Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-05
2002-12-03
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06489471
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for synthesizing carbapenem intermediates and compounds produced. Generally hydroxymethylcarbapenems are substituted at the 2-position through a CH
2
link with various sidechains to prepare anti-methicillin resistant
Staphylococcus aureus
(MRSA) compounds. The intermediate compounds are included as well. Examples of carbapenems which are substituted with a naphthosultam-containing side chain at the 2-position are found in Schmitt, S. M. et al.,
J. Antibiotics
41(6): 780-787 (1988) and U.S. Pat. No. 5,756,725, issued May 26, 1998, the teachings of which are hereby incorporated by reference. European applications 0330108, 0102239, 0212404, 0695753 and 0476649 also disclose methods for synthesizing various antibiotic derivatives.
Many of the carbapenems are useful against gram positive microorganisms, especially methicillin resistant
Staphylococcus aureus
(MRSA), methicillin resistant
Staphylococcus epidermidis
(MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS). These antibacterials thus comprise an important contribution to therapy for treating infections caused by these difficult to control pathogens. There is an increasing need for agents effective against such pathogens (MRSA/MRCNS) which are at the same time relatively free from undesirable side effects.
SUMMARY OF THE INVENTION
In one aspect of the invention, a process of synthesizing a carbapenem compound of formula 6:
is disclosed wherein:
R represents H or methyl,
P* represents H, negative charge, or a carboxy protecting group;
P represents hydrogen, hydroxyl, or hydroxy-protecting group; and
each R
1
is independently selected from: —R*; —Q; hydrogen; halo; —CN; —NO
2
; —NR
a
R
b
; —OR
c
; —SR
c
; —C(O)NR
a
R
b
; —C(O)OR
h
; —S(O)R
c
; —SO
2
R
c
; —SO
2
NR
a
R
b
; —NR
a
SO
2
R
b
; —C(O)R
a
; —OC(O)R
a
; —OC(O)NR
a
R
b
; —NR
a
C(O)NR
b
R
c
; —NR
a
CO
2
R
h
; —OCO
2
R
h
; —NR
a
C(O)R
b
; —C
1-6
straight- or branched-chain alkyl, unsubstituted or substituted with one to four R
d
groups; and —C
3-7
cycloalkyl, unsubstituted or substituted with one to four R
d
groups;
each R
a
, R
b
and R
c
independently represents hydrogen, —R*, —C
1-6
straight- or branched-chain alkyl, unsubstituted or substituted with one to four R
d
groups, or —C
3-7
cycloalkyl, unsubstituted or substituted with one to four R
d
groups;
or R
a
and R
b
taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR
c
, with R
c
as defined above, or —C(O)—, said ring being unsubstituted or substituted with one to four R
i
groups;
or R
b
and R
c
taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, NR
a
, with R
a
as defined above, or —C(O)—, said ring being unsubstituted or substituted with one to four R
i
groups;
each R
d
independently represents halo; —CN; —NO
2
; —NR
e
R
f
; —OR
g
; —SR
g
; —CONR
e
R
f
; —COOR
g
; —SOR
g
; —SO
2
R
g
; —SO
2
NR
e
R
f
; —NR
e
SO
2
R
f
; —COR
e
; —NR
e
COR
f
; —OCOR
e
; —OCONR
e
R
f
; —NR
e
ONR
f
R
g
; —NR
e
CO
2
R
h
; —OCO
2
R
h
; —C(NR
e
)NR
f
R
g
; —NR
e
C(NH)NR
f
R
g
; —NR
e
C(NR
f
)R
g
; —R* or—Q;
R
e
, R
f
and R
g
represent hydrogen; —R*; —C
1-6
straight- or branched-chain alkyl unsubstituted or substituted with one to four R
i
groups;
or R
e
and R
f
taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, —C(O)—or NR
g
with R
g
as defined above, said ring being unsubstituted or substituted with one to four R
i
groups;
each R
i
independently represents halo; —CN; —NO
2
; phenyl; —NHSO
2
R
h
; —OR
h
, —SR
h
; —N(R
h
)
2
; —N
+
(R
h
)
3
; —C(O)N(R
h
)
2
; —SO
2
N(R
h
)
2
; heteroaryl; heteroarylium; —CO
2
R
h
; —C(O)R
h
; —OCOR
h
; —NHCOR
h
; guanidinyl; carbamimidoyl or ureido;
each R
h
independently represents hydrogen, a —C
1-6
straight or branched-chain alkyl group, a —C
3-6
cycloalkyl group or phenyl, or when two R
h
groups are present, said R
h
groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO
2
, —C(O)—, NH and NCH
3
;
Q is selected from the group consisting of:
wherein:
a and b are 1, 2 or 3;
L− is a pharmaceutically acceptable counterion;
&agr; represents O, S or NR
s
;
&bgr;, &dgr;, &lgr;, &mgr; and &sgr; represent CR
t
, N or N
+
R
s
, provided that no more than one of &bgr;, &dgr;, &lgr;, &mgr; and &sgr; is N
+
R
s
;
R* is selected from the group consisting of:
wherein:
d represents O, S or NR
k
;
e, g, x, y and z represent CR
m
, N or N
+
R
k
, provided that no more than one of e, g, x, y and z in any given structure represents N
+
R
k
;
R
k
represents hydrogen; —C
1-6
straight- or branched-chain alkyl, unsubstituted or substituted with one to four R
i
groups; or —(CH
2
)
n
Q where n=1, 2 or 3 and Q is as previously defined;
each R
m
independently represents a member selected from the group consisting of: hydrogen; halo; —CN; —NO
2
; —NR
n
R
o
; —OR
n
; —SR
n
; —CONR
n
R
o
; —COOR
h
; —SOR
n
; —SO
2
R
n
; —SO
2
NR
n
R
o
; —NR
n
SO
2
R
o
; —COR
n
; —NR
n
COR
o
; —OCOR
n
; —OCONR
n
R
o
; —NR
n
CO
2
R
h
; —NR
n
CONR
o
R
h
; —OCO
2
R
h
; —CNR
n
NR
o
R
h
; —NR
n
CNHNR
o
R
h
; —NR
n
C(NR
o
)R
h
; —C
1-6
straight- or branched-chain alkyl, unsubstituted or substituted with one to four R
i
groups; —C
3-7
cycloalkyl, unsubstituted or substituted with one to four R
i
groups; and —(CH
2
)
n
Q where n and Q are as defined above;
R
n
and R
o
represent hydrogen, phenyl; —C
1-6
straight- or branched-chain alkyl unsubstituted or substituted with one to four R
i
groups;
each R
s
independently represents hydrogen; phenyl or —C
1-6
straight- or branched-chain alkyl, unsubstituted or substituted with one to four R
i
groups;
each R
t
independently represents hydrogen; halo; phenyl; —CN; —NO
2
; —NR
u
R
v
; —OR
u
; —SR
u
; —CONR
u
R
v
; —COOR
h
; —SOR
u
; —SO
2
R
u
; —SO
2
NR
u
R
v
; —NR
u
SO
2
R
v
; —COR
u
; —NR
u
COR
v
; —OCOR
u
; —OCONR
u
R
v
; —NR
u
CO
2
R
v
; —NR
u
CONR
v
R
w
; —OCO
2
R
v
; —C
1-6
straight- or branched-chain alkyl, unsubstituted or substituted with one to four R
i
groups;
R
u
and R
v
represent hydrogen or —C
1-6
straight- or branched-chain alkyl, unsubstituted or substituted with one to four R
i
groups;
or R
u
and R
v
together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR
w
or —C(O)—, said ring being unsubstituted or substituted with one to four R
i
groups;
each R
w
independently represents hydrogen; —C
1-6
straight- or branched-chain alkyl, unsubstituted or substituted with one to four R
i
groups; C
3-6
cycloalkyl optionally substituted with one to four R
i
groups; phenyl optionally substituted with one to four R
i
groups, or heteroaryl optionally substituted with 1-4 R
i
groups;
or R
h
and R
w
taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO
2
, NH or NCH
3
;
R
x
represents hydrogen or a C
1-8
straight- or branched-chain alkyl, optionally interrupted by one or two of O, S, SO, SO
2
, NR
w
, N
+
R
h
R
w
, or —C(O)—, said chain being unsubstituted or substituted with one to four of halo, CN, NO
2
, OR
w
, SR
w
, SOR
w
, SO
2
R
w
, NR
h
R
w
, N
+
(R
h
)
2
R
w
, —C(O)—R
w
, C(O)NR
h
R
w
, SO
2
NR
h
R
w
, CO
2
R
w
, OC(O)R
w
, OC(O)NR
h
R
w
, NR
h
C(O)R
w
, NR
h
C(O)NR
h
R
w
, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R
i
groups or with one to two C
1-3
straight- or branched-chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R
i
groups;
R
y
and R
z
represent hydrogen; phenyl; —C
1-6
straight or branched chain alkyl, unsubstituted or substituted with one to four R
i
groups, and optionally interrupted by O, S, NR
w
, N
+
R
h
R
w
or —C(
Humphrey Guy R.
Miller Ross A.
Yasuda Nobuyoshi
Ayler Sylvia A.
Berch Mark L.
Camara Valerie J.
Daniel Mark R.
Merck & Co. , Inc.
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