US 6,664,240 B2Granted

Tylosin derivatives having antibacterial activity

AssigneeEnanta Pharmaceuticals, Inc.

InventorsLy Tam Phan, Marina V. Busuyek, Yat Sun Or

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Abstract

There are described novel substituted tylosin analogs and pharmaceutically acceptable compositions comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier. Also described is a method for treating bacterial infections by administering to a mammal a pharmaceutical composition containing a therapeutically-effective amount of a compound of the invention, and processes for the preparation of such compounds.

Claims8

Dependent claims

A compound represented by Formula I, or a pharmaceutically acceptable salt, ester or prodrug thereof, where Formula I is:

In Formula I:
Z is selected from the group consisting of:
(1) —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—;
(2) —NR7C(O)—R9, where R7 is as previously defined and R9 is selected from the group consisting of:
(a) C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
(b) C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
(c) C2-C6-alkynyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
(d) aryl;
(e) substituted aryl;
(f) heterocyclic;
and
(g) substituted heterocyclic;
(3) —NR7C(O)—NR8R9, where R7, R8, and R9 are as previously defined;
(4) —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;
(5) —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;
(6) —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;
(7) —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
(8) —O—M—Y, where M is:
(a) absent,
(b) —C(O)—
(c) —C(O)N(R7)-, where R7 is as previously defined,
(d) —C1-C6-alkyl-N(R7)-, where R7 is as previously defined,
(e) —C2-C6-alkenyl-N(R7)-, where R7 is as previously defined, or
(f) —C2-C6-alkynyl-N(R7)-, where R7 is as previously defined;
and where Y is:
(a) hydrogen,
(b) hydroxy protecting group,
(c) C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic,
(d) C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic,
(e) C2-C6-alkynyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic,
(f) aryl,
(g) substituted aryl,
(h) heterocyclic, or
(i) substituted heterocyclic;
R1 and R2 are each independently selected from the group consisting of:
(a) hydrogen;
(b) hydroxy;
(c) protected hydroxy;
(d) 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;
(e) O—R7, where R7 is as previously defined;
(f) halogen;
(g) R1 and R2 taken together are oxo;
and
(h) NR7R8, where R7 and R8 are as previously defined;
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 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;
R4 is -D-E;
where D is:
(a) absent,
(b) —C(O)N(R7)-, where R7 is as previously defined,
(c) —C1-C6-alkyl-N(R7)-, where R7 is as previously defined,
(d) —C2-C6-alkenyl-N(R7)-, where R7 is as previously defined, or
(e) —C2-C6-alkynyl-N(R7)-, where R7 is as previously defined;
and where E is:
(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,
(e) aryl,
(f) substituted aryl,
(g) heterocyclic, or
(h) substituted heterocyclic;
provided that when D is absent E is not hydrogen;
and
Rp1 and Rp2 are each independently hydrogen or a hydroxy protecting group.

69 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound represented by Formula I, or a pharmaceutically acceptable salt, ester or prodrug thereof, where Formula I is:

In Formula I:
Z is selected from the group consisting of:
(1) —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—;
(2) —NR7C(O)—R9, where R7 is as previously defined and R9 is selected from the group consisting of:
(a) C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
(b) C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
(c) C2-C6-alkynyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
(d) aryl;
(e) substituted aryl;
(f) heterocyclic;
and
(g) substituted heterocyclic;
(3) —NR7C(O)—NR8R9, where R7, R8, and R9 are as previously defined;
(4) —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;
(5) —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;
(6) —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;
(7) —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
(8) —O—M—Y, where M is:
(a) absent,
(b) —C(O)—
(c) —C(O)N(R7)-, where R7 is as previously defined,
(d) —C1-C6-alkyl-N(R7)-, where R7 is as previously defined,
(e) —C2-C6-alkenyl-N(R7)-, where R7 is as previously defined, or
(f) —C2-C6-alkynyl-N(R7)-, where R7 is as previously defined;
and where Y is:
(a) hydrogen,
(b) hydroxy protecting group,
(c) C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic,
(d) C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic,
(e) C2-C6-alkynyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic,
(f) aryl,
(g) substituted aryl,
(h) heterocyclic, or
(i) substituted heterocyclic;
R1 and R2 are each independently selected from the group consisting of:
(a) hydrogen;
(b) hydroxy;
(c) protected hydroxy;
(d) 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;
(e) O—R7, where R7 is as previously defined;
(f) halogen;
(g) R1 and R2 taken together are oxo;
and
(h) NR7R8, where R7 and R8 are as previously defined;
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 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;
R4 is -D-E;
where D is:
(a) absent,
(b) —C(O)N(R7)-, where R7 is as previously defined,
(c) —C1-C6-alkyl-N(R7)-, where R7 is as previously defined,
(d) —C2-C6-alkenyl-N(R7)-, where R7 is as previously defined, or
(e) —C2-C6-alkynyl-N(R7)-, where R7 is as previously defined;
and where E is:
(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,
(e) aryl,
(f) substituted aryl,
(g) heterocyclic, or
(h) substituted heterocyclic;
provided that when D is absent E is not hydrogen;
and
Rp1 and Rp2 are each independently hydrogen or a hydroxy protecting group.

69 more elements