US2015038478A1PendingUtilityA1
Beta-lactamase inhibitors
Est. expiryMar 30, 2032(~5.7 yrs left)· nominal 20-yr term from priority
A61K 31/496A61K 31/439A61K 31/546A61K 31/5377A61K 31/4545A61K 45/06C07D 471/08Y02A50/30
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Claims
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
exact text as granted — not AI-modified1 .- 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,
e.
wherein R 5 is selected from H or aminoalkyl,
f.
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-
A
K.
pneumoniae
EU784136
2 SEQID 6
CTX-
pBR-CBST-
A
K.
pneumoniae
JF775516
M-15
CTX-M-15
SEQ ID 7
SHV-12
pBR-CBST-
A
K.
pneumoniae
AY008838
SHV-12
SEQ ID 8
P99
pBR-CBST-P99
C
E.
cloacea
XO7274
AmpC
AMPC
SEQ ID 9
OXA-15
pBR-CBST-
D
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;
b.
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;
c.
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;
e.
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;
f.
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;
g.
h.
wherein each of R 4* R 6* and R 7* is as described previously;
i.
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;
j.
k.
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;
l.
m.
n.
o. (C 1 -C 3 )-unsubstituted alkyl; and
p.
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,
n.
wherein R 5 is selected from H or aminoalkyl,
o.
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-
A
K.
pneumoniae
EU784136
2 SEQID 6
CTX-
pBR-CBST-
A
K.
pneumoniae
JF775516
M-15
CTX-M-15
SEQ ID 7
SHV-12
pBR-CBST-
A
K.
pneumoniae
AY008838
SHV-12
SEQ ID 8
P99
pBR-CBST-P99
C
E.
cloacea
XO7274
AmpC
AMPC
SEQ ID 9
OXA-15
pBR-CBST-
D
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;
r.
wherein
R 2* is selected from
and
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;
s.
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;
u.
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;
v.
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;
w.
x.
wherein each of R 4* , R 5* , R 6* and R 7* is as described previously;
y.
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;
z.
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,
w.
wherein R 5 is selected from H or aminoalkyl,
x.
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-
A
K.
pneumoniae
EU784136
2 SEQID 6
CTX-
pBR-CBST-
A
K.
pneumoniae
JF775516
M-15
CTX-M-15
SEQ ID 7
SHV-12
pBR-CBST-
A
K.
pneumoniae
AY008838
SHV-12
SEQ ID 8
P99
pBR-CBST-P99
C
E.
cloacea
XO7274
AmpC
AMPC
SEQ ID 9
OXA-15
pBR-CBST-
D
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,
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;
ii.
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;
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
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;
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
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