Methods and compositions for treating bacterial infection

Patent metadata

Field	Value
Publication number	US-9504688-B2
Application number	US-201314397798-A
Country	US
Kind code	B2
Filing date	May 2, 2013
Priority date	May 2, 2012
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

Abstract

The present invention relates to chemical compounds, methods for their discovery, and their therapeutic and research use. In particular, the present invention provides compounds as therapeutic agents against bacterial infections (e.g., biofilms).

First claim

We claim:

1. A pharmaceutical composition, comprising:
a compound selected from the group consisting of a)

Wherein X is S, NH, or O, R 1 and R 2 are, independently, selected from the group consisting of a C1-C8 alkyl, a C1-C8 alkenyl, and a C1-C8 cycloalkyl, wherein said C1-C8 alkyl, a C1-C8 alkenyl, and a C1-C8 cycloalkyl are optionally substituted with F, CN, OR 6 , NR 6 2 , COR 6 , CO 2 R 6 , CONHR 6 , aryl or heteroaryl, wherein one or more alkyl carbons may be replaced by O;
R 3 and R 4 are joined in a cycloalkyl ring of 3-7 carbons wherein at least one ring CH 2 is replaced by 0 or N-G;
G is selected from the group consisting of H, C(═O)R 6 , SO 2 R 6 and C(═O)OR 6 ;
R 5 is selected from the group consisting of H, C1-C6 alkyl, CN, OR 6 , NR 6 2 , COR 6 , CO 2 R 6 , CONHR 6 , aryl, heteroaryl, SO 2 R 6 , NHCOR 6 , SO 2 NHR 6 , and OCOR 6 ;
R 6 is selected from the group consisting of H, C1-C6 alkyl, C0-C3 alkyl-aryl, and C0-C3 alkyl-heteroaryl, all optionally substituted; and
R 11 is H or a C1 alkyl;
b) a compound having the structure

Wherein X is S, R 1 is a C-C8 alkyl substituted with at least one F, R 2 is selected from the group consisting of a C1-C8 alkyl, a C1-C8 alkenyl, and a C1-C8 cycloalkyl, wherein said C1-C8 alkyl, a C1-C8 alkenyl, and a C1-C8 cycloalkyl are optionally substituted with F, CN, OR 6 , NR 6 2 , COR 6 , CO 2 R 6 , CONHR 6 , aryl or heteroaryl, wherein one or more alkyl carbons may be replaced by O;
R 3 and R 4 are independently a C1-C8 alkyl, H, or joined in a cycloalkyl ring of 3-7 carbons wherein at least one ring CH 2 is replaced by O or N-G;
G is selected from the group consisting of H, C(═O)R 6 , SO 2 R 6 and C(═O)OR 6 ;
R 5 is selected from the group consisting of H, C1-C6 alkyl, CN, OR 6 , NR 6 2 , COR 6 , CO 2 R 6 , CONHR 6 , aryl, heteroaryl, SO 2 R 6 , NHCOR 6 , SO 2 NHR 6 , and OCOR 6 ;
R 6 is selected from the group consisting of H, C1-C6 alkyl, C0-C3 alkyl-aryl, and C0-C3 alkyl-heteroaryl, all optionally substituted; and
R 11 is H or a C1 alkyl; and
c) a compound having the structure:

Wherein R 1 and R 2 are, independently, selected from the group consisting of a C1-C8 alkyl, a C1-C8 alkenyl, and a C1-C8 cycloalkyl, wherein said C1-C8 alkyl, a C1-C8 alkenyl, and a C1-C8 cycloalkyl are optionally substituted with F, CN, OR 6 , NR 6 2 , COR 6 , CO 2 R 6 , CONHR 6 , aryl or heteroaryl, wherein one or more alkyl carbons may be replaced by O;
R 5 is selected from the group consisting of H, C1-C6 alkyl, CN, OR 6 , NR 6 2 , COR 6 , CO 2 R 6 , CONHR 6 , aryl, heteroaryl, SO 2 R 6 , NHCOR 6 , SO 2 NHR 6 , and OCOR 6 ;
R 6 is selected from the group consisting of H, C1-C6 alkyl, C0-C3 alkyl-aryl, and C0-C3 alkyl-heteroaryl, all optionally substituted;
R 7 and R 8 are independently selected from the group consisting of H, C1-C6 alkyl, and joined in a cycloalkyl ring of 3-7 carbons, wherein one of the ring CH 2 groups may be replaced by O or N-G;
R 9 is a C1-C5 alkyl; and
R 10 is a C2-C8 alkyl or alkenyl or cycloalkyl, optionally substituted with F, CN, OR 6 , NR 6 2 , CO 2 R 6 , CONHR 6 , aryl or heteroaryl, wherein one or more alkyl carbons may be replaced by O.

2. The composition of claim 1 , wherein said compound is selected from the group consisting of:

3. The composition of claim 1 , further comprising a pharmaceutically acceptable carrier.

4. The composition of claim 1 , wherein said composition inhibits growth or biological activity of S. aureus and/or S. epidermidis.

5. The composition of claim 1 , wherein said composition inhibits biofilm formation by S. aureus and/or S. epidermidis.

6. The composition of claim 4 , wherein said S. aureus and/or S. epidermidis are in a biofilm.

7. The composition of claim 1 , wherein said composition further comprises a known antibiotic compound.

8. A method of inhibiting the growth or biological activity of S. aureus and/or S. epidermidis , comprising contacting said S. aureus and/or S. epidermidis with a compound having the structure of Formula I, II, III or IV

Wherein X is S, NH, or O, R 1 and R 2 are, independently, selected from the group consisting of a C1-C8 alkyl, a C1-C8 alkenyl, and a C1-C8 cycloalkyl, wherein said C1-C8 alkyl, a C1-C8 alkenyl, and a C1-C8 cycloalkyl are optionally substituted with F, CN, OR 6 , NR 6 2 , COR 6 , CO 2 R 6 , CONHR 6 , aryl or heteroaryl, wherein one or more alkyl carbons may be replaced by O;
R 3 and R 4 are independently H, a C1-C8 alkyl, or joined in a cycloalkyl ring of 3-7 carbons wherein at least one ring CH 2 is replaced by O or N-G;
G is selected from the group consisting of H, C(═O)R 6 , SO 2 R 6 and C(═O)OR 6 ;
R 5 is selected from the group consisting of H, C1-C6 alkyl, CN, OR 6 , NR 6 2 , COR 6 , CO 2 R 6 , CONHR 6 , aryl, heteroaryl, SO 2 R 6 , NHCOR 6 , SO 2 NHR 6 , and OCOR 6 ;
R 6 is selected from the group consisting of H, C1-C6 alkyl, C0-C3 alkyl-aryl, and C0-C3 alkyl-heteroaryl, all optionally substituted;
R 7 and R 8 are independently selected from the group consisting of H, C1-C6 alkyl, and joined in a cycloalkyl ring of 3-7 carbons, wherein one of the ring CH 2 groups may be replaced by O or N-G;
R 9 is a C1-C5 alkyl;
R 10 is a C2-C8 alkyl or alkenyl or cycloalkyl, optionally substituted with F, CN, OR 6 , NR 6 2 , CO 2 R 6 , CONHR 6 , aryl or heteroaryl, wherein one or more alkyl carbons may be replaced by O; and
R 11 is H or a C1 alkyl,
wherein said compound inhibits the growth or biological activity of said S. aureus and/or S. epidermidis.

9. The method of claim 8 , wherein said S. aureus and/or S. epidermidis are present in a biofilm.

10. The method of claim 9 , wherein said compound prevents biofilm formation by said S. aureus and/or S. epidermidis.

11. The method of claim 8 , further comprising the step of contacting said S. aureus and/or S. epidermidis with a known antibiotic compound.

12. A surface coated in a compound of claim 1 .

13. The surface of claim 12 , wherein said surface is a surface of a medical device.

Assignees

• Univ Michigan Regents
• Univ Missouri

Inventors

• Ginsburg David
• Larsen Scott D
• Yestrepsky Bryan
• Sun Hongmin

Classifications

• A61P31/02

  Local antiseptics · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• C07D239/56

  One oxygen atom and one sulfur atom · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title