Antibacterial 4,5-substituted aminoglycoside analogs having multiple substituents

1. 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 11 ;

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 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 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:

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 .

2. The compound of claim 1 wherein:

Q 3 is —OR 13 ,

wherein:

R 13 is —(CH 2 ) n -(L 1 ) m -(CH 2 ) nn -E 1 .

3. The compound of claim 1 wherein:

Q 4 is —OR 13 ,

wherein:

R 13 is —(CH 2 ) n -(L 1 ) m -(CH 2 ) nn -E 1 .

4. The compound of claim 1 wherein:

Q 5 is halogen, cyano, azido, —OH 14 or —NR 10 R 11 ,

wherein:

R 14 is 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 .

5. The compound of claim 1 wherein Q 3 and Q 4 are each —OR 13 , wherein each R 13 is, independently, —(CH 2 ) n -(L 1 ) m -(CH 2 ) nn -E 1 .

6. The compound of claim 1 wherein:

Q 3 is —OR 13 ; and

Q is halogen, cyano, azido, —OR 14 or —NR 10 R 11 ;

wherein:

R 13 is —(CH 2 ) n -(L 1 ) m -(CH 2 ) nn -E 1 ; and

R 14 is 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 .

7. The compound of claim 1 wherein:

Q 4 is —OR 13 ; and

Q 5 is halogen, cyano, azido, —OR 14 or —NR 10 R 11 ;

wherein:

R 13 is —(CH 2 ) n -(L 1 ) m -(CH 2 ) nn -E 1 ; and

R 14 is 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 .

8. The compound of claim 1 wherein Z 1 and Z 2 are both H.

9. The compound of claim 1 wherein Z 1 and Z 2 are both hydroxyl or protected hydroxy.

10. The compound of claim 1 wherein one of Z 1 and Z 2 is H.

11. The compound of claim 1 wherein Q 2 is an optionally protected group having the formula —N(H)C(O)C(H)(OH)(CH 2 ) 2 NH 2 .

12. The compound of claim 1 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, —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 can be unsaturated, partially saturated or fully saturated and optionally includes can include 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.

13. The compound of claim 1 having the configuration:

14. The compound of claim 1 having the configuration:

15. The compound of claim 1 wherein the compound is:

N-1-haba-6′-phenylpropyl neomycin;

N-1-haba-2″-O-phenylethylaminoethyl-6′-phenylpropyl neomycin;

N-1-haba-6′-phenylpropyl-5″-fluoro neomycin; or

N-1-haba-6′-phenylpropyl-5″-isopropylamino neomycin.

16. A method of treating a bacterial infection in a mammal comprising administering to the mammal an effective amount of a compound of claim 1 .