用于治疗听力损伤和眩晕的β-咔啉

摘要

本发明涉及β-咔啉（优选9-烷基-β-咔啉（9-烷基-β-BC））、其制备及其在预防和治疗听力损伤、耳鸣、急性声创伤、眩晕及前庭障碍中的用途，以及包含这些β-咔啉的药物组合物。

主权项

1.通式（I）的化合物的用途，其中，R¹是下述基团中的一种：–R¹²、–CR⁴R⁵R⁶、-NR¹²R¹³、–CO-NH–R¹²、–CO–O–R¹²；R²–R⁶独立地代表以下基团：–R⁷、–R⁸、–R⁹、–R¹⁰、–R¹¹、–H、–OH、–OR⁷、–OCH₃、–OC₂H₅、–OC₃H₇、–O–cyclo-C₃H₅、–OCH(CH₃)₂、–OC(CH₃)₃、–OC₄H₉、-OPh、-OCH₂-Ph、-OCPh₃、–SH、–SCH₃、–SC₂H₅、–SC₃H₇、–S–cyclo-C₃H₅、–SCH(CH₃)₂、–SC(CH₃)₃、-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、–OOC-CH₃、–OOC–C₂H₅、–OOC–C₃H₇、–OOC–cyclo-C₃H₅、–OOC–CH(CH₃)₂、–OOC–C(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、-NHCOCH(CH₃)₂、-NHCOC(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、-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-CS-NH₂、-NH-CS-NHCH₃、-NH-CS-NHC₂H₅、-NH–CS–NHC₃H₇、-NH–CS-NH–cyclo-C₃H₅、-NH–CS-NH[CH(CH₃)₂]、-NH–CS-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、-NH–C(=NH)-NH₂、-NH–C(=NH)-NHCH₃、-NH–C(=NH)-NHC₂H₅、-NH–C(=NH)-NHC₃H₇、–OC₆H₄-OCH₃、-NH–C(=NH)-NH–cyclo-C₃H₅、-NH–C(=NH)-NH[CH(CH₃)₂]、-CF₂Cl、-NH–C(=NH)-NH[C(CH₃)₃]、-NH–C(=NH)-N(CH₃)₂、-NH–C(=NH)-N(C₂H₅)₂、-NH–C(=NH)-N(C₃H₇)₂、-NH–C(=NH)-N(cyclo-C₃H₅)₂、–OC₆H₄-CH₃、-NH–C(=NH)-N[CH(CH₃)₂]₂、-NH–C(=NH)-N[C(CH₃)₃]₂、–O–CO-NH₂、–O–CO-NHCH₃、–O–CO-NHC₂H₅、–O–CO-NHC₃H₇、–O–CO-NH–cyclo-C₃H₅、–O–CO-NH[CH(CH₃)₂]、–O–CO-NH[C(CH₃)₃]、–O–CO-N(CH₃)₂、–O–CO-N(C₂H₅)₂、–O–CO-N(C₃H₇)₂、–O–CO-N(cyclo-C₃H₅)₂、–O–CO-N[CH(CH₃)₂]₂、–O–CO-N[C(CH₃)₃]₂、–O–CO–OCH₃、–O–CO–OC₂H₅、–O–CO–OC₃H₇、–O–CO–O–cyclo-C₃H₅、–O–CO–OCH(CH₃)₂、–O–CO–OC(CH₃)₃、–CH₂–COOH、–CH₂–COOCH₃、–CH₂–COOC₂H₅、–CH₂–COC₃H₇、–CH₂–CO–cyclo-C₃H₅、–CH₂–COCH(CH₃)₂、–CH₂–COC(CH₃)₃。R⁷–R¹³独立地代表以下基团：-CH₂F、-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、-CH₂-CH=CH-CH=CH₂、-CH=CH-CH=CH-CH₃、-CH=CH-CH₂-CH=CH₂、-C(CH₃)=CH-CH=CH₂、-CH=C(CH₃)-CH=CH₂、-CH=CH-C(CH₃)=CH₂、-C₂H₄-C(CH₃)=CH₂、-CH₂-CH(CH₃)-CH=CH₂、-CH(CH₃)-CH₂-CH=CH₂、-CH₂-CH=C(CH₃)₂、-CH₂-C(CH₃)=CH-CH₃、-CH(CH₃)-CH=CH-CH₃、-CH=CH-CH(CH₃)₂、-CH=C(CH₃)-C₂H₅、-C(CH₃)=CH-C₂H₅、-C(CH₃)=C(CH₃)₂、-C(CH₃)₂-CH=CH₂、-CH(CH₃)-C(CH₃)=CH₂、-C(CH₃)=CH-CH=CH₂、-CH=C(CH₃)-CH=CH₂、-CH=CH-C(CH₃)=CH₂、-C₄H₈-CH=CH₂、–C₃H₆–CH=CH–CH₃、–C₂H₄–CH=CH–C₂H₅、–CH₂–CH=CH–C₃H₇、–CH=CH–C₄H₉、–C₃H₆–C(CH₃)=CH₂、-CH₂-CH₂-CH₂-OCH₃、–C₂H₄–CH(CH₃)–CH=CH₂、–CH₂–CH(CH₃)–CH₂–CH=CH₂、-CH₂NH₂、–CH(CH₃)–C₂H₄–CH=CH₂、–C₂H₄–CH=C(CH₃)₂、–C₂H₄–C(CH₃)=CH-CH₃、–CH₂–CH(CH₃)–CH=CH–CH₃、–CH(CH₃)–CH₂–CH=CH–CH₃、-CH₂OH、-CH₂SH、–CH₂-CH=CH–CH(CH₃)₂、–CH₂–CH=C(CH₃)–C₂H₅、-CH₂-CH₂-CH₂NH₂、–CH₂–C(CH₃)=CH–C₂H₅、–CH(CH₃)–CH=CH–C₂H₅、-CH₂-CH₂NH₂、–CH=CH–CH₂–CH(CH₃)₂、–CH=CH–CH(CH₃)–C₂H₅、–CH=C(CH₃)–C₃H₇、–C(CH₃)=CH–C₃H₇、–CH₂–CH(CH₃)–C(CH₃)=CH₂、-CH₂-CH₂SH、–CH(CH₃)–CH₂–C(CH₃)=CH₂、–CH(CH₃)–CH(CH₃)-CH=CH₂、-CH₂-CH₂-CH₂OH、–CH₂–C(CH₃)₂–CH=CH₂、–C(CH₃)₂–CH₂–CH=CH₂、–CH₂–C(CH₃)=C(CH₃)₂、–CH(CH₃)–CH=C(CH₃)₂、–C(CH₃)₂–CH=CH-CH₃、-CH₂-CH₂-CH₂SH、–CH(CH₃)–C(CH₃)=CH-CH₃、–CH=C(CH₃)–CH(CH₃)₂、–C(CH₃)=CH–CH(CH₃)₂、–C(CH₃)=C(CH₃)–C₂H₅、–CH=CH–C(CH₃)₃、–C(CH₃)₂–C(CH₃)=CH₂、–CH(C₂H₅)–C(CH₃)=CH₂、–C(CH₃)(C₂H₅)–CH=CH₂、–CH(CH₃)–C(C₂H₅)=CH₂、–CH₂–C(C₃H₇)=CH₂、–CH₂–C(C₂H₅)=CH–CH₃、–CH(C₂H₅)–CH=CH-CH₃、–C(C₄H₉)=CH₂、–C(C₃H₇)=CH–CH₃、–C(C₂H₅)=CH-C₂H₅、–C(C₂H₅)=C(CH₃)₂、–C[C(CH₃)₃]=CH₂、–C[CH(CH₃)(C₂H₅)]=CH₂、–C[CH₂–CH(CH₃)₂]=CH₂、–C₂H₄–CH=CH–CH=CH₂、-C₆H₄-OCH₃、–CH₂–CH=CH–CH₂–CH=CH₂、–CH=CH–C₂H₄–CH=CH₂、-C₆H₄-OH、–CH₂–CH=CH–CH=CH–CH₃、–CH=CH–CH₂–CH=CH–CH₃、-CH₂-CH₂-OCH₃、–CH=CH–CH=CH–C₂H₅、-CH₂-CH=CH-C(CH₃)=CH₂、-CH₂-CH₂OH、-CH₂-CH=C(CH₃)-CH=CH₂、–CH₂–C(CH₃)=CH–CH=CH₂、-CH₂-OCH₃、–CH(CH₃)–CH=CH–CH=CH₂、-CH=CH-CH₂-C(CH₃)=CH₂、-CH=CH-CH(CH₃)-CH=CH₂、-CH=C(CH₃)-CH₂-CH=CH₂、–C(CH₃)=CH–CH₂-CH=CH₂、–CH=CH–CH=C(CH₃)₂、-CH₂-C₆H₄-OCH₃、-CH=CH-C(CH₃)=CH-CH₃、-CH=C(CH₃)-CH=CH-CH₃、-CH₂-C₆H₄-OH、–C(CH₃)=CH-CH=CH-CH₃、–CH=C(CH₃)–C(CH₃)=CH₂、–C(CH₃)=CH–C(CH₃)=CH₂、-C(CH₃)=C(CH₃)-CH=CH₂、-CH=CH-CH=CH-CH=CH₂、-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、-CH(CH₃)-C≡CH  、-CH₂-CH(CH₃)-C≡CH  、-CH(CH₃)-CH₂-C≡CH  、-CH(CH₃)-C≡C-CH₃、-C₄H₈-C≡CH、-C₃H₆-C≡C-CH₃、-C₂H₄-C≡C-C₂H₅、-CH₂-C≡C-C₃H₇、-C≡C-C₄H₉、-C≡C-C(CH₃)₃、-C₂H₄-CH(CH₃)-C≡CH、-CH₂-CH(CH₃)-CH₂-C≡CH、-CH₂-C≡C-CH(CH₃)₂、-CH(CH₃)-C₂H₄-C≡CH、-CH₂-CH(CH₃)-C≡C-CH₃、-CH(CH₃)-CH₂-C≡C-CH₃、-CH(CH₃)-C≡C-C₂H₅、-C≡C-CH(CH₃)-C₂H₅、-C≡C-CH₂-CH(CH₃)₂、-CH(C₂H₅)-C≡C-CH₃、-C(CH₃)₂-C≡C-CH₃、–CH(C₂H₅)-CH₂–C≡CH、–CH₂–CH(C₂H₅)-C≡CH、–C(CH₃)₂–CH₂–C≡CH、–CH₂–C(CH₃)₂–C≡CH、–CH(CH₃)–CH(CH₃)-C≡CH、–CH(C₃H₇)-C≡CH、–C(CH₃)(C₂H₅)–C≡CH、–C≡C–C≡CH、–CH₂–C≡C–C≡CH、–C≡C–C≡C–CH₃、–CH(C≡CH)₂、–C₂H₄–C≡C–C≡CH、–CH₂–C≡C–CH₂–C≡CH、–C≡C–C₂H₄–C≡CH、–CH₂–C≡C–C≡C–CH₃、–C≡C–CH₂–C≡C–CH₃、–C≡C–C≡C–C₂H₅、–C≡C–CH(CH₃)-C≡CH、–CH(CH₃)–C≡C–C≡CH、–CH(C≡CH)–CH₂–C≡CH、–C(C≡CH)₂–CH₃、–CH₂–CH(C≡CH)₂、–CH(C≡CH)–C≡C–CH₃、–C₁₄H₂₉、–CH₂–CH₂-N(CH₃)₂；以及药学上可接受的盐、溶剂化物、水合物、络合物、对映异构体、非对映异构体以及前述化合物的外消旋体，用于制备预防和治疗听力损伤、眩晕和前庭障碍的药物组合物。