C-2 modified erythromycin derivatives

Details C-2 modified erythromycin derivatives C-2 modified erythromycin derivatives

1999-05-14

2002-03-12

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007200, C536S007400, C536S018500

Reexamination Certificate

active

06355620

ABSTRACT:

TECHNICAL FIELD
The present invention relates to semisynthetic macrolides and compositions which are antibacterial agents, processes for making the compounds, synthetic intermediates employed in the processes, and methods for treatment and prevention of bacterial infections in a mammal.
BACKGROUND OF THE INVENTION
Erythromycins A through D, represented by formula (E),

Erythromycin
R
a
R
b
A
—OH
—CH
3
B
—H
—CH
3
C
—OH
—H
D
—H
—H
are well-known and potent antibacterial agents which are widely used to treat and prevent bacterial infection. As with other antibacterials, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify new erythromycin derivative compounds which have improved antibacterial activity, less potential for developing resistance, the desired Gram-negative activity, or unexpected selectivity against target microorganisms. Consequently, numerous investigators have prepared chemical derivatives of erythromycin in an attempt to obtain analogs having modified or improved profiles of antibiotic activity.
Kashimura, et al. have disclosed 6-O-methylerythromycin derivatives having a tricyclic basic nuclear structure in European Application 559896, published Nov. 11, 1991, and Asaka, et al. have disclosed 5-O-desoaminylerythronolide derivatives 1991, and Asaka, et al. have disclosed 5-O-desoaminylerythronolide derivatives containing a tricyclic carbamate structure in PCT Application WO 93/21200, published Apr. 22, 1992.
SUMMARY OF THE INVENTION
In one embodiment of the present invention are compounds selected from the group consisting of
a compound of formula (I)
a compound of formula (II)
 and
a compound of formula (III)
wherein, in formulas (I)-(III),
Y and Z together are selected from the group consisting of
(1) oxo,
(2) ═N—OH,
(3) ═N—OR
1
wherein R
1
is selected from the group consisting of
(a) —C
1
-C
12
-alkyl,
(b) —C
1
-C
12
-alkyl substituted with aryl,
(c) —C
1
-C
12
-alkyl substituted with substituted aryl,
(d) —C
1
-C
12
-alkyl substituted with heteroaryl,
(e) —C
1
-C
12
-alkyl substituted with substituted heteroaryl,
(f) —C
3
—C
12
-cycloalkyl,
(g) —Si(R
2
)(R
3
)(R
4
), wherein R
2
, R
3
, and R
4
, are each independently —C
1
-C
12
— alkyl or aryl, and
(h) —(CH
2
)
n
NR
5
R
6
wherein n is two to six, and R
5
and R
6
are independently selected from the group consisting of
(i) hydrogen,
(ii) —C
1
-C
12
-alkyl,
(iii) —C
1
-C
12
-alkyl substituted with aryl,
(iv) —C
1
-C
12
-alkyl substituted with substituted aryl,
(v) —C
1
-C
12
-alkyl substituted with heteroaryl, and
(vi) —C
1
-C
12
-alkyl substituted with substituted heteroaryl,
 or
 R
5
and R
6
taken together with the atom to which they are attached are C
3
-C
12
-heterocycloalkyl,
 and
(4) ═N—OC(R
7
)(R
8
)(—OR
1
), wherein R
1
is defined above, and R
7
and R
8
are independently selected from the group consisting of
(i) hydrogen,
(ii) —C
1
-C
12
-alkyl,
(iii) —C
1
-C
12
-alkyl substituted with aryl,
(iv) —C
1
-C
12
-alkyl substituted with substituted aryl,
(v) —C
1
-C
12
-alkyl substituted with heteroaryl, and
(vi) —C
1
-C
12
-alkyl substituted with substituted heteroaryl,
 or
 R
7
and R
8
taken together with the atom to which they are attached are C
3
-C
12
-cycloalkyl, or
one of Y and Z is hydrogen, and the other is selected from the group consisting of
(1) hydrogen,
(2) hydroxy,
(3) —OR
1
wherein R
1
is defined above, and
(4) —NR
5
R
6
wherein R
5
and R
6
are defined above;
T is selected from the group consisting of
(1) —O—,
(2) —NH—, and
(3) —N(W(R
g
))— wherein W is absent or selected from the group consisting of
(a) —O—,
(b) —(CH
2
)
p
— wherein p is one to six, and
(c) —NH—,
 and
 R
g
is selected from the group consisting of
(a) hydrogen,
(b) —C
3
-C
7
-cycloalkyl,
(c) aryl,
(d) substituted aryl,
(e) heteroaryl,
(f) substituted heteroaryl,
(g) —C
1
-C
6
-alkyl,
(h) —NR
5
R
6
wherein R
5
and R
6
are defined above, and
(i) —C
1
-C
6
-alkyl substituted with one or more substituents independently selected from the group consisting of
(i) aryl,
(ii) substituted aryl,
(iii) heteroaryl,
(iv) substituted heteroaryl,
(v) hydroxy,
(vi) —OR
1
, and
(vii) —NR
5
R
6
wherein R
5
and R
6
are defined above;
R
a
is selected from the group consisting of
(1) —C
1
-C
10
-alkyl optionally substituted with one or more substituents independently selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) —OR
1
,
(d) oxo,
(e) —NR
5
R
6
wherein R
5
and R
6
are defined above,
(f) —CO
2
R
1
wherein R
1
is defined above,
(g) —C(O)NR
5
R
6
wherein R
5
and R
6
are defined above,
(h) ═N—OR
1
wherein R
1
is defined above,
(i) cyano,
(j) —S(O)
q
R
1
wherein R
1
is defined above and q is zero to two,
(k) aryl,
(l) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) heterocycloalkyl,
(p) substituted heterocycloalkyl,
(q) —NHC(O)R
1
wherein R
1
is defined above,
(r) —NHC(O)NR
5
R
6
wherein R
5
and R
6
are defined above,
(s) ═NNR
5
R
6
wherein R
5
and R
6
are defined above,
(t) ═NNHC(O)R
1
wherein R
1
is defined above, and
(u) ═NNHC(O)NR
5
R
6
wherein R
5
and R
6
are defined above,
(2) —C
3
-alkenyl,
(3) —C
3
-alkynyl,
wherein (2) and (3) can be optionally substituted with a substituent selected from the group consisting of
(a) halogen,
(b) carboxaldehyde,
(c) —CO
2
R
1
wherein R
1
is defined above,
(d) —C(O)R
1
wherein R
1
is defined above,
(e) —C(O)NR
5
R
6
wherein R
5
and R
6
are defined above,
(f) cyano,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl, and
(j) substituted heteroaryl,
(4) —C
4
-C
10
-alkenyl, and
(5) —C
4
-C
10
-alkynyl,
wherein (4) and (5) can be optionally substituted with one or more substituents independently selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) —OR
1
,
(d) oxo,
(e) —NR
5
R
6
wherein R
5
and R
6
are defined above,
(f) —CO
2
R
1
wherein R
1
is defined above,
(g) —C(O)NR
5
R
6
wherein R
5
and R
6
are defined above,
(h) ═N—OR
1
wherein R
1
is defined above,
(i) cyano,
(j) S(O)
q
R
1
wherein R
1
and q are defined above,
(k) aryl,
(l) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) heterocycloalkyl,
(p) substituted heterocycloalkyl,
(q) —NHC(O)R
1
wherein R
1
is defined above,
(r) —NHC(O)NR
5
R
6
wherein R
5
and R
6
are defined above,
(s) ═NNR
5
R
6
wherein R
5
and R
6
are defined above,
(t) ═NNHC(O)R
1
wherein R
1
is defined above, and
(u) ═NNHC(O)NR
5
R
6
wherein R
5
and R
6
are defined above;
R
b
is hydrogen or a hydroxy protecting group;
R is selected from the group consisting of
(1) —C
1
-C
10
-alkyl optionally substituted with one or more substituents independently selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) —OR
1
,
(d) oxo,
(e) —NR
5
R
6
wherein R
5
and R
6
are defined above,
(f) —CO
2
R
1
wherein R
1
is defined above,
(g) —C(O)NR
5
R
6
wherein R
5
and R
6
are defined above,
(h) ═N—OR
1
wherein R
1
is defined above,
(i) cyano,
(j) —S(O)
q
R
1
wherein R
1
and q are defined above,
(k) aryl,
(l) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) heterocycloalkyl,
(p) substituted heterocycloalkyl,
(q) —NHC(O)R
1
wherein R
1
is defined above,
(r) —NHC(O)NR
5
R
6
wherein R
5
and R
6
are defined above,
(s) ═NNR
5
R
6
wherein R
5
and R
6
are defined above,
(t) ═NNHC(O)R
1
wherein R
1
is defined above, and
(u) ═NNHC(O)NR
5
R
6
wherein R
5
and R
6
are defined above,
(2) —C
3
-alkenyl,
(3) —C
3
-alkynyl,
wherein (2) and (3) can be optionally substituted with a substituent selected from the group consisting of
(a) halogen,
(b) carboxaldehyde,
(c) —CO
2
R
1
wherein R
1
is defined above,
(d) —C(O)R
1
wherein R
1
is defined above,
(e) —C(O)NR
5
R
6
wherein R
5
and R
6
are defined above,
(f) cyano,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl,
(j) substituted heteroaryl,
(4) —C
4
-C
10
-alkenyl, and
(5) —C
4

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