Bicyclic ketolide derivatives

Details Bicyclic ketolide derivatives Bicyclic ketolide derivatives

2003-06-05

2004-07-20

Owens, Amelia A. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C549S270000

Reexamination Certificate

active

06765016

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel semisynthetic macrolides having antibacterial activity and which are useful in the treatment and prevention of bacterial infections. More particularly, the invention relates to 11,12-cyclized erythromycin derivatives, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
BACKGROUND OF THE INVENTION
Erythromycins A through D, represented by formula (E) as illustrated below,
are well-known and potent antibacterial agents, used widely 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 possess improved antibacterial activity, which have less potential for developing resistance, which possess the desired Gram-negative activity, or which possess 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. Also, Asaka et al. have disclosed 5-O-desoaminylerythronolide derivatives containing a tricyclic carbamate structure in PCT Application WO 93/21200, published Apr. 22, 1992.
Recently erythromycin derivatives containing a variety of substituents at the 6-O position have been disclosed in U.S. Pat. Nos. 5,866,549, 6,075,011 and 6,420,555 B1 as well as PCT Applications WO 00/78773 and WO 03/024986. Furthermore, Ma et. al. have described erythromycin derivatives with aryl groups tethered to the C-6 position in
J. Med Chem
., 44, pp 4137-4156 (2001).
More recently, erythromycin derivatives containing a lactone moiety at the C11-C12 position have been disclosed in PCT Application WO 02/16380, published Feb. 28, 2002 as well as WO 02/50091 and WO 02/50092, both published Jun. 27, 2002 and WO 03/024986, which published on Mar. 27, 2003.
SUMMARY OF THE INVENTION
The present invention provides a novel class of C11-C12 cyclized erythromycin compounds that possess antibacterial activity.
In one aspect of the present invention there are disclosed novel bicyclic erythromycin compounds represented by formula I as illustrated below:
as well as the pharmaceutically acceptable salts, esters and prodrugs thereof.
In formula I:
A is selected from:
(a) —OH;
(b) —OR
p
, where R
p
is a hydroxy protecting group;
(c) —R
1
, where R
1
is selected from:
1. aryl;
2. substituted aryl;
3. heteroaryl; and
4. substituted heteroaryl;
(d) —OR
1
, where R
1
is as previously defined;
(e) —R
2
, where R
2
is selected from:
1. hydrogen;
2. halogen;
3. C
1
-C
6
alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S and N, optionally substituted with one or more substituents selected from halogen, cyano, oxo, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
4. C
2
-C
6
alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S and N, optionally substituted with one or more substituents selected from halogen, cyano, oxo, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and
5. C
2
-C
6
alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S and N, optionally substituted with one or more substituents selected from halogen, cyano, oxo, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
(f) —OR
2
, where R
2
is previously defined;
(g) —S(O)
n
R
11
, where n=0, 1 or 2, and R
11
is selected from hydrogen, R
1
and R
2
, where R
1
and R
2
are as previously defined
(h) —OC(O)R
11
, where R
11
is as previously defined;
(i) —C(O)R
11
, where R
11
is as previously defined;
(j) —C(O)NHR
11
, where R
11
is as previously defined;
(k) —OC(O)NHR
11
, where R
11
is as previously defined;
(l) —NHC(O)R
11
, where R
11
is as previously defined;
(m) —NHC(O)NHR
11
, where R
11
is as previously defined;
(n) —NHS(O)
n
R
11
, where n and R
11
are as previously defined;
(o) —NR
14
R
15
, where R
14
and R
15
are each independently R
11
, where R
11
is as previously defined; and
(p) —NHR
3
, where R
3
is an amino protecting group;
B is selected from:
(a) hydrogen;
(b) deuterium;
(c) —CN;
(d) —NO
2
;
(e) halogen;
(f) —OH;
(g) —R
1
, where R
1
is as previously defined;
(h) —R
2
, where R
2
is as previously defined; and
(i) —OR
p
, where R
p
is as previously defined;
provided that when B is halogen, —NO
2
, —OH or OR
p
, A is R
1
or R
2
; or, alternatively, A and B taken together with the carbon atom to which they are attached are selected from:
(a) C═O;
(b) C(OR
2
)
2
, where R
2
is as previously defined;
(c) C(SR
2
)
2
, where R
2
is as previously defined;
(d) C(OR
12
)(OR
13
), where R
12
and R
13
taken together are —(CH
2
)
m
—, and where m is 2 or 3;
(e) C(SR
12
)(SR
13
), where R
12
and R
13
taken together are —(CH
2
)
m
and, where m is as previously defined,
(f) C═CR
11
R
14
, where R
11
and R
14
are as previously defined;
(g) C═N—O—R
11
, where R
11
is as previously defined;
(h) C═NNHR
11
, where R
11
is as previously defined;
(i) C═NNHC(O)R
11
, where R
11
is as previously defined;
(j) C═NN═CR
11
R
14
, where R
11
and R
14
are as previously defined;
(k) C═NNHC(O)NHR
11
, where R
11
is as previously defined;
(l) C═NNHS(O)
n
R
11
, where n and R
11
are as previously defined;
(m) C═NNHR
3
, where R
3
is as previously defined; and
(n) C═NR
11
, where R
11
is as previously defined;
one of X and Y is hydrogen and the other is selected from:
(a) hydrogen;
(b) deuterium;
(c) —OH;
(d) —OR
p
, where R
p
is as previously defined; and
(e) —NR
4
R
5
, where R
4
and R
5
are each independently selected from:
1. hydrogen; and
2. C
1
-C
12
alkyl, optionally substituted with one or more substituents selected from halogen, cyano, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or
R
4
and R
5
, taken together with the nitrogen atom to which they are attached form a 3-10 membered heteroalkyl ring containing 0-2 additional hetero atoms selected from O, S and N; or
alternatively, X and Y taken together with the carbon atom to which they are attached are selected from:
(a) C═O;
(b) C═NR
11
, where R
11
is as previously defined;
(c) C═NC(O)R
11
, where R
11
is as previously defined;
(d) C═N—OR
6
, where R
6
is selected from:
1. hydrogen;
2. —CH
2
O(CH
2
)
2
OCH
3
,
3. —CH
2
O(CH
2
O)
n
CH
3
, where n is as previously defined;
4. —C
1
-C
12
alkyl, optionally substituted with one or more substituents selected from halogen, cyano, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
5. C
3
-C
12
cycloalkyl;
6. C(O)—C
1
-C
12
alkyl;
7. C(O)—C
3
-C
12
cycloalkyl;
8. C(O)—R
1
, where R
1
is as previously defined; and
9. —Si(R
a
)(R
b
)(R
c
), wherein R
a
, R
b
and R
c
are each independently selected from C
1
-C
12
alkyl, aryl and substituted aryl; and
(e) C═N—O—C(R
7
)(R
8
)—O—R
6
, where R
6
is as previously defined, provided that R
6
is not C(O)—C
1
-C
12
alkyl, C(O)—C
3
-C
12
cycloalkyl, or C(O)—R
1
; and R
7
and R
8
taken together with the carbon atom to which they are attached form a C
3
-C
12
cycloalkyl group or each is independently selected from:
1. hydrogen; and
2. C
1
-C
12
alkyl;
L is selected from:
(a) —CH(OH)CH
3
;
(b) C
1
-C
6
alkyl, optionally substituted with one or more substituents selected from halogen, cyano, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
(c) C
2
-C
6
alkenyl, optionally substituted with one or more substituents selected from halogen, cyano, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
(d) C
2
-C
6
alkynyl, optionally substituted with one or more substituents selected from halogen, cyano, aryl, substituted

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