US 2007/0185015 A1 · Semi-synthetic desmethyl-vancomycin-based glycopeptides with antibiotic activity

Abstract

Semi-synthetic glycopeptides that have antibacterial activity are based on modifications of the desmethyl-vancomycin scaffold, in particular, acylation of the amino substituent on the amino-substituted sugar moiety on this scaffold with certain acyl groups; and/or conversion of the acid moiety on the macrocyclic ring of this scaffolds to certain substituted amides. In addition, compounds of the invention include desmethyl-vancomycin scaffolds on which the acid moiety on the macrocyclic ring is converted to certain substituted amides and the amino substituent on the amino-substituted sugar moiety is alkylated with certain alkyl groups. Also provided are methods for synthesis of the compounds, pharmaceutical compositions containing the compounds, and methods of use of the compounds for the treatment and/or prophylaxis of diseases, especially bacterial infections.

A compound having a formula selected from the group consisting of:

wherein,
R1 is C(═O)CR7R7aNR8R8a, wherein,
R7 and R7a are independently hydrogen, the side chain of a naturally occurring or non-naturally occurring amino acid, alkyl, or alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, alkoxyalkoxy, carboxyl, carboxyl ester, —C(═O)NR8R8a, —NR8R8a, aryl, substituted aryl, heteroaryl, substituted heteroaryl, mercapto, or thioalkoxy, or R7 and R7a together with the atom to which they are attached form a cycloalkyl ring which optionally contains a heteroatom selected from the group consisting of optionally substituted O, N, and S;
R8 and R8a are independently selected from the group consisting of hydrogen and unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, arylalkyl, alkylaryl, and heteroaryl, said aryl, alkylaryl, arylalkyl or heteroaryl group optionally containing one or more optionally substituted aryl, heteroaryl, or condensed rings, or R8 and R8a together with the atom to which they are attached form a cycloalkyl ring which optionally contains a heteroatom selected from the group consisting of optionally substituted O, N, and S;
R1A is selected from the group consisting of H, CHR5R5a, and C(═O)R6, wherein,
R5 and R5a are independently selected from the group consisting of hydrogen and unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, arylalkyl, alkylaryl, and heteroaryl, said aryl, alkylaryl, arylalkyl or heteroaryl group optionally containing one or more optionally substituted aryl, heteroaryl, or condensed rings, or R5 and R5a together with the atom to which they are attached form a cycloalkyl ring which optionally contains a heteroatom selected from the group consisting of optionally substituted O, N, and S, and
R6 is selected from the group consisting of unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, arylalkyl, alkylaryl, and heteroaryl containing a heteroatom selected from the group consisting of optionally substituted O, N, and S, said aryl, alkylaryl, arylalkyl or heteroaryl group optionally containing one or more optionally substituted aryl, heteroaryl, or condensed rings;
R2 is selected from the group consisting of,
(1) OH,
(2) 1-adamantanamino,
(3) 2-adamantanamino,
(4) 3-amino-1-adamantanamino,
(5) 1-amino-3-adamantanamino,
(6) 3-loweralkylamino-1-adamantanamino,
(7) 1-loweralkylamino-3-adamantanamino,
(8) amino,
(9) NR9R9a wherein R9 and R9a are independently selected from the group consisting of hydrogen, loweralkyl or substituted lowerakyl, or
R9 and R9a together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, which may optionally be substituted with one or more substituents independently selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) C1-C3-alkoxy,
(d) C1-C3-alkoxy-C1-C3-alkoxy,
(e) oxo,
(f) C1-C3-alkyl,
(g) halo-C1-C3-alkyl, and
(h) C1-C3-alkoxy -C1-C3-alkyl;
R2A is selected from the group consisting of
(1) 1-adamantanamino,
(2) 2-adamantanamino,
(3) 3-amino-1-adamantanamino,
(4) 1-amino-3-adamantanamino,
(5) 3-loweralkylamino-1-adamantanamino,
(6) 1-loweralkylamino-3-adamantanamino;
and
R3 is selected from the group consisting of hydrogen and aminoloweralkyl, wherein the aminoloweralkyl amino group is further substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, alkylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy;
or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer or prodrug thereof.

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Semi-synthetic desmethyl-vancomycin-based glycopeptides with antibiotic activity

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Semi-synthetic desmethyl-vancomycin-based glycopeptides with antibiotic activity

Life of this patent

Abstract

Claims16