IP Library › Patent Application 14505432

Patent Application

App. No. 14/505,432

BETA-LACTAMASE INHIBITORS

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US None
App. No.: 14/505,432

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

Aryl substituted diazabicyclooctanes (DBO) compounds that inhibit β-lactamases of class A, class C or class D and potentiate β-lactam antibiotics are disclosed. In particular, this disclosure provides DBO compounds that, when used in the disclosed Synergy MIC Assay with a β-lactam antibiotic at a fixed concentration have an MIC of 8 μg/mL or less against one or more isogenic β-lactamase expressing bacterial strains.

Claims (423)

1 .- 6 . (canceled)

7 . A pharmaceutical composition comprising a beta-lactam antibiotic and a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I, when used in the Synergy MIC Assay of Example 23 with an antibiotic selected from ceftolozane or ceftazidime at a fixed concentration of 4 μg/mL, has an MIC of 8 μg/mL or less against one or more isogenic β-lactamase expressing bacterial strains from Table X, wherein the compound of Formula (I) is:

wherein

Z is selected from the group consisting of isoxazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-thiadiazole;

R is selected from

and

R 1 is selected from:

a. hydrogen,

b. cyano,

c. (C 1 -C 3 )-unsubstituted alkyl,

d. (C 1 -C 3 )-alkyl substituted with at least one substituent selected from hydroxyl,

wherein each of R 2 , R 3 and R 4 is independently selected from hydrogen, (C 1 -C 3 )-alkyl, aminoalkyl, aminocycloalkyl, or hydroxyalkyl,

wherein R 5 is selected from H or aminoalkyl,

g. amino,

h. (C 1 -C 3 )alkylamino, or

i. a 4-6 membered heterocyclyl containing 1-2 heteroatoms selected from O and N, or NX, wherein X is H,

wherein Table X is:

TABLE X

GenBank

Accession

Species

Number

β-

Name & SEQ. ID

β-

Origin

of β-

Lactamase

of plasmids

Lacta-

of β-

Lactamase

Expressing

producing

mase

Lactamase

Gene

Strain

β-Lactamase

Gene

Class

Sequence

KPC-2

pBR-CBST-KPC-

K. pneumoniae

EU784136

2 SEQID 6

CTX-

pBR-CBST-

K. pneumoniae

JF775516

M-15

CTX-M-15

SEQ ID 7

SHV-12

pBR-CBST-

K. pneumoniae

AY008838

SHV-12

SEQ ID 8

P99

pBR-CBST-P99

E. cloacea

XO7274

AmpC

AMPC

SEQ ID 9

OXA-15

pBR-CBST-

P. aeruginosa

PAU63835

OXA-15

SEQ ID 10

8 . The pharmaceutical composition of claim 7 wherein the β-lactamase is selected from a KPC, CTX-M, SHV or AmpC β-lactamase.

9 . The pharmaceutical composition of claim 7 wherein the β-lactamase is an OXA β-lactamase.

10 . The pharmaceutical composition of claim 9 wherein the OXA β-lactamase is OXA-15.

11 . The pharmaceutical composition of claim 7 wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof has inhibition kinetics of at least 250 mM −1 s −1 according to the assay described in Example 24.

12 . The pharmaceutical composition of claim 7 wherein the compound of Formula (A-I) or a pharmaceutically acceptable salt thereof has the Formula:

wherein

Z is selected from the group consisting of 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-thiadiazole;

R * is selected from

and

R 1* is selected from:

a. hydrogen;

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 or (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 2 ,

wherein each of R 4* , R 5* , R 6* and R 7* is as described previously and each of R 9 ,

R 10 , and R 11 is independently selected from hydrogen or (C 1 -C 6 )-alkyl, provided that at least one of R 9 , R 10 , and R 11 is hydrogen;

d. amino;

wherein Z* is selected from CR 12 R 13 or NR 14 ,

each of R 12 and R 13 is independently selected from H, NH 2 and

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

alternatively, R 12 and R 13 together with the carbon to which they are attached, form a cycloalkyl or heterocyclyl ring containing 4-6 ring members,

R 14 is selected from H and

wherein each of R 15 , R 16 and R 17 is independently selected from hydrogen, (C 1 -C 6 )-alkyl, aminoalkyl, aminocycloalkyl, and hydroxyalkyl, provided that at least one of R 15 , R 16 and R 17 is hydrogen,

R 18 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 19 is selected from NH 2 and

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

R 20 is selected from amino and hydroxyl, and

w is selected from 0 and 1;

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

wherein R 21 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 M is selected from NR 22 , CR 23 R 24 and O,

wherein R 22 is H or

wherein each of R 15 , R 16 and R 17 is as described previously,

each of R 23 and R 24 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;

o. (C 1 -C 3 )-unsubstituted alkyl; and

13 . The compound of claim 12 wherein Z is 1,3,4-oxadiazole.

14 . A pharmaceutical composition comprising a beta-lactam antibiotic selected from the group consisting of: a cephalosporin, a carbapenem, a monobactam, and a penicillin; and a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I, when used in the Synergy MIC Assay of Example 23 with an antibiotic selected from ceftolozane or ceftazidime at a fixed concentration of 4 μg/mL, has an MIC of 8 μg/mL or less against one or more isogenic β-lactamase expressing bacterial strains from Table X, wherein the compound of Formula (I) is:

wherein

Z is selected from the group consisting of isoxazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-thiadiazole;

R is selected from

and

R 1 is selected from:

j. hydrogen,

k. cyano,

l. (C 1 -C 3 )-unsubstituted alkyl,

m. (C 1 -C 3 )-alkyl substituted with at least one substituent selected from hydroxyl,

wherein each of R 2 , R 3 and R 4 is independently selected from hydrogen, (C 1 -C 3 )-alkyl, aminoalkyl, aminocycloalkyl, or hydroxyalkyl,

wherein R 5 is selected from H or aminoalkyl,

p. amino,

q. (C 1 -C 3 )alkylamino, or

r. a 4-6 membered heterocyclyl containing 1-2 heteroatoms selected from O and N, or NX, wherein X is H,

wherein Table X is:

TABLE X

Name &

Species

GenBank

β-

SEQ. ID

Origin

Accession

Lactamase

of plasmids

β-Lacta-

of β-

Number of β-

Expressing

producing

mase

Lactamase

Lactamase Gene

Strain

β-Lactamase

Class

Gene

Sequence

KPC-2

pBR-CBST-KPC-

K. pneumoniae

EU784136

2 SEQID 6

CTX-

pBR-CBST-

K. pneumoniae

JF775516

M-15

CTX-M-15

SEQ ID 7

SHV-12

pBR-CBST-

K. pneumoniae

AY008838

SHV-12

SEQ ID 8

P99

pBR-CBST-P99

E. cloacea

XO7274

AmpC

AMPC

SEQ ID 9

OXA-15

pBR-CBST-

P. aeruginosa

PAU63835

OXA-15

SEQ ID 10

15 . The pharmaceutical composition of claim 14 wherein the β-lactamase is selected from a KPC, CTX-M, SHV or AmpC β-lactamase.

16 . The pharmaceutical composition of claim 14 wherein the β-lactamase is an OXA β-lactamase.

17 . The pharmaceutical composition of claim 16 wherein the OXA β-lactamase is OXA-15.

18 . The pharmaceutical composition of claim 14 wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof has inhibition kinetics of at least 250 mM −1 s −1 according to the assay described in Example 24.

19 . The pharmaceutical composition of claim 14 wherein the compound of Formula (A-I) or a pharmaceutically acceptable salt thereof has the Formula:

wherein

Z is selected from the group consisting of 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-thiadiazole;

R * is selected from

and

R 1* is selected from:

q. hydrogen;

wherein

R 2* is selected from

and

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

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 2 ,

wherein each of R 4* , R 5* , R 6* and R 7* is as described previously and each of R 9 , R 10 , and R 11 is independently selected from hydrogen or (C 1 -C 6 )-alkyl, provided that at least one of R 9 , R 10 , and R 11 is hydrogen;

t. amino;

wherein Z* is selected from CR 12 R 13 or NR 14 ,

each of R 12 and R 13 is independently selected from H, NH 2 and

wherein each of R 4* , R 5* , R 6* and R 7* is as described previously, alternatively, R 12 and R 13 together with the carbon to which they are attached, form a cycloalkyl or heterocyclyl ring containing 4-6 ring members,

R 14 is selected from H and

R 18 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 19 is selected from NH 2 and

wherein each of R 4* ,

R 5* , R 6* and R 7* is as described previously,

R 20 is selected from amino and hydroxyl, and

w is selected from 0 and 1;

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

wherein R 21 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;

aa.

wherein M is selected from NR 22 , CR 23 R 24 and O,

wherein R 22 is H or

wherein each of R 15 , R 16 and R 17 is as described previously,

each of R 23 and R 24 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;

bb.

cc.

dd.

ee. (C 1 -C 3 )-unsubstituted alkyl; and

ff.

20 . The compound of claim 19 wherein Z is 1,3,4-oxadiazole.

21 . A pharmaceutical composition comprising a compound selected from the group consisting of: ceftazidime, meropenem, aztreonam, and piperacillin, and a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I, when used in the Synergy MIC Assay of Example 23 with an antibiotic selected from ceftolozane or ceftazidime at a fixed concentration of 4 μg/mL, has an MIC of 8 μg/mL or less against one or more isogenic β-lactamase expressing bacterial strains from Table X, wherein the compound of Formula (I) is:

wherein

Z is selected from the group consisting of isoxazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-thiadiazole;

R is selected from

and

R 1 is selected from:

s. hydrogen,

t. cyano,

u. (C 1 -C 3 )-unsubstituted alkyl,

v. (C 1 -C 3 )-alkyl substituted with at least one substituent selected from hydroxyl,

wherein each of R 2 , R 3 and R 4 is independently selected from hydrogen, (C 1 -C 3 )-alkyl, aminoalkyl, aminocycloalkyl, or hydroxyalkyl,

wherein R 5 is selected from H or aminoalkyl,

y. amino,

z. (C 1 -C 3 )alkylamino, or

aa 4-6 membered heterocyclyl containing 1-2 heteroatoms selected from O and N, or NX, wherein X is H,

wherein Table X is:

TABLE X

Name &

Species

GenBank

β-

SEQ. ID

Origin

Accession

Lactamase

of plasmids

β-Lacta-

of β-

Number of β-

Expressing

producing

mase

Lactamase

Lactamase Gene

Strain

β-Lactamase

Class

Gene

Sequence

KPC-2

pBR-CBST-KPC-

K. pneumoniae

EU784136

2 SEQID 6

CTX-

pBR-CBST-

K. pneumoniae

JF775516

M-15

CTX-M-15

SEQ ID 7

SHV-12

pBR-CBST-

K. pneumoniae

AY008838

SHV-12

SEQ ID 8

P99

pBR-CBST-P99

E. cloacea

XO7274

AmpC

AMPC

SEQ ID 9

OXA-15

pBR-CBST-

P. aeruginosa

PAU63835

OXA-15

SEQ ID 10

22 . The pharmaceutical composition of claim 21 wherein the β-lactamase is selected from a KPC, CTX-M, SHV or AmpC β-lactamase.

23 . The pharmaceutical composition of claim 21 wherein the β-lactamase is an OXA β-lactamase.

24 . The pharmaceutical composition of claim 23 wherein the OXA β-lactamase is OXA-15.

25 . The pharmaceutical composition of claim 21 wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof has inhibition kinetics of at least 250 mM −1 s −1 according to the assay described in Example 24.

26 . The pharmaceutical composition of claim 21 wherein the compound of Formula (A-I) or a pharmaceutically acceptable salt thereof has the Formula:

wherein

Z is selected from the group consisting of 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-thiadiazole;

R * is selected from

and

R 1* is selected from:

gg. hydrogen;

hh.

wherein

R 2* is selected from

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

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

m is selected from 1, 2 and 3;

ii.

wherein R 8* is selected from NH 2 ,

jj. amino;

kk.

wherein Z* is selected from CR 12 R 13 or NR 14 ,

each of R 12 and R 13 is independently selected from H, NH 2 and

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

alternatively, R 12 and R 13 together with the carbon to which they are attached, form a cycloalkyl or heterocyclyl ring containing 4-6 ring members,

R 14 is selected from H and

R 18 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;

ll.

wherein R 19 is selected from NH 2 and

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

R 20 is selected from amino and hydroxyl, and

w is selected from 0 and 1;

mm.

nn.

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

oo.

wherein R 21 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;

pp.

qq.

wherein M is selected from NR 22 , CR 23 R 24 and O,

wherein R 22 is H or

wherein each of R 15 , R 16 and R 17 is as described previously,

each of R 23 and R 24 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;

rr.

ss.

tt.

uu. (C 1 -C 3 )-unsubstituted alkyl; and

vv.

Assignments (3)

NUNC PRO TUNC ASSIGNMENT Recorded Aug 6, 2015

From: CUBIST PHARMACEUTICALS LLC

To: MERCK SHARP & DOHME CORP.

Reel/Frame 036268/0626 →

CHANGE OF NAME Recorded Aug 5, 2015

From: CUBIST PHARMACEUTICALS, INC.

To: CUBIST PHARMACEUTICALS LLC

Reel/Frame 036283/0189 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 18, 2015

From: GU, YU GUI; HE, YONG; YIN, NING; ALEXANDER, DYLAN C.; CROSS, JASON B.; BUSCH, ROBERT

To: CUBIST PHARMACEUTICALS, INC.

Reel/Frame 035943/0337 →