SE461734B - NEW CARBAPENEM ANTIBIOTICS AND PROCEDURES FOR PREPARING THEREOF - Google Patents

Description

461,734 obtained by fermenting Streptomyces cattleya (U.S. Patent 3,950,357). Thienamycin is an exceptionally potent broad-spectrum antibiotic, which exhibits remarkable activity with respect to various Pseudomonas species, microorganisms that are notoriously resistant to β-lactam antibiotics.

Other natural products containing the carbapenem core include olivic acid derivatives, such as the antibiotic HM 13902 of the formula: H3 _ scn = axnscocza3 aoas I o / FN cooa disclosed in U.S. Patent 4,113,856, the antibiotic MM 17880 of the formula CH 3 6 // J \\ W CHZCHZNHCOCH3 HOBS I FN COOH 6 disclosed in U.S. Patent 4,162,304, the antibiotic MM 4550A of formula 2? A s-ca = cnnncoca3 no3s I i 04 "- 'N coon disclosed in U.S. Patent 4,172,129, and the antibiotic 890A§ of the formula OI C33 | cn = camaccza3 Hoaso - N coon v: ¿5,463,754 disclosed in U.S. Patent 4,264,735. In addition to these natural products, the compound desacetyl-890A10 is disclosed by the formula of U.S. Patent 4,264,734 and is prepared by enzymatic deacylation of the corresponding N-acetyl compound.

Various derivatives of the naturally occurring olivic acids have also been synthesized, for example compounds of the formula s (0) n \ _ '/ nzcoca3 01 "" N coznl C53 wherein COZR1 is a free, salt-bound 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 discloses isolation of the compound SCH2CH2NHCOCH3 and coon of Streptomyces.

A Carbapenems which are unsubstituted in the 6-position have also been synthesized. Thus, U.S. Patent 4,210,661 discloses compounds of the formula wherein R 2 is phenyl or unsubstituted phenyl, U.S. Patent 4,267,177 discloses compounds of the formula S-31 cam wherein R 1 is an optionally substituted pyridyl group, U.S. Patent 4,255,441 discloses compounds of the formula -CR 2 = CR 3 R 4; f "_n cmm wherein R 2 and R 3 are hydrogen or alkyl and R 4 is NH-CO phenyl and n are 1 or 2, and U.S. Patent 4,282,236 discloses compounds of the formula = CR 1 R 2 45 461 734 wherein R 1 is hydrogen or alkyl and R 2 is CN or CO 2 R 3, where R 3 is hydrogen, alkyl, aryl or aralkyl.

Carbapenems of the general formula a alma- p 'x * - N O' coon wherein R 1 is hydrogen or acyl and R 8 is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl. heredity, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heterocyclyl or heteronyclylalkyl, are disclosed in U.S. Patent 4,218,463. alkylene group A at a ring carbon atom.

The natural product thienamycin has the absolute configuration 5R, 65, 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 .LO 461,734 on ÉUCK N-cozpns 0 wherein p NB is p-nitrobenzyl.

Due to the exceptional biological activity of thienamycin, a large number of derivatives have been prepared and disclosed in the literature. These include (1) N-formimidoyl-thienamycin of the formula OH '= - "' H sczzxxn or 2 t EN coon disclosed in European Patent Application 6639; (2) N-heterocycle derivatives of thienamycin of the formula ß 2 os (23 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, disclosed in U.S. Patent 4,189,493; (3) substituted N-methylene derivatives of thienamycin of the formula OH 0 coon wherein x and Y are hydrogen, R, oR, sn or NR 1 R 2, wherein R is 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 OR3 //, L \\ w scH2cH2NR1R2 04 "Nm wherein R3 is aryl, alkyl, acyl or aralkyl and R1 and R2 are independently hydrogen or acyl (including acyl of the type 3 11 I 11 -C-R, where R is a quaternary ammonium group, for example, 9 / x is inter alia alkyl substituted with a 461,754 disclosed in U.S. Patent 4,226,870; (5) compounds of formula _113 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 type 3 -CR, wherein Rv is alkyl substituted with a quaternary ammonium group, for example o (_ ELGfQNd / u \> is disclosed in British Patent 1,604,276 (see also U.S. Patent 4,235,917); (6) compounds of the formula OH C) 5 6 7 SCHZCHZNR RRN coo 9 O _ wherein RS, R6 and R 7 are independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, of veils in U.S. Patent 4,235,920; (7) compounds of formula Wherein R 1 and R 2 are independently a group of the type defined for R, a hydrogen atom or nitro, hydroxyl, C 1-6 alkoxyl, amino, C 1-6 alkylamino, di (C 1-6 -alkyl) -amino or tri (C 1-6 alkyl) -amino, wherein an additional anion is present in the latter case, or R 1 and R 2 together with the nitrogen atom to which they are attached form 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, consisting of oxygen, sulfur or hydrogen; R is a cyano group or substituted or unsubstituted carbamoyl, carboxyl, (C 1-10 alkoxy) carbonyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 4-12 cycloalkylalkyl, C 5-10 alkeno-cycloalkyl, C 3-10 alkenyl C5-12 cycloalkenylalkenyl, C4-12 cycloalkenylalkyl, C6-10 aryl, C7-16 aralkyl, C8-16 aralkenyl, C8-16 aralkynyl or monocyclic or bicyclic heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, consisting of oxygen, sulfur or nitrogen and wherein the alkyl group in the heteroalkyl or heterocyclylalkyl group contains 1-6 carbon atoms; wherein the substituent or substituents on R 1, R 1, R 2 or on the ring formed by R 1 and R 2 are 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 is a hydrogen atom, an acyl group or a group of the type defined for R; R is C 1-10 alkyl; substituted carbonyl methyl; C 1-6 alkoxy) - (C 1-6 alkyl), (C 3-6 cycloalkoxy) - (C 1-6 alkyl); C 2-12 alkanoylcalkylkyl; partially or completely halogenated C 1-6 alkyl, where the halogen or halogens are chlorine, bromine or fluorine: aminoalkyl; C 2-10 alkenyl; C 20-10 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 4-10 ring atoms, 1-3 carbon atoms in the alkyl group and 1-4 heteroatoms, which are oxygen, sulfur and / or nitrogen; substituted aralkyl or heteroaralkyl, wherein the substituent is chlorine, fluorine, bromine iodine or C 1-6 alkyl; aryl or aryl-substituted aryl containing 6-10 ring carbon atoms and wherein a substituent optionally present in the core is hydroxy, C 1-6 alkyl, chlorine, fluorine or bromine; aralkoxyalkyl; C 2-12 alkylthioalkyl; C 4-12 cycloalkylthioalkyl; (C 2-10 acylthio) - (C 1-6 alkyl); èllersphenylalkenyl, where alkenyl contains 2-6 carbon atoms; R is substituted or unsubstituted C 1-10 alkyl; C 2-10 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; C 6-10 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 are acid, nitrogen 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 present in the latter case, hydroxy, C 1-6 alkoxy , C 1-6 alkyl) amino, wherein an additional anion is alkylthioalkyl; carboxyl; oxo, (C 1-6 alkoxy) carbonyl; C20-10 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, -OR4, SR4, -NHR4, -N-R4, \ 4R -OM, -OQ or, when the compound is in zwitterionic form, -0_, in which case A- is not present; A, when the compound is not in zwitterionic form, is a counterion; M is a pharmaceutically acceptable cation; and Q is a blocking group of the type indicated, disclosed in British Patent 1,604,275; and (8) compounds of the formula scazcazna- 'N I wherein C)? Q) attached 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, -NR 2, -NR 2 OR or CN, disclosed in European Patent Application 21082. Among the compounds disclosed in U.S. Patent 4,235,920 may be mentioned H CH CB 2CH2N (CH3) 3] A COOH 0. wherein A is a pharmaceutically acceptable anion. The above-mentioned quaternary amine derivatives are also disclosed in Recent Advances in the Chemistry of ß-Lactam Antibiotics, Royal Society 12 461 734 of Chemistry, London, 1981, pages 240-254, where its antibacterial activity is stated to be on average about 1/2 to 2 / 3 of the activity of thienamycin.

Carbapenem derivatives with many different 6-substituents in addition to those mentioned above have also been synthesized. For example, (1) European Patent Application 40408 discloses compounds of the formula Ii II - CH3-ca \ san 04 * N coon wherein R1 is hydrogen, methyl or hydroxyl and R51 is a monovalent organic group which includes heterocyclomethyl ; (2) European Patent Application 8514 discloses compounds of formula n 2 sR 0 OOH wherein R 1 is an optionally substituted pyrimidinyl group and R 2 is hydrogen or a group CR 3 R 4 R 5, wherein R 3 is hydrogen or hydroxy, R 4 is hydrogen or alkyl and R 5 is hydrogen, alkyl, benzyl or phenyl or R 5 and R 4 together form a carbocyclic ring; (3) European Patent Application 38869 discloses compounds of the formula R 7 - N I I - ODH 2 9. wherein R 6, R 7 and R 8 are independently hydrogen, substituted or unsubstituted alkyl, alkenyl or alkynyl having 1-10 carbon atoms; cycloalkyl, cycloalkyalkyl 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 with respect to said groups are -XO halo (chlorine, bromine, fluorine) -OH hydroxy -oR1 alkoxy, aryloxy O '1 2 _ -OCNR R carbamoylox1 H -CNR1R2 carbamoyl -NR1R2 amino NR1 / amidino NR1R2 R1 -NO2enitro G) -N (R1) 3 tri-substituted amino (R1- group independently selected) a1 -è = NOR2 oximino -SR1 alk- and arylthio -SOZNR R sulfonamido O -NHëNR1R2 ureido OH R1CNR2-amido -có - CO H carboxy 2 1 R carboxylate 2 O - gR1 acyl 61 14 7 4 LN \ -OCR1 acyloxy -SH mercapto -ER1 alkyl- and aryl-sulfinyl 0 -% R1 alkyl and aryl-sulfonyl O -CN cyano -N3 azido where R1 and R 2 are independently hydrogen, alkyl, alkenyl or alkynyl having 1 to 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 atoms are 1-4 oxygen, hydrogen or sulfur atoms and wherein the alkyl groups contain 1-6 carbon atoms. (See also European Patent Applications 1627, 1628, 10317, 17992, 37080, 37081 and 37082). Patent application 24832 discloses the compound of formula (4) wherein R 1 is hydrogen or a group consisting of OH, OSO3H or a salt or C1-4 alkyl ester thereof, OR2, SR3, ocoxz, oco2R3 or ocoNHR3, where R2 is a C1-6 alkyl group or an optionally substituted benzyl group and R is a C1-6 alkyl group or an optionally substituted benzyl- is C 1-6 alkyl, C 2-6 alkenyl, C 3-6 alkynyl, where the triple bond is not present on the carbon or phenyl group and R 12 atom which is the adjacent sulfur atom, aralkyl, C 1-6 alkanoyl, 461,754 aralkanoyl, aryloxyalkanoyl or arylcarbonyl, the groups may be substituted, as antibacterial agents.

European Patent Application 44 170 discloses carbapenem derivatives of the formula (o) 3 1 HN = NR 2 -X - N / I \ h IY 0/1 N CO 23 R 4 wherein R 3 is hydrogen or an organic group attached to the carbapenem ring via a carbon atom, n is 0 or 1, X is a saturated or unsaturated hydrocarbon group optionally substituted with bromine or chlorine, and R 4 is C 1; C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 10 is optionally substituted. However, there is no -aralkyl or aryl, where R is even- revealing any compounds where the tetrazole ring is attached to X via a quaternized nitrogen atom, i.e. a positively charged nitrogen atom, which is not attached to a hydrogen atom.

The aforementioned European Patent Application 38 869 discloses the synthesis of the carbapenem derivatives via the intermediate of the general formula R7 'R6 O N 2' o 02k wherein R6 and R7 have the meanings given above and R2 'is an easily removable carboxyl protecting group. It also discloses as intermediates compounds of formula 16 461 734 where X is described as a leaving group.

At the Gordon Research Conference on Medicinal Chemistry, held in New London, New Hampshire on August 2-6, 1982, a stencil was distributed, revealing a variety of carbapenem antibiotics. Among the compounds disclosed on page 9 of said stencil are the carbapenems of formula o H I; A cozzi which differs from the compounds of the present invention in that the quaternized heteroaromatic ring in the 2-substituent is bonded directly to the sulfur atom instead of to the sulfur atom. the carbon atom of an alkylene group.

European patent application S0 334 discloses carbapenem derivatives of the general formula R7. wherein R 6 and R 7 are, inter alia, independently, hydrogen, alkyl, alkenyl, aryl or aralkyl; A is a direct single bond which binds together the indicated S and C atoms, or is a cyclic or acyclic linking group which includes alkyl, cycloalkyl, aryl, heteroaryl or heteroalkyl; R 1 and R 2, which define the carbamimidoyl function, are, inter alia, independently hydrogen, alkyl or aryl; in addition, said carbamimidoyl is characterized by cyclic structures which are obtained by bonding the two nitrogen atoms through their substituents and by bonding to the bonding group A: in addition, "carbamimidiums" are revealed by quaternization of one of the nitrogen atoms in said carbamimidoyl. said application is disclosed as a possible 2-substituent group 17 461 754 anal II ° -SAc '; 1.

N1 "wherein R 1 is hydrogen, substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl and the two nitrogen atoms" are included in cyclic structures indicated by the dashed lines ". Some specific disclosures reveal carbamimidoyl groups containing a quaternized nitrogen atom do not exist on page 22 discloses a cyclized carbamimidoyl group of the formula In view of the stated definitions of the substituent R1, European patent application 50 334 cannot be considered generically disclosing any of the compounds of the present invention. The European patent application is so vague as to the nature of the cyclical structures, we have considered it appropriate to refer to this application.

While the known literature describes carbapenem derivatives having a 2-substituent of the general formula -SA-Het wherein A is an alkylene group and Het is a heteroaromatic group: as far as we know, no carbapenems are disclosed where Het is a group of the formula in which R 5 has the meaning given in claim 1 and is a certain defined quaternized nitrogen-containing aromatic heterocycle attached to the alkylene carbon atom via a ring carbon atom.

As mentioned above, carbapenems in C113 have 3A / CH: as 2-substituent substituents as well as a carbapenem with a quaternized heteroaromatic ring attached directly to the 2-sulfur substituent.

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 of the formula 461 734 wherein - R 1 is hydrogen, alkyl or hydroxyl substituted alkyl having 1-10 carbon atoms; R 2 is hydrogen, an anionic charge or a conventional, easily removable carboxyl protecting group, provided that when R 2 is hydrogen or a protecting group, a counter anion is also present; E15 is alkyl of 1-10 carbon atoms; A is straight or branched C 1 -C 5 alkylene; and O is a group of formula (a) ns wherein R 5 is C 1 -C 6 alkyl and R 6 is hydrogen or C 1 -C 6 alkyl; (b) wherein R 5 is C 1 -C 6 alkyl and R 6 and 87 are hydrogen or c 1 -C 6 -alkyl; 461 734 zo (G) R \ B N -RS ./ í-n. 2: 1 wherein R 5 is C 1 -C 6 -alkyl and R 1f is C 1 -C 6 -alkyl or phenyl- (c, -c-; 1xy1): '~ (å)'. _ / \ N_ - 5. w = t¿š_k% __ 15 s- ¶ _ .. 6 \\ vari ns az c1-c¿-alkyl Och a (Ö) 5 zu “Q är 01-C¿-alkyl; R wherein R 5 is C 1 -C 6 alkyl and R is C 1 -C 6 alkylz (f). - | f - I I S \ s) R wherein R 5 is C 1 -C 4 alkyl; or (9) _____N_n .11 _ Rsf wherein R5 is C1-C1-4alkyl and R is C1-C1-4alkyl; and pharmaceutically acceptable salts thereof. 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-mentioned novel carbapenem derivatives.

The novel compounds of the general formula I above contain the carbapenem core N 652 ¿; __. N 3 \ ° '4 and can thus be called 1-carba-2-penem-3-carboxylic acid derivatives. Alternatively, the compounds can be considered to have the basic structure 7 N o ”1 and are called 7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylic acid derivatives. Although the present invention includes compounds wherein the relative stereochemistry of the 5,6-protons is cis as well as trans, the preferred compounds have the SR, 68 (trans) stereochemistry as is the case with thienamycin.

The compounds of formula I may be unsubstituted in the 6-position or substituted. R 1 may be hydrogen or an alkyl or hydroxyalkyl substituted group having 1-10 carbon atoms.

Zuf 461 734 22 A preferred substituent R 15 is C 1 -C 6 alkyl, especially methyl. The substituent R 15 may be in either the α or β configuration and the present invention includes both the individual α and β isomers and mixtures thereof. The most preferred 1-substituted compounds are those having the B-configuration, especially those having the B-methyl substituent.

Regarding the definitions for R 1 and R 1 the alkyl group may be straight or branched chain with 1-10 carbon atoms, preferably 1-6 and in particular 1-4 carbon atoms.

The term "conventional readily removable carboxyl protecting group" refers to known ester groups which have been used to entrap a carboxyl group during the chemical reaction steps described above and which can be readily removed, if desired, by methods which do not result in any significant degradation of the other part 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, allyl, benzyl, trichlorethyl, silyl such as trimethylsilyl, phenazyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl, 4-pyridylmethyl and C 1 -C 6 -alkyl such as methyl, ethyl or t-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. c is to be obtained by catalytic hydrogenation. The pharmaceutically acceptable salts referred to above 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, citric acid; succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid and malic acid. The compounds of formula I in the form of the acid addition salts may be written in the following manner 46 "! 754 23 R2 IH or protecting group where X is the acid anion. The moiety X <:) may be selected so as to obtain pharmaceutically acceptable salts for therapeutic administration but may, when the intermediate of formula I may also be a toxic anion, in which case the ion may subsequently be removed or replaced with a pharmaceutically acceptable anion for the preparation of an active end product for therapeutic use.

Compounds of formula I and pharmaceutically acceptable salts thereof are useful as antibacterial agents.

A preferred embodiment of the present invention relates to compounds of formula I, wherein R 1 is hydrogen, CH 3 CH 2 -C33 CH 3 ° | H QR ::: FH 2, \ -C- or CH 3 CH- -Q33 VLCHS In this subclass, preferred compounds are such wherein R 1 is R 1 H 3 CH 3 CH-, the most preferred compounds having the absolute configuration SR, 65, 8R.

The alkylene group (i.e. substituent A) in the compounds of formula I may be straight or branched chain and may contain 1-6 carbon atoms. A preferred embodiment comprises those compounds wherein A is - (CH 2) n -, where n is 1 or 2, and a particularly preferred embodiment relates to such compounds wherein A is -CH 2 -. The alkylene group A is bonded via a ring carbon atom to an N-substituted quaternized aromatic heterocycle having the general formula 6 __ R 5 wherein the R 5 substituent has the meanings given above and in claim 1.

A particularly preferred embodiment of the present invention relates to compounds of formula I, wherein the group. e .é fn-RS is a group of the formula (a) f \ ° (b) N-cH3 i / \ _Næ \ cH3 Cfse / \ C / \ N - crx ca ca << => (d) _ zzs cn maa. '93 \ N CH. \ 3 / \ w HN (g) (h) / »C53 (i) - NQ: CH3 \ (k) <1) ß” N / _ - NN H3 c 3 1: 3 H 3 3 f * N Ne ( m) / \ æ (n) / WS -C33 or N cns In the preferred embodiment described above, preferred compounds are those wherein A is - (CH 2) n -, where n is 1 or 2, in particular those wherein A are -CH 2 - and wherein R 1 is Hydrogen, CH 3 CH 2, f, OH Particularly preferred are those compounds wherein R 1 is CH 3 - H-, especially compounds having the absolute configuration 5R, 6S, 8R. .

Specific preferred compounds of the present invention are those of formula 461 734 26 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, there is also a counterion present. and wherein the group is (a) -scnz / \ Níc fi / \ _ '2 3 W) -scaz / \ (d) __ N \ CH3 CH \ k3 G / \ - \ (e) -5C32C32 ___ (E) -SCH2 / I 0 u ZCHZCHB ca 39 N (9) -scn / \ 2 CH3 ca e '3 NI lá \ l / I “f cn 1% - 3 gi 1s H CH g12 (m) -sçyïš 7 Q / N CH3 CH () i 3 0 -sc fi \ h 2 _ V \ // 6 N - CH3 vari 1 27 461 734 (n) -scn \\ (P) _ScHí _ <; f \\ Ne 'NET§åk * cH3 HNMR ( Dzm spectrum .Shows characteristic peaks 6: d; J = 6y4. 112); AqL-J-: jygy 8,9 q '8); The HNMR (D 2 O) spectrum shows characteristic peaks at 6: 1.23 (3H, d, J = 6.4 Hz), 3, (2H, q, J = 3.7, 9.9 Hz), 3.37 (1H, q, J = 2.6, 6.0 Hz), 3.95 ~ 4.65 (10H, m) , 8.62 (1 H, s); (r) (V) / CH3 _ ef 'C33 cooe ÖÄ (s) '62 -scnz \ Qëw KL-cH3 (u) CH 3 åe 7 N ___ š or / ca A particularly preferred embodiment of the present invention relates to the compounds: In formula 1, wherein the group 461 734 29 is the group In the preferred embodiment described above, preferred compounds are those wherein A is - (CH 2) n -, where n is 1 or 2, in particular, those wherein A is -CH2- and wherein R1 is hydrogen, CH3CH-, 2 C53-, caa ox OH-. r I '\ cn-, \ clz- or CHBCH-.

C213 / C213 X - Particularly preferred are those compounds wherein R1 is? H CHBCH-, especially compounds with the absolute configuration SR, 66, BR.

The carbapenem derivatives of the general formula I are prepared from starting materials of the formula nä: wherein R 1 and R 15 have the meanings given above, R 8 is hydrogen and wherein R 2 'is a conventional, easily removable carboxyl protecting group. For example, compounds of formula III have been disclosed in European Patent Application 38,869 (Compound 7) and in European Patent Application 54,917 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: RB 1: 1 Rls 21-- š, _N 2. of 'cooR III RB f! RI É L HS-fA NI i-ä O / 7_N conz 'TL = conventional outgoing Group n -x' xe 9 5 N-'R eventual unblocking 5 ïu 31 461 734 --R A variant of the procedure described above is given in the following reaction scheme: ns-A avblockerin R -x 'å IIa 1U Js 461 754 32 Ia This process can be described in more detail as follows. The starting material III is reacted in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with approximately an equimolar amount of an agent R 1 -L such as p-toluenesulfonic anhydride, p-nitrobenzenesulfonic anhydride, 2,4,6-triisopropylbenzene sulfonic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, diphenyl chlorophosphate, toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride or the like, wherein L is the corresponding leaving group such as toluenesulfonyloxy, p-nitrobenzenephenyloxyphenyloxy, for the person skilled in the art. The reaction leading to the leaving group in the 2-position of intermediate III is advantageously carried out in the presence of a base such as diisocropylethylamine, triethylamine, 4-dimethylaminopyridine or the like, at a temperature of from -20 ° to + 40 ° C, especially at about 0 ° C. The leaving group L in intermediate IV may also be halogen, in which case said group is introduced by reacting intermediate III with a halogenating agent such as ø3PCl2, ø3PBr2, (øO) 3PBr2, oxalyl chloride or the like in a solvent such as CH2Cl2 , CH 3 CN, THF or the like, in the presence of a monobasic such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine or the like. 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 II: 2: 461 754 by means of a conventional displacement reaction. Thus, intermediate IV can be reacted with approximately an equimolar amount of a heteroaralkyl mercaptan reagent of formula HS-A wherein A is straight or branched chain C 1 -C 6 alkylene and the group N is a monocyclic aromatic heterocyclic group containing a quaternizable nitrogen atom in the ring , said ring being bonded to A via a ring carbon atom, 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-dimethylaminopyramid. The temperature of the displacement reaction is not critical but an advantageous temperature is from -40 ° C to ° C. The reaction is conveniently carried out under cooling, for example at about -3 ° C to -4 ° C.

The quaternization of the ring nitrogen atom in the heteroaralkyl group of intermediate II is carried out by reacting intermediate II in an inert organic solvent having at least one equivalent (up to about a 50% molar excess) of an alkylating agent of the formula nas-x 'wherein R and X 'is a conventional leaving group such as halo (chlorine, bromine or iodine, especially iodine) or a sulfonate ester group such as mesylate, tosylate or triflate. Examples of suitable non-reactive organic solvents are chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethyl sulfoxide and dimethylformamide. The temperature of the alkylation reaction is not critical and temperatures in the range of about 0 ° C to 40 ° C are preferred. The reaction step is advantageously carried out at room temperature. Intermediate I 'has an associated counterion X' (derived, for example, from the alkylating agent used), which at this stage or at a later stage, for example after the deblocking step, can be replaced by another counterion. for example one that is more pharmaceutically acceptable, by conventional methods. Alternatively, the motion can then be removed during the unblocking step.

The deblocking step to remove the carbonyl protecting group R2 'in intermediate I' is performed by conventional methods such as solvolysis, chemical reduction or hydrogenation. When a protecting group such as p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl is used, which can be removed by catalytic hydrogenation, the intermediate I 'can be treated in a suitable solvent such as dioxane-water-ethanol, tetrahydrofuran-dipotassium hydrogen phosphate aqueous solution - 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 0-50 ° C for 0.24-4 hours.

When R2 'is a group such 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. The allyl protecting group can be removed with a catalyst comprising a mixture of a palladium compound and triphenylphosphine in an aprotic solvent such as tetrahydrofuran, diethyl ether or methylene chloride. Likewise, other conventional carboxyl protecting groups can be removed by methods known to those skilled in the art. Finally, as mentioned above, compounds of formula If, wherein R 9 'is a physiologically hydrolysable ester, such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc., can be administered directly to the host animal without deprotection. since such esters 461,734 esters are hydrolyzed in vivo under physiological conditions.

It will be appreciated that when the substituent R 1, R 5 or R 15 or the heteroaromatic ring attached to the substituent A contains a functional group which may interfere with the intended course of the reaction, such a group must be protected by a conventional blocking group and then unblocked to give the desired functional group. Suitable blocking groups and methods for introducing and removing such groups are well known to those skilled in the art.

In a variant of the above procedure, the carboxyl protecting group in intermediate II can be removed before the quaternization step. Thus, the carboxyl protecting group is removed as described above to obtain the corresponding free carboxylic acid and the free acid is then quaternized with the alkylating agent RS-X 'to obtain the desired quaternized product of formula I. When the unblocked intermediate IIa is quaternized the solvent is water or a non-reactive organic solvent or a mixture thereof. Examples of suitable solvents include water, organic solvents such as chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethyl sulfoxide and dimethylformamide, and mixtures of water-organic solvents such as water-acetone or water-dimethylformamide. The temperature for the quaternization of intermediate IIa is not critical and temperatures from about -40 ° C to about room temperature can be used to advantage. The reaction is carried out in particular around 0 ° C. When an unprotected intermediate IIa is obtained as a carboxylate salt, it is desirable to add a strong acid such as ppluenesulfonic acid to generate the free carboxylic acid before the quaternization. This has been found to considerably facilitate the selective quaternization of the ring nitrogen atom.

The process variant described above is particularly useful when the carboxyl protecting group is more easily removed from the non-quaternized intermediate II than from the quaternized intermediate I '. Thus, for example, in the preparation of the product of the formula in fm: ~ on H \ 9 (R) 'J%: SCH2' / \ É / - ¿o / cooe, the removal of the allyl protecting group before quaternization results in significantly improved yields of the desired end product. Although the process described above is suitable for the preparation of the compounds of the present invention, it is also possible to use a novel process for the preparation of compounds of formula I. This alternative process is described in more detail below and in the working examples.

In the alternative process for the preparation of compounds of formula I, an intermediate of the formula wherein R 1, R 8 and R 15 have the meanings given above, R 2 'is a conventional, easy-to-remove base carboxyl protecting group 37 in 461 754 and L is a conventional leaving group such as toluene sulfonyloxy, p-nitrobenzenesulfonyloxy, diphenoxyphosphinyloxy or halo, with a thiol compound of formula IE) v11: Hs-A 'R X6 wherein A and <9 have the meanings given above and X (3 is a counter anion, in an inert solvent and in the presence of a base for the preparation of a carbapenem product of formula II I wherein R 1, R 8, R 2, A, R 15, if c) have the meanings given above, after which, if desired, I and X are removed, the carboxyl protecting group R 2 is removed to obtain the corresponding unblocked compound of formula I, or a pharmaceutically acceptable salt thereof.

The alternative process utilizes the intermediate of the formula TU '61 734 38 OOR2 'which, as mentioned above, has been disclosed, for example, in European patent applications 38 869 and 54 917 and which can be prepared by the general methods described therein.

L is a conventional leaving group (defined as "X" in European Patent Application 38 869) such as chlorine, bromine, iodine, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxyphenoxyphyloxy, triphenoxy - oxi. The preferred leaving group is diphenoxyphosphinyloxy.

The intermediates of formula IV are generally prepared in situ by reacting an intermediate of formula III wherein R1, R8, E15 and R2 'have the meanings given above, with a suitable acylating agent RO-L. The preferred intermediate product, wherein L is diphenoalphosphinyloxy, can be prepared by reacting the ketoester III 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, 4-dimethylamino- or pyridine or the like at temperatures from about -20 ° C to + 40 ° C , in particular around OOC. Intermediate IV can be isolated, if desired, but is suitably used as a starting material for the alternative process without isolation or purification.

The carbapenem intermediate IV is reacted with a quaternary amine thiol compound of the formula šß 5 ns-A -R wherein the G) ion is carried out in an inert solvent such as acetonitrile, has the meaning given above and X is a counter anion. React acetonitrile-dimethylformamide, tetrahydrofuran, tetrahydrofuran water, acetonitrile water or acetone in the presence of a base. The nature of the base is not critical. Suitable bases include sodium hydroxide, diisopropylethylamine, 1,8-diazabicyclo (5.4.0) undec-7-ene, 1,5-diazabicyclo (4.3.0) non-5-ene and tri (C 1 -C 4 alkyl) amines such as such as triethylamine, tributylamine or tripropylamine. The reaction of the intermediate IV and the thiol VII can be carried out in a wide temperature range, for example from -15 ° C up to room temperature, but is preferably carried out at a temperature in the range from about -15 ° C to f15 ° C, in particular around 0 ° C.

The carbapenem product produced by reacting the quaternary amine thiol VII with the intermediate IV PO G; 2 2 'has an associated counterion (e.g. vds (CGHSO) or the counterion associated with the CICD thiol) near the block, which at this stage can be replaced by another counterion, for example one which is more pharmaceutically acceptable, by conventional procedures. Alternatively, the motion can be removed during the subsequent unblocking step. 461 754 40 When the quaternized carbapenem compound and counterion form an insoluble product, the product may crystallize out as it is formed_and simply recovered by filtration.

After formation of the desired carbapenem product, the carboxyl protecting group R2 'in compound I' may optionally be removed by conventional methods such as solvolysis, chemical reduction or hydrogenation. When a protecting group such as p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl is used, which can be removed by catalytic hydrogenation, the intermediate I 'can be treated in a suitable solvent such as dioxane-water-ethanol, tetrahydrofuran. diethyl ether buffer, tetrahydrofuran-dipotassium-hydrogen phosphate aqueous solution-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 below 0.24 -4 hours. When R2 'is a group such as o-nitrobenzyl, photolysis can also be used for deblocking. Protecting groups such as 2,2,2-trichloroethyl can be removed by mild zinc reduction. The allyl protecting group can be removed with a catalyst which comprises a mixture of a palladium in a suitable aprotic solvent such as tetrahydrofuran, diethyl ether or methylene chloride. Likewise, other conventional carboxyl protecting groups can be removed by methods known to those skilled in the art. Finally, as mentioned above, compounds of formula I 'where R?' is a physiologically hydrolyzable ester such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc., compound and triphenylphosphine are administered directly to the host animal without deblocking, since such esters are hydrolyzed in.vivo under physiological conditions.

The thiol intermediates of the formula VIII can be prepared, for example, from the corresponding: thiolacetate compounds of the formula I R - I CHBJCS-A-Ü , said ring being bonded to A via 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 X' is a conventional leaving group such as halo (chlorine, bromine or iodine, in particular iodine) or a sulfonate ester group such as mesylate, tosylate or triflate. The temperature of the alkylation reaction is not critical and temperatures in the range of about 0 ° C to 40 ° C are preferred.

Prior to the reaction with the carbapenem intermediate IV, the quaternized thiolacetate compound is subjected to acidic or basic hydrolysis to produce the quaternary thiol intermediate VII. This hydrolysis is preferably carried out immediately before the coupling with the compound IV in order to minimize the decomposition of the relatively unstable quaternary thiol.VII.

By suitable choice of solvent, the reaction of the intermediate III to the final product I can be carried out without isolating the various intermediate products, i.e. by means of a single reactor process.

As is the case with the other δ-lactam antibiotics, the compounds of general formula I can be converted by means of known methods into pharmaceutically acceptable salts, which for the purposes of the present invention are substantially equivalent to the salt-free 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, for example, solvent precipitation, lyophilization, etc. When other basic or acidic functional groups are present in the compounds of formula I, pharmaceutically acceptable base addition salts and acid addition salts can likewise be prepared by similar methods.

It will be appreciated that certain products, which fall into formula I, may exist as optical isomers as well as in the form of epimer mixtures. The present invention encompasses all such optical isomers and epimer mixtures.

For example, when the 6-substituent is hydroxyethyl, such a substituent may be in either the R or S configuration and the resulting isomers as well as the epimer mixtures thereof fall within the scope of the present invention.

A compound of formula I, wherein R is hydrogen or an anionic 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 is a conventional carboxyl protecting group, converted to the corresponding compound, where R 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, or pharmaceutically acceptable salts thereof, are potent antibiotic active agents with respect to various gram-positive and gram-negative bacteria and can therefore be used, for example, as additives in animal feed to promote growth, as preservatives in foods, as.bactericides in industrial use, for example in water-based paints and in the backwater for paper use 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 especially useful for the treatment of infectious diseases in humans and other animals, which are 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 component, comprise a pharmaceutically acceptable carrier or diluent. The compounds can be administered in a variety of ways; those of principal interest include oral, local or parenteral administration (intravenous or intramuscular injection).

The pharmaceutical compositions may be in solid form such as capsules, tablets, powders, etc. or in liquid form as solutions, suspensions or emulsions.

Compositions for injection, which are the preferred mode 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 carrier such as sterile water.

The dose administered by the vaccine depends to a large extent on the particular compound used in question, the particular preparation prepared in question, the mode of administration, the nature and condition of the host animal and the particular situation and organism being treated. The choice of the particular preferred dosage and mode of administration is therefore determined by the physician. In general, however, the compounds may be administered parenterally or orally to host mammals in an amount of S-200 mg / kg / day. The administration is usually performed in divided doses, for example three to four times a day.

The invention is further illustrated by the following working examples. '-1 Hocs * Q fi m / \ n) J \ co21> Ns / wozzt ___ 2 ______ ê WG 21> N3 ____.___ 9 0 Ls 1 3 461 754 44 Example 1 Preparation of 3- [É- (N-methylpyridinium) -metantiq7-6¿ - - (R) -HYDROXYLTHE-7-4β -methyl-7-oxo-1-azabicyclo- [§.2.§7- hept-2-ene-2-carboxylate OH C53 Å]: P3-nitrobenzyl-2-diazo-3-oxo-n-valerate (4) A solution of 50 g (0.35M) of ethyl-3-oxo-n-valerate and 54 g g (0.5M) p-nitrobenzyl alcohol in 400 ml of toluene was heated at 130-140 ° for 18 hours without reflux condenser Evaporation of the solvent gave a yellow crystalline material which was recrystallized from Et 2 O-pentane to give 75 g (86% yield). ) p-nitrobenzyl-3-oxo-n-valerate (3) with melting point 33-34 °. Ia (xsnY 1140 and 1705 according to ". mm (CDCl 3) δ 1.20 (3H, t, J = 7.0 Hz ), 2.65 (ZH, q, J = 7.0 Hz), 3:60 (2H, s), 5.28 (ZH, s), 7.45 (2H, d, J = 9.5 Hz ) and 8.18 (2H, d, J = 9.5 Hz) To a solution of 55.5 g (0.22M) of compound 3 in 500 ml of CH 3 CN was added at 0 ° C 45 g (0.44M) of TEA, followed by 50 g (022M) of β-carboxybenzenesulfonyl azide. and the mixture was stirred for 90 minutes. The precipitate was filtered off and washed with CH 3 CN and the filtrate was concentrated to a volume of about 100 ml and diluted with 800 ml of ethyl acetate. The organic solution was washed with an aqueous solution of sodium bicarbonate and brine and dried over magnesium sulfate. Evaporation of the dried solvent gave S5 g (90% yield) of compound 4 as light yellow crystals, m.p. 96-97 °. (IR (Kax)) / 2120 and 1710 cm -1. una (coc13) ¿1.20 (sa, t, J = 7.0 Hz), 2.85 (2H, q, J = 7.0 Hz), 5.40 (2H, s), 7.50 ( 2H, d, J = 8.0 Hz) and 8.15 (2H, d, J = 8.0 Hz).

O? 1 "¥ \\ V,) co PNB NZ" 2 ¿5, \, fx / B. 1-p-nitrobenzyloxycarbonyl-1-diazo-2-t-butyldimethylsilyloxy-2-butene (5) To a cooled (0O) solution of 54 g (0.2M) of compound 4 in 400 ml of CH 2 Cl 2 was added 41.4 g (0.4M) of TEA, followed by 56 g (0.21M) of t-butyldimethylsilyl chloride in 30 ml of CH The solution was stirred for 120 minutes and then washed with ice water, CH 2 Cl 2 was dried over magnesium sulphate, filtered and evaporated in vacuo to give 68 g (89% yield) of compound 5 as a yellow solid, m.p. IR (xßr) γ 2080 and 1695 cm-1. NMR of compound 5 showed that this was obtained as a P / Z mixture at the olefinic position in a ratio of 9: 1. NMR (CDCl 3; major isomer) § 0.15 (6H, s), 0.90 (9H, s), 1.58 (3H, d, J = 7.0 Hz), 5.15 (2H, s), 7.30 (zu, a , J = 9.0 az and 0.0 (zu, a, J = 9.0 Hz). 46, æm- s_1 + '\ N OAe cozma ____> / \ 3. + N o 02mm 2 6 5 7 r \ 4β--1-methyl-3-diazo-3-p-nitrobenzyloxycarbonyl-2-oxo-propyl) -3β-β] - (R) -t-butyl To a suspended solution of 12.5 g (0.1M) of anhydrous zinc chloride in 700 ml of CH 2 Cl 2 was added 60.4 g (021M) of compound 6 and stirred for 15 minutes at 23 ° and cooled. then to Oo.

A solution of 106 g (0.27M) of compound 5 in 200 ml of CH 2 Cl 2 was added dropwise to the above reaction solution over 90 minutes and then stirred for 120 minutes without cooling bath. The reaction mixture was washed with 4 x 150 ml of an aqueous solution of sodium hydrogencarbonate, water, brine and dried over magnesium sulfate. Evaporation of the dried solvent gave a dark oil which was purified by a column of silica; elution of the column with EtOAc-CH 2 Cl 2 (1: 9) gave 51.5 g (54%) of compound 7 as a white crystalline material, m.p. 112-114 °. IR (mar) y 213o, 1160 cm-1. 360 MHz NMR for compound 7 showed that this was obtained as a mixture in the 1-methyl position in a ratio of 2: 1. NMR (CDCl 3) δ 0.3-0.6 (6H, 2s), 0.82 (93, 2s), 1.05-1.15 (GH, m), 2.68 (0.66 H, q, J = 6.6 and 2.0 Hz), 2.88 (0.34, q, J = 6.6 and 2.0 Hz) 3.57 (1H, m), 3.84 (fH, * m), 4.09 (1H, m), 517 (25, two), 5.84 (0.66 H, s), 5.95 (0.34H, s), 7.52 (2H, d , J = 8.5 Hz) and 8.23 (2H, d, J = 8.5 Hz). 47 l os i * ox 1J \\ 3 R ._-_--;> / l ~ N 3 ° zmæ 02mm ° o 1 a l- “l f? D. 4E> - (1-Methyl-3-diazo-3-p-nitrobenzyloxycarbonyl-2-oxo-propyl) -304-L] - (R) -hydroxyethyl] -azetidin-2-one (8) To a solution of 30 g (59.5 mmol) of compound 7 in 400 ml of meon was added at z3 ° 150 ml of 1N HCl and stirred for 18 hours.

The reaction mixture was concentrated to a volume of about 200 ml and extracted with 3 x 200 ml of ethyl acetate. The combined ethyl acetate extracts were washed with water, aqueous sodium bicarbonate solution and brine. Evaporation of the magnesium sulfate dried solvent gave 22.3 g (96%) of compound 8 as a white crystalline material, m.p. 147 DEG-14 DEG. IR (xBr) - f 3400, 2135 and 1750 cm -1. 360 MHz NMR for compound 8 showed that this was obtained as a mixture in the 4-methyl position in a ratio of 2: 1. NMR (DMSO-d 6) δ 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 2.0 Hz), 3.55-3.90 (3H, m), 5.25 (zu, S), 7.70 (za, d, J = 9, 0 Hz), 8.05 (0.66H, s), 8.10 (0.34H, s) and 8.27 (2H, d, J = 9.0 Hz).

OH H2 gg C33 Å (from Å O CO2? NB ---- Q) N 0 0 -002PNB 3 9 734 48 E. p-nitrobenzyl-Gu - [3- (R) -hydroxyethyl] -4-methyl- 3-, 7-Dioxo-1-azabidyclo- [B.2.07heptane-2-carboxylate (9) A solution of 14.0 g (35.86 mmol) of compound 8 and 70 mg of rhodium (II) octanate was refluxed. minutes under nitrogen.

The mixture was evaporated in vacuo to give compound 9 as a foam. m (cHc13nf 3400 and 1750 cm -1). 360 Mraz NMR of compound 9 showed that this was obtained as a mixture in the 4-methyl position in a ratio of 2: 1. NOE (Nuclear Overhauser Effects) was used to determine the configuration. When H5 in the main isomer is irradiated, an approximately 7% signal increase is observed for the 4-methyl protons, which shows the cis ratio between 85 and 4-methylene. no signal increase for 4-methylene is observed, indicating the trans ratio of H5 to 4-methylene for the biisomer.

NMR (CDCl 3) for the major isomer δ 1.24 (3H, d, J = 7.35 Hz), 1.40 (3H, d, J = 6.3 Hz), 2.40 (1H, m), 3, 24 (1H, q, J = 6.6 and 7.2 Hz), 3.67 (1H, g, J = 8.0 and 2.2 Hz), 4.18 (1H, m), 4.84 (1H, s), 24 (1H, d, J = 6.3Hz), 6.18 (1H, d, J = 6.3Hz), 7.60 (1H, d, J = 8.5Hz) and 8.22 (1H, d, J = 8.5 Hz). NMR (CDCl 3) for the bisomer δ S 1.0 (3H, d, H = 7.35 Hz), 1.40 (3H, d, J = 6.3 Hz), 2.83 (1H, m) 3.25 (1H, q, J = 6.6 and 1.50 Hz), 4.14 (1H, q, J = 7.36 and 1.50 Hz), 4.67 (1H, s), 5.24 (1H, d, J = 6.3 Hz), 6.18 (1H, d, J = 6.3 Hz) and 7.60 (1H, d, J = 8.5 Hz) and 8, 22 (1H, d, J = 8.5 Hz). on cn3 on: H3% \ Ä 'lo' .______ ..; _ _ N o N, oz- (oø), EE O - ~ cozma cozrua s ° io fäß '15 v oa '% - ° 461 734 49 F. p-nitrobenzyl-3-diphenoxyphosphinyl-6g_-Lj- (R) -Hydroxyethyl7- -43-methyl-7-oxo-1-azabicyclo [2.2.1] yept-2-ene-2-carboxylate (10) To a cooled (00) of 20.0 g (55.2 mmol) of the ketom intermediate 9 in 150 ml of CH 3 CN, 7.18 g (55 mmol) of diisopropylethylamine were added, followed by 14.85 g (55 mmol) of diphenyl chlorophosphonate in 20 ml of CH 3 CN for 5 minutes. The resulting solution was stirred for 60 minutes at 0 ° C, then diluted with 600 ml of ethyl acetate and washed with ice-cold 10% phosphoric acid and brine. Evaporation of the magnesium sulfate dried solvent gave a crude oil which was purified by a silica column; elution of the column with 10% ethyl acetate in CH 2 Cl 2 gave 3.7 g (11.5%) of the phosphonate as a white foam. Ir (CHCl 3) Y 3400, 1190 fl. mm (cnc13) g 1.20 (an, a, J = 7.2 Hz), 1.38 (3H, d, H = 7.3 Hz), 3.35 (1H, 1, J = 6.7 and 2.0 Hz), 3.50 (1H, m), 4.2-4.25 (ZH, m), 5.20 (1H, d, J = 10.5 Hz), 5.37 (1H , d, J = 10.5 Hz) f>, 1-7.4 (10H, m), 7.56 (1H, d, J = 9.0 Hz) and 8.10 (1H, d, Js9, 0 Hz). NEO was used to determine the configuration of 4-methylene in compound 10. When H5 is irradiated, no signal increase for 4-methylene is observed, indicating a trans ratio of H5 to 4-methylene. us - <}: \> H, 03mm, ___-__; Ål u S ß 'o cozms. 07 "" / 1o 11 f \ J -G. P-Nitrobenzyl-3-Lyryridin-2-yl-methanetho7 * 6o ([1- (R) -hydroxyethyl] -4β-methyl-7-oxo-1- to a cooled (-15 °) solution of 1.2 g (2 mmol) of the phosphonate 461 734 50 in 10 ml of CH 3 CN was added 390 mg (azabicyclo [2.7] hept-2-ene-2-carboxylate). 3 mmol) diisopropylethylamine, followed by 370 mg (3 mmol) 2-mercaptomethylpyridine under nitrogen.

The reaction mixture was stirred for 60 minutes at -150 and then for a further 60 minutes at 00. The reaction mixture was diluted with ethyl acetate, washed with ice water and brine and dried over magnesium sulfate. Evaporation of the solvents in vacuo gave a yellow oil which was purified by a silica column; elution of the column with 20% ethyl acetate in CH 2 Cl 2 gave 375 mg (40% yield) of compound 11 as a white amorphous foam. Ia (mr) Y 3400, 1775 and 1710 on). mm (coCl 3 m 2.14 (3H, d, J = 6.7 HzH). 2.19 (3H, d, J = 6.7 Hz), 3.14 (1H, q, J = 6.2 and 2 .0 Hz), 3.40 (1H, m), 4.0 (1H, d, J = 7.6 Hz), 4.12 (1H, d, J = 7.6 Hz), 4.18 ( 1H, q, J = 6.7 and 2.0 Hz), 4.25 (1H, m), 25 (1H, d, J = 11.3 Hz), 5.40 (1H, d, J = 11.3 Hz), 7.15-8.2 (4H, m). Ia ”0 C83 H f“ Q fä;. / “Ss: PM 0 mzø Be E, 12 * - ~~ _ r \« ~ H. 3- [2- (N-methylpyridinium) methanyl] -70 (-Lj- (R) -hydroxyethyl] -46-methyl-7-oxo-1-azabicyclo 0.2. 0) nept z-en-carboxylate (12) To a solution of 1.0 g (2 mmol) of compound 11 in 10 ml of CH 2 Cl 2 was added 450 mg (3.3 mmol) of methyl trifluoromethanesulfonate and stirred for 90 minutes at 23 °. CHCl 3 in vacuo gave the quaternized pyridine as a buffer, if hydrogenated immediately without further purification, the crude pyridinium salt was dissolved in TMF-ether buffer pH 7 (1: 1: 1, 100 ml each). followed by 600 mg of 10% palladium on charcoal.

The mixture was hydrogenated under a pressure of 2.45 kg / cm 2 in a Parr shaker for 45 minutes. The mixture was filtered through a pad of Celite and the catalyst was washed with 2 x 10 ml of water. The combination of filtrate and washings was extracted with 2 x 100 ml of ether and lyophilized to give a yellow powder, which was purified on 10 g of a reverse phase column C18 BONDPAK eluting with 5% CH 3 CN in water under a pressure of 0.56 kg. / cmz high pressure liquid chromatography and fractions with an ultraviolet. Each 15-ml fraction was alkalized by light absorption at Å max 300 nm was taken up and lyophilized to give 58 mg (11% yield) of the title compound as a pale yellow powder. IR (KBr) Y 3400, 1750 and 1590 crf). λ max (H 2 O) 292 nm (ε 7081). Nm (nzo) S 1.13 13n, d, J = 6.5 sz), 1.23 (an, a, J = e, s Hz), 3.18 (1H, m), 3.45 (1H , q, J = 6.0 and 2.1 Hz), 4.0-4.4 (48, m), 4.65 (3H, s), 7.79 (2H, m), 8.30 ( 1H, m) and 8.60 (TH, m). 461 754 S 52 Example Gel 2 Preparation of 3- [N- (1-methylpyridinium methanti] 7-6OK-β- (R) -hydroxyethyl {7-4β-methyl-7-oxo-1-azabicyclo [3.2.Q7hept- 2-en-2- -carboxylate 1 »m ca;. 2) cr3so3ca3 / L n N / s" 6, o-Pwøvz -------} o '' Gå 3) PCI / Hz coze cøzmæ in r [14- [3- [Z- (1-methylpyridinium methanethyl] -6BL-L1- (R) -hydroxyethyl] -45-methyl-7-oxo-1-azabicyclo [3.2.1] hept-2-en-2 carboxylate (14) This compound was obtained as a yellow powder in 15% yield starting from compound 10 in the same manner as described in Example 1. m (xsryY 3410, 1750 and 1so cnff. uv Amax (H 2 O) 293 nm (f 7295) NMR (D 2 O) (f 1.15 (BH, d, J = 6.5 Hz), 1.20 (BH, d, J = 6.5 Hz), 3.20 (TH, m) , 3.45 (111, q, J = 6.0 and 2.0 Hz) 4.11 (1H, q, J = 8.0 and 2.0 Hz), 4.20 (1H, m) and 4 , 35 (sa, s), 7.95 (zn, d, J = s, 2 Hz) a 8.72 (2a, 'd, J = s, 2 Hz) 461 734 53 Example 3 Preparation of 3- Β- (1-methylpyridinium) methanethyl-606-f- (R) -hydroxyethyl] -4 fl) -methyl-7-oxo-1-azabicyclo [3.2.2] hept-2-en-2-carboxylate 1) ss j ”æ.

C33 2) "aæaæz O '5 u N /' Q f oP (oø) 2 o _ \ .ways e: '15' ^ / f \ / 3- [3- (1-methylpyridinium) methantiq7-6% ° ÅJ - (R) -Hydroxyethyl7- 413-methyl-oxo-1-azabicyclo [§.2.07hept-2-ene-2-carboxylate (15) This compound was obtained as a yellow powder in 27% yield starting from compound 10 on the same procedure as described in Example 1. IR (KBr) Y δ 3420, 1750 and 1610 cm -1. UV λ max (H 2 O) 295 nm (g 8750) NMR (D 2 O) δ 1.10 (an, d, J = 6.9 Hz), 1.25 (BH, d, J = 6.9 Hz), 1.27 (1H, m), 1.43 (1H, q, J = 6.2 and 1.8 Hz) , 4.1-4.35 (4H, m), 4.39 (33, s), 8.0 (1H, t, J = 8.5 and 6.2 Hz), 8.45 (1H, d , J = 8.5 Hz), 8.70 (1H, d, J = 6.2 Hz), and 8.82 (1H, s).

Analysis Ber. for C 17 H 20 N 2 O 4 25H 2 O: C 51.90 H 6.36 N 7.12 C 51.92 H 5.71 N 6.88.

Found: 461 734 54 Example 4 Preparation of 3- [3- (1,2-dimethylpyridinium) methanethyl-Sd - -13- (n) -nexaryxyl- (β -methyl-7-exe-1-azebicyl) gj en-2-carboxylate 1) HS CH 2 CE,. ' 'CH _ z) crasoacaa J, 3. 5 '8 U ... 4: 3 N / I 4) \ G; / - O-HOMZ. _ / __ o \ 3) P 11/32 C02 E) 513 C02? N. 16 '. , \ __ AJ 3- (3- (1, 2-dimethylpyridinium) methenoq7-s ° (-fi- (m-hydrexyethyl) 7-4β -methyl-7-oxo-1-azabicyclo] .2.Q7hept -2-ene-2-carboxylate (16) This compound was obtained as a yellow powder in 14% yield starting from compound 10 in the same manner as described in Example 1. IR (xBnY 3410, 1750 and 1600 emfï. Uv Zs max (1120) 296 nm (á asoo) NMR (nzo) ä 1.25 (sa, a, J = e, s Hz), 1.30 (3H, d, J = 6.5 Hz), 2, 95 (BH, s), 3.40 (1H, m), 3.50 (1H, q, J = 6.2 and 1.8 Hz), 4.2-4.4 (4H, m), 4 35 (3H, S), 7.82 (m, t, J = s, s eeh 6.3 ml, 8.40 (m, a, J = s, s Hz) and 8.72 (m, d, J = e, 3: mf 55 461 734 Example gel Preparation of L fi- (2,4-dimethyl-1,2,4-triazolium) -methanethio- - δ-ö-β- (R) -hydroxyethyl] 71 / Örmethyl-7-oxo-1-azabicyclo- L3.2.Qjhept-2-en-2-carboxylate ° f = 1) as ca CE? G9 A Máu 21 æsæsæß / J ° e? Å ¿I s): fa [H- [2,3-dimethyl-1,2,4-triazolium) methantio] -6M> - [T- (R) -hydroxyethyl] -es-methyl-7-oxo-1- azabicyclo fi.2. Q] hept-2-ene-2-carboxylate (17) This compound was obtained as a yellow powder in 9% yield starting from compound 10 in the same manner as described in Example 1. IR (KsnY 3420, 1756 and 1605 cm -1). uvP) max (H20) 291 nn) (2,7850). NMR (D 2 O) g 1.15 (3H, o, J = 6.3 Hz, 1.22 (an, d, J = 6.3 Hz) 3.35 (m, m), 3.48 (m, q, J = 6.0 eeh 1.8 Hz), 3.90 (33, s), 4.05 (3H, _s), 4.2-4.4 (4H, m) and 8.80 (1H 461 734 56 Example 56 Preparation of 3- (2- (1,3-dimethylimidazoliummethane] -6GL- -L] - (R) -hydroxyethyl] [4] -methyl-7-oxo-1-azabicyclo 3.2_07- hept-2-ene-2-carboxylate l di: "on GE« n ß / XB 03 N, / Sx: i ° / s I '' 2) cF3 $ ° 3F33 CL: e? / S o- 'š (om 2 0 CO PNB 2 a) * N52 '13 _' r ~. / 3- [2- (1,3-dimethylimidazolium methantio) -6¿ -¿T- (R) -hydroxyethyl7- -4¿ - methyl fl-oxo-1-azabicyclo [2.2.1] hept-2-ene-2-carboxylate (18) This compound was obtained as a yellow powder in 32% yield starting from compound 10 in the same manner as described in Example 1. IR ( KBR) ï '3400, 1758 and 1600 cm-1. UV, ä max (Hzo) 294 mn (e 7194) .Nm (nzmâ 1.10 (an, d, J = 6.3 az), 1.25 ( BH, d, J = 6.3 Hz), 3.30 (1H, m), 3.42 (1H, 1, J = 6.0 and 2.2 Hz), 3.85 (6H, s), 4.2-4.6 (4H, m), and 7.0 (2H, s) 461 754 57 Exgmgg] 7.

H s / "a J" c 3 SI x * w IN 'N _ I (SR, 68) -6- (IR-hydroxyethyl) -4R-methyl-3 - [(1,3-dimethyl-1,2, 3-triazolium-4-yl) -methylthio] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate HO H3 9 furnace --- * S ß 0 I COZPIB COZPIB I 461 734 58 A cold (5 ° C) solution of 4.0 mol (SR, 68) -paranitrobenzyl-6- (1R-hydroxyethyl) -3- (diphenylphosphono) -4R-methyl-7-oxo-1-azabicyclo- [3.2.0] hept-2-ene-2-carboxylate in 20 ml of CH 3 CN was treated with 735 mg (5.7 mmol) of 4-mercaptomethyl-1-methyl-1,2,3-triazole and 646 mg (5 mol; 0.87 ml) diisopropylethylamine After stirring at 5 ° C for 15 minutes and at room temperature for 1 hour, the reaction mixture was diluted with 75 ml of EtOAc, washed with cold water, dried over magnesium sulphate and evaporated, the remaining foam was chromatographed on the filter SiO 50 g) eluting with cold (s ° c) stone (zoo ml) and then cH3cn (200 ml) The fractions in question were combined and evaporated to give a foamy solid Yield: 1.1 g (58, l%). m (cuzclz) name: ssos (-ou), 1713 (ß-lextem), 11104 (eaten.

Iam: (cnc13) d '= a, 21 (za, d, am aromeciex), 1.63 (zu, a, se aromatic), 7.45 (13, s, Ar-H), 5.34 (2H, Aßq, H-benzyl), 4.40-3.80 (23, m, H-1 ', HS), 4.03 (28, Aßq, -SC82-), 4.06 (33, B , N-CH3), 3.16 (m, m, H1), 3.27 (ln, de, .15_6 = 2, s, .11, _6 = s, s Hz, ns), 1.34 (an , a, .11, _2, = s, 1, ar), 1.29 (an, a,: r1_CH3-1,1, 1-cx3). a .ß j; S (amg 3 å? Mira-f ~ f ”BM fw cozrua ga cozvns L: æzø [åt-ä A solution of 1.1 g (2.32 mmol) (SR, 65) -paranitrobenzyl-6- (1R- hydroxyethyl) -4R-methyl) -3 - [(1-methyl-1,2,3-triazol-4-yl) methylthio] -7-oxo-1-azabicyclo [3.2.0] hept-2-en-2 carboxylate in 6 ml of CH 2 Cl 2 and 5 ml of Et 2 O were treated dropwise at room temperature with 419 mg (2.55 mol; 0.29 ml) of methyl trifluoromethanesulfonate. An oil precipitated see 461 754 immediately. After stirring for 1 hour, decant the supernatant and oil triturated in Et 2 O to give a light yellow powder. Yield: 1.31 g (88.6%). 1.02 g (1.6 ml) of the quaternary compound, dissolved in 25 ml of THF, 25 ml of Et 2 O and 16 ml of phosphate buffer (1.2M; pH 7.0) were hydrogenated for 60 minutes in the presence of 10% Pd. C (1.09); pressure: 2.80 kg / cmz. Then the reaction mixture was cooled in 1 g and filtered and the filtrate was extracted with 2 x 20 ml of Bt 2 O. The aqueous solution was chromatographed on reverse phase -S10 2 (20 g) eluting with 200 ml of cold (5 ° C) water and 100 ml of 5% CH 3 CN in water. The fractions in question were combined and lyophilized. Yield: 320 mg (same). m (Nujol) 0 u: 1151 (za-laxen), 1eoo m * (carbaxylate). lm (nusoa; 8.90 (111, s, Ar-n), 4, ss-a, 1s (m, complex pattern, H-1 ', H-5, -S-CH2-), 4.27 ( SH, B, NCH 3) 2], 3.2-2, a (za, m, 11-1, 11-6), 1.14 (311, d, .11, _2, = s, 2, n- zq, 0.96 (an, d, JI_CH3 = G, 9, 1-cn3). uv Åmax px 1.4: 296 my (vaos).

Claims (1)

1. 0 15 20 25 30 35 461% 754 6 ° 1. Compounds of the formula RIS "HI n __Eä: fi 2: I 0" in 25 4 "" coon O wherein R 1 is hydrogen, alkyl or hydroxyl-substituted alkyl of 1-10 carbon atoms; R 2 is hydrogen, an anionic charge or a conventional, readily removable carboxyl protecting group, provided that when R 2 is hydrogen or a protecting group, a counter anion is also present; R 15 is alkyl of 1 to 10 carbon atoms; is straight or branched C 1 -C 5 alkylene, and f 1, is a group of the formula (a) ns E 5 85 wherein ns is c 1 -C 4 -alkyl and ne (b) R 6 is a C 1 -C 4 alkyl and R 6 is C 1 -C 6 alkyl: is hydrogen or C 1 -C 6 alkyl; 7 and R are hydrogen or 461 754 61 (c) IL var as ar c1-c¿ -alkyl and a by c, -c¿-nxyl or phenyl- (G1-C¿-alkyl) (4) | I: 1 vari as ar c1-c¿ alkyl and R 5 are C 1 -C 6 alkyl; (6) * x I š go * ER wherein R 5 is C 1 -C 6 alkyl and R is C 1 -C 6 alkyl; Wherein N 5 is C 1 -C 4 alkyl, or (9) wherein R 5 is C 1 -C 4 alkyl and a is C 1 -C 4 alkyl; aceutically fertilizable salts thereof. -n 10 15 20 25 30 35 62 2. Compounds according to claim 1, that R 1 is characterized by,? H CH 3 CH- and that the absolute configuration is SR, GS, BR. Compounds according to claim 1 or 2, wherein A is -CH 2 - or -CH 2 CH 2 -. Compounds according to claim 1, wherein k 8, wherein - R is a group of the formula (a) CO 43: (b) / _ \ e \ cH3 cese I \ ao (c) Ö U _ -cazcnzcna can (0) \ 3 '(5) .-: äs / \ _í_ \ en: ... \ s ena 10 15 20 25 30 35 461 734 63. cu 63 ": ca an, s (e) (n) ï / sk NH , 3 “ß i? (1) (i) 4:32 N 0? § \ / 2 ena e 'ena (k) Û u) / °. Ca C33' ON 3 C33 C33 m eller (n) 03 n / A / uv s / u -caa / C53 and pharmaceutically acceptable salts thereof. Compounds according to claim 1, characterized in that (b) - Tsm2 ° “2_ © ø '°” 3 10 15 20 25 30 35 64 1 1 f * 0 (e) (d) -scaz / \ 'scaz | 0: ëw fl z (f) 0 (etscxzcnz-Ö -S flfl z-G' 'cazc fl zcña (q) _SCH2 / \ lth) -scnz \\ C113 G13 ca efua »g 3 u» / \ CH -scaz fn] 'S932 y 3_ (111-3 / e. (M) (n) -SCH2 I \ z C113 * fo SCB 2 cáa' 2 (l O | PI 'I - I 3 en _ 3 -scnz-íàca 3 an: 1 till !! (Dzl fi- spectx-'umet shows characteristic peaks at G: 1,23 (33, 6, J = 6,4 Hz), 3 , 12 (28, -q, J1.4, 8.9 Hz), 3.39 (18, q, J = 2.7, 6.0 Ez), 4.07-4.68 (103), nl , i, 8.19 (13, s) 1 10 15 20 25 30 The (G) aar1 ss 461 734 HNMR (D 2 O) spectrum shows characteristic peaks 6: d 'J = 6 | 4 32)' q; Jg3g7 | Qrø Hz) | q] 119216; 610 82); 3 | 95 "4p65 m) | 8.62 (18, 8); (r) -scuz N 'e, M2 / ß -C33 CH | 3 (t) u ° -scaríïq -cn coo 2 eller 9 3 CH ( v) [Mur a. in 1%! CH and pharmaceutically acceptable salts dlray 6. Compounds according to claim 5, characterized in that R 2 is p-nitrobenzyl or an anionic charge 461 734 66 Compounds according to claim 1 , characterized in that they have the formula OH 5 (R) JII '10 wherein the substituents have the meanings given in claim 1. Compounds according to claim 7 of the formula oa C83 1s (zu / LW § 20 wherein R2 is hydrogen, an anionic charge or a conventional, readily removable carbonyl protecting group, with the proviso that, when R 2 is hydrogen or a protecting group, a counterion is also present, and pharmaceutically acceptable salts thereof Compounds according to claim 7 of the formula CH 30 ° H 2 * 3 / t fl- í scazcaz f \ (a) I n * '.O | Ä N cooaz CH; wherein R 2 has the meaning given in claim 3. Compounds according to claim 7 of the formula 461 734 \ Ae. Scazca fi / Nç fl; 3 OOR 67 vari R2 has the meaning specified in claim 3. Compounds according to claim 7 of the formula. C33 OH \ 0 R. () W, / \ 0 / wherein R2 has the meaning given in claim 8. . Compounds according to claim 7 of the formula wherein R 2 has the meaning given in claim 8. Compounds according to claim 7 of the formula - - - - - .. v "aa -... qvv-r - .n 461 734 68 wherein R 2 has the meaning given in claim 3. 144 Compounds according to claim 7 of the formula wherein R 2 has the meaning given in claim 8. Compounds according to claim 7 of the formula øa (R) or 'wherein R 2 has the meaning given in claim 3. Compounds according to claim 7 of the formula 2 wherein R has the meaning given in claim 8. Compounds according to claim 7 having the formula 461 734 69 3 wherein R 2 has the meaning given in claim 8. Compounds according to claim 7 having the formula OH S m;, 1 ,, \ IJ e, ef 'C113 wherein R 2 has the Compounds according to Claim 7 of the formula CH OH 3 CH (R) u '| 3 / \ ° f S-CH N-CHB f / ° ocaz wherein R 2 has the meaning given in claim 3. Compounds according to claim 7 having the formula 461 734 vo cs ox H 3 _ ïaz f- * Llfl: E '] I 2 \ /. E? 4h __' N ° ooaz C33 wherein R2 has the meaning given in claim 8. 21. Compounds. according to claim 7 with the formula wherein R 2 has the one specified in claim 8 na meaning. Compounds according to claim 7 having the formula wherein R has the meaning specified in claim 8. . Compounds according to claim 7 of the formula ¿1 461 754 cícoo "" (R) § @ 2 saü \ \ Ke OOR2 ÉH3 wherein R 2 has the meaning given in claim 8. Compounds according to claim 7 of the formula oz I 9.3 (R) 'I Ne' ll than: <9 N when ÉH -cooe wherein 122 has the meaning given in claim 3. Compounds according to claim 7 of the formula CH CH3 I 3 wherein R 2 has the meaning given in claim 8. 26 Compounds according to claim 7 of the formula 461 734 72 nu: NN / ena SCH2 1 / I .FN \ oo1z2: H3 wherein R2 has the meaning given in claim 8. Compounds according to claim 7 of the formula | on _ CH: | 5 C33 I (R) '2' '' was N wherein R2 has the meaning given in claim 8. Compounds according to claim 7 of formula 03 (ä) 'I 11. then wherein R 2 has the meaning given in claim 8. Compounds according to claim 7 of the formula 461 734 73 (R) wherein R 2 has the meaning given in claim 3. 30. Process for the preparation of compounds of the formula R 15 0 R; NR? 4 / "'; N 0/20 wherein R1, R2, R15 have the meanings given in claim 1 and R8 ä Hydrogen, characterized in that the compound is "(1) reactes a nilane product with the parent compound wherein R 1, R 8 and R 15 have the meanings given above and R 2 'is a conventional, readily removable carboxyl protecting group. in an inert organic solvent with a reagent capable of introducing a conventional leaving group L in the 2-position of intermediate III 2 to give an intermediate of formula 15 ag R nl 5 I-IV COORZ 'wherein R1 , R 8, R 15 and R 2 'have the meanings given above and L is a conventional leaving group; (2) reacting the intermediate IV in an inert organic solvent and in the presence of a base with a mercaptan reagent of the formula HS-A N p wherein A has the meaning given above and is a monocyclic, aromatic heterocyclic group containing a quaternizer nitrogen atom in the ring, said ring being bonded to A via a ring carbon atom, to obtain an intermediate of the formula wherein III, Ra, E15, A, few and have the above meanings: (3) reactes the intermediate II in an inner: organic solvent with an alkylating agent of the formula RS-x 'wherein RS is as defined above and X' is a conventional leaving group, so that the Rs group is quaternized with the ring nitrogen atom in the substituent N 1 the intermediate II and forms a compound of the formula I 'G wherein R 1, R a, R fi. 112., NIC: -35 and X 'have the meanings given above: and that, if desired, nptjmun X' is replaced with another ion and, if desired, the carbocyl protection group Ra 'is removed to obtain the desired deblocked compound of formula I or a pharmaceutically acceptable salt thereof. A process according to claim 30, characterized in that the quaternization step is carried out after removal of the carboxyl protecting group R2 '.