Aliphatic pyrazinoylguanidine sodium channel blockers with beta agonist activity

Abstract

The present application provides sodium channel blockers exemplified by the following structure: The compounds of the invention useful for treating chronic bronchitis, cystic fibrosis, sinusitis, vaginal dryness, dry eye, Sjogren's disease, distal intestinal obstruction syndrome, dry skin, esophagitis, dry mouth (xerostomia), nasal dehydration, ventilator-induced pneumonia, asthma, primary ciliary dyskinesia, otitis media, chronic obstructive pulmonary disease, emphysema, pneumonia, constipation, and chronic diverticulitis, for example.

1 . A compound represented by formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 X is hydrogen, halogen, trifluoromethyl, lower alkyl, unsubstituted or substituted phenyl, lower alkyl-thio, phenyl-lower alkyl-thio, lower alkyl-sulfonyl, or phenyl-lower alkyl-sulfonyl; 
 Y is hydrogen, hydroxyl, mercapto, lower alkoxy, lower alkyl-thio, halogen, lower alkyl, unsubstituted or substituted mononuclear aryl, or —N(R 2 ) 2 ; 
 R 1  is hydrogen or lower alkyl; 
 each R 2  is, independently, —R 7 , —(CH 2 ) m —OR 8 , —(CH 2 ) m —NR 7 R 10 , —(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 CH 2 O) m —R 8 , —(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —(CH 2 ) n —C(═O)NR 7 R 10 , —(CH 2 ) n —Z g —R 7 , —(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 ) n —CO 2 R 7 , or 
 
       
         
           
           
               
               
           
         
         R 3  and R 4  are each, independently, hydrogen, a group represented by formula (A), lower alkyl, hydroxy lower alkyl, phenyl, phenyl-lower alkyl, (halophenyl)-lower alkyl, lower-(alkylphenylalkyl), lower (alkoxyphenyl)-lower alkyl, naphthyl-lower alkyl, or pyridyl-lower alkyl, with the proviso that at least one of R 3  and R 4  is a group represented by formula (A):
   —(C(R L ) 2 ) O - x -(C(R L ) 2 ) P —CR 5 R 6 R 6   (A)
 
 
         each R L  is, independently, —R 7 , —(CH 2 ) n —OR 8 , —O—(CH 2 ) m —OR 8 , —(CH 2 ) n —NR 7 R 10 , —O—(CH 2 ) m —NR 7 R 10 , —(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 CH 2 O) m —R 8 , —O—(CH 2 CH 2 O) m —R 8 , —(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —O—(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —(CH 2 ) n —C(═O)NR 7 R 10 , —O—(CH 2 ) m —C(═O)NR 7 R 10 , —(CH 2 ) n —(Z) g —R 7 , —O—(CH 2 ) m —(Z) g —R 7 , —(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 ) n —CO 2 R 7 , —O—(CH 2 ) m —CO 2 R 7 , —OSO 3 H, —O-glucuronide, —O-glucose, 
       
       
         
           
           
               
               
           
         
         each o is, independently, an integer from 0 to 10; 
         each p is an integer from 0 to 10; 
         with the proviso that the sum of o and p in each contiguous chain is from 1 to 10; 
         each x is, independently, O, NR 10 , C(═O), CHOH, C(═N—R 10 ), CHNR 7 R 10 , or represents a single bond; 
         each R 5  is, independently, 
         Link —(CH 2 ) n —CR 11 R 11 -CAP, Link —(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CR 11 R 11 -CAP, Link —(CH 2 CH 2 O) m CH 2 —CR 11 R 11 -CAP, Link —(CH 2 CH 2 O) m —CH 2 CH 2 —CR 11 R 11 -CAP, Link —(CH 2 ) n —(Z) g —CR 11 R 11 -CAP, Link —(CH 2 ) n (Z) g (CH 2 ) m —CR 11 R 11 -CAP, Link —(CH 2 ) n —NR 13 —CH 2 (CHOR 8 )(CHOR 8 ) n —CR 11 R 11 -CAP, Link —(CH 2 ) n —(CHOR 8 ) m CH 2 —NR 13 —(Z) g —CR 11 R 11 -CAP, Link —(CH 2 ) n NR 13 —(CH 2 ) m (CHOR 8 ) n CH 2 NR 13 —(Z) g —CR 11 R 11 -CAP, Link —(CH 2 ) m (Z) g —(CH 2 ) m —CR 11 R 11 -CAP, Link NH—C(═O)—NH—(CH 2 ) m —CR 11 R 11 -CAP, Link —(CH 2 ) m —C(═O)NR 13 —CH 2 ) m —CR 11 R 11 -CAP, Link —(CH 2 ) n —(Z) g —(CH 2 ) m —(Z) g —CR 11 R 11 -CAP, or Link —Z g —(CH 2 ) m -Het-(CH 2 ) m —CR 11 R 11 -CAP, 
         each Link is, independently, 
         —O—, (CH 2 ) n —, —O(CH 2 ) m —, —NR 13 —C(═O)—NR 13 , —NR 13 —C(═O)—(CH 2 ) m —, —C(═O)NR 13 —(CH 2 ) m , —(CH 2 ) n Z g —(CH 2 ) n , —S—, —SO—, —SO 2 —, SO 2 NR 7 —, SO 2 NR 10 —, or -Het-; 
         each CAP is, independently, 
       
       
         
           
           
               
               
           
         
         each R 6  is, independently, —R 7 , —OR 7 , —OR 11 , —N(R 7 ) 2 , —(CH 2 ) m —OR 8 , —O—CH 1 ) m —OR 8 , —(CH 2 ) n —NR 7 R 10 , —O—(CH 2 ) m —NR 7 R 10 , —(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 CH 2 O) m —R 8 , —O—(CH 2 CH 2 O) m —R 8 , —(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —O—(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —(CH 2 ) n —C(═O)NR 7 , R 10 , —O—(CH 2 ) m —C(═O)NR 7 R 10 , —(CH 2 ) n —(Z) g —R 7 , —O—(CH 2 ) m (Z) g —R 7 , —(CH 2 ) n —NR 11 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 ) n —CO 2 R 7 , —O—(CH 2 ) m —CO 2 R 7 , —OSO 3 H, —O-glucuronide, —O-glucose, 
       
       
         
           
           
               
               
           
         
         wherein when two R 6  are —OR 11  and are located adjacent to each other on a phenyl ring, the alkyl moieties of the two R 6  may be bonded together to form a methylenedioxy group; 
         with the proviso that when at least two —CH 2 OR 8  are located adjacent to each other, the R 8  groups may be joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane, 
         each R 7  is, independently, hydrogen, lower alkyl, phenyl, or substituted phenyl; 
         each R 8  is, independently, hydrogen, lower alkyl, —C(═O)—R 11 , glucuronide, 2-tetrahydropyranyl, or 
       
       
         
           
           
               
               
           
         
         each R 9  is, independently, —CO 2 R 13 , —CON(R 13 ) 2 , —SO 2 CH 2 R 13 , or —C(═O)R 13 ; 
         each R 10  is, independently, —H, —SO 2 CH 3 , —CO 2 R 7 , —C(═O)NR 7 R 9 , —C(═O)R 7 , or —(CH 2 ) m —(CHOH) n —CH 2 OH; 
         each Z is, independently, CHOH, C(═O), —(CH 2 ) n —, CHNR 13 R 13 , C═NR 13 , or NR 13 ; 
         each R 11  is, independently, hydrogen, lower alkyl, phenyl lower alkyl or substituted phenyl lower alkyl; 
         each R 12  is independently, —(CH 2 ) n —SO 2 CH 3 , —(CH 2 ) n —CO 2 R 13 , —(CH 2 )—C(═O)NR 13 R 13 , —(CH 2 ) n —C(═O)R 13 , —(CH 2 ) n —(CHOH) n —CH 2 OH, —NH—(CH 2 ) n —SO 2 CH 3 , NH—(CH 2 ) n —C(═O)R 11 , NH—C(═O)—NH—C(═O)R 11 , —C(═O)NR 13 R 13 , —OR 11 , —NH—(CH 2 ) n —R 10 , —Br, —Cl, —F, —I, SO 2 NHR 11 , —NHR 13 , —NH—C(═O)—NR 13 R 13 , NH—(CH 2 ) n —SO 2 CH 3 , NH—(CH 2 ) n —C(═O)R 11 , —NH—C(═O)—NH—C(═O)R 11 , —C(═O)NR 13 R 13 , —OR 11 , —(CH 2 ) n —NHR 13 , —NH—C(═O)—NR 13 R 13 , or —NH—(CH 2 ) n —C(═O)—R 13 ; 
         each R 13  is, independently, hydrogen, lower alkyl, phenyl, substituted phenyl, 
       
       
         
           
           
               
               
           
         
         with the proviso that NR 13 R 13  can be joined on itself to form a group represented by one of the following: 
       
       
         
           
           
               
               
           
         
         each Het is independently, —NR 13 , —S—, —SO—, —SO 2 —, —O—, —SO 2 NR 13 —, —NHSO 2 —, —NR 13 CO—, or —CONR 13 —; 
         each g is, independently, an integer from 1 to 6; 
         each m is, independently, an integer from 1 to 7; 
         each n is, independently, an integer from 0 to 7; 
       
       
         
           
           
               
               
           
         
         with the proviso that when V Is attached directly to a nitrogen atom, then V can also be, independently, R 7 , R 10 , or (R 11 ) 2 ; 
         wherein for any of the above compounds when two —CH 2 OR 8  groups are located 1,2- or 1,3- with respect to each other the R 8  groups may be joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane, 
         or a pharmaceutically acceptable salt thereof, and inclusive of all racemates, enantiomers, diastereomers, tautomers, polymorphs and pseudopolymorphs thereof. 
       
     
     
         2 - 99 . (canceled)