11-O-substituted macrolides and their descladinose derivatives

Details 11-O-substituted macrolides and their descladinose derivatives 11-O-substituted macrolides and their descladinose derivatives

2001-12-03

2004-01-06

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007200, C536S007400, C536S018500

Reexamination Certificate

active

06673774

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 a novel class of 11-O-substituted Clarithromycin derivatives, 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 search for macrolides active against MLS
B
-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 a novel class of 11-O-substituted derivatives of erythromycin with the general formulae (I) and (II), as well as the pharmaceutically acceptable salts, esters and prodrugs thereof.
In formulae (I) and (II) 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:
i. halogen;
ii. aryl;
iii. substituted aryl;
iv. heteroaryl;
v. substituted heteroaryl;
vi. —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; and
vii. —O—C
1
-C
6
-alkyl-R
5
, where R
5
is as previously defined;
viii. —O—C
2
-C
6
-alkenyl-R
5
, where R
5
is as previously defined;
ix. —O—C
2
-C
6
-alkynyl-R
5
, where R
5
is as previously defined; and
x. —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)NR7-, —NR
6
C(N)NR7-, 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;
R
2
is selected from the group consisting of:
(1) hydroxy protecting group;
(2) R
5
, as previously defined;
(3) —X—Y—R
5
, where X=—C(O), —C(O)O—, —C(O)NH—, or absent, and Y=C
1
-C
6
-alkyl or absent, and R
5
is as previously defined; and
(4) 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 as previously defined;
g. —O—C
1
-C
6
-alkyl-R
5
where R
5
is as previously defined;
h. —O—C
2
-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 as previously defined;
Rp
1
is hydrogen or hydroxy protecting group; and
Z is selected from the group consisting of:
(1) hydrogen;
(2) hydroxy protecting groups; and
(3) —X—R
3
, where X and R
3
are as previously defined.
In another aspect of the present invention 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 are provided processes for the preparation of macrolide derivatives of formulae (I) and (II) above.
DETAILED DESCRIPTION OF THE INVENTION
The present invention includes compounds represented by formulae (I) or (II), their pharmaceutical salts, esters or prodrugs thereof, as described above.
Representative compounds of the present invention include compounds illustrated below:
A=—CH
2
CH═CH
2
, R
1
=H, R
P1
=H, Z=acetyl;  Compound of formula I
A=—CH
2
CH═CH-(3-quinolyl), R
1
=H, R
P1
=H, Z=acetyl;  Compound of formula I
A=—CH
2
CH
2
CH
2
-(3-quinolyl), R
1
=H, R
P1
=H, Z=acetyl;  Compound of formula I
A=—CH
2
CH
2
CH
2
-(3-quinolyl), R
1
=H, R
P1
=H, Z=H;  Compound of formula I
A=—CH
2
CH═CH-(3-quinolyl), R
1
=H, R
P1
=H, Z=H;  Compound of formula I
A=R
1
=—CH
2
CH═CH
2
, R
P1
=H, Z=acetyl;  Compound of formula I
A=—CH
2
CH═CHCH
2
-(4-phenyl-1-imidazolyl), R
1
=H, R
P1
=H, Z=acetyl;  Compound of formula I
 A=—CH
2
CH
2
CH
2
CH
2
-(4-phenyl-1-imidazolyl), R
1
=H, R
P1
=H, Z=acetyl;  Compound of formula I
A=—CH
2
CH
2
CH
2
CH
2
-(4-phenyl-1-imidazolyl), R
1
=H, R
P1
=H, Z=H;  Compound of formula I
A=—CH
2
CH
2
CH
2
CH
2
-(4-phenyl-1-imidazolyl), R
1
=—CH
2
CH═CH
2
, R
p1
=H, Z=acetyl;  Compound of formula I
A=—CH
2
CH═CHCH
2
CH
2
-(4-phenyl-1-imidazolyl), R
1
=R
p1
=H, Z=acetyl;  Compound of formula I
A=—CH
2
CH
2
CH
2
CH
2
CH
2
-(4-phenyl-1-imidazolyl), R
1
=—CH
2
CH═CH
2
, R
p1
=H, Z=acetyl;  Compound of f

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