CA1198440A - Carbapenem antibiotics - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

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

Description

t ~ 4`~

~ACKGROUND OF THE INVENTION

1 Field of the Invention The present invention is directed to new carbapenem antib;otics in which the 2-substituent has the formula ~R10 ---S--A~S Rll wherein A is C2-C6 straight or branched chain al~ylene and R10 and Rll each independently represent optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, heterocyclyl, heterocyclyl-aliphatic, heteroaryl or heteroar-aliphatic radicals, or R10 and Rll when taXen together with the ~
s to which they are attached represent an optionally substituted sulfur-containing heterocyclic ring.

2. Description of the Prior Art A number of B-lactam derivatives containing the carba-penem nucleus have been disclose~ in the literature~ These carbapenem deri~atives have been reported to possess utility as anti-bacterial agents and/or B-lactamase inhibitors.
The initial carbapenem compounds were natural products such as thienamycin of the formula o OH
SC~2~H2N~2 ~ N COOH

obtained by fermentation of Streptomy~es catt~ 5U.S.
Patent 3,950,357). Thienamycin is an exceptionally potent broad-spectrum antibiotic which possesses notable activity against various P5eU~QmOnaS species, organisms which have been notoriously resistant to B-lactam antibiotics.
Other nat~ral prod~cts containing the carbapenem nucleus include olivanic acid derivatives such as antibiotic MM 13902 of the formula CH~

Ho3so~ ``l - ~c5cH=cHNH~ocH3 O ~ COOH

disclosed in U.S. Patent 4,113,856, antibiotic MM 17880 of the formula HO3 ~ CH2cH2NHcoc~3 O COOH

disclosed in U.S. Patent 4,162,304, antibiotic MM 4550A of the formula CH o ~ ~ S-CH=CHNHCOCH3 ~ N --COOH
disclosed in U.S. Patent 4,172,129 and antibiotic 890A of the formula /\ ~ =CHNHCCH 3 H0350 _~

0~ N COOH
disclosed in U.S~ Patent 4,264 r 735. In addition to the natural products, the cGmpound desacetyl 890~1~ of the ormula H03 ~ CH2cH2NH2 O N COOH

is disclosed in U.S. Patent 4,264,734 as being prepared by an enzymatic dea~ylation of the corresponding N-acetyl compound.
Various derivati~es of the naturally-occurring olivanic acids have also been synthesized, e.g. the compounds of the formula ~2~ () ~ HCOCH3 O N C2Rl wherein C02R1 is a free, salted or ester~fied carboxyl gro~p, n is O or 1 and R2 is ~, an acyl gro-lp or a group of the formula R303S wherein R3 is a salting ion or a methyl or ethyl group, disclosed in European Patent Application 8885.
U.S. Patent 4,235,922 (see also European Patent Application 2058) discloses the car~apenem derivative of the formula ~; !; CH 2 CH 2N~ 2 00~

~8~ ~

while ~.X. Patent Application 1,598,Q52 reports isolation of the compound SCH2CH2NHCOt:H3 ~~~ N COO~

from a St~ myces fermentation broth.
Carbapenems which are unsubstituted in the 6-position have also been synthesized. Thus, U.S~ Patent 4,210,661 dis-closes compounds of the formula ~S-R2 O N COOH

wherein R2 is phenyl or substituted phenyl, U.S. Patent 4,267,177 discloses compounds of the formula S-Rl FN ~L
COOH

wherein Rl is an optionally substituted pyridyl group~ U.S.
Patent 4,25S,441 discloses compounds of the formula f ~--CR2=CR3R4 . 11 0~~~ N COOH

wherein R2 and ~3 are ~ or alkyl ana R~ is NH-CO~R6 in which R~ is alkyl, phenyl or substituted phenyl and n i~ 1 or 2, and U.S. Patent 4,282,236 discloses compounds of the formula F~ H=CRlR2 N ooH

wherein Rl is H or alkyl and R2 is CN or C02R3 in which R3 is H, alkyl, aryl or aralkyl.
Carbapenems of the general formula ~ ~S R8 ~ N l_ O ~OOH

wherein Rl is H or acyl and R8 is H or substituted or unsub-stituted: alkyl, alkenyl, alkynyl, cycloal~yl, cycloalkylalkyl, alkylcycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, are disclosed in V.S. Patent 4,218, 463. There is no disclosure of any ~8 substituents of the type . ~3 A- S
in which A is aIkylene.

8~L~0 The natural product thienzmycin has the absolute configuration SR, 6S, 8R. This isomer, as well as the re-maining seven thienamycin isomers, may be obtained vLa total synthesis as disclosed in U.S. Patent 4,234,596. Total synthesis procedures for thienamycin are also disclosed, for example, in U.S. Patents 4,287,123, 4,2b9,772, 4,282,148, 4,273,709, 4,290,947 and European Patent Application 7973. A key inter-mediate in the disclosed synthetic methods is OH

wherein pNB represents p-nitrobenzyl.
Because of the exceptional biological activity of thiena-mycin, a large number of derivatives have been prepared and disclosed in the literature. Among these are (1) N-formimidoyl thienamycin of the formula OH
SCH2CH2N=I NH2 N coOH

disclosed in European Patent Application 6639; (2) N-heterocyclic derivatives of thier~amycin having the formula .`. ~^L~

OH
i ~ r ~ ~ \ SCH2~H~N ~Cl2)~

COOH Rl lp OH and SCH2C1~2N~B ) wherein: the bifunctional ring may contain additional unsaturation in the ring; and wherein n is an integer selected ~rom 1-6;
p is O, 1 or 2; Rl is Hy alkyl or aryl; and Z is imino, oxo, H, ~mino or alkyl, disclosed in U.S. Patent 4,189,493; (3) substituted N-methylene derivati~es of thienamycin having the formula OH

~F'~SC~l2cH2N=~-x N COO~

wherein X and Y are H, R, OR, SR or NRlR2 in which R is substitu~ed vr unsubsti~uted: alkyl, alkenyl, alXynyl, cycloalkyl, cyclo-alkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hetexo-cyclyl or heterocyclylalkyl ~ and Rl and R2 are H or R, disclosed in ~5. Patent 4 t 194,047; (4) compounds of the formula _ 9 _ OR
. ,~SC~2C~;~NR

N --COOH

wherein R3 is aryl, alkyl ~ a ::yl or aralkyl and Rl and R2 are independently selected from H a~d acyl ( including acyl of the type -C~Rl in which Rll may inter alia be alkyl substituted by a quaternary ammonium group, e . g .

~C-CH2~

disclosed in U. 5 . Patent 4, 226, 870; ( 5) compounds of the f orlr.ula oR3 O COOB

wherein R3 i5 H, acyl or a~ uni~ralent optionally substituted hydrocarl~on radical; R is optional}.y substituted alkyl, alkenyl, alXynylO cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cyclo-alkylalkyl, aryl, aralXyl, heteroa~l or heteroaralkyl and is acyl (including acyl of the type -C-R in which R is alkyl substituted ~y a ~uaternary aTrunoniuin g~OuE~, e. 9.

~ CH2 N~

disclosed in U.K. Paten~ 1,604,276 (see also U.S. Patent 4,235,917); (63 Compounds of the formula ~8~ ~

OH
ScH2cH2NR R R
~ N CO ~

wherein R5, R6 and R7 are independen~ly selected from H and sub-stituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or hetexoaralkyl, are disclosed in V.S. Patent 4,235,920; (7) compounds of the formula oR3 1~.5 63 \ C~ CH N-C-NRlR2 A~3 COX

wherein each of Rl and R2, independently of the other, is a radical of the type defined for R, a hydrogen atom, or a nitro, hydroxyl, Cl 6 alkoxyl, amino, Cl 6 alkylamino, di(Cl 6 alkyl3-ami~o or tri(Cl 6 alkylamino) radical, an extra anion being present in the latter case; or R and R are joined together to form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted monocyclic or ~icyclic heteroaryl or heterocyclyl residue containing 4-10 ring atoms, one or more of which may ~e an additional hetero atom selected from oxygen, sulphur and nitrogen; R is a cyano group or a substituted or unsu~stituted carbamoyl, carboxyl, (Cl 10 alkoxy)-carbonyl, Cl_10 alkyl, C2_10 alkenYl~ C2-10 alkYnYl~ C3 10 cyclo-alkyl, C4 1~ cycloalXylalkyl, C5 12 cycloalkylalXenyl, C3 10 cycloal~enyl, C5 12 cycloalkenylalkenyl, C4 12 cycloaIkenylalkyl, C6_10 aryl~ C7_16 aralkyl, C8_16 aralkenyl, C8_16 aralkynyl or monocyclic or bicyclic heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl ~omprising 4 to 10 ring atoms one or more of which is a hetero atom selected from oxygen, sulphur and nitrogen and in which the alkyl residue of the hetesoaralkyl or hetero~yclylalkyl radical contains from 1 to 6 carbon atoms;
the substituent or substituents on R, R , R or on the ring ~ ~84 ~

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

3~9~

thioalkyl; carboxyl; oxo, (C~. 6 alkoxy) carbonyl; C2 10 acyloxy; carbamoyl; (Cl 4 alkyl) carbamoyl; di (Cl_4 alkyl~ -carbamoyl; cyanothio (-SCN) or nitro; ~6 is hydrogen, hydroxy, mercapto, ~, -OR, -SR or NRlR~, where R, Rl and R2 are as defined above;
X is hydroxy, mercapto, ami no, acyloxy -oR4, -sR4, -NHR4, -~-R4, ~4 -OM, -OQ or, when the compound is in zwitterionic form, -O , in which case A is absent;
A, when the compound is not in zwitterionic form, is a counter ion;
M is a pharmaceutically acceptable cation; and Q is a blocking group as herein defined, are disclosed in .K. Patent 1,604,275; and (8) compounds of the form~la ~H

H2cH2NH--N CO
O

wherein ~l attached to the amino nitrogen group of thienamycin represents a mono- or polycyclic N-containing heterocyclic group and R is H, substitutea or unsu~stituted: alkyl, aryl, alkenyl, hetero-cyclylaIkenyl, aralkenyl, heterocyclylalkyl, aralkyl, -NR2, COOR, CONR2, -OR, or CN, are disclosed in European Patent Appli-ca~ion 210a2. Among the compounds disclosed in U.S. Patent

4,235,9~0 is 84 ~) CH2N(C~3~¦ A
N

COOH

wherein A is a pharmaceutically acceptable anion- The above-mentioned quAternary amine derivative is also described in Recent Advances in the ChemistrY of B-~a~tam Antibiotics, Royal Society of Chemistry, ~ondon, 1981, pg 240-2S4, where its anti-bac~erial acti~ity on average is reported as approximately 1/2 to 2/3 that of thienamycin.
Applicants are aware of no literature disclosing carba-penem derivatives of the present invention having a 2-substituent of the type - S - A-S ~ , although there are se~eral recent patent references which, in their broadest disclosure, maY generically include such compounds.
Thus, for example, European Patent Application 40408 discloses compounds of the foDmula 3 ~ SR
0~~~ N COOH

wherein Rl is H, methyl or hydroxyl and R51 is a monovalent organic group incluaing inter alia substituted alkyl or a group of the formula -CH2R7 in which ~ is an optionally substituted

5- or 6-membered heterocyclic group; t2) European ~atent Appli-cation 38869 discloses compounds o~ the formula Ba~10 - R~ i ~ il N - ~ ~

wherein R6, R7, and R8 are independently selected from the group consistlng of hydrogen, substituted and unsubstituted:
alXyl, alkenyl, and alkynyl, having from 1-10 carbon atoms;
cycloalkyl~ cycloalkylalkyl, and alkylcycloalkyl, having 3-6 caxbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; aryl, such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moeity is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wh~rein the substituent or substituents relative to the above-named radicals are selected from the group consisting of:
-X~ halo (chloro, bromo, fluoro~
-OH hydroxy _9Rl alkoxy, aryloxy -OCNR R carbamoyloxy -CNRlR carbamoyl -NRlR2 amino NRl 4 ~idino \ NlE~.lR2 Rl --NO~ nitro ~ 1 -N(Rl)3 tri-substituted amino (R group independently chosen) ~8~ ~

-C=NOR oximino -S~ alkyl- and arylthio -S02NRlR sulfonamldo -NHCNRlR2 ureido O
RlCNR - amido -C02~ carboxy - 02R carboxylate _~Rl a~yl ~1 -O R acyloxy -SH mercapto O
_5Rl alXyl and aryl sulfinyl -~Rl alkyl and aryl sulfonyl O
--CN cy ano -N3 azido wherein, relative to the above listed substituents on R6, R , and R8, the g-oups Rl and R2 are independently selected from:
hydrogen, alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloaIkyl, having 3-6 carbon atoms in the cy~loal~yl ring and 1-6 carbon atoms in the alkyl moieties; aryl, such as phenyl; araIkyl, aralkenyl, and aralkynyl wherein the aryl moiety is ~henyl ana the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaraIkyl, hetero-cyclyl and heterocyclylalkyl and wherein the hetero atom or atoms in the above-namea heter~cyclic moieties are selectea from t~e ., " 119~

~roup consisting of 1-4 oxygen, nitrogen or sulphur atoms and wherein the al~yl moieties associated with said hetero-cyclic moietie~ have 1-6 carbo~ atoms. (See also European Patent Applications 1627, 1628~ 10317, 17992, 37080, 37081 and 37Q82)t ~4) European Patent Application 24832 discloses ~ompounds of the formula Rl C~3-CaF~CSRl2 . N CO2H

wherein Rl is ~ or a group selected from OH, OSO ~ or a salt or C~ 4 alkyl ester thereof, oR2, sR3, OCOR~, oCO2R3 or OCONHR , where R is a Cl 6 alkyl group or an optionally substituted benzyl group and R is a Cl 6 alkyl group or an ! optionally substituted benzyl or phenyl group and R12 is Cl 6 al~yl, C2 6 alkenyl, C3 6 alXynyl wherein the triple bond is not present ~n the carbon adjacent to the sulfur atom, aralkyl, Cl 5 alkanoyl, aralkanoyl, aryloxyalkanoyl or arylcarbonyl, any of such ~12 groups being optionally substituted, as antibacterial agents.
European Patent Application 38,869 mentioned above discloses synthesis of the carbapenem derivatives via inter-mediates of the general formula R

R6~0 N ~ O2R2' o wherein R6 and R7 are as defined above and R2 is a readily removable carboxyl ~rotecting group. Also disclosed as intermediates are compounds of the formula ~N 3 ~02R

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

- ~8 SUMMARY OF THE INV~NTIO~
.

The present i~ention provides a novel series of carbapene~ derivati~es characteriæed by a 2-substituent of the formula ,10 -S - A - S
~Rll wherein A i5 C2-~6 straight or branched chain alkylene and R10 and Rll each independently represent optionally sub-stituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, a~yl, heterocyclyl, heterocyclyl-aliphatic, heteroaryl or heteroaraliphatic radicals, or R10 and Rll when taken together with the ~

to which they are attached represent an optionally s~bstituted sulfur-containing heterocyclic ring containing 0-2 double bonds and 0-2 additional heteroatoms selected from O, N and S, said ring ~eing attached to A through a sulfur atom, thereby form-ing a sulfonium group. More specifically, the present invention provides car~apenem deri~atives of the formula R8 H ~ R10 Rl ~ S -A -S ~ Rll N ~ ooR2 wherein RB is hydrogen and Rl is selected from the group consisting of hydrogen; su~stituted and unsubstituted:
alkyl, alXenyl and al~ynyl, having ~rom 1-~0 car~on atoms;

~1~84a~

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

--CNR R

NR

\N R R
--SO;~NR R

--NHcNR3R

R CNR ----Co2R3 =O

. .

~ 20 ~
f~ 3 -OCR
sR3 ~I g --SR.

O, --CN

-oso2R3 --N R S C)2R

NR3f=NR

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

except that it may not be hydrogen; or wherein Rl an~ x8 taken together represent C2-C10 alkylidene or C2-C10 al~yliden~
substituted by hydroxy; A is C2-C6 straight or ~ranched chain alkylene; R2 is hyarogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter anion, and R10 and Rll each independently represents ~a3 Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cyclo-alkyl or cycloalXylalkyl having 3-6 carbon atoms i~ the cycloalXyl ring and 1-6 oarbon atoms in the al~yl moiety, said alkyl, alkenyl, al~ynyl, cycloalkyl or cycloalkyl-alXyl group being optionally substituted by 1-3 substituents independently selected from hydroxy, Cl-C6 alkoxy, Cl-C6 alkanoyloxy, carboxy, Cl-C6 alkoxycarbonyl, amino, Cl-C6 alkylamino, di(Cl-C6)al~ylamin, Cl-C6 alkanoylamino, phenyl, phenyl substituted by 1-3 halo, Cl-C6 alkoxy, Cl-C6 alkyl, carboxy, carboxy(Cl-C6)alkyl, amino, Cl-C6 alkylamino, di(Cl-C6)alkylamino or di-~Cl-C6)alkylamino(Cl-C6)alkyl, halo or oxo;
(b) phenyl optionally substituted by 1-3 halo, Cl-C6 alkoxy, Cl-C6 alkyl, carboxy, amino, Cl-C6 ~lkylamino or di(cl-c6)alkylamino groups;
~c) heterocyclyl or heterocyclylalXyl wherein the hetero-cyclic moiety is a 4-6 membered ring havin~ 1-3 hetero atoms selected from O, N and S and the alkyl moiety has 1-6 carbon atoms, said heterocyclyl or heterocyclylalkyl ring being optionally substituted by 1-3 Cl-C6 alkyl or Cl-C6 alkoxy groups; or ~d) heteroaryl or heteroaralkyl wherein the heterocyclic moiety is a 5-6 membered aromatic ring having 1-3 hetero atoms selected from O, N an~ S and the alkyl moiety has 1-6 caxbon atoms, said heteroaryl or heteroaralkyl ring being optionally substituted by 1-3 Cl-C6 alkyl, Cl-C6 alkoxy, carboxy, carboxy(Cl-C6)al~yl, amino, Cl-C6 alkyl-1 3..~B4~0 - 2~ -amino, di(Cl-C6)al~ylamino, amino~Cl-C6)alkyl or di(Cl-C~)-alkylamino(Cl-C~al~yl groups; or wherein R and R l taken together with the ~3 S

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

DETAI LED DXS CR3:PTI ON
____~

The novel compounds of general formula I above contain the carbapenem nucleus ~~
. .

and may thus be named as l-carba-2-penem-3-carboxylic acid derivatives. Alternatively, the co~pounds may be considered to have the basic structure

6 ~ 3 ll ~ 7 N 1 and named as 7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylic acid derivatives. While th2 present invention includes com-pounds wherein the relative stereochemistry of the 5,6-protons is c~s as well as trans, the preferred compounds have the SR,6S ltrans) stereochemistry as in the case of thienamycin.
The compounds of formula I may be unsubstitutea in the 6-position or substituted by substituent groups previously disclosed for other carbapenem derivatives. More specifically, R8 may be hydrogen and Rl may be hydrogen or a non-hydrogen substituent disclosed, for example, in European Patent Application 38,869 (see definit;on of R6). Alternatively, R8 and Rl taken together may be C2-C10 alkylidene or C2-C10 alkylidene substituted, for ~xampls, by hydroxy.
To elaborate on the definitions for ~1 and R8:
(a) The aliphatic ~alkyl~, "alkenyl~ and "alkynyl~ groups may be straight or branched chain having 1-10 carbon atoms;
preferrea are 1-6, most preferably 1-4, carbon atoms; when part of another substituent, e.g. as in cycloalkylalkyl, or ~984 .

heteroaral~yl or aralXenyl, the alkyl, alkenyl and al~ynyl group preferably contains 1-6, most preferably 1-4, carbon atoms.
(b) "heteroaryl~ includes mono-, bi- and polycyclic aromatic heterocyclic groups containing 1-4 0, N or S a oms;
preferred are 5- or 6-memberea heterocyclic rings such as thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, iso-thiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimiainyl, pyridazinyl, pyrrolyl, pyrazolyl, etc.
(c) ~heterocyclyl" includes mono-, ~i- and polycyclic saturated or unsaturatea non-aromatic heterocyclic groups containing 1-4 0, N or S atoms; preferred are 5- or 6-membered heterocyclic rings such as morpholinyl, piperazinyl, piperidyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, etc.
(d) "halo" (used also to define RlO and Rll) incluaes chloro, bromo, fluoro and iodo and is preferably chloro or bromc.
The term ~conventional readily removable carboxyl pro-tecting group~ refers to a ~nown ester group which has been employed to block a carboxyl group during the chemical reaction steps described below and which can be removed, if desired, by methods which do not result in any appreciable destruction of ~he remaining portion-of the molecule, e.g. by chemical or enzymatic hydrolysis, tre~tme~t with chemical reducing agent~ under mild conditions, irradiation with ultraYiolet light or catalytic hydrogenation~ Examples of such ester protec~ing groups include benzhyaryl, p-nitrobenzyl, 2-naphthylmethyl, benzyl, trichloroethyl, silyl such as tri-methyl~ilyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl, 4-pyridylmet~yl and Cl-C6 alkyl such as methyl, ethyl or t-butyl. Included within such protecting groups are those ~8~0 ~ 2~ ~

which are hydrolyzed under physiologic~l conditions s~ch as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl. . A particularly ad~rantageous car~oxyl protecting group is p-nitrobenzyl which may be readily removed by cat~lytic hydrogenolysis.
The pharmaceutically acceptable salts referred to above include the nontoxic acid addition salts, e.g. salts with mineral acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, etc. and salts with organic acids such as maleic, acetic, citric, succinic, benzoic, tartaric, fumaric, mandelic, ascorbic, lactic, gluconic and malic~ Compounds of formula I in the form of acid additions sa~ts may ~e written as Rl (3 Rl N oOR2 R = H or protecting group where X ~ represents the acid anion. The counter anion X ~
may be selected so as to provide pharmaceutically acceptable salts for therapeutic administration but, in ~he oase of intermediate eompQunds of formula ~, X ~ may also be a toxic anion. In such a case the ion can be subsequently removed or substituted by a pharmaceutically acceptable anion to form an active end product for therapeutic use. When acidic or basic groups axe present in the Rl group or on the R10 or Rll substitutents, the ~resent invention may also include suitable base or acid salts of these functional groups, e.g.
acid addition salts in the case of a basic group and metal salts te.g. sodium, potassium, calci~m and aluminum)~ the ammonium salt and salts with nontox~c amines I e.g. tri-~L9~4 ~() alkylamsnes, pr~caine, dibenzylamineO l-ephenamine, ~-benzyl-B-phenethylamine, N,N'-dibenzylethylenediamine, etc.) i~ the case of an acidic group.
Compounds of formula I wherein R2 is hydrogen, an anionic charge or a physiologically hydrolyzable ester group together with pharmaceutically acceptable salts thereof are useful as antibacterial agents. The remaining com~ounds of formula I are valuable intermedia~es which can be converted into the above-mentioned ~iologically active compounds.
A preferred embodiment of the present invention com-prises compounds of formula I wherein R8 is hydrogen and ~1 is hydrogen, CH3CH2-, CH~ CH~ H OIH
CH-, C- or CH3CH~
CH~ CH3 Among this subclass, the preferred compounds are those in which Rl is ~H
CH3CH-, most preferably compounds having the absolute configuration SR, 65, 8R.
Another preferred embodiment comprises compounds of formula I in which Rl and R8 taken together form an alkylidene radical of the formula HOCH
2\ C-The alkylene (i.e. substituent ~An) radical in the compounds of formula I may ~e straight or branched chain and may contain from 2 to 6 carbon atoms. A preferred embodi-ment comprises those compounds in which A is ~(CH2)n~ in which n is 2, 3 or 4 and a particularly preferred embodiment comprises those compounds where A is -CX2CH2-.

- .... .
'; ' `' ' ~84~(~

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

Cl-C6 alkyl, carboxy, carboxy-Cl-C6 alXyl, amino, Cl-C6 alkylamino, d~(Cl-C6)al~yl~mino or di(Cl-C6)al~ylamino-(Cl-C6)al~yl, halo or oxo. _ _ _ _ _ The Rl~ and/or Rll substltuents may also be aryl (C6-C10 aromatic hydrocarbon) which is most especially phenyl~
The aryl group or groups may be unsubstituted or substituted by 1-3, preferably 1-2, substituents selected from halo, Cl-C6 alkoxy, Cl-C6 alkyl, carboxy, amino, Cl-C6 alkylamino and di~Cl-C~)alkylamino.
When R10 and/or ~11 represent he~erocyclyl or hetero-cyclyl-aliphatic, the heterocyclyl moiety is a 4-6 membered no~-aromatic ring containing 1-3 hetero atoms selected from O, N and S. The aliphatic moiety associated with heterocyclyl-aliphatic is preferably Cl-C6 alkyl. The heterocyclic rin~
of such groups may be unsubstituted or substituted by 1-3, preferably 1-2, C~-C6 alkyl or Cl-C6 alkoxy substituents.
When R10 and/or Rll represents heteroaryl or hetero-araliphatic, the heterocyclic moiety is a 5-6 membered aromatic ring containing 1-3 hetero atoms selected from o, ~ and S and the aliphatic (preferably alkyl) moiety has 1-6 carbon atoms. The heteroaryl ring of such sub~tituents may be unsubstituted or substituted by 1-3, preferably 1-2, substituents selected from Cl-C6 alkyl, Cl-C6 alkoxy, carboxy, carboxy(Cl-C6)alkyl, amino, (Cl-C6)alkylamino, di(Cl-C6)alkyl-amino, amino(Cl-C6)alkyl and di(Cl-C6)alkylamino(Cl-C6)alkyl.

The R10 and Rll -substituents taken together with the S ~ to which they are attached may also represent a 4-6 member sulf~r-containing heterocyclic ring containing 0-2 double bonds ana 0-2 additional heteroatoms selected from O, N and 5, said ring ~eing attached ~o the alkylene (A) group through a sulfur atom, thereby forming a sulfonium group. The heterocyclic ring fonmed by ~

4 ~ ~
. - 29 -may be ~nsub~tituted or s~bstituted by 1-3, prefer~bly 1~2, substi uents selected from:
Cl-C6 al~yl optionally substituted by 1-3 hydroxy, Cl-C6 alkoxy, oarboxy, halo, amino, Cl-C6 alkylamino or di(Cl C6)alkylamino groups;
hydroxy;
Cl-C6 al~oxy;
Cl-C6 alkanoyloxy;
amino;
Cl-C6 alkylamino;
di~Cl-C6)alXylaminO;
Cl-C6 alkanoylamino;
carboxy;
Cl-C6 alkoxycarbonyl;
halo;
oxo; and phenyl.
The heterocyclic ring may also be fused to a C5-C6 car~ocyclic ring, a phenyl ring, a 5-6 member heterocyclic (containing 1-4 h tero a~oms selected from 0, N and S) ring or a 5-6 member heteroaryl (containing 1-4 hetero atoms selected from 0~ N and S) ring, all of which fused rin~s may be optisnally substituted by 1-3, preferably 1-2, of the substituents describea abo~e in connection with the sulf~r-containing heterocyclic ring.
A particularly preferred embodiment of the present in~ention comprises compounds of formula I wherein ei~her ~a) Rl~ and * 1 each independently represents Cl-C6 al~yl or (b) R10 and * 1 taken to~ether with the S ~) to which they are attached represent -S ~ or -S ~ ; and pharmaceutically acceptable salts thereof.
Examples of preferred 2-substituents wherein R10 and R11 are alkyl include and Within this subclass, the preferred compounds are those wherein A is -(CH2)n- in which n is 2, 3 or 4, most preferably those in which A is -CH2CH2- and wherein either (a) R1 and R8 taken together represent or (b) R8 is hydrogen and R1 represents hydrogen, CH3-CH2-, ~84 ~) - 31 ~

CH3~ C~3 OH . ~
C- , ~ C- or C~3~ - .

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

or (b) R8 is hydrogen and Xl represents hydrogen, CH3CH2-, C~3~ CH3 ~ 01~ ~~
~ C~ or C~3CH- ~

c~3 C~3 8 Particularly preferred are the compounds wherein R is hydrogen and ~1 is O~~I
CH3C~-, preferably compounds having the ab301~te configuration 5~, 6S, 8R, o The most preferred embodiment of the present invention comprises the comp~unds of the formula OH

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

wherein Rl and ~8 are definea above and wherein R2 represents . ~,g~O

a conventional readi~y removable carboxyl protecting groups.
Compounas of formula III have been disclosed, ~or example, in European Patent Application 38,869 (compound 7) and may be prepared by the general methods described therein.
The process for preparing compounds I from starting materials III may be summarized by the following reaction scheme:

R ~ 2' N OOR
III

Rl ~oC6115~3 >

. R8 H

Rl~A-OH

00*
' V

11~8~ ~0 R~ A OS 2 3 ~ N COOR2 ' VI

Rl~ 2 ' COOR
II

R8 H ~3 R10 ~3 R~ ~ S-A- ~ 11 optional ; , 1 _ 2' R de:~locking ~ N COOR - - >
- I' R ~1 ~) R
~S--A--S

COOR
.

To elaborate on the above process, starting material III
is reacted in the inert organic solYent such as methylene chloride, acetonitrile or dimethylformamide with about an equi-molar amount of diphenyl chlorophosp~ate in the presence of - a base su~h as diisopropylethylamine, triethylamine, 4-dimethyl-aminopyridine or the like to give intermediate IV. The acylation to est~blish the diphenylphosphoryloxy leaving group at the ~g~4~0 - 3S ~

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

84 ~0 I. The intermediates of general fo~mula II~ therefore, comprise a preferrea embodiment of the present invention.
The displacement of the methanesulfonyloxy leaving group is carried out by reacting intermediate VI with a source of iodide ions in an inert organic solvent such as acetone, dimethylformamide or dimethylsulfoxide. Any com-pound which ionizes in the solvent employed to provide iodide ions may be used, e.g~ an alkali metal iodide such as NaI or XI. The temperature for the displacem~nt is not critical, but temperatures of room temperature or above are most advan-tageous for achieving completion of the reaction in a reason-able time period. The source of iodide ions is employed in an amount so as to provide approximately an equi~alent or excess of iodide ion relative to intermediate VI.
Preparation of the desired carbapenems derivatives of formula I is carried out by a nucleophilic displacement of the iodo leaving group of intermediate II by the desired sulfide of the general formula ~ Rl S

Intermediate II is reacted with at least an equiYalent, prefer-ably an excess, of the desired sulfiae in an inert organic solvent and in the presence of silYer ion. Suitable inert organic solvents include, for example, tetrahydrofuran, diox~ne, methylene chloriae, diglyme, dimethoxyethane, and the li~e.
Any silver compound which substantially ionizes in the solvent and to give silver ions and an inert anion may be used as the source of silver ion, e.g. AgC104. Generally, we prefer to use approximately an equivalent amo~nt (relative to intermediate II) of silver ion to,~acilîtate the displacement. The reaction may be carried out over a wide temperature range, e.g. from about -25C to about ~25C, but is preferably conaucted at around 0C.

1~84 ~0 ~ 37 -Intermediate I' will have a counter anion (derived fro~
the silver salt used3 associated with it which may at this stage be substituted by a different counter anion, e.gO
one which is pharmaceutically acceptable, by conventional procedure~. Alternatively, the counter ion may be subse-quently removed during the de-blocking step, $he de-blocking step to remo~e the carboxyl protecting group R2 of intermediate I' is accomplished by conventional procedures such as solvolysis, chemical reduction or hydro-genation. Where a protecting group such as p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl is used which can be removed by catalytic hydrogenation, intermediate I' in a suitable solvent such as dioxane-water-ethanol, tetrahydro-furan-aqueous dipotassium hydrogen phosphate-isopropanol or the like may be treated under a hydrogen pressure of from 1 to 4 atmospheres in the presence of a hydrogenation catalyst such as palladium on charcoal, palladium hydroxide, platinum oxide or th~ like at a temperature of from 0 to 50~C for from about 0.24 to 4 hours. When R is a group such as o-nitro-benzyl, photolysis may also be used for debloc~ing. Protecting gsoups such as 2,2,2-trichloroethyl may be removed by mild zinc reduction. Similarly, other conventional carboxyl protecting groups may be removed by methods ~nown to those skilled in the art. Finally, as mentioned aboYe, compounds of formula I' where R2 is a physiologically hydrolyzable ester such as acetoxymethyl, phthalidyl, indanyl, piYaloyloxymethyl, methoxymethyl, etc. ~ay be administered directly to the host without de-blocking since such esters are hydrolyzed in vivo under physiological conditions.
It will be understood that where the Rl and/or R8 substituent or the heteroaromatic nucleophile attached to substituen~ A contain a functional group which might interfere with the intended course of reaction, such group may be protected by a conventional blocking group and then subsequently de-blocked to regenerate the desired functional group. Suitable blocking ~19~34 ~0 group~ and pr~ceaures for ~ntroducing and removing such groups are well known to those skilled in the art.
AS in the case of other B-lactam antibiotics, com-pounds of general formula I may be co~verted by known procedures to pharmaceutically acceptable salts which, for purposes of the present inven~ion, are substantially equivalent to the non-salted compounds. ThUS, for example, one may dissolve a compound of formula I wherein R2 is an anionic charge in a suitable inert solvent and ~hen add an equivalent of a phanmaceutically acceptable acid. The desired acid addition salt may be recovered by conventional procedures, e.g. solvent precipitation, lyophilization, etc.' Where other basic or acidic functional groups are present in the compound of formula I, pharmaceutically acceptable base addition salts and acid addition salts may be similarly prepared by known methods.
A compound of formula I where R2 is hydrogen or an anionic charge, or a pharmaceutically acceptable salt thereof may also be converted by conventional procedures to a corres-ponding compound where'R2 is a physiologically hydrolyzable ester group, or a csmpouna of formula I wherein R2 is a conventional carboxyl'protecting group may be converted to the corresponding compouna where R2 is hydrogen, an anionic charge or a physiologically hydrolyzable ester group, or a pharmace~tically acceptable'salt thereof.
The novel car~apenem deriYati~es of general formula I
wherein R2 is hyarogen, an anionic charge or a physiologically hydrolyzable carboxyl protecting group, or the pharmaceutically acceptable salts thereof, are potent antibiotics active against various gra~-positive and gram-negatiYe bacteria and they may be used, for example, as animal feed additiYes for promotion of growth, as preservatives in food, as bactericides in industrial applications, for example in waterbased paint and in the white water of paper mills to inhibit the growth of harmful bacteria and as disin~ectants for aestroying or i .. ~ . . .. . . .. . . . . . . . . . .
, .

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

1~98~

-- 40 ~

tetrahydrothiophenium3 ethylthiol -6a- [1- tR) -hydroxyethyl]-7-oxo-l-azabicyclo~3.2.0]hept-2-ene-2-carboxylate prepared in Example 1.
In Vitro Activity A sample of the above-identified carbapenem compollnd after solut~ on in water and dilution with Nutrient 13roth was found to exhibit the following Minimum Inhibitory Concentrations (M.I.C.~ in mcg/ml versus the indicated microorganisms as detenninea by overnigh~ incubation at 37C by tube dilution.
N-Formimidoyl thienamycin was included as a comparison compound.

In Vi tro Antibacterial Activity of Carbapenem Derivative of Exam le 1 P
MIC (mcq/ml) Orqanism New Compound N-Formimidoyl Thienamycin S. pneumoniae A-9585 0 . 002 0.û04 S. pyoqenes A-9604 0. û04 0 .001 5. aureus 1~-9537 0.008 0.004 5. aureus + 50% serum A-9537 0~03 O.OlS
S. aureus (Pen-res.) A-9606 0.016 0.008 S. aureus tMeth-res.) A15097 2 0.5 S. faecalis A20688 0. 5 0 .5 E. coli (10-4 ail.) A15119 - 0.03 0.016 E coli o (10 3) AlSll9 0.06 0.03 E. coli .
( 10 ) A15 119 0 . 0 6 0 . 0 6 E. coli (10 4) A2Q341-1 0.l33 0.03 8 ~

In vitro antibacterial activity of carbapenem deri~ative of . . Example 1 ~ continued MIC (mcg~ml) Or~anis~ New Compound N-Formimidoyl Thienamycin E. coli (10 3) A20341-1 0^03 0-03 E. coli (10 ) A20341-1 0.06 0.13 ~ pneumoniae A-9664 0.06 0.13 K. pneumoniae A20468 0.13 0.06 P. mirabilis A-9900 0.13 0.06 P. vulqaris A21559 0.03 0.03 P morqanii A15153 0.06 0.13 P~ rettgeri A22424 0.25 0.25 S. marcescens A20019 Q.06 0.03 E. cloacae A-9659 0.13 0.06 E. cloacae A-9656 0.13 0.06 P. aeruginosa A-9 843A
P. aeru~inosa A21213 0.25 0.25 H. influenzae A-9833 B 16 . influenzae A2Q178 8 32 .
. influenzae A21518 8 32 ~. influenzae A21522 8 32 B fraqilis ~22862 0.06 0.016 B fragiiis A22053 0.06 0.06 B. fra~ilis A22696 0.25 0.13 .

~. fragilis A22863 0.06 1 .

. _ - In Vi~o Activity .
The in vivo therapeutic efficacy of the compound of Ex~mple 1 and N-formimiaoyl thienamycin after intramuscular a~ministration to mice experimentally infected with various organisms is shown in the following Table. The PDSo (dose in mg/kg require~ to give protection to 50% of the in~ected mice) is indicatea.

'' . .

.

"" 42 _ ~ h V ~ D O O I ~

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

* E~

' ' ' 1:~98~ ~0 . ~ 43 ~

. .
The toxicity of the compound of Example 1 after intra-cranial administration to mice was determined and is shown in the following Table.

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

.
, .. Vrinary Recovery The urinary recovery of the compouna of Example 1 after intramuscular administration t20 ~g/kg3 to mice i~
shown in the following Table.

Urinary Reco~rery - Intramuscular Administration of 20 mq/kg to Mi ce Percentage of Dose Reco~ered 0-3 3-6 6-~4 0-~4 Compound ~ours After Administration Compound of Example 1 15.6 2.1 <0.2 17.7~2.9 N-Forminidoyl Thienamycin 12.1 0.1 <0.1 . 12.2~3.6 Compounds were solubilizea in 0.1 M phosphate buffer p~ 7. Values are from a single test: 4 mice per compound.

, The following examples illustrate but do not limit the scope of the present invention.

.', , .

.

~g~

_ 45 -Example 1 Preparation of 3-~2-(1-tetrahyarothiophenium)e~hYlthio]-6~-11-(R)-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0~hept-2- ene- 2-carboxYlate 2CH ;~--S~

N O

A. ~-Nitrobenzyl 3-(2-hydroxyethylthio~-63-[l-(R~-hYdro~~
ethYl~-7-oxo-1-azabicyclo [3.2.0~hept-2-e~e-2-carboxylate OH
J~o O C02p 0~
- J ` ` -,_, SC~2CH2H

N . ~CO pNB
: . 2 pNB = -~H2 ~ 2 4~

-- 46 ~

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

_ .. .

. ~
9~ ~0 - 4? -B. p-Nitrobenz~l a-~2-m~than~sulfony~oxyethyl~hio)=

2-ene-2-carboxylate OH
J~ d~sc~ on ~

co2PNB

J ~ ~ S~H~ 2 2 3 11_ N CO2P~B

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

o ~ 4~ ~
. . .
:, C. ~-Nitrobenzyl 3-~2-iodoethYlth~tR)-hydroxyethyll -7-oxo-1-azabicyclo ( 3 . 2 . û) hept=
2-ene- 2-car~oxy~ate 0~

J ~ ,Sc~2c~12oso2cH3 L I 11 ,~ .
o C02pN~ .

.
T H

,, ~ ~scH2cH2I

o co2PNB

A sol~tion of 350 mg ~0-.72 n~oole) of intermediate 3 and 216 mg (1.4 ~nole) of sodiu~ ic>dide in 20 ml of acetone was heated at ref lux f or 4 hours . Evaporation of the acetone ga~e a white amorphous solid which was suspended in ether ( 10 ml) -water (10. :ml) . Filtration of the white solid and ~.racuum drying produced 300 mg (80~6 yiel~3 of the title compol~nd 4 as a white ~morphous pawa~r.
NMR ~DMS0-d6) ~. 1.18 ~3~, d, J=6,0 ~z), 3.20-3.60 (7~, m), 3.80-4.25 (2H, m)~ 5.10 (1~, a, J=5.5 ~z), 5.25 (1H, d, J=12.0 Hz), 5.45 (1~, d, J=12.0 Rz), 7.70 ~2H, d, J=8.S Hz), and 8.27 (2~, d, J-8.5 ~z); ir lXBr) ymax: 3500, 1768 and 1700 cm Anal. Calc'd for C18H1gN206I C, 41,71; H, 3.70; N, 5.41;
I, 24.4B. Found- C, 42.10; ~, 3.75; N, 5.9?; I, 23.20.

4 ~

D- 3-[2-tl-Tetrah~rot~ioP enium~ethYlthi~]-6u-[l-(R)~hydroxyeth~1]-7-oxo-1-azabicYclo[3.2.Q~hept-2-ene-2-carboxylate ~H
2CH2 >

O , 02pNB

OH r~~~~
SCH~CH2 S

O N CO2pNB

O COO~) To a solution of p-nitrobenzyl 3-(2-iodoethylthio)-6a-[1-~R)-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0~hept-2-ene-2-ca~boxylate (104 mg; 0.2 mmole) in S ml of tetrahydrofuran there was added tetrahydrothiophene (0.3 ml; 0.35 mmole~
followed by a solution of silYer perchlorate (60 mg; 0.3 mmole~
in 0.5 ml.of tetrahydrofuran. The mixture was stirred at room temperature.for 60 minutes. The solvent was evaporated.in vacuo af ording compound ~ as a yellow gum. This gum was digested with 100 ml of OE LITE to give an amorphous solid.

~ . ~ ' ' ' `"

. . , : .

84~

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

-, -....

Claims (44)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of ~ compound of the formula wherein R8 is hydrogen and R1 is selected from the group consisting of hydrogen;
alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms;
cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-cyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group con-sisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are independently selected from the group consisting of C1-C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo wherein, relative to the above-named substituents, the groups R3 and R4 are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; and heteroaryl, herteoaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms, or R3 and R4 taken together with the nitrogen to which at least one is attached may form a 5-or 6-membered nitrogen-containing heterocyclic ring; R9 is as defined for R3 except that it may not be hydrogen; or wherein R1 and R8 taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy; A is C2-C6 straight or branched chain alkylene; R2 is hydrogen, and anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter anion, and R10 and R11 each independently represents (a) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cyclo-alkyl or cycloalkylalkyl having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety, said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkyl-alkyl group being optionally substituted by 1-3 substituents independently selected from hydroxy, C1-C6 alkyoxy, C1-C6 alkanoyloxy, carboxy, C1-C6 alkoxycarbonyl, amino, C1-C6 alkylamino, di(C1-C6) alkylamino, C1-C6 alkanoylamino, phenyl, phenyl substituted by 1-3 halo, C1-C6 alkoxy, C1-C6 alkyl, carboxy, carboxy (C1-C6) alkyl, amino, C1-C6 alkylamino, di(C1-C6) alkylamino or di-(C1-C6)alkylamino(C1-C6)alkyl, halo or oxo;
(b) phenyl optionally substituted by 1-3 halo, C1-C6 alkoxy, C1-C6 alkyl, carboxy, amino, C1-C6 alkylamino or di(C1-C6)alkylamino groups;
(c) heterocyclyl or heterocyclylalkyl wherein the hetero-cyclic moiety is a 4-6 membered ring having 1-3 hetero atoms selected from O, N and S and the alkyl moiety has 1-6 carbon atoms, said heterocyclyl or heterocyclylalkyl ring being optionally substituted by 1-3 C1-C6 alkyl or C1-C6 alkoxy groups; or (d) heteroaryl or heteroaralkyl wherein the heterocyclic moiety is a 5-6 membered aromatic ring having 1-3 hetero atoms selected from O, N and S and the alkyl moiety has 1-6 carbon atoms, said heteroaryl or heteroaralkyl ring being optionally substituted by 1-3 C1-C6 alkyl, C1-C6 alkoxy, carboxy, carboxy(C1-C6)alkyl, amino, C1-C6 alkyl-amino, di(C1-C6)alkylamino, amino(C1-C6)alkyl or di(C1-C6)-alkylamino(C1-C6)alkyl groups; or wherein R10 and R11 taken together with the S?
to which they are attached represent a 4-6 member sulfur-containing heterocyclic ring containing 0-2 double bonds and 0-2 additional heteroatoms selected from O, N and S, said ring being attached to A through a sulfur atom, thereby forming a sulfonium group, said heterocyclic ring being optionally substituted by 1-3 substitutents independently selected from:
C1-C6 alkyl optionally substituted by 1-3 hydroxy, C1-C6 alkoxy, carboxy, halo, amino, C1-C6 alkylamino or di(C1-C6)alkylamino groups, hydroxy, C1-C6 alkoxy, C1-C6 alkanoyloxy, amino, C1-C6 alkylamino, di(C1-C6)-alkylamino, C1-C6 alkanoylamino, carboxy, C1-C6 alkoxy-carbonyl, halo, oxo or phenyl; or wherein said hetero-cyclic ring is fused to a C5-C6 carbocyclic ring, a phenyl ring, a 5-6 member heterocyclic ring or a 5-6 member hetero-aryl ring, all of which rings may be optionally sub-stituted by 1-3 of the substituents referred to above for the ring; or a pharmaceutically acceptable salt thereof, which process comprises subjecting an intermediate of the formula II

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

wherein R1 and R8 are as defined above and R2 is a con-ventional readily removeable carboxyl protecting group in an inert organic solvent with diphenyl chlorophosphate in the presence of base to give an intermediate of the formula IV

wherein R1, R8 and R2' are as defined above;
(2) reacting intermediate TV in an inert organic solvent and in the presence of base with a mercaptan reagent of the formula HS-A-OH
wherein A is as defined ahove to give an intermediate of the formula V

wherein R1, R8, A and R2' are as defined above;
(3) reacting intermediate V in an inert organic solvent and in the presence of base with methanesulfonyl chloride or a functional acylating equivalent thereof to give an intermediate of the formula VI

wherein R1, R8 A and R2' are as defined above;
(4) reacting intermediate VI in an inert organic solvent with a source of iodide ion so as to displace the methanesulfonyloxy group with an iodo group and form an intermediate of the formula II

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

2. A process for the preparation of a compound of the formula wherein R8 is hydrogen and R1 is selected from the group consisting of hydrogen;
alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms;
cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-cyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group con-sisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are independently selected from the group consisting of C1-C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo 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 from a 5-or 6-membered nitrogen-containing heterocyclic ring; R9 is as defined for R3 except that it may not be hydrogen; or wherein R1 and R8 taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy; A is C2-C6 straight or branched chain alkylene; R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter anion, and R10 and R11 each independently represents (a) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cyclo-alkyl or cycloalkylalkyl having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety, said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkyl-alkyl group being optionally substituted by 1-3 substituents independently selected from hydroxy, C1-C6 alkoxy, C1-C6 alkanoyloxy, carboxy, C1-C6 alkoxycarbonyl, amino, C1-C6 alkylamino, di(C1-C6)alkylamin0, C1-C6 alkanoylamino, phenyl, phenyl substituted by 1-3 halo, C1-C6 alkoxy, C1-C6 alkyl, carboxy, carboxy(C1-C6)alkyl, amino, C1-C6 alkylamino, di(C1-C6)alkylamino or di-(C1-C6)alkylamino(C1-C6)alkyl, halo or oxo;
(b) phenyl optionally substituted by 1-3 halo, C1-C6 alkoxy, C1-C6.alkyl, carboxy, amino, C1-C6 alkylamino or di(C1-C6)alkylamino groups;
(c) heterocyclyl or heterocyclylalkyl wherein the hetero-cyclic moiety is a 4-6 membered ring having 1-3 hetero atoms selected from 0, N and S and the alkyl moiety has 1-6 carbon atoms, said heterocyclyl or heterocyclylalkyl ring being optionally substituted by 1-3 C1-C6 alkyl or Cl-C6 alkoxy groups; or (d) heteroaryl or heteroaralkyl wherein the heterocyclic moiety is a 5-6 membered aromatic ring having 1-3 hetero atoms selected from 0, N and S and the alkyl moiety has 1-6 carbon atoms, said heteroaryl or heteroaralkyl ring being optionally substituted by 1-3 C1-C6 alkyl, C1-C6 alkoxy, carboxy, carboxy(C1-6)alkyl, amino, C1-C6 alkyl-amino, di(C1-C6)alkylamino, amino(C1-C6)alkyl or di(C1-C6)-alkylamino(C1-C6)alkyl groups; or wherein R10 and R11 taken together with the to which they are attached represent a 4-6 member sulfur-containing heterocyclic ring containing 0-2 double bond and 0-2 additional heteroatoms selected from O, N and S, said ring being attached to A through a sulfur atom, thereby forming a sulfonium group, said heterocyclic ring being optionally substituted by 1-3 substituents independently selected from:
C1-C6 alkyl optimally substituted by 1-3 hydroxy, C1-C6 alkoxy, carboxy, halo, amino, C1-C6 alkylamino or di(C1-C6) alkylamino groups, hydroxy, C1-C6 alkoxy, C1-C6 alkanoyloxy, amino, C1-C6 alkylamino, di(C1-C6) alkylamino, C1-C6 alkanoylamino, carboxy, C1-C6 alkoxy-carbonyl, halo, oxo or phenyl; or wherein said hetero-cyclic ring is fused to a C5-C6 carbocyclic ring, phenyl ring, a 5-6 member heterocyclic ring or a 5-6 member hetero-aryl ring, all of which rings may be optionally sub-stituted by 1-3 of the substituents referred to above f or the ring; or a pharmaceutically acceptable salt thereof, which process comprises subjecting an intermediate of the formula II

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

3. A process for the preparation of a compound of the formula I

wherein R8 is hydrogen and R1 is selected from the group consisting of hydrogen;
alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms;
cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-cyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group con-sisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are independently selected from the group consisting of C1-C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo wherein, relative to the above-named substituents, the groups R3 and R4 are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms, or R3 and R4 taken together with the nitrogen to which at least one is attached may form a 5-or 6-membered nitrogen-containing heterocyclic ring; R9 is as defined for R3 except that it may not be hydrogen; or wherein R1 and R8 taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy: A is C2-C6 straight or branched chain alkylene; R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter anion, and R10 and R11 each independently represents (a) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cyclo-alkyl or cycloalkylalkyl having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety, said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkyl-alkyl group being optionally substituted by 1-3 substituents independently selected from hydroxy, C1-C6 alkoxy, C1-C6 alkanoyloxy, carboxy, C1-C6 alkoxycarbonyl, amino, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkanoylamino, phenyl, phenyl substituted by 1-3 halo, C1-C6 alkoxy, C1-C6 alkyl, carboxy, carboxy(C1-C6)alkyl, amino, C1-C6 alkylamino, di(C1-C6)alkylamino or di-(C1-C6)alkylamino(C1-C6)alkyl, halo or oxo;
(b) phenyl optionally substituted by 1-3 halo, C1-C6 alkoxy, C1-C6 alkyl, carboxy, amino, C1-C6 alkylamino or di(C1-C6)alkylamino groups;
(c) heterocyclyl or heterocyclylalkyl wherein the hetero-cyclic moiety is a 4-6 membered ring having 1-3 hetero atoms selected from O, N and S and the alkyl moiety has 1-6 carbon atoms, said heterocyclyl or heterocyclylalkyl ring being optionally substituted by 1-3 C1-C6 alkyl or C1-C6 alkoxy groups; or (d) heteroaryl or heteroaralkyl wherein the heterocyclic moiety is a 5-6 membered aromatic ring having 1-3 hetero atoms selected from O, N and S and the alkyl moiety has 1-6 carbon atoms, said heteroaryl or heteroaralkyl ring being optionally substituted by 1-3 C1-C6 alkyl, C1-C6 alkoxy, carboxy, carboxy(C1-C6)alkyl, amino, C1-C6 alkyl-amino, di(C1-C6)alkylamino, amino(C1-C6)alkyl or di(C1-C6)-alkylamino(C1-C6)alkyl groups; or wherein R10 and R11 taken together with the S?
to which they are attached represent a 4-6 member sulfur-containing heterocyclic ring containing 0-2 double bonds and 0-2 additional heteroatoms selected from O, N and S, said ring being attached to A through a sulfur atom, thereby forming a sulfonium group, said heterocyclic ring being optionally substituted by 1-3 substituents independently selected from:
C1-C6 alkyl optionally substituted by 1-3 hydroxy, C1-C6 alkoxy, carboxy, halo, amino, C1-C6 alkylamino or di(C1-C6)alkylamino groups, hydroxy, C1-C6 alkoxy, C1-C6 alkanoyloxy, amino, C1-C6 alkylamino, di(C1-C6)-alkylamino, C1-C6 alkanoylamino, carboxy, C1-C6 alkoxy-carbonyl, halo, oxo or phenyl; or wherein said hetero-cyclic ring is fused to a C5-C6 carbocyclic ring, a phenyl ring, a 5-6 member heterocyclic ring or a 5-6 member hetero-aryl ring, all of which rings may be optionally sub-stituted by 1-3 of the substtuents referred to above for the ring; or a pharmaceutically acceptable salt thereof, which process comprises the steps of (1) reacting an intermediate of the formula III

wherein R1 and R8 are as defined above and R2 is a con-ventional readily removable carboxyl protecting group in an inert organic solvent with diphenyl chlorophosphate in the presence of base to give an intermediate of the formula IV

wherein R1, R8 and R2 are as defined above;
(2) reacting intermediate IV in an inert organic solvent and in the presence of base with a mercaptan reagent of the formula HS-A-OH
wherein A is as defined above to give an intermediate of the formula V
wherein R1, R8, A and R2. are as defined above;
(3) reacting intermediate V in in inert organic solvent and in the presence of base with methanesulfonyl chloride or a functional acylating equivalent thereof to give an intermediate of the formula VI

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

4. A process as in claim 1 wherein R1 is hydrogen, CH3CH2-, or

5. A process as in claim 1 wherein R1 and R8 taken together represent

6. A process as in claim 1 wherein R1 is

7. A process as in claim 1 wherein R1 is and the absolute configuration is 5R, 6S, 8R.

8. A process as in claim 1 wherein A is -CH2CH2-.

9. A process for the preparation of a compound of the formula wherein R8 is hydrogen and R1 is selected from the group consisting of hydrogen;
alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms;
cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-cyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group con-sisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are independently selected from the group consisting of C1-C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo wherein, relative to the above-named substituents, the groups R3 and R4 are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms, or R3 and R4 taken together with the nitrogen to which at least one is attached may form a 5-or 6-membered nitrogen-containing heterocyclic ring; R9 is as defined for R3 except that it may not be hydrogen; or wherein R1 and R8 taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy; A is C2-C6 straight or branched chain alkylene; R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter anion, and R10 and R taken together with the to which they are attached represent a pharmaceutically acceptable salt thereof, which process comprises subjecting an intermediate of the formula II
wherein R1, R8 and A are as defined above and R2' is a conventional readily removable carboxyl protecting group to nucleophilic dis-placement in an inert organic solvent and in the presence of silver ion with a sulfide reagent of the formula wherein R10 and R11 are as defined above so as to displace the iodo group of intermediate II with group and form a compound of the formula I' wherein X- is a counter anion and R1, R8, A, R10, R11 and R2' are as defined above, and, if desired, removing the carboxyl protecting group R2' to give the corresponding deblocked compound of the formula I, or a pharmaceutically acceptable salt thereof;

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

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

10. A Process as in claim 9 wherein R1 is hydrogen, CH3CH2-, or

11. A process as in claim 9 wherein R1 and R8 taken together represent

12. A process as in claim 9 wherein R1 is

13. A process as in claim 9 wherein R1 is and the absolute configuration is 5R, 6S, 8R.

14. A process according to claim 9 wherein A is -CH2CH2-.

15. A process for producing the compound of the formula wherein R8 is hydrogen and R1 is selected from the group consisting of hydrogen;
alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms;
cycloalkyl and cycloalkylalkyl having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-cyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group con-sisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are independently selected from the group consisting of C1-C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo wherein, relative to the above-named substituents, the groups R3 and R4 are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms, or R3 and R4 taken together with the nitrogen to which at least one is attached may form a 5-or 6-membered nitrogen-containing heterocyclic ring; R9 is as defined for R3 except that it may not be hydrogen; or wherein R1 and R8 taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy; A is C2-C6 straight or branched chain alkylene; R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter anion: and R10 and R11 taken together with the to which they are attached represent or a pharmaceutically acceptable salt thereof, which process comprises subjecting an intermediate of the formula wherein R1, R8 and A are as defined above and R2' is a conventional readily removable carboxyl protecting group to nucleophilic dis-placement in an inert organic solvent and in the presence of silver ion with a sulfide reagent of the formula wherein R10 and R11 are as defined above so as to displace the iodo group of intermediate II with the group and form a compound of the formula wherein X is a counter anion and R1, R8, A, R10, R11 and R2' are as defined above, and, if desired, removing the carboxyl protecting group R2 to give the corresponding deblocked compound of the formula I, or a pharmaceutically acceptable salt thereof, which process comprises the steps of (1) reacting an intermediate of the formula III
wherein R1 and R8 are R5 defined above and R2' is a con-ventional readily removable carboxyl protecting group in an inert organic solvent with diphenyl chlorophosphate in the presence of base to give an intermediate of the formula IV
wherein R1, R8 and R2' are as defined above;
(2) reacting intermediate IV in an inert organic solvent and in the presence of base with a mercaptan reagent of the formula HS-A-OH
wherein A is as defined above to give an intermediate of the formula wherein R1, R8, A and R2' are as defined above;
(3) reacting intermediate V in an inert organic solvent and in the presence of base with methanesulfonyl chloride or a functional acylating equivalent thereof to give an intermediate of the formula VI
wherein R1, R8, A and R2' are as defined above;
(4) reacting intermediate VI in an inert organic solvent with a source of iodide ion so as to displace the methanesulfonyloxy group with an iodo group and form an intermediate of the formula wherein R1, R8, A and R2 are as defined above; and (5) subjecting intermediate II to nucleophilic dis-placement in an inert organic solvent and in the presence of silver ion with a sulfide reagent of the formula wherein R10 and R11 are as defined above so as to displace the iodo group of intermediate II with the group and form a compound of the formula wherein X? is a counter anion and R1, R8, A, R10, R11 and R2 are as defined above, and, if desired removing the carboxyl protecting group R2 to give the corresponding deblocked compound of formula I, or a pharmaceutically accept-able salt thereof.

16. A process as in claim 15 wherein R1 is hydrogen, CH3CH2-,

17. A process as in claim 15 wherein taken together represent

18. A process as in claim 15 wherein

19. A process as in claim 15 wherein and the absolute configuration is 5R, 6S, 8R.

20. A process as in claim 15 wherein A is -CH2CH2-.

21. A process for preparing the compound of the formula wherein R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter anion, or a pharmaceutically acceptable salt thereof, which process comprises subjecting an intermediate of the formula wherein R1, R8 and A are as defined above and R2' is a conventional readily removable carboxyl protecting group to nucleophilic dis-placement in an inert organic solvent and in the presence of silver ion with a sulfide reagent of the formula wherein R10 and R11 are as defined above so as to displace the iodo group of intermediate II with the group and form a compound of the formula I' wherein X is a counter anion and R1, R8, A, R10, R11 and R2' are as defined above, and, if desired, removing the carboxyl protecting group R2' to give the corresponding deblocked compound of the formula I, or a pharmaceutically acceptable salt thereof;
or alternately a process comprising the steps of (1) reacting an intermediate of the formula III
wherein R1 and R8 are as defined above and R2' is a con-ventional readily removable carboxyl protecting group in an inert organic solvent with diphenyl chlorophosphate in the presence of base to give an intermediate of the formula IV

wherein R1, R8 and R2' are as defined above;
(2) reacting intermediate IV in an inert organic solvent and in the presence of base with a mercaptan reagent of the formula HS-A-OH
wherein A is as defined above to give an intermediate of the formula wherein R1, R8, A and R2' are as defined above;
( 3) reacting intermediate V in an inert organic solvent and in the presence of base with methanesulfonyl chloride or a functional acylating equivalent thereof to give an intermediate of the formula VI

wherein R1, R8, A and R2' are as defined above;
(4) reacting intermediate VI in an inert organic solvent with a source of iodide ion so as to displace the methanesulfonyloxy group with an iodo group and form an intermediate of the formula II

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

22. A process as in claim 21 wherein R2 is p-nitrobenzyl.

23. A process as in claim 21 wherein R2 is an anionic charge.

24. A compound of the formula wherein R8 is hydrogen and R1 is selected from the group consisting of hydrogen;
alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms;
cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-cyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group con-sisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are independently selected from the group consisting of C1-C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo wherein, relative to the above-named substituents, the groups R3 and R4 are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms, or R3 and R4 taken together with the nitrogen to which at least one is attached may form a 5-or 6-membered nitrogen-containing heterocyclic ring; R9 is as defined for R3 except that it may not be hydrogen; or wherein R1 and R8 taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy; A is C2-C6 straight or branched chain alkylene; R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter anion, and R10 and R11 each independently represents (a) C1-C6 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cyclo-alkyl or cycloalkylalkyl having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety, said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkyl-alkyl group being optionally substituted by 1-3 substituents independently selected from hydroxy, C1-C6 alkoxy, C1-C6 alkanoyloxy, carboxy, C1-C6 alkoxycarbonyl, amino, C1-C6 alkylamino, di(C1-C6)alkylamino C1-C6 alkanoylamino, phenyl, phenyl substituted by 1-3 halo, C1-C6 alkoxy, C1-C6 alkyl, carboxy, carboxy(C1-C6)alkyl, amino, C1-C6 alkylamino, di(C1-C6)alkylamino or di-(C1-C6)alkylamino(C1-C6)a1kyl, halo or oxo;
(b) phenyl optionally substituted by 1-3 halo, C1-C6 alkoxy, C1-C6 alkyl, carboxy, amino, C1-C6 alkylamino or di(C1-C6)alkylamino groups;
(c) heterocyclyl or heterocyclylalkyl wherein the hetero-cyclic moiety is a 4-6 membered ring having 1-3 hetero atoms selected from O, N and S and the alkyl moiety has 1-6 carbon atoms, said heterocyclyl or heterocyclylalkyl ring being optionally substituted by 1-3 C1-C6 alkyl or C1-C6 alkoxy groups; or (d) heteroaryl or heteroaralkyl wherein the heterocyclic moiety is a 5-6 membered aromatic ring having 1-3 hetero atoms selected from O, N and S and the alkyl moiety has 1-6 carbon atoms, said heteroaryl or heteroaralkyl ring being optionally substituted by 1-3 C1-C6 alkyl, C1-C6 alkoxy, carboxy, carboxy(C1-C6)alkyl, amino, C1-C6 alkyl-amino, di(C1-C6)alkylamino, amino(C1-C6)alkyl or di(C1-C6)-alkylamino(C1-C6)alkyl groups; or wherein R and R
taken together with the S?
to which they are attached represent a 4-6 member sulfur-containing heterocyclic ring containing 0-2 double bonds and 0-2 additional heteroatoms selected from O, N and 5, said ring being attached to A through a sulfur atom, thereby forming a sulfonium group, said heterocyclic ring being optionally substituted by 1-3 substituents independently selected from:

C1-C6 alkyl optionally substituted by 1-3 hydroxy, C1-C6 alkoxy, carboxy, halo, amino, C1-C6 alkylamino or di(C1-C6)alkylamino groups, hydroxy, C1-C6 alkoxy, C1-C6 alkanoyloxy, amino, C1-C6 alkylamino, di(C1-C6)-alkylamino, C1-C6 alkanoylamino, carboxy, C1-C6 alkoxy-carbonyl, halo, oxo or phenyl; or wherein said hetero-cyclic ring is fused to a C5-C6 carbocyclic ring, a phenyl ring, a 5-6 member heterocyclic ring or a 5-6 member hetero-aryl ring, all of which rings may be optionally sub-stituted by 1-3 of the substituents referred to above for the ring; or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

25. A compound according to Claim 24 wherein R1 is hydrogen, CH3CH2- , whenever prepared by the process of claim 4 or by an obvious chemical equivalent thereof.

26. A compound according to Claim 24 wherein R1 and R8 taken together represent whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

27. A compound according to Claim 24 wherein R1 is whenever prepared by the process of claim 6 or by an obvious chemical equivalent thereof.

28. A compound according to Claim 24 wherein R1 is and the absolute configuration is 5R, 6S, 8R, whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.

29. A compound according to Claim 24, wherein A is -CH2CH2-, whenever prepared by the process of claim 8 or by an obvious chemical equivalent thereof.

30. A compound of the formula wherein R8 is hydrogen and R1 is selected from the group consisting of hydrogen;
alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms;
cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-cyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group con-sisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are independently selected from the group consisting of C1-C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo wherein, relative to the above-named substituents, the groups R3 and R4 are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms, or R3 and R4 taken together with the nitrogen to which at least one is attached may form a 5-or 6-membered nitrogen-containing heterocyclic ring; R9 is as defined for R3 except that it may not be hydrogen; or wherein R1 and R taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy; A is C2-C5 straight or branched chain alkylene; R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter anion, and R10 and R11 each independently represents C1-C6 alkyl; or wherein R10 and R11 taken together with the to which they are attached represent a pharmaceutically acceptable salt thereof.
whenever prepared by the process of claim 9 or by an obvious chemical equivalent thereof.

31. A compound according to Claim 30 wherein R1 is hydrogen CH3CH2-, , or whenever prepared by the process of claim 10 or by an obvious chemical equivalent thereof.

32. A compound according to Claim 30 wherein R1 and R8 taken together represent , whenever prepared by the process of claim 11 or by an obvious chemical equivalent thereof.

33. A compound according to Claim 30 wherein R1 is , whenever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.

34. A compound according to Claim 30 wherein R is and the absolute configuration is 5R, 6S, 8R, whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof.

35. A compound according to Claim 30, wherein A is -CH2CH2-, whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.

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

or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 15 or by an obvious chemical equivalent thereof.

37. A compound according to Claim 36 wherein R1 hydrogen, CH3CH2-, , or , whenever prepared by the process of claim 16 or by an obvious chemical equivalent thereof.

38. A compound according to Claim 36 wherein R1 and R8 taken together represent , whenever prepared by the process of claim 17 or by an obvious chemical equivalent thereof.

39. A compound according to Claim 36 wherein R1 is , whenever prepared by the process of claim 18 or by an obvious chemical equivalent thereof.

40. A compound according to Claim 36 wherein R1 is and the absolute configuration is 5R, 6S, 8R, whenever prepared by the process of claim 19 or by an obvious chemical equivalent thereof.

41. A compound according to Claim 36 wherein A is -CH2CH2-, whenever prepared by the process of claim 20 or by an obvious chemical equivalent thereof.

42. A compound of the formula wherein R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter anion, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 21 or by an obvious chemical equivalent thereof.

43. The compound according to Claim 19 wherein R2 is p-nitrobenzyl, whenever prepared by the process of claim 22 or by an obvious chemical equivalent thereof.

44. The compound according to Claim 19 wherein R2 is an anionic charge, whenever prepared by the process of claim 23 or by an obvious chemical equivalent thereof.