CARBAPENEM ANTIBIOTIQUES

CARBAPENEM ANTIBIOTICS

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
Disclosed are novel carbapenem derivatives of the
formula
< IMG >
characterized by a 2-substituent of the formula
< IMG >
wherein A represents C2-C6 straight or branched chain alkylene
group and R10 and R11 each independently represents optionally
substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,
aryl, heterocyclyl, heterocvclyl-alinhatic, heteroaryl or
heteroaraliphatic, or R10 and R11 taken together with the S?
to which they are attached represent an optionally substituted
sulfur-containing heterocyclic ring. Such derivatives are
useful as potent antibacterial agents. Also disclosed are
processes for the preparation of such derivatives.

Revendications

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A process for the preparation of ~ compound of the
formula
< IMG >
wherein R8 is hydrogen and R1 is selected from the group
consisting of hydrogen;
alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms;
cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in
the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl
moiety is phenyl and the aliphatic portion has 1-6 carbon
atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-
cyclylalkyl wherein the hetero atom or atoms in the above-
named heterocyclic moieties are selected from the group con-
sisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl
moieties associated with said heterocyclic moieties have 1-6
carbon atoms; wherein the substituent or substituents relative
to the above-named radicals are independently selected from the
group consisting of
C1-C6 alkyl optionally substituted by
amino, halo, hydroxy or carboxyl
halo
< IMG >
51

< IMG >
wherein, relative to the above-named substituents, the groups
R3 and R4 are independently selected from hydrogen; alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl,
cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms
in the cycloalkyl ring and 1-6 carbon atoms in the alkyl
moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein
the aryl moiety is phenyl and the aliphatic portion has 1-6
carbon atoms; and heteroaryl, herteoaralkyl, heterocyclyl
52

and heterocyclylalkyl wherein the hetero atom or atoms in the
above-named heterocyclic moieties are selected from the group
consisting of 1-4 oxygen, nitrogen or sulfur atoms and the
alkyl moieties associated with said heterocyclic moieties have
1-6 carbon atoms, or R3 and R4 taken together with the nitrogen
to which at least one is attached may form a 5-or 6-membered
nitrogen-containing heterocyclic ring; R9 is as defined for R3
except that it may not be hydrogen; or wherein R1 and R8 taken
together represent C2-C10 alkylidene or C2-C10 alkylidene
substituted by hydroxy; A is C2-C6 straight or branched chain
alkylene; R2 is hydrogen, and anionic charge or a conventional
readily removable carboxyl protecting group, providing that
when R2 is hydrogen or a protecting group, there is also present
a counter anion, and R10 and R11 each independently represents
(a) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cyclo-
alkyl or cycloalkylalkyl having 3-6 carbon atoms in the
cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety,
said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkyl-
alkyl group being optionally substituted by 1-3 substituents
independently selected from hydroxy, C1-C6 alkyoxy,
C1-C6 alkanoyloxy, carboxy, C1-C6 alkoxycarbonyl,
amino, C1-C6 alkylamino, di(C1-C6) alkylamino, C1-C6
alkanoylamino, phenyl, phenyl substituted by 1-3 halo,
C1-C6 alkoxy, C1-C6 alkyl, carboxy, carboxy (C1-C6) alkyl,
amino, C1-C6 alkylamino, di(C1-C6) alkylamino or di-
(C1-C6)alkylamino(C1-C6)alkyl, halo or oxo;
(b) phenyl optionally substituted by 1-3 halo, C1-C6
alkoxy, C1-C6 alkyl, carboxy, amino, C1-C6 alkylamino or
di(C1-C6)alkylamino groups;
(c) heterocyclyl or heterocyclylalkyl wherein the hetero-
cyclic moiety is a 4-6 membered ring having 1-3 hetero
atoms selected from O, N and S and the alkyl moiety has
1-6 carbon atoms, said heterocyclyl or heterocyclylalkyl
ring being optionally substituted by 1-3 C1-C6 alkyl or
C1-C6 alkoxy groups; or
(d) heteroaryl or heteroaralkyl wherein the heterocyclic
moiety is a 5-6 membered aromatic ring having 1-3 hetero
53

atoms selected from O, N and S and the alkyl moiety has
1-6 carbon atoms, said heteroaryl or heteroaralkyl ring
being optionally substituted by 1-3 C1-C6 alkyl, C1-C6
alkoxy, carboxy, carboxy(C1-C6)alkyl, amino, C1-C6 alkyl-
amino, di(C1-C6)alkylamino, amino(C1-C6)alkyl or di(C1-C6)-
alkylamino(C1-C6)alkyl groups; or wherein R10 and R11
taken together with the
S?
to which they are attached represent a 4-6 member sulfur-
containing heterocyclic ring containing 0-2 double bonds
and 0-2 additional heteroatoms selected from O, N and S,
said ring being attached to A through a sulfur atom,
thereby forming a sulfonium group, said heterocyclic ring
being optionally substituted by 1-3 substitutents
independently selected from:
C1-C6 alkyl optionally substituted by 1-3 hydroxy,
C1-C6 alkoxy, carboxy, halo, amino, C1-C6 alkylamino
or di(C1-C6)alkylamino groups, hydroxy, C1-C6 alkoxy,
C1-C6 alkanoyloxy, amino, C1-C6 alkylamino, di(C1-C6)-
alkylamino, C1-C6 alkanoylamino, carboxy, C1-C6 alkoxy-
carbonyl, halo, oxo or phenyl; or wherein said hetero-
cyclic ring
< IMG >
is fused to a C5-C6 carbocyclic ring, a phenyl ring,
a 5-6 member heterocyclic ring or a 5-6 member hetero-
aryl ring, all of which rings may be optionally sub-
stituted by 1-3 of the substituents referred to above
for the
< IMG >
ring; or a pharmaceutically acceptable salt thereof,
which process comprises subjecting an intermediate of
the formula
< IMG >
II
54

wherein R1, R8 and A are as defined abov and R2 is a conventional
readily removable carboxyl protecting group to nucleophilic dis-
placement in an inert organic solvent and in the presence of
silver ion with a sulfide reagent of the formula
< IMG >
wherein R10 ad R11 are as defined above so as to displace the
iodo group of intermediate II with the group
< IMG >
and form a comound of the formula
< IMG >
wherein X is a counter anion and R1, R8, A, R10, R11 and
R2' are as defined above, and, if desired, removing the carboxyl
protecting group R2' to give the corresponding deblocked compound
of the formula I, or a pharmaceutically acceptable salt thereof;
or alternately a process comprising the steps of
(1) reacting an intermediate of the formula
< IMG >
III

wherein R1 and R8 are as defined above and R2 is a con-
ventional readily removeable carboxyl protecting group in
an inert organic solvent with diphenyl chlorophosphate in
the presence of base to give an intermediate of the formula
< IMG >
IV
wherein R1, R8 and R2' are as defined above;
(2) reacting intermediate TV in an inert organic
solvent and in the presence of base with a mercaptan
reagent of the formula
HS-A-OH
wherein A is as defined ahove to give an intermediate of the
formula
< IMG >
V
wherein R1, R8, A and R2' are as defined above;
(3) reacting intermediate V in an inert organic
solvent and in the presence of base with methanesulfonyl
chloride or a functional acylating equivalent thereof to
give an intermediate of the formula
< IMG >
VI
56

wherein R1, R8 A and R2' are as defined above;
(4) reacting intermediate VI in an inert organic
solvent with a source of iodide ion so as to displace
the methanesulfonyloxy group with an iodo group and form
an intermediate of the formula
< IMG >
II
wherein R1, R8, A and R2 are as defined above; and
(5) subjecting intermediate II to nucleophilic dis-
placement in an inert organic solvent and in the presence of
silver ion with a sulfide reagent of the formula
< IMG >
wherein R10 and R11 are as defined above so as to displace the
iodo group of intermediate II with the group
< IMG >
ana form a compouna of the formula
X?
< IMG >
wherein X? is a counter anion and R1, R8, A, R10, R11
and R2' are as defined above, and, of desired, removing the
carboxyl protecting group R2' to give the corresponding
deblocked compound of formula I, or a pharmaceutically accept-
able salt thereof.
57

2. A process for the preparation of a compound of the
formula
< IMG >
wherein R8 is hydrogen and R1 is selected from the group
consisting of hydrogen;
alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms;
cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in
the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl
moiety is phenyl and the aliphatic portion has 1-6 carbon
atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-
cyclylalkyl wherein the hetero atom or atoms in the above-
named heterocyclic moieties are selected from the group con-
sisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl
moieties associated with said heterocyclic moieties have 1-6
carbon atoms; wherein the substituent or substituents relative
to the above-named radicals are independently selected from the
group consisting of
C1-C6 alkyl optionally substituted by
amino, halo, hydroxy or carboxyl
halo
-OR3
< IMG >

< IMG >
wherein, relative to the above-named substituents, the groups
R3 and R4 are independently selected from hydrogen; alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl,
cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms
in the cycloalkyl ring and 1-6 carbon atoms in the alkyl
moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein
the aryl moiety is phenyl and the aliphatic portion has 1-6
carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl
and heterocyclylalkyl wherein the hetero atom or atoms in the
above-named heterocyclic moieties are selected from the group
consisting of 1-4 oxygen, nitrogen or sulfur atoms and the
alkyl moieties associated with said heterocyclic moieties have
1-6 carbon atoms, or R3 and R4 taken together with the nitrogen
59

to which at least one is attached may from a 5-or 6-membered
nitrogen-containing heterocyclic ring; R9 is as defined for R3
except that it may not be hydrogen; or wherein R1 and R8 taken
together represent C2-C10 alkylidene or C2-C10 alkylidene
substituted by hydroxy; A is C2-C6 straight or branched chain
alkylene; R2 is hydrogen, an anionic charge or a conventional
readily removable carboxyl protecting group, providing that
when R2 is hydrogen or a protecting group, there is also present
a counter anion, and R10 and R11 each independently represents
(a) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cyclo-
alkyl or cycloalkylalkyl having 3-6 carbon atoms in the
cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety,
said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkyl-
alkyl group being optionally substituted by 1-3 substituents
independently selected from hydroxy, C1-C6 alkoxy,
C1-C6 alkanoyloxy, carboxy, C1-C6 alkoxycarbonyl,
amino, C1-C6 alkylamino, di(C1-C6)alkylamin0, C1-C6
alkanoylamino, phenyl, phenyl substituted by 1-3 halo,
C1-C6 alkoxy, C1-C6 alkyl, carboxy, carboxy(C1-C6)alkyl,
amino, C1-C6 alkylamino, di(C1-C6)alkylamino or di-
(C1-C6)alkylamino(C1-C6)alkyl, halo or oxo;
(b) phenyl optionally substituted by 1-3 halo, C1-C6
alkoxy, C1-C6.alkyl, carboxy, amino, C1-C6 alkylamino or
di(C1-C6)alkylamino groups;
(c) heterocyclyl or heterocyclylalkyl wherein the hetero-
cyclic moiety is a 4-6 membered ring having 1-3 hetero
atoms selected from 0, N and S and the alkyl moiety has
1-6 carbon atoms, said heterocyclyl or heterocyclylalkyl
ring being optionally substituted by 1-3 C1-C6 alkyl or
Cl-C6 alkoxy groups; or
(d) heteroaryl or heteroaralkyl wherein the heterocyclic
moiety is a 5-6 membered aromatic ring having 1-3 hetero
atoms selected from 0, N and S and the alkyl moiety has
1-6 carbon atoms, said heteroaryl or heteroaralkyl ring

being optionally substituted by 1-3 C1-C6 alkyl, C1-C6
alkoxy, carboxy, carboxy(C1-6)alkyl, amino, C1-C6 alkyl-
amino, di(C1-C6)alkylamino, amino(C1-C6)alkyl or di(C1-C6)-
alkylamino(C1-C6)alkyl groups; or wherein R10 and R11
taken together with the
< IMG >
to which they are attached represent a 4-6 member sulfur-
containing heterocyclic ring containing 0-2 double bond
and 0-2 additional heteroatoms selected from O, N and S,
said ring being attached to A through a sulfur atom,
thereby forming a sulfonium group, said heterocyclic ring
being optionally substituted by 1-3 substituents
independently selected from:
C1-C6 alkyl optimally substituted by 1-3 hydroxy,
C1-C6 alkoxy, carboxy, halo, amino, C1-C6 alkylamino
or di(C1-C6) alkylamino groups, hydroxy, C1-C6 alkoxy,
C1-C6 alkanoyloxy, amino, C1-C6 alkylamino, di(C1-C6)
alkylamino, C1-C6 alkanoylamino, carboxy, C1-C6 alkoxy-
carbonyl, halo, oxo or phenyl; or wherein said hetero-
cyclic ring
< IMG >
is fused to a C5-C6 carbocyclic ring, phenyl ring,
a 5-6 member heterocyclic ring or a 5-6 member hetero-
aryl ring, all of which rings may be optionally sub-
stituted by 1-3 of the substituents referred to above
f or the
< IMG >
ring; or a pharmaceutically acceptable salt thereof,
which process comprises subjecting an intermediate of
the formula
< IMG >
II
61

wherein R1, R8 and A are as defined above and R2' is a conventional
readily removable carboxyl protecting group to nucleophilic dis-
placement in an inert organic solvent and in the presence of
silver ion with a sulfide reagent of the formula
< IMG >
wherein R10 and R11 are as defined above so as to displace the
iodo group of intermediate II with the group
< IMG >
and form a compound of the formula
< IMG >
wherein X- is a counter anion and R1, R8, A, R10, R11 and
R2 are as defined above, and, if desired, removing the carboxyl
protecting group R2' to give the corresponding deblocked compound
of the formula I, or a pharmaceutically acceptable salt thereof.
3. A process for the preparation of a compound of the
formula
< IMG >
I
62

wherein R8 is hydrogen and R1 is selected from the group
consisting of hydrogen;
alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms;
cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in
the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl
moiety is phenyl and the aliphatic portion has 1-6 carbon
atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-
cyclylalkyl wherein the hetero atom or atoms in the above-
named heterocyclic moieties are selected from the group con-
sisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl
moieties associated with said heterocyclic moieties have 1-6
carbon atoms; wherein the substituent or substituents relative
to the above-named radicals are independently selected from the
group consisting of
C1-C6 alkyl optionally substituted by
amino, halo, hydroxy or carboxyl
halo
-OR3
< IMG >
63

< IMG >
wherein, relative to the above-named substituents, the groups
R3 and R4 are independently selected from hydrogen; alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl,
cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms
in the cycloalkyl ring and 1-6 carbon atoms in the alkyl
moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein
the aryl moiety is phenyl and the aliphatic portion has 1-6
carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl
and heterocyclylalkyl wherein the hetero atom or atoms in the
above-named heterocyclic moieties are selected from the group
consisting of 1-4 oxygen, nitrogen or sulfur atoms and the
alkyl moieties associated with said heterocyclic moieties have
1-6 carbon atoms, or R3 and R4 taken together with the nitrogen
to which at least one is attached may form a 5-or 6-membered
nitrogen-containing heterocyclic ring; R9 is as defined for R3
except that it may not be hydrogen; or wherein R1 and R8 taken
together represent C2-C10 alkylidene or C2-C10 alkylidene
substituted by hydroxy: A is C2-C6 straight or branched chain
alkylene; R2 is hydrogen, an anionic charge or a conventional

readily removable carboxyl protecting group, providing that
when R2 is hydrogen or a protecting group, there is also present
a counter anion, and R10 and R11 each independently represents
(a) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cyclo-
alkyl or cycloalkylalkyl having 3-6 carbon atoms in the
cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety,
said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkyl-
alkyl group being optionally substituted by 1-3 substituents
independently selected from hydroxy, C1-C6 alkoxy,
C1-C6 alkanoyloxy, carboxy, C1-C6 alkoxycarbonyl,
amino, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6
alkanoylamino, phenyl, phenyl substituted by 1-3 halo,
C1-C6 alkoxy, C1-C6 alkyl, carboxy, carboxy(C1-C6)alkyl,
amino, C1-C6 alkylamino, di(C1-C6)alkylamino or di-
(C1-C6)alkylamino(C1-C6)alkyl, halo or oxo;
(b) phenyl optionally substituted by 1-3 halo, C1-C6
alkoxy, C1-C6 alkyl, carboxy, amino, C1-C6 alkylamino or
di(C1-C6)alkylamino groups;
(c) heterocyclyl or heterocyclylalkyl wherein the hetero-
cyclic moiety is a 4-6 membered ring having 1-3 hetero
atoms selected from O, N and S and the alkyl moiety has
1-6 carbon atoms, said heterocyclyl or heterocyclylalkyl
ring being optionally substituted by 1-3 C1-C6 alkyl or
C1-C6 alkoxy groups; or
(d) heteroaryl or heteroaralkyl wherein the heterocyclic
moiety is a 5-6 membered aromatic ring having 1-3 hetero
atoms selected from O, N and S and the alkyl moiety has
1-6 carbon atoms, said heteroaryl or heteroaralkyl ring
being optionally substituted by 1-3 C1-C6 alkyl, C1-C6
alkoxy, carboxy, carboxy(C1-C6)alkyl, amino, C1-C6 alkyl-
amino, di(C1-C6)alkylamino, amino(C1-C6)alkyl or di(C1-C6)-
alkylamino(C1-C6)alkyl groups; or wherein R10 and R11
taken together with the
S?
to which they are attached represent a 4-6 member sulfur-
containing heterocyclic ring containing 0-2 double bonds
and 0-2 additional heteroatoms selected from O, N and S,

said ring being attached to A through a sulfur atom,
thereby forming a sulfonium group, said heterocyclic ring
being optionally substituted by 1-3 substituents
independently selected from:
C1-C6 alkyl optionally substituted by 1-3 hydroxy,
C1-C6 alkoxy, carboxy, halo, amino, C1-C6 alkylamino
or di(C1-C6)alkylamino groups, hydroxy, C1-C6 alkoxy,
C1-C6 alkanoyloxy, amino, C1-C6 alkylamino, di(C1-C6)-
alkylamino, C1-C6 alkanoylamino, carboxy, C1-C6 alkoxy-
carbonyl, halo, oxo or phenyl; or wherein said hetero-
cyclic ring
< IMG >
is fused to a C5-C6 carbocyclic ring, a phenyl ring,
a 5-6 member heterocyclic ring or a 5-6 member hetero-
aryl ring, all of which rings may be optionally sub-
stituted by 1-3 of the substtuents referred to above
for the
< IMG >
ring; or a pharmaceutically acceptable salt thereof,
which process comprises the steps of
(1) reacting an intermediate of the formula
< IMG >
III
66

wherein R1 and R8 are as defined above and R2 is a con-
ventional readily removable carboxyl protecting group in
an inert organic solvent with diphenyl chlorophosphate in
the presence of base to give an intermediate of the formula
< IMG >
IV
wherein R1, R8 and R2 are as defined above;
(2) reacting intermediate IV in an inert organic
solvent and in the presence of base with a mercaptan
reagent of the formula
HS-A-OH
wherein A is as defined above to give an intermediate of the
formula
< IMG >
V
wherein R1, R8, A and R2. are as defined above;
(3) reacting intermediate V in in inert organic
solvent and in the presence of base with methanesulfonyl
chloride or a functional acylating equivalent thereof to
give an intermediate of the formula
< IMG >
VI
67

wherein R1, R8, A and R2 are as defined above;
(4) reacting intermediate VI in an inert organic
solvent with a source of iodide ion so as to displace
the methanesulfonyloxy group with an iodo group and form
an intermediate of the formula
< IMG >
wherein R1, R8, A and R2 are as defined above; and
(5) subjecting intermediate II to nucleophilic dis-
placement in an inert organic solvent and in the presence of
silver ion with a sulfide reagent of the formula
< IMG >
wherein R10 and R11 are as defined above so as to displace the
iodo group of intermediate II with the group
< IMG >
and form a compound of the formula
< IMG >
wherein X? is a counter anion and R1, R8, A, R10, R11
and R2 are as defined above,and, if desired, removing the
carboxyl protecting group R2'to give the corresponding
deblocked compound of formula I, or a pharmaceutically accept-
able salt thereof.
68

4. A process as in claim 1 wherein R1 is hydrogen,
CH3CH2-,
< IMG > or < IMG >
5. A process as in claim 1 wherein R1 and R8 taken
together represent
< IMG >
6. A process as in claim 1 wherein R1 is
< IMG >
7. A process as in claim 1 wherein R1 is
< IMG >
and the absolute configuration is 5R, 6S, 8R.
8. A process as in claim 1 wherein A is -CH2CH2-.
9. A process for the preparation of a compound of the
formula
< IMG >
wherein R8 is hydrogen and R1 is selected from the group
consisting of hydrogen;
alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms;
cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in
the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl
69

moiety is phenyl and the aliphatic portion has 1-6 carbon
atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-
cyclylalkyl wherein the hetero atom or atoms in the above-
named heterocyclic moieties are selected from the group con-
sisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl
moieties associated with said heterocyclic moieties have 1-6
carbon atoms; wherein the substituent or substituents relative
to the above-named radicals are independently selected from the
group consisting of
C1-C6 alkyl optionally substituted by
amino, halo, hydroxy or carboxyl
halo
-OR3
< IMG >
72

< IMG >
wherein, relative to the above-named substituents, the groups
R3 and R4 are independently selected from hydrogen; alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl,
cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms
in the cycloalkyl ring and 1-6 carbon atoms in the alkyl
moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein
the aryl moiety is phenyl and the aliphatic portion has 1-6
carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl
and heterocyclylalkyl wherein the hetero atom or atoms in the
above named heterocyclic moieties are selected from the group
consisting of 1-4 oxygen, nitrogen or sulfur atoms and the
alkyl moieties associated with said heterocyclic moieties have
1-6 carbon atoms, or R3 and R4 taken together with the nitrogen
to which at least one is attached may form a 5-or 6-membered
nitrogen-containing heterocyclic ring; R9 is as defined for R3
except that it may not be hydrogen; or wherein R1 and R8 taken
together represent C2-C10 alkylidene or C2-C10 alkylidene
substituted by hydroxy; A is C2-C6 straight or branched chain
alkylene; R is hydrogen, an anionic charge or a conventional
readily removable carboxyl protecting group, providing that
when R2 is hydrogen or a protecting group, there is also present
a counter anion, and R10 and R taken together with the
< IMG >
to which they are attached represent
71

< IMG >
a pharmaceutically acceptable salt thereof,
which process comprises subjecting an intermediate of
the formula
< IMG >
II
wherein R1, R8 and A are as defined above and R2' is a conventional
readily removable carboxyl protecting group to nucleophilic dis-
placement in an inert organic solvent and in the presence of
silver ion with a sulfide reagent of the formula
< IMG >
wherein R10 and R11 are as defined above so as to displace the
iodo group of intermediate II with group
< IMG >
and form a compound of the formula
< IMG >
I'
wherein X- is a counter anion and R1, R8, A, R10, R11 and
R2' are as defined above, and, if desired, removing the carboxyl
protecting group R2' to give the corresponding deblocked compound
of the formula I, or a pharmaceutically acceptable salt thereof;

or alternately a process comprising the steps of
(1) reacting an intermediate of the formula
< IMG >
III
wherein R1 and R8 are as defined above and R2' is a con-
ventional readily removable carboxyl protecting group in
an inert organic solvent with diphenyl chlorophosphate in
the presence of base to give an intermediate of the formula
< IMG >
wherein R1, R8 and R2' are as defined above;
(2) reacting intermediate IV in an inert organic
solvent and in the presence of base with a mercaptan
reagent of the formula
HS-A-OH
wherein A is as defined above to give an intermediate of the
formula
< IMG >
wherein R1, R8, A and R2' are as defined above;
(3) reacting intermediate V in an inert organic
solvent and in the presence of base with methanesulfonyl
chloride or a functional acylating equivalent thereof to
give an intermediate of the formula
< IMG >
VI

wherein R1, R8, A and R2' are as defined above;
(4) reacting intermediate VI in an inert organic
solvent with a source of iodide ion so as to displace
the methanesulfonyloxy group with an iodo group and form
an intermediate of the formula
< IMG > II
wherein R1, R8, A and R2; are as defined above; and
(5) subjecting intermediate II to nucleophilic dis-
placement in an inert organic solvent and in the presence of
silver ion with a sulfide reagent of the formula
< IMG >
wherein R10 and R11 are as defined above so as to displace the
iodo group of intermediate II with the group
< IMG >
and form a compound of the formula
< IMG >
wherein X? is a counter anion and R1, R8, A, R10, R11
and R2' are as defined above, and , if desired, removing the
carboxyl protecting group R2' to give the corresponding
deblocked compound of formula I, or a pharmaceutically accept-
able salt thereof.

10. A Process as in claim 9 wherein R1 is hydrogen,
CH3CH2-,
< IMG > or < IMG >
11. A process as in claim 9 wherein R1 and R8 taken
together represent
< IMG >
12. A process as in claim 9 wherein R1 is
< IMG >
13. A process as in claim 9 wherein R1 is
< IMG >
and the absolute configuration is 5R, 6S, 8R.
14. A process according to claim 9 wherein A is
-CH2CH2-.
15. A process for producing the compound of the formula
< IMG >
wherein R8 is hydrogen and R1 is selected from the group
consisting of hydrogen;
alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms;
cycloalkyl and cycloalkylalkyl having 3-6 carbon atoms in
the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl
moiety is phenyl and the aliphatic portion has 1-6 carbon

atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-
cyclylalkyl wherein the hetero atom or atoms in the above-
named heterocyclic moieties are selected from the group con-
sisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl
moieties associated with said heterocyclic moieties have 1-6
carbon atoms; wherein the substituent or substituents relative
to the above-named radicals are independently selected from the
group consisting of
C1-C6 alkyl optionally substituted by
amino, halo, hydroxy or carboxyl
halo
-OR3
< IMG >

< IMG >
wherein, relative to the above-named substituents, the groups
R3 and R4 are independently selected from hydrogen; alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl,
cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms
in the cycloalkyl ring and 1-6 carbon atoms in the alkyl
moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein
the aryl moiety is phenyl and the aliphatic portion has 1-6
carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl
and heterocyclylalkyl wherein the hetero atom or atoms in the
above-named heterocyclic moieties are selected from the group
consisting of 1-4 oxygen, nitrogen or sulfur atoms and the
alkyl moieties associated with said heterocyclic moieties have
1-6 carbon atoms, or R3 and R4 taken together with the nitrogen
to which at least one is attached may form a 5-or 6-membered
nitrogen-containing heterocyclic ring; R9 is as defined for R3
except that it may not be hydrogen; or wherein R1 and R8 taken
together represent C2-C10 alkylidene or C2-C10 alkylidene
substituted by hydroxy; A is C2-C6 straight or branched chain
alkylene; R2 is hydrogen, an anionic charge or a conventional
readily removable carboxyl protecting group, providing that
when R2 is hydrogen or a protecting group, there is also present
a counter anion: and R10 and R11 taken together with the
< IMG >
to which they are attached represent
< IMG >
or a pharmaceutically acceptable salt thereof,
77

which process comprises subjecting an intermediate of
the formula
< IMG >
wherein R1, R8 and A are as defined above and R2' is a conventional
readily removable carboxyl protecting group to nucleophilic dis-
placement in an inert organic solvent and in the presence of
silver ion with a sulfide reagent of the formula
< IMG >
wherein R10 and R11 are as defined above so as to displace the
iodo group of intermediate II with the group
< IMG >
and form a compound of the formula
< IMG >
wherein X is a counter anion and R1, R8, A, R10, R11 and
R2' are as defined above, and, if desired, removing the carboxyl
protecting group R2 to give the corresponding deblocked compound
of the formula I, or a pharmaceutically acceptable salt thereof,
78

which process comprises the steps of
(1) reacting an intermediate of the formula
< IMG >
III
wherein R1 and R8 are R5 defined above and R2' is a con-
ventional readily removable carboxyl protecting group in
an inert organic solvent with diphenyl chlorophosphate in
the presence of base to give an intermediate of the formula
< IMG >
IV
wherein R1, R8 and R2' are as defined above;
(2) reacting intermediate IV in an inert organic
solvent and in the presence of base with a mercaptan
reagent of the formula
HS-A-OH
wherein A is as defined above to give an intermediate of the
formula
< IMG >
wherein R1, R8, A and R2' are as defined above;
(3) reacting intermediate V in an inert organic
solvent and in the presence of base with methanesulfonyl
chloride or a functional acylating equivalent thereof to
79

give an intermediate of the formula
< IMG >
VI
wherein R1, R8, A and R2' are as defined above;
(4) reacting intermediate VI in an inert organic
solvent with a source of iodide ion so as to displace
the methanesulfonyloxy group with an iodo group and form
an intermediate of the formula
< IMG >
wherein R1, R8, A and R2 are as defined above; and
(5) subjecting intermediate II to nucleophilic dis-
placement in an inert organic solvent and in the presence of
silver ion with a sulfide reagent of the formula
< IMG >
wherein R10 and R11 are as defined above so as to displace the
iodo group of intermediate II with the group
< IMG >
and form a compound of the formula
< IMG >
wherein X? is a counter anion and R1, R8, A, R10, R11

and R2 are as defined above, and, if desired removing the
carboxyl protecting group R2 to give the corresponding
deblocked compound of formula I, or a pharmaceutically accept-
able salt thereof.
16. A process as in claim 15 wherein R1 is hydrogen,
CH3CH2-,
< IMG >
17. A process as in claim 15 wherein
taken together represent
< IMG >
18. A process as in claim 15 wherein
< IMG >
19. A process as in claim 15 wherein
< IMG >
and the absolute configuration is 5R, 6S, 8R.
20. A process as in claim 15
wherein A is -CH2CH2-.
21. A process for preparing the compound of the formula
< IMG >
wherein R2 is hydrogen, an anionic charge or a conventional
readily removable carboxyl protecting group, providing that
when R2 is hydrogen or a protecting group, there is also present
a counter anion, or a pharmaceutically acceptable salt thereof,
81

which process comprises subjecting an intermediate of
the formula
< IMG >
wherein R1, R8 and A are as defined above and R2' is a conventional
readily removable carboxyl protecting group to nucleophilic dis-
placement in an inert organic solvent and in the presence of
silver ion with a sulfide reagent of the formula
< IMG >
wherein R10 and R11 are as defined above so as to displace the
iodo group of intermediate II with the group
82

< IMG >
and form a compound of the formula
< IMG >
I'
wherein X is a counter anion and R1, R8, A, R10, R11 and
R2' are as defined above, and, if desired, removing the carboxyl
protecting group R2' to give the corresponding deblocked compound
of the formula I, or a pharmaceutically acceptable salt thereof;
or alternately a process comprising the steps of
(1) reacting an intermediate of the formula
< IMG >
III
wherein R1 and R8 are as defined above and R2' is a con-
ventional readily removable carboxyl protecting group in
an inert organic solvent with diphenyl chlorophosphate in
the presence of base to give an intermediate of the formula
< IMG >
IV
wherein R1, R8 and R2' are as defined above;
(2) reacting intermediate IV in an inert organic
solvent and in the presence of base with a mercaptan
reagent of the formula
HS-A-OH
wherein A is as defined above to give an intermediate of the

formula
< IMG >
wherein R1, R8, A and R2' are as defined above;
( 3) reacting intermediate V in an inert organic
solvent and in the presence of base with methanesulfonyl
chloride or a functional acylating equivalent thereof to
give an intermediate of the formula
< IMG >
VI
wherein R1, R8, A and R2' are as defined above;
(4) reacting intermediate VI in an inert organic
solvent with a source of iodide ion so as to displace
the methanesulfonyloxy group with an iodo group and form
an intermediate of the formula
< IMG > II
wherein R1, R8, A and R2' are as defined above; and
(5) subjecting intermediate II to nucleophilic dis-
placement in an inert organic solvent and in the presence of
silver ion with a sulfide reagent of the formula
< IMG >
wherein R10 and R11 are as defined above so as to displace the
84

iodo group of intermediate II with the group
< IMG >
and form a compound of the formula
< IMG >
wherein X? is a counter anion and R1, R8, A, R10, R11
and R2' are as defined above, and, if desired, removing the
carboxyl protecting group R2' to give the corresponding
deblocked compound of formula I, or a pharmaceutically accept-
able salt thereof.
22. A process as in claim 21 wherein R2 is p-nitrobenzyl.
23. A process as in claim 21 wherein R2 is an anionic
charge.
24. A compound of the formula
< IMG >
wherein R8 is hydrogen and R1 is selected from the group
consisting of hydrogen;
alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms;
cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in
the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl
moiety is phenyl and the aliphatic portion has 1-6 carbon
atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-
cyclylalkyl wherein the hetero atom or atoms in the above-

named heterocyclic moieties are selected from the group con-
sisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl
moieties associated with said heterocyclic moieties have 1-6
carbon atoms; wherein the substituent or substituents relative
to the above-named radicals are independently selected from
the group consisting of
C1-C6 alkyl optionally substituted by
amino, halo, hydroxy or carboxyl
halo
< IMG >

< IMG >
wherein, relative to the above-named substituents, the groups
R3 and R4 are independently selected from hydrogen; alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl
cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms
in the cycloalkyl ring and 1-6 carbon atoms in the alkyl
moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein
the aryl moiety is phenyl and the aliphatic portion has 1-6
carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl
and heterocyclylalkyl wherein the hetero atom or atoms in the
above-named heterocyclic moieties are selected from the group
consisting of 1-4 oxygen, nitrogen or sulfur atoms and the
alkyl moieties associated with said heterocyclic moieties have
1-6 carbon atoms, or R3 and R4 taken together with the nitrogen
to which at least one is attached may form a 5-or 6-membered
nitrogen-containing heterocyclic ring; R9 is as defined for R3
except that it may not be hydrogen; or wherein R1 and R8 taken
together represent C2-C10 alkylidene or C2-C10 alkylidene
substituted by hydroxy; A is C2-C6 straight or branched chain
alkylene; R2 is hydrogen, an anionic charge or a conventional
readily removable carboxyl protecting group, providing that
when R2 is hydrogen or a protecting group, there is also present
a counter anion, and R10 and R11 each independently represents
(a) C1-C6 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cyclo-
alkyl or cycloalkylalkyl having 3-6 carbon atoms in the
cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety,
said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkyl-
alkyl group being optionally substituted by 1-3 substituents
87

independently selected from hydroxy, C1-C6 alkoxy,
C1-C6 alkanoyloxy, carboxy, C1-C6 alkoxycarbonyl,
amino, C1-C6 alkylamino, di(C1-C6)alkylamino C1-C6
alkanoylamino, phenyl, phenyl substituted by 1-3 halo,
C1-C6 alkoxy, C1-C6 alkyl, carboxy, carboxy(C1-C6)alkyl,
amino, C1-C6 alkylamino, di(C1-C6)alkylamino or di-
(C1-C6)alkylamino(C1-C6)a1kyl, halo or oxo;
(b) phenyl optionally substituted by 1-3 halo, C1-C6
alkoxy, C1-C6 alkyl, carboxy, amino, C1-C6 alkylamino or
di(C1-C6)alkylamino groups;
(c) heterocyclyl or heterocyclylalkyl wherein the hetero-
cyclic moiety is a 4-6 membered ring having 1-3 hetero
atoms selected from O, N and S and the alkyl moiety has
1-6 carbon atoms, said heterocyclyl or heterocyclylalkyl
ring being optionally substituted by 1-3 C1-C6 alkyl or
C1-C6 alkoxy groups; or
(d) heteroaryl or heteroaralkyl wherein the heterocyclic
moiety is a 5-6 membered aromatic ring having 1-3 hetero
atoms selected from O, N and S and the alkyl moiety has
1-6 carbon atoms, said heteroaryl or heteroaralkyl ring
being optionally substituted by 1-3 C1-C6 alkyl, C1-C6
alkoxy, carboxy, carboxy(C1-C6)alkyl, amino, C1-C6 alkyl-
amino, di(C1-C6)alkylamino, amino(C1-C6)alkyl or di(C1-C6)-
alkylamino(C1-C6)alkyl groups; or wherein R and R
taken together with the
S?
to which they are attached represent a 4-6 member sulfur-
containing heterocyclic ring containing 0-2 double bonds
and 0-2 additional heteroatoms selected from O, N and 5,
said ring being attached to A through a sulfur atom,
thereby forming a sulfonium group, said heterocyclic ring
being optionally substituted by 1-3 substituents
independently selected from:
88

C1-C6 alkyl optionally substituted by 1-3 hydroxy,
C1-C6 alkoxy, carboxy, halo, amino, C1-C6 alkylamino
or di(C1-C6)alkylamino groups, hydroxy, C1-C6 alkoxy,
C1-C6 alkanoyloxy, amino, C1-C6 alkylamino, di(C1-C6)-
alkylamino, C1-C6 alkanoylamino, carboxy, C1-C6 alkoxy-
carbonyl, halo, oxo or phenyl; or wherein said hetero-
cyclic ring
< IMG >
is fused to a C5-C6 carbocyclic ring, a phenyl ring,
a 5-6 member heterocyclic ring or a 5-6 member hetero-
aryl ring, all of which rings may be optionally sub-
stituted by 1-3 of the substituents referred to above
for the
< IMG >
ring; or a pharmaceutically acceptable salt thereof,
whenever prepared by the process of claim 1 or by an
obvious chemical equivalent thereof.
25. A compound according to Claim 24 wherein R1 is hydrogen,
CH3CH2- ,
< IMG >
whenever prepared by the process of claim 4 or by an obvious
chemical equivalent thereof.
26. A compound according to Claim 24 wherein R1 and R8 taken
together represent
< IMG >
whenever prepared by the process of claim 5 or by an obvious
chemical equivalent thereof.
89

27. A compound according to Claim 24 wherein R1 is
< IMG >
whenever prepared by the process of claim 6 or by an obvious
chemical equivalent thereof.
28. A compound according to Claim 24 wherein R1 is
< IMG >
and the absolute configuration is 5R, 6S, 8R,
whenever prepared by the process of claim 7 or by an obvious
chemical equivalent thereof.
29. A compound according to Claim 24, wherein A is -CH2CH2-,
whenever prepared by the process of claim 8 or by an obvious
chemical equivalent thereof.
30. A compound of the formula
< IMG >
wherein R8 is hydrogen and R1 is selected from the group
consisting of hydrogen;
alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms;
cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in
the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl
moiety is phenyl and the aliphatic portion has 1-6 carbon
atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-
cyclylalkyl wherein the hetero atom or atoms in the above-
named heterocyclic moieties are selected from the group con-
sisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl
moieties associated with said heterocyclic moieties have 1-6
carbon atoms; wherein the substituent or substituents relative
to the above-named radicals are independently selected from the
group consisting of

C1-C6 alkyl optionally substituted by
amino, halo, hydroxy or carboxyl
halo
< IMG >
91

< IMG >
wherein, relative to the above-named substituents, the groups
R3 and R4 are independently selected from hydrogen; alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl,
cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms
in the cycloalkyl ring and 1-6 carbon atoms in the alkyl
moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein
the aryl moiety is phenyl and the aliphatic portion has 1-6
carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl
and heterocyclylalkyl wherein the hetero atom or atoms in the
above-named heterocyclic moieties are selected from the group
consisting of 1-4 oxygen, nitrogen or sulfur atoms and the
alkyl moieties associated with said heterocyclic moieties have
1-6 carbon atoms, or R3 and R4 taken together with the nitrogen
to which at least one is attached may form a 5-or 6-membered
nitrogen-containing heterocyclic ring; R9 is as defined for R3
except that it may not be hydrogen; or wherein R1 and R taken
together represent C2-C10 alkylidene or C2-C10 alkylidene
substituted by hydroxy; A is C2-C5 straight or branched chain
alkylene; R2 is hydrogen, an anionic charge or a conventional
readily removable carboxyl protecting group, providing that
when R2 is hydrogen or a protecting group, there is also present
a counter anion, and R10 and R11 each independently represents
C1-C6 alkyl; or wherein R10 and R11 taken together with the
< IMG >
to which they are attached represent
< IMG >
a pharmaceutically acceptable salt thereof.
whenever prepared by the process of claim 9 or by an obvious
chemical equivalent thereof.
92

31. A compound according to Claim 30 wherein R1 is hydrogen
CH3CH2-,
< IMG > , < IMG > or < IMG >
whenever prepared by the process of claim 10 or by an obvious
chemical equivalent thereof.
32. A compound according to Claim 30 wherein R1 and R8 taken
together represent
< IMG > ,
whenever prepared by the process of claim 11 or by an obvious
chemical equivalent thereof.
33. A compound according to Claim 30 wherein R1 is
< IMG > ,
whenever prepared by the process of claim 12 or by an obvious
chemical equivalent thereof.
34. A compound according to Claim 30 wherein R is
< IMG >
and the absolute configuration is 5R, 6S, 8R,
whenever prepared by the process of claim 13 or by an obvious
chemical equivalent thereof.
35. A compound according to Claim 30, wherein A is -CH2CH2-,
whenever prepared by the process of claim 14 or by an obvious
chemical equivalent thereof.

36. A compound of the formula
< IMG >
wherein R8 is hydrogen and R1 is selected from the group
consisting of hydrogen;
alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms;
cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in
the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl
moiety is phenyl and the aliphatic portion has 1-6 carbon
atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-
cyclylalkyl wherein the hetero atom ox atoms in the above-
named heterocyclic moieties are selected from the group con-
sisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl
moieties associated with said heterocyclic moieties have 1-6
carbon atoms; wherein the substituent or substituents relative
to the above-named radicals are independently selected from the
group consisting of
94

C1-C6; alkyl optionally substituted by
amino, halo, hydroxy or carboxyl
halo
< IMG >

< IMG >
wherein, relative to the above-named substituents, the groups
R3 and R4 are independently selected from hydrogen; alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl,
cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms
in the cycloalkyl ring and 1-6 carbon atoms in the alkyl
moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein
the aryl moiety is phenyl And the aliphatic portion has 1-6
carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl
and heterocyclylalkyl wherein the hetero atom or atoms in the
above-named heterocyclic moieties are selected from the group
consisting of 1-4 oxygen, nitrogen or sulfur atoms and the
alkyl moieties associated with said heterocyclic moieties have
1-6 carbon atoms, or R3 and R4 taken together with the nitrogen
to which at least one is attached may form a 5-or 6-membered
nitrogen-containing heterocyclic ring; R9 is as defined for R3
except that it may not be hydrogen; or wherein R1 and R8 taken
together represent C2-C10 alkylidene or C2-C10 alkylidene
substituted by hydroxy; A is C2-C6 straight or branched chain
alkylene; R2 is hydrogen, an anionic charge or a conventional
readily removable carboxyl protecting group, providing that
when R2 is hydrogen or a protecting group, there is also present
a counter anion; and R10 and R11 taken together with the
S?
to which they are attached represent
< IMG > ;
or a pharmaceutically acceptable salt thereof,
whenever prepared by the process of claim 15 or by an obvious
chemical equivalent thereof.
96

37. A compound according to Claim 36 wherein R1 hydrogen,
CH3CH2-,
< IMG >, < IMG > or < IMG > ,
whenever prepared by the process of claim 16 or by an obvious
chemical equivalent thereof.
38. A compound according to Claim 36 wherein R1 and R8
taken together represent
< IMG > ,
whenever prepared by the process of claim 17 or by an obvious
chemical equivalent thereof.
39. A compound according to Claim 36 wherein R1 is
< IMG >,
whenever prepared by the process of claim 18 or by an obvious
chemical equivalent thereof.
40. A compound according to Claim 36 wherein R1 is
< IMG >
and the absolute configuration is 5R, 6S, 8R,
whenever prepared by the process of claim 19 or by an obvious
chemical equivalent thereof.
41. A compound according to Claim 36 wherein A is -CH2CH2-,
whenever prepared by the process of claim 20 or by an obvious
chemical equivalent thereof.
97

42. A compound of the formula
< IMG >
wherein R2 is hydrogen, an anionic charge or a conventional
readily removable carboxyl protecting group, providing that
when R2 is hydrogen or a protecting group, there is also present
a counter anion, or a pharmaceutically acceptable salt thereof,
whenever prepared by the process of claim 21 or by an obvious
chemical equivalent thereof.
43. The compound according to Claim 19 wherein R2 is
p-nitrobenzyl, whenever prepared by the process of claim 22
or by an obvious chemical equivalent thereof.
44. The compound according to Claim 19 wherein R2 is
an anionic charge, whenever prepared by the process of claim 23
or by an obvious chemical equivalent thereof.
98

Description

t ~ 4`~
~ACKGROUND OF THE INVENTION
1 Field of the Invention
The present invention is directed to new carbapenem
antib;otics in which the 2-substituent has the formula
~R10
---S--A~S Rll
wherein A is C2-C6 straight or branched chain al~ylene and
R10 and Rll each independently represent optionally substituted
aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl,
heterocyclyl, heterocyclyl-aliphatic, heteroaryl or heteroar-
aliphatic radicals, or R10 and Rll when taXen together with
the ~
s
to which they are attached represent an optionally substituted
sulfur-containing heterocyclic ring.
2. Description of the Prior Art
A number of B-lactam derivatives containing the carba-
penem nucleus
have been disclose~ in the literature~ These carbapenem
deri~atives have been reported to possess utility as anti-
bacterial agents and/or B-lactamase inhibitors.
The initial carbapenem compounds were natural products
such as thienamycin of the formula

o
OH
SC~2~H2N~2
~ N COOH
obtained by fermentation of Streptomy~es catt~ 5U.S.
Patent 3,950,357). Thienamycin is an exceptionally potent
broad-spectrum antibiotic which possesses notable activity
against various P5eU~QmOnaS species, organisms which have
been notoriously resistant to B-lactam antibiotics.
Other nat~ral prod~cts containing the carbapenem
nucleus include olivanic acid derivatives such as antibiotic
MM 13902 of the formula
CH~
Ho3so~ ``l - ~c5cH=cHNH~ocH3
O ~ COOH
disclosed in U.S. Patent 4,113,856, antibiotic MM 17880 of the
formula
CH3
HO3 ~ CH2cH2NHcoc~3
O COOH
disclosed in U.S. Patent 4,162,304, antibiotic MM 4550A of the
formula
CH o
~ ~ S-CH=CHNHCOCH3
HO3
~ N --COOH
disclosed in U.S. Patent 4,172,129 and antibiotic 890A of the
formula

CH3
/\ ~ =CHNHCCH 3
H0350 _~
0~ N COOH
disclosed in U.S~ Patent 4,264 r 735. In addition to the
natural products, the cGmpound desacetyl 890~1~ of the ormula
CH3
H03 ~ CH2cH2NH2
O N COOH
is disclosed in U.S. Patent 4,264,734 as being prepared by an
enzymatic dea~ylation of the corresponding N-acetyl compound.
Various derivati~es of the naturally-occurring olivanic acids
have also been synthesized, e.g. the compounds of the formula
~2~ () ~ HCOCH3
O N C2Rl
wherein C02R1 is a free, salted or ester~fied carboxyl gro~p,
n is O or 1 and R2 is ~, an acyl gro-lp or a group of the
formula R303S wherein R3 is a salting ion or a methyl or ethyl
group, disclosed in European Patent Application 8885.
U.S. Patent 4,235,922 (see also European Patent Application
2058) discloses the car~apenem derivative of the formula
~; !; CH 2 CH 2N~ 2
00~

~8~ ~
while ~.X. Patent Application 1,598,Q52 reports isolation of
the compound
SCH2CH2NHCOt:H3
~~~ N COO~
from a St~ myces fermentation broth.
Carbapenems which are unsubstituted in the 6-position
have also been synthesized. Thus, U.S~ Patent 4,210,661 dis-
closes compounds of the formula
~S-R2
O N COOH
wherein R2 is phenyl or substituted phenyl, U.S. Patent 4,267,177
discloses compounds of the formula
S-Rl
FN ~L
COOH
wherein Rl is an optionally substituted pyridyl group~ U.S.
Patent 4,25S,441 discloses compounds of the formula
f ~--CR2=CR3R4
. 11
0~~~ N COOH

wherein R2 and ~3 are ~ or alkyl ana R~ is NH-CO~R6 in which
R~ is alkyl, phenyl or substituted phenyl and n i~ 1 or 2,
and U.S. Patent 4,282,236 discloses compounds of the formula
F~ H=CRlR2
N ooH
wherein Rl is H or alkyl and R2 is CN or C02R3 in which R3 is
H, alkyl, aryl or aralkyl.
Carbapenems of the general formula
~ ~S R8
~ N l_
O ~OOH
wherein Rl is H or acyl and R8 is H or substituted or unsub-
stituted: alkyl, alkenyl, alkynyl, cycloal~yl, cycloalkylalkyl,
alkylcycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl,
heteroaralkyl, heterocyclyl or heterocyclylalkyl, are disclosed
in V.S. Patent 4,218, 463. There is no disclosure of any ~8
substituents of the type
. ~3
A- S
in which A is aIkylene.

8~L~0
The natural product thienzmycin has the absolute
configuration SR, 6S, 8R. This isomer, as well as the re-
maining seven thienamycin isomers, may be obtained vLa total
synthesis as disclosed in U.S. Patent 4,234,596. Total synthesis
procedures for thienamycin are also disclosed, for example,
in U.S. Patents 4,287,123, 4,2b9,772, 4,282,148, 4,273,709,
4,290,947 and European Patent Application 7973. A key inter-
mediate in the disclosed synthetic methods is
OH
N CO2PNB
wherein pNB represents p-nitrobenzyl.
Because of the exceptional biological activity of thiena-
mycin, a large number of derivatives have been prepared and
disclosed in the literature. Among these are (1) N-formimidoyl
thienamycin of the formula
OH
SCH2CH2N=I NH2
N coOH
disclosed in European Patent Application 6639; (2) N-heterocyclic
derivatives of thier~amycin having the formula

.`. ~^L~
-- 8 --
OH
i ~ r ~ ~ \ SCH2~H~N ~Cl2)~
COOH Rl
lp
OH and
SCH2C1~2N~B )
wherein: the bifunctional ring may contain additional unsaturation
in the ring; and wherein n is an integer selected ~rom 1-6;
p is O, 1 or 2; Rl is Hy alkyl or aryl; and Z is imino, oxo,
H, ~mino or alkyl, disclosed in U.S. Patent 4,189,493; (3)
substituted N-methylene derivati~es of thienamycin having the
formula OH
~F'~SC~l2cH2N=~-x
N COO~
wherein X and Y are H, R, OR, SR or NRlR2 in which R is substitu~ed
vr unsubsti~uted: alkyl, alkenyl, alXynyl, cycloalkyl, cyclo-
alkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hetexo-
cyclyl or heterocyclylalkyl ~ and Rl and R2 are H or R, disclosed
in ~5. Patent 4 t 194,047; (4) compounds of the formula

_ 9 _
OR
. ,~SC~2C~;~NR
11
N --COOH
wherein R3 is aryl, alkyl ~ a ::yl or aralkyl and Rl and R2
are independently selected from H a~d acyl ( including acyl
of the type
-C~Rl in which Rll may inter alia
be alkyl substituted by a quaternary ammonium group, e . g .
~C-CH2~
disclosed in U. 5 . Patent 4, 226, 870; ( 5) compounds of the
f orlr.ula oR3
SCH2CH2NR R
O COOB
wherein R3 i5 H, acyl or a~ uni~ralent optionally substituted
hydrocarl~on radical; R is optional}.y substituted alkyl, alkenyl,
alXynylO cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cyclo-
alkylalkyl, aryl, aralXyl, heteroa~l or heteroaralkyl and
is acyl (including acyl of the type
-C-R in which R is alkyl substituted
~y a ~uaternary aTrunoniuin g~OuE~, e. 9.
~ CH2 N~
disclosed in U.K. Paten~ 1,604,276 (see also U.S. Patent
4,235,917); (63 Compounds of the formula

~8~ ~
OH
ScH2cH2NR R R
~ N CO ~
wherein R5, R6 and R7 are independen~ly selected from H and sub-
stituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl,
heteroaryl or hetexoaralkyl, are disclosed in V.S. Patent
4,235,920; (7) compounds of the formula
oR3 1~.5 63
\ C~ CH N-C-NRlR2 A~3
COX
wherein each of Rl and R2, independently of the other, is a
radical of the type defined for R, a hydrogen atom, or a nitro,
hydroxyl, Cl 6 alkoxyl, amino, Cl 6 alkylamino, di(Cl 6 alkyl3-
ami~o or tri(Cl 6 alkylamino) radical, an extra anion being
present in the latter case; or R and R are joined together
to form, together with the nitrogen atom to which they are
attached, a substituted or unsubstituted monocyclic or ~icyclic
heteroaryl or heterocyclyl residue containing 4-10 ring atoms,
one or more of which may ~e an additional hetero atom selected
from oxygen, sulphur and nitrogen; R is a cyano group or a
substituted or unsu~stituted carbamoyl, carboxyl, (Cl 10 alkoxy)-
carbonyl, Cl_10 alkyl, C2_10 alkenYl~ C2-10 alkYnYl~ C3 10 cyclo-
alkyl, C4 1~ cycloalXylalkyl, C5 12 cycloalkylalXenyl, C3 10
cycloal~enyl, C5 12 cycloalkenylalkenyl, C4 12 cycloaIkenylalkyl,
C6_10 aryl~ C7_16 aralkyl, C8_16 aralkenyl, C8_16 aralkynyl or
monocyclic or bicyclic heteroaryl, heteroaralkyl, heterocyclyl
or heterocyclylalkyl ~omprising 4 to 10 ring atoms one or more
of which is a hetero atom selected from oxygen, sulphur and
nitrogen and in which the alkyl residue of the hetesoaralkyl or
hetero~yclylalkyl radical contains from 1 to 6 carbon atoms;
the substituent or substituents on R, R , R or on the ring

~ ~84 ~
1 2
formed by joining R and R are chlorine; bromine; iodine;
fluorine; azido~ Cl_4 alXyl; mercapto; s~lpho; phosphono; cyanO-
thio (-5CN); nitro; cyano; amino; hydrazin; amino or hydrazino
havi~g up to three Cl 6 alkyl substituents hydroxy; Cl 6 alkoxy;
Cl 6 alXylthio; carboxyl; oxo; ~Cl ~ alkoxy)carbonyl; C2_10 acyloxy
carbamoyl; ~Cl_4 alkyl) carbamoyl or di(Cl 4 alkyl) carbamoyl;
R3 is a hydrogen atom, an acyl raaical or a radical of the type
defined for R; R is Cl 10 alkyl; substitutea carbonylmethyl;
Cl_6 alkXY) ~ (Cl_6 alkyl), (C3_6 cycloalkoxy) - (Cl_6 alkyl);
C2 12 alkanoyloxyaIkyl; partially or completely halogenated
C 6 aIkyl in which the halogen(s) is/are chlorine, bromine or
1--
fluorine; aminoa~Xyl; C2_10 al~enyl; C2_ 10 a lkyny 1; acyl; C3_14
alkoxycarbonylalkyl; C4_21 dialkylaminoaceto~yalkyl; C2 13
alkanoylaminoalkyl; ar-(Cl 3 alkyl) in which the aryl residue
contains from 6 to 10 carbon atoms; monocyclic or bicyclic
heteroaraIkyl or heterocyclylaIkyl containing 4 to 10 ring atoms,
1 to ~ carbon atoms in the alkyl residue, and 1-4 hetero atoms
selected from oxygen, sulphur and/or nitrogen; nuclear-substituted
araIkyl or heteroaralkyl in which the substituent is chlorine,
fluorine, bromine, iodine or Cl 6 alXyl; aryl or nuclear-sub-
stit~ted aryl containing 6 to 10 ring carbon atoms and in which
any nuclear substituent is hydroxy, Cl 6 alkyl, chlorine, fluorine
or bromine; aralkoxyalkyl; C2 12 alkylthioal~yl; C4 12 cyclo-
aIkyl~hioaIkyl; (C2_10 acylthio)-(Cl_6 a kyl); or phenylalkenyl
in which alkenyl has 2-6 carbon atoms; R is substituted or un-
Cl_10 alkyl; C2_l0 aIkenyl or al~ynyl; ring substi-
. tuted and unsubstitutea cycloalkyl, cycloalXenyl, cycloalkenyl- alkyl, and cycloalkyl-a~kyl having 3-6 ring carbon atoms and
up to 6 carbon atoms in any chain; C6 10 aryl; araIkyl having
6-10 ring carbon atcms and 1-6 carbon atoms in the aIkyl chain;
monocyclic or bicyclic heteroaryl or heteroaralXyl containing
4-10 ring atoms, one or more of which is oxygen, nitrogen or
sulphur, and 1-6 carbon atoms in the alkyl chain; and the rinS
or chain substituent(s) is/are chlorine, bromine, iodine,
fluorine, aziao, cyano, amino, Cl_6 alXy`lamino, di(Cl 6 aIkyl)_
amino or tri (Cl_6 alkylamino) radical, an e~ctra anion being
present in the latter case, hydroxy, Cl 6 alkoxy, Cl 6 alkyl-

3~9~
-- 12 --
thioalkyl; carboxyl; oxo, (C~. 6 alkoxy) carbonyl; C2 10
acyloxy; carbamoyl; (Cl 4 alkyl) carbamoyl; di (Cl_4 alkyl~ -
carbamoyl; cyanothio (-SCN) or nitro; ~6 is hydrogen, hydroxy,
mercapto, ~, -OR, -SR or NRlR~, where R, Rl and R2 are as
defined above;
X is hydroxy, mercapto, ami no, acyloxy -oR4, -sR4,
-NHR4, -~-R4,
~4
-OM, -OQ or, when the compound is in zwitterionic form, -O ,
in which case A is absent;
A, when the compound is not in zwitterionic form, is
a counter ion;
M is a pharmaceutically acceptable cation; and
Q is a blocking group as herein defined, are disclosed in
.K. Patent 1,604,275; and (8) compounds of the form~la
~H
H2cH2NH--
N CO
O
wherein ~l
attached to the amino nitrogen group of thienamycin represents
a mono- or polycyclic N-containing heterocyclic group and R is
H, substitutea or unsu~stituted: alkyl, aryl, alkenyl, hetero-
cyclylaIkenyl, aralkenyl, heterocyclylalkyl, aralkyl, -NR2,
COOR, CONR2, -OR, or CN, are disclosed in European Patent Appli-
ca~ion 210a2. Among the compounds disclosed in U.S. Patent
4,235,9~0 is

84 ~)
- 13 -
CH2N(C~3~¦ A
N
COOH
wherein A is a pharmaceutically acceptable anion- The above-
mentioned quAternary amine derivative is also described in
Recent Advances in the ChemistrY of B-~a~tam Antibiotics, Royal
Society of Chemistry, ~ondon, 1981, pg 240-2S4, where its anti-
bac~erial acti~ity on average is reported as approximately 1/2
to 2/3 that of thienamycin.
Applicants are aware of no literature disclosing carba-
penem derivatives of the present invention having a 2-substituent
of the type
- S - A-S ~ ,
although there are se~eral recent patent references which, in
their broadest disclosure, maY generically include such compounds.
Thus, for example, European Patent Application 40408 discloses
compounds of the foDmula
3 ~ SR
0~~~ N COOH
wherein Rl is H, methyl or hydroxyl and R51 is a monovalent
organic group incluaing inter alia substituted alkyl or a group
of the formula -CH2R7 in which ~ is an optionally substituted
5- or 6-membered heterocyclic group; t2) European ~atent Appli-
cation 38869 discloses compounds o~ the formula

Ba~10
- R~ i ~ il
N - ~ ~
wherein R6, R7, and R8 are independently selected from the
group consistlng of hydrogen, substituted and unsubstituted:
alXyl, alkenyl, and alkynyl, having from 1-10 carbon atoms;
cycloalkyl~ cycloalkylalkyl, and alkylcycloalkyl, having 3-6
caxbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the
alkyl moieties; aryl, such as phenyl; aralkyl, aralkenyl, and
aralkynyl wherein the aryl moeity is phenyl and the aliphatic
portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl,
heterocyclyl and heterocyclylalkyl; wh~rein the substituent or
substituents relative to the above-named radicals are selected
from the group consisting of:
-X~ halo (chloro, bromo, fluoro~
-OH hydroxy
_9Rl alkoxy, aryloxy
-OCNR R carbamoyloxy
-CNRlR carbamoyl
-NRlR2 amino
NRl
4 ~idino
\ NlE~.lR2
Rl -
-NO~ nitro
~ 1
-N(Rl)3 tri-substituted amino (R group
independently chosen)

~8~ ~
-C=NOR oximino
-S~ alkyl- and arylthio
-S02NRlR sulfonamldo
-NHCNRlR2 ureido
O
RlCNR - amido
-C02~ carboxy
- 02R carboxylate
_~Rl a~yl
~1
-O R acyloxy
-SH mercapto
O
_5Rl alXyl and aryl sulfinyl
-~Rl alkyl and aryl sulfonyl
O
--CN cy ano
-N3 azido
wherein, relative to the above listed substituents on R6, R ,
and R8, the g-oups Rl and R2 are independently selected from:
hydrogen, alkyl, alkenyl, and alkynyl, having from 1-10 carbon
atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloaIkyl, having
3-6 carbon atoms in the cy~loal~yl ring and 1-6 carbon atoms
in the alkyl moieties; aryl, such as phenyl; araIkyl, aralkenyl,
and aralkynyl wherein the aryl moiety is ~henyl ana the aliphatic
portion has 1-6 carbon atoms; heteroaryl, heteroaraIkyl, hetero-
cyclyl and heterocyclylalkyl and wherein the hetero atom or atoms
in the above-namea heter~cyclic moieties are selectea from t~e

., " 119~
- 16 -
~roup consisting of 1-4 oxygen, nitrogen or sulphur atoms
and wherein the al~yl moieties associated with said hetero-
cyclic moietie~ have 1-6 carbo~ atoms. (See also European
Patent Applications 1627, 1628~ 10317, 17992, 37080, 37081
and 37Q82)t ~4) European Patent Application 24832 discloses
~ompounds of the formula
Rl
C~3-CaF~CSRl2
. N CO2H
wherein Rl is ~ or a group selected from OH, OSO ~ or a
salt or C~ 4 alkyl ester thereof, oR2, sR3, OCOR~, oCO2R3
or OCONHR , where R is a Cl 6 alkyl group or an optionally
substituted benzyl group and R is a Cl 6 alkyl group or an
! optionally substituted benzyl or phenyl group and R12 is
Cl 6 al~yl, C2 6 alkenyl, C3 6 alXynyl wherein the triple
bond is not present ~n the carbon adjacent to the sulfur
atom, aralkyl, Cl 5 alkanoyl, aralkanoyl, aryloxyalkanoyl
or arylcarbonyl, any of such ~12 groups being optionally
substituted, as antibacterial agents.
European Patent Application 38,869 mentioned above
discloses synthesis of the carbapenem derivatives via inter-
mediates of the general formula
R
R6~0
N ~ O2R2'
o
wherein R6 and R7 are as defined above and R2 is a readily
removable carboxyl ~rotecting group. Also disclosed
as intermediates are compounds of the formula

-- 17 -
~N 3
~02R
wherein X is described as a leaving group~
While, as in~icated above, the ~rior art has described
car~apenem derivatives having a 2-substituen~ of the type
-~ - A-N ~
and derivatives having a 2 substituent of the type
- S ~ A-S - Rl
where Rl is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
~ycloalkylalkyl, alkyl~yc~oalkyl, phenyl, aralkyl, aralkenyl,
aralkynyl, heteroaryl, heteroaralkyl, heterocyclyl or hetero-
cyclylalkyl, there has been no disclosure of which applicants
are aware tPaching carbapenems having a 2-substituent wherein
the aIkylene yroup A is attached directly to a sulfonium group,
i . e . a group of the type
:: - S A-S ~
., .
Despite the vast number of car~apenem derivatives dis-
closed i~ the literature, there is still a need for new carba-
penems since kn~wn derivatives may be improved upon in terms
of spectrum of activity, potency, stability and/or toxic side
effects.

- ~8
SUMMARY OF THE INV~NTIO~
.
The present i~ention provides a novel series of
carbapene~ derivati~es characteriæed by a 2-substituent
of the formula
,10
-S - A - S
~Rll
wherein A i5 C2-~6 straight or branched chain alkylene and
R10 and Rll each independently represent optionally sub-
stituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,
a~yl, heterocyclyl, heterocyclyl-aliphatic, heteroaryl or
heteroaraliphatic radicals, or R10 and Rll when taken together
with the ~
to which they are attached represent an optionally s~bstituted
sulfur-containing heterocyclic ring containing 0-2 double bonds
and 0-2 additional heteroatoms selected from O, N and S, said
ring ~eing attached to A through a sulfur atom, thereby form-
ing a sulfonium group. More specifically, the present invention
provides car~apenem deri~atives of the formula
R8 H ~ R10
Rl ~ S -A -S ~ Rll
N ~ ooR2
wherein RB is hydrogen and Rl is selected from the group
consisting of hydrogen; su~stituted and unsubstituted:
alkyl, alXenyl and al~ynyl, having ~rom 1-~0 car~on atoms;

~1~84a~
~ 19 --
cyctoalkyl and cyctoal3c~1alkyl, having 3-6 carbon atoms in
the cycloalXyl ring ana 1-6 carbon atoms in the alkyl moietie~;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl
moiety is phenyl and the aliphatic portion has 1-6 carbon
atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-
cyclylalkyl wherein the hetero atom or atoms in the above-
named heterocyclic moietieS are selected from the group con-
sisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl
moieties associated with s2id heterocyclic moieties have 1-6.
carbon atoms; wherein the substituent or substituents relative
to the above-named radicals are independently selecte~ from
the group consisting of
Cl-C6 alkyl optionally substituted by
amino, halo, hydroxy or carboxyl
halo
--oR3
O
--OCNR R
--CNR R
--NR3 R
NR
\N R R
--SO;~NR R
--NHcNR3R
R CNR --
--Co2R3
=O
. .

0
~ 20 ~
f~ 3
-OCR
sR3
~I g
--SR.
O,
--CN
N3
-OSO3R
-oso2R3
--N R S C)2R
NR3f=NR
R3
-NR3Co2R4
-N02
wherein, relative to the above-named substituents, the groups
R3 ana R4 are independently selected from hydrogen; alkyl,
alkenyl and aIky~yl, having from 1-10 carbon atoms; cycloalkyl,
cycloaIkylalkyl and alkylcycloaIkyl, having 3-6 car~on atoms
in the cycloalkyl ring and 1-6 carbon atoms in the al~yl
moieties; ph~nyl; aralXyl~ aralkenyl and aralkynyl wherein
the aryl moiety is phenyl and the aliphatic portion has 1-6
carbon atoms; and heteroaryl~ heteroaralkyl, heterocyclyl
and heterocyclylaIkyl wherein the hetero atom or atoms in the
a~ove-named heterocyclic moieties are selected from the group
consisting of 1-4 oxygen, nitrogen or sulfur atoms and the
alkyl moieties associated with said heterocyclic moieties have
1-6 car~on atoms t or R3 and R4 taken toqether with the nitrogen
to which at least one is attached may form a S-or 6-membered
nitroge~-containing heterocyclic ring; R9 is as defined for R

0
- 21 -
except that it may not be hydrogen; or wherein Rl an~ x8 taken
together represent C2-C10 alkylidene or C2-C10 al~yliden~
substituted by hydroxy; A is C2-C6 straight or ~ranched chain
alkylene; R2 is hyarogen, an anionic charge or a conventional
readily removable carboxyl protecting group, providing that
when R2 is hydrogen or a protecting group, there is also present
a counter anion, and R10 and Rll each independently represents
~a3 Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cyclo-
alkyl or cycloalXylalkyl having 3-6 carbon atoms i~ the
cycloalXyl ring and 1-6 oarbon atoms in the al~yl moiety,
said alkyl, alkenyl, al~ynyl, cycloalkyl or cycloalkyl-
alXyl group being optionally substituted by 1-3 substituents
independently selected from hydroxy, Cl-C6 alkoxy,
Cl-C6 alkanoyloxy, carboxy, Cl-C6 alkoxycarbonyl,
amino, Cl-C6 alkylamino, di(Cl-C6)al~ylamin, Cl-C6
alkanoylamino, phenyl, phenyl substituted by 1-3 halo,
Cl-C6 alkoxy, Cl-C6 alkyl, carboxy, carboxy(Cl-C6)alkyl,
amino, Cl-C6 alkylamino, di(Cl-C6)alkylamino or di-
~Cl-C6)alkylamino(Cl-C6)alkyl, halo or oxo;
(b) phenyl optionally substituted by 1-3 halo, Cl-C6
alkoxy, Cl-C6 alkyl, carboxy, amino, Cl-C6 ~lkylamino or
di(cl-c6)alkylamino groups;
~c) heterocyclyl or heterocyclylalXyl wherein the hetero-
cyclic moiety is a 4-6 membered ring havin~ 1-3 hetero
atoms selected from O, N and S and the alkyl moiety has
1-6 carbon atoms, said heterocyclyl or heterocyclylalkyl
ring being optionally substituted by 1-3 Cl-C6 alkyl or
Cl-C6 alkoxy groups; or
~d) heteroaryl or heteroaralkyl wherein the heterocyclic
moiety is a 5-6 membered aromatic ring having 1-3 hetero
atoms selected from O, N an~ S and the alkyl moiety has
1-6 caxbon atoms, said heteroaryl or heteroaralkyl ring
being optionally substituted by 1-3 Cl-C6 alkyl, Cl-C6
alkoxy, carboxy, carboxy(Cl-C6)al~yl, amino, Cl-C6 alkyl-

1 3..~B4~0
- 2~ -
amino, di(Cl-C6)al~ylamino, amino~Cl-C6)alkyl or di(Cl-C~)-
alkylamino(Cl-C~al~yl groups; or wherein R and R l
taken together with the
~3
S
to which they are attached represent a 4-6 member sulfur-
containing heterocyclic ring containing 0-2 double bonds
and 0-2 additional heteroatoms selected from O, N and S,
said rin~ being attached to A through a sulfur atom,
thereby forming a sulfonium group, said heterocyclic ring
being optionally substitu~ed by 1-3 substituents
independently selected from:
Cl-C6 alkyl optionally substituted by 1-3 hydroxy,
Cl-C6 alkoxy, carboxy, halo, amino, Cl-C6 alkylamino
or di ~Cl-C6)alkylamino groups, hydroxy, Cl-C6 alkoxy,
Cl-C6 alkanoyloxy, amino, Cl-C6 alkylamino, di(Cl-C6)-
alkylamino, Cl-C6 alkanoylamino, carboxy, Cl-C6 alkoxy-
carbonyl, halo, oxo or phenyl; or wherein said hetero-
cyclic ring ~3
is fused to a C5-C6 czrbocyclic ring, a phenyl ring,
a 5-6 member heterocyclic ring or a 5-6 member hetero-
aryl ring, all of which rings may be optionally sub-
stitute~ by 1-3 of the substituents referred to above
: for the
~10_S--Rll .
ring; and pharmaceutically acceptable salts thereof.
The compounds of formula I are potent antibacterial agents or
intermediates useful in the preparation of such agents,
- ~lso includ~d in the invention are processes for preparlng
the novel carbapenem derivatives described above and pharmaceutical
compositions containing the biologically active carbapenem
derivatiYes in combination with pharmaceutically acceptable carriers
or dilue~t .
;

- 23
DETAI LED DXS CR3:PTI ON
____~
The novel compounds of general formula I above contain
the carbapenem nucleus
~~
. .
and may thus be named as l-carba-2-penem-3-carboxylic acid
derivatives. Alternatively, the co~pounds may be considered
to have the basic structure
6 ~ 3
ll
~ 7 N 1
0
and named as 7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylic
acid derivatives. While th2 present invention includes com-
pounds wherein the relative stereochemistry of the 5,6-protons
is c~s as well as trans, the preferred compounds have the
SR,6S ltrans) stereochemistry as in the case of thienamycin.
The compounds of formula I may be unsubstitutea in
the 6-position or substituted by substituent groups previously
disclosed for other carbapenem derivatives. More specifically,
R8 may be hydrogen and Rl may be hydrogen or a non-hydrogen
substituent disclosed, for example, in European Patent Application
38,869 (see definit;on of R6). Alternatively, R8 and Rl taken
together may be C2-C10 alkylidene or C2-C10 alkylidene substituted,
for ~xampls, by hydroxy.
To elaborate on the definitions for ~1 and R8:
(a) The aliphatic ~alkyl~, "alkenyl~ and "alkynyl~ groups
may be straight or branched chain having 1-10 carbon atoms;
preferrea are 1-6, most preferably 1-4, carbon atoms; when
part of another substituent, e.g. as in cycloalkylalkyl, or

~984
-- 24 --
.
heteroaral~yl or aralXenyl, the alkyl, alkenyl and al~ynyl
group preferably contains 1-6, most preferably 1-4, carbon
atoms.
(b) "heteroaryl~ includes mono-, bi- and polycyclic
aromatic heterocyclic groups containing 1-4 0, N or S a oms;
preferred are 5- or 6-memberea heterocyclic rings such as
thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, iso-
thiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl,
oxazolyl, pyridyl, pyrazinyl, pyrimiainyl, pyridazinyl,
pyrrolyl, pyrazolyl, etc.
(c) ~heterocyclyl" includes mono-, ~i- and polycyclic
saturated or unsaturatea non-aromatic heterocyclic groups
containing 1-4 0, N or S atoms; preferred are 5- or 6-membered
heterocyclic rings such as morpholinyl, piperazinyl, piperidyl,
pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
pyrrolinyl, pyrrolidinyl, etc.
(d) "halo" (used also to define RlO and Rll) incluaes
chloro, bromo, fluoro and iodo and is preferably chloro or
bromc.
The term ~conventional readily removable carboxyl pro-
tecting group~ refers to a ~nown ester group which has been
employed to block a carboxyl group during the chemical reaction
steps described below and which can be removed, if desired,
by methods which do not result in any appreciable destruction
of ~he remaining portion-of the molecule, e.g. by chemical
or enzymatic hydrolysis, tre~tme~t with chemical reducing
agent~ under mild conditions, irradiation with ultraYiolet
light or catalytic hydrogenation~ Examples of such ester
protec~ing groups include benzhyaryl, p-nitrobenzyl, 2-
naphthylmethyl, benzyl, trichloroethyl, silyl such as tri-
methyl~ilyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl,
4-pyridylmet~yl and Cl-C6 alkyl such as methyl, ethyl or
t-butyl. Included within such protecting groups are those

~8~0
~ 2~ ~
which are hydrolyzed under physiologic~l conditions s~ch
as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl
and methoxymethyl. . A particularly ad~rantageous car~oxyl
protecting group is p-nitrobenzyl which may be readily
removed by cat~lytic hydrogenolysis.
The pharmaceutically acceptable salts referred to
above include the nontoxic acid addition salts, e.g. salts
with mineral acids such as hydrochloric, hydrobromic,
hydroiodic, phosphoric, sulfuric, etc. and salts with
organic acids such as maleic, acetic, citric,
succinic, benzoic, tartaric, fumaric, mandelic, ascorbic,
lactic, gluconic and malic~ Compounds of formula I in the
form of acid additions sa~ts may ~e written as
Rl (3 Rl
N oOR2
R = H or protecting group
where X ~ represents the acid anion. The counter anion X ~
may be selected so as to provide pharmaceutically acceptable
salts for therapeutic administration but, in ~he oase of
intermediate eompQunds of formula ~, X ~ may also be a toxic
anion. In such a case the ion can be subsequently removed
or substituted by a pharmaceutically acceptable anion to
form an active end product for therapeutic use. When acidic
or basic groups axe present in the Rl group or on the R10
or Rll substitutents, the ~resent invention may also include
suitable base or acid salts of these functional groups, e.g.
acid addition salts in the case of a basic group and metal
salts te.g. sodium, potassium, calci~m and aluminum)~ the
ammonium salt and salts with nontox~c amines I e.g. tri-

~L9~4 ~()
-- 26 --
alkylamsnes, pr~caine, dibenzylamineO l-ephenamine, ~-benzyl-
B-phenethylamine, N,N'-dibenzylethylenediamine, etc.) i~ the
case of an acidic group.
Compounds of formula I wherein R2 is hydrogen, an
anionic charge or a physiologically hydrolyzable ester
group together with pharmaceutically acceptable salts thereof
are useful as antibacterial agents. The remaining com~ounds
of formula I are valuable intermedia~es which can be converted
into the above-mentioned ~iologically active compounds.
A preferred embodiment of the present invention com-
prises compounds of formula I wherein R8 is hydrogen and ~1
is hydrogen, CH3CH2-,
CH~ CH~ H OIH
CH-, C- or CH3CH~
CH~ CH3
Among this subclass, the preferred compounds are those in
which Rl is ~H
CH3CH-, most preferably compounds
having the absolute configuration SR, 65, 8R.
Another preferred embodiment comprises compounds of
formula I in which Rl and R8 taken together form an alkylidene
radical of the formula
HOCH
2\ C-
- CH3
The alkylene (i.e. substituent ~An) radical in the
compounds of formula I may ~e straight or branched chain
and may contain from 2 to 6 carbon atoms. A preferred embodi-
ment comprises those compounds in which A is ~(CH2)n~ in which
n is 2, 3 or 4 and a particularly preferred embodiment comprises
those compounds where A is -CX2CH2-.
- .... .
'; ' `' '

~84~(~
27 --
T~e 2-subctituent of the present compounds i~
characterized by the presence of a sulfonium group attacned
to the alkylene radical A. As indicated above, R10 and p~ll
may each independently be selected from optionally sub-
stituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic~
aryl, heterocyclyl, heterocyclyl-aliphatic, hetexoaryl or
heteroaraliphatic. Alternati~ely, the R10 and Rll substituents
when taken together with the
S ~
to which they are attached may form a 4-6 membered, optionally
substituted, sulfur-containing heterocyclic ring containing
0-2 double bonds and 0-2 addi~ional heteroatoms selected
from O, N and S, said ring being attached to A through a
sulfur atom, thereby forming a sulfonium group. In the latter
case where
Rl- S - R
represents a heterocyclic ring, the ring may also be fused
to a C5-C6 carbocyclic ring, a phenyl ring or a 5-6 membered
heteroaryl ring ~containing 1-4 O, N or S) and any of such
fused rings may also be optionally substituted.
The aliphatic R and/or Rll substituents are preferably
Cl-C~ alkyl, C2-C6 alkenyl or C2-C6 alkynyl. Cy~loaliphatic
substituents are preferably C3-C6 cycloalkyl while cyclo-
aliphatic-aliphatic refers especially to C3-C6 cycloalXyl-Cl-
C6 alkyl. Such aliphatic, cycloaliphatic and cycloaliphatic-
alipha~ic substit~ents may be unsubstituted or substituted
lpreferably by 1-3 substituents) by the following: hydroxy,
C1-C6 alkoxy, Cl-C6 alkanoyloxy, car~oxy, Cl-C6 alkoxycarbonyl
(e.~. -C-OC2H5 or -~-OC3~7), a~ino, Cl-C6 alkylamino, di(Cl-C6)-
alkylamino, Cl-C6 alkanoylamino, phenyl~ phenyl substituted by,
preferably 1-3 and most preferably 1-2, halo, Cl-C6 alkoxy,

3~3~4(~
-- 28 --
Cl-C6 alkyl, carboxy, carboxy-Cl-C6 alXyl, amino, Cl-C6
alkylamino, d~(Cl-C6)al~yl~mino or di(Cl-C6)al~ylamino-
(Cl-C6)al~yl, halo or oxo. _ _ _ _ _
The Rl~ and/or Rll substltuents may also be aryl
(C6-C10 aromatic hydrocarbon) which is most especially phenyl~
The aryl group or groups may be unsubstituted or substituted
by 1-3, preferably 1-2, substituents selected from halo,
Cl-C6 alkoxy, Cl-C6 alkyl, carboxy, amino, Cl-C6 alkylamino
and di~Cl-C~)alkylamino.
When R10 and/or ~11 represent he~erocyclyl or hetero-
cyclyl-aliphatic, the heterocyclyl moiety is a 4-6 membered
no~-aromatic ring containing 1-3 hetero atoms selected from
O, N and S. The aliphatic moiety associated with heterocyclyl-
aliphatic is preferably Cl-C6 alkyl. The heterocyclic rin~
of such groups may be unsubstituted or substituted by 1-3,
preferably 1-2, C~-C6 alkyl or Cl-C6 alkoxy substituents.
When R10 and/or Rll represents heteroaryl or hetero-
araliphatic, the heterocyclic moiety is a 5-6 membered
aromatic ring containing 1-3 hetero atoms selected from
o, ~ and S and the aliphatic (preferably alkyl) moiety has
1-6 carbon atoms. The heteroaryl ring of such sub~tituents
may be unsubstituted or substituted by 1-3, preferably 1-2,
substituents selected from Cl-C6 alkyl, Cl-C6 alkoxy, carboxy,
carboxy(Cl-C6)alkyl, amino, (Cl-C6)alkylamino, di(Cl-C6)alkyl-
amino, amino(Cl-C6)alkyl and di(Cl-C6)alkylamino(Cl-C6)alkyl.
The R10 and Rll -substituents taken together with the
S ~ to which they are attached may also represent a 4-6 member
sulf~r-containing heterocyclic ring containing 0-2 double bonds
ana 0-2 additional heteroatoms selected from O, N and 5, said
ring ~eing attached ~o the alkylene (A) group through a sulfur
atom, thereby forming a sulfonium group. The heterocyclic
ring fonmed by ~

4 ~ ~
. - 29 -
may be ~nsub~tituted or s~bstituted by 1-3, prefer~bly 1~2,
substi uents selected from:
Cl-C6 al~yl optionally substituted by 1-3 hydroxy,
Cl-C6 alkoxy, oarboxy, halo, amino, Cl-C6 alkylamino
or di(Cl C6)alkylamino groups;
hydroxy;
Cl-C6 al~oxy;
Cl-C6 alkanoyloxy;
amino;
Cl-C6 alkylamino;
di~Cl-C6)alXylaminO;
Cl-C6 alkanoylamino;
carboxy;
Cl-C6 alkoxycarbonyl;
halo;
oxo; and
phenyl.
The heterocyclic ring may also be fused to a C5-C6
car~ocyclic ring, a phenyl ring, a 5-6 member heterocyclic
(containing 1-4 h tero a~oms selected from 0, N and S) ring
or a 5-6 member heteroaryl (containing 1-4 hetero atoms
selected from 0~ N and S) ring, all of which fused rin~s may
be optisnally substituted by 1-3, preferably 1-2, of the
substituents describea abo~e in connection with the sulf~r-
containing heterocyclic ring.
A particularly preferred embodiment of the present
in~ention comprises compounds of formula I wherein ei~her
~a) Rl~ and * 1 each independently represents Cl-C6 al~yl or
(b) R10 and * 1 taken to~ether with the
S ~)
to which they are attached represent
-S ~ or -S ~ ; and

- 30 -
pharmaceutically acceptable salts thereof.
Examples of preferred 2-substituents wherein
R10 and R11 are alkyl include
< IMG >
and
< IMG >
Within this subclass, the preferred compounds are those wherein
A is -(CH2)n- in which n is 2, 3 or 4, most preferably those in
which A is -CH2CH2- and wherein either (a) R1 and R8 taken
together represent
< IMG >
or (b) R8 is hydrogen and R1 represents hydrogen, CH3-CH2-,

~84 ~)
- 31 ~
CH3~ C~3 OH . ~
C- , ~ C- or C~3~ - .
3 3
Particularly preferred are the compounds wherein R8 is
hydrogen and ~1 is IOH
CH3CH-, preferably compounds
having the absolute configuration 5R, 6S, 8R.
A most preferred embodiment of the present invention
comprises compounds of formula I wherein
Rlo~ 11 represents
~/~
; ~ , and
pharmaceutically acceptable salts thereof. Within this sub-
class, the preferred compounds are those wherein A is -(CH~)n
in which n is 2, 3 or 4, most preferably those in which A is
-CR2C~2- and wherein either (al ~1 and R taken together
represent
HOCE{
~C=
CH3
or (b) R8 is hydrogen and Xl represents hydrogen, CH3CH2-,
C~3~ CH3 ~ 01~ ~~
~ C~ or C~3CH- ~
c~3 C~3 8
Particularly preferred are the compounds wherein R is hydrogen
and ~1 is
O~~I
CH3C~-, preferably compounds
having the ab301~te configuration 5~, 6S, 8R,

o
- 32 -
The most preferred embodiment of the present invention
comprises the comp~unds of the formula
OH
(R) ~ ~ ~ S-C~2CN2 S
O ~ N COOR2
wherein R2 is hydrogen, an anionic charge or a conventional
readily removable carboxyl protecting group, providing that
when R2 is hydrogen or a protecting group, there is also
present a counter anion7 and pharmaceutically acceptable acid
addition salts thereof~
It ~ill be appreciated that when Rl~ and Rll in formula
I are different, there may be formed both the R and S optical
isomers of such com~ounds as well as epimeric mixtures thereof.
It is intended that the present invention include within its
scope all such optical isomers and epimeric mixtures. Similarly,
the 6-substituen~ may in certain cases, e.g. as in hydroxyethyl,
be in either the-~ or S configuration and the resulting isomers
as well as epimeric mixtures thereof are encompassed by the
present invention.
The car~ape~em deriYatives of general formula I are
prep~red from sta~ting materials of the formula
R
~,
O III COOR
wherein Rl and ~8 are definea above and wherein R2 represents

. ~,g~O
33 -
a conventional readi~y removable carboxyl protecting groups.
Compounas of formula III have been disclosed, ~or example,
in European Patent Application 38,869 (compound 7) and may
be prepared by the general methods described therein.
The process for preparing compounds I from starting
materials III may be summarized by the following reaction
scheme:
8 H
R ~ 2'
N OOR
III
Rl ~oC6115~3 >
. R8 H
Rl~A-OH
00*
' V

11~8~ ~0
-- 34 --
R8 H
R~ A OS 2 3
~ N COOR2 '
VI
R8 H R10
Rl~ 2 '
COOR
II
R8 H ~3 R10 ~3
R~ ~ S-A- ~ 11 optional
; , 1 _ 2' R de:~locking
~ N COOR - - >
- I'
R ~1 ~) R
~S--A--S
COOR
.
To elaborate on the above process, starting material III
is reacted in the inert organic solYent such as methylene
chloride, acetonitrile or dimethylformamide with about an equi-
molar amount of diphenyl chlorophosp~ate in the presence of
- a base su~h as diisopropylethylamine, triethylamine, 4-dimethyl-
aminopyridine or the like to give intermediate IV. The acylation
to est~blish the diphenylphosphoryloxy leaving group at the

~g~4~0
- 3S ~
2-position of in~ermediate III is adYantageously carried out
at a temperature of from about -209 to +40 C, most preferab~y
at about 0C. Intermediate I~ may be isolated if desired~
but is con~eniently used for the next step without isolation
or purification.
Intermediate IV is next converted to intermediate Y
by a conventional displacement reaction. Thus~ intermediate
IV may be reacted with approximately an equimolar amount of
a mercaptan reagent of the formula
HS-A-O~
wherein A represents C2-C6 straight or branched chain alkylene
in an inert organic sol~ent such as dioxane, dimethylformamide,
aimethylsulfoxide or acetonitrile and in the presence~ of a
base such as diisopropylethylamine, triethylamine, sodium
hydrogen carbonate, potassium carbonate or 4-dimethylamino-
pyridine. The temperature for the displacement is not critical,
but an advantageous temperature range is from about -40C to
25C. Most conveniently, the reaction is carried out with
cooling, e.g. at about 0C.
Intermediate Y is then acylated with methanesulfonyl
chloride or a functional acylating equivalent thereof such as
methanesulfonic acid anhydriae in an inert organic solvent and
in the presence of base to provide the methanesulfonyloxy leaving
group of intermediate VI. The acylation is carried out in an
inert organic sol~ent such as tetrahydrofuran~ methylene
chloride, acetonitrile or dimethylformamide and in the presence
of a suita~le base such as diisopropylethylamine, triethylamine,
4-d~ethylaminopyridine, and the liXe. The reaction may be
carried out OVOE a wide temperature range, e.g. -40C to ~40C,
but is most adYantageously conauctea with cooling, e.g. at about
-30~C to -40C.
Intermediate ~I is next subjected to a aisplacement
reaction so as to provîde in intermediate II the iodo leaving
~roup. This particular group has been found to greatly
facilitate preparation o~ the carbapenem end-products of ~ormula
.; . . . ~ . .

84 ~0
- 36 -
I. The intermediates of general fo~mula II~ therefore,
comprise a preferrea embodiment of the present invention.
The displacement of the methanesulfonyloxy leaving
group is carried out by reacting intermediate VI with a
source of iodide ions in an inert organic solvent such as
acetone, dimethylformamide or dimethylsulfoxide. Any com-
pound which ionizes in the solvent employed to provide iodide
ions may be used, e.g~ an alkali metal iodide such as NaI or
XI. The temperature for the displacem~nt is not critical,
but temperatures of room temperature or above are most advan-
tageous for achieving completion of the reaction in a reason-
able time period. The source of iodide ions is employed in
an amount so as to provide approximately an equi~alent or
excess of iodide ion relative to intermediate VI.
Preparation of the desired carbapenems derivatives
of formula I is carried out by a nucleophilic displacement of
the iodo leaving group of intermediate II by the desired
sulfide of the general formula
~ Rl
S
Intermediate II is reacted with at least an equiYalent, prefer-
ably an excess, of the desired sulfiae in an inert organic
solvent and in the presence of silYer ion. Suitable inert
organic solvents include, for example, tetrahydrofuran, diox~ne,
methylene chloriae, diglyme, dimethoxyethane, and the li~e.
Any silver compound which substantially ionizes in the solvent
and to give silver ions and an inert anion may be used as the
source of silver ion, e.g. AgC104. Generally, we prefer to
use approximately an equivalent amo~nt (relative to intermediate
II) of silver ion to,~acilîtate the displacement. The reaction
may be carried out over a wide temperature range, e.g. from about
-25C to about ~25C, but is preferably conaucted at around 0C.

1~84 ~0
~ 37 -
Intermediate I' will have a counter anion (derived fro~
the silver salt used3 associated with it which may at this
stage be substituted by a different counter anion, e.gO
one which is pharmaceutically acceptable, by conventional
procedure~. Alternatively, the counter ion may be subse-
quently removed during the de-blocking step,
$he de-blocking step to remo~e the carboxyl protecting
group R2 of intermediate I' is accomplished by conventional
procedures such as solvolysis, chemical reduction or hydro-
genation. Where a protecting group such as p-nitrobenzyl,
benzyl, benzhydryl or 2-naphthylmethyl is used which can be
removed by catalytic hydrogenation, intermediate I' in a
suitable solvent such as dioxane-water-ethanol, tetrahydro-
furan-aqueous dipotassium hydrogen phosphate-isopropanol or
the like may be treated under a hydrogen pressure of from
1 to 4 atmospheres in the presence of a hydrogenation catalyst
such as palladium on charcoal, palladium hydroxide, platinum
oxide or th~ like at a temperature of from 0 to 50~C for from
about 0.24 to 4 hours. When R is a group such as o-nitro-
benzyl, photolysis may also be used for debloc~ing. Protecting
gsoups such as 2,2,2-trichloroethyl may be removed by mild
zinc reduction. Similarly, other conventional carboxyl
protecting groups may be removed by methods ~nown to those
skilled in the art. Finally, as mentioned aboYe, compounds of
formula I' where R2 is a physiologically hydrolyzable ester
such as acetoxymethyl, phthalidyl, indanyl, piYaloyloxymethyl,
methoxymethyl, etc. ~ay be administered directly to the host
without de-blocking since such esters are hydrolyzed in vivo
under physiological conditions.
It will be understood that where the Rl and/or R8
substituent or the heteroaromatic nucleophile attached to
substituen~ A contain a functional group which might interfere
with the intended course of reaction, such group may be protected
by a conventional blocking group and then subsequently de-blocked
to regenerate the desired functional group. Suitable blocking

~19~34 ~0
38
group~ and pr~ceaures for ~ntroducing and removing such
groups are well known to those skilled in the art.
AS in the case of other B-lactam antibiotics, com-
pounds of general formula I may be co~verted by known
procedures to pharmaceutically acceptable salts which, for
purposes of the present inven~ion, are substantially
equivalent to the non-salted compounds. ThUS, for example,
one may dissolve a compound of formula I wherein R2 is an
anionic charge in a suitable inert solvent and ~hen add
an equivalent of a phanmaceutically acceptable acid. The
desired acid addition salt may be recovered by conventional
procedures, e.g. solvent precipitation, lyophilization, etc.'
Where other basic or acidic functional groups are present
in the compound of formula I, pharmaceutically acceptable
base addition salts and acid addition salts may be similarly
prepared by known methods.
A compound of formula I where R2 is hydrogen or an
anionic charge, or a pharmaceutically acceptable salt thereof
may also be converted by conventional procedures to a corres-
ponding compound where'R2 is a physiologically hydrolyzable
ester group, or a csmpouna of formula I wherein R2 is a
conventional carboxyl'protecting group may be converted to
the corresponding compouna where R2 is hydrogen, an anionic
charge or a physiologically hydrolyzable ester group, or a
pharmace~tically acceptable'salt thereof.
The novel car~apenem deriYati~es of general formula I
wherein R2 is hyarogen, an anionic charge or a physiologically
hydrolyzable carboxyl protecting group, or the pharmaceutically
acceptable salts thereof, are potent antibiotics active against
various gra~-positive and gram-negatiYe bacteria and they may
be used, for example, as animal feed additiYes for promotion
of growth, as preservatives in food, as bactericides in
industrial applications, for example in waterbased paint and
in the white water of paper mills to inhibit the growth of
harmful bacteria and as disin~ectants for aestroying or
i
.. ~ . . .. . . .. . . . . . . . . . .
,
.

- 39 -
inhibi~ing the ~rowth of harmful bacteria on medical and
dental equipment. They are especially useful, however,
in the treatment of infectious disease in humans and other
animals caused by gram-positive or gram-negative bacteria.
The pharmaceutically active compounds of this
inventîon may be used alone or formulated as pharmaceutical
compositions comprising, in addition to the active carba-
penem ingredient, a pharmaceutically acceptable carrier or
diluent. The compounds may ~e administered by a variety of
means; those of principal interest include: orally, topically
or parenterally (intravenous or intramuscular injection).
The pharmaceutical compositions may be in solid form such as
capsules, tablets, powders, etc. or in liquid form such as
solutions, suspensions or emulsions. Compositions for injection,
the preferred route of delivery, may be prepared in unit dose
form in ampules or in multidose containers and may contain
formulatory agents such as suspending, stabilizing and dis-
persing agents. The CompositiQns may be in ready to use form
or in powder form for r~constitution at the time of delivery
with a sui~able vehicle such as sterile water.
Th~ aosage to be administered depends to a large extent
on the particular compound being used, the particular composition
formulated, the route of administration, ~he nature and condition
of the host and the particular situs and organism being treated.
Selection of the particular preferred dosage and ro~te of
applicatio~, then, is lef~ to the discretion of the therapist,
In general, however, the compounds may be administered paren-
terally o~ orally to mammalian hosts in an amount of from about
5 to 200 mg~kg~day. Administration is generally carried out in
ai~ided doses, e.g. three to four times a day.
To illustrate the potent broad-spectrum antibacterial
activity of the carbapenems of the present invention, both in
~itro ana in v~vo, and the low toxicity of the compounds,
biological data is provided below relating to the preferred
carbapenem compoun~ o~ the present invention, i.e. 3-[2-(1-
.

1~98~
-- 40 ~
tetrahydrothiophenium3 ethylthiol -6a- [1- tR) -hydroxyethyl]-7-
oxo-l-azabicyclo~3.2.0]hept-2-ene-2-carboxylate prepared in
Example 1.
In Vitro Activity
A sample of the above-identified carbapenem compollnd
after solut~ on in water and dilution with Nutrient 13roth was
found to exhibit the following Minimum Inhibitory Concentrations
(M.I.C.~ in mcg/ml versus the indicated microorganisms as
detenninea by overnigh~ incubation at 37C by tube dilution.
N-Formimidoyl thienamycin was included as a comparison compound.
In Vi tro
Antibacterial Activity of Carbapenem
Derivative of Exam le 1
P
MIC (mcq/ml)
Orqanism New Compound N-Formimidoyl Thienamycin
S. pneumoniae A-9585 0 . 002 0.û04
S. pyoqenes A-9604 0. û04 0 .001
5. aureus 1~-9537 0.008 0.004
5. aureus
+ 50% serum A-9537 0~03 O.OlS
S. aureus
(Pen-res.) A-9606 0.016 0.008
S. aureus
tMeth-res.) A15097 2 0.5
S. faecalis A20688 0. 5 0 .5
E. coli
(10-4 ail.) A15119 - 0.03 0.016
E coli
o
(10 3) AlSll9 0.06 0.03
E. coli
.
( 10 ) A15 119 0 . 0 6 0 . 0 6
E. coli
(10 4) A2Q341-1 0.l33 0.03

8 ~
In vitro antibacterial activity of carbapenem deri~ative of
. . Example 1 ~ continued
MIC (mcg~ml)
Or~anis~ New Compound N-Formimidoyl Thienamycin
E. coli
(10 3) A20341-1 0^03 0-03
E. coli
(10 ) A20341-1 0.06 0.13
~ pneumoniae A-9664 0.06 0.13
K. pneumoniae A20468 0.13 0.06
P. mirabilis A-9900 0.13 0.06
P. vulqaris A21559 0.03 0.03
P morqanii A15153 0.06 0.13
P~ rettgeri A22424 0.25 0.25
S. marcescens A20019 Q.06 0.03
E. cloacae A-9659 0.13 0.06
E. cloacae A-9656 0.13 0.06
P. aeruginosa A-9 843A
P. aeru~inosa A21213 0.25 0.25
H. influenzae A-9833 B 16
. influenzae A2Q178 8 32
.
. influenzae A21518 8 32
~. influenzae A21522 8 32
B fraqilis ~22862 0.06 0.016
B fragiiis A22053 0.06 0.06
B. fra~ilis A22696 0.25 0.13
.
~. fragilis A22863 0.06 1 .
. _
- In Vi~o Activity
.
The in vivo therapeutic efficacy of the compound of
Ex~mple 1 and N-formimiaoyl thienamycin after intramuscular
a~ministration to mice experimentally infected with various
organisms is shown in the following Table. The PDSo (dose in
mg/kg require~ to give protection to 50% of the in~ected mice)
is indicatea.
'' . .
.

"" 42 _
~ h
V ~ D O O I ~
~ ~ ~ S ~ ~
o -
V
2 1o
~n ~ ~
E~ ~o O ~ -3 ~D O
aU' ~ ~ O _i ~ ~ r~ ~ ~ ~ In O o_, ,~ s
~1 P. E~ Ei f ~In
: t~ X
~ g ,
. U o o o o o o o o o o o o ~ -- ~ ~
J ~ o ~ x x x x x ~c x ~ x ~ x x O a~
Z C ~ O O
V . - ' . ~ ~ o~
-; O ~ a~ o o~ cn
O ~ O U~ W ~ ~ ~r ~D ~
w O O O
* E~
' ' '

1:~98~ ~0
. ~ 43 ~
. .
The toxicity of the compound of Example 1 after intra-
cranial administration to mice was determined and is shown
in the following Table.
Toxicity After Intracranial
Aaministration to Mice
Highest Dose (mg/kg)
~ LD50 Without Clinical
Compound (m~/kq) Siqns of Toxicity
Compound of
Example 1 >40 ~5
N-Formimidoyl
Thienamycin 32 ~5
*Averaqe of 25 mice/comvound
Blood Levels in Mice
After Intramuscular A~ministration
Blood levels and the half-life of the compound of
Example 1 after intramuscular administration of 20 mg/kq in
mice are shown in the Table ~elow.
Blood Level (~q/ml)
Compound 10 20 . 30 45 60 90 *tl/2 **AUC
. Minutes after Administration (min) ~g.h/ml)
ccmpou~ of
Example i 14.713.5 8.7 3.2 0.9 <0.6 9 7.4
N-Formimiaoyl
Thienamycin 12.69.9 7.3 2.6 0.7 ~0~3 9 6
_
Compounas were solubilized in 0.1 M phosphate buffer pH 7.
- Values are from a single test; 4 mice used per compound.
* tl/2 refers to half-life in minutes
** AUC refers to the area under the curve
.
.
,

.. Vrinary Recovery
The urinary recovery of the compouna of Example 1
after intramuscular administration t20 ~g/kg3 to mice i~
shown in the following Table.
Urinary Reco~rery
- Intramuscular Administration
of 20 mq/kg to Mi ce
Percentage of Dose Reco~ered
0-3 3-6 6-~4 0-~4
Compound ~ours After Administration
Compound of
Example 1 15.6 2.1 <0.2 17.7~2.9
N-Forminidoyl
Thienamycin 12.1 0.1 <0.1 . 12.2~3.6
Compounds were solubilizea in 0.1 M phosphate buffer
p~ 7. Values are from a single test: 4 mice per compound.
, The following examples illustrate but do not limit
the scope of the present invention.
.', , .
.

~g~
_ 45 -
Example 1
Preparation of 3-~2-(1-tetrahyarothiophenium)e~hYlthio]-
6~-11-(R)-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0~hept-
2- ene- 2-carboxYlate
2CH ;~--S~
N O
A. ~-Nitrobenzyl 3-(2-hydroxyethylthio~-63-[l-(R~-hYdro~~
ethYl~-7-oxo-1-azabicyclo [3.2.0~hept-2-e~e-2-carboxylate
OH
J~o
O C02p
0~
- J ` ` -,_, SC~2CH2H
N . ~CO pNB
: . 2
pNB = -~H2 ~ 2

4~
-- 46 ~
.. . .. . . . . _ . .. . . ........... .
A solution of 1. 69 g ~ 4 . 85 ~T ole) of p-nitrobenzyl
5Q~ ) -hydroxyethyl~ -3 ,7-aioxo-1-azabicyclo (3 ., 2, 0) hept-2
ene-2-carbo~ylate (1) in 20 ml o ace~onitrile was cooled to
O~C under a nitrogen. atmc)sphereO ~. solution of 726 mg (7,18
nmlole) of diisopropylethylamine in 2 ml of acetonitAle was
aaded followed ~y a drop~ise adaition of 1.51 g (5.60 mmole) of
aiphenyl chlorophosphate in 12 ml c~f a--etonitrile oYer a period
of 3 minutes, The Iesulting solution was stirrea at 0~ for 20
minutes to pro~Tide p-nitro~enzyl 3- (diphenylphosphorylox5r) -6~-
~l-(}?)-hydroxyethyl~-7-oxo-1-azabicyclo (3.2.0~hept-2-ene-2-
carboxylate. To this solution was added a solution of 726 mg
~7.18 mmole) of diisopropylethylamine in 2 ml of acetonitrile
followed by a solution of 439 ~g (5~63 mmole) of 2-mercapto-
ethanol in 2 ml of acetonitrile. The reaction solution was
stirred at 0C for 3 hours and then ~iluted with 200 ml of ethyl
acetate and washed with 200 ml of water, 100 ml of 20~ aqueous
H3PO4, and brine. Evaporation o~ the dried lMgSO4) solution
ga~e a semisolid wh~ch was triturated with methylene chloriae
and filterea to yield 1.2 9 (61% yield) of title proauct 2 as a
white amo~phous solid.
NMR (DMS0-d6) ~:1.20 (3~, d, J=6.0 Hz), 2.9-3.2 (9H,m), ~,22(1H,
~, J=8.5 ~z) ana 8.23 ~2H, d, J=8.5 Hz); ir (~Br) ~max: 3500,
1770 and 1700 cm ; ~nai. Calcld for C18H20N2075: C, 52.93;
n, 4094; N, 6.86;- S,- 7.85. ~ound: C,-52.83; H, 4.90; ~, 6.42;
5" 8.31.
.. .
_ .. .

. ~
9~ ~0
- 4? -
B. p-Nitrobenz~l a-~2-m~than~sulfony~oxyethyl~hio)=
2-ene-2-carboxylate
OH
J~ d~sc~ on ~
co2PNB
2 OH H
J ~ ~ S~H~ 2 2 3
11_
N CO2P~B
To a solution o~ 4.2 9 (10.3 mmole) of 2 in 200 ml
of tetrahydrofuran there was added at -40C 1.3 g ~11.3 mmole)
of methanesulfonyl chloriae followed by a dropwise addition of
1.26 g (12.4 mmole3 of triethylamine in S ml of tetrahydrofuran.
The reaction mixture was stirre~ for S hours at -40C, the~
stirred for 2 hours at ~30C under a nitrogen atmosphere and
then pourea into a mixture of ethyl acetate (700 ml) and 5%
a~ueous phosphoric acid.~l000 ml). The organic layer was washed
with brine, dried over ~gS04, filtered and condensed to a syrup.
~hi~ material was purified by silica ~el column chromat~graphy
lelution with methylene chloride-ethyl acetate (3:1 ~/Y)~ to
give 3.55 g (75~ yield) of the title compound.as a white amorphous
SOlia.
NMR (~DC13) ~: 1.25 (3H,-d, J=6.0 Hz)~ 3.05 (3H, s), 3,06-3,40
(5~ 4.05-4.40 ~4H, m), 5.25 (lH, d, J=14.0 Hz)~ 5.50 (l~,
d, J-14.0 Hz), 7O70 t2H, a, J=8.5 ~z) and a.23 (2H~ a~ J=8.5 Hz);
ir ~KBr~ ymax: 3400~ 1770 and 1600 cm l, Anal. Calc'd for
Cl9~22N~OgS2: C, 46.90; 8, 4.56; N, 5.76. Found: C, 46,52;
PO~ 4.32; N, 5.91~

o
~ 4~ ~
. . .
:, C. ~-Nitrobenzyl 3-~2-iodoethYlth~tR)-
hydroxyethyll -7-oxo-1-azabicyclo ( 3 . 2 . û) hept=
2-ene- 2-car~oxy~ate
0~
J ~ ,Sc~2c~12oso2cH3
L I 11 ,~ .
o C02pN~ .
.
T H
,, ~ ~scH2cH2I
o co2PNB
A sol~tion of 350 mg ~0-.72 n~oole) of intermediate
3 and 216 mg (1.4 ~nole) of sodiu~ ic>dide in 20 ml of acetone
was heated at ref lux f or 4 hours . Evaporation of the acetone
ga~e a white amorphous solid which was suspended in ether ( 10 ml) -
water (10. :ml) . Filtration of the white solid and ~.racuum drying
produced 300 mg (80~6 yiel~3 of the title compol~nd 4 as a white
~morphous pawa~r.
NMR ~DMS0-d6) ~. 1.18 ~3~, d, J=6,0 ~z), 3.20-3.60 (7~, m), 3.80-
4.25 (2H, m)~ 5.10 (1~, a, J=5.5 ~z), 5.25 (1H, d, J=12.0 Hz),
5.45 (1~, d, J=12.0 Rz), 7.70 ~2H, d, J=8.S Hz), and 8.27
(2~, d, J-8.5 ~z); ir lXBr) ymax: 3500, 1768 and 1700 cm
Anal. Calc'd for C18H1gN206I C, 41,71; H, 3.70; N, 5.41;
I, 24.4B. Found- C, 42.10; ~, 3.75; N, 5.9?; I, 23.20.

4 ~
49 -
D- 3-[2-tl-Tetrah~rot~ioP enium~ethYlthi~]-6u-
[l-(R)~hydroxyeth~1]-7-oxo-1-azabicYclo[3.2.Q~hept-
2-ene-2-carboxylate
~H
2CH2 >
O , 02pNB
OH r~~~~
SCH~CH2 S
O N CO2pNB
2C 2
O COO~)
To a solution of p-nitrobenzyl 3-(2-iodoethylthio)-
6a-[1-~R)-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0~hept-2-ene-
2-ca~boxylate (104 mg; 0.2 mmole) in S ml of tetrahydrofuran
there was added tetrahydrothiophene (0.3 ml; 0.35 mmole~
followed by a solution of silYer perchlorate (60 mg; 0.3 mmole~
in 0.5 ml.of tetrahydrofuran. The mixture was stirred at room
temperature.for 60 minutes. The solvent was evaporated.in
vacuo af ording compound ~ as a yellow gum. This gum was
digested with 100 ml of OE LITE to give an amorphous solid.
~ . ~ ' ' ' `"
. . , : .

84~
- 50 -
_R (KBr) ymax: i400~ 1i72, 1700 ana lloo c~ 1. Without
any further purification, compound 5 was hydrogenated as
follaws: T.o a suspenaea solution of compound 5 in 20 ml
of ether and 20 ml of tetrahydrofuran there was added a
solution of potassium bicarbonate ~40 mg; 0.4 mmole) and
dibasic potassium phosphate t 35 mg; 0 . 2 mmole) in 20 ml of
water. ~hen, 120 mg of 10% palladium on charcoal was addea
an~ the mixture was hydrogenated at 40 psi on the Parr
Shaker for 60 minutes. The mixture was then filtered and
the catalyst was washed with water ( 2 x 5 ml) . The combined
filtrate and washing was extracted with ether (2 x 50 ml) and
then lyophilized t~ give ~ yellow powder. This crude material
was purified o~ a C18 BONDAPAK reverse phase column (7 g~
(Waters Associates), eluting with water under a 8 psi pressure.
Each fraction (15 ml) was screened by high pressure liquid
chromato~raphy, and fractions ha~ing an ultraviolet absorption
AmaX 300 nm were collected and lyophilized to give 12 mg (18%
yield based on compound 4) of title product as a white solid.
NMR (D2O)~: 1.23 (3H, d, J=6.0 Hz), 2.25-2.45 (4~, m), 3.0-
3.70 (ll~I, m), 3.95-4.30 ~2H, m); ir (KBr) ~max: 3400, 1760
and 1590 cm 1. UV ~max (C~2CH20H) 289 nm (~=6200).
-, -
....