4'-substituted leucomycins

Details 4'-substituted leucomycins 4'-substituted leucomycins

2001-07-27

2004-01-20

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007100

Reexamination Certificate

active

06680299

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 4′-substituted 16-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. Natural 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 josamycin.
The 1 6-membered ring macrolide antibiotics constitute an important clinically useful series of naturally occurring compounds within the macrolide class of antibiotics, as they show some advantages over 14-membered ring compounds (gastrointestinal tolerance and activity against strains expressing resistance of the inducible type. Sixteen membered macrolides usually contain an amino disaccharide-4-O-(L-mycarosyl)-D-mycaminose and/or D-desosamine. One class has only neutral sugars. The sixteen membered macrolides can be classified into two major groups—the leucomycins and the tylosin series.
The leucomycins differ from each other in terms of the acyl group at positions O-3 and O-4″ and the C12, 13 epoxy group. Within a given chromophoric group, it is possible to differentiate the various compounds by the substituent at C-3 and C-4″.

Leucomycin
R3
R4
A1
H
C(O)CH2CHMe2
(Kitasamycin) A5
H
C(O)CH2CH2CH3
A7
H
C(O)CH2CH3
A9
H
C(O)CH3
V(A11)
H
H
(Josamycin) A3
C(O)CH3
C(O)CH2CHMe2
A4
C(O)CH3
C(O)CH2CH2CH3
A6
C(O)CH3
C(O)CH2CH3
A8
C(O)CH3
C(O)CH3
U
C(O)CH3
H
Miokamycin
1
C(O)CH2CH3
C(O)CH2CH2CH3
Rokitamycin
2
H
C(O)CH2CH2CH3
1
9-OAc; 3”-OAc
2
3″-OC(O)CH2CH3; 4″-OC(O)CH2CH2CH3
The search for macrolides active against MLS-resistant strains (MLS=Macrolides-Lincosamides-Streptogramines) has become a major goal, together with retaining the overall profile of the macrolides in terms of stability, tolerance and pharmacokinetics. Semisynthetic molecules have recently been developed from erythromycin A; new compounds containing a 14-membered lactone ring with chemical modifications to enhance acid stability and prevent anhydro formation include roxithromycin and clarithromycin.
However, less research has been done to improve the sixteen membered macrolides to overcome resistance and to improve its acid stability.
SUMMARY OF THE INVENTION
The present invention provides a novel class of 4′-substituted 16-membered macrolides possessing increased antibacterial activity toward Gram positive and Gram negative bacteria as well as macrolide resistant Gram positives. In addition, the present invention provides a class of 16-membered macrolides that are more acid stable.
In one embodiment, the present invention provides compounds represented by Formula I, or a pharmaceutically acceptable salt, ester or prodrug thereof:
In Formula I
A is selected from the group consisting of;
(1) CHO or a protected aldehyde,
(2) CH
2
X, wherein X is selected from the group consisting of;
a. hydroxy or protected hydroxy,
b. halogen,
c. NR7R8, wherein R7 and R8 are each independently selected from hydrogen, C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic, C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic, C2-C6-alkynyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic or R7R8 taken with the nitrogen atom to which they are connected form a 3- to 7-membered ring which may optionally contain a hetero function selected from the group consisting of —O—, —NH—, —N(C1-C6-alkyl)-, —N(aryl)-, —N(heteroaryl)-, —S—, —S(O)— and —S(O)
2
—,
d. NR7C(O)—R9, where R7 is as previously defined and R9 is selected from the group consisting of;
i. C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic,
ii. C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic,
iii. C2-C6-alkynyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic,
iv. aryl,
v. substituted aryl,
vi. heterocyclic, and
vii. substituted heterocyclic
e. NR7C(O)—NR8R9, where R7, R8, and R9 are as previously defined,
f. S(O)
n
—R10, where R10 is selected from the group consisting of aryl, substituted aryl, heterocyclic and substituted heterocyclic and where n=0, 1 or 2,
g. S(O)
n
—(C1-C6-alkyl), optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic, where n is as previously defined,
h. S(O)
n
—(C2-C6-alkenyl), optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic, where n is as previously defined
i. S(O)
n
—(C2-C6-alkynyl), optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic, where n is as previously defined, and
j. O—M—Y, where M is
(i) absent,
(ii) —C(O)—
(iii) —C(O)N(R7)—, where R7 is as previously defined,
(iv) C1-C6-alkyl-N(R7)—, where R7 is as previously defined,
(v) C2-C6-alkenyl-N(R7)—, where R7 is as previously defined, and
(vi) C2-C6-alkynyl-N(R7)—, where R7 is as previously defined
and where Y is
(i) hydrogen
(ii) C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic,
(iii) C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted hetreocyclic,
(iv) C2-C6-alkynyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic,
(v) aryl,
(vi) substituted aryl,
(vii) heterocyclic, or
(viii) substituted heterocyclic,
(3) substituted or unsubstituted imidazole, arylimidazole or heteroarylimidazole,
(4) substituted or unsubstituted oxazole, aryloxazole or heteroaryloxazole,
(5) substituted or unsubstituted thioxazole, arylthioxazole or heteroarylthioxazole,
(6) substituted or unsubstituted imidazoline, arylimidazoline or heteroarylimidazoline,
(7) substituted or unsubstituted oxazoline, aryloxazoline or heteroaryloxazoline, and
(8) substituted or unsubstituted thioxazoline, arylthioxazoline and heteroarylthioxazoline,
R1 and R2 are each independently selected from the group consisting of;
(1) hydrogen,
(2) hydroxy,
(3) protected hydroxy,
(4) OC(O)—C1-C12-alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, O—R7 and NR7R8 where R7 and R8 are as previously defined,
(5) O—R7, where R7 is as previously defined,
(6) halogen,
(7) R1 and R2 taken together are oxo, and
(8) NR7R8, where R7 and R8 are as previously defined;
R3 is selected from the grou

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