Treatment of bacterial infectious diseases

摘要

Novel pharmacological treatment of bacterial infectious diseases in humans by use of apramycin of formula (I) or apramycin derivatives having significantly low toxicity.;

主权项

1. A method of treatment of bacterial infectious diseases in humans, comprising administering to a patient in need thereof, an effective amount of an apramycin derivative or an acid addition salt thereof of formula (II), wherein R1 is hydrogen, C1-C7-alkyl, cyclopropylmethyl, optionally substituted benzyl, amino-C1-C7-alkyl, acetylamino-C1-C7-alkyl, hydroxy-C1-C7-alkyl, amino-hydroxy-C1-C7-alkyl, acetylamino-hydroxy-C1-C7-alkyl, C3-C7-cycloalkyl, C1-C4-alkenyl, C1-C7-acyl, amino-C1-C7-acyl, acetylamino-C1-C7-acyl, hydroxy-C1-C7-acyl, amino-hydroxy-C1-C7-acyl, acetylamino-hydroxy-C1-C7-acyl, aminoacetyl derived from the 20 naturally occurring essential α-amino acids, aroyl, heteroaroyl, SO2OH, or PO(OH)2; R2 is hydrogen, C1-C4-alkyl, or C1-C4-alkenyl; R3 is hydrogen, C1-C7-alkyl, cyclopropylmethyl, optionally substituted benzyl, amino-C1-C7-alkyl, acetylamino-C1-C7-alkyl, hydroxy-C1-C7-alkyl, amino-hydroxy-C1-C7-alkyl, acetylamino-hydroxy-C1-C7-alkyl, C3-C7-cycloalkyl, C1-C4-alkenyl, C1-C7-acyl, amino-C1-C7-acyl, acetylamino-C1-C7-acyl, hydroxy-C1-C7-acyl, amino-hydroxy-C1-C7-acyl, acetylamino-hydroxy-C1-C7-acyl, aminoacetyl derived from the 20 naturally occurring essential α-amino acids, aroyl, heteroaroyl, SO2OH, or PO(OH)2; R4 is hydrogen, C1-C4-alkyl, or C1-C4-alkenyl; R5 is hydrogen, C1-C4-alkyl, cyclopropylmethyl, optionally substituted benzyl, amino-C1-C7-alkyl, acetylamino-C1-C7-alkyl, hydroxy-C1-C7-alkyl, amino-hydroxy-C1-C7-alkyl, acetylamino-hydroxy-C1-C7-alkyl, C1-C4-alkenyl, C1-C7-acyl, amino-C1-C7-acyl, acetylamino-C1-C7-acyl, hydroxy-C1-C7-acyl, amino-hydroxy-C1-C7-acyl, acetylamino-hydroxy-C1-C7-acyl, aminoacetyl derived from the 20 naturally occurring essential α-amino acids, aroyl, heteroaroyl, SO2OH, or PO(OH)2; R6 is hydrogen, C1-C4-alkyl, cyclopropylmethyl, optionally substituted benzyl, amino-C1-C7-alkyl, acetylamino-C1-C7-alkyl, hydroxy-C1-C7-alkyl, amino-hydroxy-C1-C7-alkyl, acetylamino-hydroxy-C1-C7-alkyl, C1-C4-alkenyl, C1-C7-acyl, amino-C1-C7-acyl, acetylamino-C1-C7-acyl, hydroxy-C1-C7-acyl, amino-hydroxy-C1-C7-acyl, acetylamino-hydroxy-C1-C7-acyl, aminoacetyl derived from the 20 naturally occurring essential α-amino acids, aroyl, heteroaroyl, SO2OH, or PO(OH)2; R1 and R6 together represent C1-C7-alkyl-CH, phenyl-CH, (C1-C7-alkyl)2C, cyclo-(CH2)4C, cyclo-(CH2)5C, or C═O; or R5 and R6 together represent C1-C7-alkyl-CH, phenyl-CH, (C1-C7-alkyl)2C, cyclo-(CH2)4C, cyclo-(CH2)5C, or C═O; R7 is hydrogen, C1-C7-alkyl, cyclopropylmethyl, optionally substituted benzyl, amino-C1-C7-alkyl, acetylamino-C1-C7-alkyl, hydroxy-C1-C4-alkyl, amino-hydroxy-C1-C7-alkyl, acetylamino-hydroxy-C1-C7-alkyl, C3-C7-cycloalkyl, C1-C4-alkenyl, C1-C7-acyl, amino-C1-C7-acyl, acetylamino-C1-C7-acyl, hydroxy-C1-C7-acyl, amino-hydroxy-C1-C7-acyl, acetylamino-hydroxy-C1-C7-acyl, aminoacetyl derived from the 20 naturally occurring essential α-amino acids, aroyl, heteroaroyl, SO2OH, or PO(OH)2; R8 is hydrogen, C1-C4-alkyl, or C1-C4-alkenyl; R9 is hydrogen, C1-C4-alkyl, cyclopropylmethyl, optionally substituted benzyl, amino-C1-C7-alkyl, acetylamino-C1-C7-alkyl, hydroxy-C1-C7-alkyl, amino-hydroxy-C1-C7-alkyl, acetylamino-hydroxy-C1-C7-alkyl, C1-C4-alkenyl, C1-C7-acyl, amino-C1-C7-acyl, acetylamino-C1-C7-acyl, hydroxy-C1-C7-acyl, amino-hydroxy-C1-C7-acyl, acetylamino-hydroxy-C1-C7-acyl, aminoacetyl derived from the 20 naturally occurring essential α-amino acids, aroyl, heteroaroyl, SO2OH, or PO(OH)2; R10 is hydrogen, C1-C7-alkyl, cyclopropylmethyl, optionally substituted benzyl, amino-C1-C7-alkyl, acetylamino-C1-C7-alkyl, hydroxy-C1-C7-alkyl, amino-hydroxy-C1-C7-alkyl, acetylamino-hydroxy-C1-C7-alkyl, C3-C7-cycloalkyl, C1-C4-alkenyl, C1-C7-acyl, amino-C1-C7-acyl, acetylamino-C1-C7-acyl, hydroxy-C1-C7-acyl, amino-hydroxy-C1-C7-acyl, acetylamino-hydroxy-C1-C7-acyl, aminoacetyl derived from the 20 naturally occurring essential α-amino acids, aroyl, heteroaroyl, SO2OH, or PO(OH)2; or R9 and R10 together represent C1-C7-alkyl-CH, phenyl-CH, (C1-C7-alkyl)2C, cyclo-(CH2)4C, cyclo-(CH2)5C, or C═O; R11 is hydrogen, C1-C7-alkyl, cyclopropylmethyl, optionally substituted benzyl, amino-C1-C7-alkyl, acetylamino-C1-C7-alkyl, hydroxyl-C1-C7-alkyl, amino-hydroxy-C1-C7-alkyl, acetylamino-hydroxy-C1-C7-alkyl, C1-C4-alkenyl, C1-C7-acyl, amino-C1-C7-acyl, acetylamino-C1-C7-acyl, hydroxy-C1-C7-acyl, amino-hydroxy-C1-C7-acyl, acetylamino-hydroxy-C1-C7-acyl, aminoacetyl derived from the 20 naturally occurring essential α-amino acids, aroyl, heteroaroyl, SO2OH or PO(OH)2; R12 is hydrogen, C1-C7-alkyl, cyclopropylmethyl, optionally substituted benzyl, amino-C1-C7-alkyl, acetylamino-C1-C7-alkyl, hydroxy-C1-C7-alkyl, amino-hydroxy-C1-C7-alkyl, acetylamino-hydroxy-C1-C7-alkyl, C1-C4-alkenyl, C1-C7-acyl, amino-C1-C7-acyl, acetylamino-C1-C7-acyl, hydroxy-C1-C7-acyl, amino-hydroxy-C1-C7-acyl, acetylamino-hydroxy-C1-C7-acyl, aminoacetyl derived from the 20 naturally occurring essential α-amino acids, aroyl, heteroaroyl, SO2OH, or PO(OH)2; or R11 and R12 together represent C1-C7-acyl-CH, phenyl-CH, (C1-C7-alkyl)2C, cyclo-(CH2)4C, cyclo-(CH2)5C, or C═O; R13 is hydrogen, C1-C7-alkyl, cyclopropylmethyl, optionally substituted benzyl, amino-C1-C7-alkyl, acetylamino-C1-C7-alkyl, hydroxy-C1-C7-alkyl, amino-hydroxy-C1-C7-alkyl, acetylamino-hydroxy-C1-C7-alkyl, C3-C7-cycloalkyl, C1-C4-alkenyl, C1-C7-acyl, amino-C1-C7-acyl, acetylamino-C1-C7-acyl, hydroxyl-C1-C7-acyl, amino-hydroxy-C1-C7-acyl, acetylamino-hydroxy-C1-C7-acyl, aminoacetyl derived from the 20 naturally occurring essential α-amino acids, aroyl, heteroaroyl, SO2OH, or PO(OH)2; or R12 and R13 together represent C1-C7-alkyl-CH, phenyl-CH, (C1-C7-alkyl)2C, cyclo-(CH2)4C, cyclo-(CH2)5C, or C═O; R14 is hydrogen, C1-C4-alkyl, or C1-C4-alkenyl; or R15 is hydrogen, C1-C7-alkyl, cyclopropylmethyl, optionally substituted benzyl, amino-acetylamino-C1-C7-alkyl, hydroxy-C1-C7-alkyl, amino-hydroxy-C1-C7-alkyl, acetylamino-hydroxy-C1-C7-alkyl, C1-C7-acyl, amino-C1-C7-acyl, acetylamino-C1-C7-acyl, hydroxy-C1-C7-acyl, amino-hydroxy-C1-C7-acyl, acetylamino-hydroxy-C1-C7-acyl, aminoacetyl derived from the 20 naturally occurring essential α-amino acids, aroyl, heteroaroyl, SO2OH, or PO(OH)2; or R13 and R15 together represent C1-C7-alkyl-CH, phenyl-CH, (C1-C7-alkyl)2C, (CH2)4C, (CH2)5C, or C═O; R16 is hydrogen, C1-C4-alkyl, cyclopropylmethyl, cyclopropyl, or C1-C4-alkenyl; or N—R10 and R16 together represent a saturated or partially unsaturated heterocycle; and R17 is hydrogen; amino, C1-C7-alkylamino, cyclopropylmethylamino, optionally substituted benzylamino, amino-C1-C7-alkylamino, acetylamino-C1-C7-alkylamino, hydroxy-C1-C7-alkylamino, amino-hydroxy-C1-C7-alkylamino, acetylamino-hydroxy-C1-C7-alkylamino, C3-C7-cycloalkylamino, C1-C4-alkenylamino, C1-C7-acylamino, amino-C1-C7-acylamino, acetylamino-C1-C7-acylamino, hydroxy-C1-C7-acylamino, amino-hydroxy-C1-C7-acylamino, acetylamino-hydroxy-C1-C7-acylamino, aminoacetylamino, wherein aminoacetyl is derived from the 20 naturally occurring essential α-amino acids, aroylamino, heteroaroylamino, NHSO2OH, NHPO(OH)2; hydroxy, C1-C7-alkoxy, cyclopropylmethoxy, optionally substituted benzyloxy, amino-C1-C7-alkoxy, acetylamino-C1-C7-alkoxy, hydroxy-C1-C7-alkoxy, amino-hydroxy-C1-C7-alkoxy, acetylamino-hydroxy-C1-C7-alkoxy, C1-C4-alkenyloxy, C1-C7-acyloxy, amino-C1-C7-acyloxy, acetylamino-C1-C7-acyloxy, hydroxy-C1-C7-acyloxy, amino-hydroxy-C1-C7-acyloxy, acetylamino-hydroxy-C1-C7-acyloxy, aminoacetoxy wherein aminoacetyl is derived from the 20 naturally occurring essential α-amino acids, aroyloxy, heteroaroyloxy, OSO2OH, or OPO(OH)2; with the proviso, that when R16 is methyl and R17 is hydrogen, at least one of the substituents R1 to R15 is different from hydrogen; derivatives thereof, wherein one or more amino group are in protected form; or a pharmaceutically acceptable acid addition salt thereof.