Antibacterial 4,5-substituted aminoglycoside analogs having multiple substituents

• US 7,893,039 B2
• Filed: 05/30/2008
• Issued: 02/22/2011
• Est. Priority Date: 12/02/2005
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Adhikari, Susanta Sekhar, Hanessian, Stephen, Migawa, Michael T., Pachamuthu, Kandasamy, Szychowski, Janek, Wang, Xiaojing, Griffey, Richard H., Swayze, Eric E.
• Primary Examiner(s): Lewis; Patrick T
• Application Number:
  US12/130,048
• Publication Number:
  US 20080293649A1
• Time in Patent Office: 998 Days
• Field of Search: None
• US Class Current: 514/54
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07H 15/23 with only two saccharide radicals in the molecule, e.g. ambutyrosin, butyrosin, xylostatin, ribostamycin
• CPC Class Codes: C07H 15/232 with at least three saccharide radicals in the molecule, e.g. lividomycin, neomycin, paromomycin

Abstract

The present invention is directed to analogs of aminoglycoside compounds as well as their preparation and use as prophylactic or therapeutics against microbial infection.

Claims

1. A compound having the following formula I:

2. The compound of claim 1 wherein:

Q₃ is —

OR₁₃,

wherein;

R₁₃ is —

(CH₂)_n-(L₁)_m-(CH₂)_nn-E₁.

3. The compound of claim 1 wherein:

Q₄ is —

OR₁₃,

wherein;

R₁₃ is —

(CH₂)_n-(L₁)_m-(CH₂)_nn-E₁.

4. The compound of claim 1 wherein:

Q₅ is halogen, cyano, azido, —

OH₁₄ or —

NR₁₀R₁₁,

wherein;

R₁₄ is C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substituted C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl or —

(CH₂)_n-(L₁)_m-(CH₂)_nn-E₁.

5. The compound of claim 1 wherein Q₃ and Q₄ are each —

OR₁₃, wherein each R₁₃ is, independently, —

(CH₂)_n-(L₁)_m-(CH₂)_nn-E₁.

6. The compound of claim 1 wherein:

Q₃ is —

OR₁₃; and

Q is halogen, cyano, azido, —

OR₁₄ or —

NR₁₀R₁₁;

wherein;

R₁₃ is —

(CH₂)_n-(L₁)_m-(CH₂)_nn-E₁; and

R₁₄ is C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substituted C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl or —

(CH₂)_n-(L₁)_m-(CH₂)_nn-E₁.

7. The compound of claim 1 wherein:

Q₄ is —

OR₁₃; and

Q₅ is halogen, cyano, azido, —

OR₁₄ or —

NR₁₀R₁₁;

wherein;

R₁₃ is —

(CH₂)_n-(L₁)_m-(CH₂)_nn-E₁; and

R₁₄ is C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substituted C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl or —

(CH₂)_n-(L₁)_m-(CH₂)_nn-E₁.

8. The compound of claim 1 wherein Z₁ and Z₂ are both H.

9. The compound of claim 1 wherein Z₁ and Z₂ are both hydroxyl or protected hydroxy.

10. The compound of claim 1 wherein one of Z₁ and Z₂ is H.

11. The compound of claim 1 wherein Q₂ is an optionally protected group having the formula —

N(H)C(O)C(H)(OH)(CH₂)₂NH₂.

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 C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substituted C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl, C₅-C₂₀ aryl or substituted C₅-C₂₀ aryl, heterocyclic radical, substituted heterocyclic radical, heteroaryl, substituted heteroaryl, C₅-C₇ alicyclic radical, substituted C₅-C₇ alicyclic radical, halogen, —

OJ₃, —

NJ₁J₂, —

SJ₃, —

N₃, —

COOH, —

C(═

O)—

X, —

CN, —

S(═

O)₂—

X, —

C(═

O)—

NJ₁J₂, —

N(H)C(═

O)-J₁, —

N(J₁)-(CH₂)_nm—

OJ₃ and —

N(J₁)-(CH₂)_nm—

NJ₁J₂ 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 J₃ is, independently, H, C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substituted C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl, C₁-C₁₂ aminoalkyl, substituted C₁-C₁₂ 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.