11,12-substituted lactone ketolide derivatives having...

Details 11,12-substituted lactone ketolide derivatives having... 11,12-substituted lactone ketolide derivatives having...

2002-08-19

2004-04-27

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007200, C536S007300, C536S007400

Reexamination Certificate

active

06727229

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel macrolides having antibacterial activity and useful in the treatment and prevention of bacterial infections. More particularly, the invention relates to novel 11,12-lactone ketolides, 14-membered macrolides, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
BACKGROUND OF THE INVENTION
Macrolide antibiotics play a therapeutically important role, particularly with the emergence of new pathogens. Structural differences are related to the size of the lactone ring and to the number and nature (neutral or basic) of the sugars. Macrolides are classified according to the size of the lactone ring (12, 14, 15 or 16 atoms). The macrolide antibiotic families (14-, 15- and 16-membered ring derivatives) exhibit a wide range of characteristics (antibacterial spectrum, side-effects and bioavailability). Among the commonly used macrolides are erythromycin, clarithromycin and azithromycin.
Erythromycins A through D, represented by formula (E) as illustrated below,
are well-known and potent antibacterial agents and are 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.
EP 559896 of Kashimura et al, published Nov. 11, 1991, discloses 6-O-methylerythromycin derivatives having a tricyclic basic nuclear structure. Also, International Application WO 93/21200, published Apr. 22, 1992, of Asaka et al. discloses 5-O-desoaminylerythronolide derivatives containing a tricyclic carbamate structure.
Recently erythromycin derivatives containing a variety of substituents at the 6-O position have been disclosed in U.S. Pat. Nos. 5,866,549 and 6,075,011 as well as published International Application WO 00/78773. 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).
International Application WO 02/16380 of Angehrn et al, discloses 14-membered macrolides as do published International Applications WO 02/50091 and WO 02/50092. Also, U.S. Pat. No. 6,124,269 discloses 2-halo-6-O-substituted ketolide; derivatives
SUMMARY OF THE INVENTION
The present invention provides a novel class 2-substituted 14-membered macrolide compounds possessing antibacterial activity toward Gram positive and Gram negative bacteria as well as macrolide resistant Gram positives. The compounds of the present invention are represented by the general formula I as illustrated below
as well as the pharmaceutically acceptable salts, esters or prodrugs thereof.
In formula I above:
L is selected from the group consisting of:
(1) —CH(OH)CH
3
;
(2) C
1
-C
6
alkyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;
(3) C
2
-C
6
alkenyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; and
(4) C
2
-C
6
alkynyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;
R
1
is selected from the group consisting of C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl and C
2
-C
6
-alkynyl, each optionally substituted with one or more substituents selected from the group consisting of:
(1) halogen;
(2) aryl;
(3) substituted aryl;
(4) heteroaryl;
(5) substituted heteroaryl;
(6) —O—R
5
, where R
5
is selected from the group consisting of:
a. hydrogen;
b. aryl;
c. substituted aryl;
d. heteroaryl; and
e. substituted heteroaryl;
(7) —O—C
1
-C
6
-alkyl-R
5
, where R
5
is as previously defined;
(8) —O—C
2
-C
6
-alkenyl-R
5
, where R
5
is as previously defined;
(9) —O—C
2
-C
6
-alkynyl-R
5
, where R
5
is as previously defined; and
(10) —N
6
R
7
, where R
6
and R
7
are each independently selected from the group consisting of: hydrogen; C
1
-C
6
-alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic; C
2
-C
6
-alkenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic; and C
2
-C
6
-alkynyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic:and substituted heterocyclic; or R
6
R
7
taken together with the nitrogen atom to which they are attached form a 3- to 7-membered ring which may optionally contain one or more hetero functions selected from the group consisting of —O—, —NH—, —N(C
1
-C
6
-alkyl)—, —N(aryl)-, —N(heteroaryl)-, —S—, —S(O)— and —S(O)
2
—;
R
2
is selected from the group consisting of:
(1) hydrogen;
(2) C
1
-C
6
-alkyl, optionally substituted with one or more substituents selected from the group consisting of:
a. halogen;
b. aryl;
c. substituted aryl;
d. heterocyclic;
e. substituted heterocyclic;
f. —O—R
3
, where R
3
is selected from the group consisting of:
i. hydrogen;
ii. aryl;
iii. substituted aryl;
iv. heteroaryl; and
v. substituted heteroaryl;
g. —O—C
1
-C
6
-alkyl-R
3
, where R
3
is as previously defined;
h. —O—C
2
-C
6
-alkenyl-R
3
, where R
3
is as previously defined;
i. —O—C
2
-C
6
-alkynyl-R
3
, where R
3
is as previously defined; and
j. —NR
6
R
7
, where R
6
and R
7
are as previously defined;
(3) C
2
-C
6
-alkenyl, optionally substituted with one or more substituents selected from the group consisting of:
a. halogen;
b. aryl;
c. substituted aryl;
d. heterocyclic;
e. substituted heterocyclic;
f. —O—R
3
, where R
3
is as previously defined;
g. —O—C
1
-C
6
-alkyl-R
3
, where R
3
is as previously defined;
h. —O—C
2
-C
6
-alkenyl-R
3
, where R
3
is as previously defined;
i. —O—C
2
-C
6
-alkynyl-R
3
, where R
3
is as previously defined; and
j. —NR
6
R
7
, where R
6
and R
7
are as previously defined; and
(4) C
2
-C
6
-alkynyl, optionally substituted with one or more substituents selected from the group consisting of:
a. halogen;
b. aryl;
c. substituted aryl;
d. heterocyclic;
e. substituted heterocyclic;
f. —O—R
3
, where R
3
is as previously defined;
g. —O—C
1
-C
6
-alkyl-R
3
, where R
3
is as previously defined;
h. —O—C
2
-C
6
-alkenyl-R
3
, where R
3
is as previously defined;
i. —O—C
2
-C
6
-alkynyl-R
3
, where R
3
is as previously defined; and
j. —NR
6
R
7
, where R
6
and R
7
are as previously defined;
X is selected from the group consisting of:
(1) S(O)n, where n is 0, 1, or 2; and
(2) O;
Z is selected from the group consisting of:
(1) hydrogen;
(2) halogen; and
(3) methyl;
provided that when X is S(O)n, R
1
is not methyl, and Rp is hydrogen or a hydroxy protecting group.
In another aspect of the present invention there are disclosed pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier and treatment of bacterial infections with such compositions. Suitable carriers and methods of formulation are also disclosed. The compounds and compositions of the present invention have antibacterial activity.
In a further aspect of the present invention there are provided processes for the preparation of bicyclic macrolide derivatives of formula I wherein L, Z, X, R
1
, R
2
and Rp are as previously described

Affiliated with

Also associated with

Rating

11,12-substituted lactone ketolide derivatives having... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with 11,12-substituted lactone ketolide derivatives having..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 11,12-substituted lactone ketolide derivatives having... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3246501