Phenoxy thiophene sulfonamides and other compounds for use as inhibitors of bacterial glucuronidase

Abstract

This invention relates generally to compounds that are glucuronidase inhibitors. The glucuronidase inhibitors include phenoxy thiophene sulfonamides, and other compounds such as pyridine sulfonyls, benzene sulfonyls, thiophene sulfonyls, thiazole sulfonyls, thiophene carbonyls, and thiazole carbonyls. These compounds include nialamide, isocarboxazid, phenelzine, amoxapine, loxapine and mefloquine. Also compositions including one or more of such compounds for use in inhibiting glucuronidase and methods of using one or more of such compounds for selective inhibition of bacterial β-glucuronidase. These compounds may be used as a co-drug in combination with the anticancer drug CPT-11. Also a method for screening compounds to determine their usefulness in reducing diarrhea associated with irinotecan chemotherapy.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof wherein: 
         each of R 1  and R 2  is the same or different and is selected from H, naphthalene, naphthalene-(C 1 -C 4 ) alkyl, naphthalene-1-ylmethyl, naphthalene-1-ylethyl, naphthalene-1-ylpropyl, 3-fluorobenzyl, 3-chlorobenzyl, 3-bromobenzyl, 3-iodobenzyl, 3-(trifluoromethyl)benzyl, 3-(trichloromethyl)benzyl, 3-(tribromomethyl)benzyl, 3-(triiodomethyl)benzyl, 3-(C 1 -C 4  alkyl)-benzyl, 3-methylbenzyl, 3-ethyl-benzyl, 3-propylbenzyl, 3,5-dichlorobenzyl, 3,5-difluorobenzyl, 3,5,-dibromobenzyl, 3,5-diiodobenzyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 3-iodophenyl, 3-(C 1 -C 4  alkyoxy)phenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3-propoxyphenyl, 4-methoxyphenyl, 4-(C 1 -C 4  alkyoxy)phenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-iodobenzyl, 3-iodobenzyl, 4-iodobenzyl, 3-(C 1 -C 4  alkyoxy)benzyl; 3-methoxybenzyl, 4-methoxybenzyl, 3-ethoxybenzyl, 4-ethoxybenzyl, 3-propoxybenzyl, 4-(C 1 -C 4  alkyoxy)phenyl and 4 propoxybenzyl; 
         each of R 3  and R 4  is the same or different and is selected from H, F, Cl, Br, and I, and 
         R 5  is selected from 3-(R-1-yl)phenyl, and 4-(R-1-yl)phenyl, wherein R is selected from piperazin, 4-(C 1 -C 4  alkyl) piperazin, 4-methylpiperazin, 4-ethyl-piperazin, and 4-propylpiperazin, 
         or a pharmaceutically acceptable salt of the compound. 
       
     
     
         2 . A method of treating a subject in need of a glucuronidase inhibitor comprising administering to the subject a composition comprising an amount of compound that is effective as an inhibitor of glucuronidase activity, or a pharmaceutically acceptable salt of the compound. 
     
     
         3 . The method of  claim 2 , wherein the compound is selected from one or more of phenoxy thiophene sulfonamides, pyridine sulfonyls, benzene sulfonyls, thiophene sulfonyls, thiazole sulfonyls, thiophene carbonyls, and thiazole carbonyls. 
     
     
         4 . A method according to  claim 2 , wherein the compound is of formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof 
         wherein: 
         each of R 1  and R 2  is the same or different and is selected from H, naphthalene, naphthalene-(C 1 -C 4 ) alkyl, naphthalene-1-ylmethyl, naphthalene-1-ylethyl, naphthalene-1-ylpropyl, 3-fluorobenzyl, 3-chlorobenzyl, 3-bromobenzyl, 3-iodobenzyl, 3-(trifluoromethyl)benzyl, 3-(trichloromethyl)benzyl, 3-(tribromomethyl)benzyl, 3-(triiodomethyl)benzyl, 3-(C 1 -C 4  alkyl)-benzyl, 3-methylbenzyl, 3-ethyl-benzyl, 3-propylbenzyl, 3,5-dichlorobenzyl, 3,5-difluorobenzyl, 3,5,-dibromobenzyl, 3,5-diiodobenzyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 3-iodophenyl, 3-(C 1 -C 4  alkyoxy)phenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3-propoxyphenyl, 4-methoxyphenyl, 4-(C 1 -C 4  alkyoxy)phenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-iodobenzyl, 3-iodobenzyl, 4-iodobenzyl, 3-(C 1 -C 4  alkyoxy)benzyl; 3-methoxybenzyl, 4-methoxybenzyl, 3-ethoxybenzyl, 4-ethoxybenzyl, 3-propoxybenzyl, 4-(C 1 -C 4  alkyoxy)phenyl and 4 propoxybenzyl; 
         each of R 3  and R 4  is the same or different and is selected from H, F, Cl, Br, and I, and 
         R 5  is selected from 3-(R-1-yl)phenyl, and 4-(R-1-yl)phenyl, wherein R is selected from piperazin, 4-(C 1 -C 4  alkyl)piperazin, 4-methylpiperazin, 4-ethyl-piperazin, and 4-propylpiperazin. 
       
     
     
         5 . A compound that is an inhibitor of glucuronidase, or a pharmaceutically acceptable salt of the compound, wherein the compound is chosen from one or more of phenoxy thiophene sulfonamides, pyridine sulfonyls, benzene sulfonyls, thiophene sulfonyls, thiazole thiophene carbonyls, and thiazole carbonyls. 
     
     
         6 . A composition comprising a compound according to  claim 5  and one or more pharmaceutically acceptable carriers, diluents and excipients. 
     
     
         7 . A method for making a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,
 wherein: 
 each of R 1  and R 2  is the same or different and is selected from H, naphthalene, naphthalene-(C 1 -C 4 ) alkyl, naphthalene-1-ylmethyl, naphthalene-1-ylethyl, naphthalene-1-ylpropyl, 3-fluorobenzyl, 3-chlorobenzyl, 3-bromobenzyl, 3-iodobenzyl, 3-(tri fluoromethyl)benzyl, 3-(trichloromethyl)benzyl, 3-(tribromomethyl)benzyl, 3-(triiodomethyl)benzyl, 3-(C 1 -C 4  alkyl)-benzyl, 3-methylbenzyl, 3-ethyl-benzyl, 3-propylbenzyl, 3,5-dichlorobenzyl, 3,5-difluorobenzyl, 3,5,-dibromobenzyl, 3,5-diiodobenzyl, 1,3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 3-iodophenyl, 3-(C 1 -C 4  alkyoxy) phenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3-propoxyphenyl, 4-methoxyphenyl, 4-(C 1 -C 4  alkyoxy)phenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-iodobenzyl, 3-iodobenzyl, 4-iodobenzyl, 3-(C 1 -C 4  alkyoxy)benzyl; 3-methoxybenzyl, 4-methoxybenzyl, 3-ethoxybenzyl, 4-ethoxybenzyl, 3-propoxybenzyl, 4-(C 1 -C 4  alkyoxy)phenyl and 4 propoxybenzyl; 
 each of R 3  and R 4  is the same or different and is selected from H, F, Cl, Br, and I, and 
 R 5  is selected from 3-(R-1-yl)phenyl and 4-(R-1-yl)phenyl, wherein R is selected from piperazin, 4-(C 1 -C 4  alkyl)piperazin, 4-methylpiperazin, 4-ethyl-piperazin, and 4-propylpiperazin, comprising the steps of: 
 (a) reacting a halo thiophene-sulfonyl halo and R 1 —N—H 2 , wherein R 1  as defined above to form an N-monoprotected thiophene sulfonamide having a first N-protecting group comprising R 1 , 
 (b) reacting the resultant N-monoprotected thiophene sulfonamide with R 2 —N-halo wherein R 2  is as defined above and a catalyst in a base, forming a resultant N,N-diprotected thiophene sulfonamide having a second N-protecting group comprising R 2 , 
 (c) reacting the N,N-diprotected thiophene sulfonamide of step (b) with Cs 2 CO 3 ; and a phenol substituted by R, wherein R is selected from piperazin, 4-(C 1 -C 4  alkyl) piperazin, 4-methylpiperazin, 4-ethylpiperazin, and 4-propylpiperazin, in a solvent, and then removing the solvent, to obtain N,N-diprotected phenoxy thiophene sulfonamide, and 
 (d) reacting the N,N-diprotected phenoxy thiophene sulfonamide with a deprotecting agent that is selective for deprotecting the second N-protecting group, removing the second N-protecting group, and forming a N-monoprotected phenoxy thiophene sulfonamide. 
 
       
     
     
         8 . The method of  claim 7 , for making a compound of formula (I) wherein:
 (a) the halothiophene sulfonyl halo is dichlorothiophene-sulfonyl chloride and the group R 1 —N—H is naphthylmethylamine, and the dichlorothiophene-sulfonyl chloride and naphthylmethylamine, are mixed and cooled, thereby forming a N-monoprotected thiophene sulfonamide, having a first N-protecting group that comprises naphthylmethyl,   (b) adding with mixing and cooling to the resultant N-monoprotected thiophene sulfonamide, methoxybenzyl bromide and a catalyst in a base that is sodium hydride, thereby forming a N,N-diprotected thiophene sulfonamide having also a second N-protecting group that comprises methoxybenzyl,   (c) adding with mixing and heating to the resultant N,N-diprotected thiophene sulfonamide, and Cs 2 CO 3  and butyl(hydroxyphenyl)piperazine-carboxylate in a solvent, and then removing the solvent, to obtain a resultant N,N-diprotected phenoxy thiophene sulfonamide, and   (d) mixing the resultant N,N-diprotected phenoxy thiophene sulfonamide with a deprotecting agent that is selective for deprotecting the second N-protecting group, thereby removing the methoxy benzyl that is the second N-protecting group, and forming a N-monoprotected phenoxy thiophene sulfonamide.   
     
     
         9 . The method of  claim 8 , wherein (i) the dichlorothiophene-sulfonyl chloride is 4,5-dichlorothiophene-2-sulfonyl chloride, (ii) the naphthylmethylamine is 1-naphthylmethylamine, (iii) the methoxybenzyl bromide is 4-methoxybenzyl bromide, (iv) the catalyst is tetrobutylamonium iodide, (v) the butyl(hydroxyphenyl)piperazine-carboxylate is tert-butyl-4-(3-hydroxyphenyl)piperazine-1-carboxylate, (vi) the solvent is dimethyl formamide, or (vii) the selective deprotecting agent comprises dichloromethane and trifluoroacetic acid; or a combination of two or more thereof. 
     
     
         10 . A method for screening compounds for their usefulness in reducing diarrhea associated with irinotecan chemotherapy, the method comprising:
 (a) assaying the compounds for activity in inhibiting purified bacterial β-glucuronidase;   (b) assaying the compounds for activity in inhibiting purified mammalian β-glucuronidase; and   (c) selecting from the compounds assayed in steps (a) and (b) a compound that inhibits the bacterial β-glucuronidase in step (a) with a potency that is more than 250-fold greater than the compound inhibits the mammalian β-glucuronidase in step (b).   
     
     
         11 . The method according to  claim 10 , wherein the assaying in step (a) comprises assaying the compounds for activity in inhibiting purified  E. coli  bacterial β-glucuronidase. 
     
     
         12 . The method according to  claim 10 , wherein the assaying in step (a) comprises also assaying the compounds for activity in inhibiting endogenous β-glucuronidase activity in a culture comprising intact bacterial cells. 
     
     
         13 . The method according to  claim 12 , wherein the intact bacterial cells are  E. coli  cells. 
     
     
         14 . The method according to  claim 10 , wherein the assaying in step (b) comprises assaying the compounds for inhibiting mammalian β-glucuronidase from  B. taurus.    
     
     
         15 . The method according to  claim 10 , further comprising administering the selected compound to a patient to whom irinotecan chemotherapy is being or will be administered. 
     
     
         16 . The method according to  claim 11 , wherein the selected compound generates an average IC 50  value of 388 nM or less in the  E. coli  β-glucuronidase enzyme assay. 
     
     
         17 . A method for inhibiting or reducing diarrhea in a patient being treated with a drug that metabolizes to form a metabolite that is a substrate for a bacterial β-glucuronidase enzyme, the method comprising administering to the patient a compound in an amount effective to inhibit the bacterial β-glucuronidase enzyme, wherein the compound is selected from the group consisting of nialamide, isocarboxazid, phenelzine, amoxapine, loxapine and mefloquine. 
     
     
         18 . The method according to  claim 17 , wherein the drug is irinotecan.