SE460197B - NEW CARBAPENE MEMBER DERIVATIVES AND PROCEDURES FOR PREPARING THEREOF - Google Patents

Description

460 197 [on CH 2 NH 2 ClO 8 obtained by fermentation of Streptomyces cattleya (U.S. Patent 3,950,357). Thienamycin is an exceptionally potent broad-spectrum antibiotic, which shows remarkable activity with respect to various Pseudomonas species, organisms that are notoriously resistant to beta-lactam antibiotics.

Other natural products which contain the carbapenem core include olivic acid derivatives such as the antibiotic MM 13902 of the formula 3 no soÄ scn = cnnacocx30 COOH as disclosed in U.S. Patent 4,113,856, the antibiotic MM 17880 of the formula 3 U // J \\\ CHZCHZNHCOCHB 4, - N coon disclosed in U.S. Patent 4,162,304, the antibiotic 460 197 MM 4550A of the formula C33 '0 I Ho sd, / J \\\ ___ T, f' coon disclosed in U.S. Patent 4,172,129 and antibiotic 890A of the formula C53 0: I cn = cxNxccH3 no so 3 N oon disclosed in U.S. Patent 4,264,735. In addition to these natural products, the compound desacetyl-890A1O is disclosed in the form C H ° 35o /// L \ ñl :: \ íñ :::: H: ïCHZCEZNHZ ON COOH in U.S. Patent 4,264,734, according to which the compound flour is prepared by enzymatic deacylation of the corresponding N- -acetyl compound. Various derivatives of the naturally occurring olivanic acids have also been synthesized, for example the compounds of formula 460 197 4 C33 (K s (mnLd / NHCQCHB R: I '-5- o ^ "_ N coznl wherein COZR1 is a free, salt-present or esterified carboxyl group, n is 0 or 1 and R 2 is hydrogen, an acyl group or a group of the formula R 3 O 3 S, wherein R 3 is a salt-forming ion or a methyl or ethyl group.These compounds are disclosed in European Patent Application 8885.

U.S. Patent 4,235,922 (see also European Patent Application 2058) discloses carbapenem derivatives of the formula while British Patent Application 1,598,062 reports isolation of the compound SCHZCHZNHCOCHB 0 COOH from a Streptomyces culture fluid.

Carbapenems, which are unsubstituted in the 6-position, have also been synthesized. Thus, U.S. Patent 4,210,661 discloses compounds of formula 460 197 wherein R 2 is phenyl or substituted phenyl, U.S. Patent 4,267,177 discloses compounds of formula wherein R 1 is an optionally substituted pyridyl group. U.S. Patent 4,255,441 discloses compounds with the formula -CR 2 = CR 3 R 4 o "- N coon wherein R 2 and R 3 are hydrogen or alkyl and R 4 is NH-COn R 6, where R 6 is alkyl, phenyl or substituted phenyl and n is 1 or 2, and U.S. Patent 4,282,236 discloses compounds with the formula I fl = cnl oy_ 'N oox R: wherein R 1 is hydrogen or alkyl and R 2 is CN or CO 2 R 3, wherein R 3 is hydrogen, alkyl, aryl or aralkyl.

Carbapenems of the general formula 460 197 wherein R 1 is hydrogen or acyl and R 8 is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroclylalkyl, heterocyl terocyclylalkyl, is disclosed in U.S. Patent 4,218,463.

However, no R8 substituents of the type ® _ __ / I -A S \\ are disclosed where A is alkylene.

The natural product thienamycin has the absolute configuration 5R, 6S, 8R. This isomer as well as the other seven thienamycin isomers can be obtained via the total synthesis 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 and 4,290,947 and in the European patent application 7973. A key intermediate in the synthetic methods disclosed is NO cozpns wherein pNB is p-nitrobenzyl.

Due to the exceptional biological activity of thienamycin, a large number of derivatives have been prepared and disclosed in the 460,197 literature. These include (1) N-formimidOyl-thienamycin of the formula OH SCH2CH2N =? - NH2 H 1 COOH disclosed in European Patent Application 6639; (2) N-heterocyclyl derivative of thienamycin of the formula ou (z) P scnzcnzu (° š2) n N '\ / I coon RI and (fl p OH _ sc fl zcazn _ (CHZM ff 60 m, M II- wherein the bifunctional ring may contain additional unsaturation in the ring and wherein n is an integer 1-6; p is 0, 1 or 2; R 1 is hydrogen, alkyl or aryl; and Z is imino, oxo, hydrogen, amino or alkyl, is disclosed in U.S. Patent 4,189,493; (3) substituted N-methylene derivatives of thienamycin of the formula 460 197 OH scHcgn - x 2 2: N '' Q COOH 1R2, where R is sub- wherein X and Y are hydrogen, R , OR, SR or NR substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl and R 1 and R 2 are hydrogen or R, are disclosed in U.S. Patent 4,194,047 (4) compounds of the formula on 3 - 04 wherein R 3 is aryl, alkyl, acyl or aralkyl and R 1 and R 2 are independently hydrogen or acyl (including acyl of the type in -CR, wherein R 11 may be, inter alia, ra a alkyl substituted with a quaternary ammonium group, for example ï ~ C +) / \ -c-cn2-) __. disclosed in U.S. Patent 4,226,870; (5) compounds of the formula OR '12 SCH2CH2NR R ¿N COOH 460 197 wherein R 3 is hydrogen, acyl or a monovalent, optionally substituted hydrocarbon group; R 1 is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl and R 2 is acyl (including acyl of the type O 11 -CR, where R is alkyl substituted with a quaternary ammonium group, for example disclosed in British Patent 1,604,276 (see also U.S. Patent 4,235,917); (6) compounds of the formula OH (9 scxzcazuns as n7: ° ~ Goa 6 and R7 independently are wherein R 5, R 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 formula 3 wherein R 1 and R 2 are each independently a group of the type defined above for R 1, a hydrogen atom or nitro, hydroxy, C 1-6 hydrocarbon. alkoxy, amamino, C 1-6 alkylamino, di (C 1-6 alkyl) amino or tri (C 1-6 a alkyl) amino, wherein a true an- and R together with the nitrogen atom to which they are attached is a substitution are present in the latter case; or R is a substituted or unsubstituted monocyclic or bicyclic heteroaryl or heterocyclyl group containing 4-10 ring atoms, one or more of which may be an additional heteroatom, which is oxygen, sulfur and / or nitrogen; R is a cyano group or substituted or unsubstituted carbamoyl, carboxyl, (C 1-6 alkoxycarbonyl, C 1-4 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3 -C 10 doalkyl 4 C 4-12 cycloalkylalkyl, C 5-12 alkene-cycloalkyl -cycloalkenylalkyl, C6-10 aryl, C7-16 aralkyl, C8-16 alkenyl, C8-16 aralkynyl or monocyclic or bicyclic heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl comprising 4-10 ring atoms, of which one or more , sulfur and / or nitrogen and wherein the alkyl group of the heteroaralkyl or heterocyclylalkyl group contains 1-6 carbon atoms, the substituent or substituents on R 1, R 1, R 2 or on the ring formed by R 1 and R 2 together being chlorine; bromine; iodine; fluorine; azido; C 1-4 alkyl; mercapto; sulfo; phosphono; cyanothio (-SCN); nitro; cyano; amino; hydrazine; amino or hydrazino having up to three C 1-6 alkyl substituents; hydroxy; C 1-6 alkoxy; C 1-6 alkylthio ; carboxyl; oxo; (C 1-6-alkoxy) carbonyl; C2-10 acyloxy; carbamoyl; (C 1-4 alkyl) -carbamoyl or di (C 1-4 alkyl) -carbamoyl; R 3 is a hydrogen atom, an acyl group or a group of the type defined for R 4; R 4 is C 1-10 alkyl; substituted carbonylmethyl; C 1-6 alkoxy) - - (C 1-6 alkyl), (C 3-6 cycloalkoxy) - (C 1-6 alkyl); C2-12 yloxyalkyl; fully or partially halogenated C 1-6 alkyl, wherein the ha- alkanologen is chlorine, bromine or fluorine; aminoalkyl; C 2-10 alkenyl; C 2-10 alkynyl; acyl; C3-14 alkoxycarbonylalkyl; C4-21 dialkylaminoacetoxyalkyl; C2-13 alkanoylaminoalkyl; ar- (C 1-3 alkyl), where the aryl group contains 6-10 carbon atoms; monocyclic or bicyclic heteroaralkyl or heterocyclylalkyl having 4 to 10 ring atoms, 1 to 3 carbon atoms in the alkyl fluorine and 1 to 4 heteroatoms consisting of oxygen, sulfur and / or nitrogen; Aralkyl or heteroaralkyl substituted in the nucleus, wherein the substituent is chlorine, fluorine, bromine, iodine or C 1-6 alkyl; aryl or aryl-substituted aryl having 6-10 ring carbon atoms and wherein the optional core substituent is hydroxy, C 1-6 alkyl, chlorine, fluorine or bromine; aralkoxyalkyl; C 2-12 alkylthioalkyl; C4-12 cycloalkylthioalkyl; (C 2-10 acylthio) - (C 1-6 alkyl); or phenylalkenyl, where alkenyl has 2-6 carbon atoms; R 5 is substituted or unsubstituted C 1-10 alkyl; C 20-10 alkenyl or alkynyl; ring-substituted or unsubstituted cycloalkyl, cycloalkenyl, cycloalkenylalkyl or cycloalkylalkyl having 3-6 ring carbon atoms and up to 6 carbon atoms in an optional chain; C5-10 aryl; aralkyl having 6-10 ring carbon atoms and 1-6 carbon atoms in the alkyl chain; monocyclic or bicyclic heteroaryl or heteroaralkyl having 4-10 ring atoms, one or more of which are oxygen, nitrogen and / or sulfur, and 1-6 carbon atoms in the alkyl chain; and the ring or chain substituent or substituents are chlorine, bromine, iodine, fluorine, azido, cyano, amino, C 1-6 alkylamino, di- (C 1-6 alkyl) amino or tri (C 1-6 alkylamino), an additional anion being present in the latter case, hydroxy, C 1-6 alkoxy, C 1-6 alkylthioalkyl; carboxyl; oxo, (C 1-6 alkoxy) carbonyl; C2-10 acyloxy; carbamoyl; (C 1-4 alkyl) carbamoyl; di (C 1-4 alkyl) carbamoyl; cyanothio (-SCN) or nitro; R is hydrogen, hydroxy, mercapto, R, -OR, -SR or NR 1 R 2, where R, R 1 and R 2 have the meanings given above; X is hydroxy, mercapto, amino, acyloxy, -OR 4, -SR 4, -NHR 4, -N-R 4, -OM, -OQ or, when the compound is in zwitterionic form, -O-, in which case A- not present; A is a counterion when the compound is not in zwitterionic form; M is a pharmaceutically acceptable cation; and Q is a more defined blocking group, disclosed in British Patent 1,604,275; and (8) compounds of formula 460 197 12 H are! n / KÛSæZGaZNH-Q 'I // _ N cocø O vari 8. » 6 bonded to the amino nitrogen group of thienamycin is a mono- or polycyclic N-containing heterocyclic group and R is hydrogen, substituted or unsubstituted alkyl, aryl, alkenyl, heterocyclylalkenyl, aralkenyl, heterocyclylalkyl, aralkyl, -NR 2.

COOR, CONR2, -OR êllêr.CN, disclosed in European Patent Application 21082- Among the compounds disclosed in U.S. Patent 4,235,920 is the compound wherein A is a pharmaceutically acceptable anion. The above quaternary amine derivatives are also described in Recent Advances in the Chemistry of B-Lactam Antibiotics, Royal Society of Chemistry, London, 1981, p. 240-254, where its antibacterial activity is stated to be on average about 1/2 to 2/3 of the activity of thienamycin.

We are not aware of any disclosure in the literature of carbapenem derivatives of the present invention having a 2-substituent of the type 460 197 13 (i) -S- "Ä-S <: r although there are several recently published patent publications which to the widest extent can generically include such associations. Thus, European Patent Application 40408 discloses compounds of formula f; Wherein R 1 is hydrogen, methyl or hydroxyl and R 51 is a monovalent organic group which includes, inter alia, substituted alkyl or a group of the formula -CH 2 R 7, wherein R 7 is an optionally substituted 5- or 6-membered heterocyclic group; (2) European Patent Application 38869 discloses compounds of the formula OOH wherein R 6, R 7 and R 8 are independently hydrogen, substituted or unsubstituted alkyl, alkenyl or alkynyl of 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl or alkylcycloalkyl having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl groups; aryl such as phenyl; aralkyl, aralkenyl or aralkynyl, wherein the aryl group is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; wherein the substituent or substituents on the above groups are -XO halo (chloro, bromo, fluoro) -OH hydroxy -OR1 alkoxy, aryloxy 460 197 14 -OCNR1R2 carbamoyloxy O U -CNR1R2 carbamoyl -NR1R2 amino NR; / I amidino NRIRZ -NO nitro -N (R1) 3 trisubstituted amino (R1 independently selected) RT -¿ = NOR2 oximino SR1 alkyl- and arylthio -SO2NR1R2 sulfonamido O '12.

-NHCNR R ureldo R1CNR2- amino -CO23 carboxy -CO2R1 carboxylate O * in 1 -CR acyl 1 -OCR1 acyloxy -SH mercapto H -SR1 alkyl and aryl-sulfinyl "ä -ÉR1 alkyl- and aryl-sulfonyl -CN cyano -N3 azido 460 197 wherein the groups R 1 and R 2 are independently hydrogen, alkyl, alkenyl or alkynyl having 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl or alkylcycloalkyl having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl groups; aryl such as phenyl; aralkyl, aralkenyl or aralkynyl, wherein the aryl group is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, wherein the heteroatom or heteroatoms in said heterocyclic groups consist of 1-4 oxygen, nitrogen and / or sulfur atoms and wherein the alkyl groups associated with said heterocyclic groups contain 5-6 carbon atoms. (See also European Patent Applications 1627, 1628, 10317, 17992, 37080, 37081 and 37082): (4) European Patent Application 24832 discloses compounds of the formula CH3-CH-I SR12. ¿7- N 0 CO 23 wherein R 1 is hydrogen or OH, OSO 3 H or a salt or a C 1-4 alkyl ester thereof, OR 2, SR 3, OCOR 2, OCO 2 R 3 or OCONHR 3, wherein R 2 is a C 1-6 alkyl group or an optionally substituted benzyl group and R 3 is a C 1-6 alkyl group or an optionally substituted benzyl or phenyl group and R 12 is C 1-6 alkyl, C 2-6 alkenyl, C 3-6 alkynyl, where the triple bond is not present on the carbon atom adjacent to the sulfur atom, aralkyl, C 1-6 -alkanoyl, aralkanoyl, aryloxyalkanoyl or arylcarbonyl, each of these R 12 groups being optionally substituted as antibacterial agents.

The aforementioned European Patent Application 38869 discloses the synthesis of the carbapenem derivatives via intermediates of the general formula 460 197 16 wherein R 6 and R 7 have the meanings given above and R 2 'is an easily removable carboxyl protecting group. As intermediates, compounds of the formula wherein X is described as a leaving group are also disclosed.

Although the above state of the art describes carbapenem derivatives having a 2 -substituent of the type ® -sAN α á and derivatives having a 2-substituent of the type -sAs-R1 wherein R 1 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl , alkylcycloalkyl, phenyl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, we do not know of any disclosure in the literature on carbapenems having a 2-substituent in which the alkylene group A is directly attached to a sulfonium group, i.e. a group of type 69 J --s -gx-s \. 460 197 17 Despite the large number of carbapenem derivatives that have been revealed in the literature, there is still a need for new carbapenems, as known derivatives can be improved in terms of activity spectrum, potency, stability and / or toxic side effects. The present invention relates to a new series of carbapenem derivatives, which are characterized by a 2-substituent of the formula R10 / \ R11 wherein A is straight or branched chain C2-C5-alkylene and R10 and R11 together with -S-year-S so to which they are bonded is a 4-6 membered sulfur-containing heterocyclic ring, said ring being bonded to A via the sulfur atom and thereby forming a sulfonium group. More particularly, the invention relates to carbapenem derivatives of the formula Q R 10 wherein A is a straight or branched chain C 2 -C 5 alkylene group; R 8 is hydrogen; R 1 is a hydroxyalkyl group having 1-10 carbon atoms; R 2 is hydrogen, an anionic charge or a conventional, easily removable carboxyl protecting group, with the proviso that when R 2 is hydrogen or a protecting group, a counter anion is also present and R 10 and R 11 together with S a 4-6 membered sulfur-containing heterocyclic ring, said ring being bonded to A via the sulfur atom and thereby forming a sulfonium group. The compounds of formula I are potent antibacterial agents or intermediates useful in the preparation of such agents.

The invention also relates to processes for the preparation of the above-described novel carbapenem derivatives and pharmaceutical compositions containing the biologically active carbapenem derivatives in combination with pharmaceutically acceptable carriers or diluents.

The novel compounds of general formula I above contain the carbapenem core and may thus be called 1-carba-2-penem-3-carboxylic acid derivative. Alternatively, the compounds can be considered to have the basic structure S 3 / j-N z O 1 and in this case are called 7-oxo-1-azabicyclo (3.2.0) hept-2-ene--2-carboxylic acid derivatives. Although the present invention encompasses compounds wherein the relative stereochemistry of the 5,6 protons is both cis and trans, the preferred compounds have the 5R, 6S (trans) stereoconfiguration as is the case with thienamycin. The term "conventional readily removable carboxyl protecting group" refers to known ester groups which have been used to block a carboxyl group during the chemical reaction steps described above and which can be removed by methods which do not result in any significant degradation of the rest of the molecule, for example 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, p--nitrobenzyl, 2-naphthylmethyl, benzyl, trichloroethyl, silyl such as trimethylsilyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl, 4-pyridylmethyl and C1-C6-alkyl such as methyl, ethyl or p-butyl. Such protecting groups also include 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 can be easily removed by catalytic hydrogenation.

The above pharmaceutically acceptable salts include non-toxic acid addition salts, for example salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid etc. and salts with organic acids such as maleic acid, acetic acid, citric acid, succinic acid, succinic acid, succinic acid fumaric acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid and malic acid. Compounds of formula I in the form of the acid addition salts may be written as 460 197 ,, / S \\ ~ R11 XC) R = H or protecting group wherein X 9 is the acid anion. The counterion X <3 can be selected in such a way as to obtain pharmaceutically acceptable salts for therapeutic administration, but in the case of intermediates of formula I, X 9 may also be a toxic anion. In such a case, the ion can subsequently be removed or replaced with a pharmaceutically acceptable anion to obtain an active end product for therapeutic use. When acidic or basic groups are 11-substituents present in the R1 group or on the R10 or Rs, the present invention also encompasses suitable base or acid salts of these functional groups, for example acid addition salts in the case of a basic group and metal salts (for example salts of sodium, potassium, calcium and aluminum), the ammonium salt and salts with non-toxic amines (for example trialkylamines, procaine, dibenzylamine, 1-ephenamine, N- -benzyl-beta-phenethylamine, N, N ' -dibenzylethylenediamine etc.) in the case of acidic groups.

Compounds of formula I, wherein R 2 is hydrogen, an anionic charge or a physiologically hydrolysable ester group, together with pharmaceutically acceptable salts thereof are useful as antibacterial agents. Other compounds of formula I are valuable intermediates, which can be converted into the above-mentioned biologically active compounds.

A preferred embodiment of the present invention comprises compounds of formula I, wherein R 8 is hydrogen and R 1 is H CH ... "ca x 2 \? 'C ° or CH cen / 3 460 197 21-22 Such compounds are preferred wherein R H is about C11-, with the most preferred compounds having the absolute configuration SR, 6S, 8R.

The R 10 and R 11 substituents are together with S (§> to which they are attached a 4-6 membered sulfur-containing heterocyclic ring, said ring being attached to the alkylene (A) group via a sulfur atom and thereby forming a sulfonium group.

An especially preferred embodiment of the present invention relates to compounds of formula I, wherein R 10 and R 11 together with SG) to which they are attached are 3- or "S G 9 and pharmaceutically acceptable salts thereof. A particularly preferred embodiment of the present invention invention relates to compounds of formula I, wherein R 1 __ (? __ R 11 is (E) and pharmaceutically acceptable salts thereof. Within this subclass, the preferred compounds are those wherein A is - (CH 2) n -, where n is 2, 3 or 4, in particular those wherein A is -CH 2 CH 2 -, and wherein - R 8 is hydrogen and R 1 is CH OH OH 3 \\ |. than C- or CH 3 - C 5 3 Particularly preferred are those compounds wherein R 8 is hydrogen and R 1 is 24,460 197 m OH I ca3cn-, preferably compounds with the absolute configuration 5R, 65, BR.

The most preferred embodiment of the present invention relates to compounds of the formula OH (RA / LL 'wherein R 2 is hydrogen, an anionic charge or a conventional readily cleavable carboxyl protecting group, provided that when R 2 is hydrogen or a protecting group a counter anion is also present, and The 6-substituent may in some cases, for example as in hydroxyethyl, be in either the R or S configuration and the resulting isomers as well as the epimeric mixtures thereof fall within the scope of the present invention.

The carbapenem derivatives of the general formula I are prepared from starting materials of the formula 460 197.-É;%> IU% COOR fN "-" _ L- 2 '0 / III 8 wherein R1 and R have the meanings given above and R2' is a conventional easily removable carboxyl protecting group. Compounds of formula III are disclosed, for example, in European Patent Application 38869 (compound 7) and may be prepared by the general methods described therein.

The process for the preparation of the compounds I starting from the starting materials III can be summarized by the following reaction scheme: 3 0 ß n 1 P (æs fl s) 2 RI à fl- 'N 00122' _ °: v ..._- L 460 197 26 optionally As an example of this process, the starting material III is reacted in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with approximately an equimolar amount of diphenylchlorophosphate in the presence of a base such as diisopropylethylamine, triethylamine or triethylamine, 4-dimethylamine obtaining the intermediate IV. The acylation reaction which introduces the leaving diphenylphosphoryloxy group in the 2-position of intermediate III is advantageously carried out at a temperature of from -20 to + 40 ° C, in particular about 0 ° C. Intermediate IV can be isolated, if desired, but is suitably used in subsequent steps without isolation or purification.

Intermediate IV is then converted to intermediate V by a conventional displacement reaction. Thus intermediate IV can be reacted with approximately an equimolar amount of a mercaptan reagent of the formula HS-OH-OH wherein A is straight or branched chain C2-C6-alkylene, in an inert organic solvent such as dioxane, dimethylformamide, dimethylsulfoxide or acetonitrile and in the presence of a base such as diisopropylethylamine, triethylamine, sodium bicarbonate, potassium carbonate or 4-dimethylaminopyridine. The temperature in the displacement reaction is not critical, but a favorable temperature range is from -40 ° C to 25 ° C. The reaction is advantageously carried out during cooling, for example around 0 ° C. Intermediate V is then acylated with methanesulfonyl chloride or a functional acylating equivalent thereof such as methanesulfonic anhydride in an inert organic solvent and in the presence of a base to provide the leaving methanesulfonyloxy group in intermediate VI. The acylation is carried out in an inert organic solvent such as tetrahydrofuran, methylene chloride, acetonitrile or dimethylformamide and in the presence of a suitable base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine and the like. The reaction can be carried out within a wide temperature range, for example from -400 to + 40 ° C, but is advantageously carried out under cooling, for example at from -30 ° C to -40 ° C.

Intermediate VI is then subjected to a displacement reaction for the introduction of the leaving iodine group into intermediate II. This particular group has been found to greatly facilitate the preparation of the carbapenem end products of formula I.

The intermediates of general formula II therefore relate to a preferred embodiment of the present invention. The displacement of the leaving methanesulfonyloxy group is carried out by reacting intermediate VI with an iodide ion source in an inert organic solvent such as acetone, dimethylformamide or dimethylsulfoxide. Any compound which ionizes in the solvent used to provide iodide ions may be used, for example an alkali metal iodide such as NaI or KI. The temperature of the displacement reaction is not critical, but temperatures around room temperature or above are extremely advantageous in order to complete the reaction within a reasonable time. The iodide ion source is used in such an amount that approximately one equivalent or excess of iodide ions is provided relative to intermediate VI.

The preparation of the desired carbapenem derivatives of formula I is carried out by means of a nucleophilic displacement of the leaving iodine group in intermediate II with the desired sulphide of the general formula / "R" \\ Rll S Intermediate II is reacted with at least one equivalent, preferably an excess of the desired sulfide in an inert organic solvent and in the presence of silver ions. Suitable inert organic solvents include, for example, tetrahydrofuran, dioxane, methylene chloride, diglyme, dimethoxyethane and the like. Any silver compound that substantially ionizes in the solvent to give silver ions and an inert anion can be used as a silver ion source, for example AgClO 4. It is generally preferred to use approximately an equivalent amount (with respect to intermediate II) of silver ions to facilitate the displacement reaction. The reaction can be carried out within a wide temperature range, for example from about -25 ° C to about + 25 ° C but is preferably carried out around 0 ° C. The intermediate I '460 197 29 has an associated counter anion (derived from the silver salt used), which at this stage can be replaced by another counter anion, for example one which is pharmaceutically acceptable, by conventional methods. Alternatively, the motion can be removed later during the unblocking step.

The deblocking step for removing the carboxyl protecting group R2 'in intermediate I' is carried out by conventional methods such as solvolysis, chemical reduction or hydrogenation. When using a protecting group such as p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl, which can be removed by catalytic hydrogenation, intermediate I 'can be treated in a suitable solvent such as dioxane-water-ethanol, tetrahydrofuran-aqueous solution of dipotassium hydrogen phosphate-isopropanol or the like under a hydrogen pressure of 1-4 atmospheres in the presence of a hydrogenation catalyst such as palladium on charcoal, palladium hydroxide, platinum oxide or the like at a temperature of 0-SOOC for about 0.24-4 hours. When R2 | is such a group as o-nitrobenzyl, photolysis can also be used for deblocking. Protecting groups such as 2,2,2-. -trichlorethyl can be removed by mild zinc reduction. Other conventional carboxyl protecting groups can likewise be removed by methods known to those skilled in the art. Finally, as mentioned above, compounds of formula I ', wherein R 2' is a physiologically hydrolyzable ester group such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc., can be administered directly to the host animal without unblocking, since such esters hydrolyzed in vivo under physiological conditions.

It will be appreciated that when the R 1 substituent or the heteroaromatic nucleophile attached to substituent A contains a functional group which may interfere with the intended course of the reaction, such a group may be protected by a conventional protecting group and then unblocked to produce the desired functional group. Suitable blocking groups and methods for introducing and removing such groups are well known to those skilled in the art. As with other beta-lactam antibiotics, the compounds of general formula I can be converted by known methods into pharmaceutically acceptable salts which, for the purposes of the present invention, are substantially equivalent to the non-salt compounds. For example, one may dissolve a compound of formula I, wherein R 2 is an anionic charge, in a suitable inert solvent and then add one equivalent of a pharmaceutically acceptable acid. The desired acid addition salt can be recovered by conventional methods, such as solvent precipitation, lyophilization, etc. When other basic or acidic functional groups are present in the compound of formula I, pharmaceutically acceptable base addition salts and acid addition salts may likewise be prepared by known methods. 2 is hydrogen or an anionic A compound of formula I wherein R is a charge, or a pharmaceutically acceptable salt thereof may also be converted by conventional methods into a corresponding compound, wherein R 2 is a physiologically hydrolysable ester group, or a compound of Formula I, wherein R 2 is a conventional carboxyl protecting group, is converted to the corresponding compound, wherein R 2 is hydrogen, an anionic charge or a physiologically hydrolyzable ester group or a pharmaceutically acceptable salt thereof.

The novel carbapenem derivatives of the general formula I, in which R2 is hydrogen, an anionic charge or a physiologically hydrolysable carboxyl protecting group, and the pharmaceutically acceptable salts thereof are potent antibiotics which are active against various gram-positive and gram-negative bacteria and they can For example, they can be used as animal feed additives to promote growth, as food preservatives, as bactericides for industrial use, for example in water-based paints and in the backwater of paper beech, to inhibit the growth of harmful bacteria and as disinfectants to inhibit or inhibit the growth of harmful bacteria on medical equipment and dental equipment. However, they are particularly useful for the treatment of infectious diseases in humans and other animals caused by gram-positive or gram-negative bacteria.

The pharmaceutically active compounds of the present invention may be used separately or formulated as pharmaceutical compositions which, in addition to the active carbapenem compound, contain a pharmaceutically acceptable carrier or diluent. The compounds can be administered in many different ways; those of principal interest include oral, local or parenteral (intravenous or intramuscular injection) administration. The pharmaceutical compositions may be in solid form as capsules, tablets, powders, etc. or in liquid form as solutions, suspensions or emulsions. Compositions for injection, the preferred route of administration, may be prepared in unit dosage form in ampoules or in multiple dose containers and may contain such preparations as suspending agents, stabilizing agents and dispersing agents. The compositions may be in ready-to-use form or in powder form for reconstitution at the time of administration with a suitable vehicle such as sterile water.

The dose administered depends to a large extent on the particular compound in question used, the particular composition in question used, the mode of administration, the nature and condition of the host animal and the particular situation and organism to be treated. The choice of the particularly preferred dosage and mode of administration is determined by the physician. In general, however, the compound may be administered parenterally or orally to host mammals in an amount of 5-200 mg / kg / day. The administration is generally performed in divided doses, for example 3 to 4 times daily.

To illustrate the potent antibacterial broad spectrum activity of the carbapenems of the present invention, both in vitro and in vivo, and the low toxicity of the compounds, reference is made to the accompanying biological data below for the preferred carbapenem compound of the present invention. Organism 460 197 32 ning, i.e. 3- (2- (1-tetrahydrotiophenium) ethylthio) -6L (- (1- (R) -hydroxyethyl) -7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate , prepared according to Example 1.

In vitro activity A sample of the above carbapenem compound was found after dissolution in water and dilution with nutrient solution to show the following minimum inhibitory concentrations (MIC) in pg / ml with respect to the indicated microorganisms by tube dilution after overnight incubation at 37 ° C. N-formimidoyl-thienamycin has been incorporated as a comparative compound.

In vitro antibacterial activity of the carbapenem derivative according to Example 1 MIK (μg / ml) before. according to. ex. 1 N- fi nm fi müínd-th fl aumnmin S. Eneumoniae A-9585 0.002 l 0.004 S. Exogenes Ar9604 0.004 0.001 S. aureus _A-9537 0.008 - 0.004 S. aureus + S0! serum A-9537 0.03 0.016 S. aureus h (Pen-res.) A-9606 0.016 0.008 S. aureus (Meth-res.) Al5097 2 0.5 S. faecalís A20688 0.5 0.5 E. coli _ - _ un * an.) msns - 0.03 mois E. coli j _ (104) 1015119 0.06 0.03 B. coli (104) Aisna 0.06 0.06 E. coli (10%) 1-.20341-1 0.03 0.03 460 197 33 Antibacterial activity in vitro for the carbapenem derivative en- ligt exemgel - (continued) MIK (gg / ml) O: anism _ Paren. according to. ex. 1 N-fonmmaøyl-auenarfycm E. coli I (104) A20341-1 0.03 0.03 E. coli (104) 1020341-1 0-06 0.13 X. gneumoniae Ar9664 0-06 0.13 K. Eneumoniae A20468 0 0.13 0.06 p mirabiiis A -ssoo 0.13 0.06 P. vulgaris A2l5S9 0.03 0.03 P. morganii AlSl53 0.06 0.13 P. rettgeri A22424 0.25 0.25 S. marcescens A200l9 0.06 0.03 E. cloacae A-9559 0-13 _ .. _. _ - 0.06 E- cloacae Af9656 0.13 0.06 P. aeruginosa A ~ 9843A 1 l P. aeruginosa A2lÉl3 Û-25 0.25 H. influenzae A-9833 8 16 H. influenzae A20l78 8 32 H. influenzae A2lSl8 8 32 H. influenzae A2l522 8 32 fragilis Azzssz -0.0s' 0.015 pp. Fragilis 0322053 0.06 ~ 0.06 B. fragilis A22696 0-25 0.13 B. fragilis A228S3 0.05 1 In vivo activity The in vivo therapeutic activity of the compound of Example 1 and N-formimidoyl -thienamycin after intramuscular administration to mice that had been experimentally infected with various organisms is shown in the table below. The PD50 value (the dose in mg / kg required to protect 50% of infected mice) is indicated. 460 197 34 Ammmom 4 .fi æwomá .mmvwmá ~ oomm4 _N | ßmfmw4 .mmmr ~ <. .xmmuww mnum> www mwø: w> cm wmmë Eww “Amm fi H> © m fi amv co fl uxwmc fi umuwm uøëë fi u m ~ m nuo f umaam co fl uxmuc fl umumm umñë fl u w zoo o cmawwewxw fi um wmm uw www nm ww m um ww n.A vo fl x Q v. ° @. = vc fl x n .m. ° @. ° vad x M 1 m wc fi x Q | fi. m mo fi x B mw ~. @ ßo fi xm 1 m. «mc fl xv« mH \ «n ~ .ß wø fi xv 1 ~ .H wc fi x <.«. ~ m wc fi x ». ~. ~ w. fi vad xw. «« ø.e _ @ ~. ° rmmmxw H Hmñm flfl c fl oæëmcm fl zu f Hmm fi wxw nmmno m fl ußw | H> OU fl E fl EHOH | Z vm flfifl w m flfl ümnßm l fi a fl u Hmu fi ë ^ mx \ mx. @ = HHw = m§wn \ omom ammo fl <fl mvo ~ <mmvæmld mmmo fl æ @ ~ »~ wHmH <mmm- <°° wm« <mmwm | <vmwmza m flfi m fl a @ ° w @ | <mmmm fl mmmm fl zqw mmmmwwmwmma WU mM mUWMM « «Mmmmma \« m «uwm» umn_.mm «umm fi ø> .m m fififl ßmu fl a .Ä mmomo fi o .m mmwcoëøwcm .M flfi OU .N W fl @ H5 fl -W 1J flfl HHdJHW EmaGmwuO WWÛE 0ÜMHÜXHUHHWHH ~%? nwvmmMwmww fl wPåv fi w 460 1972 Toxicity The toxicity of the compound of Example 1 after intracranial administration to mice was determined and shown in the table below.

Toxicity after intracranial administration to mice Maximum dose (mg / kg) without * clinical signs of tox- Compound _§D5o (mg / kgl icity Compound according to example 1> 40 'V 5 N ~ formimidoyl-thienamycin 32 V 5 * Mean value for 25 mice / compound Blood levels in mice after intramuscular administration The blood levels and half-life of the compound of Example 1 after intramuscular administration of 20 mg / kg to mice are shown in the table below.

Blood level (Eg / ml) Compound 10 20 30 45 so eo * m / 2 “was Minutes after administration (min.) Ggg.h / ml) Compound acc. Example 1 14.7 13.5 8.7 3.2 0.9 <0.6 9 7.4 N-formimidoylthienamycin 12.6 9.9 7.3 2.6 0.7 <0.3 9 The compounds were solubilized in 0.1 M phosphate buffer pH 7. The values are from a single test; four mice were used per compound. * t1 / 2 refers to the half-life in minutes ** YUK refers to the area under curve 460 197 36 Excretion with the urine The excretion of the compound of Example 1 with the urine after intramuscular administration (20 mg / kg) to mice is shown in the table below.

Urinary excretion after intramuscular administration of 20 mg / kg to mice Percentage excreted dose 0-3 3-6 6-24 0-24 Compound hours after administration Compound of Example 1 15.6 2.1 <0.2 17.7I2.9 N-formimidoylthienamycin 12.1 0.1 The compounds were solubilized in 0.1 M phosphate buffer pH 7. The values are from a single test; four mice per compound.

The invention is further illustrated by the following exemplary embodiments.

Example 1 Preparation of 3- (2- (1-tetrahydrotiophenium) ethylthio) -6- (R) -hydroxyethyl) -7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate 460 197 37 A. p-Nitrobenzyl 3- (2-hydroxyethylthio) -6-7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate OH) 'ärf- llf, .1.

PNB + C52 A solution of 1.69 g (4.85 mmol) of p-nitrobenzyl-6-oxyethyl) -3,7-dioxo-1-azabicyclo (3.2_0) hept-2-ene-2-carboxylate (1) in 20 ml of acetonitrile was cooled to 0 ° C under a nitrogen atmosphere.

A solution of 726 mg (7.18 mmol) of diisopropylethylamine in 2 ml of acetonitrile was added, followed by dropwise addition of 1.51 g (5.60 mmol) of diphenyl chlorophosphate in 12 ml of acetonitrile over 3 minutes.

The resulting solution was stirred at 0 ° C for 20 minutes to give p-nitrobenzyl-3- (diphenylphosphoryloxy) -6 <1- (1- (R) -hydroxyethyl) -7-oxo-1-azabicyclo (3.2.0). ) hept-2-ene-2-carboxylate.

To this solution was added a solution of 726 mg (7.18 mmol) of diisopropylethylamine in 2 ml of acetonitrile, followed by a solution of 439 mg (5.63 mmol) of 2-mercaptoethanol in 2 ml of acetonitrile. The reaction solution was stirred for 3 hours at 0 ° C and then diluted with 200 ml of ethyl acetate and washed with 200 ml of water, 100 ml of a 20% aqueous solution of phosphoric acid and brine. Evaporation of the magnesium sulfate dried solution gave 46Û 197 38 a semi-solid which was triturated with methylene chloride and filtered to give 1.2 g (61% yield) of the title product 2 as a white, amorphous solid. .

NMR (1H, d, J = 8.5 Hz) and 8.23 (2H, d, J = 8.5 Hz); IR (KBr) λmax: 3500, 1770 and 1700 cm -1; Analysis Ber. for C 18 H 20 N 2 O 7 S: C 52.93 H 4.94 N 6.86 S 7.85 Found: C 52.83 H 4.90 N 6.42 S 8.31 B. p-nitrobenzyl-3- (2-methanesulfonyloxyethylthio) -Gd .- (1- (R) -Hydroxyethyl) -7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate scn2cn2oso2cn3 OO zpna To a solution of 4.2 g (10 1.3 mmol) of compound 2 in 200 ml of tetrahydrofuran was added at -4000 1.3 g (11.3 mmol) of methanesulfonyl chloride, followed by dropwise addition of 1.26 g (12.4 mmol) of triethylamine in 5 ml of tetrahydrofuran . The reaction mixture was stirred for 5 hours at -40 ° C, then stirred for 2 hours at 3030 ° C under a nitrogen atmosphere and then poured into a mixture of 700 ml of ethyl acetate and 1000 ml of a 5% aqueous solution of phosphoric acid. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to a syrup. This material was obtained by silica gel column chromatography (eluting with methylene chloride / ethyl acetate 3: 1 by volume) to give 3.55 g (7S% yield) of the title compound as a white amorphous solid.

NMR (CDCl 3) δ: 1.25 (3H, d, J = 6.0 Hz), 3.05 (3H, S), 3.06-3.40 (SH, m), 4.05-4, 40 (4H, m), 5.25 (1H, d, J = 14.0 Hz), 5.50 (1H, d, J = 14.0 Hz), 7.70 (2H, d, J = 8 .5 Hz) Och 8.23 (ZH, d, J = 8.5 H2), - IR (mar) gmax: 3400, 1770 and 1600 m4.

Analysis Ber. for C 19 H 22 N 2 O 9 S 2: C 46.90 H 4.56 N 5.75 Found: C 46.52 H 4.32 N 5.91 C. p-nitrobenzyl-3- (2-dimethylthio) -6Ci- (1- (R ) -hydroxyethyl) -7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate A solution of 350 mg (0.72 mmol) of intermediate 3 and 216 mg (1.4 mmol) sodium iodide in 20 ml of acetone was refluxed for 4,460,197 hours. Evaporation of the acetone gave a white amorphous solid which was suspended in 10 ml of ether ~ 10 ml of water. Filtration of the white solid and vacuum drying gave 300 mg (80% yield) of the title compound 4 as a white amorphous powder.

NMR (DMSO-66) δ: 1.18 (3H, d, J = 6.0 Hz), 3.20-3.60 (7H, m), 3.80-4.25 (2H, m), 5.10 (TH, d, J = 5.5 Hz), 5.25 (1H, d, J = 12.0 Hz), 5.45 (1H, d, J = 12.0 Hz), 7, 70 (2H, d, J = 8.5 Hz) and 8.27 (ZH, d, J = 8.5 Hz); IR (KBr) λ max: 3500, 1768 and 1700 -1 cm 7 Analysis Ber. for C 18 H 19 N 2 O 6 I: C 41.71 H 3.70 N 5.41 I 24.48 Found: C 42.10 H 3.75 N 5.97 I 23.20 D. 3- (2- (1-tetrahydrotiophenium) ethylthio ) -6d ~% 1- (R) -hydroxyethyl) -7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate To a solution of 104 mg (0.2 mmol) p-nitrobenzyl 3- (2-iodo-ethylthio) -6CL- (1- (R) -hydroxyethyl) -7-oxo-1-azabicyclo (3.2.0) - hept-2-ene-2-carboxylate to 5 ml of tetrahydrofuran was added 0.3 ml (0.3S mmol) of tetrahydrothiophene, followed by a solution of 60 mg (0.3 mmol) of silver perchlorate in 0.5 ml of tetrahydrofuran. The mixture was stirred for 60 minutes at room temperature. The solvent was evaporated in vacuo to give compound 5 as a yellow gum. This rubber was slurried with 100 ml of Celite to give an amorphous solid.

: R (rar) gmax = 3400, 1172, 1700 and 11oo cm "1.

Without further purification, compound 5 was hydrogenated as follows: To a suspended solution of compound 5 in 20 ml of ether and 20 ml of tetrahydrofuran was added a solution of 40 mg (0.4 mmol) of potassium bicarbonate and 35 mg (0.2 mmol) of dibasic potassium phosphate in 20 ml of water. Then, 120 mg of 10% palladium on charcoal was added and the mixture was hydrogenated at 40 psi for 60 minutes in a Parr shaker. The mixture was then filtered and the catalyst was washed with 2 x 5 ml of water. The combination of filtrate and washings was extracted with 2 x 50 ml of ether and then lyophilized to give a yellow powder.

This crude material was purified on a C18BONDAPAK reverse phase column (7 g) (Waters Associates) eluting with water under a pressure of 8 psi. Each fraction (15 ml) was examined by high performance liquid chromatography and fractions with an ultraviolet absorption of 1-max 300 nm were collected and lyophilized to obtain 12 mg (18% yield) based on the compound 4) of the title product as a white solid material.

NMR (D 2 O) δ; 1.23 (aa, a, J = 6.0 az), 2.25-2.45 (4n, m), 3.0--3.70 (113, m), 3.95-4.30 (2H, m); IR (KBr) gmax: 3400, 1760 _1 _ And 1590 Cm. UV ÄmaX (CH 2 CH 2 OH) 289 Dm (C - 6200).

Claims (8)

460 197 L / Q Patent application no. 8301928-l PATENTKEB! Compounds of formula Waffle A8 are a straight or branched chain C2-C6 alkylene group; RI is hydrogen; R 2 is a hydroxyalkyl group having 1 to 10 carbon atoms; R is hydrogen, an anionic charge or a conventional, easy-to-remove bacarboxyl protecting group, with the proviso that, when R is hydrogen or a protecting group, a counter anion is also present and R and R together with S to which they are attached are a 4- 6-membered sulfur-containing heterocyclic ring, said ring being bonded to A via the sulfur atom and thereby forming a sulfonium group. Compounds according to claim 1, characterized in that R is il? CH3 'and that the absolute configuration is 5R,' 6S, 8R. Compounds according to claim 1 or 2, characterized in that A is ~ CH 2 CH 2 -. 460 197 Compounds according to any one of claims 1 - 3, k 8 n n e - t e c k n a d e thereof, wherein R and R together with SG) to which they are attached are 9 -s and pharmaceutically acceptable salts thereof. Compounds according to claim 4 of the formula wherein R 2 is hydrogen, an anionic charge or a conventional, readily removable carboxyl protecting group, provided that, when R is hydrogen or a protecting group, a counter anion is also present, and pharmaceutically acceptable salts hence. Compounds according to claim 5, characterized in that R is p-nitrobenzyl. A process for the preparation of the compounds according to claim 1 'of the formula 460 197 97 69 am \ R 11 OOR 2 _12s1o11 _ _ wherein R, R, R, R, R and A have the meanings given in claim 1, characterized in that submits an intermediate of formula I wherein R 1, R 8 and A are as defined above and R is a conventional, readily removable carboxyl protecting group, a nucleophilic displacement reaction in an inert organic solvent and in the presence of silver ions with a sulphide reagent of the formula _ // ' E10 wherein R and R have the meanings given above, for exchanging the iodine group in intermediate II for the group 460 197 I in which X- is a monionion and R1, RB, A, Rio, R1 and R have the meanings given above and removing the carboxyl protecting group R if desired to give the corresponding unblocked compound of formula I or a pharmaceutically acceptable salt thereof. Process according to Claim 7, characterized in that (1) is reacted an intermediate of the formula COOR 2 III wherein R and R have the meanings given in claim 1 and R is a conventional, easily removable carboxyl protector. group, in an inert organic solvent with diphenyl chlorophosphate in the presence of a base to give an intermediate of formula 18 wherein R, R and R have the meanings given above; (2) reacting intermediate IV in an inert organic solvent and in the presence of a base with a mercaptan reagent of the formula HS -A-OH wherein A has the meaning given in claim 1, to obtain an intermediate of formula H § I 1 8 2 wherein R, R, A and R have the meanings given above; (3) reacting intermediate V in an inert organic solvent and in the presence of a base with methanesulfonyl chloride or a functional acylating equivalent thereof to give an intermediate of formula 460 197 Lz? -A-osozcæxzi VI 1 8 'wherein R, R, A and R have the meanings given above; (4) reacting intermediate VI in an inert organic solvent with an iodide ion source to exchange the methanesulfonyloxy group for an iodine group to form an intermediate product of formula S ~ Ä-I II I OOR2 I 1 8 wherein R, R, A and R have the meanings given above and (5) subject intermediate II to a nucleophilic displacement reaction in an inert organic solvent and in the presence of silver ions with a sulphide reagent of formula 10 wherein R 1 and R 2 are as defined in claim 1, to exchange the iodine group in the intermediate. II against group 460 197 e! and form a compound of the formula I wherein X - is a counter anion and R, R, A, R, R and R have the meanings given above and that, if desired, the carboxyl protecting group R to obtain the corresponding unblocked compound of formula I or a pharmaceutically acceptable salt thereof.