Soluble amide & ester pyrazinoylguanidine sodium channel blockers

A pyrazinoylguanidine 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
• wherein when 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;
• 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)n—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)n—NR10—CH2(CHOR8)(CHOR8)n—CH2OR8, —(CH2)n—CO2R7, —O—(CH2)m—CO2R7, —OSO3H, —O-glucuronide, —O-glucose,
• wherein when 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;
• 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;
• each R5 is, independently, —(CH2)n—CO2R13, Het-(CH2)m—CO2R13, —(CH2)n-Zg-CO2R13, Het-(CH2)m-Zg-CO2R13, —(CH2)n—NR10—(CH2)m(CHOR8)n—CO2R13, Het-(CH2)m—NR10—(CH2)m(CHOR8)n—CO2R13, —(CH2)n—(CHOR8)—CO2R13, Het-(CH2)m—(CHOR8)m—CO2R13, —(CH2)n—(CHOR8)mZg-CO2R13, Het-(CH2)n—(CHOR8)m-Zg-CO2R13, —(CH2)n-Zg-(CH2)m—CO2R13, —(CH2)n-Zg-(CH2)m—CO2R13, —(CH2)n-Zg(CHOR8)m-Zg-CO2R13, Het-(CH2)n-Zg-(CHOR8)m-Zg-CO2R13, —(CH2)n—CONH—C(═NR13)—NR13R13, Het-(CH2)n—CO—NH—C(═NR13)—NR13R13, —(CH2)n-Zg-CONH—C(═NR13)—NR13R13, Het-(CH2)n-Zg-CONH—C(═NR13)—NR13R13, —(CH2)n—NR10—(CH2)m(CHOR8)n—CONH—C(═NR13)—NR13R13, Het-(CH2)n—NR10—(CH2)m(CHOR8)n—CONH—C(═NR13)—NR13R13, —(CH2)n—(CHOR8)m—CONH—C(═NR13)—NR13R13, Het-(CH2)n—(CHOR8)m—CONH—C(═NR13)—NR13R13, —(CH2)n—(CHOR8)m-Zg-CONH—C(═NR13)—NR13R13, Het-(CH2)n—(CHOR8)m-Zg-CONH—C(═NR13)—NR13R13, —(CH2)n-Zg-(CH2)mCONH—C(═NR13)—NR13R13, Het-(CH2)n-Zg-(CH2)mCONH—C(═NR13)—NR13R13, —(CH2)n-Zg-(CHOR8)m-Zg-CONH—C(═NR13)—NR13R13, Het-(CH2)n-Zg-(CHOR8)m-Zg-CONH—C(═NR13)—NR13R13, —(CH2)n—CONR7—CONR13R13, Het-(CH2)n—CONR7—CONR13R13, —(CH2)n-Zg-CONR7—CONR13R13, —(CH2)n-Zg-CONR7—CONR13R13, —(CH2)n—NR10—(CH2)m(CHOR8)n—CONR7—CONR13R13, Het-(CH2)—NR10—(CH2)m(CHOR8)n—CONR7—CONR13R13, —(CH2)n—(CHOR8)n—CONR7—CONR13R13, Het-(CH2)n—(CHOR8)m—CONR7—CONR13R13, —(CH2)n—(CHOR8)m-Zg-CONR7—CONR13R13, Het-(CH2)n—(CHOR8)m-Zg-CNR7—CONR13R13, —(CH2)n-Zg-(CH2)mCONR7—CONR13R13, Het-(CH2)n-Zg-(CH2)mCONR7—CONR13R13, —(CH2)n-Zg(CHOR8)m-Zg-CONR7—CONR13R13, Het-(CH2)n-Zg(CHOR8)m-Zg-CONR7—CONR13R13, —(CH2)n—CONR7SO2NR13R13, Het-(CH2)m—CONR7SO2NR13R13, —(CH2)n-Zg-CONR7SO2NR13R13, Het-(CH2)m-Zg-CONR7SO2NR13R13, —(CH2)n—NR10—(CH2)m(CHOR8)n—CONR7SO2NR13R13, Het-(CH2)m—NR10—(CH2)m(CHOR8)n—CONR7SO2NR13R13, —(CH2)n—(CHOR8)m—CONR7SO2NR13R13, Het-(CH2)m—(CHOR8)m—CONR7SO2NR13R13, —(CH2)n—(CHOR8)m-Zg-CONR7SO2NR13R13Het (CH2)n—(CHOR8)m-Zg-CONR7SO2NR13R13, —(CH2)n-Zg-(CH2)mCONR7SO2NR13R13, Het-(CH2)n-Zg-(CH2)mCONR7SO2NR13R13, —(CH2)n-Zg-(CHOR9)-Zg-CONR7SO2NR13R13, Het-(CH2)n-Zg-(CHOR8)m-Zg-CONR7SO2NR13R13, —(CH2)n—SO2NR13R13, Het-(CH2)—SO2NR13R13, —(CH2)n-Zg-SO2NR13R13, Het-(CH2)m-Zg-SO2NR13R13, —(CH2)n—NR10—(CH2)n(CHOR8)n—SO2NR13R13, Het-(CH2)m—NR10—(CH2)m(CHOR8)n—SO2NR13R13, —(CH2)n—(CHOR8)m—SO2NR13R13, Het-(CH2)m—(CHOR8)m—SO2NR13R13, —(CH2)n—(CHOR8)m-Zg-SO2NR13R13, Het-(CH2)n—(CHOR8)m-Zg-SO2NR13R13, —(CH2)n-Zg-(CH2)mSO2NR13R13, Het-(CH2)n-Zg-(CH2)mSO2NR13R13, —(CH2)n-Zg-(CHOR8)m-Zg-SO2NR13R13, Het-(CH2)n-Zg-(CHOR8)m-Zg-SO2NR13R13, —(CH2)n—CONR13R13, Het-(CH2)n—CONR13R13, —(CH2)n-Zg-CONR13R13, Het-(CH2)m-Zg-CONR13R13, —(CH2)n—NR10—(CH2)m(CHOR8)n—CONR13R13, Het-(CH2)m—NR10—(CH2)m(CHOR8)n—CONR13R13, —(CH2)n—(CHOR8)m—CONR13R13, Het-(CH2)m—(CHOR8)m—CONR13R13, —(CH2)n—(CHOR8)-Zg-CONR13R13, Het-(CH2)n—(CHOR8)m-Zg-CONR13R13, —(CH2)n-Zg-(CH2)mCONR13R13, Het-(CH2)n-Zg-(CH2)mCONR13R13, —(CH2)n-Zg-(CHOR8)m-Zg-CONR13R13, Het-(CH2)n-Zg-(CHOR8)m-Zg-CONR13R13, —(CH2)n—CONR7COR13, Het-(CH2)m—CONR7COR13, —(CH2)n-Zg-CONR7COR13, Het-(CH2)m-Zg-CONR7COR13, —(CH2)n—NR10—(CH2)m(CHOR8)n—CONR7COR13, Het-(CH2)m—NR10—(CH2)m(CHOR8)n—CONR7COR13, —(CH2)n—(CHOR8)m—CONR7COR13, Het-(CH2)m—(CHOR8)m—CONR7COR13, —(CH2)n—(CHOR8)m-Zg-CONR7COR13, Het-(CH2)n—(CHOR8)m-Zg-CONR7COR13, —(CH2)n-Zg-(CH2)m—CONR7COR13, —(CH2)n-Zg-(CH2)mCONR7COR13, Het-(CH2)n-Zg-(CHOR8)m-Zg-CONR7COR13, —(CH2)n—CONR7CO2R13, —(CH2)n-Zg-CONR7CO2R13, Het-(CH2)m-Zg-CONR7CO2R13, —(CH2)n—NR10—(CH2)m(CHOR8)n—CONR7CO2R13, Het-(CH2)m—(CH2)m(CHOR8)n—CONR7CO2R13, —(CH2)n—(CHOR8)m—CONR7CO2R13, Het-(CH2)m—(CHOR8)m—CONR7CO2R13, —(CH2)n—(CHOR8)m-Zg-(CONR7CO2R13, Het-(CH2)n—(CHOR8)m-Zg-CONR7CO2R13, —(CH2)n-Zg-(CH2)mCONR7CO2R13, Het-(CH2)n-Zg-(CH2)mCONR7CO2R13, —(CH2)n-Zg-(CHOR8)m-Zg-CONR7CO2R13, Het-(CH2)n-Zg-(CHOR8)m-Zg-CONR7CO2R13, —(CH2)n—NH—C(═NR13)—NR13R13, Het-(CH2)n—NH—C(═NR13)—NR13R13, —(CH2)n-Zg-NH—C(═NR13)—NR13R13, Het-(CH2)m-Zg-NH—C(═NR13)—NR13R13, —(CH2)n—NR10—(CH2)m(CHOR8)n—NH—C(═NR13)—NR13R13, Het-(CH2)m—NR10—(CH2)m—(CHOR8)n—NH—C(═NR13)—NR13R13, —(CH2)n—(CHOR8)m—NH—C(═NR13)—NR13R13, Het-(CH2)m—(CHOR8)m—NH—C(═NR13)—NR13R13, —(CH2)n—(CHOR8)m-Zg-NH—C(═NR13)—NR13R13, Het-(CH2)n—(CHOR8)m-Zg-NH—C(═NR13)—NR13R13, —(CH2)n-Zg-(CH2)mNH—C(═NR13)—NR13R13, Het-(CH2)n-Zg-(CH2)mNH—C(═NR13)—NR13R13, —(CH2)n-Zg-(CHOR8)m-Zg-NH—C(NR13)—NR13R13, Het-(CH2)n-Zg-(CHOR8)m-Zg-NH—C(═NR13)—NR13R13, —(CH2)n—C(═NR13)—NR13R13, Het-(CH2)m—C(═NH)—NR13R13, —(CH2)n-Zg-C(═NH)—NR13R13, Het-(CH2)m-Zg-C(═NH)—NR13R13, —(CH2)n—NR10—(CH2)m(CHOR8)n—C(═NR13)—NR13R13, Het-(CH2)m—NR10—(CH2)m(CHOR8)n—C(═NR13)—NR13R13, —(CH2)n(CH2)n—(CHOR8)m—C(═NR13)—NR13R13, Het-(CH2)m(CHOR8)m—C(NR13)—NR13R13, —(CH2)n—(CHOR8)m-Zg-C(═NR13)—NR13R13, Het-(CH2)n—(CHOR8)m-Zg-C(═NR13)—NR13R13, —(CH2)n-Zg-(CH2)n—C(═NHC(═NR13)—NR13R13, Het-(CH2)n-Zg-(CH2)n—C(═NR13)—NR13R13, —(CH2)n-Zg-(CHOR8)m-Zg-C(═NR13)—NR13R13, Het-(CH2)n-Zg-(CHOR8)n-Zg-C(═NR13)—NR13R13;
• wherein when 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;
• each R6 is, independently, —R5, —R7, —OR8, —N(R7)2, —(CH2)3—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 form a methylenedioxy group, and
• wherein when 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;
• each R7 is, independently, hydrogen lower alkyl, phenyl, substituted phenyl or —CH2(CHOR)8m—R′″;
• each R8 is, independently, hydrogen, lower alkyl, —C(═O)—R11, glucuronide, 2-tetrahydropyranyl, or
• each R9 is, independently, —CO2R7, —CON(R7)2, —SO2CH3, or —C(═O)R7;
• each R′″ is, independently, —H, —SO2CH3, —CO2R7, —C(═O)NR7R9, —C(═O)R7, or —(CH2)m—(CHOH)n—CH2OH;
• each Z is, independently, CHOH, C(═O), —(CH2)n—, CHNR7R10, C═NR10, or NR10;
• each R11 is, independently, lower alkyl;
• each R12 is independently, —SO2CH3, —CO2R7, —C(═O)NR7R9, —C(═O)R7, or —CH2—(CHOH)n—CH2OH;
• each R13 is, independently, hydrogen, R7, R10, —(CH2)m—NR7R10,
• with the proviso that at least one R13 must be a group other than hydrogen, R7, or R10;
• with the additional proviso that NR13R13 can be joined on itself to form a ring comprising one of the following:
• each Het is independently, —NR7, —NR10, —S—, —SO—, —SO2—;
• —O—, —SO2NH—, —NHSO2—, —NR7CO—, or —CONR7—;
• 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—
• with the proviso that when V is attached directly to a nitrogen atom, then V can also be, independently, R7, R10, or (R11)2;
• wherein when 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.