Indian Patents
Title of Invention

GLYCOPEPTIDE ANTIBIOTIC DERIVATIVES AND PROCESS OF PREPARATION THEREOF
Abstract 1. A compound of the formula: or salt thereof, wherein: X and Y are each independently hydrogen or chloro; R is hydrogen, 4-epi-vancosaminyl, actinosaminyl, or ristosaminyl; R1 is hydrogen or mannose; R2 is -NH2, -NHCH3, or -N(CH3)2; R3 is -CH2CH(CH3)2, [p-OH, w-Cl]phenyl, p-rhamnose-phenyl, [p-rhamnose- galactose]phenyl, [p-galactose-galactose]phenyl, or |p-CH3O-rhamnose]phenyl; R4 is -CH2(CO)NH2, benzyl, [p-OH]phenyl or [p-OH, m-Cl]phenyl; R5 is hydrogen or mannose; R6 is 4-epi-vancosaminyl, L-acosaminyl, L-ristosaminyl, L-actinosaminyl or vancosaminyl; R7 is (C2-C16)alkenyl, (C2-C12)alkynyl, (C,-C12alkyl)-R8, (C1-C12alkyl)-halo, (C2- C6alkenyl)-R , (C2-C6alkynyl)-R , or (C1-C12 alkyl)-O-R , and is attached to the amino group of R6; R8 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, (in) nitro, (iv)(C1-C6)alkyl, (v) (C2-C6)alkenyl, (vi) (C2-C6)alkynyl, (vii)(C1-C6)alkoxy, (viii) halo-(C1-C6)alkyl, (ix) halo-(C1-C6)alkoxy, (x) carbo-(C1-C6)alkoxy, (xi) carbobenzyloxy, (xii) carbobenzyloxy substituted with (C1-C6)alkyl, (C1-C6)alkoxy, halo, or nitro, (xiii) a group of the formula -S(O)n-R9, wherein n' is 0-2 and R is (C1-C6)alkyl, phenyl, or phenyl substituted with (C1-C6)alkyl, (C1-C6)alkoxy, halo, or nitro, and (xiv) a group of the formula -C(O)N(R10)2 wherein each R10 substituent is independently hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, phenyl, or phenyl substituted with (C1-C6)-alkyl, (C1-C6)-alkoxy, halo, or nitro; b) heteroaryl unsubstituted or substituted with one or more substituents independently selected from the group consisting of: (i) halo, (ii) (C1C6)alkyl, (iii)(C1-C6)alkoxy, (iv)halo-(C1-C6)alkyl, (v) halo-(C1-C6)alkoxy, (vi) phenyl, (vii) thiophenyl, (viii) phenyl substituted with halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, or nitro, (ix) carbo-(C1-C6)alkoxy, (x) carbobenzyloxy, (xi) carbobenzyloxy substituted with (C1-C6)alkyl, (C1-C6)aIkoxyl, halo, or nitro, (xii) a group of the formula -S(O)n'-R , as defined above, (xiii) a group of the formula -C(O)N(Rl0)2 as defined above, and (xiv) thienyl; c) a group of the formula: wherein A1 is -OC(A2)2-C(A2)2-O-, -O-C(A2)2-O-, -C(A2)2-O-, or -C(A2)2-C(A2)2-C(A2)2- C(A2)2-, and each A2 substituent is independently selected from hydrogen, (C1-C6)-alkyl, (C1- C6)alkoxy, and (C4-C10)cycloalkyl; d) a group of the formula: wherein p is from 1 to 5, and R11 is independently selected from the group consisting of: (i) hydrogen, (ii) nitro, (iii) hydroxy, (iv) halo, (v) (C1-C8)alkyl, (vi)(C1-C8)alkoxy, (vii) (C9-C12)alkyl, (viii) (C2-C9)alkynyl, (ix) (C9-C12)alkoxy, (x) (C1-C3)alkoxy substituted with (C1-C3)alkoxy, hydroxy, halo(C1-C3)alkoxy, or (C1-C4)alkylthio, (xi) (C2-C6)alkenyloxy, (xii) (C2-C13)alkynyloxy (xiii) halo-(C1-C6)alkyl, (xiv) halo-(C1-C6)alkoxy, (xv) (C2-C6)alkylthio, (xvi) (C2-C10)alkanoyloxy, (xvii) carboxy-(C2-C4)alkenyl, (xviii) (C1-C3)alkylsulfonyloxy, (xix) carboxy-(C1-C3)alkyl, (xx)N-[di(C1-C3)-alkyl]amino-(C1-C8)alkoxy, (xxi) cyano-(C1-C6)alkoxy, and (xxii) diphenyl-(C1-C6)alkyl, with the proviso that when R11 is (C1-C8)alkyl, (C1-C6)alkoxy, or halo, p must be greater or equal to 2, or when R7 is (C1-C3alkyl)-R8 then R11 is not hydrogen, (C1- C8)alkyl, (C1-C8)alkoxy, or halo; e) a group of the formula: wherein q is 0 to 4; R12 is independently selected from the group consisting of: (i) halo, (ii) nitro, (iii) (C1-C6)alkyl, (iv) (C1-C6)alkoxy, (v) halo-(C1-C6)alkyl, (vi)halo-(C1-C6)alkoxy, (vii) hydroxy, and (vii) (C1-C6)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 (C1-C6)alkyl unsubstituted or substituted with hydroxy, (C1- C6)alkyl, or (C1-C6)alkoxy, (iii) divalent (C2-C6)alkenyl, (iv) divalent (C2-C6)alkynyl, or (v) a group of the formula -(C(R14)2)S-R15- or -R15-(C(R14)2)s-, wherein s is 0-6; wherein each R14 substituent is independently selected from hydrogen, (C1- C6)-aIkyl, or (C4-C10) cycloalkyl; and R15 is selected from -O-, -S-, -SO-, - SO2-, -SO2-O-, -C(O)-, -OC(O)-, -C(O)O-, -NH-, -N(C1-C6 alkyl)-, and - C(O)NH-, -NHC(O)-, -N=N-; R13 is independently selected from the group consisting of: (i) (C4-C10)heterocyclyl, (ii) heteroaryl, (iii) (C4-C10)cycloalkyl unsubstituted or substituted with (C1-C6)alkyl, or (iv) phenyl unsubstituted or substituted with 1 to 5 substituents independently selected from: halo, hydroxy, nitro, (C1-C]0)alkyl, (C1-C10)alkoxy, halo-(C1- C3)alkoxy, halo-(C1-C3)alkyl, (C1-C3)alkoxyphenyl, phenyl, phenyl-(C1-C3)alkyl, (C1-C6)alkoxyphenyl, phenyl-(C2-C3)alkynyl, and (C1-C6)alkylphenyl; f) (C4-C10)cycloalkyl unsubstituted or substituted with one or more substituents independently selected from the group consisting of: (i) (C1-C6)alkyl, (ii) (C1-C6)alkoxy, (iii) (C2-C6)alkenyl, (iv) (C2-C6)alkynyl, (v) (C4-C10)cycloalkyl, (vi) phenyl, (vii) phenylthio, (viii) phenyl substituted by nitro, halo, (C1-C6)alkanoyloxy or carbocycloalkoxy, and (ix) a group represented by the formula -Z-R13 wherein Z and R1 are as defined above; and g) a group of the formula: wherein A and A4 are each independently selected from (i) a bond, (ii) -O-, (iii) -S(O),-, wherein t is 0 to 2, (iv) -C(R17)2-, wherein each R17 substituent is independently selected from hydrogen, (C1-C6)alkyl, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, or both R17 substituents taken together are O, (v) -N(R18)2-, wherein each R18 substituent is independently selected from hydrogen; (C1-C6)alkyl; (C2-C6)alkenyl; (C2-C6)alkynyl; (C4-C10)cycloalkyl; phenyl; phenyl substituted by nitro, halo, (C1-C6)alkanoyloxy; or both R18 substituents taken together are (C4-C10)cycloalkyl; R16 is R12 or R13 as defined above; and u is 0-4; other than the compounds where R, R1 and R5 are H, R3 is -CH2CH(CH3)2, R4 is -CH2(CO)NH2, R6 is vancosaminyl, X and Y are chloro and R7 is 6-bromo-n-hexyl and R2 is NHCH3, R7 is 3-phenyl-n-(prop-2-enyl) and R2 is NHCH3, R7 is (pyrid-3-yl)methyl and R2 is NHCH3, R7 is (indo-3-yl)methyl and R2 is NHCH3, R7 is (adamant-l-yl)methyl and R2 is NHCH3, R7 is (pyrid-3-yl)methyl and R2 is N(CH3)2, R7 is cyclohexylmethyl and R2 is NHCH3, R7 is pyrrol-2-ylmethyl and R2 is NUCH3, R7 is pyridin-2-ylmethyl and R2 is NHCH3, R7 is furan-2-ylmethyl and R2 is NHCH3, R7 is 6-nitro-3,4-dimethoxybenzyl and R2 is NHCH3, and R7 is p-hydroxybenzyl and R2 is NHCH3, and salts of these compounds.
Full Text Field of Invention:
The present invention relates to a glycopeptide derivative of the formula 1 and the
process of preparation of the compound thereof. The present invention further relates to
compounds possessing antibacterial activity against vancomycin-resistant isolates.


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,
therefore, 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. Patent 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 July 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. Patent 3,067,099); A82846A, A82846B and
A82846C (U.S. Patent 5,312,738, European Patent Publication 256,071 Al); PA-42867
factors A, C, and D (U.S. Patent No.5,187,082); avoparcin (U.S. Patent 3.338,786 and
U.S. Patent No.4,322,343); actinoidin, also known as K288 (J. Antibiotics SAeries 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 Report 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.
The present invention provides compounds of the formula I:


or salt thereof, wherein:
X and Y are each independently hydrogen or chloro;
R is hydrogen, 4-epi-vancosaminyl, actinosaminyl, or
ristosaminyl;
R1 is hydrogen, or mannose;
R2 is -NH2, -NHCH3, or-N(CH3)2;
R3 is -CH2CH(CH3)2, [p-OH, m-Cl]phenyl, p-rhamnose-phenyl, or
[p-rhamnose-galactose]phenyl, [p-galactose-galactose]phenyl, [p-
CH30-rhamnose]phenyl;
R4 is -CH2(CO)NH2, benzyl, [p-OH]phenyl, or [p-OH, m-
Cl]phenyl;
R5 is hydrogen, or mannose;
R6 is 4-epi-vancosaminyl, L-acosaminyl, L-ristosaminyl, or L-
actinosaminyl;
R7 is (C2-C16)alkenyl, (C2-C12)alkynyl, (C1-C12 alkyl)-R8, (C1-
C12 alkyl)-halo, (C2-C6 alkenyl)-R8, (C2-C6 alkynyl)-R8, (C1-C12
alkyl)-0-R8, and is attached to the amino group of R6;
R8 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) (C1-C6)alkyl,
(v) (C2-C6)alkenyl,
(yi) (C2-C6)alkynyl,
(vii) (C1-C6)alkoxy,
(viii) halo-(C1-C6)alkyl,
(ix) halo-(C1-C6)alkoxy,
(x) carbo-(C1-C6)alkoxy,
(xi) carbobenzyloxy,
(xii) carbobenzyloxy substituted with (C1-C6) alkyl, (C1-
C6)alkoxy, halo, or nitro,
(xiii) a group of the formula -S(O)n'-R9, wherein n' is 0-2
and R9;is (C1-C6) alkyl, phenyl, or phenyl substituted with (C1-
C6)alkyl, (C1-C6)alkoxy, halo, or nitro, and

(xiv) a group of the formula -C(O)N(R10)2 wherein each R10
substituent is independently hydrogen, (C1-C6)-alkyl, (C1-C6)-
alkoxy, phenyl, or phenyl substituted with (C1-C6)-alkyl, (C1-
C6)-alkoxy, halo, or nitro;
b) heteroaryl unsubstituted or substituted with one or more
substituents independently selected from the group consisting
of:
(i) halo,
(ii) (C1-C6)alkyl,
(iii) (C1-C6)alkoxy,
(iv) halo- (C1-C6)alkyl,
(v) halo-(C1-C6)alkoxy,
(vi) phenyl,
(vii) thiophenyl,
(viii) phenyl substituted with halo, (C1-C6)alkyl, (C2-
C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, or nitro,
(ix) carbo-(C1-C6)alkoxy,
(x) carbobenzyloxy,
(xi) carbobenzyloxy substituted with (C1-C6)alkyl, (C1-C6)
alkoxy, halo, or nitro,
(xii) a group of the formula -S(O)n'-R9, as defined above,
(xiii) a group of the formula -C(O)N(R10)2 as defined
above, and
(xiv) thienyl;
c) a group of the formula:

wherein A1 is -OC (A2)2-C (A2) 2-O- , -O-C (A2)2-O-, -C (A2) 2-O-,
or -c(A2)2-C (A2)2-C (A2)2-C(A2)2-, and each A2 substituent is
independently selected from hydrogen, (C1-C6)-alkyl, (C1-
C6) alkoxy, and (C4-C10) cycloalkyl;
d) a group of the formula:


wherein p is from 1 to 5; and
R11 is independently selected from the group consisting of:
(i) hydrogen,
(ii) nitro,
(iii) hydroxy,
(iv) halo,
(v) (C1-C8)alkyl.
(vi) (C1-C8)alkoxy,
(vii) (C9-C12)alkyl,
(viii)(C2-C9)alkynyl,
(ix) (C9-C12)alkoxy,
(x) (C1-C3)alkoxy substituted with (C1-C3)alkoxy,
hydroxy, halo(C1-C3)alkoxy, or (C1-C4)alkylthio,
(xi) (C2-C5)alkenyloxy,
(xii) (C2-C13)alkynyloxy
(xiii) halo-(C1-C6)alkyl,
(xiv) halo- (C1-C6)alkoxy,
(xv) (C2-C6)alkylthio,
(xvi) (C2-C10)alkanoyloxy,
(xvii) carboxy-(C2-C4)alkenyl,
(xviii) (C1-C3)alkylsulfonyloxy,
(xix) carboxy-(C1-C3)alkyl,
(xx) N- [di (C1-C3) -alkyl] amino- (C1-C3) alkoxy,
(xxi) cyano-(C1-C6)alkoxy, and
(xxii) diphenyl-(C1-C6) alkyl,
with the proviso that when R11 is (C1-C8)alkyl, (C1-C6) alkoxy, or
halo, p must be greater or equal to 2, or when R7 is (C1-C3
alkyl)-R8 then R11 is not hydrogen, (C1-C8)alkyl, (C1-C6)alkoxy,
or halo;
e) a group of the formula:

wherein q is 0 to 4;

R12 is independently selected from the group consisting of:
(i) halo,
(ii) nitro,
(iii) (C1-C6)alkyl,
(iv) (C1-C6)alkoxy,
(v) halo- (C1-C6)alkyl,
(vi) halo-(C1-C6)alkoxy,
(vii) hydroxy, and
(vii) (C1-C6)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 (C1-C6)alkyl unsubstituted or
substituted with hydroxy, (C1-C6)alkyl, or (C1-C6)alkoxy,
(iii) divalent (C2-C6)alkenyl
(iv) divalent (C2-C6)alkynyl and
(v) a group of the formula - (C (R14) 2)S-R15- or -R15-
[C(R14)2)s-, wherein s is 0-6; wherein each R14 substituent is
independently selected from hydrogen, (C1-C6)-alkyl, or (C4-C10)
cycloalkyl; and R15 is selected from -O-, -S-, -SO-, -SO2-,
-SO2-O-, -C(O)-, -OC(O)-, -C(O)0-, -NH-, -N(C1-C6 alkyl)-, and
-C(O)NH-, -NHC(O)-, N=N;
R13 is independently selected from the group consisting of:
(i) (C4-C10)heterocyclyl,
(ii) heteroaryl,
(iii) (C4-C10) cycloalkyl unsubstituted or substituted
with (C1-C6)alkyl, and
(iv) phenyl unsubstituted or substituted with 1 to 5
substituents independently selected from: halo, hydroxy, nitro,
(C1-C10) alkyl, (C1-C10)alkoxy, halo-(C1-C3)alkoxy, halo-(C1-
C3)alkyl, (C1-C3)alkoxyphenyl, phenyl, phenyl-(C1-C3) alkyl, (C1-
C6)alkoxyphenyl, phenyl-(C2-C3) alkynyl, and (C1-C6)alkylphenyl;
f) (C4-C10) cycloalkyl unsubstituted or substituted with one
or more substituents independently selected from the group
consisting of:
(i) (C1-C6)alkyl,
(ii) (C1-C6)alkoxy,

(iii) (C2-C6)alkenyl,
(iv) (C7-C6)alkynyl,
(v) (C4-C10)cycloalkyl,
(vi) phenyl,
(vii) phenylthio,
(viii) phenyl substituted by nitro, halo, (C1-
C6)alkanoyloxy, or carbocycloalkoxy, and
(ix) a group represented by the formula -Z-R13 wherein Z
and R13 are as defined above; and
g) a group of the formula:

wherein
A3 and A4 are each independently selected from
(i) a bond,
(ii) -O-,
(iii) -S(O)t-, wherein t is 0 to 2,
(iv) -C(R17)2-, wherein each R17 substituent is
independently selected from hydrogen, (C1-C6)alkyl, hydroxy,
(C1-C6)alkyl, (C1-C6)alkoxy, or both R17 substituents taken
together are O,
(v) -N(R18)2-. wherein each R18 substituent is
independently selected from hydrogen; (C1-C6)alkyl; (C1-
C6)alkenyl; (C2-C6)alkynyl; (C4-C10)cycloalkyl; phenyl; phenyl
substituted by nitro, halo, (C1-C6) alkanoyloxy; or both R18
substituents taken together are (C4-C10)cycloalkyl;
R16 is R12 or R13 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.

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, 0, 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 " (C4-C10)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 C5 to C10 cycloalkenyl groups such as
cyclopentenyl and cyclohexenyl. The term " (C4-C10)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- (C1-C6)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 (C1-C6)alkyl" represents an
unsubstituted or substituted, straight or branched divalent
alkyl chain having from one to six carbon atoms. Typical
divalent (C1-C6)alkyl groups include methylene, ethylene,
propylene, isopropylene, butylene, isobutylene, sec-butylene, t-
butylene, pentylene, neo-pentylene, and hexylene. Such divalent
(C1-C6)alkyl groups may be substituted with substituents such as
alkyl, alkoxy, and hydroxy.
The term "divalent (C2-C6)alkenyl" represents a straight or
branched divalent alkenyl chain having from two to six carbon
atoms. Typical divalent (C2-C6)alkenyl include ethenyl, 1-
propenyl, 2-propenyl, 1-butenyl, 2-butenyl and the like.
The term "divalent (C2-C6)alkynyl" represents a straight or
branched divalent alkynyl chain having from two to six carbon
atoms. Typical divalent (C2-C6)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- (C1-C6)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- (C1-C6)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- (C1-C6)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-(C1-C6)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,

aerylate, 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-1-
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
rounds of the formula:

The compounds of formula II are defined in Table 1.


aAbbreviations for the formula II compounds are: actin = actinosaminyl;
acos = acosaminyl; 4-epi = 4-epi-vancosaminyl; gal = galactosyl; keto = 4-
keto-vancosaminyl; man = mannose; rha = rhamnosyl; rha-gal = rhamnosyl-
galactosyl; risto = ristosaminyl; van = vancosaminyl.

preferred embodiment of the invention, the formula I
are prepared from the A82846 antibiotics (A82846A,
and A82846C) and PA-42867-A. in a more preferred
eliment, the compounds of the present invention are prepared
BA82846B ("A82846B derivatives"). A82846B is represented by
formula I compounds wherein R is 4 -epi~vancosaminyl, R1 is
hydrogen, R2 is NHCH3/ R3 is CH2CH(CH3)2, R4 is CH2(CO)NH2, R5 is
hydrogen, R6 is 4-epi-vancosaminy 1 and X and Y are Cl. A82846B
derivatives of the present invention having substituents at
position R7 of formula I are list herein in the manner "R7-
A82846B". For example, the compound "phenylbenzyl-A82846B" has a
phenylbenzyl substituent at position R7 in formula I.
Preferred formula I compounds include those A82846B
derivatives wherein R7 is - (C1-C12-alkyl) -R8, with -CH2.-R8 being
more preferred, and R8 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 R7 is - (C1-C12-alkyl)-R8, with -CH2-R8 being
more preferred, and R8 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 R7 is - (C1-C12-alkyl)-R8, with -CH2-
R8 being more preferred, and R8 is a group of the formula:

wherein p is 1 and R11 is selected from (C2-C5)alkenyloxy, halo-
(C1-C6)alkoxy, (C2-C10)alkanoyloxy, (C1-C3)alkoxy substituted
with (C1-C4)alkylthio, and dipheny1-(C1-C6) alkyl. Of this
group, trifluromethoxybenzyl-A8284 6B, diphenylmethylbenzyl-
A82846B, thiopropylethoxybenzyl-A82 846B, acetoxybenzyl-A82846B,
nonanoyloxybenzyl-A82846B, and tetrafluoroethoxybenzyl-A82846B
are more preferred.

f
urther preferred compounds of formula I include
B46B derivatives wherein R7 is - (C1-C12-alkyl) -R8, with
being more preferred, and R8 is a group of the formula:

H
erein q is o to 4; r is 1; Z is selected from a single bond,
lent (C1-C6)alkyl, divalent (C2-C6)alkenyl, and -R15-
S1(R14)2)s-, wherein R15 is selected from -O-, -S-, -SO2-, and
-OC(O)-, each R14 substituent is hydrogen, and s is 0 or 1; and
R13 is selected from: (C4-C10) cycloalkyl; phenyl; and phenyl
substituted by nitro, halo, (C1-C10) alkyl, (C1-C10) alkoxy, or
halo(C1-C3)alkyl. Of this group, chlorophenylbenzyl-A82846B,
phenylbenzyl-A82846B, benzylbenzyl-A82846B, methylphenylbenzyl-
A82846B, pentylphenylbenzyl-A82846B, methoxyphenylbenzyl-
A82846B, pentoxyphenylbenzyl-A82846B, nitrophenoxybenzyl-
A82846B, fluorophenylbenzyl-A82846B, phenylethynylbenzyl-
A82846B, phenoxybenzyl-A82846B, benzyloxybenzyl-A8284 6B,
nitrophenylbenzyl-A82846B, chlorophenoxybenzyl-A82846B,
chlorobenzyloxybenzyl-A82846B, butylphenoxybenzyl-A82846B,
trif luoromethylphenoxybenzyl-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 R7 is - (C1-C12-alkyl)-R8, with -CH2-
R8 being more preferred, and R8 is (C4-C10)cycloalkyl substituted
with (C4-C10) 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
o
dimethylformamide and methanol, at a temperature of about 25 C
to about 100 C. The reaction is preferably carried out at a

temperature from about 60 ºC to about 70 ºC 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 ºC to about 100 ºC 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 ºC to

about 70 ºC 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 ºC to about 100 ºC for 1 to 5 hours. The
reaction is preferably carried out at a temperature from about

60 ºC to about 70 ºC 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 ºC to about 100 ºC. The reaction is preferably carried
out at a temperature from about 60 C to about 70 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 R1 in
Formula II compounds) to other products (products that are
substituted at the amino groups of substitutents denoted as R
and/or R3 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 R3 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 C18 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% CH3CN at time=0
minutes to 20% aqueous buffer/80% CH3CN 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 x 300 mm steel) or Waters Nova-pak C18
RCM column (8 x 100 mm) with UV (235 nm or 280 nm) detection. A
30 minute gradient solvent system consisting of 95% aqueous
buffer/5% CH3CN at time=0 minute to 20% aqueous buffer/80% CH3CN
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 R1 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 R1 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 R3, and the amino group of the amino sugars designated
as R or R1 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 R3, and the amino group of the amino
sugars designated as R or R1 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 R1 in formula II with the sidechain listed. All of the
compounds listed are monosubstituted derivatives.

iisubstituted derivatives are the derivatives where a hydrogen
atom at two of the locations selected from the amino group at
position R3 and the amino group of the amino sugars designated
as R or R1 in formula II, are replaced by the reduced aldehyde
moiety. The trisubstituted derivatives are the derivatives
where a hydrogen atom at three cf the locations selected from
the amino group at position R3, and the amino group of the amino
sugars designated as P. or R1 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-giycosyi
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 giycopeptide antibiotics
other than A8284 6B. The compounds of Table 23 are
monosubstituted at the amino group of the amino sugar designated
as R1 in formula II with the sidechain listed. All of the
compounds listed are monosubstituted derivatives.



















The formula X 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.















































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 ED50 value
(effective dose in mg/kg to protect 50% of the test animals: see
W. Wick et al., J. Bacteriol. 81, 233-235 (1961)). ED50 values
observed for illustrative compounds are given in Table 4.





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-susceptible 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.













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 al., Reviews of Infectious Disease 12:602-610
(1990); Ruoff et 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.




Pharmaceutical formulations of the formula I compounds are
also part of this invention. Thus, the compound, preferably in
the form of a pharmaceuticaily acceptable salt, can be
formulated for oral or parenteral administration for the
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 3 0%. 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 5 0 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 operation 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°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°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% CH3CN/94.8% H2O with 0.2% TEAP
held constant and at 20 minutes was 60% CH3CN/3 9.8% H2O with
0.2% TEAP held constant. The UV wavelength used was 235 ran and
the flow rate was 2 ml/minute. Analysis was done using a Waters
Nova-pak C18 RCM column (8 X 100mm) with a Nova-pak C18 guard
insert. It is 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 H2O. 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•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 x 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-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, 0.2 9 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°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 x (40 x 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%
CH3CN to t = 30 minutes 20% TEAP/80% CH3CN) 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 CH3CN/H2O, CH3CN,
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 x 10-3 mol) and methanol (1000 mL) under a nitrogen
atmosphere. 4'-chlorobiphenylcarboxaldehyde (2.88 g, 1.33 x 10-
2 mol, 1.1 eq.) was added to this stirred mixture, followed by
methanol (500 mL). Finally, sodium cyanoborohydride (0.84 g,
1.33 x 10-2 mol, 1.1 eq.) was added followed by methanol (500
mL). The resulting mixture was heated to reflux (about 65°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°C). 1 N NaOH (22.8 mL) was added dropwise
to adjust the pH to 9.0 (at 54.7°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 40-45°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°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% CH3CN at time=0 minutes to
40% aqueous buffer/60% CH3CN at time=20 minutes was used, where
the aqueous buffer was TEAP (5 ml CH3CN, 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.













EXAMPLE 6
Capsule Formulation
Capsules containing 2 50 mg of Compound 2 are prepared using
the following ingredients:
Ingredient Weight
Compound 2 HCl salt 255.4 mg
Corn starch flowable powder 150 mg
Corn starch 144.6 mg
Compound 2 (HC1 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 mg
Corn starch flowable powder 150 mg
Corn 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 following 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
Lecithin 1%
Sodium citrate 2%
Propylparaben 0.015%
Distilled water q.s. to desired volume

EXAMPLE 10
Tablet Formulation
Tablets containing 250 rng 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 mg
Microcrystalline cellulose 101.1 mg
Croscarmellose sodium 12.0 mg
Providone 12.0 mg
Magnesium stearate 3.0 mg
Stearic acid 4.0 mg
Purified 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 mg
Microcrystalline cellulose 101.1 mg
Croscarmellose sodium 12.0 mg
Providone 12.0 mg
Magnesium stearate 3 . 0 mg
Stearic acid 4.0 mg
Purified water 0.16 ml

WE CLAIM:
1. A compound of the formula:

or salt thereof, wherein:
X and Y are each independently hydrogen or chloro;
R is hydrogen, 4-epi-vancosaminyl, actinosaminyl, or ristosaminyl;
R1 is hydrogen or mannose;
R2 is -NH2, -NHCH3, or -N(CH3)2;
R3 is -CH2CH(CH3)2, [p-OH, w-Cl]phenyl, p-rhamnose-phenyl, [p-rhamnose-
galactose]phenyl, [p-galactose-galactose]phenyl, or |p-CH3O-rhamnose]phenyl;
R4 is -CH2(CO)NH2, benzyl, [p-OH]phenyl or [p-OH, m-Cl]phenyl;
R5 is hydrogen or mannose;
R6 is 4-epi-vancosaminyl, L-acosaminyl, L-ristosaminyl, L-actinosaminyl or
vancosaminyl;
R7 is (C2-C16)alkenyl, (C2-C12)alkynyl, (C,-C12alkyl)-R8, (C1-C12alkyl)-halo, (C2-
C6alkenyl)-R , (C2-C6alkynyl)-R , or (C1-C12 alkyl)-O-R , and is attached to the amino group of
R6;
R8 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,

(in) nitro,
(iv)(C1-C6)alkyl,
(v) (C2-C6)alkenyl,
(vi) (C2-C6)alkynyl,
(vii)(C1-C6)alkoxy,
(viii) halo-(C1-C6)alkyl,
(ix) halo-(C1-C6)alkoxy,
(x) carbo-(C1-C6)alkoxy,
(xi) carbobenzyloxy,
(xii) carbobenzyloxy substituted with (C1-C6)alkyl, (C1-C6)alkoxy, halo, or nitro,
(xiii) a group of the formula -S(O)n-R9, wherein n' is 0-2 and R is (C1-C6)alkyl,
phenyl, or phenyl substituted with (C1-C6)alkyl, (C1-C6)alkoxy, halo, or nitro, and
(xiv) a group of the formula -C(O)N(R10)2 wherein each R10 substituent is
independently hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, phenyl, or phenyl
substituted with (C1-C6)-alkyl, (C1-C6)-alkoxy, halo, or nitro;
b) heteroaryl unsubstituted or substituted with one or more substituents independently
selected from the group consisting of:
(i) halo,
(ii) (C1C6)alkyl,
(iii)(C1-C6)alkoxy,
(iv)halo-(C1-C6)alkyl,
(v) halo-(C1-C6)alkoxy,
(vi) phenyl,
(vii) thiophenyl,
(viii) phenyl substituted with halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(C1-C6)alkoxy, or nitro,
(ix) carbo-(C1-C6)alkoxy,
(x) carbobenzyloxy,
(xi) carbobenzyloxy substituted with (C1-C6)alkyl, (C1-C6)aIkoxyl, halo, or nitro,
(xii) a group of the formula -S(O)n'-R , as defined above,
(xiii) a group of the formula -C(O)N(Rl0)2 as defined above, and
(xiv) thienyl;
c) a group of the formula:

wherein A1 is -OC(A2)2-C(A2)2-O-, -O-C(A2)2-O-, -C(A2)2-O-, or -C(A2)2-C(A2)2-C(A2)2-
C(A2)2-, and each A2 substituent is independently selected from hydrogen, (C1-C6)-alkyl, (C1-
C6)alkoxy, and (C4-C10)cycloalkyl;
d) a group of the formula:


wherein p is from 1 to 5, and R11 is independently selected from the group consisting of:
(i) hydrogen,
(ii) nitro,
(iii) hydroxy,
(iv) halo,
(v) (C1-C8)alkyl,
(vi)(C1-C8)alkoxy,
(vii) (C9-C12)alkyl,
(viii) (C2-C9)alkynyl,
(ix) (C9-C12)alkoxy,
(x) (C1-C3)alkoxy substituted with (C1-C3)alkoxy, hydroxy, halo(C1-C3)alkoxy, or
(C1-C4)alkylthio,
(xi) (C2-C6)alkenyloxy,
(xii) (C2-C13)alkynyloxy
(xiii) halo-(C1-C6)alkyl,
(xiv) halo-(C1-C6)alkoxy,
(xv) (C2-C6)alkylthio,
(xvi) (C2-C10)alkanoyloxy,
(xvii) carboxy-(C2-C4)alkenyl,
(xviii) (C1-C3)alkylsulfonyloxy,
(xix) carboxy-(C1-C3)alkyl,
(xx)N-[di(C1-C3)-alkyl]amino-(C1-C8)alkoxy,
(xxi) cyano-(C1-C6)alkoxy, and
(xxii) diphenyl-(C1-C6)alkyl,
with the proviso that when R11 is (C1-C8)alkyl, (C1-C6)alkoxy, or halo, p must be
greater or equal to 2, or when R7 is (C1-C3alkyl)-R8 then R11 is not hydrogen, (C1-
C8)alkyl, (C1-C8)alkoxy, or halo;
e) a group of the formula:

wherein q is 0 to 4;
R12 is independently selected from the group consisting of:
(i) halo,
(ii) nitro,
(iii) (C1-C6)alkyl,
(iv) (C1-C6)alkoxy,

(v) halo-(C1-C6)alkyl,
(vi)halo-(C1-C6)alkoxy,
(vii) hydroxy, and
(vii) (C1-C6)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 (C1-C6)alkyl unsubstituted or substituted with hydroxy, (C1-
C6)alkyl, or (C1-C6)alkoxy,
(iii) divalent (C2-C6)alkenyl,
(iv) divalent (C2-C6)alkynyl, or
(v) a group of the formula -(C(R14)2)S-R15- or -R15-(C(R14)2)s-, wherein s is 0-6;
wherein each R14 substituent is independently selected from hydrogen, (C1-
C6)-aIkyl, or (C4-C10) cycloalkyl; and R15 is selected from -O-, -S-, -SO-, -
SO2-, -SO2-O-, -C(O)-, -OC(O)-, -C(O)O-, -NH-, -N(C1-C6 alkyl)-, and -
C(O)NH-, -NHC(O)-, -N=N-;
R13 is independently selected from the group consisting of:
(i) (C4-C10)heterocyclyl,
(ii) heteroaryl,
(iii) (C4-C10)cycloalkyl unsubstituted or substituted with (C1-C6)alkyl, or
(iv) phenyl unsubstituted or substituted with 1 to 5 substituents independently
selected from: halo, hydroxy, nitro, (C1-C]0)alkyl, (C1-C10)alkoxy, halo-(C1-
C3)alkoxy, halo-(C1-C3)alkyl, (C1-C3)alkoxyphenyl, phenyl, phenyl-(C1-C3)alkyl,
(C1-C6)alkoxyphenyl, phenyl-(C2-C3)alkynyl, and (C1-C6)alkylphenyl;
f) (C4-C10)cycloalkyl unsubstituted or substituted with one or more substituents
independently selected from the group consisting of:
(i) (C1-C6)alkyl,
(ii) (C1-C6)alkoxy,
(iii) (C2-C6)alkenyl,
(iv) (C2-C6)alkynyl,
(v) (C4-C10)cycloalkyl,
(vi) phenyl,
(vii) phenylthio,
(viii) phenyl substituted by nitro, halo, (C1-C6)alkanoyloxy or carbocycloalkoxy,
and
(ix) a group represented by the formula -Z-R13 wherein Z and R1 are as defined
above; and
g) a group of the formula:


wherein A and A4 are each independently selected from
(i) a bond,
(ii) -O-,
(iii) -S(O),-, wherein t is 0 to 2,
(iv) -C(R17)2-, wherein each R17 substituent is independently selected from
hydrogen, (C1-C6)alkyl, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, or both R17
substituents taken together are O,
(v) -N(R18)2-, wherein each R18 substituent is independently selected from
hydrogen; (C1-C6)alkyl; (C2-C6)alkenyl; (C2-C6)alkynyl; (C4-C10)cycloalkyl;
phenyl; phenyl substituted by nitro, halo, (C1-C6)alkanoyloxy; or both R18
substituents taken together are (C4-C10)cycloalkyl;
R16 is R12 or R13 as defined above; and
u is 0-4;
other than the compounds where R, R1 and R5 are H, R3 is -CH2CH(CH3)2, R4 is
-CH2(CO)NH2, R6 is vancosaminyl, X and Y are chloro and
R7 is 6-bromo-n-hexyl and R2 is NHCH3,
R7 is 3-phenyl-n-(prop-2-enyl) and R2 is NHCH3,
R7 is (pyrid-3-yl)methyl and R2 is NHCH3,
R7 is (indo-3-yl)methyl and R2 is NHCH3,
R7 is (adamant-l-yl)methyl and R2 is NHCH3,
R7 is (pyrid-3-yl)methyl and R2 is N(CH3)2,
R7 is cyclohexylmethyl and R2 is NHCH3,
R7 is pyrrol-2-ylmethyl and R2 is NUCH3,
R7 is pyridin-2-ylmethyl and R2 is NHCH3,
R7 is furan-2-ylmethyl and R2 is NHCH3,
R7 is 6-nitro-3,4-dimethoxybenzyl and R2 is NHCH3, and
R7 is p-hydroxybenzyl and R2 is NHCH3,
and salts of these compounds.
2. A compound of the formula:


or salt thereof, wherein:
X and Y are each independently hydrogen or chloro;
R is hydrogen, 4-epi-vancosaminyl, actinosaminyl, or ristosaminyl;
R1 is hydrogen or mannose;
R2 is -NH2, -NHCH3, or-N(CH3)2;
R3 is -CH2CH(CH3)2, phenyl, [p-OH, m-Cl [phenyl, p-rhamnose-phenyl, or [p-
rhamnose-galactose]phenyl;
R4 is -CH2(CO)NH2, benzyl, [p-OH]phenyl, or [p-OH, m-Cl]phenyl;
R5 is hydrogen or mannose;
R6 is 4-epi-vancosaminyl, L-acosaminyl, L-ristosaminyl or L-actinosaminyl;
R7 is -(CH2)n-R8, or -C(CH3)CH-R8, and is attached to the amino group of R6;
n is 1-10;
R8 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)(C1-C6)alkyl,
(v) (C2-C6)alkenyl,
(vi) (C2-C6)alkynyl,
(vii)(C1-C6)alkoxy,
(viii) halo-(C1-C6)alkyl,


(ix) halo-(C1-C6)alkoxy,
(x) carbo-(C1-C6)alkoxy,
(xi) carbobenzyloxy,
(xii) carbobenzyloxy substituted with (C1-C6)alkyl, (C1-C6)alkoxy, halo, or nitro,
(xiii) a group of the formula -S(O)n'-R9, wherein n' is 0-2 and R is (C1-C6)alkyl,
phenyl, or phenyl substituted with (C1-C6)alkyl, (C1-C6)alkoxy, halo, or nitro, and
(xiv) a group of the formula -C(O)N(Rl0)2 wherein each R10 substituent is
independently hydrogen, (C1-C6-alkyl, (C1-C6)-alkoxy, phenyl, or phenyl
substituted with (C1-C6)-alkyl, (C1-C6)-alkoxy, halo, or nitro;
b) heteroaryl unsubstituted or substituted with one or more substituents
independently selected from the group consisting of:
(i) halo,
(ii) (C1-C6)alkyl,
(iii) (C1-C6)alkoxy,
(iv) halo-(C1-C6)alkyl,
(v) halo-(C1-C6)alkoxy,
(vi) phenyl,
(vii) thiophenyl,
(viii) phenyl substituted with halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(C1-C6)alkoxy, or nitro,
(ix) carbo-(C1-C6)alkoxy,
(x) carbobenzyloxy,
(xi) carbobenzyloxy substituted with (C1-C6)alkyl, (C1-C6)alkoxy, halo, or nitro,
(xii) a group of the formula -S(O)n'-R , as defined above, and
(xiii) a group of the formula -C(O)N(Rl0)2 as defined above;
c) a group of the formula:

wherein A1 is -OC(A2)2-C(A2)2-O-, -O-C(A2)2-O-, -C(A2)2-O-, or -C(A2)2-C(A2)2-C(A2)2-
C(A2)2-, and each A2 substituent is independently selected from hydrogen, (C1-C6)-alkyl, (C1-
C6)alkoxy, and (C4-C10)cycloalkyl;
d) a group of the formula:
wherein p is from 1 to 5; and R11 is independently selected from the group consisting of:
(i) nitro,

(ii) hydroxy,
(iii) (C9-C12)alkyl,
(iv) (C9-C12)alkoxy,
(v) (C2-C6)alkenyloxy,
(vi) halo-(C1-C6)alkyl,
(vii) halo-(C1-C6)alkoxy,
(viii) (C2-C6)alkylthio,
(ix) (C2-C6)alkynyl,
(x) (C2-C10)alkanoyloxy,
(xi) carboxy-(C2-C4)alkenyl,
(xii) (C1-C3)alkylsulfonyloxy,
(xiii) carboxy-(C1-C3)alkyl,
(xiv) (C1-C3)alkoxy substituted with (C1-C3)alkoxy, hydroxy, halo(C1-C3)alkoxy,
or (C1-C4)alkylthio,
(xv) N-[di(C1-C3)-alkyl]amino-(C1-C3)alkoxy,
(xvi) cyano-(C1-C6)alkoxy,
(xvii) (C1-C12)alkyl, (C1-C12)alkoxy, or halo when p is greater or equal to 2,
(xviii) diphenyl-(C1-C6)alkyl, and
(xix) hydrogen, (C1-C6)alkyl, or (C1-C6)alkoxy when n greater or equal to 4;
e) a group of the formula:

wherein q is 0 to 4;
R12 is independently selected from the group consisting of:
(i) halo,
(ii) nitro,
(iii)(C1-C6)alkyl,
(iv)(C1-C6)alkoxy,
(v) halo-(C1-C6)alkyl,
(vi) halo-(C1-C6)alkoxy,
(vii) hydroxy, and
(vii) (C1-C6)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 (C1-C6)alkyl unsubstituted or substituted with hydroxy, (C1-C6)alkyl,
or (C1-C6)alkoxy,
(iii) divalent (C2-C6)alkenyl,
(iv) divalent (C2-C6)alkynyl, or


(v) a group of the formula -(C(R14)2)S-R15- or -R15-(C(R14)2)S-, wherein s is 0-6;
each R14 substituent is independently selected from hydrogen, (C1-C6)-alkyl, or
(C4-C10)cycloalkyl; and R15 is selected from -O-, -S-, -SO-, -SO2-, -SO2-O-, -
C(O)-, -OC(O)-, -C(O)O-, -NH-, -N(C1-C6alkyl)-, and -C(O)NH-;
R13 is independently selected from the group consisting of:
(i) (C4-C10)heterocyclyl,
(ii) heteroaryl,
(iii) (C4-C10)cycloalkyl unsubstituted or substituted with (C1-C6)alkyl, or
(iv) phenyl unsubstituted or substituted with 1 to 5 substituents independently
selected from: halo, hydroxy, nitro, (C1-C10)alkyl, (C1-C10)alkoxy, halo-(C1-
C3)alkoxy, halo-(C1-C3)alkyl, (C1-C3)alkoxyphenyl, phenyl, phenyl-(C1-C3)alkyl,
(C1-C6)alkoxyphenyl, phenyl-(C2-C3)alkynyl, and (C1-C6)alkylphenyl;
f) (C4-C10)cycloalkyl unsubstituted or substituted with one or more substituents
independently selected from the group consisting of:
(i) (C1-C6)alkyl,
(ii)(C1-C6)alkoxy,
(iii) (C2-C6)alkenyl,
(iv) (C2-C6)alkynyl,
(v)(C4-C10)cycloalkyl,
(vi) phenyl,
(vii) phenylthio,
(viii) phenyl substituted by nitro, halo, (C1-C6)alkanoyloxy or carbocycloalkoxy,
and
(ix) a group represented by the formula -Z-R13 wherein Z and R13 are as defined
above; and
g) a group of the formula:

wherein:
A3 and A4 are each independently selected from
(i) a bond,
(ii) -O-,
(iii) S(O)t-, wherein t is 0 to 2,
(iv) -C(R17)2-, wherein each R17 substituent is independently selected from
hydrogen, (C1-C6)alkyl, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, or both R17
substituents taken together are O,
(v) -N(R18)2-, wherein each R18 substituent is independently selected from
hydrogen; (C1-C6)alkyl; (C2-C6)alkenyl; (C2-C6)alkynyl; (C4-C10)cycloalkyl;


phenyl; phenyl substituted by nitro, halo, (C1-C6)alkanoyloxy; or both R18
substituents taken together are (C4-C10)cycloalkyl;
R16 is R12 or R13 as defined above; and
u is 0-4.
3. A compound as claimed in Claim 1 wherein R is 4-epi-vancosaminyl, R1 is
hydrogen, R2 is NHCH3, R3 is CH2CH(CH3)2, R4 is CH2(CO)NH2, R5 is hydrogen, R6 is 4-epi-
vancosaminyl, X is H or Cl and Y is Cl.
4. A compound as claimed in Claim 2 wherein R is 4-epi-vancosaminyl, R1 is
hydrogen, R2 is NHCH3, R3 is CH2CH(CH3)2, R4 is CH2(CO)NH2, R5 is hydrogen, R6 is 4-epi-
vancosaminyl, X is H or Cl and Y is Cl.
5. A compound as claimed in Claim 1 wherein R is 4-epi-vancosaminyl, R1 is
hydrogen, R2 is NHCH3, R3 is CH2CH(CH3)2, R4 is CH2(CO)NH2, R5 is hydrogen, R6 is 4-epi-
vancosaminyl, and X and Y are Cl.
6. A compound as claimed in Claim 2 wherein R is 4-epi-vancosaminyl, R1 is
hydrogen, R2 is NHCH3, R3 is CH2CH(CH3)2, R4 is CH2(CO)NH2, R5 is hydrogen, R6 is 4-epi-
vancosaminyl, and X and Y are Cl.
7. A compound as claimed in any of Claims 1-6 in which R7 = -CH2-R8.
8. A compound as claimed in any of Claims 1-7 in which R8 is multicyclic aryl,
which compound is selected from naphthylmethyl-A82846B, acenapthlenyl-methyl-A82846B,
and fluorenylmethyl-A82846B.
9. A compound as claimed in any of Claims 1-7 in which R8 is heteroaryl, which
compound is selected from [1-oxa]fluorenylmethyl-A82846B, chlorophenylbenzoxazolemethyl-
A82846B, and phenylthienylmethyl-A82846B
10. A compound as claimed in any of Claims 1-7 in which R8 is

wherein p is 1 and R11 is selected from (C2-C5)alkcnyloxy, halo-(C1-C6)alkoxy,
(C2-Cl0)alkanoyloxy, (C1-C3)alkoxy substituted with (C1-C4)alkylthio, and diphenyl-(C1-C6)alkyl.
11. A compound as claimed in any of Claims 1-7 in which R8 is



wherein q is 0 to 4; r is 1; Z is selected from a single bond, divalent (C1-C6)alkyl, divalent
(C2-C6)alkenyl, and -RI5-(C(R14)2)s-, wherein R15 is selected from -O-, -S-, -SO2-, and -OC(O)-,
each R14 substituent is hydrogen, and s is 0 or 1: and R13 is selected from (C4-C10)cycloalkyl,
phenyl, and phenyl substituted by nitro, halo, (C1-C10)alkyl, (C1-C10)alkoxy or halo(C1-C3)alkyl.
12. A compound as claimed in any of claims 1-5 in which R8 is (C4-C10) cycloalkyl as defined.
13. A compound as claimed in Claim 7, wherein the compound of formula (I) is
chlorophenylbenzyl-A82846B,
phenylbenzyl-A82846B,
benzylbenzyl-A82846B,
methylphenylbenzyl-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,
cyclohexylbenzyl-A82846B,
cyclohexylethoxybenzyl-A82846B,
chlorophenoxynitro-benzyl-A82846B,
benzylmethoxybenzyl-A82846B,
chlorophenoxynitro-benzyl-A82846B,
phenoxymethoxybenzyl-A82846B,


benzoyloxy-dimethoxybenzyl-A82846B,
cyclohexanoyloxy-dimethylbenzyl-A82846B,
trifluoromethylphenylbenzyl-A82846B,
butylphenylthiobenzyl-A82846B, or
bromophenylbenzyl-A82846B,
or a salt thereof.
14. The compound 4-phenylbenzyl-A82846B or a salt thereof.
15. A pharmaceutical composition comprising a compound as claimed in claims 1 to
14, or a pharmaceutically acceptable salt thereof, along with one or more pharmaceutically
acceptable carriers therefor.
16. A pharmaceutical composition as claimed in claim 15 for use in treating
susceptible bacterial infections.
17. A process for the preparation of a compound as claimed in any one of claims 1 to
14 which comprises
a) reacting in methanol at about 25°C to about 100°C under an inert atmosphere:
i) a glycopeptide antibiotic of the formula:


wherein:
X and Y are each independently hydrogen or chloro;
R is hydrogen, 4-epi-vancosaminyl. actinosaminyl or ristosaminyl;
R1 is 4-epi-vancosaminyl, acosaminyl, ristosaminyl, 4-keto-vancosaminyl or
vancosaminyl;
R2 is hydrogen or mannose;
R3 is -NH2, -NHCH3, or -N(CH3)2;
R4 is -CH2CH(CH3)2, [p-OH, m-Cl]phenyl, p-rhamnose-phenyl, [p-rhamnose-
galactose]phenyl, [p-galactose-galactose]phenyl or [p-CH3O-rhamnose]phenyl;
R5 is -CH2(CO)NH2, benzyl, [p-OH]phenyl or [p-OH, m-Cl]phenyl; and
R6 is hydrogen or mannose, with
ii) an aldehyde corresponding to the group R7 as defined in claim 1 at about 25°C
to about 100°C;
b) continuing the reaction until formation of a Schiffs base; and
c) reducing the Schiffs base by addition of a metal borohydride to the mixture at 25°C to
about 100°C.
18. A process for the preparation of a compound as claimed in any one of claim 1 to
14 which comprises reacting in a polar solvent at about 25°C to about 100°C under an inert
atmosphere:


i) a glycopeptide antibiotic of the formula:

wherein:
X and Y are each independently hydrogen or chloro;
R is hydrogen, 4-epi-vancosaminyl, actinosaminyl, or ristosaminyl;
R1 is 4-epi-vancosaminyl, acosaminyl, ristosaminyl, 4-keto-vancosaminyl or
vancosaminyl;
R2 is hydrogen or mannose;
R3 is -NH2, -NHCH3, or -N(CH3)2;
R4 is -CH2CH(CH3)2, [p-OH, m-Cl]phenyl, p-rhamnose-phenyl, [p-rhamnose-
galactose]phenyl, [p-galactose-galactose]phenyl or [p-CH3O-rhamnose]phenyl;
R5 is -CH2(CO)NH2, benzyl, [p-OH]phenyl or [p-OH, m-Cl]phenyl; and
R6 is hydrogen or mannose, with
ii) an aldehyde corresponding to the group R7 as defined in claim 1, in the presence of
iii) a reducing agent selected from a metal borohydride and a homogeneous or
heterogeneous catalytic hydrogenation agent or agents; for a time sufficient to produce a
compound of any one of claims 1 to 14.
19. The process as claimed in claim 18, wherein the reducing agent is sodium
cyanoborohydride, and the reaction is carried out for about 20 to 28 hours at a temperature of
about 60°C to about 70°C.


20. The process as claimed in claim 18, wherein the aldehyde is 4'-
biphenylcarboxaldehyde.
21. The process as claimed in claim 18 wherein the aldehyde is 4-chloro-4'-
biphenylcarboxaldehyde.
22. A compound as claimed in the formula (I)

or salt thereof, wherein:
R6 is vancosaminyl;
R7 is (C1-C12 alkyl)-R8 or (C2-C6 alkenyl)-R8, and is attached to the amino group of R6;
R8 is selected from the group consisting of:
a) heteroaryl substituted with one or more substituents independently selected
from the group consisting of:
(i) phenyl,
(ii) phenyl substituted with halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-
C6)alkynyl, (C1-C6)alkoxy, or nitro,
(iii) a group of the formula -S(O)n'-R9. wherein n' is 0-2 and R9 is (C1-
C6)alkyl, phenyl or phenyl substituted with (C1-C6)alkyl, (C1-C6)alkoxy,
halo or nitro, and


(iv) thienyl;
b) a group of the formula:
wherein:
q is 0 to 4;
R12 is independently selected from the group consisting of:
(i) halo,
(ii) nitro,
(iii) (C1-C6)alkyl,
(iv) (C1-C6)alkoxy,
(v) halo-(C1-C6)alkyl,
(vi) halo-(C1-C6)alkoxy,
(vii) hydroxy, and
(vii)(C1-C6)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 (C1-C6)alkyl unsubstituted or substituted with hydroxy,
(C1-C6)alkyl, or (C1-C6)alkoxy,
(iii) divalent (C2-C6)alkenyl,
(iv) divalent (C2-C6)alkynyl, or
(v) a group of the formula -(C(R14)2)S-R15- or -R15-(C(R14)2)S-,
wherein s is 0-6; wherein each R14 substituent is independently
selected from hydrogen. (C1-C6)-alkyl, or (C4-C10) cycloalkyl; and
R15 is selected from -O-, -S-, -SO-, -SO2-, -SO2-O-, -C(O)-,
-OC(O)-, -C(O)O-, -NH-, -N(C1-C6alkyl)-, -C(O)NH-, -NHC(O)-,
and N=N;
R13 is independently selected from the group consisting of:
(i) heteroaryl, and
(ii) phenyl unsubstituted or substituted with 1 to 5 substituents
independently selected from halo, hydroxy, nitro, (C1-C10)alkyl,
(C1-C10)alkoxy, halo-(C1-C3)alkoxy, halo-(C1-C3)alkyl,
(C1-C3)alkoxyphenyl, phenyl, phenyl-(C1-C3)alkyl,
(C1-C6)alkoxyphenyl, phenyl-(C2-C3)alkynyl and
(C1-C6)alkylphenyl; and
c) a group of the formula:



wherein
A3 and A4 are each independently selected from
(i) a bond,
(ii) -O-,
(iii) -S(O),-, wherein t is 0 to 2,
(iv) -C(R17)2-, wherein each R17 substituent is independently selected from
hydrogen, (C1-C6)alkyl, hydroxy, (C1-C6)alkyl,(C1-C6)alkoxy, or both R17
substituents taken together are O,
(v) -N(R18)2-, wherein each R18 substituent is independently selected from
hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkyny, (C4-C10)cycloalkyl,
phenyl, phenyl substituted by nitro, halo, (C1-C6)alkanoyloxy, or both R18
substituents taken together are (C4-C10)cycloalkyl;
R16 is R12 or R13 as defined above; and
u is 0-4.
23. A compound as claimed in claim 22 wherein R7 is -CH2-R8.
24. A compound as claimed in claim 22, wherein R8 is

as defined.
25. A pharmaceutical composition comprising a compound as claimed in any of
claims 22-24, along with one or more pharmaceutically-acceptable carriers thereof.



Field of Invention:
The present invention relates to a glycopeptide derivative of the formula 1 and the
process of preparation of the compound thereof. The present invention further relates to
compounds possessing antibacterial activity against vancomycin-resistant isolates.


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,
therefore, 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. Patent 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 July 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. Patent 3,067,099); A82846A, A82846B and
A82846C (U.S. Patent 5,312,738, European Patent Publication 256,071 Al); PA-42867
factors A, C, and D (U.S. Patent No.5,187,082); avoparcin (U.S. Patent 3.338,786 and
U.S. Patent No.4,322,343); actinoidin, also known as K288 (J. Antibiotics SAeries 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 Report 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.
The present invention provides compounds of the formula I:


or salt thereof, wherein:
X and Y are each independently hydrogen or chloro;
R is hydrogen, 4-epi-vancosaminyl, actinosaminyl, or
ristosaminyl;
R1 is hydrogen, or mannose;
R2 is -NH2, -NHCH3, or-N(CH3)2;
R3 is -CH2CH(CH3)2, [p-OH, m-Cl]phenyl, p-rhamnose-phenyl, or
[p-rhamnose-galactose]phenyl, [p-galactose-galactose]phenyl, [p-
CH30-rhamnose]phenyl;
R4 is -CH2(CO)NH2, benzyl, [p-OH]phenyl, or [p-OH, m-
Cl]phenyl;
R5 is hydrogen, or mannose;
R6 is 4-epi-vancosaminyl, L-acosaminyl, L-ristosaminyl, or L-
actinosaminyl;
R7 is (C2-C16)alkenyl, (C2-C12)alkynyl, (C1-C12 alkyl)-R8, (C1-
C12 alkyl)-halo, (C2-C6 alkenyl)-R8, (C2-C6 alkynyl)-R8, (C1-C12
alkyl)-0-R8, and is attached to the amino group of R6;
R8 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) (C1-C6)alkyl,
(v) (C2-C6)alkenyl,
(yi) (C2-C6)alkynyl,
(vii) (C1-C6)alkoxy,
(viii) halo-(C1-C6)alkyl,
(ix) halo-(C1-C6)alkoxy,
(x) carbo-(C1-C6)alkoxy,
(xi) carbobenzyloxy,
(xii) carbobenzyloxy substituted with (C1-C6) alkyl, (C1-
C6)alkoxy, halo, or nitro,
(xiii) a group of the formula -S(O)n'-R9, wherein n' is 0-2
and R9;is (C1-C6) alkyl, phenyl, or phenyl substituted with (C1-
C6)alkyl, (C1-C6)alkoxy, halo, or nitro, and

(xiv) a group of the formula -C(O)N(R10)2 wherein each R10
substituent is independently hydrogen, (C1-C6)-alkyl, (C1-C6)-
alkoxy, phenyl, or phenyl substituted with (C1-C6)-alkyl, (C1-
C6)-alkoxy, halo, or nitro;
b) heteroaryl unsubstituted or substituted with one or more
substituents independently selected from the group consisting
of:
(i) halo,
(ii) (C1-C6)alkyl,
(iii) (C1-C6)alkoxy,
(iv) halo- (C1-C6)alkyl,
(v) halo-(C1-C6)alkoxy,
(vi) phenyl,
(vii) thiophenyl,
(viii) phenyl substituted with halo, (C1-C6)alkyl, (C2-
C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, or nitro,
(ix) carbo-(C1-C6)alkoxy,
(x) carbobenzyloxy,
(xi) carbobenzyloxy substituted with (C1-C6)alkyl, (C1-C6)
alkoxy, halo, or nitro,
(xii) a group of the formula -S(O)n'-R9, as defined above,
(xiii) a group of the formula -C(O)N(R10)2 as defined
above, and
(xiv) thienyl;
c) a group of the formula:

wherein A1 is -OC (A2)2-C (A2) 2-O- , -O-C (A2)2-O-, -C (A2) 2-O-,
or -c(A2)2-C (A2)2-C (A2)2-C(A2)2-, and each A2 substituent is
independently selected from hydrogen, (C1-C6)-alkyl, (C1-
C6) alkoxy, and (C4-C10) cycloalkyl;
d) a group of the formula:


wherein p is from 1 to 5; and
R11 is independently selected from the group consisting of:
(i) hydrogen,
(ii) nitro,
(iii) hydroxy,
(iv) halo,
(v) (C1-C8)alkyl.
(vi) (C1-C8)alkoxy,
(vii) (C9-C12)alkyl,
(viii)(C2-C9)alkynyl,
(ix) (C9-C12)alkoxy,
(x) (C1-C3)alkoxy substituted with (C1-C3)alkoxy,
hydroxy, halo(C1-C3)alkoxy, or (C1-C4)alkylthio,
(xi) (C2-C5)alkenyloxy,
(xii) (C2-C13)alkynyloxy
(xiii) halo-(C1-C6)alkyl,
(xiv) halo- (C1-C6)alkoxy,
(xv) (C2-C6)alkylthio,
(xvi) (C2-C10)alkanoyloxy,
(xvii) carboxy-(C2-C4)alkenyl,
(xviii) (C1-C3)alkylsulfonyloxy,
(xix) carboxy-(C1-C3)alkyl,
(xx) N- [di (C1-C3) -alkyl] amino- (C1-C3) alkoxy,
(xxi) cyano-(C1-C6)alkoxy, and
(xxii) diphenyl-(C1-C6) alkyl,
with the proviso that when R11 is (C1-C8)alkyl, (C1-C6) alkoxy, or
halo, p must be greater or equal to 2, or when R7 is (C1-C3
alkyl)-R8 then R11 is not hydrogen, (C1-C8)alkyl, (C1-C6)alkoxy,
or halo;
e) a group of the formula:

wherein q is 0 to 4;

R12 is independently selected from the group consisting of:
(i) halo,
(ii) nitro,
(iii) (C1-C6)alkyl,
(iv) (C1-C6)alkoxy,
(v) halo- (C1-C6)alkyl,
(vi) halo-(C1-C6)alkoxy,
(vii) hydroxy, and
(vii) (C1-C6)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 (C1-C6)alkyl unsubstituted or
substituted with hydroxy, (C1-C6)alkyl, or (C1-C6)alkoxy,
(iii) divalent (C2-C6)alkenyl
(iv) divalent (C2-C6)alkynyl and
(v) a group of the formula - (C (R14) 2)S-R15- or -R15-
[C(R14)2)s-, wherein s is 0-6; wherein each R14 substituent is
independently selected from hydrogen, (C1-C6)-alkyl, or (C4-C10)
cycloalkyl; and R15 is selected from -O-, -S-, -SO-, -SO2-,
-SO2-O-, -C(O)-, -OC(O)-, -C(O)0-, -NH-, -N(C1-C6 alkyl)-, and
-C(O)NH-, -NHC(O)-, N=N;
R13 is independently selected from the group consisting of:
(i) (C4-C10)heterocyclyl,
(ii) heteroaryl,
(iii) (C4-C10) cycloalkyl unsubstituted or substituted
with (C1-C6)alkyl, and
(iv) phenyl unsubstituted or substituted with 1 to 5
substituents independently selected from: halo, hydroxy, nitro,
(C1-C10) alkyl, (C1-C10)alkoxy, halo-(C1-C3)alkoxy, halo-(C1-
C3)alkyl, (C1-C3)alkoxyphenyl, phenyl, phenyl-(C1-C3) alkyl, (C1-
C6)alkoxyphenyl, phenyl-(C2-C3) alkynyl, and (C1-C6)alkylphenyl;
f) (C4-C10) cycloalkyl unsubstituted or substituted with one
or more substituents independently selected from the group
consisting of:
(i) (C1-C6)alkyl,
(ii) (C1-C6)alkoxy,

(iii) (C2-C6)alkenyl,
(iv) (C7-C6)alkynyl,
(v) (C4-C10)cycloalkyl,
(vi) phenyl,
(vii) phenylthio,
(viii) phenyl substituted by nitro, halo, (C1-
C6)alkanoyloxy, or carbocycloalkoxy, and
(ix) a group represented by the formula -Z-R13 wherein Z
and R13 are as defined above; and
g) a group of the formula:

wherein
A3 and A4 are each independently selected from
(i) a bond,
(ii) -O-,
(iii) -S(O)t-, wherein t is 0 to 2,
(iv) -C(R17)2-, wherein each R17 substituent is
independently selected from hydrogen, (C1-C6)alkyl, hydroxy,
(C1-C6)alkyl, (C1-C6)alkoxy, or both R17 substituents taken
together are O,
(v) -N(R18)2-. wherein each R18 substituent is
independently selected from hydrogen; (C1-C6)alkyl; (C1-
C6)alkenyl; (C2-C6)alkynyl; (C4-C10)cycloalkyl; phenyl; phenyl
substituted by nitro, halo, (C1-C6) alkanoyloxy; or both R18
substituents taken together are (C4-C10)cycloalkyl;
R16 is R12 or R13 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.

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, 0, 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 " (C4-C10)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 C5 to C10 cycloalkenyl groups such as
cyclopentenyl and cyclohexenyl. The term " (C4-C10)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- (C1-C6)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 (C1-C6)alkyl" represents an
unsubstituted or substituted, straight or branched divalent
alkyl chain having from one to six carbon atoms. Typical
divalent (C1-C6)alkyl groups include methylene, ethylene,
propylene, isopropylene, butylene, isobutylene, sec-butylene, t-
butylene, pentylene, neo-pentylene, and hexylene. Such divalent
(C1-C6)alkyl groups may be substituted with substituents such as
alkyl, alkoxy, and hydroxy.
The term "divalent (C2-C6)alkenyl" represents a straight or
branched divalent alkenyl chain having from two to six carbon
atoms. Typical divalent (C2-C6)alkenyl include ethenyl, 1-
propenyl, 2-propenyl, 1-butenyl, 2-butenyl and the like.
The term "divalent (C2-C6)alkynyl" represents a straight or
branched divalent alkynyl chain having from two to six carbon
atoms. Typical divalent (C2-C6)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- (C1-C6)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- (C1-C6)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- (C1-C6)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-(C1-C6)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,

aerylate, 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-1-
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
rounds of the formula:

The compounds of formula II are defined in Table 1.


aAbbreviations for the formula II compounds are: actin = actinosaminyl;
acos = acosaminyl; 4-epi = 4-epi-vancosaminyl; gal = galactosyl; keto = 4-
keto-vancosaminyl; man = mannose; rha = rhamnosyl; rha-gal = rhamnosyl-
galactosyl; risto = ristosaminyl; van = vancosaminyl.

preferred embodiment of the invention, the formula I
are prepared from the A82846 antibiotics (A82846A,
and A82846C) and PA-42867-A. in a more preferred
eliment, the compounds of the present invention are prepared
BA82846B ("A82846B derivatives"). A82846B is represented by
formula I compounds wherein R is 4 -epi~vancosaminyl, R1 is
hydrogen, R2 is NHCH3/ R3 is CH2CH(CH3)2, R4 is CH2(CO)NH2, R5 is
hydrogen, R6 is 4-epi-vancosaminy 1 and X and Y are Cl. A82846B
derivatives of the present invention having substituents at
position R7 of formula I are list herein in the manner "R7-
A82846B". For example, the compound "phenylbenzyl-A82846B" has a
phenylbenzyl substituent at position R7 in formula I.
Preferred formula I compounds include those A82846B
derivatives wherein R7 is - (C1-C12-alkyl) -R8, with -CH2.-R8 being
more preferred, and R8 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 R7 is - (C1-C12-alkyl)-R8, with -CH2-R8 being
more preferred, and R8 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 R7 is - (C1-C12-alkyl)-R8, with -CH2-
R8 being more preferred, and R8 is a group of the formula:

wherein p is 1 and R11 is selected from (C2-C5)alkenyloxy, halo-
(C1-C6)alkoxy, (C2-C10)alkanoyloxy, (C1-C3)alkoxy substituted
with (C1-C4)alkylthio, and dipheny1-(C1-C6) alkyl. Of this
group, trifluromethoxybenzyl-A8284 6B, diphenylmethylbenzyl-
A82846B, thiopropylethoxybenzyl-A82 846B, acetoxybenzyl-A82846B,
nonanoyloxybenzyl-A82846B, and tetrafluoroethoxybenzyl-A82846B
are more preferred.

f
urther preferred compounds of formula I include
B46B derivatives wherein R7 is - (C1-C12-alkyl) -R8, with
being more preferred, and R8 is a group of the formula:

H
erein q is o to 4; r is 1; Z is selected from a single bond,
lent (C1-C6)alkyl, divalent (C2-C6)alkenyl, and -R15-
S1(R14)2)s-, wherein R15 is selected from -O-, -S-, -SO2-, and
-OC(O)-, each R14 substituent is hydrogen, and s is 0 or 1; and
R13 is selected from: (C4-C10) cycloalkyl; phenyl; and phenyl
substituted by nitro, halo, (C1-C10) alkyl, (C1-C10) alkoxy, or
halo(C1-C3)alkyl. Of this group, chlorophenylbenzyl-A82846B,
phenylbenzyl-A82846B, benzylbenzyl-A82846B, methylphenylbenzyl-
A82846B, pentylphenylbenzyl-A82846B, methoxyphenylbenzyl-
A82846B, pentoxyphenylbenzyl-A82846B, nitrophenoxybenzyl-
A82846B, fluorophenylbenzyl-A82846B, phenylethynylbenzyl-
A82846B, phenoxybenzyl-A82846B, benzyloxybenzyl-A8284 6B,
nitrophenylbenzyl-A82846B, chlorophenoxybenzyl-A82846B,
chlorobenzyloxybenzyl-A82846B, butylphenoxybenzyl-A82846B,
trif luoromethylphenoxybenzyl-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 R7 is - (C1-C12-alkyl)-R8, with -CH2-
R8 being more preferred, and R8 is (C4-C10)cycloalkyl substituted
with (C4-C10) 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
o
dimethylformamide and methanol, at a temperature of about 25 C
to about 100 C. The reaction is preferably carried out at a

temperature from about 60 ºC to about 70 ºC 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 ºC to about 100 ºC 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 ºC to

about 70 ºC 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 ºC to about 100 ºC for 1 to 5 hours. The
reaction is preferably carried out at a temperature from about

60 ºC to about 70 ºC 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 ºC to about 100 ºC. The reaction is preferably carried
out at a temperature from about 60 C to about 70 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 R1 in
Formula II compounds) to other products (products that are
substituted at the amino groups of substitutents denoted as R
and/or R3 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 R3 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 C18 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% CH3CN at time=0
minutes to 20% aqueous buffer/80% CH3CN 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 x 300 mm steel) or Waters Nova-pak C18
RCM column (8 x 100 mm) with UV (235 nm or 280 nm) detection. A
30 minute gradient solvent system consisting of 95% aqueous
buffer/5% CH3CN at time=0 minute to 20% aqueous buffer/80% CH3CN
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 R1 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 R1 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 R3, and the amino group of the amino sugars designated
as R or R1 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 R3, and the amino group of the amino
sugars designated as R or R1 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 R1 in formula II with the sidechain listed. All of the
compounds listed are monosubstituted derivatives.

iisubstituted derivatives are the derivatives where a hydrogen
atom at two of the locations selected from the amino group at
position R3 and the amino group of the amino sugars designated
as R or R1 in formula II, are replaced by the reduced aldehyde
moiety. The trisubstituted derivatives are the derivatives
where a hydrogen atom at three cf the locations selected from
the amino group at position R3, and the amino group of the amino
sugars designated as P. or R1 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-giycosyi
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 giycopeptide antibiotics
other than A8284 6B. The compounds of Table 23 are
monosubstituted at the amino group of the amino sugar designated
as R1 in formula II with the sidechain listed. All of the
compounds listed are monosubstituted derivatives.



















The formula X 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.















































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 ED50 value
(effective dose in mg/kg to protect 50% of the test animals: see
W. Wick et al., J. Bacteriol. 81, 233-235 (1961)). ED50 values
observed for illustrative compounds are given in Table 4.





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-susceptible 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.













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 al., Reviews of Infectious Disease 12:602-610
(1990); Ruoff et 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.




Pharmaceutical formulations of the formula I compounds are
also part of this invention. Thus, the compound, preferably in
the form of a pharmaceuticaily acceptable salt, can be
formulated for oral or parenteral administration for the
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 3 0%. 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 5 0 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 operation 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°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°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% CH3CN/94.8% H2O with 0.2% TEAP
held constant and at 20 minutes was 60% CH3CN/3 9.8% H2O with
0.2% TEAP held constant. The UV wavelength used was 235 ran and
the flow rate was 2 ml/minute. Analysis was done using a Waters
Nova-pak C18 RCM column (8 X 100mm) with a Nova-pak C18 guard
insert. It is 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 H2O. 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•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 x 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-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, 0.2 9 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°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 x (40 x 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%
CH3CN to t = 30 minutes 20% TEAP/80% CH3CN) 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 CH3CN/H2O, CH3CN,
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 x 10-3 mol) and methanol (1000 mL) under a nitrogen
atmosphere. 4'-chlorobiphenylcarboxaldehyde (2.88 g, 1.33 x 10-
2 mol, 1.1 eq.) was added to this stirred mixture, followed by
methanol (500 mL). Finally, sodium cyanoborohydride (0.84 g,
1.33 x 10-2 mol, 1.1 eq.) was added followed by methanol (500
mL). The resulting mixture was heated to reflux (about 65°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°C). 1 N NaOH (22.8 mL) was added dropwise
to adjust the pH to 9.0 (at 54.7°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 40-45°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°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% CH3CN at time=0 minutes to
40% aqueous buffer/60% CH3CN at time=20 minutes was used, where
the aqueous buffer was TEAP (5 ml CH3CN, 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.













EXAMPLE 6
Capsule Formulation
Capsules containing 2 50 mg of Compound 2 are prepared using
the following ingredients:
Ingredient Weight
Compound 2 HCl salt 255.4 mg
Corn starch flowable powder 150 mg
Corn starch 144.6 mg
Compound 2 (HC1 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 mg
Corn starch flowable powder 150 mg
Corn 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 following 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
Lecithin 1%
Sodium citrate 2%
Propylparaben 0.015%
Distilled water q.s. to desired volume

EXAMPLE 10
Tablet Formulation
Tablets containing 250 rng 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 mg
Microcrystalline cellulose 101.1 mg
Croscarmellose sodium 12.0 mg
Providone 12.0 mg
Magnesium stearate 3.0 mg
Stearic acid 4.0 mg
Purified 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 mg
Microcrystalline cellulose 101.1 mg
Croscarmellose sodium 12.0 mg
Providone 12.0 mg
Magnesium stearate 3 . 0 mg
Stearic acid 4.0 mg
Purified water 0.16 ml

WE CLAIM:
1. A compound of the formula:

or salt thereof, wherein:
X and Y are each independently hydrogen or chloro;
R is hydrogen, 4-epi-vancosaminyl, actinosaminyl, or ristosaminyl;
R1 is hydrogen or mannose;
R2 is -NH2, -NHCH3, or -N(CH3)2;
R3 is -CH2CH(CH3)2, [p-OH, w-Cl]phenyl, p-rhamnose-phenyl, [p-rhamnose-
galactose]phenyl, [p-galactose-galactose]phenyl, or |p-CH3O-rhamnose]phenyl;
R4 is -CH2(CO)NH2, benzyl, [p-OH]phenyl or [p-OH, m-Cl]phenyl;
R5 is hydrogen or mannose;
R6 is 4-epi-vancosaminyl, L-acosaminyl, L-ristosaminyl, L-actinosaminyl or
vancosaminyl;
R7 is (C2-C16)alkenyl, (C2-C12)alkynyl, (C,-C12alkyl)-R8, (C1-C12alkyl)-halo, (C2-
C6alkenyl)-R , (C2-C6alkynyl)-R , or (C1-C12 alkyl)-O-R , and is attached to the amino group of
R6;
R8 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,

(in) nitro,
(iv)(C1-C6)alkyl,
(v) (C2-C6)alkenyl,
(vi) (C2-C6)alkynyl,
(vii)(C1-C6)alkoxy,
(viii) halo-(C1-C6)alkyl,
(ix) halo-(C1-C6)alkoxy,
(x) carbo-(C1-C6)alkoxy,
(xi) carbobenzyloxy,
(xii) carbobenzyloxy substituted with (C1-C6)alkyl, (C1-C6)alkoxy, halo, or nitro,
(xiii) a group of the formula -S(O)n-R9, wherein n' is 0-2 and R is (C1-C6)alkyl,
phenyl, or phenyl substituted with (C1-C6)alkyl, (C1-C6)alkoxy, halo, or nitro, and
(xiv) a group of the formula -C(O)N(R10)2 wherein each R10 substituent is
independently hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, phenyl, or phenyl
substituted with (C1-C6)-alkyl, (C1-C6)-alkoxy, halo, or nitro;
b) heteroaryl unsubstituted or substituted with one or more substituents independently
selected from the group consisting of:
(i) halo,
(ii) (C1C6)alkyl,
(iii)(C1-C6)alkoxy,
(iv)halo-(C1-C6)alkyl,
(v) halo-(C1-C6)alkoxy,
(vi) phenyl,
(vii) thiophenyl,
(viii) phenyl substituted with halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(C1-C6)alkoxy, or nitro,
(ix) carbo-(C1-C6)alkoxy,
(x) carbobenzyloxy,
(xi) carbobenzyloxy substituted with (C1-C6)alkyl, (C1-C6)aIkoxyl, halo, or nitro,
(xii) a group of the formula -S(O)n'-R , as defined above,
(xiii) a group of the formula -C(O)N(Rl0)2 as defined above, and
(xiv) thienyl;
c) a group of the formula:

wherein A1 is -OC(A2)2-C(A2)2-O-, -O-C(A2)2-O-, -C(A2)2-O-, or -C(A2)2-C(A2)2-C(A2)2-
C(A2)2-, and each A2 substituent is independently selected from hydrogen, (C1-C6)-alkyl, (C1-
C6)alkoxy, and (C4-C10)cycloalkyl;
d) a group of the formula:


wherein p is from 1 to 5, and R11 is independently selected from the group consisting of:
(i) hydrogen,
(ii) nitro,
(iii) hydroxy,
(iv) halo,
(v) (C1-C8)alkyl,
(vi)(C1-C8)alkoxy,
(vii) (C9-C12)alkyl,
(viii) (C2-C9)alkynyl,
(ix) (C9-C12)alkoxy,
(x) (C1-C3)alkoxy substituted with (C1-C3)alkoxy, hydroxy, halo(C1-C3)alkoxy, or
(C1-C4)alkylthio,
(xi) (C2-C6)alkenyloxy,
(xii) (C2-C13)alkynyloxy
(xiii) halo-(C1-C6)alkyl,
(xiv) halo-(C1-C6)alkoxy,
(xv) (C2-C6)alkylthio,
(xvi) (C2-C10)alkanoyloxy,
(xvii) carboxy-(C2-C4)alkenyl,
(xviii) (C1-C3)alkylsulfonyloxy,
(xix) carboxy-(C1-C3)alkyl,
(xx)N-[di(C1-C3)-alkyl]amino-(C1-C8)alkoxy,
(xxi) cyano-(C1-C6)alkoxy, and
(xxii) diphenyl-(C1-C6)alkyl,
with the proviso that when R11 is (C1-C8)alkyl, (C1-C6)alkoxy, or halo, p must be
greater or equal to 2, or when R7 is (C1-C3alkyl)-R8 then R11 is not hydrogen, (C1-
C8)alkyl, (C1-C8)alkoxy, or halo;
e) a group of the formula:

wherein q is 0 to 4;
R12 is independently selected from the group consisting of:
(i) halo,
(ii) nitro,
(iii) (C1-C6)alkyl,
(iv) (C1-C6)alkoxy,

(v) halo-(C1-C6)alkyl,
(vi)halo-(C1-C6)alkoxy,
(vii) hydroxy, and
(vii) (C1-C6)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 (C1-C6)alkyl unsubstituted or substituted with hydroxy, (C1-
C6)alkyl, or (C1-C6)alkoxy,
(iii) divalent (C2-C6)alkenyl,
(iv) divalent (C2-C6)alkynyl, or
(v) a group of the formula -(C(R14)2)S-R15- or -R15-(C(R14)2)s-, wherein s is 0-6;
wherein each R14 substituent is independently selected from hydrogen, (C1-
C6)-aIkyl, or (C4-C10) cycloalkyl; and R15 is selected from -O-, -S-, -SO-, -
SO2-, -SO2-O-, -C(O)-, -OC(O)-, -C(O)O-, -NH-, -N(C1-C6 alkyl)-, and -
C(O)NH-, -NHC(O)-, -N=N-;
R13 is independently selected from the group consisting of:
(i) (C4-C10)heterocyclyl,
(ii) heteroaryl,
(iii) (C4-C10)cycloalkyl unsubstituted or substituted with (C1-C6)alkyl, or
(iv) phenyl unsubstituted or substituted with 1 to 5 substituents independently
selected from: halo, hydroxy, nitro, (C1-C]0)alkyl, (C1-C10)alkoxy, halo-(C1-
C3)alkoxy, halo-(C1-C3)alkyl, (C1-C3)alkoxyphenyl, phenyl, phenyl-(C1-C3)alkyl,
(C1-C6)alkoxyphenyl, phenyl-(C2-C3)alkynyl, and (C1-C6)alkylphenyl;
f) (C4-C10)cycloalkyl unsubstituted or substituted with one or more substituents
independently selected from the group consisting of:
(i) (C1-C6)alkyl,
(ii) (C1-C6)alkoxy,
(iii) (C2-C6)alkenyl,
(iv) (C2-C6)alkynyl,
(v) (C4-C10)cycloalkyl,
(vi) phenyl,
(vii) phenylthio,
(viii) phenyl substituted by nitro, halo, (C1-C6)alkanoyloxy or carbocycloalkoxy,
and
(ix) a group represented by the formula -Z-R13 wherein Z and R1 are as defined
above; and
g) a group of the formula:


wherein A and A4 are each independently selected from
(i) a bond,
(ii) -O-,
(iii) -S(O),-, wherein t is 0 to 2,
(iv) -C(R17)2-, wherein each R17 substituent is independently selected from
hydrogen, (C1-C6)alkyl, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, or both R17
substituents taken together are O,
(v) -N(R18)2-, wherein each R18 substituent is independently selected from
hydrogen; (C1-C6)alkyl; (C2-C6)alkenyl; (C2-C6)alkynyl; (C4-C10)cycloalkyl;
phenyl; phenyl substituted by nitro, halo, (C1-C6)alkanoyloxy; or both R18
substituents taken together are (C4-C10)cycloalkyl;
R16 is R12 or R13 as defined above; and
u is 0-4;
other than the compounds where R, R1 and R5 are H, R3 is -CH2CH(CH3)2, R4 is
-CH2(CO)NH2, R6 is vancosaminyl, X and Y are chloro and
R7 is 6-bromo-n-hexyl and R2 is NHCH3,
R7 is 3-phenyl-n-(prop-2-enyl) and R2 is NHCH3,
R7 is (pyrid-3-yl)methyl and R2 is NHCH3,
R7 is (indo-3-yl)methyl and R2 is NHCH3,
R7 is (adamant-l-yl)methyl and R2 is NHCH3,
R7 is (pyrid-3-yl)methyl and R2 is N(CH3)2,
R7 is cyclohexylmethyl and R2 is NHCH3,
R7 is pyrrol-2-ylmethyl and R2 is NUCH3,
R7 is pyridin-2-ylmethyl and R2 is NHCH3,
R7 is furan-2-ylmethyl and R2 is NHCH3,
R7 is 6-nitro-3,4-dimethoxybenzyl and R2 is NHCH3, and
R7 is p-hydroxybenzyl and R2 is NHCH3,
and salts of these compounds.
2. A compound of the formula:


or salt thereof, wherein:
X and Y are each independently hydrogen or chloro;
R is hydrogen, 4-epi-vancosaminyl, actinosaminyl, or ristosaminyl;
R1 is hydrogen or mannose;
R2 is -NH2, -NHCH3, or-N(CH3)2;
R3 is -CH2CH(CH3)2, phenyl, [p-OH, m-Cl [phenyl, p-rhamnose-phenyl, or [p-
rhamnose-galactose]phenyl;
R4 is -CH2(CO)NH2, benzyl, [p-OH]phenyl, or [p-OH, m-Cl]phenyl;
R5 is hydrogen or mannose;
R6 is 4-epi-vancosaminyl, L-acosaminyl, L-ristosaminyl or L-actinosaminyl;
R7 is -(CH2)n-R8, or -C(CH3)CH-R8, and is attached to the amino group of R6;
n is 1-10;
R8 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)(C1-C6)alkyl,
(v) (C2-C6)alkenyl,
(vi) (C2-C6)alkynyl,
(vii)(C1-C6)alkoxy,
(viii) halo-(C1-C6)alkyl,


(ix) halo-(C1-C6)alkoxy,
(x) carbo-(C1-C6)alkoxy,
(xi) carbobenzyloxy,
(xii) carbobenzyloxy substituted with (C1-C6)alkyl, (C1-C6)alkoxy, halo, or nitro,
(xiii) a group of the formula -S(O)n'-R9, wherein n' is 0-2 and R is (C1-C6)alkyl,
phenyl, or phenyl substituted with (C1-C6)alkyl, (C1-C6)alkoxy, halo, or nitro, and
(xiv) a group of the formula -C(O)N(Rl0)2 wherein each R10 substituent is
independently hydrogen, (C1-C6-alkyl, (C1-C6)-alkoxy, phenyl, or phenyl
substituted with (C1-C6)-alkyl, (C1-C6)-alkoxy, halo, or nitro;
b) heteroaryl unsubstituted or substituted with one or more substituents
independently selected from the group consisting of:
(i) halo,
(ii) (C1-C6)alkyl,
(iii) (C1-C6)alkoxy,
(iv) halo-(C1-C6)alkyl,
(v) halo-(C1-C6)alkoxy,
(vi) phenyl,
(vii) thiophenyl,
(viii) phenyl substituted with halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(C1-C6)alkoxy, or nitro,
(ix) carbo-(C1-C6)alkoxy,
(x) carbobenzyloxy,
(xi) carbobenzyloxy substituted with (C1-C6)alkyl, (C1-C6)alkoxy, halo, or nitro,
(xii) a group of the formula -S(O)n'-R , as defined above, and
(xiii) a group of the formula -C(O)N(Rl0)2 as defined above;
c) a group of the formula:

wherein A1 is -OC(A2)2-C(A2)2-O-, -O-C(A2)2-O-, -C(A2)2-O-, or -C(A2)2-C(A2)2-C(A2)2-
C(A2)2-, and each A2 substituent is independently selected from hydrogen, (C1-C6)-alkyl, (C1-
C6)alkoxy, and (C4-C10)cycloalkyl;
d) a group of the formula:
wherein p is from 1 to 5; and R11 is independently selected from the group consisting of:
(i) nitro,

(ii) hydroxy,
(iii) (C9-C12)alkyl,
(iv) (C9-C12)alkoxy,
(v) (C2-C6)alkenyloxy,
(vi) halo-(C1-C6)alkyl,
(vii) halo-(C1-C6)alkoxy,
(viii) (C2-C6)alkylthio,
(ix) (C2-C6)alkynyl,
(x) (C2-C10)alkanoyloxy,
(xi) carboxy-(C2-C4)alkenyl,
(xii) (C1-C3)alkylsulfonyloxy,
(xiii) carboxy-(C1-C3)alkyl,
(xiv) (C1-C3)alkoxy substituted with (C1-C3)alkoxy, hydroxy, halo(C1-C3)alkoxy,
or (C1-C4)alkylthio,
(xv) N-[di(C1-C3)-alkyl]amino-(C1-C3)alkoxy,
(xvi) cyano-(C1-C6)alkoxy,
(xvii) (C1-C12)alkyl, (C1-C12)alkoxy, or halo when p is greater or equal to 2,
(xviii) diphenyl-(C1-C6)alkyl, and
(xix) hydrogen, (C1-C6)alkyl, or (C1-C6)alkoxy when n greater or equal to 4;
e) a group of the formula:

wherein q is 0 to 4;
R12 is independently selected from the group consisting of:
(i) halo,
(ii) nitro,
(iii)(C1-C6)alkyl,
(iv)(C1-C6)alkoxy,
(v) halo-(C1-C6)alkyl,
(vi) halo-(C1-C6)alkoxy,
(vii) hydroxy, and
(vii) (C1-C6)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 (C1-C6)alkyl unsubstituted or substituted with hydroxy, (C1-C6)alkyl,
or (C1-C6)alkoxy,
(iii) divalent (C2-C6)alkenyl,
(iv) divalent (C2-C6)alkynyl, or


(v) a group of the formula -(C(R14)2)S-R15- or -R15-(C(R14)2)S-, wherein s is 0-6;
each R14 substituent is independently selected from hydrogen, (C1-C6)-alkyl, or
(C4-C10)cycloalkyl; and R15 is selected from -O-, -S-, -SO-, -SO2-, -SO2-O-, -
C(O)-, -OC(O)-, -C(O)O-, -NH-, -N(C1-C6alkyl)-, and -C(O)NH-;
R13 is independently selected from the group consisting of:
(i) (C4-C10)heterocyclyl,
(ii) heteroaryl,
(iii) (C4-C10)cycloalkyl unsubstituted or substituted with (C1-C6)alkyl, or
(iv) phenyl unsubstituted or substituted with 1 to 5 substituents independently
selected from: halo, hydroxy, nitro, (C1-C10)alkyl, (C1-C10)alkoxy, halo-(C1-
C3)alkoxy, halo-(C1-C3)alkyl, (C1-C3)alkoxyphenyl, phenyl, phenyl-(C1-C3)alkyl,
(C1-C6)alkoxyphenyl, phenyl-(C2-C3)alkynyl, and (C1-C6)alkylphenyl;
f) (C4-C10)cycloalkyl unsubstituted or substituted with one or more substituents
independently selected from the group consisting of:
(i) (C1-C6)alkyl,
(ii)(C1-C6)alkoxy,
(iii) (C2-C6)alkenyl,
(iv) (C2-C6)alkynyl,
(v)(C4-C10)cycloalkyl,
(vi) phenyl,
(vii) phenylthio,
(viii) phenyl substituted by nitro, halo, (C1-C6)alkanoyloxy or carbocycloalkoxy,
and
(ix) a group represented by the formula -Z-R13 wherein Z and R13 are as defined
above; and
g) a group of the formula:

wherein:
A3 and A4 are each independently selected from
(i) a bond,
(ii) -O-,
(iii) S(O)t-, wherein t is 0 to 2,
(iv) -C(R17)2-, wherein each R17 substituent is independently selected from
hydrogen, (C1-C6)alkyl, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, or both R17
substituents taken together are O,
(v) -N(R18)2-, wherein each R18 substituent is independently selected from
hydrogen; (C1-C6)alkyl; (C2-C6)alkenyl; (C2-C6)alkynyl; (C4-C10)cycloalkyl;


phenyl; phenyl substituted by nitro, halo, (C1-C6)alkanoyloxy; or both R18
substituents taken together are (C4-C10)cycloalkyl;
R16 is R12 or R13 as defined above; and
u is 0-4.
3. A compound as claimed in Claim 1 wherein R is 4-epi-vancosaminyl, R1 is
hydrogen, R2 is NHCH3, R3 is CH2CH(CH3)2, R4 is CH2(CO)NH2, R5 is hydrogen, R6 is 4-epi-
vancosaminyl, X is H or Cl and Y is Cl.
4. A compound as claimed in Claim 2 wherein R is 4-epi-vancosaminyl, R1 is
hydrogen, R2 is NHCH3, R3 is CH2CH(CH3)2, R4 is CH2(CO)NH2, R5 is hydrogen, R6 is 4-epi-
vancosaminyl, X is H or Cl and Y is Cl.
5. A compound as claimed in Claim 1 wherein R is 4-epi-vancosaminyl, R1 is
hydrogen, R2 is NHCH3, R3 is CH2CH(CH3)2, R4 is CH2(CO)NH2, R5 is hydrogen, R6 is 4-epi-
vancosaminyl, and X and Y are Cl.
6. A compound as claimed in Claim 2 wherein R is 4-epi-vancosaminyl, R1 is
hydrogen, R2 is NHCH3, R3 is CH2CH(CH3)2, R4 is CH2(CO)NH2, R5 is hydrogen, R6 is 4-epi-
vancosaminyl, and X and Y are Cl.
7. A compound as claimed in any of Claims 1-6 in which R7 = -CH2-R8.
8. A compound as claimed in any of Claims 1-7 in which R8 is multicyclic aryl,
which compound is selected from naphthylmethyl-A82846B, acenapthlenyl-methyl-A82846B,
and fluorenylmethyl-A82846B.
9. A compound as claimed in any of Claims 1-7 in which R8 is heteroaryl, which
compound is selected from [1-oxa]fluorenylmethyl-A82846B, chlorophenylbenzoxazolemethyl-
A82846B, and phenylthienylmethyl-A82846B
10. A compound as claimed in any of Claims 1-7 in which R8 is

wherein p is 1 and R11 is selected from (C2-C5)alkcnyloxy, halo-(C1-C6)alkoxy,
(C2-Cl0)alkanoyloxy, (C1-C3)alkoxy substituted with (C1-C4)alkylthio, and diphenyl-(C1-C6)alkyl.
11. A compound as claimed in any of Claims 1-7 in which R8 is



wherein q is 0 to 4; r is 1; Z is selected from a single bond, divalent (C1-C6)alkyl, divalent
(C2-C6)alkenyl, and -RI5-(C(R14)2)s-, wherein R15 is selected from -O-, -S-, -SO2-, and -OC(O)-,
each R14 substituent is hydrogen, and s is 0 or 1: and R13 is selected from (C4-C10)cycloalkyl,
phenyl, and phenyl substituted by nitro, halo, (C1-C10)alkyl, (C1-C10)alkoxy or halo(C1-C3)alkyl.
12. A compound as claimed in any of claims 1-5 in which R8 is (C4-C10) cycloalkyl as defined.
13. A compound as claimed in Claim 7, wherein the compound of formula (I) is
chlorophenylbenzyl-A82846B,
phenylbenzyl-A82846B,
benzylbenzyl-A82846B,
methylphenylbenzyl-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,
cyclohexylbenzyl-A82846B,
cyclohexylethoxybenzyl-A82846B,
chlorophenoxynitro-benzyl-A82846B,
benzylmethoxybenzyl-A82846B,
chlorophenoxynitro-benzyl-A82846B,
phenoxymethoxybenzyl-A82846B,


benzoyloxy-dimethoxybenzyl-A82846B,
cyclohexanoyloxy-dimethylbenzyl-A82846B,
trifluoromethylphenylbenzyl-A82846B,
butylphenylthiobenzyl-A82846B, or
bromophenylbenzyl-A82846B,
or a salt thereof.
14. The compound 4-phenylbenzyl-A82846B or a salt thereof.
15. A pharmaceutical composition comprising a compound as claimed in claims 1 to
14, or a pharmaceutically acceptable salt thereof, along with one or more pharmaceutically
acceptable carriers therefor.
16. A pharmaceutical composition as claimed in claim 15 for use in treating
susceptible bacterial infections.
17. A process for the preparation of a compound as claimed in any one of claims 1 to
14 which comprises
a) reacting in methanol at about 25°C to about 100°C under an inert atmosphere:
i) a glycopeptide antibiotic of the formula:


wherein:
X and Y are each independently hydrogen or chloro;
R is hydrogen, 4-epi-vancosaminyl. actinosaminyl or ristosaminyl;
R1 is 4-epi-vancosaminyl, acosaminyl, ristosaminyl, 4-keto-vancosaminyl or
vancosaminyl;
R2 is hydrogen or mannose;
R3 is -NH2, -NHCH3, or -N(CH3)2;
R4 is -CH2CH(CH3)2, [p-OH, m-Cl]phenyl, p-rhamnose-phenyl, [p-rhamnose-
galactose]phenyl, [p-galactose-galactose]phenyl or [p-CH3O-rhamnose]phenyl;
R5 is -CH2(CO)NH2, benzyl, [p-OH]phenyl or [p-OH, m-Cl]phenyl; and
R6 is hydrogen or mannose, with
ii) an aldehyde corresponding to the group R7 as defined in claim 1 at about 25°C
to about 100°C;
b) continuing the reaction until formation of a Schiffs base; and
c) reducing the Schiffs base by addition of a metal borohydride to the mixture at 25°C to
about 100°C.
18. A process for the preparation of a compound as claimed in any one of claim 1 to
14 which comprises reacting in a polar solvent at about 25°C to about 100°C under an inert
atmosphere:


i) a glycopeptide antibiotic of the formula:

wherein:
X and Y are each independently hydrogen or chloro;
R is hydrogen, 4-epi-vancosaminyl, actinosaminyl, or ristosaminyl;
R1 is 4-epi-vancosaminyl, acosaminyl, ristosaminyl, 4-keto-vancosaminyl or
vancosaminyl;
R2 is hydrogen or mannose;
R3 is -NH2, -NHCH3, or -N(CH3)2;
R4 is -CH2CH(CH3)2, [p-OH, m-Cl]phenyl, p-rhamnose-phenyl, [p-rhamnose-
galactose]phenyl, [p-galactose-galactose]phenyl or [p-CH3O-rhamnose]phenyl;
R5 is -CH2(CO)NH2, benzyl, [p-OH]phenyl or [p-OH, m-Cl]phenyl; and
R6 is hydrogen or mannose, with
ii) an aldehyde corresponding to the group R7 as defined in claim 1, in the presence of
iii) a reducing agent selected from a metal borohydride and a homogeneous or
heterogeneous catalytic hydrogenation agent or agents; for a time sufficient to produce a
compound of any one of claims 1 to 14.
19. The process as claimed in claim 18, wherein the reducing agent is sodium
cyanoborohydride, and the reaction is carried out for about 20 to 28 hours at a temperature of
about 60°C to about 70°C.


20. The process as claimed in claim 18, wherein the aldehyde is 4'-
biphenylcarboxaldehyde.
21. The process as claimed in claim 18 wherein the aldehyde is 4-chloro-4'-
biphenylcarboxaldehyde.
22. A compound as claimed in the formula (I)

or salt thereof, wherein:
R6 is vancosaminyl;
R7 is (C1-C12 alkyl)-R8 or (C2-C6 alkenyl)-R8, and is attached to the amino group of R6;
R8 is selected from the group consisting of:
a) heteroaryl substituted with one or more substituents independently selected
from the group consisting of:
(i) phenyl,
(ii) phenyl substituted with halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-
C6)alkynyl, (C1-C6)alkoxy, or nitro,
(iii) a group of the formula -S(O)n'-R9. wherein n' is 0-2 and R9 is (C1-
C6)alkyl, phenyl or phenyl substituted with (C1-C6)alkyl, (C1-C6)alkoxy,
halo or nitro, and


(iv) thienyl;
b) a group of the formula:
wherein:
q is 0 to 4;
R12 is independently selected from the group consisting of:
(i) halo,
(ii) nitro,
(iii) (C1-C6)alkyl,
(iv) (C1-C6)alkoxy,
(v) halo-(C1-C6)alkyl,
(vi) halo-(C1-C6)alkoxy,
(vii) hydroxy, and
(vii)(C1-C6)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 (C1-C6)alkyl unsubstituted or substituted with hydroxy,
(C1-C6)alkyl, or (C1-C6)alkoxy,
(iii) divalent (C2-C6)alkenyl,
(iv) divalent (C2-C6)alkynyl, or
(v) a group of the formula -(C(R14)2)S-R15- or -R15-(C(R14)2)S-,
wherein s is 0-6; wherein each R14 substituent is independently
selected from hydrogen. (C1-C6)-alkyl, or (C4-C10) cycloalkyl; and
R15 is selected from -O-, -S-, -SO-, -SO2-, -SO2-O-, -C(O)-,
-OC(O)-, -C(O)O-, -NH-, -N(C1-C6alkyl)-, -C(O)NH-, -NHC(O)-,
and N=N;
R13 is independently selected from the group consisting of:
(i) heteroaryl, and
(ii) phenyl unsubstituted or substituted with 1 to 5 substituents
independently selected from halo, hydroxy, nitro, (C1-C10)alkyl,
(C1-C10)alkoxy, halo-(C1-C3)alkoxy, halo-(C1-C3)alkyl,
(C1-C3)alkoxyphenyl, phenyl, phenyl-(C1-C3)alkyl,
(C1-C6)alkoxyphenyl, phenyl-(C2-C3)alkynyl and
(C1-C6)alkylphenyl; and
c) a group of the formula:



wherein
A3 and A4 are each independently selected from
(i) a bond,
(ii) -O-,
(iii) -S(O),-, wherein t is 0 to 2,
(iv) -C(R17)2-, wherein each R17 substituent is independently selected from
hydrogen, (C1-C6)alkyl, hydroxy, (C1-C6)alkyl,(C1-C6)alkoxy, or both R17
substituents taken together are O,
(v) -N(R18)2-, wherein each R18 substituent is independently selected from
hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkyny, (C4-C10)cycloalkyl,
phenyl, phenyl substituted by nitro, halo, (C1-C6)alkanoyloxy, or both R18
substituents taken together are (C4-C10)cycloalkyl;
R16 is R12 or R13 as defined above; and
u is 0-4.
23. A compound as claimed in claim 22 wherein R7 is -CH2-R8.
24. A compound as claimed in claim 22, wherein R8 is

as defined.
25. A pharmaceutical composition comprising a compound as claimed in any of
claims 22-24, along with one or more pharmaceutically-acceptable carriers thereof.

1. A compound of the formula:

or salt thereof, wherein:
X and Y are each independently hydrogen or chloro;
R is hydrogen, 4-epi-vancosaminyl, actinosaminyl, or ristosaminyl;
R1 is hydrogen or mannose;
R2 is -NH2, -NHCH3, or -N(CH3)2;
R3 is -CH2CH(CH3)2, [p-OH, w-Cl]phenyl, p-rhamnose-phenyl, [p-rhamnose-
galactose]phenyl, [p-galactose-galactose]phenyl, or |p-CH3O-rhamnose]phenyl;
R4 is -CH2(CO)NH2, benzyl, [p-OH]phenyl or [p-OH, m-Cl]phenyl;
R5 is hydrogen or mannose;
R6 is 4-epi-vancosaminyl, L-acosaminyl, L-ristosaminyl, L-actinosaminyl or
vancosaminyl;
R7 is (C2-C16)alkenyl, (C2-C12)alkynyl, (C,-C12alkyl)-R8, (C1-C12alkyl)-halo, (C2-
C6alkenyl)-R , (C2-C6alkynyl)-R , or (C1-C12 alkyl)-O-R , and is attached to the amino group of
R6;
R8 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,

(in) nitro,
(iv)(C1-C6)alkyl,
(v) (C2-C6)alkenyl,
(vi) (C2-C6)alkynyl,
(vii)(C1-C6)alkoxy,
(viii) halo-(C1-C6)alkyl,
(ix) halo-(C1-C6)alkoxy,
(x) carbo-(C1-C6)alkoxy,
(xi) carbobenzyloxy,
(xii) carbobenzyloxy substituted with (C1-C6)alkyl, (C1-C6)alkoxy, halo, or nitro,
(xiii) a group of the formula -S(O)n-R9, wherein n' is 0-2 and R is (C1-C6)alkyl,
phenyl, or phenyl substituted with (C1-C6)alkyl, (C1-C6)alkoxy, halo, or nitro, and
(xiv) a group of the formula -C(O)N(R10)2 wherein each R10 substituent is
independently hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, phenyl, or phenyl
substituted with (C1-C6)-alkyl, (C1-C6)-alkoxy, halo, or nitro;
b) heteroaryl unsubstituted or substituted with one or more substituents independently
selected from the group consisting of:
(i) halo,
(ii) (C1C6)alkyl,
(iii)(C1-C6)alkoxy,
(iv)halo-(C1-C6)alkyl,
(v) halo-(C1-C6)alkoxy,
(vi) phenyl,
(vii) thiophenyl,
(viii) phenyl substituted with halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(C1-C6)alkoxy, or nitro,
(ix) carbo-(C1-C6)alkoxy,
(x) carbobenzyloxy,
(xi) carbobenzyloxy substituted with (C1-C6)alkyl, (C1-C6)aIkoxyl, halo, or nitro,
(xii) a group of the formula -S(O)n'-R , as defined above,
(xiii) a group of the formula -C(O)N(Rl0)2 as defined above, and
(xiv) thienyl;
c) a group of the formula:

wherein A1 is -OC(A2)2-C(A2)2-O-, -O-C(A2)2-O-, -C(A2)2-O-, or -C(A2)2-C(A2)2-C(A2)2-
C(A2)2-, and each A2 substituent is independently selected from hydrogen, (C1-C6)-alkyl, (C1-
C6)alkoxy, and (C4-C10)cycloalkyl;
d) a group of the formula:


wherein p is from 1 to 5, and R11 is independently selected from the group consisting of:
(i) hydrogen,
(ii) nitro,
(iii) hydroxy,
(iv) halo,
(v) (C1-C8)alkyl,
(vi)(C1-C8)alkoxy,
(vii) (C9-C12)alkyl,
(viii) (C2-C9)alkynyl,
(ix) (C9-C12)alkoxy,
(x) (C1-C3)alkoxy substituted with (C1-C3)alkoxy, hydroxy, halo(C1-C3)alkoxy, or
(C1-C4)alkylthio,
(xi) (C2-C6)alkenyloxy,
(xii) (C2-C13)alkynyloxy
(xiii) halo-(C1-C6)alkyl,
(xiv) halo-(C1-C6)alkoxy,
(xv) (C2-C6)alkylthio,
(xvi) (C2-C10)alkanoyloxy,
(xvii) carboxy-(C2-C4)alkenyl,
(xviii) (C1-C3)alkylsulfonyloxy,
(xix) carboxy-(C1-C3)alkyl,
(xx)N-[di(C1-C3)-alkyl]amino-(C1-C8)alkoxy,
(xxi) cyano-(C1-C6)alkoxy, and
(xxii) diphenyl-(C1-C6)alkyl,
with the proviso that when R11 is (C1-C8)alkyl, (C1-C6)alkoxy, or halo, p must be
greater or equal to 2, or when R7 is (C1-C3alkyl)-R8 then R11 is not hydrogen, (C1-
C8)alkyl, (C1-C8)alkoxy, or halo;
e) a group of the formula:

wherein q is 0 to 4;
R12 is independently selected from the group consisting of:
(i) halo,
(ii) nitro,
(iii) (C1-C6)alkyl,
(iv) (C1-C6)alkoxy,

(v) halo-(C1-C6)alkyl,
(vi)halo-(C1-C6)alkoxy,
(vii) hydroxy, and
(vii) (C1-C6)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 (C1-C6)alkyl unsubstituted or substituted with hydroxy, (C1-
C6)alkyl, or (C1-C6)alkoxy,
(iii) divalent (C2-C6)alkenyl,
(iv) divalent (C2-C6)alkynyl, or
(v) a group of the formula -(C(R14)2)S-R15- or -R15-(C(R14)2)s-, wherein s is 0-6;
wherein each R14 substituent is independently selected from hydrogen, (C1-
C6)-aIkyl, or (C4-C10) cycloalkyl; and R15 is selected from -O-, -S-, -SO-, -
SO2-, -SO2-O-, -C(O)-, -OC(O)-, -C(O)O-, -NH-, -N(C1-C6 alkyl)-, and -
C(O)NH-, -NHC(O)-, -N=N-;
R13 is independently selected from the group consisting of:
(i) (C4-C10)heterocyclyl,
(ii) heteroaryl,
(iii) (C4-C10)cycloalkyl unsubstituted or substituted with (C1-C6)alkyl, or
(iv) phenyl unsubstituted or substituted with 1 to 5 substituents independently
selected from: halo, hydroxy, nitro, (C1-C]0)alkyl, (C1-C10)alkoxy, halo-(C1-
C3)alkoxy, halo-(C1-C3)alkyl, (C1-C3)alkoxyphenyl, phenyl, phenyl-(C1-C3)alkyl,
(C1-C6)alkoxyphenyl, phenyl-(C2-C3)alkynyl, and (C1-C6)alkylphenyl;
f) (C4-C10)cycloalkyl unsubstituted or substituted with one or more substituents
independently selected from the group consisting of:
(i) (C1-C6)alkyl,
(ii) (C1-C6)alkoxy,
(iii) (C2-C6)alkenyl,
(iv) (C2-C6)alkynyl,
(v) (C4-C10)cycloalkyl,
(vi) phenyl,
(vii) phenylthio,
(viii) phenyl substituted by nitro, halo, (C1-C6)alkanoyloxy or carbocycloalkoxy,
and
(ix) a group represented by the formula -Z-R13 wherein Z and R1 are as defined
above; and
g) a group of the formula:


wherein A and A4 are each independently selected from
(i) a bond,
(ii) -O-,
(iii) -S(O),-, wherein t is 0 to 2,
(iv) -C(R17)2-, wherein each R17 substituent is independently selected from
hydrogen, (C1-C6)alkyl, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, or both R17
substituents taken together are O,
(v) -N(R18)2-, wherein each R18 substituent is independently selected from
hydrogen; (C1-C6)alkyl; (C2-C6)alkenyl; (C2-C6)alkynyl; (C4-C10)cycloalkyl;
phenyl; phenyl substituted by nitro, halo, (C1-C6)alkanoyloxy; or both R18
substituents taken together are (C4-C10)cycloalkyl;
R16 is R12 or R13 as defined above; and
u is 0-4;
other than the compounds where R, R1 and R5 are H, R3 is -CH2CH(CH3)2, R4 is
-CH2(CO)NH2, R6 is vancosaminyl, X and Y are chloro and
R7 is 6-bromo-n-hexyl and R2 is NHCH3,
R7 is 3-phenyl-n-(prop-2-enyl) and R2 is NHCH3,
R7 is (pyrid-3-yl)methyl and R2 is NHCH3,
R7 is (indo-3-yl)methyl and R2 is NHCH3,
R7 is (adamant-l-yl)methyl and R2 is NHCH3,
R7 is (pyrid-3-yl)methyl and R2 is N(CH3)2,
R7 is cyclohexylmethyl and R2 is NHCH3,
R7 is pyrrol-2-ylmethyl and R2 is NUCH3,
R7 is pyridin-2-ylmethyl and R2 is NHCH3,
R7 is furan-2-ylmethyl and R2 is NHCH3,
R7 is 6-nitro-3,4-dimethoxybenzyl and R2 is NHCH3, and
R7 is p-hydroxybenzyl and R2 is NHCH3,
and salts of these compounds.

Documents:

63-CAL-1995-(05-01-2012)-FORM-27.pdf

63-CAL-1995-CORRESPONDENCE.pdf

63-CAL-1995-FORM 27.pdf

63-cal-1995-granted-abstract.pdf

63-cal-1995-granted-claims.pdf

63-cal-1995-granted-correspondence.pdf

63-cal-1995-granted-description (complete).pdf

63-cal-1995-granted-examination report.pdf

63-cal-1995-granted-form 1.pdf

63-cal-1995-granted-form 13.pdf

63-cal-1995-granted-form 18.pdf

63-cal-1995-granted-form 2.pdf

63-cal-1995-granted-form 26.pdf

63-cal-1995-granted-form 3.pdf

63-cal-1995-granted-form 5.pdf

63-cal-1995-granted-pa.pdf

63-cal-1995-granted-reply to examination report.pdf

63-cal-1995-granted-specification.pdf

63-cal-1995-granted-translated copy of priority document.pdf


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Patent Number 231354
Indian Patent Application Number 63/CAL/1995
PG Journal Number 10/2009
Publication Date 06-Mar-2009
Grant Date 04-Mar-2009
Date of Filing 24-Jan-1995
Name of Patentee ELI LILLY AND COMPANY
Applicant Address LILLY CORPORATE CENTER, CITY OF INDIANAPOLIS, STATE OF INDIANA
Inventors:
# Inventor's Name Inventor's Address
1 ROBIN DAVID GREY COOPER 6740 DOVER ROAD, INDIANAPOLIS, INDIANA 46220
2 RICHARD CRAIG THOMPSON 763 NORTH COUNTY ROAD, 900 WEST FRANKFORT, INDIANA 46041
3 MICHAEL JOHN RODRIGUEZ 1825 SAILING COURT, INDIANAPOLIS, INDIANA 46260
4 NANCY JUNE SNYDER 10760 EAST U.S. 40, CHARLOTTESVILLE, INDIANA 46117
5 MARK JAMES ZWEIFEL 7519 HIGDON COURT, INDIANAPOLIS, INDIANA 46214
6 BRET EUGENE HUFF 201 OAK HILL LANE, MOOREVILLE, INDIANA 46158
7 JOHN THOMAS QUATROCHE 8671 PROMONTORY ROAD, INDIANAPOLIS, INDIANA 46236
8 MICHAEL ALEXANDER STASZAK 4515 NORTH LAKERIDGE DRIVE, INDIANAPOLIS, INDIANA 46234
9 STEPHEN CHARLES WILKIE 7522 NORTH LIPPINCOTT WAY, INDIANAPOLIS, INDIANA 46268
10 THALIA IOANNA NICAS 8218 MEADOWBROOK DRIVE, INDIANAPOLIS, INDIANA 46240
PCT International Classification Number A61K 31/70,C07K 9/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 08/356,413 1994-12-15 U.S.A.
2 08/189,393 1994-01-28 U.S.A.