NZ205626A

NZ205626A - Carbapenem antibiotics

Info

Publication number: NZ205626A
Application number: NZ205626A
Authority: NZ
Inventors: Un Kim Choung
Original assignee: Bristol Myers Co
Priority date: 1982-09-28
Filing date: 1983-09-16
Publication date: 1986-12-05
Also published as: AU1934283A; NO163284B; KR840006249A; GB2128187A; ES525983A0; IL69824A0; DE3334937C2; SE461734B; DD212255A5; OA07548A; YU43196B; HU191066B; CS247168B2; FR2533568B1; ZW20783A1; DK442383D0; NL8303310A; PT77404B; SE8305217L; SE8305217D0

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £05626 fi,.r IrL No.: Date: Priority Date(s): $4.,. %\ & Complete Specification Filed: . Class: <r.c?7. $ CJ. KI if. hi, 4/£.. Publication Date: ?.$ PJrP.$??. ■ • • P.O. Journal, No: 16SEPI985°| ; V^g^/GSA • • •. / NEW ZEALAND ■- TSTJiNTS ACT, 1953 / I I f COMPLETE SPECIFICATION 205626 "CARBAPENEM ANTIBIOTICS" ^We> BRISTOL-MYERS COMPANY, a Delaware Corporation, with offices at 345 Park Avenue, New York 10154, United States of America hereby declare the invention for which I / we pray that a patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- V 205 626 - 2 - background of the invention 1. Field of the Invention ■ The present invention is directed to new carbapenem antibiotics in which the 2-substituent has the formula o in which A represents a straight or branched chain alkvlene group; R5 represents an optionally substituted aliphatic, cyclo-aliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, hetero-aryl, heteroaraliphatic, neterocyclyl or heterocyclyl-aliphatic radical; and represents a nitrogen-containing aromatic beterocycle attached to the alkylene group a ?.t a ring carbon atom and quaternized by substituent 2. Description of the Trior Art A number of B-lactam derivatives containing the carbapenem nucleus 205626 - 3 - have been disclosed in the literature. These carbapenen derivatives have been reported to possess utility as antibacterial agents and/or S-lactaioase inhibitors. The initial carbapeiiero compounds .were natural products such as thiena^iycin of the formula * 5 " ^ ?:2CH2NH2 COOH 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 6-lactam antibiotics. Other natural products containing the carbapenea nucleus include olivanic acid derivatives such as antibiotic MM 13902 of the formula CH. hojso CH=CHNKCOCH. COOH J 1 205626 - 4 ~ disclosed in U.S. Patent 4,113,856, antibiotic MM 178B0 of the formula ho3so 2CH2NHCOC33 cooh disclosed in U.S. Patent 4,162,304, antibiotic MM 4550A of the formula -ch=chnhcoce. cooh disclosed in U.S. Patent 4,172,129 and antibiotic B9^)Ag' of'" the formula SCH 0 =chns(^ch. r~ "^iOOH J disclosed in U.S. Patent 4,264,735. In addition to the natural formula natural products, the compound desacetyl 890A^0 of the ji'> (tp\ f' -6 AUG 1984Vf 1 205626 - 5 - 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-occuring olivanic acids have also been synthesized, e.g. the compounds of the formula NHCOCH. wherein is a free, salted or esterified carboxyl group, n is 0 or 1 and is H, an acyl group 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 carbapenera derivative of the formula 205626 - 6 while O.K. Patent Application 1,598,062 reports isolation of the compound ^r-N CH2CH2NHCOCH3 "COOT from a Streptomyces fermentation broth. Carbapenems which are unsubstituted in the 6-position have also been synthesized. Thus, U.S. Patent 4,210,661 discloses compounds of the formula O COOH wherein R2 is phenyl or substituted phenyl, U.S. Patent 4,267,177 discloses compounds of the formula wherein R^ is an optionally substituted pyridyl group, U.S. Patent 4,25 5,4 41 discloses compounds of the formula I 205626 - 7 - -CR-=CR,R, 2 3 4 ^-COOH wherein R, and R, are H or alkyl and R, is NH-CO R- in which as 4 no Rg is alkyl-, phenyl or substituted phenyl and n is 1 or 2, and U.S. Patent 4,282,236 discloses comDOunas of the formula ^ N [=cRlR2 1200H I ■ wherein R^ .is H or alkyl and R£ is CN or CC^R^ in which R^ is H, alkyl, "aryl or aralkyl. Carbapenems of the general formula '—COOH 1 8 wherein R is H or acyl and R is H or substituted or unsub- stituted: alkyl, alkehyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkyIcycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, are disclosed in U.S. Patent 4,218,463. There is no disclosure of any 8 - heteroaraUcyL R substituents of the type in which A is alkylene and N-R" J 20 N— is a guaternized nitrogen-containing aromatic heterocycle attached to the alkylene group A at a ring carbon atom. 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 4,234,596. Total synthesis 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 European Patent Application 7973. a key intermediate in the disclosed synthetic methods is 'C02pNB 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 SCH2CH2N=C-N"H2 H "COOH disclosed in European Patent Application 6639; (2) N-heterocyclic derivatives of thienamycin having the formula 205626 - 9 - OH P and ,sch2C32N_ ~COOH II wherein: the bifunctional ring jnay contain additional unsaturaticn in the ring; and wherein' n is an integer selected from-1-6; p is 0, 1 or 2; R^" is H, alkyl or aryl? and Z is ixaino, oxo, H, amino or alkyl, disclosed in U.S. Patent 4,189, 493? (3) substituted N-methylene derivatives of thienasiy'cin having the formula OH N SCH,CH,N=C-X C003 wherein X and Y are H, H, OR, SR or Nr^R2 in which R is substituted cr uvjsubstituted; alkyl, alkenyl, alkynyl, cycloalkyl, cyclo-alkylalkyl, aryl, aralkyl, heterc-aryl, heteroaralkyl, hetero-cyclyl or heterocyclylalkyl, and R^" and R^ are H or Rr disclosed in U.S. Patent 4,19 4,047; (4) compounds of the formula % o AUu i984 3t-J, ft 205626 - 10 - sch2ch2nr1r2 cooe 3 1 ■> wherein R is aryl, alkyl, acyl or aralkyl and R .and R are independently selected from H-and acyl (including acyl of the type ,11 ... .11 -C-R in which R may. inter alia be alkyl substituted by a quaternary ammonium group, e.g. s , -C-CH. disclosed in U.S. Patent 4,226,870; (5) compounds of the formula ,3 SCHjCHJNRV COOH wherein R^ is H, acyl or an univalent optionally substituted hydrocarbon radical; R^" is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cyclo- alkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl and R is acyl (including acyl of the type 0 II -C-R m which R is alkyl substituted by a quaternary ammonium group, e.g. ° e f/ \ ) AUG 1984 2.0562.6 - ii - disclosed in U.K. Patent 1,604,276 (see also U.S. Patent 4,235,917); (6) compounds of the formula SCH2OJ2NR5R6R7 COO6 wherein R5, R6 and R7 are independently, selected from H and substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, are disclosed'in U.S. Patent 4,235,920? (7) compounds of the formula I ® 1 2 CH,CH,N-C=NR R 2 2 R6 cox wherein each of R^" and R2, independently of the other, is a radical of the type defined for R, a hydrogen atom, or a nitro, hydroxyl, alkoxyl, amino, C^_g alkylamino, di(C^_g alkyl)* amino or tri(C. , alkylamino) radical, an extra anion being 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 heteroaryl or heterocyclyl residue containing 4-10 ring atoms, one or more of which may be an additional hetero atcm selected from oxygen, sulphur and nitrogen; R is a cyano group or a substituted or unsubstituted carbamoyl, carboxyl, £^oxy) ~. carbonyl, alkyl, C2_1Q alkenyl, C2_1Q alkynyl, C3_1Q cyclo alkyl, C4 l2 cvcloalkylalkyl, C5 12 cycloalkylalkenyl, c3 , ^ .4" f\\ 1^.-6 AUG 1984 \v 205626 - 12 - cycloalkenyl, C5_12 cycloalkenvlalkenyl, C4_12 cycloalkenylalkyl, C6-10 ary1' C7-16 aralkyi- Cg_16 aralkenyl, Cg_16 aralkynyl or monocyclic or bicyclic heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl comprising 4 to 10 ring atoms one or more of which is a heterc 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; 1 2 the substituent or substituents on r, r , r or. on the ring 12 formed by joining r and r are chlorine; bromine; iodine; fluorine; azido; C^_4 alkyl; mercapto; sulpho; phosphono; cyanothio (-SCN); nitro;■cyano; amino; hydrazino; "amino.or hydrazino having up to three C^_g alkyl substituents; hydroxy; alkoxy; C^_g alkylthio; carboxyl; oxo; (C1_g alkoxy) carboiiyl; C2_1Q acyloxy; carbamoyl; (<^-4 alkyl) carbamoyl or di(C1_4 alkyl) carbamoyl; R^ is a hydrogen atom, an acyl radical or a radical of the type defined for R4; R4 is C1-10 alkyl; substituted carbonylmethyl; (C]__g alkoxy)-(C^_g alkyl), (C3_e cycloalkoxy)-(C^_g alkyl) ; C2-12 ^^anoyloxyalkyl; partially or completely h'alogenated alkyl in which the halogen (s) is/are chlorine, bromine or fluorine; aminoalkyl; C2^1Q alkenyl; C2_10 alkynyl; acyl; alkoxycarbonylalkyl; C4_2- dialkylaminoacetoxyalkyl; C2_j2 alkanoylaminoalkyl; ar-(C^_2 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 C^_g alkyl; aryl or nuclear-r substituted aryl containing 6 to 10 ring carbon atoms and in which any nuclear substituent is hydroxy, C^_g alkyl, chlorine, fluorine or bromine; aralkoxyalkyl; C2_^2 alkylthioalkyl; C4_^2 cyclo-alkylthioalky1; (C2_^q acylthio)-(C^_g alkyl); or phenylalkenyl in which alkenyl has 2-6 carbon atoms; R"' is substituted or v ' / 205626 - 13 - unsubstituted alkyl; C2_10 alkenyl or alkynyl; ring substituted and unsubstituted cycloalkyl, cycloalkenyl, cyclo--alkenylalkyl, and cycloalkylalkyi:having. 3-6 ring carbon atoms and up to 6 carbon atoms in any chain; 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, C^_g alkylamino/ di (C^g alkyl) amino or tri(C^_g alkylamino) radical, an extra anion being present in the latter case, hydroxy, C^_g alkoxy, C^_g alkylthioalkyl; carboxyl; oxo, (C^_g alkoxy) carbonyl; acyloxy; carbamoyl;- (<^,.4 alkyl)- carbamoyl; di(C, . alkyl) carbamoyl; cyanothio (-SCN) or nitro; 6 a—* ^ 2 R is hydrogen, hydroxy, mercapto, R, -OR, -SR or NR R , where R, R^" and R2 are as defined above; 4 4 X is hydroxy, mercapto, ammo, acyloxy -OR , -SR , -NHR4, -N-R4, R4 -OM, OQ or, when the compound is in zwitterionic form, -0 , in which case A is absent; A, when the -compound is not in zwittericr.ic form, is a counter ion; M is a pharmaceutically acceptable cation; and Q is a blocking group as herein defined, are disclosed in O.K. Patent 1> 604 , 275; and (8) compounds of the formula A % \ - 14 - wherein R e| a 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, -NRj, COOR, CONR2, -OR, or CN, are disclosed in European Patent Application 21082. Among the compounds disclosed in U.S. Patent 4,235,920 is S . e SCH2CH2N(CS3)3] A cooh wherein A is a pharmaceutical^ acceptable anion, The above-mentioned quaternary amine derivative is also described in Recent Advances in the Chemistry of E-Lactam Antibiotics, Royal 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. Carbapenem derivatives having a wide variety of 5-substituents in addition to those mentioned above have also been synthesized. Thus, for example, (1) European Patent Application 40408 discloses compounds of the formula m 205626 - 15 - wherein ^ is H, methyl or hydroxyl and R$1 is a monovalent organic group including inter alia heterocyclicalkyl; • (2) European Patent Application 8514 discloses compounds of the formula wherein R^ is an optionally substituted pyrimidinyl group and R2 is hydrogen or a group CR3R4R5 wherein R^ is hydrogen or hydroxy, R^ is hydrogen or alkyl and Rs is hydrogen, alkyl, benzyl or phenyl, or R^ and R^ together form a carbocyclic ring; (3) European Patent Application 38869 discloses compounds of the formula S 7 8 wherein R , R , and R are independently selected from the group consisting of hydrogen, substituted and unsubstitirted: alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkyIcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1~6 carbon atoms in the alkyl moieties; aryl, such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: \~ I 205626 - 16 - -X° halo (chloro, bromo, fluoro -OH hydroxy -OR"1" alkoxy, aryloxy 0 " 12 -OCNR R carbamoyloxy • 0 II J2 -CNR R carbamoyl I 2 -NR R amino yNR1 —\ amidino \r1r2 R1 -N02 nitro © -NCR"1") ^ tri-substituted amino (R^" group independently chosen) R1 ' 2 ... -C=N0R oxiim.no -SR"*" alkyl- and arylthio 1 2 -S02NR R sulfonamido 0 II i o -NHCNR R ureido 0 ill 2 -R CNR - amido -CO„H carboxy -C02R carboxylate 0 -CR1 acyl 0 " 1 -OCR acyloxy -SH mercapto '/ 20562$ 17 - 0 !Ll • -SR alkyl and aryl sulfinyl alkyl and aryl sulfonyl -L1 -CN cyano -Nj azido vherein, -relative-to the above listed substituents on R6,-R7., 8 1 2 and R the groups R and R are independently selected .from:' hydrogen, • alkyl,--alkenyl, and alkynyl, having from 1-1D. carbon .• atoms; .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 vherein the aryl moiety is phenyl-and the'aliphatic portion has 1-6 carbon atoms; heteroaryl,'heteroaralkyl, hetero-r \ cyclyl and heterocyclylalkyl and wherein the ,'hetero atom or atoms . in the _aboye-nair.ed heterocyclic moieties are selected from .the group consisting of 1-4 oxygen, nitrogen or sulphur atoms _ and wherein'the alkyl'moieties associated with said hetero- • cyclic moieties have 1-6 carbon atoms'. '{See also European . ■patent Applications 1627, 162B, 10317, 1799 237080 , 37081• and 370B2); (4) European Patent Application 24832 discloses . compounds of the formula ' '. L-6 AUG 1984 205626 101 - 18 - wherein R is H or a group selected from OH, 0S03H or ■ a salt or .C. . alkyl ester thereof, OR2, SR3, OCOR2, 3 3 2 OCO^R 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 C1-6 alkyl, C2-£ a3Jtenyl» c3_6 alkynyl wherein the triple bond is rot present on the carbon adjacent to the sulfur. atom, aralkyl, C, , alkanoyl, aralkanoyl, aryloxyalkanoyl or 12 arylcarbonyl, any of such R groups being optionally substituted, as antibacterial agents. European Patent Application 44170 discloses carba-penem derivatives of the formula (O) I n ^N=N S—X—N • >} wherein R is hydrogen or an organic group bonded via a carbon atom to the carbapenera ring, n is 0 or 1, X is a saturated or unsaturated hydrocarbon radical optionally 4 substituted by bromo or chloro, and R is a C^_g alkyl, C2~C6 alkenyl, aralkyl or aryl group, any of such groups R4 being optionally substituted. There is no disclosure, however, of any compounds wherein the tetrazole ring is bonded to X via a guaternized nitrogen atom, i.e. a positively charged nitrogen which is not attached to a hydrogen atom. European Patent Application 38,869 mentioned above discloses synthesis of the carbapenem derivatives via intermediates of the general formula /* (.',-6 AUG 1984 205626 - 19 - _7 N "^o2R2' wherein R6 and R7 are as defined above and R2 • is a readily removable carboxyl protecting group. Also disclosed as intermediates are compounds of the formula _,7 -N C02R wherein X is described as a leaving group. At the Gordon Research Conference on Medicinal Chemistry held at New London, New Hampshire on August 2-6, 19 82, a handout was distributed in which a variety of carbapenem antibiotics were disclosed. Among the compounds disclosed on page 9 of the handout is the carbapenem of the formula •O' which differs from the compounds of the present invention in that the quatemizea heteroaromatic ring in the 2-substituent is bonded directly to the sulfur atom instead of to the carbon atom of an alkvlene group. AUG 1984 - 20 - European Patent Application 50,334 discloses carbapenem derivatives of the general formula ,1 R6 nr U I? s-a-c-nr r "cooh wherein R6 and R*7 are, inter alia, independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl and aralkyl; A is a direct, single bond connecting the indicated S and C atoms, or A is a cyclic or acyclic connecting group selected, inter alia, from alkyl, cycloalkyl, aryl, heteroaryl or heteroalkyl; R1 and R^, which define the carbaminiidoyl function are, inter alia, independently selected from hydrogen, alkyl and aryl; additionally, said carbamimidoyl is characterized by .cyclic structures achieved by the joinder of the two nitrogen atoms via their substituents and by their joinder to connecting group A; additionally "carbamimidiunis" are disclosed by quaternization of one of the nitrogen atoms of said carbaminiidoyl. On page 12 of this application, there is disclosed as a possible 2-substituent the group ■ e i NR a -s-A-c ; NR1'' wherein R1 is defined as hydrogen, substituted and unsubstituted: alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalky1, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl and the two nitrogen atoms "participate in cyclic structures which are indicated by the dotted lines". No specific disclosure is provided of any cyclized carbamimidoyl groups containing a quaternized nitrogen atom, but page 22 does disclose a cyclized carbamimidoyl group of the formula 205626 - 21 - Based on the indicated definitions of substituent R\ applicant does not believe that European Patent Application 50,334 generically discloses any of his compounds. However, since the language in the reference application is so vague as to the nature of the intended cyclic structures, applicant is making this reference of record in the present application. While, as indicated above, the prior art has described carbapenem derivatives having a 2-substituent of the general formula -S-A-Het wherein A represents an alkylene group ana Het represents a heterocyclic or heteroaranatic group, there has been no disclosure of which applicants are aware teaching carbapenems wherein Het is a radical of the formula in which R^ is an optionally substituted aliphatic, cyclo-aliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, hetero aryl, heteroaraliphatic, heterocyclyl or heterocyclylaliphatic radical and represents a quaternized nitrogen-containing aromatic hetero-cycle bonded to the alkylene carbon via a ring carbon atom. As mentioned above, the carbapenem having - 22 - -S-CH2CH2N CH 2 \ 3 CH, as the 2-substituent has been reported as well as the carbapenem having a quaternized heteroaromatic ring bonded directly to the sulfur 2-substituent. 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 effects. The present invention provides a novel series of carbapenem derivatives characterized by a 2-substituer.t of the formula m which A represents a C,-C- straight or branched chain 5 alkylene group; R represents an optionally substituted slip, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclyl-aliphatic radical; and represents a q-uatemized nitrogen-containing aromatic hetero-cycle bonded to the alkylene group A via a ring carbon atom. More specifically, the present invention provides carbapenem derivatives of the formula summary of the invention V % ^6AU6S984 I •/ lift 205626 -23- © e N—R~ y g 1 wherein R is hydrogen and 'R is selected from the'group consisting of hydrogen; and substituted and unsubstituted: alkyl, alkenyl'' and alkynyl, having up to lo carbon atoms; cycloalkyl ana cyclo-alkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties'; phenyl; aralkyl, aralkenyl and aralkyrivl vherein the aryl moiety-is phenyl .and the aliphatic portion has up to 6 carfcon atcms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl vherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moieties associated with.said heterocyclic, moieties . have 1-6 carbon atoms; wherein the substituent or-substituents relatiye • to the above—named radicals are independently-seTeeted-rrom.the group consisting of - C^-C " alkyl optionally ^substituted by. amino, halo, hydroxy or carboxyl . •• halo • . ' -OH3 . -ocnr3r4 ' . ' ? 3 4 -CNR R -nr3r4 ~ 24 - 205626 o ft 34 -nhcnr r o 3ll 4 rjcnr*- -C02R3 -op(o)(or3)(or4) ~0 0 -ocr3 -sr3 0 » 9 -SR3 O ft 9 -SR* fl 0 -cn -n3 -0s03r3 o " 9 -os-r M o 0 3 (i q -nr s-r M 0 -nr3c=nr4 { 3 rj -NR3C02R4 and -NO 2 N.Z. PATENT OFFICE RECEIVED 1 205626 -25- wherein, relative to 'the above-named substituents, the groups R3 and R4 are independently, selected from hydrogen; alkyl, • alkenyl and alkynyl, having up to io 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 up to 6 carbon atoms; and heteroaryl, heteroaralkyl,- heterocyclyl and heterocyclylalkyl. wherein the hetero-atoia or atoms in.the above-named heterocyclic moieties are selected from' the" group consisting.of 1-4 oxygen,. nitrogen and/or sulfur atoms and the'alkyl moieties associated with 3 4 said heterocyclic moieties. have 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-raembered nitrogen-containing heterocyclic ring; 9 3 R is as defined for R except that it may not be hydrogen; or 1 8 wherein R and R taken together represent C2-C^0 alkylidene or <'2-C10 al*ylidene substituted by hydroxy; .R5 is. selected from the group consisting of substituted' and unsubstituted:• alkyl, alkenyl and alkynyl, having up to lo 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 up to 6 carbon atoms; heteroaryl, heteroaralkylt hetero-* cyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the ahove-named R5 radicals are optionally substituted by 1-3 substituents independently selected from: C.-Cc alkyl optionally substituted by amino, 1 o fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 r^T 23SEP J986 ■N. I * 205626 - 26 - -oco2r -ocor3 -oconr3r4 0 11 9 -os-r ll 0 -oxo 3 4 -NR R 3 4 R CONR - 3 4 -NR CO.R 3 3 4 -NR CONR R 0 3" 9 -NR S-R II 0 -SR3 O Q -S-R o o q -S-R -S0,R3 3 -CO-R 3 4 -CONR R -CN ; and phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, 3 _3„4 „3 _ „3 C^-C, alkyl, -OR , -NR"R 3 4 3 4 -CONR R , wherein R , R . tuents are as defined above; -SO-R , -C0„R and 9 5 and R in such R substi- 205626 - 27 - or R^ may be attached also to at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain one or more additional, preferably up to 2, hetero atoms selected from 0, N and S; R"*"^ is selected from the group consisting of hydrogen; and substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to io carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; spirocycloalkyl having 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms; -2«- •X- A is C^-Cg straight or branched chain alkylene; R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl 2 protecting group, providing that when R is hydrogen or a protecting group, there is also present a counter ion; and represents a substituted or unsubstituted mono-, bi- or poly-cyclic aromatic heterocyclic radical containing at least one nitrogen in the ring and attached to A through a ring carbon atom and having a ring nitrogen which is quaternized by the group R^ ; and pharmaceutical^ acceptable salts thereof. The compounds of formula I a_re potent antibacterial agents or intermediates useful in the preparation of such agents. Also included in the invention are processes for preparing the novel .carbapeneja derivatives described above and pharmaceutical compositions containing the biologically active carbapenem derivatives in combination vith" phantiaceutically acceptable carriers or diluents. DETAILED DESCRIPTION The novel compounds of general formula I above contain the carbapenem nucleus 1 ■ . i v, .. 205626 tm I -M- and ~.ay thus be named as l-carba-2-penem-3-carboxylic acid derivatives. Alternatively., the compounds may be considered to have the basic structure ^ and named as 7-oxo-l-azabicyclo (3. 2.0)he?t-2-ene-2-carboxylic acid derivatives. While the present invention includes compounds wherein the relative stereochemistry of 'the 5,6-protons '-s els as well as trans, the preferred compounds have the 5R,6S (trans) stereochemistry as in the case of thienamycin. The compounds of formula I may be unsubstituted in the S-position or substituted by substituent groups previously disclosed for other carbapenem derivatives. More soecifically, 3 1 R may be hydrogen and R may be hydrogen or a non-hydrogen substituent disclosed, for example, in European Patent Application 38,SS9 (see definition of Rg).' Alternatively, a,® and R~ taken together may be C2-Clo a^cY^dene or alkylidene' substituted, for example, by hydroxy. The compounds of formula I may also be unsubstituted at the 1-position (R1S=H) or substituted by substituent groups previously disclosed for other carbapeneia derivatives. More specifically, R15 may be hydrogen or any of the non-hydrogen 1-substituents disclosed for example, in European Patent Application 54,917 (see definition of R1 or R2 therein) or in U.S. Patent 4,350,631. Preferred non-hydrogen R1S substituents include C,-C, alkvl, most preferably methyl; phenyl; and 1 6 j_5 phenyl(C1"Cg)alkyl. The non-hydrogen R substituent may be in either the a- or 8- configuration, and it is intended that the present invention include the individual c- and 9- isomers, as well as mixtures thereof. The most preferred 1-substituted compounds are those having the S- configuration, especially those having the S-methyl substituent. \ 205626 -3o- 1 8 15 To elaborate on the definitions for R , R and R : (a) The aliphatic "alkyl", "alkenyl" and "alkynyl" groups may be straight or branched chain having up to 10 carbon atoms; preferred are up to 6, most preferably up to 4, . carbon groups; when part of another substituente. g. as in cycloalkylalkyl, or heteroaralkyl or aralkenyl, the alkyl, alkenyl and alkynyl group preferably contains up to 6, most preferably up to 4, carbon atoms. (b) "heteroaryl" includes mono-, bi- and polycyclic aromatic heterocyclic groups containing' 1-4 0, N and/or S . atoms; preferred are 5- or 6-membered heterocyclic rings such as thienvl, furyl, thiadiazolyl, oxaaiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolvl, isoxazolyl, N.Z. PATENT OFFICE 23SEP I . ; I 203626 -a- tetrazolyl, oxazolyl, py'ridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, etc. (c) "heterocyclyl" includes mono-, bi- and polycyclic saturated or unsaturated non-aromatic heterocyclic ' groups containing 1-4 O, N and/or s atoms; preferred are 5- or 6-membered heterocyclic rings such as morpholinyl, piperazinyl, piperiavl, pyrazolinyl, pyrazolidinyl, imidazolinyl, iroidazolidinyl, pyrrolinyl, pyrroliainyl, Cd) "halo" includes chloro, bromo, fluoro and iodo and is preferably chloro, fluoro or bromo. protecting 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 inolecrule, e.g. by chemical or enzymatic hydrolysis, treatment with chemical reducing agents under mild conditions irradiation with ultraviolet light or catalytic hydrogenation. Examples of such ester protecting groups include benzhydryl, ally!,-'p-nitrobenzyiv' 2-naphthylmethyl, benzyl, trichloroethyl, silyl such as trimethylsilyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitxobenzyl, 4-pyridylraethyl and C^-Cg alkyl such as methyl, ethyl or t-butyl. Included within such' protecting groups are those which are hydrolyzed under physiological conditions such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl. A particularly advantageous carboxyl protecting group is p-nitrobenzyl which may be readily removed by catalytic hydrogenolysis. etc. The'terro "conventional readily removable carboxyl 205626 The pharmaceutical^ acceptable salts referred to above include the nontoxic acid addition salts, e.g. salts with mineral acids such as hydrochloric, hydro- bromic, 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 fornula I in the form of acid addition salts nay be written as ,15 « R e —R X e coor2 R = H or protecting group where X^ represents the acid anion. The counter anion 2® may be selected so as to provide pharmaceutical^ acceptable salts fox therapeutic •'administration but,, in the case of intermediate compounds of formula I, 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 fora an active end product for therapeutic use. When acidic or basic groups are present in the R^" or R^ grout?-or 'Cn the radical, the present 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 (e.g. sodium, potassium, calcium and aluminum), the ammonium salt and salts with'nontoxic amines (e.g. tri-alkylanines, procaine, dibensylamine, 1-ephenamine/ N-benryl-5-phenethyla-mine, N,N'-dibenzylethylenediamine, etc.) in the case of an acidic group. f V • ■ ■ f 205626 V -3V Compounds of formula X wherein R is hydrogen, an Anionic charge or a physiologically hydrolyzable ester croup together with pharmaceutically acceptable salts thereof are useful as antibacterial agents. The "remaining con-pounds or formula I are valuable intermediates which can be converted into the above-mentioned biologically active compounds. A preferred embodiment of the present invention S comprises compounds of formula I wherein R is hydrogen and R* is hydrogen, CH^CE^ ch. CH-, CH, OH 3H- CH. OH I or CHCE- Among this 'subclass, the preferred compounds are those in which R is f most preferably compounds having the absolute configuration 5R, SS, SR. Another preferred embodiment comprises compounds of *'18 formula I in which R and R taken together form an alkylidene radical of the formula HOCH2^ ' c= CH. """ ch^ch- The alkylene (i.e. substituent "A") radical in the compounds of formula I may be straight or branched chain and may contain from 1 to 6"carbon atoms. A preferred embodiment comprises those compounds in which A is in which n is 1 or 2 and a particularly preferred embodiment those compounds where A is -CHj-* comprises j! °-6AliGt984 J 205626 -s*- The alkylene moiety "A" is attached via a ring carbon atom to an N-substituted quaternized aromatic heterocycle of the general formula wherein the R^ substituent is preferably an optionally substituted C-^-Cg alkyl, C2~C10 alkenyl, C2~Calkynyl, C^-Cg cycloalkyl, C3~Cg cycloalkyl-C^-Cg alkyl, phenyl, phenyl-C1~Cg alkyl, phenyl-C2-Cg alkenyl, phenyl-C2~Cg alkynyl, heteroaryl, heteroaralkyl in which the alkyl moiety has 1-6 carbon atoms, heterocyclyl or heterocyclylalkyl in which the alkyl moiety has 1-6 carbon atoms. The heteroaryl (or heteroaryl portion of heteroaralkyl) substituent may be a mono-, bi- or polycyclic aromatic heterocyclic group containing 1-4 O, N and/or S atoms; preferred are 5- or 6-membered heterocyclic rings such as thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, •isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pvrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl and pyrazolyl.- -The heterocyclyl (or heterocyclyl portion of heterocyclylalkyl) substituent may be a.mono-, bi- or polycyclic saturated or unsaturated non-aromatic heterocyclic group containing 1-4 0, N and/or s atcms; preferred are 5- or 6-membered heterocyclic rings such as morpholinyl, piperazinyl, piperiayl, pyrazolinyl, pyrazolidinyl, imiaazolinyl, imidazolidinyl, pyrrolinyl and pyrrolidiny1. The R5 substituent may-be optionally substituted by 1-3 substituents independently selected from: 205626 (a) (b) (c) (d) (e) (f) (g) (h) (i) (j) (k) (1) (m) (n) (o) (P) C^-Cg alkyl optionally substituted by, preferably 1-3, amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR3 -0C02R3 ; -OCOR3 ; -OCONR3R4 ; 0 II 9 -0S-R* ; II 0 -oxo ; 3 4 -NR R ; 3 4 R CONR - ; -NR3C0 R4 ; 3 3 4 -NR CONR R ; 0 3" 9 -NR S-R ll 0 -SR3 ; 9 -SOR* ; 0 II g -S-R ; 23Sfp i986 Jieceived (q) -S03RJ ; (r) -C02R3 ; (s) -CONR3R4 ; (t) -CN ; and (u) phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, ^-Cg alkyl, -OR3, -NR3R4, -S03R3, -C02R3 and -C0NR3R4, wherein, relative to the above-named R5 substituents, the groups 3 4 R and R are independently selected from hydrogen; alkyl, 20562® ' alkenyl and alkynyl, having- up to 10 carbon atoms; cyclop alkyl, 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 up to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroaryl and heterocyclyl group or portion of a group is as defined above for R and the alkyl moieties associated with said heterocyclic moieties have 1-6 3 4 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 nitrogen-containing heterocyclic (as defined 5 9 ' 3 above for R) ring;*'and R is as defined above for R 5 except that it may not be hydrogen. A most preferred R substituent is alkyl, especially methyl. In addition, the substituent, together with.another ring atom of the moiety, may form a fused heterocyclic or heteroaromatic ring, which ring may contain one or more additional, preferably 1 or 2, hetero atoms selected from 0, N and S. For example may be N.Z. PATENT OFFICE _ 2 3 SEP 1986 RECEIVED 205626 .> - >7 - The group preferably represents a substituted or unsubstituted mono-, bi-or polycyclic aromatic heterocycle containing at least one nitrogen in the ring and 0-5 additional ring hetero atoms selected from 0, S and N, said heterocyclic ring being attached to A through a ring carbon atom and having a ring nitrogen atom quaternized by the group . The heteroaromatic ring may be optionally substituted at available ring carbon atoms by preferably 1-5, most preferably 1-3, substituents independently selected from the group consisting of c^~c4 alkyl; C1-C4 alkyl substituted by, preferably 1-3, substituents independently selected from hydroxy, amino, C^-Cj alkylamino, di^-C^)alkylamino, Cj-C alkoxy, carboy, halo (hereinafter intended to mean chloro, bromo, fluoro or iodo; preferably chloro, bromo or fluoro)and sulfo; C^-Cg cycloalkyl; C_-Cg cycloalkyl (C-^-C^) alkyl optionally substituted by 1-3 substituents mentioned above in connection with C^-C^ alkyl; alkoxy; C^~C4 alkylthio; amino; C^-C^ alkylamino; di(C^-C^)alkylamino; halo; alkanoyl- amino; alkanoyloxy; carboxy; sulfo; 0 -C-0-C1-C4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C^-C^ alkyl, alkoxy, C^-C4 alkylamino, di (C^-C^ alkylamino, carboxy and sulfo; phenyl(C^-C^)-alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with alkyl; and heteroaryl or hetero aralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4 0, S and/or N atcnsand the alkyl moiety 205626 disassociated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethy1, C^-C^ alkyl, C^-C^ alkoxy, C^-C^ alkylamino, di (C-^-C ^) alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C^-C^ alkylamino, di (C^-C^) alkylamino, alkoxy, carboxy, halo and sulfo. In addition, available ring nitrogen atoms (other than the quaternized nitrogen) may be substituted by 1-3 substituents independently selected from the group consisting of C1~C4 alkyl; C^-C4 alkyl substituted by, preferably 1-3, substituents independently selected from hydroxy, amino, Cj-Cj alkylamino, di(C^-c4)alkylamino, C-^-Cj alkoxy, carboxy, halo and sulfo groups; C^-Cg cycloalkyl; c3"cg cycloalkyl(C^-C^)alkyl optionally substituted by 1-3 substituents mentioned above in connection with C]_~C4 phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C^-C4 alkyl, C^-C4 alkoxy, Ci-C4 alkylamino, di (C^-C^)alkylamino, carboxy and sulfo; phenyl(C1~C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C^-C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4 0, S and N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trif luoromethyl, C-j-C^ alkyl, C1~C4 alkoxy, C-^C^ alkylamino, di(C^-C^)alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, alkylamino, di(C1~C4)alkylamino, C^-C^ alkoxy, carboxy, halo and sulfo. The most preferred ring carbon and nitrogen substituents are C^-C^ alkyl, especially methyl. 160CTI986J'! 205626 -3<?- Within the above-described preferred embodiment, the preferred compounds are those in which A is -(ch2)- in which n is 1 or 2, most preferably those in which A is -CH2~ and wherein (a) R^" and R® taken together represent HOCH. CH. C= 8 l or (b) R is hydrogen and R represents hydrogen, CH,CH 3 2 CH CH3 OH CH- CH. '\l c- CH. oh , or CH caff articular ly preferred are the compounds wherein R8 is hydrogen and R^" is OH CH^CH- , especially compounds having the absolute configuration 5R, 6S, 8R. In a preferred embodiment the group represents an aromatic 5- or 6- membered, N-containing heterocyclic ring containing 0-3 additional hetero atoms selected from O, S and N. Such aromatic heterocycle may, where possible, be fused to another ring which may be a saturated or unsaturated carbocyclic ring, preferably a Ccarbocyclic ring, an aromatic carbocyclic ring preferably a phenyl ring, a 4-7 membered heterocyclic ring (saturated or unsaturated) containing 1-3 hetero atoms selected from O, S, N and NR11 in which R11 is hydrogen, ^-Cg alkyl optionally substituted by 1-2 substituents independently selected from -OR3, -NR3R4, -C02R3, oxo, phenyl, fluoro, chloro, bromo, N.Z. PATENT OFRCE 2 3nEP 1986 RECEIVED \ 1 205626 f 3 3 4 . -SO,R and -CONR R , or phenyl optionally substituted by 1-3 J 3 substituents independently selected from C^-Cg alkyl, -OR , -NR3R4, fluoro, chloro, bromo, -SO,R3, -CO,R3 and -CONR^R4, 3 4 11 wherein R and .R in such R substituents are as -defined above in connection with substituent r\ or a 5-6 -membered hete'ro- aroinatic ring containing 1-3 hetero atoms selected from 0, S, N and NR"^ .in which R11 is as defined above.. The 5- or 6- membered aromatic quaternized ring or, where appropriate, the carbocyclic, heterocyclic or heteroaromatic rang fused thereto, or both such rings, may be optionally substituted on available ring atoms by, preferably up to a total of five substituents for the total ring system, the substituents mentioned above in connection with the group o Within the above-described preferred embodiment, the • preferred compounds are those in which A is -(CH2)- in which n is 1 or 2, most preferably those in which A is -CH_- and 18 wherein (a) R and R taken together represent HOCH- 2n^c= CH^ or (b) R8 is hydrogen and R1 represents hydrogen, CH3CH2", CH ' CH, OH OH ■'x1 I CH- , C- , or CH,CH- . CH3 CH3 g Particularly preferred are the compounds wherein R is hydrogen and is ?H CH3CH-, especially, compounds having the absolute configuration 5R, 6S, 8R. I / 205626 -4-1- Still another- preferred embodiment of the comprises•compounds of formula I wherein present invention represents a radical selected from the group consisting of wherein R^, S? and R^ are independently selected .from hydrogen ; C^-C^ alkyl? alkyl substituted by, "preferably 1-3, hydroxy, C^-C^ alkylamino, difC^-C^ alkyl)amino, C^-C^ alkoxy, amino, sulfo,. carboxy or halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C^-Cg cycloalkyl; C^-C^ alkoxy; C^-C^ alkvlthio; amino; C^-C^ alkylamino; di(C^-C4' alkyl) amino;. halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); Cn-C^ aIkanovlamino; C^-C^ alkanoyloxy; carboxy; 0 ii -C-OC^-C^ alkyl; hydroxy; amiaino;-guaniaino; phenyl; phenyl substituted by one, two or three substituents independently selected from amino, halo (chloro, broiro, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trif luoromethyl, alkyl and C^-C^ alkoxy groups; phenyl (C^-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C2_~C4 alkyl.; .and heteroaryl and heteroaralkyl in which the hetero atom or atoms .in the above- • named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; or wherein two of R^, R^and taken together may be a fused saturated carbocyclic ring, a fused aromatic carbocyclic ring, a fused non-aromatic heterocyclic ring or a fused heteroaromatic ring, said fused rings being optionally substituted by 1 or 2 of the substituents defined above for R^ , R^ and R^; J 205626 (b) R el R J R ® I v cr optionally substituted on a carbon atom by one to three substituents independently selected from C^-Cj, ..alkyl; alkyl substituted by, preferably 1-3; hydroxy, C^.-C^ aLkyl2ru.no, sulfo, ditC^-C^ alky1)amino, C^~C4 alkoxy, amino, carboxy or halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C3~Cg cycloalkyl; C^-C^ alkoxy; C;]_~C4 alkylthio; amino; C^-C^ alkylamino; di (C^-C^ alkyl) a^iir.o; halo ' (chloro, bromo, fluoro or iodo; preferably .chloro, fluoro or bromo) ; alkanoylarai.no; alkanoyloxy; carboxy; 0 it . -C-OC^-C^ alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three substituents independently selected from amino, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl trif luoromethyl, C1~C4 alkyl and C^-C^ alkoxy croups;- ■ phenyl (C^-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C]_-C4 alkyl? .and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the grcuD consisting of 1-4 oxygen, nitrogen and/or"sulfur atoms and the alkvl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic-ring optionally substituted by 1 or 2 of the substituents defined above; s I 20562S -Vh- (c) N S^N R5 ®J .N N \ s N ^NS\\ J II N optionally substituted on a carbon atom by'one or two substituents independently selected from C^-C^ alkyl; C^-C^ alkyl substituted by, preferably 1-3, hydroxy, C^-C^ alkylamino, sulfo, di(C^-C^ alkyl)amino, C-^-C^ alkoxy, amino, carboxy or halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C3-Cg cycloalkyl; alkoxy; C-j-C^ alkylthio; 2mino;' C^-C4 alkylamino; ai(C^-C^ alkyl) amino; halo (chloro, bromo, fluoro or ioco; Dreferably chloro, fluoro or bromo); C,~C. 1 A alkanoylajnino; C-j_~C4 alkanoyloxy; carboxy; 0 i' . -C-OC^C^ alkyl; hydroxy; amidino; guanidino, phenyl; phenyl substituted by one, two or three substituents independently selected frcm amino, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or brato), hydroxyl, ' ( trifluoromethyl, alkyl and C^-C^ alkoxy groups; phenyl (C^-C^) alkyl in which the phenyl portion may be ~~ optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with alkyl.; .and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above; 205626 -4-4 (d) .T >1 or e I N Nf • N- opticnally substituted on a carbon atom by a substituent independently selected from C^-C^. alkyl;. alkyl substituted by, preferably■1-3, .hydroxy, ci"c4 alkyl^i11©/ difC^-C^, alkyl)-amino, sulfo, C^-C^ alkoxy, amino, carboxy or halo (ch-loro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C^-Cg cycloalkyl; C2_-C4 alkoxy; alkylthio; amino; cj_~c^ alkyl amino; aifC^-C^ alkyl)amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C-,-C^ alkanoylamino; C^-C^ alkanoyloxy; carboxy; O -C-OC^-C^ alkyl; hydroxy; amicino; guanidino., phenyl; phenyl substituted by one, two or three substituents independently selected from amino, halo (chloro, brono, fluoro. or iodo; preferably chloro, fluoro or brcno), hydroxyl, trifluoromethyl, C^-C^ alkyl and C^-C^ alkoxy groups; phenyl (C^-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C^-C^ alkyl.; .and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the g_oup consisting of 1-4 oxygen, nitrogen and/or sulfur atcms ana the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; ■*r- 205626 (e) -N-JT J or -N-R" wherein X is O, S or NR in which R is C,-C. alkvl; C,-C alkv1 14 *14 J substituted by 1-3 substituents independently selected frcm hydroxy, amino,. C^-C^ alkylamino, di (C-^-C,)alkylamino, C-^-C^ alkoxy, carboxy, halo and sulfo groups; C^-Cg cycloalkyl; C^-C^ cycloalkyl(C^-C^) alkyl optionally substituted by 1-3 substituents mentioned above in connection with C^-C^ alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy', trif luoromethyl, cq_~c4 alkyl, alkoxy, C^-C^ alkylamino, di(C^-C^)alkylamino, carboxy and sulfo; phenyl(C^-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be-optionally substituted by 1-3 substituents mentioned above in connection with alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4 O, S and/or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C1~C4 alkyl, C1~C4 alkoxy, C1~C4 alkylamino, di (C^-C^) alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C^-C4 alkylamino, di (C^-C^)alkylamino, C1~C4 alkoxy, carboxy, halo and sulfo; said heteroaromatic radical being optionally substituted on a carbon atom by one or more 'substituents independently selected from C^-C4 alkyl; alkyl substituted by, preferably 1-3, hydroxy, amino, C1~C4 alkylamino,' di (C,-C. alkyl)amino, C.-C alkoxy, sulfo, carboxy or halo 14 14 (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C^-Cg cycloalkyl; C1~C4 alkoxy; C1~C4 alkylthio; amino; C1~C4 alkylamino; di(C^-C4 alkyl)amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C^-C^ alkanoylamino; C^-C4 alkanoyloxy; carboxy; O II -C-OCC4 alkyl; hydroxy; amidino; N - / .. •; / 205626 -ti - cuanidino; phenyl; phenyl substituted by one, two or three substituents independently selected frcm amino, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluorcmethyl, C^-Cj alkyl and Cj-Cj alkoxy qroups; phenyl (Cj-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C^-C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms the alkyl moiety associated with said hetero aralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above; (f) R5- G -X 1 N~ I ~rr N N-R- ■ ft-?." N-R" or N- -N-R" x-^ wherein X is 0, S or NR in which R is alkyl; C^-C^, alkyl substituted by 1-3 substituents independently selected from hydroxy, amino, C^-C^ alkylamino, di(C^-C^)alkylamino, alkoxy, carboxy, halo and sulfo groups; C3~C6 cycloalkyl; C3-Cg cycloalkyl (C^C^) alky 1 optionally substituted by 1-3 substituents mentioned above in connection with C1~C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected fro:a amino, halo, hydroxy, trifluoromethyl, C^-C^ alkyl, alkoxy, C1~C4 alkylamino, ci (C^-C^) alkylamino, carboxy and sulfo; phenyl(C1-C4)alky 1 in which the phenyl portion -av be optionally ' N./. PATENT 2 3SEP 1906 - I 2056,26 substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by l-3 substituents mentioned ah>ove in connection with C -C alkvl* 14"*' and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected xrom the group consisting of 1-4 0, S and/or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy', amino, halo, trif luoromethyl, C1~C4 C1~C4 r Cl~CA ci (C^-C^) alkylamino, carboy a^d sulfo and in the alxvl moiety by 1-3 substituents selected from hydroxy, amino, alkylamino, di (C^-C^) alkylamino, Cx-C4 alkoxy,.. carboxy, halo anc sulfo; said heteroaromatic radical being optionally substituted on a carbon atom by a substituent selected from C1~C4 alkyl; C^-C^ alkyl substituted by, preferably 1-3, hydroxy, amino," C^-C^ alkylamino, ci(Cn-C4 alxyl)amino, ci~c4 alkoxy, sulfo, carboxy or halo (chloro, bromo., fluoro or iodo; preferably chloro, flucro cr bromo) ; C3~CS cycl°£-^y-^ CT~C4 £l^°xy; C1-C4 alkylthio; amino; C^-C^ alkylamino; c-(C^-C^ alkyl) amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro cr bromo) ; alkanovlamino; C^-C^ alkanoyloxy; carboxy; 0 -C-OC^-C^ alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or threesubstituents independently selected from amino, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluorcroethy 1, C^-C^ alkyl and C2-C4 alkoxy groups; phenyl (C^-C^) alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C^-C^ alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; and . ... fENI 0: • i • t 2.: Si i RECEIVE j 205626 -4-? - = c t- e (5) . N N-RJ R -N K _ J N-R J V V N N-R n-r n-r li1 J-R5 6 II or wherein R is C-j-C^ alkyl; C1-Cj} alkyl substituted by 1-3 substituents independently selected from hydroxy, amino, C^_C^ alkylamino, di(C^-C^)alkylamino, C^-C^ alkoxy, carboxy, halo and sulfo groins; C^-Cg cycloalkyl; C3~C5 cycloalkyl (C^-C^) alkyl optionally substituted by 1-3 substituents mentioned above in connection with alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C^-C^ alkyl, alkoxy, C^-C^ alkylamino, ci(C^-C^)alkylamino, carboxy and sulfo; phenyl (C^-C^) alkyl in which the phenyl portion rr.av be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C^-C^ alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are'selected from the group consisting of 1-4 0, S and/or N atcms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, Ci~C4 alkyl, alkoxy, alkylamino, di(C^-C^)alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, alkylamino, di (C^-C^) alkylamino, C1~C4 alkoxy, carboxy, halo and sulfo. The R and R5 groups may , 7. 20SGZ6 also be taken together to form a fused heterocyclic or heteroaromatic ring. Within the above-described preferred embodiment, the preferred compounds are those in which A is in which n is 1 or 2, most preferably those in which A is -CH,- and 18 wherein (a) R and R taken together represent HOCH CH. 2\. C= 8 . 1 or (b) R is hydrogen and R represents hydrogen, CR^CE^-, CH CH. \h- CH. CH. £ , ?H or CH^CH- 8 Particularly preferred are the compounds wherein R is hydrogen and R^" is CH^CH-, especially compounds having the absolute configuration 5R, 6S, 8R. A particularly preferred embodiment of the present invention comprises compounds of formula I wherein -0: represents a radical of the formula -^X aX^ wherein R®, R7 and R^ are independently selected from the group consisting of hydrogen, C.-C* alkyl, C.-C alkoxy, - x 4 -L 4 carboxyl and carbamoyl and R is as defined above, and is preferably C^-Cg alkyl, most preferably -CH^. ■ 6 AUG 1984 20562.6 (SM* -So. -X- Within the above-described preferred embodiment, the preferred compounds are those in which A is in which n is 1 or 2, most preferably those in which A is -CH2- and 18 wherein fa) R and R taken together represent HOCH CH. S- 8 i or (b) R is hydrogen and R represents hydrogen, CH^CHj-, CH. ■\ ;ch- CH. CH3vf CH, or CH Particularly preferred are the compounds wherein R8 is hydrogen and R • is OH I CHjCH-, especially compounds having the absolute configuration 5R, SS, 8R. Another preferred embodiment comprises compounds of formula I wherein represents a radical of the formula „5 - -6 (a) wherein R5 is alkyl, most preferably methyl, and R6 represents hydrogen or C^-C^ alkyl; J " ' V- "" R5 (b) ®l n6 ^ +-J 20562S -5i- - wherein R^ is alkyl, most preferably methyl and R£ and R7 are hydrogen or C1~C4 alkyl; (c) 5 R-N N,-R ■w vherein R5 is alkyl, most preferably methyl and R is C^-C^ alkyl or phenyl (C^-C^)alkyl; (d) ^ jrdf"—r6 R5 wherein R^ is C^"C4 alJcyl> most preferably methyl and R® is Cj-C4 alkyl, most preferably methyl; (e) R5 / R wherein R5 is C^-C4 alkyl, most preferably methyl and R is C1~C4 alkyl, most preferably methyl; or 105626 - -sfc-- (f) CN }V-R5 wherein R° is C^-C^ alkyl, most preferably methyl. Within the above-described embodiment/ the preferred compounds are those in which A is ~(CH2^n~ wh^-ch n 1 or 2, most preferably those in which A is -CH-- and wherein 18 (a) R and R taken together represent HOCH \c 8 1 or (b) R is hydrogen and R represents hydrogen, CH-jC^-, CH.3 CH, OH OH \ 3 1 7 CH- , C- , or CH-CH- . / / 3 ch3 ch3 g Particularly preferred are the compounds wherein R is hydrogen and R^" is OH CH^CH-, especially compounds having the absolute configuration 5R, 6S, 8R. A most preferred embodiment of the present invention comprises compounds of formula I wherein N-R5 represents a radical of the formula - 53- 205626 (a) (c) N—CH. CH \ 3© ^3 (b) (d) CH. -TV N—CH_CH0CH, w 2 2 3 (e) CH. V (f) (g) (i) CH. I CH (h) (j) CH„ J 2 -O N ' CH. J I -54-- x- 205626 Ck) CH, | 9 CH, (m) ; or (1) (n) /7 3 ch3 N N / CH, Within this above-described embodiment, the preferred compounds are those in which A is -(CH2)n~ in which n is 1 or 2, most preferably those in which A is -(CH,)- and wherein (a) R^" and 8 R taken together represent HOCH, C= ch3 8 1 or (b) R is hydrogen and R represents hydrogen, CH^Hj-, • C^3 CH, OH OH \ v3 I I ^CH- , , or CH3CH- . ch3 ch3 g Particularly preferred are the compounds wherein R is hydrogen and R^" is OH CH^H-, especially compounds having the absolute configruxation 5R, 6S, 8R. Specific preferred compounds of the present invention are those of the formula i.. i f ■ 205626 fa--*. OH J. (R) wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion and wherein -S—A' IS a f 4 ^ -6 AUG 1984"■ \ 205626 (k) -sch2-^ ■- J5-K- (h) CH, -SCH2- X)—CH3 (j) -SCH. CH, ®^CH3 -CH. (1) <?H3 /"A* -—L/- (O) ?V / Wv (™) -SCH^-< > CH, ^3 -SCH, . ^ 2 J // ® N-2-CH. (n) -SCH. (p) CH ' f® J CH, "SCBrLi- CH. CH. wherein the HNMR(DjO) spectrum shows characteristic peaks at 5: 1.23(3H, d, J=6.4 Hz), 3.12(2H, q, J=1.4, 8.9 Hz), 3.39(LH, q, J=2.7, 6.0 Hz), 4.07-4.68(10H, m) , 8.19C1H, s); (q) -SCH£ CH3 wherein the ^HNMR(DjO) spectrum shows characteristic peaks at 5: 1,23(3H, d, J=6.4 Hz), 3.1S(2H, q, J=3.7, 9.0 Hz), 3.3 7(1H, q, J=2.6, 6.0 Hz), 3.95-4. 65 (10H, m), 8.62(1H, s); 2D562£ (r) -SCH. i ^h3 (s) •SCH COO / CH, —CH. (t) -SCH. (V) CH, W ../ N -N—CH2COOs /H3 /N>fl —<f | (u) CH, 'ff3 NT -SCH, -r> N N / CH, or CH. A most preferred embodiment of the present invention comprises compounds of formula I wherein represents N—R" CH. <3 Within the above-described embodiment, the preferred compounds are those in which A is -(CH,)- in which n is 1 or 2, 1 most preferably those in which A is -CHr and wherein (a) R and 8 R. taken together represent HOCH, 2\_ CH 8 1J or (b) R is hydrogen and R represents hydrogen, CH^CHj-, CH 3^ CH- CH, OH >• , or CHjCH- . CH 205626 A g Particularly preferred are the compounds wherein R is hydrogen and R^" is OH I CH^CH-, especially compounds having the absolute configuration 5R, 6S, 8R. The carbapenem derivatives of general formula I are prepared from starting materials of the formula p8 I ?15 ,1 ■COOR III 1 8 15 2' wherein R , R and R are defined above and wherein R represents a conventional readily removable carboxyl protecting group. Compounds of formula III have been disclosed, for example, in European Patent Application 38,869 (compound 1) and in European Patent Application 54,917, 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: H .15 8 = R COOR III 205626 & - d#- R8 H * 15 hs—a- ■n " coor L=conventional leaving group iv —a- N ^OOR1 r5-x' ii ,8 h r 15 ^ N 0 I' -S—A' -coor'1 x,e ^5 optional N r - . , , - ae-blockmg _ H R15 R — n "^COOR2 (po 205626 A variation of the above-described process is shown in the following reaction scheme: >15 COOR' HS—A' N IV R 15 R H N- tcoor2 ' de-blocking II .15 ,8 H //— N -S—A- ^COOH R5—X1 Ila r, tt R ,8 H [ 15 • N 3—A—(— N—R- COO ,© la 1 To elaborate on the above process, starting material III is reacted in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformajnide with about an equi-molar amount of an agent R"-L such as p-toluenesulfonic acid anhydride, p-nitrobenzenesulfonic acid anhydride, 2,4,6-triisopropylbenzenesulfonic acid anhydride, methanesulfonic acid anhydride, trifluororoethanesulfonic acid anhydride, diphenyl chlorophosphate, toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, or the like, wherein L is the corresponding leaving group such as toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, diphenoxvphosphinyloxy, and other leaving groups which are established by conventional procedures and are well-known in the art. The reaction to establish the leaving group at the 2-position of intermediate III is advantageously carried out in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, or the like, at a temperature of from about -20° to *40eC, most preferably at about 0eC. The leaving group L of intermediate IV may also be halogen in which case such group is established by reacting intermediate III with a halc-genating agent such as 03PC12, 0^3^, (OOJ^PBr^, oxalylchloride or the like in a solvent such as CH^C^, CH^CN, TEF, or the like, in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, or the like. Intermediate IV may be isolated if desired, but is conveniently used for the next step without isolation or purification. 205626 i ■ i i Intermediate IV is next converted to intermediate II by a conventional displacement reaction. Thus, intermediate IV may be reacted with approximately an equimolar amount of a heteroaralkyl mercaptan reagent of the formula wherein A represents C^-Cg straight or branched chain alkylene and represents a mono-/ bi-or polycyclic aromatic heterocyclic radical containing a quaternizable nitrogen in the ring, said ring being attached to A through a ring carbon atom, in an inert organic solvent such as dioxane, dimethyl-formamide, dimethylsulfoxide 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 -40°C to 25°C. Most conveniently, the reaction is carried out with cooling, e.g. at about 0"C to -10°C. Quaternization of the ring nitrogen in the heteroaralkyl group of intermediate II is carried out by reacting intermediate II in an inert organic solvent with at least an equivalent (up - ■& - to about a 50% molar excess) of an alkylating agent of the formula R5 X' wherein R5 is as defined above and X' is a conventional leaving group such as halo (chloro, bromo or iodo most preferably iodo) or a sulfonate ester moiety such as a mesylate, tosylate or triflate. Examples of suitable non-reactive organic solvents are chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethylsulfoxide and dimethy1formamide. The temperature for the alkylation reaction is not critical and temperatures in the range of from about 0°C to 408C are preferred. Most conveniently, the reaction step is carried out at room temperature. Intermediate I' will have a counter ion X' (e.g. derived from the alkylating agent used) associated with it which at this stage or at a later stage, i.e. following the de-blocking step, may be substituted by a different counter ion, e.g. one which is more pharmaceutical^ acceptableby conventional procedures. Alternatively, the counter ion may be subsequently removed during the de-blocking step. The de-blocking step to remove the carboxyl protecting 2 1 group R 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 I1 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 the like at a temperature of from 0 to 50°C for from about 2 1 0.24 to 4 hours. When R is a group such as o-nitrobenzyl, photolysis may also be used for deblocking. Protecting groups w " *>6AUGM4 ' -s i 20 56 2 6 - J&3r - such as 2,2,2-trichloroethy1 may be removed by mild zinc reduction. The allyl protecting group may be removed with a catalyst comprising a mixture of a palladium compound and triphenylphosphine in an aprotic solvent such as tetrahydro- furan, diethyl ether or methylene chloride. Similarly, other conventional carboxyl protecting groups may be removed by methods known to those skilled in the art. Finally, as 2 1 mentioned above, compounds of formula I1 where R is a physiologically hydrolyzable ester such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc. may be administered directly to the host without de-blocking since such esters are hydrolyzed in vivo under Dhysiological conditions. 18 5 15 It will be understood that where the R , R r R or R substituent or the heteroaromatic ring 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 groups and procedures for introducing and removing such groups are well known to those skilled in the art. In a variant of the above process, the carboxyl protecting group of intermediate II may be removed prior to the quaterniza-tion step. Thus, the carboxyl protecting group is removed as described above to give the corresponding free carboxylie acid and the free acid is then quaternized with alkylating agent R^-X1 to give the desired quaternized product of formula I. When the de-protected intermediate Ila is quaternized, the solvent may be water or a non-reactive organic solvent, or mixtures thereof. Examples of suitable solvents include water, organic solvents such as chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethylsulfoxide and dimethylformamide and water-organic solvent mixtures such as water-acetone or water-dimethyIformamide. The temperature for the quaternization of intermediate Ila is not critical and temperatures in the range of from about -40°C to about room 205626 - J0- temperature may be conveniently employed. Most advantageously, the reaction is carried out at about 0°C. When deprotected intermediate Ila is obtained as a carboxylate salt, it is desirable to add a strong acid such as toluenesulfonic acid to generate the free carboxylic acid prior to quaternization. This is found to greatly facilitate the preferential quaternization of the ring nitrogen. The above-described variant procedure is especially useful when the carboxyl protecting group is more easily removed from the unquaternized intermediate II than from quaternized intermediate I'. For example, in preparing the product of the formula CH 1 from the intermediate of the formula 0 ZoftSiC - 6 b ~ removal of the allyl protecting group prior to quaternization results in substantially improved yields of the desired end-product . While the above-described process is suitable for preparing the compounds of the present invention, an alternative process can be used to prepare compounds of formula I. This alternative process, is described below and in the Examples which follow. In the alternative process for preparation of compounds of formula I, an intermediate of the formula ,15 COOR IV 1 8 15 0 1 wherein R , R and R are as defined above, R is a conventional readily removable carboxyl protecting group and L is a conventional leaving group such as toluenesulfonyloxy, p-nitrobenzesulfonyloxy, diphenoxyphosphinyloxy or halo is reacted with a thiol compound of the formula HS-A- 0-! VII wherein A and <y*5 are as defined above and X ® is a counter anion in an inert solvent and in the presence of base to produce a carbapenem product of the formula 67 - « - 205626 s-a- © « n-r- COOR 2 1 x© wherein R r8, r2' , a, r15, © c N-R- and X © are as defined above and, if desired, the carboxyl 2 f protecting group R is removed to give the corresponding deblocked compound of formula I, or a pharmaceutical^ acceptable salt thereof. The alternative process utilizes the intermediate of the formula r8h A N COOR" iv which, as mentioned before, has been disclosed, for example, in European Patent Applications 3 8,869 and 54,917 and which may be prepared by the general methods described therein. L represents conventional leaving group (defined as "X" in European Patent Application 38,869) such as chloro, bromo, iodo, benzene-sulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, diphenoxyphosphinyloxy or di(trichloroethoxy)phosphinyloxy. The preferred leaving group is diphenoxyphosphinyloxy. & - fee - 2 0 5 6 2 6 Intermediates of Formula IV are generally formed in situ by reacting an intermediate of the formula COOR III ,8 15 2' R and R are as defined above with a suitable wherein R , R' acylating agent Ru-L. The preferred intermediate IV where L is diphenoxyphosphinyloxy may be prepared by reacting keto ester III in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with about an equimolar amount of diphenyl chlorophosphate in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine or the like at a temperature of from about -20°C to +40°C, most preferably at about 0°C. Intermediate IV may be isolated, if desired, but is conveniently used as the starting material for the alternative process without isolation or purification. Carbapenem intermediate IV is reacted with a quaternary amine thiol compound of the formula HS- N -R- ,0 VII wherein N -R" is as defined above and Xv is a counter anion. The reaction is carried out in an inert solvent such as acetonitrile, acetonitrile-dimethylformamide, tetrahydrofuran, tetrahydro-furan-H20, acetonitrile-H20 or acetone in the presence of base. The nature of the base is not critical. Suitable bases include sodium hydroxide, diisopropylethylamine, 1,8- J 205626 diazabicyclo[5.4.0]undec-7-ene, 1< 5-diazabicyclo[4.3.0]non-5-erie and tri(C^-C^)alkylamines such as triethylamine, tributyl-amine or tripropylamine. Reaction of intermediate IV and thiol VII may be carried out over a wide temperature range, e.g. -15°C up to room temperature, but is preferably done at a temperature in the range of from about -15°C to +15°C, most preferably at around 0°C. The carbapenem product produced by reaction of the quaternary amine thiol VII with intermediate IV will have a. counter anion associated with it [e.g. (CgH50)2?02 ® , CI ® or the anion associated with the quaternary thiol] which may at this stage be substituted by a different counter anion, e.g. one which is more pharmaceutical^ acceptable, by conventional procedures. Alternatively, the counter anion may be removed during the subsequent de-blocking step. Where the quaternized carbapenem compound and counter anion form an insoluble product, the product may crystallize out as it is formed and be collected pure by filtration. Following formation of the desired carbapenem product, 2 ' the carboxyl protecting group R of Compound I' may be optionally removed by conventional procedures such as solvolysis, chemical reduction or hydrogenation. Where a protecting group such as p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylaethyl is used which can be removed by catalytic hydrogenation, intermediate I' in a suitable solvent such as dioxane-water-ethanol, tetrahydrofuran-diethylether-buffer, tetrahydrofuran-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 the like at a temperature of from 0 to 50"C for from about 0.24 to 4 hours. 1 1 When R is a group such as o-nitrobenzyl, photolysis may also be used for deblocking. Protecting groups such as 2,2,2-trichloroethyl may be removed by mild zinc reduction. The allyl protecting group may be removed by using a catalyst comprising a mixture of a palladium compound and triphenyl phosphine in a f*' - • -6AUGi984 J v. "' /' \ , ? •" suitable aprotic solvent such as tetrahydrofuran, methylene chloride or diethyl ether. Similarly, other conventional carboxyl protecting groups may be removed by methods known to chose skilled m the art. Finally, as mentioned above, compounds of Formula I' where R^ is a physiologically hydrolyzable ester such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxy-methyl, etc. , may be administered directly to the host without de-blocking since such esters are hydrolyzed in vivo under physiological conditions. The thiol intermediates of Formula VII may be prepared,, for example, from the corresponding thiolacetate compound of the formula i? CH,CS-A- -0 wherein A is as defined above and -o represents a mono-, bi- or polycyclic aromatic heterocyclic radical containing a quaternizable nitrogen in the ring, said ring being attached to A through a ring carbon atom. The thiolacetate compound is quaternized by reacting it in an inert organic solvent such as diethyl ether, dichloromethane, methylene chloride, dioxane, benzene, xylene, toluene or mixtures thereof with a suitable alkylating agent of the formula RS-X' wherein R5 is as defined above and X1 is a conventional leaving group such as halo (chloro, bromo or iodo, most preferably iodo) or a sulfonate ester moiety such as mesylate, tosylate or triflate. The temperature for the alkylation reaction is not critical, and temperatures in the range of from about 0cC to 40°C are preferred. AUG $84 2 Of Prior to reaction with carbapenem intermediate IV, the quaternized thiolacetate compound is subjected to acidic or basic hydrolysis to generate quaternary thiol intermediate VII. This hydrolysis is preferably done immediately prior to coupling with IV so as to minimize decomposition of the relatively unstable quaternary thiol VII. 3y proper selection of the solvents, the reaction from intermediate III to end product I may be carried out without isolation of the various intermediates, i.e. in a "one-pot" process. An example of such a process is illustrated below in Example 22. As in the case of other B-lactam antibiotics, compounds of general formula I may be converted by known procedures to pharmaceutical^ acceptable salts which, for purposes of the present invention, are substantially equivalent to the non-salted compounds. Thus, for example, one may dissolve a 2 compound of formula I wherein R is an anionic charge in a suitable inert solvent and then add an equivalent of a pharmaceutical^ acceptable acid. The desired acid addition salt may be recovered by conventional procedures, e.g. solvent precipitation, lvophilization, 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. It will be appreciated that certain products within the scope of formula I may be formed as optical isomers as well as epimeric mixtures thereof. It is intended that the present invention include within its scope all such optical isomers and epimeric mixtures. For example, when the 6-substituent is hydroxyethyl, such substituent may be in either the R or S configuration and the resulting isomers as well as epimeric mixtures thereof are encompassed by the present invention. ,*-6AUG 1984 F rf- j +* / (a&k 2056! -It- A compound of fonnula I where R2 is hydrogen or an anionic charge, or a pharmaceutical^ acceptable salt thereof may also be converted by conventional procedures to a corresponding compound where R2 is a physiologically hydrolyzable ester group, or a ccinpound of formula I wherein R2 is a conventional carboxyl protecting group may be converted to the corresponding compound 2 where R is hydrogen, an anionic charge or a physiologically hydrolyzable ester group, or a pftarmaceutically acceptable salt thereof. The novel carbapenem derivatives of general formula I 2 wherein R is hydrogen, an anionic charge or a physiologically hydrolyzable carboxyl protecting group, or the pharmaceutical^ acceptable salts thereof, are potent antibiotics active against various gram-positive and gram-negative bacteria and they may be used, for example, as animal feed additives 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 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 carbapenem ingredient, a pharmaceutically acceptable carrier or diluent. The compounds may be administered by a variety of means; those of principal interest include: orally, topically or parenterally (e.g. 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. 205626 -3?- 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 dispersing agents. The compositions may be in ready to use form or In powder form'for reconstitution at the time of delivery 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. 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 about 5 to 200 mg/kg/day. Administration is generally carried out in 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 compounds, biological data is provided below relating to the presently preferred carbapenem compounds of the present invention. 6 AUG 1984 205626 In Vitro Activity Samples of the carbapenem compounds prepared in Examples 1-2 after solution in water and dilution with Nutrient Broth were found to exhibit the following Minimum Inhibitory Concentrations (M.I.e.) in mcg/ral versus the indicated microorganisms as determined by overnight incubation at 37°C by tube dilution. N-Formimicoyl thienamycin is included in the following tables as a comparison compound. In Vitro Antibacterial Activity of Carbapenem Derivative of Example 1 MIC (meg/ml) Orcanism New ConrDOiind S. pneumoniae A-9585 0. 25 0.004 S. pyocenes A-960 4 0. 06 0.001 S. aureus A- 9 5 3 7 0. 13 0.004 S. aureus + 50% serum A-9537 0. 03 0.016 S. aureus (?en-res.) A-9606 0 .06 0.008 S. aureus {Meth-res.) S. faecalis E. coli (10-4 dil.) E. coli (lO-3) 5. coli (10'2)' 5.- coli do"4) 5. coli dO"3) 5. coli dO"2) A15097 A20688 A15119 A15119 A15119 A20341-1 A20341-1 A20341-1 4 0.5 0.06 0.03 0.5 0.5 0.016 0.03 0.06 0.03 0.03 0.13 2D5&2S - In vitro antibacterial activity of carbapenem derivative of Example 1 - continued MIC (mcg/ml) Groan' sa New Ccmsound N-Forminidoyl Thienanycin K. Dne\mcniae A-9664 0.25 0.13 X. oneumoniae A20468 0.25 O.OS F. mirabilis A-9900 0.13 0.05 P. vulgaris A21559 0..13- 0.03 P. morganii A15153 0.13 0.13 P. rettceri A22424 0.25 0.25 S. marcescens A20019 -0.13- 0.03 E. cloacae A-9569 0.13 0.06 E. cloacae A-9S56 0.13 0.06 P. aeruginosa A-9 843A 4 1 P. aeruginosa A21213 1 ■ 0.25 H. influenzae A- 9 8 3 3 16 16 H. influenzae A20178 32 32 H. influenzae A21518 16- 32 H. influenzae A21522 8 32 B. fragilis A22862 0.03 0.016 3. fragilis A22053 - 0.03 0.06 B. fraqilis A22S96 0.25 0.13 a. fraailis A22863 0.03 1 205 6 26 % - & - In Vitro Antibacterial Activity of Carbapenem Derivative of Example 2 MIC (mcg/ml) Organism New Compound N-Formimidoyl Thienamycin S. pneumoniae A-9585 0.001 0.002 S. pyoqenes A-9604 0.001 0.002 S. aureus A-9537 0.004 0.004 S. aureus A-9537 0.016 0.016 +50% serum S. aureus A-9606 0.008 0.008 (Pen-res.) S. aureus A 15097 8 4 (Meth.-res.) S. faecalis A 20688 0.25 0.5 E. coli A 15119 0.016 0.016 E. coli A 20341-1 0. 016 0.03 K. pneumoniae A9664 0.06 0.06 K. pneumoniae .A20468 0.13 0.13 P. mirabilis A9900 0.03 0.06 P. vulgaris A2155 9 0.016 0.03 P. morganii A15153 o • o 0.13 P.. rettgeri A22424 0.13 0.13 S. marcescens A20019 0.03 0.03 E. cloacae A9659 0.13 0.06 E. cloacae A9656 0.25 0.06 P. aeruginosa A9 843A 8 1 P. aeruginosa A21213 2 0.25 205626 "77 - •£§* - In Vivo Activity The in vivo therapeutic efficacy of the compound of Example 1 and N-formimidoy1 thienamycin after intramuscular administration to mice experimentally infected with various organisms are shown in the following Table. The PD^q (dose in mg/kg required to give protection to 50% cf the infected mice) is indicated. Protective Effect in the Intramuscular Treatment of Infected Mice PDjg/Treatment (mg/kg) Cha, llenge (NO . of Compound of N-?orreimidoyl Or sanism organisms) Exaurole 1 Thienamycin P. mirabilis A-9900 3.5 X 106 3 .3 3*/15* P. aeruginosa A-9843a 5.5 X 10 4 0 .3 0.5* P. aeruginosa A-20481 5.4 X 104 0 ■ S3 0.4* p, aeruginosa A-20599 1. 4 X 105 108 0 .7 * CO f—1 o S. aureus A-9606 6.6 X 0 .09 0.07* S. faecalis A-20688 2.3 X 108 3 .3 2.8* E. coli A-15119 6.2 X 106 0 .5 2.5* K. Dneumoniae A-99S4 5.1 X 106 2 .5 2.2* * Historical data Treatment Schedule: Except fcr E^_ coli A15119 and K. pneumoniae A9964, mice were treated i.m. with drugs 0 and 2 hours postinfection. For E^_ coli and K^_ pneumoniae the treatment schedule was 1 and 3.5 hours post-infection. 5 mice per dose were used for each test o.. ~6 AUG 1984 • \ r) : j' 2 0 56 2 6 -t- Toxi city 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 Compound of Example 1 N-Formimidoyl Thienamycin *LD50 (mg/kg) 14 Highest Dose (mg/kg) Without Clinical Signs of Toxicity 32 ^5 *Averaqe of 25/mice/compound Blood Levels in Mice After Intramuscular Administration Blood levels and the half-life of the compound of Example 1 after intramuscular administration of 20 mg/kg in mice are shown in the Table below. Blood Level.(yg/ml) Compound 10 20 30 45 60 90 *tl/2 **AUC Minutes after Administration (min) (yig.h/ml) Compound of Example 1 14 10.8 6.8 2.6 0.8 <0.6 10 6.3 N-Formimidoyl 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 ** AUC refers to the area under the curve 205626 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 Compound Hours After Administration Compound of Example 1 26.1 0.5 0.1 26.7+6.7 N-Formimidoyl 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. ft** - - Additional Biological Data 20562 In Vitro Activity Samples of the carbapenem compounds indicated below (identified by example number) after solution in water and dilution with Nutrient Broth were found to exhibit the following Minimum Inhibitory Concentrations (M.I.C.) in mcg/ml versus the indicated microorganisms as determined by overnight incubation at 37°C by tube dilution. N-Formimidoyl thienamycin is included in the following tables as a comparision compound. Organism EX. . 3 Ex. 4 Ex. 5 Ex. 6 Ex. . 7 MX 0 7 87* 5. pneumoniae A-9585 0 .002 0 .002 0.004 0 .004 0 .004 0.002 S. pyooenes A-9 6 0 4 0 .002 0 .001 0.004 0 .004 0 .004 0.00 2 S. faecalis A20688 0 -5 0 .5 0.25 0.5 0 .13 0.5 S. aureus A-9537 0 .016 0 . 00 B 0.004 0.03 0 .00 B 0.004 S. aureus A-9537 0. .016 o. .03 0.016 0.06 0 .03 0.016 +501 serum S. aureus A-9606 0, .016 0. .016 0.008 0.03 o. .016 0.008 {Pen-res) S. aureus A15097 4 4 a 4 2 4 (Meth-res) E. eoli A15119 0. .03 0, .016 0.016 0.06 0, .004 0.016 E. coli A 20 3 41-1 0. .016 0. .016 0.016 0.06 0. .004 0.03 K. pneumoniae A-9664 0. .06 0. .03 0.03 0.13 0. .016 0.06 K. pneumoniae A20468 0. .06 0. .03 0.06 0.25 o. .016 0.13 E. cloacae A-9659 0. ,13 0. .03 0.06 0.25 0. .016 0.06 E. cloacae A-9656 0. .13 0. .06 0.13 0.25 0. .016 0 .06 P. mirabilis A-9900 0. ,13 0. .06 0.03 0.025 0. .016 0.06 P. vuloaris A21559 0. .016 0. .016 0.016 0.06 0. ,008 0.03 M. morcanii A15153 0. 13 0. .016 0.06 0.13 0. ,016 0.13 P. rettqeri A22424 0. 25 0. 13 0.13 0.25 0. ,06 0.13 S. marcescens A20019 0. 016 0. 03 0.06 0.13 0. ,008 0.03 P. aeruainosa A-9843a 2 2 4 a 1 0.25 P. aeruainosa A21213 0. 5 0. 13 2 1 0. 25 0.25 H. influenzae A-9833 2 2 4 >32 >32 16 H. influenzae A21518 2 2 4 >32 >32 16 8. fragilis A22862 0. 25 0. 06 0.03 0.03 0. 016 0.06 3. fraqilis A22696 0. 5 0. 5 0.25 0.25 0. 25 0.13 • N-Formimidoyl Thienamycin 205626 JBr Organism S■ pneumoniae S. pyogenes S. faecalis S. aureus 5. aureus + SOX serusi S. aureus (Pen-res) S. aureus (Meth-res) E. coli E. coli X. pneumoniae K. pneumoniae E. cloacae E. cloacae P. mirabilis P. vulgaris M. morcanii P. rettaeri S. marcescens P. aeruginosa P. aeruginosa MIC (uq/nl) A-9585 A-9604 A20668 A-9537 A-9537 A-9606 A1S097 A15119 A20341-1 A-9664 A2046B A-9659 A-9656 A-9900 A215S9 A15133 A22424 A20019 A-984JA A21213 0.002 0.002 0.5 0.0 OS 0.03 Ex. 9 EX. 10 Ex. 11 0.03 0.016 0.03 0.03 0.13 0.13 0.06 0.13 0.03 0.13 0.13 0.06 1 0.25 0.001 0.001 0.13 0.004 0. 00B o.aos o.oos 0.004 0.016 0.03 0.03 0.03 0.016 0.006 0.03 0.06 0.016 2 0.13 0.001 0.001 0.25 0,008 0.06 O.OOB 0.016 0.008 0.06 0.13 0.13 0.13 0.13 0.016 0.13 0.13 0.06 32 2 0.002 0.002 0.5 0.004 0.016 0.016 0 .016 0.03 0.03 0.13 0.06 0.13 0.03 0.03 0.06 0.13 0.06 0.5 0.13 MX 07B7 0.002 0.002 0.25 0.002 0.D16 0.008 0.016 0.016 0.03 0.13 0.13 0.06 0.03 0.016 0.06 0.13 0.03 1 0.13 * H-Forainidcyl IJiienamycin *6 AUG *984 205626 to. - £0 - HIC (ug/rnl) Orcanism EX. 12 Ex. 13 Ex. 14 MK 0787' S. oneunoniae A-9585 0 .002 0.0005 0.0005 0.002 S. cvooenes A-9604 0 .004 0.0005 0.0005 0.002 S. faecalis A2068B 0 .5 0.13 0.13 0.25 S. aureus A-9537 0 .008 0.008 0.008 0.002 S. aureus A-9537 0 .016 0 .016 0.03 0.008 ♦ 501 serum S. aureus A-9 6 0 6 0 .03 0.008 0.016 0.008 (Pen-res) S. aureus A15097 - - - - (Meth-res) Z. coli A15119 0. .016 0.004 0.008 0.016 £. coli A20341-1 0. .008 0.008 0.008 0.016 K. Dneumoniae A-9664 0. .03 D.03 * 0.03 0.03 K. oneononiae A20468 0. .06 0.13 0.03 0.06 E. cloacae A-9659 0. 06 0-06 0.03 0.06 E. cloacae A-9656 0. .03 0-03 0.03 0.06 P. mirabilis A-9900 0. 03 Q-016 0.016 0.016 P. vuloaris A21559 0. 016 o.ooa 0.016 0.016 M. morganii A15153 0. 06 0.016 0.03 0.06 P. rettaeri A22424 0. 13 0.25 0.06 0.13 5. marcescens A20019 0. 03 0.016 0.016 0.03 P. aeruginosa A-9843A 16 32 8 1 P. aeruginosa A21213 2 2 0.5 0.13 • N-Foraitaidoyl Thi&naoycin i \ I k I V 2G5626 ■8T- KIC (ug/cl) Oreanism Ex. 15*X" E*. 15-3* Ex. 15-C" ttX 0787* 5. Dr.eur>oniae A~9 5fl5 0.0005 0.0005 0.0005 0.002 S. ovoaenes A-9604 0.0005 0.001 0.0002 • 0.002 S. faecalia A206 88 0.13 0.5 0.5 0.25 S. aureus A-9537 0.03 0*004 0.016 0.004 S. aureus A-9537 0.D3 0.016 0.06 0 .008 + 50% serua S. aureus A-9606 0.004 0.009 0.03 0.008 (Pen-res) S. aureus A15097 - - - - (Keth-res) E. coli A15119 0.004 0.00 8 0.06 0.008 E. coli A20341-1 0.004 0.000 0.03 0.016 K. Dneujaoniae A-9664 0.008 0.03 0.06 0.03 K. Dneujnoniae A20468 0.008 0.016 0.13 0.06 E. cloacae A-9659 0.016 0.016 0.13 0.13 E. cloacae A-9656 0.016 0.03 0.13 0.13 P. ciraMlif A-9900 0.008 0.03 0.06 0.06 P. vu 1 c a ri s A21559 0.008 0.008 0.06 0.016 M. ocrcanii A15153 0.03 0 .06 0.25 0.13 P. rettceri A22424 0.03 0.13 0.25 0.13 S. marcescens A20019 O.OOS 0.016 0.13 0.016 P. aerucinoxa A-9 6 <3A 0.5 2 8 0.5 P. aerucinosa A21213 0.03 0.13 0.5 0.13 • K-Forciaidoyl Thienaasycin 205626 Organism s- pneumoniae A-95BS £i pyogenes A-9604 h. f'ecaljj A2068B aureus A-9537 s- aureus A-9537 + 501 sensa aureus A-9606 (Pen-r«i) ii aureus A15097 (Meth-res) coli A15119 coll A20341-1 Dneimonia* A-9664 L. pneumoniae A20468 L. cloacae A-9659 £• cloacae A-9656 airabilis A-9900 pi vulcaris A21559 ciorqanii A15153 L. rettoeri A22424 marcescens A20019 aeruginosa A-9043A L. aeruginosa A21213 Ex. 16 0.002 0.002 1 O.OOS 0.03 0.016 0.016 0.016 0.06 0.06 o.oe 0.06 0.06 0.03 0.13 0.25 0.06 0.25 0.13 Ex. 17 0.016 0.016 4 0.25 1 D.5 0.6 0.6 0.13 0.5 2 2 0.13 0.13 0.5 2 0.13 >63 16 ♦MK 0787 0.001 0.001 0.25 0.001 0.008 0.002 0.00B 0.008 0.03 0.06 0.06 0.06 0.016 0.008 0.06 0.06 0.016 0.5 0.13 * N-Forminiidoyl Thienamycin 205626 -•*$ - Organism Ex. ia Ex. 19 Ex. 20 •MX 078 S. pneumoniae A-9SB5 1 0.002 0.06 0.001 S. svonenes A-9604 2 o o o 0.13 0.002 S. faecalis A206 88 S3 0.5 16 0.25 5. aureus A-9537 32 0.004 0.5 0.002 S. aureus A-9537 >63 0.008 2 0.004 + 50% serum 5. aureus A-9606 >125 0.016 ' >125 0.004 (Pen-res) S. aureus A15097 - - - _ (Heth-res) E. coli A15119 16 . 0.008 1 0.016 E. coll A20341-1 1£ 0.008 2 0.016 K. pneumoniae A-9664 32 0.03 4 0.03 K. onetmoniae A20468 63 0.06 4 0.06 E. cloacae A-9659 63 0.03 8 0.06 E. cloacae A-9656 125 0.03 IS 0.06 P. airabilis A-9900 32 0.03 4 0.016 P. vulcaris A21559 32 0.016 4 0.016 K. noroanii A15153 32 0.06 8 0.06 P. rettoeri A22424 32 0.13 8 0.13 S. narcaicens A20019 32 0.03 4 0.03 P. aeruginosa A-9843A 63 0.5 32 0.5 P. aeruginosa A21213 63 0.06 16 0.13 * N-Forminiidoyl Thienamycin 205626 In Vivo Activity The in vivo therapeutic efficacy of certain compounds of the present invention and N-formimidoyl thienamycin (MK 0787) after intramuscular administration to mice experimentally infected with various organisms is shown below. The (dose in mg/kg) required to give protection to 50% of the infected mice is indicated. Protective Effect in the Intramuscular Treatment of Infected Mice PDjg/treatment (mg/kg) S. aureus A9606 A15119 E. coli pneumoniae A9664 P. mirabilis A9 900 P. aeruginosa A9843A P. aeruginosa A24081 Ex. 6 0.4 Ex. 8 EX. 9 0.21 0.86 1.8 1.4 0.19 0.33 Ex. 12 EX. 14 EX. EX. 15 CA") IS CB") 1.2 1.8 7.1 0.19 0.19 0.89 1. B 0.07 0.45 0.39 0.69 MK 0787 0.07 3 3 9 1 0.4 EX. Ex. Ex. 3 4 7 MX 0787 s. aureus A9606 0.07 0.1 0.2 0.07 E. coli A15119 1 0.4 0.2 3 K. pneumoniae A9664 3 3 1 3 P. mirabilis A9900 2 4 2.4 9 P. aeruginosa A9843A 0.5 0.2 0.2 0.5 P. aeruginosa A24081 0.8 0.2 0.1 0.4 S. aureus E. coli K. pneumoniae P. mirabilis P. aeruainosa A9843A Ex. 5 0.2 4 3 10 1.6 MK 0787 0.07 2.2 2.3 9 0.5 «7 - & - 205626 Blood Levels in Mice After Intramuscular Administration Blood levels and the half-life of certain compounds of the present invention after intramuscular administration of 20 mg/kg in mice are shown below. Compound (no/ml) (min) (ug.h/nl) Example 1 14 10 6.3 Example 2 13.9 9 5.3 Example 3 14.5 10 6.9 Example 4 15.5 11 7.7 Example 5 - - - Example 6 17.7 9 8.5 Example 7 19.2 11 11.8 Example 6 18.8 11 10.5 Example 9 16.7 12 8.5 Example 10 . 20.1 11 9.5 Example 11 14.9 11 7.4 Example 13 14.8 11 6.4 Example 14 15.8 13 7.6 Example 15 "A" 16.7 12 9.5 Example 15 "B" 15.9 10 7.4 Example 15 "C" 15.1 10 7.3 MK 0787 14.6 10 6 Example 17 11 -8 3.4 Example 18 14.9 6 3.9 Example 19 27 16.7 15.1 Example 20 28.4 14 15.6 Compounds were solubilized in 0.1 M phosphate buffer, pH 7. Valves based on a single test; 4 mice per compound. *Tl/2 re'era t0 half-life in minutes •*AUC refers to the area under the blood concentration-time curve The following examples illustrate but do not limit the scope of the present invention. 205626 - - Example 1 Preparation of l-Methyl-4-[2-carboxy-6a-[1(R) -"hydroxyethyl]-7-oxo-l-azabicyclo [3.2.0]hept-2-en-3-thioniethyl]pyridiniuni hydroxide inner salt CH. C02pNB CH3I OH H 0 cr -C02pNB .6 -■& A solution of 673 rag (1.86 mnol) of p-nitrobenzyl 5a-[ 1- (R) - hydroxyethyl]-3,7-dioxo-l-azabicyclo [3.2.0Jhept-2-ene-2-carboxylate (1) in 10 ml of acetonitrile was cooled to -10°C under- a nitrogen atmosphere. A solution of 245 mg (1.90 mmol) of diisopropylethylamine in 1 ml of acetonitrile was added followed by a dropwise addition of 510 rag (1.90 mmol) of dipnenyl chlorophosphate in 1 ml of acetonitrile over • a period of 2 minutes. The resulting solution was stirred at -10°C for 15 minutes to provide a p-nitrobenzyl 3-(diphenyl-phosphoryloxy)-6a- [1-(R)-hydroxyethyl]-7-oxo-l-azaiicyclo-[3.2.0]hept-2-ene-2-carboxylate. To this solution was added a solution of 245 mg (1.90 mmol) of diisopropylethylamine in 0.5 ml of acetonitrile followed by a solution of 270 mg (2.16 mmol) of 4-mercaptomethylpyridine in 0.5 ml of acetonitrile. The reaction mixture was stirred at -10eC for 60 minutes and the white precipitate which formed was collected by filtration and washed with 5 ml of ice-cold acetonitrile to give 660 mg (76% yield) of compound _2 as white crystals, m.p. 145°C. NMR(DMSO-dS) 6: 1.20(3H, d, J=6.0 Kz) , 3.2-3.4 (33, m) , 3.7-4.1 (2H, m) , 4.25 (2H, s) , 5.05 (IE, d, J=4.0 Hz), 5.25 (IB, A, J=14.0 Hz), 5.48 (IE, d, J=14.0 Hz), 7.40 (2H, d, J=5.5 Hz), 7.70 (2H, d, J=8.5 Hz), 8.23 (2H, d, J=8.5 Hz) and 8.58 (2H, d, J=5.5 Hz). IR (K3r) ymax: 3400, 1790, 1695 and 1600 cm"1. Anal. Calc'd for C^H^NjOgS: C, 58.01; H, 4.56; N, 9.23; S, 7.04. Found: C, 57.74; H, 4.56; N, 9.58; S, 7.21. To a solution of 660 mg (1.41 mmol) of intermediate 2 in 140 ml of acetone there was added 5 ml of methyl, iodide. The reaction solution was stirred for S hours at 25°C. The solvent was evaporated in vacuo affording a slightly yellow solid which was triturated with diethyl, ether to give 779 mg (90% yield) of ' the title compound 3 as a white amorphous solid, m.p. 130 °C (cecomp.) . -6 AUG 1984 205626 NMR (DMSO-d6)6: 1.15 (3H, d, J=6.0 Hz), 3.2-3.4 (3H, m) , 3.7-4.1 (2H, m), 4.25 (3Hr s) , 4.30 (2H, s) , 5.25 (1H, d, J= 14.0 Hz^ , 5.50 (1H, d, J=14.0 Hz), 7.70 (2H, d, J=9.0 Hz), 8.10 (2H, d, J=7.0 Hz), 8.25 (2H, d, J=9.0 Hz) and 8.90 (2K, d, J=7.0 Hz). IR (KBr) ymax: 3400, 1770, 1690 and 1640 cm"1. Anal. Calc'd for C23H24N306SI-H20: C, 44.39; H, 4.22; N, 6.82; S, 5.20. Found: C, 44.66? H, 4.01; N, 6.84; S, 5.64. B. .6 N 0 3 H H — SCH'j-^ ^~CH3 ^-CO,pNB Pd/C -> r~N 4 •SCH •CO •a- e CH. To a solution of 779 mg (1.27 mmol) of compound 3 in tetrahydrofuran-water-diethyl ether (80 ml-80 ml-100 ml), there was added 140 mg (1.4 mmol) of potassium bicarbonate and 125 mg (0.7 mmol) of dibasic potassium phosphate. Then, 700 mg of 10% palladium on charcoal was added and the mixture was hydrogenated at 4 0 psi for 4 5 min on the Parr Shaker. The mixture was then filtered.and the catalyst was washed with water (2 X 10 ml). The combined filtrate and washings were extracted with diethyl ether (150 ml) and then lyophilized to give a r 2 0 5 6 2 6 brown powder. This crude material was purified on a BONDAPAK reverse phase column (30 g) .(Waters Associates), eluting with water under a 8 psi pressure. Each fraction (20 ml) was screened by high pressure liquid chromatography/ and fractions having an ultraviolet absorption at Amax=300 nm were collected and lyophilized to give 135 mg (32% yield) of the title compound _4 as a slightly yellow solid. NMR (D20) 6: 1.25 (3H, d, J=6.0 Hz), 2.7-3.2 (2E, m) , 3.40 (1H, q, J=9.0.and 2.5 Hz), 3.9-4.2 (2H, m) , 4.40 (3H, s) , 4.72 (2H, s) , 8.10 (2H, d, J=6.0 Hz), 8.72 (2H, d, J=6,0 Hz). IR (KBr) ymax: 3400, 1755, 1640 and 1590 cm UV Xmax (H^O): 296 nm (e=7782), 258 nm (e-6913). Example 2 OH 2 205626 A. (R) - oh N. o2pnb NH ■> OH /?—N c02pnb ■> cojpnb PNB = p-nitrobenzyl 205626 93 - - A suspension of 1.1'g (2.93 m moles) of diazo compound 1 was purged at room temperature with nitrogen for 5 minutes in 30 ml dry benzene. It was treated with 25 mg of rhodium acetate dimer and the mixture was heated to reflux for 45 minutes. The warm solution was diluted with ethyl acetate (25 ml) , filtered to remove the catalyst and evaporated to dryness to give the keto compound as a white solid. This was dissolved in dry acetonitrile (20 ml) and cooled to -10°C. To this solution was added, under nitrogen, diisopropylethylamine (417 mg, 3.2 m moles) followed by 810 rag (3.0 m moles) of diphenyl chlorophosphate and the reaction mixture was stirred at -10°C for-20 mantes. The reaction mixture was then treated with diisopropylethylamine (420 mg, 3.2 m moles) and 2-(4-pyridyl) ethane thiol (560 mg; 4.03 m moles) in 2 ml acetonitrile [J^ Org. Chem. '26: 82 (1961) Ludwig Bauer and Libero A. Garaella Jr.]. The reaction mixture was stirred at -5°C to -10°C for 1 hour, then diluted with methylene chloride (100 ml) and washed successively with brine - H20 (1:1), 4% H^PO^, 5% NaHC03, HjO and brine. The organic phase was dried (MgSO^) and evaporated to give a white solid. This solid was washed with diethyl ether:hexane (1:1) and dried under high vacuum to give 901 mg (63.9%) of compound 3_* .IR(KBr) 1790, 1690 cm"*1 NMR (CDCl^/DMSO) <5 1.20 (3H, d, J=3.0 Hz, CH3) , 2.8 to 3.2 (7H, m) , 3.9 to 4.4 (2H, n) , 5.1 (1H, d) , 5.4 (2H, q) , 7.3 (2H, d), 8.5 (2H, q), 7.76 (2H, d) , 8.3 (2H, q). 205626 -If. OH B. ^ n ^ // C02PNB ch3i * A suspension of carbapenem 3_ ( 890 mg, 1.85 m moles) and 7 ml of iodomethane in 200 ml dry acetone and 12 ml methylene chloride was stirred at 25°C for 24 hours. The reaction mixture became a clear solution in 18 hours. The solvent was removed under reduced pressure, then the residue was washed with diethyl ether to give 920 mg (1.48 m moles) (79.8%) of 4 as a foamy solid. IR(KBr) 1765, 1690 cm"1 NMR (DMSO) 5 1.3 (3H, d, J=3.0 Hz), 3.1 to 3.7 (7H,.m), 4.1 (3H, m), 4.3.(3H, s), 5.38 (2H, q, J=7.0 Hz), 8.1 (2H, d, J=3.0 Hz), 8/9 (2H, d, J=3"."0 -'Hz) , 7.6 (2H, d, J=4.0 Hz), 8.2 (2H, d, J=4.0 Hz). 205626 •3^ - C. -CH. ch) The carbapenem _4 (9 20 mg, 1.4 7 m moles) , dissolved in 9 0 ml tetrahydrofuran, 90 ml diethyl ether and 90 ml water, was treated with 265 mg (1.51 m moles) dibasic potassium phosphate, 190 mg (1.9 m moles) potassium hydrogen carbonate and 800 mg 10% palladium on carbon. It was hvdrogenated at 45 psi for 1 hour. The catalyst was filtered off through CELITE and the filtrate was washed with diethyl ether (3 x 25 ml). The aqueous layer was lyophilized to give a brownish material which was then purified twice by chromatography through a 12 column (^0) to give 5 5 mg of 5. IR(XBr) 1750, 1640 cm"1. NMR (D20) <5 1.30 (3H, d, J=3.0 Hz), 3.0 to 3.5 (7H, m) , 4.3 (3H, s), 4.0 to 4.5 (3H, m) , 7.90 (2H, d) , 8.70 (2H, d) . * C, 0 BONDAPAK reverse phase column (Waters Associates) j. 8 205626 OH Example 3 Preparation of 3-(N-Hethylpyridine-3-yl-methanethlo)-6a- [l-(R)-hydroxyethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate 205626 -% 1) >-N-< 0 II ClP(O0), 2) -> CO.pNB 19 p-Nitrobenzyl 3-(pyridine-3-yl-methane thio)- 6o-[l-(R)-hydroxy ethyl]-7-QKo-l-a2abicyclo (3.2.0) hept-2-ene-2-carboxylate. To a cooled (0°) solution of 925 ng (2.66 caoLe) of the keto intermediate 5_ in 14 ml of acetonitrile was added a solution of 377 mg (2.9 naole) of diisopropyl ethylaaine in 1 ml of acetonitrile followed by 786 mg (2.9 mmole) of diphenyl chlorophosphonate in 1 ml of acetonitrile under a nitrogen atnosphere. The resulting solution was stirred for 15 min at 0°C, and there was then added a solution of 377 mg (2.9 craole) of 3-mercaptocethyl pyridine [prepared by the procedure described in Can. J. Chem., _56, 3068 (1978)] in 2 ml of acetonitrile. The reaction solution was stirred for 90 ninutes at 0°. The precipitate was collected by filtration and washed with 20 ml of ethylacerate to give 950 mg (60Z yield) of the title product as white crystals. NMR(DMS0-d6) 5: 1.30(3K, d, J=6.0Hz), 3.4-4.2(5H, m) 4.25(2K, s), 5.1(1H, d, J=4.5Hz), 5.40(2H, ABq, J=14.4Hz), 7.2-8.5(8K, n) . IR (KBr) -jTaax 3500, 1775, and 1580 cm Anal Calc'd. for ^22^21^3^6^1: C, 58.01; H, 4.65; N, 9.23; S, 7.OA. Found: C, 57.19; H, 5.19; N, 8.76; S, 7.08. |*-6 AUG 1984 \ / 20562-6 ch3I 19 C02pNB OH C02p.VB 20 Pd/C, H 3-(N-Mathylpyridine-3-yl-methane thio)-6a-[1-(R)-hydroxyethyl] -7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To a solution of 730 Eg (1.56 mmole) of compound 19 in 120 ml of acetone was added 5 ml of methyl iodide and the reaction mixture was stirred for 18 hours at room temperature. The precipitate was collected by filtration and washed with acetone (10 ml) to give 940ng (1002 yield) of the quaternized pyridine 2£ as a slightly yellow powder. NMR (DMS0-d6) 6: 1.25(3H, d, >5.8Hz), 3.6-4.3(5H, in), 4.20C3H, s), 4.25(2H, s) 5.25(1H, d, J=7.2Hz), 5.40(2H, ABq, J=12,16Kz), and 7.6-9.2 (9H, m). IR(K3r) X max: 3300, 1765 and 1690 en"1. Anal Calc'd. for C-.H-.N,0,S.l.: C, 46.24; H, 4.05; N, 7.03; S, 5.37. 2.3 /4 ] D 1 1 45.82; H, 4.11; N, 6.87; S, 6.10. F ound: C„ To a solution of 933 mg (1.6 nnole) of cocpound 2Q_ in 90 ml of tetrahydrofuran and 90 cl of ether was added 200 mg of KHCO^ and 349 ng of K^HPO^ in 90 nl of water followed by 1.0 g of palladium on charcoal. The mixture was hydrogenated at 45 psi on the Parr shaker for 45 minutes. The mixture was filtered through a Celi i r>~ £ i> 205626 catalyst was washed with water (2 x 10 nl). The combined filtrate and washing were extracted with ether (2 x 100 nl) and lyophilized to give a yellow solid which was purified on a C,Q BONDAPAK (Waters Associates) lo reverse phase column (8 g), eluting with 52 acetonitrile in water under 8 psi pressure- Each 15 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at A max 300 nm were collected and lyophilized to give 230 mg (43% yield) of the title product as slightly yellow crystals, m.p. 130°C (decomp) NMR (D20) 6: 1.25(3H, d, J=7.0Hz), 3.12C2H, d.d, J=7.9Hz, 1.6Hz), 3.42(1H, q, J=7.2 Hz, 1.6Hz), 3.9-4.6(3H, m), 4.25(2H, s), 4.42(3H, s) and 8.0-9.0(4H,m). IR(KBr) ^max: 3400, 1750 amd 1580 cm UVA max (H20): 298 nm (e=8058). Anal. Calc'd. for C^H^N^Sj^l^O: C, 51.87; H, 5.44; N, 7.56. Found C, 51.95; H, 5.66; N.7.56. 205626 \p> - & " Example 4 Preparation of 3-(N-Methylpyridine-2-yl-aethane thio)-6e-[1-(R)- hydroxyethyl] -7-oxo-l-azabicyclo (3.2,0) hept-2-ene'-2-carboxylate J 205626 0S l°l ■ C02pNB 1) r 0 II C1P(O0). 2) HS p-Nitrobenzyl-3-(pyridine-2-yl-methar.e thio)-6a-fl-(R)-hydroxyethyl] -7-oxo-l-azabicyclo(3.2.0) hept-2-ene-2-carboxylate To a cooled (0°) solution of 925 eg (2.65 cmole) of the keto intermediate 5_ in 14 ml of acetonitrile was added a solution of 377 mg (2.92 canole) of diisopropyl ethylaciine in 1 nl of acetonitrile followed by 786 mg (2.90 caole) of diphenyl chlorophosphate in 1 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred for 15 minutes at 0°, and there was then added a solution of 377 mg (2.92 m mole) of diisopropyl ethylamine in 1 nl of acetonitrile followed by 350 mg (3.0 nmole) of 2-Eercaptomethyl pyridine [prepared by the procedure described in Can. J. Chem., _56, 3068 (1978)] in 1 ml of acetonitrile. The reaction solution was stirred for 2 hours at -10°C. The precipitate was collected by filtration and washed with 20 ml of methylene chloride to give 650 ng (54% yield) of the title product as a yellow powder. NMR(DMS0-d6) 5: 1.26(3H, d, J=7.0Hz), 2.7-3.5 (4H, c), 3.9-4.3(2H, m), 4.2(2H, s),5.42(2H, ABq, J=14.4Hz) and 7.2-8.8 (8H,m). IR(K3r) ynax: 3400, 1775 and 1690 cn *. , Anal. Calc'd fox C,.H_,N,0,S.:4 C, 58.01; H, 4.65; N, 9.23; S, 7.04. ZZ /I J 0 1 Found: C, 57,56, H, 4,92, N, 8.94; S, 7.03. ■' / 205626 2- - 10 f - 22 C02pNB ch3i acetone 24 3-(N-Methyl pyridine-2-yl-methane thio)-6a-f l-(R)-hydro:tyethyl] -7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To a solution of 650 mg (1.39 naaole) of compound _22 in 100 ml of acetone was added 4 ml of methyl iodide. The reaction mixture was stirred for 3 days at room temperature. The precipitate was collected by filtration and washed with acetone (10 ml) to give 500 eg (602 yield) of the quaterized pyridine 23 as a slightly yellow solid. NMR (DMS0-d6) 6: 1.26(3H, d, J=7.0Hz) 3.9-4.2(2H, n), 4.4(3H, s), 4.78(2H,s), 5.2(1H, d, J=3.9Hz), 5.50(2H, ABq, J=14Hz) and 7.8-9.4 (8H, m). IR (KBr) -y max: 3400,1765, and 1690 cm Anal. Calc'd for C C, 46.24; K, 4.05; N, 7.03; S, 5.37. Found: C, 45.62; H, 4.27; N, 6.80; S, 5.30. , 7" 2 0 5 6 26 To a solution of 1.0 g (1.167 mmole) of compound _23 in 90 ml of tetrahydrofuran and 90 ml of ether was added 215 mg (2.15 m mole) of KHCO^ and 374 mg (2.1 mmole) of K^HPO^, in 90 ml of water followed by 1.0 g of 10% palladium on charcoal. The mixture was hydrogenated at 45 psi on the Parr shaker for 45 minutes. The mixture was filtered through a Celite pad and the catalyst was washed with water (2 x 10 ml). The combined filtrate and washing were extracted with ether (2 x 200 ml) and lyophilized to give a yellow solid which was purified on a C,„ BONDAPAK lo (Waters Associates) reverse phase column (10 g), eluting with 57. acetonitrile in water under 8 psi pressure. Each 15 ml fraction.was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at Amax 300 nm were collected and lyophilized to give 390 mg (44% yield) of the title product. Recrystallization of this material from water-acetone-ethanol produced fine needles. m.p. 194-196°C. (decomp). NMR (D20) 6: 1.30(3H, d, J=6.2Hz)» 3.2(2H, q, J- 9.0Hz, 3.6Hz) -3.46(1H, q, J=6.0Hz, 2.7 Hz), 4.1-4.6(3H, m), 4.60(3H, s) and 7.9-8.9(4H, m). IR (KBr) y aax: 3400, 1755,and 1590 cm-1. UV Amax (H20): 292 nm (e=8092). Anal Calc'd for C.i.J.O.S .2H„0: C, 51.87; H, 5.44; N, 7.56. Found: C, 51.37; H, lo 2o 2. k 1 £. 5.69; N, 7.37. / % 107 - 20 56 Exar.ple 5 Preparation of 3-(N-Methylpyridine-2-yl-ethane thio]-6a-[l-(R)- hydroxyethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate i 2.0562.6 P-Nitrobenzy 1-3- (pyridine-2-yl-ethane thio) -6c- f 1- (R)-hydroxyethy1] -7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carborvlate. To a cooled solution of 1.78 g (5.Onsaole) of the ketc intermediate 5 in 25 ml of acetonitrile was added 710 ag (5.5 caole) of diisopropyl ethylamine in 1 ml of acetonitrile followed by 1.4 g (5.0 cnole) of diphenylchlorophosphate in 1 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred for 20 cinutes at 0°C, and there was then added a solution of 710 eg (5.5 n—ole) of diisopropyl ethylamine in 1 nl of acetonitrile followed by a solution of 850 mg (6.1 icmole) of the thiol [prepared by the procedure described in J. Org. Chem., _26^ 82 (1961)] in 2 nl of acetonitrile. The reaction mixture was stirred for 60 minutes at 0°C. The precipitate was collected by filtration and washed with methylene chloride (20 ml) to give 1.3 g (57%) of the title product as a yellow solid. NMRtCDCl^) 6:1.25 (3H, d, J=6.5Hz), 2.6-3.A (7H, o), 4.2-4.6 (2H, m), 5.30 and 5.65 (1H each, ABq, J=14Hz) and 7.2-8.5 (SH, a). IR(KBr) 3400, 1780 and 1680cm 3-(N-Methyl pyridine-2-yl-ethane thio)-6c-Cl-(R)-hydroxyethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To a suspended solution of 800 teg (1.7 nmole) of compound 53 in 50 ml of acetone was added 5 ml of methyl iodide. The reaction mixture was stirred for 48 hours at room temperature. The precipitate was collected by filtration and washed with acetonitrile (15 ml) to give 810 tag (76% yield) of the quarternized pyridine _55 as a slightly yellow powder. NMR (DMS0-d6) 6: 1.20 (3H, d, J=5.6 Ez), 3.2-4.3 (9H, a), 4.20 (3H, s), 5.26 and 5.55 (1H each, ABq, J=15 Ez) and 7.8-9.2 (SH, m) . IX(KBr) ymax: 3400, 1770 and 1690 cm To a solution of 790 eg (1.27 mmole) of compound 55_ in 100 ml of tetrahydrofuran and 100 ml of ether was added 100 ml of pH = 7.0 buffer solution followed by 1.0 g of 10% palladium on charcoal. The mixture was hydrogenated at 40 psi on the Parr shaker for 40 minutes. The* mixture was filtered through a Celite pad and the catalyst was washed with water (2 x 10 ml). - lojl - 205626 The combined filtrate and washing were extracted with ether (3 x 100 ml) and lyophilized to give a yellow powder which was purified on a C lo BONDAPAK (Waters Associates) column (30 g), eluting with 10% acetonitrile in water under 8 psi pressure. Each 15 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at Amax 300 nm were collected arid lyophilized to give 65 Eg (152! yield) of the title product as a yellow powder. NMR (D20) 5: 1.25 (3H. d, J=6.2 Hz), 3.1-3.6 (7H, m), 4.0-4.3 (2H, m), 4.32 (3H, s) and 7.8-8.9 (4H, m). IR(K3r) ymax: 3400, 1750 and 1590 cm UV Amax (H^O): 300 nm (e=8108). 2 0 5 6 2 6 - 10 t OH ^ © C02u Example 6 Preparation of 3-(l-Propylpyridine-4-yl-:nethaiie thio)-6ct-f 1-(R)-hydroethyl]-7-oxo-l-a2abicyclo (3.2.0) hept-2-ene-2-carboxylate i J v I v .. 'r J . 205626 \ 1Cf - OH X 4- CO pNB C02pNB P-Nitrobenzyl-3-(pyridine-4-yl-methane chio)-6c-[l-(R)-hydroxvet:hvn -7-oxo-l-azabicyclo (3.2.0)-hept-2-ene-2-carboxylate. A solution of 673 mg (1.86 m mole) of p-nitrobenzyl 6c-[-(R) -hydroxyethyl]-3,7-dioxo-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (5) in 10 ml of acetonitrile was cooled to -10°C under a nitrogen atmosphere. A solution of 245 tag (1.90 n mole) of diisopropylethylanine in 1 ml of acetonitrile was added followed by a dropwise addition of 510 mg (1.90 m mole) of diphenyl chlorophosphate in 1 nl of acetonitrile over a period of 2 minutes. The resulting solution was stirred at -10"C for 15 minutes to provide a p-nitrobenzyl 3-(diphenylphosphoryloxy)--6a-[1-(R)-hydroxyethyl]-7-oxo-l-azabicyclo-(3.2.0) hept-2-ene-2— carboxylate. To this solution was added a solution of 245 mg (1.90 m mole) of diisopropylethylamine in 0.5 ml of acetontrile followed by a solution of 270 mg (2.16 n mole) of 4-mercaptonethylpyridine in 0.5 ml of acetonitrile. The reaction mixture was stirred at -10°C for 60 minutes and the white precipitate which forced was collected by filtration and washed with 5 ml of ice-cold acetonitrile to give 660 eg - (76% yield) of conpound 5_1_ as white crystals, n.p. 145°C. NHR ^ (DMS0-d6) 6: 1.20(3H, d, J=6.0Hz), 3.2-3.4(3H, n), 3.7-4.1 (2H, m) , 4.25 f.fc>6AUGf984 ( 2H,s), 5.05(1H, d, J=4.0Hz) , 5.35(1H, d, J=14.0Hz), 5.48(1H, d, , \A J=14.0Hz), 7.40(2H, d, J=5.5Hz), 7.70(2H, d, J=8.5Hz), 8.23 (2H, d, 'fir V J=8.5Hz) and 8.58 (2H,d, J=5.5Hz). IR(F3r) Y*ax: 3400, 1790 and 1695 J 205626 r * l Q - ie* - cm . Anal. Calc'd f°rC22H21N306S: C' 58-01; H. *-56; N, 9.23; S, 7.04. Found: C, 57.74; H, 4.56; N, 9.""- S, 7.21. Br acetone Na I // ^=/ C02pNB 1 SI 52 3-(1-Allyl pyridine-4-yl-methane thio)-6c-f l-(R)-hydroxyethyl]-7-oxo-l-azabicyclo (3.2.0)-hept-2-en3-2-cgrboxylate. To a solution of 900 mg (2.13 m mole) of compound in 150 ml of acetone was added 2 ml of allyl bromide and 330 mg of sodium iodide. The mixture was stirred for 48 hours at room temperature and the solvent was evaporated in vacuo to give a yellow solid. This material was suspended into 120 ml of acetonitrile, filtered and evaporated _in vacuo to give 1.0 g (87% yield) of the title product as a yellow solid. NMR (CD CN)5: 1.20(3H, d, J=6.2Hz), 3.0-3.4(4H, m), 4.0-4.4(4H, m), 5.1-5.6 (4H, m) and 7.4-7.9(8H, m). IR(KBr) yzias: 3400, 1770 and 1690 cm"1. Anal. Calc'd for <^25H26N3°6S1I1: C' ^ 4,21; N, 6,74; S, 5.15. Found: C, 48.55; H, 4.46; N, 6.69; S, 5.15. 2Q5G2& ii IDS. - Oli Oil A Pd/C 0 H 2 0 CO 2 CO^pN'B 1 52 S3 3-(1-Propyl pyridine-4-yl-iae thane thio)-6o-[l-(R)-hydroxyethyl]-7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To a solution of 1.27 g (2.15 m mole) of compound ^2 in LOO ml of tetrahydrofuran and 100 ml of ether was added 100 ml of pH=7.0 buffer solution followed by 1.0 g of 10% palladium on charcoal. The mixture was hydrogenated at 40 psi on the Parr shaker for 40 minutes. The mixture was filtered through a Celite pad and the catalyst was washed with water (2 x 10 ml). The combined filtrate and washing were extracted with ether (3 x 100 ml) and lyophilized to give a yellow powder which was purified on a C BONDAPAK (Haters Associates) column lo (40 g), eluting with 10% acetonitrile in water under 8 psi pressure. Each 15 ml fraction W2S assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at Anax 300 nm were collected and lyophilized to give 48 mg (6% yield) of the title product as a yellow powder. NMR^D^O) <5: 0.95(3H, t, J=7.5Hz), 1.25(3H, d, 7.0Hz), 2.05(2H, sextet, J=7.5Kz) 3.10(2H,dd, J=10 Hz, 2.5Hz) 3.35(1H, dd, J=6.5Hz, 2.5Hz), 4.0-4.8 (6H, m), 7.1 (2H, d, J=6.0Hz) and 7.80(2H, d, J=6.0Kz). IR(K3r) "naax: 3400, 1750, and 1590 cm"1. Anal. Calc'd for C gH N 0^.2^0: C, 54.52; H, 6.10; N, 7.07. Found: C, 54.32; H, 6.03; N, 6.99. # I*. - 15S) - 2 0 5 6 2 6 Example 7 Preparation of 3-(N-Methyl-3-methylpyxidine-2-rcethane thio)-6a-f1-(R)-hydroxyethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate - 114, - 2056 26 3 ch sh: 3 CI N N 2) NaOH HC1 36 37 3-Methyl-2-mercaptomethyl pyridine. A solution of 2.45 g (17.0 mmole) of the chloro compound 36_ and 1.37 g (18.0 m mole) of thiourea in 60 ml of absolute ethanol was heated at reflux for 5 hours. Evaporation of ethanol followed by addition of ether give 3.08 g (72% yield) of the isothiouronium salt which was dissolved in 10 ml of water containing 1.44 g (26 m mole) of sodium hydroxide. The solution was then heated at 100°C for 5 minutes under a nitrogen atmosphere. The reaction mixture was cooled to 5°C, adjusted to pH 6.4 by addition of acetic acid and extracted with ether (4 x 50 ml). The combined ether extracts were washed with 5% aqueous sodium bicarbonate and brine. Evaporation of dried (MgSO^) solvent gave 1.4 g (83% Yield) of the thiol 3_7_ as a yellow oil which was used for the next step without further purification. NMR (CDC1^)6: 2.20(3H, s), 2.5-2.7(1H, broad s), 3.8(2H,t, J=6.5He) and 6.9-8.2(3K, m). I •/... 205626 on X C02pNB "v- r — N— 0 II C1P(O0), 2) CH US to OH J. a\ C02pNB 3B 37 P-Nitrobenzyl-S-fS-methyl pyridine-2-yl-methane thio]-6o-[I—(R>— hydroxyethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To a cooled (0cC) solution of 1.74 g (5.0 mmole) of the keto intermediate _5 in 25 ml of acetonitrile was added 960 mg (5.8 m mole) of diisopropyl ethylamine in 2 ml of acetonitrile followed by 1.4 g (5.8 mnole) of diphenyl chlorophosphate in 2 ml of acetonitrile under a nitrogen atmopshere. The. resulting solution was stirred for 20 minutes at 0°C, and there was then added a solution of 760 mg (5.8m mole) of diisopropyl ethylamine in 2 ml of acetonitrile followed by 810 mg of the nercaptonethyl pyridine 3_7 in 3 ml of acetonitrile. The reaction mixture was allowed to stir for 2 hours at 0°C. The precipitate was collected by filtration and washed with acetonitrile to give 1.56 g (66 X yield) of the title product as a white solid. n.p. 145°C. NMR (DMS0-d6) 6: 1.23(3H, d, J=6.5Hz), 2.30(3H, s), 3.1-4.3(6H, m), 4.35(2H, s), 5.20 and 4.45(1H each, ABq,J=15.0Hz) and 7.3-8.4(7H,m). IR(KBr) ymax: 3400, 1767 and 1695 cm Anal. Calc'd for C_.H_,N_0oSoF: C, 47.91; H, 4.69; N, 6.98; S, 10.66. Ik lo J y I Found: C, 47.72; H, 4.34; N, 6.72; S, 11.22. |*-6AUG1984 )J * */! v^<>/ I 205626 liX- on C02pNB 38 40 3-(N-Methyl-3-methyl pyridine-2-yl-methane chio)-6a-[1-(R)-hydrroxy ethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To a solution of 680 mg (1.45 mmole) of compound 38 in 120 ml of methylene chloride was added 270 ng (2.33 mmole) of methyl fluorosulfonate. The reaction mixture was stirred for 3 hours at room temperature. The precipitate was collected by filtration and washed with methylene chloride (5 ml) to give 840 mg (992 yield) of the quaternized pyridine 39 as white crystals. NMR (DMS0-d6)S: 1.15(3H, d, J= 5.8Hz) 2.62(3H, s) , 3.2-4.4(5H, m), 4.45(3H,s), 4.60 and 4.82 (1H each, ABq, J=9.2Hz), 5.30 and 5.46 (1H each, ABq, J=12.8Hz), and 7.6-8.9(7H, m). IR(K3r) ymax: 3400, 1750 and 1590 cm"1. Anal. Calc'd for C H^N^S F: C, 49.14; H, 4.47; N, 7.13; S, 11.43. Found: C, 49.56; H, 4.16; N, 7.26; S, 11.03. To a solution of 810 mg (1.39 mmole) of compound _39 in 100 ml of tetrahycirofuran and 100 ml of ether was added 100 ml of pH=7.0 buffer solution followed by 750 mg of 10£ palladium on charcoal. The mixture ~ 6 AUG 1984 - ink- 205626 was hydrogenated at 45 psi oil the Parr shaker for 60 min. in the cold room (4-6°C). The mixture was filtered through a Celite pad and the catalyst was washed with ether (2 x 10 nl). The combined filtrate and washing were extracted with ether (2 x40 ml) and lyophilized to give a yellow solid which was purified on the C^g BONDAPAK (Waters Associates) column (20 g), eluting with 5% acetonitrile in water under 8 psi pressure. Eash 15 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at Amax 300 nm were collected and lyophilized to give 141 mg(30% yield) of the title product as a yellow solid. NMR (0^0)6: 1.24(3H, d, J=7.0Hz), 2.62(3H, s), 3.2-3.5(311, m) , 4.2-4.4(2H, m), 4.45 (3H,s), 4.50 and 4.59(1H each, ABq, J=12.6Hz), 7.82(1H, q, J=7.0Hz, 6.5Hz), 8.35(1H, d, J=7.0Hz) and 8.65(1H, d, J=6.5 Hz). IR(KBr) ymax: 3400, 1750 and 1580 cm UV Amax (H^O): 296 nm (e=8014). Anal. Calc'd for C17H20N2°4S1 *^ H20: C' 51'85> H» 5-85i N' 7*94' Found: C, 58.60; H, 5.86; N, 7.87. 2 0 5 6 2 6 i - 115s- 0H Example 8 Preparation of 3-(2-Methyl-N-roethylthiazole-4-yl-methane thio)-6c- ri-(R)-hydroxyethvll -7-oxo-l-a2abicvclo (3.2.0) hept-ene-2-carboxyLate V - ' >. OH x£>'~Ci 0 | N CH C02pMB 9 p-Nitrobenzyl 3-[2-methyl thiazole-4-yl-methane thio]-6a-[l-(R)-hydroxyethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To a cooled (0°) solution of 1.4 g (4.0 imnole) of the keto intermediate _5 in 12 ml of acetonitrile was added 0.83 ml (4.6 mmole) of diisopropylethylamine followed by 1.16 g (4.3 maole) of diphenylchlorophosphate in 2 ml of acetonitrile under a nitrogen atnospere. The resulting solution was stirred at 0° for 30 minutes to provide p-nitrobenzyl 3- (diphenylphosphoryloxy)-6a-[l-(R)-hydroxyethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To this solution was added a solution of 0.83 ml (4.6 caole) of diisopropylethylamine in 2 ml of acetonitrile followed by a solution of 0.62 g (4.2 mmole) of 2-methyl-4-mercaptomethyl thiazole [prepared by the procedure described in J. Amer. Chem Soc. , 7_1_, 3570 (1949)] in 3 ml of acetonitrile. The reaction solution was stirred for 40 minutes at 0°. The precipitate was collected and washed with ether (30 nl) to give 943 mg of the title product as a white solid. -4 OH A v~ o C0,pNB 1) r 0 CI P(O0). -> 2) JIS CH, NKR (CDC13) 6: 1.32(3H, d, 3. 76(1H, d, J=5.5Hz), 4.16(2H, 7.06(1H, S), 7.68(2H, d, J=8Hz) 3500, 1770, and 1700 cm"1. J=7Hz), 2.68(3H, S), 3.20(2H, m) S), 4.20(1H, n), 5.40(2H, q, J=14Hz), and 8.24(2H, d, J=8Hz). IR(KBr) ymax: \'"V- I *• A 205626 C02pNB C02^8 CH, Pd/C, H, — fso3q CH V 3-(2-Methyl-N-methyl-thiazole-4-yl-methane thio)-6-a-f 1-(R) -hydroxyethyl-]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To a solution of 525 mg (1.1 mmole) of compound 9 in 20 ml of methylene chloride was added 0.27 nl (3.3 nnole) of methyl fluorosulfonate. The reaction mixture vas stirred for 90 minutes at room temperature. The precipitate was collected by filtration and washed with methylene chloride (50 ml) to give 650 Eg (100Z yield) of the quaternized thiazole _1_0 which was used for the next step without further purification. Thus, to a solution of compound _10^ in 100 ml of tetrahydrofuran and 100 ml of ether was added 100 ml of pK=7.0 buffer solution followed by 500 mg of 10% palladium on charcoal. The mixture was hydrogenated at 35 psi on the Parr shaker for 45 minutes. The mixture was filtered, through a Celite pad and the catalyst was washed with water (2 x 10 ml). The combined filtrate and washings were extracted with ether (2 x 100 ml) and lyopholized to give a yellow powder which was purified on a C)B BONDAPAK reverse phase column (8 g) (Water Associates), eluting v °A-'\with 5% acetonitrile in water under 8 psi pressure. Each 15 ml fraction 'V '0)\ .....-6 AUG1984 V \ •v 205626 was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at Amax 300 nm were collected and lyophilized to give 145 mg (48% yield) of the title compound as a pale yellow powder. NMR (CDC13) 6: 1.20(3H, d, J=7Hz), 2.92(3H, S), 3.08(1H, d, J=3.5Hz), 3.20(1H, d, H=3Hz), 3.44(1H, dd, J=lHz, J=3.5Hz), 4.00(3H, 5), 4.20(3H, m), 4.36(2H, m) and 7.88(1H, s). IR(KBr) ymax: 3400, 1750 and 1585 cm1. UV Amax (^0): 296 nm (e= 7500). Anal. Calc'd. for 21^0: C, 46.15; H, 5.64; N, 7.17; S, 16.41. Found: C, 4"6.50; H, 5.26; N, 7.13; S, 16.20. 205626 \ 11 ll9» - Example 9 Preparation of 3-(N,N'-Dimethyl imidazole-2-yl-methane thio)-6a- [I-(R)-hydroxyethyl]-7-oxo-l-a2abicyclo (3.2.0) hept-2-ene-2-car&oxylate J 205626 CH 3 CH 3 N CI 2) EtOH, A SH N HC1 HC1 31 32 2-frierceptomethyl N-methylimidazola To a solution of 10.4 g (58 m mole) of 2-chloroaethyl-N-methylimidazole 31 [prepared by the procedure described in J. Amer. Chen. Soc., 71, 383 (1949)] in 200 ml of acetonitrile was added 7.1 g (60 m cole) of N-acetyl thiourea and, the reaction mixture was heated at reflux for 90 minutes. The precipitate was filtered and washed with acetonitrile (20 ml) to give the isothiouronium salt which was then dissolved into 120 ml of ethanol and heated at reflux for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, condensed _in vacuo to about 60 ml of volume and the precipitate was removed by filtration. Evaporation of the filtrate i£ vacuo gave 2-mercaptomethyl-N-methylimidazole as a yellow oil which was used for the next step without further purification. NMR (D^O) 6: 3.90(3K, s), 4.10(2H, s) and 7.25(2H, S) J V 20SGZ6 3 - 12\ ■ OH X C02pNB J) 0 Cl'l>(O0), 2) CH. I 3 -N. // SH -N nci 32 p-Nitrobenzyl-3-[N-methyl imidazole-2-yl-methane thio]6c.-f1-(R)-hydroxyethy1]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To a cooled (0°C) solution of 7.24 g (20.3 m nole) of the keto intermediate 5 in 35 ml of acetonitrile was added 2.8g (21.3 m mole) of diisopropyl ethylamine in 2 ml of acetonitrile followed by 5.5 g (20.4 m mole) of diphenyl chlorophosphate in 2 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred at 0cC for 15 minutes and there was then added a solution of 4.1 g (3.0 m mole) of diisopropyl ethylamine in 2 ml of acetonitrile followed by 4.6 g (31.0 m mole) of the thiol 32. The reaction uixture was allowed to stir for 60 minutes at 0°C. The white precipitate was collected by filtration and washed with methylene chloride (20 nl) to give 6.6 g (71% yield) of the title product as a white solid. M.p. 142°. NKR (DMS0-d6) 5: 1.32(3H, d, J=7.0Hz), 3.2-4.5(5H, m), 3.2(2H, s), 3.9(3H, s), 5.50(2H, ABq, J=l4.0Hz), 7.65(2E, d, J=6.5Kz), 7.70(2H, s) and 8.24(2H, d, J=6.6Hz). IR(KBr)y max: 3450, 1770 and 1690 cm Anal. Calc'd for C„ H„.N.O.S,.1% H_0; C, 52.18; H, 4.79; N, 11.59. Found: 21 20 4 6 1 I C, 52.22; H, 4.91; N, 12.16. 20 b&U 3- (N,-N'-Dimethyl iiaida2ole-2-yl-methane thio) -6a-[1-(R)-hydroxye thyl] -7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To a suspended solution of 1.34 g (3.0 ra mole) of compound _33 in 270 ml of acetone was added 20 ml of methyl iodide. The reaction mixture was stirred for 4 days at room temperature. The precipitate was collected by filtration and washed with acetone (20 nl) to give 1.70 g (96 % yield) of the quaternized imidazole _34 as yellow crystals, m.p. 175-177°C. NMR (DKS0-d6) 6: 1.10(3H, d, H=6.2Hz), 3.30(2H, s), 3. 2-4.3(6H, m), 3.95(6H, s), 5.45(2H, ABq, J=14Hz), 7.65(2H, d, J=6.0Hz). IR (KBr) vrnax: 3400, 1750 and 1600 cm1. Anal. Calc'd for C..H__N.O,S : C, 43.08; H ,9.60; N, 5.48. Found: C, 43.02; 21 22 h 0 1 H, 9.02; N, 5.44. \ To a solution of 1.30 g (1.86 m mole) of conpound 34_ in 120 ml of tetrahydrofuran and 120 ml of ether was added 120 nl of pH=7.0 buffer solution followed by 900 mg of 30% palladium on Celite. The mixture was hydrogenated at 40 psi on the Parr shaker for 40 minutes. The mixture ; -<? ^ - AUG 1984 *.■! t' ■S 205626 - 12\ - was filtered through a Celite pad and the catalyst was washed with water (2 x 15 ml). The combined filtrate and washing were extracted with ether (3 x 100 ml) and lyophilized to give a yellow amorphous powder which was purified on a C,D BONDAPAK (Waters Associates ) column(30 g), lo eluting with 10% acetonitrile in water under 8 psi pressure. Each 20 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at ^max 300 nm were collected and lyophilized to give 220 ng (35% yield) of the title product as a yellow powder.. NMR(D20)6: 1.12(3H; d, J=7.0Hz), 3.08(1H, dd, J=13.0Hz, 6.4Hz), 3.15 (1H, dd, J=13.0Hz, 6.4 Hz), 3.45 (1H, dd, J=3.2Hz, 4.5Hz) 3.85(6H, s,) 4.1-4.3 (2H, m), 4.40 (1H, d, J=13.5 Hz), 4.52 (1H, d, J=13.5 Hz) and 7.40 (2H, s). IR(KBr) ymax: 3500, 1750 and 1590' cm-1. UV Anax (H O): 296 nm (e=8411). Anal. Calc'd for C^H^N^S.^O: C, 51.68; H, 5.67; N, 12.06; S, 9.50. Found: C, 49.93: H, 5.94: N, 11.46: S, 9.03. t 20 5 6 26 - 12\ - Example 10 Preparation of 3-(2>3,4,-Trimethyl thiazole-5-yl-methane thio)-6ot [l-(R)-hydroxyethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate v 205626 2,-4-Dimethyl-5-nercaptomethyl thiazole To a solution of 4.8 g (26.0 mmole) of the chloro conpound 46 [prepared by the procedure described in J. Aner. Chem. Soc., 104, 4461 (1982)] in 50 ml of absolute ethanol was added 2.4 g (30 rnnole) of thiourea. The reaction mixture was heated at reflux for 18 hours. The precipitate was collected by filtration and washed with ether (20 ml) to give the isothiouronium salt which was dissolved into 22 ml of IN-sodium hydroxide and heated at 100°C for 4 minutes under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature, adjusted to pH 7.0 with IN hydrochloric acid and extracted with ether (3 x 50 ml). The combined ether phases were washed with water, brine and dried over MgSO^. Evaporation of dried solvent gave 780 mg (49% yield) of the thiol 4_7 as a colorless oil which was used for the next step without further purification. NMR (DC1,) 6: 2.05 (3H, s), 2.35 (3H, s) and 3.60 (2H, d^J=6.5 Ez). ScO< '6 AUG 1984 205626 P-Nitroben2yl-3-[2,^-dimethyl thiazole-S-yl-methane thio) 6a-[l-(R)-hydroxy ethyll-7-oxo-l-azabicyclo (3.2.0) hepC-2-ene-2-carboxylate. To a cooled (0°C) solution of 1.4 g (4.0 mmole) of the keto intermediate 5 in 25 ml of acetonitrile was added 610 mg (4.7 mmole) of diisopropyl ethylamine in 1 ml of acetonitrile followed by 1.15 g (4.3 mmole) of diphenylchlorophosphate in 1 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred for 20 minutes at 0°C, and there was then added a solution of 610 mg (4.7 mmole) of diisopropyl ethylamine in 1 ml of acetonitrile followed by 750 mg (4.7 mmole) of the thiol jT7 in 205626 2 ml of acetonitrile. The reaction mixture was allowed to stir for 3 hours at 0°C. The precipitate was collected by filtration and washed uith methylene chloride (20 nl) to give 1.14 g (612 yield) of the titl>» product as a white solid. NltR (DMS0-c6) o: 1.25(3H, d, J=6.4Hz), 2.30 (3H,s), 2.65(3H,s), 3.l-3.4(3H,m), 4.10(IH, broad s), 4.0-4.5(3H>n), 5.25 and 5.50(1H each, ABq, J=4Hz), 7.68 (2E, d, J=8.5 Hz) and 8.25 (2H, d, J=8.5Hz). IR(KBr) Ynax: 3500, 1770 and 1690 cn"1. Anal. Calc'd for C22H23N3°6s2: c» 53.73; K, 4.71; N, 8.57; S, 13.44. Found: C, 53.97; H, 4.74; N, 8.58; S, 13.10. 3-(2, 3,4-Trinethyl thiazole-5-yl-methane thio)-6c-[ l-(?Q-hydroxyethyn -7-oxo-l-azabicyclo (3.2.0) hept-2-er.e-2-carboxylate. To a solution of 1.97 g (4.0 m mole) of cozpour.d 48. in 180 ml of x methylene chloride was added a solution of 0.SS ir.l (13 o cole) of ciet^yl fluorosulfonate in 2 nl of methylene chloride. The reaction cixture was stirred for 70 ninutes at roon temperature. The reaction mixture was poured into a solution of ether (400 nl) ar.d n-pentane (100 nl). The precipitate was collected by L-6AUGJ984J 30 - 12-6- - 2 0 5 6 2 £ filtration and washed with ether (20 nl) to give 1.6 g (65.5% yield) of the quaternized thiazole A9_ as a white amorphous powder. NMR (DMS0-d6) 6. 1. 25 (3H, s, J=6.5Hz) , 2.45(3H,s), 2.80(3H,s), 3.2-4.5(6H,m), 3.90(3H,s), 5.30(2H, broad s), 7.60 and 8.2(1H each, d, J=8.5Hz). IR(KBr) ymax: 3400, 1770 and 1690 cm Anal. Calc'd for C23H26N3°9S3F*lsH20: C' 45*09^ H» N» 6'86' C, 44.50; H, 4.38; N, 6.58. To a solution of 1.0 g (1.72 mmole) of compound _4£ in 100 ml of tetra-hydrofuran and 100 ml of ether was added 100 ml of pH=7.0 buffer solution followed by 1.0 g of 10% palladium on charcoal. The mixture was hydrogenated at 40 psi on the Parr shaker for 40 minutes. The mixture was filtered through a Celite pad and the catalyst was washed with water (2 x 10 ml). The combined filtrate and washing were extracted with ether (3 x 100 ml) and lyophilized to give a yellow powder which was purified on a C10 BONDAPAK (Waters Associates) column lo (40 g), eluting with 10% acetonitrile in water under 8 psi pressure. Each 15 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at Amax 300 nm were collected and lyophilized to give 315 mg (50% yield) of the title product as a yellow solid. NMR (D20) 6: 1.25 (3H, d, J=7.0He), 2.25 (3H, s), 2.90 (3H, s), 3.0-3.30 (3H, n), 3.90 (3H, s) and ' 4.1-4.4 (4H, m). IR(KBr) ynax 3400,1750 and 1580 cm"1. UV AmaxifH^O): 297nm (e=8994). Anal. Calc'd for C15H19N3°4S'2H2°: C' 48'25; H' 6*09' N' 7'79- Found: c> 47.96; H, 5.83; N, 7.89. - lik- 205G2 6 2 \ Example 11 Preparation of 3-[2-(N-Methylthiazolimn) methyl thio)-6g-[l-(R)- hydroxyethyl3-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate J I 2. - 13ff OH SOC1. "N HC1 2056 26 § CI -H2N;ivnh2 HCl -> \L // 2HC1 2-Mercaptomethyl thiazole To a chloroform solution (30 ml) of thionyl chloride (3.81ml, 0.052M) was added at room temperature 3.60 g (0.026M) of the hydroxymethyl thiazole _1_ followed by heating at 50° for 2 hours. Chloroform was evaporated in vacuo leaving a brown solid which was dissolved in 30 ml of absolute ethanol. There was then added 2.04 g (0.026M) of thiourea. The mixture was then heated at reflux for 18 hours." The precipitate was collected by filtration, washed with ethanol and ether to give 3.4 g (55% yield) of the isothiouronium salt 3. The isothiouronium salt 3 was dissolved in 30 ml of water and purged with for 20 minutes. There was added 1.10 g (0.027 M) of sodium hydroxide and the mixture was heated at 100° for two minutes. The cooled (0°) solution's pH was adjusted to 6.0 with acetic acid followed by ethylacetate (35ml x 2) extraction. The organic layer was dried (MgSO^) and evaporated _in vacuo to give 0.75g (42% yield) of the thiol 4 as a yellow oil which was used without further purification; NMR (CDCl^) 6: 2.1(1H, t), 0 4.0(2H, d, J=10Hz), 7.27(1H, d, J=3.0Hz) and 8.85(1H, d, J=3.0Hz). 205626 OH 3 - 13"^- PJ s 0 \)Y«-( /..v « )=" j j //~5/ ci-Wot)2 L «■ 1 f-f NJ! COzPMB 3) C02PNB H5/\ \ p-Nitrobenzyl 3-[(2-thiazole) methyl thio]- 6a-[l-(R)-hydroxyethyl] -7-oxo-l-azabicyclo (3.2.0) hept-2-eae-2-carboxrylate. To a cooled (0°) solution of 1.4 g (4.0 Ecole) of the keto intermediate 5^ in 8 ml of acetonitrile was added 0.79 nl (4.4 naole) of diisopropyl ethylamine followed by 1.17 g (4.4 cmole) of diphenyl chlorophosphate under a nitrogen atmosphere. The resulting solution was stirred at 0° for 30 minutes to provide p-nitrcbenzyl 3-(diphenyl phosphoryloxy)-6-[l-(R)-hydroxyethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To this solution was added a solution of 0.79 ml (4.4 mmole) of diisopropyl ethylasine in 2 ml of acetonitrile followed by a solution of 0.72 g of the thiol _4 in 2 nl of acetonitrile. The reaction solution was stirred for 60 ninutes at 0° and then diluted with 50 ml of ethylacetate and washed with 30 ml of water, 20 ml of 10% aqueous and 30 nil of brine. Evaporation of dried (MgSO^) solvent gave a crystalline solid which was triturated with ether to yield 782 mg (42% yield) of the title product 6^ as a white crystalline material. m.p. 158-160°C. N>£R (CDCl^) 5: 1.32(3H, d, J=7.0Hz), 3.28(3H, m) , 4.20(2H, a), 4.36(2K, s), 5.40(2H, q), 7.40(1H, d, J=4.0Hz), 7.64(2H, d, J=8Hz), 7.76(1H, d, J=4.0Hz) and 8.24(2H, d, J=8Hz) IR(Or) ynax: 3500, 1770 and 1700 cm Anal. Calc'd. for c2oHl9N3°6S21 52'05; H' N» 9,10; S> 13-69j Found: C, 52.35: H, 4.40; N, 8.72; S, 13.90. a ~ \ (*' ■ 6 AUG 1984 "l \ V 2QS626 „g> CO 2PNB 13<- OH OH FSO20!-1e *// CH K © 3-[2-(K-Methyl thiazolium) methylthio]-6a-[L-(R)-hydroxyethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To a solution of 782 mg (1.36 mmole) of compound 6 in 55 ml of methylene chloride was added 0.5 ml of methyl fluorosulfonate and stirred for 90 minutes at room temperature. The precipitate was collected by filtration and washed with methylene chloride (30 ml) and ether (20 ml) to give 630 mg of a crude quaternized thiazole _7 which was used for next the step without further purification. Thus, to a solution of compound _7 in 140 ml of tetrahydrofuran and 120 ml of ether was added 140 ml of pH=7.0 buffer solution followed by 650 mg of 10% palladium on charcoal. The mixture was hydrogenated at 30 psi on the Parr shaker for 35 minutes. The mixture was then filtered and the catalyst was washed with water (2 x 10 ml). The combined filtrate and washing were extracted with ether (2 x 150 ml) and lyophilized to give a yellow powder. The crude yellov powder was purified on a C^g B0NDAPAK reverse phase column (7 g) (Waters Associates) , eluting with 5% acetonitrile in water under 8 psi pressure. Each 15 ml fraction wag assayed by high pressure liquid chromatography, and fractions having an ultraviolet absorption at Amax 300 nm were collected and lyophilized to 6 auG1984 If give 23 mg (5% yield) of the title compound as a yellow amorphous solid. -13\- 205626 NKR (D20) 6: 1.28(3H, d, J=7.0Hz), 3.12(2H, d, J=7.0 Hz), 3.44(1H, dd, J=1.0Hz and 3.0Hz), 4.20(3K, s), 4.24(2H, m), 4.76 (3H, m), 8.12(1H, d, J=4Hz) and 8.24(1H, d, J= Hz): IR(KBr) ymax: 3400, 1740 and 1580 cm"1, uv Amax (H20) 292 run (e=7285). J t 205626 - 13*>- x to© Example 12 Preparation of 3-[l-(RS)-Methyl-N-methyl-pyridine-3-yl-methane thio] 6q-[l-(R)-hydroxyethyl]-7-oxo-l-azabicyclo (3.2.0) hep t-2-ene-2-carboxylate 205626 OH if = 0 C02PNB ^—N—^ 1} « C1-P{0*)2 1 - 13\- 2) CH HS' <7 DH COzPNB 27 28 P-Nitrobenzyl-3-[l-(R,S)methyl-pyridine-3-yl-methane thio] 6a-[l-(R)~ hydroxyethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate To a cooled (0°C) solution of 1.85 g (5.3 mmole) of the keto intermediate _5 in 20 ml of acetonitrile was added 754 ng (5.8 mmole) of diisopropyl ethylamine in 1 ml of acetonitrile followed by a solution of 1.57 g (5.84 mmole) of diphenyl chlorophosphate in 2 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred for 15 minutes at 0°C, and there was then added a solution of 754 mg (5.8 mmole) of diisopropyl ethylamine in 1 ml of acetonitrile followed by 814 mg (5.8 mmole) of the thiol 2J_ in 2 ml of acetonitrile. The mixture was stirred at 0° for 3 hours, and then the reaction mixture was diluted with 200 ml of ethylacetate, and washed with ice-cold brine (200 ml), water (200 ml), aqueous bicarbonate (100 ml) and brine (100 ml). Evaporation of dried (MgSO^) solvent gave a yellow oil which was purified by silica gel column chromatography, eluting with 50% acetone-50% methylene chloride to give 1.65 g of the title product as a yellow solid. NMR (CDCl^) 6: 1.22 and 1.25(3H each d, J=7.0Hz), 1.46 and 1.50(3H each d, J=7.2Kz), 2.4-3.3(3H, m), 3.8-4.2(3H, m), 5.35(2H, ABq, J=l4.5Hz) and 7.2-8.6(8H, id). IR(KBr) vnax: 3400, 1765 and 1690 en"1. Anal. Calc'd. for C23H23N3°3Si: C' 58-835 H« 4-945 N> 8-95>* S> 6-83-Found: C, 57.15; H, 5.04; N, 8.28; S, 6.78. ! - 6 AUG 1984 I. ... ... .. V, ... 205626 &-(! '-nercapcoethyD-pyridine To a solution of 25 g of l-(4-pyridyl)-ethanol _25 (prepared by the procedure described in J. Chem. Soc., Ferlcin II, 1462 (1974)] in 100 ml of chloroform was added 50 g of thionyl chloride. The mixture was re.fluxed for 2 hours. Evaporation of solvents la vacuo gave the chloro compound 26 as a seal solid which was used for the next step without further purification. Thus, to a solution of _26 in 160 ml of ethanol was added a hot solution of 14.4 g of thiourea in 75 ml of ethanol. The reaction mixture was heated at reflux for 18 hours. Ethanol was evaporated and residue was dissolved in 100 ml of water and adjusted to pH 10 by addition of 2NNaOH, The mixture was stirred at room temperature for 90 minutes, adjusted to pH 6.0 by addition of 6NHC1 and extracted vith ether (1 x 200 ml). Evaporation of dried (MgSO^) solvent gave a yellow oil which was distilled at 5 irmSg and collected at the boiling range 60-65*C to give 11.0 g (382 yield) of the pure thiol 27 as a colorless oil. HKR (CDC13) 6: 1.70(3H, d, J-6.0Hz), 2.05(1H, d, J«5.8Hz), 4.20(IH, t, J-6.0Hz, 5.8Hz), 7.20(2H, d, J»6.2Hz) and B.5(2H, d, >6.2Hz). ** 205626 - iA - OH 30 t+O - 19-fr - 205626 3- [ 1-(RS)-methy1-N-methyl-pyridine-3-yl-pethane thio]-6a-[1-(R)-hydroxy-ethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate To a solution of 1.1 g (2.34 mmole) of compound 28_ in 100 ml of acetone was added 10 ml of methyl iodide. The reaction mixture was stirred for 18 hours at room temperature. The precipitate was collected by filtration and washed with methylene chloride (10 ml) to give 1.4 g (100% yield) of the quaternized pyridine 2£ as a yellow powder. NMR (DMSO-d6) 6: 1.10 (3H, d, J=6.5 Hz), 1.62 (3H, d, J=7.5 Hz), 2.6-4.2 (6H, m), 4.39 (3H, s), 5.42 (2H, ABq, J=13.6 Hz) and 7.9-9.2 (8H, m). IR(KBr) vmax: 3400, 1770 and 1190 cm-1. Anal. Calc'd. for C^H^N^S^: C, 47.14; H, 4.29; N, 6.87; S, 5.24. Found: C, 47.19; H, 4.78; N, 6.11; S, 5.41. To a solution of 1.45 g (2.37 mmole) of compound _29_ in 120 ml of tetrahydrofuran and 120 ml of ether was added 120 ml of pH=7.0 buffer solution followed by 1.5 g of 10% palladium on charcoal. The mixture was hydrogenated at 45 psi on the Parr shaker for 60 minutes. The mixture was filtered through a Celite pad and the catalyst was washed with water (2 x 15 ml). The combined filtrate and washing were extracted with ether (2 x 200 ml) and lyophilized to give a yellow solid which was purified on a C,0 BONDAPAK (Waters Associates) reverse phase 1 o column (50 g), eluting with 5% acetonitrile in water under 8 psi pressure. Each 20 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at Amax 300 nm were collected and lyophilized to give 200 mg (24% yield) of the title product as a yellow amorphous solid. NMR (D20) 6: 1.32 (3H, d, J=7.0 Hz), 1.63 (3H, d, J=7.2 Hz), 2.5-4.6 (6H, m), 4.32 (3H, s) and 8.2-8.9 (4H, m). IR(KBr) vmax: 3400, 1750 and 1590 cm"1. UV Xmax (H20): 296 nm (e=7573). Anal. Calc'd. for C.,Ho.N„0.S.1% H.O: C, 54.38; H, 5.77; N, 7.46 17 20 2 A 1 2 Found: C, 54.39; H, 5.98; N, 7-68 - ISO. - 205626 Example 13 Preparation of 3-(N-Methyl-N1-benzyl imidazole-2-yl-ipethane thio)- 6a-[1-(R)-hydroxyethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate J \ HC1 N 2 - 14^ - S H 1)H2N-"-N-AC CI 2)EtOH . A 41 2056 26 HC1 42 N-Benzyl-2-mercaptomethyl imidazole To a solution of 3.23 g (13.0 mmole) of the chloro compound 41_ [prepared by the procedure described in J. Amer. Chem. Soc., 71, 383 (1949)] in 80 ml of acetonitrile was added 1.72 g (14.5 mmole) of N-acetylthiourea. The reaction mixture was heated at reflux for 3 hours. The precipitate was collected by filtration and washed with acetonitrile (10 ml) to give the isothiouronium salt which was then dissolved into 80 ml of absolute ethanol and heated at reflux for 18 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, condensed in vacuo to about 30 ml of volume and the precipitate was removed by filtration. Evaporation of the filtrate in vacuo gave 3.5 g (97% yield) of the thiol ^ as a yellow thick syrup. NMR (CDC13) 5: 2.1(1H, t, J=4.5Hz), 3.80(2H, s), 5.20(2H, s) and 6.8-7.5(7H, m). 205626 - OH I nr> " >a 0 Cl-P(o^), J N / — 0 - 2) CD2PMB r"1 \ 42 OH t // C02PNB 43 P-Nitrobenzy 1-3-fK-benzylinidazole-2-yl-aethane thio] 6a-[ l-(R)-hydxoxy-ethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To a cooled (0°) solution of 3.03 g (8.5 mmole) of the keto intermediate _5 in 70 ml of acetonitrile was added 1.17g (9.0 mmole) of diisopropyl ethylamine in 2 ml of acetonitrile followed by 2.4 g (9.0 mmole) of diphenyl chlorophosphate in 2 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred for 20 minutes at 0°C, and there was then added a solution of 1.17 g (9.0 mmole) of diisopropyl ethylamine in 2 ml of acetonitrile followed by 4.8 g (15 mmole) of the thiol 42_. An additional 1.93g (15 m ml) of diisopropyl ethylamine was added and the reaction mixture was allowed to stir for 2 hours at 0°C. The precipitate was collected by filtration and washed with cold methylene chloride (20 ml) to give 2.5 g (55% yield) of the title product as a white solid. NKR (DMS0-d6) 6: 1.23(3H, d, J=7.2Ez), 2.5-4.1(6H,n), 4.25(2H, s), 5.20(2H, s), 5.20 and 5.45 (1H each.d, J=14.5Hz) and 6.9-8.3 (llH,m). IR(KBr) Ymax: 3400, 1775 and 1690cm"1. 2056*6 - ii£- OH r* / x\ II FS°3CH3 f r r! \ C02PNB N' K 43 44 Pd/C V I r* ' + ch3+ 45 3-(N Methyl-N'-benzyl inidazole-2-yl-methane thio)-6a-[1-(R)-hydroxy ethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To a solution of 1.76 g (3.3 mmole) of compound 43 in 1.1 1 of methylene chloride was added 1.15 nil (13.4 cmole) of methyl fluorosulfonate. The reaction mixture was stirred for 2 hours at room temperature. The reaction was concentrated iji vacuo to about 15 ml of volume. The precipitate was collected by filtration and washed with methylene chloride (10 ml) to give 1.58g (74% yield) of the quaternized imidazole 44 as a white solid. NMR (DKS0-d6) 6: 1.15(3H, d, J=7.0Hz), 3,2-4.4(6K,m), 4.70 and 5.0(1H each, ABq, J=10.8Hz), 5.24 and 5.46 (1H each, ABq, J=14 Hz), 5.50(2H,s) and 7.4-8.4(llH,m), IR(KBr) 3500, 1770 and 1700 cm"1. Anal. Cald'd for C28H29N4°9S2F: C' 51-48' H' liA1' N, 8.67; S, 10.20. Found: C, 51.84; H, 4.52; N, 8.65; S, 9.87. *<>\\ Ov *fc6AU€ja§Tl 205626 To a solution of l.llg (1.71 m mole) of compound 4ji in 100 ml of tetrahydrofuran and 100 ml of ether was added 120 ml of pH=7.0 buffer solution followed by 1.0 g of 10% palladium on charcoal. The mixture was hydrogenated at 45 psi on the Parr shaker for 45 minutes. The mixture was filtered through a Celite pad and the catalyst was washed with water (2 x 10 ml). The combined filtrate and washing were extracted with ether (2 x 70 ml) and lyophilized to give a yellow powder which was purified on a C BONDAPAK (Waters Associates) column (40g), Xo eluting with 10% acetonitrile in water under 8 psi pressure. Each 15 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at Amax 300nm were collected and lyophilized to give 305 mg (43%) of the title product as a slightly yellow amorphous solid. NMR (DMSO) 6: 1.40(3K, d, J=7.0Hz), 2.9-3.4(3H,m), 3.98(3H,s), 4.0-4.2(2H,m),4.23(2H, broad s), 5.57(2H,s) and 7.2-7.65 (7H,m). IR(KBr) y max: 3400, 1760 and 1590 cm"1. UV Xmax (H20): 299 nm (e=8807). Anal. Calc'd for C^H^N^O^S^. C, 57.25; H, 5.94; N, 9.54; S, 7.28. Found: C, 56.66; H, 5.70; N, 9.49; S, 8.30. - 14X- 205626 OH Example 1A Preparation, of 3-(2-Methyl-N-methylpyridipe-3-yl-methane thio)- 6a-[l-(R)-hydroxyethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate J 12 - 14^ C02 Et L A H 205626 13 S0C1 - .CI 1 )H2NANH2 2) NaOH . SH 14 15 2-Methy1-3-mercaptomethyl pyridine The ester _12 was prepared by the procedure described in J. Org. Chem., 21 800 (1956). To a cooled (0°) suspended solution of 2.86 g of lithium aluminum hydride in 50 ml of dry tetrahydrofuran was added dropwise a solution of 6.23 g (0.038 M) of the ester _1_2 in 15 ml of tetrahydrofuran over a 15 minute period. The mixture was stirred for 60 minutes at 0°, and there was then added 50 ml of ethylacetate. The precipitate was filtered, and washed with aqueous saturated ammonium chloride. The organic layer was dried over MgSO^, filtered and evaporated in vacuo affording 3.2 g (70% yield) of the hydroxyiaethyl pyridine 13 as a yellow oil. NMR (CDCl^) of compound JL3 6: 2.46 (3H, S), 4.73 (2H, S), 5.1 (1H, broad), 7.2 (1H, dd, J=8Hz), 7.8(1H, dd,J=8Hz, J=lHz) and 8.3 (1H, dd, J=7Hz, J=lHz) and 8.3 (1H, dd J=7Ez, J=lHz). To a cooled (0°) solution of 4 ml of thionyl chloride in 10 ml of methlene chloride was added dropwise a solution of 3.2 g (0.026 M) of the alcohol _13 in 10 ml of methylene chloride over a 15 minute period under a nitrogen atmosphere. Cooling bath was removed and the reaction was allowed to stir for 3 hours at room temperature. All solvents were evaporated in vacuo leaving compound _14 as a brown solid which was used for the next step without purification. The crude brown solid was - 14% - 205626 dissolved in 30 ml of absolute ethanol. There was then added 2.5 g (0.032 M) of thio urea and the mixture was heated at 65-70°C for 18 hours. The mixture was cooled to room temperature. The precipitate was collected by filtration and washed with ethanol (20 ml) and ether (50 ml) to yield 30 g of the isothiouronium salt. This salt was dissolved in 10 ml of water and a solution of 640 mg (0.016 M) of sodium hydroxide in 10 ml water was added under nitrogen. The reaction mixture was heated at 100° for 2 minutes and then cooled to 0°, adjusted to pH=6.0 with acetic acid and extracted with chloroform (2 x 35 ml). Evaporation of dried (MgSO^) chloroform gave 941 mg (46% yield) of the thiol as a yellow oil. NMR (C0C13) of the thiol _15 <5: 1.8(1H, t), 2.60(3H, S), 3.73(2H, d, J=10 Hz), 7.13(1H, dd, J=8 Hz) 7.57(1H, dd, J=8Hz), and 8.43(1H, dd, J=8Hz, 3Hz). OH OH 0^ —N 0 o ClP(0$)2 C02pNB COoPNB J 16 P-Nitrobenzyl-3-(2-methylpyridine-3-yl-methane thio)- 6ct-[l-(R)-hydroxyethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To a cooled (0°) solution of 1.52 g (4.37 mmole) of the keto intermediate 5_ in 5 ml of acetonitrile was added 0.86 ml (4.80 nmole) of diisopropyl ethylamine followed by a solution of 1.17 g (4.37 mmole) of diphenylchlorophosphate in 3 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred for 30 minutes at 0"C to provide p-nitrobenzy1-3-(diphenylphosphoryloxy) -6a-[l-(R)-hydroxy ethyl]-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To this solution was added a solution of 0.86 ml (4.80 mmole) of diisopropyl ethyl amine in 2 ml of acetronitrile followed by a solution of 940 mg (6.76 mmole) of the thiol 15 in 2 nl of acetonitrile. The reaction 205626 mixture was stirred for 60 minutes at 0°C. The precipitate was collected by filtration and washed with ether (30 ml) to give 1.12 g (55% yield) of the title product as a pale yellow solid. M.P. 186-188°C. (decoiap) . NMR (DMS0-d6) 6: 1.20(3H, d, J=7Hz), 2.60(3H, S), 3.40(m, 2E), 4.16(m, 2H), 4.32(2H, S), 5.16(1H, d, J=5Hz), 5.44(2H, q, J=14Hz), 7.32 (2H, m), 7.8(2H, d, J=8Hz) 8.36(2H, d, J=8Hz) and 8.48 (1H, dd, J=5.5Ez,1.5Hz). IR (KBr)Yma*: 3500, 1770 and 1750 cm"1. Anal. Calc'd. for C2JH 4K 0 S: C,58.83; H.4.94; N,8.94; S.6.83. Found: C.58.63; H,4.99; N,9.06; S.6.58. OH 16 17 Pd/C,H2 OH v .1 v . ■ 205626 3-(2-Methyl-N-methylpyridine-3-yl-methane thio)-6a[l-(R)-hydroxyethyl1 -7-oxo-l-azabicyclo(3.2.0) hept-2-ene-2-carboxylate. To a solution of 697 mg (1.19 mmole) of compound _16 in 100 ml of methylene chloride was added dropwise at 10°C 0.5 ml (6.18 mmole) of methyl fluorosulfonate over a 10 minute period. The mixture was stirred for 2.5 hours at room temperature. The precipate was collected by filtration and washed with 30 ml of methylene chloride to give 777 mg (90%) of the quaternized pyridine _17 as a yellcv. solid. NMR (C0C13) of compound 175: 1.20(3H, d, J=7Hz), 2.82(3H, s), 4.36(3R, s), 4.16(2H> m), 4.60(2H,s), 5.20(1H, m), 5.42 (2H, q, J=14Hz), 7.80(2H, d, J=8Hz), 8.04(1H, dd, J=7Hz, 6.5Hz), 8.32(2H, d, J=8Hz) 8.64(1H, d, J=7.5 Hz) and 9.08(1H, d, J=7.5 Hz). IR (KBr) vmax: 3500 and 1765 cm *. Anal. Calc'd. for C^H^FN^S: C.48.91; H,4.55; N.7.23; S.11.04. Found: C,49.39; H.3.97; N,7.20; S.10.98. To a solution of 1.10 g (1.88 mmole) of compound _17_ in 80 ml of tetrahydrofuran and 80 ml of ether was added 80 ml of pH 7.0 buffer solution followed by 800 mg of 10% palladium on charcoal. The mixture was hydrogenated at 30 psi on the Parr shaker for 40 minutes. The mixture was filtered through a Celite pad and the catalyst was washed with water (2x10 ml). The combined filtrate and washing were extracted with ether (2x100 ml) and lyophilized to give a yellow powder which was purified by HP-20 column chromatogrpahy, eluting with water followed by 5% acetonitrile in water. Each 15 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at Amax 300 nm were collected and lyophilized to give 614 mg (42% yield) of the title product as a slightly yellow powder. NMR (D20) 6: 1.28(d, 3H, J=7Hz), 2.86(3H, s), 3.20(2H, dd, J=10Hz, 3.5Hz), 3.42(1H, dd, J=5.4Hz, 3.5Hz), 4.20(3H, m), 4.32(3H, s), 4.35(2H, S), 9.88(1H, dd, J=7.2Hz, 6.5Hz), 8.5(1H, d, J=8Hz) and 8.70(1H, d, J=8Hz). IR(KBr) ymax: 3400, 1760, and 1590 cm UV Amax (H20): 298 nm (e=8391). Anal. Calc'd. for C^^N^S'H^: C,55. 73; K,5.46; N.7.65; S,8.74. Found: C,55.50; H,6.05; N,7.74; S,8.68. 205626 - i!i- Exarnple 15 Preparation of 3- [ 4- (NfN-dimethyl-1, 2,3-triazolium) -methylthio]-6a-[1-(R)-hydroxyethyl]-7-oxo-l-azabicyclo (3.2.0)hept-2-ene-2-carboxylate OH i. Preparation of isomer A SAc a) MeOTf b) Aq. NaOH d) H2/Pd-C co2pnb I V ... - 205626 -15/ - Methyltrifluoromethane sulfonate (0.58 mL, 5.16 mmol) was added dropwise to an ice-cooled, stirred, solution of 4-(methanethiolacetate)-1-methyl-l,2,3-triazole (590 mg, 3.52 mmol) in dry methylene chloride (2 mL) under nitrogen. After 0.5 h, the bath was removed and after 1 h, the solvent was removed with an aspirator. The residual oil was dissolved in a few mL of water and this solution was cooled in an icebath. A cold solution of sodium hydroxide (305 mg, 7.59 rnmol) in a few mL of water was then added and the reaction was left stirring for 0.75 h. The solution was diluted to 25 mL with water and the pH was adjusted to 7.5 by the addition of solid sodium dihydrogen phosphate monohydrate. Then, 14 mL of this solution (ca. 1.9 mmol of the triazolium thiol) was added to an ice-cooled, stirred, solution of the enol phosphate (1.0 g, 1.72 mmol) in tetrahydrofuran (THF) (10 mL). This was left stirring for 0.75 h (some crystalline material, presumably Na^HPO^ is deposited during the course of this reaction). The suspension was transferred to a pressure bottle with the aid of some THF (20 mL) and water (20 mL). Ether (30 mL) and 10% palladium on charcoal (1.0 g) were added and the mixture hydrogenated (40 P.S.I.) for 1 h. The organic phase was separated and washed with water (2x5 mL). The combined aqueous phases were filtered and the filtrate was concentrated under high vacuum (ca. 0.5 mm, 1.5h). The yellow solution was then chromatographed (medium pressure reverse phase column, 35 x 90 mm, ^0 as eluent) to afford, after lyophilization, 395 mg of the carbapenem slightly contaminated with some inorganic material. It was purified by HPLC (10 x 300 ram Waters Microbondapack C-18 column, multiple injections, H20 as 205626 ; * 3 -15X - eluent) to give 310 mg (57%) of isomer A as a tan-colored powder: 1HNMR (D20) 6: 1.23 (3H, d, J=6.4 Hz), 3.10 (2H, d, J=9.1 Hz) , 3.24 (1H, q, J=2.7, 6.1Hz), 4.03-4.71 (10H, m), 8.46 (1H, s) ; IR (nujol) 1760 cm uv (phosphate buffer, pH 7.4, M=0.05U : 296 (e = 7,500). IllaX B. Preparation of isomer B and isomer C SAC „N —Me -n/ (tentative structure) a) MeOTf b) aq. NaOH co2pnb d) H2/Pd-C Methyltrifluoromethane sulfonate (1.60 mL, 14.0 mmol) was added dropwise to an ice-cooled solution of 4-(methanethiolacetate)-2-methyl-l, 2, 3-triazole (1.20 g,' 7.02 mmol) in dry methylene chloride (6 mL) under nitrogen. This was allowed to warm to room temperature and left stirring for 16 h. Additional methyltrifluoromethane sulfonate (0.40 mL, 3.56 mmol) was added and after 3 h at room temperature, the solvent was removed with an aspirator. The residual oil was triturated with ether and the resulting gum was dissolved in water (5 mL) . This was cooled in an icebath and a solution of sodium hydroxide (844 mg, 21.1 mmol) in water (5 mL) was added. After stirring for 0.75 h, this solution was diluted to 60 mL with water and the pH adjusted to 8 by the addition of solid potassium dihydrogen phosphate. Then, 40 mL of this solution (ca. 4.7 mmol of a mixture of isomeric triazolium thiols) was added to an 205626 - 15\- ice-cooled, stirred, solution of the enol phosphate (2.00 g, 3.45 mmol) in THF (60 mL) . This mixture was left stirring in the icebath for 0.5 h after which it was transferred to a pressure bottle containing a suspension of 10% palladium on charcoal (2.00 g) and ether (60 mL). The mixture was hydrogenated (40 P.S.I.) for 1 h. The organic phase was separated and washed with water (2 x 10 mL). The combined aqueous phases were filtered and the filtrate was concentrated under high vacuum (ca. 0.5 mm, 1.5 h). The remaining solution was then chromatographed (medium pressure reverse phase column, 45 x 130 mm, H20 as eluent) to afford, after lyophilization, 595 mg of a mixture of isomeric carbapenems which were contaminated with a little inorganic material. These were separated and purified by HPLC (10 x 300 mm Waters Micro-bondapack C-18 column, multiple injections, H20 as eluent) to afford, in order of elution: isomer B; 153 mg (13%) ; 2HNMR (D20) 6: 1.23 (3H, d, J=6.4 Hz), 3.12 (2H, q, J=1.4, 8.9 Hz), 3.39 (1H, q, 3=2.1, 6.0 Hz), 4. 07-4.68 (10H, m) , 8.19 (1H, s); IR (nujol) 1755 cm 1; uv (phosphate buffer, pH=7.4, M=0.05) X : 296 nm (e=6, 700); and isomer C;284 mg . itlelx (24%); HNMR (DjO) 6: 1.23 (3H, d, H=6.4 Hz), 3.15 (2H, q, J=3.7, 9.0 Hz), 3.37 (1H, q, J=2.6, 6.0 Hz), 3.95-4.65 (10H, m) , 8.62 (1H, s); IR (nujol) 1750 cm"1; uv (phosphate buffer, pH 7.4, M=0.05) A : 298 nm (e=7,600). max V 205626 4 - 15\-Example 16 (5R,65) 6-(lR-hydroxyethyl)-3-(2-methyl-l,2,3-thiadia2olium-4-ylmethylthio)-7-oxo-l-azabicyclo[3.2■0)hept-2-ene-2-carboxylate A. Ethyl 1,2,3-thiadi.a2ol-4-ylcarboxylate .c CH ^ ^CO£t NHCOEt SOC1. -OEt A solution of ethyl a-N-carbethoxyhydrazonoproprionate (31.2 g, 0.154 mol) in thionyl chloride (80 mL) was stirred at 23°C for 3 h and heated at 70°C for 20 rain. Thionyl chloride was evaporated and the residue was triturated in hexane (4 x 30 mL) . The red solid was dissolved in dichloromethane (150 mL) and the solution was washed with saturated sodium bicarbonate solution and water. After drying over Na2SO^ the solution was concentrated until the compound crystallized. After standing at 23°C for a while, the crystals were filtered; 16.8 g, mp 86°C, 69%. The filtrate was concentrated and purified by chromatography on a silica gel column with dichloromethane as eluting solvent to give 3.17 g, mp 86°C, 13%, ir (KBr)v : 1720 (ester) cm ^Hmr (CDC1,) rr.ax j 6: 1.52 (3H, t, J=7. 1 Hz, Ci^CHjO) , 4.57 (2H, q, J=7.1 H2, CH-jCHjO) , 9.47 (1H, s, H of thiadia20le). ^"C.D. Hurd and R.I. Mori, J. Am. Chem. Soc. , 77, 5359 (1955). '» , -6 AUG 1984" t \ I V i. 205626 (? - is\- B. 1,2,3-thiadiazol-4-ylmethanol^" To a suspension of ethyl 1,2,3-thiadiazol-4-ylcarboxylate (18.35 g, 0.116 mol) in ether (400 ml) was added portionwise lithium aluminum hydride (2.47 g, 0.065 mol) over 1 h period. The reaction mixture was stirred at 23°C for 7 h and treated with lithium aluminum hydride (2.47 g, 0.065 mL). The stirring was continued for 24 h before adding successively water (7 mL), 15% sodium hydroxide solution (7 mL) and water (21 mL). After stirring for 15 min, the ether solution was decanted and the gum was extracted with ether ( 5 x 100 mL). The ether extracts were combined, dried (MgSO^) and concentrated (5.4 g). The crude material was purified on silica gel column (120 g, 4 x 16 cm) , with ether as eluting solvent to give 1.3 g (7%) of ethyl 1,2,3-thiadiazol-4-ylcarboxylate and 2.45 g (18%) of 1,2,3-thiadiazol-4-ylmethanol; ir (film)v.„ : 3380 (OH) cm ^Hmr (CDC1,)5: 2.31 IDaJC j (1H, s, OH), 5.22 (2H, s, CHjO) , 8.50 (1H, s, H of thiadia'zole) . ^"S.I. Ramsby, S.O. Ogren, S.B. Ross and N.E. Stjernstrom, Acta Pharro. Succica., 10, 285-96 (1973); C.A., 79, 137052W (1973). //■£ U-6AUG19M J 1c* \' I 205G26 C. 1,2,3-thiadiazol-4-ylmethanol methanesulfonate A solution of 1,2,3-thiadiazol-4-ylmethanol (0.75 g, 6.5 mmol) in dichloromethane (20 mL) was cooled to 5°C under a nitrogen atmosphere and treated with triethylamine (1.018 mL, 7.3 mmol) and methanesulfonyl chloride (0.565 mL, 7.3 mmol). After 15 min, the ice-bath was removed and the reaction mixture was stirred for 2 h. The solution was washed with IN hydrochloric acid solution (2x2 mL) and water, dried (MgS04 + MgO) and concentrated. The residue was purified by chromatography (silica gel column 1.5 x 21 cm) with ether as eluting solvent to give 0.90 g (71%) of 1,2,3-thiadiazol-4-ylmethanol methanesulfonate; ir (film)vm : 1350 (SO,) cm-1, 1172 (SO,) cm"1; "Wr (CDC1,)6: ItlaX £ £ u 3.09 (3H, s, CH3), 5.75 (2H, s, CH2), 8.72 (1H, s, H of thia- diazole) ; uv (CH,C1,)A. : 251 (£1990). Anal, calcd for 2 2 max CgHgNjO^S: C 24.73, H 3.11, N 14.42, S 33.02; found: C 24.78 H 3.09, N 14.66, S 31.94 and 0.13 q (19%) of di-(1,2,3-thiadiazol- 4-ylmethyl)ether; ir (film)v : 1272, 1242, 1200, 986, 805, . . max 728 cm ; Hmr (CDC13)6: 5.16 (s, 4H, CHj), 8.42 (s, 2H, H's of thiadiazole). 2056ZG D. 4-acetylthiomethyl-l,2,3-thiadiazole ^CH OMs P ^CH stCH r$ ^ , IS 2 3 To a solution of l,2,3-thiadiazol-4-ylmethanol methanesulfonate (0.90 g, 4.6 mmol) in tetrahydrofuran (9 mL) was added an aqueous solution (2 mL) of sodium thiolacetate [prepared from thiolacetic acid (0.38 ml, 5.3 mmol) and sodium bicarbonate (0.445 g, 5.3 mmol)]. The resulting mixture was stirred at 23°C for 1 h and diluted with ether (75 ml) . The organic solution was washed with water (3x3 mL), dried (MgSO^) and concentrated. The crude mixture was purified by chromatography (silica gel column: 1.4 x 19 cm) with 50% ether in hexane as eluting solvent to give 0.60 g (75%); ir (film) v : 1675 (C=0) cm-1; 1Hmr (CDC1J6: 2.37 (3H, s, CH,) , max >3 j 4.58 (2H, s, CH2), 8.44 (1H, s, H of thiadiazole). Anal, calcd for C5HgN2OS2: C 34.47, H 3.47, N 16.08, S 36.80; found; C 34.48, H 3.83, N 16.28, S 36.80. 265626 E. 4-acetylthiomethyl-2-methy1-1,2,3-thiadiazolium trifluoro-methanesulfonate and 4-acetylthiomethyl-3-iDethyl-l, 2, 3-thiadiazoliura trifluromethane sulfonate (0.60 g, 3.44 inmol) in a mixture of ether (4 mL) and dichloromethane (0.4 mL) were added a few crystals of the title compounds and trifluoromethanesulfonate (0.407 mL, 3.6 mmol) over 5 min period. The reaction mixture was stirred at 23°C under a nitrogen atmosphere for 6 h. The white solid that was a mixture of the two title compounds was filtered and washed with ether, 1.05 g, 90%; ir (KBr)vm : 1675 (C=0) cm"1; himr (DMSO, d-6)<5: jnax 2.43 (3H, s, CH3C0S), 3,33 (s, CHj on N-3), 4.57 (s, CH3 on N-2), 4.66 (2H, s, CH2), 9.55 (H on thiadiazolium N-2), 9.66 ( H on thiadiazolium N-3). Anal, calcd for C7HgN204S3F3: C 20.27, H 2.38, N 9.45, S 32.46; found: C 24.61, H 2.57, N 8.47, S 28.21. + I To a solution of 4-acetylthiomethyl-l,2,3-thiadiazole 205626 F. 4-mercaptomethy1-2-methy1-1/2,3-thiadiazolium trifluoromethanesulfonate and 4-mercaptomethyl-3-methyl-l, 2,3-thiadiazoliuni trifluoromethanesulfon a te A solution of a mixture of 4-acetylthiomethyl-2-methyl-1,2;3-thiadiazolium trifluoromethanesulfonate and 4-acetylthiomethyl-3-methyl-l,2,3-thiadiazolium trifluoromethanesulfonate (1.05 g, 3.1 mmol) in 6N hydrochloric acid (10 mL) was heated at 65°C under a nitrogen atmosphere for 1.75 h. The solvent was evaporated under reduced pressure leaving a yellow syrup 0.91 g. This compound was used in the next step without purification. HCl, 6H + w G. (5R,6S) 6- (lR-hydroxyethyl)-3- (2-methyl-l, 2, 3-thiadiazolium-4-ylmethylthio)-7-oxo-l-azabicyclo[3■2.0]hept-2-ene-2-carboxylate A cold (5°C) solution of (5R,6S) paranitrobenzy1 6-(lR-hydroxyethyl)-3-(diphenylphosphono)-7-oxo-l-azabicyclo(3.2.0)-hept-2-ene-2-carboxylate (1.7 g, 2.92 mmol) in tetrahydrofuran (10 mL) was treated with a solution of a crude mixture of 4-mercaptomethyl-2-methyl-l,2,3-thiadiazolium trifluoromethanesulfonate and 4-mercaptomethyl-3-methyl-l,2,3-thiadiazolium trifluoromethanesulfonate (0.9 g) in a mixture of phosphate buffer (pH 7.2, 0.3M, 15 mL) and tetrahydrofuran (5 mL). The reaction mixture was stirred for 1 h and the pH was kept at 7.2 with 2N sodium hydroxide solution. The stirring was continued for one more hour before adding ether (50 mL) and 10% palladium on charcoal (1 g). The resulting mixture was hydrogenated at 23°C under 45 psi for 2 h and filtered through a Celite pad. The organic phase was separated, diluted with ether (50 mL) and phosphate buffer (pH 7.2, 0.3M, 20 mL) and hydrogenated (2 g of 10% palladium on charcoal) for 2 h under 50 psi. The aqueous phases were combined (from the first and second hydrogenolysis), washed with ether and purified by chromatography on PrepPak 500-C/18 with water as eluting solvent to give 0.22 g of crude material. It was repurified by hplc with water as eluting coo 205626 "16 ^ " solvent to give 0.0 40 g (4%) of the title compound after lyophilization, ir (K3r)v : 3400 (br, OH), 1745 (C=0 of ItlcX « * 6-lactam) , 1580 (carboxylate) cm" ; Tlmr (D20) 6 : 1. 23 (3H, d, J=6.3 Hz, CHjCHOH), 3.04, 3.05, 3.16 (2H, m, H-4) , 3.38 (1H, dd, J=2.8 Hz, J=6.0 Hz, H-6), 3.9-4.6 (2H, m, H-5, CH3CHOH), 4.51, 4.53 (2"s"/ SCH2), 4.61 (s, N+CH3); uv (H2°) ^majc: 224 (£4345), 262 (e4980), 296 (E6885) , [a]" 18° (c 0.18, H20) ; T^2=9.8 h (measured at a concentration-of 10"4 M in phosphate buffer pH 7.4 at 36.8°C). * 6AUGWM 205626 Example 17 Potassium 3 - [ 5- (1-carboxy latomethyl-3-methy 1-1, 2, 3-triazoliuro) -methanethio]-6a- [ 1- (R) -hydroxyethyl]-7-oxo-l-azabicyclo[3.2.0 jhept-2-ene-2-carboxy late HO^s-n. x> 1) LAH 2) MsCl/NSt^ KSCOCH, CO, 0 a) KOH oh H H N AcS b) c) Hj/Pci-C of (Oljl) 2 C02?NB BrCH^COEt o2zt Br ,0 ' 'V ,^T6 Nr -©AUG 1984* 205626 - 16\- Lithium aluminum hydride (2.83 g, 70.9 mmol) was added in small portions to a stirred suspension of 1-methyl-1,2,3-triazole-4-carboxylic acid1 (9.00 g, 70.9 mmol) in dry THF (200 mL). The mixture was left stirring at room temperature for 15 h after which a 20% aqueous solution of sodium hydroxide (20 mL) was carefully added in ca. 1 mL aliquots. The resulting granular suspension was filtered and the solid washed with additional THF (5 x 75 mL). The combined THF solutions were dried (MgSO^) and the solvent removed. The .residual yellow oil was flash chromatographed on a silica gel column (90 x 35 mm) [100 mL portions of hexane, mixtures of ethyl acetate-hexane (1:1) and (1:3), and lastly ethyl acetate-methanol (9:1) as eluent]. This afforded 4-hydroxymethyl-l-methyl-l,2,3-triazole (3.18 g, 40%) as a colourless oil: ^HNMR (CDCl^) 6 4.07 (3H, s), 4.73 (2H, d), 7.52 (1H, s); IR (neat) 3320 cm . Methanesulfonyl chloride (3.82 mL, 49.6 mmol) was added dropwise to an ice-cooled, stirred, solution of the alcohol (4.67 mL, 41.3 mraol) and triethylamine (7.47 mL, 53.7 mmol) in methylene chloride (20 mL) . After 0.5 h, the solvent was removed and the residual solid was taken up in acetonitrile (30 mL). Potassium thiolacetate (7.06 g, 62.0 mmol) was then added and the suspension was left stirring at room temperature for 3 h. An additional quantity of potassium thiolacetate (3.0 g, 26.3 mmol) was added and the suspension was left stirring for a further 16 h. The dark-coloured suspension was then concentrated and t water (10 mL) was added. This mixture was extracted with methylene chloride (5 x 40 raL). The combined extracts were dried (MgSO^) and the solvent removed. The residual oil was flash chromatographed on a silica gel column (90 x 36 mm) [hexane followed by a mixture 1C. Pederson, Acta. Chem. Scand., 1959, 13, 888 4 - 16\- of hexane-ethyl acetate (1:1) being used as eluent]. This afforded 4-(methanethiolacetate)-1-methyl-1,2,3-triazole (5.95 g, 84%) as a faint pink coloured solid: ^HNMR (CDCl^) 6 2.40 (3H, s), 4.10 (3E, s) , 4.20 (2H, s), 7.53 (1H, s); IR (nujol mull) 1675 cm \ A solution of the triazole (1.00 g, 5.85 mmol) and ethyl bromoacetate (1.48 ml, 13.3 mmol) in dry acetonitrile (10 mL) was heated at 60" for 90 h under nitrogen. The solvent was removed and the residual oil was triturated with ether (4 x 25 mL) to leave 1-methy1-3-(ethyl carboxyraethyl)-4-methanethiolacetate-1,2,3-triazolium bromide as a brownish gum which was used directly. A cold solution of KOH (0.66 g, 12 mmol) in water (5 mL) was added to an ice-cooled, stirred, solution of the triazolium bromide in water (20 mL). After 20 min, this was diluted to 35 mL and sufficient solid potassium dihydrogen phosphate was added to bring the pH of this solution to 8.0. This was then added to a stirred, ice-cooled, solution of the enol phosphate in THF (35 mL). After 0.5 h, this mixture was transferred to a pressure bottle containing ether (35 mL) and 10% palladium on charcoal (1.5 g). It was hydrogenated at 40 p.s.i. for 55 min. The organic phase was then separated and washed with water (2x5 mL). The combined aqueous phases were filtered and the filtrate concentrated under high vacuum. The residual material was chromatographed on a reverse phase column (35 x 120 mm) with water as eluent. Lyophilization of the carbapenem containing fractions left 1.20 g of a green-coloured solid. This was rechromatographed or a Waters Prep. 500 HPLC (PrepPAK-500/C^g column) with 2% acetonitrile-water as eluent. The fractions containing the carbapenem were combined and lyophilized. This material was again rechromatographed by HPLC (10 x 300 mm Waters Microbondapack C-18 column) - 16\- with water as eluent to afford, after lyophilization, pure title compound (190 mg, 17%) as a pale yellow solid: 1HNMR (D20) 5 1.24 (3H, d, J=6.4 Hz), 3.07 (2H, d, J=9 Hz), 3.38 (1H, q, J=2.7, 6.0 Hz), 4.02-4.30 (3H, n), 4.29 (3H, s), 5.23 (2H, s), 8.52 (1H, s) ; IR (nujol mull) 1750 cm"1; UV (phosphate buffer, pH 7.4)X 296 nm (e=7,520). itlclx Example IB Potassium 3-[4-(l-carboxylatomethyl-3-methvl-l,2,3-tria2oliiim)-methanethio]-6a-[1-(R)-hydroxyethyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate hcL- EtO?CH2N3 J 4j EtO£( b) Ka5H :c1,ks VNv^° y~ oE-N«) hscch 6 3 (?' 'A OH "a) He OK b) ko:-i OH On, K H c) •OP (0$) 2 CO PN3 2 d) Hj/Pd-C A mixture of ethyl azidoacetate (30.0 g, 0.23 mol) and propiolic acid (14.3 mL, 0.23 mol) in toluene (75 mL) was stirred at room temperature. The reaction remained mildly exothermic for 1.5 h after which it quickly became vigorously exothermic and cooling with an ice bath was necessary. After this exothermic phase had passed, the reaction was heated at reflux for 0.5 h. After being cooled in an ice bath, the crystalline material was collected by filtration and washed with a little toluene. The crude material obtained in this manner (33.3 g, 7 2%) consisted of a single isomer [^HNMR (DMSO-dg) 6 1.20 (3H, t, J=7 Hz), 4.15 (2H, q, J=7 Hz), 5.42 (2H, s), 8.67 (1H, 3)], presumably 1-(ethyl carboxymethyl) -' 1,2,3-triazole-4-carboxylic acid by analogy with earlier work1. A solution of the carboxylie acid (5.00 g, 25.1 mmol) and triethylamine (3.68 mL, 26.4 mmol) in dry methylene chloride (50 mL) was added to an ice-cooled, stirred, solution of ethyl-chloroformate (2.52 mL, 26.4 mmol) in dry methylene chloride (50 mL). The purple coloured solution was left stirring for 0.5 h afterwhich it was washed with water (10 mL), dried (MgSO^) and the solvent removed. The crude mixed anhydride was dissolved in THF (50 mL) and added slowly to an ice-cooled suspension of sodium borohydride (0.72 g, 18.9 mmol) in THF (50 mL). After stirring for 0.5 h, additional sodium borohydride (0.30 g, 7.9 mmol) was added and the reaction was left in the ice bath for 1 h. Water (5 mL) was then added and after 10 min, this was followed by 10% aqueous HCl (3 mL). After gas evolution had ceased, solid potassium carbonate (2 g) was added with ^C. Pederson, Acta. Chem. Scand., 1959, 22' ®^8 205626 stirring. The organic phase was then removed and the residual white paste was extracted with additional THF. The combined organic phases were dried (MgSO^) and the solvent removed. Flash column chromatography on silica gel, eluting with hexane, mixtures of ethyl acetate-hexane, and finally ethyl acetate afforded l-(ethyl carboxymethyl)-4-hydroxymethyl-l,2,3-triazole (2.04 g, 44%) as a crystalline solid: ^HNMR (CDCl^) <5 1.28 (3H, t, J=7 Hz), 4.23 (2H, g, J=7 Hz), 4.75 (2H, s) , 4.85 (2H, s) , 7.73 (1H, s). Diisopropylazodicarboxylate (4.11 mL, 20.8 mmol) was added dropwise to an ice-cooled solution of triphenylphosphine (5.47 g, 20.8 mmol) in dry THF (100 mL) under nitrogen. After 0.5 h, an ice-cooled solution of the alcohol (1.93 g, 10.4 mmol) and thiolacetic acid (1.49 mL, 20.8 mmol) in dry THF (50 mL) under nitrogen was added to this mixture. This was left for 2 h in the ice bath and then for an additional 12 h at room temperature; afterwhich the solvent was removed. The reaction mixture was flash chromatographed on silica gel (40 g; eluting with 100 mL portions of hexane, 5%, 10%, 15%...50% ethyl acetate-hexane) . Fractions containing the thiolacetate were combined and rechromatographed on silica gel (6 0 g) [elution with 200 mL portions of: hexane, 5%, 10%, 15%, 20% ethyl acetate-hexane and 22.5, 25, 27.5...35% ethyl acetate-hexane]. This afforded 1.24 g (49%) of 1-(ethyl carboxymethyl)-4-methanethiolacetate-l, 2,3-triazole as a crystalline solid [^HNMR 6 1.28 (3H, t, J=7 Hz) , 2.37 (3H, s), 3.87 (2H, s) , 3.90 (2H, q, J=7 Hz), 5.12 (2H, s) , 7.63 (1H, s) ; IR (nujol mull) , 1735, 1780 cm-1] and an additional 1.40 g of material contaminated with triphenylphosphine oxide. \ I 205626 m Methyl trifluoromethane sulfonate (0.51 mL, 4.53 mmol) was added dropwise to an ice-cooled, stirred, solution of the triazole (1.00 g, 4.12 mmol) in dry methylene chloride (5 mL) . The bath was removed after 0.5 h and after an additional 0.5 h, the solvent was removed with an aspirator vacuum. This left a white solid which was suspended in water (15 mL) and this stirred mixture was cooled in an icebath. A solution of KOH (0.69 g, 12.4 mmol) in water (5 mL) was added and the reaction was left stirring for 1 h. It was then diluted to 30 mL with water and solid potassium dihydrogen phosphate was added to bring the pH to 8.0. A portion of this solution (22 mL, ca. 3.0 mmol of the thiolcarboxylate) was added to an ice-cooled, stirred solution of the enol phosphate (1.60 g, 2.76 mmol) in TKF (30 mL) . After 0.5 h, the reaction was taken and put under high vacuum to remove the THF. The yellow solution was then chromatographed on a reverse phase column (35 x 120 mm) eluting with water (300 mL) followed by 100 mL portions of 5, 10, 15... 30% acetonitrile-water. Lyophilization of the desired fractions afforded the p-nitrobenzyl ester as a yellow solid (930 mg) . This was transferred to a pressure bottle containing ether (25 mL) , THF (25 mL) , and phosphate buffer [25 mL, prepared by dissolving potassium dihydrogen phosphate (1.36 g, 0.01 raol) in water (100 mL) and adjusting the pH to 7.4 by adding 45% aqueous KOH] and 10% palladium on charcoal (900 mg). The hydrogenation was conducted at 40 p.s.i. for 1 h after which the organic phase was separated and washed with water (2x5 mL) . The combined aqueous phases were filtered and then concentrated under high vacuum. The residual solution was chromatographed on a reverse phase column (35 x 120 mm) eluted with water. Fractions containing the carbapenem were combined and lyophilized to afford 1.21 g of a pale greenish solid. This was then purified by HPLC (10 x 300 mm water microbondapack C-18 column, H2O as eluent) to give pure title product, 480 mg (41%)-: ^NMR (D20) <5 1.23 (3H, d, J=6.4 Hz)^L , - 6 AUb 1984 i 1 ZQ5&Z6 > - 18*- 3.11 (2H, d, J=9 Hz), 3.37 (iH, g, J=3.0, 6.1 Hz), 4.02 (7H, m) , 5.18 (2H, s) , 8.53 (1H, s): IF. (nujol mull) 1750 cm-1: UV (phosphate buffer, pH 7.4)'.^ 205 nm (e=7,810). Example 19 3- 15~ (1/ 4-Dimezhvl-1, 2, 4-triazolium) methanethio] -6c- [1- (R) -hydroxyethyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate A t A. l-methy 1-5-methane thiolacetate-1,2,4-triazole it* o„ ^ r\J~ NjT b) CH3CSH/NEt3 ^ Methanesulfonyl chloride (0.46 mL, 6.0 mmol) was added dropwise to an ice-cooled, stirred, solution of l-methyl-5-hydroxymethy1-1,2,4-triazole* (565 mg, 5.0 mmol) and triethylamine (0.91 mL, 6.5 mmol) in methylene chloride (5 mL) . After 20 min, additional triethylamine (1.05 mL, 7.5 mmol) followed by thiol-acetic acid (0.53 ml, 7.5 mmol) was added and stirring was continued for 45 min. The reaction was then diluted with *R.G. Jones and C. Ainsworth, J. Amer. Chem. Soc., 1955, 77, 1938. 71 - iw«- methylene chloride and washed with water. The aqueous phase was extracted with methylene chloride (3x5 mL) and the combined organic phases were dried (MgSO^) and the solvent removed. Column chromatography on silica gel afforded pure l-methyl-5-methanethiolacetate-l,2,4-triazole (570 mg) as a yellow oil [in addition, an impure fraction (200 mg) was rechromatographed (preparative TLC, silica gel) to give a further 100 mg of pure material (total yield: 85%)]: ^HNMR (CDC13) 6 2.38 (3H, s), 3.90 (3H, s), 4.25 (3H, s), 7.80 (1H, s). B. 3- [5- (1, 4-dimethvl-l,2, 4-triazoliura) -methanethio 1 -6a-[1-(R)-hydroxyethyl]-7-oxo-l-azabicyclo[3.2.0Jhept-2-ener 2-carboxylate was added dropwise to an ice-cooled solution of l-methyl-5-raethanethiolacetate-1,2,4-triazole (730 mg, 4.27 mmol) in methylene chloride (7 mL). The reaction mixture was slowly allowed to warm to room temperature over 3 h after which it was concentrated. The residual oil was triturated with ether to leave crude l,4-dimethyl-5-methanethiolacetate-l,2,4-triazolium trifluoromethanesulfonate (1.46 g) which was used directly. OH C0jPN3 d) H2/Pd-C Methyl trifluoromethanesulfonate (1.20 mL, 10.7 mmol) 17; f A solution of sodium hydroxide (512 mg, 12.8 mmol) in water (5 mL) was added to an ice-cooled solution of the triazolium salt (1.45 g, 4.35 mmol) in water (5 mL). After 45 min, this was diluted to 25 mL with water and the pH was adjusted to 7.5 with solid potassium dihydrogen phosphate. This solution was then added to an ice-cooled, stirred, solution of the enol phosphate (2.00 g, 3.45 mmol) in THF (25 mL). After 30 min, the reaction mixture was transferred to a pressure bottle containing ether (40 mL) and 101 palladium on charcoal (2.0 g). This was hydrogenated (45 p.s.i.) for 1.25 h. The reaction mixture was then diluted with ether (25 mL) and filtered. The organic phase was separated and washed with water (2x5 mL). The combined aqueous phases were washed with ether (3 x 25 mL) and then concentrated under vacuum. Column chromatography (reverse phase, 45 x 130 mm, water as eluent), followed by lyophilization of the carbapenem-containing fractions afforded 650 mg of crude material. This was rechromatographed to give pure title product (450 mg, 39%) : ^HNMR (DjO) 5 1.24 (3H, d, J=6.4 Hz), 3.19 (2H, q, J=2.6, 9.2 Hz), 3.45 (1H, q, J=2.8, 6.0 Hz), 3.91 (3H, s), 4.05 (3H, s), 4.08-4.36 (2H, m) , 4.54 (2H, d, J=2.8 Hz), 8.71 (1H, s); IR (nujol mull) 1755 cnfL; CJV (phosphate buffer, pH 7.4) *maj£ 294 nm (e = 8,202); Tjy2 (phosphate buffer, pH 7.4, M=0.067, T=370C) 9.1 h. 205626 2056.26 5 - iAr Example 20 (1' R,5R,6S) 3-[(1,3-dimethyl-5-tetrazoliunQ-methylthiol-6-(l-hydroxyethyl)-7-oxo-l-azabicyclot 3.2.0]hept-2-ene- 2-carboxylate °H - i .ca. co>/ t33« A. 5-carbethoxy-2-methyltetrazole and 5-carbethoxy-l-methyltetrazole CH N n^-N 0 P k>-<V ■\ "W. \,3 la. Methylation with diazomethane A solution of 5-carbethoxytetrazole1 (9.17 g, 0.064 2 mmol) in ethyl ether (80 mL) was cooled to 0°C and treated ^D.Moderhack, Chem. Ber., 108, 887 (1975). ^The use of a mixture of ethanol and ether gave the same ratio of isomers. dropwise (15 rein) with a solution of diazomethane (3 g, 0.071ranol) in ether (200 mL). The light yellow solution was stirred for 30 min and the excess of diazomethane was destroyed by addition of acetic acid (1 mL). Evaporation of the solvent and distillation of the residue gave a clear oil: bp 95-100°C/0.5 torr; 9.64 g, (96%). *Hmr indicated a mixture of 1-methyl and 2-methyl isomers in a ratio 5:4. Separation of the two isomers could not be done by distillation nor hplc: ir (film) v : 1740 cm 1 ^ IHaX (C=0 of ester); Hmr (CDCl^) 6: 1.53 (3H, two overlapping t, J=7.0, CH2CH3), 4.46 and 4.53 (3H, 2S, CH3 of 1-methyl and 2-methyl tetrazoles, ratio 6:4. The methyl of the 2-isomer is at lower field and is the minor product), 4.5 ppm (2H, two overlapping q, CH2CH3!. lb. 5-Carbethoxy-2-methyltetrazole N-"N. CH,1 ll V— CO.Et + J CO Et *- | A—CO Et 2- 2 i3°°c of-** NCH3 CH3 3 A mixture of 5-carbethoxy-2-methyltetrazole and 5-carbethoxy-l-methyltetrazole (0.252 g, 1.61 mmol, ratio of the two isomers 1:1) in iodomethane (0.5 mL) was selaed in a glass tube and heated at 100°C for 15 h and at 130°C for 6 h. Distillation of the reaction mixture gave the title compound as a light yellow oil: 0.139 g (55%); bp 95-100°C/0.5 torr (air bath temperature): ir (film) : 1740 cm 1 (C=0 of ester); . IQoA Hmr (CDC13) <5: 1.46 (3H, t, J=7.0, CH3CH2> , 4.53 (3H, s, CH3~2] , 4.5 (2H, q, J=7.0, CHjCH^ . 205625 -nj - 2. Methylation with dimethyl sulfate A solution of 5-carbethoxytetrazole (1.42 g, 0.01 mol) in dry acetone (20 mL) was treated with anhydrous potassium carbonate (1.38 g, 0.01 mol) and dimethyl sulfate (1.26 g, 0.01 mol). The mixture was heated under reflux for 12 h. The carbonate was filtered and the solvent evaporated under reduced pressure. The residue was diluted with dichloromethane (30 mL), washed with saturated sodium bicarbonate (10 mL) , brine (10 mL) and dried over anhydrous sodium sulfate. Evaporation of the solvent and distillation under vacuum gave a clear oil: 1.45 g (93%); b.p. 85-110°C/0.5 torr. ^Hmr indicated the presence of two isomers in a ratio 1:1. B. 5-Hydroxymethy1-2-methyltetrazole + ubh4 ► 1. By reduction of the mixture of esters. A mixture of 5-carbethoxy-l-methyltetrazole and 5-carbethoxy-2-methyltetrazole (ratio 6:4) (7.60 g, 0.049 mol) in dry tetrahydrofuran (50 mL) was cooled to 0°C and treated with lithium borohydride (1.06 g, 0.049 mmol) added in small portions over 15 rain. The mixture was maintained at 10°C for 30 addition min and then stirred at 20°C for 4 h. The mixture was cooled to 0°C and the excess hydride was carefully destroyed by addition of 6N HCl (pH of 7 after no more gas was evolved). The solvent was concentrated under vacuum and the residual oil diluted with dichloromethane (200 mL), washed with brine (10 mL) and finally dried over Na.SO^. Concentration of the solvent # A i*-6AUG!984 1 *Jt 205626 -17 f- and distillation of the residue under vacuum gave 1.93 g (338) of a clear oil. ^Hrar of this material indicated the product was 5-hydroxymethyl-2-methyltetrazole. 2. By reduction of 5-carbethoxy-2-methyltetrazole. To a solution of 5-carbethoxy-2-methyltetrazole (0.139 g, 0.89 mmol, obtained by isomerization of the mixture of esters with methyl iodide) in dry tetrahydrofuran (1 mL) at 10°C was added solid lithium borohydride (0.019 g, 0.87 mmol) . The mixture was slowly warmed up to room temperature and stirred for 4 h. The excess borohydride was destroyed by careful addition of 6N HCl at 0°C (pH 7). The solvent was evaporated and the residue dissolved in dichloromethane (25 mL) and dried over anhydrous sodium sulfate. Evaporation of the solvent gave the title compound as a clear oil: 0.092 g (91%) ; bp 90-120°C/0.5 torr with decomposition; ir (film) v _ : « infix 3350 cm"1 (broad, OH); Tlmr (CDClj) 6: 4.4 (2H, s, CH3~2), 4.93 (2H, s, CH2-5). C. 5-AcetyImercaptomethyl-2-methyltetrazole 1) MsCl, Et3N J£>v 21 °JC0S,; ■ J>"V j I v '—I ■ ' V- ' -W. • 205626 /?»A To a solution of 5-hydroxymethyl-2-methyltetrazole (1.83 g, 11.7 mmol) in dry dichloromethane (25 mL) at 0°C was added methanesulfonyl chloride (1.47 g, 12.9 mmol) followed by triethylamine (1.30 g, 12.9 mmol) added dropwise over five min. The mixture was stirred at 0°C for 1 h, and then treated with a solution of potassium thioacetate (1.60 g, 14.0 mmol) in dry N,N-dimethylformamide (10 mL). The resulting gel was stirred at 0°C for 3 h. The reaction mixture was diluted with dichloromethane (200 mL), washed with brine (20 mL) and dried over anhydrous sodium sulfate. Evaporation of the solvent under vacuum and chromatography of the resulting oil over silica gel (2 x 15 cm, eluting with dichloromethane and dichloromethane-acetone 5%) gave the title compound as a clear oil: 1.31 g (65%); ir (film) v = : 1696 cm 1 (C=0 of thioester); ^Hmr (CDC1,) 5: max 3 2.43 (3H, s, SAc) , 4.36 (3H, s, 2-CH.j) , 4.38 ppm (2H, s, 5-CH2) . D. 5-mercaptomethyl-l,3-dimethyltetrazolium trifluoromethane-sulfonate CF. SO CH NaOH V-v, I 1 1 1, ——- 0>-ca /""•N C< N CH3 3 /ch3 cf so ® n 3 3 c3 5h A solution of 5-acetylmercaptomethyl-2-methyltetrazole (0.400 g, 2.32 mmol) in dry dichloromethane (3 mL) was treated with methyltriflate (0.76 g, 4.64 mmol) and stirred at 22°C for 16 h. Evaporation of the solvent under vacuum gave a red oil. This salt was dissolved in cold oxygen-free water (5 mL) and - lvf~ treated with 4 M sodium hydroxide (0.8 mL, 3.2 mmol) . The mixture was stirred at 0eC for 40 min, diluted with water (7 mL), and the pH was adjusted to 7.3 with saturated KHjPO^. The clear resulting solution was maintained under nitrogen and used immediately for the following step. 205626 (1'R,5R, 6S) 3-[1,3-dimethyl-5-tetrazolium)-roethvlthio]-6-(l-hy<3roxyethyl) -7-oxo-l-azabicyclo (3. 2.0) hept-2-ene-2-carboxylate A solution of enol phosphate (0.915 g, 1.58 mmol) in tetrahydrofuran (8 mL) was cooled to 0°C and treated dropwise with the solution of 5-mercaptomethyl-l,3-dimethyltetrazolium trifluoromethanesulfonate (2.32 mmol, prepared above) over a period of 20 min. The pH of the reaction mixture was stable at 6.5 throughout the addition. After 20 additional min. the pH of the solution was adjusted to 7.0 with saturated sodium bicarbonate. The mixture was transferred to a hydrogenation ft*7 x 205626 -4 bottle, diluted with THF (10 mL), ether (20 mL) and ice (20 g) . The carbapenem was hydrogenated over 10% palladium on activated carbon under 45 psi while slowly increasing the temperature to 22°C for 90 min. The catalyst was filtered and washed with cold water (5 mL) and ether (20 mL). The aqueous phase was washed with ether (20 mL) and maintained under vacuum for 20 min to remove traces of organic solvent. Chromatography on PrePaJc 500-C/18 and elution with water gave the title compound as a 23 white powder after lyophilization 0.266 g (49%); [oJg +13° (c 1.04, H.O); UV (H,0, pH 7.4) A : 29 4 nm (e7,500l; ir (KBr) £ 6 luax ^ j v : 1755 (C=0 of 6-lactam), 1600 cm (broad, C=0 of carboxylate); .. max TJmr (D20) <5: 1.24 (3H, d, J=6.4 Hz, CHjCHOH), 3.0-3.3 (2H, m, H-4), 3.42 (1H, dd, J=5.8, J=2.9, H-6), 4-4.2 (2H, m, H-5 and CHjCHOH), 4.34 and 4.57 (2 x 3H, 2S, CH3"1 and 3 of tetrazole), 4.49 and 4.51 (2H, 2s, CH2S). The product has a half life of 10.5 h at 37°C (c of 10~4 M in pH 7.4 phosphate buffer. 8 o - 1w - Example 21 Alternate Procedure for Preparation of 3-(N-Methylpyridine-2-yl-methanethio)-6a-[1-(R)-hydroxyethyl]-7-oxo-l-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate 7 \\ ©i "co2® ch3 a. J^C02CB3 In a 2 1 flask equipped with a magnetic stirrer,-equipped for a vigreaux column for distillation, a heating mantle and N^, there was added 4.0 mole (432 ml) of methyl acetoacetate and 8.0 mole (464.6 g) of allyl alcchol. The reaction mixture was distilled for 12 hours at 92°C. There was added 136 ml (2.0 mole) of allyl alcohol and the mixture was distilled 23 hours. There was then added 13 6 ml (2.0 mole) of allyl alcohol and the mixture was distilled 16 hours. The reaction mixture was then distilled under vacuum and product was collected at 105-'110°C/35 mm Hg. There was obtained 414 g of allyl acetoacetate (73% yield). TsN, -V" 2 205G26 - ITS To a solution of allyl acetoacetate (226.5 g, 1.594 mole) in 3 1 acetonitrile and triethylamine (243.4 ml, 1.753 mole), there was added p-toluenesulfonyl azide (345.3 ml, 1.753 mole) over a 1 hour period while keeping the temperature at ^20°C with a cooling bath. The reaction mixture became yellow. The reaction mixture was then stirred at room temperature under a nitrogen atmosphere for 18 hours. The mixture was concentrated on a rotary evaporator. The residue was dissolved in diethyl ether (2.6 1) and 1M aqueous KOH (800 ml). The organic phase was washed five times with 1M KOH (500 ml) and once with brine (400 ml). After drying over MgSO^ and concentration on a rotary evaporator (temp. <30°C) , there was obtained 260.2 g (97%) of the title product. A-1 OSi-{- N2 To a stirred suspension of allyl diazoacetoacetate (203 g, 1.195 mole) in 2 1 methylene'chloride and 199 ml (1.434 mole) triethylamine at 5°C, there was added 302 ml (1.315 mole) of t-butyldimethylsilyl triflate over a 45 minute period. The mixture was stirred 1 hour at 5°C and then another 1 hour without cooling. The' reaction mixture was washed 4 times with 500 ml H^O and then once with 500 ml brine. It was then dried over Na2S04 and concentrated to 344 g of orange oil. This oil was used directly in the next step. D. 0Si4- OCOCH, ZnCl. y 205626 - 13jj - To a mixture of (1'R,3R,4R)-3-(1'-tert-butyldimethyl- ftlr'l A u.v ' silyloxyethyl)-4-acetoxy-azetidin-2-one (28,7 g, 0.1 mole) and freshly fused ZnCl2 (6.8 g, 0.05 mole) in dry CH2C12 (700 ml), there was added dropwise a solution of allyl 2-diazo-3-tert-butyldimethylsilyloxy-3-butenoate (33.84 g, 0.12 mole) in CH2C12 (50 ml) over a 5 hour period. The mixture was stirred at room temperature for 2 hours at which time TLC (thin layer chromatography) 'showed a small amount of remaining starting material. An additional quantity of allyl 2-diazo-3-tert-butyldimethyl-silyloxy-3-butenoate (4.23 g, 0.015 mole) in 10 ml of CH2C12 was added over a 1 hour period and stirring was continued at room temperature for 10 hours. The reaction was then diluted with ethyl acetate (750 ml), washed (2 x 300 ml saturated NaHCO^, 300 ml brine), dried (MgSO^) and evaporated to give 62.5 g of dark orange oil which was dissolved in methanol (500 ml) and treated with IN aqueous HCl (110 ml). The resulting mixture was stirred at room temperature for 2 hours after which time there was added 10 ml IN HCl followed by an additional 2 hours of stirring. The reaction mixture was concentrated to 1/2 volume and poured into a mixture of ethyl acetate (800 ml) and water (800 ml). The organic phase was separated, washed with water (800 ml) and the combined aqueous extracts washed with ethyl acetate (400 ml). The"combined organic extracts were washed with brine (2 x 4 00 ml), dried (MgSO^) and concentrated to 32 g of dark orange red oil. Flash chromatography afforded 9.33 g (33% yield) of title product as a gold-yellow oil which solidified to a light yellow solid. 1H-nmr (CDC13) 6: 6.20-5.72 (m, 2H), 5.48-5.21 (m, 2H) , 4.74 (dt, J=5.8, J'=1.2Hz, 2H), 4.30-3.88 (m, 2H) , 3.30-3.20 (m, 2H), 2.89 (dd, J=7.3, J'=2.1, 1H), 2.18 (s, 1H), 1.32 (d, J=6,2, 3H) . E. OH < 205626 A mixture of a-diazo ester prepared in Step D above (9.2 g, 32.7 mmole) and rhodium acetate [Rh2(OAc)4] in benzene (1 1) was refluxed for 1 hour. The solution was treated with activated charcoal and filtered through a Celite pad. The pad was washed with 100 ml of hot benzene. Concentration of the filtrate afforded 8.08 g (97% yield) of title product as a light brown crystalline solid. 1H-nmr (CDClj) 6: 6.15-5.68 (m, 1H), 5.45-5.18 (m, 2H) , 4.71-4.60 (m, 2H) , 4.40-4.05 (m, 2HJ, 3.17 (dd, J=7.1, J'=2.0, 1H) , 2.95 (dd, J=6.9, J'=18.9, 1H), 2.42 (dd, J=7.6, J'=18.8, 1H), 1.88 (s, 1H) , 1.39 (d, J=6.3, 3H) . F- ■ OH OH . To a solution of keto ester prepared in Step E (7.5 g, 0.03 mole) there was added at 0°C under a N2 atmosphere di-isopropylamine (6.08 ml, 0.035 mole) followed by diphenyl-phosphoryl chloride. After 15 minutes, TLC showed no remaining starting material. To the reaction mixture there was added diisopropylamine (6.26 ml, 0.036 mole) and a solution of freshly distilled 2-mercaptomethylpyridine (4.5 g, 0.036 mole) in 5 ml acetonitrile. After stirring at 0°C for 2 hours, the mixture was poured into ethyl acetate (1 1) , washed with water (2 x 150 ml), saturated NaHCO^ (150 ml) , H20 (150 ml) and brine (200 ml). The organic phase was dried (MgSO^) and concentrated to a dark orange-yellow gum. Flash chromatography afforded the product as a golden yellow oil. The product was dissolved in diethyl ether and cooled to 0°C. Filtration afforded 4.8 g (44% yield) of the purified title product as cream-colored crystals. ^H-nmr (CDCl^) \ 1 205626 4- - 18/- 6: 8.6-8.4 (m, 1H) , 7.85-7.15 (in, 3H) , 6.20-5.74 (m, 1H) , 5.54-5.15 (m, 2H) , 4 . 80-4.66 (m, 2H) , 4.29-4 .03 (m, 1H) , 4.19 (s, 2H) , 3. 69-2. 85 (m, 1H) , 2.97 (s, 1H), 1.32 (d, J=6.2, 3H). G. ■> ft.. .. To a solution of the allyl ester prepared in Step F (1.79 g, 4.97 mmole), tetrakistriphenylphosphine palladium (175 mg, 0.15 mmole) and triphenylphosphine (175 mg, 0.67 mmole] in CHjClj (25 ml) , there was added a solution of potassium 2-ethyl-hexanoate (1.085 g, 5.96 mmole) in ethyl acetate (12 ml). After stirring at room temperature for 1 hour, TLC showed only a trace of starting material. The reaction mixture was diluted with anhydrous diethyl ether (150 ml) and the precipitate was collected by filtration, washed with ethyl acetate and then ether to give a light-brown solid. This solid was dissolved in K^O (10 ml) and purified by reversed phase chromatography to give 1.85 g of title product as a cream-colored solid. This material was further purified by slurrying in acetone to afford 1.47 g (83%) of pure title product. ^H-nmr (D^O) : 8.45-8.36 (m, 1H), 7.92-7.22 (n, 3H) , 4.78-3.91 (m, 2H), 4.69 (s, 2H), 3.34-2.71 (m, 3H), 1.19 (d, J=6-4, 3H). H. y*>f -18?- 205626 Toluenesulfonic acid (27.6 mg, 0.16 mmole) was added to a cooled (0°C) suspension of potassium 6-hydroxyethyl-2-(2-pyridylmethylthio)-carbapenem-3-carboxylate (53.8 mg, 0.15 mmole) in acetone (2 ml). The mixture was stirred at 0°C for 20 minutes and then treated with methyl triflate (0.02 ml). After stirring at 0°C for 60 minutes, LA-1 resin was added followed by hexane (6 ml). The mixture was extracted with water (4 x 0.5 ml) and the combined aqueous phases purified by reversed phase HPLC to give 10 mg of the title product. (? - 18/ - Example 22 Preparation of 3-(N-Methylpyridine-2-yl-methanethio)-6a-[1- (R) -hydroxyethyl]-7-oxo-l-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate Via "One Pot" Process 205626 C02PNB CH, © L c?3so3 SAc © chjcn , 4 5 min. V OH A 0 Cl^(Ojzf)2 EtN (iPr)2 rN^<0. :o2pnb NaOH K20r 0°C, 1 h. © v ch 3 ^2S03 sh pH 6,5-7.5 THF, H20 205621 / - 18, b oh A e"3© B - n op {ofs). co2pnb OH A H2 Pd-C 10% 5°C, 2 h. CH, ®L 0 A. Preparation of enol phosphate (_2) OH X h h 'h^vo , A— a' -- C02 PNB C02PNB An ice-cooled solution of ketone 1_ (3 g, 8.62 mmoles) in acetonitrile (30 ml) was treated with ethyl diisopropylamine (9 mmoles, 1.04 eg, 1.57 ml) (addition time ca. 2 minutes) and chlorodiphenyl phosphate (9 itunoles, 1.04 eg, 1.87 ml) (addition time ca. 2 minutes). The reaction was stirred for 45 minutes and TLC (ethyl acetate, silica gel) showed disappearance of ketone _1. The solution was diluted with ethyl acetate (60 ml), washed with cold water (2 x 50 ml) and brine, dried over sodium sulfate and concentrated (bath temperature below 20°C) to give a foam which was used as such. I 201 8 .18 f - 3. Preparation of thiol (J) CH «® " "aOT/"2° Tf® ©J"3 rrsr^sac o°' i h. tf^ 2) kh2p04 SH An ice-cooled solution of thioacetate 2 (3.31 g, 10 mmoles) in water purged with nitrogen for 5 minutes was treated dropwise (ca. 5 minutes) with a cooled solution of sodium hydroxide (1.7S eq, 17.5 mmoles, 0.7 g) in water (8 ml). The mixture became yellow. After 75 minutes under nitrogen the pH was adjusted to 7.4 with saturated aqueous solution of KH^PO^. The reaction mixture was diluted with water (15 ml). This aqueous solution of thiol £ (50 ml, 0.2 mmoles/ml) was used as such. C. Coupling OH 4 A 0 || THF-H,0 *■ pH 6.5-7.5 0 ^ 0', 1 h. cojpnb 2 OH g) ©. fH3 S C02PNB An ice-cooled solution of 2 (crude, prepared in A, 8.62 mmoles) in tetrahydrofuran (50 ml) was treated dropwise with the aqueous solution of thiol £ prepared in B (5 ml of solution every 5 minutes) . During the course of the reaction the pH of the reaction mixture was maintained around 6.5-7.5 (preferably 7) by adding cooled 2N sodium hydroxide solution. The reaction was followed by TLC (a) silicagel, ethyl acetate; (b) reversed phase Analtech RPSF, CH-jCN- pH 7 buffer (4:6). 205626 At the end 1.15 eq of thiol was used (50 ml of solution) . The reaction was complete after 1 hour at 0°C and the mixture was used as such for the hydrogenation after the pH was adjusted to 7. D. Hydrogenation A & CH. "W<\ C02PNB 45 psi H2/Pd-C 10% THF-H20-ether 0°C, 2 h. The reaction mixture containing 5 (prepared in C) was transferred into a Parr flask with THF (10 ml), phosphate buffer (pH 7, 0.1 M) (10 ml), ether (75 ml) and Pd-C 10% (5 g) and hydrogenated at 45 psi at 3-10°C for 2 hours. Then the catalyst was filtered, washed with water (3 x 10 ml) and the pH adjusted to 6.2 carefully with cold 2N NaOH. Ether was added and the aqueous phase was separated and washed again with ether. The aqueous phase was purged of organic solvent under vacuum and then purified on Bondapak C-18 column (100 g, 4.5 x 13 cm) with cold distilled water. The light yellow fractions containing the product (checked by U.V. and TLC) were lyophilized to give 1.46 g (50%)* of 6 as a yellow powder. A 293, e = 9000, A 271, c= 11064 *yield calculated from bicyclic ketone 205626 -190- Example 23 Preparation of (5R,6£>)-3-{[(l,3-dimethylpyridinium-4-yl)methyl]thlo}-6-[ 1-(R)-hydroxyethylJ-7-oxo-l-azabicyclof3.2.0jhepC-2-ene-2--carboxylat€ (2 3A) and (4R,5R, 6S)-3-{ ([113-dimethylpyridinium-4-yl)mathyl]thio]—6—[l-(R)-hydro*y-ethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2~ene-2-carboxylate (23B) 2 3 A' ■ 23B R - H R - CH, N.Z. PATENT OFFICE 2 3SEP1986 received f 205 -191- Preparatlon of 4-Hydroxymethyl-3-methylpyridlne 15 H2°2 2) aej3 3) h3d^ The general procedure of Boekelheide1 for the preparation of, hydroxymethylpyridines was used. Thus, a solution of freshly distilled. 3,4-lutidine (46.0 g, 0.43 mol) in 120 mL of glacial acetic acid was cooled at 0°C and then 64 mL of 30Z *^2 was added dropwise. The resulting solution was heated at 75"C (oil-bath temperature), for 3 h. Another 20 mL of 302 ^^2 WaS t^ien at^ed and heating was continued for 18 h. Finally, 20 mL . of 30Z H2°2 was a£a-'-n added and the reaction was kept at 75"C for another 3 h. The solution was then concentrated to about 100 mL under vater-aspirator pressure, 50 mL of H^O was added and the mixture was concentrated to about one half volume. The resulting mixture was cooled (0-5#C) and basified to about pH 10 tsing cold 40Z aqueous NaOH. The mixture was then extracted with CHgClg (5 x) and the extract vas dried (NajCO^ + Na2S0^) and concentrated on the roto-vap to give a yellow solution. Dilution of this solution with hexane afforded a solid which was collected by filtration and then dried Zil VO-CLLO to give 3,4-lutidine-N-oxide (48.0 g, 83%) as an off-white solid. 205626 -192-tv The N-oxide was added portionwise to 60 oL of acetic anhydride and the resulting dark orange solution was heated (water-bath) at abc^r. 90°C for 1 h. The excess acetic anhydride was then distilled off under reduced pressure and the material boiling at 90-120°C/0.1 torr (39.0 g) was collected. Chromatography of this oil (silica gel/ethyl acetate-pet.ether i « 2:3) afforded pure 4-acetoxymethyl-3-methylpyridine (19.0 g, 30Z) as an oil: ir (neat) 1745 cm"*. The acetate was then taken up in 100 mL of 10Z aqueous HCl and j i refluxed for 1 h. The resulting solution was cooled at 0°C, basified with ; solid K2C03 an<* t^ien extracted with CH2C*2 ^ X or8anic \ extract was washed (brine), dried (l^SO^) and evaporated to give 11.0 g of 1 l an off-white solid, n.p. 70-72°C. This solid was triturated with cold ] ether to give pure 4-hydroxymethyl-3-methylpyridine (9.5 g, 67Z) as a white solid, m.p. 77-806C (lit.2 m.p. 81-82°C): 'Hrrnir (CDC13) 5 8.27, 7.41 (ABq, J-5Hz, 2H), 8.18 (s, 1H), 5.63 (br s, -OH), 4.67 (s, CH2), 2.20 (s, CH3); • ir (nujol) 3170 cm""1. 1. V. Boekelheide, W.J. Linn, JACS, 76, 1286 (1954). •2. W.L.F. Armarego, B.A. Milloy, S.C. Sharma, JCS, 2485 (1972). a i -193 - 205626 B. Preparation of 4-(Acetylthiomethyl)-3—methylpyrldine CH.OH CH^SAc CH 3 > n N To an ice-cold, mechanically stirred solution of triphenylphosphine (17.04 g, 0.065 mol) in 250 mL of dry THF was added dropwise diisopropyl azodicarboxylate (12.8 oL, 0.065 mol) and the resulting slurry was stirred at 0°C for 1 h. To this mixture was added dropwise a solution of 4-hydroxymethyl-3-methylpyridine (4.0 g, 0.0325 mol) in 100 mL of dry THF, followed by freshly distilled thiolacetic acid .(4.64 mL, 0.065 mol). The resulting mixture was stirred at 0eC for 1 h and then at room temperature for 1 h to give an orange solution. The solution was concentrated (rotary evaporator) and then diluted with petroleum ether. The resulting mixture was filtered and the filtrate was evaporated to give an orange oil. Chromatography (silica gel/hexane then 10Z + 50Z ethyl acetate-hexane) of this oil gave 7.0 g of an oil which was distilled (Kugelrohr) to give the pure product (6.0 g, 100 Z) as a yellow oil, b.p. (air-bath temperature) 95-100°C/0.1 torr: 'Hnmr (CDCl^) 5 8.40, 7.20 (ABq, J-5Hz, 2H), 8.37 (s, 1H), 4.08 (s, CH2), 2.35 (s, CH3), 2.32 (s, CH3); ir (neat) 1695 cm *■» 7 r r I'W / ^ c r 1: ' RECEIVED J ■( -194- 205626 Preparation of 4-(Acetylthlomethyl)-l,3-dlmethylpyridiniua triflate To an Ice-cold solution of the thloacetate (2.95 g» 0.016 mol) In 10 mL of methylene chloride was added dropwise methyl trifluoromethane-sulfonate (4.60 mL, 0.04 mol) and the mixture was stirred at 0*C under Nj for 1 h. The reaction mixture was then evaporated to dryness and the residue was triturated with ether. The resulting solid was collected by filtration and dried -In vacuo to give the product (4.0 g, 72X) as a white solid: 'Hnmr (CDC13) S 8.72 (s, 1H), 8.58, 7.87 (ABq, J-6Hz, 2H), 4.39 (s, N-CH3), 4.17 (s, CH2), 2.53 (s, CH3), 2.36 (s, CE^); ir (neat) 1700 cm"1. N.Z. PATENT OFF iCE 2 3SEPI986 received ((' -195- 205626 • Preparation of (5R, 6S)-3-( f (1>3-dlmethylpyridinium-4-yl)methyl]thio}-6[ 1-(R)-hydroxyethyl {-7-oxo- l-azabicyclo f 3.2.0 ]hep t-2-ene-2-carboxylate in 10 mL of H^O was added the thioacetate (1.40 g, 0.004 mol) and the mixture was stirred at 0°C under for 1 h. After the pH was adjusted to 7.2-7.3 using IQX aqueous potassium dihydrogen phosphate the resulting solution was added dropwise to an ice-cold solution of the enol phosphate (1.45 g, 0.0025 mol) in 20 mL of THF. The mixture was stirred at 0°C for 1 h and was then transferred to a pressure bottle. To this mixture was added 20 mL of ether, 25 mL of 0.1M phosphate buffer (pH 7.4) and 1.4 g of 10Z palladium-on-charcoal. The mixture was then hydrogenated at 45 psi for 1 h. The reaction mixture was filtered through a pad of Celite and the pad was washed with additional ether and pH 7.4 phosphate buffer. The aqueous phase was separated and residual solvents were removed Zn. vacuo. The resulting aqueous solution was applied to a reverse-phase column (C^g BondaPak) which was eluted with H^O and thea 10% acetonitrile-^O. Lyo-philization of the relevant fractions gave 0.9 g of an orange solid. This cc^pnb 3) H2, Pd/C To an ice-cold, N^-purged solution of NaOH (0.324 g, 0.008 mol) 2 3sep 4936 rerciucn 205626 material va6 rechromatographed using and then 22 acetonitrile-fl^O as eluant, Lyophilization afforded pure .. 23A (0.25 g, 57Z) as a yellow solid: 1Hnnr (D20) 6 8.55 (s, 1H), 8.53, 7.96 (ABq, J-6.8 Hz, 2H), 4.30-3.99 (n, 2H), 4.27 (s, 5H), 3.35 (dd, JL-2.8 Hz, J2-6.0 Hz, 1H), 3.05 (d, J-8.8 Hz, 2H), 2.50 (s, 3H), 1.23 (d, J-6.3 Hz, 3H); ir (KBr) 1755, 1590 cm S uv (phosphate buffer, pH 7) 295 on (e7180). i. -197- 205626 Preparation of (4R,5R,6S)-3-{[(I,3-dimethylpyrldinlua-4-yl)tnethvlIthio}-6~ [l-(R)-hydroxyethyll-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-car-boxylate Me 3) H2, Pd/C An ice-cold solution,of the bicyclic ketone (0.906 g, 0.0025 mol) in 10 mL of acetonitrile was treated successively with diphenyl chlorophosphate (0.544 mL, 0.00263 mol), diisopropylethylamine (0.457 mL, 0.00263 mol) and 4-dimethylaminopyridine (0.3 mg). After 50 min the reaction mixture was diluted with cold ethyl acetate and then washed with cold water and brine. The organic phase was dried (Na^SO^,) and evaporated at room temperature to give the enol phosphate as an off-white foam. This foam was taken up in 20 mL of THF, cooled at -30°C under and then treated with an aqueous solution of the thiolate [prepared as done previously from 0.3 g of NaOH (7.5 mmol) and 1.3 g of the thioacetate (3.76 mmol) in 10 mL of H^O]. The reaction mixture was stirred at -30°C for 30 min-, then at 0°C for 75 min and finally it was transferred to a pressure bottle containing 20 mL of ether, 30 mL of 0.1K phosphate buffer (pH 7.4) and 1.5 g of 10Z palladium-on-charcoal. After hydrogenating at 45 psi for 1 h the mixture was j m.z.ratc.nror-fice 2 7 rrp :eived -198- filtered through Celite and the aqueous phase was separated and concentrated <Jl V&CUO. The resulting solution wa3 applied to a reverse phase (C^g BondaPak) column which was eluted with 1^0. Lyophilization of the relevant fractions gave 1.2 g of a yellow solid. This material was rechromatographed (eluting with H^O to 42 acetonitrile-H^O) to give, after lyophilization, pure 23B (0.250 g, 28Z) as a yellow solid: 1Hnor (I^O) 6 8.53 (s, 1H), 8.49, 7.81 (ABq, J-6.2 Hz, 2H), 4.38-3.98 (m, 4H), 4.27 (s, 3H), 3.49-3.18 (m, 2H), 2.51 (s, 3H), 1.25 (d, J-6.7 Hz, 3H), 1.16 (d, J-7.6 Hz, 3H); ir (KBr) 1750, 1595 cm uv (phosphate buffer, pH 7) 292 nm (e7930). ('• -199 Example 24 Preparation of (5R,6S)-3-{ [ (l,2-dimethylpyridinium-4~yl)methyl}thio}-6-f 1—CR) -hydroxyethyl )-7-oxo-l-azabicyclo [3.2.0 ]hept-2~ene-2-carboxylate (24a) and 205626 (4R,5R,6S)-3-{ [ (l>2-dimethylpyridinium-4~yl)methyl]thio)-6-[ 1-(R)-hydroxy ethyl]-4-methyl-7-oxo-I-azabicyclo[3.2.Q]hept-2-ene-2-carboxylate ( 24B) ' OH R i i i 24A R - H . j 24B R - CH3 205626 -200- Preparatlon of 4-Hydroxymethyl-2-methylpyridine To a suspension of 95Z lithium aluminum hydride (2.4 g, 0.06 mol) in 150 mL of anhydrous ether was added a solution of methyl 2-methylisoni-cotinate1 (14.0 g, 0.093 mol) in 50 mL of anhydrous ether, at -5eC under The resulting mixture was 'stirred at room temperature for 30 ™-fn and was then refluxed for 2 h. An additional 1.2 g (0.03 mole) of lithium aluminum hydride was added portionwise and refluxing was continued for 1 h. The reaction mixture was then cooled at 0°C and treated successively with 3; 75 mL H^O, 3.75 mL 152 aqueous NaOH and finally 11.25 mL of H^O. This suspension was then filtered and the filter cake was washed with ether and then ethyl acetate. The filtrate was evaporated to give a dark yellow oil which was taken up in acetonitrile and then filtered through a pad of silica gel (elution with acetonitrile and then acetone). This gave the product (7.7 g, 67Z) as a yellow oil: 'Hnmr (CDCl^) $ 8.30, 7.10 (ABq, J-5 Hz, 2H), 7.17'(s, 1H), 5.42 (s, -OH), 4.70 (s, CH2), 2.50 (s, CH3). '0. Efimovsky, P. Rumpf, Bull, soc. chim. Fr., 648 (1954). N.Z. PATENT Ql-PiCS- 23SEP )986 received ^ 1 205626 • -201-. / B. Preparation of 4-(Acetylthiomethyl)-2-methylpyridine To a solution of triphenylphosphine (31.4 g, 0.12 mol) in 200 mL of dry THF, at -5"C under N^» was added dropwise diisopropyl azodicarboxy-late (23.6 mL, 0.12 mol) and the mixture was stirred at -5°C for 1 h. To the resulting slurry was added a solution of 4-hydroxymethyl-2-methylpyri-dine (7.60 g, 0.062 mol) and freshly distilled thiolacetic acid (8.60 mL, 0.12 mol) in 40 mL of dry THF over about 10 min. The reaction was stirred at 0#C for 30 min and then at room temperature for 1 h. The resulting suspension was filtered and the filtrate was . concentrated to give an orange-yellow liquid which was diluted with ether and filtered. The filtrate was evaporated and the residual oil was chromatographed (silica gel/ethyl acetate-hexane-1:1) to give the thioacetate (8.87 g, 79Z) as a yellow oil: 'Enrnr (CDClj) 5 8.4?i 7.03 (ABq, J-5Rz, 2H), 7.08 (s, 1H), 4.04 (s, CH2), 2.55 (s, CH3), 2.39 (s, CH3); ir (neat) 1695 cm"1. N.i. HATEN i O--MCE 2 7 "fr '5r,~a RECEIVED J -202- < 205623 C. Preparation of 4-Mercaptomethyl-2-methylpyridinc CH^SAc ch2sh ch 3 ch 3 To 15 mL of ice-cold, N^-purged IN NaOH was added all at once 4-(acetylthiomethyl)-2-methylpyridine (1.358 g, 0.0075 mol); After stirring for 15 min at 0°C the reaction mixture was washed with ether (2 x 5 mL), neutralized with concentrated HCl and extracted with methylene chloride (3 x 10 mL). Evaporation of the methylene chloride solution afforded the thiol (0.B9 g, 96%) as a pale yellow oil which gradually became pink on standing: 'Hnmr (CDCl^) 5 8. A3, 7.37 (ABq, J=5 Hz, 2H), 7.43 (s, 1H), 3.63 (d, J-7.5 Hz, CH2), 2.55 (s, CH3), 1.81 (t,'J-7.5 Hz, SH). N.t . cr. i t 2 35EP 1986 received -203- 205626 p^tenr Orpirp 2 3SFP J9gj Preparation of Allyl (5R,6S)-3-{ [ (2-methylpyridin-4-yl)methyl]thlo}-6-[l-(R) -hydroxy ethyl 1-7-oxo-l-azablcyclo [3.2.0]hept-2-ene-2-carboxylate To an ice-cold solution of the bicyclic ketone (0.760 g, 0.003 i i mol) in 8 mL of acetonitrile was added successively diphenyl chlorophos- j phate (0.653 mL, 0.00315 mol), diisopropylethylamine (0.550 mL, 0.00315 j mol), and dimethylaminopyridine (O.B.mg). After stirring the mixture at 0°C for 1 h it was cooled at -20°C and 4-mercaptomethyl-2-methylpyridine (0.620 g, 0.00446 mol), followed by diisopropylethylamine (0.550 mL, ; 0.00315 mol), was added. The reaction was stirred at -20°C for 1.5 h and j | then allowed to warm to room temperature. The resulting mixture was j diluted with 50 mL of ethyl acetate, washed (H^O, sat. NaHCO^, sat. NH^Cl), j dried (Na^SO^) and evaporated. The residual material was chromatographed ! on silica gel.,(eluted with ethyl acetate then acetonitrile) to give a solid : i i which was triturated with ether to give the pure product (0.820 g, 73Z) as j i a white solids lHnmr (CDCl^) S 8.45, 7.09 (ABq, J*5 Hz, 2H), 7.15 (s, 1H), j 6.25-5.80 (m, 1H), 5.60-5.20 (m, 2H), 4.82-4.68 (m, 2H), 4.55-4.05 (m, 2H), j 3.97 (s, 2H), 3.16-2.93 (m, 3H), 2.55 (s, 3H), 1.84 (br s, 1H), 1.32 (d, J-6 Hz, 3H); ir (neat) 1777, 1695 cm 205626 ft.Z. PATENT OFF -204- 23SEP j?36 RECEIVED /' i E. Preparation of (5R,6S)-3-{ [ (l,2-dimethylpyrldinium-4-yl)methyl]thio}-6-[l-(R)-hydroxyethyl )-7-oxo-l-azabicyclof 3.2.0)hept-2-ene-2-carboxylate dry acetonitrile was cooled at -5*C and treated with methyl trifluorome-thanesulfonate (0.111 nL, 0.983 mmol). After 15 min a solution of tetra-kis(triphenylphosphine)palladium (0.027 g, 2.5 molZ) and triphenylphosphine (0.027 g) was added. After stirring the reaction mixture for 5 m-fn pyrrolidine (0.082 mL, 0.983 mmol) was added dropwise. A solid slowly began to separate from the resulting brown solution. The mixture was vigorously stirred at 0°C for 20 min, then 15 mL of cold (0"C) acetone was slowly added and stirring was continued at 0°C for 20 min. The resulting suspension was filtered and the residue was washed with cold acetone and then dried ■in. va.CJU.0 to give 0.345 g of a beige powder. This material was taken up in a small amount of pH 7 phosphate buffer (0.05M) and applied to a short reverse-phase (C^g BondaPak) column. Elution with H^O and lyophi-lization of the relevant fractions gave 0.255 g of a light yellow solid. This material was rechromatographed, as done before, to afford (after lyophilization) pure. • 24A (0.195 g, 60Z) as a light yellow solid: xHnmr (D^O) 5 8.58, 7.83 (ABq, J-6.4 Hz, 2H), 7.87 (s, 1H), 4.32-3.95 (m, 2H), 4.22 (s, 2H), 4.17 (s, 3H), 3.32 (dd, Jj-2.6 Hz, J£-6.1 Hz, 1H), ' OH A solution of the allyl ester (0.350 g, 0.936 mmol) in 6 nL of -205- 205626 3.06-2.93 (m, 2H), 2.74 (s, 3H), 1.22 (d, J-5,4 Hz, 3H); ir (KBr) 1757, 1590 cm S uv (phosphate buffer, pH 7.4) 296 nm (c7446). ' ' ' 111 _m-z. patent 1 23S£r$ pecffy -206- 205626 Preparation of Allyl (4R,5R,6S)-3-( f (2-methylpyridin-4-yl)methyl Ithlo )-6-f 1— CR) -hydroxye thyl ]-4-me thyl-7-oxo-l-azablcyclo [3.2.0 Ihept-2-ene-2-carbo-xylate A solution of the a-diazo ester (1.50 g, 0.00508 mol) in 12 nL of ethyl acetate-hexane (3:1) was heated to a gentle reflux under ^ and than 0.020 g of rhodium octanoate was added all at once. Rapid evolution was observed for about 5 min and after refluxing for another 10 min the reaction was complete (tic). The solvents were subsequently removed under reduced pressure and the residual gum was taken up in 15 mL of acetonitrile. The solution was cooled at -5°C and treated with diphenyl chlorophosphate (1.10 mL, 0.00533 mol), diisopropylethylamine (0.927 mL^ 0.00533 mol) and 4-dimethylaminopyridine (0.6 mg, 0.1 mol %). The reaction mixture was stirred at 0°C for 1 h and was then cooled to -20°C and treated with a solution of 4-mercaptomethyl-2-methylpyridine (0.656 g, 0.00533 mol) in 1 mL of acetonitrile, followed by 0.927 mL (0.00533 mol) of diisopropylethylamine. The resulting mixture was stirred at -10°C for 1.5 h and was then treated with additional thiol (0.066 g, 0.53 mmol) and diisopropylethylamine (0.093 mL, 0.53 mmol). The reaction was allowed to warm to about 10eC over 1 h and was then diluted with 75 mL of cold ethyl acetate, washed (H^O, brine), dried (Na^SO^) and evaporated (bath temperature <30°C). The resulting gum was chromatographed on silica gel. Elution with ethyl n-<2. patent"ormcjT~~" 2 3 SEP 1986 RECPl\/en ' -207- 20562S acetate removed Impurities and subsequent elutlon with acetonitrile afforded the product (1.04 g, 532) which was obtained as a pale yellow foam: 'Hnmr (CDClj) 5 S.43, 7.07 (ABq, J-5 Hz, 2H), 7.10 (s, 1H), 6.20-5.75 (m, 1H), 5.51-5.29 (m, 2H), 4.81-4.69 (m, 2H), 4.29-4.03 (a, 2H), 3.96 (s, 2H), 3.35-3.05 (m, 2H), 2.53 (s, 3H), 2.16 (br s, 1H), 1.33 (d, J-6.3 Hz, 3H), 1.22 (d, J-7.3 Hz, 3H); ir (neat) 1770, 1705 cm"1. -208- 20SG26 G. Preparation of (4R,5R, 6S)-3-{ f (1,2-dimethylpyrldinium-4-yl)methyl]thio)-6-[ 1 -(R)-hydroxye thyl ]-4-me thyl-7-oxo- l-azabicyclo [3.2.0 )hept-2-ene-2-carbo-xylate dry acetonitrile was treated with methyl trifluoromethanesulfonate (0.178 (triphenfylphosphine)palladium (0.035 g, 2 mol Z) and triphenylphosphine (0.035 g) in 1 mL of methylene chloride was added, followed after 5 min by 0.131 mL (1.575 mmol) of pyrrolidine.. The resulting mixture was stirred at 0°C for 20 min and then 30 mL of cold (0°C) acetone was added. The mixture was vigorously stirred at 0°C for 15 min -and then the precipitate was collected by filtration, washed w£th cold acetone and dried Zn vaciLO to give 0.520 g of' a- beige powder. By diluting the filtrate with ether another 0.041 g of the crude product was obtained. The combined solids were dissolved in a small amount of pH 7.4 phosphate buffer (0.05M) and applied to a reverse-phase (C^g BondaPak) column. Elution with H^O and then 2X acetonitrile-I^O afforded, after lyophilization," 24B (0.413 OH A solution of the allyl ester (0.582 g, 0.0015 mol) in 15 mL of mL, 1.575 mmol) at -5°C under N^. After 15 min a solution of tetrakis- -209- 205626 g, 76Z) as a yellow solid: lHnmr (D20) 6 8.55, 7.76 (ABq, J-6.3 Hz, 2H), 7.81 (s, 1H), 4.4-3.7 (m, 2H), 4.19 (s, 2H), 4.16 (s, 3H), 3.47-3.14 (n, 2H), 2.73 (s, 3H), 1.24 (d, J-6.4 Hz, 3H), 1.16 (d, J-7.3 Hz, 3H), ir (KBr) 1750, 1595 cm ; uv (phosphate buffer, pH 7.4) 293 nm (e7170). 205626 ■-210- Example 25 Preparation of (5R,6S) 3-[1,6-dimethyl-pyridinium-2-yl) methylthio]-6-(lR-hydroxyethyl)-4R-methyl-7-oxo-l-azabicyclo-[3.2.0] hept-2-ene-2-carboxylate n.z. patent OFFICE 2.35EPJ986 received 205626 -211- A. (1,6-dimethylpyridlnium-2-yl)methylthlol> trifluoromethanesulfonate salt CH. MeOTf SCC«3 Ether HCl. 6N SH, TfO A solution of (6-methylpyridin-2-yl)methylthio acetate (1.0 g, 5.52 mmol) in dry ether (5 mL) kept under a nitrogen atmosphere was treated with methyl triflate (0.74 mL, 6.5 mmol) and stirred at 23°C for 4 h. The ether was decanted and the white solid was washed twice with ether (2 mL) and dissolved into hydrochloric acid solution (15 mL, 6N, 90.0 mmol). The resulting solution was heated at 7Q°C for 4 h under a nitrogen atmosphere and then concentrated under reduced pressure to a yellow syrup. Traces of hydrochloric acid were removed by codistillation with water (2 x 10 mL). The crude material was purified by reversed phase column chromatography (2.2 x 13.0 cm, PrepPak C-18) with water as eluting solvent. Appropriate fractions were combined and lyophylized to give a white powder; 1.43 g, 85.4z; ir (KBr) v : 2565 (SH), 1626 (pyridinium), 1585 (pyridinium) cm max uv (H-0) X : 278 (e7355); Anal, calc'd for C_H.,N0,S-F,: C 35.64, H z max _ y L i J £ 2 3.99, N 4.62, S 21.14; found: C 35.49, H 4.05, N 4.56, S 20.99. N.Z. PATu ■ •«C£ 235FPIT- i 205626 B- (5R,6S) 3-[ CI. 6-dime thylpyridiniua-2-yl)me thyl thio 3-6-C lR-hydroxyethyl)-4R-methyl-7—oxo-l-azabicyclof 3.2.0]hept-2-ene-2-carboxylate OH i CH. w- COOPNB s? 1- (PhO) PCI 2- NEt(iPr). c 3- Thiol 4- NEt(iPr) H t Pd/C > CH Buffer 7.0 Ether THF To a cold (5°C) solution of (5R,6j>) paranitrobenzyl 3,7-dioxo-6-(lR-hydroxyethyl)-4RS-methyl-l-azabicyclo[3.2.0]heptane-2-R-carboxylate (1.11 g, 3.06 mmol, R/S: 86/14) In dry acetonitrile (90 mL) kept under a nitrogen atmosphere was added simultaneously diphenyl chlorophosphate (0.68 mL, 3.3 nmol) and diisopropylethylamine (0.57 mL, 3.3 mmol) over 10 min period. The cold (5#C) mixture was stirred for 1 h, cooled to -30#C and treated simultaneously with a solution of (l,6-dimethylpyridinium~2-yl)-methylthiol, trifluoromethanesulfonate salt (1.03 g, 3.4 mmol) in dry acetonitrile (2 mL) and diisopropylethylamine (0.59 mL, 3.4 mmol) over 15 min period. The resulting mixture was stirred for 0.5 h at -30®C, warmed up until 0*C and stirred for 1.0 h before being diluted with cold water (35 mL). The resulting emulsion was poured on top of reversed phase column (prepPak C-18, 2.5 x 18 cm) which was then eluted with a mixture of 25-50Z acetonitrile in. water. Lyophilization of appropriate fractions gave a sticky yellow solid, 1.69 g which was solubilized into wet tetrahydrofuran (40 mL). To the resulting solution was added ether (70 mL), potassium dihydrogenphosphate-sodium hydroxide buffer (pH 7.0, 0.2M, 50 mL) and 10X palladium on charcoal (1.69 g) and the resulting mixture was hydrogenated under 42 psi at 23#C for 2 h and then filtered on a Celite pad. The two t*.L. PATENT OFFICE 2 3 5 E P v?36 205626 -213- phases were separated and an aqueous phase was washed with ether (2 x 20 mL) and concentrated under high vacuum at <23°C to 15 mL which was applied on top of reversed phase column (prepPak C-18). Elutlon with a mixture of 4X acetonitrile in water gave after lyophilization of appropriate fractions 0.23 g of title compound mixed with potassium-sodium diphenylphosphate (24Z in mole). Repurification on reversed phase column (2.5 x 14 cm, prepPak C-18) with water (400 mL) and a mixture of 10Z acetonitrile in water (200 mL) as eluting solvent gave after lyophilization of appropriate fractions a yellow powder, 0.17 g, 15.3Z; ir (KBr) v : 1750 (C»0 of g-lactam), 1625 (pyridinium), 1600 (C*0 of carboxylate) cm S 'Hmr <5: 1.12 (d, J-7.2 Hz, CH3 on C-4), 1.24 (d, J-6.4 Hz, C^CHOH), 2.80 (s, CH^ on C-6 of pyridinium), 4.18 (CH^ on N of pyridinium), 4.41 (center of AB quartet,. CH^S), 7.5-8.4 (H's on pyridinium); uv .(Buffer 0.05M, pH 7.0) 278 (c 11504); [Q]d« -256.4* (c 0.22, H20); t^2 - 20.8 h measured at 37°C in -4 buffer (pH 7-4) for a concentration of 10 M. !. -214- 205626 ; Example 26 Preparation of (5R,6S) 3- [ (1, 6-dimethyipyridiniuia-2-yl)-methylthio]-6- (lR-hydtoxyethyl)-7-oxo-l-azabicyclo [3.2.0] hept 2-ene-2-carboxylate ch. CH, COO© \ (A ■ -215- (. 205626 A. (5R, 6S) paranitrobenzyl 3-f (l,6-dimethylpyridinium-2-yl)methylthlo]-6-(lR-hydroxyethyl)-7-oxo-l-azabicyclo[3.2.0jhept-2-ene-2-carboxylate, trifluoro-methanesulfonate and diphenylphosphate salt 1- NaOH 2- KH_PO. 2 4 . p CH OH A to- COOPNB 1- (PhO)2POCl 2- NEt(iPr). 3- Thiol 4- NEt(iPr). COOPNB , Tf (Ph0)2P02 0 To a cold (5°C) solution of (5R,6j3) paranitrobenzyl 6-(lR-hydro-xyethyl)-3,7-dioxo-l-azabicyclo[3.2.0]heptane-2R-carboxylate (2.14 g, 6.14 mmol) in dry acetonitrile (18 mL) kept under a nitrogen atmosphere was added diphenyl chlorophosphate (1.37 mL, 6.6 mmol), diisopropylethylamine (1.15 mL, 6.6 mmol) at such a rate that the temperature was kept at 5°C (7-10 min) and 4-dinethylaminopyridine (6 mg, 0.05 mmol). The mixture was stirred for 1.5 h at 5°C and, was used as it was; this mixture will be called 'solution A1 further in the procedure. A solution of (6-methyl-pyridin-2-yl)methylthio acetate (1.23 g, 6.8 mmol) in dry ether (10 mL) kept under a nitrogen atmosphere was treated with methyl triflate (0.85 mL, 7.5 mmol) and stirred for 1.5 h at 23°C. The ether was decanted and the white powder was washed twice with ether (2 x 10 mL) and dissolved in water N.2. PATENT OFFJCE' 2-? SEP 1986 —N -216- 205623 (20 mL). The resulting aqueous solution was cooled to 0°C under oxygen free atmosphere and treated with sodium hydroxide (4N, 3.4 mL, 13.6 mmol). The mixture was stirred at 2*C for 1 h and then the pH was adjusted at 7.6 by ' the addition of potassium dihydrogenphosphate; this mixture will be called 'solution B' further in the procedure. The cold (5°C) 'solution A' was treated with 'solution B' over 0.5 h period while the pH was kept between 7.25-7.35 by the dropwise addition of 4N sodium hydroxide solution. The mixture was stirred for 0.5 h and poured on top of reversed phase column (4.0 x 18 cm), prePak C-18); the column was eluted with a mixture of 25-50% acetonitrile in water. Lyophilization of appropriate fractions gave the title compound as a yellow powder, 2.82 g (51% (PhO)2?02 , 49%, CF,S0 ~), 80%; ir (KBr) v : 3700-3000 (OH), 1772 (C=0 of fl-lactam), 1700 J J max (C=0 of ester), 1625 (pyridinium), 1590 (pyridinium) cm S JHmr (DMSO, d-6) 6: 1.15 (d, J=6.2 Hz, C^CHOH), 2.84 (s, CH3 on C-6 of pyridinium), 4.16 (s, CH^ on N of pyridinium), 4.79 (s, SC^), 6.6-7.5 [(Ph0)2P02 ], 7.5-8.7 (H's on pyridinium and H's of PNB ester). -217- a 205S26 B. (5R,6S) 3-[(1,6-dimethylpyridinium-2-yl)methylthio]-6-(lR-hydroxyethyl)-7-oxo-l-azabicyclof3.2.0]hept-2-ene-2-carboxylate To a solution of (5R,6S) paranitrobenzyl 3-[ (1,6-dimethylpyridin-ium-2-yl)methylthio]-6-(lR-hydroxyethyl)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate, trifluoromethanesulfonate and diphenylphosphate (49:51) salt (0,87 g, 1.27 mmol) in vet tetrahydrofuran (50 mL) was added ether (50 mL), potassium dihydrogenphosphate-sodium hydroxide buffer (0.1H, 40 mL, pH 7.0) and 10Z palladium on charcoal (0.87 g). The mixture was hydrogenated under 36 psi at 23°C for 2 h and filtered on a Celite pad. The two phases were separated and aqueous phase was washed with ether (2 x 15 mL), concentrated under high vacuum until 30 mL and poured on top of reverse phase column (PrepPak C-18, 2.2 x 13 cm). Elution of the column was done with water. Appropriate fractions were combined and lyophilized to give a yellow powder, 0.179 g, 40Z; ir (KBr) * 1755 (C-0 of B-lactam), 1628 (pyridinium), 1590 (C-0 of carboxylate) cm JHmr (D^O) 6: 1.25 (d, J-6.4 Hz, CH3CH0H), 2.82 (s, CH3 on C-6 of pyridinium), 3.12 ('dd', J-9.2 Hz, J-2.9 Hz, H-4), 3.39 (dd, J-6.0 Hz, J-2.8 Hz, H-6), 3.7-4.4 (C^CHOH, N.Z. PATENT OFFICE 2 3SEP 1936 received 205G2S H-5, CH^ on N of pyridinium), 4.48 (s, CH^S), 7.6-8.4 (H's on pyridinium)} uv (H„0) X : 279 (e9628) with shoulder at 296; [a]" 55.0°C (c 0.63, i. max . u H2O); t^12*12.5 h measured at 37°C in buffer pH 7.4 for a concentration, of -4 • 10 M. -219- aUD0*40 W.2. fcAlHEMT OFFICE ■#■ 2 3SEF1986 Example 27 . rece.weq, Preparation of 3-[2-(N-Methylpyridinium) methanethio]-6g-[1-(R)-hydroxyethyl]-4 8-methyl-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate CH. 3 OH ob, 0 -^~~V-N0o _ _ J"L O-Et H0CH,-A_y~wu2 ^ /'\/\cO,PNB 2 \=/ ^ /^v^\co-PNB V n 2 7 71 2 ^ o A 4 p-Nitrobenzyl-2-diazo-3-oxo-n-valerate(4). A solution of 50 g (0.35M) of ethyl 3-oxo-n-valerate and 54 g (0.35M) of p-nitrobenzyl alcohol in 400 ml of toluene was heated at 130-140° without a refluxing condenser for 18 h. Evaporation of solvent gave a yellow crystalline material which was recrystallized from Et^O-pentane to 'produce 75 g (86Z yield) of p-nitrobenzyl 3-oxo-n-valerate (3). m.p. 33-34°. IR (Or) y 1740 and 1705 cm""1. NMR (CDCl^ 5 l-.20(3H,t,J«7.0Hz), 2.65(2H,q,J«7.0Hz), 3.60(2H,s). 5.28(2H,s), 7.45 (2H,d, J»=9.5Hz) , and 8.18(2H,d, J«=9.5Hz). To a solution of 55.5 g (0.22M) of compound _3 in 500 ml of CH^CN was added at 0° 45 g (0.44M) of TEA followed by 50 g (0.22M) of p-carboxybenzenesulfonyl azide. The ice bath was removed and the mixture was allowed to stir for min.. The precipitate was filtered, washed with CH^CN and the ■ 90 CA filtrate was concentrated to 100 ml volume and diluted with 800 ml of EtOAc. The organic solution was washed with aq. NaHCO^, brine and dried (HgSO^). Evaporation of the dried solvent gave 55 g (90% yield) of conpound 4_ as a slightly yellow crystals, m.p. 96-97°. IR (KBr) y 2120 and 1710cm"1. NMR (CDC13) 5 1.20(3H,t,J-7.0Ez), 2.85(2H,q,J«7.0Hz), 5.40(2H,s), 7.50 (2H,d,J-8.0Hz), and 8.15(2H,d,J«8.0Hz). ( 205626 /"""V C02PNB N. -220- OSlH- > N- c02pnb B. l-p-Nitrobenzyloxycarbonyl-l-diazo-2-t-butyldimethylsilyloxy-2-buten (5). To a cooled (0°) solution of 54 g (0.2M) of compound <4 in 400 ml of CH2C12 vas added 41.4 g (0.4M) of TEA followed by 56 g (0.21M) of _t-butyldimethylsilyl chloride .in 30 ml of CS2C12 over 40 min. The solution was stirred for 120 min, then washed with ice-water. The CH2C12 was dried (MgSO^), filtered and evaporated in vacuo to give 68 g (89Z yield) of compound 5_ as yellow solids, m.p.54-55°. IB. (KBr) T 2080 and 1695 an The NMR of compound 5_ indicated that compound •![ was obtained as a E/Z mixture at the olefinic position in a ratio of • 9:1. NMR (CDCl^ major isomer) 6 0.15(6H»s), 0.90(9H,s), 1.58(3H,d,J«7.0Hz), 5.15(2H,s), 7.30(2H,d,J«9.0Hz) and 8.0(2H, d, j-9.0Hz). N.Z. PATENT OFFICE 2 3SEPV986 received 1 -221- ('( 20562* 2oSG2& 1 OSi+ I I / s x1 >0AC .n: i OSi+ OS1-+ ,co2pnb \ n, c02pnb C. 4B-l-Methyl-3-diazo-3-p-nltrobenzyloxycarbonyl-2-o:co-propyl)-3Q-fl-(R)-t-butyldimethylsilyloxy ethyl]-azetidin-2-one • l To a suspended solution of 12.5 g (0.1M) of anhydrous ZnCl^ in 700 ml of CR^Cl^ was added 60.4 g (0.21M) of compound 6_ and stirred for 15 min at 23° then cooled to 0°. A solution of 106 g (0.27M) of compound 5_ in 200 ml of CH^Cl^ was added dropwise to the above reaction solution over 1 90 min, then stirred for 120 min without the cooling bath. The reaction i mixture was washed with aq. NaHC0„ (4 x 150 ml), water, brine and dried j ** I (MgSO^). Evaporation of dried solvent gave a dark oil, which was j purified by Si02 column; elution of the column with EtOAc-CH^Clj (1:9) j gave 5L.5 g (54Z) of compound 7_ as a white crystalline material, m.p. 112-114°. IR (KBr) y 2130,1760 and 1720 cm"1. The 360MHz nmr of compound ]_ indicated that compound 7_ was obtained as a mixture at the 1-methyl position in a ratio of 2:1. NMR (CDCl^) 5 0.3-0.6(6H, 2s), 0.8Z(9H,2s), 1.05-1.15(6H,m), 2.68(0.66H,q,J=6.6 and 2.0Hz), 2.88 (0.34,q,J-6.6 and 2.0Hz) 3.57(lH,m), 3.84 (lH,m), 4.09(lH,a), 517(2H,twos), 5.84(0.66H,s), 5.95(0.34H,s), 7.52(2H,d,J»8.5Hz) and 8.23(2H,d,J=8.5Hz). -222 r (' 205625 OSi on C02PNB > -X 33 & > f >f\c0,pnb P* 0 D. 4 g- (l-Methyl-3-diazo-3-p-nitrobenzyloxycarbonyl-2-oxo-propyl) -3a- T 1-00 -hydroxyethyl]-azetidin-2-one (8). To 'a solution of 30 g (59.5 mmol) of compound 1_ in 400 ml of MeOH vas added at 23° 150 ml of 1N-HC1 and stirred for 18 h. The reaction vas concentrated to 200 ml of volume and extracted with EtOAc (3 x 200 ml). The combined EtOAc vas vashed with vater, aq. NaHCO^ and • brine. Evaporation of dried (MgSO^) solvent gave 22.3 g (96Z) of compound 8 as a vhite crystalline material, m.p. 147-148°. IE (KBr) f 3400, 2135, and 1750 cm The 360 MHz nmr of compound 8_ indicated that compound 8 vas obtained as a mixture at the 4—methyl position in a ratio of 2:1. NMR (DMSO-d) 6 1.07-1.10(6H,m), 2.75(0.66H,q,J«6.6 and 2.0 Hz), 2.85(0.34H,J=6.6 and 2.0Hz), 3.55-3.90(3H,m), 5.25(2H,s) . 7.70(2H,d,J«9.0Hz), 8.05(0.66H,s), 8.10(0.34H,s) and 8.27(2H,d,J«9.0Hz). N.Z. HATf'N 1 2: ::r REGS'' -223- 205626 oh n 2 oh PPT c02pnb 0 0 c02pnb 8 t— 9 p-Nitrobenzyl-6a-ri-(R)-hydroxyethyl]-4-raethyl-3-,7-dio%o-l-azabicyclo [3.2.0] heptane-2-carboxylate (9). A solution of 14,0 g (35.86 mmol) of compound jB and 70 mg of rhodium(II) octanatate in ethylacetate vas heated at reflux for 20 min under N^. The mixture vas evaporated in vacuo to give compound 9 as a form. IR (CHCl^) Y 3400 and 1750 cm The 360 MHz nir.r of compound 9_ indicated that compound 9_ vas obtained as a mixture as the 4-methyl position in a ratio of 2:1. Nuclear Overhauser Effects (NOE) vere used to determine the configuration of the 4-methyl. When the H^ of major isomer is irradiated, an approximately 7Z signal increase for the 4-methyl protons vas observed, indicating the cis relationship of the H^ and the 4-methyl. On the other hand, vhen the H^ of minor isomer is irradiated, no signal increase was observed for the 4-methyl, indicating-the trans relationship of the H^ and the 4-methyl for the minor isomer. NMR (CDCl^) for the major isomer 5 1.24(3H,d,J«7.35Hz), 1.40(3H,d,J=6.3Hz), 2.40(lH,m), 3.24(lH,q,J-6.6 and 7.2Hz), 3.67(lH,q, J-8.0 and 2.2 Hz)," 4.18(lH,m)) 4.82(lH,s), 5.24(lH,d, J«6.3Hz), 6.18 (lH,d,J«6.3Hz), 7.60(lH,d,J«8.5Hz), and 8.22(lH,d, J-=8.5Hz).' NHR (CDC13) for the minor isomer 6 1.0(3H,d,H-7.35Hz) , 1.40(3H,d,J"'6.3Ez), 2.83(lH,m), 3.25(lH,q,J°6.6 and 1.50Hz), 4.14(lH,q,J-7.36 and 1.50Hz), 4.67(lH,s), 5.24 (lH,d,J«6.3Hz), 6.18(lH,d,J=6.3Hz) and 7.60(1H,d, J"=8.5Hz)and 8.22(lH,d,J-8.5Hz) . N.Z. PAif.fJl 01 ICE -224- 205SW oh ch co2pnb oh ch3 J 0 ^ > r II /I—0 0 1 ~O-P(O0) c02pnb c -\ 10 F. p-Nltrobenzyl-3-diphenoxyphosphinyl-6a-[l-(R)-hydro3cyethyl]-46-methyI-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate (10). To a cooled (0°) solution of 20.0 g (55.2 mmol) of the keto intermediate 9_ in 150 ml of CH^CN was added 7.18 g (55 mmol) of diisopropylethylamine followed by 14.85 g (55 mmol) of diphenylchlorophosphonate in 20 ml of CH^CN over 5 min. The resulting solution was stirred for 60 min at 0° f then diluted with 600 ml of ETOAc, washed with ice cold 10% and brine. Evaporation of the dried (MgSO^) solvent gave a crude oil which was purified by SiO^ column; elution of the column with 102 EtOAc in CR^Cl^ gave 3.7 g (11.5%) of the phosphonate _1£ as a white form. IR (CHC13) y 3400, 1790 and 1720 cm-1. NMR (CDC13) 5 1.20(3H,d,J=7.2Hz), 1.38(3H,d,H-7.3Hz), 3.35(lH,l,J-6.7 and 2.0Hz), 3.50(lH,m), 4.2-4.25(2H,m), 5.20(lH,d,J-10.5Hz), 5.37 (lH,d,J-10.5Hz), 7.l-7.4(10H,m), 7.56(lH,d,J-9.0Hz), and 8.10 (lH,d,J=9.0Hz). Nuclear Overhauser Effects were used to determine the configuration of the 4-methyl of compound 10. When the is irradiated, no signal increase was observed for the 4-methyl, indicating the trans relationship of the H5 and the 4-methyl. ■-225- f-'-\ 205626 OH 0 I! HS w i />-o-p(o0)2 C02PNB 'XfA. 4% c02pnb 10 11 G. p-I7itrobenzyl-3-rPYridine-2-vl-methanethlo'l-6gri-(R)-hydro3cyetiiy3.J-4B-methyl-7-oxo-l-azabicyclo (3.2.0) hept -2-ene-2-carboxylate (11). To a cooled (-15°) solution of 1.2 g (2 mmol) of the phosphonate _10_ in 10 ml of CH^CN was added 390 mg (3 mmol) of diisopropylethylamine followed by 370 mg (3 mmol) of 2-mercaptomethylpyridine under N2« The reaction mixture was allowed to stir for 60 min at -15® then additional 60 min at 0°. The reaction was diluted with EtoAc, washed with ice water, brine and dried (MgSO^). Evaporation of solvents in vacuo gave a yellow oil which was purified by SiO^ column; elution of the column with 20% EtOAc in CH CI- gave 375 mg (40% yield) of compound _11_ as a white -1 amorphous foam. IR (KBr) y 3400,1775, and 1710cm . NMR (CDCl^) 6 2.14 (3H,d,J«6.7HzH), 2.19(3H,d,J>=6.7Hz), 3.14(lH,q,J=6.2 and 2.0Hz), 3.40 (lH,m), 4.0(lH,d,J«7.6Hz) 4.12(lH,d,J-7.6Hz), 4.18(lH,q,J=6.7.and 2.0Hz) 4.25(lH,m), 5.25(lH,d,J«*11.3Hz), 5.40(lH,d,J-11.3Hz), 7.15-8.2(4H,m). &' ^ .. -226- 206 62S co2pnb "O oh ch, ^rris v~N"^r" 11 CO, © ;A© i h30 12 h. 3-f2-(N-Methylpyridinium)methane thio]-6g-[l-OQ-hydroxyethyl]-4B-methyl -7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2—carboxylate (12). To a solution of 1.0 g (2 mmol) of compound _11_ in 10 ml of CH^Cl^ was added 450 mg (3.3 mmol) of methyltrifluoromethanesulfonate and stirred at 23° for 90 min. Evaporation of CH^Cl^ in vacuo gave the quaternized pyridine as a foam which wash hydrogenated Immediately without any further purification. The crude pyridinium salt was dissolved into TMF-ether-PH 7 buffer (1:1:1, 100 ml each) followed by 600 mg of 10Z, palladium on charcoal. The mixture was hydrogenated at 35 psi on the par shaker for 45 min. The mixture was filtered through a celite pad and the catalyst was washed with water (2 x 10 ml). The combined filtrate and washings were extracted with ether (2 x 100 ml) and lypholized to give a yellow powder .which was purified on a C^g BONDPAK reverse phase column (10 g), eluting with 52 CH^CN in water under 8 psi pressure. Each 15 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at Xmax 300 nm were collected and lyophilized to give 58 mg (11Z yield) of the title compound as a pale yellow powder. IR (KBr) y 3400,1750, and 1590 cm"1. Amax (H20) 292 nm (e 7081). KHR 6 1.13(3H,d,J-6.5Hz), 1.23(3H,d,J«6.5Hz), 3.18(lH,m), 3.45(lH,q,J«6.0 and 2.1Hz), 4.0-4.4 (4H,m), 4.65(3H,s), 7.79(2H,m), 8.30(lH,m), and 8.60(lH,m). \ '- I \ 20562S -227- Example 28 Preparation of 3- [2- (1, 4-Dimethylpyridiniuro)methane thio]-6a-f1-1R)-hydroxyethyl]-4g-methyl-7-oxo-l-azabicyclo (3.2.0)hept-2-ene-2-carboxylate CH, 0 II >-0-P (00) 2 C02PNB 1) 2) HS VN-CF^SO^CHg 3) Pd/E, 10 13 3-T 2-(1,4-Dimethylpyridinium)methana thio] -6a-[1-(R)-hydroxyethyl]-4S -nethyl-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate (13). This compound was obtained as yellow powder in 17% yield from compound 10 in the same manner as that described < Example 27» -1 UV \ max (H20) 300 nm (c 7600). NMR IR Y 3400, 1755, and 1600 cm (D20) <5 1.20(3H,d,J=6.7Hz), 1.28(3H,d,J=6.7Hz), 2.60(3H,s), 3.4-3.5(2H,m), 4.2-4.4(4H,o), 4.52(3H,s), 7.82(lH,t,J-6.5 and 4.2Hz), 8.32(lH,d,J«6.5Hz), and 8.60(lH,d,J-4.2Hz). N.Z. PATENT PERCE 2 3 S E P 1986 RECEIVED 205626 Example 29 Preparation of 3- [4-(l-methylpyridiniummethane-thio] -6g- [1- (R)-hydroxyethyl] -4 g-methyl-7-oxo-l-azabicyclo (3 ♦ 2. 0) hept-2-ene-2-carboxylate 10 14 3-r4-(l-methylpyridinium methane thio] -6a-[l-(R)-hydrosyethyl]-4g-methyl-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carborylate (14). This compound vas obtained as yellov povder in 15Z yield from compound 10 in the same manner as that described in Exairple 27. IR (KBr) Y 3410, 1750 and 1650 cm-1 UV Amax.(H20) 293 nm (e 7295).NMR (D20) 6 1.15(3H,d,J=6.5Hz), 1.20(3H, d,J«6.5Hz), 3.20(lH,m), 3.45(lH,q,J-6.0 and 2.0Hz), 4.11(lB,q,J-8.0 and 2.0Hz), 4.20(1H, m), and 4.35(3H,s), 7.95(2H,d,J-5.2Hz) and 8.72(2H,d,J-5.2Hz). 205626 Example 30 Preparation of 3- [3-(l-methylpyridinium)methanethio] — 6 g —[1-(R)-hydroxyethyII-4 8-methyl-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate OH CH A 3 J, >O-P(O0)2 « hsag ch 2) CF3S03CH3 X —> 3) Pd/H2 CO- ©' ® ai. co2pnb 10 15 3-f3-(1-Methylpyridinium) methanethio ]-6'af l-(R)-bydroxyetbyl]-4B-metbyl- . 7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate (15). This compound was obtained as yellow powder in 27% yield from compound 10 in the same manner as that described - in Example 27. IR (KBr) y 3420, 1750 and 1610 cm"1. UV Xmax (H20) 295 nm (e 8750) NMR j (D20) 6 1.10(3H,d,J«6.9Hz), 1.25(3H,d,J-6.9Hz), 1.27(lH,m), j 1.43(lH,q,J-6.2 and 1.8Ez), 4.1-4.35(4H,m), 4.39(3H,s), 8.0(lH,t,J«8.5 ! and 6.2Hz), 8.45(lH,d,J-8.5Ez), 8.70(lH,d,J-6.2Hz), and 8.82(lH,s). | Anal. Calcd for C.5190; H,6.36; N,7.12. j Found: C, 51.92; H,5.71; N.6.88. { 205626 -230-Example 31 Preparation of 3-[3-(1,2-Dimethylpyridinium)methane-thio]-6a-[l-(R)-hydroxyethyl]-46-methyl-7-oxo-l-azabicyclo(3.2.0) hept-2-ene-2-carboxylate oh 1) 2) CF3S03CH3 ch 3) Pd/H2 co2pnb . 10 : is- 3- [ 3- (1,2-Dime thylpyridinium) me thane thio ] -6a- [ 1- (R) -hydroxyethyl] -4S-methyl-7-oxo-l-azabicyclo (3,2,0). hept-2-ene-2-carboxylate (16). This compound was obtained as yellow powder in 14Z yield from compound 10 in the same manner as that described in .Example '27. IR (KBr) y 3410, 1750 and 1600 cm"1. UV Xmax (HgO) 296 nm (e 8500). NMR (D20)5 1.25(3H,d,J«6.5Hz), 1.30(3H,d,J«6.5Hz), 2.95(3H,s), •3.40(lE,m), 3.50(lH,q,J-6.2 and 1.8Hz), 4.2-4.4(4H,n), 4.35(3H,s), 7.82(lH,t,J-8.5 and 6.3Hz), 8.40(lH,d,J-8.5Hz) and 8.72(lH,d,J-6.3Hz). ( ''' 205626 -231-Example 32 Preparation of [3-(2,4-Dimethyl-l,2,4-triazolium)-methanethio]-6a-[1-(R)-hydroxyethyl]-]4g-methyl-7-oxo-l-azabicyclo (3 .2. 0)hept-2-ene-2-carboxylat'e CH, l3 [3-(2,4-Dimethyl-l,2,4-triazolium)methanethiol -6a-[1-(R)-hydroxyethyl]-]-46-methyl-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate (17). This compound was obtained as yellow powder in 9Z yield from compound _10 in the same manner as that described Sii Example 27. __ IR "(KBr) y 3420, 1756, and 1605 cm"1. UV Xmax (HjO) 291 nm (e 7850). NMR (D20) 5 1.15(3H,d,J-=6.3Hz), 1.22(3H,d,J>=6.3Hz) , 3.35(lH,m), | 3.48(lH,q,J=6.0 and 1.8Hz), 3.90(3H,s), 4.05(3H,s), 4.2-4.4(4H,m), j and 8.80 (lH,s). I I i " ! I 'I l -232- 20562S Example 33 Preparation of 3- [2t- (l, 3-Dimethyliniidazolium-methanethio]-6a-f1-(R)-hydroxyethyl]-]4 B-methyl-7-oxo-l-azabicyclo(3.2.0)hept-2-ene-2-carboxylate co2pnb 10 1) 2) ch, I N- HS N- CF3S°3CH3 3) *4^2 18 3-f2-(l,3-Dimethyllmidazolluffl methanethio) -6a-fl-(R)-hydroryethyl]-4S-methyl-7-oxo-l-azablcyclo (3.2.0) hept-2-ene-2-carboxylate (18). This compound was obtained as yellow'powder in 32Z yield from compound 10 in the same manner as that described ■ in Exairple_ 27. : -1 UV Xmax 294 nm (e 7194). NMR IR (Or) Y 3400,1758 and 1600cm (D20) 6 1.10(3E,d,J«6.3Hz), 1.25(3H,d,J=6.3Hz), 3.30(lH,m), 3.42(1E,1,J«6.0 and 2.2Ez) 3.85(6E,s), 4.2-4.6(4B,n) and 7.40 (2E,s). 2 3SEP mi USSSlVtn 205626 -233- Exainple 34 N.Z. PATENT OF f: ICE 2 3 SEP 1986 RECEIVED Following the general procedures of Examples 1- 33, the following carbapenem products are made by using the intermediate of the formula C02pNB s -A—h- N-H cocP Ex. No. ^~\© c L/-R- © -34 a ~CE2~ ~\ /'"°H3 34 b -CH2CH2- -T 34 c ~CH2~ 34 d -CH2- '/ \N Cli3© 3 \n—\ <3 . ( 34e -234- -ch2ch2- CH 20562® 3 © nN—v ^3 34f "CH2~ W ch2ch2ch3 34 g 34h 34 i 34 3 -ch2- -ch2- -ch2- -ch2- ch ch, © A^CH3 ?H3 I CH, © CH3-T—Nr^ S- CH3 34k -ch2- -a © N- I ch. 341 34m 34 n ch, l3 -ch- -ch2~ -ch2- £>! © -ch- ch_ / 2 r© N ch i, « ~o. ch3 * © i h. 34 o 34, 34q 34 r 34 S 34 t -235--ch^- -ch„ - -ch2- -ch2- -ch2- -ch2- Example 205626 ch. @ (mixture of 3 pos-sible iso mers) ■N cocP t / 1*2 N •J ?H^© ~Q > fi.3© ch /r N N ch. ch2-cocP i—n—ch. © :L [ —N Following the general procedures of Examples 1-33, the following carbapenem products are made using the intermediate of the formula l^n&patent office C02pNB 23SEP19S6 RECEIVED - ' I •• t • -236- 205626 / oa ch, I H f 3 /~\ © «> r-r Tf N Ex. No. 'cocP © O- 35a -ch2ch2- 35b -CH2CV ch 3 © \ 35 c -ch2- n-ch2ch2ch3 35 a *CH2~ ch © A srrCH3 © N-CH- 35 B -cv r i1 3 s- CE3 35 f "CH2~ ' © 5 ch. J 205626 -237- f ch3 -£)?ch3 ':C -ch- 35h ~CH2~ ■ ^ CH^ o cr—" s 35 -CH2- © ch. ch. (mixture of 3 possible iso roers) 35: j 35 k . ■CH2- -ch2- -I N /- © -ch. ■c ^cocP (fH2 d:H^ </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 205626 r ( 351 -238- -CV 35 in -CBj- 35n -ca2- SH3 ir> © 0 CH. CH--CO (P N N .N—N-CH. i 1 CH- Example 36 If in the procedure of Example 22, the keto intermediate 1 is replaced by an equimolar amount of the corresponding la-methyl intermediate, there is obtained the carbapenem end product indicated above. - 23 7- WHAT WE CLAIM IS:

1. A compound of the fonnula 8 1 wherein R is hydrogen and R is selected from the gtoup consisting of hydrogen; and substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 10 carbon atoms; cycloalkyl and cyclo-alkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 205626 C^-Cg alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -or3 0 "34 -ocnr r 0 "34 -cnr r 3 -nr3r4 nr" '/ nr3r4 II 34 -s-nr r 0 " 3 4 -nhcnr r r3cnr4--co2R3 =0 0 -ocr3 -sr3 0 " 9 -sr O II 9 -sr II O -cn "n3 -0s03r3 0 " 9 -os-r It O O 3/' 9 -nr s-r II 0 -op(0) (or3) (or4) \" I -14t- 3 4 -NR C=NR R -NR3C02R4 and -N0„ 205626 wherein, relative to the above-named substituents, the 3 4 groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having up to 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 up to 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 and/or sulfur atcros and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon 3 4 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 nitrogen-containing heterocyclic ring; R is as defined 3 1 for R except that it may not be hydrogen; or wherein R g and R taken together represent C2~C^0 alkylidene or C2-Ci0 alkylidene substituted by hydroxy; R is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-cycl}3alkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R^ radicals are optionally substituted by 1-3 substituents independently selected from: 20562^ C^-Cg alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; 3 -or ; -0c02r3 ; -0c0r3 ; -oconr3r4 ; 0 " 9 -os-r ; II 0 -oxo ; 3 4 -nr r ; 3 4 r conr - ; -nr3c02r4 ; -nr3conr3r4 ; 3" 9 -nr s-r li 0 3 -SR ; N.Z. PATENT OFFICE 2 3 sep 1986 received 0 T 9 -s-r ; 0 0 K P g -s-r ; -so3r3 ; -co2r3 , 3 4 -conr r -cn; and phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, 3 C1-Cg alkyl, -OR", -NR-'R 3 4 3 3 " -SO R , -CO_R and • 3 4 3 4 9 5 -CONR R , wherein R , R and R in such R substituents are as defined above; 205626 4t& / i 2 3 SEP1986 5 ^ or R may be attached also to O -^§CEiypn at another•point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain one or more additional hetero atoms selected from 0, S and N; A.is C.-C, straight or branched chain alkylene; 2 . R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting 2 group, providing that when R is hydrogen or a protecting group, there is also present a counter ion; and O1 represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical containing at least one nitrogen in the ring, said ring being attached to A through a ring carbon atom and having a ring nitrogen which is quaternized by the group acceptable salt thereof. 5 quaternized by the group R ; or a pharmaceutically

2. A compound according to Claim 1 wherein R1 is hydrogen, ch3ch2-, " CH3- r a oh CH- , ^c- or ch3ch- ch3 ch3 1 8

3. a compound according to Claim 1 wherein R and R taken- together represent hoch 2\ c= CH3 205626 - 24V /—^^I^roFP,ce or R^ may be attached also to ZSEPfigt N - at another•point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain one or more additional hetero atoms selected from 0, S and N; A. is Cn-Cc straight or branched chain alkylene; 2 . . R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting 2 group, providing that when R is hydrogen or a protecting group, there is also present a counter ion; and O1 represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical containing at least one nitrogen in the ring, said ring being attached to A through a ring carbon atom and having a ring nitrogen which is quaternized by the group acceptable salt thereof. quaternized by the group R^; or a pharmaceutically A compound according to Claim 1 wherein R^" is hydrogen, <*3. ' =a3. r •H OH CH- , ^c- or CH3CH- ch3ch2-, ch3 ch3 1 ' 8

3. a compound according to Claim 1 wherein R and R taken- together represent HOCH 2\ C= . CH3 20562* 4. ^^^loPFJce 2 3SEP /og6 Jl££El\/EO A compound according to Claim 1 wherein is oh CH3CH- . 5. A compound according to Claim 1 wherein R1 is CH OH is- and the absolute configuration is 5R, 6S, 8R. 6. A is 7. A compound according to Claim 1, 2, 3, A or 5 wherein -CH2- or -CH2CH2- A compound of the formula ,8 COOR 8 1 wherein R is hydrogen and R is selected from the group consisting of hydrogen; and substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom .or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 - 7.*$- ^ 205626 C^-Cg alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -or3 0 "34 -ocnr r . 0 II 34 -cnr r 3 4 -nr r 3 /nr -4 ^nr3R4 0 " 3 4 -s-nr r II 0 0 11 3 4 -nhcnr r 0 r3cnr4--co2r3 =0 o -ocr3 -sr3 0 II 9 -sr a U 9 -sr ll 0 -cn -n3 -0s03r3 0 " 9 -os-r K 0 0 3 ll 9 -nr s-r II 0 -op(0)(or3)(or4) 205626 -iq-L- 3 4 -NR C=NR J* -NR3C02R4 and -no2 wherein, relative to the above-named substituents, the 3 4 groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having up to 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 up to 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 and/or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon 3 4 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 nitrogen-containing heterocyclic ring; R is as defined 3 1 for R except that it may not be hydrogen; or wherein R g and R taken together represent C2-C,Q alkylidene or alkylidene substituted by hydroxy; R is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-cycl^alkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R^ radicals ■are optionally substituted by 1-3 substituents independently selected from: -2-4-7- 205626 C,-C, alkyl optionally substituted by amino, JL D fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; 3 -OR ? -0C02R3 ; -OCOR3 ; -OCONR3R4 ; 0 " 9 -OS-R ; ll 0 . -oxo ; 3 4 -NR R ; 3 4 R CONR - ; 3 4 -NR COjR ; 3 3 4 -NR CONR R ; _^cnrrop^c£ 235EPJ986 RECEIVED 0 711 c -NR S-R' ii 0 -SR3 ; 0 •r g -S-R ; 0 O K ? g -S-R ; -S03R3 ; -C02R3 ; 3 4 -CONR R ; -CN; and phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, C,-Cfi alkyl, -OR3, -NR3R4, -SO,R3, -CO,R3 and 1 3„4 .... „3 „4 £9 „5 -conr^r", wherein r r' and r in such r substituents are as defined above; -24.*-- 205626 may be attached also to Oe- at another point on the ring so as form a fused heterocyclic or heteroaromatic ring, which ring may contain one or more additional hetero atcms selectea from 0, £ and N; A is C^-Cg straight or branched chain alkylene; R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter ion; and v. represents an aromatic mono-, bi- or polycyclic N-containing heterocyclic ring containing 0-5 additional hetero atoms selected from O, S and N, said heterocyclic ring being attached to A through a ring carbon atom and having a ring nitrogen quaternized by the group R5, and said heterocyclic ring being optionally substituted at available ring carbon atoms by 1-5 substituents independently selected from the group consisting of C^-C4 alkyl; Cj-C^ alkyl substituted by 1-3 substituents independently selected from hydroxy, amino, C^-C^ alkylamino, di(C^-C^)alkylamino, C^-C^ alkoxy, carboxy, halo aid sulfo; C^-Cg cycloalkyl; C3~Cg cycloalkyl(C^-C^)alkyl optionally substituted by 1-3 substituents mentioned above in connection with alkyl; Cj-C^ alkoxy; C1~C4 alkylthio; amino; C1~C4 alkylamino; di(C^-C^)alkylamino; halo; C^-C4 alkanoyl-amino; C1~C4 alkanoyloxy; carboxy; sulfo; 0 -C-0-C1-C4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, 2C562G trifluoromethyl, Ci-C4 alkyl, alkoxy, C^-C^ alkylamino, di (C^-C^)alkylamino, carboxy, and sulfo; phenyl(C^-C^)alkyl in which the phenyl portion is optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion is optionally substituted by 1-3 substituents mentioned above in connection with alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4 0, S and/or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, alkyl, C2~C4 alkoxy, C1~C4 alkylamino, di(C^-C^)-alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, alkylamino, di(C^-C^)alkylamino, C^-C^ alkoxy, carboxy, halo and sulfo, and said heterocyclic ring being optionally substituted at available ring nitrogen atoms by 1-3 substituents independently selected from the group consisting of C^-Cj alkyl; C^-C^ alkyl substituted by 1-3 substituents independently selected from hydroxy, amino, C^-Cj alkylamino, di(C^-C^)alkylamino, C^-C^ alkoxy, carboxy, halo and sulfo groups; cycloalkyl; C^~C^ cycloalkyl(C^-C^)- alkyl optionally substituted by 1-3 substituents mentioned above in connection with C2.-C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C1~C4 alkyl, alkoxy, alkylamino, di(Cj-C4)alkylamino, carboxy and sulfo; phenyl-(C1-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 zs~a- 205626 ch3ch2-, substituents mentioned above in connection with C^-C^ alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4 0, S and/or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trif luoromethyl, alkyl, ci~C4 alkoxy' C^-C^ alkylamino, di(C^-C^)alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, alkylamino, di(C^-C^)alkylamino, C^~C4 alkoxy, carboxy, halo and sulfo; or a pharmaceutically acceptable salt thereof. A compound according to Claim 7 wherein R^" is hydrogen, ch-, ch, oh oh i ■ ,CH- , or CH3CH- ' CT3 CH3 1 8

9. A compound according to Claim 7 wherein R and R taken together represent hoch c= 2" CH3"

10. A compound according to Claim 7 wherein R^" is oh I ch3ch-

11. A compound according to Claim 7 wherein R"*" is oh I ch3ch- and the absolute configuration is 5R, 6S, 8R.

12. A compound according to Claim 7, 8, 9, 10 or 11 wherein A is or -CH2CH2~ . 205626 -2<Zt ~

13. A compound of the fonnula 8 1 wherein R is hydrogen and R is selected from the group consisting of hydrogen; and substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 UP to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 C^-Cg alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo . 1 \ 205626 // ^nr3R4 II 3 4 -s-nr r ll 0 0 " 3 4 -NHCNR R O 3II d r cnr - -co2r3 =0 O -ocr3 -sr3 0 " 9 -sr 0 " 9 -sr If 0 -cn "N3 -0s03r3 0 " 9 -OS-R H O 0 31' 9 -nr s-r II O -0p(0) (or3) (or4) I 205626 -1ST.- J 3 4 -NR C=NR L> -NR3C02R4 and -N02 wherein, relative to the above-named substituents, the 3 4 groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atcms; 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 and/or sulfur atcsns and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon 3 4 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 nitrogen-containing heterocyclic ring; R is as defined 3 1 for R except that it may not be hydrogen; or wherein R g and R taken together represent c2-ctq alkylidene or ^""^lO alkylidene substituted by hydroxy; R is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atcms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R^ radicals are optionally substituted by 1-3 substituents independently selected from: \ " I ■ ■ ■ y '— _ ^ *■ ' 205626 C^-Cg alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 ; -oco2r3 ; -ocor3 ; -oconr3r4 ; 0 II a -os-r* II 0 -oxo ; 3 4 -nr r ; 3 4 r conr - ; 3 4 -nr°co2r -nr3conr3r4 ; 0 3" 9 -nr s-r ; ii 0 -sr3 ; 0 T- 9 -S-R ; 0 O K a -S-R ; -so3r3 ; -c02r3 ; 3 4 -conr r -CN; and phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, c -c alkyl, -or3, -nr3r4, -so..r3, -co r3 and 1 3 4 3 4 9 5 -conr r , wherein r , r , and r in such r substituents are as defined above; J160CTJ986 h / -tsv- or R^ may be attached also to Q- at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional one or more hetero atoms selected from 0, N and S; A is C,-C- straight or branched chain alkylene; 2 R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, pro- 2 viding that when R is hydrogen or a protecting group, there is also present a counter ion; and represents an aromatic 5- or 6-membered N-containing heterocyclic ring containing 0-3 additional hetero atoms selected from N, S and 0, said heterocyclic ring being optionally substituted at available ring carbon atoms by 1-5 substituents independently selected from the group consisting of C^-C^ alkyl; C^-C^ alkyl substituted by 1-3 substituents independently selected from hydroxy, amino, C^-C^ alkylamino, di(c^-C^)alkylamino, C^-C4 alkoxy, carboxy, halo and sulfo; C^-Cg cycloalkyl; C3~Cg cycloalkyl(C1_C4)alkyl optionally substituted by 1-3 substituents mentioned above in connection with C^-C^ alkyl; C^-C^ alkoxy; C^-C^ alkylthio; amino; alkylamino; di(C^-C^)- alkylamino; halo; alkanoylamino; Ci-C4 alkanoyloxy; carboxy; sulfo; 0 il —C—0-C^—C4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, 20562$ 205626 trif luoromethyl, alkyl, C^-C^ alkoxy7~ ' C-^-C^ alkylamino, di (C^-C^) alkylamino, carboxy, and sulfo; phenyl (C-^-C^) alkyl in which the phenyl portion is optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion is optionally substituted by 1-3 substituents mentioned above in connection with alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4 O, S and/or N atcms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C^-C^ alkyl, C2_-C4 alkoxy, C2-('4 alkylamino, di(C^-C^)-alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, alkylamino, di (C^-C^)alkylamino, C^-C^ alkoxy, carboxy, halo and sulfo, and said heterocyclic ring being optionally substituted at available ring nitrogen atoms by 1-3 substituents independently selected from the group consisting of Cx-C4 alkyl; C^-C^ alkyl substituted by 1-3 substituents independently selected from hydroxy, amino, C-^-C^ alkylamino, cii(C^-C^)alkylamino, C^_C^ alkoxy, carboxy, halo and sulfo groups; C-^-Cg cycloalkyl; C3~Cg cycloalkyl (C^-C^)-alkyl optionally substituted by 1-3 substituents mentioned above in connection with alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C1~C4 alkyl, C1~C4 alkoxy, alkylamino, di (C^-C^) alkylajnino, carboxy and sulfo; phenyl-(C^-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 205626 -ZGl- substituents mentioned above in connection with C]_-C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms are selected from the group consisting or 1-4 0, S and/or N atons and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, alkyl, alkoxy, C^-C^ alkylaminor di(C^-C^)alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, alkylamino, di (C1-C4)alkylamino, C^-C^ alkoxy, carboxy, halo and sulfo; or a pharmaceutically acceptable salt thereof.

14. A compound according to Claim 13 wherein the heterocyclic ring is optionally substituted at available ring carbon or nitrogen atoms by up to 5 substituents independently selected from C^-Cg alkyl.

15. A compound according to Claim 14 wherein A is -CH, -CH2CH2- or CH -ch- .

16. A compound according to Claim 13, 14 or 15 wherein R^" is oh ch3<!:h- and the absolute configuration is 5R, 6S, 8R. n.z. patent opf1cf 2 3SEP W REceivn r 205626 - iss- 17. A compound of the formula 8 1 wherein R is hydrogen and R is selected from the group consisting of hydrogen; and substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 C^-Cg alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -OR3 0 'I 3 4 -OCNR R _SATE:'rr OFFICE II 3 4 -CNR R 3 4 -NR R ! ?.'^P!986 c. deceived '/ nr3 -2s<i- 2 0 5 6 26 A- 3 4 nr r 0 II 34 -s-nr r li 0 " 3 4 -nhcnr r 0 r3cnr4- -c02r3 =0 -ocr3 -sr3 0 " 9 -sr 0 " 9 -sr ll 0 -cn -n3 -0s03r3 o " 9 -os-r3 It 0 3 ll q -NR S-R II 0 -OP(0)(OR3)(OR4) J | —yJjo- 205626 3 4 -NR C=NR i* -NR3C02R4 and -N02 N.Z. PAT£?;"f 0 ! — i 2 2 SEP 1986 RECEIVfO i wherein, relative to the above-named substituents, the 3 4 groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having up to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkyIcycloalkyl, 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 up to 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 and/or sulfur atoms;and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon 3 4 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 nitrogen-containing heterocyclic ring; R is as defined 3 1 for R except that it may not be hydrogen; or wherein R g and R taken together represent C2~cio a^ylidene or ^2-C^q alkylidene substituted by hydroxy; R is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-cyclyalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atcnis and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R^ radicals are optionally substituted by 1-3 substituents independently selected from: \ - I 205626 -lb I' C.-C,. alkyl optionally substituted by amino, J- 6 fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 ; -0C02R3 ; —OCOR3 ; -OCONR3R4 ; 0 " 9 -OS-R ; 1/ 0 -oxo ; 3 4 -NR R ; 3 4 R CONR - ; -NR3C02R4 ; 3 3 4 -NR CONR R ; 3" 9 -NR S-R n 0 -SR3 ; 0 T- Q -S-R ; n.z. PATENT 0! PiCfc 23sep 1986 RECEIVED R Pf D -S-R? ; -so3r3 ; -c02r3 ; 3 4 -CONR R ; -CN; and phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, "3 -NR3R4, -S0..R3, -C0„R3 and 4 9 5 R , and R in such R substituents are as defined above; °r R~* rnay he attached also to O- Cn-Cc alkyl, -OR" 3 4 . " -CONR R , wherein R~ at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain one or more additional hetero atoms selected from 0, N and S; - 205626 A is C, -Cc straight or branched chain alkylene; 2 R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, 2 providing that when R is hydrogen or a protecting group, there is also present a counter ion; and 6 represents a radical selected from the group consisting of R5- (a) R1 -r6 wherein R6, R7 and R10 are independently selecfed~froi?Tilhyfljrocfen; C^-C^ alkyl; alkyl substituted by hydroxy, alkylamino, di(C1-C4 alkyl) amino, alkoxy, amino, sulfo, carboxy or halo; C3-C6 cycloalkyl; Cj-C^ alkoxy; C-j-C^ alkylthio; amino; C^-C^ alkylamino; di (C^-C4 alkyl) amino; halo; alkanoylamino; Cj-C4 alkanoyloxy; carboxy; 0 n -C-OCj-Cq alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three substituents independently selected from amino, halo, hydroxyl, trif luoromethyl, C^-C^ alkyl and Cj-C^ alkoxy groups; phenyl (C^-C^J alkyl in which the phenyl portion may be optionally substituted by 1-3 substitutents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C^-C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms in the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; or wherein two of R6, R*7 and R1"0 taken together may be a fused saturated carbocyclic ring, a fused aromatic carbocyclic ring, a fused non-aromatic heterocyclic ring or a fused heteroaromatic ring, said fused rings being optionally substituted by 1 or 2 of the substituents defined above for R^, R7 and R^; 205£26 R 5 5 ©I x'N r' (b) or c optionally substituted on a carbon atom by 1-3 substituents independently selected from c1~c4 alkyl; alkyl substituted by hydroxy, C^-C^ alkylamino, di(C^-C^ alkyl)amino, sulfo, C^-C^ alkoxy, amino, carboxy or halogen;. C^-Cg cycloalkyl; Cl-C4 al^oxy; ci_c-*4 alkylthio; amino; alkylamino; di(C^-C4 alkyl)amino; halo; C^-C4 alkanoylamino; C^-C^ . . alkanoyloxy; carboxy; O IJ -C-OC^-C^ alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three substituents independently selected fran amino, halo, hydroxyl, trifluoromethyl, C^-C4 alkyl and C^-C^ alkoxy groups; phenyl (C^-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C^-C4 alkyl;.and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atcms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above; 5 5 r" 5 r" K (c) n V «•#- \S yj R ®l — 2-^4-- ^ e /N ■ \fiT/ R ©.' s % or ^\, optionally substituted on a carbon atom by one or two substituents independently selected from C^~C4 alkyl; C^-C^ alkyl substituted by hydroxy, C^-C^ alkylamino, di (C^-C^ alkyl) amino, Cx-C alkoxy, sulfo, amino, carboxy or halogen; C,-C 3 6 cycloalkyl; C^-C^ alkoxy; C^-C^ alkylthio; amino; C^-C^ alkylamino; difC^-C^ alkyl) amino; halo; C^-C^ alkanoylamino; C^-C^ alkanoyloxy; carboxy; O 1/ -C-OC^-C^ alkyl; hydroxy, amidino, guanidino, phenyl; phenyl substituted by one, two or three substituents independently selected frcm amino, halo, hydroxyl, trif luoromethyl, alkyl and C,-^ alkoxy groups; phenyl alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned. above in connection with alkyl;.and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected .from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atcrns ^d the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above; (d) e1 R" el -N 4 l:w 5 R" ,1 °N or -•l/s"' 205626 optionally substituted on a carbon atom by a substituent independently selected from alkyl; alkyl sub stituted by hydroxy, amino, alkylamino, di(C^-C^ alkyl)- amino, alkoxy, sulfo, carboxy or halogen; C^-Cg cyclo alkyl; alkoxy; alkylthio; amino; C^-C^ alkylamino; di(C^-C^ alkyl)amino; halo; C^-C^ alkanoylamino; alkanoyloxy; carboxy; 0 II -C-OC^-C^ alkyl; hydroxy; amidino; guanidino, phenyl; phenyl substituted by one, two or three substituents independently selected from amino, halo, hydroxyl, trifluoromethyl, C^-C^ alkyl and C-j-C^ alkoxy groups; phenyl (C^-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with alkyl;.and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; (e) e e 5 N-R" N-R I or wherein X is O, S or NR in which R is alkyl; alkyl siibstituted by 1-3 substituents independently selected frcm hydroxy, amino, Cj-C^ alkylamino, di(C^-C4) alkylamino, C^-C4 alkoxy, carboxy, halo and sulfo groups; C^-Cg cycloalkyl; C^-Cg cycloalkyl(C^-C^)alkyl optionally substituted by 1-3 substituents mentioned a±>ove in connection with C-]_~C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trif luoromethyl, C-j-C^ alkyl, C^-C^ alkoxy, C^-C^ alkylamino, di(C^-C^)alkylamino, carboxy and sulfo; phenyl(C^-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents 20562& mentioned above in connection with C2~C4 alkyl7 an^ heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4, 0, S and/or N atans and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C2~C4 alkyl, C2-C4 alkoxy, Cj_-C4 alkylamino, di(C^-C^)-alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, alkyl amino, di(C^-C^)alkylamino, alkoxy, carboxy, halo and sulfo, said radical being optionally substituted on a carbon atom by one or more substituents independently selected from alkyl; cjl_c4 alkyl substituted by hydroxy, alkylamino, di (C^-C^ alkyl)amino, alkoxy, amino, sulfo, carboxy or halogen; C^-Cg cycloalkyl; alkoxy; alkylthio; amino; C^-C^ alkylamino; di (C^-C^ alkyl)amino; halo; C-j-C^ alkanoylamino; alkanoyloxy; carboxy; O -C-OC^-C^ alkyl; hydroxy; amidino; guanidino, phenyl; phenyl substituted by one, two or three substituents independently selected from amino, halo, hydroxyl, trif luoromethyl, C^-C^ alkyl and C^-C^ alkoxy groups; phenyl (C^-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above; / 205626 wherein X is O, S or NR in which R is C^-C^ alkyl? C]/"C4 alkyl substituted by 1-3 substituents independently selected from hydroxy, amino, Cj-C^ alkylamino, di(Cj-C^)alkylamino, Cj-C^ alkoxy, carboxy, halo and sulfo groups? cycloalkyl; C3~Cg cycloalkyl(C^-C^)alkyl optionally substituted by 1-3 substituents mentioned above in connection with" alkyl? phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C^-C^ alkyl, alkoxy, C^-C^ alkylamino, di(C^-C^)alkylamino, carboxy and sulfo; phenyl (C^-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C^-C^ alkyl; and heteroaryl and heteroaralkyl in which .the hetero atom or atoms are selected from the group consisting of 1-4, 0, S and/or N atans and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally-substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoro-methyl, c1~c4 alkyl, C1"C4 alkoxy, alkylamino, di(C^-C4)- alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, alkyl amino, di(C^-C4)alkylamino, C^-C^ alkoxy, carboxy, halo and sulfo, said heteroaromatic radical being optionally substituted on a carbon atom by a substituent selected from C^-C4 alkyl; C -C alkyl substituted by hydroxy, C,-C. alkylamino, 14 di(C1-C4 alkyl)amino, C1~C4 alkoxy, amino, sulfo, carboxy or halogen; C3-Cg cycloalkyl; C^-C^ alkoxy; C^-C^ alkylthio; amino; alkylamino; di (C-^-C^) alkylamino; halo; C^-C4 alkanoylamino; C^-C4 alkanoyloxy; carboxy; 0 -C-0C1~C4 alkyl; hydroxy; amidino? guanidino; phenyl; phenyl 205626 -ih- substituted by one, two or three substituents independently selected frcm amino, halo, hydroxyl, trif luoromethyl, C^-C^ alkyl" ana C-j-C^ alkoxy groups; phenyl (C^-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with alkyl;.and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; and (g) © r ■N-R" -N-R wherein R is C^~C4 alkyl; C]l~^4 alkyl substituted £>3^-1-3 substituents independently selected frcm hydroxy, amino, C^-C^ alkylamino, di(C^-C^)alkylamino, C^-C^ alkoxy, carboxy, halo and sulfo groups; C3-Cg cycloalkyl; cycloalkyl (C^-C^) alkyl optionally substituted by 1-3 substituents mentioned above in connection.with alkyl 205626 phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, alkyl, cj_~c4 alkoxy, c1~c4 alkylamino, di (C^-C^) alkylamino, carboxy and sulfo; phenyl (C^-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C^-C^ alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4, 0, S and/or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoro-methyl, C-)_-C4 alkyl, c1~c4 alkoxy, alkylamino, difC^-C^)- alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C^-C4 alkylamino, di(C^—C4)alkylamino, C^-C4 alkoxy, carboxy, halo anc sulfo or a pharmaceutically acceptable salt thereof.

18. A compound according to Claim 17 wherein n.2. pathkt office 2 3 SEP 1986 received \ I -21° 205626 2V wherein is C-^-Cg alkyl and R^, r"7 and R^® are each independently hydrogen or C2~C4 alkyl; (b) r" N? r^' A r" N9 N' or wherein R is C^-Cg alkyl and wherein available ring carbon atoms are optionally substituted by 1-3 substituents independently selected from alkyl; (c) r" le r^N r" r5 N® r^% r5 I. n n r" or <N. N- J :N-N ' -2?i- 205626 wherein R is C^-Cg alkyl and wherein available ring carbon atoms are optionally substituted by 1 or 2 substituents independently selected from C.-C^ alkyl; (d) ©. N • J* ,5 e1 N' .n - I e N I il or a ,5 . wherein R is C,-C,. alkyl and wherein an available ring JL b carbon atom is optionally substituted by C-|__C4 a^kyl; (e) N-R-X or _N-R" wherein R is ^-Cg alkyl, X is 0, S or NR in which R is C^-C^ alkyl and wherein one or more available ring carbon atoms is optionally substituted by alkyl; (f) • © c N-R" SU5 © 2Q>$' & ^ ■2-72- ,5 . wherein R is C1-Cg alkyl, X is 0, S or NR in which R is C^-C^ alkyl and wherein one or more available ring carbon atoms is optionally substituted by alkyl; and (g) N- N. N-R" N-R R5 e i^l W. N ' 5 L R -15 -R N. , N-R N-R' © 5 , R5 © -N N N-R or N R5-N N-R ,5 . wherein R is C2_~Cg alkyl and R is C^-C^ alkyl.

19. A compound according to Claim 18 wherein R"*" is hydrogen, CH^CH^, CH 3\ CH- , CH. CH- OH 3\ I C- CH ^ OH I or CH3CH- 1 8

20. A compound according to Claim 18 wherein R and R taken together represent HOCH 2\ CH. C= V v\, ! . \ 20562S -vn-

21. A compound according to Claim 18 wherein R is oh I ch3ch- .

22. A compound according to Claim 18 wherein R is oh I ch3ch- and the absolute configuration is 5R/ 6S, 8R.

23. A compound according to Claim 17, 18, 19, 20, 21 or 22 wherein A is -CH^-or 24. A compound of the formula 8 1 wherein R is hydrogen and R is selected from the group consisting of hydrogen; and substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 \" I J~- -TCTr- -937 - 205626 C2~^6 °Pti°r>ally substituted by amino, halo, hydroxy or carboxyl halo -or3 0 " 3 4 -0cnr r 0 ll 34 -cnr r -nr3r4 /NR3 ^nr3R4 0 II 34 -s-nr r ll 0 " 3 4 -nhcnr r 3" 4 r cnr - -c°2k3 =0 -ocr3 -sr3 O " 9 -sr O ll g -sr II 0 -cn "»3 3 -0s03r O ll 9 -0s-r3 /( 0 3/' 9 -nr s-r II 0 -op (o) (or3) (or4) wherein, relative to the above-named substituents, the 3 4 groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having up to 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 up to 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 and/or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon 3 4 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 nitrogen-containing heterocyclic ring; R is as defined 3 1 for R except that it may not be hydrogen; or wherein R O and R taken together represent ^"^lO alkylidene or alkylidene substituted by hydroxy; R is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atans and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R^ radicals are optionally substituted by 1-3 substituents independently selected from: -471- 205626 C^-Cg alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; 3 -or ; -0CO2R3 ; -OCOR3 ; -OCONR3R4 ; 0 » g -0s-r3 II . 0 -OXO ; 3 4 -NR R ; 3 4 R CONR - ; -NR3C02R4 ; 3 3 4' -NR CONR R ; 0 3" 9 -NR S-R ; ll 0 -SR3 ; 0 T- q -S-R ; 0 0 /<; 7T g -S-R ; -S03R3 ; -C02R3 ; 3 4 -conr r ; -CN; and phenyl optionally si±istituted by 1-3 substituents independently sel- 3 3 4 3 ected from fluoro, chloro, brcmo, C.-C, cQkyl, -OR , -NR R , -SO.R , 3 4 3 4 9 5 -CO~RJ and -CONR R , wherein R , R , and R in such R substituents 5 are as defined above; or R may be attached also to at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain one or more additional hetero atoms selected from 0, N and S; 205626 USt:i.PAT^r^~ ] -X77 - A is C.-C, straight or branched chain alkylene; 2 R is hydrogen, en anionic charge or a conventional readily removable carboxyl protecting group, 2 providing that when R is hydrogen or a protecting group, there is also present a counter ion; and e represents a radical selected from the group consisting of ,7 K5- ® r1 ,6 wherein R6, R7 and R10 are independently selected from hydrogen; C1-C4 alkyl; C1~C4 alkyl substituted by hydroxy, C1-C(J alkylamino, di(C1-C4 alkyl)amino, C1~C4 alkoxy, amino, sulfo, carboxy or halo; C3-Cg cycloalkyl; C-j-C^ alkoxy; C1~C4 alkylthio; amino; C-j-C^ alkylamino; di(C^-C4 aIky1)amino; halo; C^—C4 alkanoylamino; C4 alkanoyloxy; carboxy; 0 il -C-OC^-C4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three substituents independently selected from amino, halo, hydroxyl, trif luoromethyl, Cj-Cj ^ alkoxy groups ; phenyl (C^-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substitutents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C2~C4 a^yl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms in the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; or wherein two of R®, R^ and R^° taken together may be a fused saturated carbocyclic ring, a fused aromatic carbocyclic ring, a fused non-aromatic heterocyclic ring or a fused heteroaromatic ring, said fused rings being optionally substituted by 1 or 2 of the substituents defined above for R^, R7 and R^; or a pharmaceutical^ acceptable salt thereof. I ,/ 205626 —2-7-2 -

25. A compound according to Claim 24 wherein R1 is hydrogen, CR^CYl^-, ch3v ch3-v oh oh \ "X ch- , / CH„ CH t- or CH^H- 3 1 8

26. A compound according to Claim 24 wherein R and R taken together represent hoch2 . / CH3 27. A compound according to Claim 24 wherein R"*" is OH l CH CH- .

28. A compound according to Claim 24 wherein r is OH 1 CH3CH- and the absolute configuration is 5R, 6S, 8R. 29. A compound according to Claim 24, 25, 26, 27 or 28 wherein A is -CH2~ or -CH2CH2~. 30. A compound of the formula r8 h r- /7 0 "n © -S—A—f N—R" —coor 2 23SEP \ / 205&26 / 8 1 wherein r is hydrogen and r is selected from the group consisting of hydrogen; and substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 UP to 6 carbon atcms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 C^-Cg alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo . -or3 0 " 3 4 -ocnr r 0 II 34 -cnr r 3 4 -nr r NR" 3 4 nr r 0 II 34 -S-NR R II 0 0 » 34 -nhcnr r 0 3" 4 r cnr - -co2r3 =0 0 -ocr3 -sr3 N.Z. patent On :pt 235CP 1986 recf 1 205626 'l&O- -SR " 9 -sr II 0 -CN "»3 3 -0s03rj> 0 Jl g -os-r 0 -NR3S-R9 ll o -OP (0) (OR3) (OR4) • -nr3c=nr4 ■ i3 -NR3C02R4 and . -NO2 wherein, relative to the above-named substituents, the groups 34, r and r are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having up to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-5 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein .the aryl moiety is phenyl and the aliphatic portion has up to 6 carbon atans; 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 and/or sulfur atoms and the alkyl moieties associated with 3 4 said heterocyclic moieties have 1-6'carbon atoms, or r and r I !',! -> *. sr 205626 -IS"!- .taken together with the nitrogen to which at least one is attached may form a 5-or 6-membered nitrogen-containing heterocyclic rino; 9 . 3 R is as defined for R except that it may not be hydrogen; or 1 8 wherein R and R taken together represent C2~C^0'alkylidene or alkylidene siibstituted by hydroxy; "8? is. selected from the group consisting of s'ubstitruted ana unsubstituted:- alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atans; heteroaryl, heteroaralkyl, hetero^ cyclyl and heterocyclylalkyl wherein the hetero atom or atoms in -the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atcms ana the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named radicals are optionally substituted by 1-3 substituents independently selected from: 205&,26 C^-Cg alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3; -0C02R3 ; rOCOR3 ; ~0C0NR3R4 ; 0 n 9 -OS-R II 0 -oxo ; 3 4 -NR R ; 3 4 R CONR - ; 3 4 -NR C02R ; -NR3CONR3R4 ; O -C02R3 ; 3 4 -CONR R ; -CN; and phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, C -Cfi alkyl, -OR3, -NR3R4, -SO.R3, -CO R3 and 3 4 .3 4 9 5 -CONR R , wherein R , R , and R in such R substituents are as defined above; or R^ may be attached also to at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain one" or more additional hetero atoms selected from 0, N and S; 205626 A^is straight or branched chain alkylene; R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R^ is hydrogen or a protecting group, there is also present a counter ion; and represents a radical of the formula e| XT R 5 5 or •N optionally substituted on a carbon atom by 1-3 substituents independently selected from C^-C^ alkyl; alkyl substituted by hydroxy, alkylamino, di(C^-C^ alkyl)amino, sulfo, C1~C4 a-^oxy' amino' carboxy or halogen;. C^-Cg cycloalkyl; C^-C^ alkoxy; alkylthio; amino; C]_~C4 alkylamino; di(C1~C4 alkyl)amino; halo; C^-C^ alkanoylamino; C^-C^ . . alkanoyloxy; carboxy; 0 11 -C-OC^-C^ alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three substituents independently selected frcm amino, halo, hydroxyl, trifluoromethyl, C^-Cj alkyl and Cj-C^ alkoxy groups; phenyl (C1~C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C^-C4 alkyl;.and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring -m- 205 626, optionally substituted by 1 or 2 of the substituents defined above; or a pharmaceutically acceptable salt thereof.

31. A compound according to Claim 30 wherein is NS-R5

32. A compound according to Claim 30 wherein is R" eJ n€-r5 33. is A compotmd according to Claim 30 wherein ,5 R' ef ( n®-R^

34. A compound according to Claim 30, 31, 32 or 33 wherein R"*" is hydrogen, CH^CH^-, ch. CH. x CH- CH 3V OH xi- f or CH^CH-. CH. •: ' / t» 2056 26

35. A compound according to Claim 30, 31, 32 or 33 1 8 wherein R and R taken together represent HOCH- 2\ C= • . / ^3

36. A compound according to Claim 30, 31, 32 or 33 wherein R"^ is oh I ch3ch- .

37. A compound according'to Claim 30, 31, 32 or 33 wherein R"*" is oh I ch3ch- and the absolute configuration is 5R, 6S, 8R.

38. A compound according to Claim 30, 31, 32 or 33 wherein A is -CH2- or -CH2CH2~, R^" is OH I CH3CH- and the absolute configuration is 5R, 6S, 8R. 20562S 39 . A compound of the formula 8 1 wherein R is hydrogen and R is selected from the group consisting of hydrogen; and substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atcms ; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 C^-Cg alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo . -OR3 0 ll 3 4 -OCNR R -cnr3r4 -nrV /nr K7 3 4 nr r II 34 -s-nr r ll 0 V>-| V 205626 -Zvi- II 34 -NKCJ7R R 0 3II 4 r cnr - -co2r3 =0 0 -ocr3 -sr3 -SR O ' H g -SR* ll 0 -CN ""S 3 -oso^r O ll g —OS-R ri 0 . O 3'' 9 -NR S-R II 0 -OP(O) (OR3) (OR4) -nr3c=nr4 • i3 3 ' 4 -NR C02R and -no2 205626 _2S3- wherein, relative to the above-named substituents, the 3 4 .groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atcms; 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 and/or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon 3 4 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 nitrogen-containing heterocyclic ring; R is as defined for R3 except that it may not be hydrogen; or wherein R"*" 8 and R taken together represent alkylidene or c2~C]_o alkylidene substituted by hydroxy; R is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R^ radicals are optionally substituted by 1-3 substituents independently selected from: r I^^P}986 jiiEvSr ^tsci 205^^ C^-Cg alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -or3 ; -OC02R3 ; -ocor3 -oconr3r4 ; O ll 9 -os-r 11 • O -oxo ; va3 4 - nr r ; r3conr4- ; 3 4 ' -nr c02r ; -nr3conr3r4 D 3" 9 -NR S-R ; ii 0 -sr3 ; 0 -s-r9 ; 0 0 K q -s-r ; -S03R3 ; -C02R3 ; . -conr3r4 ? -CN; and phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, C -C alkyl, -OR3, -NR3R4, -SO.R3, -CO-R3 and ,3„4 „3 „4 „9 . 2, 5 -CONR R , wherein R" R' and R in such R substituents are as defined above; or R my be attached also to © N— at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain one or more additional hetero atoms selected from 0', N and s; 20562# A is C,-C, straight or branched chain alkylene; K is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting■group, providing that when R2 is hydrogen, or a protecting group, there is also present a counter ion? and r^e s t N-X eDresents a radical of the formula •-N • 1). „n a-\ 5^- % or optionally substituted on a carbon atom by 1-3 substituents independently selected from C^-C^ alkyl? C^-C^ alkyl substituted by hydroxy, C^-C^ alkylamino, di (C^-C^ alkyl) amino, .sulfo, C1-C4 alkoxy, amino, carboxy or halogen;. cycloalkyl; C^-C4 alkoxy; C-|_-C4 alkylthio; airi.no; alkylamino? di(C^-C4 alkyl) amino; halo; alkanoylamino? C^-C4 . . alkanoyloxy? carboxy; O ll -C-OC^-C^ alkyl; hydroxy; aicidino; c-jeniaino; phenyl; phenyl substituted by one, two or three substituents independently selected from amiip, halo, hydroxyl, trif luoromethyl, C^-C^ alkyl and C^-C^ alkoxy groups; phenyl (C^-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with alkyl; and heteroaryl or heteroaralkyl 205626 I — in which the hetero atom or atoms in the above-named heterocyclic moieties are selected frwm the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above; or a pharmaceutically acceptable salt thereof.

40. A compound according to Claim 39 wherein R^" is hydrogen, CH^CI^-, 3\ CH3 OH ?H / CH_ ' ^C- or CH-CE- . CH3 • CH3" 3 1 8

41. A compound according to Claim 39 wherein R and R taken together represent HOCH- C= CH3

42. A compound according to Claim 39 wherein R^" is OH I CH3CH- .

43. A compound according to Claim 39 wherein R"*" is OH I CH3CH- and the absolute configuration is 5R, 6S, 8R.

44. A compound according to Claim 39, 40, 41, 42 or 43 wherein A is -CI^- or -CH2CH2"*. ■ v' !■ ■■ ■< _ ■ .V • ~v..* ■ ' v>-;" / 205626 ** <■>

45. A compound of the formula 8 1 wherein R is hydrogen and R is selected from the gfoup consisting of hydrogen; and substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 N.Z. PATENT OFF ICE 2 3sep19s6 RECEIVED \ 2 05626 C^-Cg alkyl optionally siibstituted by amino, halo, hydroxy or carboxyl halo -or3 O " 3 4 -ocnr r 0 -cnr3r4 -nr3r4 /nr3 ^nr3R4 0 " 3 4 -s-nr r ll 0 0 ii 3 4 -nhcnr r 0 3II 4 r cnr - -co2r3 =0 0 i 3 ii 3 -ocr -sr 0 II 9 -sr 0 " 9 -sr II 0 -cn -n3 -oso3r3 o '' 9 -os-r fl 0 0 3" 9 -nr s-r II \ 0 i 3 4 ! -op (0) (or ) (or ) | i 1 •205626 -W- wherein, relative to the above-named substituents, the 3 4. .groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, haying up to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkyIcycloalkyl, 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 up to 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 and/or sulfur atcms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon 3 4 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 nitrogen-containing heterocyclic ring; R is as defined for R3 except that it may not be hydrogen; or wherein R"*" g and R taken together represent alkylidene or C2-C10 alkylidene substituted by hydroxy; R is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atans and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R** radicals are optionally substituted by 1-3 substituents independently selected from: -MS" 205626 C^-C, alkyl optionally substituted by amino, x b fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 ; -0C02R3 ; -0C0R3 ; -OCONR3R4 ; 0 ii g -OS-R II . 0 -oxo ; 3 4 -NR R ; 3 4 R CONR - ; 3 4 -NR C02R 3 3 4 -NR CONR R ; O - 3'1 9 -NR S-R ; ii O -SR3 ; 0 9 -S-R ; 0 0 KP q -S-R ; -S03R3 ; -C02R3 ; -C0NR3R4 ; -CN; and phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, C.-Cf. alkyl, -OR3, -NR3R4, -SO^R3, -CO R3 and 3 4 3 4 9 5 -CONR R , wherein R , R , and R in such R substituents are as defined above; -%<](- or R may be attached also to N - at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain one or more additional hetero atoms selected from 0, N and S; 2 A is C1~C6 straight or branched chain alkylene; R is hydrogen, an anionic charge or a conventional readily removable carboxyl . . 2 protecting group, providing that when R is hydrogen or a protecting group, there is also, present a counter ion; and N-R" represents a radical of the formula or VN ~w- 20562S optionally substituted on one carbon atom by a substituent independently selected from C^-C^ alkyl; alkyl substituted by hydroxy, amino, Cj-C^ alkylamino, diCC-^-C^ alkylamino, sulfo, Ci-C4 alkoxy, carboxy or halogen; C3~Cg cycloalkyl; C-j_-C4 a^oxy'" Ci-C4 alkylthio; amino; C^-C^ alkylamino; di(C^-C^)alkylamino; halo; C^-C^ alkanoylamino; C2~C4 alkanoyloxy; carboxy; 0 -C-OC^-C^ alkyl; hydroxy; amidino; guanidino, phenyl; phenyl substituted by one, two or three substituents independently selected from amino, halo, hydroxyl, trif luoromethyl, C-j-C^ alkyl and Cj-C^ alkoxy groups; phenyl (C^-C^) alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with cjl~C4 a^y^' an<i heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group~consisting of 1-4 oxygen, nitrogen and/or sulfur atans and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof. 46 . A compound according to .Claim 45 wherein R"*" is hydrogen, ch^ch.,-, ^3 CH,' \ \ ? OH Cn~ ' C- or ch £h- / -3 Cn3 CH3 i g

47. A compound according to Claim 45 wherein R and R taken together represent boch2 c-- 205626 -z<?2

48. A compound according to Claim 45 wherein R is OH l CH3CH- . ,1 .

49. A compound according to Claim 45 wherein R is OH I CH3CH- and the absolute configuration is 5R, 6S, 8R.

50. A compound according to Claim 45, 46, 47, 48 or 49 wherein A is ~c^2~ or -CH2CH2~~'

51. A compound of the formula R8 H R j N COOR © = N—R" N.Z. PATENT OFFICE 2 3 5 e p 1986 received 8 1 wherein R is hydrogen and R is selected from the gtoup consisting of hydrogen; and substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 10 carbon atoms; cycloaUcyl 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 up to 6 carbon atans; .heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 <r -zw- 20 56 2 6 C..-C- alkyl optionally substituted by amino, halo, x 6 hydroxy or carboxyl halo -or3 0 "34 -ocnr r . O II 34 -cnr r -nr3r4 nr3 3 4 NR R ii 3 4 -S-NR R 0 " 3 4 -nhcnr r 0 r3cnr4- -co2R3 =0 0 -ocr3 -sr3 0 n 9 -sr o " 9 -sr ii 0 -cn "N3 3 -0s03r 0 ll 9 -os-r n o o 3 /' 9 -nr s-r ii 0 -op(0) (or3) (or4) I ~Zoo-r~ 205626 wherein, relative to the above-named substituents, the 3 4 groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having up to 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 up to 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 and/or sulfur atone and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon 3 4 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 nitrogen-containing heterocyclic ring; R is as defined 3 1 for R except that it may not be hydrogen; or wherein R ' g and R taken together represent C2~C10 alkylidene or alkylidene substituted by hydroxy; R is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-cycl}3alkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R"* radicals are optionally substituted by 1-3 substituents independently selected from: -2,c?\- 2056ZS C^-Cg alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3. ' 3 -0C02R ; -OCOR3 ; -OCONR3R4 ; 0 » 9 -OS-R 11 ■ 0 -oxo ; 3 4 -NR R ; 3 4 R CONR - ; 3 4 -NR C02R ; -NR3CONR3R4 ; 0 3" 9 -NR S-R ll 0 -SR3 ; O T* Q -S-R 0 O r 7> q -S-R ; -S03R3 ; -C02R3 ; 3 4 -CONR R ; -CN; and phenyl optionally substituted by 1-3 substituents independently 3 ... 3 4 selected from fluoro, chloro, bromo, Q.~C alkyl, -OR , -NR R , -SO R , -CO-R'5 and -C0NRJR , wherein R , 5 substituents are as defined above; or R may be attached also to 4 g.... . 5 R , and R m such R N - at another point on the ring so as to form a fused hetero cyclic or heteroaromatic ring, which ring may contain one or more additional hetero atoms selected from 0, N and S; 205626 A is straight or branched chain alkylene; R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R^ is hydrogen, or a protecting 9^-oup, there is also present a counter ion; and reoresents a radical of the formula or X wherein X is O, S or NR in which R is C^-C4 alkyl; C1-C^ alkyl substituted by 1-3 substituents independently selected from hydroxy, amino, Cj-C^ alkylamino, di(C^-Cj)alkylamino, c^-C^ alkoxy, carboxy,halo and sulfo groups; C^~C^ cycloalkyl; C^-Cg cycloalkyl(C^-C^)alkyl optionally substituted by 1-3 substituents mentioned above in connection with c-j__C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trif luoromethyl, C2.-("*4 alkyl, alkoxy, alkylamino, di(C^-C^)alkylamino, carboxy and sulfo; phenyl(C^-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C-|_-C4 a^kyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4, 0, S and/or N atans and the alkyl moiety associated with heteroaralkyl has 1-6 carbon N.Z. PATENT OFFICE 2 3 sep 1986 -3£>3- 205626 atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoro-methyl, C1-C4 alkyl, alkoxy, C1~C4 alkylamino, di • alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, alkyl amino, di(C^-C^)alkylamino, alkoxy, carboxy, halo and sulfo, said heteroaromatic radical being optionally substituted on a carbon atom by one or more substituents independently selected from C^-C^ alkyl; C^-C^ alkyl substituted by hydroxy, alkylamino, di (C^-C^) alkylamino, C-j-C^ alkoxy, amino, sulfo, carboxy or halogen; cycloalkyl; C-|_*~C4 alkoxy, Ci-C4 alkylthio; amino; C1~C4 alkylamino; di (C^-C^) alkylamino; halo; C^-C4 alkanoylamino; C^-C4 alkanoyloxy; carboxy; 0 W -C-0C^-C4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three substituents independently selected from amino, halo, hydroxyl, trif luoromethyl, C^-C^ alkyl and C^-C^ alkoxy groups; phenyl (C^-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C^-C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above; or a pharmaceutically acceptable salt thereof. M | ill i—| f N.Z. PATENT OFFICE 1 23sepi936 receive 7C5&26 r""\ r 1

52. A compound according to Claim 51 wherein R1 is hydrogen, CH3CH2~, CH„ rn 3\ 3 DH OH - CH. CH- X ' I • ' C- or CH3CH-. GH3^ 1 8

53. A compound according to Claim 51 wherein R and R taken together represent I. HOCH2 ■ c<C= •

54. A compound according to Claim 51 wherein R^" is OH l CH3CH- .

55. A compound according to Claim 51 wherein R* is OH I CH CH- arid the absolute configuration is 5R, 6S, 8R.

56. A compound of Claim 51, 52, 53, 54 or 55 wherein A is -CH - or -CH2CH2- . ti.£ », i f, ; ; '■ •',£ 2 5StP 1936 RECEIVED 205S26 | - sor-

57. A compound of the formula 8 1 wherein R is hydrogen and R is selected from the group consisting .of hydrogen; and substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to lo 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 up to 6 carbon atcms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 C^-Cg alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -3ok : ^NR3 \nr3R4 " 3 4 -S-nr^R* 0 " 3 4 -nhcnr r 0 3II 4 r cnr - -co2r3 =0 0 -ocr3 -sr3 0 " 9 -sr 0 // g -sr ll 0 -cn "n3 3 -oso3Rj 0 ll D -0s-r3 it 0 0 3'' 9 nr s-r ii 0 0p(0) (or3) (or4) -3.P7- 205623 3 4 -NR C=NR wherein, relative to the above-named substituents, the 3 4 .groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atcms; 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 and/or sulfur atone and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon 3 4 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 nitrogen-containing heterocyclic ring; R is as defined for R3 except that it may not be hydrogen; or wherein R"*" O and R taken together represent C2~C^q alkylidene or ^"^lO alkylidene substituted by hydroxy; R is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to>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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atcms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R^ radicals are optionally substituted by 1-3 substituents independently selected from: V4-'- I -3oS 205626 C.-C- alkvl optionally substituted by amino, J- o fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 ; -0C02R3 ; r-OCOR3 -OCONR3R4 ; 0 « g -OS-R ; II 0 -OXO ; 3 4 -NR R ; 3 4 R CONR - ; 3 4 -NR CO R ; -NR3CONR3R4 ; 0 3" 9 -NR S-R ; ii O -SR3 ; 235EP 1986 jRgCEfVED f 9 -s-R ; 0 0 Q -S-R ; -s03r3 ; -C02R3 ; 3 4 -CONR R ; -CN; and phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, C -C alkyl, -OR3, -NR3R4, -S0,R3, -CO.R3 and 3 4 .3 4 9 5 -CONR R , wherein R , R , and R in such R substituents are as defined above; or R^ may be attached also to O- at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain one or more additional hetero atoms selected from 0, N and S; 2Q5G26 -vt- , 25SEP It RECEn/m" 205&24 is C^-Cg straigh-i or branched chain alkylene; R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, 2 providing that when R is hydrogen or a protecting group, there is also present a counter ion; and 6 j. N-R represents a radical of the formula u-r~ © c -N.-R" x S-r5 ^:N^ N X R5—N N 1 N-R" \ or N X A wherein X is 0, S or NR in which R is C^-C^ alkyl; C^-C^ alkyl substituted by 1-3 substituents independently selected frcm hydroxy," amino, C^-C^ alkylamino, di (C^-C^)alkylamino, C^-C4 alkoxy, carboy, halo and sulfo groups; cycloalkyl; cycloalkyl(C^-C^)alkyl optionally substituted "by 1-3'substituents mentioned above in connection with C-^-C^ alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trif luoromethyl, C2_C"4 alkyl, alkoxy, C2~C4 alkylamino, di(C^-C^)alkylamino, carboxy and sulfo; phenyl(C^-C4)alky1 in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C^-C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4, 0, S and/or N atcms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being 205626 -3>lt>- optionally substituted in the heterocyclic ring moiety by 1-3 substitutents independently selected from hydroxy, amino, halo, trifluoromethyl, alkyl, C^-C^ alkoxy, C^-C^ alkylamino, di (C-^-C^) alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, alkyl amino, di (C-j-C^) alkylamino, C^-C4 alkoxy, carboxy, halo and sulfo, said heteroaromatic radical being optionally substituted on a carbon atom by a substituent selected from alkyl; C2.-C4 ^^yl substituted by hydroxy, alkylamino, di(C-^C^)alkylamino, C1-C4 alkoxy, amino, sulfo, carboxy or halogen; C3~Cg cycloalkyl; Cx-C4 alkoxy; alkylthio; amino; C-L~C4 alkylamino; difCj-C^)- alkylamino; halo; alkanoylamino; C^-C^ alkanoyloxy; carboxy; O • 1/ -C-OC^-C^ alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three substituents independently selected from amino, halo, hydroxyl, trifluoromethyl, C^-C^ alkyl or C^-C^ alkyl and C^-C^ alko:xy groups; phenyl (Cj-C^) alkyl in which the phenyl portion may be optionally siibstituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof. N.2. PATENT OFFICE 2 3SEPI986 RECEIVED 205626 -3i/ -

58. A compound according to Claim 5 7 wherein R^" is hydrogen, CH^CH^-, CH3 CH3 OH OH I CH- , C- or CH..CH-. CE^ CH3 1 8

59. A compound according to Claim 57 wherein R and R taken together represent hoch2 ^0= .

60. A compound according to Claim 57 wherein R^" is oh I ch3ch- .

61. A compound according to Claim 5 7 wherein R^" is oh I ch3ce- and the absolute configuration is 5R, 6S, 8R.

62. A compound according to Claim 57, 58, 59, 60 or 61 wherein A is -CH2~ or -CH2CH2~. N.Z. PATENT OFFICE 2 3SEPI986 -1 -3<2L- 205626 63. A compound of the formula ^^COOR © S—A—r N—R" 8 . 1 wherein R is hydrogen and R is selected from the group consisting of hydrogen; and substituted and unsubstituted: alkyl, alkenyl and alkynyl/ having up to lo 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 ajna the aliphatic portion has up to 6 carbon atcras; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalky1 wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 C^-Cg alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -OR3 0 ll 34 —OCNR R -cnr3r4 -nrV WENT Gf;MCE 2 35ep 1986 RECEIVED -3n- 205626 r3 ^nr3R4 II 34 -s-nr r ll 0 " 3 4 -nhcnr r 0 3II 4 r cnr - -c02r3 =0 -ocr3 -sr3 0 " 9 -sr 0 " 9 -sr ii 0 -cn 3 -oso3r 0 " 9 -os-r /( 0 0 3'' 9 -nr s-r ii 0 -op(0)(or3)(or4) 205626 -3-14- and wherein, relative to the above-named substituents, the 3 4 .groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atans,- and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from t±ie group consisting of 1-4 oxygen, nitrogen and/or sulfur atcms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon 3 4 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 nitrogen-containing heterocyclic ring; R is as defined 3 1 for R except that it may not be hydrogen; or wherein R g and R taken together represent C2~ciq alkylidene or c2""cio alkylidene substituted by hydroxy; R is selected from the gjroup consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to lo 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atcms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R radicals are optionally substituted by 1-3 substituents independently selected from: j ^'j' All' V i'. V . ~ i '.;; i £ I i ' •jo 3 4 -NR C=NR 3 4 -NR COjR -N02 RECEIVED -z1c-- 205626 Ci-C alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3; -0C02R3 ; r-OCOR3 ; -0C0NR3R4 ; 0 " 9 -OS-R* II ■ O -oxo ; -NR3R4 ; 3 4 R CONR - ; 3 4 -NR C02R ; -NR3C0NR3R4 ; 3" 9 -NR S-R ll 0 -SR3 ; -S-R* n P q -S-R ; -S03R3 ; -C02R3 ; 3 4 -CONR R -CN; and phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, C..-C,- alkyl, -OR3, -NR3R4, -SO-R3, -CO„R3 and 1 T 4 3 4 9 5 -CONR R , wherein R , R , and R in such R substituents are as defined above; or R^ may be attached .also to N- at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain one or more additional hetero atoms selected from 0, N and S; 205626 A is C^-Cg straight or branched ch.ain alkylene; R^ is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, . . 2 ' providing that when R is hydrogen or a protecting group, there is also present.a counter ion; and \Q r- N-R represents a radical of the formula e N N-R" N-R N. N. N. N-R N-R" wherein R is alkyl; alkyl substituted by 1-3 sub stituents independently selected frcm hydroxy, amino, C^-C^ al]<ylamino, di-(C^^C4)alkylamino, C^-C^ alkoxy, carboxy, halo-and sulfo groups; C^-Cg cycloalkyl; C3"Cg cycloalkyl (C^-C^) alkyl optionally substituted by 1-3 substituents mentioned above in connection with Cj_-C4 alkyl; 205626 phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluororoethyl, C^-C^ alkyl, C^rC^ alkoxy, C^~C4 alkylamino, ci (C^—)alkylamino, carboxy and sulfo; phenyl(C^-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C^-C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4, 0, S and/or n atcms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally-substituted in the heterocyclic ring moiety by 1-3 substituents , independently selected from hydroxy, amino, halo, trifluoro-.. methyl, C^-C^ alkyl, C^-C^ alkoxy, alkylamino, di(C^-C^)- alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C^-C^ alkylamino, di(C^-C^)alkylamino, C^-C^ alkoxy, carboxy, halo and sulfo; or a pharmaceutically acceptable salt thereof.

54. a compound according to Claim 63 wherein R is hydrogen, CH^Cf^-, CHo - CH

3.

3 OH OH ^ \l I J:H- , or CH - CK-. 3 CH3 CH3 X 8

55. a compound according to Claim 6 3 wherein R and R taken together represent koch2 x'c= 3 N.Z. PATENT OFFICE 23SEPI986 RECEIVED 205626 -31 v '

66. A compound according to Claim 63 wherein R"*" is OH l CH3CH- . 67.- A compound according to Claim 63 wherein R^" is OH I CH3CH- and the absolute configuration is 5R, 6S, 8R.

68. A compound according to Claim 63, 64, 65, 66 or 67 . wherein A is -CH2-# -CE^CI^-. 69 . A compound of the formula H —R~ N.Z. PATENT OFFICE COOR 2 3SEPJ986 REceiveo wherein R is hydrogen and R is selected from the group consisting of hydrogen; and substituted and -unsubstituted: alkyl, alkenyl and alkynyl, having up to lo 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 up to 6 carbon atoms,- heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms 2_nd 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 I -3i1- 205626 Cx-C alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -OH3 0 " 3 4 -ocnr r 0 -cnr3r4 -nr3r4 /nr3 ^nr3R4 0 II 34 -s-nr r ll 0 " 3 4 -nhcnr r 0 3" 4 r cnr - -co2r3 =0 -ocr -sr3 0 ii 9 -sr 0 ll g -sr ii 0 -cn -"3 3 -0s03r 0 " 9 -0s-r if 0 o 31' 9 -nr s-r ii O -op(0) (or3) (or4) wherein, relative to the above-named substituents, the 3 4 groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having up to 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 up to 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 and/or sulfur atcms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon 3 ^ 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 nitrogen-containing heterocyclic ring; R is as defined for R3 except that it may not be hydrogen; or wherein R^" O and R taken together represent C2-C,Q alkylidene or C2-C10 alkylidene substituted by hydroxy; R is selected from the group consisting of siibstituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atcms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R^ radicals are optionally substituted by 1-3 substituents independently selected from: -3a r- 205626 C^-Cg alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -or3 . f -0c02r3 ; -0c0r3 ; -oconr3r4 0 ll 9 -os-r II . 0 -oxo ; 3 4 -nr r ; 3 4 r conr - ; -nr3c02r4 ; 3 3 4--nr conr r ; O 3" 9 -nr s-r ; ii 0 -sr3 •T- q -s-r ; 0 0 R P q -s-r ; -E03R3 ; -c02r3 ; -c0nr3r4 ; -cn; and phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, c.-c, alkyl, -or3, -nr3r4, -s0_,r3, -c0or3 and 1 ^ 4 3 4 9 2 5 -conr r , wherein r , r , and r in such r substituents are as defined above; ; N.Z. PATENT OFFICE 2 3SEP 1986 received 205626 A is C^-Cg straight or branched chain alkylene; R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R is hydrogen or a protecting group, there is also present a counter ion? and N -R" represents a radical of the formula j <5 wherein R6, R7 and R10 are independently selected from the group consisting of hydrogen, C,-C. alkoxy, carboxy and carbamoyl; or a pharma- JL H ceutically acceptable salt thereof.

70. ch3ch2-, A compound according to Claim 69 wherein R^" is hydrogen. CH. N CH- CH. CH, OH crj^ OH-' ■/ or ch3ch- 1 8

71. A compound according to Claim 69 wherein R and R taken together represent HOCH. 2\ C= -5,2, V 205626

72. A compound according to Claim 69 wherein R^" is OH / CH3CH- . 73- A compound according to Claim 69 wherein R^" is OH i CH3CH- and the absolute configuration is 5R, 6S, 8R.

74. A compound according to Claim 69, 70, 71, 72 or 73 wherein A is -CH2- or -CH2CH2-.

75. A compound having the formula wherein A is C.-Cc straight or branched chain alkylene; 2 R is hydrogen, an anionic charge or a conventional readily 2 removable carboxyl protecting group, providing that when R is hydrogen or a protecting group, there is also present a represents a radical of the formula 205626 - 324-- U) 5 6 wherein R is C^-C^ alkyl and R represents hydrogen or CrC4 a^yl; R - (b) N ® R _s' -R 5 6 7 wherein R is C^-C^ alkyl and R and R are hydrogen or C1~C4 alky1' R \ (c) ,5 . wherein R is C^_C4 alkyl and R is alkyl or phenyl- (C1-C4) alkyl; (d) N N -R -N wherein R^ is Ci-C4 alkyl and R^ is ci~C4 alkyl; R5 (e) I© N \ / N R ,5 . wherein R is C^-C^ alkyl and R is C^-C^ alkyl; or -3*£- 2 0 56 26 - (f) N. wherein is C^-C^ alkyl; or a pharmaceutically acceptable salt thereof.

76. A compound having the formula wherein A is C,-C, straight or branched chain alkylene; 2 R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when 2 R is hydrogen or a protecting group, there is also present a counter ion; and N—R" represents a radical of the formula (a) N-CH. (b) CH. (c) (e) -p CH„ (d) (f) ch2ch2ch3 CH0 la3 n: s -CH. -3Z(e- 205626 (g) (i) CH- 6« 3 n N I CH. if" CH. (h) (j) CH. N /CH3 // \' jD CH. -o 'I CH. H. (k) CH CH. Cl) CH. (m) ^ "CH3 ? or (n) CH. Iffi-Nv / CH. or a pharmaceutically acceptable salt thereof.

77. A compound having the fonnula OH COOR2 2 . wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion and wherein N-R is J -327- <2 -v*b~ 205626 (a) -SCH2 —^\I®-CH3 (b) -SCH2CH2-<( r-CHj (C> 2~\ / a"3™3 <e)-ECH2CH2-<^) (d) (f) CH, ©I 3 -sch2-£) - S CH 2—\^jt~ CH 2 (g) (i) -SCH ch V 3ffi SCH2 \ \ ch 3 ch_ ffil 3 yN> i -4 1 2 \ 1 | ch3 (k) -SCH 2 v (h) (j) CH (m) . -SCH CH. i rD CH. CH. (o) -sch2- KT_ N—CH. (n) -SCH. (P) CH, ,© CH. -SCHj-f^ 3 I / -32®- 205626' wherein the HNMR (D20) spectrum shows characteristic peaks at 6: 1.23 (3H, d, J=6.4 Hz), 3.12 (2H, q, J=1.4, 8.9 Hz), 3.39 (1H, q, 3=2.1, 6.0 Hz), 4.07-4. 68 (10H, m) , 8.19 (1H, s); (q) -SCH wherein the HNMR (D20) spectrum shows characteristic peaks at 5: 1.23 (3H, d, J=6.

4 Hz), 3.15 (2H, q, J=3.7, 9.0 Hz), 3.37 (1H, q, J=2.6, 6.0 Hz), 3.9 5-4.65 (10H, m) , 8.62 QH, s) ; ^COO9 (r) CH_ <s) > -SCH=— -SCH, N // -CH. CH. CH, i (t) /Nx -SOW; % \\ / © ^—N-CH2COO or (v) CH, / 3 '/ i CH„ CH. (u) -SCHlf // N / CH or a pharmaceutically acceptable salt thereof. I 5" 205626

78. A compound of the formula 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. 2

79. The compound according to Claim 78 wherein R is p-nitrobenzyl. 2

80. The compound according to Claim 78 wherein R is an anionic charge.

81. A compound of the formula 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that o when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. 2

82. The compound according to Claim 81 wherein R is p-nitrobenzyl. -33o - an anionic charge.

84. A compound of the formula 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. 2 .

85. The compound according to Claim 84 wherein R is p-nitrobenzyl. 2

86. The compound according to Claim 84 wherein R is an anionic charge. 87. A compound of the formula oh (R) SCH :oor' wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. -331- 205626

88. The compound according to Claim 87 wherein R is p-nitrobenzyl. 2

89. The compound according to Claim 87 wherein R is an anionic charge. 90. A compound of the formula COOR2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. 2

91. The compound according to Claim 90 wherein R is p-nitrobenzyl. 2

92. The compound according to Claim 90 wherein R is an anionic charge. 93. A compound of the formula (R> —k N- // N SCH 2 ^-CH2CH2CH3 "cOOR2 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. 332 205626 2 9 4. The compound according to Claim 9 3 wherein R is p-nitrobenzyl. 2

95. The compovmd according to Claim 93 wherein R is an anionic charge.

96. A compound of the formula OH (R) I 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. 2

97. The compound according to Claim 96 wherein R is p-nitrobenzyl. 2 9 8. The compound according to Claim 9 3 wherein R is an anionic charge.

99. A compound of the formula 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. .53* - 2 056 26 2

100. The compound according to Claim 99 wherein R is p-nitrobenzyl. 2

101. The compound according to Claim 99 wherein R is an anionic charge. 10 2. A compound of the formula 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion? or a pharmaceutically acceptable salt thereof. 2 10 3. The compound according to Claim 10 2 wherein R is p-nitrobenzyl. 2

104. The compound according to Claim 10 2 wherein R is an anionic charge.

105. A compound of the formula 7 , Vr I j * Xs / CH3 J N I COOR 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. -334" 2056 26' 2

106. The compound according to Claim 105 wherein R is p-nitrobenzyl. 2

107. The compound according to Claim 10 5 wherein R is an anionic charge. 10 8. A compound of the formula OH 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. 2

109. The compound according to Claim 10 8 wherein R is p-nitrobenzyl. 2

110. The compound according to Claim 10 8 wherein R is an anionic charge.

111. A compound of the formula OH CR) c:oor2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. I -335- -j&3. - 205626 2

112. The compound according to Claim 111 wherein R is p-nitrobenzyl. 2

113. The compound according to Claim 111 wherein R is an anionic charge.

114. A compound of the formula CH0 f 2 SCH O // N 2 CH, COOR 3 ,2 . wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof.

115. The compound according to Claim 114 wherein R is p-nitrobenzyl. 2

116. The compovmd according to Claim 114 wherein R is an anionic charge.

117. A compound of the formula OH (r) - sch ^wCH3 'ft CH. ,2 . wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 1 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. -3^- 205626 ./ 2

118. The compound according to Claim 117 wherein R is p-nitrobenzyl. 2

119. The compound according to Claim 117 wherein R is an anionic charge.

120. A compound of the formula OH SCH, 1 V-CB, :oor wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof.

121. The compound according to Claim 120 wherein R is p-nitrobenzyl. 2

122. The compound according to Claim 120 wherein R is an anionic charge.

123. A compound of the formula / ch. COO 9 N SCH, K 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. COOR2 i CH. -^^roFnc£ 23sepi986 jtecelved 337" 2 0 5 6 2 6 2

124. The compound according to Claim 123 wherein R is p-nitrobenzyl. 2

125. The compound according to Claim 123 wherein R is an anionic charge. 126. A compound of the formula m -A SCH, :oor CH- 'ffl3 „N X/ -n7 i CH2"COO wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. 2 12 7. The compound according to Claim 126 wherein R is p-nitrobenzyl. 2 12 8. The compound according to Claim 126 wherein R is an anionic charge. 129. A compound of the formula SCH, coor' ,2 . CH. / H3C wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. ■y&- 205626 .2 .

130. The compound according to Claim 129 wherein R is p-nitrobenzyl. 2

131. The compound according to Claim 129 wherein R is an anionic charge. 132. A compound of the formula OH (R) --i, h sch. COOR' .2 . , n // ^•N /CH3 „N' -n ch. wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. 2

133. The compound according to Claim 132 wherein R is p-nitrobenzyl. 2

134. The compound according to Claim .132 wherein R is an anionic charge. 135. A compound of the formula OH CR) sch. CH, i J -M\ :oor I » ch // wherein readily 2 when R present thereof R is hydrogen, an anionic charge or a conventional removable carboxyl protecting group, providing that is hydrogen or a protecting group, there is also a counter ion; or a pharmaceutically acceptable salt 331 20 5 6 26 -m- 2

136. The compovmd according to Claim 135 wherein R is p-nitrobenzyl. 2

137. The compound according to Claim 135 wherein R is an anionic charge.

138. A compound of the formula wherein the "*"HNMR (D20) spectrum shows characteristic peaks at 6: 1.23 (3H, d, J=6.4 Hz), 3.12 (2H, q, J=1.4, 8.9 Hz), 3.39 (1H, q, J=2.7, 6.0 Hz), 4.07-4.68 (10H, m), 8.19 (1H, s), or a pharmaceutically acceptable salt or ester thereof.

139. The compovmd according to Claim 138 wherein the carboxyl group is protected as a p-nitrobenzyl ester. 140. A compound of the formula SCH, COO9 n N—N CH, CH. wherein the HNMR (D20) spectrum shows characteristic peaks at 5: 1.23 (3H, d, J=6.4 Hz), 3.15 (2H, q, J=3.7, 9.0 Hz), 3.37 (1H, q, J=2.6, 6.0 Hz), 3.95-4.65 (10H, m), 8.62 (1H, s), or a pharmaceutically acceptable salt or ester thereof.

141. The compovmd according to Claim 140 wherein the carboxyl group is protected as a p-nitrobenzyl ester. 20562& — 54^ - 14 2. A process for the preparation of a compound of the fonnula 8 1 vherein R is hydrogen and R is selected from the gfoup consisting of hydrogen; and substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 10 carbon atoms; cycloalkyl and cycloalkylalkyl, having 3-5 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 up to 6 carbon atcms; 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 oxy'gen, nitrogen and/or sulfur atcms 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 -*<- 2 056 26 C.-C alkyl optionally substituted by amino, halo, x 6 hydroxy or carboxyl halo -OR3 0 "34 -ocnr r 0 "34 -cnr r I ,3 -nr3r4 /NR" ^nr3R4 11 3 4 -s-nr r 0 ii 3 4 -nhcnr r 0 3" 4 r cnr - -c02*3 =0 0 -ocr3 -sr3 ii 9 -sr 0 " 9 -sr ii 0 -cn "n3 -0s03r3 0 ll g -os-r u 0 0 3'1 9 -nr s-r ii 0 -op(0)(or3)(or4) ■ -54-jl- 205626 -nr3c=nr4 R 3 -no 2 wherein, relative to the above-named substituents, the 3 4 groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having up to 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 up to 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 and/or sulphur atoms the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon 3 4 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 nitrogen-containing heterocyclic ring; R is as defined 3 1 ' • for R except that it may not be hydrogen; or wherein R 8 and'R taken together represent C2-C,Q alkylidene or c2~cxq alkylidene substituted by hydroxy; R is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulphur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R^ radicals are optionally substituted by 1-3 substituents independently selected from: 205626 c,-cc alkyl optionally substituted by amino, 1 6 fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; 3 -OR' ; -0C02R3 ; -OCOR3 ; -OCONR3R4 ; O " 9 -OS-R II 0 -oxo ; 3 4 -NR R ; 3 4 R CONR - ; 3 4 -NR C02R ; 3 3 4 -NR CONR R O 3" 9 -NR S-R ; <i O -SR3 0 T> Q -s-r ; 0 O * q -s-r ; -s03r3 ; -c02r3 . ; -conr3r4 -CN; and -H^I!NTOFF)ce 2 3SEP 1986 jkceived phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, Cn-C, alkyl, -OR3, -NR3R4, -S0,R3, -C0_R3 and 3 4 .3 4 9 5 -CONR R , wherein R , R , and R in such R substituents are as defined above; 205526 ' 5 or R may be attached also to at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain one or more additional hetero atoms selected from 0, S and N; 15 R is selected from the group consisting of hydrogen; and substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; spirocycloalkyl having 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has ud to 6carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro., cyano and carboxy; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms; 23sepq86 -3^T" 205626 A is C^-Cg straight or branched chain alkylene; R2 is hydrogen, an anionic charge-or a conventional readily removable carboxyl protecting 2 group, providing that when R is hydrogen or a protecting group, there is also present a counter ion; and represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical containing at least one nitrogen in the ring, said ring being attached to A through a ring carbon atom and having a ring nitrogen which is quaternized by the group R^; or a pharmaceutically acceptable salt thereof, which process comprises the steps of J 344- 2056 2 6 (1) reacting an intermediate of the formula R H N. 15 III N:oor2 ' wherein r\ R® and R^ are as defined above and R2 is a conventional readily removable carboxyl protecting group in an inert organic solvent with a reagent capable of introducing a conventional leaving group L at the 2-position of intermediate III to give an intermediate of the formula r15 K8 H R IV \ 2' NCOOR .8 k 2' R , L and R are as defined above and L is a wherein R , R" conventional leaving group; (2) reacting intermediate IV in an inert organic solvent and in the presence of base with a mercaptan reagent of the formula HS-A wherein A is as defined above and represents a mono-, bi- or polycyclic aromatic heterocyclic radical containing a quaternizable nitrogen in the ring, said ring being attached to A through a ring carbon atom, to give an intermediate of the formula - 34-1- 205626 II N are as defined above; (3) reacting intermediate II in an inert organic solvent with an alkylating agent of the formula r -x' wherein R is as defined above and X' is a conventional leaving group so as to quaternize with the R5 group a ring nitrogen of subsfcituen'fc Q on intermediate II and form a compound of the formula «15 e R8 H S-A- n-r5 x'9 coor 1 8 15 2' f^ 6 5 wherein R', R , R < R /A/ I N-R and X' are as defined above; and, if desired, replacing counter ion X' by a different counter ion and, if desired, removing the carboxyl protecting group R2 to cive the desired de-blocked compound of formula I, or a pharmaceutically acceptable salt thereof. 205626 -5m -

143. A process according to Claim 142 but wherein the quaternization step is carried out after removal of the 2' carboxyl protecting group R .

144. A process for the preparation of a compound of the formula 8 1 wherein R is hydrogen and R is selected from the gtoup consisting of hydrogen; and substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 ana aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen,nitrogen and/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 ! 205626 C.~Cc alkyl optionally substituted by amino, halo, 1 6 hydroxy or carboxyl halo -or3 O U 3 4 -ocnr r O -cnr3r4 -nr3r4 ,nr3 J* ^nr3R4 -s~nr3r4 ll 0 0 II 3 4 -nhcnr r 0 311 4 r cnr - -co/3 =0 0 -ocr3 -sr3 0 II 9 -sr 0 " 9 -sr ll 0 -cn -N-j 3 3 -oso3r 0 i! 9 -os-r /{ 0 0 3'i r,9 -nr s-r ii 0 -op (0) (or ) (or ) / 205626 -nr3c=nr4 -NR3C02R4 and -no2 wherein, relative to the above-named substituents, the 3 4 groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atcms; 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 and/or sulfur atans and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon 3 4" 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 nitrogen-containing heterocyclic ring; R is as defined 3 1 for R 'except that it may not be hydrogen; or wherein R O and R taken together represent C2~C^0 alkylidene or C2~C^0 alkylidene siibstituted by hydroxy; R is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting or 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R^ radicals are optionally substituted by 1-3 snhq + i'tnpnfi; independently selected from: N.Z. PATENT OFFICE 2 3SEP 1986 \ I 205626 -3 r J- ..y C.-C. alkyl optionally substituted by amino, 1 6 fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -or3 ; -0c02r3 ; -0c0r3 ; -0c0nr3r4 ; O " 9 -os-r ll o -oxo ; 3 4 -nr r ; 3 4 r conr - ; 3 4 -nr c02r -nr3conr3r4 ; 0 3" 9 -nr s-r ; ii 0 -sr3 ; 0 t- 9 -s-R ; o o p q -s-r -S03R3 ; -C02R3 ; -conr3r4 ; -CN; and phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, c -c alkyl, -or3, -nr3r4, -so,r3, -c0„r3 and 3 4 3 4 9 5 -conr r , wherein r , r , and r in such r substituents are as defined above; ! n.z. patent office 23SEP1986 RECEIVED 265626 -%sr%- or ir.ay be attached also -to ■ o ■ . ■ at another• point on the ring so as to form a fused- heterocyclic or heteroaromatic ring, which ring may contain one or more additional • hetero atoms selected from 0, S and N; R^"* is selected from the group consisting of hydrogen; and substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; spirocycloalkyl having 3-6 carbon atoms? phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has up to 6 carbon atcms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above-recited substituents have 1-G carbon atoms; 205626 A . is C,-C, straight or branched chain alkylene; ^ is hvdrogen, an anionic charge or a conventional readily removable carboxyl protecting 2 . . group, providing that vhen R is hydrogen or a protecting group, there is also present a counter ion? and represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical containing at least one nitrogen in the ring, said ring being attached to A through a ring carbon atom and having a ring nitrogen which is quaternized by the group ; or a pharmaceutically acceptable salt thereof, which process comprises reacting an intermediate of the formula S-A- H Xi. COOR ,8 ,15 „2 1 wherein R , R , R and A are as defined above, R is a conventional readily removable carboxyl protecting "group and 205626 -3s-*- : represents a mono-, bi- or polycyclic aromatic heterocyclic radical containing a quaternizable nitrogen in the ring, said ring being attached to A through a ring carbon atom, in an inert organic solvent with an alkylating agent of the formula R5—X* wherein R5 is as defined above and X' is a conventional leaving group so as to quaternize with the R5 group a ring nitrogen of substituent on intermediate II and form a compound of the formula wherein R , R ,R , K ,A, "X1 are as defined above; ana, if desired, replacing counter ion X' by a different counter ion and, if desired, removing the carboxyl protecting croup to give the desired de-blocked compound of formula I, or a pharmaceutically acceptable salt thereof. 145, • The process according to Claim 144 but wherein the quaternization step is carried out after removal of the carboxyl 2' protecting group R . 2 05 626 - SSY- A compound of the fonnula 8 . 1 wherein R is hydrogen ana R is selected from the ci-oup consisting of hydrogen and substituted and unsubstituted: alkyl, alkenv and alkynyl, having up to 10 carbon atoms; cycloalkyl anc cycloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl rinc and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkeny and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion up to 6 carbon atoms? heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 205626 C^-Cg alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -or3 0 "34 -ocnr r 0 " 34 -cnr r -nr3r4 /nr3 \NsV ii 3 4 -s-nr r 0 " 3 4 -nhcnr r 0 3ii 4 r cnr - -co2r3 =0 -ocr3 -sr3 0 n 9 -sr 0 " 9 -sr ii 0 -cn ~n3 3 -oso3r 0 " 9 -os-r // • 0 0 31/ 9 -nr s-r ii 0 -op (0) (or3) (or4) 205626 3 4 -NR C=NR R 3 -NO -NR3C02R4 and 2 wherein, relative to the above-named substituents, the 3 4 groups R and R are independently selected from hydrogen; alkvl> alkenyl and alkynyl, having up to 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 up to 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 and/or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon 3 &■ atoms, or R ana R taken together with the nitrogen to which at least one is attached may form a 5-or 6-membered 9 nitrogen-containing heterocyclic ring; R is as defined 3 I for R except that it may not be hydrogen; or wherein R g and R taken together represent C2-C^q alkylidene or C^-C^q alkylidene substituted by hydroxy; R is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named radicals are optionally substituted by 1-3 substituents independently selected from: s j •I I 2Q5&2S —3 !T8 — C^-Cg alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 ; -0C02R3 ; -OCOR3 ; -OCONR3R4 0 " 9 -OS-R ; 1/ 0 -oxo ; -NR3R4 ; 3 4 R CONR - ; 3 4 -NR C02R ; 3 3 4 -NR CONR R 0 3" 9 -NR S-R ii 0 -SR3 ; 0 t- 9 -S-R 0 0-K 7* q -S-R ; -S03R3 ; -co2R3 ; 3 4 -CONR R ; -CN; and phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, ' C--C, alkyl, -OR3, -NR3R4, -SO-R3, -CO R3 and 3 4 3 4 9 5 -CONR R , wherein R , R , and R m such R substituents are as defined above; -r" 23SEP 205626 at another•point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain one or more additional hetero atoms selected from 0, S and N; R15 is selected from the group consisting of hydrogen; and substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having up to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; spirocycloalkyl having 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion hasup to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 selected from the group consisting' of: amino, mono-, di- and trialkylami.no, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms; —3 <>°\~ or may be attached also to O • n i ■ - - ■■ v . " ' >.. •;/ ■ 205626 A is C.-C straight or branched chain alkylene; 2 . R as hvcroger., an anionic charge or a conventional readily removable carboxyl protecting 2 group, providing that vhen R is hydrogen or a protecting group, there is also present a counter ion; ana represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical containing at least one nitrogen in the ring, said ring being attached to A through a ring carbon atom and having a ring nitrogen which is quaternized by the group R^; or a pharmaceutically acceptable salt thereof.

147. A compound of the formula 8 wherein R is hydrogen and R~ is selected from the g£oup consisting of hydrogen; and substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 10 carbon atoms; cycloalkyl and cycloalkylalkyl, having 3-6 carbon atcms in the cycloalkyl ring ana 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl vherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxv'gen, nitrogen and/or sulfur atcms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; vherein the substituent or substituents relative to the above-named radicals are independently selected from the crouo consisting of 1 N.Z. PATENT OFFICE 23SEP 1986 Received "36,_ 205626 C-j-Cg alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -or3 0 "34 -ocnr r 0 -cnr3r4 •-nr3r4 /nr3 J \ 3 4 xnr r O II 34 -s-nr h ll 0 0 ii 34 -nhcnr r 0 3" 4 r cnr - -c02r3 =0 0 -ocr3 -sr3 0 II 9 -sr* 0 ll 9 -sr ll 0 -cn -n3 -0s03r3 ll a--os-r ll 0 0 3 il 9 -nr s-r ll 0 -0?(0)(or3)(or4) • • N i -nr3c=nr4 205626 -NR3C02R4 and -NO- wherein, relative to the above-named substituents, the 3 4 groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having up to lo carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring ana 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion up to 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 and/or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon 3 t . atoms, or R ana R* taken togetner with the nitrogen to which at least one is attached may form a 5-or 6-membered 9 nitrogen-containing heterocyclic ring; R is as defined for R3 except that it may not be hydrogen; or wherein R~ g and R taken together represent C2-C"^0 or C2-C"i0 alkylidene substituted by hydroxy; R is selected frcm the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to S carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R3 radicals are optionally substituted by 1-3 substituq^tstyj!g\jq^pen£eH'£-ly selected from: 2 3SEPI986 r>f»ir -3^3 205626 C.-C- alkyl optionally substituted by amino, JL 6 fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -or3 ; -OC02R3 ; -ocor3 ; -oconr3r4 ■; 0 " 9 -os-r ; If O -oxo ; -nr3r4 ; 3 4 r conr - ; 3 4 -nr c02r ; 3 3 4 -nr conr r ; 3" 9 -nr s-r ii 0 -sr3 : -s-r9 ; O 0 K P q -s-r ; -so3r3 -co2r3 -conr3r4 -cn; and phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, C. -C alkyl, -OR3, -NR3R4, -S0,R3, -CO_R3 and 3 4 3 4 9 5 -CONR R , wherein R , R , and R in such R substituents are as defined above; -3^4- 205626 or R ir.ay be attached also to G-- at another•point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain one or more additional hetero atcms selected from 0, S and N ; 16 R is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having up to 10 carbon atoms; cycloalkyl, • cycloalkylalkyl and alkvlcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; spirocycloalkyl having 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl vherein the aryl moiety is phenyl and ^ the aliphatic portion has up to6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named' heterocyclic moieties are select? from the group consisting of 1-4 cxvcen, nitrogen and/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 selected from the group consisting' of: amino, mono-, di- anc trialkylamino, hydroxy!, alkoxy1, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, c-uanidinc nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms; Us- 205626 yxlf- A. is C^-Cg straight cr branched chain alkylene; 3? is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting croup, providing that vhen R is hycrogen or a protecting group, there is also present a counter ion; and ^ ^ e H— represents a substituted or unsinstituted mono-, bi- or polycyclic aromatic heterocyclic radical containing at least one nitrogen in the ring, said ring being attached to X through a ring carbon atom and having a ring nitrogen vhich is quaternized by the group R ; or a pharmaceutically acceptable salt thereof.

148. A compound according to Claim 147 wherein is os I - ,16 ■ CH^CH- i ana R is mstnyl. A compound according to Claim 147 wherein 5^" is OH CH^S- « R1S is re thyl and the absolute configuration is 55, 65, 85. ISO'. a compound according to Claim 147, 148, cr 149 vherain A is -CH2~ O- —CH2^"2~ • 205626 -)u~ ■: 151- A conpound of the formula vherein H is hydrocea and 3. is selected frcm the croup consisting of hydroqen; and substituted ana unsubstituted: alkyl, alkenyl and alkynyl, having up to 10 carbon atoros; .cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-S carbon atoins in the alkyl noieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl -.ciety 'is phenyl and the aliphatic portion has up to 6 carbon atcjns; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl vherein the hetero atoa .or atoms in the ebove-nanisd heterocyclic moieties are selected frcm the group consisting of 1-4 oxygen, nitrogen and/or sulfur, atonis and the alkyl moieties associated vith said heterocyclic noieties have 1-S carbon atorns; vherein the substituent or substituents relative to the above-na-ed radicals are independently selected froa the croup consisting of ^ ^7' 2056 C^-Cg alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -or3 0 "34 -ocnr r , 0 If 34 -cnr r .-nr3r4 /nr3 -i ^nr3R4 0 ii 3 4 -s-nr r ll 0 0 u 34 -nhcnr r 0 r3cnr4--co2r3 =0 0 -ocr3 -sr3 0 " 9 -sr 0 it 9 -sr ii 0 -cn -n 3 -oso3r 0 " 9 -os-r H 0 0 31' 9 -nr s-r ll 0 -0?(0)(or3)(or4) I L 205626 3 4 -NR C=NR RJ -NR3C02R4 and -no2 wnerein, relative to the above-named substituents, the 3 4 croups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from i±e group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms, and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon 3 4 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 nitrogen-containing heterocyclic ring; R is as defined for R3 except that it may not be hydrogen; or wherein R^" g ana R taken together represent C2-C1Q alkylidene or C2~C1q alkylidene substituted by hydroxy; R^ is selected from the croup consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 raoietv is phenyl and the aliphatic portion has up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen,nitrogen and/or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R radicals are optionally substituted by 1-3 substituents independently selected from; 305626 C^-Cg alkvl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 ; -0C02R3 ; -0C0R3 ; -OCONR3R4 ; 0 " 9 -OS-R II ' O -oxo ; 3 4 -NR R ; 3 4 R CONR*- ; 3 4 -NR C02R -NR3CONR3R4 ; 0 3" 9 -NR S-R ; ii 0 -SR3 ; T Q -s-R 0 o r p O -S-R" -S03R3 ; -C02R3 ; -CONR3R4 ; -CN; and phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, C--C, alkyl, -OR3, -NR3R4, -SO-R3, -CO R3 and 3 4 3 4 9 5 -CONR R , wherein R , R , and R m such R substituents are as defined above; _ , N,Z. PATENT OFFICE 13SEP 1986 -31 o — 205G26 _5 . . may r>e attacnea also to O e Et cjiozher point: on the ring so as forn a fused heterocyclic or hetero'aromatic ring, which rincmay contain one or more additional hetero atoms selected from 0, S, and N; R^ is selected from the group consisting of substituted and Unsubstituted: alkyl, alkenyl, and alkynyl, having up to 10 carbon atoms; cycloalkyl, cycloalkylalkyl ana alkylcvcloalkyl, having. 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; spirocycloalkyl having 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has up to 6 carbon atoms • heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, -nitrogen and/or sui fuj- atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6- carbon atoms; wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting' of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxy1, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms; -77 i - 20562$ A is C^-Cg straight or branched chain 2 alkylene; R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting ! group, providing that when R2 is hydrogen cr a protecting group, there is also present a counter i on; and ^. L/- represents an aromatic mono-, bi- cr polycvclic N-containiag heterocyclic ring containing 0-5 additional'hetero' atoms selected from 0, Sand N, said heterocyclic ring being attached to ?. through a ring carbon atom £.nd having a ring nitrogen quaternized by the group R"5, and said heterocyclic ring being optionally substituted at available ring carbon atoms by 1-5 substituents independently selected from the group consisting of C^-C^ alkyl; C^-C^ alkyl substituted by 1-3 substituents independently selected from hydroxy, amino, C^-C^ alkylamino, di (C^-C^) alkylamino, C^-C^ alkoxy, carboxy, halo and sulfo; cycloalkyl; C3_Cg cycloalkyl(C^-C^)alkyl optionally substituted by 1-3 substituents mentioned above in connection with C,-C, alkvl; 14 - , ' Cn-C4 alkoxy; alkylthio; amino; alkyl amino; di(C1-C4)alkylamino; halo; C^—alxanoyl-amino; C-j-C^ alkanoyloxy; carboxy; sulfo; O ii ... . -. -C-O-C -C alkvl; hvcroxv; amic.ino; guanicino; 1 4 ' ~ phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, liocrms!! 205626 trifluoromethyl, C^-C^ alkyl, C-^-C^ alkoxy, C1~C4 alkylamino, di (C-^-C^) alkylamino, carboxy, and sulfo; phenyl alkyl in which the phenyl portion is optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion is optionally substituted by 1-3 substituents mentioned above ■. in connection with alkyl; and heteroaryl or heteroaralkyl in-which the hetero atom or atoms are selected from the croup consisting of 1-4 0, S and/orNatoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C^-C4 alkyl, C^-C4 alkoxy, C^-C4 alkylamino, di(C1-C4)-alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C-]_~C4 alkylamino, di (C^-C4) alky laiaino, C^-C4 alkoxy, carboxy, halo and sulfo, ana said heterocyclic ring being optionally substituted at available ring nitrogen atoms by 1-3 substituents independently selected from the group consisting of C^-C4 alkyl; C^-C4 alkyl substituted by 1-3 substituents independently selected frcm hydroxy, amino, C^-C^ alkylamino, di (C-j-Cj)alkylamino, C^-C^ alkoxy, carboxy, halo and sulfo groups; C^-C^ cycloalkyl; ^3~^6 cyc-'-0£-'-^y^ ^i~ alkyl optionally substituted by 1-3 substituents mentioned above in connection with Cn-C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C1-C4 alkyl, C-|_~~C4 a-^oxy' Ci-C4 £lkylatino, di(C.-C.)alkylamino, carboxy and sulfo; phenyl-14 (Cj-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned v above in connection with phenyl and the alkyl oortion rnav be ootionally substituted by 1-3 V 205626 -373- substituents mentioned above in connection with C1-C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms are selected from the group consisting or 1-4 O, S and/or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic' ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trif luoromethyl, C^-C^ alkyl, C^-C^ alkoxy, C^-C^ alkylamino, ci alkylamino, carboxy and sulfo and in the alkvl moiety by 1-3 substituents selected from hydroxy, amino, alkylamino,. di(C^-C^)alkylamino, C^-C^ alkoxy, carboxy, halo ana sulfo; or a pharmaceutically acceptable salt thereof. 152. A. compound according to Claim 151 wherein R^ is Oa ,, ana R is methyl. 153. A compound according to Claim 151 wherein R^" is and the

154. A. coTPiTDOunc according to Claim 151, 152, or 153 wherein A is -CH2- or -CK2CH2-. / 205825 -3>"74-

155. A compound of the formula 8 1 wherein R is hydrocen and R is selected frcm the group consisting ofhydrogen; and substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 C,-C, alkyl ootionally substituted by amino, _L 0 halo, hydroxy or carboxyl halo . -OR3 O "34 -OCNR R • O /I 3 i -CNR R' -nrV 2056 26 ,nr3 ' ^NR3R4 0 " 3 4 -s-nr r 0 II 3 4 -nhcnr r 0 3II 4 r cnr - -co2r3 =0 0 -ocr3 -sr3 0 " 9 -sr O ll g -sr ii 0 -cn -n3 -oso3r3 0 ll 9 -os-r h 0 0 31/ 9 nr s-r ii 0 0p(0) (or3) (or4) I --nl- ' 205626 3 4 -NR C=NR • ^ -NR3C02R4and -no2 wherein, relative to the above-named substituents, the 3 4 .groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having up to 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 up to 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 and/or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon 3 4 . atoms, or R and R taken together with tne nitrogen to which at least one is attached may form a 5-or 6-membered 9 nitrogen-containing heterocyclic ring; R is as defined 3 .1 for R except that it may not be hydrogen; or wherein R 8 and R taken together represent C2~C^q alkylidene or ^2~C^q alkylidene substituted by hydroxy; H is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen/nitroqen and/or sulfur atoms ana the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R radicals are optionally substituted by 1-3 substituents independently selected from: -7,11- 205626 c,-c_ alkyl optionally substituted by amino, -l 6 fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -or3 ; -0c02r3 ; -ocor3 ; -oconr3r4 ; ' 0 ii q -os-r" It 0 -oxo ; 3 4 -nr r ; 3 4 r conr - ; 3 4 -nr c02r ; 3 3 4 -nr conr r 3" 9 -nr s-r it 0 -sr3 ; -s-r 0 o R ?! g -s-r" -s03r ; -C02R3 ; -conr3r4 -cn; and phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, C--C, alkyl, -OR3, -NR3R4, -SO R3, -C0„R3 and 3 4 3 4 9 5 -CONR R , wherein R , R , and R in such R substituents are as defined above; —3~? 8 20562S or R^ may be attached also to \® N at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain one or more additional hetero atans selected from O, N and S; 16 R is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having up to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; spirocycloalkyl having 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cvano and carboxy; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms; WiZ. PATENT OFFICE "y -t err -171 - 205626 A is C^-Cg straight or branched chain alkylene; R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, pro- 2 viding that when R is hydrogen or a protecting group, there is also present a counter ion; and represents an aromatic 5- or 6-membered N-containing heterocyclic ring containing 0-3 additional hetero atoms selected from N, 0, said heterocyclic ring being optionally substituted at available ring carbon atoms by 1-5 substituents independently selected from the group consisting of alkyl; C-j-C^ alkyl- substituted by 1-3 substituents independently selected frcm hydroxy, amino, C^-C^ alkylamino, 'di(C^-C^) alkylamino, C^-C^ alkoxy, carboxy, halo and sulfo; C^-Cg cycloalkyl; C^-Cg cycloalkyl(C^-C^) alkyl optionally substituted by 1-3 substituents mentioned above in connection with C]_-C4 alkyl; alkoxy; C^-C^ alkylthio; amino; alkylamino; di(C^-C^)- alkylamino; halo; alkanoylamino; C-]__C4 alkanoyloxy; carboxy; sulfo; O il -C-O-C^-C^ alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, 205S26 trifluoromethyl, C^—C4 alkyl, C^-C^ alkoxy, C1-C4 alkylamino, di(C^-C^)alkylamino, carboxy, and sulfo; phenyl (Cj^-C^) alkyl in which the phenyl portion is optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion is optionally substituted by 1-3 substituents mentioned above in connection with C^-C^ alkyl; and heteroaryl or heteroaralkyl in-which the hetero atom or atoms are selected from the group consisting of 1-4 0, S and/or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, alkyl, C^-C^ alkoxy, alkyl=^ino, ai(C^-C^)- alkvlamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C^-C^ alkylamino, di (C1~C^)alkylamino, C^-C^ alkoxy, carboxy, halo and sulfo, and said heterocyclic ring being optionally siibstituted at available ring nitrogen atoms by 1-3 substituents independently selected from the group consisting of C^-C^ alkyl; alkyl substituted by 1-3 substituents independently selected frcm hvdroxv, amino, C,-C. '14 alkylamino, di(C-j-C^)alkylamino, C-j-C^ alkoxy, carboxy, halo and sulfo qroups; c3_c5 cycloalkyl; C3-Cg cycloalkyl(C^-C^) -alkyl optionally substituted by 1-3 substituents mentioned above in connection with C3_-C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C^-C^ alkyl, cj__c4 alkoxy, alkylamino, di(C^-C^)alkylamino, carboxy and sulfo; phenvl-(C^-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection'with phenyl and the alkyl portion may be optionally substituted by 1-3 205626 -"s>2 i ~ substituents mentioned above in connection with C^-C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms are selected from the group consisting or 1-4 O, S and/or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups.being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, Cj_~C4 alkyl, alkoxy, C^-C^ alkylamino, di(C^-C^)alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C^-C^ alkylamino, di (C^-C^j) alkylamino, C^-C^ alkoxy, carboxy, halo and sulfo;. or a pharmaceutically acceptable salt thereof. is ootionally substituted at available ring carbon or nitrogen atoms by up to 5 substituents independently selected iron C1~C6 alkyl.

157. a compound according to Claim 156 wherein A is -G^-, -Q^CE^- or Cxi, i 3 -CH- .

158. A compound according to Claim 155 , 156 or 157 wherein R1 is 0H is I t R is methyl ch3ch- 1 and the absolute configuration is 5R, 6S, 8R. 205626 159. A compound of the formula 16 jr— N ~~C00R2 0 8 1 wherein R is hydrogen and R is selected from the group consisting of hydrogen; andsubstituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 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 pftenyl and the aliphatic portion up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 C^-Cg alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo NR" nrV 0 " 3 4 -S-NRJR* ll 0 11 3 A -NHCNR R 0 3« 4 R CNR - -C02R3 -0 3&- - ^<1 - 205626 -OCR3 -SR3 0 // 9 -SR 0 // 9 -SR ll 0 -CN -n3 -0S03R3 0 l! g -OS-R u 0 0 3 tl 9 -KR S-R ll 0 -OP(O)(OR3)(OR4) "3-S4-- -nr3c=nr4 i' -NR3C02R4 and •no2 20562G wherein, relative to the above-named substituents, the 3 4 groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having up to 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 aliphati'c portion has up to 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 and/or' sulfur atoms and the alkyl moieties associated .with said heterocyclic moieties have 1-6 carbon 3 4 atoms, or R and R" taken together with the nitrogen to which at least one is attached may form a 5-or 6-membered nitrogen-containing heterocyclic ring; R is as defined for R3 except that it may not be hydrogen; or wherein R^ and R taken together represent C2-C1Q alkylidene or C2-C^^ alkylidene substituted by hydroxy; RD is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having up to 10 carbon atoms; cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in the cloalkyl 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 up to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen,nitrogen and/or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R radicals are optionally substituted by 1-3 substituents independently selected from: 205626 C^-Cg alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -or3 ; -0c02r3 ; •-ocor3 ; •-oconr3r4 ; 0 " 9 -os-r II 0 -oxo ; -nr3r4 ; 3 4 r conr - ; 3 4 -nr c02r ; -nr3conr3r4 o 3" 9 -nr s-r ; n O 7 -sr" T Q -s-r ; 0 O ft o -s-r" ; -SD3R3 ; -C02R3 ; -conr3r4 -cn; and phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, C..-C., alkyl, -OR3, -NR3R4, -SO R3, -CO R3 and 3 4 3 4 9 5 -CONR R , wherein R , R , and R in such R substituents are as defined above; or R^ may be attached also to fV ji 60ctl98&j ~lsl- o 205626 at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain one or more additional hetero atcras selected frcm 0, N and S; 16 R is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having up to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; spirocycloalkyl having 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has up to 6 carbon atoms; heteroaryl, heteroaralkyl', heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/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 selected from the group consisting' of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamovl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms; N.Z. PATENT OFFICE 23SEP1986 RECEIVED 205626 -3&1- A is C1 -C straight or branched chain alkylene; 2 . R is hydrogen, an anionic charge or a conventional readily removable carboxyl Drotecting grouD, 2 providing that when R is hydrogen or a protecting group, there is also present a counter ion; and 2 . represents a radical selected from the group consisting of •^7 R' .5 Ca) 6 wherein R6, R7 ana R10 are independently selected from hydrogen; C^-C^ alkyl; Cj_-C4 £lkvl substituted by hydroxy, alkylamino, di(C1-C4 alkyl)amino, C^-C^ alkoxy, amino, sulfo, carboxy or halo; C3-Cg cycloalkyl; C1~C4 alkoxy; C-j-C^ alkylthio; amino; C],-C4 alkylamino; di(C^-C4 alkyl) amino; halo; C1-C4 alkanoylamino; C2_~C4 alkanoyloxy; carboxy; 0 u -C-OC^-C^ alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by .one, two or three substituents independently selected frcm amino, halo, hydroxyl, trifluoromethyl, C^-C^ alkyl and C^-C4 alkoxy groups; phenyl (C.,-C4) alkyl in which the phenyl portion may be optionally substituted by 1-3 substitutents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C^-C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms in the group consisting of 1-4 oxygen,nitrogen and/or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; or wherein two of R^, R7and R-(^ taken together may be a fused saturated carbocyclic ring, a fused aromatic carbocyclic ring, a fused non-aromatic heterocyclic ring or a fused heteroaromatic ring, said fused rings being optionally substituted by 1 or 2 of the substituents defined above for R6, • R7 and R °; n.Z^teait OFFICE 205628 -w (b) ,N or r^N N<" optionally substituted on a carbon atom by 1-3 substituents independently selected from C^-C^, alkyl; C1~C4 alkyl substituted by hydroxy, C^-C^ alkylamino, di(C.,-C4 alkyl) amino, sulfo, C^-C^ alkoxy, amino, carboxy or halogen;. C^-C^ cycloalkyl; C^-C^ alkoxy; alkylthio; amino; C^-C^, alkylamino; di(C^-C^ alkyl)amino; halo; C^-C^ alkanoylamino; Cn-C4 . . alkanoyloxv; carboxy; O ll -C-OC^-C^ alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three substituents independently selected frcm amino, halo, hydroxyl, trifluoranethyl, C.j-C4 alkyl and Cj-C^ alkoxy groins; phenyl (C^-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with alkyl;.and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from .the group consisting of 1-4 oxygen, nitrogen and/or sulfur atcms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above; (c) <N- ,N ■mt&rgprlce 2 3SEP J9S6 RECEiVEP 1 .205626 -58f' H5 or opuionally substituted on a carbon atom by one or two substituents independently selected from C^-C^ alkyl; C1-C<, alkyl substituted by hydroxy, C^-C^ alkylamino, di (C^ alkyl) amino, alkoxy, sulfo, amino, carboxy or halogen; C^-C^ cycloalkyl; C^-C^ alkoxy; Circ4 alkylthio; amino; C-,-C4 alkylamino; di^-C^ alkyl) amino; halo; C^-C^ alkanoyla.-r.ino; C1-C4 alkanoyloxy; carboxy; O \l "C-OC^-C^ alkyl; hydroxy-, amidino*, guanidino-, phenyl; phenyl substituted by one, two or three substituents independently selected frcm amino, Halo, hydroxyl, trifluorcmethyl, C^-C^ alkyl and Cj-C^ alkoxy groups; phenyl (C^-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned-above in connection with C^-C^ alkyl;.and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected -from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above; (a) \2. "ATcNT OFFICE 2 3 SEP 1986 received 205626 I -¥lo- optionally substituted on a carbon atom by a substituent independently selected from C^-C^ alkyl; C^-C^ alkyl substituted by hydroxy, amino, C^-C^ alkylamino, di(C^-C4 alkyl} -amino, C^-C^ alkoxy, sulfo, carboxy or halogen; C^-Cg cycloalkyl; alkoxy; Ci-C4 alkylthio; amino; alkylamino; di (C^-C^ alkyl) amino; halo; Ci-Ci} £lkanoylamino; C2~C4 alkanoyloxv; carboxy; 0 ii -C-OC^-C ^ alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three substituents independently selected frcm amino, halo, hydroxyl, trifluorcmethyl, C^-C^ alkyl and C^-C^ alkoxy groups; phenyl (C^-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally siibstituted by 1-3 substituents mentioned above in connection with alkyl; .and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen,nitrogen and/or sulfur atoms ana the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; wherein X is 0, S or NH in which R is C.-C, alkvl; C,-C, 14 * 1.4 alkyl siibstituted by 1-3 substituents independently selected from hydroxy, amino, C^-C^ alkylamino, di (C-j-C^) alkylamino, C^-C^ alkoxy, carboxy, halo and sulfo groups;C^—C^ cycloalkyl; C^-Cg cycloalkyl(C^-C^)alky1 optionally substituted by 1-3 substituents mentioned above in connection with alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trif luoromethyl, C^-C4 alkyl, alkoxy, C^-C^ alkylamino, fii(C^-C^)alkylamino, carboxy and sulfo; phenyl (C^-C^) alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents c 20562* ■¥t\ mentioned above in connection with C]_~C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4, 0, S and/or N atans and the alkyl moiety associated with heteroaralkyl has 1-6.carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoro-methyl, C2-C4 alkyl, ci~c4 alkoxy' C]_~C4 alkylamino, dilC^-C^)-alkyland.no, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected fronj hydroxy, amino, alkyl amino, di(C^-C^)alkylamino, alkoxy, carboxy, halo and sulfo, said radical being optionally substituted on a carbon atom by one or more substituents independently selected from C-J_-C4 alkyl; C^-C^ alkyl substituted by hydroxy, alkylamino, di(C^-C^ alkyl)amino, alkoxy, amino, sulfo, carboxy or halogen; C^-Cg cycloalkyl; C^-C^ alkoxy; alkylthio; amino; C^-C^ alkylamino; di (C^-C^ alkyl)amino; halo; C^-C^ alkanoylamino; C^-C4 alkanoyloxy; carboxy; 0 ' il —C—OCj—C^ alkyl; hydroxy; amidino; guanidino, phenyl; phenyl substituted by one, two or three substituents independently selected frcm amino, halo, hvdroxyl,. trif luoromethyl, C^-C^ alkvl and C^-C^ alkoxy groups; phenvl (C -C ) alkyl in which the phenyl portion may be 1 4 optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C^-C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitroqen and/or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moietv has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic • ring optionally siibstituted by 1 or 2 of - the substituents defined above; / v. >' ./ 205626 -3^2- wherein X is O, S or NR in which R is C,-C„ alkyl; C.-C, 14 -I 4 alkyl subs ti >-U i_ed by 1—3 substituents independently selected frcm hydroxy, amino, C^-C^ aUtylamino, di (C-^-C^) alkylamino, C^-C^ alkoxy, carboxy, halo and sulfo groups; C^-C^ cycloalkyl; C3~Cg cycloalky 1 (C.,-C^) alkyl optionally substituted by 1-3 substituents mentioned above in connection with" C^-C^ alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trif luoromethyl, 0.,-C^ alkyl, alkoxy, C^-C^ alkylaiuino, di (C1-C^) alkylamino, carboxy and sulfo; phenyl (C^-C^) alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may_be optionally substituted by 1-3 substituents mentioned above in connection with C -C. alkyl; and heteroaryl J. 4 anc heteroaralkyl in which .the hetero atom or atoms are selected from the group consisting of 1-4, 0, S and/or N atans and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaraUcyl croups being optionally-substituted in the -heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoro-nethyl, C^-C^ alkyl, C-,-C4 alkoxv, C^-C^ alkylamino, di (C.,-Chalky laiuino, carboxy and sulfo ana in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C^-C^ alkylamino, di (C..-C .) alkylamino, C.-C. alkoxy, carboxy, halo and sulfo, 14 14 said heteroaromatic radical being optionally substituted on a carbon atom by a substituent selected from C^-C^ alkyl; C^-C^ alkyl substituted by hydroxy, alkylamino, di(C1-C4 alkyl)amino, alkoxy, amino, sulfo, carboxy or halogen; C,-C. cvcloalkvl; C..-C. alkoxv; C..-C. alkvlthio; Jo" * 14 "1-4 amino; alkylamino; di (C^-C^)alkylamino; halo; alkanoylamino; C.,-C4 alkanovloxv; carboxy; 0 ii -C—OC^ —C4 alkyl; hydroxy; amidino; guanidino; phenyl; a* i -><33- / phenyl substituted by one, two or three substituents independently selected from amino, halo, hydroxyl, trif luoromethyl, C^-C^ alkyl and C^-C^ alkoxy groups; phenyl(C,-C)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C2_~C4 alkyl.; .and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and/or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; and (?) N. N-R R5 0 -R N- N •=5 ei R -iv -R N N-R -R" e R^ B N -N-R or R5-* ■N-R wherein R is Cj_-C4 alkyl; C^-C^ alkyl substituted by 1-3 substituents independently selected frcm hydroxy, amino, C-j-C^ alkylamino, di alkylamino, C1-C4 alkoxy, carboxy, halo and sulfo groups; C3-Cg cyclo alkyl; C3-Cg cycloalkyl(C^-C^)alkyl ODtionally substituted by 1-3 substituents mentioned above in connection with alkyl; J 22°crmE' ^ /■ 205626 -itt- phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C^-C^ alkyl, C2_rC4 alkoxy, C1-C4 alkylamino, di (C^-C^) alkylamino, carboxy and sulfo; phenyl (C^-C^)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl ana the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the 'group consisting of 1-4,0, S and/or >7 atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl , C^-C4 alkyl, C^-C4 alkoxy, C^-C4 alkylamino, di (C^-C^) -alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C^-C4 alkylamino, di (C^-C^)alkylamino, C^-C4 alkoxy, carboxy, halo anc sulfo; or a pharmaceutically acceptable salt tiiereoif.

160. A compound according to Claim 159 wherein represents a radical selected from the group consisting of N.Z, PATSMT OFFICE 2 35EP 1936 RECEIVED 2056 26 wherein R^ is C^-Cg alkyl and R6, R7 and R"1"0 are each independently hydrogen or alkyl; (b) f A N N © fl or wherein R is C^-Cg alkyl and wherein available ring carbon atoms are optionally substituted by 1-3 siibstituents independently selected from alkyl; (c) [f N ,5 © R" ■ NS r^'S, II N N" N. ^N. or N 3%- 205626 - zw- ,5 . wherein R is C^Cg alkyl and wherein available ring carbon atoms are optionally substiru-sd by 1 or 2 substituents independently selected from C.-C, alkyl; (d) ' 0 I ^ > ST N, or CI wherein is C^-Cg alkvl and wherein an available ring carbon atom is optionally substituted by Cn-C^ alkyl; (e) . N-R- _n-r" or wherein R is C^-Cg alkyl, X is 0, S or NR in which R is Cj-C4 alkyl and wherein one or more available ring carbon atoms is optionally substituted by alkyl; (f) N-R -N,-R" n" x •n-r" or \ e ■ n x q\-; J AiV* - 6 AUG 5984 'V'V » 'a'f c\ .<$ 205626 ,5 . wherein R is C^-Cg alkyl, X is O, S or NR in which R is C1-C4 alkyl and wherein one or more available ring carbon atoms is optionally substituted by alkyl; and (5) N- N. n-r" N-R R5 e E- -N N jtf-R N- -K R5 -r N. N-R h-R' e 5 R5 e N N-R II ' N ^ .5 . or wherein R is C^~C6 alkyl and R is C}.~C4 161. A compound according to Claim 160 wherein R"*" is oh ch3ch- and R"^ is methyl. 162. A compound according to Claim 160 wherein R is oh is . methyl Cti and the absolute configuration is 5R, 6S, 8R.

163. A compound according to Claim 159, 160 , 161 or 162 wherein A is -CH^- or -CH^CH^-. i *20 562k

164. A compound having the formula wherein A is C.-Cc straight or branched chain alkvlene; 2 R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when is hydrogen or a protecting group, there is also present a counter ion; and 5 6 wherein R is alkyl and R represents hydrogen or C.-C, alkyl; _ -511- 205626 wherein R is C^-C^ alkyl and R^ ana R7 are hydrogen or Cx-C4 alkyl; R e (c) R5 ,5 . wherein R is C-j-C^ alkyl and R is C1~C4 alkyl or phenyl-(C1-C4)alkyl; (d) ^ N N^-T N ls -R wherein R5 is C-,-C4 alkyl and R6 is C-^-C^ alkyl; (e) ' N k. / R N wherein R is' C^-C4 alkyl and R is C^-C4 alkyl; or (f) t l|. "s wherein R is C1~C4 alkyl; or a pharmaceutically acceptable salt thereof. 205626 165 A compovmd having the formula IR) -J., S—A—f- N R- COOR2 wherein A is C,-Cfi straight or branched chain alkylene; 2 R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when 2 R is hydrogen or a protecting group, there is also present a counter ion; and represents a radical of the formula (e) (a) 3© -Q CH. (b) (d) (f) / \\ \ CH. o CH2CH2CH3 9r6© - 2 0 5 § 2 6 (g) (i) e CH. I • N „ N - I CH. N " I ch. © (h) (j) CH. N /"s // \' JO H. CH. -D 'I CH. (k) CH3 j© CH. (1) Y\e CH. (m) ~N. ; or- (n) CH. "e- ~o / CH-, or a pharmaceutically acceptable salt thereof.

166. A compound of the formula 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. - 3 •• ^f-02L- 205626 167. A compound of the formula ch. sch2ch2 coor ^3 « N —' ® I CH3 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion? or a pharmaceutically acceptable salt thereof. 168, A compound of the formula ch. (R) sch2ch2- OOR O wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. -4-03- 205626 169. A compound of the formula OH .. CH. (R> _Jv, I sch :oor" wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof.

170. A compound of the formula 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. 171. -h-qhr- A compound of the formula 205626 N—CH_CH_CH 2 2 3 00 R 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. 172. A compound of the formula OH CH- (R> 1 '^OOR2 CH3 wherein 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 ion; or a pharmaceutically acceptable salt thereof.

173. a compound of the formula wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that n when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. 1 -tpt- 205 26 174 A compound of the formula (R) J sch. :oor' ? :h. © i J K.I N- / ch. wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. 175. A compound of the formula (R) 1 SCH :oor' wherein 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 ion; or a pharmaceutically acceptable salt thereof. 205626

176. A compotmd of the formula 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof.

177. a compound of the formula wherein 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 ion; or a pharmaceutically acceptable salt thereof. -/$- 2 0 56 26 178 A compound of the formula SCH COOR2 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof.

179. A compound of the formula wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. J 2056 26 180 A compound of the formula oh ch. h | 3 SCH. ^^COOR2 // \) •S^ -CH. 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R is hydrogen or a protecting group, there is also present a counter ion; or a phamaceutically acceptable salt thereof. 181. A compound of the formula SCH. / ch I © N coo K i CH. "^:oor2 wherein R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. -*<X- ^05626

182. A compound of the formula 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof.

183. A compound of the formula 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. h _^*rno- 205626 184 A compound of the formula SCH COOR2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that 2 when R as hydrogen or a protecting group, there is also present a counter ion? or a pharmaceutically acceptable salt thereof.

185. A compound of the formula 2 wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. J ./Hi- 205626

186. A compound of the formula SCK. COOR -N CH. * wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof.

187. A compound of the formula SCH COOR' ch3 \ © n- <0 # wherein R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing 2 that when R is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof. oi. u ,k :fB8S yo DATED THIS DAY OF A. J- PARK & SON PER. 2$ AGENTS FOR THE APPLICANTS </div>