11-O-substituted ketolide derivatives

Details 11-O-substituted ketolide derivatives 11-O-substituted ketolide derivatives

2001-12-04

2003-12-30

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007200, C536S007400, C536S018500

Reexamination Certificate

active

06670331

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel macrolides having antibacterial activity that are useful in the treatment and prevention of bacterial infections. More particularly, the present invention relates to a novel class of 11-O-substituted ketolide derivatives of clarithromycin 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 family (14-, 15- and 16-membered ring derivatives) shows a wide range of characteristics (antibacterial spectrum, side-effects and bioavailability). Among the commonly used macrolides are erythromycin and clarithromycin. The 3-descladinose-3-oxo-clarithromycin macrolides are known as ketolides. Ketolides have shown enhanced activity towards gram-negative bacteria and macrolide resistant gram-positive bacteria. The search for macrolide compounds which are active against MLSB-resistant strains (MLS
B
=Macrolides-Lincosamides-type B Streptogramines) has become a major goal, together with retaining the overall profile of the macrolides in terms of stability, tolerance and pharmacokinetics.
SUMMARY OF THE INVENTION
The present invention provides novel 11-O-substituted ketolide derivatives having antibacterial activity and their pharmaceutically acceptable salts, esters and prodrugs thereof. The compounds of the present invention are represented by the general formula (I) as illustrated below.
In formula (I) above,
A is selected from the group consisting of:
(1) C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl or 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. heteroaryl;
e. substituted heteroaryl;
f. —O—R
5
, where R
5
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
5
, where R
5
is as previously defined;
h. —O—C
1
-C
6
-alkenyl-R
5
, where R
5
is as previously defined
i. —O—C
2
-C
6
-alkynyl-R
5
, where R
5
is as previously defined; and
j. —NR
6
R
7
, where R
6
and R
7
are each independently selected from 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, 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 with the nitrogen atom to which they are connected 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
—;
(2) —C(O)—R
5
, where R
5
is as previously defined;
(3) —C(O)—C
1
-C
6
-alkyl—R
5
, where R
5
is as previously defined;
(4) —C(O)—C
2
-C
6
-alkenyl—R
5
, where R
5
is as previously defined;
(5) —C(O)—C
2
-C
6
-alkynyl—R
5
, where R
5
is as previously defined;
(6) —C
1
-C
6
-alkyl—M—R
5
, where M=—OC(O)—, —OC(O)O—, —OC(O)NR
6
—, —NR
6
C(O)—, —NR
6
C(O)O—, —NR
6
C(O)NR
7
—, —NR
6
C(N)NR
7
—, S(O)
n
—, where n=0, 1 or 2, and where R
5
, R
6
, R
7
are as previously defined;
(7) —C
2
-C
6
-alkenyl—M—R
5
where M=—OC(O)—, —OC(O)O—, —OC(O)NR
6
—, —NR
6
C(O)—, —NR
6
C(O)O—, —NR
6
C(O)NR
7
—, —NR
6
C(N)NR
7
—, S(O)
n
—, where n=0, 1 or 2, and where R
5
, R
6
, R
7
are as previously defined; and
(8) —C
2
-C
6
-alkynyl—M—R
5
where M=—OC(O)—, —OC(O)O—, —OC(O)NR
6
—, —NR
6
C(O)—, —NR
6
C(O)O—, —NR
6
C(O)NR
7
—, —NR
6
C(N)NR
7
—, S(O)
n
—, where n=0, 1 or 2, and where R
5
, R
6
, R
7
are as previously defined;
R
1
is selected from the group consisting of:
(1) hydrogen;
(2) R
3
, where R
3
is C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl or 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. heteroaryl;
e. substituted heteroaryl;
f. —O—C
1
-C
6
-alkyl—R
5
, where R
5
is as previously defined;
g. —NR
6
R
7
, where R
6
and R
7
are as previously defined.
(3) —C(=O)—R
4
, where R
4
is H or R
3
as previously defined;
(4) —C(=O)O—R
3
, where R
3
is as previously defined; and
(5) —C(=O)N—R
6
R
7
, where R
6
and R
7
are as previously defined;
D and M are selected from the group consisting of:
(1) one of D and M is hydrogen and the other is selected from the group consisting of:
i. hydrogen;
ii. hydroxy;
iii. protected hydroxy; and
iv. —NR
6
R
7
, where R
6
and R
7
are as previously defined; and
(2) D and M taken together define Y, where Y is selected from the group consisting of:
a. =O;
b. =N—OH;
c. =N—O—R
8
, where R
8
is a C
1
-C
6
-alkyl group, optionally substituted with a group selected from an aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and
d. =N—O—C(R
9
)(R
10
)—O—R
11
, where R
9
and R
10
are each independently selected from the group consisting of hydrogen or C
1
-C
6
-alkyl, and R
11
is selected from the group consisting of:
i. R
8
, as previously defined;
ii. —C
1
-C
6
-alkyl, optionally substituted with C
1
-C
6
-alkoxy; and
iii. —C
1
-C
6
-alkyl—O—C
1
-C
6
-alkyl—R
5
, where R
5
is as previously defined;
X is selected from the group consisting of:
(1) hydrogen;
(2) methyl; and
(3) halogen;
R
13
is selected from:
(1) hydrogen,
(2) C
1
-C
6
-alkyl optionally substituted with halogen,
(3) C
2
-C
6
-alkenyl,
(4) C
2
-C
6
-alkynyl, or
(5) —CH
2
—R″, where R″ is selected from hydrogen, C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl or phenyl, optionally substituted with halogen, or C
1
-C
6
-alkyl optionally substituted with R
5
, where R
5
is as defined previously;
(6) —C
3
-C
8
-cycloalkyl; and
Rp is hydrogen or hydroxy protecting group.
Another embodiment of the present invention pertains to pharmaceutical compositions comprising a therapeutically effective amount of compound(s) of the present invention in combination with a pharmaceutically acceptable carrier and treatment of bacterial infections with such compositions. In yet another embodiment, the present invention pertains to carriers and methods of formulation suitable for use with the compounds and compositions of the present invention. In particular, the compounds and compositions of the present invention have antibacterial activity.
In a further embodiment, the present invention pertains to processes for the preparation of ketolide derivatives of formula (I) above.
DETAILED DESCRIPTION OF THE INVENTION
A first embodiment of the invention is a compound represented by formula I as described above.
Representative compounds of the invention are those selected from the group consisting of:
Compound of formula I: A=—CH
2
CHCH
2
, R
1
=R
p
=H, X=H, R
13
=ethyl, and D, M taken together=O;
Compound of formula I: A=—CH
2
CHCH—(3-quinolyl), R
1
=R
p
=H, X=H, R
13
=ethyl, and D, M taken together=O;
Compound of formula I: A=—CH
2
CH
2
CH
2
—(3-quinolyl), R
1
=R
p
=H, X=H, R
13
=ethyl, and D, M taken together=O;
Compound of formula I: A=—CH
2
CH
2
CH
2
CH
2
-(4-phenyl-1-imidazolyl), R
1
=R
p
=H, X=H, R
13
=ethyl, and D, M taken together=O;
Compound of formula I: A=—CH
2
CH
2
CH
2
CH
2
-(4

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