6,11-bicyclic erythromycin derivatives

1. A compound represented by the formula

as well as its pharmaceutically acceptable salts, esters and prodrugs,

wherein

A is:

a) —OR p , where R p is a hydroxy protecting group;

b) —R 1 , where R 1 is independently:

(1) aryl;

(2) substituted aryl;

(3) heteroaryl; or

(4) substituted heteroaryl;

c) —OR 1 ;

d) —R 2 , where R 2 is:

(1) hydrogen;

(2) halogen;

(3) C 1 –C 12 alkyl optionally containing 0, 1, 2, or 3 heteroatoms selected from the group consisting of O, S or N, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

(4) C 2 –C 12 alkenyl optionally containing 0, 1, 2, or 3 heteroatoms selected from the group consisting of O, S and N, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and

(5) C 2 –C 12 alkynyl optionally containing 0, 1, 2, or 3 heteroatoms selected from the group consisting of O, S and N, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

e) —OR 2 ;

f) —S(O) n R 11 , where n=0, 1 or 2, and R 11 is independently hydrogen, R 1 or R 2 ;

g) —NHC(O)R 11 ;

h) —NHC(O)NHR 11 ;

i) —NHS(O) 2 R 11 ;

j) NR 14 R 15 , where R 14 and R 15 are each independently R 11 ; or

k) —NHR 3 , where R 3 is an amino protecting group;

B is:

a) hydrogen;

b) deuterium;

c) halogen;

d) —OH;

e) R 1 ;

f) R 2 ; or

g) —OR p ,

h) provided that when B is halogen, —OH, or —OR p , A is R 1 or R 2 ;

or alternatively, A and B taken together with the carbon atom to which they are attached are:

a) C═O;

b) C(OR 2 ) 2 ;

c) C(SR 2 ) 2 ;

d) C(OR 12 )(OR 13 ), where R 12 and R 13 are independently C 1 –C 6 alkyl or taken together are —(CH 2 ) m —, where m=2 or 3;

e) C(SR 12 )(SR 13 );

f) C═CHR 11 ;

g) C═N—O—R 11 ;

h) C═N—O—Ar 1 —M—Ar 2 , wherein

(1) —Ar l — is R 31 , where R 31 is independently selected from:

(a) —R 1 ;

(b) —C 1 –C 12 alkyl optionally containing 0, 1, 2, or 3 heteroatoms selected from the group consisting of O, S or N, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

(c) —C 2 –C 12 alkenyl optionally containing 0, 1, 2, or 3 heteroatoms selected from the group consisting of O, S and N, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or

(d) —C 2 –C 12 alkynyl optionally containing 0, 1, 2, or 3 heteroatoms selected from the group consisting of O, S and N, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

(2) -M- is absent or selected from the group consisting of:

(a) —C 1 –C 12 alkyl optionally containing:

1. 0–3 heteroatoms selected from the group consisting of O, S and N; and

2. 0–3 groups selected from the group consisting of —C═N—, —N═N— and C(O);

(b) —C 2 –C 12 alkenyl optionally containing:

1. 0–3 heteroatoms selected from the group consisting of O, S and N; and

2. 0–3 groups selected from the group consisting of —C═N—, —N═N—, and C(O);

(c) —C 2 –C 12 alkynyl optionally containing;

1. 0–3 heteroatoms selected from the group consisting of O, S and N; and

2. 0–3 groups selected from the groups consisting of —C═N—, —N═N—, and C(O);

(d) substituted aryl;

(e) substituted heteroaryl; and

(f) substituted heterocycloalkyl; and

(3) -Ar 2 is:

(a) aryl;

(b) substituted aryl;

(c) heteroaryl; or

(d) substituted heteroaryl;

i) C═NNHR 11 ;

j) C═NNHC(O)R 11 ;

k) C═NNHC(O)NHR 11 ;

l) C═NNHS(O) 2 R 11 ;

m) C═NNHR 3 ;

n) C═NR 11 ;

o) C═N—N—CHR 11 ; and

one of X and Y is hydrogen and the other is:

a) hydrogen;

b) deuterium;

c) —OH;

d) —OR p ;

e) —NR 4 R 5 , where R 4 and R 5 are each independently:

(1) hydrogen;

(2) C 1 –C 12 alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or

(3) R 4 and R 5 , taken together with the nitrogen atom to which they are attached form a 3–10 membered heteroalkyl ring containing 0–2 additional hetero atoms selected from the group consisting of O, S and N; or

alternatively, X and Y taken together with the carbon atom to which they are attached are:

a) C═O;

b) C═NQ, wherein Q is:

(1) R 11 ;

(2) amino protecting group;

(3) C(O)R 11 ; or

(4) OR 6 , where R 6 is independently:

(a) hydrogen;

(b) —CH 2 O(CH 2 ) 2 OCH 3 ,

(c) —CH 2 O(CH 2 O) n CH 3 ;

(d) —C 1 –C 12 alkyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;

(e) C 3 –C 12 cycloalkyl;

(f) C(O)—C 1 –C 12 alkyl;

(g) C(O)—C 3 –C 12 cycloalkyl;

(h) C(O)—R 11 ; or

(i) —Si(R a )(R b )(R c ), wherein R a , R b and R c are each independently C 1 –C 12 alkyl, aryl or substituted aryl; or

(5) O—C(R 7 )(R 8 )—O—R 6 , provided that R 6 is not C(O)—C 1 –C 12 alkyl, C(O)—C 3 –C 12 cycloalkyl, or C(O)—R 1 , and R 7 and R 8 taken together with the carbon atom to which they are attached form a C 3 –C 12 cycloalkyl group or each independently is:

1. hydrogen; or

2. C 1 –C 12 alkyl;

L is:

a) —CH(OH)CH 3 ;

b) C 1 –C 6 alkyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

c) C 2 –C 6 alkenyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or

d) C 2 –C 6 alkynyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

W is —NR 14 R 15 , where R 14 and R 15 are each independently:

a) hydrogen;

b) C 1 –C 12 alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

c) C 1 –C 12 alkenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

d) C 1 –C 12 alkynyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or

e) R 14 and R 15 , taken together with the nitrogen atom to which they are attached form a heterocycloalkyl moiety;

Z is:

a) hydrogen;

b) —OR p ;

c) —OR 11 ;

d) —OC(O)R 11 ;

e) —OC(O)NHR 11 ;

f) —S(O) n R 11 ; or

g) —

 where

i. R 3 ″ is hydrogen or methyl; and

ii. where one of J or G is hydrogen, the other is selected from:

1. hydrogen;

2. deuterium;

3. —OR 4 ″, where R 4 ″ is hydrogen or R p ; or

4. —NR 4 R 5 ; or

iii. in the alternative, J and G are taken together with the carbon atom to which they are attached form a group selected from the group consisting of:

1. C═O; and

2. C═N—Q; and

R 2 ′ is hydrogen or R p .

2. A compound according to claim 1 , which is represented by formula II:

3. A compound according to claim 1 , which is represented by formula III:

4. A compound according to claim 1 , which is represented by formula IV:

5. A compound according to claim 1 , which is represented by formula V:

6. A compound according to claim 1 , which is represented by formula VI:

7. A compound according to claim 1 , which is represented by formula VII:

8. A compound according to claim 1 , which is represented by formula VIII:

9. A compound according to claim l, which is represented by formula IX:

10. A compound according to claim 1 , which is represented by formula X:

11. A compound according to claims 1 , 4 , or 5 which is selected from the group consisting of:

Compound of formula IV: A and B taken together with the carbon atom to which they are attached=C═CH 2 , Q=OH, R 2 ′ is H, and R 4 ″=Ac;

Compound of formula IV: A and B taken together with the carbon atom to which are attached=C═CH 2 , Q=H, R 2 ′=H, and R 4 ″=Ac;

Compound of formula V: A and B taken together with the carbon atom to which they are attached=C═CH 2 , Q=H, and R 2 ′=H;

Compound of formula V: A and B taken together with the carbon atom to which they are attached=C═CH 2 , Q=Ac, and R 2 ′=H;

Compound of formula IV: A and B taken together with the carbon atom to which they are attached=C═CH 2 , Q=O—CH 2 OCH 3 , R 2 ′=H, and R 4 ″=Ac;

Compound of formula V: A and B taken together with the carbon atom to which they are attached=C═CH 2 , Q=O—CH 2 OCH 3 , and R 2 ′=H;

Compound of formula I: A and B taken together with the carbon atom to which they are attached=C═CH 2 , X and Y taken together with the carbon atom to which they are attached=C═NAc, L=CH 2 CH 3 , W is N(CH 3 ) 2 , Z=H and R 2 ′=H;

Compound of formula I: A and B taken together with the carbon atom to which they are attached=C═CH 2 , X and Y taken together with the carbon atom to which they are attached=C═NAc, L=CH 2 CH 3 , Z=OC(O)(p-nitrophenyl) and R 2 ′=H;

Compound of formula I: A and B taken together with the carbon atom to which they are attached=C═CH 2 , X and Y taken together with the carbon atom to which they are attached=C═NAc, L=CH 2 CH 3 , W is N(CH 3 ) 2 , Z=OC(O)[2-(NO 2 ), 4-(CF 3 )Phenyl] and R 2 ′=H;

Compound of formula I: A and B taken together with the carbon atom to which they are attached=C═CH 2 , X and Y taken together with the carbon atom to which they are attached=C═NAc, L=CH 2 CH 3 , W is N(CH 3 ) 2 , Z=OC(O)CH 2 (p-methoxyphenyl) and R 2 ′=H;

Compound of formula IV: A and B taken together with the carbon atom to which they are attached=C═CH 2 , Q=Ac, R 2 ′=H, and R 4 ″=Ac;

Compound of formula I: Compound of formula IV: A and B taken together with the carbon atom to which they are attached=C═O, Q=Ac, R 2 ′=H, and R 4 ″=Ac;

Compound of formula IV: A and B taken together with the carbon atom to which they are attached=C═OBz, Q=Ac, R 2 ′=H, and R 4 ″=Ac;

Compound of formula IV: A and B taken together with the carbon atom to which they are attached=C═CH-(3-quinolyl), Q=Ac, R 2 ′=H, and R 4 ″=Ac;

Compound of formula I: A and B taken together with the carbon atom to which they are attached=C═CH 2 , X and Y taken together with the carbon atom to which they are attached=C═O, L=CH 2 CH 3 , W is N(CH 3 ) 2 , Z=4-acetoxycladinose and R 2 ′=H;

Compound of formula I: A and B taken together with the carbon atom to which they are attached=C═CH-quinolin-3-yl, X and Y taken together with the carbon atom to which they are attached=C═O, L=CH 2 CH 3 , W is N(CH 3 ) 2 , Z=4-acetoxycladinose and R 2 ′=H;

Compound of formula I: A and B taken together with the carbon atom to which they are attached=C═CH-quinolin-3-yl, X and Y taken together with the carbon atom to which they are attached=C═O, L=CH 2 CH 3 , W is N(CH 3 ) 2 , Z=OH, and R 2 ′=H;

Compound of formula I: A and B taken together with the carbon atom to which they are attached=C═CH 2 , X and Y taken together with the carbon atom to which they are attached=C═O, L=CH 2 CH 3 , W is N(CH 3 ) 2 , Z=OH and R 2 ′=H;

Compound of formula IV: A and B taken together with the carbon atom to which they are attached=C═CH 2 -phenyl, Q=OH, R 2 ′=H, and R 4 ″=Ac;

Compound of formula V: A and B taken together with the carbon atom to which they are attached are C═CH-phenyl, Q=Ac, and R 2 ′=H;

Compound of formula I: A and B taken together with the carbon atom to which they are attached=C═O, X and Y taken together with the carbon atom to which they are attached=C═NAc, L=CH 2 CH 3 , W is N(CH 3 ) 2 , Z=OCH 2 CH═CH(quinolin-3-yl), and R 2 ′=H;

Compound of formula I: A and B taken together with the carbon atom to which they are attached=C═CHCHCH-phenyl, X and Y taken together with the carbon atom to which they are attached=C═NAc, L=CH 2 CH 3 , W is N(CH 3 ) 2 , Z=OC(O)-benzyl and R 2 ′=H;

Compound of formula I: A and B taken together with the carbon atom to which they are attached=C═CHCHCH-phenyl, X and Y taken together with the carbon atom to which they are attached=C═NAc, L=CH 2 CH 3 , W is N(CH 3 ) 2 , Z=OC(O)CH 2 (2-pyridyl) and R 2 ′=H;

Compound of formula I: A and B taken together with the carbon atom to which they are attached=C═CH 2 , X and Y taken together with the carbon atom to which they are attached=C═NOH, L=CH 2 CH 3 , W is N(CH 3 ) 2 , Z=4-oxocladinose and R 2 ′=H;

Compound of formula I: A and B taken together with the carbon atom to which they are attached=C═CH 2 , X and Y taken together with the carbon atom to which they are attached=C═NOH, L=CH 2 CH 3 , W is N(CH 3 ) 2 , Z=4-oximecladinose and R 2 ′=H;

Compound of formula IV: A and B taken together with the carbon atom to which they are attached are C═CH 2 , Q=OH, and R 2 ′=R 4 ″=H; or

Compound of formula I: Compound of formula IV: A and B taken together with the carbon atom to which they are attached=C═CH 2 , Q=OH, R 2 ′=H, and R 4 ″=Ac.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically-acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier.

13. A method for treating a bacterial infection in a subject in need of such comprising administering to an animal a therapeutically-effective amount of a pharmaceutical composition according to claim 12 .

14. A process for preparing a compound according to claim 1 represented by the formula:

comprising:

(a) reacting a compound represented by the formula

with an alkylating agent represented by the formula

in the presence of a palladium catalyst to provide a compound represented by the formula

(b) deprotecting the compound from step (a) by reaction with a base to provide a compound represented by the formula

(c) reacting the compound from step (b) with a sulfite reducing agent or TiCl 3 to provide a compound represented by the formula

(d) reacting the compound from step (c) to provide a compound represented by the formula

and

(e) cyclizing the compound from step (d) using palladium catalyst.

15. A process for the preparation of a compound according to claim 1 represented by the formula (IX):

comprising the steps of:

(a) reacting a compound represented by the formula (16a)

with a reagent or reagents capable of performing oxidative cleavage;

(b) reacting a compound from step (a) represented by the formula (16b)

with a compound of the formula Ar 1 -M-Ar 2 -O—NH 2 in the presence of an acid or a base; and

(c) optionally deprotecting the compound from step (d).

16. A compound according to claim 1 of formula I, whcrein A and B taken together with the carbon to which they are attached are C═CH 2 .

17. A compound according to claim 1 of formula I, wherein A and B taken together with the carbon to which they are attached are C═CH 2 and Z is

18. A compound according to claim 1 of formula I, wherein A and B taken together with the carbon to which they are attached are C═CH 2 , L is ethyl, X and Y taken together with the carbon to which they are attached are C═N—Ac, W is N(CH 3 ) 2 , R 2 ′ is Ac, and Z is

19. A compound according to claim 1 of formula I, wherein A and B taken together with the carbon to which they are attached are C═CH 2 , L is ethyl, X and Y taken together with the carbon to which they are attached are C═NH, W is N(CH 3 ) 2 , R 2 is Ac, and Z is OH.

20. A compound according to claim 1 of formula I, wherein A and B taken together with the carbon to which they are attachcd are C═CH 2 , L is ethyl, X and Y taken together with the carbon to which they are attached are C═NH, W is N(CH 3 ) 2 , R 2 ′ is H, and Z is OH.

21. A compound according to claim 1 of formula I, wherein A and B taken together with the carbon to which they are attached are C═CH 2 , L is ethyl, X and Y taken together with the carbon to which they are attached are C═N—Ac, W is N(CH 3 ) 2 , R 2 ′ is Ac, and Z is OH.

22. A compound according to claim 1 of formula I, wherein A and B taken together with the carbon to which they are attached are C═CH 2 , L is ethyl, X and Y taken together with the carbon to which they are attached are C═N—Ac, W is N(CH 3 ) 2 , R 2 ′ is hydrogen, and Z is OH.

23. A compound according to claim 1 of formula I, wherein A and B taken together with the carbon to which they are attached are C═O.

24. A compound according to claim 1 of formula I, wherein A and B taken together with the carbon to which they are attached are C═O and Z is

25. A compound according to claim 1 of formula I, wherein A and B taken together with the carbon to which they are attached are C═O, L is ethyl, X and Y taken together with the carbon to which they are attached are C═N—Ac, W is N(CH 3 ) 2 , and Z is

26. A compound according to claim 1 of formula I, wherein A and B taken together with the carbon to which they are attached are C═O L is ethyl, X and Y taken together with the carbon to which they are attached are C═N—Ac, W is N(CH 3 ) 2 , R 2 ′ is Ac, and Z is OH.

27. A process for preparing a compound according to claim 1 of formula I, wherein A and B are taken together with the carbon to which they are attached are C═CHR 11 , X and Y taken together with the carbon to which they are attached are C═N-Q, and Z is

comprising the step of:

a) providing a compound represented by the following formula:

and

b) reacting said compound with a compound of R 12 —OC(O)—CH 2 [C═CHR 11 ]CH 2 —OC(O)—R 12 , wherein R 12 is independently C 1 –C 6 alkyl and R 11 is as defined in claim 1 .

28. A process according to claim 27 , wherein R 11 is hydrogen.

29. A process according to claim 27 , wherein R 12 is tert-butyl.

30. A process according to claim 27 , wherein R p is Ac.

31. A process according to claim 27 , wherein Q is OAc.

32. A process according to claim 27 , wherein R 11 is hydrogen, L is ethyl, Q is OAc, W is N(CH 3 ) 2 , and R 2 ′=R 4 ″=hydrogen.

33. A process according to claim 27 , wherein said palladium catalyst is a palladium (0) catalyst.

34. A process according to claim 27 , wherein the reacting is carried out in an aprotic solvent.

35. A process according to claim 34 , wherein said aprotic solvent is tetrahydrofuran.