Antibacterial 4,5-substituted aminoglycoside analogs having multiple substituents

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound having the following formula VI:

or a prodrug or pharmaceutically acceptable salt thereof,

wherein:

Q 1 is —NR 10 R 11 ;

Q 2 is

each Q 3 and Q 4 is —OR 7 ,

Q 5 is —OR 8 ;

each of R 1 , R 6 , R 7 and R 8 is, in each instance, H;

each R 2 and R 10 is, independently, H, C 1 -C 12 alkyl or substituted C 1 -C 12 alkyl;

R 11 is cyano, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted C 2 -C 12 alkynyl or —(CH 2 ) n -(L 1 ) m —(CH 2 ) nn -E 1 ;

L 1 is S, O or NJ 1 ;

n is an integer from 1 to 8;

m is 0 or 1;

nn is 0 or an integer from 1 to 8;

mm is 1 or 2;

E 1 is H, hydroxyl, halogen, cyano, —NJ 1 J 2 , C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted C 2 -C 12 alkynyl, C 5 -C 20 aryl, substituted C 5 -C 20 aryl, heteroaryl, substituted heteroaryl, a heterocyclic radical, a substituted heterocyclic radical or a substituted or unsubstituted mono or poly cyclic structure that is unsaturated, partially saturated or fully saturated and optionally includes one or more heteroatoms selected from O, N and S;

each J 1 and J 2 is, independently, H, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted C 2 -C 12 alkynyl, C 5 -C 20 aryl, substituted C 5 -C 20 aryl, —C(═O)—X, a heterocyclic radical or a substituted heterocyclic radical;

each X is, independently, H, C 1 -C 12 alkyl or substituted C 1 -C 12 alkyl; and

Z 1 and Z 2 are each, independently, H or —OH.

2. A pharmaceutical composition according to claim 1 , wherein mm is 1.

3. A pharmaceutical composition according to claim 1 , wherein mm is 2.

4. A pharmaceutical composition according to claim 1 , wherein each R 2 is H.

5. A pharmaceutical composition according to claim 1 , wherein Z 1 is —OH.

6. A pharmaceutical composition according to claim 1 , wherein R 10 is H.

7. A pharmaceutical composition according to claim 6 , wherein R 11 is substituted C 1 -C 12 alkyl.

8. A pharmaceutical composition according to claim 1 , wherein:

R 10 is H;

R 11 is substituted C 1 -C 12 alkyl;

each R 2 is H; and

Z 1 is —OH.

9. A pharmaceutical composition according to claim 1 , wherein said compound of formula VI has the configuration:

10. A pharmaceutical composition according to claim 9 , wherein mm is 1.

11. A pharmaceutical composition according to claim 9 , wherein mm is 2.

12. A pharmaceutical composition according to claim 9 , wherein each R 2 is H.

13. A pharmaceutical composition according to claim 9 , wherein Z 1 is —OH.

14. A pharmaceutical composition according to claim 9 , wherein R 10 is H.

15. A pharmaceutical composition according to claim 14 , wherein R 11 is substituted C 1 -C 12 alkyl.

16. A pharmaceutical composition according to claim 9 , wherein:

R 10 is H;

R 11 is substituted C 1 -C 12 alkyl;

each R 2 is H; and

Z 1 is —OH.

17. A pharmaceutical composition according to claim 16 , wherein mm is 1.

18. A pharmaceutical composition according to claim 16 , wherein mm is 2.

19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound having the following formula I:

or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,

wherein:

Q 1 is azido or —NR 10 R 1l ;

Q 2 is —NR 10 R 12 ,

each Q 3 and Q 4 is —OR 7 ,

Q 5 is H, halogen, cyano, azido, —OR 8 , —NR 2 R 3 , a protected amino group or a nitrogen containing heterocyclic radical which optionally includes one or more additional heteroatoms selected from N, O and S wherein the heterocyclic radical is covalently linked through said nitrogen atom;

each R 1 is, independently, H or a hydroxyl protecting group;

each R 2 is, independently, H, an amino protecting group, C 1 -C 12 alkyl or substituted C 1 -C 12 alkyl;

each R 3 is, independently, H, an amino protecting group, cyano, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted C 2 -C 12 alkynyl or —(CH 2 ) n -(L 1 ) m —(CH 2 ) nn -E 1 ;

each R 6 is, independently, H or an amino protecting group;

each R 7 is, independently, H, a hydroxyl protecting group or —(CH 2 ) n -(L 1 ) m -(CH 2 ) nn -E 1 ;

R 8 is H, a hydroxyl protecting group, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted C 2 -C 12 alkynyl or —(CH 2 ) n -(L 1 ) m —(CH 2 ) nn -E 1 ;

each R 10 is, independently, H, C 1 -C 12 alkyl or substituted C 1 -C 12 alkyl;

each R 11 is, independently, cyano, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted C 2 -C 12 alkynyl or —(CH 2 ) n -(L 1 ) m —(CH 2 ) nn -E 1 ; and

R 12 is a group having the following formula III:

each L 1 is, independently, S, O or NJ 1 ;

L 2 is CH or N;

each n is, independently, an integer from 1 to 8;

each m is, independently, 0 or 1;

each nn is, independently, 0 or an integer from 1 to 8;

mm is 1 or 2;

each E 1 is, independently, H, hydroxyl, halogen, cyano, —NJ 1 J 2 , C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted C 2 -C 12 alkynyl, C 5 -C 20 aryl, substituted C 5 -C 20 aryl, heteroaryl, substituted heteroaryl, a heterocyclic radical, a substituted heterocyclic radical or a substituted or unsubstituted mono or poly cyclic structure that is unsaturated, partially saturated or fully saturated and optionally includes one or more heteroatoms selected from O, N and S;

each J 1 and J 2 is, independently, H, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted C 2 -C 12 alkynyl, C 5 -C 20 aryl, substituted C 5 -C 20 aryl, —C(═O)—X, a heterocyclic radical or a substituted heterocyclic radical;

each X is, independently, H, C 1 -C 12 alkyl or substituted C 1 -C 12 alkyl;

each Z 1 and Z 2 is, independently, H, hydroxyl or a protected hydroxyl; and

Z 3 is a group having the following formula IV:

and

wherein when Q 2 is —N(H)C(═O)C(H)(OH)CH 2 CH 2 NH 2 then Q 1 is other than —N(H)CH 3 or —N(H)CH 2 CH 3 and Q 5 is other than —N(H)C(═NH)NH 2 or —N(H)CH═NH 2 .

20. A pharmaceutical composition according to claim 19 , wherein one of Z 1 and Z 2 is H.

21. A pharmaceutical composition according to claim 19 , wherein:

each of said substituted groups, is, independently, mono or poly substituted with optionally protected substituent groups independently selected from C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted C 2 -C 12 alkynyl, C 5 -C 20 aryl or substituted C 5 -C 20 aryl, heterocyclic radical, substituted heterocyclic radical, heteroaryl, substituted heteroaryl, C 5 -C 7 alicyclic radical, substituted C 5 -C 7 alicyclic radical, halogen, —OJ 3 , —NJ 1 J 2 , —SJ 3 , —N 3 , —COOH, —C(═O)—X, —CN, —S(═O) 2 —X, —S(═O)—X, —C(═O)—NJ 1 J 2 , —N(H)C(═O)-J 1 , —N(J 1 )—(CH 2 ) nm —OJ 3 and —N(J 1 )-(CH 2 ) nm —NJ 1 J 2 and a substituted or unsubstituted mono or poly cyclic structure that is unsaturated, partially saturated or fully saturated and optionally includes one or more heteroatoms selected from O, N and S;

each J 3 is, independently, H, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted C 2 -C 12 alkynyl, C 1 -C 12 aminoalkyl, substituted C 1 -C 12 aminoalkyl or a hydroxyl protecting group; and

nm is an integer from 1 to 20.

22. A pharmaceutical composition according to claim 19 , wherein said compound of formula I has the configuration:

23. A pharmaceutical composition according to claim 19 , wherein said compound of formula I has the configuration:

24. A pharmaceutical composition according to claim 8 , wherein mm is 1.

25. A pharmaceutical composition according to claim 8 , wherein mm is 2.