Capped pyrazinoylguanidine sodium channel blockers

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(R2)2;
• R1 is hydrogen or lower alkyl;
• each R2 is, independently, —R7, —(CH2)m—OR8, —(CH2)m—NR7R10, —(CH2)n(CHOR8)(CHOR8)n—CH2OR8, —(CH2CH2O)nm—R8, —(CH2CH2O)m—CH2CH2NR7R10, —(CH2)n—C(═O)NR7R10, —(CH2)n-Zg-R7, —(CH2)m—NR10—CH2(CHOR8)(CHOR8)n—CH2OR8, —(CH2)n—CO2R7, or
• R3 and R4 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 R3 and R4 is a group represented by formula (A):
• wherein
• each RL is, independently, —R7, —(CH2)n—OR8, —O—(CH2)m—OR8, —(CH2)n—NR7R10, —O—(CH2)m—NR7R10, —(CH2)n(CHOR8)(CHOR8)n—CH2OR8, —O—(CH2)m(CHOR8)(CHOR8)n—CH2OR8, —(CH2CH2O)m—R8, —O—(CH2CH2O)m—R8, —(CH2CH2O)m—CH2CH2NR7R10, —O—(CH2CH2O)m—CH2CH2NR7R10, —(CH2)n—C(═O)NR7R10, —O—(CH2)m—C(═O)NR7R10, —(CH2)n-(Z)g-R7, —O—(CH2)m-(Z)g-R7, —(CH2)n—NR10—CH2(CHOR8)(CHOR8)n—CH2OR8, —O—(CH2)m—NR10—CH2(CHOR8)(CHOR8)n—CH2OR8, —(CH2)n—CO2R7, —O—(CH2)m—CO2R7, —OSO3H, —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, NR10, C(═O), CHOH, C(═N—R10), CHNR7R10, or represents a single bond;
• wherein each R5 is, independently, Link —(CH2)n—CAP, Link —(CH2)n(CHOR8)(CHOR8)n—CAP, Link —(CH2CH2O)m—CH2—CAP, Link —(CH2CH2O)m—CH2CH2—CAP, Link —(CH2)n-(Z)g-CAP, Link —(CH2)n(Z)g-(CH2)m—CAP, Link —(CH2)n—NR13—CH2(CHOR8)(CHOR8)n—CAP, Link —(CH2)n—(CHOR8)mCH2—NR13-(Z)g-CAP, Link —(CH2)nNR13—(CH2)m(CHOR8)nCH2NR13-(Z)g-CAP, Link —(CH2)m-(Z)g-(CH2)m-CAP, Link —NH—C(═O)—NH—(CH2)m—CAP, Link (CH2)m—C(═O)NR13—(CH2)m—C(═O)NR10R10, Link —(CH2)m—C(═O)NR13—(CH2)m—CAP, Link —(CH2)m—C(═O)NR11R11, Link —(CH2)m—C(═O)NR12R12, Link —(CH2)m-(Z)g-(CH2)m-(Z)g-CAP, Link -Zg-(CH2)m-Het-(CH2)m—CAP;
• each Link is, independently, —O—, —(CH2)n—, —O(CH2)m—, —NR13—C(═O)—NR13, —NR13—C(═O)—(CH2)m—, —C(═O)NR13—(CH2)m, —(CH2)n-Zg-(CH2)n, —S—, —SO—, —SO2—, —SO2NR7—, —SO2NR10—, or -Het-;
• each CAP is, independently, thiazolidinedione, oxazolidinedione, heteroaryl-C(═O)N R13R13, heteroaryl-W, —CN, —O—C(═S)NR13R13, -ZgR13, —CR10(ZgR13)(ZgR13), —C(═O)OAr, —C(═O)NR13Ar, imidazoline, tetrazole, tetrazole amide, —SO2NHR13, —SO2NH—C(R13R13)-(Z)g-R13, a cyclic sugar or oligosaccharide, a cyclic amino sugar or oligosaccharide,
• each Ar is, independently, phenyl, substituted phenyl, wherein the substituents of the substituted phenyl are 1-3 substituents independently selected from the group consisting of OH, OCH3, NR13R13, Cl, F, and CH3, or heteroaryl;
• each W is independently, thiazolidinedione, oxazolidinedione, heteroaryl-C(═O)NR13R13, —CN, —O—C(═S)NR13R13, -ZgR13, —CR10(ZgR13)(ZgR13), —C(═O)OAr, —C(═O)NR13Ar, imidazoline, tetrazole, tetrazole amide, —SO2NHR13, —SO2NH—C(R13R13)-(Z)g-R13, a cyclic sugar or oligosaccharide, a cyclic amino sugar or oligosaccharide,
• each R6 is, independently, —R7, —OR7, —OR11, —N(R7)2, —(CH2)m—OR8, —O—(CH2)m—OR8, —(CH2)n—NR7R10), —O—(CH2)m—NR7R10, —(CH2)n(CHOR8)(CHOR8)n—CH2OR8, —O—(CH2)m(CHOR8)(CHOR8)n—CH2OR8, —(CH2CH2O)m—R8, —O—(CH2CH2O)m—R8, —(CH2CH2O)m—CH2CH2NR7R10, —O—(CH2CH2O)m—CH2CH2NR7R10, —(CH2)n—C(═O)NR7R10, —O—(CH2)m—C(═O)NR7R10, —(CH2)n-(Z)g-R7, —O—(CH2)m-(Z)g-R7, —(CH2)n—NR10—CH2(CHOR8)(CHOR8)n—CH2OR8, —O—(CH2)m—NR10—CH2(CHOR8)(CHOR8)n—CH2OR8, —(CH2)n—CO2R7, —O—(CH2)m—CO2R7, —OSO3H, —O-glucuronide, —O-glucose,
• wherein when two R6 are —OR11 and are located adjacent to each other on a phenyl ring, the alkyl moieties of the two R6 may be bonded together to forrn a methylenedioxy group;
• each R7 is, independently, hydrogen lower alkyl, phenyl, substituted phenyl or —CH2(CHOR)8m—R10;
• each R8 is, independently, hydrogen, lower alkyl, —C(═O)—R11, glucuronide, 2-tetrahydropyranyl, or
• each R9 is, independently, —CO2R13, —CON(R13)2, —SO2CH2R13, or —C(═O)R13;
• each R10 is, independently, —H, —SO2CH3, —CO2R13, —C(═O)NR13R13, —C(═O)R13, or —(CH2)m—(CHOH)n—CH2OH;
• each Z is, independently, CHOH, C(═O), —(CH2)n—, CHNR13R13, C═NR13, or NR13;
• each R11 is, independently, lower alkyl;
• each R12 is independently, —SO2CH3, —CO2R13, —C(═O)NR13R13, —C(═O)R13, or —CH2—(CHOH)n—CH2OH;
• each R13 is, independently, hydrogen, R7, R10, —(CH2)m—NR13R13, +—(CH2)m—NR13R13R13, —(CH2)m—(CHOR8)m—(CH2)m—NR13R13, —(CH2)m—NR10R10, +—(CH2)m—(CHOR8)m—(CH2)mNR13R13R13.
• with the proviso that NR13R13 can be joined on itself to form a ring comprising one of the following:
• each Het is independently, —NR13, —S—, —SO—, or —SO2—;
• 'O—, —SO2NR13—, —NHSO2—, —NR13CO—, or —CONR13—;
• 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;
• each Q is, independently, C—R5, C—R6, or a nitrogen atom, wherein at most three Q in a ring are nitrogen atoms;
• each V is, independently, (CH2)m—NR7R10, (CH2)m—NR7R7, —(CH2)m—+NR11R11R11, —(CH2)m—(CHOR8)m—(CH2)mNR7R10, —(CH2)n—NR10R10, +—(CH2)n—(CHOR8)m—(CH2)mNR7R7, —(CH2)n—(CHOR8)m—(CH2)mNR11R11R11, with the proviso that when V is attached directly to a nitrogen atom, then V can also be, independently, R7, R10, or (R11)2;
• with the proviso that, when any two —CH2OR8 groups are located 1,2 or 1,3- with respect to each other, the R8 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 enantiomers, diastereomers, and racemic mixtures thereof.