Methods of treating infection by drug resistant bacteria

• US 20030199516A1
• Filed: 09/12/2002
• Published: 10/23/2003
• Est. Priority Date: 09/13/2001
• Status: Abandoned Application

• Current Assignee: Genesoft Pharmaceuticals, Inc. (Oscient Pharmaceuticals Corporation)
• Original Assignee: Genesoft, Inc. (Oscient Pharmaceuticals Corporation)
• Inventors: White, Sarah, Moser, Heinz E., Burli, Roland W., Baird, Eldon E., Ge, Yigong
• Application Number:
  US10/244,142
• Publication Number:
  US 20030199516A1
• Time in Patent Office: Days
• US Class Current: 514/252.02
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 207/34 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

Methods are provided for treating an infection by Gram-positive bacteria in a mammal, by administering to the mammal an effective amount of a compound that binds noncovalently in the minor groove of duplex DNA, the compound being identified by a number of DNA binding parameters and, in many instances, being a polyaromatic compound.

Claims

1. A method for treating an infection by Gram-positive bacteria in a mammal, said method comprising administering to said mammal an effective amount of a compound that binds noncovalently in the minor groove of duplex DNA, which compound:

i) binds with a dissociation constant of equal to or less than 100 nM to at least one of;

(a) a target sequence AAAAAGCAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;

(b) a target sequence AAAAAGACAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;

(c) a target sequence AAAAAGTACAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;

(d) a target sequence AGTACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;

(e) a target sequence AATACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;

(l) a target sequence ATTACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;

(g) a target sequence TGACAATTAAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;

(h) a target sequence GACAATTAATCA in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;

(i) a target sequence AATTAATCAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;

(j) a target sequence ACAATTA in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III; and

(k) a target sequence ACAATTAAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;

ii) exhibits a MIC of less than or equal to 2 μ

g/mL against at least one of Enterococcus faecium ATCC 51559, Staphylococcus aureus ATCC 27660, Staphylococcus aureus ATCC 33591, Staphylococcus aureus ATCC 43300, and Streptococcus pneumoniae ATCC 51422;

iii) exhibits a MIC of greater than or equal to 32 μ

g/mL against Candida albicans ATCC 38247; and

iv) has a molecular weight of from 100 to about 1100.

2. A method according to claim 1, wherein the dissociation constant is equal to or less than 50 nM.

3. A method in accordance with claim 1, wherein the dissociation constant is equal to or less than 20 nM.

4. A method in accordance with claim 1, wherein the compound has a MIC of equal to or less than 2 lug/mL against each of Enterococcus faecium ATCC 51559, Staphylococcus aureus ATCC 27660, Staphylococcus aureus ATCC 33591, Staphylococcus aureus ATCC 43300, and Streptococcus pneumoniae ATCC 51422.

5. A method in accordance with claim 1, wherein the compound has a MIC of equal to or less than 1 μ

g/mL against each of Enterococcus faecium ATCC 51559, Staphylococcus aureus ATCC 27660, Staphylococcus aureus ATCC ATCC 33591, Staphylococcus aureus ATCC 43300, and Streptococcus pneumoniae ATCC 51422.

6. A method in accordance with claim 1, wherein the compound has a molecular weight of from about 400 to about 800.

8. A method in accordance with claim 1, wherein X/Y is equal to or greater than 32.

20. A method in accordance with claim 1, wherein said compound exhibits less than or equal to 90% protein binding in an in vitro protein binding assay.

7. A method for treating an infection by Gram-positive bacteria in a mammal, said method comprising administering to said mammal an effective amount of a compound that binds noncovalently to duplex DNA, which compound

i) binds with a dissociation constant of equal to or less than 100 nM to at least one of:

(a) a target sequence AAAAAGCAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;

(b) a target sequence AAAAAGACAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;

(c) a target sequence AAAAAGTACAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;

(d) a target sequence AGTACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;

(e) a target sequence AATACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;

(f) a target sequence ATTACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;

(g) a target sequence TGACAATTAAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;

(h) a target sequence GACAATTAATCA in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;

(i) a target sequence AATTAATCAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;

(j) a target sequence ACAATTA in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III; and

(k) a target sequence ACAATTAAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;

ii) has activity ratio X/Y equal to or greater than 16, wherein X is the MIC of the compound against Candida albicans ATCC 38247 and Y is the lowest MIC of the compound from among the MIC'"'"'s for Enterococcus faecium ATCC 51559, Staphylococcus aureus ATCC 27660, Staphylococcus aureus 33591, Staphylococcus aureus ATCC 43300, and Streptococcus pneumoniae ATCC 51422; and

iii) has a molecular weight of from 100 to about 1100.

9. A method in accordance with claim 7, wherein said compound binds with a dissociation constant of equal to or less than 100 nM to at least three of the target sequences in (a) through (k).

10. A method in accordance with claim 7, wherein said compound binds with a dissociation constant of equal to or less than 100 nM to at least five of the target sequences in (a) through (k).

11. A method in accordance with claim 7, wherein said compound binds with a dissociation constant of equal to or less than 100 nM to each of the target sequences in (a) through (k).

12. A method in accordance with claim 7, wherein said compound has a half-life of greater than four hours in plasma.

13. A method in accordance with claim 7, wherein said compound has the formula:

A-((L¹)_p-Ar¹)_n-L^x-B 

 

(I)

wherein

A is member selected from the group consisting of a substituted or unsubstituted aryl or heteroaryl group, a substituted or unsubstituted heterocyclic group, an amino group and a mono- or di-alkyl amino group;

the subscript n is an integer of from 2 to 7;

the subscript p in each instance is an integer of from 0 to 1, indicating the presence or absence of each linking group (L¹);

L¹ is a linking group in which the superscript i is an integer of from 1 to n, and each linking group can be the same or different from the other linking groups and is selected from the group consisting of-NH—

, —

NR—

, —

CONH—

, —

SO₂NH—

, —

CONR—

, —

SO₂NR—

, (C₁-C₆)alkylene, (C₁-C₆)heteroalkylene, and combinations thereof in which each R is independently (C₁-C₆)alkyl;

Ar¹ is a substituted or unsubstituted aryl or heteroaryl group, in which the superscript i is an integer of from 1 to n and denotes the position away from A that is occupied by each aryl or heteroaryl group, and each Ar group can be the same or different from any other Ar group;

L^x is a linking group selected from —

NH—

, —

NR—

, —

CONH—

, —

SO₂NH—

, —

CONR—

, —

SO₂NR—

, (C₁-C₆)alkylene, (C₁-C₆)heteroalkylene, and combinations thereof in which each R is independently (C₁-C₆)alkyl; and

B is a member selected from the group consisting of a substituted or unsubstituted aryl or heteroaryl group, a substituted or unsubstituted heterocyclic group, an amino group and a mono- or di-alkyl amino group;

or a pharmaceutically acceptable salt, prodrug form or protected form thereof.

14. A method in accordance with claim 13, wherein said compound has a formula selected from the group consisting of:

15. A method in accordance with claim 13, wherein said compound has the formula A-L¹-Ar¹-L²-Ar²L³-Ar³-L⁴-Ar⁴L^x-B.

16. A method in accordance with claim 13, wherein said compound has the formula A-L¹-Ar¹-L²-Ar-L³-Ar³-L^x-B.

17. A method in accordance with claim 13, wherein said compound binds in the minor groove of a DNA duplex comprising an AT-rich sequence selected from the group consisting of the target sequences (a) through (t).

18. A method in accordance with claim 13, wherein said compound binds in the minor groove of a DNA duplex comprising an AT-rich sequence selected from the group consisting of the target sequences (g) through (k).

19. A method in accordance with claim 13, wherein said compound is soluble in water at pH 7.5 in an amount greater than or equal to 0.1 mg/mL.

21. A compound useful for the treatment of an infection by Gram-positive bacteria, said compound having the formula:

A-((L¹)_p-Ar¹)_n-L¹-B 

 

(I)

wherein

A is member selected from the group consisting of a substituted or unsubstituted aryl or heteroaryl group, a substituted or unsubstituted heterocyclic group, an amino group and a mono- or di-alkyl amino group;

the subscript n is an integer of from 2 to 7;

the subscript p in each instance is an integer of from 0 to 1, indicating the presence or absence of each linking group (L¹);

L¹ is a linking group in which the superscript i is an integer of from 1 to n, and each linking group can be the same or different from the other linking groups and is selected from the group consisting of —

NH—

, —

CONH—

, —

SO₂NH—

, —

CONR—

, —

SO₂NR—

, (C₁-C₆)alkylene, (C₁-C₆)heteroalkylene, and combinations thereof;

Arⁱ is a substituted or unsubstituted aryl or heteroaryl group, in which the superscript i is an integer of from 1 to n and denotes the position away from A that is occupied by each aryl or heteroaryl group, and each Ar group can be the same or different from any other Ar group;

L^x is a linking group selected from —

CONH—

, —

SO₂NH—

, —

CONR—

, —

SO₂NR—

, (C₁-C₆)alkylene, (C₁-C₆)heteroalkylene, and combinations thereof; and

B is a member selected from the group consisting of a substituted or unsubstituted aryl or heteroaryl group, a substituted or unsubstituted heterocyclic group, an amino group and a mono- or di-alkyl amino group;

or a pharmaceutically acceptable salt, prodrug form or protected form thereof;

wherein said compound

i) binds with a dissociation constant of equal to or less than 100 nM to at least one of;

(a) a target sequence AAAAAGCAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;

(b) a target sequence AAAAAGACAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;

(c) a target sequence AAAAAGTACAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;

(d) a target sequence AGTACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;

(e) a target sequence AATACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;

(f) a target sequence ATTACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;

(g) a target sequence TGACAATTAAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;

(h) a target sequence GACAATTAATCA in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;

(i) a target sequence AATTAATCAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;

(j) a target sequence ACAATTA in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III; and

(k) a target sequence ACAATTAAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;

ii) has activity ratio X/Y equal to or greater than 16, wherein X is the MIC of the compound against Candida albicans ATCC 38247 and Y is the lowest MIC of the compound from among the MIC'"'"'s for Enterococcus faecium ATCC 51559, Staphylococcus aureus ATCC 27660, Staphylococcus aureus 33591, Staphylococcus aureus ATCC 43300, and Streptococcus pneumoniae ATCC 51422; and

iii) has a molecular weight of from 100 to about 1100.

22. A compound in accordance with claim 21, having a formula selected from the group consisting of:

23. A compound in accordance with claim 21, wherein each Ar is independently selected from the group consisting of substituted and unsubstituted thienyl, substituted and unsubstituted thiazolyl, substituted and unsubstituted isothiazolyl, substituted and unsubstituted imidazolyl, substituted and unsubstituted pyrrolyl, substituted and unsubstituted oxazolyl, substituted and unsubstituted triazolyl, substituted and unsubstituted isoquinolyl, substituted and unsubstituted pyrazolyl, substituted and unsubstituted benzothienyl, substituted and unsubstituted pyrazinyl, substituted and unsubstituted pyradinyl and substituted and unsubstituted phenyl.

24. A compound in accordance with claim 21, wherein each Ar is independently selected from the group consisting of substituted and unsubstituted thienyl, substituted and unsubstituted thiazolyl, substituted and unsubstituted isothiazolyl, substituted and unsubstituted imidazolyl, substituted and unsubstituted isoquinolyl, substituted and unsubstituted pyrazolyl, substituted and unsubstituted benzothienyl, substituted and unsubstituted pyrazinyl, substituted and unsubstituted pyradinyl and substituted and unsubstituted pyrrolyl;

and each Y is independently selected from the group consisting of —

C(O)—

, —

NEC(O)— and

—

C(O)NH—

.

25. A compound in accordance with claim 21, wherein said compound has a molecular weight of from 100 to 750.

26. The use of a compound of claim 21 for the preparation of a medicament useful for the treatment of an infection by Gram-positive bacteria in a mammal.