4′-O-substituted tylosin analogs

Details 4′-O-substituted tylosin analogs 4′-O-substituted tylosin analogs

2001-11-08

2003-06-10

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007100, C536S018500

Reexamination Certificate

active

06576615

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. 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) exhibits a wide range of characteristics (antibacterial spectrum, side-effects and bioavailability). Among the commonly used macrolides are erythromycin and josamycin.
The 16-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 tylosin series is divided into two groups-IIA and IIB which differ at the C-6-side chain and the nature of the sugars on the chromophore. Tylosin consists of a substituted 16-membered ring lactone (tylonolide), an aminosugar (D-mycaminose) attached to C-5, two neutral sugars (D-mycinose attached at C-23 and L-mycarose attached at C-4′) and an acetaldehyde at C-6.
Considerable research efforts have been carried out on tylosin and its derivatives but not much success has been observed with this subclass. The search for macrolides active against MLS-resistant strains (MLS═Macrolides-Lincosamides-Streptogramines) has become a major goal, in addition to improving the overall profile of the macrolides in terms of acid stability, tolerance and pharmacokinetics.
SUMMARY OF THE INVENTION
The present invention provides a novel class of 4′-substituted tylosin analogs 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 4′-substituted tylosin derivatives that are more acid stable and overcome bacterial resistance.
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; and
b. halogen;
(3) —CN;
(4) —CH═N—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
—;
(5) —CH═N—OR7, wherein R7 is as previously defined;
(6) substituted or unsubstituted imidazole, arylimidazole or heteroarylimidazole;
(7) substituted or unsubstituted oxazole, aryloxazole or heteroaryloxazole, substituted or unsubstituted thioxazole, arylthioxazole or heteroarylthioxazole;
(8) substituted or unsubstituted imidazoline, arylimidazoline or heteroarylimidazoline;
(9) substituted or unsubstituted oxazoline, aryloxazoline or heteroaryloxazoline; and
(10) 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) —NR7R8, where R7 and R8 are as previously defined; and
(8) R1 and R2 taken together are oxo;
R3 is selected from the group consisting of:
(1) hydrogen;
(2) a hydroxy protecting group;
(3) —C(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;
(4) C1-C6-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) C2-C6-alkenyl, 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; and
(6) C2-C6-alkynyl, optionally substituted with one or more substitutents selected fron the group consisting of halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, O—R7 and NR7R8 where R7 and R8 are as previously defined;
R4 is —M—Y,
where M is:
(1) absent,
(2) —C(O)—,
(3) —C(O)N(R7)-, where R7 is as previously defined,
(4) —C1-C6-alkyl-N(R7)-, where R7 is as previously defined,
(5) —C2-C6-alkenyl-N(R7)-, where R7 is as previously defined, or
(6) —C2-C6-alkynyl-N(R7)-, where R7 is as previously defined;
and where Y is:
(1) hydrogen,
(2) hydroxy protecting group,
(3) C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic, —OR7 where R7 is as previously defined,
(4) C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted hetreocyclic, —OR7 where R7 is as previously defined,
(5) C2-C6-alkynyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic, —OR7 where R7 is as previously defined,
(6) aryl,
(7) substituted aryl,
(8) heterocyclic, or
(9) substituted heterocyclic; and
R
p
is hydrogen or a hydroxy protecting group.
In another embodiment, the present invention provides a process for preparing novel compounds represented by Formula I wherein the groups A, R1, R2, R3, R4 and R
p
are as previously defined.
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=—CHO, R1 and R2 taken together=O, R3=H, R4=—CH
2
CHCH
2
and R
p
=H;
Compound of Formula I: A=—CHO, R1 and R2 taken together=O, R3=—CH
2
CHCH
2
, R4=H and R
p
=H;
Compound of Formula I: A=—CHO, R1 and R2 taken together=O, R3=H, R4=—CHCHCH
2

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