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 a compound of
the formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
silting of hydrogen; substituted and unsubstituted: alkyl, alkenyl
and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cyclo-
alkylkyl, 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, hetero-
cyclyl and heterocyclylalkyl wherein the hereto 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; 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>
237
<IMG>
-NR3R4
<IMGS>
-CO2R3
=O
<IMG>
-SR3
<IMGS>
-CN
-N3
-OSOR3
<IMGS>
-OP(O)(OR3)(OR4)
238
<IMG>
-NR3CO2R4
-NO2
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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms: cyclo-
alkyl 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-
233
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl:
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG> ;
-OXO ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG> ;
-SR3 ;
<IMGS> ;
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
240
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above;
or R5 may be attached to
<IMG>
at another point on the ring so as to form
a fused heterocyclic or heteroaromatic ring,
which ring may contain additional hetero atoms
selected from O, S and N ;
R15 is selected from the group consisting of hydrogen;
substituted and unsubstituted: 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; spirocycloalkyl
having 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl
wherein the aryl moiety is phenyl and the aliphatic portion has
1-6 carbon atoms; 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 and 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 selected from the group consisting
of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl,
mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino,
nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the
alkyl moieties of the above-recited substituents have 1-6 carbon
atoms;
A is C1-C6 straight or branched chain alkylene;
R2 is hydrogen, an anionic charge or a conven-
tional readily removable carboxyl protecting
241
group, providing that when R2 is hydrogen or
a protecting group, there is also present a
counter ion; and
<IMG>
represents a substituted or unsubstituted mono-,
bi- or polycyclic aromatic heterocyclic radical
containing at least one nitrogen in the ring,
said ring being attached to A through a ring
carbon atom and having a ring nitrogen Which is
quaternized by the group R5; or a pharmaceutically
acceptable salt thereof; which process comprises reacting an
intermediate of the formula
<IMG>
wherein R1, R8, R15, A and R2 are as defined above and
<IMG>
represents a mono-, bi- or polycyclic aromatic heterocyclic
radical containing a quaternizable nitrogen in the ring, said
ring being attached to A through a ring carbon atom, in an
inert organic solvent with an alkylating agent of the formula
R5~X'
242
wherein R5 is as defined above and X' is a conventional
leaving group so as to quaternize with the R5 group a
ring nitrogen of substituent
<IMG>
on intermediate II and form a compound of the formula
<IMG>
wherein R1, R8, R15, R2',A, <IMG> and -X t are as defined above;
and, if desired, replacing counter ion X' by a different counter
ion and, if desired, removing the carboxyl protecting group R2'
to give the desired de-blocked compound of formula I, or a
pharmaceutically acceptable salt thereof.
2, The process according to Claim 1 wherein the
quaternization step is carried out after removal of the carboxyl
protecting group R2'.
3. A process for the preparation of a compound of
the formula
<IMG>
243
Wherein R 8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: alkyl, alkenyl
and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cyclo-
alkylalkyl, 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, hetero-
cyclyl 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; 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
<IMGS>
-NR3R4
<IMGS>
244
-CO2R3
=O
<IMG>
-SR3
<IMGS>
-CN
-N3
-OSO3R3
<IMGS>
-OP (O) (OR3) (OR4)
<IMG>
-NR3CO2R4
-NO2
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,
245
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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
246
<IMG> ;
-OXO ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG> ;
-SR3 ;
<IMGS>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above;
or R5 may be attached to
<IMG>
at another point on the ring so as to form a
fused heterocyclic or heteroaromatic ring, which
ring may contain additional hetero atoms selected
from O, S and N;
247
R15 is selected from the group consisting of hydrogen;
substituted and unsubstituted: 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; spirocycloalkyl
having 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl
wherein the aryl moiety is phenyl and the aliphatic portion has
1-6 carbon atoms; 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 and 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 selected from the group consisting
of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl,
mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino,
nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the
alkyl moieties of the above-recited substituents have 1-6 carbon
atoms;
A is C1-C6 straight or branched chain alkylene;
R2 is hydrogen, an anionic charge-or a conven-
tional readily removable carboxyl protecting
group, providing that when R2 is hydrogen or
a protecting group, there is also present a
counter ion; and
<IMG>
represents a substituted or unsubstituted mono-,
bi- or polycyclic aromatic heterocyclic radical
containing at least one nitrogen in the ring,
said ring being attached to A through a ring
carbon atom and having a ring nitrogen which is
248
quaternized by the group R5; or a pharmaceutically
acceptable salt thereof; which process comprises
the steps of
(1) reacting an intermediate of the formula
<IMG>
wherein R1, R8 and R15 are as defined above and R2 is a
conventional readily removable carboxyl protecting group in
an inert organic solvent with a reagent capable of introducing
a conventional leaving group L at the 2-position of intermediate
III to give an intermediate of the formula
<IMG>
wherein R1, R8, R15, L and R2' are as defined above and L is a
conventional leaving group;
(2) reacting intermediate IV in an inert organic
solvent and in the presence of base with a mercaptan reagent of
the formula
<IMG>
wherein A is as defined above and <IMG> represents
249
a mono-, bi- or polycyclic aromatic heterocyclic radical contain-
ing a quaternizable nitrogen in the ring, said ring being attached
to A through a ring carbon atom, to give an intermediate of
the formula
<IMG>
wherein R1, R8, R15, A, R2' and <IMG > are as defined above;
(3) reacting intermediate II in an inert organic
solvent with an alkylating agent of the formula
R5-X'
wherein R5 is as defined above and X' is a conventional
leaving group so as to quaternize with the R5 group a
ring nitrogen of substituent
<IMG>
on intermediate II and form a compound of the formula
<IMG>
wherein R1, R8, R15, R2' ,A, <IMG> and -X' are as defined above;
250
and, if desired, replacing counter ion X' by a different counter
ion and, if desired, removing the carbonyl protecting group R2'
to give the desired de-blocked compound of formula I, or a
pharmaceutically acceptable salt thereof.
4. A process according to claim 3 wherein the
quaternization step is carried out after removal of the
carboxyl protecting group R2'.
5. 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; substituted and
unsubstituted: alkyl, alkenyl and alkynyl, having
from 1-10 carbon atoms; cycloalkyl and cyclo-
alkylalkyl, 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, hetero-
cyclyl and heterocyclylalkyl wherein the hetero atom
or atoms in the above-named heterecyclic 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
251
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
<IMGS>
-NR3R4
<IMGS>
-CO2R3
=O
<IMG>
-SR3
<IMGS>
-CN
-N3
-OSO3R3
252
<IMGS>
-OP (O) (OR3) (OR4)
<IMG>
-NR3CO2R4
-NO2
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: R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl and cycloalkylalkyl, having 3-6 carbon atoms in the
253
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-
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG> ;
-oxo ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG> ;
-SR3 ;
<IMGS>
254
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above;
or R5 may be attached to
<IMG>
at another point on the ring so as to form
a fused heterocyclic or heteroaromatic ring,
which ring may contain additional hetero atoms
selected from O, S and N ;
A is C1-C6 straight or branched chain alkylene;
R2 is hydrogen, an anionic charge or a conven-
tional readily removable carboxyl protecting
group, providing that when R2 is hydrogen or
a protecting group, there is also present a
counter ion; and
<IMG>
represents a substituted or unsubstituted mono-,
bi- or polycyclic aromatic heterocyclic radical
containing at least one nitrogen in the ring,
said ring being attached to A through a ring
carbon atom and having a ring nitrogen which is
quaternized by the group R5; or a pharmaceutically
255
acceptable salt thereof; which process comprises reacting an
intermediate of the formula
<IMG>
wherein R1, R8, A and R2' are as defined above and
<IMG>
represents a mono-, bi- or polycyclic aromatic heterocyclic
radical containing a quaternizable nitrogen in the ring, said
ring being attached to A through a ring carbon atom, in an
inert organic solvent with an alkylating agent of the formula
R5~X'
wherein R5 is as defined above and X' is a conventional
leaving group so as to quaternize with the R5 group a
ring nitrogen of substituent
<IMG>
on intermediate II and form a compound of the formula
<IMG>
256
wherein R1, R8, R2 ,A, <IMG> and ~X' are as defined above;
and, if desired, replacing counter ion X' by a different counter
ion and, if desired, removing the carboxyl protecting group R2'
to give the desired de-blocked compound of formula I, or a
pharmaceutically acceptable salt thereof.
6. A process according to claim 1 wherein R1
is hydrogen, CH3CH2-, <IMGS>
7. A process according to claim 1 wherein R1
and R8 taken together represent <IMG>.
8. A Process according to claim 1 wherein R1
is <IMG>.
9. A process according to claim 1 wherein R1
is <IMG> and the absolute configuration is
5R, 6S, 8R.
10. A process according to claim 1 wherein A
is -CH2- or -CH2CH2-.
11. A process for the preparation of a compound
of the formula
257
<IMG>
wherein R8 is hydrogen and R1 is selected from the group
consisting of hydrogen substituted and unsubstituted:
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
<IMGS>
-NR3R4
<IMG>
258
<IMGS>
-CO2R3
=O
<IMG>
-SR3
<IMGS>
-CN,
-N3
-OSO3R3
<IMGS>
-OP(O)(OR3)(OR4)
<IMG>
-NR3CO2R4
-NO2
259
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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms: cyclo-
alkyl 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-
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
260
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG> ;
-oxo ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG> ;
-SR3 ;
<IMGS> ;
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above;
261
or R5 may be attached to
<IMG>
at another point on the ring so as form a fused
heterocyclic or heteroaromatic ring, which ring
may contain additional hetero atoms selected from
O, S and N; A is C1-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
ion; and
<IMG>
represents an aromatic mono-, bi- or polycyclic
N-containing heterocyclic ring containing 0-5
additional hetero atoms selected from O, S or N,
said heterocyclic ring being attached to A through
a ring carbon atom and having a ring nitrogen
quaternized by the group R5, and said heterocyclic
ring being optionally substituted at available ring
carbon atoms by 1-5 substituents independently
selected from the group consisting of C1-C4 alkyl;
C1-C4 alkyl substituted by 1-3 hydroxy, amino,
C1-C4 alkylamino, di(C1-C4)alkylamino, C1-C4
alkoxy, carboxy, halo or sulfo; C3-C6 cycloalkyl;
C3-C6 cycloalkyl(C1-C4)alkyl optionally
substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl;
C1-C4 alkoxy; C1-C4 alkylthio; amino; C1-C4 alkyl-
amino; di(C1-C4)alkylamino; halo; C1-C4 alkanoyl-
amino; C1-C4 alkanoyloxy; carboxy; sulfo;
<IMG> alkyl; hydroxy; amidino; guanidino;
262
phenyl; phenyl substituted by 1-3 substituents
independently selected from amino, halo, hydroxy,
trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylamino, di(C1-C4)alkylamino, carboxy,
and sulfo; phenyl(C1-C4)alkyl in which the
phenyl portion is optionally substituted by 1-3
substituents mentioned above in connection with
phenyl and the alkyl portion is optionally
substituted by 1-3 substituents mentioned above
in connection with C1-C4 alkyl; and heteroaryl or
heteroaralkyl in which the hetero atom or atoms
are selected from the group consisting of 1-4 O,
S or N atoms and the alkyl moiety associated
with heteroaralkyl has 1-6 carbon atoms, said
heteroaryl and heteroaralkyl groups being
optionally substituted in the heterocyclic ring
moiety by 1-3 substituents independently selected
from hydroxy, amino, halo, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)-
alkylamino, carboxy and sulfo and in the alkyl
moiety by 1-3 substituents selected from hydroxy,
amino, C1-C4 alkylamino, di (C1-C4) alkylamino,
C1-C4 alkoxy, carboxy, halo and sulfo, and said
heterocyclic ring being optionally substituted at
available ring nitrogen atoms by 1-3 substituents
independently selected from the group consisting
of C1-C4 alkyl; C1-C4 alkyl substituted by 1-3
hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkyl-
amino, C1-C4 alkoxy, carboxy, halo or sulfo
groups; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C1-C4)-
alkyl optionally substituted by 1-3
substituents mentioned above in connection
with C1-C4 alkyl; phenyl; phenyl
substituted by 1-3 substituents independently
selected from amino, halo, hydroxy, trifluoromethyl,
263
C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,
di(C1-C4) alkylamino, carboxy and sulfo; phenyl-
(C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl
portion may be optionally substituted by 1-3
substituents mentioned above in connection with
C1-C4 alkyl; and heteroaryl or heteroaralkyl in
which the hetero atom or atoms are selected
from the group consisting or 1-4 O, S or N atoms
and the alkyl moiety associated with heteroaralkyl
has 1-6 carbon atoms-, said heteroaryl and hetero-
aralkyl groups being optionally substituted in
the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, amino, halo,
trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylamino, di(C1-C4)alkylamino, carboxy
and sulfo and in the alkyl moiety by 1-3 substituents
selected from hydroxy, amino, C1-C4 alkylamino,
di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo
and sulfo; or a pharmaceutically acceptable salt
thereof; which process comprises reacting an
intermediate of the formula
<IMG>
wherein R1, R8, R15, A and R2 are as defined above and
<IMG>
264
represents a mono-, bi- or polycyclic aromatic heterocyclic
radical containing a quaternizable nitrogen in the ring, said
ring being attached to A through a ring carbon atom, in an
inert organic solvent with an alkylating agent of the formula
R5-x'
wherein R5 is as defined above and X' is a conventional
leaving group so as to quaternize with the R5 group a
ring nitrogen of substituent
<IMG>
on intermediate II and form a compound of the formula
<IMG>
wherein R1, R8, R15, R2',A, <IMG> and X' are as defined above;
and, if desired, replacing counter ion X' by a different counter
ion and, if desired, removing the carboxyl protecting group R2'
to give the desired de-blocked compound of formule I, or a
pharmaceutically acceptable salt thereof.
265
12. A process according to claim 11 wherein R1
is hydrogen, CH3CH2-,
<IMGS>
13. A process according to claim 11 wherein R1
and R8 taken together represent
<IMG>
14. A process according to claim 11 wherein R1
is <IMG>
15. A process according to claim 11 wherein R1
is <IMG> and the absolute configuration is
5R, 6S, 8R.
16. A process according to claim 11 wherein
A is -CH2 - or -CH2CH2 -.
17. A process for the preparation of a compound
of the formula
<IMG>
266
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: 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, hetero-
aralkyl, 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 an d the alkyl moieties associated with said hetero-
cyclic 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
<IMGS>
-NR3R4
267
<IMGS>
-CO2R3
=O
<IMG>
-SR3
<IMGS>
-CN
-N3
-OSO3R3
<IMGS>
-OP(O)(OR3)(OR4)
268
<IMG>
-NR3CO2R4
-NO2
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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl wherein the hetero atom or atoms in the above-
named heterocyclic moieties are selected from the group
269
consisting of 1-4 oxygen, nitrogen or sulfur atoms and the
alkyl moieties associated with said heterocyclic moieties
have 1-6 carbon atoms; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-oxo ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
<IMGS>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
270
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above;
or R5 may be attached to
<IMG>
at another point on the ring so as to form a fused
heterocyclic or heteroaromatic ring, which ring may
contain additional hetero atoms selected from O,
N and S;
A is C1-C6 straight or branched chain alkylene:
R2 is hydrogen, an anionic charge or a conventional
readily removable carboxyl protecting group, pro-
viding that when R2 is hydrogen or a protecting group,
there is also present a counter ion; and
<IMG>
represents an aromatic 5- or 6-membered N-containing
heterocyclic ring containing 0-3 additional hetero
atoms selected from N, S or O, said heterocyclic ring
being optionally substituted at available ring carbon
atoms by 1-5 substituents independently selected from
the group consisting of C1-C4 alkyl; C1-C4 alkyl
substituted by 1-3 hydroxy, amino, C1-C4 alkylamino,
di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo or
sulfo; C3-C6 cycloalkyl; C3-C6 cycloalkyl (C1-C4) alkyl
optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl; C1-C4 alkoxy;
C1-C4 alkylthio; amino; C1-C4 alkylamino: di(C1-C4)-
alkylamino; halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy; sulfo;
271
<IMG> alkyl; hydroxy; amidino; guanidino;
pheny; phenyl substituted by 1-3 substituents
independently selected from amino, halo, hydroxy,
trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylamino, di(C1-C4)alkylamino, carboxy,
and sulfo; phenyl (C1-C4) alkyl in which the
phenyl portion is optionally substituted by 1-3
substituents mentioned above in connection with
phenyl and the alkyl portion is optionally
substituted by 1-3 substituents mentioned above
in connection with C1-C4 alkyl; and heteroaryl or
heteroaralkyl in which the hetero atom or atoms
are selected from the group consisting of 1-4 O,
S or N atoms and the alkyl moiety associated
with heteroaralkyl has 1-6 carbon atoms, said
heteroaryl and heteroaralkyl groups being
optionally substituted in the heterocyclic ring
moiety by 1-3 substituents independently selected
from hydroxy, amino, halo, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)-
alkylamino, carboxy and sulfo and in the alkyl
moiety by 1-3 substituents selected from hydroxy,
amino, C1-C4 alkylamino, di(C1-C4)alkylamino,
C1-C4 alkoxy, carboxy, halo and sulfo, and said
heterocyclic ring being optionally substituted at
available ring nitrogen atoms by 1-3 substituents
independently selected from the group consisting
of C1-C4 alkyl C1-C4 alkyl substituted by 1-3
hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkyl-
amino, C1-C4 alkoxy, carboxy, halo or sulfo
groups; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C1-C4)-
alkyl optionally substituted by 1-3
substituents mentioned above in connection
with C1-C4 alkyl; phenyl; phenyl
272
substituted by 1-3 substituents independently
selected from amino, halo, hydroxy, trifluoromethyl,
C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,
di(C1-C4) alkylamino, carboxy and sulfo; phenyl-
(C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl
portion may be optionally substituted by 1-3
substituents mentioned above in connection with
C1-C4 alkyl; and heteroaryl or heteroaralkyl in
which the hetero atom or atoms are selected
from the group consisting or 1-4 O, S or N atoms
and the alkyl moiety associated with heteroaralkyl
has 1-6 carbon atoms, said heteroaryl and hetero-
aralkyl groups being optionally substituted in
the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, amino, halo,
trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylamino, di(C1-C4) alkylamino, carboxy
and sulfo and in the alkyl moiety by 1-3 substituents
selected from hydroxy, amino, C1-C4 alkylamino,
di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo
and sulfo; or a pharmaceutically acceptable salt
thereof; which process comprises reacting an
intermediate of the formula
<IMG>
273
wherein R1, R8, R15, A and R2 are as defined above and
<IMG>
represents a mono-, bi- or polycyclic aromatic heterocyclic
radical containing a quaternizable nitrogen in the ring, said
ring being attached to A through a ring carbon atom, in an
inert organic solvent with an alkylating agent of the formula
R5-X'
wherein R5 is as defined above and X' is a conventional
leaving group so as to quaternize with the R5 group a
ring nitrogen of substituent
<IMG>
on intermediate II and form a compound of the formula
<IMG>
wherein R1, R8, R15, R2', A, <IMG> and X' are as defined above;
and, if desired, replacing counter ion X' by a different counter
ion and, if desired, removing the carboxyl protecting group R2'
to give the desired de-blocked compound of formula I, or 2
pharmaceutically acceptable salt thereof.
274
18. A process according to claim 17 wherein
the heterocyclic ring
<IMG>
is optionally substituted at available ring carbon or
nitrogen atoms by up to 5 substituents independently
selected from (lower)alkyl.
19. A process according to claim 18 wherein
A is - CH2 -, -CH2CH2 - or <IMG>.
20. A process according to claim 17 wherein
R1 is <IMG> and the absolute configuration is
5R, 6S, 8R.
21. A process for the preparation of a compound
of the formula
<IMG>
275
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: 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, hetero-
aralkyl, 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 hetero-
cyclic 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
<IMGS>
-NR3R4
276
<IMGS>
-CO2R3
=O
<IMG>
-SR3
<IMGS>
-CN
-N3
-OSO3R3
<IMGS>
-OP (O) (OR3) (OR4)
277
<IMG>
-NR3CO2R4
-NO2
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 l-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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl wherein the hetero atom or atoms in the above-
named heterocyclic moieties are selected from the group
278
consisting of 1-4 oxygen, nitrogen or sulfur atoms and the
alkyl moieties associated with said heterocyclic moieties
have 1-6 carbon atoms; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-COR3 ;
-OCONR3R4 ;
<IMG> ;
-oxo ;
-NR3R4
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG> ;
-SR3 ;
<IMGS> ;
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
279
phenyl optionally substituted. by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above; or R5 may be attached to
<IMG>
at another point on the ring so as to form a fused
heterocyclic or heteroaromatic ring, which ring may
contain additional hetero atoms selected from O, N and
S;
A is C1-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 ion; and
<IMG>
represents a radical selected from the group consisting of
<IMG>
wherein R6, R7 and R10 are independently selected from hydrogen;
C1-C4 alkyl; C1-C4 alkyl substituted by hydroxy, C1-C4 alkylamino,
di(C1-C4 alkyl)amino, C1-C4 alkoxy, amino, sulfo, carboxy or halo;
C3-C6 cycloalkyl; C1-C4 alkoxy; C1-C4 alkylthio; amino; C1-C4 alkyl-
amino; di(C1-C4 alkyl)amino; halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy;
280
<IMG> alkyl; hydroxy; amidino; guanidino; phenyl; phenyl
substituted by one, two or three amino, halo, hydroxyl,
trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4) alkyl in which the phenyl portion may be
optionally substituted by 1-3 substitutents mentioned above
in connection with phenyl and the alkyl portion may be
optionally substituted by 1-3 substituents mentioned above
in connection with C1-C4 alkyl; and heteroaryl and heteroaralkyl
in which the hetero atom or atoms in the group consisting of
1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety
associated with said heteroaralkyl moiety has 1-6 carbon
atoms; or wherein two of R6, R7 or R10 taken together may be
a fused saturated carbocyclic ring, a fused aromatic carbocyclic
ring, a fused non-aromatic heterocyclic ring or a fused hetero-
aromatic ring, said fused rings being optionally substituted
by 1 or 2 of the substituents defined above for R6, R7 and R10;
<IMGS>
optionally substituted on a carbon atom by 1-3 substituents
independently selected from C1-C4 alkyl; C1-C4 alkyl substituted
by hydroxy, C1-C4 alkylanino, di(C1-C4 alkyl) amino, sulfo,
C1-C4 alkoxy; amino; carboxy or halogen; C3-C6 cycloalkyl;
C1-C4 alkoxy; C1-C4 alkylthio; amino; C1-C6 alkylamino;
di(C1-C4 alkyl)amino; halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy;
281
<IMG> alkyl; hydroxy; amidino; guanidino; phenyl; phenyl
substituted by one, two or three amino, halo, hydroxyl,
trifluoromethyl C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl portion
may be optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl; and heteroaryl
or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety
has 1-6 carbon atoms, or optionally substituted so as to form
a fused carbocyclic, heterocyclic or heteroaromatic ring
optionally substituted by 1 or 2 of the substituents defined
above;
<IMGS>
optionally substituted on a carbon atom by one or two sub-
stituents independently selected from C1-C4 alkyl; C1-C4 alkyl
substituted by hydroxy, C1-C4 alkylamino, di(C1-C4 alkyl) amino,
C1-C4 alkoxy, sulfo, amino, carboxy or halogen; C3-C6
cycloalkyl; C1-C4 alkoxy; C1-C4 alkylthio; amino; C1-C4
282
alkylamino; di (C1-C4 alkyl) amino; halo; C1-C4 alkanoylamino;
C1-C4 alkanoyloxy; carboxy;
<IMG>; hydroxy; amidino, guanidino, phenyl; phenyl
substituted by one, two or three amino, halo, hydroxyl, tri-
fluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4) alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl portion
may be optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl and heteroaryl
or heteroaralkyl in which 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
moiety associated with said heteroaralkyl moiety has 1-6 carbon
atoms, or optionally substituted so as to form a fused carbo-
cyclic, heterocyclic or heteroaromatic ring optionally substituted
by 1 or 2 of the substituents defined above;
<IMGS>
optionally substituted on a carbon atom by a substituent
independently selected from C1-C4 alkyl; C1-C4 alkyl sub-
stituted by hydroxy, amino, C1-C4 alkylamino, di(C1-C4 alkyl)-
amino, C1-C4 alkoxy, sulfo, carboxy or halogen; C3-C6 cyclo-
283
alkyl; C2-C4 alkoxy: C1-C4 alkylthio: amino: C1-C4 alkylamino;
di(C1-C4 alkyl)amino; halo; C1-C4 alkanoylamino: C1-C4
alkanoyloxy; carboxy;
<IMG>; hydroxy; amidino: guanidino, phenyl; phenyl
substituted by one, two or three amino, halo, hydroxyl, tri-
fluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl portion
may be optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl; and heteroaryl
or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety
has 1-6 carbon atoms:
<IMGS>
wherein X is O, S or NR in which R is C1-C4 alkyl; C1-C4
alkyl substituted by 1-3 hydroxy, amino, C1-C4 alkylamino,
di (C1-C4) alkylamino, C1-C4 alkoxy, carboxy, halo or sulfo
groups: C3-C6 cycloalkyl: C3-C6 cycloalkyl(C1-C4)alkyl
optionally substituted by 1-3 substituents mentioned above
in connection with C1-C4 alkyl; phenyl; phenyl substituted
by 1-3 substituents independently selected from amino, halo,
hydroxy, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4
alkylamino, di (C1-C4) alkylamino, carboxy and sulfo:
phenyl(C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl
portion may be optionally substituted by 2-3 substituents
284
mentioned above in connection with C1-C4 alkyl; and heteroaryl
and heteroaralkyl in which the hetero atom or atoms are selected
from the group consisting of 1-4, O, S or N atoms and the
alkyl moiety associated with heteroaralkyl has 1-6 carbon
atoms, said heteroaryl and heteroaralkyl groups being optionally
substituted in the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, amino, halo, trifluoro-
methyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C2-C4)-
alkylamino, carboxy and sulfo and in the alkyl moiety by
1-3 substituents selected from hydroxy, amino, C1-C4 alkyl-
amino, di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo
and sulfo, said radical being optionally substituted on a
carbon atom by one or more substituents independently selected
from C1-C4 alkyl; C1-C4 alkyl substituted by hydroxy, C1-C4
alkylamino, di(C1-C4 alkyl)amino, C1-C4 alkoxy, amino, sulfo,
carboxy or halogen; C3-C6 cycloalkyl: C1-C4 alkoxy; C1-C4
alkylthio: amino; C1-C4 alkylamino: di(C1-C4 alkyl)amino;
halo; C1-C4 alkanoylamino; C2-C4 alkanoyloxy: carboxy:
<IMG>; hydroxy; amidino; guanidino, phenyl;
phenyl substituted by one, two or three amino, halo,
hydroxyl, trifluoromethyl, C2-C4 alkyl or C1-C4 alkoxy groups:
phenyl (C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned above
in connection with phenyl and the alkyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl;
and heteroaryl or heteroaralkyl in which the hetero atom or
atoms in the above-named heterocycle moieties are selected
from the group consisting of 1-4 oxygen, nitrogen or sulfur
atoms and the alkyl moiety associated with said heteroaralkyl
moiety has 1-6 carbon atoms, or optionally substituted so as
to form a fused carbocyclic, heterocyclic or heteroaromatic
ring optionally substituted by 1 or 2 of the substituents
defined above:
285
<IMGS>
wherein X is O, S or NR in which R is C1-C4 alkyl; C1-C4
alkyl substituted by 1-3 hydroxy, amino, C1-C4 alkylamino,
di (C1-C4) alkylamino, C1-C4 alkoxy, carboxy, halo or sulfo
groups: C3-C6 cycloalkyl: C3-C6 cycloalkyl (C1-C4) alkyl
optionally substituted by 1-3 substituents mentioned
above in connection with-C1-C4 alkyl:
phenyl; phenyl substituted by 1-3 substituents independently
selected from amino, halo, hydroxy, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)alkylamino,
carboxy and sulfo; phenyl (C1-C4)alkyl in which the phenyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with phenyl and the alkyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with C1-C4 alkyl; and heteroaryl
and heteroaralkyl in which the hetero atom or atoms are selected
from the group consisting of 1-4, O, S or N atoms and the
alkyl moiety associated with heteroaralkyl has 1-6 carbon
atoms, said heteroaryl and heteroaralkyl groups being optionally
substituted in the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, amino, halo, trifluoro-
methyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di (C1-C4)-
alkylamino, carboxy and sulfo and in the alkyl moiety by
1-3 substituents selected from hydroxy, amino, C1-C4 alkyl-
amino, di (C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo and sulfo,
said heteroaromatic radical being optionally substituted on a
carbon atom by a substituent selected from C1-C4 alkyl:
C1-C4 alkyl substituted by hydroxy, C1-C4 alkylamino,
di(C1-C4 alkyl)amino, C1-C4- alkoxy, amino, sulfo, carboxy
286
or halogen; C3-C6 cycloalkyl; C1-C4 alkoxy: C1-C4 alkylthio:
amino; C1-C4 alkylamino; di(C1-C4)alkylamino: halo; C1-C4
alkanoylamino; C1-C4 alkanoyloxy; carboxy;
<IMG>; hydroxy; amidino; guanidino; phenyl;
phenyl substituted by one, two or three amino, halo, hydroxyl,
trilfuoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl portion
may be optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl; and heteroaryl
or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety has
1-6 carbon atoms; and
<IMGS>
287
wherein R is C1-C4 alkyl: C1-C4 alkyl substituted by 1-3
hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkylamino,
C1-C4 alkoxy, carboxy, halo or sulfo groups: C3-C6 cyclo-
alkyl: C3-C6 cycloalkyl(C1-C4)alkyl optionally substituted
by 1-3 substituents mentioned above in connection With C1-C4 alkyl;
phenyl; phenyl substituted by 1-3 substituents independently
selected from amino, halo, hydroxy, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)alkylamino,
carboxy and sulfo; phenyl(C1-C4)alkyl in which the phenyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with phenyl and the alkyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with C1-C4 alkyl: and heteroaryl
and heteroaralkyl in which the hetero atom or atoms are selected
from the group consisting of 1-4, O, S or N atoms and the
alkyl moiety associated with heteroaralkyl has 1-6 carbon
atoms, said heteroaryl and heteroaralkyl groups being optionally
substituted in the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, amino, halo, trifluoro-
methyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di (C1-C4)-,
alkylamino, carboxy and sulfo and in the alkyl moiety by
1-3 substituents selected from hydroxy, amino, C1-C4 alkyl-
amino, di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo and sulfo;
or a pharmaceutically acceptable salt thereof; which process
comprises reacting an intermediate of the formula
<IMG>
288
wherein R1, R8, R15, A and R2 are as defined above and
<IMG>
represents a mono-, bi- or poly cyclic aromatic heterocyclic
radical containing a quaternizable nitrogen in the ring, said
ring being attached to A through a ring carbon atom, in an
inert organic solvent with an alkylating agent of the formula
R5~X'
wherein R5 is as defined above and X' is a conventional
leaving group so as to quaternize with the R5 group a
ring nitrogen of substituent
<IMG>
on intermediate II and form a compound of the formula
<IMG>
wherein R1, R8, R15, R2',A, <IMG> ~X' are as defined above;
and, if desired, replacing counter ion X' by a different counter
ion and, if desired, removing the carboxyl protecting group R2
to give the desired de-blocked compound of formula I, or a
pharmaceutically acceptable salt thereof.
289
22. A process according to claim 21 wherein
<IMG>
represents a radical selected from the group consisting of
(a)
<IMG>
wherein R5 is C1-C6 alkyl and R6, R7 and R10 are each
independently hydrogen or C1-C4 alkyl;
(b)
<IMGS>
wherein R is C1-C6 alkyl and wherein available ring carbon
atoms are optionally substituted by 1-3 substituents
independently selected from C1-C4 alkyl
290
<IMGS>
wherein R5 is C1-C6 alkyl and wherein available ring
carbon atoms are optionally substituted by 1 or 2
substituents independently selected from C1-C4 alkyl;
<IMG>
wherein R5 is C1-C6 alkyl and wherein an available
ring carbon atom is optionally substituted by C1-C4
alkyl;
291
<IMGS>
wherein R5 is C1-C6 alkyl, X is O, S or NR in which R
is C1-C4 alkyl and wherein one or more available ring
carbon atoms is optionally substituted by C1-C4
alkyl;
<IMGS>
wherein R5 is C1-C6 alkyl, X is O, S or NR in which R
is C1-C4 alkyl and wherein one or more available ring
carbon atoms is optionally substituted by C1-C4
alkyl; and
<IMGS>
292
<IMG>
wherein R5 is C1-C6 alkyl and R is C1-C4alkyl.
23. A process according to claim 22 wherein R1
is hydrogen, CH3CH2-,
<IMGS>
24. A process according to claim 22 wherein R1
and R8 taken together represent <IMG>.
25. A process according to claim 22 wherein
R1 is <IMG>.
26. A process according to claim 22 wherein
R1 is <IMG> and the absolute configuration is 5R, 6S, 8R.
27. A process according to claim 21 wherein
A is -CH2- or -CH2CH2-.
28. A precess for the preparation of a compound
of the formula
<IMG>
293
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: 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, hetero-
aralkyl, 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 hetero-
cyclic 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
<IMGS>
-NR3R4
<IMGS>
-CO2R3
=O
294
<IMG>
-SR3
<IMGS>
-CN
-N3
-OSO3R3
<IMGS>
-OP(O)(OR3)(OR4)
<IMG>
-NR3CO2R4
-NO2
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
295
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-metered
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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-oxo ;
-NR3R4 ;
R3CONR4- ;
296
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
<IMGS>
-SO3R3
-CO2R3 ;
-CONR3R4 ;
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above: or R5 may be attached to
<IMG>
at another point on the ring so as to form a fused hetero-
cyclic or heteroaromatic ring, which ring may contain
additional hetero atoms selected from O, N and S;
A is C1-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 ion; and
<IMG>
297
represents a radical selected from the group consisting of
<IMG>
wherein R6, R7 and R10 are independently selected from hydrogen;
C1-C4 alkyl; C1-C4 alkyl substituted by hydroxy, C1-C4 alkylamino,
di(C1-C4 alkyl)amino, C1-C4 alkoxy, amino, sulfo, carboxy or halo;
C3-C6-cycloalkyl; C1-C4 alkoxy: C2-C4 alkylthio; amino; C1-C4 alkyl-
amino; di (C1-C4 alkyl)amino: halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy;
<IMG>; hydroxy; amidino; guanidino; phenyl; phenyl
substituted by one, two or three amino, halo, hydroxyl,
trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4) alkyl in which the phenyl portion may be
optionally substituted by 1-3 substitutents mentioned above
in connection with phenyl and the alkyl portion may be
optionally substituted by 1-3 substituents mentioned above
in connection with C1-C4 alkyl: and heteroaryl and heteroaralkyl
in which the hetero atom or atoms in the group consisting of
1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety
associated with said heteroaralkyl moiety has 1-6 carbon
atoms; or wherein two of R6, R7 or R10 taken together may be
a fused saturated carbocyclic ring, a fused aromatic carbocyclic
ring, a fused non-aromatic heterocyclic ring or a fused hetero-
aromatic ring, said fused rings being optionally substituted
by 1 or 2 of the substituents defined above for R6, R7 and R10,
or a pharmaceutically acceptable salt thereof
298
which process comprises reacting an intermediate of the
formula
<IMG>
wherein R1, R8, R15, A and R2 are as defined above and
<IMG>
represents a mono-, bi- or polycyclic aromatic heterocyclic
radical containing a quaternizable nitrogen in the ring, said
ring being attached to A through a ring carbon atom, in an
inert organic solvent with an alkylating agent of the formula
R5~X'
wherein R5 is as defined above and X' is a conventional
leaving group so as to quaternize with the R5 group a
ring nitrogen of substituent
<IMG>
on intermediate II and form a compound of the formula
<IMG>
299
wherein R1, R8, R15, R2',A, <IMG> and ~X' are as defined above;
and, if desired, replacing counter ion X' by a different counter
ion and, if desired, removing the carboxyl protecting group R2'
to give the desired de-blocked compound of formula I, or a
pharmaceutically acceptable salt thereof.
29. A process according to claim 28 wherein R1 is
hydrogen, CH3CH2-,
<IMGS>.
30. A process according to claim 28 wherein R1 and
R8 taken together represent <IMG>.
31. A process according to claim 28 wherein R1 is
<IMG>.
32. A process according to claim 28 wherein R1 is
<IMG> and tile absolute configuration is 5R, 6S, 8R.
33. A process according to claim 28 wherein
A is - CH2- or -CH2CH2-.
34. A process for the preparation of a compound of
the formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: 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, hetero-
aralkyl, 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 an d the alkyl moieties associated with said hetero-
cyclic 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
<IMGS>
-NR3R4
<IMGS>
301
<IMGS>
-CO2R3
=O
<IMG>
-SR3
<IMGS>
-CN
-N3
-OSO3R3
<IMGS>
-OP(O)(OR3)(OR4)
<IMG>
-NR3CO2R4
-NO2
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
302
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; R5 is selected from the group consisting of
substituted and unsubstituted: 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 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; wherein
the above-named R5 radicals are optionally
substituted by 1-3 substituents independently
selected from:
303
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl:
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG> :
-oxo ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CO2NR3R4 ;
<IMG>
-SR3 ;
<IMGS> ~
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
phenyl optionally substituted. by 1-3 fluoro, chloro,
bromo, C2-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above; or R5 may be attached to
304
<IMG>
at another point on the ring so as to form a fused
heterocyclic or heteroaromatic ring, Which ring may
contain additional hetero atoms selected from O, N and
S;
A is C1-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 ion; and
<IMG>
represents a radical of the formula
<IMGS>
optionally substituted on a carbon atom by 1-3 substituents
independently selected from C1-C4 alkyl; C1-C4 alkyl substituted
by hydroxy, C1-C4 alkylamino, di (C1-C4 alkyl) amino, sulfo,
C1-C4 alkoxy, amino, carboxy or halogen; C3-C6 cycloalkyl;
C1-C4 alkoxy; C1-C4 alkylthio; amino; C1-C4 alkylamino;
di (C1-C4 alkyl) amino; halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy;
305
<IMG>
<IMG>; hydroxy; amidino; guanidino; phenyl; phenyl
substituted by one, two or three amino, halo, hydroxyl,
trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl portion
may be optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl; and heteroaryl
or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety
has 1-6 carbon atoms, or optionally substituted so as to form
a fused carbocyclic, heterocyclic or heteroaromatic ring
optionally substituted by 1 or 2 of the substituents defined above;
or by a pharmaceutically acceptable salt thereof; which process
comprises reacting an intermediate of the formula
<IMG>
wherein R1, R8, R15, A and R2 are as defined above and
<IMG>
represents a mono-, bi- or polycyclic aromatic heterocyclic
radical containing a quaternizable nitrogen in the ring, said
ring being attached to A through a ring carbon atom, in an
inert organic solvent with an alkylating agent of the formula
R5~X'
wherein R5 is as defined above and X' is a conventional
leaving group so as to quaternize with the R5 group a
ring nitrogen of substituent
<IMG>
on intermediate II and form a compound of the formula
<IMG>
wherein R1, R8, R15, R2' ,A, <IMG> and ~X' are as defined above;
and, if desired, replacing counter ion X' by a different counter
ion and, if desired, removing the carboxyl protecting group R2'
to give the desired de-blocked compound of formula I, or a
pharmaceutically acceptable salt thereof.
35. A process according to claim 34 wherein
is <IMGS>
307
36. A process according to claim 34 wherein
is <IMGS>
37. A process according to claim 34 wherein
is <IMGS>
38. A process according to claim 34 wherein
R1 is hydrogen, CH3CH2-,
<IMGS>
39. A process according to claim 34 wherein
R1 and R6 taken together represent <IMG>.
308
40. a process according to claim 34 wherein
R1 is <IMG>.
41. A process according to claim 34 wherein
R1 is <IMG> and the absolute configuration is
5R, 6S, 8R.
42. A process according to claim 34 wherein
A is -CH2- or -CH2CH2-, R1 is
<IMG>
and the absolute configuration is 5R, 6S, 8R.
43. A process for the preparation of a compound of
the formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: 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, hetero-
aralkyl, 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 hetero-
309
cyclic 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
<IMGS>
-NR3R4
<IMGS>
-CO2R3
=O
<IMG>
-SR3
<IMGS>
310
-CN
-N3
-OSO3R3
<IMGS>
-OP(O)(OR3)(OR4)
<IMG>
-NR3CO2R4
-NO2
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
311
and R8 taken together represent C2-C10 alkylidene or C2-C10
alkylidene substituted by hydroxy; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-oxo ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
312
<IMG>
-SR3 ;
<IMG>
-SO3R3 ;
-CO2R3 :
-CONR3R4 ;
-CN: or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5
substituents are as defined above; or R5 may be
attached to
<IMG>
at another point on the ring so as to form a fused
heterocyclic or heteroaromatic ring, which ring may
contain additional hetero atoms selected from O, N
and S;
A is C1-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 ion; and
<IMG>
313
represents a radical of the formula
<IMGS>
optionally substituted on a carbon atom by 1-3
substituents independently selected from C1-C4 alkyl;
C1-C4 alkyl substituted by hydroxy, C1-C4 alkylamino,
di(C1-C4 alkyl)amino, sulfo, C1-C4 alkoxy, amino,
carboxy and halogen; C3-C6 cycloalkyl; C1-C4
alkoxy; C1-C4 alkylthio; amino; C1-C4 alkylamino;
di(C1-C4 alkyl)amino; halo; C1-C4 alkanoylamino; C1-
C4 alkanoyloxy; carboxy;
O
-C-OC1-C4 alkyl; hydroxy; amidino; guanidino; phenyl;
phenyl substituted by one, two or three amino, halo,
hydroxyl, trifluoromethyl, C1-C4 alkyl or C1-C4
alkoxy groups; phenyl (C1-C4) alkyl in which the
phenyl portion may be optionally substituted by 1-3
substituents mentioned above in connection with
phenyl and the alkyl portion may be optionally
substituted by 1-3 substituents mentioned above in
connection with C1-C4 alkyl; and heteroaryl or
heteroaralkyl in which 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 moiety associated with
said heteroaralkyl moiety has 1-6 carbon
314
atoms, or optionally substituted so as to form a fused
carbocyclic, heterocyclic or heteroaromatic ring
optionally substituted by 1 or 2 of the substituents defined
above or a pharmaceutically acceptable salt thereof ;
which process comprises the steps of reacting an intermediate
of the formula
<IMG>
wherein R1, R8, R15, A and R2 are as defined above and
<IMG>
represents a mono-, bi- or polycyclic aromatic heterocyclic
radical containing a quaternizable nitrogen in the ring, said
ring being attached to A through a ring carbon atom, in an
inert organic solvent with an alkylating agent of the formula
R5-X'
wherein R5 is as defined above and X' is a conventional
leaving group so as to quaternize with the R5 group a
ring nitrogen of substituent
<IMG>
on intermediate II and form a compound of the formula
315
<IMG>
wherein R1, R8, R15, R2 ,A, <IMG> and 'X' are as defined above;
and, if desired, replacing counter ion X' by a different counter
ion and, if desired, removing the carboxyl protecting croup R2'
to give the desired de-blocked compound of formula I, or a
pharmaceutically acceptable salt thereof.
44. A process according to claim 43 wherein R1 is hydrogen,
CH3CH2-,
<IMGS>
45. A process according to claim 43 wherein R1 and R8 taken
together represent
<IMG>
46. A process according to claim 43 wherein R1 is
<IMG>
316
47. A process according to claim 43 wherein R1 is
<IMG> and the absolute configuration is 5R, 6S, 8R.
48. A process according to claim 43 wherein A is
-CH2- or -CH2CH2- .
49. A process for the preparation of a compound of the
formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: alkyl, alkenyl
and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cyclo-
alkylalkyl, 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, hetero-
cyclyl 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; wherein the substituent or substituents relative
to the above-named radicals are independently selected from the
group consisting of
317
C1-C6 alkyl optionally substituted by amino, halo,
hydroxy or carboxyl
halo
-OR3
<IMG>
<IMG>
-CO2R3
=O
<IMG>
-SR3
<IMG>
-CN
-N3
-OSO3R3
<IMG>
318
<IMG>
-OP(O)(OR3)(OR4)
<IMG>
-NO2
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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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
319
moiety is phenyl and the aliphatic portion has 1-6 carbon
atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-oxo ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
<IMG>
-SO3R3 ;
320
-CO2R3 ;
-CONR3R4 ;
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SOR3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above;
or R5 may be attached to
<IMG>
at another point on the ring so as to form a fused hetero-
cyclic or heteroaromatic ring, which ring may contain
additional hetero atoms selected from O, N and S;
A is C1-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 ion; and
<IMG>
represents a radical of the formula
<IMGS>
321
optionally substituted on a carbon atom by a substituent
independently selected from C1-C4 alkyl; C1-C4 alkyl
substituted by hydroxy, amino, C1-C4 alkylamino, di(C1-C4)
alkylamino, sulfo, C1-C4 alkoxy, carboxy or halogen;
C3-C6 cycloalkyl; C1-C4 alkoxy; C1-C4 alkylthio; amino;
C1-C4 alkylamino; di(C1-C4) alkylamino; halo; C1-C4 alkanoyl-
amino; C1-C4 alkanoyloxy; carboxy;
<IMG> alkyl; hydroxy; amidino; guanidino, phenyl; phenyl
substituted by one, two or three amino, halo, hydroxyl, tri-
fluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4) alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned above in
connection with phenyl and the alkyl portion may be optionally
substituted by 1-3 substituents mentioned above in connection
with C1-C4 alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said
heteroaralkyl moiety has 1-6 carbon atoms; or a pharmaceutically
acceptable salt thereof; which process comprises the steps of
reacting an intermediate of the formula
<IMG>
wherein R1, R8, R15, A and R2 are as defined above and
<IMG>
322
represents a mono-, bi- or polycyclic aromatic heterocyclic
radical containing a quaternizable nitrogen in the ring, said
ring being attached to A through a ring carbon atom, in an
inert organic solvent with an alkylating agent of the formula
R5-X'
wherein R5 is as defined above and X' is a conventional
leaving group so as to quaternize with the R5 group a
ring nitrogen of substituent
<IMG>
on intermediate II and form a compound of the formula
<IMG>
wherein R1, R B, R15, R2 ,A, <IMG> and 'X' are as defined above;
and, if desired, replacing counter ion X' by a different counter
ion and, if desired, removing the carboxyl protecting group R2'
to give the desired de-blocked compound of formula I, or a
pharmaceutically acceptable salt thereof.
50. A process according to claim 49 wherein R1 is hydrogen,
CH3CH2- , <IMGS>
323
51. A process according to claim 49 wherein R1 and R8
taken together represent
<IMG>
52. A process according to claim 49 wherein R1 is
<IMG>
53. A process according to claim 49 wherein R1 is
<IMG> and the absolute configuration is 5R, 6S, 8R.
54. A Process according to claim 49 wherein A is -CH2-
or -CH2CH2-.
55. A process for the preparation of a compound of the
formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: alkyl, alkenyl
and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cyclo-
alkylalkyl, 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, hetero-
cyclyl and heterocyclylalkyl wherein the hetero atom or atoms in
the above-named heterocyclic moieties are selected from the group
324
consisting 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>
-NR3R4
<IMG>
=O
<IMG>
325
-CN
-N3
-OSO3R3
<IMG>
-OP(O)(OR3)(OR4)
<IMG>
-NO2
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; R5 is selected from the
326
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-oxo ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
327
<IMG>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above: or R5 may be attached to
<IMG>
at another point on the ring so as to form a fused hetero-
cyclic or heteroaromatic ring, which ring may contain
additional hetero atoms selected from O, N and S;
A is C1-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 ion; and
<IMG>
represents a radical of the formula
<IMGS>
wherein X is O, S or NR in which R is C1-C4 alkyl; C1-C4
alkyl substituted by 1-3 hydroxy, amino, C1-C4 alkylamino,
di (C1-C4) alkylamino, C1-C4 alkoxy, carboxy, halo or sulfo
328
groups; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C1-C4)alkyl
optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl;
phenyl; phenyl substituted by 1-3 substituents independently
selected from amino, halo, hydroxy, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)alkylamino,
carboxy and sulfo; phenyl(C1-C4)alkyl in which the phenyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with phenyl and the alkyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with C1-C4 alkyl; and heteroaryl
and heteroaralkyl in which the hetero atom or atoms are selected
from the group consisting of 1-4, O, S or N atoms and the
alkyl moiety associated with heteroaralkyl has 1-6 carbon
atoms, said heteroaryl and heteroaralkyl groups being optionally
substituted in the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, amino, halo, trifluoro-
methyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)-
alkylamino, carboxy and sulfo and in the alkyl moiety by
1-3 substituents selected from hydroxy, amino, C1-C4 alkyl-
amino, di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo
and sulfo, said heteroaromatic radical being optionally
substituted on a carbon atom by one or more substituents
independently selected from C1-C4 alkyl; C1-C4 alkyl substituted
by hydroxy, C1-C4 alkylamino, di(C1-C4)alkylamino, C1-C4 alkoxy,
amino, sulfo, carboxy or halogen; C3-C6 cycloalkyl; C1-C4 alkoxy,
C1-C4 alkylthio; amino; C1-C4 alkylamino, di(C1-C4)alkylamino;
halo; C1-C4 alkanoylamino; C1-C4 alkanoyloxy; carboxy;
<IMG> alkyl; hydroxy; amidino; guanidino, phenyl; phenyl
substituted by one, two or three amino, halo, hydroxyl,
trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4)alkyl in which the phenyl portion may be optionally
substituted by 1-3 substituents mentioned above in connection
with phenyl and the alkyl portion may be optionally substituted
329
by 1-3 substituents mentioned above in connection with C1-C4
alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said
heteroaralkyl moiety has 1-6 carbon atoms, or optionally
substituted so as to form a fused carbocyclic, heterocyclic
or heteroaromatic ring optionally substituted by 1 or 2 of
the substituents defined above: or a pharmaceutically acceptable
salt thereof; which process comprises the steps of reacting an
intermediate of the formula
<IMG>
wherein R1, R8, R15, A and R2 are as defined above and
<IMG>
represents a mono-, bi- or polycyclic aromatic heterocyclic
radical containing a quaternizable nitrogen in the ring, said
ring being attached to A through a ring carbon atom, in an
inert organic solvent with an alkylating agent of the formula
R5-X'
wherein R5 is as defined above and X' is a conventional
leaving group so as to guaternize with the R5 group a
ring nitrogen of substituent
<IMG>
330
on intermediate II and form a compound of the formula
<IMG>
wherein R1, R8, R15, R2' ,A, <IMG> and 'X' are as defined above;
and, if desired, replacing counter ion X' by a different counter
ion and, if desired, removing the carboxyl protecting croup R2'
to give the desired de-blocked compound of formula I, or a
pharmaceutically acceptable salt thereof.
56. A process according to claim 55 wherein R1 is hydrogen,
CH3CH2- , <IMGS>
57. A process according to claim 55 wherein R1 and R8
taken together represent <IMG>
58. A process according to claim 55 wherein R1 is
<IMG>
59. A process according to claim 55 wherein R1 is
<IMG> and the absolute configuration is 5R, 6S, 8R.
331
60. A process according to claim 55 wherein A is
-CH2- or -CH2CH2-.
61. A process for the preparation of a compound of the
formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: 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, hetero-
aralkyl, 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 hetero-
cyclic 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>
-NR3R4
332
<IMG>
-CO2R3
=O
<IMG>
SR3
<IMG>
-CN
-N3
-OSO3R3
<IMG>
-OP(O)(OR3)(OR4)
333
<IMG>
-NR3CO2R4
-NO2
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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl wherein the hetero atom or atoms in the above-
named heterocyclic moieties are selected from the group
334
consisting of 1-4 oxygen, nitrogen or sulfur atoms and the
alkyl moieties associated with said heterocyclic moieties
have 1-6 carbon atoms; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl:
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-oxo ;
-NR3R4;
R3CONR4 ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
<IMG>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
335
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 OR -
-CONR3R4, wherein R3, R4, and R9 in such R5
substituent are as defined above; or R5 may be
attached to
<IMG>
at another point on the ring so as to form a fused
heterocyclic or heteroaromatic ring, which ring may
contain additional hetero atoms selected from O, N
and S;
A is C1-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 ion; and
<IMG>
represents a radical of the formula
<IMGS>
wherein X is O, S or NR in which R is C1-C4 alkyl;
C1-C4 alkyl substituted by 1-3 hydroxy, amino, C1-C4
alkylamino, di(C1-C4)alkylamino, C1-C4 alkoxy,
carboxy, halo or sulfo
336
groups; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C1-C4)alkyl
optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl; phenyl;
phenyl substituted by 1-3 substituents independently
selected from amino, halo, hydroxy, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)alkylamino,
carboxy and sulfo; phenyl(C1-C4)alkyl in which the phenyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with phenyl and the alkyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with C1-C4 alkyl; and heteroaryl
and heteroaralkyl in which the hetero atom or atoms are selected
from the group consisting of 1-4, O, S or N atoms and the
alkyl moiety associated with heteroaralkyl has 1-6 carbon
atoms, said heteroaryl and heteroaralkyl groups being
optionally substituted in the heterocyclic ring moiety by 1-3
substitutents independently selected from hydroxy, amino, halo,
trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,
di(C1-C4)alkylamino, carboxy and sulfo and in the alkyl moiety
by 1-3 substituents selected from hydroxy, amino, C1-C4 alkyl-
amino, di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo and sulfo,
said heteroaromatic radical being optionally substituted on a
carbon atom by a substituent selected from C1-C4 alkyl; C1-C4 alkyl
substituted by hydroxy, C1-C4 alkylamino, di(C1-C4)alkylamino,
C1-C4 alkoxy, amino, sulfo, carboxy or halogen; C3-C6 cycloalkyl;
C1-C4 alkoxy, C1-C4 alkylthio; amino; C1-C4 alkylamino; di(C1-C4)-
alkylamino; halo; C1-C4 alkanoylamino; C1-C4 alkanoyloxy; carboxy;
<IMG> alkyl; hydroxy; amidino; guanidino; phenyl; phenyl
substituted by one, two or three amino, halo, hydroxyl,
trifluoromethyl, C1-C4 alkyl or C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4)alkyl in which the phenyl portion may be optionally
substituted by 1-3 substituents mentioned above in connection
with phenyl and the alkyl portion may be optionally substituted
by 1-3 substituents mentioned above in connection with C1-C4 alkyl;
337
and heteroaryl or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety
has 1-6 carbon atoms; or a pharmaceutically acceptable salt
thereof; which process comprises the steps of reacting an
intermediate of the formula
<IMG>
wherein R1, R8, R15, A and R2~ are as defined above and
<IMG>
represents a mono-, bi- or polycyclic aromatic heterocyclic
radical containing a quaternizable nitrogen in the ring, said
ring being attached to A through a ring carbon atom, in an
inert organic solvent with an alkylating agent of the formula
R5-X'
wherein R5 is as defined above and X' is a conventional
leaving group so as to quaternize with the R5 group a
ring nitrogen of substituent
<IMG>
on intermediate II and form a compound of the formula
338
<IMG>
wherein R1, R8, R15, R2' ,A, <IMG> and X' are as defined above;
and, if desired, replacing counter ion X' by a different counter
ion and, if desired, removing the carboxyl protecting group R2'
to give the desired de-blocked compound of formula I, or a
pharmaceutically acceptable salt thereof.
62. A process according to claim 61 wherein R1 is hydrogen,
CH3CH2-, <IMGS>
63. A process according to claim 61 wherein R1 and R8 taken
together represent <IMG>
64. A process according to claim 61 wherein R1 is
<IMG>
65. A process according to claim 61 wherein R1 is
<IMG> and the absolute configuration is 5R, 6S, 8R.
66. A process according to claim 61 wherein A is
-CH2- or -CH2CH2-.
339
67. A process for the preparation of a compound of the
formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: 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, hetero-
aralkyl, 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 hetero-
cyclic 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
<IMGS>
-NR3R4
340
<IMGS>
-CO2R3
=O
<IMG>
-SR3
<IMGS>
-CN
-N3~~
-OSO3R3
<IMGS>
-OP(O)(OR3)(OR4)
341
<IMG>
-NR3CO2R4
-NO2
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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl 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
342
alkyl moieties associated with said heterocyclic moieties
have 1-6 carbon atoms; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-oxo ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
<IMGS>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
343
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above; or R5 may be attached to
<IMG>
at another point on the ring so as to form a fused
heterocyclic or heteroaromatic ring, which ring may
contain additional hetero atoms selected from O, N and
S;
A is C1-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 ion: and
<IMG>
represents a radical of the formula
<IMGS>
344
<IMGS>
wherein R is C1-C4 alkyl; C1-C4 alkyl substituted by 1-3
hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkylamino,
C1-C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cyclo-
alkyl; C3-C6 cycloalkyl(C1-C4)alkyl optionally substituted
by 1-3 substituents mentioned above in connection with C1-C4 alkyl;
phenyl; phenyl substituted by 1-3 substituents independently
selected from amino, halo, hydroxy, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)alkylamino,
carboxy and sulfo; phenyl(C1-C4)alkyl in which the phenyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with phenyl and the alkyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with C1-C4 alkyl; and heteroaryl
and heteroaralkyl in which the hetero atom or atoms are selected
from the group consisting of 1-4, O, S or N atoms and the
alkyl moiety associated with heteroaralkyl has 1-6 carbon
atoms, said heteroaryl and heteroaralkyl groups being optionally
substituted in the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, amino, halo, trifluoro-
methyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)-
alkylamino, carboxy and sulfo and in the alkyl moiety by
1-3 substituents selected from hydroxy, amino, C1-C4 alkyl-
amino, di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo and sulfo;
or a pharmaceutcally acceptable salt thereof; which process comprises
the step of reacting an intermediate of the formula
345
<IMG>
wherein R1, R8, R15, A and R2 are as defined above and
<IMG>
represents a mono-, bi- or poly cyclic aromatic heterocyclic
radical containing a quaternizable nitrogen in the ring, said
ring being attached to A through a ring carbon atom, in an
inert organic solvent with an alkylating agent of the formula
R5-X'
wherein R5 is as defined above and X' is a conventional
leaving group so as to quaternize with the R5 group a
ring nitrogen of substituent
<IMG>
on intermediate II and form a compound of the formula
<IMG>
346
wherein R1, R8, R15, R2' ,A, <IMG> and ~X' are as defined above;
and, if desired, replacing counter ion X' by a different counter
ion and, if desired, removing the carboxyl protecting group R2'
to give the desired de-blocked compound of formula I, or a
phamaceutically acceptable salt thereof.
68. A process according to claim 67 wherein R1 is hydrogen,
CH3CH2-,
<IMGS>
69. A process according to claim 67 wherein R1 and R8
taken together represent <IMG>
70. A process according to claim 67 wherein R1 is
<IMG>
71. A process according to claim 67 wherein R1 is
<IMG> and the absulute configuration is 5R, 6S, 8R.
72. A process according to claim 67 wherein A is
-CH2 or -CH2CH2-.
73. A process for the preparation of a compound of the
formula
347
<IMG>
wherein R8 is hydrogen and R1 is selected from the group
consisting of hydrogen; substituted and unsubstituted: 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, hetero-
aralkyl, 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; 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
<IMGS>
-NR3R4
<IMG>
348
<IMGS>
-CO2R3
=O
<IMG>
-SR3
<IMGS>
-CN
N3
OSO3R3
<IMGS>
-OP(O)(OR3)(OR4)
<IMG>
-NR3CO2R4
-NO2
349
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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
350
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-oxo ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
<IMGS>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above;
351
A is C1-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 ion; and
<IMG>
represents a radical of the formula
<IMG>
wherein R6, R7 and R10 are independently selected
from the group consisting of hydrogen, C1-C4 alkyl,
C1-C4 alkoxy, carboxy and carbamoyl; or a
pharmaceutically acceptable salt thereof; which
process comprises reacting an intermediate of the
formula
<IMG>
wherein R1, R8, R15, A and R2 are as defined above
and
<IMG>
352
represents a mono-, bi- or polycyclic aromatic heterocyclic
radical containing a quaternizable nitrogen in the ring, said
ring being attached to A through a ring carbon atom, in an
inert organic solvent with an alkylating agent of the formula
R5~X'
wherein R5 is as defined above and X' is a conventional
leaving group so as to quaternize with the R5 group a
ring nitrogen of substituent
<IMG>
on intermediate II and form a compound of the formula
<IMG>
wherein R1, R8, R15, R2' ,A, <IMG> and ~X' are as defined above;
and, if desired, replacing counter ion X' by a different counter
ion and, if desired, removing the carboxyl protecting group R2'
to give the desired de-blocked compound of formula I, or a
pharmaceutically acceptable salt thereof.
74. A process according to claim 73 wherein R1 is hydrogen,
CH3CH2-,
<IMGS>
353
75. A process according to claim 73 wherein R1 and R8
taken together represent <IMG>
76. A process according to claim 73 wherein R1 is
<IMG>
77. A process according to claim 73 wherein R1 is
<IMG> and the absolute configuration is 5R, 6S, 8R.
78. A process according to claim 73 wherein A is
-CH2- or -CH2CH2-.
79. A process according to claim a which comprises
reacting a compound of the formula
<IMG>
wherein A is C1-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 ion; and wherein
<IMG>
represents a radical of the formula
354
<IMG>
wherein R6 represents hydrogen or C1-C4 alkyl;
<IMG>
wherein R6 and R7 are hydrogen or C1-C4 alkyl;
<IMG>
wherein R is C1-C4 alkyl or phenyl(C1-C4)alkyl;
<IMG>
wherein R6 is C1-C4 alkyl;
<IMG>
wherein R is C1-C4 alkyl; or
355
<IMG>
with an alkylating agent of the formula
R5 - X'
wherein R5 is C1-C4 alkyl and X' is a conventional leaving
group; and where desired, forming a pharmaceutically acceptable
salt of the reaction product thereby obtained.
80. A process according to claim 9 which comprises
reacting a compound of the formula
<IMG>
wherein A is C1-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 ion; and wherein
<IMG>
represents a radical of the formula
<IMGS>
356
<IMGS>
with an alkylating agent of the formula
CH3X' or (in the case where
<IMG> is (d) above), CH2CH2CH3X',
wherein X' is a conventional leaving group; and where desired,
forming a pharmaceutically acceptable salt of the reaction
product thereby obtained.
357
81. A process according to claim 9 which comprises
reacting 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 ion; and wherein
<IMGS>
358
<IMGS>
wherein the 1HNMR (D2O) spectrum shows characteristic peaks
at .delta.: 1.23 (3H, d, J=6.4 Hz), 3.12 (2H, q, J=1.4, 8.9 Hz),
3.39 (1H, q, J=2.7, 6.0 Hz), 4.07-4.68 (10H, m), 8.19 (1H, s);
<IMG>
wherein the 1HNMR (D2O) spectrum shows characteristic peaks
at .delta.: 1.23 (3H, d, J=6.4 Hz), 3.15 (2H, q, J=3.7, 9.0 Hz),
3.37 (1H, q, J=2.6, 6.0 Hz), 3.95-4.65(10H, m), 8.62 (1H, s);
<IMGS>
359
<IMGS>
with an alkylating agent of the formula
CH3X', or (in the case where <IMG> is (f) above) CH2CH2CH3X',
wherein X' is a conventional leaving group; and where desired,
forming a pharmaceutically acceptable salt of the reaction
product thereby obtained.
82. A process according to claim 9 which comprises reacting
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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
83. The process of claim 82 wherein R2 is p-nitrobenzyl.
84. The process of claim 82 wherein R2 is an anionic
charge.
360
85. A process according to claim 9 which comprises
reacting 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
86. The process of claim 85 wherein R2 is p-nitrobenzyl.
87. The process of claim 85 wherein R2 is an anionic
charge.
88. A process according to claim 9 which comprises
reacting 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
361
89. The process of claim 88 wherein R2 is p-nitrobenzyl.
90. The process of claim 88 wherein R2 is an anionic
charge.
91. A process according to claim 9 which comprises
reacting 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
92. The process of claim 91 wherein R2 is p-nitrobenzyl.
93. The process of claim 91 wherein R2 is an anionic
charge.
94. A process according to claim 9 which comprises
reacting a compound of the formula
<IMG>
362
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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
95. The process of claim 94 wherein R2 is p-nitrobenzyl.
96. The process of claim 94 wherein R2 is an anionic
charge.
97. A process according to claim 9 which comprises
reacting 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 ion; with an alkylating agent of the formula
CH2CH2CH3X', wherein X' is a conventional leaving group; and
where desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
98. The process of claim 97 wherein R2 is p-nitrobenzyl.
99. The process of claim 97 wherein R2 is an anionic
charge.
363
100. A process according to claim 9 which comprises
reacting 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
101. The process of claim 100 wherein R2 is p-nitrobenzyl.
102. The process of claim 100 wherein R2 is an anionic
charge.
103. A process according to claim 9 which comprises
reacting 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
364
104. The process of claim 103 wherein R2 is p-nitrobenzyl.
105. The process of claim 103 wherein R2 is an anionic
charge.
106. A process according to claim 9 which comprises
reacting 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
107.The process of claim 106 wherein R2 is p-nitrobenzyl.
108. The process of claim 106 wherein R2 is an anionic
charge.
109. A process according to claim 9 which comprises
reacting a compound of the formula
<IMG>
365
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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
110. The process of claim 109 wherein R2 is p-nitrobenzyl.
111. The process of claim 109 wherein R2 is an anionic
charge.
112. A process according to claim 9 which comprises
reacting 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
113. T'ne process of claim 112 wherein R2 is p-nitrobenzyl.
114. The process of claim 112. wherein R2 is an anionic
charge.
366
115. ~A process according to claim 9 which comprises
reacting 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
116.~The process of claim 115 wherein R2 is p-nitrobenzyl.
117.~The process of claim 115 wherein R2 is an anionic
charge.
118. A process according to claim 9 which comprises reacting
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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
367
119. ~The process of claim 118 wherein R2 is p-nitrobenzyl.
120. ~The process of claim 118 wherein R2 is an anionic
charge.
121. A process in accordance with claim 9 which comprises
reacting 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
122. The process of claim 121 wherein R2 is p-nitrobenzyl.
123. The process of claim 121 wherein R2 is an anionic
charge.
124. A process in accordance with claim 9 which comprises
reacting a compound of the formula
<IMG>
368
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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
125. The process of claim 124 wherein R2 is p-nitrobenzyl.
126. The process of claim 124 wherein R2 is an anionic
charge.
127. A process in accordance with claim 9 which comprises
reacting 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 ion; with a compound of the formula CH2COOX',
wherein X' is a conventional leaving group; and where desired,
forming a pharmaceutically acceptable salt of the reaction
product thereby obtained.
128. The process of claim 127 wherein R2 is p-nitrobenzyl.
129. The process of claim 127 wherein R2 is an anionic
charge.
130. A process in accordance with claim 9 which comprises
reacting a compound of the formula
369
<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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
131. The process of claim 130 wherein R2 is p-nitrobenzyl.
132. The process of claim 130 wherein R2 is an anionic charge.
133. A process in accordance with claim 9 which comprises
reacting 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
134. The process of claim 133 wherein R2 is p-nitrobenzyl.
135. The process of claim 133 wherein R2 is an anionic charge.
370
136. A process in accordance with claim 9 which comprises
reacting 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
137. The process of claim 136 wherein R2 is p-nitrobenzyl.
138. The process of claim 136 wherein R2 is an anionic charge.
139. A process in accordance with claim 9 which comprises
reacting 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
140. The process of claim 139 wherein R2 is p-nitrobenzyl.
141. The process of claim 139 wherein R2 is an anionic charge.
391
142. A process in accordance with claim 9 which comprises
reacting a compound of the formula
<IMG>
wherein the 1HNMR (D2O) spectrum shows characteristic peaks at .delta.: 1.23
(3H,
d, J=6.4 Hz), 3.12 (2H, q, J=1.4, 8.9 Hz), 3.39 (1H, q, J=2.7, 6.0 Hz), 4.07-
4.68 (10H, m), 8.19 (1H, s), with an alkylating,agent of the formula CH3X',
wherein X' is a conventional leaving group; and where desired, forming a
pharma-
ceutically acceptable salt or ester of the reaction product thereby obtained.
143. The process of claim 142 wherein the carboxyl group is protected
as a p-nitrobenzyl ester.
144. A process in accordance with claim 9 which comprises reacting a
compound of the formula
<IMG>
wherein the 1HNMR (D2O) spectrum shows characteristic peaks at .delta.: 1.23
(3H, d,
J=6.4 Hz), .3.15 (2H, q, J=3.7, 9.0 Hz), 3.37 (1H, q, J=2.6, 6.0 Hz), 3.95-
4.65
(10H, m), 8.62 (1H, s), with an alkylating agent of the formula CH3X', wherein
X' is a conventional leaving group; and where desired, forming a
pharmaceutically
acceptable salt or ester of the reaction product thereby obtained.
145. The process of claim 144 wherein the carboxyl group is protected
as a p-nitrobenzyl ester.
146. A compound of the formula
<IMG>
wherein R B is hydrogen and R l is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: alkyl, alkenyl
and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cyclo-
372
alkylalkyl, 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, hetero-
cyclyl 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; 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>
-NR3R4
<IMG>
-C02R3
=0
<IMG>
-SR3
373
3 73
<IMG>
-CN
-N3
-OSO3R3
<IMG>
-OP (O) (OR3) (OR4)
-NR3C=NR4
¦
R3
-NR3CO2R4
-NO2
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
374
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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms: cyclo-
alkyl 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-
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;~
-OCONR3R4 ;
O
¦¦
-OS-R9 ;
¦¦
O
-OXO ;
-NR3R4 ;
R3CONR4- ;
-NR3C02R4
375
-NR3CONR3R4 ;
O
¦¦
-NR3S-R9 ;
¦¦
O
-SR3
<IMG>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, Cl-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above;
or R5 may be attached to
<IMG>
at another point on the ring so as to form
a fused heterocyclic or heteroaromatic ring,
which ring may contain additional hetero atoms
selected from O, S and N ;
A is C1-CS straight or branched chain alkylene;
R2 is hydrogen, an anionic charge or a conven-
tional readily removable carboxyl protecting
group, providing that when R2 is hydrogen or
a protecting group, there is also present a
counter ion; and
<IMG>
376
represents a substituted or unsubstituted mono-,
bi- or polycyclic aromatic heterocyclic radical
containing at least one nitrogen in the ring,
said ring being attached to A through a ring
carbon atom and having a ring nitrogen which is
quaternized by the group R5; or a pharmaceutically
acceptable salt thereof.
147. A compound according to claim 146 wherein R1 is
hydrogen, CH3CH2-,
<IMG>
148. A compound according to claim 146 wherein R1 and R8
taken together represent
<IMG>
149. A compound according to claim 146 wherein R1 is
<IMG>
377
150. A compound according to claim 146 wherein R1 is
<IMG>
and the absolute configuration is 5R, 6S, 8R.
151. A compound according to claim 146 wherein
A is -CH2- or -CH2CH2-.
152. A compound of the formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group
consisting of by hydrogen; substituted and unsubstituted:
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
378
Cl-C6 alkyl optionally substituted by amino, halo,
hydroxy or carboxyl
halo
-OR3
<IMG>
-NR3R4
<IMG>
-CO2R3
=O
<IMG>
-SR3
<IMG>
-CN
-N3
-OSO3R3
<IMG>
379
<IMG>
-OP (O) (OR3) (OR4)
<IMG>
-NR3CO2R4
-NO2
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 heterocy clic 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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms: cyclo-
alkyl 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
380
moiety is phenyl and the aliphatic portion has 1-6 carbon
atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-OXO ;
-NR3R4 ;
R3CONR4- ;
-NR3C02R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
<IMG>
-SO3R3 ;
381
-CO2R3 ;
CONR3R4 ;
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1 -C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above;
R5 may be attached to
<IMG>
at another point on the ring so as form a fused
heterocyclic or heteroaromatic ring, which ring
may contain additional hetero atoms selected from
O, S and N; A is C1-C6 straight or branched chain
alkvlene; 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
ion; and
<IMG>
represents an aromatic mono-, bi- or polycyclic
N-containing heterocyclic ring containing 0-5
additional hetero atoms selected from O, S or N,
said heterocyclic ring being attached to A through
a ring carbon atom and having a ring nitrogen
quaternized by the group R5, and said heterocyclic
ring being optionally substituted at available ring
carbon atoms by 1-5 substituents independently
selected from the group consisting of C1-C4 alkyl;
C1-C4 alkyl substituted by 1-3 hydroxy, amino,
C1-C4 alkylamino, di (C1-C4) alkylamino, C1-C4
alkoxy, carboxy, halo or sulfo; C3-C6 cycloalkyl;
382
C3-C6 cycloalkyl(C1-C4)alkyl optionally
substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl;
C1-C4 alkoxy; C1-C4 alkylthio; amino; C1-C4 alkyl-
amino; di (C1-C4) alkylamino; halo; C1-C4 alkanoyl-
amino; C1-C4 alkanoyloxy; carboxy; sulfo;
<IMG > alkyl; hydroxy; amidino; guanidino;
phenyl; phenyl substituted by 1-3 substituents
independently selected from amino, halo, hydroxy.
trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylamino, di(C1-C4)alkylamino, carboxy,
and sulfo; phenyl(C1-C4)alkyl in which the
phenyl portion is optionally substituted by 1-3
substituents mentioned above in connection with
phenyl and the alkyl portion is optionally
substituted by 1-3 substituents mentioned above
in connection with C1-C4 alkyl; and heteroaryl or
heteroaralkyl in which the hetero atom or atoms
are selected from the group consisting of 1-4 O,
S or N atoms and the alkyl moiety associated
with heteroaralkyl has 1-6 carbon atoms, said
heteroaryl and heteroaralkyl groups being
optionally substituted in the heterocyclic ring
moiety by 1-3 substituents independently selected
from hydroxy, amino, halo, trifluoromethyl, C1-C4
alkyl, Cl-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)-
alkylamino, carboxy and sulfo and in the alkyl
moiety by 1-3 substituents selected from hydroxy,
amino, C1-C4 alkylamino, di(C1-C4)alkylamino,
C1-C4 alkoxy, carboxy, halo and sulfo, and said
heterocyclic ring being optionally substituted at
available ring nitrogen atoms by 1-3 substituents
independently selected from the group consisting
383
of C1-C4 alkyl; C1-C4 alkyl substituted by 1-3
hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkyl-
amino, C1-C4 alkoxy, carboxy, halo or sulfo
groups; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C1-C4)-
alkyl optionally substituted by 1-3
substituents mentioned above in connection
with C1-C4 alkyl: phenyl; phenyl
substituted by 1-3 substituents independently
selected from amino, halo, hydroxy, trifluoromethyl,
C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,
di(C1-C4)alkylamino, carboxy and sulfo; phenyl-
(C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl
portion may be optionally substituted by 1-3
substituents mentioned above in connection with
C1-C4 alkyl; and heteroaryl or heteroaralkyl in
which the hetero atom or atoms are selected
from the group consisting or 1-4 O, S or N atoms
and the alkyl moiety associated with heteroaralkyl
has 1-6 carbon atoms, said heteroaryl and hetero-
aralkyl groups being optionally substituted in
the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, amino, halo,
trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylamino, di(C1-C4)alkylamino, carboxy
and sulfo and in the alkyl moiety by 1-3 substituents
selected from hydroxy, amino, C1-C4 alkylamino,
di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo
and sulfo; or a pharmaceutically acceptable salt
thereof.
384
153. A compound according to claim 152 wherein R1 is
hydrogen, CH3CH2-,
<IMG>
154. A compound according to claim 152 wherein R1 and
R8 taken together represent
<IMG>
155. A compound according to claim 152 wherein R1 is
<IMG>
156. A compound according to claim 152 wherein R1 is
<IMG>
and the absolute configuration is 5R, 6S, 8R.
157. A compound according to claim 152 wherein A is
-Ch2- or -CH2CH2-
385
158. A compound of the formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: 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, hetero-
aralkyl, 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 hetero-
cyclic 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>
-NR3 R4
386
<IMG>
-CO2R3
=O
<IMG>
-SR3
<IMG>
-CN
-N3
-OSO3R3
<IMG>
-OP (O) (OR3) (OR4)
387
<IMG>
-NR3CO2R4
-NO2
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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl wherein the hetero atom or atoms in the above-
named heterocyclic moieties are selected from the group
388
consisting of 1-4 oxygen, nitrogen or sulfur atoms and the
alkyl moieties associated with said heterocyclic moieties
have 1-6 carbon atoms; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-OXO ;
-NR3R4 ;
R3CONR4-
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
<IMG>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
389
phenyl optionally substituted. by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3 R3, -CO2 R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above;
or R5 may be attached to
<IMG>
at another point on the ring so as to form a fused
heterocyclic or heteroaromatic ring, which ring may
contain additional hetero atoms selected from O,
N and S ;
A is C1-C6 straight or branched chain alkylene;
R2 is hydrogen, an anionic charge or a conventional
readily removable carboxyl protecting group, pro-
viding that when R2 is hydrogen or a protecting group,
there is also present a counter ion: and
<IMG>
represents an aromatic 5- or 6-membered N-containing
heterocyclic ring containing 0-3 additional hetero
atoms selected from N, S or O, said heterocyclic ring
being optionally substituted at available ring carbon
atoms by 1-5 substituents independently selected from
the group consisting of C1-C4 alkyl; C1-C4 alkyl.
substituted by 1-3 hydroxy, amino, C1-C4 alkylamino,
di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo or
sulfo; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C1-C4)alkyl
optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl C1 C4 alkoxy:
C1-C4 alkylthio; amino; C1-C4 alkylamino; di(C1-C4)-
alkylamino; halo: C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy; sulfo:
390
<IMG > alkyl; hydroxy; amidino: guanidino;
phenyl: phenyl substituted by 1-3 substituents
independently selected from amino, halo, hydroxy,
trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylamino, di (C1-C4) alkylamino, carboxy,
and sulfo; phenyl (C1-C4) alkyl in which the
phenyl portion is optionally substituted by 1-3
substituents mentioned above in connection with
phenyl and the alkyl portion is optionally
substituted by 1-3 substituents mentioned above
in connection with C1-C4 alkyl; and heteroaryl or
heteroaralkyl in which the hetero atom or atoms
are selected from the group consisting of 1-4 O,
S or N atoms and the alkyl moiety associated
with heteroaralkyl has 1-6 carbon atoms, said
heteroaryl and heteroaralkyl groups being
optionally substituted in the heterocyclic ring
moiety by 1-3 substituents independently selected
from hydroxy, amino, halo, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)-
alkylamino, carboxy and sulfo and in the alkyl
moiety by 1-3 substituents selected from hydroxy,
amino, C1-C4 alkylamino, di(C1-C4)alkylamino,
C1-C4 alkoxy, carboxy, halo and sulfo, and said
heterocyclic ring being optionally substituted at
available ring nitrogen atoms by 1-3 substituents
independently selected from the group consisting
of C1-C4 alkyl: C1-C4 alkyl substituted by 1-3
hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkyl-
amino, C1-C4 alkoxy, carboxy, halo or sulfo
groups; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C1-C4)-
alkyl optionally substituted by 1-3
substituents mentioned above in connection
391
with C1-C4 alkyl; phenyl; phenyl substituted by 1-3
substituents independently selected from amino,
halo, hydroxy, trifluoromethyl, C1-C4 alkyl, C1-C4
alkoxy, C1-C4 alkylamino, di ( C1-C4 ) alkylamino,
carboxy and sulfo; phenyl-(C1-C4)alkyl in which the
phenyl portion may be optionally substituted by 1-3
substituents mentioned above in connection with
phenyl and the alkyl portion may be optionally
substituted by 1-3 substituents mentioned above in
connection with C1-C4 alkyl; and heteroaryl or
heteroaralkyl in which the hetero atom or atoms are
selected from the group consisting of 1-4 O, S or N
atoms and the alkyl moiety associated with
heteroaralkyl has 1-6 carbon atoms, said heteroaryl
and heteroaralkyl groups being optionally substituted
in the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, amino, halo,
trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4
alkylamino, di(C1-C4)alkylamino, carboxy and sulfo
and in the alkyl moiety by 1-3 substituents selected
from hydroxy, amino, C1-C4 alkylamino, di(C1-
C4)alkylamino, C1-C4 alkoxy, carboxy, halo and sulfo;
or a pharmaceutically acceptable salt thereof.
159. A compound according to claim 158 wherein
the heterocyclic ring
<IMG>
is optionally substituted at available ring carbon or
nitrogen atoms by up to 5 substituents independently
selected from (lower) alkyl.
392
160. A compound according to claim 159 wherein A is
-CH2-, -CH2CH2- or
<IMG>
161. A compound according to claim 158 wherein R1 is
<IMG>
and the absolute configuration is 5R., 6S, 8R .
162. A compound of the formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: 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, hetero-
aralkyl, 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 hetero-
cyclic 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
393
C1-C6 alkyl optionally substituted by amino,
halo, hydroxy or carboxyl
halo
-OR3
<IMG>
-NR3R4
<IMG>
-C02R3
=0
<IMG>
-CN
<IMG>
394
<IMG>
-OP (O) (OR3) (OR4)
<IMG>
-NR3C02R4
-N02
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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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
395
moiety is phenyl and the aliphatic portion has 1-6 carbon
atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-
cyclyalkyl 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; wherein the above-named.R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-OXO ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
<IMG>
-S03R3 ;
396
-CO2R3 ;
-CONR3R4 ;
-CN; or
phenyl optionally substituted. by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above; or R5 may be attached to
<IMG>
at another point on the ring so as to form a fused
heterocyclic or heteroaromatic ring, which ring may
contain additional hetero atoms selected from O, N and
S;
A is C1-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 ion; and
<IMG>
represents a radical selected from the group consisting of
<IMG>
wherein R6, R7 and R10 are independently selected from hydrogen;
C1-C4 alkyl; C1-C4 alkyl substituted by hydroxy, C1-C4 alkylamino,
di(C1-C4 alkyl)amino, C1-C4 alkoxy, amino, sulfo, carboxy or halo;
C3-C6 cycloalkyl; C1-C4 alkoxy; C1-C4 alkylthio; amino; C1-C4 alkyl-
397
amino; di ( C1-C4 al kyl ) amino; halo; C1-C4 alkanoyl -
amino; C1-C4 alkanoyl oxy; carboxy;
O
-C-OC1-C4 alkyl; hydroxy; amidino; guanidino; phenyl;
phenyl substituted by one, two or three amino, halo,
hydroxyl, trifluoromethyl, C1-C4 alkyl or C1-C4
alkoxy groups; phenyl (C1-C4)alkyl in which the
phenyl portion may be optionally substituted by 1-3
substituents mentioned above in connection with
phenyl and the alkyl portion may be optionally
substituted by 1-3 substituents mentioned above in
connection with C1-C4 alkyl; and heteroaryl and
heteroaralkyl in which the hetero atom or atoms in
the group consisting of 1-4 oxygen, nitrogen or
sulfur atoms and the alkyl moiety associated with
said heteroaralkyl moiety has 1-6 carbon atoms; or
wherein two of R6, R7 or R10 taken together may be a
fused saturated carbocyclic ring, a fused aromatic
carbocyclic ring, a fused non-aromatic heterocyclic
ring or a fused heteroaromatic ring, said fused rings
being optionally substituted by 1 or 2 of the
substituents defined above for R6, R7 and R10;
<IMG>
optionally substituted on a carbon atom by 1-3
substituents independently selected from C1-C4 alkyl;
C1-C4 alkyl substituted by hydroxy, C1-C4 alkylamino,
di(C1-C4 alkyl)amino, sulfo, C1-C4 alkoxy, amino,
carboxy or halogen; C3-C6 cycloalkyl;
398
C1-C4 alkoxy; C1-C4 alkylthio; amino; C1-C4
alkylamino; di ( C1-C4 alkyl ) amino; halo; C1-C4
alkanoylamino; C1-C4 alkanoyloxy; carboxy;
O~
-C-OC1-C4 alkyl; hydroxy; amidino; guanidino; phenyl;
phenyl substituted by one, two or three amino, halo,
hydroxyl, trifluoromethyl, C1-C4 alkyl or C1-C4
alkoxy groups; phenyl (C1-C4)alkyl in which the
phenyl portion may be optionally substituted by 1-3
substituents mentioned above in connection with
phenyl and the alkyl portion may be optionally
substituted by 1-3 substituents mentioned above in
connection with C1-C4 alkyl; and heteroaryl or
heteroaralkyl in which 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 moiety associated with
said heteroaralkyl moiety has 1-6 carbon atoms, or
optionally substituted so as to form a fused
carbocyclic, heterocyclic or heteroaromatic ring
optionally substituted by 1 or 2 of the substituents
defined above;
<IMG>
optionally substituted on a carbon atom by one or two
substituents independently selected from C1-C4 alkyl;
C1-C4 alkyl substituted by hydroxy, C1-C4 alkylamino,
di (C1-C4 alkyl ) amino, C1-C4 alkoxy, sulfo, amino,
carboxy or halogen; C3-C6
399
cycloalkyl; C1-C4 alkoxy; C1-C4 alkylthio; amino;
C1-C4 alkylamino; di (C1-C4 alkyl ) amino; halo; C1-C4
alkanoylamino; C1-C4 alkanoyloxy; carboxy;
O
-C-OC1-C4 alkyl; hydroxy, amidino, guanidino, phenyl;
phenyl substituted by one, two or three amino, halo,
hydroxyl, tri-fluoromethyl, C1-C4 alkyl or C1-C4
alkoxy groups; phenyl (C1-C4)alkyl in which the
phenyl portion may be optionally substituted by 1-3
substituents mentioned above in connection with
phenyl and the alkyl portion may be optionally
substituted by 1-3 substituents mentioned above in
connection with C1-C4 alkyl; and heteroaryl or
heteroaralkyl in which 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 moiety associated with
said heteroaralkyl moiety has 1-6 carbon atoms, or
optionally substituted so as to form a fused
carbocyclic, heterocyclic or heteroaromatic ring
optionally substituted by 1 or 2 of the substituents
defined above;
<IMG>
400
optionally substituted on a carbon atom by a substituent
independently selected from C1-C4 alkyl; C1-C4 alkyl sub-
stituted by hydroxy, amino, C1-C4 alkylamino, di(C1-C4 alkyl)-
amino, C1-C4 alkoxy, sulfo, carboxy or halogen; C3-C6 cyclo-
alkyl; C1-C4 alkoxy; Cl-C4 alkylthio; amino; C1-C4 alkylamino;
di(C1-C4 alkyl)amino; halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy;
<IMG >
alkyl; hydroxy; amidino; guanidino, phenyl; phenyl
substituted by one, two or three amino, halo, hydroxyl, tri-
fluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl portion
may be optionally substituted by 1-3 substituents mentioned.
above in connection with C1-C4 alkyl; and heteroaryl
or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety
has 1-6 carbon atoms;
<IMG>
wherein X is O, S or NR in which R is C1-C4 alkyl; C1-C4
alkyl substituted by 1-3 hydroxy, amino, C1-C4 alkylamino,
di (C1-C4) alkylamino, C1-C4 alkoxy, carboxy, halo or sulfo
groups; C3-C6 cycloalkyl: C3-C6 cycloalkyl(C1-C4)alkyl
optionally substituted by 1-3 substituents mentioned above
in connection with C1-C4 alkyl; phenyl; phenyl substituted
by 1-3 substituents independently selected from amino, halo,
401
hydroxy, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4
alkylamino, di (C1-C4) alkylamino, carboxy and sulfo;
phenyl(C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with C1-C4 alkyl; and heteroaryl
and heteroaralkyl in which the hetero atom or atoms are selected
from the group consisting of 1-4, O, S or N atoms and the
alkyl moiety associated with heteroaralkyl has 1-6 carbon
atoms, said heteroaryl and heteroaralkyl groups being optionally
substituted in the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, amino, halo, trifluoro-
methyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)-
alkylamino, carboxy and sulfo and in the alkyl moiety by
1-3 substituents selected from hydroxy, amino, C1-C4 alkyl-
amino, di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo
and sulfo, said radical being optionally substituted on a
carbon atom by one or more substituents independently selected
from C1-C4 alkyl; C1-C4 alkyl substituted by hydroxy, C1-C4
alkylamino, di(C1-C4 alkyl)amino, C1-C4 alkoxy, amino, sulfo,
carboxy or halogen; C3-C6 cycloalkyl; C1-C4 alkoxy; C1-C4
alkylthio; amino; C1-C4 alkylamino; di(C1-C4 alkyl)amino;
halo; C1-C4 alkanoylamino; C1-C4 alkanoyloxy; carboxy;
<IMG > alkyl; hydroxy; amidino; guanidino, phenyl;
phenyl substituted by one, two or three amino, halo,
hydroxyl, trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned above
in connection with phenyl and the alkyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl;
and heteroaryl or heteroaralkyl in which the hetero atom or
atoms in the above-named heterocyclic moieties are selected
from the group consisting of 1-4 oxygen, nitrogen or sulfur
402
atoms and the alkyl moiety associated with said
heteroaralkyl moiety has 1-6 carbon atoms, or
optionally substituted so as to form a fused
carbocyclic, heterocyclic or heteroaromatic ring
optionally substituted by 1 or 2 of the substituents
defined above;
<IMG>
wherein X is O, S or NR in which R is C1-C4 alkyl;
C1-C4 alkyl substituted by 1-3 hydroxy, amino, C1-C4
alkylamino, di(C1-C4) alkylamino, C1-C4 alkoxy,
carboxy, halo or sulfo groups; C3-C6 cycloalkyl;
C3-C6 cycloalkyl(C1-C4)alkyl optionally substituted
by 1-3 substituents mentioned above in connection
with C1-C4 alkyl; phenyl; phenyl substituted by 1-3
substituents independently selected from amino, halo,
hydroxy, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylamino, di(C1-C4)alkylamino, carboxy and
sulfo; phenyl(C1-C4)alkyl in which the phenyl portion
may be optionally substituted by 1-3 substituents
mentioned above in connection with phenyl and the
alkyl portion may be optionally substituted by 1-3
substituents mentioned above in connection with C1-C4
alkyl; and heteroaryl and heteroaralkyl in which the
hetero atom or atoms are selected from the group
consisting of 1-4, O, S or N atoms and the alkyl
moiety associated with heteroaralkyl has 1-6 carbon
atoms, said heteroaryl and heteroaralkyl groups being
optionally substituted in the heterocyclic ring
403
moiety by 1-3 substituents independently selected
from hydroxy, amino, halo, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di (C1-
C4)alkylamino, carboxy and sulfo and in the alkyl
moiety by 1-3 substituents selected from hydroxy,
amino, C1-C4 alkyl-
404
amino, di(C1 C4)alkylamino, C1-C4 alkoxy, carboxy, halo and sulfo,
said heteroaromatic radical being optionally substituted on a
carbon atom by a substituent selected from C1-C4 alkyl;
C1-C4 alkyl substituted by hydroxy, C1-C4 alkylamino,
di(C1-C4 alkyl)amino, C1-C4 alkoxy, amino, sulfo, carboxy
or halogen; C3-C6 cycloalkyl; C1-C4 alkoxy; C1-C4 alkylthio;
amino; C1-C4 alkylamino; di(C1-C4)alkylamino; halo; C1-C4
alkanoylamino; C1-C4 alkanoyloxy; carboxy;
<IMG> alkyl; hydroxy; amidino; guanidino; phenyl;
phenyl substituted by one, two or three amino, halo, hydroxyl,
trilfuoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl portion
may be optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl; and heteroaryl
or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety has
1-6 carbon atoms; and
<IMG>
405
<IMG>
wherein R is C1-C4 alkyl; C1-C4 alkyl substituted by 1-3
hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkylamino,
C1-C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cyclo-
alkyl; C3-C6 cycloalkyl(C1-C4)alkyl optionally substituted
by 1-3 substituents mentioned above in connection with C1-C4 alkyl;
phenyl; phenyl substituted by 1-3 substituents independently
selected from amino, halo, hydroxy, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)alkylamino,
carboxy and sulfo; phenyl(C1-C4)alkyl in which the phenyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with phenyl and the alkyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with C1-C4 alkyl; and heteroaryl
and heteroaralkyl in which the hetero atom or atoms are selected
from the group consisting of 1-4, O, S or N atoms and the
alkyl moiety associated with heteroaralkyl has 1-6 carbon
atoms, said heteroaryl and heteroaralkyl groups being optionally
substituted in the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, amino, halo, trifluoro-
methyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di (C1-C4)-
alkylamino, carboxy and sulfo and in the alkyl moiety by
1-3 substituents selected from hydroxy, amino, C1-C4 alkyl-
amino, di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo and sulfo;
or a pharmaceutically acceptable salt thereof.
163. A compound according to claim 162 wherein
406
<IMG>
represents a radical selected from the group consisting of
<IMG>
wherein R5 is C1-C6 alkyl and R6, R7 and R10 are each
independently hydrogen or C1-C4 alkyl;
<IMG>
wherein R5 is C1-C6 alkyl and wherein available ring carbon
atoms are optionally substituted by 1-3 substituents
independently selected from C1-C4 alkyl;
<IMG>
407
<IMG>
wherein R5 is C1-C6 alkyl and wherein available ring carbon
atoms are optionally substituted by 1 or 2 substituents
independently selected from C1-C4 alkyl;
<IMG>
wherein R5 is C1-C6 alkyl and wherein an available ring
carbon atom is optionally substituted by C1-C4 alkyl;
<IMG>
408
wherein R5 is C1 C6 alkyl, X is O, S or NR in which R is
C1-C4 alkyl and wherein one or more available ring carbon
atoms is optionally substituted by C1-C4 alkyl;
<IMG>
wherein R5 is C1-C6 alkyl, X is O, S or NR in which R is
C1-C4 alkyl and wherein one or more available ring carbon
atoms is optionally substituted by C1-C4 alkyls and
<IMG>
409
wherein R5 is C1-C6 alkyl and R is C1-C4 alkyl.
164. A compound according to claim 163 wherein R1 is
hydrogen, CH3CH2-,
<IMG>
165. A compound according to claim 163 wherein R1 and R8
taken together represent
<IMG>
166. A compound according to claim 163 wherein R1 is
<IMG>
167. A compound according to claim 163 wherein R1 is
<IMG>
and the absolute configuration is 5R, 6S, 8R.
410
t~/ U
168. A compound according to claim 162 wherein A is
-CH2 or -CH2CH2-.
169. A compound of the formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: 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, hetero-
aralkyl, 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 hetero-
cyclic 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>
411
<IMG>
-NR3R4
<IMGS>
-CO2R3
=O
<IMG>
-SR3
<IMGS>
-CN
-N3
<IMGS>
-OP(O)(OR3)(OR4)
412
<IMG>
-NR3CO2R4
-NO2
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; R5 is selected from the
group consisting of substituted and unsubstituted; alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms cyclo-
alkyl 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-
cyclyalkyl wherein the hetero atom or atoms in the above-
named heterocyclic moieties are selected from the group
413
consisting of 1-4 oxygen, nitrogen or sulfur atoms and the
alkyl moieties associated with said heterocyclic moieties
have 1-6 carbon atoms; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-oxo ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
<IMGS>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
414
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above; or R5 may be attached to
<IMG>
at another point on the ring so as to form a fused hetero-
cyclic or heteroaromatic ring, which ring may contain
additional hetero atoms selected from O, N and S;
A is C1-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 ion; and
<IMG>
represents a radical selected from the group consisting of
<IMG>
wherein R6, R7 and R10 are independently selected from hydrogen;
C1-C4 alkyl; C1-C4 alkyl substituted by hydroxy, C1-C4 alkylamino,
di(C1-C4 alkyl)amino, C1-C4 alkoxy, amino, sulfo, carboxy or halo;
C3-C6 cycloalkyl; C1-C4 alkoxy; C1-C4 alkylthio; amino; C1-C4 alkyl-
amino; di (C1-C4 alkyl) amino; halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy;
<IMG>; hydroxy, amidino; guanidino; phenyl; phenyl
substituted by one, two or three amino, halo, hydroxyl,
415
trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substitutents mentioned above
in connection with phenyl and the alkyl portion may be
optionally substituted by 1-3 substituents mentioned above
in connection with C1-C4 alkyl; and heteroaryl and heteroaralkyl
in which the hetero atom or atoms in the group consisting of
1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety
associated with said heteroaralkyl moiety has 1-6 carbon
atoms; or wherein two of R6, R7 or R10 taken together may be
a fused saturated carbocyclic ring, a fused aromatic carbocyclic
ring, a fused non-aromatic heterocyclic ring or a fused hetero-
aromatic ring, said fused rings being optionally substituted
by 1 or 2 of the substituents defined above for R6, R7 and R10;
or a pharmaceutically acceptable salt thereof.
170. A compound according to claim 169 wherein R1 is
hydrogen, CH3CH2-,
<IMGS>
171. A compound according to claim 169 wherein R1 and R8
taken together represent
<IMG>
416
172. A compound according to claim 169 wherein R1 is
<IMG>
173. A compound according to claim 169 wherein R1 is
<IMG>
and the absolute configuration is 5R, 6S, 8R.
174. A compound according to claim 169 wherein A is
-CH2- or -CH2CH2-
175. A compound of the formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms: cycloalkyl
end 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. hetero-
aralkyl, 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
417
sulfur atoms and the alkyl moieties associated with said hetero-
cyclic 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
<IMGS>
-NR3R4
<IMGS>
-CO2R3
=O
<IMG>
-SR3
418
<IMGS>
-CN
-N3
-OSO3R3
<IMGS>
-OP(O)(OR3)(OR4)
<IMG>
-NR3CO2R4
-NO2
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
419
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 tad R8 taken together represent C2-C10, alkylidene or
C2-C10 alkylidene substituted by hydroxy; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl, alkenyl
and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cycle-
alkylalkyl, 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, hetero-
cyclyl 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; wherein the above-named R5 radicals are optionally
substituted by 1-3 substituents independently selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo:
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG> ;
-oxo ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
420
<IMG>
-SR3 ;
<IMGS> ;
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above; or R5 may be attached to
<IMG>
at another point on the ring so as to form a fused
heterocyclic or heteroaromatic ring, which ring may
contain additional hetero atoms selected from O, N and,
S;
A is C1-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 ion; and
<IMG>
421
represents a radical of the form,
<IMGS>
optionally substituted on a carbon atom by 1-3 substituents
independently selected from C1-C4 alkyl; C1-C4 alkyl substituted
by hydroxy, C1-C4 alkylamino, di (C1-C4 alkyl) amino, sulfo,
C1-C4 alkoxy, amino, carboxy or halogen; C3-C6 cycloalkyl;
C1-C4 alkoxy; C1-C4 alkylthio; amino; C1-C4 alkylamino;
di (C1-C4 alkyl) amino; halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy;
<IMG>; hydroxy; amidino; guanidino; phenyl; phenyl
substituted by one, two or three amino, halo, hydroxyl,
trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl portion
may be optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl; and heteroaryl
or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety
has 1-6 carbon atoms, or optionally substituted so as to form
a fused carbocyclic, heterocyclic or heteroaromatic ring
422
optionally substituted by 1 or 2 of the substituents defined
above; or a pharmaceutically acceptable salt thereof.
176. A compound according to claim 175 wherein
<IMGS>
177, A compound according to claim 175 wherein
<IMG>
178. A compound according to claim 175 wherein
<IMG>
423
179. A compound according to claim 175 wherein R1 is
hydrogen, CH3CH2-
<IMGS>
180. A compound according to claim 175 wherein R1 and
R8 taken together represent
<IMG>
181. A compound according to claim 175 wherein R1 is
<IMG>
182. A compound according to claim 175 wherein R1 is
<IMG>
and the absolute configuration is 5R, 6S, 8R.
183. A compound according to claim 175 wherein A is
-CH2- or -CH2CH2-, R1 is <IMG>
and the absolute configuration is 5R, 6S, 8R,
424
184. A compound of the formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: 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, hetero-
aralkyl, 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 hetero-
cyclic 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
<IMGS>
-NR3R4
<IMGS>
425
<IMGS>
-CO2R3
=O
<IMG>
-SR3
<IMGS>
-CN
-N
-OSO3R3
<IMGS>
-OP(O)(OR3)(OR4)
<IMG>
-NR3CO2R4
-NO2
426
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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-oxo ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
<IMGS>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are is defined above; or R5 may be attached to
428
<IMG>
at another point on the ring so as to form a fused
heterocyclic or heteroaromatic ring, which ring may
contain additional hetero atoms selected from O, N and
S;
A is C1-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 ion; and
<IMG>
represents a radical of the formula
<IMGS>
optionally substituted on a carbon atom by 1-3 substituents
independently selected from C1-C4 alkyl; C1-C4 alkyl substituted
by hydroxy, C1-C4 alkylamino, di(C1-C4 alkyl) amino, sulfo,
C1-C4 alkoxy, amino, carboxy or halogen; C3-C6 cycloalkyl;
429
C1-C4 alkoxy; C1-C4 alkylthio; amino; C1-C4 alkylamino;
di (C1-C4 alkyl) amino; halo: C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy;
<IMG>; hydroxy; amidino; guanidino, phenyl; phenyl
substituted by one, two or three amino, halo, hydroxyl,
trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned above
in connection with phenyl and the alkyl portion may be
optionally substituted by 1-3 substituents mentioned above
in connection with C1-C4 alkyl; and heteroaryl or heteroaralkyl
in which the hetero atom or atoms in the above-named hetero-
cyclic moieties are selected from the group consisting of 1-4
oxygen, nitrogen or sulfur atoms and the alkyl moiety associated
with said heteroaralkyl moiety has 1-6 carbon atoms, or
optionally substituted so as to form a fused carbocyclic,
heterocyclic or heteroaromatic ring optionally substituted by
1 or 2 of the substituents defined above; or a pharmaceutically
acceptable salt thereof.
185. A compound according to claim 184 wherein R1 is
hydrogen, CH3CH2-,
<IMGS>
186. A compound according to claim 184 wherein R1 and R8
taken together represent
430
<IMG>
187, A compound according to claim 184 wherein R1 is
<IMG>
188, A compound according to claim 184 wherein R1 is
<IMG>
and the absolute configuration is 5R, 6S, 8R.
188. A compound according to claim 184 wherein
A is -CH2- or -CH2CH2-.
190. A compound of the formula
<IMG>
431
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: alkyl, alkenyl
and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cyclo-
alkylalkyl, 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, hetero-
cyclyl 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; 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
<IMGS>
-NR3R4
<IMGS>
-CO2R3
432
=O
<IMG>
-SR3
<IMGS>
-CN
N3
-OSO3R3
<IMGS>
-OP(O)(OR3)(OR4)
<IMG>
-NR3CO2R4
-NO2
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
433
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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
434
-oxo ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
<IMGS>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above;
or R5 may be attached to
<IMG>
at another point on the ring so as to form a fused hetero-
cyclic or heteroaromatic ring, which ring may contain
additional hetero atoms selected from O, N and S;
A is C1-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 ion; and
435
<IMG>
represents a radical of the formula
<IMGS>
optionally substituted on a carbon atom by a substituent
independently selected from C1-C4 alkyl; C1-C4 alkyl
substituted by hydroxy, amino, C1-C4 alkylamino, di(C1-C4)
alkylamino, sulfo, C1-C4 alkoxy, carboxy or halogen;
C3-C6 cycloalkyl; C1-C4 alkoxy; C1-C4 alkylthio; amino;
C1-C4 alkylamino; di(C1-C4) alkylamino; halo; C1-C4 alkanoyl-
amino: C1-C4 alkanoyloxy; carboxy;
<IMG> alkyl; hydroxy; amidino; guanidino, phenyl; phenyl
substituted by one, two or three amino, halo, hydroxyl, tri-
fluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4) alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned above in
connection with phenyl and the alkyl portion may be optionally
substituted by 1-3 substituents mentioned above in connection
with C1-C4 alkyl: and heteroaryl or heteroaralkyl in which the
hetero atom or atoms in the above-named heterocyclic moieties
are selected from the group consisting of 1-4 oxygen, nitrogen
436
or sulfur atoms and the alkyl moiety associated with said
heteroaralkyl moiety has 1-6 carbon atoms; or a pharmaceutically
acceptable salt thereof.
191. A compound according to claim 190 wherein R1 is
hydrogen, CH3CH2-,
<IMGS>
192. A compound according to claim 190 wherein R1 and R8
taken together represent
<IMG>
193. A compound according to claim 190 wherein R1 is
<IMG>
194. A compound according to claim 190 wherein R1 is
<IMG>
and the absolute configuration is 5R, 6S, 8R.
437
195. A compound according to claim 190 wherein A is
-CH2- or -CH2CH2-.
196. A compound of the formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: alkyl, alkenyl
and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cyclo-
alkylalkyl, 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, hetero-
cyclyl 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; 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>
438
<IMG>
-NR3R4
<IMGS>
-CO2R3
=O
<IMG>
-SR3
<IMGS>
-CN
-N3
-OSO3R3
<IMGS>
-OP(O)(OR3)(OR4)
439
<IMG>
-NR3CO2R4
-NO2
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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl 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
440
alkyl moieties associated with said heterocyclic moieties
have 1-6 carbon atoms; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-oxo ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
<IMGS>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
441
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above; or R5 may be attached to
<IMG>
at another point on the ring so as to form a fused hetero-
cyclic or heteroaromatic ring, which ring may contain
additional hetero atoms selected from O, N and S;
A is C1-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 ion; and
<IMG>
represents a radical of the formula
<IMGS>
wherein X is O, S or NR in which R is C1-C4 alkyl: C1-C4
alkyl substituted by 1-3 hydroxy, amino, C1-C4 alkylamino,
di (C1-C4) alkylamino, C1-C4 alkoxy, carboxy, halo or sulfo
groups; C3-C6 cycloalkyl: C3-C6 cycloalkyl(C1-C4)alkyl
optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl;
phenyl; phenyl substituted by 1-3 substituents independently
selected from amino, halo, hydroxy, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)alkylamino,
carboxy and sulfo: phenyl(C1-C4)alkyl in which the phenyl
portion may be optionally substituted by 1-3 substituents
442
mentioned above in connection with phenyl and the alkyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with C1-C4 alkyl; and heteroaryl
and heteroaralkyl in which the hetero atom or atoms are selected
from the group consisting of 1-4, O, S or N atoms and the
alkyl moiety associated with heteroaralkyl has 1-6 carbon
atoms, said heteroaryl and heteroaralkyl groups being optionally
substituted in the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, amino, halo, trifluoro-
methyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)-
alkylamino, carboxy and sulfo and in the alkyl moiety by
1-3 substituents selected from hydroxy, amino, C1-C4 alkyl-
amino, di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo
and sulfo, said heteroaromatic radical being optionally
substituted on a carbon atom by one or more substituents
independently selected from C1-C4 alkyl; C1 C4 alkyl substituted
by hydroxy, C1-C4 alkylamino, di(C1-C4)alkylamino, C1-C4 alkoxy,
amino, sulfo, carboxy or halogen; C3-C6 cycloalkyl; C1-C4 alkoxy,
C1-C4 alkylthio; amino; C1-C4 alkylamino, di(C1-C4)alkylamino;
halo; C1-C4 alkanoylamino; C1-C4 alkanoyloxy; carboxy;
<IMG> alkyl; hydroxy; amidino; guanidino, phenyl; phenyl
substituted by one, two or three amino, halo, hydroxyl.
trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4)alkyl in which the phenyl portion may be optionally
substituted by 1-3 substituents mentioned above in connection
with phenyl and the alkyl portion may be optionally substituted
by 1-3 substituents mentioned above in connection with C1-C4
alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said
heteroaralkyl moiety has 1-6 carbon atoms, or optionally
substituted so as to form a fused carbocyclic, heterocyclic
or heteroaromatic ring optionally substituted by 1 or 2 of
the substituents defined above; or a pharmaceutically acceptable
443
salt thereof.
197. A compound according to claim 196 wherein R1 is
hydrogen, CH3CH2-
<IMGS>
198. A compound according to claim 196 wherein R1 and R8
taken together represent
<IMG>
199. A compound according to claim 196 wherein R1 is
<IMG>
200. A compound according to claim 196 wherein R1 is
<IMG>
and the absolute configuration is 5R, 6S, 8R.
201. A compound according to claim 196 wherein A is
-CH2- or -CH2CH2- .
444
202. A compound of the formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: 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, hetero-
aralkyl, 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 hetero-
cyclic 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>
-NR3R4
445
<IMG>
-CO2R3
=O
<IMG>
-SR3
<IMG>
-CN
-N3
-OSO3R3
<IMG>
-OP(O)(OR3)(OR4)
446
<IMG>
-NR3CO2R4
-NO2
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: R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl wherein the hetero atom or atoms in the above-
named heterocyclic moieties are selected from the group
447
consisting of 1-4 oxygen, nitrogen or sulfur atoms and the
alkyl moieties associated with said heterocyclic moieties
have 1-6 carbon atoms; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl:
fluoro, chloro or bromo:
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-oxo ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
<IMG>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN: or
448
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 OR
-CONR3R4, wherein R3, R4, and R9 in such R5
substituent are as defined above; or R5 may be
attached to
<IMG>
at another point on the ring so as to form a fused
heterocyclic or heteroaromatic ring, which ring may
contain additional hetero atoms selected from O, N
and S;
A is C1-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 ion; and
<IMG>
represents a radical of the formula
<IMGS>
wherein X is O, S or NR in which R is C1-C4 alkyl;
C1-C4 alkyl substituted by 1-3 hydroxy, amino, C1-C4
alkylamino, di(C1-C4)alkylamino, C1-C4 alkoxy,
carboxy, halo or sulfo
449
groups; C3-C6 cycloalkyl: C3-C6 cycloalkyl(C1-C4)alkyl
optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl: phenyl:
phenyl substituted by 1-3 substituents independently
selected from amino, halo, hydroxy, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)alkylamino,
carboxy and sulfo; phenyl(C1-C4)alkyl in which the phenyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with phenyl and the alkyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with C1-C4 alkyl: and heteroaryl
and heteroaralkyl in which the hetero atom or atoms are selected
from the group consisting of 1-4, O, S or N atoms and the
alkyl moiety associated with heteroaralkyl has 1-6 carbon
atoms, said heteroaryl and heteroaralkyl groups being
optionally substituted in the heterocyclic ring moiety by 1-3
substitutents independently selected from hydroxy, amino, halo,
trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,
di(C1-C4)alkylamino, carboxy and sulfo and in the alkyl moiety
by 1-3 substituents selected from hydroxy, amino, C1-C4 alkyl-
amino, di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo and sulfo,
said heteroaromatic radical being optionally substituted on a
carbon atom by a substituent selected from C1-C4 alkyl; C1-C4 alkyl
substituted by hydroxy, C1-C4 alkylamino, di (C1-C4)alkylamino,
C1-C4 alkoxy, amino, sulfo, carboxy or halogen: C3-C6 cycloalkyl;
C1-C4 alkoxy, C1-C4 alkylthio; amino; C1-C4 alkylamino; di(C1-C4)-
alkylamino; halo; C1-C4 alkanoylamino; C1-C4 alkanoyloxy; carboxy;
<IMG>
alkyl; hydroxy; amidino; guanidino; phenyl; phenyl
substituted by one, two or three amino, halo, hydroxyl,
trifluoromethyl, C1-C4 alkyl or C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4)alkyl in which the phenyl portion may be optionally
substituted by 1-3 substituents mentioned above in connection
with phenyl and the alkyl portion may be optionally substituted
by 1-3 substituents mentioned above in connection with C1-C4 alkyl;
450
and heteroaryl or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety
has 1-6 carbon atoms; or a pharmaceutically acceptable salt
thereof.
203. A compound according to claim 202 wherein R1 is
hydrogen, CH3CH2-,
<IMGS>
204. A compound according to claim 202 wherein R1 and
R8 taken together represent
<IMG>
205. A compound according to claim 202 wherein R1 is
<IMG>
206. A compound according to claim 202 wherein R1 is
<IMG>
and the absolute configuration is 5R, 6S, 8R,
451
207. A compound according to claim 202 wherein A is
-CH2- or -CH2CH2-.
208. A compound of the formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: 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, hetero-
aralkyl, 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 hetero-
cyclic 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>
452
<IMG>
-NR3R4
<IMG>
-CO2R3
=O
<IMG>
-SR3
<IMG>
-CN
-N3
-OSO3R3
<IMG>
-OP(O)(OR3)(OR4)
453
<IMG>
-NR3CO2R4
-NO2
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
8lkylidene substituted by hydroxy; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms: cyclo-
alkyl 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-
cyclyalkyl wherein the hetero atom or atoms in the above-
453
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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-oxo ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
<IMGS>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
455
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5
substituents are as defined above; or R5 may be
attached to
<IMG>
at another point on the ring so as to form a fused
heterocyclic or heteroaromatic ring, which ring may
contain additional hetero atoms selected from O, N
and S;
A is C1-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 ion; and
<IMG>
represents a radical of the formula
<IMGS>
456
<IMG>
wherein R is C1-C4 alkyl: C1-C4 alkyl substituted by 1-3
hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkylamino,
C1-C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cyclo-
alkyl: C3-C6 cycloalkyl(C1-C4)alkyl optionally substituted
by 1-3 substituents mentioned above in connection with C1-C4 alkyl;
phenyl; phenyl substituted by 1-3 substituents independently
selected from amino, halo, hydroxy, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)alkylamino,
carboxy and sulfo; phenyl(C1-C4)alkyl in which the phenyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with phenyl and the alkyl
portion may, be optionally substituted by 1-3 substituents
mentioned above in connection with C1-C4 alkyl; and heteroaryl
and heteroaralkyl in which the hetero atom or atoms are selected
from the group consisting of 1-4, O, S or N atoms and the
alkyl moiety associated with heteroaralkyl has 1-6 carbon
atoms, said heteroaryl and heteroaralkyl groups being optionally
substituted in the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, amino, halo, trifluoro-
methyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)-
alkylamino, carboxy and sulfo and in the alkyl moiety by
1-3 substituents selected from hydroxy, amino, C1-C4 alkyl-
amino, di(C1-C4) alkylamino, C1-C4 alkoxy, carboxy, halo and sulfo;
or a pharmaceutically acceptable salt thereof.
457
209. A compound according to claim 208 wherein R1 is
hydrogen, CH3CH2-,
<IMGS>
210. A compound according to claim 208 wherein R1 and R8
taken together represent
<IMG>
211. A compound according to claim 208 wherein R1 is
<IMG>
212. A compound according to claim 208 wherein R1 is
<IMG>
and the absolute configuration is 5R, 6S, 8R.
458
213. A compound according to claim 208 wherein A is
-CH2- or -CH2CH2-
214. A compound of the formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group
consisting of hydrogen; substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl
tad 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, hetero-
aralkyl, 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; 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>
459
-<IMG>
-NR3R4
-<IMGS>
-CO2R3
=O
<IMG>
-SR3
<IMGS>
-CN
-N3
-OSO3R3
<IMGS>
-OP(O)(OR3)(OR4)
460
<IMG>
-NR3CO2R4
-NO2
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: R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl wherein the hetero atom or atoms in the above-
named heterocyclic moieties are selected from the group
461
consisting of 1-4 oxygen, nitrogen or sulfur atoms and the
alkyl moieties associated with said heterocyclic moieties
have 1-6 carbon atoms; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-oxo ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
<IMGS>
-SO3R3
-CO2R3 ;
-CONR3R4 ;
-CN; or
462
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above;
A is C1-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 ion; and
<IMG>
represents a radical of the formula
<IMG>
wherein R6, R7 and R10 are independently selected
from the group consisting of hydrogen, C1-C4 alkyl,
C1-C4 alkoxy, carboxy and carbamoyl; or a pharma-
ceutically acceptable salt thereof.
215. A compound according to claim 214 wherein R1 is
hydrogen, CH3CH2-
<IMG>
463
216. A compound according to claim 214 wherein R1 and
R8 taken together represent
<IMG>
217. A compound according to claim 214 wherein R1 is
<IMG>
218. A compound according to claim 214 wherein R1 is
<IMG>
and the absolute configuration is 5R, 6S, 8R.
219. A compound according to claim 214 wherein A is
-CH2- or -CH2CH2-.
220. A compound having the formula
<IMG>
464
wherein A is C1-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 ion: and
<IMG>
represents a radical of the formula
<IMG>
wherein R5 is C1-C4 alkyl and R6 represents hydrogen or
C1-C4 alkyl;
<IMG>
wherein R5 is C1-C4 alkyl and R6 and R7 are hydrogen or
C1-C4 alkyl;
<IMG>
wherein R5 is C1-C4 alkyl and R is C1-C4 alkyl or phenyl-
(C1-C4) alkyl;
465
<IMG>
wherein R5 is C1-C4 alkyl and R6 is C1-C4 alkyl;
<IMG>
wherein RS is C1-C4 alkyl and R is C1-C4 alkyl; or
<IMG>
wherein R5 is C1-C4 alkyl; or a pharmaceutically acceptable
salt thereof,
221. A compound having the formula
<IMG>
wherein A is C1-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 ion; and
466
<IMG>
represents a radical of the formula
<IMGS>
467
<IMGS>
or a pharmaceutically acceptable salt thereof.
222. A compound having 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 ion and wherein
<IMG>
468
<IMGS>
469
wherein the 1HNMR (D2O) spectrum shows characteristic peaks
at .delta.: 1.23 (3H, d, J=6.4 Hz), 3.12 (2H, q, J=1.4, 8.9 Hz),
3.39 (1H, q, J=2.7, 6.0 Hz), 4.07-4.68 (10H, m), 8.19 (1H, s);
<IMG>
wherein the 1HNMR (D2O) spectrum shows characteristic peaks
at .delta.: 1.23 (3H, d, J=6.4 Hz), 3.15 (2H, q, J=3.7, 9.0 Hz),
3.37 (1H, q, J=2.6, 6.0 Hz), 3.95-4.65(10H, m), 8.62 (1H, s);
<IMGS>
or a pharmaceutically acceptable salt thereof.
470
223. 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 ion; or a pharmaceutically acceptable salt
thereof.
224. The compound according to claim 223 wherein R2 is
p-nitrobenzyl.
225. The compound according to claim 223 wherein R2 is
an anionic charge.
226. A compound of the formula
<IMG>
wherein R2 is hydrogen, an anionic charge or a conventional
readily removable carboxyl protecting group, providing that
471
when R2 is hydrogen or a protecting group, there is also
present a counter ion; or a pharmaceutically acceptable salt
thereof.
227. The compound according to claim 226 wherein R2 is
p-nitrobenzyl.
228. The compound according to claim 226 wherein R2 is
an anionic charge.
229. 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 ion; or a pharmaceutically acceptable salt thereof.
230. The compound according to claim 229 wherein R2 is
p-nitrobenzyl.
231. The compound according to claim 229 wherein R2 is
an anionic charge.
472
232. 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 ion; or a pharmaceutically acceptable salt thereof.
233. The compound according to claim 232 wherein R2 is
p-nitrobenzyl.
234. The compound according to claim 232 wherein R2 is
an anionic charge.
235. 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 ion; or a pharmaceutically acceptable salt thereof.
473
236. The compound according to claim 235 wherein R2 is
p-nitrobenzyl.
237. The compound according to claim 235 wherein R2 is
an anionic charge.
238. 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 ion; or a pharmaceutically acceptable salt thereof.
239. The compound according to claim 238 wherein R2 is
p-nitrobenzyl.
240. The compound according to claim 238 wherein R2 is
an anionic charge.
474
241. 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 ion; or a pharmaceutically acceptable salt thereof.
242. The compound according to claim 241 wherein R2 is
p-nitrobenzyl.
243. The compound according to claim 241 wherein R2 is
an anionic charge.
244. A compound of the formula
<IMG>
wherein R2 is hydrogen, an anionic charge or a conventional
readily removable carboxyl protecting group, providing that
475
when R2 is hydrogen or a protecting group, there is also present
a counter ion; or a pharmaceutically acceptable salt thereof.
245. The compound according to claim 244 wherein R2 is
p-nitrobenzyl.
246. The compound according to claim 244 wherein R2 is
an anionic charge.
247. 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 ion; or a pharmaceutically acceptable salt thereof.
248. The compound according to claim 247 wherein R2 is
p-nitrobenzyl.
249. The compound according to claim 247 wherein R2 is
an anionic charge.
476
250. 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 ion; or a pharmaceutically acceptable salt thereof.
251. The compound according to claim 250 wherein R2 is
p-nitrobenzyl.
252. The compound according to claim 250 wherein R2 is
an anionic charge
253. A compound of the formula
<IMG>
wherein R2 is hydrogen, an anionic charge or a conventional
readily removable carboxyl protecting group, providing that
477
when R2 is hydrogen or a protecting group, there is also present
a counter ion; or a pharmaceutically acceptable salt thereof.
254. The compound according to claim 253 wherein R2 is
p-nitrobenzyl.
255. The compound according to claim 253 wherein R2 is
an anionic charge.
256. 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 ion; or a pharmaceutically acceptable salt thereof.
257. The compound according to claim 256 wherein R2 is
p-nitrobenzyl.
258. The compound according to claim 256 wherein R2 is
an anionic charge.
478
259. 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 ion; or a pharmaceutically acceptable salt
thereof.
260. The compound according to claim 259 wherein R2 is
p-nitrobenzyl.
261. The compound according to claim 259 wherein R2 is
an anionic charge.
262. A compound of the formula
<IMG>
wherein R2 is hydrogen, an anionic charge or a conventional
readily removable carboxyl protecting group, providing that
479
when R2 is hydrogen or a protecting group, there is also present
a counter ion; or a pharmaceutically acceptable salt thereof.
263. The compound according to claim 262 wherein R2 is
p-nitrobenzyl.
264. The compound according to claim 262 wherein R2 is
an anionic charge.
265. 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 ion; or a pharmaceutically acceptable salt
thereof.
266. The compound according to claim 265 wherein R2 is
p-nitrobenzyl.
267. The compound according to claim 265 wherein R2 is
an anionic charge.
480
268. 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 ion; or a pharmaceutically acceptable salt thereof.
269. The compound according to claim 268 wherein R2 is
p-nitrobenzyl.
270. The compound according to claim 268 wherein R2 is
an anionic charge.
271. 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
481
present a counter ion; or a pharmaceutically acceptable salt
thereof.
272. The compound according to claim 271 wherein R2 is
p-nitrobenzyl.
273. The compound according to claim 271 wherein R2 is
an anionic charge.
274. 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 ion; or a pharmaceutically acceptable salt
thereof.
275. The compound according to claim 274 wherein R2 is
p-nitrobenzyl.
276. The compound according to claim 274 wherein R2 is
an anionic charge.
482
277. 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 ion; or a pharmaceutically acceptable salt thereof.
278. The compound according to claim 277 wherein R2 is
p-nitrobenzyl.
279. The compound according to claim 277 wherein R2 is
an anionic charge.
280. 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
483
present a counter ion; or a pharmaceutically acceptable salt
thereof.
281. The compound according to claim 280 wherein R2 is
p-nitrobenzyl.
282. The compound according to claim 280 wherein R2 is
an anionic charge.
283. A compound of the formula
<IMG>
wherein the 1HNMR (D2O) spectrum shows characteristic peaks at
.delta.: 1.23 (3H, d, J=6.4 Hz), 3.12 (2H, q, J=1.4, 8.9 Hz), 3.39
(1H, q, J=2.7, 6.0 Hz), 4.07-4.68 (10H, m), 8.19 (1H, s), or
a pharmaceutically acceptable salt or ester thereof.
284. The compound according to claim 283 wherein the
carboxyl group is protected as a p-nitrobenzyl ester.
285. A compound of the formula
484
<IMG>
wherein the 1HNMR (D2O) spectrum shows characteristic peaks at
.delta. 1.23 (3H, d, J=6.4 Hz), 3.15 (2H, q, J=3.7, 9.0 Hz), 3.37
(1H, q, J=2.6, 6.0 Hz), 3.95-4.65 (10H, m), 8.62 (1H, s), or a
pharmaceutically acceptable salt or ester thereof.
286. The compound according to claim 285 wherein the
carboxyl group is protected as a p-nitrobenzyl ester.
287. A compound of the formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: alkyl, alkenyl
and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cyclo-
alkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and
1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl
485
and aralkynyl wherein the aryl moiety is phenyl and
the aliphatic portion has 1-6 carbon atoms;
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;
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 and carboxyl
halo
-OR3
<IMGS>
-NR3R4
<IMGS>
-CO2R3
=O
<IMG>
-SR3
<IMG>
486
<IMG>
-CN
-N3
-OSO3R3
<IMGS>
-OP(O)(OR3)(OR4)
<IMG>
-NR3CO2R4
-NO2
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 nay form a 5-or 6-membered
nitrogen-containing heterocyclic ring; R9 is as defined
487
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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-oxo ;
-NR3R4
R3CONR4- ;
-NR3CO2R4
-NR3CONR3R4 ;
488
<IMG>
-SR3 ;
<IMGS>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above;
or R5 may be attached to
<IMG>
at another point on the ring so as to form
a fused heterocyclic or heteroaromatic ring,
which ring may contain additional hetero atoms
selected from O, S and N ;
R15 is selected from the group consisting of hydrogen;
substituted and unsubstituted: 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; spirocycloalkyl having
3-6 carbon atoms; phenyl; aralkyl, aralkenyl and
aralkynyl wherein the aryl moiety is phenyl and
the aliphatic portion has 1-6 carbon atoms;
489
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 and
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 selected from the group
consisting of: amino, mono-, di- and trialkylamino,
hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio,
sulfamoyl, amidino, guanidino, nitro, chloro, bromo,
fluoro, cyano and carboxy; and wherein the alkyl
moieties of the above-recited substituents have 1-6
carbon atoms;
A is C1-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 ion; and
<IMG>
represents a substituted or unsubstituted mono-, bi-
or polycyclic aromatic heterocyclic radical
containing at least one nitrogen in the ring, said
ring being attached to A through a ring carbon atom
and having a ring nitrogen which is quaternized by
the group R5; or a pharmaceutically acceptable salt
thereof.
288. A process for the preparation of a compound
of the formula
490
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: alkyl, alkenyl
and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cyclo-
alkylalkyl, 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, hetero-
cyclyl 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; 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
<IMGS>
-NR3R4
<IMG>
491
<IMGS>
-CO2R3
=O
<IMG>
-SR3
<IMGS>
-CN
-N3
<IMGS>
-OP(O)(OR3)(OR4)
<IMG>
-NR3CO2R4
-NO2
492
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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
493
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG> ;
-OXO ;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG> ;
-SR3 ;
<IMGS> ;
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above;
494
or R5 may be attached to
<IMG>
at another point on the ring so as to form
a fused heterocyclic or heteroaromatic ring,
Which ring may contain additional hetero atoms
selected from O, S and N ;
R15 is selected from the group consisting of
substituted and unsubstituted: 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; spirocycloalkyl having
3-6 carbon atoms; phenyl; aralkyl, aralkenyl and
aralkynyl wherein the aryl moiety is phenyl and
the aliphatic portion has 1-6 carbon atoms;
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
and 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 selected
from the group consisting of: amino, mono-,
di- and trialkylamino, hydroxyl, alkoxyl, mercapto,
alkylthio, phenylthio, sulfamoyl, amidino, guanidino,
nitro, chloro, bromo, fluoro, cyano and carboxy;
and wherein the alkyl moieties of the above-recited
substituents have 1-6 carbon atoms;
495
A is C1-C6 straight or branched chain alkylene;
R2 is hydrogen, an anionic charge or a conven-
tional readily removable carboxyl protecting
group, providing that when R2 is hydrogen or
a protecting group, there is also present a
counter ion; and
<IMG>
represents a substituted or unsubstituted mono-,
bi- or polycyclic aromatic heterocyclic radical
containing at least one nitrogen in the ring,
said ring being attached to A through a ring
carbon atom and having a ring nitrogen which is
quaternized by the group R5; or a pharmaceutically
acceptable salt thereof which process comprises
reacting an intermediate of the formula
<IMG>
wherein R1, R8, R15, A and R2 are as defined above and
<IMG>
496
represents a mono-, bi- or polycyclic aromatic heterocyclic
radical containing a quaternizable nitrogen in the ring, said
ring being attached to A through a ring carbon atom, in an
inert organic solvent with an alkylating agent of the formula
R5~X'
wherein R5 is as defined above and X' is a conventional
leaving group so as to quaternize with the R5 group a
ring nitrogen of substituent
<IMG>
on intermediate II and form a compound of the formula
<IMG>
wherein R1, R8, R15, R2',A, <IMG> and ~X' are as defined above;
and, if desired, replacing counter ion X' by a different counter
ion and, if desired, removing the carboxyl protecting group R2'
to give the desired de-blocked compound of formula I, or a
pharmaceutically acceptable salt thereof.
497
289. A compound of the formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the
group consisting of hydrogen; substituted and
unsubstituted: 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 heterocyclyalkyl
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; 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
<IMGS>
-NR3R4
<IMG>
498
<IMGS>
-CO2R3
=O
<IMG>
-SR3
<IMGS>
-CN
-N3
-OSO3R3
-<IMGS>
-OP(O)(OR3)(OR4)
<IMG>
-NR3CO2R4
-NO2
499
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-nursed 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 heterocycling; R9 is is 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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
500
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo:
-OR3
-OC02R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-OXO ;
-NR3R4;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4;
<IMG>
-SR3;
<IMG>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above;
-501-
or R5 may be attached to
<IMG>
at another point on the ring so as to form a fused
heterocyclic or heteroaromatic ring, which ring may
contain additional hetero atoms selected from O, S
and N;
R15 is selected from the group consisting of
substituted and unsubstituted: 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; spirocycloalkyl having
3-6 carbon atoms; phenyl; aralkyl, aralkenyl and
aralkynyl wherein the aryl moiety is phenyl and the
aliphatic portion has 1-6 carbon atoms; 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 and 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 selected from the group
consisting of: amino, mono-, di- and trialkylamino,
hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio,
sulfamoyl , amidino, guanidino, nitro, chloro, bromo,
fluoro, cyano and carboxy; and wherein the alkyl
moieties of the above-recited substituents have 1-6
carbon atoms;
-502-
A is C1-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 ion; and
<IMG>
represents a substituted or unsubstituted mono-, bi-
or polycyclic aromatic heterocyclic radical
containing at least one nitrogen in the ring, said
ring being attached to A through a ring carbon atom
and having a ring nitrogen which is quaternized by
the group R5; or a pharmaceutically acceptable salt
thereof.
290. A process according to claim 288 wherein R1
is <IMG>- and R15 is methyl.
291. A process according to claim 288 wherein R1
is <IMG>, R15 is methyl, and the absolute
configuration is 5R, 6S, 8R.
292. A process according to claim 288 wherein A
is -CH2- or -CH2CH2-.
-503-
293. 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; substituted and
unsubstituted: 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 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; 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>
-NR3R4
-504-
<IMGS>
-C02R3
-O
<IMG>
-SR3
<IMGS>
-CN
-N3
-OSO3R3
<IMG>
-OP (O) (OR3) (OR4)
-NR3C-NR4
¦
R3
-NR3COZR4
-NO2
505
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 heteroriyl,
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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl and cycloalkylalkyl, having 3-6 carbon atoms in the
cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; azalkyl, aralkenyl and aralkynyl wherein the aryl
moiety is phenyl and the aliphatic portion has 1-6 carbon
atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
506
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-OXO ;
-NR3R4;
R3CONR4- ;
-NR3CO2R4;
-NR3CONR3R4;
<IMG>
-SR3;
<IMGS>
-SO3R3;
-CO2R3 ;
-CONR3R4 ;
-CN: or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above:
507
R5 may be attached to
<IMG>
at another point on the ring so is form a fused
heterocyclic or heteroaromatic ring, which ring
may contain additional hetero atoms selected from
O, S, and N; R15 is selected from the group consisting
of substituted and unsubstituted: alkyl, alkenyl, and
alkynyl, having frog 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; spirocycloalkyl having
3-6 carbon atoms; phenyl; aralkyl, aralkenyl and
aralkynyl wherein the aryl moiety is phenyl and
the aliphatic portion has 1-6 carbon atoms;
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
and 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 selected
from the group consisting of: amino, mono-,
di- and trialkylamino, hydroxyl, alkoxyl, mercapto,
alkylthio, phenylthio, sulfamoyl, amidino, guanidino,
nitro, chloro, bromo, fluoro, cyano and carboxy:
and wherein the alkyl moieties of the above-recited
substituents have 1-6 carbon atoms;
508
A is C1-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 ion; and
<IMG>
represents an aromatic mono-, bi- or polycyclic N-
containing heterocyclic ring containing 0-5
additional hetero atoms selected from O, S or N, said
heterocyclic ring being attached to A through a ring
carbon atom and having a ring nitrogen quaternized by
the group R5, and said heterocyclic ring being
optionally substituted at available ring carbon atoms
by 1-5 substituents independently selected from the
group consisting of C1-C4 alkyl; C1-C4 alkyl
substituted by 1-3 hydroxy, amino, C1-C4 alkylamino,
di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo or
sulfo; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C1-C4)alkyl
optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl; C1-C4 alkoxy;
C1-C4 alkylthio; amino; C1-C4 alkylamino, di(C1-
C4)alkylamino; halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy, sulfo;
O
-C-O-C1-C4 alkyl; hydroxy; amidino; guanidine;
phenyl; phenyl substituted by 1-3 substituents
independently selected from amino, halo, hydroxy
509
trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4
alkylamino, di(C1-C4)alkylamino, carboxy, and sulfo;
phenyl(C1-C4)alkyl in which the phenyl portion is
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl portion
is optionally substituted by 1-3 substituents
mentioned above in connection with C1-C4 alkyl; and
heteroaryl or heteroaralkyl in which the hetero atom
or atoms are selected from the group consisting of
1-4 O, S or N atoms and the alkyl moiety associated
with heteroaralkyl has 1-6 carbon atoms, said
heteroaryl and heteroaralkyl groups being optionally
substituted in the heterocyclic ring moiety by 1-3
substituents independently selected from hydroxy,
amino, halo, trifluoromethyl, C1-C4 alkyl, C1-C4
alkoxy, C1-C4 alkylamino, di (C1-C4)-alkylamino,
carboxy and sulfo and in the alkyl moiety by 1-3
substituents selected from hydroxy, amino, C1-C4
alkylamino, di(C1-C4)alkylamino, C1-C4 alkoxy,
carboxy, halo and sulfo, and said heterocyclic ring
being optionally substituted at available ring
nitrogen atoms by 1-3 substituents independently
selected from the group consisting of C1-C4 alkyl;
C1-C4 alkyl substituted by 1-3 hydroxy, amino, C1-C4
alkylamino, di(C1-C4)alkylamino, C1-C4 alkoxy,
carboxy, halo or sulfo groups; C3-C6 cycloalkyl;
C3-C6 cycloalkyl(C1-C4)alkyl optionally substituted
by 1-3 substituents mentioned above in connection
with C1-C4 alkyl; phenyl; phenyl substituted by 1-3
substituents independently selected from amino, halo,
hydroxy, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylamino, di(C1-C4)alkylamino, carboxy and
sulfo; phenyl-
510
(C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl portion
may be optionally substituted by 1-3 substituents
mentioned above in connection with C1-C4 alkyl; and
heteroaryl or heteroaralkyl in which the hetero atom
or atoms are selected from the group consisting or
1-4 O, S or N atoms and the alkyl moiety associated
with heteroaralkyl has 1-6 carbon atoms, said
heteroaryl and heteroaralkyl groups being optionally
substituted in the heterocyclic ring moiety by 1-3
substituents independently selected from hydroxy,
amino, halo, trifluoromethyl, C1-C4 alkyl, C1-C4
alkoxy, C1-C4 alkylamino, di(C1-C4)alkylamino,
carboxy and sulfo and in the alkyl moiety by 1-3
substituents selected from hydroxy, amino, C1-C4
alkylamino, di(C1-C4)alkylamino, C1-C4 alkoxy,
carboxy, halo and sulfo; or a pharmaceutically
acceptable salt thereof; which process comprises the
steps of reacting an intermediate of the formula
<IMG>
wherein R1, R8, R15, A and R2 are as defined above
and
<IMG>
511
represents a mono-, bi- or polycyclic aromatic
heterocyclic radical containing a quaternizable
nitrogen in the ring, said ring being attached to A
through a ring carbon atom, in an inert organic
solvent with an alkylating agent of the formula
R5-X'
wherein R5 is as defined above and X' is a
conventional leaving group so as to quaternize with
the R5 group a ring nitrogen of substituent
<IMG>
on intermediate II and form a compound of the formula
<IMG>
wherein R1, R8, R15, R2', A, <IMG> and X' are as
defined above; and, if desired, replacing counter ion
X' by a different counter ion and, if desired,
removing the carboxyl protecting group R2' to give
the desired de-blocked compound of formula I, or a
pharmaceutically acceptable salt thereof.
294. A process according to claim 293 wherein R1
<IMG>
and R15 is methyl.
512
295. A process according to claim 293 wherein R1 is
<IMG>
R15 is methyl, and the absolute configuration is 5R, 6S, 8R.
296. A process according to claim 293 wherein A is
-CH2- or -CH2CH2-.
297. A process for the preparation of a compound of the
formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: 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, hetero-
aralkyl, 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 hetero-
cyclic 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
513
<IMG>
-NR3R4
<IMG>
<IMG>
-CO2R3
=O
<IMG>
-SR3
<IMG>
-CN
-N3
-OSO3R3
<IMG>
-OP(O)(OR3)(OR4)
514
<IMG>
-NR3CO2R4
-NO2
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: R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms: cyclo-
alkyl 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-
cyclyalkyl wherein the hetero atom or atoms in the above-
named heterocyclic moieties are selected from the group
515
consisting of 1-4 oxygen, nitrogen or sulfur atoms and the
alkyl moieties associated with said heterocyclic moieties
have 1-6 carbon atoms; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-oxo ;
-NR3R4
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
<IMG>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
516
phenyl optionally substituted. by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above:
or R5 may be attached to
<IMG>
at another point on the ring so as to form a fused
heterocyclic or heteroaromatic ring, which ring may
contain additional hetero atoms selected from O,
N and S;
R15 is selected from the group consisting of
substituted and unsubstituted: 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; spirocycloalkyl having
3-6 carbon atoms; phenyl: aralkyl, aralkenyl and
aralkynyl wherein the aryl moiety is phenyl and
the aliphatic portion has 1-6 carbon atoms;
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
and 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 selected
from the group consisting of: amino, mono-,
di- and trialkylamino, hydroxyl, alkoxyl, mercapto,
alkylthio, phenylthio, sulfamoyl, amidino, guanidino,
nitro, chloro, bromo, fluoro, cyano and carboxy;
517
and wherein the alkyl moieties of the above-recited
substituents have 1-6 carbon atoms:
A is C1-C6 straight or branched chain alkylene;
R2 is hydrogen, an anionic charge or a conventional
readily removable carboxyl protecting group, pro-
viding that when R2 is hydrogen or a protecting group,
there is also present a counter ion: and
<IMG>
represents an aromatic 5- or 6-membered N-containing
heterocyclic ring containing 0-3 additional hetero
atoms selected from N, S or O, said heterocyclic ring
being optionally substituted at available ring carbon
atoms by 1-5 substituents independently selected from
the group consisting of C1-C4 alkyl: C1-C4 alkyl.
substituted by 1-3 hydroxy, amino, C1-C4 alkylamino,
di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo or
sulfo; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C1-C4)alkyl
optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl: C1-C4 alkoxy:
C1-C4 alkylthio; amino; C1-C4 alkylamino; di(C1-C4)-
alkylamino; halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy; sulfo;
<IMG> alkyl; hydroxy; amidino; guanidino:
phenyl: phenyl substituted by 1-3 substituents
independently selected from amino, halo, hydroxy,
trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylamino, di(C1-C4)alkylamino, carboxy,
and sulfo; phenyl(C1-C4)alkyl in which the
phenyl portion is optionally substituted by 1-3
substituents mentioned above in connection with
phenyl and the alkyl portion is optionally
substituted by 1-3 substituents mentioned above
518
in connection with C1-C4 alkyl; and heteroaryl or
heteroaralkyl in which the hetero atom or atoms
are selected from the group consisting of 1-4 O,
S or N atoms and the alkyl moiety associated
with heteroaralkyl has 1-6 carbon atoms, said
heteroaryl acid heteroaralkyl groups being
optionally substituted in the heterocyclic ring
moiety by 1-3 substituents independently selected
from hydroxy, amino, halo, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)-
alkylamino, carboxy and sulfo and in the alkyl
moiety by 1-3 substituents selected from hydroxy,
anino, C1-C4 alkylamino, di(C1-C4)alkylamino,
C1-C4 alkoxy, carboxy, halo and sulfo, and said
heterocyclic ring being optionally substituted at
available ring nitrogen atoms by 1-3 substituents
independently selected from the group consisting
of C1-C4 alkyl; C1-C4 alkyl substituted by 1-3
hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkyl-
amino, C1-C4 alkoxy, carboxy, halo or sulfo
groups; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C1-C4)-
alkyl optionally substituted by 1-3
substituents mentioned above in connection
with C1-C4 alkyl; phenyl; phenyl
substituted by 1-3 substituents independently
selected from amino, halo, hydroxy, trifluoromethyl,
C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,
di(C1-C4)alkylamino, carboxy and sulfo; phenyl-
(C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl
portion may be optionally substituted by 1-3
519
substituents mentioned above in connection with
C1-C4 alkyl; and heteroaryl or heteroaralkyl in
which the hetero atom or atoms are selected
from the group consisting or 1-4 O, S or N atoms
and the alkyl moiety associated with heteroaralkyl
has 1-6 carbon atoms, said heteroaryl and hetero-
aralkyl groups being optionally substituted in
the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, amino, halo,
trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylamino, di(C1-C4) alkylamino, carboxy
and sulfo and in the alkyl moiety by 1-3 substituents
selected from hydroxy, amino, C1-C4 alkylamino,
di(C1-C4) alkylamino, C1-C4 alkoxy, carboxy, halo
and sulfo; or a pharmaceutically acceptable salt
thereof; which process comprises reacting an intermediate
of the formula
<IMG>
wherein R1, R8, R15, A and R2 are as defined above and
<IMG>
520
represents a mono-, bi- or polycyclic aromatic heterocyclic
radical containing a quaternizable nitrogen in the ring, said
ring being attached to A through a ring carbon atom, in an
inert organic solvent with an alkylating agent of the formula
R5~X'
wherein R5 is as defined above and X' is a conventional
leaving group so as to quaternize with the R5 group a
ring nitrogen of substituent
<IMG>
on intermediate II and form a compound of the formula
<IMG>
wherein R1, R8, R15, R2',A, <IMG> and ~X' are as defined above;
and, if desired, replacing counter ion X' by a different counter
ion and, if desired, removing the carboxyl protecting group R2'
to give the desired de-blocked compound of formula I, or a
pharmaceutically acceptable salt thereof.
521
298. A process according to claim 297 wherein the
heterocyclic ring <IMG> is optionally
substituted at available ring carbon or nitrogen atoms by up
to 5 substituents independently selected from (lower) alkyl.
299. A process according to claim 298 wherein
A is -CH2-, -CH2CH2- or <IMG>
300. A process according to claim 297 wherein R1 is
<IMG>, R15 is methyl, and the absolute configuration is
5R, 6S, 8R.
301. A process for the preparation of a compound of
the formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: 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, hetero-
aralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero
atom or atoms in the above-named heterocyclic moieties are
522
selected from the group consisting of 1-4 oxygen, nitrogen or
sulfur atoms and the alkyl moieties associated with said hetero-
cyclic 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
<IMGS>
-NR3R4
<IMGS>
-CO2R3
~O
<IMG>
-SR3
<IMG>
-SR3
<IMGS>
523
-CN
-N3
-OSO3R3
<IMGS>
-OP(O)(OR3)(OR4)
<IMG>
-NR3CO2R4
-NO2
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 nay not be hydrogen; or wherein R1
and R8 taken together represent C2-C10 alkylidene or C2-C10
524
alkylidene substituted by hydroxy; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
Cl-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-OXO ;
-NR3R4 ;
-R3CONR4-;
-NR3CO2R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
525
<IMGS>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 ;
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above; or R5 may be attached to
<IMG>
at another point on the ring so as to form a fused
heterocyclic or heteroaromatic ring, which ring may
contain additional hetero atoms selected from O, N and
S;
R15 is selected from the group consisting of
substituted and unsubstituted: 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; spirocycloalkyl having
3-6 carbon atoms; phenyl: aralkyl, aralkenyl and
aralkynyl wherein the aryl moiety is phenyl and
the aliphatic portion has 1-6 carbon atoms;
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
526
and 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 selected
from the group consisting of: amino, mono-, di- and
trialkylamino, hydroxyl, alkoxyl, mercapto,
alkylthio, phenylthio, sulfamoyl , amidino, guanidino,
nitro, chloro, bromo, fluoro, cyano and carboxy; and
wherein the alkyl moieties of the above-recited
substituents have 1-6 carbon atoms;
A is C1-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 ion; and
<IMG>
represents a radical selected from the group
consisting of
<IMG>
wherein R6, R7 and R10 are independently selected
from hydrogen; C1-C4 alkyl; C1-C4 alkyl substituted
by hydroxy, C1-C4 alkylamino, di(C1-C4 alkyl)amino,
C1-C4 alkoxy, amino, sulfo, carboxy or halo; C3-C6
cycloalkyl; C1-C4 alkoxy; C1-C4 alkylthio; amino;
C1-C4 alkylamino; di(C1-C4 alkyl) amino; halo; C1-C4
alkanoylamino; C1-C4 alkanoyloxy; carboxy;
O
-C-OC1-C4 alkyl, hydroxy; amidino; guanidino; phenyl;
phenyl substituted by one, two or three amino, halo,
hydroxyl,
527
trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups,
phenyl (C1-C4)alkyl in which the phenyl portion may
be optionally substituted by 1-3 substituents
mentioned above in connection with phenyl and the
alkyl portion may be optionally substituted by 1-3
substituents mentioned above in connection with C1-C4
alkyl; and heteroaryl and heteroaralkyl in which the
hetero atom or atoms in the group consisting of 1-4
oxygen, nitrogen or sulfur atoms and the alkyl moiety
associated with said heteroaralkyl moiety has 1-6
carbon atoms; or wherein two of R6, R7 or R10 taken
together may be a fused saturated carbocyclic ring, a
fused aromatic carbocyclic ring, a fused non-aromatic
heterocyclic ring or a fused heteroaromatic ring,
said fused rings being optionally substituted by 1 or
2 of the substituents defined above for R6, R7 and
R10;
<IMGS>
optionally substituted on a carbon atom by 1-3
substituents independently selected from C1-C4 alkyl;
C1-C4 alkyl substituted by hydroxy, C1-C4 alkylamino,
di(C1-C4 alkyl) amino, sulfo, C1-C4 alkoxy, amino,
carboxy or halogen; C3-C6 cycloalkyl; C1-C4 alkoxy;
C1-C4 alkylthio; amino; C1-C4 alkylamino; di(C1-C4
alkyl) amino; halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy;
528
<IMG> alkyl; hydroxy; amidino; guanidino; phenyl;
phenyl substituted by one, two or three amino, halo,
hydroxyl, trifluoromethyl, C1-C4 alkyl or C1-C4
alkoxy groups; phenyl (C1-C4)alkyl in which the
phenyl portion may be optionally substituted by 1-3
substituents mentioned above in connection with
phenyl and the alkyl portion may be optionally
substituted by 1-3 substituents mentioned above in
connection with C1-C4 alkyl; and heteroaryl or
heteroaralkyl in which 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 moiety associated with
said heteroaralkyl moiety has 1-6 carbon atoms, or
optionally substituted so as to form a fused
carboxycyclic, heterocyclic or heteroaromatic ring
optionally substituted by 1 or 2 of the substituents
defined above;
<IMGS>
optionally substituted on a carbon atom by one or two
substituents independently selected from C1-C4 alkyl;
C1-C4 alkyl substituted by hydroxy, C1-C4 alkylamino,
di (C1-C4 alkyl) amino, C1-C4 alkoxy, sulfo, amino,
carboxy or halogen; C3-C6 cycloalkyl; C1-C4 alkoxy;
C1-C4 alkylthio; amino; C1-C4 alkylamino; di(C1-C4
alkyl) amino; halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy;
529
<IMG> alkyl, hydroxy, amidino, guanidino, phenyl;
phenyl substituted by one, two or three amino, halo,
hydroxyl, trifluoromethyl, C1-C4 alkyl or C1-C4
alkoxy groups; phenyl (C1-C4)alkyl in which the
phenyl portion may be optionally substituted by 1-3
substituents mentioned above in connection with
phenyl and the alkyl portion may be optionally
substituted by 1-3 substituents mentioned above in
connection with C1-C4 alkyl; and heteroaryl or
heteroaralkyl in which 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 moiety associated with
said heteroaralkyl moiety has 1-6 carbon atoms, or
optionally substituted so as to form a fused
carbocyclic, heterocyclic or heteroaromatic ring
optionally substituted by 1 or 2 of the substituents
defined above;
<IMGS>
optionally substituted on a carbon atom by a
substituent independently selected from C1-C4 alkyl;
C1-C4 alkyl substituted by hydroxy, amino, C1-C4
alkylamino, di(C1-C4 alkyl) amino, C1-C4 alkoxy,
sulfo, carboxy or halogen; C3-C6 cycloalkyl; C1-C4
alkoxy; C1-C4 alkylthio; amino; C1-C4 alkylamino;
di(C1-C4 alkyl)amino; halo; C1-C4 alkanoylamino;
C1-C4 alkanoyloxy; carboxy;
530
<IMG> alkyl; hydroxy; amidino; guanidino, phenyl;
phenyl substituted by one, two or three amino, halo,
hydroxyl, trifluoromethyl, C1-C4 alkyl or C1-C4
alkoxy groups; phenyl (C1-C4) alkyl in which the
phenyl portion may be optionally substituted by 1-3
substituents mentioned above in connection with
phenyl and the alkyl portion may be optionally
substituted by 1-3 substituents mentioned above in
connection with C1-C4 alkyl; and heteroaryl or
heteroaralkyl in which 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 moiety associated with
said heteroaralkyl moiety has 1-6 carbon atoms;
<IMGS>
wherein X is O, S or NR in which R is C1-C4 alkyl;
C1-C4 alkyl substituted by 1-3 hydroxy, amino, C1-C4
alkylamino, di(C1-C4) alkylamino, C1-C4 alkoxy,
carboxy, halo or sulfo groups; C3-C6 cycloalkyl; C3-
C6 cycloalkyl (C1-C4)alkyl optionally substituted by
1-3 substituents mentioned above in connection with
C1-C4 alkyl; phenyl; phenyl substituted by 1-3
substituents independently selected from amino, halo,
hydroxy, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylamino, di(C1-C4)alkylamino, carboxy and
sulfo; phenyl(C1-C4)alkyl in which the phenyl portion
may be optionally substituted by 1-3 substituents
mentioned above in connection with phenyl and the
alkyl portion may be optionally substituted by 1-3
substituents
531
mentioned above in connection with C1-C4 alkyl; and heteroaryl
and heteroaralkyl in which the hetero atom or atoms are selected
from the group consisting of 1-4. O, S or N atoms and the
alkyl moiety associated with heteroaralkyl has 1-6 carbon
atoms, said heteroaryl and heteroaralkyl groups being optionally
substituted in the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, amino, halo, trifluoro-
methyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)-
alkylamino, carboxy and sulfo and in the alkyl moiety by
1-3 substituents selected from hydroxy, amino, C1-C4 alkyl-
amino, di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo
and sulfo, said radical being optionally substituted on a
carbon atom by one or more substituents independently selected
from C1-C4 alkyl; C1-C4 alkyl substituted by hydroxy, C1-C4
alkylamino, di(C1-C4 alkyl) amino, C1-C4 alkoxy, amino, sulfo,
carboxy or halogen; C3-C6 cycloalkyl; C1-C4 alkoxy; C1-C4
alkylthio; amino; C1-C4 alkylamino; di(C1-C4 alkyl)amino;
halo; C1-C4 alkanoylamino; C1-C4 alkanoyloxy; carboxy;
<IMG> alkyl; hydroxy: amidino: guanidino, phenyl;
phenyl substituted by one, two or three amino, halo,
hydroxyl, trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned above
in connection with phenyl and the alkyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl;
and heteroaryl or heteroaralkyl in which 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 moiety associated with said heteroaralkyl
moiety has 1-6 carbon atoms, or optionally substituted so as
to form a fused carbocyclic, heterocyclic or heteroaromatic
ring optionally substituted by 1 or 2 of the substituents
defined above;
532
<IMGS>
wherein X is O, S or NR in which R is C1-C4 alkyl;
C1-C4 alkyl substituted by 1-3 hydroxy, amino, C1-C4
alkylamino, di(C1-C4)alkylamino, C1-C4 alkoxy,
carboxy, halo or sulfo groups; C3-C6 cycloalkyl; C3-
C6 cycloalkyl(C1-C4 alkyl optionally substituted by
1-3 substituents mentioned above in connection with
C1-C4 alkyl; phenyl; phenyl substituted by 1-3
substituents independently selected from amino, halo,
hydroxy, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylamino, di(C1-C4)alkylamino, carboxy and
sulfo; phenylC1-C4 alkyl in which the phenyl portion
may be optionally substituted by 1-3 substituents
mentioned above in connection with phenyl and the
alkyl portion may be optionally substituted by 1-3
substituents mentioned above in connection with C1-C4
alkyl; and heteroaryl and heteroaralkyl in which the
hetero atom or atoms are selected from the group
consisting of 1-4, O, S or N atoms and the alkyl
moiety associated with heteroaralkyl has 1-6 carbon
atoms, said heteroaryl and heteroaralkyl groups being
optionally substituted in the heterocyclic ring
moiety by 1-3 substituents independently selected
from hydroxy, amino, halo, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino,
di(C1-C4)alkylamino, carboxy and sulfo and in the
alkyl moiety by 1-3 substituents selected from
hydroxy, amino, C1-C4 alkylamino,
533
di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo and
sulfo, said heteroaromatic radical being optionally
substituted on a carbon atom by a substituent
selected from C1-C4 alkyl; C1-C4 alkyl substituted by
hydroxy, C1-C4 alkylamino,
534
di(C1-C4 alkyl) amino, C1-C4 alkoxy, amino, sulfo,
carboxy or halogen; C3-C6 cycloalkyl; C1-C4 alkoxy;
C1-C4 alkylthio; amino; C1-C4 alkylamino;
di(C1-C4)alkylamino; halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy;
O
-C-OC1-C4 alkyl; hydroxy; amidino; guanidino; phenyl;
phenyl substituted by one, two or three amino, halo,
hydroxyl, trifluoromethyl, C1-C4 alkyl or C1-C4
alkoxy groups; phenyl (C1-C4)alkyl in which the
phenyl portion may be optionally substituted by 1-3
substituents mentioned above in connection with
phenyl and the alkyl portion may be optionally
substituted by 1-3 substituents mentioned above in
connection with C1-C4 alkyl; and heteroaryl or
heteroaralkyl in which 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 moiety associated with
said heteroaralkyl moiety has 1-6 carbon atoms; and
<IMGS>
535
<IMGS>
wherein R is C1-C4; C1-C4 alkyl substituted by 1-3
hydroxy, amino, C1-C4 alkylamino,
di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo or
sulfo groups; C3-C6 cycloalkyl; C3-C6
cycloalkyl(C1-C4)alkyl optionally substituted by 1-3
substituents mentioned above in connection with C1-C4
alkyl; phenyl, phenyl substituted by 1-3 substituents
independently selected from amino, halo, hydroxy,
trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4
alkylamino, di(C1-C4)alkylamino, carboxy and sulfo;
phenyl C1-C4 alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl portion
may be optionally substituted by 1-3 substituents
mentioned above in connection with C1-C4 alkyl; and
heteroaryl and heteroaralkyl in which the hetero atom
or atoms are selected from the group consisting of
1-4, O, S or N atoms and the alkyl moiety associated
with heteroaralkyl has 1-6 carbon atoms, said
heteroaryl and heteroaralkyl groups being optionally
substituted in the heterocyclic ring moiety by 1-3
substituents independently selected from hydroxy,
amino, halo, trifluoromethyl, C1-C4 alkyl, C1-C4
alkoxy, C1-C4 alkylamino, di(C1-C4) alkylamino,
carboxy and sulfo and in the alkyl moiety by 1-3
substituents selected from hydroxy, amino, C1-C4
alkylamino, di(C1-C4)alkylamino, C1-C4 alkoxy,
carboxy, halo and sulfo; or a pharmaceutically
acceptable salt thereof; which process comprises
reacting an intermediate of the formula
536
<IMG>
wherein R1, R8, R15, A and R2 are as defined above and
<IMG>
represents a mono-, bi- or polycyclic aromatic heterocyclic
radical containing a quaternizable nitrogen in the ring, said
ring being attaches to A through a ring carbon atom, in an
inert organic solvent with an alkylating agent of the formula
R5-X'
wherein R5 is as defined above and X' is a conventional
leaving group so as to quaternize with the R5 group a
zing nitrogen of substituent
<IMG>
on intermediate II and form a compound of the formula
<IMG>
537
wherein R1, R8, R15, R2',A, <IMG> and 'X' are as defined above;
and, if desired, replacing counter ion X' by a different counter
ion and, if desired, removing the carboxyl protecting group R2'
to give the desired de-blocked compound of formula I, or a
pharmaceutically acceptable salt thereof.
302. A process in accordance with claim 301 wherein
<IMG>
represents a radical selected from the group consisting of
<IMG>
wherein R5 is C1-C6 alkyl and R6, R7 and R10 are each
independently hydrogen or C1-C4 alkyl;
<IMGS>
538
wherein R5 is C1-C6 alkyl and wherein available ring
carbon atoms are optionally substituted by 1-3
substituents independently selected from C1-C4 alkyl;
<IMGS>
wherein R5 is C1-C6 alkyl and wherein available ring
carbon atoms are optionally substituted by 1 or 2
substituents independently selected from C1-C4 alkyl;
<IMGS>
539
wherein R5 is C1-C4 alkyl and wherein an available
ring carbon atom is optionally substituted by C1-C4
alkyl;
<IMGS>
wherein R5 is C1-C6 alkyl, X is O, S or NR in which R
is C1-C4 alkyl and wherein one or more available ring
carbon atoms is optionally substituted by C1-C4
alkyl;
<IMGS>
wherein R5 is C1-C6 alkyl, X is O, S or NR in which R
is C1-C4 alkyl and wherein one or more available ring
carbon atoms is optionally substituted by C1-C4
alkyl; and
<IMGS>
540
<IMGS>
wherein R5 is C1-C6 alkyl and R is C1-C4 alkyl.
303. A process in accordance with claim 302 wherein
R1 is <IMG> and R15 is methyl.
304. A process in accordance with claim 302 wherein
R1 is <IMG> R15 is methyl, and the absolute configuration
is 5R, 6S, 8R.
305. A process in accordance with claim 301 wherein
A is -CH2- or -CH2CH2-.
306. A process in accordance with claim 291 wherein
there is prepared a compound having the formula
<IMG>
wherein A is C1-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 ion; and wherein
541
<IMG>
represents a radical of the formula
<IMG>
wherein R6 represents hydrogen or C1-C4 alkyl;
<IMG>
wherein R6 and R7 are hydrogen or C1-C4 alkyl;
<IMG>
wherein R is C1-C4 alkyl or phenyl(C1-C4)alkyl;
<IMG>
wherein R6 is C1-C4 alkyl;
542
<IMG>
wherein R is C1-C4 alkyl; or
<IMG>
with an alkylating agent of the formula R5 - X',
wherein R5 is C1-C4 alkyl and X' is a conventional leaving
group; and where desired, forming a pharmaceutically acceptable
salt of the reaction product thereby obtained.
307. A process in accordance with claim 291 which comprises
reacting a compound having the formula
<IMG>
wherein A is C1-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 ion; and wherein
<IMG>
represents a radical of the formula
<IMGS>
543
<IMGS>
with an alkylating agent of the formula CH3X' or (in the case
where <IMG> is (d) above), CH2CH2CH3X', wherein X' is a
conventional leaving group; and where desired, forming a pharma-
ceutically acceptable salt of the reaction product thereby obtained.
544
308. A process in accordance with claim 291 which comprises
reacting a compound having 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
309. A process in accordance with claim 291 which comprises
reacting a compound having 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
310. A process in accordance with claim 291 which comprises
reacting a compound having the formula
545
<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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
311. A process in accordance with claim 291 which comprises
reacting a compound having 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
312. A process in accordance with claim 291 which comprises
reacting a compound having the formula
<IMG>
546
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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
313. A process in accordance with claim 291 which comprises
reacting a compound having 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 ion; with an alkylating agent of the formula
CH2CH2CH3X', wherein X' is a conventional leaving group; and
where desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
314. A process in accordance with claim 291 which comprises
reacting a compound having 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
547
315. A process in accordance with claim 291 which comprises
reacting a compound having 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
316. A process in accordance with claim 291 which comprises
reacting a compound having 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
317. A process in accordance with claim 291 which comprises
reacting a compound having the formula
548
<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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
318. A process in accordance with claim 291 which comprises
reacting a compound having 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
319. A process in accordance with claim 291 which comprises
reacting a compound having the formula
<IMG>
549
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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
320. A process in accordance with claim 291 which comprises
reacting a compound having 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
321. A process in accordance with claim 291 which comprises
reacting a compound having 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group: and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
550
322. A process in accordance with claim 291 which comprises
reacting a compound having 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
323. A process in accordance with claim 291 which comprises
reacting a compound having 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 ion; with a compound of the formula CH2COOX',
wherein X' is a conventional leaving group; and where desired,
forming a pharmaceutically acceptable salt of the reaction
product thereby obtained.
324. A process in accordance with claim 291 which comprises
reacting a compound having the formula
<IMG>
551
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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
325. A process in accordance with claim 291 which comprises
reacting a compound having 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
326. A process in accordance with claim 291 which comprises
reacting a compound having 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
552
327. A process in accordance with claim 291 which comprises
reacting a compound having 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
328. A process in accordance with claim 291 which comprises
reacting a compound having 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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
329. A process in accordance with claim 291 which comprises
reacting a compound having the formula
553
<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 ion; with an alkylating agent of the formula
CH3X', wherein X' is a conventional leaving group; and where
desired, forming a pharmaceutically acceptable salt of the
reaction product thereby obtained.
330. A compound according to claim 289 wherein R1 is
<IMG> , and R15 is methyl .
331. A compound according to claim 289 wherein R1 is
<IMG>
R15 is methyl and the
absolute configuration is 5R, 6S, 8R,
332. A compound according to claim 289 wherein A is
-CH2- or -CH2CH2-
333. A compound of the formula
554
<IMG>
wherein R8 is hydrogen and R1 is selected from the
group consisting of hydrogen; substituted and
unsubstituted: 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 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; 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
O
-OCNR3R4
555
O
-CNR3R4
-NR3R4
<IMG>
-556-
<IMGS>
-CO2R3
=O
<IMG>
-SR3
<IMGS>
-CN
-N3
-OSO3R3
<IMGS>
-OP(O)(OR3)(OR4)
<IMG>
-NR3CO2R4
-NO2
-557-
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; R5 is selected from the group consisting of
substituted and unsubstituted: 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 heterocyclyalkyl
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; wherein
the above-named R5 radicals are optionally
-558-
substituted by 1-3 substituents independently
selected from:
-559-
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl , hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OC02R3
-OCOR3 ;
-OCONR3R4
<IMG>
-OXO ;
-NR3R4 ;
R3CONR4- ;
-NR3C02R4 ;
-NR3CONR3R4 ;
<IMG>
-SR3 ;
<IMG>
-SO3R3 ;
-CO2R3 ;
-CONR3R4 :
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1 C6 alkyl, -OR3, -NR3R9, -SO3R3, CO2R3 or
-CONR3R4, Wherein R3, R4, and R9 in such R5 substituents
are as defined above ;
-560-
R5 may be at attached to
<IMG>
at another point on the ring so as form a fused
heterocyclic or heteroaromatic ring, which ring
may contain additional hetero atoms selected from
O, S, and N; Rl5 is selected from the group consisting
of substituted and unsubstituted: 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; spirocycloalkyl having
3-6 carbon atoms; phenyl; aralkyl, aralkenyl and
aralkynyl wherein the aryl moiety is phenyl and
the aliphatic portion has 1-6 carbon atoms;
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
and 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 selected
from the group consisting of: amino, mono-,
di- and trialkylamino, hydroxyl, alkoxyl, mercapto,
alkylthio, phenylthio, sulfamoyl, amidino, guanidino;
nitro, chloro, bromo, fluoro, cyano and carboxy;
and wherein the alkyl moieties of the above-recited
substituents have 1-6 carbon atoms;
-561-
A is C1-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 ion; and
<IMG>
represents an aromatic mono-, bi- or polycyclic N-
containing heterocyclic ring containing 0-5
additional hetero atoms selected from O, S or N, said
heterocyclic ring being attached to A through a ring
carbon atom and having a ring nitrogen quaternized by
the group R5, and said heterocyclic ring being
optionally substituted at available ring carbon atoms
by 1-5 substituents independently selected from the
group consisting of C1-C4 alkyl; C1-C4 alkyl
substituted by 1-3 hydroxy, amino, C1-C4 alkylamino,
di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo or
sulfo; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C1-C4)alkyl
optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl; C1-C4 alkoxy;
C1-C4 alkylthio; amino; C1-C4 alkylamino;
di (C1-C4)alkylamino; halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy; sulfo;
O
-C-O-C1-C4 alkyl; hydroxy, amidino, guanidino;
phenyl; phenyl substituted by 1-3 substituents
independently selected from amino, halo, hydroxy,
-562-
trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylamino, di (C1-C4) alkylamino, carboxy,
and sulfo: phenyl (C1-C4) alkyl in which the
phenyl portion is optionally substituted by 1-3
substituents mentioned above in connection with
phenyl and the alkyl portion is optionally
substituted by 1-3 substituents mentioned above .
in connection with C1-C4 alkyl; and heteroaryl or
heteroaralkyl in which the hetero atom or atoms
are selected from the group consisting of 1-4 O,
S or N atoms and the alkyl moiety associated
with heteroaralkyl has 1-6 carbon atoms, said
heteroaryl and heteroaralkyl groups being
optionally substituted in the heterocyclic ring
moiety by 1-3 substituents independently selected
from hydroxy, amino, halo, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)-
alkylamino, carboxy and sulfo and in the alkyl
moiety by 1-3 substituents selected from hydroxy,
amino, C1-C4 alkylamino, di (C1-C4) alkylainino,
C1-C4 alkoxy, carboxy, halo and sulfo, and said
heterocyclic ring being optionally substituted at
available ring nitrogen atoms by 1-3 substituents
independently selected from the group consisting
of C1 C4 alkyl,: C1-C4 alkyl substituted by 1-3
hydroxy, amino, C1-C4 alkylamino, di(C1-C9)alkyl-
amino, C1-C4 alkoxy, carboxy, halo or sulfo
groups: C3-C6 cycloalkyl; C3-C6 cycloalkyl(C1-C4)-
alkyl optionally substituted by 1-3
substituents mentioned above in connection
with C1-C4 alkyl: phenyl; phenyl
substituted by 1-3 substituents independently
selected from amino, halo, hydroxy, trifluoromethyl,
C1-C4 alkyl. C1-C4 alkoxy, C1-C4 alkylamino,
di (C1 C4) alkylamino, carboxy and sulfo; phenyl-
-563-
C1-C4 alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl portion
may be optionally substituted by 1-3 substituents
mentioned above in connection with C1-C4 alkyl; and
heteroaryl or heteroaralkyl in which the hetero atom
or atoms are selected from the group consisting or
1-4 O, S or N atoms and the alkyl moiety associated
with heteroaralkyl has 1-6 carbon atoms, said
heteroaryl and heteroaralkyl groups being optionally
substituted in the heterocyclic ring moiety by 1-3
substituents independently selected from hydroxy,
amino, halo, trifluoromethyl, C1-C4 alkyl, C1-C4
alkoxy, C1-C4 alkylamino, di (C1-C4 ) alylamino,
carboxy and sulfo and in the alkyl moiety by 1-3
substituents selected from hydroxy, amino, C1-C4
alkylamino, di (C1-C4 ) alkylamino, C1-C4 alkoxy,
carboxy, halo and sulfo; or a pharmaceutically
acceptable salt thereof.
334. A compound according to claim 333 wherein
R1 is <IMG> and R15 is methyl.
335. A compound according to claim 333 wherein
R1 is <IMG > R15 is methyl and the absolute
configuration is 5R, 6S, 8R.
-564-
336. A compound according to claim 333 wherein A is
-CH2- or -CH2CH2-.
337. A compound of the formula
<IMG>
wherein R8 is hydrogen and Rl is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: 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, hetero-
aralkyl, 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 hetero-
cyclic 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>
-NR3R4
-565-
<IMG>
-CO2R3
=O
<IMG>
-SR3
<IMG>
-CN
-N3
-OSO3R3
<IMG>
-OP (O) (OR3) (OR4)
<IMG>
-NR3CO2R4
-NO2
-566-
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 hetezoaryl,
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-C0 alkylidene or C2-C10
alkylidene substituted by hydroxy; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl 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; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
-567-
C1-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-OR3
-OCO2R3 ;
-OCOR3 ;
-OCONR3R4 ;
<IMG>
-oxo;
-NR3R4 ;
R3CONR4- ;
-NR3CO2R4 ;
-NR3CONR3R4
<IMG>
-SR3 ;
<IMGS>
-SO3R3 ;
-CO2R3
-CONR3R4 ;
-CN: or
phenyl optionally substituted by 1-3 fluoro, chloro,
bromo, C1-C6 alkyl, -OR3, -NR3R4, -S3R3, -CO2R3 or
-CONR3R4, wherein R3, R4, and R9 in such R5 substituents
are as defined above:
-568-
or R5 may be attached to
<IMG>
at another point on the ring so as to form a fused
heterocyclic or heteroaromatic ring, which ring may
contain additional hetero atoms selected from O,
N and S;
R15 is selected from the group consisting of
substituted and unsubstituted: 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; spirocycloalkyl having
3-6 carbon atoms; phenyl; aralkyl, aralkenyl and
aralkynyl wherein the aryl moiety is phenyl and
the aliphatic portion has 1-6 carbon atoms;
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
and 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 selected
from the group consisting of: amino, mono-,
di- and trialkylamino, hydroxyl, alkoxyl, mercapto,
alkylthio, phenylthio, sulfamoyl, amidino, guanidino,
nitro, chloro, bromo, fluoro, cyano and carboxy;
and wherein the alkyl moieties of the above-recited
substituents have 1-6 carbon atoms;
-569-
A is C1-C6 straight or branched chain alkylene;
R2 is hydrogen, an anionic charge or a conventional
readily removable carboxyl protecting group, pro-
viding that when R2 is hydrogen or a protecting group,
there is also present a counter ion: and
<IMG>
represents an aromatic 5- or 6-membered N-containing
heterocyclic ring containing 0-3 additional hetero
atoms selected from N, S or O, said heterocyclic ring
being optionally substituted at available ring carbon
atoms by 1-5 substituents independently selected from
the group consisting of C1-C4 alkyl; C1-C4 alkyl.
substituted by 1-3 hydroxy, amino, C1-C4 alkylamino,
di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo or
sulfo; C3-C cycloalkyl; C3-C6 cycloalkyl (C1-C4) alkyl
optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl; C1 C4 alkoxy;
C1-C4 alkylthio; amino; C1-C4 alkylamino; di(C1-C4)-
alkylamino; halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy: carboxy; sulfo;
<IMG> alkyl; hydroxy; amidino; guanidino;
phenyl; phenyl substituted by 1-3 substituents
independently selected from amino, halo, hydroxy,
trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylamino, di (C1-C4) alkylamino, carboxy,
and sulfo; phenyl (C1-C4) alkyl in which the
phenyl portion is optionally substituted by 1-3
substituents mentioned above in connection with
phenyl and the alkyl portion is optionally
substituted by 1-3 substituents mentioned above
in connection with C1-C4 alkyl; and heteroaryl or
heteroaralkyl in which the hetero atom or atoms
-570-
are selected from the group consisting of 1-4 O,
S or N atoms and the alkyl moiety associated
with heteroaralkyl has 1-6 carbon atoms, said
heteroaryl and heteroaralkyl groups being
optionally substituted in the heterocyclic ring
moiety by 1-3 substituents independently selected
from hydroxy, amino, halo, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)-
alkylamino, carboxy and sulfo and in the alkyl
moiety by 1-3 substituents selected from hydroxy,
amino, C1-C4 alkylamino, di(C1-C4)alkylamino,
C1-C4 alkoxy, carboxy, halo and sulfo, and said
heterocyclic ring being optionally substituted at
available ring nitrogen atoms by 1-3 substituents
independently selected from the group consisting
of C1-C4 alkyl; C1-C4 alkyl substituted by 1-3
hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkyl-
amino, C1-C4 alkoxy, carboxy, halo or sulfo
groups; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C1-C4)
alkyl optionally substituted by 1-3
substituents mentioned above in connection
with C1-C4 alkyl; phenyl: phenyl
substituted by 1-3 substituents independently
selected from amino, halo, hydroxy, trifluoromethyl
C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,
di (C1-C4) alkylamino, carboxy and sulfo; phenyl-
(C1-C4)alkyl in Which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl
portion may be optionally substituted by 1-3
substituents mentioned above in connection with
C1-C4 alkyl; and heteroaryl or heteroaralkyl in
which the hetero atom or atoms are selected
from the group consisting or 1-4 O, S or N atoms
and the alkyl moiety associated with heteroaralkyl
-571-
has 1-6 carbon atoms, said heteroaryl and hetero-
aralkyl groups being optionally substituted in
the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, amino, halo,
trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylamino, di (C1-C4) alkylamino, carboxy
and sulfo and in the alkyl moiety by 1-3 substituents
selected from hydroxy, amino, C1-C4 alkylamino,
di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo
and sulfo; or a pharmaceutically acceptable salt
thereof.
338. A compound according to claim 337 wherein the
heterocyclic ring
<IMG>
is optionally substituted at available ring carbon or nitrogen
atoms by up to 5 substituents independently selected from (lower)
alkyl.
339. A compound according to claim 338 wherein A is
-CH2-, -CH2CH2- or CH3
¦
-CH-
340. A compound according to claim 337 wherein R1 is
<IMG > , R15 is methyl and the
absolute configuration is 5R, 6S, 8R.
-572-
341. A compound of the formula
<IMG>
wherein R8 is hydrogen and R1 is selected from the group con-
sisting of hydrogen; substituted and unsubstituted: 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, hetero-
aralkyl, 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 hetero-
cyclic 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>
-NR3R4
-573-
-S'73-
<IMGS>
-CO2R3
=O
<IMGS>
-SR3
<IMGS>
-CN
-N3
-OSO3R3
<IMGS>
-OP (O) (OR3) (OR4)
<IMG>
-NR3CO2R4
-NO2
-574-
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 heterocvclic 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; R5 is selected from the
group consisting of substituted and unsubstituted: alkyl,
alkenyl and alkynyl, having from 1-10 carbon atoms; cyclo-
alkyl 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-
cyclyalkyl 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.l-6 carbon atoms; wherein the above-named R5 radicals
are optionally substituted by 1-3 substituents independently
selected from:
-575-
C1-C6 alkyl optionally substituted by amino, fluoro,
chloro, carboxyl, hydroxy or carbamoyl; fluoro;
chloro or bromo;
-OR3
-OCO2R3;
-OCOR3;
-OCONR3R4;
<IMG>
-OXO;
-NR3R4:
R3CONR4-;
-NR3CO2R4:
-NR3CONR3R4;
<IMG>
-SR3:
<IMG>
-SO3R3:
-CO2R3:
-CONR3R4;
-CN; or
phenyl optionally substituted by 1-3 fluor, chloro,
bromo, C1-C6 alkyl, OR3, -NR3R4, -SO3R3, -CO2R3 or -
CONR3R4, wherein R3, R4, and R9 in such R5
substituents are as defined above; or R5 may be
attached to
-576-
<IMG>
at another point on the ring so as to form a fused
heterocyclic or heteroaromatic ring, which ring may
contain additional hetero atoms selected from O, N and
S;
R15 is selected from the group consisting of
substituted and unsubstituted: 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; spirocycloalkyl having
3-6 carbon atoms. phenyl: aralkyl, aralkenyl and
aralkynyl wherein the aryl moiety is phenyl and
the aliphatic portion has 1-6 carbon atoms;
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
and 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 selected
from the group consisting of: amino, mono-,
di- and trialkylamino, hydroxyl, alkoxyl, mercapto,
alkylthio, phenylthio, sulfamoyl, amidino, guanidino,
nitro, chloro, bromo, fluoro, cyano and carboxy;
and wherein the alkyl moieties of the above-recited
substituents have 1-6 carbon atoms;
-577-
A is C1-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 ion; and
<IMG>
represents a radical selected from the group consisting of
<IMG>
wherein R6, R7 and Rl0 are independently selected from hydrogen;
C1-C4 alkyl; C1-C4 alkyl substituted by hydroxy, C1-C4 alkylamino,
di(C1-C4 alkyl)amino, C1-C4 alkoxy, amino, sulfo, carboxy or halo;
C3-C6 cycloalkyl; C1-C4 alkoxy; C1-C4 alkylthio; amino; C1-C4 alkyl-
amino; di (C1-C4 alkyl) amino; halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy;
<IMG > alkyl; hydroxy; amidino; guanidino; phenyl; phenyl
substituted by one, two or three amino, halo, hydroxyl,
trifluoromethyl, C1-C4 alkyl or C1 C4 alkoxy groups;
phenyl (C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substitutents mentioned above
in connection with phenyl and the alkyl portion may be
optionally substituted by 1-3 substituents mentioned above
in connection with C1-C4 alkyl; and heteroaryl and heteroaralkyl
in which the hetero atom or atoms in the group consisting of
1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety
associated with said heteroaralkyl moiety has 1-6 carbon
atoms: or wherein two of R6, R7 or Rl0 taken together may be
-578-
a fused saturated carbocyclic ring, a fused aromatic carbocyclic
ring, a fused non-aromatic heterocyclic ring or a fused hetero-
aromatic ring, said fused rings being optionally substituted
by 1 or 2 of the substituents defined above for R6, R7 and R10;
<IMG>
optionally substituted on a carbon atom by 1-3 substituents
independently selected from C1-C4 alkyl; C1-C4 alkyl substituted
by hydroxy, C1-C4 alkylamino, di (C1-C4 alkyl) amino, sulfo,
C1-C4 alkoxy, amino, carboxy or halogen;: C3-C6 cycloalkyl ;
C1-C4 alkoxy; C1-C4 alkylthio; amino; C1-C4 alkylamino;
di (C1-C4 alkyl) amino; halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy;
<IMG> alkyl; hydroxy; amidino; guanidino; phenyl ; phenyl
substituted by one, two or three amino, halo, hydroxyl,
trifluoromethyl, C1-C4 alkyl or C1-;C4 alkoxy groups;
phenyl (C1 C4) alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl portion
may be optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl; and heteroaryl
or heteroaralkyl in which the hetero atom or atoms
in the above-named heterocyclic moieties are selected from
-579-
the group consisting of 1-4 oxygen, nitrogen or
sulfur atoms and the alkyl moiety associated with
said heteroaralkyl moiety has 1-6 carbon atoms, or
optionally substituted so as to form a fused
carbocyclic, heterocyclic or heteroaromatic ring
optionally substituted by 1 or 2 of the substituents
defined above;
<IMG>
optionally substituted on a carbon atom by one or two
substituents independently selected from C1-C4 alkyl;
C1-C4 alkyl substituted by hydroxy C1-C4 alkylamino,
di (C1-C4 alkyl) amino, C1-C4 alkoxy, sulfo, amino,
carboxy or halogen; C3-C6 cycloalkyl; C1-C4 alkoxy;
C1-C4 alkylthio; amino; C1-C4 alkylamino; di (C1-C4
alkyl)amino; halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy;
O
-C-OC1-C4 alkyl; hydroxy, amidino, guanidino, phenyl,
phenyl substituted by one, two or three amino, halo,
hydroxyl, trifluoromethyl, C1-C4 alkyl or C1-C4
alkoxy groups; phenyl (C1-C4)alkyl in which the
phenyl portion may be optionally substituted by 1-3
substituents mentioned above in connection with
phenyl and the alkyl portion may be optionally
substituted by 1-3 substituents mentioned above in
connection with C1-C4 alkyl; and heteroaryl or
heteroaralkyl in which the hetero atom or atoms in
the above-
-580-
named heterocyclic moieties are selected from the group
consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl
moiety associated with said heteroaralkyl moiety has 1-6 carbon
atoms, or optionally substituted so as to form a fused carbo-
cyclic, heterocyclic or heteroaromatic ring optionally substituted
by 1 or 2 of the substituents defined above;
<IMG>
optionally substituted on a carbon atom by a substituent
independently selected from C1-C4 alkyl; C1-C4 alkyl sub-
stituted by hydroxy, amino, C1-C4 alkylamino, di(C1-C4 alkyl)-
amino, C1-C4 alkoxy, sulfo, carboxy or halogen; C3-C6 cyclo-
alkyl; C1-C4 alkoxy; C1-C4 alkylthio; amino; C1-C4 alkylamino;
di (C1-C4 alkyl) amino; halo; C1-C4 alkanoylamino; C1-C4
alkanoyloxy; carboxy;
<IMG> alkyl; hydroxy; amidino; guanidino, phenyl; phenyl
substituted by one, two or three amino, halo, hydroxyl, tri-
fluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl portion
may be optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl; and heteroaryl
or heteroaralkyl in which the hetero atom or atoms in
-581-
the above-named heterocyclic-moieties are selected from the
group consisting of 1-4 oxygen, nitrogen or sulfur atoms and
the alkyl moiety associated with said heteroaralkyl moiety
has 1-6 carbon atoms;
<IMGS>
wherein X is O, S or NR in which R is C1-C4 alkyl; C1-C4
alkyl substituted by 1-3 hydroxy, amino, C1-C4 alkylamino,
di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo or sulfo
groups; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C1-C4)alkyl
optionally substituted by 1-3 substituents mentioned above
in connection with C1-C4 alkyl; phenyl; phenyl substituted
by 1-3 substituents independently selected from amino, halo,
hydroxy, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4
alkylamino, di (C1-C4) alkylamino, carboxy and sulfo;
phenyl (C1-C4) alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with C1-C4 alkyl; and heteroaryl
and heteroaralkyl in which the hetero atom or atoms are selected
from the group consisting of 1-4, O, S or N atoms and the
alkyl moiety associated with heteroaralkyl has 1-6 carbon
atoms, said heteroaryl and heteroaralkyl groups being optionally
substituted in the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, amino, halo, trifluoro-
methyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)-
alkylamino, carboxy and sulfo and in the alkyl moiety by
1-3 substituents selected from hydroxy, amino, C1-C4 alkyl-
amino, di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo
and sulfo, said radical being optionally substituted on a
-582-
carbon atom by one or more substituents independently selected
from C1-C4 alkyl; C1-C4 alkyl substituted by hydroxy, C1-C4
alkylamino, di(C1-C4 alkyl)amino, C1-C4 alkoxy, amino, sulfo,
carboxy or halogen; C3-C6 cycloalkyl; C1-C4 alkoxy; C1-C4
alkylthio; amino; C1-C4 alkylamino; di(C1-C4 alkyl)amino;
halo; C1-C4 alkanoylamino; C1-C4 alkanoyloxy; carboxy;
<IMG > alkyl: hydroxy: amidino; guanidino, phenyl;
phenyl substituted by one, two or three amino, halo,
hydroxyl, trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups;
phenyl (C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned above
in connection with phenyl and the alkyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with C1-C4 alkyl;
and heteroaryl or heteroaralkyl in which 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 moiety associated with said heteroaralkyl
moiety has 1-6 carbon atoms, or optionally substituted so as
to form a fused carbocyclic, heterocyclic or heteroaromatic
ring optionally substituted by 1 or 2 of the substituents
defined above;
<IMG>
wherein X is O, S or NR in which R is C1-C4 alkyl: C1-C4
alkyl substituted by 1-3 hydroxy, amino, C1-C4 alkylanino,
di (C1-C4) alkylamino, C1-C4 alkoxy, carboxy, halo or sulfo
groups; C3-C6 cycloalkyl ; C3-C6 cycloalkyl (C1-C4) alkyl
optionally substituted by 1-3 substituents mentioned
-583-
above in connection with C1-C4 alkyl; phenyl; phenyl
substituted by 1-3 substituents independently
selected from amino, halo, hydroxy, trifluoromethyl,
C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,
di (C1-C4 ) alkyl amino, carboxy and sulfo;
phenyl(C1-C4) alkyl in which the phenyl portion may
be optionally substituted by 1-3 substituents
mentioned above in connection with phenyl and the
alkyl portion may be optionally substituted by 1-3
substituents mentioned above in connection with C1-C4
alkyl; and heteroaryl and heteroaralkyl in which the
hetero atom or atoms are selected from the group
consisting of 1-4, O, S or N atoms and the alkyl
moiety associated with heteroaralkyl has 1-6 carbon
atoms, said heteroaryl and heteroaralkyl groups being
optionally substituted in the heterocyclic ring
moiety by 1-3 substituents independently selected
from hydroxy, amino, halo, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino,
di(C1-C4)alkylamino, carboxy and sulfo and in the
alkyl moiety by 1-3 substituents selected from
hydroxy, amino, C1-C4 alkyl amino,
di(C1-C4) alkyl amino, C1-C4 alkoxy, carboxy, halo and
sulfo, said heteroaromatic radical being optionally
substituted on a carbon atom by a substituent
selected from C1-C4 alkyl; C1-C4 alkyl substituted by
hydroxy, C1-C4 alkylamino, di(C1-C4)alkylamino, C1-C4
alkoxy, amino, sulfo, carboxy of halogen; C3-C6
cycloalkyl; C1-C4 alkoxy; C1-C4 alkylthio; amino;
C1-C4 alkyl amino; di(C1-C4) alkyl amino; halo; C1-C4
alkanoylamino; C1-C4 alkanoyloxy; carboxy;
O
-C-OC1-C4 alkyl; hydroxy; amidino; guanidino; phenyl;
phenyl substituted by one, two or three amino, halo,
hydroxyl, trifluoromethyl, C1-C4 alkyl or C1-C4
alkoxy groups; phenyl(C1-C4)alkyl in which the phenyl
-584-
portion may be optionally substituted by 1-3
substituents mentioned above in connection with
phenyl and the alkyl portion may be optionally
substituted by 1-3 substituents mentioned above in
connection with C1-C4 alkyl; and heteroaryl
-585-
or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety has
1-6 carbon atoms; and
<IMGS>
wherein R is C1-C4 alkyl; C1-C4 alkyl substituted by 1-3
hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkylamino,
C1-C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cyclo-
alkyl; C3-C6 cycloalkyl(C1-C4)alkyl optionally substituted
by 1-3 substituents mentioned above in connection with C1-C4 alkyl;
phenyl; phenyl substituted by 1-3 substituents independently
selected from amino, halo, hydroxy, trifluoromethyl, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)alkylamino,
carboxy and sulfo; phenyl(C1-C4)alkyl in which the phenyl
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with phenyl and the alkyl
-586-
portion may be optionally substituted by 1-3 substituents
mentioned above in connection with C1-C4 alkyl; and heteroaryl
and heteroaralkyl in which the hetero atom or atoms are selected
from the group consisting of 1-4, O, S or N atoms and the
alkyl moiety associated with heteroaralkyl has 1-6 carbon
atoms, said heteroaryl and heteroaralkyl groups being optionally
substituted in the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, amino, halo, trifluoro-
methyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)-
alkylamino, carboxy and sulfo and in the alkyl moiety by
1-3 substituents selected from hydroxy, amino, C1-C4 alkyl-
amino, di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo and sulfo;
or a pharmaceutically acceptable salt thereof.
342. A compound according to claim 341 wherein
<IMG>
represents a radical selected from the group consisting of
<IMG>
-587-
wherein R5 is C1-C6 alkyl and R6, R7 and R10 are each
independently hydrogen or C1-C4 alkyl;
<IMGS>
wherein R5 is C1-C6 alkyl and wherein available ring carbon
atoms are optionally substituted by 1-3 substituents
independently selected from C1-C4 alkyl;
<IMGS>
wherein R5 is C1-C6 alkyl and wherein available ring carbon
atoms are optionally substituted by 1 or 2 substituents
independently selected from C1-C4 alkyl;
-588-
<IMGS>
wherein R5 is C1-C6 alkyl and wherein an available ring
carbon atom is optionally substituted by C1-C4 alkyl;
<IMGS>
wherein R5 is C1-C6 alkyl, X is O, S or NR in which R is
C1-C4 alkyl and wherein one or more available ring carbon
atoms is optionally substituted by C1-C4 alkyl;
<IMGS>
-589-
wherein R5 is C1-C6 alkyl, X is O, S or NR in which R is
C1-C4 alkyl and wherein one or more available ring carbon
atoms is optionally substituted by C1-C4 alkyl; and
<IMGS>
wherein R5 is C1-C6 alkyl and R is C1-C4 alkyl.
343. A compound according to claim 342 wherein R1 is
<IMG> and R15 is methyl.
344. A compound according to claim 342 wherein R1 is
<IMG> , R15 is methyl and the absolute
configuration is 5R, 6S, 8R.
-590-
345. A compound according to claim 341 wherein A is
-CH2 or -CH2CH2-.
346. A compound having the formula
<IMG>
wherein A is C1-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 ion; and
<IMG>
represents a radical of the formula
<IMG>
wherein R5 is C1-C4 alkyl and R6 represents hydrogen or
C1-C4 alkyl;
<IMG>
-591-
wherein R5 is C1-C4 alkyl and R6 and R7 are hydrogen or
C1-C4 alkyl;
<IMG>
wherein R5 is C1-C4 alkyl and R is C1-C4 alkyl or phenyl-
(C1-C4) alkyl;
<IMG>
wherein R5 is C1-C4 alkyl and R6 is C1-C4 alkyl;
<IMG>
wherein R5 is C1-C4 alkyl and R is C1-C4 alkyl; or
<IMG>
wherein R5 is C1-C4 alkyl; or a pharmaceutically acceptable
salt thereof.
347. A compound having the formula
-592-
<IMG>
wherein A is C1-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 ion; and
<IMG>
represents a radical of the formula
<IMGS>
-593-
<IMGS>
or a pharmaceutically acceptable salt thereof.
348. A compound of the formula
<IMG>
-594-
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 ion; or a pharmaceutically acceptable salt thereof.
349. 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 ion; or a pharmaceutically acceptable salt thereof.
350. 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 ion; or a pharmaceutically acceptable salt thereof.
-595-
351. 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 ion; or a pharmaceutically acceptable salt thereof.
352. 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 ion; or a pharmaceutically acceptable salt thereof.
353. A compound of the formula
<IMG>
-596-
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 ion; or a pharmaceutically acceptable salt thereof
354. 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 ion; or a pharmaceutically acceptable salt thereof.
355. 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 ion; or a pharmaceutically acceptable salt thereof.
-597-
356. 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 ion; or a pharmaceutically acceptable salt thereof.
357. 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 ion; or a pharmaceutically acceptable salt thereof.
358. A compound of the formula
<IMG>
-598-
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 ion; or a pharmaceutically acceptable salt thereof,
359. 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 ion; or a pharmaceutically acceptable salt thereof.
360. A compound of the formula
<IMG>
-599-
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 ion; or a pharmaceutically acceptable salt thereof.
361. 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 ion; or a pharmaceutically acceptable salt thereof.
362. 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 ion; or a pharmaceutically acceptable salt thereof.
-600-
363. 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 ion; or a pharmaceutically acceptable salt thereof.
364. 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 ion; or a pharmaceutically acceptable salt thereof.
365. A compound of the formula
-601-
<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 ion; or a pharmaceutically acceptable salt thereof.
366. 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 ion; or a pharmaceutically acceptable salt thereof.
367. A compound of the formula
<IMG>
-602-
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 ion; or a pharmaceutically acceptable salt thereof.
368. 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 ion; or a pharmaceutically acceptable salt thereof.
369. 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
-603-
a counter ion; or a pharmaceutically acceptable salt thereof;
-604-
Claims
S.D. 370 The compound, 3-[4-(1-methylpyridiniummethanethio]-
6.alpha.-[1-(R)-hydroxyethyl]-4.beta.-methyl)-7-oxo-1-azabicyclo(3.2.0)hept-
2-ene-2-carboxylate.
