Method for reducing chloride secretion by intestinal epithelial cells in situ: use of triaryl methane compounds

Abstract

A method and product for treating and preventing diarrhea and scours is provided. The method involves treating a subject who has diarrhea, or scours, or is at risk of getting diarrhea or scours with an aromatic compound of the invention. The products of the invention are a veterinary preparation of the aromatic compound of the invention and an anti-scours agent, and a pharmaceutical preparation of the aromatic compound of the invention and an anti-diarrheal agent.

We claim:  
     
         1 . A method for treating diarrhea, comprising, administering an effective amount for inhibiting Cl −  secretion of an aromatic compound to a subject, wherein the aromatic compound has the general formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or hydrate thereof, wherein: n is 0, 1, 2, 3 or 4; p is 0 or 1; X is absent, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkenyl, (C 1 -C 3 ) alkynyl, SCH 2 , OCH 2 ,or NOCH 2 ; Y is C, N, P, Si or Ge; R′ is absent, -halo, —R, —OR, —SR, —NR 2 , —ONR 2 , —NO 2 , —CN, —C(O)R, —C(S)R, —C(O)OR, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NR 2 , —C(S)NR 2 , —C(O)NR(OR), —C(S)NR(OR), —C(O)NR(SR), C(S)NR(SR), —CH(CN) 2 , —CH[C(O)R] 2 , —CH[C(S)R] 2 , —CH[C(O)OR] 2 , —CH[C(S)OR] 2 , —CH[C(O)SR] 2 , —CH[C(S)SR] 2 , aryl, or heteroaryl; Ar 1  is aryl, substituted aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl or (C 5 -C 8 ) heterocycloalkyl; Ar 2  is aryl or substituted aryl; Ar 3  is aryl, substituted aryl, biaryl, biphenyl, bibenzyl, or heteroaryl other than imidazole, nitroimidazole and triazole; each R is independently selected from the group consisting of —H, (C 1 -C 6 ) alkyl, substituted (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, substituted (C 1 -C 6 ) alkenyl (C 1 -C 6 ) alkynyl, substituted (C 1 -C 6 ) alkynyl, and (C 1 -C 6 ) alkoxy; the aryl substituents are each independently selected from the group consisting of -halo, trihalomethyl, —R, —R 1 , —OR 1 , —SR 1 , NR 12 , —NO 2 , —CN, —C(O)R 1 , —C(S)R 1 , —C(O)OR 1 , —C(S)OR 1 , —C(O)SR 1  and —C(S)SR 1 ; the alkyl, alkenyl and alkynyl substituents are each independently selected from the group consisting of -halo, —R 1 , —OR 1 , —SR 1 , N(R 1 ) 2 , —NO 2 , —CN, —C(O)R 1 , —C(S)R 1 , —C(O)OR 1 , —C(S)OR 1 , —C(O)SR 1 , —C(S)SR 1 , aryl, γ-butyrolactonyl, pyrrolidinyl and succinic anhydridyl; and each R 1  is independently selected from the group consisting of —H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl and (C 1 -C 6 ) alkynyl.  
     
     
         2 . The method of  claim 1 , wherein the aromatic compound does not include any compound encompassed by formula (II):  
       
         
           
           
               
               
           
         
       
       wherein n=0-3; wherein p=0 or 1; wherein X is selected from the group consisting of (CH 2 ) m (m=0,1,2, or 3) , CH═CH, C≡C, SCH 2 , OCH 2 , and NOCH 2 ; wherein R′ is selected from the group consisting of H, OH, SH, NO 2 , CN, CHO, ONH 2 , CCH, COR″, CO 2 H, CO 2 R″, OR″, SR″, NR″R″, CONR″R″, heteroaryl, and CONR″(OCH 3 ); wherein Ar 1  is selected from the group consisting of phenyl, substituted phenyl, and heteroaryl; wherein Ar 2  is selected from the group consisting of phenyl and substituted phenyl; wherein Ar 3  is selected from the group consisting of phenyl, substituted phenyl, biphenyl, bibenzyl, and naphthyl; wherein the phenyl substituent is selected from the group consisting of Cl, F, Br, I, R, OR″, SR″, NO 2 , CN, CF 3 , NR″R″, and CO 2 R; wherein R is selected from the group consisting of straight chain alkyl of C z(z=1-5) , substituted straight chain alkyl of C z(z=1-5) , branched alkyl of C z(z=1-5) , and substituted branched alkyl of C z(z=1-5) ; wherein the alkyl substituent is selected from the group consisting of Cl, Br, F, I, OH, OCH 3 , SH, SCH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ; and wherein R″ is selected from the group consisting of hydrogen and R.  
     
     
         3 . The method of  claim 1 , wherein the aromatic compound is selected from the group consisting of aromatic compounds wherein p=0, X is absent, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkenyl, (C 1 -C 3 ) or alkynyl; R′ is absent, -halo, —R, —OR, —SR, —NR 2 , —ONR 2 , —NO 2 , —CN, —C(O)R, —C(S)R, —C(O)OR, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NR 2 , —C(S)NR 2 , —C(O)NR(OR), —C(S)NR(OR), —C(O)NR(SR), C(S)NR(SR), —CH(CN) 2 , —CH[C(O)R] 2 , —CH[C(S)R] 2 , —CH[C(O)OR] 2 , —CH[C(S)OR] 2 , —CH[C(O)SR] 2 , —CH[C(S)SR] 2 , or aryl; Ar 1  is aryl, substituted aryl, heteroaryl other than imidazole, nitroimidazole and triazole, heteroarylium other than imidazolium, nitroimidazolium and triazolium, (C 5 -C 8 ) cycloalkyl or (C 5 -C 8 ) heterocycloalkyl; Ar 2  is aryl or substituted aryl; and Ar 3  is aryl, substituted aryl, biaryl, or heteroaryl other than imidazole, nitroimidazole and triazole.  
     
     
         4 . The method of  claim 2 , wherein the aromatic compound is administered orally.  
     
     
         5 . The method of  claim 2 , wherein the subject is a human.  
     
     
         6 . The method of  claim 5 , further comprising administering an anti-diarrheal agent to the subject.  
     
     
         7 . The method of  claim 6 , wherein the anti-diarrheal agent is an oral rehydration fluid.  
     
     
         8 . The method of  claim 2 , wherein the aromatic compound is selected from the group consisting of 7, 10, 12, 13, 14, 15, 16, 18, 20, 21, 22, 23, 24, 27, 29, 30, 31, 32, 33, 34, 35, 37, 38, 42, 43, 44, 45, 46, 47, 49, 50, 51, 52, 53, 55, 56, 58, 59, 60, 62, 64, 65, 67, 68, 69, 70, 73, 75, 78, 79, 80, 81, 82, 83, 86, 87, 88 and 90.  
     
     
         9 . A veterinary preparation comprising: 
 an aromatic compound in an amount effective to inhibit scours in a subject, the aromatic compound having the general formula:                          or a pharmaceutically acceptable salt or hydrate thereof, wherein: n is 0, 1, 2, 3 or 4; p is 0 or 1; X is absent, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkenyl, (C 1 -C 3 ) alkynyl, SCH 2 , OCH 2 ,or NOCH 2 ; Y is C, N, P, Si or Ge; R′ is absent, -halo, —R, —OR, —SR, —NR 2 , —ONR 2 , —NO 2 , —CN, —C(O)R, —C(S)R, —C(O)OR, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NR 2 , —C(S)NR 2 , —C(O)NR(OR), —C(S)NR(OR), —C(O)NR(SR), C(S)NR(SR), —CH(CN) 2 , —CH[C(O)R] 2 , —CH[C(S)R] 2 , —CH[C(O)OR] 2 , —CH[C(S)OR] 2 , —CH[C(O)SR] 2 , —CH[C(S)SR] 2 , aryl, or heteroaryl; Ar 1  is aryl, substituted aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl or (C 5 -C 8 ) heterocycloalkyl; Ar 2  is aryl or substituted aryl; Ar 3  is aryl, substituted aryl, biaryl, biphenyl, bibenzyl, or heteroaryl other than imidazole, nitroimidazole and triazole; each R is independently selected from the group consisting of —H, (C 1 -C 6 ) alkyl, substituted (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, substituted (C 1 -C 6 ) alkenyl (C 1 -C 6 ) alkynyl, substituted (C 1 -C 6 ) alkynyl, and (C 1 -C 6 ) alkoxy; the aryl substituents are each independently selected from the group consisting of -halo, trihalomethyl, —R, —R 1 , —OR 1 , —SR 1 , NR 12 , —NO 2 , —CN, —C(O)R 1 , —C(S)R 1 , —C(O)OR 1 , —C(S)OR 1 , —C(O)SR 1  and —C(S)SR 1 ; the alkyl, alkenyl and alkynyl substituents are each independently selected from the group consisting of -halo, —R 1 , —OR 1 , —SR 1 , N(R 1 ) 2 , —NO 2 , —CN, —C(O)R 1 , —C(S)R 1 , —C(O)OR 1 , —C(S)OR 1 , —C(O)SR 1 , —C(S)SR 1 , aryl, γ-butyrolactonyl, pyrrolidinyl and succinic anhydridyl; and each R 1  is independently selected from the group consisting of —H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl and (C 1 -C 6 ) alkynyl.    ; and,    an anti-scours agent    
     
     
         10 . A veterinary preparation as in  claim 9 , wherein the aromatic compound does not include any compound encompassed by formula (II):  
       
         
           
           
               
               
           
         
       
       wherein n=0-3; wherein p=0 or 1; wherein X is selected from the group consisting of (CH 2 ) m (m=0,1,2, or 3) , CH═CH, C≡C, SCH 2 , OCH 2 , and NOCH 2 ; wherein R′ is selected from the group consisting of H, OH, SH, NO 2 , CN, CHO, ONH 2 , CCH, COR″, CO 2 H, CO 2 R″, OR″, SR″, NR″R″, CONR″R″, heteroaryl, and CONR″(OCH 3 ); wherein Ar 1  is selected from the group consisting of phenyl, substituted phenyl, and heteroaryl; wherein Ar 2  is selected from the group consisting of phenyl and substituted phenyl; wherein Ar 3  is selected from the group consisting of phenyl, substituted phenyl, biphenyl, bibenzyl, and naphthyl; wherein the phenyl substituent is selected from the group consisting of Cl, F, Br, I, R, OR″, SR″, NO 2 , CN, CF 3 , NR″R″, and CO 2 R; wherein R is selected from the group consisting of straight chain alkyl of C z(z=1.5) , substituted straight chain alkyl of C z(z=1-5) , branched alkyl of C z(z=1-5) , and substituted branched alkyl of C z(z=1-5) ; wherein the alkyl substituent is selected from the group consisting of Cl, Br, F, I, OH, OCH 3 , SH, SCH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ; and wherein R″ is selected from the group consisting of hydrogen and R.  
     
     
         11 . The veterinary preparation as in  claim 9 , wherein the anti-scours agent is a colostral extract.  
     
     
         12 . The veterinary preparation as in  claim 9 , wherein the anti-scours agent is an immunological preparation of colostrum.  
     
     
         13 . The veterinary preparation as in  claim 9 , wherein the anti-scours agent is a microorganism specific immunological preparation.  
     
     
         14 . The veterinary preparation as in  claim 9 , wherein the anti-scours agent is an oral rehydration fluid.  
     
     
         15 . The veterinary preparation as in  claim 9 , wherein the anti-scours agent is a replacement electrolyte composition.  
     
     
         16 . The veterinary preparation as in  claim 9 , wherein the anti-scours agent is an antibiotic composition.  
     
     
         17 . The veterinary preparation as in  claim 9 , wherein the veterinary preparation is a dry preparation.  
     
     
         18 . The veterinary preparation as in  claim 9 , wherein the aromatic compound is selected from the group consisting of 7, 10, 12, 13, 14, 15, 16, 18, 20, 21, 22, 23, 24, 27, 29, 30, 31, 32, 33, 34, 35, 37, 38, 42, 43, 44, 45, 46, 47, 49, 50, 51, 52, 53, 55, 56, 58, 59, 60, 62, 64, 65, 67, 68, 69, 70, 73, 75, 78, 79, 80, 81, 82, 83, 86, 87, 88 and 90.  
     
     
         19 . A pharmaceutical preparation, comprising: 
 an aromatic compound in an amount effective to inhibit diarrhea, the aromatic compound having the general formula:                          or a pharmaceutically acceptable salt or hydrate thereof, wherein: n is 0, 1, 2, 3 or 4; p is 0 or 1; X is absent, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkenyl, (C 1 -C 3 ) alkynyl, SCH 2 , OCH 2 ,or NOCH 2 ; Y is C, N, P, Si or Ge; R′ is absent, -halo, —R, —OR, —SR, —NR 2 , —ONR 2 , —NO 2 , —CN, —C(O)R, —C(S)R, —C(O)OR, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NR 2 , —C(S)NR 2 , —C(O)NR(OR), —C(S)NR(OR), —C(O)NR(SR), C(S)NR(SR), —CH(CN) 2 , —CH[C(O)R] 2 , —CH[C(S)R] 2 , —CH[C(O)OR] 2 , —CH[C(S)OR] 2 , —CH[C(O)SR] 2 , —CH[C(S)SR] 2 , aryl, or heteroaryl; Ar 1  is aryl, substituted aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl or (C 5 -C 8 ) heterocycloalkyl; Ar 2  is aryl or substituted aryl; Ar 3  is aryl, substituted aryl, biaryl, biphenyl, bibenzyl, or heteroaryl other than imidazole, nitroimidazole and triazole; each R is independently selected from the group consisting of —H, (C 1 -C 6 ) alkyl, substituted (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, substituted (C 1 -C 6 ) alkenyl (C 1 -C 6 ) alkynyl, substituted (C 1 -C 6 ) alkynyl, and (C 1 -C 6 ) alkoxy; the aryl substituents are each independently selected from the group consisting of -halo, trihalomethyl, —R, —R 1 , —OR 1 , —SR 1 , NR 12 , —NO 2 , —CN, —C(O)R 1 , —C(S)R 1 , —C(O)OR 1 , —C(S)OR 1 , —C(O)SR 1  and —C(S)SR 1 ; the alkyl, alkenyl and alkynyl substituents are each independently selected from the group consisting of -halo, —R 1 , —OR 1 , —SR 1 , N(R 1 ) 2 , —NO 2 , —CN, —C(O)R 1 , —C(S)R 1 , —C(O)OR 1 , —C(S)OR 1 , —C(O)SR 1 , —C(S)SR 1 , aryl, γ-butyrolactonyl, pyrrolidinyl and succinic anhydridyl; and each R 1  is independently selected from the group consisting of —H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl and (C 1 -C 6 ) alkynyl; and,    an anti-diarrheal agent.    
     
     
         20 . The pharmaceutical preparation as in  claim 19 , wherein the aromatic compound does not include any compound encompassed by formula (II):  
       
         
           
           
               
               
           
         
       
       wherein n=0-3; wherein p=0 or 1; wherein X is selected from the group consisting of (CH 2 ) m (m=0,1,2, or 3) , CH═CH, C≡C, SCH 2 , OCH 2 , and NOCH 2 ; wherein R′ is selected from the group consisting of H, OH, SH, NO 2 , CN, CHO, ONH 2 , CCH, COR″, CO 2 H, CO 2 R″, OR″, SR″, NR″R″, CONR″R″, heteroaryl, and CONR″(OCH 3 ); wherein Ar 1  is selected from the group consisting of phenyl, substituted phenyl, and heteroaryl; wherein Ar 2  is selected from the group consisting of phenyl and substituted phenyl; wherein Ar 3  is selected from the group consisting of phenyl, substituted phenyl, biphenyl, bibenzyl, and naphthyl; wherein the phenyl substituent is selected from the group consisting of Cl, F, Br, I, R, OR″, SR″, NO 2 , CN, CF 3 , NR″R″, and CO 2 R; wherein R is selected from the group consisting of straight chain alkyl of C z(z=1-5) , substituted straight chain alkyl of C z(z=1-5) , branched alkyl of C z(z=1-5) , and substituted branched alkyl of C z(z=1-5) ; wherein the alkyl substituent is selected from the group consisting of Cl, Br, F, I, OH, OCH 3 , SH, SCH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ; and wherein R″ is selected from the group consisting of hydrogen and R.  
     
     
         21 . The pharmaceutical preparation as in  claim 20 , wherein the aromatic compound is selected from the group consisting of 7, 10, 12, 13, 14, 15, 16, 18, 20, 21, 22, 23, 24, 27, 29, 30, 31, 32, 33, 34, 35, 37, 38, 42, 43, 44, 45, 46,47, 49, 50, 51, 52, 53, 55, 56, 58, 59, 60, 62, 64, 65, 67, 68, 69, 70, 73, 75, 78, 79, 80, 81, 82, 83, 86, 87, 88 and 90.  
     
     
         22 . The pharmaceutical preparation as in  claim 20 , wherein the anti-diarrheal agent is an oral rehydration fluid.  
     
     
         23 . The pharmaceutical preparation as in  claim 20 , wherein the anti-diarrheal agent is an antibiotic.  
     
     
         24 . The pharmaceutical preparation as in  claim 20 , wherein the anti-diarrheal agent is an electrolyte composition.  
     
     
         25 . The pharmaceutical preparation as in  claim 20 , wherein the anti-diarrheal agent is an immunoglobulin preparation from bovine colostrum.  
     
     
         26 . The pharmaceutical preparation as in  claim 20 , wherein the anti-diarrheal agent is an oral sugar-electrolyte solution.  
     
     
         27 . A method for treating scours, the method comprising the step of: 
 administering to a subject in need of such treatment, an aromatic compound in an amount effective to inhibit scours, wherein the aromatic compound has the general formula:                          or a pharmaceutically acceptable salt or hydrate thereof, wherein: n is 0, 1, 2, 3 or 4; p is 0 or 1; X is absent, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkenyl, (C 1 -C 3 ) alkynyl, SCH 2 , OCH 2 ,or NOCH 2 ; Y is C, N, P, Si or Ge; R′ is absent, -halo, —R, —OR, —SR, —NR 2 , —ONR 2 , —NO 2 , —CN, —C(O)R, —C(S)R, —C(O)OR, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NR 2 , —C(S)NR 2 , —C(O)NR(OR), —C(S)NR(OR), —C(O)NR(SR), C(S)NR(SR), —CH(CN) 2 , —CH[C(O)R] 2 , —CH[C(S)R] 2 , —CH[C(O)OR] 2 , —CH[C(S)OR] 2 , —CH[C(O)SR] 2 , —CH[C(S)SR] 2 , aryl, or heteroaryl; Ar 1  is aryl, substituted aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl or (C 5 -C 8 ) heterocycloalkyl; Ar 2  is aryl or substituted aryl; Ar 3  is aryl, substituted aryl, biaryl, biphenyl, bibenzyl, or heteroaryl other than imidazole, nitroimidazole and triazole; each R is independently selected from the group consisting of —H, (C 1 -C 6 ) alkyl, substituted (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, substituted (C 1 -C 6 ) alkenyl (C 1 -C 6 ) alkynyl, substituted (C 1 -C 6 ) alkynyl, and (C 1 -C 6 ) alkoxy; the aryl substituents are each independently selected from the group consisting of -halo, trihalomethyl, —R, —R 1 , —OR 1 , —SR 1 , NR 12 , —NO 2 , —CN, —C(O)R 1 , —C(S)R 1 , —C(O)OR 1 , —C(S)OR 1 , —C(O)SR 1  and —C(S)SR 1 ; the alkyl, alkenyl and alkynyl substituents are each independently selected from the group consisting of -halo, —R 1 , —OR 1 , —SR 1 , N(R 1 ) 2 , —NO 2 , —CN, —C(O)R 1 , —C(S)R 1 , —C(O)OR 1 , —C(S)OR 1 , —C(O)SR 1 , —C(S)SR 1 , aryl, γ-butyrolactonyl, pyrrolidinyl and succinic anhydridyl; and each R 1  is independently selected from the group consisting of —H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl and (C 1 -C 6 ) alkynyl.    
     
     
         28 . The method for treating scours as in  claim 27 ,wherein the aromatic compound does not include any compound encompassed by formula (II):  
       
         
           
           
               
               
           
         
       
       wherein n=0-3; wherein p=0 or 1; wherein X is selected from the group consisting of (CH 2 ) m (m=0,1,2, or 3) , CH═CH, C≡C, SCH 2 , OCH 2 , and NOCH 2 ; wherein R′ is selected from the group consisting of H, OH, SH, NO 2 , CN, CHO, ONH 2 , CCH, COR″, CO 2 H, CO 2 R″, OR″, SR″, NR″R″, CONR″R″, heteroaryl, and CONR″(OCH 3 ); wherein Ar 1  is selected from the group consisting of phenyl, substituted phenyl, and heteroaryl; wherein Ar 2  is selected from the group consisting of phenyl and substituted phenyl; wherein Ar 3  is selected from the group consisting of phenyl, substituted phenyl, biphenyl, bibenzyl, and naphthyl; wherein the phenyl substituent is selected from the group consisting of Cl, F, Br, I, R, OR″, SR″, NO 2 , CN, CF 3 , NR″R″, and CO 2 R; wherein R is selected from the group consisting of straight chain alkyl of C z(z=1-5) , substituted straight chain alkyl of C z(z=1-5) , branched alkyl of C z(z=1-5) , and substituted branched alkyl of C z(z=1-5) ; wherein the alkyl substituent is selected from the group consisting of Cl, Br, F, I, OH, OCH 3 , SH, SCH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ; and wherein R″ is selected from the group consisting of hydrogen and R.  
     
     
         29 . The method for treating scours as in  claim 27 , wherein the aromatic compound is selected from the group consisting of 7, 10, 12, 13, 14, 15, 16, 18, 20, 21, 22, 23, 24, 27, 29, 30, 31, 32, 33, 34, 35, 37, 38, 42, 43, 44, 45, 46, 47, 49, 50, 51, 52, 53, 55, 56, 58, 59, 60, 62, 64, 65, 67, 68, 69, 70, 73, 75, 78, 79, 80, 81, 82, 83, 86, 87, 88 and 90.  
     
     
         30 . The method for treating scours as in  claim 28 , wherein the aromatic compound is administered orally.  
     
     
         31 . The method for treating scours as in  claim 28 , wherein the subject is selected from the group consisting of a horse, a cow, a pig, and a goat.  
     
     
         32 . The method for treating scours as in  claim 28 , further comprising administering an anti-scours agent to the subject.