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)m—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-CAP, Link-(CH2)n—(Z)g—(CH2)m—(Z)g-CAP, Link-(Z)g—(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—(Z)g—(CH2)n, —S—, —SO—, —SO2—, —SO2NR7—, —SO2NR10—, or -Het-;
• each CAP is, independently, —CR10((Z)gR13)((Z)gR13);
• 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 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)nCH2OR8, —(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 form a methylenedioxy group;
• each R7 is, independently, hydrogen, lower alkyl, phenyl, or substituted phenyl;
• each R8 is, independently, hydrogen, lower alkyl, —C(═O)—R11, glucuronide, 2-tetrabydropyranyl, 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), 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, lower alkyl, phenyl, substituted phenyl, —SO2CH3, —CO2R7, —C(═O)NR7R7, —C(═O)NR7SO2CH3, —C(═O)NR7—CO2R7, —C(═O)NR7—C(═O)NR7R7, —C(═O)NR7—C(═O)R7, —C(═O)NR7—(CH2)m—(CHOH)n—CH2OH;—C(═O)R7, or —(CH2)m—(CHOH)n—CH2OH;
• 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;
• each V is, independently, —(CH2)m—NR7R10, —(CH2)m—NR7R7, —(CH2)m—R11R11R11, —(CH2)n—(CHOR8)m—(CH2)mNR7R10, —(CH2)n—NR10R10, —(CH2)n—(CHOR8)m—(CH2)mNR7R7, —(CH2)n—(CHOR8)m—(CH2)mR11R11R11, 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.