US 2003/0212010 A1 · 23-O-substituted 5-O-mycaminosyltylonide derivatives

Abstract

There are described novel 5-O-mycaminosyltylonide (OMT) analogs possessing increased antibacterial activity toward Gram positive and Gram negative bacteria as well as macrolide resistant Gram positives and pharmaceutically acceptable compositions comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier. Also described are a method for treating bacterial infections by administering to a patient a pharmaceutical composition containing a therapeutically-effective amount of a compound of the invention, and processes for the preparation of such compounds

A compound represented by the Formula:

10
wherein
A is selected from the group consisting of:
(1) —CHO or a protected aldehyde;
(2) —CN;
(3) —CH═N—NR6R7, wherein R6 and R7 are each independently selected from the group consisting of:
(a) hydrogen;
(b) C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of:
halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;
(c) C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of:
halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;
(d) C2-C6-alkynyl, optionally substituted with one or more substituents selected from the group consisting of:
halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;
and
(e) R6 and R7, taken together 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—;
(4) —C═N—OR6, wherein R6 is as previously defined;
(5) —CH2X, wherein X is selected from the group consisting of:
(a) hydroxy or protected hydroxy;
(b) halogen;
(c) —NR6R7, wherein R6 and R7 are as previously defined;
(d) —NR6C(O)—R8, wherein R6 is as previously defined and R8 is selected from the group consisting of:
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 heterocyclic;
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;
and
viii. substituted heterocyclic;
(e) —NR6C(O)—NR7R8, wherein R6, R7, and R8 are as previously defined;
(f) —NR6—NR7R8, wherein R6, R7 and R8 are as previously defined;
(g) —NR6—NR7C(O)—R8, wherein R6, R7 and R8 are as previously described;
(h) —S(O)n—R9, wherein R9 is selected from the group consisting of:
aryl, substituted aryl, heterocyclic, and substituted heterocyclic, and wherein n=0, 1 or 2;
(i) —S(O)n—(C1-C6-alkyl), optionally substituted with one or more substituents selected from the group consisting of:
aryl, substituted aryl, heterocyclic, and substituted heterocyclic, wherein n is as previously defined;
(j) —S(O)n—(C2-C6-alkenyl), optionally substituted with one or more substituents selected from the group consisting of:
aryl, substituted aryl, heterocyclic, and substituted heterocyclic, wherein n is as previously defined;
(k) —S(O)n—(C2-C6-alkynyl), optionally substituted with one or more substituents selected from the group consisting of:
aryl, substituted aryl, heterocyclic, and substituted heterocyclic, wherein n is as previously defined;
and
(l) —O-M-Y,
where M is selected from:
i. absent,
ii. —C(O)—,
iii. —C(O)N(R6)—, wherein R6 is as previously defined,
iv. C1-C6-alkyl-N(R6)—, wherein R6 is as previously defined,
v. C2-C6-alkenyl-N(R6)—, wherein R6 is as previously defined, or
vi. C2-C6-alkynyl-N(R6)—, wherein R6 is as previously defined,
and wherein Y is selected from:
i. hydrogen,
ii. C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of:
halogen, —OR6, aryl, substituted aryl, heterocyclic, and substituted heterocyclic, wherein R6 is as previously defined,
iii. C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of:
halogen, —OR6, aryl, substituted aryl, heterocyclic, and substituted heterocyclic, wherein R6 is as previously defined,
iv. C2-C6-alkynyl, optionally substituted with one or more substituents selected from the group consisting of:
halogen, —OR6, aryl, substituted aryl, heterocyclic, and substituted heterocyclic, wherein R6 is as previously defined,
v. aryl,
vi. substituted aryl,
vii. heterocyclic, or
viii. substituted heterocyclic;
and
(6) heterocyclic or substituted heterocyclic;
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, —OR6, and —NR6R7, wherein R6 and R7 are as previously defined;
(5) —OR6, wherein R6 is as previously defined;
(6) halogen;
(7) —NR6R7, wherein R6 and R7 are as previously defined;
and
(8) R1 and R2 taken together are=O;
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, —OR6, and —NR6R7, wherein R6 and R7 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, —OR6, and —NR6R7, wherein R6 and R7 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, —OR6, and —NR6R7, wherein R6 and R7 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, —OR6, and —NR6R7, wherein R6 and R7 are as previously defined;
R4 is -M-Y, wherein M and Y are as previously defined;
R5 is -M-Y, wherein M and Y are as previously defined;
and
Rpis hydrogen or a hydroxy protecting group.

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23-O-substituted 5-O-mycaminosyltylonide derivatives

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23-O-substituted 5-O-mycaminosyltylonide derivatives

Life of this patent

Abstract

Claims15