Antibacterial tylosin derivatives and methods for their preparation

1. A compound represented by the formula (I):

or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof;

wherein, 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; and

c. —N 3

(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 R7 and R8 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) C3-C14-cycloalkyl;

(7) substituted C3-C14-cycloalkyl;

(8) aryl;

(9) substituted aryl;

(10) heterocyclic;

(11) substituted heterocyclic; and

(12) CH 2 —R′;

R1 and R2

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 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 -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-allcenyl-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;

R5 is selected from the group consisting of:

(1) hydrogen;

(2) hydroxy;

(3) protected hydroxy;

(4) halogen;

(5) —O—R7, where R7 is as previously defined;

(6) —N 3 or R′;

R P is hydrogen or a hydroxy protecting group;

and each R′ is independently [1,4]-epi-[1,2,3]-triazolo R; and where each R is independently selected from the group consisting of:

(1) C1-C9-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;

(2) C2-C9-alkenyl, 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;

(3) C2-C9-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;

(4) C3-C14-cycloalkyl;

(5) substituted C3-C14-cycloalkyl;

(6) aryl;

(7) substituted aryl;

(8) heterocyclic;

(9) substituted heterocyclic; and

(10) —COOR7, where R7 is as previously defined;

provided that at least one of A and R5 is a group containing R′.

2. The compound of claim 1 wherein;

A is selected from halogen, CH 2 -N 3 , hydroxy, CHO, hydroxyC 1 -6alkyl, haloC 1 -6alkyl, methyl(3,5-di(C1-C3-alkyl)-piperidino) and CH 2 —R′;

R1 and R2 taken together are oxo

R3 is H;

R4 is H;

R5 is selected from hydroxy, N 3 , halogen, 6-deoxy-2,3-di-O-methyl-b-d-allo-hexapyranosyloxy and R′; and

each R′ is independently [1,4]-epi-[1,2,3]-triazolo-R,

where each R is independently selected from the group consisting of:

(1) C1-C9-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;

(2) C2-C9-alkenyl, 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;

(3) C2-C9-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;

(4) C3-C14-cycloalkyl;

(5) substituted C3-C14-cycloalkyl;

(6) aryl;

(7) substituted aryl;

(8) heterocyclic;

(9) substituted heterocyclic; and

(10) —COOR7, where R7 is as previously defined;

provided that at least one of A and R5 is a group containing R′;

or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof.

3. The compound of claim 1 wherein;

A is CH 2 —R′;

R1 and R2 taken together are oxo;

R3 is H;

R4 is H; and

R5 is 6-deoxy-2,3-di-O-methyl-b-d-allo-hexapyranosyloxy.

4. The compound of claim 1 wherein;

A is CHO or methyl(3,5-dimethylpiperidino);

R1 and R2 taken together are oxo;

R3 is H;

R4 is H; and

R5 is R′.

5. The compound of claim 1 wherein;

A is CHO or methyl(3,5-dimethylpiperidino);

R1 and R2 taken together are oxo; and

R3 is H;

R4 is H; and

R5 is 6-deoxy-2,3-di-O-methyl-b-d-allo-hexapyranosyloxy.

6. The compound of claim 1 wherein;

R is selected from the group consisting of

7. A method for preparing a compound of the formula (I):

wherein A is CH 2 —R′ and R1, R2, R3, R4, R5, R′ and R P are as defined in claim 1 ;

which method comprises following steps:

(i) reacting a compound of the formula (II):

wherein,

A is CH 2 -hydroxy; and

the other variable groups are as defined in claim 1 , with an azide selected from diphenylphosphoryl azide (DPPA) or sodium azide (NaN 3 ) to form a compound of said formula (II) wherein A is CH 2 —N 3 and the other variable groups are as defined in claim 1 ; and

(ii) reacting the resulting compound of the formula (II) wherein A is CH 2 —N 3 and the other variable groups are as defined in claim 1 with an R—C≡CH, wherein R is as defined in claim 1 above, in the presence of a copper catalyst to form a compound of the formula (II),

wherein A is CH 2 —R′ and R3, R4, R5, R′ and R P are as defined in claim 1 .

8. A method for preparing a compound of the formula (I):

wherein R5 is R′ and A, R1, R2, R3, R4, R′ and R P are as defined in claim 1 ;

which method comprises following steps:

(i) reacting a compound of the formula (II):

wherein,

R5 is hydroxy; and

the other variable groups are as defined in claim 1 , with an azide selected from diphenylphosphoryl azide (DPPA) or sodium azide (NaN 3 ) to form a compound of said formula (II) wherein R5 is —N 3 and the other variable groups are as defined in claim 1 ; and

(ii) reacting the resulting compound of the formula (II) wherein R5 is —N 3 and the other variable groups are as defined in claim 1 with an R—C≡CH, wherein R is as defined in claim 1 , in the presence of a copper catalyst to form a compound of the formula (II),

wherein R5 is R′ and A, R3, R4, R′ and R P are as defined in claim 1 .

9. A pharmaceutical or veterinary composition comprising a compound according to claim 1 and at least one of pharmaceutically acceptable carriers.

10. A method for treating or preventing bacterial infections or disorders associated with bacterial infections in an animal, wherein the method comprises administering to the animal a therapeutically effective amount of the compound according to claim 1 .

11. The compound of claim 2 wherein;

R is selected from the group consisting of

12. The compound of claim 3 wherein;

R is selected from the group consisting of

13. The compound of claim 4 wherein;

R is selected from the group consisting of

14. The compound of claim 5 wherein;

R is selected from the group consisting of