hydrogen, C 1 -C 6  alkoxy, optionally substituted phenoxy, and NHSO 2 R 19 ; wherein R 19  is C 1 -C 6  linear or branched alkyl, phenyl, mono-, di- or tri-halosubstituted phenyl or S 2 C 6 H 5 NHSO 2 CH 3 ; and  
 R 18  is selected from hydrogen, C 1 -C 6  linear or branched alkyl, halogen, phenyl, halosubstituted phenyl and [C 6 H 2 (CH 3 ) 2 ]SO 2 NHC 6 H 5 .  
 
     
     
         17 . The method of  claim 13 , wherein the aryl urea is of the Formula (IV):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 20  to R 29  are each independently selected from hydrogen, halogen, C 1 -C 6  linear or branched alkyl and NO 2 .  
 
     
     
         18 . The method of  claim 13 , wherein the α,β-diketone is of Formula (V):  
       
         
           
           
               
               
           
         
       
       wherein R 31  and R 32  are each independently aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more hydrogen, halogen, hydroxy, C 1 -C 6  linear or branched alkyl, C 1 -C 6  linear or branched halo-alkyl, C 1 -C 6  alkoxy, NR 33 R 34 , COOH, or NO 2 ; or R 31  and R 32  may optionally be linked to form an optionally substituted polycyclic aryl or heteroaryl ring system; and R33 and R34 are independently hydrogen or C 1 -C 6  linear or branched alkyl.  
     
     
         19 . The method of  claim 13 , wherein the gastrointestinal toxicity is delayed diarrhea.  
     
     
         20 . The method of  claim 13 , wherein the drug is an anti-cancer drug.  
     
     
         21 . The method of  claim 20 , wherein the anti-cancer drug is CPT-11.  
     
     
         22 . The method of  claim 13 , where the drug and the esterase inhibitor are administered simultaneously or sequentially.  
     
     
         23 . A method of treating or ameliorating the effects of an overdose of a drug metabolized by a carboxylesterase in a patient in need thereof, which method comprises administering an esterase inhibiting amount of an esterase inhibitor selected from amides, aryl sulphonamides, aryl ureas, α,β-diketones, and mixtures thereof to the patient.  
     
     
         24 . The method of  claim 23  wherein the amide is of Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  to R 12  are each independently selected from hydrogen, C 1 -C 6  linear alkyl, C 1 -C 6  branched alkyl, substituted alkyl, phenyl, substituted phenyl, hydroxyl, halogen, and C 1 -C 6  alkoxy; and  
 optionally R 8  and R 9  are linked to form an optionally substituted aryl or heteroaryl ring system.  
 
     
     
         25 . The method of  claim 23 , wherein the amide is of Formula (II):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 11  to R 12  are each independently selected from hydrogen, C 1 -C 6  linear alkyl, C 1 -C 6  branched alkyl, substituted alkyl, phenyl, substituted phenyl, alkylphenyl, hydroxyl, halogen, and C 1 -C 6  alkoxy; and  
 Ar is optionally substituted phenyl or naphthyl.  
 
     
     
         26 . The method of  claim 23 , wherein the aryl sulphonamide is of Formula (III):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 13 , R 14 , R 16  and R 17  are each independently selected from hydrogen, halogen, and C 1 -C 6  linear or branched alkyl, or R 16  and R 17  are linked to form an optionally substituted aryl or heteroaryl ring system;  
 R 15  is selected from hydrogen, C 1 -C 6  alkoxy, optionally substituted phenoxy, and NHSO 2 R 19 ; wherein R 19  is C 1 -C 6  linear or branched alkyl, phenyl, mono-, di- or tri-halosubstituted phenyl or S 2 C 6 H 5 NHSO 2 CH 3 ; and  
 R 18  is selected from hydrogen, C 1 -C 6  linear or branched alkyl, halogen, phenyl, halosubstituted phenyl and [C 6 H 2 (CH 3 ) 2 ]SO 2 NHC 6 H 5 .  
 
     
     
         27 . The method of  claim 23 , wherein the aryl urea is of Formula (IV):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 20  to R 29  are each independently selected from hydrogen, halogen, C 1 -C 6  linear or branched alkyl and NO 2 .  
 
     
     
         28 . The method of  claim 23 , wherein the α,β-diketone is of Formula (V):  
       
         
           
           
               
               
           
         
       
       wherein R 31  and R 32  are each independently aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more hydrogen, halogen, hydroxy, C 1 -C 6  linear or branched alkyl, C 1 -C 6  linear or branched halo-alkyl, C 1 -C 6  alkoxy, NR 33 R 34,  COOH, or NO 2 ; or R 31  and R 32  may optionally be linked to form an optionally substituted polycyclic aryl or heteroaryl ring system; and R 33  and R 34  are independently hydrogen or C 1 -C 6  linear or branched alkyl.  
     
     
         29 . The method of  claim 23 , wherein the drug is selected from cocaine, heroin, meperidine, capecitabine and flumazenil.  
     
     
         30 . A formulation comprising (i) a compound active as a pesticide; and (ii) an insect esterase inhibiting amount of an esterase inhibitor selected from amides, aryl sulphonamides, aryl ureas, α,β-diketones, and mixtures thereof.  
     
     
         31 . The formulation of  claim 30 , wherein the amide is of Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  to R 12  are each independently selected from hydrogen, C 1 -C 6  linear alkyl, C 1 -C 6  branched alkyl, substituted alkyl, phenyl, substituted phenyl, hydroxyl, halogen, and C 1 -C 6  alkoxy; and  
 optionally R 8  and R 9  are linked to form an optionally substituted aryl or heteroaryl ring system.  
 
     
     
         32 . The formulation of  claim 30 , wherein the amide is of Formula (II):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 11  to R 12  are each independently selected from hydrogen, C 1 -C 6  linear alkyl, C 1 -C 6  branched alkyl, substituted alkyl, phenyl, substituted phenyl, alkylphenyl, hydroxyl, halogen, and C 1 -C 6  alkoxy; and  
 Ar is optionally substituted phenyl or naphthyl.  
 
     
     
         33 . The formulation of  claim 30 , wherein the aryl sulphonamide is of Formula (III):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 13 , R 14 , R 16  and R 17  are each independently selected from hydrogen, halogen, and C 1 -C 6  linear or branched alkyl, or R 16  and R 17  are linked to form an optionally substituted aryl or heteroaryl ring system;  
 R 15  is selected from hydrogen, C 1 -C 6  alkoxy, optionally substituted phenoxy, and NHSO 2 R 19 ; wherein R 19  is C 1 -C 6  linear or branched alkyl, phenyl, mono-, di- or tri-halosubstituted phenyl or S 2 C 6 H 5 NHSO 2 CH 3 ; and  
 R 18  is selected from hydrogen, C 1 -C 6  linear or branched alkyl, halogen, phenyl, halosubstituted phenyl and [C 6 H 2 (CH 3 ) 2 ]SO 2 NHC 6 H 5 .  
 
     
     
         34 . The formulation of  claim 30 , wherein the aryl urea is of Formula (IV):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 20  to R 29  are each independently selected from hydrogen, halogen, C 1 -C 6  linear or branched alkyl and NO 2 .  
 
     
     
         35 . The formulation of  claim 30 , wherein the α,β-diketone is of Formula (V):  
       
         
           
           
               
               
           
         
       
       wherein R 31  and R 32  are each independently aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more hydrogen, halogen, hydroxy, C 1 -C 6  linear or branched alkyl, C 1 -C 6  linear or branched halo-alkyl, C 1 -C 6  alkoxy, NR 33 R 34 , COOH, or NO 2 ; or R 31  and R 32  may optionally be linked to form an optionally substituted polycyclic aryl or heteroaryl ring system; and R 33  and R 34  are independently hydrogen or C 1 -C 6  linear or branched alkyl.  
     
     
         36 . A pharmaceutical composition comprising an esterase inhibiting amount of an esterase inhibitor selected from amides, aryl sulphonamides, aryl ureas, α,β-diketones, and mixtures thereof, and a pharmaceutically acceptable carrier or excipient.  
     
     
         37 . The composition of  claim 36 , wherein the amide is of Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  to R 12  are each independently selected from hydrogen, C 1 -C 6  linear alkyl, C 1 -C 6  branched alkyl, substituted alkyl, phenyl, substituted phenyl, hydroxyl, halogen, and C 1 -C 6  alkoxy; and  
 optionally R 8  and R 9  are linked to form an optionally substituted aryl or heteroaryl ring system.  
 
     
     
         38 . The composition of  claim 36 , wherein the amide is of Formula (II):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 11  to R 12  are each independently selected from hydrogen, C 1 -C 6  linear alkyl, C 1 -C 6  branched alkyl, substituted alkyl, phenyl, substituted phenyl, alkylphenyl, hydroxyl, halogen, and C 1 -C 6  alkoxy; and  
 Ar is optionally substituted phenyl or naphthyl.  
 
     
     
         39 . The composition of  claim 36 , wherein the aryl sulphonamide is of Formula (III):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 13 , R 14 , R 16  and R 17  are each independently selected from hydrogen, halogen, and C 1 -C 6  linear or branched alkyl, or R 16  and R 17  are linked to form an optionally substituted aryl or heteroaryl ring system;  
 R 15  is selected from hydrogen, C 1 -C 6  alkoxy, optionally substituted phenoxy, and NHSO 2 R 19 ; wherein R 19  is C 1 -C 6  linear or branched alkyl, phenyl, mono-, di- or tri-halosubstituted phenyl or S 2 C 6 H 5 NHSO 2 CH 3 ; and  
 R 18  is selected from hydrogen, C 1 -C 6  linear or branched alkyl, halogen, phenyl, halosubstituted phenyl and [C 6 H 2 (CH 3 ) 2 ]SO 2 NHC 6 H 5 .  
 
     
     
         40 . The composition of  claim 36 , wherein the aryl urea is of Formula (IV):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 20  to R 29  are each independently selected from hydrogen, halogen, C 1 -C 6  linear or branched alkyl and NO 2 .  
 
     
     
         41 . The composition of  claim 36 , wherein the α,β-diketone is of Formula (V):  
       
         
           
           
               
               
           
         
       
       wherein R 31  and R 32  are each independently aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more hydrogen, halogen, hydroxy, C 1 -C 6  linear or branched alkyl, C 1 -C 6  linear or branched halo-alkyl, C 1 -C 6  alkoxy, NR 33 R 34,  COOH, or NO 2 ; or R 31  and R 32  may optionally be linked to form an optionally substituted polycyclic aryl or heteroaryl ring system; and R 33  and R 34  are independently hydrogen or C 1 -C 6  linear or branched alkyl.  
     
     
         42 . The composition of  claim 36 , wherein the amide is selected from: 
 N-(5-chloro-2,4-dimethoxyphenyl)-3-hydroxy-2-naphthamide,    N-(4-chlorophenyl)-8-hydroxy-4aH-carbazole-7-carboxamide,    2-Benzoylamino-3-phenyl-propionic acid naphthalene-2-yl ester, and    2-naphthyl 2-(acetylamino)4-methylpentanoate.    
     
     
         43 . The composition of  claim 36 , wherein the aryl sulfonamide is selected from: 
 N-{2,3,5,6-tetrachloro-4-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide,    4-chloro-N-(4{[(4-chlorophenyl)sulfonyl]amino}-2,3,4,6-tetrafluorophenyl) benzenesulfonamide,    4-chloro-N-(4-{[(4-chlorophenyl)sulfonyl]amino}phenyl)benzenesulfonamide,    4-bromo-N-(4-phenoxyphenyl)benzenesulfonamide,    4-chloro-N-(4-{[(4-chlorophenyl)sulfonyl]amino}-1-naphthyl)benzenesulfonamide,    4,6-dimethyl-N,N′-diphenylbenzene-1,3-disulfonamide,    N-{2-methyl-4-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide,    N-[4-({4-[(methylsulfonyl)amino]phenyl}dithio)phenyl]methanesulfonamide,    N-{4-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide, and    4-chloro-N-(4-ethoxyphenyl)benzenesulfonamide.    
     
     
         44 . The composition of  claim 36 , wherein the aryl urea is selected from: 
 N-(2-chloro4-nitrophenyl)-N′-(4-chlorophenyl)urea,    N-(2,6-dimethylphenyl)-N′-(4-nitrophenyl)urea,    N-(3-fluorophenyl)-N′-(2-methyl-4-nitrophenyl)urea, and    N-(2-methyl-4-nitrophenyl)-N′-phenylurea.    
     
     
         45 . The composition of  claim 36 , further comprising a drug that is metabolized by a carboxylesterase in a patient to whom the drug is administered.  
     
     
         46 . The composition of  claim 45 , wherein the drug is an anti-cancer drug.  
     
     
         47 . The composition of  claim 46 , wherein the anti-cancer drug is CPT-11  
     
     
         48 . The composition of  claim 45 , wherein the drug is metabolized by a carboxylesterase to generate a topoisomerase I inhibitor.