Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Peptides containing saccharide radicals – e.g. – bleomycins – etc.
Patent
1998-08-31
2000-03-14
Woodward, Michael P.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Peptides containing saccharide radicals, e.g., bleomycins, etc.
530317, 530345, 514 8, 514 9, A61K 3814
Patent
active
060374470
DESCRIPTION:
BRIEF SUMMARY
The present invention is directed to certain glycopeptide dimers in which two glycopeptide units are covalently linked to one another through their disaccharide amine, via a linking radical. This invention is also directed to the monomeric intermediates. All of these compounds are useful as antibacterials, especially for the control of gram positive bacteria; the compounds are particularly useful for the control of resistant bacterial strains, such as vancomycin-resistant-enterococci ("VRE").
The compounds of the present invention are defined by the following Formulae I and II: ##STR1## In the above formulae, each of G and G' is independently selected from the group consisting of deshydrovancomycin of the formula: ##STR2## and deshydroA82846B of the formula: ##STR3## wherein Y.sup.1 is OH or ##STR4## and Y.sup.2 is defined as follows: (1) each Y.sup.2 independently represents is loweralkyl of C.sub.1 -C.sub.6 optionally substituted by from one to three substituents, each of which is independently selected from the group consisting of halo, nitro, cyano, alkoxy, haloalkyl, and haloalkoxy; and Y.sup.4 is ##STR5## wherein each Y.sup.5 is independently hydrogen or loweralkyl of C.sub.1 -C.sub.4, or Y.sup.4 is phenyl or phenyl substituted with from one to three substituents, each of which is independently five- to seven-membered heterocyclic ring optionally containing in addition to the indicated nitrogen atom one additional hetero ring atom which is nitrogen, oxygen, or sulfur, and which heterocyclic radical can be unsubstituted or substituted with from one or two substituents, each of which is loweralkyl of C.sub.1 -C.sub.2, loweralkoxy of C.sub.1 -C.sub.2, phenyl, benzyl, or C.sub.1 -C.sub.6 -alkanoyl; and L is a divalent linking radical of the formula A: ##STR6## wherein A is: alkylene of C.sub.1 -C.sub.16, wherein q is 1-3, ##STR7## each R.sup.1 is independently CH.sub.2, ##STR8## wherein each R independently represents halo, loweralkyl of C.sub.1 -C.sub.6, loweralkoxy of C.sub.1 -C.sub.6, phenyl, or phenyl substituted by from 1 to 2 substituents, each of which is independently halo, loweralkyl of C.sub.1 -C.sub.6, or loweralkoxy of C.sub.1 -C.sub.6 ; each X is independently --O-- or ##STR9## wherein R.sup.2 is H or loweralkyl of C.sub.1 -C.sub.4 ; and each X' is independently --O--, --S--, or ##STR10## wherein R.sup.2 is as defined above; or L is a divalent linking radical of the formula B: C.sub.1 -C.sub.8 -- formula ##STR11## wherein R is as defined above; and each R.sup.3 is independently CH.sub.2 or O.
The present invention also includes salts of the foregoing compounds.
DETAILED DESCRIPTION OF THE INVENTION
In compounds of Formula I, the glycopeptide units, G and G', may be identical or different. In compounds of both Formulae, linkage of the glycopeptide units is through the amine group of the disaccharide sugar. Any "alkylene" of C.sub.2 or higher can be straight chain or branched.
Certain compounds of the present invention are preferred. Compounds of Formula I, and especially symmetrical compounds (G=G' and/or both R.sup.1 are identical), are preferred for their more efficient synthesis.
Antibacterial activity is enhanced by employing preferred "L" groups. Preferences include the following, individually and in any combination: --G or to --CH.sub.2 --G' is branched C.sub.6 -C.sub.12 ; especially wherein X'=O; the alkylene is --(CH.sub.2).sub.2 --; and q=2; when R has this value on a phenyl ring within "A".
Representative compounds of the present invention are set forth in following TABLES 1 and 2. TABLE 1 identifies dimers of Formula I; TABLE 2 identifies compounds of Formula II.
TABLE 1 - Ex. # G G' L Name
1 Vanco Vanco
##STR12##
1,2-ethanediyl-bis-[(oxy- 4,1-phenylene)methylene]- bis-[vancomycin]
2 Vanco Vanco
##STR13##
1,4-butanediyl-bis-[(oxy- 2,1-phenylene)- methylene]-bis- [vancomycin
]
3 Vanco Vanco
##STR14##
1,5-pentanediyl-bis- [(oxy-4,1-phenylene)- methylene]-bis- [vancomyci
n]
4 Vanco Vanco
##STR15##
1,5-pentanediyl-bis- [(oxy-3,1-phenylene)- methylene]-bis- [vancomyci
REFERENCES:
patent: 4521335 (1985-06-01), Chan et al.
Linsdell, H., et al., J. Antibiotics, vol. 49, No. 2, 181-193.
Sundram, U.N., et al., J. Am. Chem. Soc., vol. 118, No. 51, 13107-13108 (1996).
Gerhard, J. Am. Chem. Soc. 115, 232, 1993.
Stack Douglas R
Thompson Richard C
Eli Lilly and Company
Lukton David
Musser Arlene K.
Woodward Michael P.
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