11-C-substituted derivatives of clarithromycin

Details 11-C-substituted derivatives of clarithromycin 11-C-substituted derivatives of clarithromycin

2002-06-25

2004-11-02

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007200, C536S007300, C536S007400

Reexamination Certificate

active

06812216

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-C-substituted erythromycin 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-C-substituted derivatives of clarithromycin possessing antibacterial activity toward Gram positive and Gram negative bacteria as well as macrolide Gram positives.
In one embodiment, the present invention provides compounds represented by formulae I, II, III or IV, as well as the pharmaceutically acceptable salts, esters and prodrugs thereof.
In formulae I-IV 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. heterocyclic;
V. substituted heterocyclic;
vi. —O—R
5
, where R
5
is selected from the group consisting of:
a. hydrogen;
b. aryl;
c. substituted aryl;
d. heterocyclic; and
e. substituted heterocyclic;
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 the group consisting of:
a. hydrogen;
b. C
1
-C
6
-alkyl, optionally substituted with one or more substituents selected from the group consisting of:
(I) halogen;
(II) aryl;
(III) substituted aryl;
(IV) heterocyclic; and
(V) substituted heterocyclic;
c. C
2
-C
6
-alkenyl, optionally substituted with one or more substituents selected from the group consisting of:
(I) halogen;
(II) aryl;
(III) substituted aryl;
(IV) heterocyclic; and
(V) substituted heterocyclic;
d. 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) heterocyclic; and
(V) substituted heterocyclic, or
e. 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 functions selected from the group consisting of:
(I) —O—;
(II) —NH—;
(III) —N(C
1
-C
6
-alkyl)-;
(IV) —N(aryl)-;
(V) —N(heteroaryl)-;
(VI) —S—;
(VII) —S(O)—;
(VIII) —S(O)
2
—; and
(IX) —C(O)—;
(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 is —OC(O)—, —OC(O)O—, —OC(O)NR
6
—, —C(O)NR
6
, —NR
6
C(O)—, —NR
6
C(O)O—, —NR
6
C(O)NR
7
—, —NR
6
C(NH)NR
7
— or 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 and R
5
are as previously defined; and
(8) —C
2
-C
6
-alkynyl-M—R
5
, where M and R
5
are as previously defined;
B, C, and D may be present singly or in combination and are independently selected from the group consisting of:
(1) hydrogen;
(2) halogen;
(3) C
1
-C
6
-alkyl;
(4) aryl;
(5) substituted aryl;
(6) heteroaryl;
(7) substituted heteroaryl;
(8) O—R
5
where R
5
is as previously defined;
(9) B and C taken together are ═O;
(10) B and C taken together are ═N—O—R
5
, where R
5
is as previously defined;
(11) B and C taken together are ═N—N—R
6
R
7
, where R
6
and R
7
are as previously defined;
(12) B and D taken together are —O—;
(13) B and D taken together are —S—;
(14) B and D taken together are —N(R
6
)—, where R
6
is as previously defined; and
(15) B and D taken together with the carbon atoms to which they are attached form a 4- to 8-membered ring which may optionally contain one or more functions selected from the group consisting of:
i. —O—;
ii. —NH—;
iii. —N(C
1
-C
6
-alkyl)-;
iv. —N(aryl)-;
v. —N(heteroaryl)-;
vi. —S—;
vii. —S(O)—;
viii. —S(O)
2
—; and
ix. —C(O)—;
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:
i. halogen;
ii. aryl;
iii. substituted-aryl;
iv. heteroaryl;
v. substituted-heteroaryl;
vi. —O—C
1
-C
6
-alkyl-R
5
, where R
5
is as previously defined; and
vii. —N—R
6
R
7
, where R
6
and R
7
are as previously defined;
(3) —C(O)—R
4
, where R
4
is hydrogen or R
3
, where R
3
is 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) a hydroxy protecting group;
(2) R
5
, where R
5
is as previously defined;
(3) —X—Y—R
5
, where X is —C(O), —C(O)O—, —C(O)NR
6
—, or absent, and Y is C
1
-C
6
-alkyl or absent, where R
5
and R
6
are 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:
i. halogen;
ii. aryl;
iii. substituted-aryl;
iv. heteroaryl;
v. substituted-heteroaryl;
vi. —O—R
5
where R
5
, is as previously defined;
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. —N—R
6
R
7
, where R
6
and R
7
are as previously defined;
Rp
1
is hydrogen or a hydroxy protecting group; and
Z is selected from the group consisting of:
(1) hydrogen;
(2) a hydroxy protecting group; and
(3) —X—R
3
, where X and R
3
are as previously defined.
In other embodiments, the present invention provides processes for preparing the compounds represented by formulae I-IV, compositions containing such compounds and methods for using the same.
DETAILED DESCRIPTION OF THE INVENTION
A first embodiment of the invention is a compound represented by formula I as described above, or a pharmaceutically acceptable salt, ester or prodrug thereof.
A second embodiment of the invention is a compound represented by formula II as described above, or a pharmaceutically acceptable salt, ester or prodrug thereof.
A third embodiment of the invention is a compound represented by formula III as described above, or a pharmaceutically acceptable salt, ester or prodrug thereof.
A fourth embodiment of the invention is a compound represented by formula IV as described above, or a pharmaceutically acceptable salt, ester or prodrug thereof.
Other preferred embodiments of the invention are: compounds of formula I where R
1
and Z are each hydrogen and A and Rp
1
are as previously defined; compounds of formula II where R
1
is hydrogen and A, R
2
and Rp
1
are as previously defined; compounds of formula III where R
1
and Z are each hydrogen and A, B, C, D and Rp
1
are as previously defined; and compounds of formula IV where R
1
is hydrogen and A, B, C, D, R

Affiliated with

Also associated with

Rating

11-C-substituted derivatives of clarithromycin 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-C-substituted derivatives of clarithromycin, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 11-C-substituted derivatives of clarithromycin will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3322221