Anhydrolide derivatives having antibacterial activity

Details Anhydrolide derivatives having antibacterial activity Anhydrolide derivatives having antibacterial activity

2002-11-07

2004-04-13

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

06720308

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 anhydrolides, a 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.
International Application WO 97/42205 of Elliott et al, published Nov. 13, 1997, discloses 3-descladinose-2, 3-anhydroerythromycin derivatives having a cyclic carbamate and cyclic carbazate basic nuclear structure. Further details were also disclosed in
J. Med Chem
., 41, pp 1651-1659 (1998) and
J. Med Chem
., 41, pp 1660-1670 (1998) by Elliott et al, and by Griesgraber et al, respectively.
Erythromycin derivatives containing an 11,12-&ggr;-lactone moiety are disclosed in International Applications WO 02/16380, WO 02/50091, and WO 02/50092.
SUMMARY OF THE INVENTION
The present invention provides a novel class of 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) —NR
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:
(a) S(O)n, where n is 0, 1, or 2;
(b) O; and
(c) NR
5
, where R
5
is as previously defined; 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, X, R
1
, R
2
and Rp are as previously described.
DETAILED DESCRIPTION OF THE INVENTION
A first embodiment of the present invention includes compounds represented by formula (I), as illustrated above, as well as the pharmaceutically acceptable salts, esters and prodrugs thereof.
A preferred group of compounds of the present invention are those represented by formula (I) wherein L is ethyl, X is sulfur, R
1
is methyl, and where R
2
and Rp are as previously defined.
Representative compounds of the invention are those sel

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