Glycopeptide antibiotic derivatives

Abstract

The present invention provides glycopeptide antibiotic derivative compounds. These derivative compounds possess antibacterial activity aginst a wide variety of bacteria, including activity against vancomycin-resistant isolates. Methods of making and using these glycopeptide antibiotic derivative compounds are also provided.

Description

BACKGROUND OF THE INVENTION

New improved antibiotics are continually in demand, particularly for the treatment of human diseases. Increased potency, expanded spectrum of bacterial inhibition, increased in vivo efficacy, and improved pharmaceutical properties are some of the goals for improved antibiotics.

In the search for new antibiotics, structural modification of known antibiotics is attempted whenever possible. The glycopeptide antibiotics have such complex structures that even small changes are difficult. Furthermore, it is difficult to predict the effect these changes will make in the antimicrobial and physiological properties. Processes for modifying known antibiotics and the new active derivatives made by such processes, Wherefore, continue to be of great importance.

Previously, N-alkyl and N-acyl derivatives of the glycopeptides vancomycin, A51568A, A51568B, M43A and M43D have been prepared (U.S. Pat. Nos. 4,639,433, 4,643,987, and 4,698,327). Several of these compounds exhibited microbiological activity, including activity against vancomycin-resistant isolates. Nicas et al., Antimicrobial Agents and Chemotherapy, 33(9):1477-1481 (1989). In addition, European Patent Application Publication No. 0435503, published Jul. 3, 1993, describes certain N-alkyl and N-acyl derivatives of the A82846 glycopeptides, factors A, B, and C.

The formula I compounds of this invention are new members of the glycopeptide group of antibiotics. These new compounds are derivatives of known glycopeptide antibiotics that include vancomycin (U.S. Pat. No. 3,067,099); A82846A, A82846B, and A82846C (U.S. Pat. No. 5,312,738, European Patent Publication 256,071 A1); PA-42867 factors A, C, and D (U.S. Pat. No. 4,946,941 and European Patent Publication 231,111 A2); A83850 (U.S. Pat. No. 5,187,082); avoparcin (U.S. Pat. No. 3,338,786 and U.S. Pat. No. 4,322,343); actinoidin, also known as K288 (J. Antibiotics Series A 14:141 (1961); helevecardin (Chem. Abstracts 110:17188 (1989) and Japanese Patent Application 86/157,397); galacardin (Chem. Abstracts 110:17188 (1989) and Japanese Patent Application 89/221,320); and M47767 (European Patent Publication 339,982). The references listed above which describe these glycopeptides are incorporated herein by reference.

Enterococci are important human pathogens. Infections caused by enterococci are generally difficult to treat. Glycopeptides, such as vancomycin and teicoplanin, have become important therapies in the treatment of infections due to enterococci. However, strains of Enterococcus faecium and E. faecalis have recently been isolated that are resistant to vancomycin and teicoplanin. Leclercq et al., "Plasmid Mediated Resistance to Vancomycin and Teicoplanin in Enterococcus Faecium," The New England Journal of Medicine, 319(3):157-161 (1988), and Uttley et al., "Vancomycin-Resistant Enterococci," Lancet, 1:57-58 (1988). The isolates were also found to be resistant to other antibiotics. A recent survey found 7.9% of Enterococci in United States hospitals are now vancomycin resistant. "Nosocomial Enterococci Resistant to Vancomycin" Morbidity and Mortality Weekly Resort 42 (30):597-598 (1993). In addition to their broad activity against gram-positive organisms, many of the glycopeptide compounds of this invention also exhibit improved antimicrobial activity against vancomycin-resistant isolates.

SUMMARY OF THE INVENTION

The present invention provides compounds of the formula I: ##STR1## or salt thereof, wherein:

X and Y are each independently hydrogen or chloro;

R is hydrogen, 4-epi-vancosaminyl, actinosaminyl, or ristosaminyl;

R.sup.1 is hydrogen, or mannose;

R.sup.2 is --NH.sub.2, --NHCH.sub.3, or--N(CH.sub.3).sub.2 ;

R.sup.3 is --CH.sub.2 CH(CH.sub.3).sub.2, �p-OH, m-Cl!phenyl, �p-rhamnose-phenyl, or

�p-rhamnose-galactose!phenyl, �p-galactose-galactose!phenyl, �p-CH.sub.3 O-rhamnose!phenyl;

R.sup.4 is --CH.sub.2 (CO)NH.sub.2, benzyl, �p-OH!phenyl, or �p-OH, m-Cl!phenyl;

R.sup.5 is hydrogen, or mannose;

R.sup.6 is 4-epi-vancosaminyl, L-acosaminyl, L-ristosaminyl, or L-actinosaminyl;

R.sup.7 is (C.sub.2 -C.sub.16)alkenyl, (C.sub.2 -C.sub.12)alkynyl, (C.sub.2 -C.sub.2 alkyl)-R.sub.8, (C.sub.1 -C.sub.12 alkyl)-halo, (C.sub.2 -C.sub.6 alkynyl)-R.sub.8, (C.sub.2 C6 alkynyl)-R.sub.8, (C.sub.1 -C.sub.12 alkyl)--O--R.sub.8, and is attached to the amino group of R.sup.6 ;

R.sup.8 is selected from the group consisting of:

a) multicyclic aryl unsubstituted or substituted with one or more substituents independently selected from the group consisting of:

(i) hydroxy, (ii) halo, (iii) nitro, (iv) (C.sub.1 -C.sub.6)alkyl, (v) (C.sub.1 -C.sub.6)alkenyl, (vi) (C.sub.1 -C.sub.6)alkynyl, (vii) (C.sub.1 -C.sub.6)alkoxy, (viii) halo-(C.sub.1 -C.sub.6)alkyl, (ix) halo-(C.sub.1 -C.sub.6)alkoxy, (x) carbo-(C.sub.1 -C.sub.6)alkoxy, (xi) carbobenzyloxy, (xii) carbobenzyloxy substituted with (C.sub.1 -C6)alkyl, (C.sub.1 -C.sub.6)alkoxy, halo, or nitro, (xiii) a group of the formula --S(O).sub.n' --R.sup.9, wherein n'is 0-2 and R.sup.9 is (C.sub.1 -C.sub.6)alkyl, phenyl, or phenyl substituted with (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, halo, or nitro, and

(xiv) a group of the formula --C(O)N(R.sup.10).sub.2 wherein each R.sup.10 substituent is independently hydrogen, (C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.6)- alkoxy, phenyl, or phenyl substituted with (C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.6)-alkoxy, halo, or nitro;

b) heteroaryl unsubstituted or substituted with one or more substituents independently selected from the group consisting of:

(i) halo, (ii) (C.sub. -C.sub.6)alkyl, (iii) (C.sub.1 -C.sub.6)alkoxy, (iv) halo-(C.sub.1-C.sub.6)alkyl, (v) halo-(C.sub.1 -C.sub.6)alkoxy, (vi) phenyl, (vii) thiophenyl, (viii) phenyl substituted with halo, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkenyl, (C.sub.1 -C.sub.6)alkynyl, (C.sub.1 -C.sub.6)alkoxy, or nitro, (ix) carbo-(C.sub.1 -C.sub.6)alkoxy, (x) carbobenzyloxy, (xi) carbobenzyloxy substituted with (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6) alkoxy, halo, or nitro,

(xii) a group of the formula --S(O).sub.n' --R.sup.9, as defined above,

(xiii) a group of the formula --C(O)N(R.sup.10).sub.2 as defined above, and

(xiv) thienyl;

c) a group of the formula: ##STR2##

wherein A.sup.1 is --OC(A.sup.2).sub.2 --C(A.sup.2).sub.2 --O--, --O--,C(A.sup.2).sub.2 --O--,C(A.sup.2).sub.2 --O--, or -C(A.sup.2).sub.2 -C(A.sup.2).sub.2 -C(A.sup.2).sub.2 -C(A.sup.2).sub.2 -, and each A.sup.2 substituent is independently selected from hydrogen, (C.sub.1 -C6)-alkyl, (C.sub.1 -C.sub.6)alkoxy, and (C.sub.4 13 C.sub.10)cycloalkyl;

d) a group of the formula: ##STR3##

wherein p is from 1 to 5; and

R.sup.11 is independently selected from the group consisting of:

(i) hydrogen, (ii) nitro, (iii) hydroxy, (iv) halo, (v) (C.sub.1 -C.sub.8)alkyl, (vi) (C.sub.1 -C.sub.8)alkoxy, (vii) (C.sub.9 -C.sub.12)alkyl, (viii)(C.sub.2 -C.sub.9)alkynyl, (ix) (C.sub.9 -C.sub.12)alkoxy, (x) (C.sub.1 -C.sub.3)alkoxy substituted with (C.sub.1 -C.sub.3)alkoxy, hydroxy, halo(C.sub.1 'C.sub.3)aikoxy, or (C.sub.1 -C.sub.4)alkylthio, (xi) (c.sub.2 -C.sub.5)alkenyloxy, (xii) (C.sub.1 -C.sub.13)alkynyloxy (xiii) halo-(C.sub.1 -C6)alkyl, (xiv) halo-(C.sub.1 -C.sub.6)alkoxy, (xv) (C.sub.2 -C.sub.6)alkylthio, (xvi) (C.sub.2 -C.sub.10)alkanoyloxy, (xvii) carboxy-(C.sub.2 -C.sub.4)alkenyl, (xviii) (C.sub.1 -C.sub.3)alkylsulfonyloxy, (xix) carboxy-(C.sub.1 -C.sub.3)alkyl, (xx) N-�di(C.sub.1 -C.sub.3)-alkyl!amino-(C.sub.1 -C.sub.3)alkoxy, (xxi) cyano-(C.sub.1 -C.sub.6)alkoxy, and (xxii) diphenyl-(C.sub.1 -C.sub.6)alkyl, with the proviso that when R.sup.11 is (C.sub.1 -C.sub.8)alkyl, (C.sub.1 -C.sub.8)alkoxy, or halo, p must be greater or equal to 2, or when R.sup.7 is (C.sub.1 -C.sub.3 alkyl)-R.sup.8 then R.sup.11 is not hydrogen, (C.sub.1 -C.sub.8)alkyl, (C.sub.1 -C.sub.8)alkoxy, or halo;

e) a group of the formula: ##STR4##

wherein q is 0 to 4;

R.sup.12 is independently selected from the group consisting of:

(i) halo, (ii) nitro, (iii) (C.sub.1-C.sub.6)alkyl, (iv) (C.sub.1 -C.sub.6)alkoxy, (v) halo-(C.sub.1 -C.sub.6)alkyl, (vi) halo-(C.sub.1 -C.sub.6)alkoxy, and (vii) hydroxy, and (vii) (C.sub.1 -C.sub.6)thioalkyl;

r is 1 to 5; provided that the sum of q and r is no greater than 5;

Z is selected from the group consisting of:

(i) a single bond,

(ii) divalent (C.sub.14 C.sub.6)alkyl unsubstituted or substituted with hydroxy, (C.sub.1-C 6)alkyl, or (C.sub.1 -C.sub.6)alkoxy,

(iii) divalent (C.sub.2 -C.sub.6)alkenyl,

(iv) divalent (C.sub.2 -C.sub.6)alkynyl, or

(v) a group of the formula --(C(R.sup.14).sub.2)s--R.sup.15 --or --R.sup.15 --(C(R.sup.14).sub.2).sub.s --, wherein s is 0-6; wherein each R.sup.14 substituent is independently selected from hydrogen, (C.sub.1 -C.sub.6)-alkyl, or (C.sub.4 -C.sub.10) cycloalkyl; and R.sup.15 is selected from --O--, --S--, --SO--, --SO.sub.2 --, --SO.sub.2 --O--, --C(O)--, --OC(O)--, --C(O)O--, --NH--, --N(C.sub.1 -C.sub.6 alkyl)-, and --C(O)NH--, --NHC(O)--, N.dbd.N;

R.sup.13 is independently selected from the group consisting of:

(i) (C.sub.4 -C.sub.10)heterocyclyl, (ii) heteroaryl, (iii) (C.sub.4-C.sub.10)cycloalkyl unsubstituted or substituted with (C.sub.1 -C.sub.6)alkyl, or (iv) phenyl unsubstituted or substituted with 1 to 5 substituents independently selected from: halo, hydroxy, nitro, (C.sub.1 -C.sub.10) alkyl, (C.sub.1 -C.sub.3)alkoxy, halo-(C.sub.1 -C.sub.3)alkoxy, halo-(C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3)alkoxyphenyl, phenyl, phenyl-(C1-C.sub.3)alkyl, (C.sub.1 -C.sub.6)alkoxyphenyl, phenyl-(C.sub.1-C.sub.3)alkynyl, and (C.sub.1 -C.sub.6)alkylphenyl;

f) (C.sub.4 -C.sup.10)cycloalkyl unsubstituted or substituted with one or more substituents independently selected from the group consisting of:

(i) (C.sub.1 -C.sub.6)alkyl, (ii) (C.sub.1 -C6)alkoxy, (iii) (C.sub.1 -C.sub.6)alkenyl, (iv) (C.sub.1 -C.sub.6)alkynyl, (v) (C.sub.4 -C.sub.10)cycloalkyl, (vi) phenyl, (vii) phenylthio, (viii) phenyl substituted by nitro, halo, (C.sub.1-C.sub.6)alkanoyloxy, or carbocycloalkoxy, and (ix) a group represented by the formula --Z--R.sup.13 wherein Z and R.sup.13 are as defined above; and

g) a group of the formula: ##STR5##

wherein

A.sup.3 and A.sup.4 are each independently selected from

(i) a bond, (ii) --O--, (iii) --S(O).sub.t --, wherein t is 0 to 2, (iv) --C(R.sup.17).sub.2 --, wherein each R.sup.17 substituent is independently selected from hydrogen, (C.sub.1 -C.sub.6)alkyl, hydroxy, (C.sub.l -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, or both R.sup.17 substituents taken together are O, (v) --N(R.sup.18).sub.2 --, wherein each R.sup.18 substituent is independently selected from hydrogen; (C.sub.1 -C.sub.6)alkyl; (C.sub.1 -C.sub.6)alkenyl; (C.sub.1 -C.sub.6)alkynyl; (C.sub.4 -C.sub.10)cycloalkyl; phenyl; phenyl substituted by nitro, halo, (C.sub.1 -C.sub.6)alkanoyloxy; or both R.sup.18 substituents taken together are (C.sub.4 -C.sub.10)cycloalkyl;

R.sup.16 is R.sup.12 or R.sup.13 as defined above; and

u is 0-4.

Another aspect of the invention relates to compositions for the treatment of susceptible bacterial infections comprising a compound of formula I in combination with an acceptable pharmaceutical carrier. Methods for the treatment of susceptible bacterial infections with compositions of formula I are also a part of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The alkyl substituents recited herein denote substituted or unsubstituted, straight or branched chain hydrocarbons of the length specified. The term "alkenyl" refers to a substituted or unsubstituted, straight or branched alkenyl chain of the length specified. The term "alkynyl", refers to a substituted or unsubstituted, straight or branched alkynyl chain of the length specified.

The alkoxy substituents recited herein represent an alkyl group attached through an oxygen bridge. The term "alkenoxy" represents a alkenyl chain of the specified length attached to an oxygen atom.

The term "multicyclic aryl" means a stable, saturated or unsaturated, substituted or unsubstituted, 9 to 10 membered organic fused bicyclic ring; a stable, saturated or unsaturated, substituted or unsubstituted 12 to 14 membered organic fused tricyclic ring; or a stable, saturated or unsaturated, substituted or unsubstituted 14 to 16 membered organic fused tetracyclic ring. The bicyclic ring may have 0 to 4 substituents, the tricyclic ring may have 0 to 6 substituents, and the tetracyclic ring may have 0 to 8 substituents. Typical multi-cyclic aryls include fluorenyl, napthyl, anthranyl, phenanthranyl, biphenylene and pyrenyl.

The term "heteroaryl" represents a stable, saturated or unsaturated, substituted or unsubstituted, 4 to 7 membered organic monocyclic ring having a hetero atom selected from S, O, and N; a stable, saturated or unsaturated, substituted or unsubstituted, 9 to 10 membered organic fused bicyclic ring having 1 to 2 hetero atoms selected from S, O, and N; or a stable, saturated or unsaturated, substituted or unsubstituted, 12 to 14 membered organic fused tricyclic ring having a hetero atom selected from S, O, and N. The nitrogen and sulfur atoms of these rings are optionally oxidized, and the nitrogen hetero atoms are optionally quarternized. The monocyclic ring may have 0 to 5 substituents. The bicyclic ring may have 0 to 7 substituents, and the tricyclic ring may have 0 to 9 substituents. Typical heteroaryls include quinolyl, piperidyl, thienyl, piperonyl, oxafluorenyl, pyridyl and benzothienyl and the like.

The term "(C.sub.4 -C.sub.10)cycloalkyl" embraces substituents having from four to ten carbon atoms, such as cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl which may be unsubstituted or substituted with substituents such as alkyl and phenyl. This term also embraces C.sub.5 to C.sub.10 cycloalkenyl groups such as cyclopentenyl and cyclohexenyl. The term " (C.sub.4 -C.sub.10)cycloalkyl" also embraces bicyclic and tricyclic cycloalkyls such as bicyclopentyl, bicylohexyl, bicycloheptyl, and adamantyl.

The term "alkanoyloxy" represents an alkanoyl group attached through an oxygen bridge. These substituents may be substituted or unsubstituted, straight, or branched chains of the specified length.

The term "cyano-(C.sub.1 -C.sub.6)alkoxy" represents a substituted or unsubstituted, straight or branched alkoxy chain having from one to six carbon atoms with a cyano moiety attached to it.

The term "divalent (C.sub.1 -C.sub.6)alkyl" represents an unsubstituted or substituted, straight or branched divalent alkyl chain having from one to six carbon atoms. Typical divalent (C.sub.1 -C.sub.6)alkyl groups include methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, t-butylene, pentylene, neo-pentylene, and hexylene. Such divalent (C.sub.1 -C.sub.6)alkyl groups may be substituted with substituents such as alkyl, alkoxy, and hydroxy.

The term "divalent (C.sub.2 -C6)alkenyl" represents a straight or branched divalent alkenyl chain having from two to six carbon atoms. Typical divalent (C.sub.2 -C.sub.6)alkenyl include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl and the like.

The term "divalent (C.sub.2 -C.sub.6)alkynyl" represents a straight or branched divalent alkynyl chain having from two to six carbon atoms. Typical divalent (C.sub.2 C.sub.6)alkynyl include ethynylene, 1-propynylene, 2-propynylene, 1-butynylene, 2-butynylene and the like.

The term "halo" represents chloro, fluoro, bromo or iodo.

The term "halo-(C.sub.1 -C.sub.6)alkyl" represents a straight or branched alkyl chain having from one to six carbon atoms with from 0 to 3 halogen atoms attached to each carbon. Typical halo-(C.sub.1 -C.sub.6)alkyl groups include chloromethyl, 2-bromoethyl, 1- -chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3- chloroisobutyl, iodo-t-butyl, trifluoromethyl, and the like.

The term "halo-(C.sub.1 -C.sub.6)alkoxy" represents a straight or branched alkoxy chain having from one to six carbon atoms with from 0 to 3 halogen atoms attached to each carbon. Typical halo-(C.sub.1 -C.sub.6)alkoxy groups include chloromethoxy, 2-bromoethoxy, 1-chloroisopropoxy, 3-fluoropropoxy, 2,3-dibromobutoxy, 3- chloroisobutoxy, iodo-t-butoxy, trifluoromethoxy, and the like.

The term "heterocyclyl" embraces saturated groups having three to ten ring members and which heterocyclic ring contains a hetero atom selected from oxygen, sulfur and nitrogen, examples of which are piperazinyl, morpholino, piperdyl, methylpiperdyl, azetidinyl, and aziridinyl.

The invention includes salts of the compounds defined by formula I. Although generally neutral, a compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of the above formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an inorganic base. Such salts are known as acid addition and base addition salts.

Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, g-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-l- sulfonate, napththalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid, acetic acid, and methanesulfonic acid.

Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred.

It should be recognized that the particular counterion forming a part of any salt of this invention is not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. The compounds of the present invention are prepared from compounds of the formula: ##STR6##

The compounds of formula II are defined in Table 1.

TABLE 1__________________________________________________________________________Formula II Compounds.sup.aantibiotic R R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 X Y__________________________________________________________________________vancomycin H van H NHCH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.2 (CO)NH.sub.2 H Cl ClA82846A 4-epi 4-epi H NHCH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.2 (CO)NH.sub.2 H H ClA82846B 4-epi 4-epi H NHCH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.2 (CO)NH.sub.2 H Cl ClA82846C 4-epi 4-epi H NHCH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.2 (CO)NH.sub.2 H H HPA-42867-A 4-epi 4-epi H NHCH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.2 (CO)NH.sub.2 H Cl HPA-42867-C 4-epi 4-epi H NHCH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.2 (CO)NH.sub.2 H H HPA-42867-D 4-epi 4-epi H N(CH.sub.3).sub.2 CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.2 (CO)NH.sub.2 H Cl HA83850A H keto H N(CH.sub.3).sub.2 CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.2 (CO)NH.sub.2 H Cl ClA83850B H keto H NHCH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.2 (CO)NH.sub.2 H Cl Clactinoidin actin acos H NH.sub.2 p-OH,m-Cl- benzyl man Cl H phenylavoparcin risto risto man N(CH.sub.3).sub.2 p-rha- p-OH- H H H phenyl phenylgalacardin risto risto man NHCH.sub.3 p-gal--gal- p-OH- H Cl H phenyl phenylheleve- risto risto H NHCH.sub.3 p-CH.sub.3 O--rha- p-OH,m-Cl- H Cl Hcardin or phenyl phenyl manM47767 actin acos H NHCH.sub.3 p-OH,m-Cl- benzyl man Cl H phenyl__________________________________________________________________________ .sup.a Abbreviations for the formula II compounds are: actin = actinosaminyl; acos = acosaminyl; 4epi = 4epi-vancosaminyl; gal = galactosyl; keto = 4keto-vancosaminyl; man = mannose; rha = rhamnosyl; rha--gal = rhamnosylgalactosyl; risto = ristosaminyl; van = vancosaminyl.

In a preferred embodiment of the invention, the formula I compounds are prepared from the A82846 antibiotics (A82846A, A82846B, and A82846C) and PA-42867-A. In a more preferred embodiment, the compounds of the present invention are prepared from A82846B ("A82846B derivatives"). A82846B is represented by formula I compounds wherein R is 4-epi-vancosaminyl, R.sup.1 is hydrogen, R.sup.2 is NHCH.sub.3, R.sup.3 is CH.sub.2 CH(CH.sub.3).sub.2, R.sup.4 is CH.sub.2 (CO)NH.sub.2, R.sup.5 is hydrogen, R.sup.6 is 4-epi-vancosaminyl and X and Y are Cl. A82846B derivatives of the present invention having substituents at position R.sup.7 of formula I are list herein in the manner "R.sup.7 - A82846B". For example, the compound "phenylbenzyl-A82846B" has a phenylbenzyl substituent at position R.sup.7 in formula I.

Preferred formula I compounds include those A82846B derivatives wherein R.sup.7 is --(C.sub.1 -C.sub.12 -alkyl)--R.sup.8, with --CH.sub.3 --R.sup.8 being more preferred, and R.sub.8 is an unsubstituted multicyclic aryl. of this group, naphthylmethyl-A82846B, acenapthlenyl-methyl-A82846B, and fluorenylmethyl-A82846B are more preferred.

Preferred formula I compounds also include those A82846B derivatives wherein R.sup.7 is --(C.sub.1 -C.sub.12 -alkyl)--R.sup.8, with --CH.sub.3 --R.sup.8 being more preferred, and R.sup.8 is an unsubstituted heteroaryl or a heteroaryl substituted by halophenyl. Of this group, �1-oxa!fluorenylmethyl-A82846B, chlorophenylbenzoxazolemethyl-A82846B, and phenylthienylmethyl-A82846B are more preferred.

Further preferred compounds of formula I include those A82846B derivatives wherein R.sup.7 is --(C.sub.1 -C.sub.12 -alkyl)--R.sup.8, with --CH.sub.3 --R.sup.8 being more preferred, and R.sup.8 is a group of the formula: ##STR7## wherein p is 1 and R.sup.11 is selected from (C.sub.2 -C.sub.5)alkenyloxy, halo-(C.sub.1 -C.sub.6)alkoxy, (C.sub.2 -C.sub.10)alkanoyloxy, (C.sub.1 -C.sub.3)alkoxy substituted with (C.sub.1 -C.sub.4)alkylthio, and diphenyl-(C.sub.1 -C.sub.6)alkyl. Of this group, trifluromethoxybenzyl-A82846B, diphenylmethylbenzyl- A82846B, thiopropylethoxybenzyl-A82846B, acetoxybenzyl-A82846B, nonanoyloxybenzyl-A82846B, and tetrafluoroethoxybenzyl-A82846B are more preferred.

Still further preferred compounds of formula I include those A82846B derivatives wherein R.sup.7 is --(C.sub.1 -C.sub.12 -alkyl)--R.sup.8, with --CH.sub.3 --R.sup.8 being more preferred, and R.sup.8 is a group of the formula: ##STR8##

wherein q is 1 to 5; r is 1; Z is selected from a single bond, divalent (C.sub.1 -C.sub.6)alkyl, divalent (C.sub.2 -C6)alkenyl, and --R.sup.15 --(C(R.sup.14)2)s--, wherein R.sup.15 is selected from --O--, --S--, --SO.sub.2 --, and --OC(O)--, each R.sup.14 substituent is hydrogen, and s is 0 or 1; and R.sup.13 is selected from: (C.sub.4 -C.sub.1 O)cycloalkyl; phenyl; and phenyl substituted by nitro, halo, (C.sub.1 -C.sub.10)alkyl, (C.sub.1 -C.sub.10)alkoxy, or halo(C.sub.1 -C.sub.3)alkyl. Of this group, chlorophenylbenzyl-A82846B, phenylbenzyl-A82846B, benzylbenzyl-A82846B, methylphenylbenzyl- A82846B, A82846B, pentylphenylbenzyl-A82846B, methoxyphenylbenzyl-A82846B, pentoxyphenylbenzyl-A82846B, nitrophenoxybenzyl-A82846B, fluorophenylbenzyl-A82846B, phenylethynylbenzyl-A82846B, phenoxybenzyl-A82846B, benzyloxybenzyl-A82846B, nitrophenylbenzyl-A82846B, chlorophenoxybenzyl-A82846B, chlorobenzyloxybenzyl-A82846B, butylphenoxybenzyl-A82846B, trifluoromethylphenoxybenzyl-A82846B, dichlorophenoxybenzyl- A82846B, nitrobenzyloxybenzyl-A82846B, benzoyloxybenzyl-A82846B, cyclohexyloxybenzyl-A82846B, cyclohexanoyloxybenzyl-A82846B, thiophenylbenzyl-A82846B, chlorophenylsulfonylbenzyl-A82846B, and cyclohexylbenzyl-A82846B, cyclohexylethoxybenzyl-A82846B, chlorophenoxynitro-benzyl-A82846B benzylmethoxybenzyl-A82846B, chlorophenoxynitro-benzyl-A82846B, and phenoxymethoxybenzyl-A82846B, benzoyloxy-dimethoxybenzyl-A82846B, cyclohexanoyloxy-dimethylbenzyl-A82846B, trifluoromethylphenylbenzyl-A82846B, butylphenylthiobenzyl-A82846B, and bromophenylbenzyl-A82846B more preferred.

Still further preferred compounds of formula I include A82846B derivatives wherein R.sup.7 is --(C.sub.1 -C.sub.12 -alkyl)--R.sup.8, with --CH.sub.3 --R.sup.8 being more preferred, and R.sup.8 is (C.sub.4 -C.sub.10)cycloalkyl substituted with (C.sub.4 -.sub.10)cycloalkyl. Of this group of compounds, more preferred is cyclohexyl-cyclohexylmethyl-A82846B and butyl-cyclohexylmethyl-A82846B.

Formula I compounds that are prepared from A83850A or A83850B can be prepared from the reduced forms of these compounds. The reduced forms of compounds A83850A or A83850B are produced according to the method described in U.S. Pat. No. 5,187,082, which is incorporated herein by reference.

The compounds of this invention are prepared by reacting a formula II compound with an aldehyde to form an intermediate Schiff's base, which is subsequently reduced with a metal borohydride to give the desired N-alkyl amine.

In the first method of making the compounds of this invention, hereinafter Method A (described in Examples 1 and 2), the reaction for the formation of the Schiff's base is carried out under an inert atmosphere, such as nitrogen or argon, in a polar solvent, such as dimethylformamide (DMF) or methanol (MeOH), or a mixture of polar solvents, such as a mixture of dimethylformamide and methanol, at a temperature of about 25.degree. C. to about 100.degree. C. The reaction is preferably carried out at a temperature from about 60.degree. C. to about 70.degree. C. for 30 minutes to 2 hours in a mixture of dimethylformamide and methanol, or in methanol. The intermediate Schiff's base is then reduced, preferably without isolation, to produce the corresponding N-alkyl derivative(s). The reduction of the Schiff's base can be effected using a chemical reducing agent such as a metal borohydride, for example, sodium borohydride or sodium cyanoborohydride. The reduction reaction can be carried out in a polar organic solvent, such as dimethylformamide, methanol, or a mixture of polar solvents, such as a mixture of dimethylformamide and methanol. The reduction reaction can be carried out at a temperature of about 25.degree. C. to about 100.degree.C. for 1 to 5 hours. The reduction reaction is preferably carried out using an excess of sodium cyanoborohydride in a mixture of dimethylformamide and methanol or in methanol at about 60.degree. C. to about 70.degree. C for 1 to 2 hours. Method A is preferable for benzylic aldehydes.

In a second method of making compounds of this invention, hereinafter Method B (described in Example 3), the formation of the Schiff's base is carried out under an inert atmosphere, such as nitrogen or argon, in the presence of the reducing agent, sodium cyanoborohydride, in a polar solvent, such as dimethylformamide, methanol, or a mixture of polar solvents, such as a mixture of dimethylformamide and methanol, at a temperature of about 25.degree. C. to about 100.degree. C for 1 to 5 hours. The reaction is preferably carried out at a temperature from about 60.degree. C. to about 70.degree. C. for 1 to 2 hours in a mixture of dimethylformamide and methanol. Method B is preferable for non- benzylic aldehydes.

In a third method of making compounds of this invention, hereinafter Method C (described in Example 4), the formation of the Schiff's base is carried out a) under an inert atmosphere, such as nitrogen or argon, b) in the presence of the reducing agent, such as a metal borohydride, with sodium cyanoborohydride being most preferred, or a homogenous or heterogeneous catalytic hydrogenation agent(s), such as Crabtree's catalyst, Wilkinson's catalyst, palladium on carbon, platinum on carbon, or rhodium on carbon, c) in a polar solvent, such as dimethylformamide, methanol, or a mixture of polar solvents, such as a mixture of dimethylformamide and methanol, and d) at a temperature of about 25.degree. C. to about 100.degree. C. The reaction is preferably carried out at a temperature from about 60.degree. C. to about 70.degree. C. in methanol. The reaction is allowed to continue for about 20 to about 28 hours, at which time the reaction mixture is adjusted to about pH 7.5 to about pH 10, with a pH of about 9.0 being preferred. The pH adjustment halts the reaction. Because the product is marginally soluble in polar solvents, the solvent of the reaction can be exchanged to an alcohol such as ethanol, butanol, or isopropanol, with isopropanol being preferred, to allow for precipitation of the product. Method C is a preferred method of this invention in view of the increased product yield provided by this method. Another advantage of this reaction scheme is the increased ratio of preferred product (products substituted at the amino group of the sugar denoted as R.sup.1 in Formula II compounds) to other products (products that are substituted at the amino groups of substitutents denoted as R and/or R.sup.3 of the Formula II compounds). By allowing the reaction to proceed for an extended period of time, such as 20 to 28 hours, products that are monosubstituted at positions denoted as R and R.sup.3 in the Formula II compounds are converted to disubstituted forms, making the preferred monosubstituted derivative easier to isolate.

The products of the reaction, obtained from either Method A, B, or C can be purified by preparative reverse phase HPLC utilizing Waters C13 Nova-Pak columns with ultraviolet light (UV; 235 nm or 280 nm) detection. A 30 minute gradient solvent system consisting of 95% aqueous buffer/5% CH.sub.3 CN at time=0 minutes to 20% aqueous buffer/80% CH.sub.3 CN at time=30 minutes is typically used, where the aqueous buffer is either TEAP (0.5% aqueous triethylamine adjusted to pH=3 with phosphoric acid) or TFA (0.1% trifluoroacetic acid overall concentration).

HPLC analysis of the reaction mixtures and final purified products can be accomplished utilizing a Waters C18 MicroBonda-Pak column (typically 3.9.times.300 mm steel) or Waters Nova-pak C18 RCM column (8.times.100 mm) with UV (235 nm or 280 nm) detection. A 30 minute gradient solvent system consisting of 95% aqueous buffer/5% CH.sub.3 CN at time=0 minute to 20% aqueous buffer/80% CH.sub.3 CN at time=30 minutes is typically used, where the aqueous buffer is either TEAP (0.5% aqueous triethylamine adjusted to pH=3 with phosphoric acid) or TFA (0.1% trifluoroacetic acid overall concentration).

The ratio of the aldehyde to the formula II compound and the reaction conditions determines the products of the reaction. The monosubstituted derivatives are those derivatives where a hydrogen atom of the amino group at position R.sup.1 in formula II is replaced by one of the substituents listed above for formula I. When using Methods A or B, described above, the formation of monosubstituted derivatives substituted at the amino group of the amino sugar at position R.sup.1 in the formula II compounds is favored by using a slight excess of aldehyde, a shorter reaction time, and a lower temperature. As noted above, Method C favors the formation of the monosubstituted derivative. The monosubstituted derivative is preferred. A large excess of the aldehyde favors the formation of disubstituted and trisubstituted derivatives of the formula II compounds. The disubstituted derivatives are the derivatives where a hydrogen atom at two of the locations selected from the amino .group at position R.sup.3 and the amino group of the amino sugars designated as R or R.sup.1 in formula II, are replaced by the reduced aldehyde moiety. The trisubstituted derivatives are the derivatives where a hydrogen atom at three of the locations selected from the amino group at position R.sup.3, and the amino group of the amino sugars designated as R or R.sup.1 in formula II, are replaced by the reduced aldehyde moiety.

Examples of compounds that have been prepared and are illustrative of the formula I compounds are listed in Tables 2A and 2B. Table 2A lists compounds prepared by reacting an aldehyde with the glycopeptide A82846B. Table 2A lists the sidechain substitutions on the amino group of the 4-epi-vancosaminyl sugar of the 4-epi-vancosaminyl-O-glycosyl disaccharide of the A82846B compound. All of the compounds listed are monosubstituted derivatives.

Table 2B lists those compounds that were prepared by reacting an aldehyde with a variety of glycopeptide antibiotics other than A82846B. The compounds of Table 2B are monosubstituted at the amino group of the amino sugar designated as R.sup.1 in formula II with the sidechain listed. All of the compounds listed are monosubstituted derivatives.

TABLE 2A______________________________________COMPOUND NO. SIDECHAIN______________________________________1 2-naphthylmethyl2 4-phenylbenzyl3 1-naphthylmethyl4 4-phenoxybenzyl5 4-benzyloxybenzyl6 4-trifluoromethoxybenzyl7 4-allyloxybenzyl8 4-nonyloxybenzyl9 2-methoxy-1-naphthylmethyl10 4-dodecyloxybenzyl11 9-phenanthranylmethyl12 4-decyloxybenzyl13 9-anthranylmethyl14 4-�phenylethynyl!4-phenylbenzyl15 4-methoxy-1-naphthylmethyl16 1-pyrenylmethyl17 9-�10-methyl!anthranylmethyl18 9-�10-chloro!anthranylmethyl19 2-benzthienylmethyl20 4-�4-hydroxyphenyl!benzyl21 4-�4-octylphenyl!benzyl22 4-�4-pentylphenyl!benzyl23 4-�4-octyloxyphenyl!benzyl24 3-pyridylmethyl25 5-nitro-1-naphthylmethyl26 4-pyridylmethyl27 4-quinolylmethyl28 3-quinolylmethyl29 4-stilbenzyl30 2-quinolylmethyl31 2-pyridylmethyl32 2-fluorenylmethyl33 4-phenoxyphenethyl34 4-�4-pentylcyclohexyl!benzyl35 4 -benzylphenethyl36 4-�4-biphenyl!benzyl37 4-trifluoromethylbenzyl38 trans-cinnamyl39 4-�1-oxa!fluorenylmethyl40 4-�4-pentoxyphenyl!benzyl41 4-thiomethylbenzyl42 2,3-�2-methyl-3-�4-t-butylphenyl!!propenyl43 9-(1-methyl)-acridinylmethyl44 2-hydroxy-1-naphthylmethyl45 4-�2-phenyl-6-methoxy!quinoylmethyl46 4-diphenylmethylbenzyl47 3,4 cyclohexenylmethyl48 3,4-methylenedioxylbenzyl49 3-phenoxybenzyl50 4-benzylbenzyl51 3-benzyloxy-6-methoxy benzyl52 4-benzyloxy-3-methoxybenzyl53 3,4-dibenzyloxybenzyl54 4-�4-methoxyphenyl!benzyl55 4-�3-cyanopropoxy!benzyl56 3,4-ethylenedioxybenzyl57 4-�4-nitrophenoxy!benzyl58 2,3-methylenedioxybenzyl59 2-benzyloxyphenethyl60 2-ethoxy-1-naphthylmethyl61 2-benzylfurylmethyl62 3-phenoxyphenethyl63 4-phenoxyphenethyl64 4-�4-nitrophenyl!benzyl65 6-methoxy-2-naphthylmethyl66 3-methyl-5-thienylmethyl67 5-phenyl-2-thienylmethyl68 4-benzyloxyphenethyl69 3-benzyloxyphenethyl70 4-�2-nitrophenoxy!benzyl71 5-�4-methoxyphenyl!-2-thienylinethyl72 4-difluormethoxybenzyl73 2,3,4,5,6-pentamethylbenzyl74 5-iodo-2-thienylmethyl75 4-�2-�2-chloroethoxy!ethoxy!benzyl76 3,4-dimethylbenzyl77 3-acetoxybenzyl78 4-nitrobenzyl79 4-phenylethynylbenzyl80 4-�2-chloro-6-fluorobenzyloxy!benzyl81 4-�3,4-dichlorophenoxy!benzyl82 S-�2,3-dihydrobenzfuryl!methyl83 4-�2-�N,N-diethylamino!ethoxy!benzyl84 2-bicyclo�2.1.2!heptylmethyl85 2-hydroxy-5-phenylbenzyl86 3-�4-chlorophenoxy!benzyl87 4-�3-chlorophenoxy!-3-nitrobenzyl88 4-�2-chlorophenoxy!-3-nitrobenzyl89 3,5-dimethylbenzyl90 4-�4-ethylphenyl!benzyl91 3-phenylbenzyl92 4-�3-fluorophenyl!benzyl93 4-�4-chlorobenzyloxy!benzyl94 4-�4-chlorophenoxy!-3-nitrobenzyl95 4-�4-methylphenoxy!benzyl96 4-�4-t-butylphenoxy!benzyl97 4-�4-methylphenyl!benzyl98 4-�4-methoxyphenoxy!benzyl99 4-acetoxy-3-methoxybenzyl100 4-�(2-phenyl)ethyl!benzyl101 3-�5-phenyl!pyridinylmethyl102 4-�2-nitrophenyl!benzyl103 2-�1-hydroxy!fluorenylmethyl104 4-benzyl-3-methoxybenzyl105 4-�cyclohexylmethoxy!-3-ethoxybenzyl106 3-�3,3'-dichlorophenoxy!benzyl107 4-�4-propylphenyl!benzyl108 4-thiophenylbenzyl109 4-�alpha-hydroxybenzyl!benzyl110 2,2-dinitro-4-thiophenebenzyl111 3-�3-trifluoromethylphenoxy!benzyl112 4-�t-butylethynyl!benzyl113 4-phenoxy-3-methoxy-benzyl114 4-�3-trifluoromethylphenoxy!-3-nitrobenzyl115 2-phenylthiobenzyl116 2-�4-chlorophenyl!-6-benzoxazolemethyl117 4-�alpha-methoxybenzyl!benzyl118 4-cyclohexylbenzyl119 3-�3,4-dichlorophenoxy!benzyl120 acenaphthlenylmethyl121 4-�1,1,2,2-tetrafluoroethoxy!benzyl122 4-benzoyloxy-3,3-dimethoxybenzyl123 3-�cyclohexylmethoxy!benzyl124 4-cyclohexyloxybenzyl125 3-�2-quinoylmethoxy!benzyl126 4-�alpha-ethoxybenzyl!benzyl127 4-�cyclohexylethoxy!benzyl128 4-�alpha-propoxybenzyl!benzyl129 4-�4-methyl-1-piperidino!benzyl130 2-thiophene-1,2-cyclohexenylmethyl131 4-�4-nitrobenzyloxy!benzyl132 3-�4-trifluoromethylphenoxy!benzyl133 3-benzoyl-2,4-dichlorobenzyl134 4-�2-�2-thiopropyl!ethoxy!benzyl135 4-�2-methyl-1-piperidino!benzyl136 4-hydroxybenzyl137 4-�2-pyridyl!benzyl138 4-acetoxybenzyl139 5,6-benzonorbornylmethyl140 3-phenylcyclopentylmethyl141 1-adamantylmethyl142 3-�cyclohexylmethoxy!-4-methoxybenzyl143 2-�2-glucosyl!benzyl144 4-�4-pentoxybiphenyl!benzyl145 3,4-dihydroxybenzyl146 4-�4-methylpiperazino!benzyl147 4-morpholinobenzyl148 4-�4-chlorophenylsulfonyl!benzyl149 4-methylsulfonyloxybenzyl150 4-benzoyloxybenzyl151 5-phenyl-3-pyridinylmethyl152 4-�N,N-bis(2-chloroethyl)amino!benzyl153 3-cyclohexyloxybenzyl154 4-�2-t-butoxyethoxy!benzyl155 3,3-dichloro-4-hydroxy-benzyl156 1,2,3,4,-tetrahydro-9-anthranylmethyl157 4-cyclohexanoyloxybenzyl158 4-nonanoyloxybenzyl159 4-�phenylsulfinyl!benzyl160 4-anilinobenzyl161 cyclohexylmethyl162 3-benzoyloxybenzyl163 3-nonanoyloxybenzyl164 4-�cyclohexyl!cyclohexylmethyl165 3-cyclohexanoyloxybenzyl166 4-�cyclohexanoyloxy!-3,3-�dimethoxy!benzyl167 4-�nonanoyloxy!-3,3-�dimethoxy!benzyl168 1,2,3,4-tetrahydro-6-naphthylmethyl169 2-hydroxybenzyl170 �2-�6,6-dimethyl-bicyclo�3.1.1!hept-2-enyl!methyl171 1-cyclohexenyl-4-isopropylmethyl172 4-�4-methoxyphenyl!butyl173 4-��2,3,4,5,6-pentamethyl!phenylsulfonyloxy!benzyl174 4-�1-pyrrolidinosulfonyl!benzyl175 3-�4-methoxyphenyl!propyl176 8-phenyloctyl177 4-�2,3-dihydroxypropoxy!benzyl178 4-�N-methylanilino!benzyl179 2-�2-napthyl!ethyl189 6-methyl-2-naphthylmethyl190 cis-bicyclo�3.3.0!octane-2-methyl191 2-tridecynyl192 4-butyl-2-cyclohexylmethyl193 4-�(4-fluorobenzoyl)amino!benzyl194 4-�(3-fluorobenzoyl)amino!benzyl195 8-phenoxyoctyl196 6-phenylhexyl197 10-phenyldecyl198 8-bromooctyl199 11-tridecynyl200 8-�4-methoxyphenoxy!octyl201 8-�4-phenylphenoxy!octyl202 8-�4-phenoxyphenoxy!octyl203 3-�3-trifluoromethylphenoxy!benzyl204 10-undecenyl205 4-cyclohexylbutyl206 4-phenyl-2-fluorobenzyl207 7-hexadecynyl208 3-�cyclopentyl!propyl209 4-�2-methylphenyl!benzyl210 4-�phenylazo!benzyl211 4-�4-flurophenyl!benzyl212 3-nitro-4-�4-nitrophenyl!benzyl213 3-nitro-4-�2-nitrophenyl!benzyl214 9-decenyl215 4-�3,4-dimethoxyphenyl!benzyl216 4-�4-trifluromethylphenyl!benzyl217 5-hexenyl218 4-�2-thienyl!benzyl219 4-�6-phenylhexyloxy!benzyl220 9,10-dihydro-2-phenantrene methyl221 4-�3,4-dimethylphenyl!benzyl222 4-�4-methylphenyl!-2-methylbenzyl223 4-�3-phenylpropyloxy!benzyl224 4-�3-methylphenyl!benzyl225 4-�4-methylphenyl!-3-methylbenzyl226 4-�4-pentenyloxy!benzyl227 4-�1-heptynyl!benzyl228 3-�4-t-butyl-phenylthio!benzyl229 4-�4-chlorophenyl!benzyl230 4-�4-bromophenyl!benzyl231 4-�4-cyanophenyl!benzyl232 4-�1-nonynyl!benzyl233 4-�11-tridecynyloxy!benzyl234 12-phenyldodecyl235 6-phenyl-5-hexynyl236 11-phenyl-10-undecynyl237 4-�2-methylphenyl!-3-methylbenzyl238 3-�2-thienyl!-2-thienylmethyl239 4-�benzyloxymethyl!cyclohexylmethyl240 4-�4-chlorophenoxy!benzyl241 4-�benzyl!cyclohexylmethyl242 4-benzoylbenzyl243 4-�phenoxymethyl!benzyl244 4-�4-chlorobenzyl!benzyl______________________________________ TABLE 2B______________________________________COMPOUND GLYCOPEPTIDENO. CORE SIDECHAIN______________________________________180 vancomycin 1-napthylmethyl181 vancomycin 4-phenylbenzyl182 A82846A 4-phenylbenzyl183 A82846C 4-phenylbenzyl184 A82846C 4-phenoxybenzyl185 PA-42867 A 4-phenylbenzyl186 reduced A838450A 4-phenylbenzyl187 alpha-avoparcin 4-phenylbenzyl188 beta-avoparcin 4-phenylbenzyl______________________________________

The formula I compounds have in vitro and in vivo activity against Gram-positive pathogenic bacteria. The minimal inhibitory concentrations (MIC) at which the formula I compounds inhibit certain bacteria are given in Table 3. The MIC's were determined using a standard broth micro-dilution assay.

TABLE 3__________________________________________________________________________In Vitro Activity of Formula I CompoundsMIC (mcg/ml)/Compound__________________________________________________________________________Organism vancomycin A82846A A82846B A82846C 1 2 3 4 5 6__________________________________________________________________________Staphylococcus aureus 446 0.5 0.25 0.25 0.5 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 1 0.5Staphylococcus aureus 489 0.125 0.5 .ltoreq..06 .ltoreq..06 .ltoreq.0.06 0.25 .ltoreq.0.06 .ltoreq.0.06 0.5 0.25Staphylococcus aureus 447 0.5 0.25 0.25 0.5 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.25 0.5 0.5Staphylococcus aureus X400 0.5 0.125 0.125 0.25 .ltoreq.0.06 1 .ltoreq.0.06 .ltoreq.0.06 1 1Staphylococcus aureus X778 0.5 0.125 0.125 0.5 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.5 0.25Staphylococcus aureus 491 1 0.25 0.25 1 2 .ltoreq.0.06 0.5 .ltoreq.0.06 0.5 0.125Staphylococcus aureus S13E 0.5 0.125 0.125 0.25 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 1 0.25Staphylococcus aureus SA1199 0.5 0.125 0.125 0.25 .ltoreq.0.06 0.5 0.125 .ltoreq.0.06 1 0.25Staphylococcus aureus SA1199A 0.125 .ltoreq..06 .ltoreq..06 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus SA1199B 0.5 .ltoreq..06 0.125 .ltoreq..06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus haemolyticus 105 16 0.5 1 1 4 2 4 0.5 2 0.5Staphylococcus haemolyticus 415 8 1 4 2 4 1 8 0.5 1 0.5Staphylococcus epidermidis 270 16 0.25 0.25 0.125 8 8 8 .ltoreq.0.06 0.25 0.125Entercoccus faecium 180 >64 16 8 16 0.5 0.25 0.5 0.125 .ltoreq.0.06 0.125Entercoccus faecium 180-1 0.5 0.125 0.125 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 2041 2 0.125 0.25 0.5 0.125 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 276 1 0.125 0.125 0.5 .ltoreq.0.06 0.5 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus gallinarum 245 4 0.125 0.25 0.5 4 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Haemophilus influenzae RD >64 >64 >64 >64 >64 >64Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 0.5 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 0.25 .ltoreq..06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 7 8 9 10 11 12 13 14 15 16 17__________________________________________________________________________Staphylococcus aureus 446 8 2 2 16 4 32 2 4 1 4 2Staphylococcus aureus 489 2 4 0.5 >64 1 8 1 2 .ltoreq.0.06 0.5 1Staphylococcus aureus 447 4 8 4 >64 4 32 8 8 2 4 8Staphylococcus aureus X400 1 8 0.5 >64 0.5 8 1 4 0.25 0.5 0.5Staphylococcus aureus X778 0.25 8 0.25 16 0.25 8 2 4 0.25 2 0.5Staphylococcus aureus 491 2 4 0.5 16 1 4 2 1 0.25 1 2Staphylococcus aureus S13E 2 8 0.5 8 0.5 8 0.25 4 0.5 1 1Staphylococcus aureus SA1199 4 2 0.25 8 2 8 0.5 8 0.25 2 4Staphylococcus aureus SA1199A .ltoreq.0.06 2 .ltoreq.0.06 4 .ltoreq.0.06 8 .ltoreq.0.06 0.5 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus SA1199B 1 0.25 8 2 4 8 0.25 1 1Staphylococcus haemolyticus 105 8 8 4 >64 4 16 8 4 0.5 8 8Staphylococcus haemolyticus 415 16 8 4 >64 2 32 1 8 2 4 8Staphylococcus epidermidis 270 4 4 16 >64 2 0.125 8 4 1 2 4Entercoccus faecium 180 2 1 1 8 1 4 2 1 0.5 1 2Entercoccus faecium 180-1 .ltoreq.0.06 0.5 .ltoreq.0.06 4 .ltoreq.0.06 4 .ltoreq.0.06 1 .ltoreq.0.06 0.125 .ltoreq.0.06Entercoccus faecalis 2041 0.125 4 0.25 16 0.5 16 0.125 2 .ltoreq.0.06 0.5 0.25Entercoccus faecalis 276 1 4 0.26 18 1 4 0.5 4 .ltoreq.0.06 2 0.5Entercoccus gallinarum 245 0.5 8 0.25 8 .ltoreq.0.06 32 0.25 0.25 .ltoreq.0.06 1 0.5Haemophilus influenzae RD 16 >64 .ltoreq.0.06 64 32 32Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.5 .ltoreq.0.06 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 18 19 20 21 22 23 24 25 26 27 28__________________________________________________________________________Staphylococcus aureus 446 2 0.5 0.5 >64 16 38 0.5 0.5 0.25 2 0.25Staphylococcus aureus 489 1 0.25 0.5 32 8 >64 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus 447 8 1 4 >64 16 16 1 0.25 2 8 1Staphylococcus aureus X400 1 0.25 0.5 32 8 16 0.25 .ltoreq.0.06 0.25 0.5 .ltoreq.0.06Staphylococcus aureus X778 0.5 0.25 0.25 32 8 16 0.125 .ltoreq.0.06 0.125 0.5 .ltoreq.0.06Staphylococcus aureus 491 2 2 1 64 8 16 0.5 0.125 0.5 1 0.25Staphylococcus aureus S13E 1 .ltoreq.0.06 .ltoreq.0.06 64 16 16 .ltoreq.0.06 .ltoreq.0.06 0.25 0.125 .ltoreq.0.06Staphylococcus aureus SA1199 2 0.5 2 64 16 16 0.5 .ltoreq.0.06 1 0.5 0.125Staphylococcus aureus SA1199A .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 16 4 16 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus SA1199B 2 1 0.5 64 16 16 2 0.125 0.5 1 0.125Staphylococcus haemolyticus 105 16 4 8 >64 16 4 4 1 4 16 4Staphylococcus haemolyticus 415 8 8 4 64 16 16 .ltoreq.0.06 32 8 8 8Staphylococcus epidermidis 270 8 2 2 32 4 64 1 0.5 1 4 1Entercoccus faecium 180 2 1 1 8 1 >64 4 0.5 4 8 1Entercoccus faecium 180-1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 8 .ltoreq.0.06 32 .ltoreq.0.06 .ltoreq.0.06 0.25 0.5 .ltoreq.0.06Entercoccus faecalis 2041 0.25 .ltoreq.0.06 .ltoreq.0.06 32 2 32 .ltoreq.0.06 0.25 0.25 0.125 0.25Entercoccus faecalis 276 1 .ltoreq.0.06 0.25 64 4 32 0.25 0.25 .ltoreq.0.06 0.5 .ltoreq.0.06Entercoccus gallinarum 245 1 .ltoreq.0.06 0.25 8 1 8 0.25 .ltoreq.0.06 0.125 0.5 0.25Haemophilus influenzae RD 16 32 8 >64 64 >64 >64 32 >64 >64 >64Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 2 .ltoreq.0.06 1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.5 0.25 0.5 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 29 30 31 32 33 34 35 36 37 38 39__________________________________________________________________________Staphylococcus aureus 446 1 1 0.5 1 4 32 0.5 8 0.5 0.5 0.125Staphylococcus aureus 489 1 0.125 .ltoreq.0.06 1 .ltoreq.0.06 8 .ltoreq.0.06 2 0.125 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus 447 0.25 2 0.5 0.5 0.125 8 0.125 2 0.125 0.125 0.25Staphylococcus aureus X400 0.25 .ltoreq.0.06 0.125 0.5 0.25 32 0.25 4 0.25 1 .ltoreq.0.06Staphylococcus aureus X778 .ltoreq.0.06 .ltoreq.0.06 0.125 0.5 0.5 16 .ltoreq.0.06 2 .ltoreq.0.06 0.5 .ltoreq.0.06Staphylococcus aureus 491 0.25 0.5 0.5 0.25 0.125 8 0.125 1 0.25 0.5 0.25Staphylococcus aureus S13E 1 0.125 0.25 1 .ltoreq.0.06 16 .ltoreq.0.06 2 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus SA1199 0.25 0.5 0.25 1 1 16 0.25 4 0.25 1 .ltoreq.0.06Staphylococcus aureus SA1199A .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 2 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus SA1199B 0.25 0.125 0.25 0.125 0.125 16 0.25 4 .ltoreq.0.06 0.125 .ltoreq.0.06Staphylococcus haemolyticus 105 4 4 4 4 2 32 2 4 0.25 1 2Staphylococcus haemolyticus 415 1 16 16 4 8 >64 4 8 1 1 4Staphylococcus epidermidis 270 0.5 2 1 1 2 16 1 2 0.25 0.5 0.25Entercoccus faecium 180 0.25 2 4 0.25 2 4 1 0.25 0.125 .ltoreq.0.06 0.5Entercoccus faecium 180-1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 2 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 2041 0.25 .ltoreq.0.06 0.25 0.25 .ltoreq.0.06 8 .ltoreq.0.06 1 0.125 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 276 0.25 0.25 0.25 0.125 .ltoreq.0.06 16 .ltoreq.0.06 2 1 0.5 .ltoreq.0.06Entercoccus gallinarum 245 0.25 .ltoreq.0.06 0.25 0.25 0.25 4 .ltoreq.0.06 0.25 0.125 0.125 .ltoreq.0.06Haemophilus influenzae RD >64 >64 >64 >64Escherichia coli EC14 64 >64 >64 32 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 40 41 42 43 44 45 46 47 48 49 50__________________________________________________________________________Staphylococcus aureus 446 4 2 1 0.5 0.25 1 1 0.125 0.125 0.5 0.5Staphylococcus aureus 489 4 .ltoreq.0.06 0.5 .ltoreq.0.06 .ltoreq.0.06 0.5 1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus 447 2 0.25 0.5 2 1 16 2 2 2 1 0.5Staphylococcus aureus X400 4 .ltoreq.0.06 1 0.25 .ltoreq.0.06 0.25 2 .ltoreq.0.06 .ltoreq.0.06 0.125 0.125Staphylococcus aureus X778 4 0.125 1 .ltoreq.0.06 .ltoreq.0.06 0.25 2 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.125Staphylococcus aureus 491 4 0.5 0.5 1 0.125 1 2 0.5 0.25 0.125 0.5Staphylococcus aureus S13E 4 .ltoreq.0.06 0.5 0.25 0.25 0.5 2 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.125Staphylococcus aureus SA1199 4 .ltoreq.0.06 1 0.5 0.25 2 2 0.5 0.25 2 1Staphylococcus aureus SA1199A 0.5 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.5 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus SA1199B 8 0.25 2 0.5 0.25 1 2 0.25 1 1 2Staphylococcus haemolyticus 105 2 2 2 4 2 16 2 4 2 1 0.5Staphylococcus haemolyticus 415 2 4 1 8 4 8 2 16 8 1 1Staphylococcus epidermidis 270 1 0.25 0.5 2 0.5 8 2 1 1 1 0.5Entercoccus faecium 180 1 0.25 0.25 4 8 1 0.5 2 1 0.25 0.25Entercoccus faecium 180-1 2 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 2041 1 .ltoreq.0.06 0.125 0.5 .ltoreq.0.06 0.125 1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 276 2 .ltoreq.0.06 8 0.5 0.125 0.25 0.5 .ltoreq.0.06 .ltoreq.0.06 0.25 0.25Entercoccus gallinarum 245 11 .ltoreq.0.06 1 0.5 0.5 0.5 0.25 16 1 1 1Haemophilus influenzae RD >64 >64 >64 >64 >64 >64 >64Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 51 52 53 54 55 56 57 58 59 60 61__________________________________________________________________________Staphylococcus aureus 446 0.25 .ltoreq.0.06 2 1 0.5 0.5 0.25 0.25 0.5 1 0.5Staphylococcus aureus 489 .ltoreq.0.06 0.5 2 .ltoreq.0.06 1 1 0.5 .ltoreq.0.06 0.125 0.5 1Staphylococcus aureus 447 0.5 .ltoreq.0.06 4 0.25 4 2 0.5 1 1 2 2Staphylococcus aureus X400 .ltoreq.0.06 .ltoreq.0.06 4 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.125 .ltoreq.0.06 0.25 0.5 .ltoreq.0.06Staphylococcus aureus X778 0.5 0.5 2 .ltoreq.0.06 0.5 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.25 0.125Staphylococcus aureus 491 0.25 2 0.5 0.5 0.125 1 0.5Staphylococcus aureus S13E 0.5 0.5 2 0.5 0.5 0.125 .ltoreq.0.06 .ltoreq.0.06 0.125 0.25 0.125Staphylococcus aureus SA1199 0.5 2 2 0.5 0.5 0.5 1 1 .ltoreq.0.06 0.5 0.25Staphylococcus aureus SA1199A .ltoreq.0.06 .ltoreq.0.06 1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus SA1199B 1 2 2 1 0.5 0.5 0.125 0.125 0.5 0.5 0.25Staphylococcus haemolyticus 105 0.5 0.5 2 2 4 4 8 4 8 >64 64Staphylococcus haemolyticus 415 1 1 2 1 16 16 1 8 8 16 8Staphylococcus epidermidis 270 0.5 0.5 2 0.25 1 1 0.5 4 1 2 1Entercoccus faecium 180 0.5 2 1 1 2 2 0.5 8 8 4 2Entercoccus faecium 180-1 .ltoreq.0.06 .ltoreq.0.06 2 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 2041 .ltoreq.0.06 0.5 1 .ltoreq.0.06 0.125 0.25 .ltoreq.0.06 0.5 0.5 0.25 .ltoreq.0.06Entercoccus faecalis 276 .ltoreq.0.06 0.125 8 1 0.5 0.25 0.5 0.5 0.125 0.5 0.25Entercoccus gallinarum 245 1 1 2 0.5 16 16 2 0.5 1 16 8Haemophilus influenzae RD >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 62 63 64 65 66 67 68 69 70 71 72__________________________________________________________________________Staphylococcus aureus 446 2 0.5 0.25 2 0.25 0.25 0.125 1 0.125 4 2Staphylococcus aureus 489 2 8 0.25 0.125 1 .ltoreq.0.06 0.125 0.25 .ltoreq.0.06 0.25 .ltoreq.0.06Staphylococcus aureus 447 0.5 1 0.5 1 1 1 0.25 1 0.5 4 1Staphylococcus aureus X400 .ltoreq.0.06 .ltoreq.0.06 0.125 0.125 0.125 1 .ltoreq.0.06 0.5 .ltoreq.0.06 1 0.125Staphylococcus aureus X778 0.5 0.125 2 0.5 .ltoreq.0.06 0.25 .ltoreq.0.06 0.125 .ltoreq.0.06 2 0.25Staphylococcus aureus 491 0.125 0.5 0.125 0.5 0.25 1 0.125 1 0.5 2 0.25Staphylococcus aureus S13E 0.5 0.125 2 0.5 .ltoreq.0.06 0.25 .ltoreq.0.06 0.25 .ltoreq.0.06 1 .ltoreq.0.06Staphylococcus aureus SA1199 0.25 0.25 1 0.5 0.25 1 .ltoreq.0.06 1 .ltoreq.0.06 1 1Staphylococcus aureus SA1199A .ltoreq.0.06 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.25 .ltoreq.0.06Staphylococcus aureus SA1199B 1 0.5 0.125 2 0.25 1 0.5 2 .ltoreq.0.06 4 .ltoreq.0.06Staphylococcus haemolyticus 105 2 4 64 64 64 64 2 4 2 16 1Staphylococcus haemolyticus 415 4 8 2 4 8 2 4 8 2 8 4Staphylococcus epidermidis 270 1 1 0.5 1 1 0.5 2 2 0.25 2 0.25Entercoccus faecium 180 4 16 0.125 0.5 2 0.25 2 4 0.5 4 0.5Entercoccus faecium 180-1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.25 .ltoreq.0.06Entercoccus faecalis 2041 .ltoreq.0.06 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.25 .ltoreq.0.06 1 .ltoreq.0.06Entercoccus faecalis 276 0.5 0.5 0.5 0.5 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.5 .ltoreq.0.06 2 .ltoreq.0.06Entercoccus gallinarum 245 4 8 2 4 8 2 4 8 2 8 4Haemophilus influenzae RD >64 >64 >64 >64 >64 >64 >64 >64 16 >64 32Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 73 74 75 76 77 78 79 80 81 82 83__________________________________________________________________________Staphylococcus aureus 446 0.25 4 2 0.25 .ltoreq.0.06 2 2 4 2 2 1Staphylococcus aureus 489 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 2 2 2 0.25 0.25Staphylococcus aureus 447 0.25 1 1 0.5 1 .ltoreq.0.06 2 2 2 4 2Staphylococcus aureus X400 0.5 .ltoreq.0.06 .ltoreq.0.06 0.25 .ltoreq.0.06 .ltoreq.0.06 0.25 4 1 0.25 2Staphylococcus aureus X778 1 .ltoreq.0.06 .ltoreq.0.06 0.25 .ltoreq.0.06 .ltoreq.0.06 2 0.5 1 0.5 0.5Staphylococcus aureus 491 0.25 0.125 0.25 0.25 0.25 4 1 1 1 0.5Staphylococcus aureus S13E 0 0 0.125 4 1 0.5 .ltoreq.0.06 0.125Staphylococcus aureus SA1199 0.5 .ltoreq.0.06 2 .ltoreq.0.06 .ltoreq.0.06 0.125 1 2 2 0.25 2Staphylococcus aureus SA1199A 0.25 .ltoreq.0.06 .ltoreq.0.06 0.125 .ltoreq.0.06 .ltoreq.0.06 0.125 1 0.5 0.5 0.25Staphylococcus aureus SA1199B .ltoreq.0.06 1 0.5 0.25 0.125 .ltoreq.0.06 1 1 1 1 1Staphylococcus haemolyticus 105 0.5 4 2 2 2 2 4 4 1 8 2Staphylococcus haemolyticus 415 2 4 4 4 8 16 4 4 4 8 4Staphylococcus epidermidis 270 0.125 0.5 0.5 0.25 0.5 0.5 0.5 2 1 4 2Entercoccus faecium 180 0.5 0.5 0.5 0.5 8 1 .ltoreq.0.06 0.125 .ltoreq.0.06 2 8Entercoccus faecium 180-1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.125 0.125 0.125Entercoccus faecalis 2041 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.5 0.5Entercoccus faecalis 276 0.25 .ltoreq.0.06 .ltoreq.0.06 0.25 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus gallinarum 245 2 .ltoreq.0.06 4 4 0.25 0.125 .ltoreq.0.06 .ltoreq.0.06 0.25 0.125 0.5Haemophilus influenzae RD 0.25 0.5 2 >64 64 16 16 16 64 >64Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 84 85 86 87 88 89 90 91 92 93 94__________________________________________________________________________Staphylococcus aureus 446 0.5 0.125 1 1 0.25 0.5 2 0.5 2 2 1Staphylococcus aureus 489 .ltoreq.0.06 0.25 1 0.5 0.5 0.25 2 .ltoreq.0.06 .ltoreq.0.06 0.25 2Staphylococcus aureus 447 4 0.125 0.5 0.5 0.25 1 1 0.5 0.5 0.25 0.5Staphylococcus aureus X400 .ltoreq.0.06 0.25 1 1 .ltoreq.0.06 0.25 1 0.5 0.5 .ltoreq.0.06 1Staphylococcus aureus X778 .ltoreq.0.06 0.25 1 2 0.5 0.25 1 .ltoreq.0.06 0.25 1 0.5Staphylococcus aureus 491 1 0.125 1 2 0.5 1 2 1 1 0.25 0.5Staphylococcus aureus S13E 0.125 0.5 1 0.5 1 0.25 1 .ltoreq.0.06 0.125 1 2Staphylococcus aureus SA1199 0.25 0.5 0.5 2 1 0.5 2 .ltoreq.0.06 1 2 0.5Staphylococcus aureus SA1199A .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.5 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus SA1199B 0.5 1 1 0.5 1 1 1 0.5 0.5 1 2Staphylococcus haemolyticus 105 8 1 1 1 1 1 2 2 2 1 2Staphylococcus haemolyticus 415 16 2 1 2 2 2 2 2 2 1 2Staphylococcus epidermidis 270 1 0.5 1 1 1 1 1 0.5 1 1 1Entercoccus faecium 180 4 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.125 0.125 0.25 0.5 0.125 .ltoreq.0.06 0.25Entercoccus faecium 180-1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 2041 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.125 .ltoreq.0.06 0.125 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 276 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 2 .ltoreq.0.06 0.125 0.25 0.125Entercoccus gallinarum 245 0.25 2 1 2 .ltoreq.0.06 .ltoreq.0.06 2 2 2 1 2Haemophilus influenzae RD >64Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 95 96 97 98 99 100 101 102 103 104 105__________________________________________________________________________Staphylococcus aureus 446 0.5 1 1 0.5 0.5 1 0.5 1 0.5 .ltoreq.0.06 0.25Staphylococcus aureus 489 2 1 0.25 .ltoreq.0.06 0.25 0.5 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.5Staphylococcus aureus 447 0.5 1 1 0.25 2 0.5 1 1 1 0.25 0.5Staphylococcus aureus X400 1 2 1 .ltoreq.0.06 0.125 1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.5Staphylococcus aureus X778 1 1 0.25 .ltoreq.0.06 0.5 1 0.25 .ltoreq.0.06 0.5 .ltoreq.0.06 0.5Staphylococcus aureus 491 1 1 0.5 0.25 1 .ltoreq.0.06 0.5 1 1 .ltoreq.0.06 0.25Staphylococcus aureus S13E 2 1 >64 0.5 0.5 1 0.25 1 1 .ltoreq.0.06 0.5Staphylococcus aureus SA1199 0.5 2 2 0.5 0.5 0.5 0.25 0.125 1 2 1Staphylococcus aureus SA1199A .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.5 0.125 0.5 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.25Staphylococcus aureus SA1199B 1 1 1 1 0.5 0.5 1 1 2 0.125 0.5Staphylococcus haemolyticus 105 1 2 2 1 8 1 1 2 4 2 1Staphylococcus haemolyticus 415 1 2 2 1 32 2 8 4 8 2 1Staphylococcus epidermidis 270 1 2 1 .ltoreq.0.06 1 0.5 0.5 1 1 0.25 0.25Entercoccus faecium 180 0.5 0.5 .ltoreq.0.06 0.25Entercoccus faecium 180-1 .ltoreq.0.06 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 2041 .ltoreq.0.06 1 .ltoreq.0.06 .ltoreq.0.06 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.25Entercoccus faecalis 276 0.125 0.5 .ltoreq.0.06 0.125 0.25 0.25 0.125 0.25 0.25 .ltoreq.0.06 0.25Entercoccus gallinarum 245 1 2 2 1 32 2 8 4 8 2 1Haemophilus influenzae RD >64 >64 >64 32 >64Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 106 107 108 109 110 111 112 113 114 115 116__________________________________________________________________________Staphylococcus aureus 446 2 2 2 1 0.5 2 2 .ltoreq.0.06 0.5 0.125 0.5Staphylococcus aureus 489 2 1 0.25 .ltoreq.0.06 1 1 0.25 0.125 1 0.125 1Staphylococcus aureus 447 0.25 1 0.5 1 1 1 1 0.25 0.5 0.5 1Staphylococcus aureus X400 1 1 2 .ltoreq.0.06 1 1 1 0.125 2 1 1Staphylococcus aureus X778 1 0.5 0.125 .ltoreq.0.06 0.5 2 1 1 2 1 2Staphylococcus aureus 491 0.5 1 0.25 0.25 0.25 2 1 0.25 1 0.5 0.5Staphylococcus aureus S13E 1 2 1 0.25 1 1 1 .ltoreq.0.06 2 0.25 1Staphylococcus aureus SA1199 1 1 2 .ltoreq.0.06 0.25 2 2 1 2 0.125 4Staphylococcus aureus SA1199A .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.5 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus SA1199B 2 2 2 0.5 0.5 1 0.5 .ltoreq.0.06 1 0.25 0.5Staphylococcus haemolyticus 105 1 2 2 1 4 1 2 4 2 1 2Staphylococcus haemolyticus 415 1 2 1 4 2 4 2 1 2 2 4Staphylococcus epidermidis 270 0.25 0.5 0.125 0.25 2 1 1 0.25 1 0.5 1Entercoccus faecium 180 .ltoreq.0.06 0.125 0.125 0.25 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 1 .ltoreq.0.06Entercoccus faecium 180-1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 2041 0.125 0.5 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.25 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 276 0.5 1 0.5 .ltoreq.0.06 0.5 0.5 0.5 0.25 1 0.125 0.25Entercoccus gallinarum 245 1 2 .ltoreq.0.06 .ltoreq.0.06 2 4 2 1 2 2 4Haemophilus influenzae RD >64 >64 >64 32 >64 >64 >64 >64 >64 >64 >64Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 117 118 119 120 121 122 123 124 125 126 127__________________________________________________________________________Staphylococcus aureus 446 0.5 1 2 2 2 1 2 4 4 2 1Staphylococcus aureus 489 0.125 0.25 0.5 2 1 .ltoreq.0.06 2 0.25 2 0.25 2Staphylococcus aureus 447 0.5 0.25 2 1 0.5 0.25 1 0.25 2 1 2Staphylococcus aureus X400 .ltoreq.0.06 0.25 1 0.25 0.125 .ltoreq.0.06 1 1 1 1 2Staphylococcus aureus X778 0.25 0.5 2 0.125 0.5 .ltoreq.0.06 1 0.5 2 0.5 1Staphylococcus aureus 491 0.5 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.125 1 0.25 1Staphylococcus aureus S13E .ltoreq.0.06 0.25 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 1 0.5 2Staphylococcus aureus SA1199 .ltoreq.0.06 2 2 1 1 .ltoreq.0.06 2 1 0.5 0.125 2Staphylococcus aureus SA1199A .ltoreq.0.06 .ltoreq.0.06 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.125 .ltoreq.0.06 0.25 0.25 0.25Staphylococcus aureus SA1199B 0.5 .ltoreq.0.06 0.5 0.125 0.25 .ltoreq.0.06 0.5 .ltoreq.0.06 2 1 2Staphylococcus haemolyticus 105 1 1 2 2 2 1 2 2 4 0.5 2Staphylococcus haemolyticus 415 2 1 2 2 2 1 1 1 2 2 4Staphylococcus epidermidis 270 0.5 1 2 2 1 .ltoreq.0.06 1 0.25 1 1 .ltoreq.0.06Entercoccus faecium 180 1 0.125 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.25 .ltoreq.0.06 1 1 .ltoreq.0.06Entercoccus faecium 180-1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 2041 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 276 0.25 .ltoreq.0.06 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.25 .ltoreq.0.06 2 1 .ltoreq.0.06Entercoccus gallinarum 245 2 1 2 2 2 1 1 1 12 2 4Haemophilus influenzae RD 16 16 16 16 16 16 16 >64Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 128 129 130 131 132 133 134 135 136 137 138__________________________________________________________________________Staphylococcus aureus 446 4 2 1 2 1 2 2 1 .ltoreq.0.06 0.25 0.125Staphylococcus aureus 489 1 .ltoreq.0.06 0.5 1 1 1 0.5 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus 447 1 1 1 1 2 1 1 1 2 4 2Staphylococcus aureus X400 1 0.25 0.5 1 1 0.5 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.0606Staphylococcus aureus X778 1 0.25 1 0.5 2 2 1 1 .ltoreq.0.06 .ltoreq.0.06 0.25Staphylococcus aureus 491 2 0.5 0.5 0.125 0.5 0.25 0.5 0.25 0.25 0.25 0.125Staphylococcus aureus S13E 1 0.25 0.5 1 2 1 2 1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus SA1199 0.5 0.25 1 0.25 1 0.25 0.25 1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus SA1199A 0.5 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.25 0.25 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus SA1199B 2 0.25 2 1 2 2 2 0.25 .ltoreq.0.06 .ltoreq.0.06 0.5Staphylococcus haemolyticus 105 1 4 1 1 1 2 2 0.5 2 2 4Staphylococcus haemolyticus 415 2 4 2 2 2 2 4 2 4 8 8Staphylococcus epidermidis 270 1 1 1 1 2 1 2 0.5 1 0.5 2Entercoccus faecium 180 1 4 1 .ltoreq.0.06 0.25 1 0.5 1 2 0.125 4Entercoccus faecium 180-1 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 2041 0.5 .ltoreq.0.06 0.125 .ltoreq.0.06 1 0.25 0.25 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 276 1 0.125 1 0.25 1 1 1 0.5 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus gallinarum 245 2 0.125 2 2 2 2 4 2 4 8 0.125Haemophilus influenzae RD >64Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 139 140 141 142 143 144 145 146 147 148 149__________________________________________________________________________Staphylococcus aureus 446 0.5 0.125 2 2 0.5 16 0.5 0.5 0.5 1 0.5Staphylococcus aureus 489 0.25 .ltoreq.0.06 0.25 0.5 .ltoreq.0.06 4 .ltoreq.0.06 0.25 0.25 .ltoreq.0.06Staphylococcus aureus 447 1 0.25 1 2 4 16 1 2 0.125 1 4Staphylococcus aureus X400 0.25 .ltoreq.0.06 0.25 1 0.125 8 0.25 0.5 4 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus X778 0.125 0.25 0.5 1 .ltoreq.0.06 8 0.125 .ltoreq.0.06 0.25 2 0.5Staphylococcus aureus 491 0.5 0.25 0.5 0.5 0.5 8 0.5 1 .ltoreq.0.06 0.125 0.5Staphylococcus aureus S13E .ltoreq.0.06 .ltoreq.0.06 0.25 2 0.125 8 0.125 0.5 1 1 0.25Staphylococcus aureus SA1199 0.125 .ltoreq.0.06 0.25 1 0.125 8 0.25 .ltoreq.0.06 0.5 2 0.25Staphylococcus aureus SA1199A .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 2 .ltoreq.0.06 .ltoreq.0.06 0.25 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus SA1199B 2 .ltoreq.0.06 2 2 0.25 8 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.5 1Staphylococcus haemolyticus 105 4 2 1 1 8 64 2 2 1 1 4Staphylococcus haemolyticus 415 8 8 4 1 32 >64 8 4 8 2 16Staphylococcus epidermidis 270 1 0.25 1 0.25 1 16 1 2 16 0.5 1Entercoccus faecium 180 2 1 0.5 0.5 4 8 4 8 2 0.25 1Entercoccus faecium 180-1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 4 .ltoreq.0.06 .ltoreq.0.06 2 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 2041 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.125 8 0.25 0.5 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 276 1 0.5 0.5 1 0.25 8 0.125 1 0.125 .ltoreq.0.06 .ltoreq.0.06Entercoccus gallinarum 245 8 8 4 1 32 4 0.25 0.5 0.125 2 16Haemophilus influenzae RD >64Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.5 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 150 151 152 153 154 155 156 157 158 159 160__________________________________________________________________________Staphylococcus aureus 446 1 2 2 0.5 2 2 2 0.5 2 0.5 2Staphylococcus aureus 489 0.5 .ltoreq.0.06 0.5 1 1 0.5 1 0.5 2 0.25 0.21Staphylococcus aureus 447 0.5 1 8 0.5 2 8 1 0.25 4 4 1Staphylococcus aureus X400 .ltoreq.0.06 .ltoreq.0.06 1 0.5 2 1 2 0.5 4 4 4Staphylococcus aureus X778 2 1 0.5 0.5 0.5 .ltoreq.0.06 1 0.25 4 2 4Staphylococcus aureus 491 .ltoreq.0.06 0.5 1 0.125 0.5 1 1 .ltoreq.0.06 1 2 0.125Staphylococcus aureus S13E 0.25 0.25 0.5 0.125 0.25 1 1 0.25 2 1 1Staphylococcus aureus SA1199 1 0.125 1 0.5 2 1 1 1 4 0.125 0.25Staphylococcus aureus SA1199A .ltoreq.0.06 .ltoreq.0.06 0.25 .ltoreq.0.06 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 1 .ltoreq.0.06 0.125Staphylococcus aureus SA1199B 0.5 0.25 0.5 0.25 0.25 1 0.5 1 4 .ltoreq.0.06 .ltoreq.0.06Staphylococcus haemolyticus 105 1 1 16 2 4 16 4 1 4 16 8Staphylococcus haemolyticus 415 2 4 16 1 4 16 2 1 8 8 8Staphylococcus epidermidis 270 0.25 0.5 4 0.25 0.5 1 1 0.25 4 0.5 1Entercoccus faecium 180 0.25 0.25 4 0.125 1 4 1 .ltoreq.0.06 0.25 2 0.5Entercoccus faecium 180-1 .ltoreq.0.06 .ltoreq.0.06 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.25 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 2041 .ltoreq.0.06 .ltoreq.0.06 0.125 .ltoreq.0.06 0.125 0.125 0.5 .ltoreq.0.06 1 0.125 .ltoreq.0.06Entercoccus faecalis 276 1 .ltoreq.0.06 0.25 0.5 0.5 0.25 2 .ltoreq.0.06 2 0.125 2Entercoccus gallinarum 245 2 4 16 1 4 16 2 1 8 8 8Haemophilus influenzae RD 16 2Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 161 162 163 164 165 166 167 168 169 170 171__________________________________________________________________________Staphylococcus aureus 446 0.5 0.5 1 2 1 2 1 .ltoreq.0.06 0.25 2 1Staphylococcus aureus 489 .ltoreq.0.06 0.25 8 2 2 2 16 0.125 .ltoreq.0.06 0.25 0.5Staphylococcus aureus 447 1 .ltoreq.0.06 0.5 2 0.5 2 4 .ltoreq.0.06 2 0.5 1Staphylococcus aureus X400 0.5 .ltoreq.0.06 0.5 0.5 0.5 1 1 .ltoreq.0.06 .ltoreq.0.06 0.5 .ltoreq.0.06Staphylococcus aureus X778 0.5 .ltoreq.0.06 2 1 0.125 1 16 0.5 .ltoreq.0.06 1 .ltoreq.0.06Staphylococcus aureus 491 0.5 0.25 .ltoreq.0.06 1 0.5 0.5 2 0.5 0.25 0.5 0.25Staphylococcus aureus S13E 0.125 .ltoreq.0.06 1 4 .ltoreq.0.06 4 4 .ltoreq.0.06 .ltoreq.0.06 0.25 .ltoreq.0.06Staphylococcus aureus SA1199 0.25 .ltoreq.0.06 2 2 0.25 2 2 0.5 .ltoreq.0.06 1 0.25Staphylococcus aureus SA1199A .ltoreq.0.06 .ltoreq.0.06 0.5 0.5 .ltoreq.0.06 0.125 4 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus SA1199B 0.25 .ltoreq.0.06 1 2 1 2 4 1 0.125 0.25 0.25Staphylococcus haemolyticus 105 4 0.25 8 2 4 2 32 0.5 2 4 4Staphylococcus haemolyticus 415 8 2 8 2 4 2 16 2 4 4 8Staphylococcus epidermidis 270 1 .ltoreq.0.06 4 1 1 0.5 8 0.125 0.25 1 1Entercoccus faecium 180 2 .ltoreq.0.06 1 0.5 0.5 0.25 2 0.25 1 2 1Entercoccus faecium 180-1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 2041 .ltoreq.0.06 .ltoreq.0.06 1 1 .ltoreq.0.06 .ltoreq.0.06 8 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 276 0.125 .ltoreq.0.06 1 1 0.5 0.5 4 0.125 .ltoreq.0.06 0.5 0.125Entercoccus gallinarum 245 8 2 8 2 4 2 16 2 4 4 8Haemophilus influenzae RD >64 >64Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 172 173 174 175 176 177 178 179 180 181 182__________________________________________________________________________Staphylococcus aureus 446 4 4 0.5 1 2 0.5 1 0.125 0.125 .ltoreq.0.06 2Staphylococcus aureus 489 0.5 2 .ltoreq.0.06 0.25 0.5 .ltoreq.0.06 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 2Staphylococcus aureus 447 0.5 4 4 1 1 4 0.5 0.25 0.125 .ltoreq.0.06 0.25Staphylococcus aureus X400 0.5 4 .ltoreq.0.06 0.125 1 .ltoreq.0.06 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 1Staphylococcus aureus X778 2 4 .ltoreq.0.06 0.5 1 2 1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 2Staphylococcus aureus 491 0.5 2 1 0.5 2 0.5 0.125 0.125 0.5 1Staphylococcus aureus S13E .ltoreq.0.06 4 .ltoreq.0.06 0.25 2 0.25 0.5 0.25 .ltoreq.0.06 .ltoreq.0.06 0.25Staphylococcus aureus SA1199 1 2 .ltoreq.0.06 .ltoreq.0.06 2 0.25 1 1 0.125 .ltoreq.0.06 2Staphylococcus aureus SA1199A .ltoreq.0.06 0.5 .ltoreq.0.06 0.5 >64 0.5 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus SA1199B .ltoreq.0.06 4 0.125 .ltoreq.0.06 1 0.25 1 0.125 .ltoreq.0.06 .ltoreq.0.06 4Staphylococcus haemolyticus 105 0.25 2 4 2 4 4 1 0.5 2 0.25 2Staphylococcus haemolyticus 415 2 4 16 4 2 16 2 1 2 1 4Staphylococcus epidermidis 270 0.5 2 2 0.5 0.5 1 0.25 0.25 0.125 0.125 0.25Entercoccus faecium 180 0.5 0.5 2 1 2 4 0.25 .ltoreq.0.06 8 4 2Entercoccus faecium 180-1 .ltoreq.0.06 0.5 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.125 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 2041 .ltoreq.0.06 0.5 .ltoreq.0.06 .ltoreq.0.06 0.125 0.25 .ltoreq.0.06 .ltoreq.0.06 0.25 0.125 1Entercoccus faecalis 276 0.125 2 .ltoreq.0.06 .ltoreq.0.06 2 0.25 0.5 .ltoreq.0.06 2 2 1Entercoccus gallinarum 245 2 4 16 4 2 16 2 1 0.25 .ltoreq.0.06 1Haemophilus influenzae RD 32 >64 >64 16 8 >64 4 4 32 >64Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.5 0.25 16 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.5 0.25 8 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 183 184 185 186 189 190 191 192 193 194 195__________________________________________________________________________Staphylococcus aureus 446 .ltoreq.0.06 2 .ltoreq..06 .ltoreq..06 0.5 0.25 2 0.5 0.5 .ltoreq.0.06 0.5Staphylococcus aureus 489 .ltoreq.0.06 .ltoreq..06 .ltoreq..06 .ltoreq..06 1 0.125 2 1 0.125 0.125 1Staphylococcus aureus 447 .ltoreq.0.06 .ltoreq..06 .ltoreq..06 .ltoreq..06 0.5 1 2 2 .ltoreq.0.06 0.5 1Staphylococcus aureus X400 .ltoreq.0.06 0.5 .ltoreq..06 .ltoreq..06 0.125 .ltoreq.0.06 1 1 0.25 .ltoreq.0.06 2Staphylococcus aureus X778 .ltoreq.0.06 0.5 .ltoreq..06 .ltoreq..06 0.25 0.125 2 1 .ltoreq.0.06 0.5 0.5Staphylococcus aureus 491 0.125 0.5 .ltoreq..06 .ltoreq..06 .ltoreq.0.06 0.125 1 0.5 .ltoreq.0.06 .ltoreq.0.06 0.5Staphylococcus aureus S13E .ltoreq.0.06 1 .ltoreq..06 .ltoreq..06 0.5 0.125 2 1 .ltoreq.0.06 .ltoreq.0.06 2Staphylococcus aureus SA1199 .ltoreq.0.06 0.125 .ltoreq..06 .ltoreq..06 0.5 0.25 2 2 0.125 0.5 0.5Staphylococcus aureus SA1199A .ltoreq.0.06 .ltoreq..06 .ltoreq..06 .ltoreq..06 .ltoreq.0.06 .ltoreq.0.06 0.5 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Staphylococcus aureus SA1199B .ltoreq.0.06 1 .ltoreq..06 .ltoreq..06 1 0.5 2 0.5 0.125 0.125 1Staphylococcus haemolyticus 105 .ltoreq.0.06 0.25 .ltoreq..06 0.5 1 8 2 1 0.5 1 1Staphylococcus haemolyticus 415 .ltoreq.0.06 .ltoreq..06 .ltoreq..06 1 1 8 8 2 1 2 4Staphylococcus epidermidis 270 .ltoreq.0.06 4 .ltoreq..06 0.125 0.25 2 2 1 0.25 0.5 0.25Entercoccus faecium 180 2 8 0.125 2 0.125 8 4 0.25 .ltoreq.0.06 .ltoreq.0.06 0.5Entercoccus faecium 180-1 .ltoreq.0.06 .ltoreq..06 .ltoreq..06 .ltoreq..06 .ltoreq.0.06 .ltoreq.0.06 0.25 0.1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 2041 .ltoreq.0.06 1 .ltoreq..06 .ltoreq..06 .ltoreq.0.06 .ltoreq.0.06 1 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 276 0.125 0.5 .ltoreq..06 .ltoreq..06 0.25 0.125 4 0.5 .ltoreq.0.06 0.125 0.25Entercoccus gallinarum 245 0.5 4 .ltoreq..06 2 1 8 8 2 1 2 4Haemophilus influenzae RD >64 64 8 32 >64 >64 >64 >64 >64 32Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq..06 .ltoreq..06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq..06 .ltoreq..06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 196 197 198 199 200 201 202 203 204 205__________________________________________________________________________Staphylococcus aureus 446 0.5 1 1 0.5 1 4 4 0.5 0.125 2Staphylococcus aureus 489 1 2 0.125 2 0.25 8 4 0.5 0.25 0.5Staphylococcus aureus 447 0.5 2 0.125 1 0.5 16 8 1 .ltoreq.0.06 0.5Staphylococcus aureus X400 0.5 2 0.5 2 1 4 4 1 0.125 0.5Staphylococcus aureus X778 1 2 0.125 1 0.5 4 4 1 0.5 0.5Staphylococcus aureus 491 0.25 1 .ltoreq.0.06 0.5 0.125 4 8 1 .ltoreq.0.06 0.5Staphylococcus aureus S13E 1 2 0.125 0.5 0.5 8 4 2 0.5 0.5Staphylococcus aureus SA1199 0.5 2 0.5 1 1 8 8 2 0.125 1Staphylococcus aureus SA1199A .ltoreq.0.06 1 .ltoreq.0.06 0.125 .ltoreq.0.06 2 2 0.5 .ltoreq.0.06Staphylococcus aureus SA1199B 0.5 2 0.5 1 1 16 8 1 0.25 0.5Staphylococcus haemolyticus 105 0.5 1 0.5 2 1 8 4 1 0.5 1Staphylococcus haemolyticus 415 1 4 1 4 2 8 8 2 0.25 1Staphylococcus epidermidis 270 0.25 0.5 0.25 0.5 0.25 4 4 0.5 .ltoreq.0.06 0.125Entercoccus faecium 180 0.5 0.5 .ltoreq.0.06 0.5 0.25 0.5 0.5 0.125 0.25 0.5Entercoccus faecium 180-1 .ltoreq.0.06 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.5 0.5 .ltoreq.0.06 0.125 .ltoreq.0.06Entercoccus faecalis 2041 .ltoreq.0.06 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 1 1 0.25 .ltoreq.0.06 0.25Entercoccus faecalis 276 0.25 1 0.25 1 0.5 4 4 0.5 .ltoreq.0.06 0.5Entercoccus gallinarum 245 1 4 1 4 2 8 8 2 0.25 1Haemophilus influenzae RD 32 32 32 32 32 32 32 16 2 16Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 206 207 208 209 210 211 212 213 214 215__________________________________________________________________________Staphylococcus aureus 446 0.5 8 1 1 2 1 .ltoreq.0.06 .ltoreq.0.06 1 0.5Staphylococcus aureus 489 1 4 0.5 1 1 0.25 .ltoreq.0.06 .ltoreq.0.06 1 2Staphylococcus aureus 447 0.5 8 1 1 0.5 0.5 0.25 0.25 2 0.5Staphylococcus aureus X400 0.5 8 0.25 1 .ltoreq.0.06 0.5 .ltoreq.0.06 .ltoreq.0.06 0.5 0.5Staphylococcus aureus X778 0.5 8 0.125 1 1 1 .ltoreq.0.06 .ltoreq.0.06 1 .ltoreq.0.06Staphylococcus aureus 491 .ltoreq.0.06 1 0.5 0.25 .ltoreq.0.06 0.25 .ltoreq.0.06 .ltoreq.0.06 1 0.25Staphylococcus aureus S13E 1 8 0.25 0.5 .ltoreq.0.06 0.5 .ltoreq.0.06 .ltoreq.0.06 1 2Staphylococcus aureus SA1199 0.5 8 0.5 0.25 0.5 0.5 .ltoreq.0.06 .ltoreq.0.06 0.5 .ltoreq.0.06Staphylococcus aureus SA1199A .ltoreq.0.06 4 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.125 .ltoreq.0.06 .ltoreq.0.06 0.5 0.5Staphylococcus aureus SA1199B 1 16 0.5 0.5 0.125 1 .ltoreq.0.06 .ltoreq.0.06 1 1Staphylococcus haemolyticus 105 0.5 8 0.25 0.5 1 0.5 1 0.5 1 2Staphylococcus haemolyticus 415 1 1 2 1 1 0.5 1 2 2 1Staphylococcus epidermidis 270 0.25 8 0.5 0.125 0.25 0.5 .ltoreq.0.06 0.5 .ltoreq.0.06 0.125Entercoccus faecium 180 .ltoreq.0.06 1 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.125 0.25 .ltoreq.0.06Entercoccus faecium 180-1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 2041 0.25 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.125 0.25Entercoccus faecalis 276 .ltoreq.0.06 0.25 0.125 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.25 2Entercoccus gallinarum 245 1 1 2 1 1 .ltoreq.0.06 1 2 2 64Haemophilus influenzae RD 32 16 >64 >64 >64 32 32 >64Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 216 217 218 219 220 221 222 223 224 225__________________________________________________________________________Staphylococcus aureus 446 1 0.25 4 8 1 1 0.25 0.5 1Staphylococcus aureus 489 1 .ltoreq.0.06 1 8 0.5 0.25 0.125 1 0.25 2Staphylococcus aureus 447 1 1 1 8 0.5 0.5 0.5 0.5 0.5 1Staphylococcus aureus X400 1 .ltoreq.0.06 0.25 8 0.5 0.5 0.125 1 0.125 1Staphylococcus aureus X778 0.25 .ltoreq.0.06 1 8 0.5 0.5 .ltoreq.0.06 1 0.125 0.5Staphylococcus aureus 491 1 0.25 0.5 4 .ltoreq.0.06 0.125 0.125 0.125 0.125 1Staphylococcus aureus S13E 1 .ltoreq.0.06 32 8 0.5 0.5 .ltoreq.0.06 0.5 0.25 1Staphylococcus aureus SA1199 .ltoreq.0.06 .ltoreq.0.06 4 4 1 1 1 2 0.25 1Staphylococcus aureus SA1199A 1 .ltoreq.0.06 .ltoreq.0.06 1 .ltoreq.0.06 .ltoreq.0.06 0.125 .ltoreq.0.06 .ltoreq.0.06 0.25Staphylococcus aureus SA1199B 0.5 0.125 0.25 8 0.5 1 0.125 1 0.5 2Staphylococcus haemolyticus 105 0.5 2 0.5 2 0.5 1 1 1 1 0.5Staphylococcus haemolyticus 415 0.25 8 4 2 0.5 2 1 1 0.5 4Staphylococcus epidermidis 270 0.125 0.5 1 4 1 0.125 0.5 0.5 0.25 1Entercoccus faecium 180 .ltoreq.0.06 2 .ltoreq.0.06 1 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecium 180-1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Entercoccus faecalis 2041 0.25 .ltoreq.0.06 0.25 2 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.125Entercoccus faecalis 276 0.5 .ltoreq.0.06 .ltoreq.0.06 2 0.125 0.25 .ltoreq.0.06 0.125 .ltoreq.0.06 0.25Entercoccus gallinarum 245 64 8 .ltoreq.0.06 2 0.5 2 1 1 0.5 4Haemophilus influenzae RD >64 >64 >64 32 >64 32 32 >64 32 >64Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________Organism 226 227 228 229 230 231 232 233 234 235__________________________________________________________________________Staphylococcus aureus 446 1 2 4 1 0.25 0.25 4 4 4 0.5Staphylococcus aureus 489 0.5 2 2 1 0.25 .ltoreq.0.06 8 4 4 0.5Staphylococcus aureus 447 0.5 2 4 2 0.5 0.25 16 16 8 0.25Staphylococcus aureus X400 0.25 1 1 1 0.5 .ltoreq.0.06 8 8 8 0.125Staphylococcus aureus X778 0.25 4 4 1 0.25 .ltoreq.0.06 8 8 4 0.5Staphylococcus aureus 491 0.25 2 1 0.5 0.125 .ltoreq.0.06 4 8 8 0.125Staphylococcus aureus S13E 0.5 4 8 1 0.5 .ltoreq.0.06 8 8 8 0.125Staphylococcus aureus SA1199 1 4 4 1 0.25 .ltoreq.0.06 16 32 8 0.25Staphylococcus aureus SA1199A 0.125 0.6 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 2 4 2 .ltoreq.0.06Staphylococcus aureus SA1199B 1 4 4 1 0.25 .ltoreq.0.06 32 16 8 0.5Staphylococcus haemolyticus 105 2 2 2 1 1 .ltoreq.0.06 2 >64 8 0.5Staphylococcus haemolyticus 415 1 4 4 2 2 0.5 32 >64 16 1Staphylococcus epidermidis 270 1 2 2 0.5 0.5 0.125 8 8 4 0.5Entercoccus faecium 180 .ltoreq.0.06 0.25 1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.5 2 1 0.5Entercoccus faecium 180-1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 1 2 1 .ltoreq.0.06Entercoccus faecalis 2041 .ltoreq.0.06 0.25 0.25 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 2 0.5 .ltoreq.0.06Entercoccus faecalis 276 0.25 0.5 1 0.25 .ltoreq.0.06 .ltoreq.0.06 8 8 4 0.125Entercoccus gallinarum 245 1 4 4 2 2 0.5 32 >64 16 1Haemophilus influenzae RD 32 >64 >64 2 32 32 16 >64 >64 8Escherichia coli EC14 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 0.5 0.25 .ltoreq.0.06__________________________________________________________________________ Organism 236 237 238 239 240 241__________________________________________________________________________ Staphylococcus aureus 446 1 2 1 1 1 0.5 Staphylococcus aureus 489 4 0.5 0.5 0.5 1 0.5 Staphylococcus aureus 447 4 1 0.5 0.5 0.5 1 Staphylococcus aureus X400 2 1 1 0.25 0.25 0.5 Staphylococcus aureus X778 2 0.5 0.5 0.25 0.5 1 Staphylococcus aureus 491 4 0.25 0.25 0.25 0.25 0.25 Staphylococcus aureus S13E 4 0.25 0.125 0.5 0.5 0.25 Staphylococcus aureus SA1199 4 1 0.5 0.5 0.5 1 Staphylococcus aureus SA1199A 2 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 Staphylococcus aureus SA1199B 4 0.25 0.5 0.5 0.25 1 Staphylococcus haemolyticus 105 4 1 0.5 1 1 1 Staphylococcus haemolyticus 415 4 1 2 1 2 1 Staphylococcus epidermidis 270 2 0.5 0.5 0.25 0.25 0.5 Entercoccus faecium 180 1 0.25 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 Entercoccus faecium 180-1 1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 Entercoccus faecalis 2041 1 0.125 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 Entercoccus faecalis 276 2 1 .ltoreq.0.06 0.25 0.5 .ltoreq.0.06 Entercoccus gallinarum 245 4 1 .ltoreq.0.06 1 2 .ltoreq.0.06 Haemophilus influenzae RD 32 8 >64 >64 >64 >64 Escherichia coli EC14 >64 >64 >64 >64 >64 >64 Streptococcus pyogenes C203 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 Streptococcus pneumoniae P1 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06 .ltoreq.0.06__________________________________________________________________________

The formula I compounds have also shown in vivo antimicrobial activity against experimentally-induced infections in laboratory animals. When two doses of test compound were administered to mice experimentally infected with the test organism, the activity observed was measured as an ED.sub.50 value (effective dose in mg/kg to protect 50% of the test animals: see W. Wick et al., J. Bacteriol. 81, 233-235 (1961)). ED.sub.50 values observed for illustrative compounds are given in Table 4.

TABLE 4______________________________________In Vivo Activity of Formula I Compounds ED50(mg/kg/2) Stapylococcus Streptococcus StreptococcusCompound aureus pyogenes pneumoniae______________________________________vancomycin 1.2 0.8 1.1A82846A 0.19 0.084 0.39A82846B 0.25 0.12 0.18A82846C 1.3 1.5 4.6 1 0.086 0.052 0.025 2 0.27 0.014 0.025 4 0.36 0.012 0.036 5 0.13 0.039 0.036 6 0.15 0.013 0.021 8 0.12 >0.5 0.273 12 0.13 >0.5 >0.5 14 0.43 0.37 >0.5 22 0.049 >0.5 >.05 25 0.16 0.087 0.088 29 0.088 0.1 0.054 32 0.055 0.034 0.039 36 0.19 0.28 0.31 39 0.1 0.045 <0.031 41 n.d. 0.082 0.087 46 n.d. 0.378 0.156 49 0.053 0.045 <0.031 50 0.1 0.047 0.057 51 0.16 0.057 0.036 52 0.052 0.046 0.074 53 0.077 0.16 0.071 57 0.041 0.054 0.046 64 n.d. 0.044 <0.031 87 n.d. 0.054 0.027 90 n.d. 0.058 0.049 93 n.d. 0.074 0.012 94 n.d. 0.16 0.049 97 n.d. 0.066 0.038100 n.d. 0.062 0.046104 n.d. 0.12 0.041105 n.d. 0.12 0.041106 n.d. 0.2 0.036107 n.d. 0.27 0.092108 n.d. 0.046 0.041111 n.d. 0.099 0.084114 n.d. 0.091 0.76116 n.d. 0.89 0.058118 n.d. 0.91 0.046119 n.d. 0.16 0.08120 n.d. 0.058 0.005121 n.d. 0.041 0.047122 n.d. 0.23 0.31123 n.d. 0.076 0.039124 n.d. 0.092 0.041131 n.d. <0.031 0.077204 n.d. <0.031 0.046211 n.d. <0.031 0.041223 n.d. <0.031 <0.031229 n.d. 0.058 0.078230 n.d. 0.046 0.078______________________________________ n.d. = not done

One important aspect of the antimicrobial activity of many of the formula I compounds is their activity against vancomycin- resistant enterococci. This activity is illustrated in Table 5, which summarizes a comparison of the activity of illustrative compounds against representative vancomycin-resistant and vancomycin-susceptibie enterococci (Enterococcus faecium and Enterococcus faecalis, mean geometric MIC (mcg/mL)), as determined using the standard broth micro-dilution assay. End points were read after 24-hour incubation. Modification of the amino sugar of the disaccharide moiety provides improved activity against vancomycin-resistant strains over the parent glycopeptide antibiotic.

TABLE 5______________________________________ Vancomycin VancomycinCompound Resistant SensitiveNo. Strains Strains______________________________________vancomycin 282 3.9A82846A >64 1.7A82846B 29 0.22A828460 353 1.31 0.25 0.00612 0.044 0.000383 2.8 0.114 0.50 0.0625 0.50 0.0726 1.2 0.147 2.8 0.438 1.0 0.579 11 0.3810 3.4 3.511 6.7 0.2212 1.7 1.113 19 0.7614 0.50 0.7615 6.7 0.1416 9.5 0.6717 9.5 0.3818 6.7 0.3819 4.8 0.2220 4.8 0.3821 5.7 4.322 1.0 1.523 5.7 2.024 54 0.6725 4.0 0.2226 54 0.6627 45 1.528 4.7 0.7129 0.21 0.03130 4.7 0.07131 9.5 1.232 0.50 0.08933 2.8 0.1834 4.0 3.435 5.6 0.2536 0.25 0.2137 2.4 0.2538 4.0 0.4239 1.2 0.0940 0.50 0.3141 0.84 0.2142 1.7 0.08943 13 1.144 13 0.5045 2.0 0.5046 0.71 0.5047 4.7 0.5748 4.8 0.5049 0.71 0.08350 0.12 0.05451 0.84 0.2252 0.59 0.1153 0.35 0.2554 1.7 0.5655 13 1.756 19 1.057 0.35 0.04158 5.7 0.7659 51 0.4260 19 3.061 16 0.6562 9.5 0.2263 54 0.6664 0.71 0.07765 2.4 0.2066 16 0.7667 1.7 0.1668 6.7 0.2569 13 0.4470 2.0 0.09271 11 0.5772 4.7 0.2873 11 0.2574 11 0.3375 16 0.5076 8.0 0.2978 16 0.7679 0.84 0.04280 1.7 0.2581 1.0 0.04282 22 0.5083 54 1.784 23 0.6685 3.4 0.1186 1.4 0.03687 0.71 0.04788 1.7 0.05589 11 0.4490 0.71 0.04191 2.8 0.1192 1.7 0.08293 0.42 0.04294 0.50 0.04195 1.7 0.05496 1.4 0.1197 0.71 0.05498 2.4 0.09599 72 0.76100 0.71 0.042101 4.0 0.25102 2.0 0.13103 4.0 0.33104 1.2 0.062105 0.84 0.062106 0.71 0.034107 0.59 0.082108 0.84 0.04109 72 0.22110 1.7 0.047111 0.71 0.031112 1.4 0.072111 0.84 0.054114 0.59 0.031115 8.0 0.19116 0.42 0.031117 4.8 0.14118 0.84 0.048119 0.59 0.048120 1.0 0.072121 1.0 0.063122 1.0 0.054123 1.0 0.041124 0.84 0.047125 3.4 0.14126 2.4 0.11127 1.2 0.33128 2.0 0.11129 27 1.52130 4.8 0.22131 0.84 0.028132 1.2 0.048133 4.0 0.13134 2.0 0.13135 4.8 0.22136 23 0.76137 6.7 0.38138 38 0.87139 23 0.38140 6.7 0.19141 8.0 0.25142 45 1.5143 2.0 0.048144 11 9.2145 64 1.3146 64 1.5147 25 1.3148 0.15 0.052149 45 0.66150 1.7 0.25151 4.5 0.14152 27 1.2153 1.4 0.083154 2.8 0.072155 128 1.3156 5.7 0.17157 2.0 0.054158 1.7 1.0159 27 0.50160 9.5 0.22161 23 0.44162 4.8 0.12163 2.0 0.87164 1.7 0.11165 4.0 0.062166 1.7 0.055167 1.0 0.055168 3.4 0.10169 19 0.50170 8.0 0.22171 9.5 0.22172 3.4 0.13173 2.0 0.12174 19 0.76175 9.5 0.22176 1.2 0.13178 2.8 0.13179 1.7 0.060180 >128 0.71181 8.0 0.060182 13 0.250183 23 0.130184 27 0.570185 4.7 0.060186 11 0.290189 2.4 0.10190 6.7 0.29191 6.7 0.57192 0.84 0.035193 2 0.072194 2.4 0.083195 2.0 0.042196 1.7 0.027197 1.2 0.16198 3.4 0.062199 1.4 0.036200 1.4 0.041201 1.2 0.44202 1.4 0.76203 1.0 0.036204 0.71 0.031205 1 0.036206 1.7 0.095207 1.2 0.50208 2.8 0.17209 1.2 0.136210 0.84 0.041211 0.35 0.024212 0.50 0.036213 1.0 0.55214 0.71 0.024215 2.8 0.25216 0.35 0.032217 13 0.57218 1.0 0.11219 0.71 0.044220 0.71 0.05221 0.71 0.041222 0.84 0.072223 0.79 0.055224 0.63 0.055225 0.63 0.072226 1.6 0.041227 0.71 0.11228 1.0 0.14229 0.50 0.024230 0.35 0.031231 1.7 0.11232 0.71 0.29233 1.7 1.7234 2 2235 2.4 0.25236 1.4 0.5237 1.0 0.048238 1.4 0.14239 2.8 0.095240 1.19 0.055241 1.4 0.048______________________________________

A number of the lactic acid bacteria including all Leuconostocs, all Pediococci, and some Lactobacilli, are intrinsically resistant to vancomycin. With the increased use of vancomycin, infections due to these bacteria have been reported with increasing frequency in immunocompromised patients (Handwerger et I., Reviews of Infectious Disease 12:602-610 (1990); Ruoff e: al., Journal of Clinical Microbiology 26:2064-2068 (1988)). One important aspect of the antimicrobial activity of the formula I compounds is their activity against the vancomycin-resistant lactic acid bacteria. The compounds of the present are useful in inhibiting the growth of vancomycin-resistant lactic bacteria such as Leuconostoc, Pedicocci, and Lactobacilli and thus, controlling opportunistic infections by this group of bacteria. This activity is illustrated in Table 6, which summarizes a comparison of the activity of illustrative compounds against representative vancomycin-resistant lactic acid bacteria (Pedicoccus acidilacti Pedicoccus pentosaceus, Leuconostoc lactis, Leuconostoc mesenteroides, Leuconostoc pseudomesenteroides, Leuconostoc citreum, and Lactobacillus confusus, mean geometric MIC (mcg/mL)), as determined using a standard agar dilution assay on brain-heart infusion agar.

TABLE 6__________________________________________________________________________In Vitro Activity of Formula I Compounds MIC (mcg/ml)/CompoundPedioccccus Pediococcus Leuconostoc Leuconostoc Leuconostocacidilacti pentosaceus lactis mesenteroides pseudomesent- Leuconostoc Lactobacillus(mean of 10) (mean of 2) (mean of 2) (mean of 4) eroides citreum confusus__________________________________________________________________________Vancomycin 891 1024 1024 1024 >1024 >1024 1024A82846B 141 >256 64 >256 >256 >256 >256 1 18 23 23 64 >128 >128 64 2 5.9 11 4.0 16 32 64 16 4 7.5 16 16 16 32 128 32 5 2.8 8.0 8.0 8 16 64 16 6 4.3 8.0 8.0 9.5 16 64 1614 3.7 5.7 8.0 11 32 64 3229 4.0 8.0 5.7 6.7 16 32 832 12.1 16 16 16 32 64 1636 9.2 16 16 16 32 32 3239 26 32 32 32 64 >64 3241 71 91 91 91 >128 >128 6449 55 64 64 64 128 128 6450 51 64 64 64 128 128 6451 87 91 64 76 >128 >128 6452 55 64 64 76 64 >128 6458 55 64 64 64 128 128 64108 12 23 8.0 10 32 64 16118 16 16 11 13 32 64 16122 24 16 16 16 32 64 16124 20 16 16 16 64 64 16__________________________________________________________________________

Pharmaceutical formulations of the formula I compounds are also part of this invention. Thus, the compound, preferably in the form of a pharmaceutically acceptable salt, can be formulated for oral or parenteral administration for the 5 therapeutic or prophylactic treatment of bacterial infections.

For example, the compound can be admixed with conventional pharmaceutical carriers and excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, wafers, and the like. The compositions comprising a formula I compound will contain from about 0.1 to about 90% by weight of the active compound, and more generally from about 10 to about 30%. The compositions may contain common carriers and excipients, such as corn starch or gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid.

Disintegrators commonly used in the formulations of this invention include croscarmellose, microcrystalline cellulose, corn starch, sodium starch glycolate and alginic acid.

Tablet binders that can be included are acacia, methylcellulose, sodium carboxymethylcellulose, poly-vinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose.

Lubricants that can be used include magnesium stearate or other metallic stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica.

Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring or the like can also be used.

It may be desirable to add a coloring agent to make the dosage form more attractive in appearance or to help identify the product.

For intravenous (IV) use, a water soluble form of the antibiotic can be dissolved in one of the commonly used intravenous fluids and administered by infusion. Such fluids as, for example, physiological saline, Ringer's solution, or 5% dextrose solution can be used.

For intramuscular preparations, a sterile formulation of a suitable soluble salt form of the compound, for example the hydrochloride salt, can be dissolved and administered in a pharmaceutical diluent such as pyrogen-free water (distilled), physiological saline or 5% glucose solution. A suitable insoluble form of the compound may be prepared and administered as a suspension in an aqueous base or a pharmaceutically acceptable oil base, for example, an ester of a long chain fatty acid such as ethyl oleate.

For oral use, a sterile formulation of a suitable salt form of the antibiotic, for example, the hydrochloride salt, formulated in a diluent such as distilled or deionized water, is particularly useful.

Alternatively, the unit dosage form of the antibiotic can be a solution of the antibiotic, preferably in its salt form, in a suitable diluent in sterile, hermetically sealed ampoules. The concentration of the antibiotic in the unit dosage may vary, for example, from about 1 percent to about 50 percent depending on the particular form of the antibiotic and its solubility and the dose desired by the physician.

In a further aspect, this invention provides a method for treating infectious diseases, especially those caused by Gram-positive microorganisms, in animals. The compounds of this invention are particularly useful in treating infections caused by methicillin-resistant staphylococci. Also, the compounds are useful in treating infection due to enterococci. Examples of such diseases are severe staphylococcal infections, for example, staphylococcal endocarditis and staphylococcal septicemia. The animal may be either susceptible to, or infected with, the microorganism. The method comprises administering to the animal an amount of a formula I compound which is effective for this purpose. In general, an effective amount of a formula I compound is a dose between about 0.5 and about 100 mg/kg. A preferred dose is from about 1 to about 60 mg/kg of active compound. A typical daily dose for an adult human is from about 50 mg to about 5 g.

In practicing this method, the antibiotic can be administered in a single daily dose or in multiple doses per day. The treatment regimen may require administration over extended periods of time, for example, for several days or for from one to six weeks. The amount per administered dose or the total amount administered will depend on such factors as the nature and severity of the infection, the age and general health of the patient, the tolerance of the patient to the antibiotic and the microorganism or microorganisms involved in the infection.

A convenient method of practicing the treatment method is to administer the antibiotic via intravenous infusion. In this procedure a sterile formulation of a suitable soluble salt of the antibiotic is incorporated in a physiological fluid, such as 5% dextrose solution, and the resulting solution is infused slowly IV. Alternatively, the piggy-back method of IV infusion can also be used.

In order to illustrate more fully the preparation of this invention, the following examples are provided, but are not to be construed as a limitation on the scope of the invention.

EXAMPLE 1

Method A

Preparation of Compound 2

A mixture of A82846B-triacetate, (2.25 g, 1.27 mmol, 1.0 equivalents (eq)) in 1:1 DMF/methanol (140 mL) under an atmosphere of argon was treated with 4-biphenylcarboxaldehyde (331 mg, 2.12 mmol, 1.7 eq). The resulting mixture was heated to 70.degree. C. and maintained as such for 1.75-2 hours. The solution was then treated with sodium cyanoborohydride (554 mg, 8.83 mmol, 6.9 eq). Heating at 70.degree. C. was continued for an additional 1.75-2 hours after which the reaction mixture was cooled to room temperature, concentrated in vacuo, diluted with water (150 mL), and lyophilized to give a solid. The solid was purified by preparative reverse-phase high performance liquid chromatography (HPLC) using a Waters 3 x (40 x 100 mm) C18 Nova-Pak cartridge with Waters C18 Nova-pak guard insert and utilizing TEAP buffer system. The analytical method for analysis was: 0.2% TEA/phosphoric acid (TEAP), pH=3, the gradient system at time 0 was 5% CH.sub.3 CN/94.8% H.sub.2 O with 0.2% TEAP held constant and at 20 minutes was 60% CH.sub.3 CN/39.8% H.sub.2 O with 0.2% TEAP held constant. The UV wavelength used was 235 nm and the flow rate was 2 ml/minute. Analysis was done using a Waters Nova-pak C18 RCM column (8.times.100mm) with a Nova-pak C18 guard insert. It s necessary to desalt the product after reverse phase purification when this HPLC method is used.

Desalting was accomplished by adding the purified product to 5-10 ml of H.sub.2 O. 1 N HC1 was added dropwise with stirring to dissolve the sample. The pH at this point was approximately 1-3. The pH of the solution was then raised to 8.2 with 1 N NaOH. A white solid precipitated out of solution. The mixture was cooled, filtered, and dried under vacuum at room temperature for 8-15 hours to give the zwitter ion (or neutral compound) of the desired product, compound 2 (p-phenylbenzyl.cndot.A82846B), (1.02 g, 45%).

EXAMPLE 2

Preparation of Compound 4

A mixture of A82846B-triacetate (1.5 g, 0.848 mmol, 1.0 eq) in methanol (100 mL) under an atmosphere of argon was treated with p-phenoxybenzaldehyde (298 mg, 1.51 mmol, 1.8 eq). The resulting mixture was heated to reflux and maintained as such for 2 hours. The solution was then treated with sodium cyanoborohydride (326 mg, 5.18 mmol, 6.1 eq). Heating at reflux was continued for an additional 2 hours after which the reaction mixture was cooled to room temperature and evaporated to dryness in vacuo.

The product was purified by reverse-phase HPLC with a TFA buffer. The analytical method for analysis was accomplished by using a Waters Nova-pak C18 RCM column (8 .times.100 mm) with a Nova-pak C18 guard insert, eluting with a 2.0 ml/minute linear gradient of 15% acetonitrile/0.1% TFA at time zero to 80% acetonitrile/0.1% TFA at 15 minutes. The fractions containing the products were detected by ultraviolet scan at 235 nm. The organic solvent of the desired fractions was removed and the mixture was lyophilized to a white solid to give 0.618 mg of p-phenoxybenzyl.cndot.A82846B compound 4-tris(trifluroacetate) salt (20% yield). No desalting or further purification was necessary. This method is also especially useful in the preparation of Compound 2 wherein phenylbenzaldehyde is one of the starting materials.

EXAMPLE 3

Method B

Preparation of Compound 176

A mixture of A82846B-triacetate (280 mg, 0.157 mmol, 1.0 eq) in 1:1 DMF/methanol (30 mL) was treated with 8-phenyloctanal (59 mg, 0.29 mmol, 1.8 eq) and sodium cyanoborohydride (60 mg, 0.95 mmol, 6.1 eq). The resulting mixture was heated, under an atmosphere of nitrogen, to 70.degree. C. and maintained as such for 1 hour. The reaction mixture was then cooled to room temperature and concentrated in vacuo to give a residue. Purification of the product was accomplished by reverse-phase preparative HPLC utilizing a Waters 2 .times.(40 .times.100 mm) C18 Nova-Pak cartridge with Waters C18 Nova-Pak guard insert. Elution was accomplished with a 30 minute linear gradient (time=0 minutes 95% TEAP (0.5% aqueous triethylamine adjusted to pH=3 with phosphoric acid)/5% CH.sub.3 CN to t=30 minutes 20% TEAP/80% CH.sub.3 CN) with a flow rate of 40 mL/minute and UV detection at 280 nm. The desired fraction was concentrated in vacuo then desalted with a Waters Sep-Pak cartridge as described below. This afforded compound 176 in 22% yield (60 mg).

The resulting compound was desalted as follows. A Waters Sep-Pak cartridge was pre-wet with methanol (2-3 column volumes) then conditioned with water (2-3 column volumes). The sample, dissolved in a minimum volume of water, was loaded onto the Sep- Pak column which was then washed with water (2-3 column volumes) to remove the unwanted salts. The product was then eluted with an appropriate solvent system, typically 1:1 CH.sub.3 CN/H.sub.2 O, CH.sub.3 CN, and/or methanol. The organic solvent component was removed in vacuo and the resulting aqueous solution lyophilized to give the final product.

EXAMPLE 4

Preparation of Compound 229

A three liter 3-necked flask was fitted with a condenser, nitrogen inlet and overhead mechanical stirring apparatus. The flask was charged with pulverized A82846B acetate salt (20.0 g, 1.21.times.10.sup.-3 mol) and methanol (1000 mL) under a nitrogen atmosphere. 4'-chlorobiphenylcarboxaldehyde (2.88 g, 1.33.times.10.sup.- .sup.2 mol, 1.1 eq.) was added to this stirred mixture, followed by methanol (500 mL). Finally, sodium cyanoborohydride (0.84 g, 1.33.times.10.sup.-2 mol, 1.1 eq.) was added followed by methanol (500 mL). The resulting mixture was heated to reflux (about 65.degree. C).

After 1 hour at reflux, the reaction mixture attained homogeneity. After 25 hours at reflux, the heat source was removed and the clear reaction mixture was measured with a pH meter (6.97 at 58.0.degree. C.) 1 N NaOH (22.8 mL) was added dropwise to adjust the pH to 9.0 (at 54.7.degree. C.). The flask was equipped with a distillation head and the mixture was concentrated under partial vacuum to a weight of 322.3 grams while maintaining the pot temperature between 40.degree.-45.degree. C.

The distillation head was replaced with an addition funnel containing 500 mL of isopropanol (IPA). The IPA was added dropwise to the room temperature solution over 1 hour. After approximately 1/3 of the IPA was added, a granular precipitate formed. The remaining IPA was added at a faster rate after precipitation had commenced. The flask was weighed and found to hold 714.4 grams of the IPA/methanol slurry.

The flask was re-equipped with a still-head and distilled under partial vacuum to remove the remaining methanol. The resulting slurry (377.8 g) was allowed to chill in the freezer overnight. The crude product was filtered through a polypropylene pad and rinsed twice with 25 mL of cold IPA. After pulling dry on the funnel for 5 minutes, the material was placed in the vacuum oven to dry at 40.degree. C. A light pink solid (22.87 g (theory =22.43 g)) was recovered. HPLC analysis versus a standard indicated 68.0% weight percent of Compound 229 (4-�4-chlorophenyl!benzyl-A82846B! in the crude solid, which translated into a corrected crude yield of 69.3%.

The products of the reaction were analyzed by reverse-phase HPLC utilizing a Zorbax SB-C18 column with ultraviolet light (UV; 230 nm) detection. A 20 minute gradient solvent system consisting of 95% aqueous buffer/5% CH.sub.3 CN at time=0 minutes to 40% aqueous buffer/60% CH.sub.3 CN at time=20 minutes was used, where the aqueous buffer was TEAP (5 ml CH.sub.3 CN, 3 ml phosphoric acid in 1000 ml water).

EXAMPLE 5

Table 7 summarizes the preparation and certain physical characteristics of the exemplified compounds. The yield of the product was calculated using the amount of the formula II compound as the limiting reagent. The following terms are found in Table 6 and are defined here. "Method" refers to the method of synthesis as described in Examples 1 and 2, or 3. "Reagent Equivalents" refers to the molar equivalents of the aldehyde and reducing agent relative to the formula II compound. "FAB-MS (M+3H)" refers to Fast atom bombardment-mass spectrometry.

TABLE 7______________________________________ Reagent EquivalentsCompound Yield Method/ (aldehyde/ FAB-MSNo. (%) DMF:MeOH NaBH3CN) (M + 3H)______________________________________1 28 A/1:1 1.7/6.9 1733*2 45 A/1:1 1.7/6.9 17603 28 A/1:1 1.8/7.6 1732**4 20 A/0:1 1.8/6.1 1776***5 30 A/0:1 1.8/6.1 17906 10 A/0:1 1.8/6.1 1768***7 55 A/0:1 1.8/6.1 1740***8 1 A/0:1 1.8/6.1 18269 3 A/0:1 1.8/6.1 1764***10 6 A/0:1 1.8/6.1 186811 8 A/0:1 1.8/6.1 178412 46 A/0:1 1.8/6.1 194013 32 A/0:1 1.8/6.1 1783**14 5.4 A/1:1 1.9/4.2 185915 42 A/0:1 1.8/6.1 176316 39 A/0:1 1.8/6.1 1807**17 41 A/0:1 1.8/6.1 179818 27 A/0:1 1.8/6.1 181719 30 A/0:1 1.8/6.1 173920 5 A/1:1 1.8/1.8 1775*21 11 A/1:1 1.8/1.8 1872*22 8 A/1:1 1.8/1.8 1829**23 ND A/0:1 1.8/3.6 1888***24 34 A/0:1 1.7/2.5 168525 31 A/0:1 1.8/1.6 177926 30 A/0:1 1.7/2.5 168527 19 A/0:1 1.8/2.5 1734**28 35 A/0:1 1.6/1.6 173529 39 A/0:1 1.6/1.6 1785**30 29 A/0:1 1.6/1.6 1734**31 11 A/0:1 1.7/2.5 1684**32 28 A/0:1 1.5/1.6 1771**33 ND A/1:1 1.8/1.8 178934 ND A/1:1 1.8/1.8 183635 ND A/1:1 1.8/1.8 178536 ND A/0:1 1.8/1.8 183537 31 A/0:1 1.5/1.5 1752***38 16 A/0:1 1.5/1.6 170939 46 A/0:1 1.5/1.5 177340 29 A/1:1 1.8/1.8 1846*41 46 A/0:1 1.5/1.5 172942 53 A/0:1 1.5/1.5 178043 22 A/0:1 1.1/1.5 1799***44 42 A/0:1 1.5/1.5 174945 50 A/0:1 1.1/1.5 184146 38 A/0:1 1.1/1.5 185047 40 A/0:1 1.5/1.5 168749 44 A/0:1 1.5/1.5 1776***48 22 A/0:1 1.5/1.5 1728***50 32 A/1:10 2.0/1.5 177451 32 A/0:1 1.5/1.5 182052 31 A/0:1 1.5/1.5 1819**53 43 A/0:1 1.5/1.5 189654 4 A/1:1 1.8/1.8 178955 21 A/0:1 1.5/1.5 176756 20 A/0:1 1.1/1.5 174157 29 A/0:1 1.5/1.5 1820**58 22 A/0:1 1.5/1.5 172759 ND A/1:1 1.8/1.8 180360 33 A/0:1 1.1/1.5 1777**61 24 A/0:1 1.1/1.5 172362 ND A/1:1 1.8/1.8 1789**63 ND A/1:1 1.8/1.8 1789**64 30 A/0:1 1.5/1.5 180565 24 A/0:1 1.1/1.5 176366 17 A/0:1 1.1/1.5 1704***67 22 A/0:1 1.1/1.5 1766***68 ND A/1:1 1.8/1.8 180269 ND A/1:1 1.8/1.8 180370 44 A/0:1 1.1/1.5 182171 4 A/0:1 1.1/1.5 1796***72 32 A/0:1 1.5/1.5 1750***73 ND A/1:1 1.8/1.8 175374 17 A/0:1 1.1/1.5 181575 23 A/0:1 1.5/1.5 1806***76 16 A/1:1 1.8/1.8 171177 ND A/1:1 1.8/1.8 174278 5 A/1:1 1.8/1.8 172879 ND A/1:1 1.8/1.8 1783**80 46 A/0:1 1.5/1.5 1843****81 52 A/0:1 1.5/1.5 1844***82 29 A/0:1 1.5/1.5 1726***83 7 A/0:1 1.5/1.5 1798**84 8 A/0:1 1.5/1.5 170085 30 A/0:1 1.5/1.5 177586 45 A/0:1 1.5/1.5 180987 42 A/0:1 1.1/1.5 1854**88 36 A/0:1 1.1/1.5 1854**89 43 A/1:1 1.8/1.8 171190 13 A/1:1 1.8/1.8 178791 20 A/1:10 1.511.5 1759**92 23 A/1:10 1.5/1.5 177793 42 A/0:1 1.5/1.5 182394 41 A/0:1 1.1/1.5 1854**95 49 A/0:1 1.1/1.5 1789**96 34 A/0:1 1.1/1.5 183297 42 A/1:10 1.5/1.5 1773**98 31 A/0:1 1/1.5 180599 ND A/1:1 1.8/1.8 1770**100 ND A/1:1 1.8/1.8 1787101 34 A/1:1 1.19/1.8 1761102 41 A/0:1 1.5/1.5 1805103 37 A/0:1 1/1.5 1788***104 34 A/0:1 1.1/1.5 1819**105 ND A/1:1 1.7/2.0 1838*106 ND A/1:1 1.7/2.0 1844107 ND A/1:1 1.1/1.1 1802108 ND A/0:1 1.8/1.8 1791**109 ND A/0:1 1.8/1.8 1789110 15 A/0:1 1.1/1.5 1881111 ND A/1:1 1.8/1.8 1843112 16 A/1:1 1.8/1.8 1764113 45 A/0:1 1.1/1.5 1805**114 52 A/0:1 1.1/1.5 1888**115 39 A/0:1 1.1/1.5 1791116 ND A/1:1 1.8/2.0 1834117 29 A/0.1 1.5/1.7 1803**118 28 A/0:1 2/1.5 1765**119 41 A/0:1 1/1.5 1843120 38 A/0:1 1.1/1.5 1757121 41 A/0:1 1.1/1.5 1799122 24 A/1:1 1.8/2.6 1863123 55 A/0:1 1.1/1.5 1795**124 17 A/1:10 3/1.5 1781**125 36 A/0:1 1.5/1.8 1841126 26 A/0:1 1.6/1.8 1818127 54 A/0:1 1.1/1.5 1810128 34 A/0:1 1.4/1.8 1831129 ND A/1:1 1.4/1.8 1780130 4 A/0:1 1.1/1.5 1795**131 42 A/0:1 1.1/1.5 1834**132 49 A/0:1 1.1/1.5 1843133 41 A/0:1 1.1/1.5 1855134 30 A/0:1 1.1/1.5 1801**135 ND A/1:1 1.8/1.8 1779136 ND A/1:1 1.8/1.8 1699137 ND A/1:1 1.8/1.8 1760138 ND A/1:1 1.8/1.8 1741139 13 A/1:10 2.4/1.5 1749**140 11 A/1:10 2.9/1.5 1750*141 ND A/1:1 2.3/5.3 1742142 ND A/1:1 2.5/5.4 1826143 ND A/1:1 1.8/1.8 1861144 ND A/1:1 1.5/1.5 1922145 ND A/1:1 1.1/1.1 1716146 ND A/1:1 1.35/1.8 1780*147 ND A/1:1 1.5/1.8 1769148 31 A/1:10 3/1.5 1857149 18 A/0:1 1.1/1.5 1777150 22 A/1:1 2/4.8 1803151 ND A/1:1 1.8/1.8 1760152 ND A/1:1 1.8/1.8 1826****153 22 A/1:10 2.5/1.6 1782154 ND A/1:1 1.8/1.8 1780155 13 A/0:1 1.6/1.6 1768156 41 A/1:9 1.2/1.6 1788157 9 A/1:1 2.7/5.4 1810158 ND A/1:1 1.8/4.1 1854159 13 A/1:9 1/1.6 1807160 13 A/1:9 0.95/1.6 1774161 ND A/1:1 1.8/1.8 1690162 ND A/1:1 3.1/6.9 1804163 ND A/1:1 1.9/5.3 1854164 ND A/1:1 1.8/1.8 1772165 21 A/1:1 2.0/4.9 1810166 20 A/1:1 2.0/6.2 1870167 23 A/1:1 1.8/4.1 1914168 ND A/1:1 1.8/1.8 1737169 15 A/1:1 1.8/4.1 1700170 39 A/0:1 1.2/1.1 1728171 32 A/0:1 1.2/1.5 1729**172 11 B/1:1 2.2/4.8 1755**173 51 A/1:9 1.3/1.7 1909174 35 A/1:9 1.5/1.6 1816175 22 B/1:1 1.9/6.2 1712176 21 B/1:1 1.8/6.1 1732177 ND A/1:1 3.6/1.8 1774178 33 A/1:9 1.4/1.7 1788**179 22 B/1:1 1.8/3.8 1748180 16 A/1:1 1.1/1.3 1591***181 14 A/1:1 1.1/1.3 1617182 17 A/0:1 1.6/6.3 1725183 17 A/0:1 1.6/6.3 1691**184 8 A/0:1 1.6/6.26 1707**185 21 A/1:1 1.1/3.0 1725**186 8 A/1:1 1.1/3.0 1630**187 16 A/1.1 1.6/3.0 2110**188 6 A/1.1 1.5/5.0 2976**189 20 A/1:10 1/1.2 1747**190 9 A/1:10 1.5/1.5 1716191 18 B/1:1 1.8/4.1 1771**192 11 A/0:1 ND/1.8 1738193 24 A/1:10 2.0/1.5 1820**194 27 A/1:10 2.0/1.5 1821195 18 B/1:1 1.6/3.6 1798196 18 B/1:1 1.8/3.9 1754197 35 B/1:1 1.5/3.5 1810198 14 B/1:1 1.5/3.7 1784199 ND B/1:1 1.5/2.8 1772200 11 B/1:1 1.5/3.7 1828201 14 B/1:1 1.8/6.3 1873**202 7 B/1:1 1.3/5.9 1889**203 15 A/0:1 1.1/1.1 1843204 16 B/1:1 2.0/5.6 1746205 23 B/1:1 1.8/3.7 1732206 11 A/0:1 1.1/1.1 1777207 11 B/1:1 1.6/4.2 1813**208 26 B/1:1 1.9/3.9 1703209 20 A/1:1 1.0/1.6 1774210 35 A/0:1 1.0/1.0 1788211 26 A/0:1 1.3/1.8 1777212 48 A/1:1 1.1/3.1 1849**213 56 A/1:1 1.0/3.6 1849**214 9 B/1:1 1.9/1.9 1732215 35 A/0:1 1.3/1.8 1820***216 31 A/0:1 1.3/1.8 1828***217 12 B/1:1 2.0/2.1 1676218 24 A/1:10 1.2/1.5 1766***219 24 A/1:1 1.4/3.5 1860220 21 A/0:1 1.3/1.8 1785221 42 A/0:1 1.3/1.8 1787222 20 A/0:1 1.1/1.1 1787223 32 A/1:1 2 4/4.5 1817**224 36 A/1:1 1.6/5.6 1773**225 ND A/0:1 1.1/1.1 1787226 28 A/1:1 1.5/3.0 1766*227 22 A/1:1 1.2/3.7 1777**228 21 A/0:1 1/1.1 1848**229 16 A/0:1 1/1.2 1793230 27 A/0:1 1.3/1.8 1838***231 36 A/0:1 1.3/1.8 1785*232 32 A/1:1 1.8/4.6 1806233 5 A/1:1 1.1/7.3 1878234 7 B/1:1 1.5/3.5 1836*235 15 B/1:1 1.4/4.8 1750236 4 B/1:1 1.4/6.3 1819**237 14 A/0:1 1.1/1.1 1787238 25 B/0:1 1.1/1.1 1771239 22 B/1:1 1.6/1.5 1810240 4.7 A/1:60 1.2/1.1 1810***241 24 B/1:1 1.1/2.5 1779**242 N.D. A/1:50 1.1/1.2 1787243 20 A/0:1 1.1/1.1 1790244 24 C/0:1 1.1/1.1 1808______________________________________ N.D. = Not determined *M + H **M + 2H ***M + 4H ****M + 6H

EXAMPLE 6

Capsule Formulation

Capsules containing 250 mg of Compound 2 are prepared using the following ingredients:

______________________________________Ingredient Weight______________________________________Compound 2 HCl salt 255.4 mgCorn starch flowable powder 150 mgCorn starch 144.6 mg______________________________________ Compound 2 (HCI salt form, 255.4 mg), corn starch flowable powder (150 mg) and corn starch (144.6 mg) are blended in a suitable mixer until homogenous. The mixture is used to fill a hard gelatin capsule to a net fill weight of 550 mg.

EXAMPLE 7

Capsule Formulation

Capsules containing 250 mg of Compound 229 are prepared using the following ingredients:

______________________________________Ingredient Weight______________________________________Compound 229 HCl salt 255.4 mgCorn starch flowable powder 150 mgCorn starch 144.6 mg______________________________________ Compound 2 (HCl salt form, 255.4 mg), corn starch flowable powder (150 mg) and corn starch (144.6 mg) are blended in a suitable mixer until homogenous. The mixture is used to fill a hard gelatin capsule to a net fill weight of 550 mg.

EXAMPLE 8

Suspension Formulation

A sterile insoluble form of compound 2 is milled or screened to a particle size suitable for suspension. This particulate material is suspended in the -it vehicle:

______________________________________Ingredient Weight______________________________________Lecithin 1%Sodium citrate 2%Propylparaben 0.015%Distilled water q.s. to desired volume______________________________________

EXAMPLE 9

Suspension Formulation

A sterile insoluble form of compound 229 is milled or screened to a particle size suitable for suspension. This particulate material is suspended in the following vehicle: Ingredient Weight

______________________________________Ingredient Weight______________________________________Lecithin 1%Sodium citrate 2%Propylparaben 0.015%Distilled water q.s. to desired volume______________________________________

EXAMPLE 10

Tablet Formulation

Tablets containing 250 mg of compound 2 are prepared with the following composition:

______________________________________Ingredient Weight______________________________________Lecithin 1%Sodium citrate 2%Propylparaben 0.015%Distilled water q.s. to desired volume______________________________________

EXAMPLE 11

Tablet Formulation Tablets containing 250 mg of compound 229 are prepared with the following composition:

______________________________________Ingredient Weight______________________________________Lecithin 1%Sodium citrate 2%Propylparaben 0.015%Distilled water q.s. to desired volume______________________________________

EXAMPLE 12

Tablet Formulation

Tablets containing 250 mg of compound 2 are prepared with the following composition:

______________________________________Ingredient Weight______________________________________Compound 2 HCl salt 255.4 mgMicrocrystalline cellulose 101.1 mgCroscarmellose sodium 12.0 mgProvidone 12.0 mgMagnesium stearate 3.0 mgStearic acid 4.0 mgPurified water 0.16 ml______________________________________

EXAMPLE 13

Tablet Formulation

Tablets containing 250 mg of compound 229 are prepared with the following composition:

______________________________________Ingredient Weight______________________________________Compound 229 HCl salt 255.4 mgMicrocrystalline cellulose 101.1 mgCroscarmellose sodium 12.0 mgProvidone 12.0 mgMagnesium stearate 3.0 mgStearic acid 4.0 mgPurified water 0.16 ml______________________________________

Claims

1. A compound of the formula: ##STR9## or salt thereof, wherein: R.sup.6 is vancosaminyl; and

R.sup.7 is (C.sub.1 -C.sub.12 alkyl)--R.sub.8 and is attached to the amino group of R.sup.6 ;

R.sup.8 is a group of the formula: ##STR10## wherein q is 0 to 4; R.sup.12 is independently selected from the group consisting of:

(i) halo,

(ii) nitro,

(iii) (C.sub.1 -C.sub.6)alkyl,

(iv) (C.sub.1 -C.sub.6)alkoxy,

(v) halo-(C.sub.1 -C.sub.6)alkyl,

(vi) halo-(C.sub.1 -C.sub.6)alkoxy,

(vii) hydroxy, and

(vii) (C.sub.1 -C.sub.6)thioalkyl;

r is 1 to 5; provided that the sum of q and r is no greater than 5;

Z is selected from the group consisting of:

(i) a single bond,

(ii) divalent (C.sub.1 -C.sub.6)alkyl unsubstituted or substituted with hydroxy, (C.sub.1 -C.sub.6)alkyl, or (C.sub.1 -C.sub.6)alkoxy,

(iii) divalent (C.sub.2 -C.sub.6)alkenyl,

(iv) divalent (C.sub.2 -C.sub.6)alkynyl, and

(v) a group of the formula --(C(R.sup.14).sub.2).sub.s --R.sup.15 -- or --R.sup.15 -- (C(R.sup.4).sub.2).sub.s --, wherein s is 0-6; wherein each R.sup.14 substituent is independently selected from hydrogen, (C.sub.1 -C.sub.6)-alkyl, and (C.sub.4 -C.sub.10) cycloalkyl; and R.sup.15 is selected from --O--, --S--, --SO--, --SO.sub.2 --, --SO.sub.2 --O--, --C(O)--, --OC(O)--, --C(O)O--, --NH--, --N(C.sub.1 -C.sub.6 alkyl)-, --C(O)NH--, --NHC(O)--, and N.dbd.N;

R.sup.13 is independently selected from the group consisting of:

(i) (C.sub.4 -C.sub.10) heterocyclyl,

(ii) heteroaryl,

(iii) (C.sub.4 -C.sub.10) cycloalkyl unsubstituted or substituted with (C.sub.1 -C.sub.6) alkyl, and

(iv) phenyl unsubstituted or substituted with 1 to 5 substituents independently selected from: halo, hydroxy, nitro, (C.sub.1 -C.sub.10) alkyl, (C.sub.1 -C.sub.10)alkoxy, halo-(C.sub.1 -C.sub.3)alkoxy, halo-(C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3)alkoxyphenyl, phenyl, phenyl-(C.sub.1 -C.sub.3) alkyl, (C.sub.1 -C.sub.6)alkoxyphenyl, phenyl-(C.sub.2 -C.sub.3)alkynyl, and (C.sub.1 -C.sub.3) alkylphenyl.

2. The compound of claim 1 wherein R.sup.7 represents 4-phenylbenzyl, or a salt thereof.

3. A pharmaceutical composition comprising a compound of claim 11 with one or more pharmaceutically acceptable carriers therefor.

4. A pharmaceutical composition comprising a compound of claim 2 with one or more pharmaceutically acceptable carriers therefor.

5. A method of treating susceptible bacterial infections which comprises administering an antibacterially effective amount of a composition of claim 3 to a host in need of such treatment.

6. A method of treating susceptible bacterial infections which comprises administering an antibacterially effective amount of a composition of claim 4 to a host in need of such treatment.

7. A method of claim 5 wherein the susceptible bacterial infection is caused by a vancomycin-resistant enterococcus.

8. A method of claim 6 wherein the susceptible bacterial infection is caused by a vancomycin-resistant enterococcus.

9. A process for making a compound of claim 1 which comprises

(a) reacting a compound of the formula ##STR11## wherein R.sup.1 is vancosaminyl with an aldehyde corresponding to R.sup.7 as defined in claim 1 in methanol at about 25.degree. C. to about 100.degree. C.;

(b) continuing the reaction until formation of a Schiff's base; and

(c) reducing the Schiff's base by addition of a metal borohydride to the mixture of about 25.degree. C. to about 100.degree. C.