Derivatives of pyridinone as inhibitors for tissue transglutaminase

摘要

The invention relates to pyridinone derivatives of general formula (I) as inhibitors of tissue transglutaminase, to methods for producing the pyridinone derivatives, to pharmaceutical compositions containing said pyridinone derivatives and to their use for the prophylaxis and treatment of diseases associated with tissue transglutaminase.

主权项

1. A compound of the following general formula (I):wherein
E1 and E2 are each independently —CO— or —SO2—; R* is selected from the group consisting of —H, —CH3, —C2H5, —C3H7, —CH(CH3)2, and —C4H9; R# is selected from the group consisting of NYY′, —OH, —OY, —NH—CH2—COOH, —NH—CH(CH3)—COOH, —NH—CH(CH2CH2SCH3)—COOH, —NH—CH(CH2OH)—COOH, —NH—CH(CH2SH)—COOH, —NH—CH(CH2CONH2)—COOH, —NH—CH(CH2CH2CONH2)—COOH, —NH—CH(CH2CH(CH3)2)—CH2COOH, —NH—CH(CH2Ph)-COOH, —NH—CH(CH2COOH)—COOH, —NH—CH(CH2CH2COOH)—COOH, —NH—CH(COOH)—CH(CH3)2, —NH—CH(COOH)—CH2CH(CH3)2, —NH—CH2—COOY′, —NH—CH(CH3)—COOY′, —NH—CH(CH2CH2SCH3)—COOP′, —NH—CH(CH2OH)—COOY′, —NH—CH(CH2SH)—COOY′, —NH—CH(CH2CONH2)—COOY′, —NH—CH(CH2CH2CONH2)—COOY′, —NH—CH(CH2CH(CH3)2)—CH2COOY′, —NH—CH(CH2Ph)-COOY′, —NH—CH(CH2COOH)—COOY′, —NH—CH(CH2COOY′)—COOH, —NH—CH(CH2COOY)—COOY′, —NH—CH(CH2CH2COOY)—COOY′, —NH—CH(COOH)—CH(CH3)2, —NH—CH(COOH)—CH2CH(CH3)2, Y is selected from the group consisting of: —CH2R1, —CHR1—CH2R2, —CHR1—CHR2—CH2R3, —CHR1—CHR2—CHR3—CH2R4, —CHR1—CHR2—CHR3—CHR4—CH2R5, —CHR1—CHR2—CHR3—CHR4—CHR5—CH2R6 Y′, R17, R18, R19, and R20 are each independently selected from the group consisting of: —H, —CH3, —C2H5, —C3H7, —CH(CH3)2, —C4H9, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —C(CH3)3, —C5H11, —CH(CH3)—C3H7, —CH2—CH(CH3)—C2H5, —CH(CH3)—CH(CH3)2, —C(CH3)2—C2H5, —CH2—C(CH3)3, —CH(C2H5)2, and —C2H4—CH(CH3)2; X is selected from the group consisting of —CR7R8R9, —CH2R7, —CHR7—CH2R8, —O—CH2R7, —O—CR7R8R9, —O—CHR7—CH2R8, Z is selected from the group consisting of: —CH3, —C2H5, —C3H7, —CH(CH3)2, —C4H9, -Ph, —CH2-Ph, —OCH3, —OC2H5, —OC3H7, —OCH(CH3)2, —OC4H9, —OPh, —OCH2-Ph, —OCH═CH2, and —OCH2—CH═CH2; R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are each independently selected from the group consisting of: —H, —OH, —OCH3, —OC2H5, —OC3H7, —O-cyclo-C3H5, —OCH(CH3)2, —OC(CH3)3, —OC4H9, —OPh, —OCH2-Ph, —OCPh3, —SH, —NO2, —F, —Cl, —Br, —I, —N3, —CN, —OCN, —NCO, —SCN, —NCS, —CHO, —COCH3, —COC2H5, —COC3H7, —CO-cyclo-C3H5, —COCH(CH3)2, —COC(CH3)3, —COOH, —COCN, —COOCH3, —COOC2H5, —COOC3H7, —COO-cyclo-C3H5, —COOCH(CH3)2, —COOC(CH3)3, —CONH2, —CONHCH3, —CONHC2H5, —CONHC3H7, —CONH-cyclo-C3H5, —CONH[CH(CH3)2], —CONH[C(CH3)3], —CON(CH3)2, —CON(C2H5)2, —CON(C3H7)2, —CON(cyclo-C3H5)2, —CON[CH(CH3)2]2, —CON[C(CH3)3]2, —NHCOCH3, —NHCOC2H5, —NHCOC3H7, —NHCO-cyclo-C3H5, —NHCO—CH(CH3)2, —NHCO—C(CH3)3, —NHCO—OCH3, —NHCO—OC2H5, —NHCO—OC3H7, —NHCO—O-cyclo-C3H5, —NHCO—OCH(CH3)2, —NHCO—OC(CH3)3, —NH2, —NHCH3, —NHC2H5, —NHC3H7, —NH-cyclo-C3H5, —NHCH(CH3)2, —NHC(CH3)3, —N(CH3)2, —N(C2H5)2, —N(C3H7)2, —N(cyclo-C3H5)2, —N[CH(CH3)2]2, —N[C(CH3)3]2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SOC(CH3)3, —SO2CH3, —SO2C2H5, —SO2C3H7, —SO2-cyclo-C3H5, —SO2CH(CH3)2, —SO2C(CH3)3, —SO3H, —SO3CH3, —SO3C2H5, —SO3C3H7, —SO3-cyclo-C3H5, —SO3CH(CH3)2, —SO3C(CH3)3, —SO2NH2, —OCF3, —OC2F5, —O—COOCH3, —O—COOC2H5, —O—COOC3H7, —O—COO-cyclo-C3H5, —O—COOCH(CH3)2, —O—COOC(CH3)3, —NH—CO—NH2, —NH—CO—NHCH3, —NH—CO—NHC2H5, —NH—CO—NHC3H7, —NH—CO—NH-cyclo-C3H5, —NH—CO—NH[CH(CH3)2], —NH—CO—NH[C(CH3)3], —NH—CO—N(CH3)2, —NH—CO—N(C2H5)2, —NH—CO—N(C3H7)2, —NH—CO—N(cyclo-C3H5)2, —NH—CO—N[CH(CH3)2]2, —NH—CO—N[C(CH3)3]2, —NH—C S-Nh2, —NH—C S-NhCH3, —NH—C S-NhC2H5, —NH—C S-NhC3H7, —NH—CS—NH-cyclo-C3H5, —NH—C S-Nh[CH(CH3)2], —NH—C S-Nh[C(CH3)3], —NH—CS—N(CH3)2, —NH—CS—N(C2H5)2, —NH—CS—N(C3H7)2, —NH—CS—N(cyclo-C3H5)2, —NH—CS—N[CH(CH3)2]2, —NH—CS—N[C(CH3)3]2, —NH2*HOOCCF3, —CH2F, —CF2Cl, —CHF2, —CF3, —CH2Cl, —CH2Br, —CH2I, —CH2—CH2F, —CH2—CHF2, —CH2—CF3, —CH2—CH2Cl, —CH2—CH2Br, —CH2—CH2I, cyclo-C3H5, cyclo-C4H7, cyclo-c5H9, cyclo-C6H11, cyclo-C7H13, cyclo-C8H15, -Ph, —CH2-Ph, —CPh3, —CH3, —C2H5, —C3H7, —CH(CH3)2, —C4H9, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —C(CH3)3, C5H11, —CH(CH3)—C3H7, —CH2—CH(CH3)—C2H5, —CH(CH3)—CH(CH3)2, —C(CH3)2—C2H5, —CH2—C(CH3)3, —CH(C2H5)2, —C2H4—CH(CH3)2, —C6H13, —C3H6—CH(CH3)2, —C2H4—CH(CH3)—C2H5, —CH(CH3)—C4H9, —CH2—CH(CH3)—C3H7, —CH(CH3)—CH2—CH(CH3)2, —CH(CH3)—CH(CH3)—C2H5, —CH2—CH(CH3)—CH(CH3)2, —CH2—C(CH3)2—C2H5, —C(CH3)2—C3H7, —C(CH3)2—CH(CH3)2, —C2H4—C(CH3)3, —CH(CH3)—C(CH3)3, —CH═CH2, —CH2—CH═CH2, —C(CH3)═CH2, —CH═CH—CH3, —C2H4—CH═CH2, —C7H15, —C8H17, —CH2—CH═CH—CH3, —CH═CH—C2H5, —CH2—C(CH3)═CH2, —CH(CH3)—CH═CH, —CH═C(CH3)2, —C(CH3)═CH—CH3, —CH═CH—CH═CH2, —C3H6—CH═CH2, —C2H4—CH═CH—CH3, —CH2—CH═CH—C2H5, CH═CH—C3H7, CH2CH═CH—CH═CH2, CH═CH CH═CH—CH3, CH2NH2, —CH2OH, —CH2SH, —CH2—CH2NH2, —CH2—CH2SH, —C6H4—OCH3, —C6H4—OH, —CH2—CH2—OCH3, —CH2—CH2OH, —CH2—OCH3, —CH2—C6H4—OCH3, —CH2—C6H4—OH, —C≡CH, —C≡C—CH3, —CH2—C≡CH, —C2H4—C≡CH, —CH2—C≡C—CH3, —C≡C—C2H5, —C3H6—C≡CH, —C2H4—C≡C—CH3, —CH2—C≡C—C2H5, —C≡C—C3H7, R11, R12, R13, R14, R15, and R16 are each independently selected from the group consisting of: —H, —NH2, —OH, —OCH3, —OC2H5, —OC3H7, —OCF3, —CF3, —F, —Cl, —Br, —I, —CH3, —C2H5, —C3H7, —CH(CH3)2, -Ph, and —CN; and stereoisomeric forms, E/Z isomers, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, racemates, tautomers, anomers, keto-enol-forms, betaine forms, prodrugs, solvates, hydrates, and pharmaceutically acceptable salts of the above mentioned compounds.