IE55225B1 - Carbapenem antibiotics - Google Patents

Abstract

Disclosed are novel carbapenem derivatives characterized by a 2- substitutent of the formula <IMAGE> wherein A represents C2-C6 straight or branched chain alkylene group and R<10> and R<11> each independently represents optionally substituted aliphatic, cycloaliphatic, cycloaliphatic- aliphatic, aryl, heterocyclyl, heterocyclyl-aliphatic, heteroaryl or heteroaraliphatic, or R<10> and R<11> 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. [GB2118183A]

Description

2 2 55285 Hie present invention is directed to new carbaperen antibiotics which are fully defined below, in which the. 2-substituent has the formula Θ ,10 Λ1 —S—A—S' . wherein A is Cj-Cg straight or branched chain alkylene and and each independently represent optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, heterocyclyl, heterocyclyl-aliphatic, heteroaryl or heteroar-aliphatic radicals, or R^·® and R^ when taken together with the © 10 S to which they are attached represent an optionally substituted sulfur-containing heterocyclic ring.

A number of 0-lactam derivatives containing the carba-penem nucleus have been disclosed in the literature. These carbapenem derivatives have been reported to possess utility as antibacterial agents and/or θ-lactamase inhibitors.

The initial carbapenem compounds were natural products 20 such as thienamycin of the formula 355825 Η •SCH,CH,NH COOH OH 0 obtained by fermentation of Streptomyces cattleya (U.S. Patent 3,950,357). Thienamycin is an exceptionally potent broad-spectrum antibiotic which possesses notable activity against various Pseudomonas species, organisms which have been notoriously resistant to 0-lactam antibiotics.

Other natural products containing the carbapenem nucleus include olivanic acid derivatives such as antibiotic MM 13902 of the formula disclosed in U.S. Patent 4,113,856, antibiotic MM 17880 of the formula disclosed in U.S. Patent 4,162,304, antibiotic MM 4550A of the 15 formula disclosed in U.S. Patent 4,172,129 and antibiotic 890A of the formula 4 5S225 HOjSO 3 disclosed in U.S. Patent 4,264,735« in addition to the natural products, the compound desacetyl 8901^ of the formula is disclosed in U.S. Patent 4,264,734 as being prepared by an enzymatic deacylation of the corresponding N-acetyl compound. Various derivatives of the naturally-occurring olivanic acids have also been synthesized, e.g. the compounds of the formula 10 wherein is a free, salted or esterified carboxyl group, n is O or 1 and R2 H' 311 acyl group or a group of the formula wherein Rj 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 carbapenem derivative of the formula 'SCH.CH.NH. 2v-n2nn2 N :ooh 5ssaas while Patent Specification No. 46,369 reports isolation of the compound sch2ch2nhcoch3 COOH . from a Streptomyces fermentation broth.

Carbapenems which are unsubstituted in the 6-position have also been synthesized. Thus, D.S. Patent 4,210,661 discloses compounds of the formula COOH wherein R2 is phenyl or substituted phenyl, U.S. Patent 4,267,177 10 discloses compounds of the formula S-R, COOH wherein R^ is an optionally substituted pyridyl group, D.S. Patent 4,255,441 discloses compounds of the formula -CR„ Ν =cr3r4 Ο COOH SS225 β wherein 3®** Rj are R or alkyl and R^ is NH-COnRg in which Rg is alkyl, phenyl or substituted phenyl and n is 1 or 2, and U.S. Patent 4,282,236 discloses compounds of the formula wherein R^ is H or alkyl and Rj is CN or C02R3 in which R3 is H, alkyl, aryl or aralkyl.

Carbapenems of the general formula R^HH" COOH 1 8 wherein R is H or acyl and R is H or substituted or unsub-10 stituted: alkyl, alkenyl , alkynyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl heteroaralkyl, heterocyclyl or heterocyclylalkyl, are disclosed ft in U.S. Patent 4,218, 463. There is no disclosure of any R substituents of the type . © —A— in which A is alkylene. 7 55225 The natural product thienamycin has the absolute configuration 5R, 6S, 8R. This isomer, as well as the remaining seven thienamycin isomers, may be obtained via total synthesis as disclosed in U.S. Patent 4,234,59$. Total synthesis 5 procedures for thienamycin are also disclosed, for example. in U.S. Patents 4,287,123, 4,269,772, 4,282,148, 4,273,709, 4,290,947 and Patent Specification No. 48728. A key intermediate in the disclosed synthetic methods is xo wherein pNB represents p-nitrobenzyl.

Because of the exceptional biological activity of thienamycin, a large number of derivatives have been prepared and disclosed in the literature. Among these are (1) N-formimidoyl thienamycin of the formula OH disclosed in Patent Specification No. 48356; (2) N-heteroeyclic derivatives of thienamycin having the formula 15 8 552 25 wherein: the bifunctional ring may contain additional unsaturation in the ring; and wherein n is an integer selected from 1-6; 5 p is Ο, 1 or 2; is H, alkyl or aryl; and Z is imino, oxo, H, amino or alkyl, disclosed in U.S. Patent 4,189,493; (3) substituted N-methylene derivatives of thienamycin having the formula 1 2 10 wherein X and Y are H, R, OR, SR or NR R in which R is substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalky lalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hetero-cyclyl or heterocyelylalkyl, and R and R are H or Rr disclosed in U.S. Patent 4,194,047; (4) compounds of the formula 9 55225 3 12 wherein R is aryl, alkyl, acyl or aralkyl and R and R are independently selected from H and acyl (including acyl of the type -C-R*2- in which R^ may inter alia be alkyl substituted by a quaternary ammonium group, e.g. j? -C-CH2- m ) ) disclosed in U.S. Patent 4,226,870; (S) compounds of the formula 3 OR 1 2 SCH2CH2NR R COOH wherein R^ is H, acyl or an univalent optionally substituted hydrocarbon radical; R^ is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalky lalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl and R2 is acyl (including acyl of the type -f-R in which R is alkyl substituted by a quaternary ammonium group, e.g.

-MO > disclosed in Patent Specification No. 46877 (see also U.S. Patent 4,235,917); (6) Compounds of the formula 10 65225 OH 6 7 wherein R , R and R are independently selected from H and substituted or unsubstitutedi alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, 5 heteroaryl or heteroaralkyl, are disclosed in U.S. Patent 4,235,920; (7) compounds of the formula wherein each of R and R , independently of the other, is a radical of the type defined for R, a hydrogen atom, or a nitre, 10 hydroxyl, Cj_6 alkoxyl, amino, Cj_g alkylamino, di(C2_g alkyl) - amino or tri(C. , alkylamino) radical, an extra anion being x-b 12 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 bicyclic 15 heteroaryl or heterocyclyl residue containing 4-1Q ring atoms, one or more of which may be an additional hetero atom selected from oxygen, sulphur and nitrogen; R is a cyano group or a substituted or unsubstituted carbamoyl, carboxyl, (C^_^ alkoxy)-carbonyl, C1-10 alkyl, C2_10 alkenyl, C2_1Q alkynyl, C3_w cyclo-20 alkyl, C4_12 cycloalkylalkyl, c5_12 cycloalkylalkenyl, C3_2g cycloalkenyl, Cg_12 cycloalkenylalkenyl, C^_^2 cycloalkenylalkyl, C6-10 arY1' C7-16 aralky1» c8-16 araUteny1» c8-16 or monocyclic or bicyclic heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl comprising 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 heteroaralkyl or heterocyclylalkyl radical contains from 1 to 6 carbon atoms; the substituent or substituents on R, R^, R^ or on the ring 25 11 55225 1 2 formed by joining R* and R are chlorine; bromine; iodine; fluorine; azido; C2_4 alkyl; inercapto; sulpho; phosphono; cyano-thio (-SCN); nitro; cyano; amino; hydrazino; amino or hydrazino having up to three Cj_g alkyl substituents; hydroxy; Cj_g alkoxy; Cj_g alkylthio; carboxyl; oxo; (Cj_g alkoxy)carbonyl; ^2-10 ®β/1οχν» carbamoyl; (C^_4 alkyl) carbamoyl or di(Cj_4 alkyl) carbamoyl; R3 is a hydrogen atom, an acyl radical or a radical of the type defined for R4; R4 is Cj_10 alkyl; substituted carbonylmethyl; C1-6 alkoxy)-(C^g alkyl), (C3_g cycloalkoxy)-(C^g alkyl); C2_12 alkanoyloxyalkyl; partially or completely halogenated Cj_g alkyl in which the halogen(s) is/are chlorine, bromine or fluorine; aminoalkyl; C2_1Q alkenyl; C2_1Q alkynyl; acyl; C3_14 alkoxy carbonylalkyl; C4_21 dialkylaminoacetoxyalkyl; C2-13 alkanoylaminoalkyl; ar-(Cj_3 alkyl) in which the aryl residue contains from 6 to 10 carbon atoms; monocyclic or bicyclic heteroaralkyl or heterocyclylalkyl containing 4 to 10 ring atoms, 1 to 3 carbon atoms in the alkyl residue, and 1-4 hetero atoms selected from oxygen, sulphur and/or nitrogen; nuclear-substituted aralkyl or heteroaralkyl in which the substituent is chlorine, fluorine, bromine, iodine or Cj_6 alkyl; aryl or nuclear-substituted aryl containing 6 to 10 ring carbon atoms and in which any nuclear substituent is hydros#, C^_g alkyl, chlorine, fluorine or bromine; aralkoxyalkyl; alkylthioalkyl; C4_^2 βγ&Ιο- alkylthioalkyl; (C2_l0 acylthioJ-iC^g alkyl); or phenylalkenyl in which alkenyl has 2-6 carbon atoms; R5 is substituted or unsubstituted Cj_10 alkyl; C2-10 alJteny1 or alkynyl; rin? substituted and unsubstituted cycloalkyl, cycloalkenyl, cycloalkenyl-alkyl, and cycloalkyl-alkyl having 3-6 ring carbon atoms and up to 6 carbon atoms in any chain; Cg^0 aryl; aralkyl having 6-10 ring carbon atoms and 1-6 carbon atoms in the alkyl chain; monocyclic or bicyclic heteroaryl or heteroaralkyl 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 ring or chain substituent(s) is/are chlorine, bromine, iodine, fluorine, azido, cyano, amino, Cj_g alkylamino, di(Cj_g alky 1)-amino or tri (Cj_g alkylamino) radical, an extra anion being present in the latter case, hydroxy, Cj_g alkoxy, Cj_g alkyl- thioalkyl; carboxyl; oxo, (C^g alkoxy)carbonyl; C2_1Q acyloxy; carbamoyl; (Cj_4 alkyl) carbamoyl; di(Cj_4 alkyl)- carbamoyl; cyanothio (-SCN) or nitro; R6 is hydrogen, hydroxy, 12 12 mercapto, R, -OR, -SR or NR R , where R, R and R are as defined above; 4 4 X is hydroxy, mercapto, amino, acyloxy -OR , -SR , -OM, -0Q or, when the compound is in zwitterionic form, -0**, in which case A~ is absent; A, when the compound is not in zwitterionic form, is a counter ion; H is a pharmaceutically acceptable cation; and Q is a blocking group; are disclosed in Patent Specification No. 46873; and (8) compounds of the formula wherein @>| s 0 attached to the amino nitrogen group of thienamycin represents a mono- or polycyclic N-containing heterocyclic group and R is H, substituted or unsubstituted: alkyl, aryl, alkenyl, hetero-cyclylalkenyl, aralkenyl, heterocyclylalkyl, aralkyl, -NR^,' COOR, CONRj» -OR, or CM, are disclosed in European Patent Application 21082. Among the compounds disclosed in 0.S. Patent 4,235,920 is 13 55225 Λ-τΎ Θ ca2ch2w{ch3)3J Θ A COOH wherein A is a pharmaceutically acceptable anion· The above-mentioned quaternary amine derivative is also described in Recent Advances in the Chemistry of 8-Lactam Antibiotics. Royal 5 Society of Chemistry, London, 1981, pg 240-254, where its antibacterial activity 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—, although there are several recent patent references which, in their broadest disclosure, may generically include such compounds. Thus, for example, European Patent Application 40408 discloses 15 compounds of the formula wherein is H, methyl or hydroxyl and R^ is a monovalent organic group including inter alia substituted alkyl or a group of the formula -CB^Ry in which R^ is an optionally substituted 5- or 6-membered heterocyclic group; (2) Patent Specif!-,. · cation 52,661 discloses compounds of the formula 20 14 55225 R ,6 6 7 8 wherein R , R , and R are independently selected £rom the group consisting of hydrogen, substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; 5 cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon 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, 10 heterocyclyl and heterocyclylalkyl; wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: -X* halo (ehloro, bromo, fluoro) -OH hydroxy 15 -OR1 alkoxy, aryloxy II 12 —OCNR R carb amoyloxy O II 1 2 -CNR R carbamoyl —NR^R^ amino -1-_1_2 _______ . amidino independently chosen) 20 5 10 15 15 -C«NOR oximino -SR* alkyl- and arylthio 1 2 -SOjNR R sulfonamide O || ίο -NHCNR R ureido R^R2- amido -CO^H carboxy -COgR* carboxylate O -cIr1 acyl -o!»1 acyloxy -SH mercapto -SR* alkyl and aryl sulfinyl Q -SR* alkyl and aryl sulfonyl 0 -CN cyano -N^ azido 55235 wherein, relative to the above listed substituents on R®, R7, and R , the groups R and R are · independently selected from: hydrogen, alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms: cycloalkyl, cy cloalky lalkyl, and alky Icy cloalkyl, having 3-6 carbon atoms in the eycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; aryl, such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaxyl, heteroaralkyl, hetero-cyclyl and heterocyclylalkyl and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the 20 55225 1G group consisting of 1-4 oxygen, nitrogen or sulphur atoms and wherein the alkyl moieties associated with said heterocyclic moietiee have 1-6 carbon atoms. (See also European Patent Applications 1627 and 37081, and Patent Specification Nos. 47,958 , 51,861, 52,147 and Patent Application NOS. ffSSfil and TiA? /SO . (4) European Patent Application 24832 discloses compounds of the formula 10 15 20 wherein R* is H or a group selected from OH, OSO-H or a salt or C, . alkyl ester thereof, OR2, SR3, OCOR , OCO,R3 3*2 2 or OCONHR , where R is a C^_g alkyl group or an optionally substituted benzyl group and R3 is a C^_g alkyl group or an optionally substituted benzyl or phenyl group and R12 is cj_6 alkyl, C2_g alkenyl, C3_g alkynyl wherein the triple bond is not present on the carbon adjacent to the sulfur atom, aralkyl, Cj_g alkarioyl, aralkanoyl, aryloxyalkanoyl or arylcarbony 1, any of such R12 groups being optionally substituted, as antibacterial agents. Patent Specification No. 52,661 mentioned above discloses synthesis of the carbapenem derivatives via intermediates of the general formula wherein R® and R2 are as defined above and R2 is a readily removable carboxyl protecting group. Also disclosed as intermediates are compounds of the formula 17 55225 wherein X is described as a leaving group.

While, as indicated above, the prior art has described carbapenem derivatives having a 2-substituent of the type © —S—A—N and derivatives having a 2-substituent of the type —S—A—S— where R^ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, phenyl, aralkyl, aralkenyl, 10 aralkynyl, heteroaryl, heteroaralkyl, heterocyclyl or hetero-cyclylalkyl, there has been no disclosure of· which applicants are aware teaching carbapenems having a 2-substituent wherein the alkylene group A is attached directly to a sulfonium group, i.e. a group of the type © 15 —S—A— Despite the vast number of carbapenem derivatives disclosed-in the literature, there is still a need for new carbapenems since known derivatives may be improved upon in terms of spectrum of* activity, potency, stability and/or toxic side 20 effects. 18 55225 The present invention provides a novel series of carbapenem derivatives characterized by a 2-substituent of the formula ,10 Θ -A—S 10 15 wherein A is C2-Cg straight or branched chain alkylene and R^·0 and each independently represent optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, heterocyclyl, heterocyclyl-aliphatic, heteroaryl or heteroaraliphatic radicals, or R^® and R^ when taken together with the 0 S to which they are attached represent an optionally substituted sulfur-containing heterocyclic ring containing 0-2 double bonds and 0-2 additional heteroatoms selected from Ο, N and S . These derivatives are carbapenem derivatives of the formula -a—s: :oor 8 1 wherein R is hydrogen and R is selected from hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl, having from 1-10 carbon atone; 19 55225 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 5 atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-cyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from 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 Cj-Cg alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo IS * 9 ,3 20 20 55225 -OCR3 Ο. -CN '"3 3 -0SO3RJ -oso2r3 -nr3so2r4 -nr3c=nr4 -nr3co2r4 -NOo 5 10 15 wherein, relative to the above-named substituents, the groups R and R 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 heteroaxyl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from 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-menbered nitrogen-containing heterocyclic ring; R is as defined for R * 1 fl except that it may not be hydrogen; or wherein R and R taken together represent C2-C10 alkylidene or C2_c1q alkylidene substituted by hydroxy; A is Cj-Cg straight or branched chain alkylene; R3 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group as hereinafter defined, providing that 20 2 21 55225 when R is hydrogen or a protecting group, there is also present a counter anion, and R10 and R11 each independently represents an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, heteroeyclyl, heterocyclyl-aliphatic, heteroaryl or heteroaraliphatic radical of the following categories "(a)"-"(d)": (a) Cji-Cg alkyl, Cj-Cg alkenyl, Cj-Cg alkynyl, C3~Cg cycloalkyl 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, C^-Cg alkoxy, Cj-Cg alkanoyloxy, carboxy, C^-Cg alkoxycarbonyl, amino, C^-Cg alkylamino, di (Cj-Cg) alkyl ami no, Cj-Cg alkanoylaraino, phenyl, phenyl substituted by 1-3 halo, C^-Cg alkoxy, Cj-Cg alkyl, carboxy, carboxy(C^-Cg)alkyl, amino, C^-Cg alkylamino, di (Cj-Cg) alkylamino or di-{C^-Cg)alkylamino(C^-Cg)alkyl, halo or oxo; (b) phenyl optionally substituted by 1-3 halo, Cj-Cg alkoxy, Cj-Cg alkyl, carboxy, amino, Cj-Cg alkylamino or di(Cj-Cg)alkylamino groups; (c) heteroeyclyl or heterocyclylalkyl wherein the heterocyclic moiety is a 4-6 roembered ring having 1-3 hetero atoms selected from Ο, N and S and the alkyl moiety has 1-6 carbon atoms, said heteroeyclyl or heterocyclylalkyl ring being optionally substituted by 1-3 C^-Cg alkyl or Cj-Cg 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 Ο, N and S and the alkyl moiety has 1-6 carbon atoms, said heteroaryl or heteroaralkyl ring being optionally substituted by 1-3 C^-Cg alkyl, Cj-Cg alkoxy, carboy, carboxy(C^-Cg) alkyl, amino, C^-Cg alkyl- 5522S amino, difC^Cg) alkylamino, aminotCj-Cg)alkyl or diCCj-Cg)-alkylaraino(Cj-Cg)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 Ο, N and S, said heterocyclic - ring being .optionally substituted by 1-3 substituents independently 10 selected from: Cj-Cg alkyl optionally substituted by 1-3 hydroxy, 15 20 25 Cj-Cg alkoxy, carboxy, halo, amino, C^-Cg alkylamino or di(Cj-Cg)alkylamino groups, hydroxy, C^-Cg alkoxy, C^-Cg alkanoyloxy, amino, C^-Cg alkylamino, di(Cj-Cg)-alkylamino, Cj-Cg alkanoylamino, carboxy, C^-Cg alkoxy-carbonyl, halo, όχο or jSieryl; or wherein said heterocyclic ring Θ R10_g_Rll is fused to a benzene or other C5-Cg carbocyclic ring, a 5-6 membered heterocyclic ring or a 5-6 membered heteroaryl ring, all of which rings may be optionally substituted by 1-3 of the substituents referred to .above for the © r10_S^,r11 ring; and pharmaceutically acceptable salts thereof.

The compounds of formula I are potent antibacterial agents or intermediates useful in the preparation of such agents.

Also included in the invention are processes for preparing the novel carbapenem derivatives described above and pharmaceutical compositions containing the biologically active carbapenem derivatives in combination with pharmaceutically acceptable carrier or diluents. 23 55225 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 5 derivatives. Alternatively, the compounds may be considered to have the basic structure O 1 and named as 7-oxo-l-azabicyclo(3,2.0)hept-2-ene-2-carboxylic acid derivatives. While the present invention includes com-10 pounds wherein the relative stereochemistry of the 5,6-protons is cis as well as trans, the preferred compounds have the 5R,6S (trans) stereochemistry as in the case of thienanycin.

The compounds of formula I may be unsubstituted in the 6-position or substituted by substituent groups, 15 as defined herein. More specifically, R8 may be hydrogen and R1 may be hydrogen or a non-hydrogen substituent, as specified herein. Alternatively, R8 and R1 taken together may be C2~C10 alkylidene or C2~cio altyUdene substituted, for example, by hydroxy. 8 To elaborate on the definitions for R and R : (a) The aliphatic "alkyl", "alkenyl" and "alkynyl" groups may be straight or branched chain having 1-10 carbon atoms; preferred are 1-6, most preferably 1-4, carbon atoms; when part of another substituent, e.g. as in cycloalkylalkyl, or 24 55225 heteroaralkyl or aralkenyl, the alkyl, alkenyl and alkynyl group contains 1-6 e.g. 1-4, carbon atoms. (b) "heteroaryl" includes mono-, bi- and polycyclic aromatic heterocyclic groups containing 1-4 Ο, N or S atoms; 5 preferred are 5- or 6-membered heterocyclic rings such as, e.g. thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, iso-thiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl and pyrazolyl. (c) "heterocyclyl* includes mono-, bi- and polycyclic saturated or unsaturated non-aromatic heterocyclic groups containing 1-4 Ο, N or S atoms; preferred are 5- or 6-membered heterocyclic rings such as, for exarqple, morpholinyl, piperazinyl, piperidyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 15 pyrrolinyl and pyrrolidinyl. (d) "halo" (used also to define R^° and R^) includes chloro, bromo, fluoro and iodo and is preferably chloro or bromo.

The term "conventional readily removable carboxyl pro-20 tecting group" refers to a known 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 the remaining portion of the molecule, e.g. by chemical 25 or enzymatic hydrolysis, treatment with chemical reducing agents under mild conditions, irradiation with ultraviolet light or catalytic hydrogenation. Such ester protecting groups are benzhydryl, p-nitrobenzyl, 2-naphthylmethyl, benzyl, trichloroethyl, silyl such as tri-30 methylsilyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl, 4-pyridylmethyl and C^-Cg alkyl such as methyl, ethyl or t-butyl. Included within such protecting groups are those 25 25 55225 which are hydrolyzed under physiological conditions such as pivaloyloxymethy 1, acetoxymethyl, phthalidyl, indanyl and methoxymethyl. A particularly advantageous carboxyl protecting group is p-nitrobenzyl which may be readily 5 removed by catalytic hydrogenolysis.

The pharmaceutically acceptable salts referred to above include the nontoxic acid addition salts, e.g. salts with mineral acids such as, for example, hydrochloric, hydrobranic, hydroiodic, phosphoric and sulfuric,and salts with 10 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 salts may be written as 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 the case of intermediate compounds of formula X, X ® may also be a toxic anion. In such a case the ion can be subsequently removed 2Q or substituted by a pharmaceutically acceptable anion to form an active end product for therapeutic use. When acidic or basic groups are present in the R^ group or on the R*-0 or R11 substitutents, the. present· invention may also include suitable base or acid salts of these functional groups, e.g, 25 acid addition salts in the case of a basic group and metal salts (e.g. sodium, potassium, calcium and aluminum), the ammonium salt and salts with nontoxic amines ( e.g. tri- 26 53235 alkylamines, procaine, dibenzylamina, 1-ephenamina, N-benzyl- 8-phenethylamine and Ν,Ν'-dibenzylethylenediamine) in the 5 10 case of an acidic group. Compounds of formula X 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 compounds of formula I are valuable intermediates which can be converted into the above-mentioned biologically active compounds. A preferred embodiment of the present invention com- 8 1 prises compounds of formula X wherein R is hydrogen and R is hydrogen, CH3CH2~, CH CH-, CH* CH^fH CH,''*" or CH3CH- 15 Among this subclass, the preferred compounds are those in which R1 is OH CHjCH-, most preferably compounds 20 having the absolute configuration 5R, 6S, 8R. Another preferred embodiment comprises compounds of 1 8 formula I in which R and R taken together form an. alkylidene radical of the formula HOCH c» The alkylene (i.e. substituent "A") radical in the compounds of formula X may be straight or branched chain and may contain from 2 to. 6 carbon atoms, A preferred embodiment comprises those compounds in which A is -(CH^)^- in which n is 2, 3 or 4 and a particularly preferred embodiment comprises those compounds where λ is -CH^CH^-· 25 27 27 55885 The 2-substituent of the present compounds is characterised by the presence of a sulfoniua group attached to the alkylene radical λ. As indicated above, R1® and R11 may each independently be selected from optionally sub-5 stituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, heterocyclyl, heterocyclyl-aliphatic, heteroaryl or heteroaraliphatic. Alternatively, the R*® and R** substituents when taken together with the S0 10 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 additional heteroatoms selected from 0, N and S. In the latter case where 0 R10-S-Rn 15 represents a heterocyclic ring, the ring may also be fused to a benzene or other Cg-Cg carbocyclic ring, or a 5-6 membered heteroaryl ring (containing 1-4 Ο, N or S) and any of such fused rings may also be Optionally substituted.

The aliphatic R^® and/or R*^ substituents may be 20 Cj-Cg alkyl, Cj-Cg alkenyl or C2-Cg alkynyl. Cycloaliphatic substituents may be C3-Cg cycloalkyl while cycloaliphatic-aliphatic may, e.g. be C^-Cg cycloalky 1-c^-Cg alkyl. Such aliphatic,. cycloaliphatic and cycloaliphatic-aliphatic substituents may be unsubstituted or substituted 25 (preferably by 1-3 substituents) by the following: hydroxy, Cj~Cg alkoxy, Cj-Cg alkanoyloxy, carboxy, C^-Cg alkoxycarbonyl (e.g. -?-oc2H5 or -§-0C3H7), amino, Cj-Cg alkylamino, di(Cj-Cg)-alkylamino, C^-Cg alkanoylamino, phenyl, phenyl substituted by 1-3 or 1-2, halo, G1-Cg alkoxy, 88 552^5 Cj-Cg alkyl, carboy, carboxy-C^-Cg alkyl, amino, Cj-Cg alkylamino, di(Cj-Cg) alkylamino or di(Cj-Cg) alkylamino-(Ci-Cg)alkyl, halo or oxo.

The R1,0 and/or R^* substituents may also be aryl 5 (Cg-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, Cj-Cg alkoxy, Cj-Cg alkyl, carboxy, amino, C^-Cg alkylamino and di(Cj-Cg)alkylamino.

When R10 and/or R11 represent heterocyclyl or hetero- cyclyl-aliphatic, the heterocyclyl moiety may be a 4-6 membered non-aromatic ring containing 1-3 hetero atoms selected from Ο, N and S. The aliphatic moiety associated with heterocyclyl-aliphatic is preferably Cj-Cg alkyl. The heterocyclic ring 15 of such groups may be unsubstituted or substituted by 1-3, preferably 1-2, C^-Cg alkyl or C^-Cg alkoxy substituents.

When R*·® and/or R11 represents heteroaryl or hetero-araliphatic, the heterocyclic moiety is a 5-6 membered aromatic ring containing 1-3 hetero atoms selected from 20 ο, N and S and the aliphatic (preferably alkyl) moiety has 1-6 carbon atoms. The heteroaryl ring of such substituents may be unsubstituted or substituted by 1-3, preferably 1-2, substituents selected from C^-Cg alkyl, C^-Cg alkoxy, carboy, carboxy(C^-Cg)alkyl, amino, (Cj-Cg)alkylamino, diK^-Cg)alkyl-25 amino, amino (Cj-Cg) alkyl and di (Cj-Cg) alkylamino (Cj-Cg) alkyl.

The R*° and R^ substituents taken together with the S ©to which they are attached may also represent a 4-6 member sulfur-containing heterocyclic ring containing b-2 double bonds and 0-2 additional heteroatoms selected from Ο, N and S, said ring being attached to the alkylene (A) group through a sulfur atom, thereby forming a sulfonium group. The heterocyclic ring formed by ® R10—R11 30 29 5 10 15 20 25 may be unsubetituted or substituted by 1-3, preferably 1-2, substituents selected from: Cj-Cg alkyl optionally substituted by 1-3 hydroxy, Cj-Cg alkoxy, carboxy, halo, amino, Cj-Cg alkylamino or di(Cj-Cg)alkylamino groups; hydroxy; Cj^-Cg alkoxy; Cj-Cg alkanoyloxy; amino; C^-Cg alkylamino; di(C,-Cc)alkylamino; 1 » C^-Cg alkanoylamino; carboxy; Cj-Cg alkoxycarbonyl; halo; oxo; and phenyl. The heterocyclic ring may also be fused to a Cg-Cg carbocyclic ring, a phenyl ring, a 5-6 member heterocyclic (containing 1-4 hetero atoms selected from Ο, 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 rings may be optionally substituted by 1-3, preferably 1-2, of the substituents described above in connection with the sulfur-containing heterocyclic ring. A particularly preferred embodiment of the present invention comprises compounds of formula I wherein either (a) R1® and R^ each independently represents Cj-Cg alkyl or (b) R1® and R^ taken together with the S© to which they are attached represent or and 55225 30 30 55225 pharmaceutically acceptable salts thereof.

Examples of preferred 2-substituents wherein R10 and R11 are alkyl include CH, -s-ch2ch2-s CH.

©/CH3 -S-CH 2CH 2CH2-S.

^C2H5 Θ .C2H5 -S-CH2CH2CH2CH2-S a\ * -S-CH0CH,-S —i"Pr°Py1 'i-propyl 2 2 -S-CH2CH2-S ©yCSBll C5H11 Λ -s-ch2ch2ch2ch2ch2ch2-s· α, 10 and -s-a2a2a2a2a2-s: © ^C2H5 C2H5 within this subclass, the preferred compounds are those wherein A is -(a,) - in which n is 2, 3 or 4, most preferably those in 4 n 18 which A is -α2α2~ and wherein either (a) R and R taken together represent HOa- a 8 1 or (b) R is hydrogen and R represents hydrogen, CHj-CH^-, 15 31 CH 3\ CH- CH, CH, OH or CH,^ ohcajx- . 55225 .8 Particularly preferred are the compounds wherein R is hydrogen and R3 is OH CHgCH-, preferably compounds having the absolute configuration 5R, 6S, 8R.

A most preferred embodiment of the present invention comprises compounds of formula I wherein lfl ® IT R"f —IP represents 10 15 O ., and pharmaceutically acceptable·salts thereof. 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 1 8 -CH2CH2- and wherein either (a) R and R taken together represent HOCH- ch3 8 1 or (b) R is hydrogen and R represents hydrogen, CH^CHj-, CH, CH' CH3vJj)H oh "c-. , C- or ' / 3 CH, Particularly preferred are the compounds wherein Re is hydrogen and R3, is OH CH3^H-, preferably compounds having the absolute configuration 5R, 6S, 8R. 32 55225 The most preferred embodiment: of the present invention comprises the compounds of the formula wherein R2 is hydrogen, an anionic charge or a conventional * readily removable carboxyl protecting group as hereinbefore defined, 5 providing that when R is hydrogen or a protecting group, there is also present a counter anion, and pharmaceutically acceptable acid addition salts thereof.

It will be appreciated that when R20 and R22 in formula 10 x are different, there may be formed both the R and S optical isomers of such compounds 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-substituent may in certain cases, e.g. as in hydroxyethyl, 15 be in either the rot S configuration and the resulting isomers as well as epimeric mixtures thereof are encompassed by the present invention.

The carbapenem derivatives of general formula X are prepared from starting materials of the formula wherein R1 and R8 are defined above and wherein R2' represents 33 S5225 a conventional readily removable carboxyl protecting groups. Compounds of formula III have been disclosed, for example, in Patent Specification No. 52,661 (compound T) and may be prepared by the general methods described therein.

The process for preparing compounds X from starting materials XXX may be summarized by the following reaction scheme: 34 5 5 2^5 R1 2 3 4 Η nr -A-OSOjCHj COOR VI R4 H ,10 -A-I II 11 COOR --------λ Ag+ X " ' -11 ·optional de-Blocking ,10 > To elaborate on the above process, starting material III 2 is reacted in the inert organic solvent such as methylene chloride, acetonitrile or dimethylformaraide with about an equimolar amount of diphenyl chlorophosphate in the presence of 3 a base such as, for example,diisopropylethylamine, triethylamine or 4-dimethyl-aminopyridine to give intermediate IV. The acylation 4 to establish the diphenylphosphoryloxy leaving group at the 35 56225 2-position of intermediate HI is advantageously carried out at a temperature of from -20° to +40* c, most preferably at about 0*C. Intermediate IV may be isolated if desired, but is conveniently used for the next step without isolation 5 or purification.

Intermediate XV is next converted to intermediate V by a conventional displacement reaction. Thus, intermediate IV may be reacted with approximately an equimolar amount of a mercaptan reagent of the formula 10 HS-A-OH wherein A represents C2-Cg straight or branched chain alkylene in an inert organic solvent such as dioxane, dimethylformamide, dimethylsulfoxide or acetonitrile and in the presence of a base such as diisopropylethylamine, triethylaraine, sodium 15 hydrogen carbonate, potassium carbonate or 4-diraethylamino- pyridine. The temperature for the displacement is not critical, but an advantageous temperature range is from -40°c to 25°C. Host conveniently, the reaction is carried out with cooling, e.g. at about 0*C.

Intermediate V is then acylated with methanesulfonyl chloride or a functional acylating equivalent thereof such as methanesulfonic acid anhydride in an inert organic solvent and in the presence of base to provide the roethanesulfonyloxy leaving group .of intermediate VI. The acylation is carried out in an 25 inert organic solvent such as tetrahydrofuran, methylene chloride, acetonitrile or dimethylformamide and in the presence of a suitable base such as, for example, diisopropylethylamine, tri-ethylamine and 4-dimethylaminopyridine. The reaction may be carried out over a wide temperature range, e.g. -40*C to +40*C, 30 but is most advantageously conducted with cooling, e.g. at -30*C to -40*C.

Intermediate VI is next subjected to a displacement reaction so as to provide in intermediate II the iodo leaving group. This particular group has been found to greatly facilitate preparation of the carbapenem end-products of formula i. 36 55225 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 eam-5 pound which ionizes in the solvent employed to provide iodide ions may be used, e.g. an alkali metal iodide such as Nal or KI. The temperature for the displacement is not critical, but temperatures of room temperature or above are most advantageous for achieving completion of the reaction in a reason-10 able time period. The source of iodide ions is employed in an amount so as to provide approximately an equivalent or excess of iodide ion relative to intermediate VI.

Preparation of the desired carbapenems derivatives of formula X is carried out by a nucleophilic displacement of 15 the iodo leaving group of intermediate II by the desired sulfide of the general formula S Intermediate XI is reacted with at least an equivalent, preferably an excess, of the desired sulfide in an inert.organic 20 solvent and in the presence of silver ion. Suitable inert organic -solvents include, for example, tetrahydrofuran, dioxane, methylene chloride, diglyme and dimethoxyethane.

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. AgClO^. Generally, we prefer to use approximately an equivalent amount (relative to intermediate XI) of silver ion to.facilitate the displacement. The reaction may be carried out aver a wide temperature range, e.g. from -25*C to + ‘25eCr but is preferably conducted at around 0°C. 37 55225 intermediate 1' will have a counter anion (derived from the silver salt used) associated with it which may at this stage be substituted by a different counter anion, e.g. one which is pharmaceutically acceptable, by conventional 5 procedures. Alternatively, the counter ion may be subsequently removed during the de-blocking step.

The de-blocking step to remove the carboxyl protecting 2· group R of intermediate I1 is accomplished by conventional procedures such as solvolysis, chemical reduction or hydro-10 genation. Where a protecting group such as p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl is used which can be removed by catalytic hydrogenation, intermediate 1' in a suitable solvent such as, e.g. diaxane-water-ethanol or tetrahydro-furan-aqueous dipotassium hydrogen phosphate-isopropanol 15 may be treated under a hydrogen pressure of from 1 to 4 atmospheres in the presence of a hydrogenation catalyst such as, e.g. palladium on charcoal, palladium hydroxide or platinum oxide at a temperature of from 0 to 50°C for from . 0.24 to 4 hours. When R is a group such as o-nitro- 20 benzyl, photolysis may also be used for deblocking. Protecting groups such as 2,2,2-trichloroethyl may be removed by mild zinc reduction. Similarly, other conventional carboxyl protecting groups may be removed by methods known to those skilled in the art. · Finally, as mentioned above, compounds of 25 formula I* where*R2 is a physiologically hydrolyzable ester such as, e.g. acetoxymethyl, phthalidyl, indanyl, pivaloyloxy-methyl or methoxymethyl may be administered directly to the host without de-blocking since such esters are hydrolyzed in vivo under physiological conditions.

X 8 it will be understood that where the R and/or R substituent or the heteroaramatic nucleophile attached to substituent 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 35 38 55225 groups and procedures for introducing and removing such groups are well known to those skilled in the art.

As in the case of other β-laetara antibiotics, compounds of general formula I may be converted by known 5 procedures to pharmaceutically acceptable salts which, for . purposes of the present invention, are substantially equivalent to the non-salted compounds. Thus, for example, 2 one may dissolve a compound of formula X wherein R is an anionic charge in a suitable inert solvent and then add 10 an equivalent of a pharmaceutically acceptable acid. The desired acid addition salt may be recovered by conventional procedures, e.g. solvent precipitation, or lyophilization.

Where other basic or acidic functional groups are present in the compound of formula X, pharmaceutically acceptable 15 base addition salts and acid addition salts may be similarly prepared by known methods, 2 A compound of formula X where R is hydrogen or an anionic charge, or a pharmaceutically acceptable salt thereof may also be converted by conventional procedures to a corres-20 ponding compound where R is a physiologically hydrolyzable ester group, or a compound of formula X wherein R^ is a conventional carboxyl'protecting group may be converted to the corresponding compound where* R2 is hydrogen, an anionic charge or a physiologically hydrolyzable ester group, or a 25 pharmaceutically acceptable* salt thereof.

The novel carbapenem derivatives of general formula X wherein R2 is hydrogen, an anionic charge or a physiologically hydrolyzable carboxyl'protecting group, or the pharmaceutically acceptable-salts thereof,, are potent antibiotics active against 30 various gram-positive* and gram-negative 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 disinfectants for destroying or 35 5S225 3 ί) inhibiting the growth 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 invention may be used alone or formulated as pharmaceutical compositions comprising, in addition to the active carba-penea ingredient, a pharmaceutically acceptable carrier or diluent. The compounds may be administered by a variety of 10 means; those of principal interest include: orally, topically or parenterally (intravenous or intramuscular injection).

The pharmaceutical compositions may be in solid form such as, e.g. capsules, tablets or powders or in liquid form such as solutions, suspensions or emulsions. Compositions for injection, 15 the preferred route of delivery, may be prepared in unit dose fora in ampules or in multidose containers and may contain formulatory agents such as suspending, stabilizing and dispersing agents. The compositions may be in ready to use form or in powder form for reconstitution at the time of delivery 20 with a suitable vehicle such as sterile water.

The dosage to be administered depends to a large extent on the particular compound being used, the particular composition formulated, the route of. administration, the nature and condition of the host and.the particular situs and organism being treated. 25 Selection of the-particular preferred dosage and route of- application, then, is left to the discretion of the therapist.

In general, however, the compounds may be administered parenterally. or· orally to mammalian hosts in an amount of from 5 to 200 mgA9/day. Administration is generally carried out in 30 divided 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 vitro and in vivo, and the low toxicity of the confounds, biological data is provided below relating to the preferred caxbapenem compound of the present invention, i.e. 3-[2-(1- 35 40 53225 tetrahydrothiophenium) ethy lthio] -6a- [ 1- (R) -hydroxyethyl] -7-oxo-l-azabicyclo[3.2.0]heph-2-ene-2-carboxylate prepared in Example 1.

In Vitro Rctivitv 5 λ sample of the above-identified carbapenem compound after solution in water and dilution with Nutrient Broth was found to exhibit the following Minimum Inhibitory Concentrations (M.I.C.) in mcg/ml versus the indicated microorganisms as determined by overnight incubation at 37aC by tube dilution.

N-Formimidoyl thienamycin was included as a comparison compound.

In Vitro Antibacterial Activity of Carbapenem Derivative of Example 1_ MIC (mcg/ml) 15 Organism New Compound N-Formimidoyl Thienamycin S. pneumoniae A-9585 0.002 0.004 S. pyogenes A-9604 0.004 0.001 S. aureus S. aureus A-9537 0.008 0.004 20 + 50% serum S. aureus A-9537 0.03 0.016 (Pen-res.) S. aureus A-9606 0.016 0.008 (Meth-res.) A15097 2 0.5 25 S. faecalis E. coli A20688 0.5 0.5 (10-4 dil.) E. coli A15119 - 0.03 0.016 30 do-3) E. coli A15119 0.06 0.03 (10~2) E. coli A15119 0.06 0.06 1 o H A20341-1 0.03 0.03 41 55225 In vitro antibacterial activity of carbapenem derivative of Example 1 - continued MIC (mcg/ml) Organism Mew Compound N-Formimidoyl Thienamvcin 5 E. coli (10-3) A20341-1 0.03 0.03 E. coll ΤίΡ^Γ A20341-1 0.06 0.13 X. pneumoniae A-9664 0.06 0.13 10 K. pneumoniae A20468 0.13 0.06 P. mirabilis A-9900 0.13 0.06 P. vulqaris A21559 0.03 0.03 P. morganii A15153 0.06 0.13 P. rettgeri A22424 0.25 0.25 15 S. marcescens A20019 0.06 0.03 E. cloacae A-9659 0.13 0.06 E. cloacae A-9656 0.13 0.06 P. aeruginosa A-9843A 1 1 P. aeruginosa A21213 0.25 0.25 20 B. influenzae A-9833 8 16 B. influenzae A20178 8 32 B. influenzae Α215Ϊ8 8 32 B. influenzae A21522 8 32 B. fragilis A22862 0.06 0.016 25 B. fragilis A22053 0.06 0.06 B. fragilis A22696 0.25 0.13 B. fragilis A22863 0.06 1 In Vivo Activity The in vivo therapeutic efficacy of the compound of 30 Example 1 and N-formimidqyl thienaraycin after intramuscular administration to mice experimentally infected with various organisms is shown in the following Table. The PDSg (dose in »gAg required to give protection to 50% of the infected mice) Is indicated. 4255225 c φ 6 4J Φ Φ U & U Φ ιΗ 3 Ο QJ 3 6 Φ Μ JJ C κ ο Λ σ»<ο» 6 μ C Φ Β μ Φ Φ »4 οίιη Q D. β ο| Η -Hi ^ * Ο Τ3 ο ο «Μ +» «*4 Ο Ν Φ Μ-Ι Φ C > Η Η 4J Ο Φ U Ο »4 Ο. >ι C Ο ·Η, <α ο 6 % ε c μ φ Ο -Η Ν X 1 &< 2 I <Μ Ο *0 CI g* I* ^Ο Μ φ β 01σ> ε c ΐ n Φ ο Ο* C3 ό aδ 5 S * ί 4Κ « * ΙΑ Η ο Μ \ σι • • • 1 41 ) • ο Μ ΡΜ A νο I ! * ιη Ο ο σι Η ΙΟ η (*· η • • • • ο «-# ΙΑ Η <η ρ* η • « β on tn «β jrj• · ο Η jovvovovoujinr^invov^T οοοοοοοοοοοο •4ΗΗΗΗΗΗΗΗΗΗΗκκκκκκκκκχκχ •-ΙΙΟΝ^ν^ηΝΑΐηηΑ ΙΟ οι « οι ο Η to ιη Φ Η ΙΟ φ ? 3 φ λ' I Η I I < < < «4 C4 Ο ΟΙ Ι> οι Ο ΙΟ ΙΟ <9 ΟΙ ΙΑ Η γ| Φ Η U) W) 1 W «Μ ΓΗ< < < < β ιη η η ττ οη ο ο ο» CJ I< < Η σι =ο σι -* Λ Ο Ο η 3 0 •Η »4 Η 3 Ο « Ο • β χη Η Ο (0 Ή C0 •Η •Η *ιΗ Η U Φ •Η 14 Φ c Ο Λ Φ Φ Φ φ Φ Φ 4J & 0 »4 Η 4» Μ Η -Η 3 Φ ο Ο ε 5 U ε • • • « » & 0« β. 5 2 °* < κ Φ Φ Φ Φ Φ Φ Ο Ο 0 C C C •Η Ή & fcy tr 3 3 3 >4 Vi Vi Φ Φ Φ Φ Φ Φ * . * ft ft. β.

I β •U U β * » Ο r-t * η* co «τ α β ο ο Μ ΟΙ -Η § < β X! ^ ιη Φ Ν (Ο ·* *0 GO β σ\ Φ < ο Q Ο Ο» σι 3 σι * * Ό α >4 Ο Λ +·ο * J5 η α 41 I U •Η r- 3 % \ο 0 Η J2 * ΙΑ Β Η ΙΑ • < •Η η *. Ό σι *σ Φ m C 4p ιη φ Φ *-4 Φ CM Η Μ < +> >4 Ο C Μ Ο α> -τ4 > -Uο Ο Ο Ο ·Η 73 C -υ α «ι μ Λ Ο α ο ν - 14 — Ο σι «μ σι - ιη <α ο Ο μ α < 3 Ο *U #-f +» 3 β Ό Ό Ο S 01 -Η 4Jla c Ο Ο•w ε α 4J τ' « ft φ Μ * Η 43 SS2ZS Toxicity The toxicity of the compound of Example 1 after intracranial administration to mice was determined and is shown in the following Table.

Toxicity After Intracranial Administration to Mice Compound *tD50 (mgAg) Highest Dose (mgAg) Without Clinical Signs of Toxicity Compound of Example 1 >40 *5 N-Foxmimidoyl Thienamycin 32 Ί/5 ‘Average of 25 mice/comDOund Blood Levels in Mice > After Intramuscular Administration Blood levels and the half-life of the compound of Exanple 1 after intramuscular administration of 20 mgAg in mice axe shown in the Table below.

Blood Level (uq/ml) Compound 10 20 . 30 45 60 90 Minutes after Administration *tl/2 (min) **AUC (pg.h/ml) Compound of Example 1 14.7 13.5 8.7 3,2 0.9 <0.6 9 7.4 W-Foxmimidqyl Thienamycin 12.6 9.9 7.3 2.6 0.7 <0.3 9 6 Compounds 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 ** ADC refers to the area under the curve 44 55225 Urinary Recovery The urinary recovery of the compound of Example 1 after intramuscular administration (20 mg/kg) to mice is shown in the following Table.

Urinary Recovery Intramuscular Administration of 20 mg/kg to Mice_ Percentage of Dose Recovered 0-3 3-6 6-24 0-24 10 Compound Hours After Administration Compound of Example 1 15.6 2.1 <0.2 17.7 + 2.9 N-Fonnimidoyl Thienamycin 12.1 0.1 <0.1 . 12.2+3.6 Compounds were solubilized in 0.1 M phosphate buffer pH 7. Values are from a single test; 4 mice per compound The following example illustrates but does not limit the scope of the present invention. 45 55225 Example 1 Preparation of 3-f2-(l-tetrahydrothiophenium)ethylthio1-6a-[1-(R)-hydroxyethyl]-7-oxo-l-azabicyclo[3.2,0]hept-2-ene-2-carboxylate A. p-Hitrobenzyl 3-(2-hydroxyethylthio)-6a-[1-(R)-hydroxy-ethyl] -7-oxo-l-azabicyclo [3.2.0]hept-2-ene-2-carboxylate i oa OH pNB 46 5 5 825 A solution of 1.69 g (4.85 nmole) of p-nitrobenzyl 6α-{1-(R)-hydroxyethyl0-3,7-dioxo-l-azabicyclo (3.2.0)hept-2-ene-2-carboxylate (1) in 20 ml of acetonitrile was cooled to 0*C under a nitrogen- atmosphere. A solution of 726 mg (7,18 5 mmole) of diisopropylethylamine in 2 ml of acetonitrile was added followed'by a dropwise addition of 1.51 g (5.60 mmole) of diphenyl chlorophosphate in 12 ml of acetonitrile over a period of 3 minutes. The resulting solution was stirred at 0* for 20 minutes to provide p-nitrobenzyl 3-(diphenylphosphoryloxy)-6a-10 (1-{R)-hydroxyethyl)-7-oxo-l-azabicyclo (3.2.0)bept-2-ene-2- carboxylate. To this solution was added a solution of 726 mg (7118 mmole) of diisopropylethylamine in 2 ml of acetonitrile followed by a solution of 439 mg (5.63;mmole) of 2-mercapto-ethanol in 2 ml of acetonitrile. The reaction solution was 15 stirred at 0aC for 3 hours and then diluted with 200 ml of ethyl acetate and washed with 200 ml of water, 100 ml of 20% agueous and brine. Evaporation of the dried (MgSO^) solution gave a semisolid which was triturated with methylene chloride and filtered to yield 1.2 g (61% yield) of title product 2 as a 20 white amorphous solid.

NMR (DMS0-a6) 6:1.20 (3H, d, J-6.0 Hz), 2.9-3.2 (9S,m), 5.22(1H, d, J=8.5 Hz) and 8.23 (2H, d, J*8.5 Hz); ir (KBr) γζηβχ: 3500, 1770 and 1700 cm"1; Anal. Calc'd for ClgH20N2O7Ss C, 52.93; H, 4.94; H, 6.36;· 5,- 7.85. Founds C,· 52.83; H, 4.90·; S, 6.42; S, 8.31. 4? 4? B. p-Nitrobenzyl 3-(2-mathanesuifonvloxyethylthlo) - 6a-(1-(R) -hydroxyethyll-7-oxo-l-azabicvclo (3.2.0)hept-2-ene-2-carboxylate oh To a solution of 4,2 g (10.3 nmole) of 2 in 200 ml of tetrahydrofuran there was added at -40"C 1.3 g (11.3 imnole) of methanesulfonyl chloride followed by a dropwise addition of 1.26 g (12.4 nmole) of triethylamine in 5 ml of tetrahydrofuran, 10 The reaction mixture was stirred for 5 hours at -40*C, then stirred for 2 hours at -30*C under a nitrogen atmosphere and then poured into a mixture of ethyl acetate (700 ml) and 5% aqueous phosphoric acid.(1000 ml). The organic layer was washed with brine, dried oyer MgSO^, filtered and condensed to a syrup.

This material was purified by silica gel column chromatography (elution with methylene chloride-ethyl acetate (3:1 v/v)] to give 3.55 g (75% yield) of the title compound, as a white amorphous solid.

NMR (CDC13) 6: 1.25 (3H, d, JT-6.0 Hz), 3.05 (3H, s) ; 3,06-3,40 20 (5H, m), 4.05-4.40 (4H, m), 5.25 (1H, d, J-14,0 Hz), 5,50 (JH, d, J*14.0 Hz), 7.70 (2H, d, J-8.5 Hz) and 8,23 (2H, d, J-8,5 Hz); ir (KBr) ymax: 3400, 1770 and 1600 cm-1. Anal. Calc'd for C19H22M2°9S2s C‘ .46'90' Hf 4·56* s·76· round: C, 46,52; H, 4.32; U, 5.91. 48 55225 C. p-Nitrobenzyl 3-(2-io3oethylthio)-6α-[1-(R)-' hydroxyethy11 -7-oxo-l-azahicyclo (3.2.0) hept-2-ene-2-carboxylate λ solution of 350 mg (0.72 mmole) of intermediate 2 and 216 mg (1.4 mmole) of sodium iodide in 20 ml of acetone was heated at reflux for 4 hours. Evaporation of the acetone gave a white amorphous solid which was suspended in ether (10 ml)-10 water (10.ml). Filtration of the white solid and vacuum drying produced 300 mg (80% yield) of the title compound £ as a white amorphous powder.

HMR (DHS0-d6) .6: 1.18 (3H, d, J*6.0 Hz), 3.20-3.60 (7H, m) , 3.80-4.25 (2H, m), 5.10 (1H, d, J-5.5 Hz), 5.25 (1H, d, J-12.0 Hz), 5.45 (1H, d, J-12.0 Hz), 7.70 (2H, d, J*8.5 Hz), and 8.27 (2H, d, J»8.5 Hz); ir (KBr) ymax: 3S00, 1768 and 1700 cm~*; Anal. Calc'd .for C^H^N^Is C, 41.71; H, 3.70; N, 5.41; I, 24.48. Found: C, 42.10; H, 3.75; N, 5.97; 1, 23.20. 49 55225 D. 3-f 2-(l-Tetrahvdrothiophenlum)ethylfchio]-Sail-(B)-hydroxyethy 11 -7-oxo-1-azabicyclof3.2.0Ihept-2-ene-2-carboxylate 5 To a solution of pr-nitrobenzyl 3- (2-iodoethylthio) -6a- (1-{R) -hydroxyethyl] ,-7-oxo-l-azabicyclo [3.2.0 lhept-2-ene-2-carboxylate (104 mg; 0.2 mmole) in 5 ml of tetrahydrofuran 10 there was added tetrahydrothiophene (0.3 ml; 0.35 mmole) followed by a solution of silver 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 affording compound 5 as a yellow gum. This gum was 15 digested with 100 ml of CBLXTE to give an amorphous solid.

(The word "CELITE" is a Trade Mark) IR (KBr) ymax: 3400, 1772, 1700 2nd 1100 cm"1. Without any further purification, compound 5_ was hydrogenated as follows: To a suspended solution of compound £ 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 (35 mg; 0.2 mmole) in 20 ml of water. Then, 120 mg of 10% palladium on charcoal was added and 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 (2x5 ml). The combined filtrate and washing was extracted with ether (2 x 50 ml) and then lyophilized to give a yellow powder. This crude material was purified on a C^g 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 chromatography, and fractions having an ultraviolet absorption λ 300 nm were collected and lyophilized to give 12 mg (18% ID3X yield based on compound 4) of title product as a white solid.

NMR (D20)6: 1.23 (3H, d, J=6.0 Hz), 2.25-2.45 (4H, m), 3.0- 3.70 (11H, m), 3.95-4.30 (2H, m);,ir (KBr) ymax : 3400, 1760 and 1590 cm"1. UV X„,_ (CH,CH,GH) 289 nm (c»6200). max 4 4 In the present description and claims, the terms "heterocyclyl "heterocyclylalkyl1' and "heterocyclylaliphatic" are to be read as not including "heteroaryl, "heteroaralkyl" and "heteroaraliphatic", respectively.

Claims (16)

1. 51. 55235 1λ compound of the formula s—a—s; OOR Θ^κ1 2 3 Nr4 5 6 7 8 wherein R is hydrogen and R is selected from 5 hydrogen; substituted and unsubstituted; 2 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 3 moiety is phenyl and the aliphatic portion has 1-6 carbon 4 atoms; heteroaxyl, heteroaralkyl, heterocyclyl and hetero- 5 cyclylalkyl wherein the hetero atom or atoms in the above- 6 named heterocyclic moieties are selected from 7 1-4 oxygen, nitrogen or sulfur atoms and the alkyl 8 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 5255225 5 Cj-Cg alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -OR3 -OCNR3R4 Ϊ 3 4 —cnrjr’ 3 4 -NR k* /NR3 \r3r4 10 -so2nr3r4 ?l 3 4 -NHCNRR 1.4 R CNR - -co2r3 =o 15 -OCR -SR3 O -Ir*a 9 Ύo-CN· “N3 A 3 -OS03R -oso2r3 -nr3so2r4 20 53 55225 -NR1 2 3C«NR4 5 6 ϊ3 -NR4C02R7 -»02 wherein, relative to the above-named substituents, the groups R3 and R8 9 are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcydoalkyl, 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 1-Φ oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 3 4 1-6 carbon atoms, or R and R taken together with the nitrogen to which at least one is attached may form a 5-or 6-membered 9 3 nitrogen-containing heterocyclic ring; R is as defined for H 8 2 except that it may not be hydrogen; or wherein R and R taken 3 together represent C2~C10 alkylidene or C2"C10 alkylidene 4 substituted by hydroxy; λ is Cj-Cg straight or branched chain 5 alkylene; R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group as hereinbefore defined, providing that when is hydrogen or a protecting grow?, there is also present a counter anion, and R10 and R11 each independently represents 6 an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, heterocyclyl, heterocyclyl-aliphatie, heteroaryl or heteroaraliphatic radical of the following categories (a)·-·(d)": 7 (a) Cj-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-Cg cyclo 8 alkyl or cycloalkylalkyl having 3-6, carbon, atoms in the 9 cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety, 10 said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkyl- 11 alkyl group being optionally substituted by 1-3 substituents 54 independently selected from hydroxy, Cj-Cg alkoxy, C^-Cg alkanoyloxy, carboxy, C^-Cg alkoxycarbonyl, amino, Cj-Cg alkylamino, di(Cj-Cg)alkylamino, Cj-Cg alkanoylamino, phenyl, phenyl substituted by 1-3 halo, Cj-Cg alkoxy, Cj-Cg alkyl, carboy, carboxy(C^-Cg)alkyl, amino, Cj-Cg alkylamino, di(Cj-Cg)alkylamino or di-(Cj-Cg)alkylamino(Cj-Cg)alkyl, halo or oxo; (b) phenyl optionally substituted by 1-3 halo, C^-Cg alkoxy, C^-Cg alkyl, carboxy, amino, C-j-Cg alkylamino or di(C^-Cg)alkylamino groups; (c) heterocyclyl or heterocyclylalkyl wherein the heterocyclic moiety is a 4-6 membered ring having 1-3 hetero atoms selected from Ο, N and S and the alkyl moiety has 1-6 carbon atoms, said heterocyclyl or heterocyclylalkyl ring being optionally substituted by 1-3 C^-Cg alkyl or Cj-Cg 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 Ο, N and S and the alkyl moiety has 1-6 carbon atoms, said heteroaryl or heteroaralkyl ring being optionally substituted by 1-3 Cj-Cg alkyl, Cj-Cg alkoxy, carboxy, carboxy(Cj-Cg)alkyl, amino, C^-Cg alkylamino, di(C.-Cf)alkylamino, amino(C,-C-)alkyl or di{C,-C,)- 1 6 1 10 111 6 alkylamino(Cj-Cg)alkyl groups; or wherein R and R taken together with the Θ 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 Ο, N and S, said, heterocyclic ring being optionally substituted by 1-3 substituents independently selected from: 55 55225 Cj-Cg alkyl*optionally substituted by 1-3 hydroxy, Cj-Cg alkoxy, carboxy, halo, amino, C^-Cg alkylamino or dKC^-Cg)alkylamino groups, hydroxy, Cj~Cg alkoxy, C^-Cg alkanoyloxy, amino, C^-Cg alkylamino, ditC^-Cg)-alkylamino, C^-Cg alkanoylamino, carboxy, C^-Cg alkoxy* carbcnyl, halo, oxo or phenyl; or wherein said heterocyclic ring Θ R10—^—R11 10 is fused to a benzene or other a 5-6 membered heterocyclic ring or a 5-6 membered heteroaryl ring, all of which rings may be optionally substituted by 1-3 of the substituents referred to above for the © R10— Cg-Cg carbocyclic ring; ,11 ring; or a pharmaceutically acceptable salt thereof 15. 2λ compound according to Claim 1 wherein R^ is hydrogen, ch3ch2-CH CH- ch: C- or CH3CH- 3 1 8 λ compound according to Claim 1 wherein R and R taken together represent HOCH, CH, λ compound according to Claim 1 wherein RA is CH3CH- ?H 4 20. 5522S 5 6

2. 5. A compound according to Claim 1 wherein R1 is CH, ,5- and the absolute configuration is 5Rr 6S, 6R. 6. A compound according to Claim. 1, 2, 3, 4 or 5 wherein A is -CHjCHj-.

3. 7. A compound according to Claim 1, wherein R^ and R11 each independently represents C^-Cg alkyl? or wherein R1^ and R11 taken together with the ® b 10 to which they are attached represent«ο or -Ό or a pharmaceutically acceptable salt thereof. 8. λ compound according to Claim 7 wherein Rx is hydrogen, CHjCHj-, 15 CH CH- , CH, OHH- OH or ch3

4. 10. A compound according to Claim 7 wherein R1 is 20 CHgCH-

5. 11. A compound according to Claim 7 wherein R^ is ?H' CH3CH- and the absolute configuration is 5R, 6S, 8R.

6. 12. A compound according to Claim 7, 8, 9, 10 or 11 wherein 25 A is -CHjCHj-. 57 55225 13. λ compound according to any of Claims 7 to 12, wherein R1 2 3 and R11 taken with the S® to which they are attached represent Ό ' or a pharmaceutically acceptable salt thereof,

7. 14. A compound of the formula 2 wherein R ie hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group as hereinbefore defined, 10 providing that when R2 is hydrogen or a protecting group, there is also present a counter anion, or a pharmaceutically acceptable salt thereof. 2

8. 15. The compound according to Claim 14, wherein R is p~nitrobenzyl. 2

9. 16. The compound according to Claim 14, wherein R is an ,s anionic charge.

10. 17. A process for the preparation of a compound according to Claim 1, or a pharmaceutically acceptable salt thereof, which process comprises subjecting an intermediate of the 20 formula n R A-1 COOR‘ II eg . I wherein R , R and A are as defined in Claim 1 and RZ is a „10 conventional readily removable carboxyl protecting group to nucleophilic displacement in an inert organic solvent and in the presence of silver ion with a sulfide reagent of the formula 25 "·β“ 2 wherein R*® and R** are as defined in Claim 1 so as to dis 3 place the iodo group of intermediate II with the group 38

11. 5 S 2 2 5 θ R10 -V V1 and form a compound of the formula ,8 ,10 R11 and A, R' 2' R are as defined above, and, if desired, removing the car- 2' boxyl protecting group R to give the corresponding deblocked compound of the formula I, or a pharmaceutically acceptable salt thereof.

12. 18. A process for the preparation of a compound according 10 to Claim 1 or a pharmaceutically acceptable salt thereof, which process comprises the steps of (1) reacting an intermediate Of the formula III 59 55225 18 21 wherein R' and R are as defined in Claim 1 and R is a conventional 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 5 (2) reacting intermediate IV in an inert organic solvent and in the presence of base with a mercaptan reagent of the formula 10 HS-A-OH wherein A is as defined in Claim 1 to give an intermediate of the formula 1 8 2· wherein R , R , A and R , are as defined above; 15 (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 a-oso2ch3 R° H N - COOR VI 60 55235 18 2' wherein R , R , λ and R 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 fora 5 an intermediate of the formula R R8 H S-A-I COOR XX .- 1 a 9· wherein R , R , λ and R are as defined above; and 10 15 (5) subjecting intermediate XX to nucleophilic displacement in an inert organic solvent and in the presence of silver ion with a sulfide reagent of the formula /*10 ^R11 wherein R10 and R11 are as defined in Claim 1 so as to displace the iodo group of intermediate XX with the group © .R10 —§r ^R11 and form a compound of the formula 4Γ ©/R S-A-S 10 e ^R11 COOR wherein X© is a counter anion and R^ A. R10r R 11 2' 61 55225 and R are as defined above, and, if desired, removing 21 the carboxyl protecting group R to give the corresponding deblocked compound of formula I, or a pharmaceutically acceptable salt thereof. 5 19. A process as claimed in Claim 17, substantially as described in the foregoing Example.

13. 20. A carbapenem derivative according to Claim 1, prepared by a process as claimed in Claim 17, 18 or 19.

14. 21. A pharmaceutical composition containing a biologically 10 active carbapenem derivative as claimed in any of Claims 1 to 16, or Claim 20, together with a pharmaceutically acceptable carrier or diluent.

15. 22. A compound of the formula given and defined in Claim 1, or a pharmaceutically acceptable salt thereof, substant- 15 ially as hereinbefore described with particular reference to the accompanying Example.

16. 23. A pharmaceutical composition according to Claim 21, substantially as hereinbefore described. F. R. KELLY a CO., AGENTS FOR THE APPLICANTS.