Non-beta lactam antibiotics

Patent metadata

Field	Value
Publication number	US-10662164-B2
Application number	US-201515513892-A
Country	US
Kind code	B2
Filing date	Sep 25, 2015
Priority date	Sep 25, 2014
Publication date	May 26, 2020
Grant date	May 26, 2020

Abstract

The invention provides a newly discovered oxadiazole class of antibiotics. The oxadiazoles impair cell-wall biosynthesis and exhibit activities against the Gram-positive bacteria such as the bacterium Staphylococcus aureus , including methicillin-resistant S. aureus (MRSA) and vancomycin-resistant and linezolid-resistant S. aureus . For example, 5-(1H-indol-5-yl)-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,2,4-oxadiazole (antibiotic 75b) was efficacious in a mouse model of MRSA infection, exhibiting a long half-life, a high volume of distribution, and low clearance. Antibiotic 75b antibiotic is bactericidal and is orally bioavailable. This class of antibiotics can be used as a therapeutic agent against infections by Gram-positive bacteria such as MRSA.

First claim

What is claimed is:

1. A compound of Formula (I):
A - B - C - L - D   (I)

wherein
A is 5-indolyl optionally substituted with one to three R X groups;
B is 1,2,4-oxadiazole;
C is phenyl, optionally substituted with one to four R X groups;
L is O, S, or NH;
D is phenyl, optionally substituted with one to five R X groups;
each R X is independently —H, —OH, halo, —N 3 , —NO 2 , —O-allyl, —C≡N, —CF 3 , —OCF 3 , —C(═O)CF 3 , alkyl, alkoxy, phenyl, phenoxy, benzyl, or cycloalkyl —NR a R b , or —C≡C—R Y ;
each R a and R b are independently H, alkyl, or a nitrogen protecting group; and
R Y is —H, alkyl, hydroxyalkyl, or a silicon protecting group;

or pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1 wherein D is phenyl, 4-CF 3 -phenyl, or 4-F-phenyl.

3. The compound of claim 1 that is a compound of Formula (XII):

wherein Y is H, F, or CF 3 ;
or a pharmaceutically acceptable salt or solvate thereof.

4. The compound of claim 3 wherein Y is para to the oxygen of the phenyl ring to which it is attached.

5. A compound of Formula XIII or XIV:

wherein Y is —H, —F, or —CF 3 ; and
R 1 is Cl, Br, I, NO 2 , —NH((C 1 -C 6 )alkyl), —C≡CH, —C≡N, or —C≡CCH 2 OH;

or a salt or solvate thereof.

6. The compound 75a, 75b, or 75c:

7. A method for inhibiting growth of gram positive bacteria comprising contacting gram positive bacteria with a compound of claim 1 , thereby inhibiting the growth of the bacteria.

8. A method for inhibiting growth of gram positive bacteria comprising contacting gram positive bacteria with a compound of claim 3 , thereby inhibiting the growth of the bacteria.

9. A method for inhibiting growth of gram positive bacteria comprising contacting gram positive bacteria with a compound of claim 5 , thereby inhibiting the growth of the bacteria.

Assignees

• Univ Notre Dame Du Lac

Inventors

• Chang Mayland
• Mobashery Shahriar
• Spink Edward
• Ding Derong
• Testero Sebastian
• Leemans Erika
• Boudreau Marc

Classifications

• C07D271/06

  1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07F9/65318

  having the two nitrogen atoms in positions 1 and 3 · CPC title

• C07D271/107 Primary

  with two aryl or substituted aryl radicals attached in positions 2 and 5 · CPC title