IP Library › Granted Patent US 8,927,724

Granted Patent B2

US 8,927,724 · App. 13/853,498 · Granted Jan 6, 2015

Isoxazole beta-lactamase inhibitors

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Quick Facts

Patent No.: US 8,927,724
App. No.: 13/853,498
Granted: Jan 6, 2015
Kind: B2

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Abstract

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed.

Claims (110)

1. A compound of Formula (A-I) or a pharmaceutically acceptable salt thereof:

wherein

R* is selected from

and

R 1* is selected from:

wherein R 2* is selected from

R 3* is selected from hydrogen, (C 1 -C 3 )-alkyl, aminoalkyl, aminocycloalkyl, hydroxyalkyl,

each of R 4* , R 5* , R 6* and R 7* is independently selected from hydrogen, (C 1 -C 6 )-alkyl, aminoalkyl, aminocycloalkyl, and hydroxyalkyl, provided that at least one of R 4* , R 5* , R 6* and R 7* is hydrogen,

n is selected from 1, 2, 3 and 4, and

m is selected from 1, 2 and 3;

wherein R 8 is selected from —NH(C 1 -C 3 )-alkyl and

wherein each of R 4* , R 5* , R 6* and R 7* is as described previously;

wherein Z is selected from CR 9 R 10 and NR 11 ,

each of R 9 and R 10 is independently selected from H, NH 2 , —NH(C 1 -C 3 )-alkyl and

wherein each of R 4* , R 5* , R 6* and R 7* is as described previously,

alternatively, R 9 and R 10 together with the carbon to which they are attached, form a cycloalkyl or heterocyclyl ring containing 4-6 ring members,

R 11 is selected from H and

each of R 12 , R 13 and R 14 is independently selected from hydrogen, (C 1 -C 6 )-alkyl, amino alkyl, aminocycloalkyl, and hydroxyalkyl, provided that at least one of R 12 , R 13 and R 14 is hydrogen,

R 15 is selected from NH 2 and

wherein each of R 4* , R 5* , R 6* and R 7* is as described previously,

each of p* and q* is independently selected from 0, 1, 2 and 3,

T is selected from NH and O,

t is selected from 0, 1, 2, 3, and 4, and

each of r and y is independently selected from 0 and 1;

wherein R 16 is selected from NH 2 , —NH(C 1 -C 3 )-alkyl and

wherein each of R 4* , R 5* , R 6* and R 7* is as described previously,

s is selected from 0 and 1, and,

v is selected from 0, 1, 2, and 3;

wherein R 18 is selected from NH 2 and

wherein each of R 4* , R 5* , R 6* and R 7* is as described previously,

R 17 is selected from amino and hydroxyl, and

w is selected from 0 and 1;

wherein M is selected from NR 19 , CR 20 R 21 and O,

wherein R 19 is selected from H and

where each of R 12 , R 13 and R 14 is as described previously,

each of R 20 and R 21 is independently selected from H, NH 2 and

wherein each of R 4* , R 5* , R 6* and R 7* is as described previously, and

u is selected from 0, 1 and 2; and

2. A pharmaceutical composition comprising a compound of claim 1 and at least 1 β-lactam antibiotic or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition of claim 2 wherein the β-lactam antibiotic is a cephalosporin.

4. The pharmaceutical composition of claim 3 wherein the cephalosporin is Ceftolozane.

5. The compound of claim 1 , wherein the compound of Formula A-I has the stereochemistry specified in Formula A-II

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof selected from

7. The compound according to claim 1 wherein R 1* is selected from

8. The compound according to claim 6 selected from

9. The compound according to claim 8 or a pharmaceutically-acceptable salt thereof of the Formula

10. The compound according to claim 8 or a pharmaceutically-acceptable salt thereof of the Formula

11. A pharmaceutical composition comprising a compound of claim 9 and Ceftolozane.

12. A pharmaceutical composition comprising a compound of claim 10 and Ceftolozane.

13. The compound according to claim 1 of the Formula