CH656130A5 - CARBAPEN EMANTIBIOTICS. - Google Patents

Description

The present invention relates to new carbapeneman tibiotics, wherein the substituent in the 2-position has the formula e

cooh

15, which is described in US Pat. No. 4,113,856, the antibiotic MM 17880 of the formula ce2cs2nhcoce3

cooh, U.S. Patent 4,162,304, describes the antibiotic 25 MM 4550A of the formula

-cs = chnhcoce.

0 '"cooh described in US Pat. No. 4,172,129 and the antibiotic 890A9 of the formula nr in which A is straight or branched CrC6-alkylene, R5 is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, he-teroaraliphatic, means heterocyclic or heterocyclic-aliphatic radical, and o

means a nitrogen-containing aromatic heterocycle which is bonded to the alkylene group A via a ring carbon atom and is quaternized by the substituent R5.

A number of β-lactam derivatives containing the carbapenem nucleus of the following formula

1

6 2

n 4

SCH2CH2NH2

cooh sh = cenhcch,

c: ooe described in U.S. Patent 4,264,735. In addition to the natural products, the compound Desacetyl 890AIO

sch2ce2ne2

cooh in U.S. Patent 4,264,734. It was produced by an enzymatic deacylation of the corresponding N-acetyl compound. Various derivatives of the naturally occurring olivic acids have also been synthesized, e.g. B. the compounds of the formula have been described in the literature. The properties of antibacterial agents and / or beta-lactamase inhibitors are attributed to these carbapenem derivatives.

The original carbapenem compounds were natural products, such as formula 60 thienamycin

so)

"C02R1

w nhcoch,

which was obtained by fermentation by Streptomyces cattleya (U.S. Patent 3,950,357). Thienamycin is an extra

wherein C02Rj is a free, salted or esterified carboxyl group, wherein n is 0 or 1 and R2 is hydrogen, acyl or a group of the formula R.303S, wherein R3 is a salt-forming ion, methyl or ethyl, described in European patent application 8885.

US Pat. No. 4,235,922 (see also European Patent Application 2058) describes the carbapenem derivative of the formula

656 130

16

• scs2ch2nh,

cooh while GB patent application 1,598,062 isolates the compound ch2ce2nhcoce3

describes cooh from a Streptomyces fermentation broth.

Carbapenem compounds that are unsubstituted in the 6-position have also been synthesized. The following compounds are disclosed in U.S. Patent 4,210,661

5 mean a quaternized nitrogen-containing non-aromatic heterocycle.

The natural product thienamycin has the absolute configuration 5R, 6S, 8R. This isomer as well as the remaining seven thienamycin isomers can be obtained by total synthesis as described in US Pat. No. 4,234,596. The total synthesis procedures for thienamycin are also described, e.g. See, for example, U.S. Patent Nos. 4,287,123, 4,269,772, 4,282,148, 4,273,709, 4,290,947 and European Patent Application 7973. A key intermediate in the synthesis procedures described is cooh wherein R2 is phenyl or substituted phenyl, which is described in U.S. Patent 4,267,177 the compound of formula

S-R,

cooh

'C02pK5

where pNB has the meaning p-nitrobenzyl.

Because of the exceptional biological activity of Thie-25 namyein, a large number of derivatives have been produced and described in the literature. Among these are (1) N-formimidoyl-thienamycin of the formula oh wherein Rj represents an optionally substituted pyridyl group, 30 U.S. Patent 4,255,441 describes compounds of the formula

CR ^ CR ^

sch-ch-n = c-nh_ 2 2 1 2

cooe

cooe

35 described in European patent application 6639; (2) N-heterocyclic derivatives of thienamycin of the formulas wherein R2 and R3 are H or alkyl and R4 is NH-COnRs where Re is alkyl, phenyl or substituted phenyl and n is 1 or 2, and U.S. Patent 4,282,236 describes Compounds of the formula ch = cr

1 * 2

#

cooh and wherein R is H or alkyl and R2 is CN or C02R3 where R3 is H, alkyl, aryl or aralkyl.

The carbapenem compounds of the general formula cooh in which R1 is H or acyl and R8 is hydrogen or a substituted or an unsubstituted radical from the following group: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl , Heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl are disclosed in U.S. Patent 4,218,463. However, they are not R8-heterocyclic alkyl substituents of the type

-MvJ

wherein the bifunctional ring may contain additional unsaturated bonds; and n represents an integer from 1 to 6; p is 0, 1 or 2; R1 is hydrogen, alkyl or aryl; and Z represents imino, oxo, H, amino or alkyl have been described in U.S. Patent 4,189,493; (3) substituted N-methylene derivatives of thienamicyn of the formula oh sce_ch, n = c-x where A is alkylene and

(

cooh

i 7

656 130

wherein X and Y are hydrogen, R, OR, SR or NR'R2 wherein R is a substituted or unsubstituted radical from the group alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl and R1 and R2 is H or R are described in U.S. Patent 4,194,047; (4) Compounds of the formula sch2ch2nr1r2

cooh wherein R3 is aryl, alkyl, acj'l or aralkyl and R1 and R2 are independently selected from H and acyl (including acyl of the type

II

-C-R11

wherein R'1 can be, inter alia, alkyl which is substituted by a quaternary ammonium group, e.g. B.

O

II

-c-ce.

described in U.S. Patent 4,226,870; (5) Compounds of the formula

SCH2C32NR1R2

cooh wherein R3 is H, acyl or a monovalent optionally substituted hydrocarbon residue; R1 is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl and R2 is acyl (including acyl of the type

O

II

-C-R

wherein R3 is alkyl substituted by a quaternary ammonium group, e.g. B.

«E> T ~ \

-c-ch., - n \

means) are described in GB Patent 1,604,276 (vergi, also US Patent 4,235,917); (6) Compounds of the formula

® ç g 7

sce2ce2nr3r r coo®

wherein Rs, R6 and R7 are independently selected from H and substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl are described in U.S. Patent 4,235,920; (7) Compounds of the formula in which R1 and R2 independently of one another are a radical of the type as defined for R, a hydrogen atom, nitro, hydroxyl, Ci ^ alkoxy, amino, C, .6 alkylamino, di (Ci.6-alkyl) - Amino or tri (Cl.s-alkyl-amino) mean, in the latter case an additional anion being present; or R1 and R2 are connected together, where together with the nitrogen atom to which they are attached they form a substituted or unsubstituted monocyclic or bicyclic heteroaryl or heterocyclyl radical with 4 to 10 ring atoms, one or more of these can additionally form a heteroatom io from the group oxygen, sulfur, or nitrogen; R is a cyano group or a substituted or unsubstituted carbamoyl, carboxyl, (CM0-alkoxy) carbonyl, Cw () alkyl, C2. | 0-alkenyl, C2.io-alkynyl, C3.10-cycloalkyl, C4. | , -Cycloalkylalkyl, C5., 2-Cydoalyl-alkenyl, C, .10-Cycloalkenyl, C5. | 2-Cycloalkenylalkenyl, Q., rCycloal-15 kenylalkyl, C6.I0-Aryl, C7_le-Aralkyl, Cs., 6- Aralkenyl, C8., 6-aralkynyl or monocyclic or bicyclic heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl radicals, having four to ten ring atoms, one or more of which can be a heteroatom selected from the group consisting of oxygen and nitrogen, and in which the Alkyl-20 group of heteroaralkyl or heterocyclylalkyl contains 1 to 6 carbon atoms; the substituent or substituents on R, R1, R2 or on the ring formed by connecting R1 and R2 are chlorine; Bromine; Iodine; Fluorine; Azido; CMAlkyl; Mercapto, Sulpho; Phos-phono, Cyanothio (—SCN); Nitro; Cyano; Amino; Hydrazino; 25 amion or hydrazino with up to three C | .6-alkyl substituents; Hydroxy; C | .6 alkoxy; Q.f.-alkylthio; Carboxyl; Oxo; (Cj.6-alkoxy) carbonyl; C2.io-Alcoxy; Carbamoyl; (CMAlkyl) carbamoyI or di (CMAlkyl) carbomoyI; R3 is a hydrogen atom, acyl or a radical as defined for R4; R4 is C |. (N-alkyl; substituted car-30 bonylmethyl; (C | .6-alkoxy) - (C, .6-alkyl), (C3.6-cycloalkoxy) - (C, .6-alkyl) ; C ,. |, AlkanoyloxyaIkyl; partially or fully halogenated C | .4-alkyl, in which the halogen (s) is / are chlorine, bromine or fluorine; aminoalkyl; C2. | 0-alkenyl; C , .i0-alkynyl; acyl; C3.14-alkoxy-carbonylalkyl; G, .2l-dialkylaminoacetoxyalkyl; C2. | 3-AlkanoyIami-35 noalkyl; Ar- (C | _3-alkyl) wherein the aryl radical is 6 to 10 C- Contains atoms; monocyclic or bicyctic heteroaralkyl or heterocyclylalkyl, containing 4 to 10 ring atoms, 1 to 3 carbon atoms in the alkyl radical, and I to 4 heteroatoms selected from oxygen, sulfur and / or nitrogen; nucleus-substituted aralkyl or 40 heteroaralkyl, in which the substituent is chlorine, fluorine , Bromine, iodine or C |. (, - is alkyl; aryl or nucleus-substituted aryl containing 6 to 10 ring carbon atoms and in which each nucleus substituent is hydroxy, C | .c, -alkyl, chlorine, fluorine or bromine; aralkoxyalkyl; C2. | 2 -Alkyl-thioalkyl; Cj. ^ - Cycloalkyl thioalkyl; (C2. | 0-acylthio) - (C, .6-alkyl); 45 or phenylalkenyl, in which alkenyl has 2 to 6 carbon atoms; R5 substituted or unsubstituted CM0 alkyl; C2. | 0-alkenyl or alkynyl; Ring substituted or unsubstituted cycloalkyl, cycloalkenyl, cycloalkenylalkyl and cycloalkylalkyl having 3 to 6 ring carbon atoms and up to 6 carbon atoms in each chain; so C, .o-aryl; Aralkyl of 6 to 10 ring carbon atoms and 1 to 6 carbon atoms in the alkyl chain; monocyclic or bycyclic heteroaryl or heteroaralkyl containing 4 to 10 ring atoms, one or more of which is oxygen, nitrogen or sulfur, and 1 to 6 carbon atoms in the alkyl chain; and the 55 ring or chain substituent (s) is / are chlorine, bromine, iodine, fluorine, azido, cyano, amino, C | .6-alkylamino, di (C, .6-alkyl) amino or tri ( C | .0-alkylamino), in the latter case an additional anion being present, hydroxy, C | .6-alkoxy, C, .6-alkylthioalkyl; Carboxy; Oxo (C | .6-alkoxy) carbonyl; C2.19 acyloxy; Carbamoyl; 60 (CM-alkyl) carbamoyl; di (CM-alkyl) carbamoyl; Is cyanothio (—SCN) or nitro; R6 is hydrogen, hydroxy, mercapto, R, —OR, —SR or NR1 R2, wherein R, R1 and R2 are as defined above;

X hydroxy, mercapto, amino, acyloxy, —OR4, —SR4, - NHR \ -N (R4) 2,

65 —OM, OQ or, if the compound is in the zwitterionic form, means —O ~, in which case A "is absent;

A, if the compound is not in the zwitterionic form, is a counter ion;

656 130

18th

M is a pharmaceutically acceptable calion and Q is a blocking group as defined herein are described in GB Patent 1,604,275, and (8) compounds of the formula

SCE2CE2NE

COO "

described, wherein R6, R7 and R3 are independently selected from hydrogen or a substituted or unsubstituted substituent from the group alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; Cycloalkyl, cycloalkylalkyl and alkylcyclo-5 alkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl radicals; Aryl, such as phenyl: aralkyl, aralkenyl and aralkynyl, in which the aryl radical is phenyl and the aliphatic part has 1 to 6 carbon atoms: heteroaryl, heteroaralksl, heterocyclyl and heterocyclylalkyl; wherein the substituent or the substituents of the above-mentioned radicals are selected from the group consisting of a mono- or polycyclic N-containing heterocyclic group which is attached to the amino nitrogen of thienamicyin; is linked and is RH or represents a substituted or unsubstituted radical from the following group: alkyl, aryl, alkenyl, heterocyclylalkenyl, aralkenyl, heterocyclylalkyl, aralkyl, - NR2, COOR, CONR ,, —OR or CN are described in European patent application 21082 . Among the compounds described in U.S. Patent 4,235,920, such are OH

e 6

SCE2CE2N (CE3) 3] A

—X ° halogen (chlorine, bromine, fluorine) —OH hydroxy —OR1 alkoxy, aryloxy

O

I!

—OCNR ^ 2 carbamoyloxy

COOH

wherein A is a pharmaceutically acceptable anion. The above quaternary ammonium derivative is also described in Recent Advances in the Chemistry of Beta-Lactam Antibiotics, Royal Society of Chemistry, London, 1981, pages 240-254, where the antibacterial activity is on average as about Vi to% of that indicated by thienamycin. ''

In addition to the carbapenem derivatives mentioned above, those compounds which have a wide range of 6-substituents have been synthesized. So'z. B. (l) j European patent application 40408 the compounds of the formula

COOH

described in which R, hydrogen, methyl or hydroxyl and R51 is a monovalent organic group, including heterocyclylmethyl; (2) in European patent application 8514 are compounds of the formula

* 2 S-R,

// O

"COOH

.SR

COOH

O

II

—CNR'R2 carbamoyl —NR'R2 amino .NR1 \ NR'R2

R1

in which R! an optionally substituted pyrimidinyl group and R2 is hydrogen or CR3R4.Rs, wherein R3 is hydrogen or hydroxy, R4 is hydrogen or alkyl and Rs, alkyl, benzyl or phenyl or Rs and R4 together form a carbocyclic ring; (3) in European Patent Application 38869 are the compounds of formula 7

Amidino

30 -N02 Nitro ©

—N (R ') 3 trisubstituted amino (the R' radicals are selected independently)

R1 -

35 l

—C = NOR2 oximino —SR 'alkyl and arylthio SOjNR'R2 sulfonamido O

40!

—NHCNR'R2 Ureido O

II

R1 CNR2-Amido «-C02H carboxy -CO2R 'carboxylate O

50

-CR1 acyl O

- OCR1 acyloxy '- SH Mercapto

55

O

II

—SR1 alkyl and arylsulfinyl O

60 II

- SR1 alkyl and arylsulfonyl

II

O

65

—CN Cyano —N, Azido wherein, based on the above-mentioned substituents of R6, R7 and Rs, the groups R1 and R2 are independently selected

19th

656 130

are selected from hydrogen, alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; Cycloalkyl, cycloalkylalkyl and alkylcycloalkyl with 3 to 6 C atoms in the cycloalkyl ring and 1 to 6 C atoms in the alkyl radical; Aryl such as phenyl; Aralkyl, aralkenyl and aralkynyl, in which the aryl radical is phenyl and the aliphatic part has 1 to 6 C atoms; Heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl and in which the heteroatom or the heteroatoms in the abovementioned heterocyclic parts are selected from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms, and in which the alkyl radicals which are bonded to said heterocyclic radicals are, have 1 to 6 carbon atoms. (See also European patents 1627, 1628, 10317, 17992, 37080, 37081, and 37082); (4) European patent application 24832 describes the compounds of the formula

At the "Gordon Research Conference on Medical Chemistry" held in New London, New Hampshire on August 2-6, 1982, a document was distributed in which a number of carbapenc antibiotics were disclosed. Among the compounds mentioned on p.9 of the above Scripture are described, the carbapenem of the formula

-K N-CH.

wherein R1 is H or a group selected from OH, 0SO3H or a salt or a C, .4-alkyl ester thereof, OR2, SR3, OCOR2, OCOjR3 or OCONHR3, wherein R2 is C, .6-alkyl or optionally substituted Is benzyl and R3 is C, .6-alkyl or optionally substituted benzyl or phenyl and R12 is C, .6-alkyl, C; -6-alkenyl, C3.6-alkynyl, in which the triple bond is not attached to the carbon attached to the Sulfur is bound, is present, is aralkyl, C | .6-alkanoyl, aralkanoyl, aryloxyalkanoyl or arylcarbonyl, where such R12 groups are optionally substituted, as antibacterial agents.

European patent application 44170 describes carbape-nem derivatives of the formula

3 ^ (° 'n

i4

in which R3 is hydrogen or an organic group which is bonded via a carbon atom to the carbapenem ring, n is 0 or I, X is a saturated or unsaturated hydrocarbon radical which is optionally substituted by bromine or chlorine, and R4 is a C ^ - Is alkyl, C2.6-alkenyl, Q.io-aralkyl or aryl group, each such group R4 being optionally substituted 45. However, no compounds are described in which the tetrazole ring on X via a quaternized nitrogen atom, i. H.,

is bound via a positive nitrogen atom which has no hydrogen atom.

European patent application 38,869 mentioned above describes the synthesis of carbapenem derivatives via intermediates of the general formula, 7

6

which differs from the compounds of the present invention in that the quaternized heterocyclic ring in the substituent in the 2-position is attached directly to the sulfur atom and not to the carbon atom of an alkylene group.

EP-A 50334 contains carbapenem derivatives of the general formula

NUMBER 1

"12 S-A-C-NR R

C005

described, wherein R6 and R7, among others, are independently selected from the group consisting of hydrogen. Alkyl, alkenyl, aryl and aralkyl; A represents a direct single bond that connects the indicated S and C atoms, or A represents a cyclic or acyclic connecting group selected from, among others, alkyl, cycloalkyl, aryl, heteroaryl or heteroaralkyl; R1 and R2, which define the carbamimidoyl function, are selected, inter alia, from the group hydrogen, alkyl and aryl; in addition, said carbamimidoyl is characterized by cyclic structures which are formed by the combination of 2 nitrogen atoms via their substituents and by their combination with the connecting group A; Further "carbamimidium" are described, in which a nitrogen atom of the carbamimidoyl group mentioned is quaternized. On p.12 of this application, a possible substituent of the 2-position of group e is 1

NO

II

-s-a-c:

'l--'

NO

in which R1 is hydrogen or a substituted or unsubstituted radical from the group alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl and the two nitrogen atoms which are "involved in cyclic structures with dotted lines". However, there is no specific disclosure describing cyclized carbamimidoyl groups containing a quaternized nitrogen atom; however, on p.22 there is described a cyclized carbamimidoyl group of the following formula wherein Rö and R7 are as defined above and R2, an easily removable carboxyl protecting group Intermediates of the formula 7 are also described

where X represents a leaving group.

Based on the definitions of the substituent R1 given, the applicant does not believe that EP-A 50334 generally encompasses one of its compounds. However, since the definition in the abovementioned application is indefinite with regard to the nature of the cyclic structures intended, this reference has been included in the present description.

As indicated above, in the prior art, carbapenemetry

656 130

20th

Derivatives described which have a substituent of the general formula in the 2-position

^ A riet have, where A alkylene and Het represent a heterocyclic or heteroaromatic group, but no carbapenem derivatives could be observed, wherein Het is a radical of the formula

0

wherein R5 is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic. aromatic, araliphatic, heteroaromatic, heteroaraliphatic, heterocyclic or heterocyclylaliphatic radical and

Q

means a quaternized nitrogen-containing aromatic heterocycle which is bonded to the alkylene carbon via a ring carbon. As mentioned above, a carbapenem which has the substituents i — c

CE-

CE3

and also a carbapenem, which has a quaternized heteroaromatic ring which is bonded directly to the sulfur substituent in the 2-position, has been described.

Regardless of the large number of carbapenem derivatives described in the literature, there is still a need for new carbapenem compounds, since the known derivatives can be improved in terms of the activity spectrum of activity, stability and / or toxic side effects.

The present invention thus provides a new series of carbapenem compounds which have the formula 15

^ COOR

have, wherein R1, R2, R5, R8, Rls, A, and o

are as defined in claim 1; and pharmaceutically acceptable salts thereof.

The compounds of formula I are effective antibacterial active substances or intermediates which can be used for the production of such active substances.

In the context of the present invention, processes for the preparation of the new carbapenem derivatives are also described.

The compounds of formula I described above contain the carbapenem core _

7

JT

-N 1

and can thus be referred to as l-carba-2-penem-3-carboxylic acid derivative. Alternatively, compounds can be defined according to the following formula and referred to as 7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylic acid derivatives. The present compound includes compounds in which the stereochemistry with respect to the io 5,6-protons is ice and also trans; however, the preferred compounds have 5R, 6S (trans) stereochemistry, as with thienamycin.

The possible substituents R8 in the 6-position of the compounds of the formula I have already been proposed for other carbapenem derivatives (cf. e.g. the definition of R6 in EP-A 38869). Alternatively, Rs and R1 together can be optionally substituted C2-C10-alkylidene, with hydroxy being suitable as a substituent.

The possible substituents R15 in the 1-position of the compounds 20 of the formula I have also already been proposed for other carbapenem derivatives (cf. for example the definition of R1 or R2 in EP-A 54 917; or the corresponding definition in US Pat. No. 4 350 631). Preferred substituents R! S other than hydrogen include C 1 -C 6 -alkyl, preferably methyl; Phenyl; and Phe-25 nyl (C1-C6) alkyl. The RIS other than hydrogen may be in either the a or β configuration, and the present invention is intended to encompass the individual a and β isomers as well as their mixtures. The most preferred 1-substituted compounds are those which have the β-configuration, especially those which have the β-methyl substituent.

To work out the definitions for R1, R8 and R15:

(a) The aliphatic groups "alkyl", "alkenyl" and "alkynyl" can be straight or branched and have 1-10 C atoms.

35 sen; preferred are 1-6, most preferably 1-4 C atoms; if part of another substituent, e.g. in cycloalkylalkyl or in heteroaralkyl or aralkenyl, the groups alkyl, alkenyl and alkynyl preferably contain 1-6, particularly preferably 1-4 carbon atoms.

(b) "Heteroaryl" comprises mono-, bi- and polycyclic aromatico see heterocyclic groups which contain 1-4 O, N or S atoms; preference is given to 5- or 6-membered heterocyclic rings such as thenyl, furyl, Thiadiazolyi, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl and pyrazolyl.

45 (c) “heterocyclyl” comprises mono-, bi- and polycyclic saturated or unsaturated non-aromatic heterocyclic groups which contain 1-4 O, N or S atoms; preference is given to 5- or 6-membered heterocyclic rings such as morpholinyl, Piperazinyl, pi-peridyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 5 ° pyrrolinyl and pyrrolidinyl.

(d) "Halogen" includes chlorine, bromine, fluorine and iodine and is preferably chlorine, fluorine or bromine.

The term "carboxy protecting group" refers to known ester groups which serve to block a carboxy group 55 during the chemical reaction steps described below and which, if desired, can be cleaved, for example, by methods which do not appreciably destroy the remaining part of the molecule 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, allyl, p-nitrobenzyl, 2-naphthylmethyl, benzyl, trichloroethyl, silyl such as Trimethylsilyl, phenazyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl, 4-pyridylmethyl 65 and QQ-alkyl, such as methyl, ethyl or t-butyl, such protective groups include those which are hydrolyzable under physiological conditions, for example pivaloyloxy -methyl, acetoxymethyl, phthalidyl, indanyl and nd methoxymethyl.

21st

656 130

A particularly advantageous carboxy protective group is p-nitrobenzyl, which can be easily removed by catalytic hydrogenolysis.

The pharmaceutically acceptable salts referred to above include the non-toxic acid addition salts, e.g. Salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid and sulfuric acid; and salts with organic acids such as maleic acid. Acetic acid. Citric acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid and malic acid. Compounds of formula 1 in the form of an acid addition salt can be written as follows

COOR

wherein R2 represents hydrogen or a protecting group and X represents an acid anion. Counteranion X® can be selected to provide a pharmaceutically acceptable salt for therapeutic administration, but in the case of intermediates of Formula I, X® can also be a toxic anion. In such a case, the ion can then be removed or replaced with a pharmaceutically acceptable anion to provide an active end product for therapeutic use. If acidic or basic groups in the R1 or R5 groups or in the

The present invention may also include basic or acidic salts of these functional groups, for example acid addition salts in the case of a basic group and metal salts (for example sodium, potassium, calcium and aluminum), ammonium salt and salts with non-toxic amines (for example trialkylamine, Procaine, dibenzylamine, 1-ephenamine, N-benzyl-ß-phenethyl-amine, N, N'-dibenzylethylenediamine etc.) in the case of an acidic group.

Compounds of formula I wherein R2 is hydrogen, an anionic charge, or a physiologically hydrolyzable ester group, together with pharmaceutically acceptable salts thereof, are useful antibacterial agents. The remaining compounds of formula I are valuable intermediates which can be converted into the above-mentioned biologically active compounds.

A preferred embodiment of the present invention comprises compounds of the formula I in which R8 is hydrogen and R1 is hydrogen, CH3CH2-, (CH3) 2CH, (CH3) 2C (OH) - or CH3CH (OH) -.

Under this subclass the preferred compounds are those in which R1 is CH3CH (OH) -, particularly preferred compounds have the absolute configuration 5R, 6S, 8R.

A further preferred embodiment comprises compounds of the formula I in which R1 and R8 taken together are an alkylidene radical of the formula and a particularly preferred embodiment comprises those compounds in which A is —CH2—.

The alkylene radical "A" is attached to a ring carbon atom of an N-substituted quaternized aromatic heterocycle of the formula

O5

wherein R3 is preferably optionally substituted C, -C6-alkyl, C, -C10-alkenyl, C2-C10-alkynyl, C3-C6-cycloalkyl, C3-C6-cyclo-alkyl (Ci-C6) alkyl, phenyl, phenyl (C1 -C6) alkyl, phenyl (C2-C6) alkenyl, phenyl (C2-C6) alkynyl, heteroaryl, heteroaralkyl, in which the alkyl radical has 1-6 C atoms, heterocyclyl or heterocyclylalkyl, in which the alkyl radical 1-6 C- Has atoms. The heteroaryl substituent R5 or the heteroaryl part of a heteroaralkyl substituent R5 can be a mono-, bi- or polycyclic aromatic heterocyclic group which has 1-4 O, N or S atoms; 5- or 6-membered heterocyclic rings, such as thienyl, fu-ryl, thiadiazolyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, 20 imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrididinyl, pyridazinyl, pyridazinyl, are preferred . The heterocyclic radical R5 or heterocyclic part of a heterocyclylalkyl radical R5 can be a mono-, bi- or polycyclic saturated or unsaturated non-aromatic heterocyclic group which has 1-4 O, N-25 or S atoms; 5- or 6-membered heterocyclic rings, such as morpholinyl, piperazinyl, piperidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, and pyrrolidinyl, are preferred.

The substituent R5 can optionally be substituted by I -3 substituents 30, which are selected independently of one another from:

(a) Q-Cfi-alkyl, optionally substituted by preferably 1-3 amino, fluorine, chlorine, carboxy, hydroxy or carbamoyl;

(b) fluorine, chlorine or bromine;

(c) -OR3;

35 (d) -OCOjR3;

(c) - OCOR3;

(f) - 0C0NR3R4;

O II

40 (g) -OS-R9;

II

O

(h) -OXO;

(i) - NR3R4;

45 (j) R3CONR4-;

(k) —NR3C02R4;

(1) - NR3CONR3R4;

O II

so (m) - NR3S -R9;

/ C

CH

form.

The alkylidene radical (ie the substituent “A”) in the compounds of the formula I can be straight or branched and can have 1-6 C atoms. A preferred embodiment comprises those compounds in which A is - (CH,) “- in which n is 1 or 2

O

(n) -SR3;

(o) -SOR9;

O

II

(p) -S-R9;

II

O

(q) —S03R3;

(r) —CO, R3;

(s) - CONR3R4;

(t) - CN. or

(u) phenyl, optionally substituted by 1-3 substituents independently selected from chlorine, bromine, C, -C6-alkyl, -OR3, -NR3R4, -S03R \ -C02R3 or -CONR3R4, wherein related to the above substituents R5 , R3 and R4 are independently selected from hydrogen, alkyl, alkenyl and alkynyl, with 1-10 C atoms; Cycloalkyl, cycloalkylalkyl and AI-

656 130

22

kylcycloalkyl with 3-6 C atoms in the cycloalkyl ring and 1-6 C atoms in the alkyl part; Phenyl; Aralkyl, aralkenyl and aralkynyl, in which the alkyl radical is phenyl and the aliphatic part has 1-6 C atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl, in which the heteroaryl and heterocyclyl group or part of a group is as defined above for R5 and the alkyl part which is combined with the heterocyclic radicals mentioned has 1-6 C atoms; or R3 and R * together with the nitrogen atom to which at least one of the two radicals is attached forms a 5- or 6-membered nitrogen-containing heterocyclic ring (as defined above for R5); and R ,; is defined as above for R3 except that it cannot be hydrogen. A particularly preferred radical Rs is Cj-Q-alkyl, especially methyl.

In addition, the substituent R5 together with another ring atom of the

The rest form a condensed heterocyclic or heteroaromatic ring which can additionally have 1 or 2 heteroatoms selected from the group O, N and S. E.g.

can or mean. The group e N-

preferably represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocycle which contains at least one ring nitrogen atom and additionally 0-5 ring heteroatoms selected from the group O, S and N, said heterocyclic ring is at A via a ring carbon atom bound and has a ring nitrogen atom which is quaternized by the group Rs.

The heteroaromatic

N-

Ring can optionally be substituted on an existing ring atom by preferably 1-5, particularly preferably 1-3, substituents which are selected independently of one another from the group C, -C4-alkyl; C1-C4-alkyl, preferably substituted by 1-3 hydroxy, amino, C, -C4-alkylamino, di (CrC4) alkyl-amino, Cj-C4-alkoxy, carboxy, halogen or sulfo; C3-C6 cycloalkyl; C3-C6-cycloalkyl (C, -C4) alkyl, optionally substituted by 1-3 substituents, as mentioned above in connection with CrC4-alkyl; CrC4 alkoxy; C, -C4 alkylthio; Amino; C, -C4 alkylamino; Di (CI-C4) alkylamino; Halogen; C, -C4 alkanoylamino; C, -C4 alkanoyloxy; Carboxy; Sulfo;

O II

—C — O— (Q — C4) alkyl; Hydroxy; Amidino; Guanidino; Phenyl; Phenyl, substituted by 1-3 substituents which are independently selected from amino, halogen, hydroxy, trifluoromethyl, C, -C4-alkyl, Cj-Ct-alkoxy, C, -C4-alkylamino, di (C! -C4) alkylamino, carboxy and sulfo; Phenyl (C! -C4) alkyl, in which the phenyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with phenyl, and the alkyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with QQ-alkyl are mentioned, is substituted; and heteroaryl or heteroaralkyl, wherein the heteroatom or heteroatoms are selected from the group consisting of 1-4 O-. S or N atoms and the alkyl part which is combined with the heteroaralkyl has 1-6 C atoms, the hetero-5-ryl and heteroaralkyl groups mentioned are optionally substituted in the heterocyclic ring by 1-3 substituents which are selected independently of one another are from hydroxy, amino, halogen, trifluoro-metlivl. C, -C4 alkyl. C ', - C4 alkoxy. C, -C4-alkylamino, di (C, -Cjalkvlamino. Carboxy and sulfo and in the alkyl part by 1-3 Subii) styluenten. which are selected from the group hydroxy, amino, C, -C4-alkylamino. Di (C, -C4) alkylamino, C, -C4 alkoxy, carboxy, halogen and sulfo. In addition, other ring stick stole atoms present (other than the quaternized nitrogen) can be substituted by 1-3 substituents which are selected independently of one another from the group C, -C4-alkyl; CrC4-alkyl, preferably substituted by 1-3 hydroxy, amino, C, -C4-alkylamino, di (C, -C4) alkyiamino, C, -C4-alkoxy, carboxy, halogen or sulfo: CrC (, - cycloalkyl; C3 -Cf] cycloalkyl (C, -C4) alkyl, optionally substituted by 1-3 of the substituents as mentioned above in connection with C, -C4-Alkvl: phenyl; phenyl, substituted by 1-3 substituents, the are independently selected from amino, halogen, hydroxy, trifluoromethyl, Cr C4-alkyl, QQ-alkoxy, C, -C4-alkylamino, di (C! -C4) alkylamino, carboxy and sulfo; phenyl (C, -C4) alkyl , in which the phenyl part is optionally substituted by 1-3 substituents as mentioned above in connection with phenyl, and the alkyl part is optionally substituted by I -3 substituents as mentioned above in connection with C 1 -C 4 -alkyl are substituted; and heteroaryl or heteroaralkyl, in which the heteroatom or the heteroatoms are selected from the group consisting of 1-4 O, S or N atoms and the alkyl part, which is purified with the heteroaralkyl, has 1-6 C atoms, the heteroaryl and heteroaralkyl groups mentioned are optionally substituted in the heterocyclic ring part by 1-3 substituents which are selected from hydroxy, 35 amino, halogen, trifluoromethyl, C, -C4 -Alkyl, C, -C4-alkoxy, Ci-C4-alkylamino, di (C | -C4) alkylamino, carboxy and sulfo and the alkyl part is substituted by 1-3 substituents which are selected from hydroxyl, amino, C, - C4-alkylamino, di (C, -C4) alkyIamino, C, -C4-alkoxy, carboxy, halogen and sulfo. The most preferred ring carbon and nitrogen substituents are CrC6 alkyl, especially methyl.

Among the preferred embodiments described above, the preferred compounds are those in which A - (CH2) is "-, in which n is 1 or 2, particularly preferred are those in which 45 A is --CH; - and in which (a) R1 and Rs together

C =

mean or (b) R8 is hydrogen and R1 is hydrogen, CH3CH2-,

CH3_ CH

3 \

OH

OH I

or CH3CH-

ch3

: CH -

55 is CH3.

The compounds in which Rs is hydrogen and R 'is CH3CH (OH) - are particularly preferred. especially connections with the absolute configuration 5R. 6S, 8R. In a preferred embodiment, group e means

65 an aromatic 5- or 6-membered N-containing heterocyclic ring which contains 0-3 additional heteroatoms selected from the group O, S or N. Such aromatic heterocycles can, if possible, be fused to a further ring, the

23

656 130

the latter includes the following groups. Saturated or unsaturated carbocyclic ring, preferably C4-C7-carbocyclic ring, aromatic carbocyclic ring, preferably phenyl, 4-7-membered heterocyclic ring (manufactured or unfinished), containing 1-3 heteroatoms from the group O, S, N or NR1 \ wherein R11 is hydrogen, C, -C6 alkyl, optionally substituted by 1-2 substituents which are independently selected from —OR3, —NR3R4, —COzR3, oxo, phenyl, fluorine, chlorine, bromine, —S03R3 and - CONR3R4, or phenyl optionally substituted by 1-3 substituents which are independently selected from C1-C6-alkyl, —OR3, —NR3R4, fluorine, chlorine, bromine, —SO3R3, —C02R3 and —CONR3R4, in which R3 and R4 in such R11 substituents are as defined above in connection with the substituent R1, or a 5-6-membered heteroaromatic ring which contains 1-3 heteroatoms selected from O, S, N or NR11, in which R11 is as defined above. The 5- or 6-membered aromatic quaternized ring or, if necessary, the carbocyclic, heterocyclic or heteroaromatic ring which is fused to it, or both such rings can optionally be substituted on existing ring atoms by, preferably up to 5, substituents for the entire ring system, substituents as mentioned above in connection with the group

1, 2 or 3 amino, halogen (chlorine, bromine, fluorine or iodine; preferably chlorine, fluorine or bromine), hydroxy, trifluoromethyl, C, -C4-alkyl or C, -C4-alkoxy; Phenyl (C, -C4) alkyl, in which the phenyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with phenyl, and the alkyl part is optionally substituted by 1-3 substituents, as mentioned above are mentioned with C, -C4-alkyl, substituted; and heteroaryl and heteroaralkyl, in which the heteroatom or the heteroatoms in the abovementioned heterocyclic radicals are selected from io the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl radical which is combined with said heteroaralkyl, 1-6 Has C atoms; or wherein 2 of R6, R7 or R10 together form a condensed, saturated, carbocyclic ring, a condensed, aromatic, carbocyclic ring, 15 a condensed non-aromatic, heterocyclic ring or a condensed heteroaromatic ring, the condensed rings mentioned being optionally represented by 1 or 2 of the substituents as defined above for R6, R7 and R10 are substituted;

(b)

o e

or

are mentioned.

Among the preferred embodiments described above, the preferred compounds are those in which A is - (CH2) n—, where n is 1 or 2, particularly preferred those in which A is - CH2— and where (a) R1 and R8 together are high ,

~ c =

ch3

or (b) R8 is hydrogen and R1 is hydrogen, ch3ch2 -, ch3_ ^ ch3v

J ^ rCH -

ch3

3 ch, -

Oh

J

X-

OH

I.

.or CHjCH-

mean.

The compounds in which R8 is hydrogen and R1 is CH3CH (OH) - are particularly preferred, in particular compounds with the absolute configuration 5R, 6S, 8R.

A further preferred embodiment of the present invention comprises compounds of the formula I in which

Jpf-t means a residue selected from the following group.

(a)

optionally substituted on a carbon atom by 1-3 substituents which are independently selected from Cr C4-alkyl; C 1 -C 4 alkyl substituted by preferably 1-3 hydr-30 oxy, C 1 -C 4 alkylamino, sulfo, di (C 1 -C 4 alkyl) amino, C 1 -C 4 alkoxy; Amino, carboxy or halogen (chlorine, bromine, fluorine or iodine; preferably chlorine, fluorine or bromine); C3-C6 cycloalkyl; Cr C4 alkoxy; CrC4 alkylthio; Amino; Q-Q alkylamino; Di (C 1 -C 4 alkyl) amino; Halogen (chlorine, bromine, fluorine or iodine; preferably chlorine, fluorine or bromine); CrC4 alkanoylamino; Cj-C4 alkanoyloxy; Carboxy; - CO - O - (C, -C4) alkyl; Hydroxy; Amidino; Guanidino; Phenyl; Phenyl substituted by 1, 2 or 3 amino, halogen (chlorine, bromine, fluorine or iodine; preferably chlorine, fluorine or bromine), hydroxy, trifluoromethyl, Q-Q-alkyl 40 or Q-Q-alkoxy; Phenyl (CrC4) alkyl, in which the phenyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with phenyl, and the alkyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with C 1 -C 4 -alkyl are mentioned, is substituted; and heteroaryl or 45 heteroaralkyl, in which the heteroatom or the heteroatoms in the abovementioned heterocyclic radicals are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl part which is combined with the said heteroaralkyl radical, 1 -6 has C atoms, or is optionally sub-50 so that it forms a fused carbocyclic, heterocyclic or heteroaromatic ring which is optionally substituted by one or two of the above-mentioned substituents;

55 (c)

wherein R6, R7 and R10 are independently selected from hydrogen; C ^ C ^ alkyl; Ci-C4-alkyl, preferably substituted by 1-3 hydroxy, Q-Cj-alkylamino, the (C1-C4-alkyl) amino, Ci-C4-alkoxy, amino, sulfo, carboxy or halogen (chlorine, bromine, fluorine or Iodine; preferably chlorine, fluorine or bromine); C3-C6 cycloalkyl; CrC4 alkoxy; Ci-C4 alkylthio; Amino; C, -C4 alkylamino; Di (Ct-C4 alkyl) amino; Halogen (chlorine, bromine, fluorine or iodine; preferably chlorine, fluorine or bromine); CrC4 alkanoylamino; C, -C4 alkanoyloxy; Carboxy; —CO — O— (CI-C4) alkyl;

Hydroxy; Amidino; Guanidino; Phenyl; Phenyl substituted by

ÏC

© I

N "

or

NO-v optionally substituted on a carbon atom by 1-3 substituents which are selected independently of one another Cj-C ^ alkyl; Q-C ^ alkyl, preferably substituted by 1-3 hydroxy,

656 130

24th

C, -C4-alkylamino, sulfo, DiCCVC ^ -AlkyOamino, C, -C4-alkoxy, amino, carboxy or halogen (chlorine, bromine, fluorine or iodine; preferably chlorine, fluorine or bromine); C3-C6 cycloalkyl; Q-C4 alkoxy; C, -C4 alkylthio; Amino; Cj-Gt alkylamino; Di (C 1 -C 4 alkyl) amino; Halogen (chlorine, bromine, fluorine or iodine; preferably chlorine, fluorine or bromine); C1-C4 alkanoylamino; C1-C4 alkanoyl oxy; Carboxy; CO — O— (Q-CJ-alkyl; hydroxy; amidino; guanidino; phenyl; phenyl, substituted by 1, 2 or amino, halogen (chlorine, bromine, fluorine or iodine; preferably chlorine, fluorine or bromine), hydroxy, Trifluoromethyl, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy; phenyl-C 1 -C 4 -alkyl, where the phenyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with phenyl, and the alkyl part is optionally substituted by 1- 3 substituents as mentioned above in connection with CrC4-alkyl is substituted, and heteroaryl and heteroaralkyl, in which the heteroatom or the heteroatoms in the abovementioned heterocyclic radicals are selected from the group consisting of 1-4 oxygen, nitrogen, or sulfur atoms and the alkyl part, which is combined with the heteroaralkyl mentioned, has 1-6 C atoms, or is optionally substituted, so that a fused carbocyclic, heterocyclic or heteroaromatic ring is formed, which may be represented by 1 or 2 of the substituents defined above is substituted;

(d)

1

,1

K

II

N

© ev no. r

or

k-

optionally substituted on a carbon atom by a substituent selected from Cl-C4-alkyl; C1-C4-alkyl, preferably substituted by 1-3 hydroxy, Cj-C ^ alkylamino, di (C, -C4-alkyl) amino, sulfo, Cj-C4-alkoxy, amino, carboxy or halogen (chlorine, bromine, fluorine or iodine; preferably chlorine, fluorine or bromine); C3-C6 cycloalkyl; C1-C4 alkoxy; C1-C4 alkylthio; Amino; C, -C4 alkylamino; Di (C1-C4 alkyl) amino; Halogen (chlorine, bromine, fluorine or iodine; preferably chlorine, fluorine or bromine); C, -C4 alkanoylamino; C1-C4 alkanoyloxy; Carboxy; —CO— O— (C1-C4) alkyl; Hydroxy; Amidino; Guanidino; Phenyl; Phenyl substituted by 1, 2 or 3 amino, halogen (chlorine,

Bromine, fluorine or iodine; preferably chlorine, fluorine or bromine), hydroxy, trifluoromethyl, C1-C4-alkyl or Cj-Q-alkoxy; PhenyltQ-C4-alkyl), in which the phenyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with phenyl, and the alkyl part is optionally substituted by 1-3 substituents, as described above in connection with C1-C4-alkyl are mentioned, is substituted; and heteroaryl or heteroaralkyl, in which the heteroatom or the heteroatoms in the abovementioned heterocyclic radicals are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl part which is combined with said heteroaralkyl, 1-6 C Has atoms;

C <3-cycloalkyl (C, -C4) alkyl, optionally substituted by 1-3 substituents as mentioned above in connection with C, -C4-alkyl; Phenyl; Phenyl substituted by 1-3 substituents which are independently selected from amino, halogen, 5 hydroxy, trifluoromethyl, CrC4-alkyl, Ct-C4-alkoxy, C, -C4-alkylamino, DifQ-GJalkylamino, carboxy and sulfo; Phenyl (Ct-C4) alkyl, in which the phenyl part is optionally substituted by 1-3 substituents as mentioned above in connection with phenyl, and the alkyl part is optionally substituted by 1-2 substituents, 10 as mentioned above in connection with C, -C4 Alkyl are mentioned, is substituted; and heteroaryl and heteroaralkyl, in which the heteroatom or the heteroatoms are selected from the group consisting of 1-4 O, S or N atoms and the alkyl part which is combined with the heteroaralkyl has 1-6 C atoms, the 15 heteroaryl and heteroaralkyl groups mentioned in the heterocyclic ring part are optionally substituted by 1-3 substituents which are selected independently of one another from hydroxy, amino, halogen, trifluoromethyl, C1-C4-alkyl, C, -C4-alkoxy, C1-C4-alkylamino , Di (C1-C4) alkylamino, carboxy and sulfo and in the alkyl part is substituted by 1-20 3 substituents which are selected from hydroxy, amino, C] -C4-alkylamino, di (Ct-C4) alkylamino, C, - C4 alkoxy, carboxy, halogen and sulfo; the heteroaromatic radicals mentioned are optionally substituted on a carbon atom by one or more substituents which, independently of one another, are selected from C 1 -C 4 -alkyl; C, -C4-alkyl, preferably substituted by 1-3 hydroxy, amino, C, -C4-alkylamino, di (C, -C4-alkyl) amino, Cj-C4-alkoxy, sulfo, carboxy or halogen (chlorine, bromine , Fluorine or iodine; preferably chlorine, fluorine or bromine); C3-C6 cycloalkyl; C, -C4 alkoxy; Q-Q alkylthio; Amino; Q-Q-alkyl-30 amino; Di (C 1 -C 4 alkyl) amino; Halogen (chlorine, bromine, fluorine or iodine; preferably chlorine, fluorine or bromine); C [-C4 alkanoylamino; Q-Q-alkanoyloxy; Carboxy; —CO — O— (C, -C4) alkyl; Hydroxy; Amidino; Guanidino; Phenyl; Phenyl substituted by 1, 2 or 3 amino, halogen (chlorine, bromine, fluorine or iodine; preferably 35 chlorine, fluorine or bromine), hydroxy, trifluoromethyl, CrC4-alkyl or Q-Q-alkoxy; Phenyl (C, -C4) alkyl, in which the phenyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with phenyl, and the alkyl part is optionally substituted by 1-3 substituents, as described above in connection with 40 with CrC4- alkyl are mentioned, substituted; and heteroaryl or heteroaralkyl, in which the heteroatom or the heteroatoms in the above-mentioned heterocyclic radicals are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl radical which is combined with said heteroaralkyl 45, 1-6 Has C atoms, or is optionally substituted such that a fused carbocyclic, heterocyclic or heteroaromatic ring, optionally substituted by 1 or 2 of the substituents defined above, is formed;

50 (f)

-F

0 5 v t -5

£> ■ C? ■ Of •

N X «!)" R

© "n ~

or

(e)

® 5 -N.-K

or

_ k — h "

J

wherein X is O, S or NR, where R is a radical from the following group: Q-Q-alkyl; C1 -C4 alkyl substituted by 1-3 hydroxy, amino, C1 -C4 alkylamino, D ^ Q-QJ alkylamino, C1 -C4 alkoxy, carboxy, halogen or sulfo; C3-Cfi cycloalkyl; C3-

wherein X represents O, S or NR, wherein R is selected from the following group Q-Q-alkyl; CrC4 alkyl substituted by 1-3 Hy-60 hydroxy. Amino, Q-C ^ alkylamino, di (C, -C4) alkylamino, C, -C4 alkoxy, carboxy, halogen or sulfo; C3-Cfi-cycloalkyl; C3-Cö-cycloalkyl (C, -C4) alkyl, optionally substituted by 1-3 substituents as mentioned above in connection with C, -C4-alkyl; Phenyl; Phenyl, substituted by 1-3 substituents which are independently selected from amino, halogen, hydroxy, difluoromethyl, CrC4-alkyl, C, -C4-alkoxy, C, -C4-alkyIamino, di (C, -C4 ) alkylamino, carboxy and sulfo; Phenyl (C, -C4) alkyl, wherein the phenyl radical is optionally substituted by 1-3 substituents, such as

25th

656 130

mentioned above in connection with phenyl, is substituted and the alkyl part is optionally substituted by 1-3 substituents as mentioned above in connection with C 1 -C 4 -alkyl; and heteroaryl and heteroaralkyl, wherein the heteroatom or the heteroatoms are selected from the group consisting of 1-5 4 O, S or N atoms and the alkyl part which is combined with heteroaralkyl has 1-6 C atoms; the heteroaryl and heteroaralkyl groups mentioned are optionally substituted in the heterocyclic ring by 1-3 substituents which are selected independently of one another from hydroxy, amino, halogen, trifluoromethyl, C 10 -C 4 alkyl, C 4 -C 4 alkoxy C -C4-alkylamino, di (C, -C4) alkylamino, carboxy and sulfo and the alkyl part is substituted by 1-3 substituents selected from hydroxy, amino, CrC4-alkylamino, di (C, -C4) alkylamino, CrC4-alkoxy , Carboxy, halogen and sulfo; said heterocyclic radical is optionally substituted on a C-15 atom by a substituent selected from the following group C, -C4-alkyl; Q-Q-alkyl, preferably substituted by 1-3 hydroxy, amino, Q-Q-alkylamino, C, -C4-alk-oxy, carboxy, halogen and sulfo; said heteroaromatic radical is optionally substituted on a C atom by a substituent 20 which is selected from Q-Q-alkyl; C, -C4-alkyl, preferably substituted by 1-3 hydroxy, amino, C, -C4-alkylamino, di (C, -C4-alkyl) amino, C, -C4-alkoxy, sulfo, carboxy or halogen (chlorine, Bromine, fluorine or iodine; preferably chlorine, fluorine or bromine); C3-C6 cycloalkyl; C, -C4 alkoxy; Cj-Q-alkylthio; Amino; 25 C, -C4 alkylamino; Di (C, -C4 alkyl) amino; Halogen (chlorine, bromine, fluorine or iodine; preferably chlorine, fluorine or bromine); C1-C4-alka-noylamino; C, -C4 alkanoyloxy; Carboxy; - CO — O— (Q-Q) alkyl; Hydroxy; Amidino; Guanidino; Phenyl; Phenyl, substituted by 1, 2 or 3 amino, halogen (chlorine, bromine, fluorine or iodine; 30 preferably chlorine, fluorine or bromine) hydroxy, trifluoromethyl, C, -C4-alkyl or C, -C4-alkoxy; Phenyl (C, -C4) alkyl, in which the phenyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with phenyl, and the alkyl part is optionally substituted by 1-3 substituents, as above in connection with 3s C, -C4-alkyl are mentioned, is substituted; and heteroaryl or heteroaralkyl, in which the heteroatom or the heteroatoms in the above-mentioned heterocyclic radicals are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl part which is combined with the said heteroaral 40 kyl 1 -6 C atoms, and the group consisting of 1-4 O, S or N atoms and the alkyl part, which is combined with the heteroaralkyl, has 1-6 C atoms, said heteroaryl and heteroaralkyl groups optionally substituted on the heterocyclic ring by 1-3 substituents which are selected independently of one another from hydroxy, amino, halogen, trifluoromethyl, CrQ-alkyl, C [-C4-alkoxy, CrC4-alkylamino, di (C, -C4) alkylamino, Have carboxy and sulfo and in the alkyl part 1-3 substituents which are selected from hydroxy, amino, CrQ-alkylamino, di (CrC4) alkylamino, CpCi-alkoxy, carboxy, halogen and sulfo; the R and R5 groups can also together form a fused heterocyclic or heteroaromatic ring.

Among the preferred embodiments described above, the preferred conditions are those in which A is - (CH,) “-, in which n is 1 or 2, particularly preferred are those in which A is —CH2— and in which

(a) R1 and R8 together

HIGH, ^

^ C =

CH3 ^

mean or

(b) R8 is hydrogen and R1 is hydrogen, CH3CH2 -, (CH3) 2CH -, (CH3) 2C (OH) - or CH3CH (OH) -.

The compounds in which R8 is hydrogen and R1 is CH3CH (OH) -, in particular compounds with the absolute configuration 5R, 6S, 8R, are particularly preferred.

A particularly preferred embodiment of the present invention comprises compounds of the formula I in which

- © ** ■

a remainder of the formula

-5 e

"10

(G)

© 5 • N-R

© • K-

K-R

.NO

NO

©

-, 5th

©

.Jv-R

NO

R -N

r-R

/ 4S

-NO

N "° the RS-®K

wherein R is a residue selected from: C, -C4 alkyl; C 1 -C 4 alkyl substituted by 1-3 hydroxy, amino, Q-Cr alkylamino, di (Ci- 55 C4) alkylamino, CrC4 alkoxy, carboxy, halogen or sulfo; C3-Cö-cycloalkyl; C3-C6-cycloalkyl (C, -C4) alkyl, optionally substituted by 1-3 substituents, as mentioned above in connection with C, -C4-alkyl; Phenyl; Phenyl substituted by 1-3 substituents which are independently selected from 60 amino, halogen, hydroxy, trifluoromethyl, CpQ-alkyl, CrC4-alkoxy, C, -C4-alkylamino, di (C, -C4) alkylamino, carboxy and Sulfo; Phenyl (C, -C4) alkyl, in which the phenyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with phenyl, and the alkyl part is optionally substituted by 65 1-3 substituents, as described above in connection with C, -C4 alkyl are mentioned, is substituted; and heteroaryl and heteroaralkyl,

wherein the heteroatom or heteroatoms are selected from, wherein R6, R1 and R '° are independently selected from the group consisting of hydrogen, C1 -C4 alkyl. CrC4 alkoxy, carboxy and carbamoyl and Rs is as defined above and is preferably C, -C6 alkyl and most preferably —CH3.

Among the preferred embodiments described above, the preferred conditions are those in which A is - (CH,) n—, in which n is 1 or 2, particularly preferred are those in which A is - CH2— and in which

(a) R1 and R8 together

HIGH2 ^

^ c =

CH3 ^

mean or

(b) R8 is hydrogen and R1 is hydrogen, CH3CH2 -, (CH3) 2CH -, (CH3) 2C (OH) - or CH3CH (OH) -.

The compounds in which R8 is hydrogen and R 'is CH3CH (OH) -, in particular compounds with the absolute configuration 5R, 6S, 8R, are particularly preferred.

A further preferred embodiment comprises compounds of formula 1, wherein

HIGH2> ^

^ c =

CH3 ^

means a radical of a formula of the following group:

(a)

656 130

26

wherein R5 is C, -C4 alkyl, most preferably methyl, and R6 is hydrogen or C, -C4 alkyl;

(e)

(b)

R el, N

CH.

i

(f)

-CB.

u in which R5 is C, -C + -alkyl, particularly preferably methyl and -R6 and R7 are hydrogen or C, -C4 -alkyl; "io

(G)

(c)

-W

wherein R is C, -C4 alkyl, particularly preferably methyl and R is C, - 15 C4 alkyl or phenyl (C, -C4) alkyl;

(0

(d)

N

20th

wherein R5 is C, -C4-alkyl, particularly preferably methyl and R6 is C, -C4-alkyl, particularly preferably methyl;

r5 25

(e> le

(k)

/

// -N '

(m)

wherein R5 is C, -C4-alkyl, particularly preferably methyl and R Cr is C4-alkyl, particularly preferably methyl; or or

(H)

G)

(1)

(n)

(f)

N \\

Ss./

©

NO'

Among the preferred embodiments described above, the preferred conditions are those in which A is - (CH2) n -, in which n is 1 or 2, particularly preferred are those in which A is - CH2- and in which R5 is C 1 -C 4 -alkyl , particularly preferably methyl.

In preferred embodiments 40 (a) R 'and R8 together described above, the preferred conditions are those in which A - (CH2) "-

in which n is I or 2, particularly preferred are those in which A is —CH2— and in which - -

(a) R1 and R8 together

45

hoch2 ^

CH., - "" /

HIGH2 CH,

C =

mean or

(b) R8 is hydrogen and R1 is hydrogen, CH3CH2-, (CH3) 2CH- (CH3) 2C (OH) - or CH3CH (OH) -.

mean or

(b) R8 is hydrogen and R 'is hydrogen, CH3CH2- :, (CH3) 2CH-, 50 (CH3) 2C (OH) - or CH3CH (OH) -.

The compounds in which Rs is hydrogen and Rl is CH3CH (OH) - are particularly preferred, in particular compounds with the absolute configuration 5R, 6S. 8R.

A particularly preferred embodiment of the present invention comprises compounds of the formula I in which

The compounds in which R8 is hydrogen and R1 is CH3CH (OH) -, in particular compounds with the absolute configuration 5R, 6S, 8R, are particularly preferred.

Specific preferred compounds of the present invention are those of the formula

S-A

NO"

represents a radical of the formula from the following group:

(a)

60

COOR

(c)

(b)

(n-

65

wherein R2 is hydrogen, an anionic charge or carboxy protecting group, provided that if R2 is hydrogen or a protecting group there is also a counter ion and wherein

(d)

\ _ ^ ~ CH2CH2CB3

—S — A-

-R

27th

656 130

represents a radical of the formula from the following group:

(a)

(c)

// ^ e

-ses 2- / N-I: E3

-sch ce,

CH,

(e)

(G)

-schjce.

-SCE.

// what,

V®

(0

it,

CH,

«Ti

-SCE2 \

I.

CH.

Ì2CE2 - <^ ~ ^ -CH3

-sch.

C \ E3

e.

f / \\

-SCH

O

-SCH

CH.

CH.

CH.

-SCH.

N

// \\

CH.

(t)

(b)

(d)

-SCH.

or (v) //

CH.

\\> s

-N-CH ^ COO / CH3

»V

-SCH.

CH, M®

K N

/

CH,

(u)

«H2CH2CB3

(f)

(H)

Œ3

A particularly preferred embodiment of the present invention comprises the compounds of the formula I in which

NO

the meaning

(j)

CH,

i »

-o has.

Among the preferred embodiments described above, the preferred conditions are those in which A is - (CH2) “-, in which n is 1 or 2, particularly preferred are those in which

(k)

-SCH;

(m)

E

Yo

ÎS2

V

-SCH

e /

CH

(O)

-SCE.

3rd

f: 3

"1

-CH.

-SCH

CE.

CH.

30 (a) R1 and R8 together (1) HIGH,

ch3- "

mean or

35 (b) R8 hydrogen and R1 hydrogen, CH3CH2—, (CH3) 2CH -,

(n)

(CH3) 2C (OH) ~ or CH3CH (OH) - means.

The compounds in which R8 is hydrogen and R1 is CH3CH (OH) -, in particular compounds with the absolute configuration 5R, 6S, 8R, are particularly preferred.

40 The carbapenem compounds of the formula I are, starting from the starting compounds of the formula III

(P)

45

COOH

prepared wherein R1, R8 and R15 are as defined above and wherein R2 represents a carboxy protecting group. Compounds of the formula wherein the 'NHMR (D20) spectrum characteristic peaks at 8 so III are known, e.g. B. from EP-A 38869 (compound 7) and from shows: 1.23 (3H, d, J = 6.4 Hz), 3.12 (2H, q, J = 1.4, 8.9 Hz ), 3.39 (1H, EP-A 54927 and can by general methods, q, J = 2.7, 6.0 Hz), 4.07-4.68 (10H, m), 8.19 (1H, s); which are described there.

The process for the preparation of the compounds of formula I.

(q)

-SCH

T

CH

starting compounds of the formula III can be summarized by the following 55 reaction scheme.

where the 'HNMR (D20) spectrum shows characteristic peaks at 8: 1.23 (3H, d, J = 6.4 Hz), 3.15 (2H, q, J = 3.7, 9.0 Hz) , 3.37 (1H, "jq, J = 2.6, 6.0 Hz), 3.95-4.65 (10H, m), 8.62 (1 H, s);

, 6th

-SCH ,.

(r) 2

7 N

Rw

-CH.

-SCH.

COO. ,

/ (s)

CH i e 2

i

N-CH,

65

ES — A—

L = leaving group (IV)

656130

28

Deblocking

R5 — X '

/ y — N o (Ha)

"COOH

a temperature of from -20 to +40 "C., particularly preferably at about 0 C. The leaving group L of the intermediate IV can also be halogen, such a group being introduced by the intermediate III with a halogenating agent, such as 03PC12, 03PBr2, (0O) 3PBr2, oxalyl chloride is introduced in a solvent such as CH2C12, CH3CN and THF in the presence of a base such as diisopropylethylamine, triethylamine and 4-dimethylaminopyridine, but intermediate IV can be isolated if desired but is isolated expediently used for the next step without isolation or cleaning.

The intermediate product IV is then converted into the intermediate product II by a conventional displacement reaction. The intermediate IV can be mixed with about an equimolar amount of a heteroaralkyl mercaptan reagent of the formula

HS — A-

are implemented, where A is straight or branched Cj-Cj-alkylene 20, and

A variant of the process described above is represented by the following reaction scheme:

HS — A-

To carry out the abovementioned processes, the starting material of the formula III is in an inert organic solvent, such as methylene chloride, acetonitrile or dimethylformamide, with about an equimolar amount of a reagent R ° -L, such as p-toluenesulfonic anhydride, p-nitrobenzenesulfonic anhydride, 2,4,6 -Triisopropylbenzenesulfonsäureanhydrid, methanesulfonic acid anhydride, trifluoromethanesulfonic anhydride, diphenylchlorophosphate, toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, reacted, where L the corresponding leaving group such as toluenesulfonyl, the imid and the standpone groups, imit, and other processes used Technology are known means. The reaction to introduce the leaving group in the 2-position of intermediate III is advantageously in the presence of a base, such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, in the case of a mono-, bi- or polycyclic aromatic heterocyclic radical, which has a quaternizable nitrogen atom in the Ring contains, said ring being bonded to A via a ring carbon atom, in an inert organic solvent such as dioxane, dimethylformamide, dimethyl sulfoxide or acetonitrile and in the presence of a base such as diisopropylethylamine, triethylamine, 30 sodium hydrogen carbonate, potassium carbonate or 4-dimethylamino-nopyridine , are implemented. The temperature for the displacement is not critical, but is advantageously in the temperature range from -40 to +25 "C. The reaction is most conveniently carried out with cooling, for example at 0 to -10" C. 35 The quaternization of the ring nitrogen in the heteroaralkyl group of intermediate II is achieved by reacting intermediate II in an inert organic solvent with at least one equivalent (up to about 50 mol% excess) of an alkylating agent of the formula

40

R5-X ''

wherein Rs is as defined above and X 'contains a common leaving group such as halogen (chlorine, bromine or iodine, preferably iodine), or a sulfonate ester group such as a mesylate, tosylate or triflate. Examples of suitable non-reactive organic solvents are chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethyl sulfoxide and dimethylformamide. The temperature for the alkylation reaction is not critical and temperatures in the range 50 from 0 to 40 ° C. are preferred. The reaction step is most conveniently carried out at room temperature.

A counterion X '(e.g. derived from the alkylating agent used) is assigned to intermediate I' in this step or in a later step, i. H. after the deblocking step 55 a counter ion can be replaced by another counter ion, for example a more pharmaceutically acceptable one can be introduced by conventional methods. However, the counter ion can also be removed during the deblocking step.

The deblocking step for removing the carboxy-protecting group 60 "of the intermediate I 'is carried out by customary methods, such as solvolysis, chemical reduction or hydrogenation. If a group such as p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl is used as the protecting group , this can be removed by catalytic hydrogenation by the intermediate I 'in a suitable solvent, such as dioxane-water-ethanol or tetrahydrofuran-aqueous dipotassium hydrogen phosphate isopropanol, under a hydrogen pressure of 100-400 kPa in Presence of a hydrogenation catalyst such as palladium

29

656 130

Ladium on carbon, palladium hydroxide or platinum oxide, can be treated at a temperature of 0-50 ° C for about 0.24-4 h. If R2 is a group such as o-nitrobenzyl, deblocking can also be carried out by photolysis. Protecting groups such as 2,2,2-trichloroethyl can be removed by mild zinc reduction. The allyl protecting group can be removed by a catalyst containing a mixture of a palladium compound and triphenylphosphine in an aprotic solvent such as tetrahydrofuran, diethyl ether or methyl chloride. Similarly, other common carboxy protecting groups can be removed in a known manner by those skilled in the art. Finally, as mentioned above, compounds of the formula I 'in which R2 is a physiologically hydrolyzable ester group, such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl or methoxymethyl, can be administered to the host organism without deblocking, since such esters are produced in vivo under physiological conditions Conditions are hydrolyzed.

It goes without saying that if the substituent R1, R8, R5 or R15 or the heteroaromatic ring which is bonded to substituent A contains a functional group which could interact with the intended course of the reaction, this group passes through a common blocking group can be protected and then unblocked in order to regain 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 process described above, the carboxyl protecting group of intermediate II can be removed before the quaternization. The carboxy protecting group is removed as described above in order to obtain the corresponding free carboxylic acid, the free acid then being quaternized with an alkylating agent R5 -X ', the desired quaternized product of the formula I being obtained. When the deblocked intermediate IIa is quaternized, the solvent can be water or a non-reactive organic solvent or mixtures thereof. Examples of suitable solvents include water, organic solvents such as chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethyl sulfoxide and dimethylformamide and mixtures of water and organic solvents such as water acetone or water dimethylformamide. The temperature for the quaternization of intermediate IIa is not critical and temperatures in the range from -40 ° C. to room temperature can be used expediently. The reaction is most advantageously carried out at about 0 ° C.

When the deblocked intermediate IIa is obtained as the carboxylic acid salt, it is desirable to add a strong acid, such as toluenesulfonic acid, to generate the free carboxylic acid prior to quaternization. It has been found that this greatly facilitates the preferred quaternization of the ring nitrogen atom.

The process variant described above is particularly useful if the carboxy protecting group can be removed more easily from the non-quaternized intermediate of formula II than is the case with the quaternized intermediate of formula I. In the preparation of the compound of the formula

CH3

\ 3 6

K-

(R)

from the intermediate of formula OH H

»A

SCH.

COO

V \

causes z. B. the removal of the allyl protecting group prior to quaternization, a marked improvement in the yields of the desired product.

While the process described above is suitable for the preparation 5 of compounds according to the invention, an author name Pierre Dextraze has invented a new process which can also be used for the preparation of the compounds of the formula I. This alternative method, which is disclosed and claimed in a US patent application having the same filing date as the priority document of the present application, is described below and in the examples that follow.

In this alternative process for the preparation of the compounds of formula I an intermediate of formula

8th

, 15th

(IV)

V COOR

wherein R1, Rs and R15 are as defined above, R2 is a carboxy protecting group and L is a leaving group such as toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, diphenoxyphosphinyloxy or halogen '

25, with a thiol compound of the formula

© <

ES-A-

* ~ R "

where A and xQ

(vii)

30th

-ö *

as defined above and Xe is a counter anion, reacted in an inert solvent in the presence of a base, a Car-35 bapenem compound of the formula 15

^ ~ \ © s

S-A r-N-R

(n

</ - N

yß

COOR

is obtained, wherein R1, R8, R ", A, RIS,

l © r

NO

and Xe are as defined above and, if desired, the carboxy protecting group R "is removed to give the corresponding compound of formula I or a pharmaceutically acceptable salt thereof.

The alternative process uses the intermediates of formula IV which, as mentioned above, are disclosed, for example, in EP-A 38869 and EP-A 54917 and which can be prepared by the general methods described there. L 55 denotes a customary leaving group (defined as "X" in EP-A 38869), such as chlorine, bromine, iodine, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, methanesulfonyloxy, trifluoromethylsulfonyloxy, diphenoxyphosphinyloxy or di (trichloroethoxy) -phosphinyloxy The preferred leaving group is diphenoxy-60 phosphinyloxy.

Intermediates of formula IV are generally formed in situ by reacting an intermediate of formula III

(III)

COOR

656 130

30th

wherein R1, R8, R15 and R2 are as defined above, with a suitable acylating agent R ° -L. The preferred intermediates IV, in which L is diphenoxyphosphinyloxy, can be obtained by reacting the keto ester III in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with about an equimolar amount of diphenylchlorophosphate in the presence of a base such as diisopropylethylamine, triethylamine or 4-dimethylaminopyridine Temperature of about -20 "C- + 40 C, preferably at about 0 ° C. Intermediate IV can be isolated if desired, but is conveniently used as a starting material for the alternative process without isolation or purification.

The carbapenem intermediate IV is with a quaternary rcn amine thiol compound of formula VII

hs-i implemented in which is as defined above and X- is a counter anion. The reaction is carried out in an inert solvent such as acetonitrile, acetonitrile-dimethylformamide, tetrahydrofuran, tetrahydrofuran-H20, acetonitrile-H20 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 (ÇI: Ç4.) Alkylamines, such as triethylamine, Tributylamine or tripfopylamine. The reaction of intermediate IV and thiol VII. Can be carried out at a temperature in a wide range, for example. from -15 ° C to room temperature, but preferably at a temperature in the range of -15 ° C- + 15 ° C, preferably at about 0 ° C.

The carbapenem products which are obtained by the reaction of the quarterly amine thiol VII with the intermediate IV have an associated counterion. [E.g. . (CsHs0) 2P02_, Cl ~ or the quaternary thiol-associated anion], which can be replaced in this step by a typical method by another counter anion, for example by one which is pharmaceutically acceptable. The. Counter anion can also be removed during the following deblocking step.

If the quaternized carbapenem and the counter anion form an insoluble product, the product can be crystallized out and the product obtained can be obtained purely by filtration.

Following the formation of the desired carbapenem product, the carboxy protective group R2- of the compound I 'can optionally be removed by customary processes such as solvolysis, chemical reduction or hydrogenation.

If the protecting group is a group such as p-nitrobenzyl, benzyl, benzhydryl, or 2-naphthylmethyl, this can be removed by catalytic hydrogenation by the intermediate I 'in a suitable solvent such as dioxane-water-ethanol or tetrahydrofuran-aqueous dipotassium hydrogen. phosphate-isopropanol, under a hydrogen pressure of 100-400 kPa, in the presence of a hydrogenation catalyst such as palladium on carbon, palladium hydroxide or platinum oxide, at a temperature of 0-50 ° C for about 0.23-4 h. If R2 is a group such as o-nitrobenzyl, deblocking can also be carried out by photolysis. Protecting groups such as 2,2,2-trichloroethyl can be removed by mild zinc reduction. The allyl protecting group can be removed by a catalyst containing a mixture of a palladium compound and triphenylphosphine in an aprotic solvent such as tetrahydrofuran, diethyl ether or methyl chloride. Similarly, other common carboxy protecting groups can be removed in a known manner by those skilled in the art. Finally, as mentioned above, compounds of the formula I 'in which R2 is a physiologically hydrolyzable ester group, such as acetoxymethyl, phthaiidyl, indanyl, pivaloyloxymethyl or methoxymethyl, can be administered to the host organism without deblocking, since such esters are produced in vivo under physiological conditions Conditions are hydrolyzed.

The thiol intermediates of formula VII can, for example, from the corresponding thiol acetate compounds of formula i?

ch3cs-a wherein A is as defined above and

"O.

means a mono-, bi- or polycyclic aromatic heterocyclic radical which has a quaternizable nitrogen atom in the ring, said ring being bonded to A via a ring carbon atom. The thiol acetate compound is quaternized by being 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 'a conventional leaving group, such as halogen (chlorine, bromine or iodine, particularly preferably iodine) or a sulfonate ester residue, such as mesylate, tosylate or trifluorate, is reacted. The temperature for the alkylation reaction is not critical and temperatures in the range of 0 ° C-40 ° C are preferred.

Before the reaction with the carbapenem intermediate IV, the quaternized thiol acetate compound is subjected to acidic or basic hydrolysis, the quaternary thiol intermediate VII being formed. This hydrolysis is preferably carried out immediately before the coupling with IV, so that the decomposition of the relatively unstable quaternary thiol VII is kept to a minimum.

With a suitable choice of solvents, the reaction from intermediate III to the end product I can be carried out without isolation of the various intermediates, that is to say in a “one-pot” process. An example of such a process is explained in the example.

As with other β-antibiotics, the compounds of general formula I can be converted into pharmaceutically acceptable salts by known methods, which for the purposes of the present invention are essentially equivalent to the unsalted compounds. For example, a compound of formula I in which R2 is an anionic charge can be dissolved in a suitable inert solvent and then an equivalent of a pharmaceutically acceptable acid can be added. The desired acid addition salt can be obtained by customary methods, for example by solvent precipitation or lyophilization. Similarly, if other acidic or basic functional groups are present in the compound of formula I, pharmaceutically acceptable base addition salts and acid addition salts can be prepared by known methods.

It can also be seen that certain products which fall under the definition of formula I can be obtained as optical isomers as well as epimeric mixtures thereof. All such optical isomers and epimeric mixtures are intended to fall within the scope of the present invention. If, for example, the substituent in the 6-position is hydroxyethyl, such a substituent can be present either in the R or in the S configuration and the corresponding isomers as well as the epimeric mixtures thereof are encompassed by the present invention.

A compound of formula I wherein R2 is hydrogen or an anionic charge or a pharmaceutically acceptable salt

5

io

15

20th

25th

30th

35

40

45

50

55

60

65

31

656 130

thereof, can also be converted into a corresponding compound by customary processes in which R2 is a physiologically hydrolyzable ester-forming group or a compound of the formula I in which R2 is a customary carboxy protective group can be converted into a corresponding compound in which R2 is hydrogen, is an anionic charge or a physiologically hydrolyzable ester-forming group or be converted into a pharmaceutically acceptable salt thereof.

The new carbapenem derivatives of the general formula I, in which R 2 is hydrogen, an anionic charge or a physiologically hydrolyzable carboxy protective group, or a pharmaceutically acceptable salt thereof, are effective antibiotics which are active against various gram-positive and gram-negative bacteria, and which, for example, as animal feed additives for growth promotion, as preservatives in food, as bactericides in industrial applications, for example in water-based paint and in white water of the paper industry, in order to prevent the growth of harmful bacteria and as a disinfectant to destroy or inhibit the growth of harmful bacteria on medical and dental equipment. However, they are particularly effective in treating infectious diseases in humans and animals caused by gram-positive or gram-negative bacteria.

The pharmaceutically active compounds of this invention can be used alone or formulated as pharmaceutical compositions in which the latter contain, in addition to the active carapene component, a pharmaceutically acceptable carrier or diluent. The compounds can be administered in various ways; those of primary interest include oral, topical, or parenteral (e.g., intravenous or intramuscular injection) administration. The pharmaceutical compositions can be in solid form, such as capsules, tablets and powder, or in liquid form, as solutions, suspensions or emulsions. Compositions for injection, the preferred route of delivery, may be packaged in unit dosage form in ampoules or in multi-dose containers and may contain formulating agents such as suspending, stabilizing and dispersing agents. The compositions may be in a ready-to-use form or in powder form for reconstitution at the time of administration with an appropriate vehicle, such as sterile water.

The dosage to be administered depends to a large extent on the particular compound used, the particular formulation formulated, the route of administration, the nature and condition of the host warm-blooded animal and the particular location and the organism treated.

A selection of the particularly preferred dosages and the routes of application is left to the treating therapist. In general, however, the compounds are administered parenterally or orally to warm-blooded animals in an amount of about 5-200 mg / kg / day. Administration is generally in divided doses, for example three to five times a day.

The biological data below, which relate to the currently preferred carbapenem compounds of the present invention, serve to explain the strong broad-spectrum antibacterial activity of the carbapenem of the present invention, both in vitro and in vivo, and the small toxicity of the compounds.

In vitro activity

Samples of the carbapenem compounds prepared according to Examples 1-2, after dissolving in water and diluting with nutrient broth, showed the following minimum inhibitory concentrations (Minimum Inhibitory Concentrations, M.I.C.) in ng / ml against the specified microorganisms. It was determined by overnight incubation at 37 ° C. using a series of dilutions. N-

Formimidoyl-thienamycin was included in the following tables as a comparative compound.

In vitro antibacterial activity of carbapenem derivatives of Example 1

30th

40

MIC (Html)

organism

New

N-formimidoyl

Compound thienumycin

S. pneumoniae A-9585

0.25

0.004

S. pyogenes A-9604

0.06

0.001

S. aureus A-9537

0.13

0.004

5. aureus

+ 50% serum A-9537

0.03

0.016

S. aureus

(Pen-res.) A-9606

0.06

0.008

S. aureus

(Meth-res.) A15097

4th

0.5

S.faecalis A20688

0.5

0.5

E. coli

(IO "4 dil.) A15119

0.06

0.016

E. coli

(105) A15119

-

0.03

E. coli

(IO "2) A15119

-

0.06

E. coli

(IO "4) A20341-1

0.03

0.03

E. coli

(IO3) A20341-1

-

0.03

E. coli

(IO "2) A20341-1

-

0.13

K. pneumoniae A-9664

0.25

0.13

K, pneumoniae A20468

0.25

0.06

P. mirabilis A-9900

0.13

0.06

P. vulgaris A21559

0.13

0.03

P. morganii A15153

0.13

0.13

P. rettgeri A22424

0.25

0.25

S. marcescens A20019

0.13

0.03

E. cloacae A-9569

0.13

0.06

E. cloacae A-9656

0.13

0.06

P. aeruginosa A-9843A

4th

1

P. aeruginosa A21213

1

0.25

H. influenzae A-9833

16

16

H. influenzae A20178

32

32

In vitro antibacterial activity of the carbapenem derivatives of Example 2

MIC (ligi ml)

organism

New

N-formimidoyl

Compound thienamycin

S. pneumoniae A-9585

0.001

0.002

S. pyogenes A-9604

0.001

0.002

S. aureus A-9537

0.004

0.004

S. aureus A-9537

+ 50% serum

0.016

0.016

S. aureus A-9606

(Pen-res.)

0.008

0.008

5. aureus

(Meth.-res.) A 15097

8th

4th

S.faecalis A 20688

0.25

0.5

E. coli A 15119

0.016

0.016

-E. coli A 20341-1

0.016

0.03

K. pneumoniae A9664

0.06

0.06

K. pneumoniae A20468

0.13

0.13

656 130

32

MIC (Hg! Ml)

organism

New

N-formimidoyl

Compound thienamycin

P. mirabilis A9900

0.03

0.06

P. vulgaris A21559

0.016

0.03

P. morganii A15153

0.06

0.13

P. rettgeri A22424

0.13

0.13

5. marcescens A20019

0.03

0.03

E. cloacae A9569

0.13

0.06

E. cloacae A9656

0.25

0.06

P. aeruginosa A9843A

8th

1

P. aeruginosa A21213

2nd

0.25

In vivo activity

The in vivo therapeutic activity of the compound of Example 1 and N-fromimidoyl-thienamycin after intraumuscular administration to mice, which was determined experimentally by various

Microorganisms infected are shown in the following table. The PD50 values are given (dose in mg / kg, which gives 50% protection of the infected mouse).

Protective effect in the intramuscular treatment of an infected mouse

organism

PDso! Treatment (mg / kg)

Number of organisms administered

Connection of example 1

N-formimidoyl-thienamycin

P. mirabilis A-9900

3.6 x 10 6

3.3

3 * / 15 *

P. aeruginosa A-9843a

5.5 x 10 4

0.3

0.5 *

P. aeruginosa A-20481

5.4 x 10 4

0.63

0.4 *

P. aeruginosa A-20599

1.4 x 10 5

0.7

0.18 *

• p. aureus A-9606

6.6 x 108

0.09

0.07 *

S.faecalis A-20688

2.3 x 108

3.3

2.8 *

E. coli A-15119

6.2 x 10 6

0.6

2.5 *

K. pneumoniae A-9964

5.1 x 10 6

2.5

2.2 *

* Historical data

Treatment plan: With the exception of E. coli AI5119 and K. pneumoniae A9964, the mice were given i.m. drugged 0 and 2 h after infection. For E. coli and K. pneumoniae, the treatment schedule was 1 and 3.5 hours after infection. 5 mice per dose were used for each test.

toxicity

The toxicity of the compound of Example 1 after intracranial administration to mice was determined and is shown in the following table.

Toxicity after intracranial administration to mice

40

connection

* LDso mgjkg

Highest dose mg / kg with no clinical signs of toxicity

Connection of the

Example 1

14

5

N-formimidoyl

Thienamycin

32

~ 5

* Average of 25 mice / compound

Blood levels in mice after intramuscular administration

The blood level and half-life of the compound of Example 1 after intramuscular administration of 20 mg / kg in mice are shown in the tables below.

connection

Blood level (ng / ml)

* tVz min

** AUC (ßgjijml)

10 20 30 45 60 90 minutes after administration

connection

of example 1

14

10.8

6.8

2.6

0.8

<0.6

10th

6.3

N-formimidoyl

Thienamycin

12.6

9.9

7.3

2.6

0.7

<0.3

9

6

The compounds were solubilized in 0.1 molar phosphate buffer with a pH of 7. The values are from a single test; 4 mice were used per compound. * t Vi refers to the half-life in min ** AUC refers to the area under the curve

Yield from urine

The yield from the urine of the compound of Example 1 after 5S intramuscular administration (20 mg / kg) to mice is shown in the following table.

Result from urine intramuscular administration of 20 mgjkg to mice

60

65

connection

Percent yield per dose

0-3 3-6 6-24 0-24 hours after administration

connection

of example 1

26.1

0.5

0.1

26.7 ± 6.7

N-formimidoyl

-

thienamycin

12.1

0.1

<0.1

I2.2 ± 3.6

33

656 130

The compounds were solubilized in 0.1 molar phosphate buffer, pH 7. The values are from a single test: 4 mice per compound.

Additional biological data In vitro activity

Samples of the carbapenem compounds (identified below, identified by the sample number), after dissolution in water and dilution with nutrient broth, showed the following minimum inhibitory concentrations (M.I.C.) in Hg / ml against the indicated microorganisms. They were incubated at 5 an overnight at 37 :! C determined by a series of dilutions. N-formimidoyl-thienamycin is shown in the following tables as a comparative compound.

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0

0

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> 32

> 32

rr 0 0

0 0

u- »

co O

vo 0

co 0

VO O

VO

0

CO

10 CN

Vi CN

from CN

"O CN O

vO O

CO

«0 CN

co

0

0

0

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0

0

■ ^ r

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0

0

O

O

O

O

O

0

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0 00

-

CN

CN

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o "©"

m co

A A

Q,

V)

CQ

"* 3 *

Tt *

VO

OO

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vo

vo

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OK

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co vo vo co co

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fO «n o cn m rf o o ci co

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vo

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m

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<<

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; "O

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: «M <3y

• a c

3rd

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M

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00

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J-

ON

î:

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t <<

tî- 00

s s vo S CN a \

■ <<2

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VP o ^ O

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656130

34

MIC (ng / ml)

organism

Ex. 12

Ex. 13

Ex. 14

M K. 0787 *

Example 15 "A"

Example 15 "B"

Example "C"

MK 0787 *

S. pneumoniae A-9585

0.002

0.0005

0.0005

0.002

0.0005

0.0005

0.0005

0.002

S. pyogenes A-9604

0.004

0.0005

0.0005

0.002

0.0005

0.001

0.0003

0.002

S.faecalis A20688

0.5

0.13

0.13

0.25

0.13

0.5

0.5

0.25

S. aureus A-9537

0.008

0.008

0.008

0.002

0.03

0.004

0.016

0.004

S. aureus A-9537

+ 50% serum

.016

0.016

0.03

0.008

0.03

0.016

0.06

0.008

S. aureus A-9606

(Pen-res)

0.03

0.008

0.016

0.008

0.004

0.008

0.03

0.008

S. aureus A15097

(Meth-res)

-,

_

-

-

-

-

-

E. coli A15119

0.016

0.004

0.008

0.016

. 0.004

0.008

0.06

0.008

E. coli A20341-1

0.008

0.008

0.008

0.016

: 0.004

0.008

0.03

0.016

K. pneumoniae A-9664

0.03 1

0.03

0.03

0.03

0.008

0.03

0.06

0.03

K. pneumoniae A20468

0.06:

0.13

0.03

0.06

0.008

0.016

0.13

0.06

E. cloacae A-9659

0.06.

0.06

0.03

0.06

0.016

0.016

0.13

0.13

E. cloacae A-9656

0.03 '.

0.03

0.03

0.06

0.016

0.03

0.13

0.13

P. mirabilis A-9900

0.03 "

0.016

0.016

0.016

0.008

0.03

0.06

0.06

P. vulgaris A21559

0J) I6

■ 0.008

0.016

0.016

0.008

0.008

0.06

0.016

M. morganii A15153

0.06 -

0.016

0.03

0.06

0.03

0.06

0.25

0.13

P. rettgeri A22424

0.13

0.25

0.06

0.13

0.03

0.13

0.25

0.13

S. marcescens A20019

0.03

0.016

0.016

0.03

0.008

0.016

0.13

0.016

P. aeruginosa A-9843A

16 '.'-.

32

8th

1

. 0.5

2nd

8th

0.5

P. aeruginosa A21213

2 ''

2nd

0.5

0.13

0.03

0.13

0.5 -

0.13

* N-formimidoyl-thienamycin

MIC (ng / ml)

organism

Ex. 16

Ex. 17

MK0787 *

Ex. 18

Ex. 19

Ex. 20

MK 0787 *

S. pneumoniae A-9585 •

0.002

0.016

0.001

1

0.002

0.06

0.001

S. pyogenes A-9604 '

• 0.002

0.016

0.001

2nd

0.002

0.13

0.002

S.faecalis A20688

1

4th

0.25

63

0.5

16

0.25

S. aureus A-9537

0.008

0.25

■ 0.001

32

0.004

0.5

0.002

S. aureus A-9537

+ 50% serum

0.03

1

■ 0.008

> 63

0.008

2nd

0.004

S. aureus A-9606

(Pen-res)

0.016

0.5

. 0.002

> 125

0.016

> 125

0.004

S. aureus A15097

(Meth-res)

-

-

; -

-

-

-

-

E. coli A15119

0.016

0.6

0.008

16

0.008

1

0.016

E. coli A20341-1

0.016

0.6

. 0.008

16

0.008

2nd

0.016

K. pneumoniae A-9664

0.06

0.13

0.03

32

0.03

4th

0.03

K. pneumoniae A20468

0.06

0.5

0.06

63

0.06

4th

0.06

E. cloacae A-9659

0.06

2nd

0.06

63

0.03

8th

0.06

E. cloacae A-9656

0.06

2nd

0.06

125

0.03

16

0.06

P. mirabilis A-9900

0.06

0.13

0.016

32

0.03

4th

0.016

P. vulgaris A21559

0.03

0.13

0.008

32

0.016

4th

0.016

M. morganii A15153

0.13

0.5

0.06

32

0.06

8th

0.06

P. rettgeri A22424

0.25

2nd

0.06

32

0.13

8th

0.13

S. marcescens A20019

0.06

0.13

0.016

32

0.03

4th

0.03

P. aeruginosa A-9843A

0.25

> 63

0.5

63

0.5

32

0.5

P. aeruginosa A21213

0.13

16

0.13

63

0.06

16

0.13

* N-formimidoyl-thienamycin

35

656 130

In vivo activity

The in vivo therapeutic efficacy of certain compounds of the present invention and N-formimidoyl-thienamycin (MK 9787) after intramuscular administration to mice experimentally infected with various organisms is given below. The PD50 values (dose in mg / kg) which are necessary to protect 50% of the infected mice are given.

Protective effect in the intramuscular treatment of infected mice

organism

P D s o / treatment / mg / kg

Ex. 6

Ex. 8

Ex. 9

Ex. 12

Ex. 14

Ex. 15 ("A")

Ex. 15 ("B")

MK 0787

, P. aureus A9606

0.21

0.89

0.07

0.07

E. coli A15119

-

0.86

1.2

-

-

-

3rd

K. pneumoniae A9664

-

1.8

1.8

-

-

-

3rd

P. mirabilis A9900

-

1.4

7.1

-

-

-

9

P. aeruginosa A9843A

0.4

0.19

0.19

1.8

0.45

0.39

0.89

1

P. aeruginosa A24081

-

0.33

0.19

-

-

-

-

0.4

organism

PDS0 / treatment / mg / kg

Ex. 3

Ex. 4

Ex. 7

MK 0787

Ex. 5

MK 0787

S. aureus A9606

0.07

0.1

0.2

0.07

0.2

0.07

E. coli A15119

1

0.4

0.2

3rd

4th

2.2

K. pneumoniae A9664

3rd

3rd

1

3rd

3rd

2.3

P. mirabilis A9900

2nd

4th

2.4

9

10th

9

P. aeruginosa A9843A

0.5

0.2

0.2

0.5

1.6

0.5

P. aeruginosa A24081

0.8

0.2

0.1

0.4

-

-

Blood levels in mice after intramuscular administration

The blood level and half-lives of various compounds of the present compound after intramuscular administration of 20 mg / kg to mice are given below.

Connection c

^ max

(| ig / ml)

* T, / t (min)

** AUC (Hg • h / ml)

example 1

14

10th

6.3

2nd

13.9

9

5.3

3rd

14.5

10th

6.9

4th

C.

15.5

11

7.7

D

6

17.7

9

8.5

1

19.2

11

11.8

8th

18.8

11

10.5

9

16.7

12

8.5

10th

20.1

11

9.5

11

14.9

11

7.4

13

14.8

11

6.4

14

15.8

13

7.6

15 "A"

16.7

12

9.5

15 "B"

15.9

10th

7.4

15 "C"

15.1

10th

7.3

MK 0787

14.6

10th

6

17th

11

-8th

3.4

18th

14.9

6

3.9

19th

27th

16.7

15.1

20th

28.4

14

15.6

The following examples illustrate the invention.

Example I

35 Preparation of l-methyl-4- (2-carboxy-6a (l (R) -hydroxy-ethyl) -7-oxo-l-azabicyclo (3.2) hept-2-en-3-thiomethyl) pyridinium hydroxide -Internal salt

The compounds were solubilized in 0.1 molar phosphate buffer with a pH of 7. The values were based on a single test; 4 mice / connection. 65

* T., refers to the half-life in min.

** AUC refers to the area under the blood concentration-time curve.

"7

ch.

CD2pNB

■ "O" 1

C02pNB

dK3 = —CK-

/ \ N

NO.

656130

36

A solution of 673 mg (1.86 mmol) of p-nitrobenzyl-6a- (l- (R) -hydroxyethyl) -3,7-dioxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate (1) in 10 ml of acetonitrile was cooled to -10 ° C under a nitrogen atmosphere. A solution of 245 mg (1.90 mmol) of diisopropylethylamine in 1 ml of acetonitrile was added, followed by dropwise addition of 510 mg (1.90 mmol) of diphenylchlorophosphate in 1 ml of acetonitrile over a period of 2 min. The solution obtained was stirred at -10 ° C. for 15 min, during which p-nitrobenzyl-3- (diphenylphosphoryloxy) -6cc- (l- (R) -hydroxyethyl) -7-oxo-l-azabicyclo- (3.2.0) hept-2-en-2-carboxylate was obtained. To this solution was added a solution of 245 mg (1.90 mmol) of diisopropylethylamine in 0.5 ml of acetonitrile, followed by a solution of 270 mg (2.16 mmol) of 4-mercaptomethylpyridine in 0.5 ml of acetonitrile. The reaction mixture was stirred at -10 ° C for 60 min and the white precipitate that formed was collected by filtration and washed with 5 ml of ice-cold acetonitrile, giving 660 mg (76% yield) of Compound 2 as white crystals with a melting point of 145 ° C were obtained.

NMR (DMSO-d6) 8: 1.20 (3H, d, J = 6.0 Hz), 3.2-3.4 (3H, m), 3.7-4.1 (2H, m), 4.25 (2H, s), 5.05 (1H, d, J = 4.0 Hz), 5.25 (1H, d, J = 14.0 Hz), 5.48 (1H, d, J = 14.0 Hz), 7.40 (2H, d, J = 5.5 Hz), 7.70 (2H, d, J = 8.5 Hz), 8.23 (2H, d, J = 8 , 5 Hz), and 8.58 (2H, d, J = 5.5 Hz).

IR (KBr) y max: 3400.1790, 1695 and 1600 cm "1.

Analysis for C22 H21N306S:

Calc .: C 58.01 H 4.56 N 9.23 S 7.04%

Found: C 57.75 H 4.56 N9.58 S 7.21%

5 ml of methyl iodide were added to a solution of 660 mg (1.41 mmol) of intermediate 2 in 140 ml of acetone. The reaction solution was stirred at 25 ° C for 8 h. The solvent was evaporated in vacuo to give a pale yellow solid which was triturated with diethyl ether to give 779 mg (90% yield) of the title compound 3 as a white amorphous solid, mp 130 ° C (decomposed).

NMR (DMSO-d6) 8: 1.15 (3H, d, J = 6.0 Hz), 3.2-3.4 (3H, m), 3.7-4.1 (2H, m), 4.25 (3H, s), 4.30 (2H, s), 5.25 (1H, d, J = 14.0 Hz), 5.50 (1H, d, J = 14.0 Hz), 7.70 (2H, d, J = 9.0 Hz), 8.10 (2H, d, J = 7.0 Hz), 8.25 (2H, d, J = 9.0 Hz), and 8 , 90 (2H, d, J = 7.0 Hz).

IR (KBr) ymax: 3400, 1770, 1690 and 1640 cm-1.

Analysis for C23H24N306Si-H20:

Calc .: C44.39 H 4.22 N 6.82 S 5.20%

Found: C 44.66 H 4.01 N 6.84 S 5.64%

B -6

Pò / C

Shaker hydrogenated. The mixture was then filtered and the catalyst was washed with water (2 x 10 ml). The combined filtrates and wash water were extracted with diethyl ether (150 ml) and then lyophilized, whereby a brown Pul-5 was obtained. This raw material was purified on a Cl 8 "BON-DAPAK" reverse phase column (30 g) ("Water Associates"), eluting with water under a pressure of 445 kPa. Each fraction (20 ml) was scanned by high pressure liquid chromatography and fractions with an ultraviolet absorption io at ymax = 300 nm were collected and lyophilized to give 135 mg (32% yield) of the title compound 4 as a pale yellow solid.

NMR (D20) 8: 1.25 (3H, d, J = 6.0 Hz), 2.7-3.2 (2H, m), 3.40 (1H, q, J = 9.0 and 2 , 5 Hz), 3.9-4.2 (2H, m), 4.40 (3H, s), 4.72 (2H, 15 s), 8.10 (2H, d, J = 6.0 Hz), 8.72 (2H, d, J = 6.0 Hz).

IR (KBr) ymax: 3400, 1755, 1640 and 1590 cm- '.

UV ymax (H20): 296 nm (e = 7782), 258 nm (8 = 6913).

Example 2

20 0 =

oe

30th

CR}

i c02pnb

//

.ne

■ f-.

^ -C02pKB

SCH

■ CO.

To a solution of 779 mg (1.27 mmol) of compound 3 in tetrahydrofuran-water-diethyl ether (80 ml-80 ml-100 ml) were added 140 mg (1.4 mmol) of potassium dicarbonate and 125 mg (0.7 mmol) of the dibasic potassium phosphate added. Then 700 mg of 10% palladium on charcoal was added and the mixture was placed on a parrot at 2.27 mPa for 45 min.

co2pnb

50 PBN = p-nitrobenzyl

A suspension of 1.1 g (2.93 mmol) of diazo compound / in 30 ml of dry benzene was blown with nitrogen for 5 min. It was treated with 25 mg rhodium acetate dimer and the mixture was heated under reflux for 45 minutes. The warm solution was diluted with ethyl acetate (25 ml), filtered to remove the catalyst and evaporated to dryness to give keto compound 2 as a white solid. This was dissolved in dry acetonitrile (20 ml) and cooled to 60-10 ° C. To this solution was added diisopropylethylamine (417 mg, 3.2 mmol) under nitrogen, followed by the addition of 810 mg (3.0 mmol) of diphenyl chlorophosphate, and the reaction mixture was stirred at -10 ° C for 20 minutes. The reaction mixture was then treated with diisopropylethylamine 65 (420 mg, 3.2 mmol) and then with 2- (4-pyridyl) ethanethiol (560 mg, 4.03 mmol) in 2 ml acetonitrile ("J. Org. Chem . ", 26, 82 (1961) Ludwig Bauer and Libero A. Gardella Jr.). The reaction mixture was kept at -5 ° C to -10 ° C for 1 h

37

656 130

stirred and then diluted with methylene chloride (100 ml) and washed successively with brine-H20 (1: 1), 4% H3P04, 5% NaHC03, H20 and brine. The organic phase was dried (MgSO4) and evaporated to give a white solid. This solid was washed with diethyl ether: hexane (1: 1) and dried under high vacuum to give 901 mg (63.9%) of compound 3.

IR (KBr) 1790, 1690 cm- '.

NMR (CDCl2 / DMSO) 5: 1.20 (3H, d, J = 3.0 Hz, CH3), 2.8-3.2 (7H, m), 3.9-4.4 (2H, m ), 5.1 (1H, d), 5.4 (2H, q), 7.3 (2H, d), 8.5 (2H, q), 7.76 (2H, d), 8.3 (2H, q).

IR (KBr) 1750, 1640 cm'1.

NMR (D, Ö) 5: 1.30 (3H, d, J = 3.0 Hz), 3.03-5 (7H, m), 4.3 (3H, s), 4.0-4, 5 (3H, m), 7.90 (2H, d), 8.70 (2H, d).

OH

B

CK3I

Example 3

Preparation of 3- (N-methylpyridin-3-yl-inethylthio) -6a - ((1- (R) -hydroxyethyl)) -7-oxo-l-azabicyclo (3.2.0) hept-2-en-2- carboxylate

OH

x tX>

c02pnb

A suspension of carbapenem compound 3 (890 mg, 1.85 mmol) and 7 ml of iodomethane in 200 ml of dry acetone and 12 ml of methylene chloride were stirred at 25 ° C. for 24 hours. The reaction mixture became a clear solution after 18 h. The solvent was removed under reduced pressure and the residue was then washed with diethyl ether to give 920 mg (1.48 mmol, 79.8% yield) of 4 as a foam-like solid.

IR (KBr) 1765, 1690 cm-1.

NMR (DMSO) 5: 1.3 (3H, d, J = 3.0 Hz), 3.1-3.7 (7H, m), 4.1 (3H, m), 4.3 (3H, s), 5.38 (2H, q, J = 7.0 Hz), 8.1 (2H, d, J = 3.0 Hz), 8.9 (2H, d, J = 3.0 Hz) , 7.6 (2H, d, J = 4.0 Hz), 8.2, (2H, d, J = 4.0 Hz).

CO pNB

p-Nitrobenzy! -3- (pyridin-3-yl-methanthio) -6a- ((l- (R) -hydroxy-ethyl)) -7-oxo-l-azabicyclo (3.2.0) hept-2-ene -2-carbaxylate

30 To a cooled solution (0 C) of 925 mg (2.66 mmol) of the keto intermediate 5 in 14 ml of acetonitrile was added to a solution of 377 mg (2.9 mmol) of diisopropylethylamine in 1 ml of acetonitrile followed by 786 mg ( 2.9 mmol) of diphyl chlorophosphate in 1 ml of acetonitrile under hydrogen pressure. The resulting solution was stirred at 0 C for 15 min and then a solution of 377 mg (2.9 mmol) of 3-Mcrcaptomeihyl-pyridine (prepared according to the method described in Can. J. Chem. 56, 3068 ( 1978) is added) in 2 ml of acetonitrile. The solution was stirred at 0 C for 90 min. The precipitate was collected by filtration 40 and washed with 20 ml of ethyl acetate to give 950 mg (60% yield) of the title product as white crystals.

NMR (DMSO-d6) S: 1.30 (3H, d, J = 6.0 Hz), 3.4-4.2 (5H, m), 4.25 (2H, s), 5.1 (1H , d, J = 4.5 Hz), 5.40 (2H, ABq, J = 14.4 Hz), 45 7.2-8.5 (8H, m).

IR (KBr) ymax: 3500, 1775, and 1580 cm- '.

Analysis for C ^ Ht ^ O ^ S,:

Calc .: C 58.01 H 4.65 N 9.23 S 7.04%

so found: C 57.19 H 5.19 N 8.76 S 7.08%

The carbapenem 4 (920 mg, 1.47 mmol), dissolved in 90 ml of tetrahydrofuran, 90 ml of diethyl ether and 90 ml of water, were treated with 265 mg (1.51 mmol) of dibasic potassium phosphate, 190 mg (1.9 mmol) of potassium hydrogen carbonate and 800 mg of 10% palladium-on-carbon treated. It was hydrogenated at a pressure of 3 MPa for one hour. The catalyst was filtered off with "Celite" and the filtrate was washed with diethyl ether (3 x 25 ml). The aqueous layer was freeze-dried to give a brownish material which was subsequently subjected to chromatography twice on a 12 g CIS "Bondapak" Reverse phase column (Waters Associates) (H20) purified to give 55 mg of J.

656 130

38

3- (N-Methylpyridin-3-yl-methylthio) -6a- ((I- (R) -hydroxy-ethyl)) -7-oxo-I-ci'ahicyclo (3.2.0) hep t-2-ene carboxylate

5 ml of methyl iodide were added to a solution of 730 mg (1.56 mmol) of compound 19 in 120 ml of acetone and the reaction mixture was stirred at room temperature for 18 h. The precipitate was collected by filtration and washed with acetone (10 ml) to give 940 mg (100% yield) of the quaternized pyridine 20 as a pale yellow powder.

NMR (DMSO-d6) 8: 1.25 (3H, d, J = 5.8 Hz), 3.6-4.3 (5H, m), 4.20 (3H. S), 4.25 (2H, s), 5.25 (1H, d, J = 7.2 Hz), 5.40 (2H, ABq, J = 12.16 Hz), and 7.6-9.2 (9H, m).

IR (KBr)) onax: 3300, 1765 and 1690 cm-1 ..

Analysis for C23H24N306S, I,:

Calc .: C 46.24 H 4.05 N 7.03 S 5.3-7%

Found: C 45.82 H 4.11 N 6.87 S 6.10%

To a solution of 933 mg (1.6 mmol) of compound 20 in 90 ml of tetrahydrofuran and 90 ml of ether were added 200 mg of KHC03 and 349 mg of K.2HP04 in 90 ml of water, followed by 1.0 g of palladium-on- Charcoal added. The mixture was hydrogenated at a pressure of 3 MPa, on a Parr shaker for 45 min. The mixture was filtered with "Celite" and the catalyst was washed with water (2 × 10 1). The combined filtrates and wash water were extracted with ether (2 × 100 ml) and lyophilized to give a yellow solid which was placed on a C13 - "Bondapak" - (Waters Associates) reverse phase column (8 g) cleaned, with 5% acetonitrile in water, eluted under a pressure of 550 kPa. Each 15 ml fraction was subjected to high pressure liquid chromatography and fractions with UV absorption at> .max 300 nm were collected and lyophilized to give 230 mg (43% yield) of the title product as pale yellow crystals, melting point 130 "C (decomposition).

NMR (D, 0) 8: 1.25 (3H, d, J '7.0 Hz), 3.12 (2H, d, d, J = 7.9 Hz, 1.6 Hz), 3, 42 (IH, q, J = 7.2 Hz, 1.6 Hz), 3.9-4.6 (3H, m), 4.25 (2H, s), 4.42 (3H, s) and 8.0-9.0 (4H, m).

IR (KBr) -ymax: 3400, 1750 and 1580 cm ". '.

UV Xmax (H20): 298 nm (see 8058).

Analysis for C16H18N204S, -2H20:

Calc .: C 51.87 H 5.44 N 7.56%

Found: C 51.95 H 5.66 N 7.56% '

OH

CH,

CO.

Example 4

Preparation of 3- (N-methylpyridin-2-yl-methyl) -6a - ((1- (R) -hydroxyethyl)) -7-oxo-Ia: akicyclo (3.2.0) hept-2-en-2- carboxylate

OH

HS

12

p-nitrobene: yl-3- (pyridin-2-methylthio) -6a- ((I- (R) -hydroxyethyl)) -7-oxo-la: abicyclo (3.2.0) hept-2-en-2- carboxylate

To a cooled solution (0 C) of 925 mg (2.65 mmol) of the keto intermediate J in 14 ml of acetonitrile was added a solution of 377 mg (2.92 mmol) of diisopropylethylamine in 1 ml of acetonitrile, followed by 386 mg (2 , 90 mmol) of diphenyl chlorophosphate in 1 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred at 0 C for 15 min and then a solution of 277 mg (2.92 mmol) diisopropylethylamine in 1 ml acetonitrile, followed by 350 mg (3.0 mmol) 2-mercaptomethylpyridine (prepared according to the method described in Can. J. Chem., 56, 3068 (1978)) in 1 ml of acetonitrile. The reaction solution was stirred at -10'C for 2 hours. The precipitate was collected by filtration and washed with 20 ml of methylene chloride to give 650 mg (54% yield) of the title product as a yellow powder.

NMR (DMSO-d6) 8: 1.26 (3H 'd, 3 = 1.0 Hz), 2.7-3.5 (dH, m), 3.9-4.3 (2H, m), 4.2 (2H, s), 5.42 (2H, ABq, J = 14.4 Hz) and 7.2-8.8 (8H, m).

IR (KBr) ymax: 3400, 1775 and 1690 cm "'.

Analysis for C22H2iN306S1: 4

Calc .: C 58.01 H 4.65 N 9.23 S 7.04%

Found: C 57.56 H 4.92 N 8.94 S 7.03%

OH

OH

CH, I

acetone

CO-pNB

22

Pd / C

CH

CH.

CO.

3- (N-methylpyridin-2-yl-methylthio) -6a- ((l- (R) -hydroxy-ethyl)) - 7-oxo-l-azabicyclo (3.2.0) hept-2-en-2- carboxylate

4 ml of methyl iodide was added to a solution of 650 mg (1.93 mmol) of compound 22 in 100 ml of acetone. The reaction mixture was stirred for 3 d at room temperature. The precipitate was collected by filtration and washed with acetone (10 ml) to give 500 mg (60% yield) of the quaternized pyridine 23 as a pale yellow solid.

NMR (DMSO-d6) 8: 1.26 (3H, d, J = 7.0 Hz), 3.9-4.2 (2H, m), 4.4 (3H, s), 4.78 ( 2H, s), 5.2 (1H, d, J = 3.9 Hz), 5.50 (2H, ABq, J = 14 Hz) and 7.8-9.4 (8H, m).

IR (KBr) ymax: 3400, 1765 and 1690 cm-1.

Analysis for C23H24N30 (5S, I1:

Calc .: C 46.24 H 4.05 N 7.03 S 5.37%

Found: C 45.62 H 4.27 N 6.80 S 5.30%

To a solution of 1.0 g (1.167 mmol) of compound 23 in 90 ml of tetrahydrofuran and 90 ether were added 215 mg (2.15 mmol) of KHC03 and 374 mg (2.1 mmol) of K2HP04 in 90 ml of water, followed by 1 , 0 g 10% palladium-on-carbon, added. The mixture was hydrogenated at a pressure of 3 MPa, on a Parr shaker for 45 min. The mixture was then filtered with "Celite" and the catalyst was washed with water (2x10 ml). The combined filtrates and wash water were extracted with ether

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

39

656 130

(2 x 200 ml) and lyophilized to give a yellow solid which was purified on a C18 "Bondapak" (Waters Associates) reverse phase column (10 g), eluting with 5% acetonitrile in water under a Pressure of 545 kPa. Each 15 ml fraction was subjected to high pressure liquid chromatography and fractions with UV absorption at X.max 3 mm were collected and lyophilized to give 390 mg (44% yield) of the title product, recrystallization of this material from water-acetone-ethanol gave fine needles, mp 194-196 ° C (decomposition).

NMR (D20) 5: 1.30 (3H, d, J = 6.2 Hz), 3.2 (2H, q, J = 9.0 Hz, 3.6 Hz), 3.46 (1H, q , J = 6.0 Hz, 2.7 Hz), 4.1-4.6 (3H, m), 4.60 (3H, s) and 7.9-8.9 (4H, m).

IR (KBr) Ymax .: 3400, 1755 and 1590 cm- '.

UV A.max (H20): 292 nm (s = 8092).

Analysis for • 2H20:

Calc .: Found .:

C 51.87 H 5.44 N 7.56% C 51.37 H 5.69 N7.37%

Example 5

Preparation of 3- (N-methylpyridin-2-yl-ethylthio) -6a - ((l- (R) -hydroxyethyl)) -7-oxo-l-azabicyclo (3.2.0) hept-2-en-2- carboxylate co2pnb

55

WC

20th

p-nitrobenzyl-3- (pyridin-l-yl-ethylthio) -6a- ((l- (R) -hydroxyethyl)) ■ 7-oxo-l-azabicyclo (3.2.0) hept-2-en-2- carboxylate

To a chilled solution of 1.78 g (5.0 mmol) of keto intermediate 5 in 25 ml acetonitrile was added 71Ó mg (5.5 mmol) diisopropylamine in 1 ml acetonitrile, followed by 1.4 g (5.0 mmol) of diphenylchlorophosphate in 1 ml of acetonitrile added under a nitrogen atmosphere. The obtained solution was stirred at 0 ° C for 20 minutes, and then 710 mg (5.5 mmol) of diisopropylethylamine in 1 ml of acetonitrile, followed by a solution of 850 mg (6.1 mmol) of the thiol 54 (prepared by the method , which is described in J. Org. Chem., 26, 82 (1961)) in 2 ml of acetonitrile. The reaction mixture was stirred at 0 ° C for 60 min. The precipitate was collected by filtration and washed with methylene chloride (20 ml) to give 1.3 g (57%) of the title compound as a yellow solid.

NMR (CDC13) 5: 1.25 (3H, d, J = 6.5 Hz), 2.6-3.4 (7H, m), 4.2-4.6 (2H, m), 5, 30 and 5.65 (1H all, ABq, J = 14 Hz) and 7.2-8.5 (8H, m).

IR (KBr) ymax: 3400, 1780 and 1680 cm- '.

'2 56

3- (N-Methyl-pyridin-2-yl-ethylthio) -6a- ((l- (R) -hydroxyethyl)) -7-oxo-azabicyclo (3.2.0) hept-2-en-2-carboxylate

5 ml of methyl iodide were added to a suspended solution of 800 mg (1.7 mmol) of compound 53 in 50 ml of acetone.

30 The reaction mixture was stirred at room temperature for 48 h. The precipitate was collected by filtration and washed with acetonitrile (15 ml) to give 810 mg (76% yield) of the quaternized pyridine 55 as a light yellow powder.

35 NMR (DMSO-d6) 5: 1.20 (3H, d, J = 5.6 Hz), 3.2-4.3 (9H, m), 4.20 (3H, s), 5.26 and 5.55 (1H all, ABq, J = 15 Hz) and 7.8-9.2 (8H, m).

IR (KBr) ymax: 3400.1770 and 1690 cm-1.

To a solution of 790 mg (1.27 mmol) of compound 55 in

40 100 ml of tetrahydrofuran and 100 ml of ether were added to 100 ml of a pH = 7.0 buffer solution, followed by 1.0 g of palladium-on-carbon. The mixture was hydrogenated at a pressure of 2.72 MPa, on the Parr shaker for 40 min. The mix was through. "Celite" filtered and the catalyst was washed with water

45 water (2 x 10 ml) washed. The combined filtrate and wash water were extracted with ether (3 x 100 ml) and lyophilized to give a yellow powder which was purified on a C18 "Bondapak" column (30 g) (Waters Associates) and washed with 10% acetonitrile in Water, eluted at a pressure of 545 kPa.

50 Each 15 ml fraction was subjected to high pressure liquid chromatography and the fractions with UV absorption. at Xmax 300 nm were collected and lyophilized to give 65 mg (15% yield) of the title product as a yellow powder.

55 NMR (D20) 5: 1.25 (3H, d, J = 6.2 Hz), 3.1-3.6 (7H, m), 4.0-4.3 '(2H, m), 4.32 (3H, s) and 7.8-8.9 (4H, m).

IR (KBr) ymax: 3400, 1750 and 1590 cm-1.

UV Xmax: (H20): 300 nm (e = 8108).

60

Oh

656130

40

Example 6

Preparation of 3- (l-propylpyridin-4-yl-methylthio) -6a - ((l- (R) -hydroxyethyl)) -7-oxo-l-azabicyclo (3.2.0) hept-2-en-2- carboxylate.

OH OH

S

CO-pNB

CO-pNB

S SI

p-nitrobenzyl-3- (pyridin-4-yl-methyltliio) -6a - ((l- (R) -hydroxy-ethyl)) -7-oxo-I-azabicyclo (3.2.0) hept-2-en- 2-carboxylate

A solution of 673 mg (1.86 mmol) of p-nitrobenzyl-6a - ((- (R) -hydroxyethyl)) - 3,7-dioxo-l-azabicyclo (3.2.0) hept-2-en-2- carboxylate (5) in 10 ml acetonitrile was cooled to -10 ° C under a nitrogen atmosphere. A solution of 275 mg (1.90 mmol) diisopropylethylamine in 1 ml acetonitrile was added, followed by dropwise addition of 510 mg (1.90 mmol) diphenyl chlorophosphate in 1 ml acetonitrile over a period of 2 min. The resulting solution was stirred at -10 ° C for 15 min, during which p-nitrobenzyl-3- (diphenylphosphoryloxy) -6a - ((l- (R) -hydroxy-ethyl)) - 7-oxo-l-azabicyclo (3.2 .0) hept-2-en-2-carboxylate was obtained. To this solution was added a solution of 245 mg (1.90 mmol) of diisopropylethylamine in 0.5 ml of acetonitrile, followed by a solution of 270 mg (2.16 mmol) of 4-mercaptomethylpyridine in 0.5 ml of acetonitrile. The reaction mixture was stirred at -10 ° C for 60 min and the white precipitate formed was collected by filtration and washed with 5 ml of ice-cooled acetonitrile, giving 660 mg (76% yield) of compound 51 as white crystals with a melting point of 145 ° C was obtained.

NMR (DMSO-d6) 5: 1.20 (3H, d, J = 6.0 Hz), 3.2-3.4 (3H, m), 3.7-4.1 (2H, m), 4.25 (2H, s), 5.05 (1H, d, J = 4.0 Hz), 5.35 (1H, d, J = 14.0 Hz), 5.48 (1H, d, J = 14.0 Hz), 7.40 (2H, d, J = 5.5 Hz), 7.70 (2H, d, J = 8.5 Hz), 8.23 (2H, d, J = 8 , 5 Hz) and 8.58 (2H, d, J = 5.5 Hz).

IR (KBr) ymax: 3400.1790 and 1695 cm-1.

Analysis for C22H2iN306S:

Calc .: C58.01 H 4.56 N9.23 S 7.04%

Found: C 57.74 H 4.56 N9.58 S 7.21%

OH

- /

OH

He

S

acetone

3- (l-allyl-pyridin-4-yl-methylthio) -6a- ((l- (R) -hydroxy-ethyl)) -7-oxo-l-azabicyclo (3.2.0) hept-2-en- 2-carboxylate

2 ml of allyl bromide and 380 mg of sodium iodide were added to a solution of 900 mg (2.13 mmol) of compound 5 / in 150 ml of acetone. The mixture was stirred at room temperature for 48 hours and the solvent was evaporated in vacuo to give a yellow solid. This material was suspended in 120 ml of acetonitrile, filtered and evaporated in vacuo to give 1.0 g (87% yield) of the title product as a yellow solid.

NMR (CD3CN) 5: 1.20 (3H, d, J = 6.2 Hz), 3.0-3.4 (4H, m), 4.0-4.4 (4H, m), 5, 1-5.6 (4H, m) and 7.4-7.9 (8H, m).

IR (KBr) ymax: 3400.1700 and 1690 cm-1.

Analysis for QwHmNsCW ^

Calc .: C48.16 H 4.21 N6.74 S 5.15%

Found: C 48.55 H 4.46 N6.69 S 5.15%

OH

S

52 OH

Pd / C

2nd

CO,

2nd

53

3- (l-propyl-pyridin-4-yl-methylthio) -6a- ((-! - (RJ-hydroxyethyl)) -7-oxo-la: abicyclo (3.2.0) hept-2-en-2- carboxylate

To a solution of 1.27 g (2.15 mmol) of Compound 52 in 100 ml of tetrahydrofuran and 100 ml of ether was added 100 ml of pH = 7.0 buffer solution, followed by 1.0 g of 10% palladium on carbon . The mixture was hydrogenated on the Parr shaker at a pressure of 2.72 MPa for 40 minutes. The mixture was filtered through "Celite" and the catalyst was washed with water (2x10 ml). The combined filtrates and wash water were extracted with ether (3 x 100 ml) and lyophilized to give a yellow powder which was measured on a Q s - "Bondapak" column (Waters Associates) (40 g) was purified and eluted with 10% acetonitrile in water under a pressure of 545 kPa. Each 15 ml fraction was subjected to high pressure chromatography and the fractions with UV absorption at Xmax 300 nm were collected and lyophilized to give 48 mg (6% "yield) of the title product as a yellow powder.

NMR (D, 0) 5: 0.95 (3H, t, J = 7.5 Hz), 1.25 (3H, d, 7.0 Hz), 2.05 (2H, sextet, J = 7, 5 Hz), 3.10 (2H, dd, J = 10Hz, 2.5 Hz), 3.35 (1H, dd, J = 6.5 Hu, 2.5 Hz), 4.0-4.8 (6H, m), 7.1 (2H, d, J = 6.0 Hz) and 7.8 (2H, d, J = 6.0 Hz).

IR (KBr) ymax: 3400, 1750 and 1590 cm "'.

Analysis for CI8H22N2C> 4.S * 2H20:

Ber. : C 54.52 H 6.10 N 7.07%

Found: C 54.32 H 6.03 N6.99%

OH

CH.

CO.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

41

656130

Example 7

Preparation of 3- (N-methyl-3-methylpyridin-2-inethylthio) 6-a- ((1- (R) -hydroxyethylj j-7-oxo-azabicyelo (3.2.0) hept-2-en-2- carboxylate

H-N ^ î

l) H2N ^ NH2

2) NaOH

3-methyl-2-mercaptomethyl-pyridine

A solution of 2.45 g (17.0 mmol) of the chlorine compound 36 and 1.37 g (18.0 mmol) of thiourea in 60 ml of absolute ethanol were heated under reflux for 5 h. Evaporation of the ethanol followed by the addition of ether gave 3.08 g (72% yield) of the isothiouronium salt which was dissolved in 10 ml of water containing 1.44 g (26 mmol) of sodium hydroxide. The solution was then heated to 100'C for 5 min under a nitrogen atmosphere. The reaction mixture was cooled to 5 ° C., the pH was adjusted to 6.4 by adding acetic acid and the mixture was then extracted with ether (4 × 50 ml). The combined ether extracts were washed with 5% aqueous sodium bicarbonate and brine. Evaporation of the dried (MgS04) solvent gave 1.4 g (83% yield) of thiol 37 as a yellow oil which was used for the next step without further purification.

NMR (CDCy 5: 2.20 (3H, s), 2.5-2.7 (1H, broad s), 3.8 (2H, t, J = 6.5 Hz) and 6.9-8, 2 (3H, m).

_s.y / \ p ^ J.1

C02pNB CH u Pd / C 39 © SO.F

2)

C02pNB

38

37

p-nitrobenzyl-3- (methyl-pyridin-2-yl-methylthio) -6a- ((l- (R) -hydro-xyethyl)) -7-oxo-l-azabicyclo (3.2.0) hept-2- en-2-carboxylate

To a cooled (0 ° C) solution of 1.74 g (5.0 mmol) of the Ke-to intermediate 5 in 25 ml of acetonitrile was added 960 mg (5.8 mmol) of diisopropylethylamine in 2 ml of acetonitrile, followed by 1.4 g (5.8 mmol) of diphenyl chlorophosphate in 2 ml of acetonitrile were added under a nitrogen atmosphere. The solution obtained was stirred at 0 ° C. for 20 min and a solution of 760 mg (5.8 mmol) of diisopropylethylamine in 2 ml of acetonitrile was then added, followed by 810 mg of mercaptomethyl-pyridine 37 in 3 ml of acetonitrile. The reaction mixture was stirred at 0 ° C for 2 h. The precipitate was collected by filtration and washed with acetonitrile to give 1.56 g (66% yield) of the title product as a white solid. Mp 145 ° C.

NMR (DMSO-d6) 5: 1.23 (3H, d, J = 6.5 Hz), 230 (3H, s), 3.1-4.3 (6H, m), 4.35 (2H , s), 5.20 and 4.45 (1H all, ABq, J = 15.0 Hz) and 7.3-8.4 (7H, m).

IR (KBr) ymax: 3400, 1767 and 1695 cm "1.

Analysis for C24H26N3O9S2F:

Calc .: C 47.91 H 4.69 N 6.98 S 10.66%

Found: C 47.71 H 4.34 N 6.72 S 11.22%

3- (N-Methyl-3-3-methyl-pyridin-2-yl-methylthio) -6a- ((I- (R) -hydroxyethyl) -7-oxo-azabicyclo (3.2.0) hept -2-en-2-carboxylate

20 To a solution of 680 mg (1.45 mmol) of compound 38 in 120 ml of methylene chloride was added 270 mg (2.33 mmol) of methyl fluorosulfonate. The reaction mixture was stirred at room temperature for 2 hours. The precipitate was collected by filtration and washed with methylene chloride (5 ml) to give 25,840 mg (99% yield) of the quaternized pyridine 39 as white crystals.

NMR (DMSO-d6) 8: 1.15 (3H, d, J = 5.8 Hz), 2.62 (3H, s), 3.2-4.4 (5H, m), 4.45 ( 3H, s), 4.60 and 4.82 (1H all, ABq, J = 9.2 Hz), 5.30 and 5.46 (1H all, ABq, J = 12.8 Hz) and 7.6 -8.9 (7H, m). 30 IR (KBr) ymax: 3400, 1750 and 1590 cm-1.

Analysis for C24H24N309S2F:

Calc .: C 49.14 H 4.47 N 7.13 S 11.43%

Found: C49.56 H 4.16 N 7.26 S 11.03%

35 To a solution of 810 mg (1.39 mmol) of compound 39 in 100 ml of tetrahydrofuran and 100 ml of ether was added 100 ml of p-7.0 buffer solution, followed by 750 mg of 10% palladium-on-carbon. The mixture was hydrogenated at a pressure of 3 MPa on the Parr shaker for 60 min in a cold room (4-6 ° C). The mixture was filtered through "Celite" and the catalyst was washed with ether (2 x 10 ml). The combined filtrates and wash water were filtered with ether (2 x 40 ml) and lyophilized to give a yellow solid which was separated a C18 "Bondapak" column (Waters Associates) (20 g) was purified; 45 was eluted with 5% acetonitrile in water under a pressure of 545 kPa. Each 15 ml fraction was subjected to high pressure liquid chromatography and the fractions with UV absorption at Xmax 300 nm were collected and lyophilized to give 141 mg (30% yield) of the title product as a yellow solid.

NMR (D20) 5: 1.24 (3H, d, J = 7.0 Hz), 2.62 (3H, s), 3.2-3.5 (3H, m), 4.2-4, 4 (2H, m), 4.45 (3H, s), 4.50 and 4.59 (1H all, ABq, J = 12.6 Hz), 7.82 (1H, q, J = 7.0 Hz, 6.5 Hz), 8.35 (1H, d, J = 7.0 Hz) and 8.65 (1 H, d, J = 6.5 Hz).

55 IR (KBr) ymax: 3400, 1750 and 1580 cm "'.

UV Xmax (H20): 296 nm (s = 8014).

Analysis for CI7H20N2O4S, • '/ 4H20:

Calc .: C 57.85 H 5.85 N7.94%

«0 Found: C 58.60 H 5.86 N 7.87%

-Me

656130

42

Example 8

Preparation of 3- (2-methyl-N-methylthiazol-4-yl-methylthio-6a- ((l- (R) -hydroxyethyl)) -7-oxo-l-azabicyclo (3,2.0) heptene-2-carboxylate p-nitrobenzyl-3- ((2-methyl-thiazol-4-yl-methylthio)) -6a- ((I- (R) -hydroxyethyl)) - 7-oxo-l-azabicyclo (3.2.0) hept- 2-en-2-carboxylate

To a cooled (0 'C) solution of 1.4 (4.0 mmol) of the keto intermediate J in 12 ml of acetonitrile was added 0.83 ml (4.6 mmol) of diisopropylethylamine, followed by 1.6 g (4, 3 mmol) of di-phenylchlorophosphate in 2 ml of acetonitrile were added under a nitrogen atmosphere. -hydroxyethyl)) - 7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate was obtained. To this solution was added a solution of 0.83 ml (4.6 mmol) of diisopropylethylamine in 2 ml of acetonitrile, followed by a solution of 0.62 g (4.2 mmol) of 2 methyl-4-mercaptomethyl-thiazole (prepared by the method described in J. Amer. Chem. Soc., 71, 3570 (1949)) in 3 ml of acetonitrile. The reaction solution was stirred for 40 min at 0 "C. The precipitate was collected and washed with ether (30 ml), whereby 942 mg of the title product was obtained as a white solid.

NMR (CDC13) 5: 1.32 (3H, d, J = 7 Hz), 2.68 (3H, m), 3.76 (1H, d, J = 5.5 Hz), 4.16 (2H , s), 4.20 (1H, m), 5.40 2H, q, J = 14Hz), 7.06 (1H, s), 7.68 (2H, d, J = 8 Hz) and 8, 24 (2H, d, J = 8 Hz).

IR (KBr) ymax: 3500, 1770 and 1700 cm-1.

Hydrogenated on a Parr shaker for 45 min. The mixture was filtered through "Celite" and the catalyst was washed with water (2x 10 ml). The combined filtrates and wash water were extracted with ether (2x 100 ml) and lyophilized to give a yellow powder, which was coated on a CI8 "Bondapak Reverse Phase Column" (8 g) (Water Associates) was purified, eluted with 5% acetonitrile in water under a pressure of 545 kPa. Each 15 ml fraction was subjected to high pressure liquid chromatography and fractions with an ultraviolet absorption at /.max 300 nm were collected and lyophilized to give 145 mg (48% yield) of the title compound as a pale yellow powder.

NMR (CDCI3) 5: 1.20 (3H, d, J = 7 Hz), 2.92 (3H, S), 3.08 (1H, d, J = 3.5 Hz), 3.20 (IH .-d, H = 3 Hz), 3.44 (1H, dd, J = 1 Hz, J = 15 3.5 Hz), 4.00 (3H, 5), 4.20 (3H, m), 4.36 (2H, m) and 7.88 (1H, s).

IR (KBr) Xmax: 3400.1750 and 1585 cm "'.

UV A.max (H20): 296 nm (s = 7500).

Analysis for C15H18N204S2-2H20:

Calc .: Found .:

C 46.15 H 5.64 N7.17 S 16.41% C 46.50 H 5.26 N7.13 S 16.20%

CH,

Example 9

Preparation of 3- (N, N'-dimethyl-imidazol-2-yl-methylthio) -6a- [1- (R) -hydroxyethyl] -7-oxo-l-azabicyclo (3.2.0) hept-2-ene -2-carboxylate

CH. 1 ■>

U

35

w

Cl

1)

JLh

K2N - ^> K -

Ac

HCl

23

EtOK, A

ch3 -X

HCl

SH

31

32

C02 «3

3- (2-Methyl-N-methylthiazol-4-yl-methylthio) -6a- ((1- (R) -hydroxyethyl)) -7-oxo-l-azabicyclo (3.2.0) hept-2- en-2-carboxylate

0.27 ml (3.3 mmol) of methyl fluorosulfonate was added to a solution of 525 mg (1.1 mmol) of compound 9 in 20 ml of methylene chloride. The reaction mixture was stirred at room temperature for 90 minutes. The precipitate was collected by filtration and washed with methylene chloride (50 ml) to give 650 mg (100% yield) of the quaternized thiazole 10, which was used for the next reaction step without further purification.

100 ml of pH = 7.0 buffer solution were then added to a solution of compound 10 in 100 ml of tetrahydrofuran and 100 ml of ether, followed by 500 mg of 10% palladium-on-carbon. The mixture was held at a pressure of 2.38 MPa

2-mercaptomethyl-N-methylimidazole

To a solution of 10.4 g (58 millimoles) of 2-chloromethyl-N-methylimidazole 31 [prepared by the method described in J. Amer. Chem. Soc., 71, 383 (1949)] in 200 ml of acetonitrile 45, 7.1 g (60 millimoles) of N-acetylthiourea were added and the reaction mixture was heated under reflux for 90 minutes. The residue was filtered and washed with acetonitrile (20 ml) to give the isothiouronium salt, which was then dissolved in 120 ml of ethanol and then heated under 50 reflux for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated in vacuo to about 60 ml volume and the precipitate was removed by filtration. Evaporation of the filtrate in vacuo gave 2-mercaptomethyl-N-methyl-55 imidazole 32 as a yellow oil, which was used for the next step without further purification.

NMR (D20) 8: 3.90 (3H, s), 4.10 (2H, s) and 7.25 (2H, S).

60

CH.

1 0

32

43

656 130

p-nitrobenzyl-3- [N-methylimidazol-2-ylmethylthio] -6a- [1- (R) -hydroxyethyl] -7-oxo-l-azabicyclo (3.2.0) hept-2-en- 2-carboxylate

To a chilled (0 ° C) solution of 7.24 g (20.3 millimoles) of keto intermediate 5 in 35 ml of acetonitrile was added 2.8 g (21.3 millimoles) of diisopropylethylamine in 2 ml of acetonitrile, followed by 5 , 5 g (20.4 millimoles) of diphenyl chlorophosphate in 2 ml of acetonitrile, under a nitrogen atmosphere. The resulting solution was stirred at 0: C for 15 minutes and then a solution of 4.1 g (3.0 millimoles) of diisopropylethylamine in 2 ml of acetonitrile was added, followed by 4.6 g (31.0 millimoles) of the thiol 32. The reaction mixture was stirred at 0 ° C for 60 minutes. The white precipitate is collected by filtration and washed with methylene chloride (20 ml) to give 6.6 g (71% yield) of the title compound as a white solid. Mp 142 ° C.

NMR (DMSO-d6) 8: 1.32 (3H, d, J = 7.0 Hz), 3.2-4.5 (5H, m), 3.2 (2H, s), 3.9 ( 3H, s), 5.50 (2H, ABq, J = 14.0 Hz), 7.65 (2H, d, J = 6.5 Hz), 7.70 (2H, s) and 8.24 ( 2H, d, J = 6.6 Hz).

IR (KBr) Ymax: 3450.1770 and 1690 cm-1.

Analysis for C21H20N4O6S1 • 1 'Aii20:

Calc .: C 52.18 H 4.79 N 11.59%

Found: C 52.22 H 4.91 N 12.16%

with 10% acetonitrile in water under a pressure of 545 kPa. Each 20 ml fraction was subjected to high pressure liquid chromatography and the fractions which had UV absorption at tanax 300 nm were collected and lyophilized to give 220 mg (35% yield) of the title compound as a yellow powder.

NMR (D20) 8: 1.12 (3H, d, J = 7.0 Hz), 3.08 (1H, dd, J = 13.0 Hz, 6.4 Hz), 3.15 (1H, dd , J = 13.0 Hz, 6.4 Hz), 3.45 (1H, dd, J = 3.2 Hz, 4.5 Hz), 3.85 (6H, s), 4.1-4, 2 (2H, m), 4.40 (1H, d, J = 13.5 Hz), 4.52 (1H, d, J = 13.5 Hz) and 7.40 (2H, s).

IR (KBr) ymax: 3500, 1750 and 1590 cm "1.

UV tanax (H20): 296 nm (e = 8411).

Analysis for Ci5H19N304S-H20:

Calc .: C 51.68 H 5.67 N 12.06 S 9.50%

Found: C 49.93 H 5.94 NI 1.46 S 9.03%

OH

25 Example 10

Preparation of 3- (2,3,4-trimethylthiazol-5-yl-methylthio) -6a- [1- (R) -hydroxyethyl] -7-oxo-l-azabicyclo (3.2.0) hept-2- en-2-carboxylate

1) H.KA.NH

CH-

2) KaQH

SH

'ch.

47

3-N, -N'-Dimethyl-imidazol-2-yl-methylthio) -6a- [l- (R) -hydroxy-ethyl] -7roxo-l-azabicyclo (3.2.0) hept-2-en-2 carboxylate

To a suspended solution of 1.34 g (3.0 millimoles) of compound 33 in 270 ml of acetone was added 20 ml of methyl iodide. The reaction mixture was stirred at room temperature for 4 days. The precipitate was collected by filtration and washed with acetone (20 ml) to give 1.70 g (96% yield) of the quaternized imidazole 34 as yellow crystals with a melting point of 175-177 ° C.

NMR (DMSO-d6) 8: 1.10 (3H, d, H = 6.2 Hz), 3.30 (2H, s), 3.2-4.3 (6H, m), 3.95 ( 6H, s), 5.45 (2H, ABq, J = 14 Hz), 7.65 (2H, d, J = 6.0 Hz).

IR (KBr) v max: 3400.1750 and 1600 cm1.

Analysis for C21H22N4OeS1:

Calc .: C43.08 H 9.60 N5.48%

Found: C 43.02 H 9.02 N5.44%

To a solution of 1.30 g (1.86 millimoles) of compound 34 in 120 ml of tetrahydrofuran and 120 ml of ether was added 120 ml of pH = 7.0 buffer solution, followed by 900 mg of 30% palladium from "Celite" Mixture was hydrogenated at 2.72 nPa pressure on the Parr shaker for 40 minutes, the mixture was filtered through Celite and the catalyst was washed with water (2x15 ml). The combined filtrates and wash water were washed with ether (3 x 100 ml) and lyophilized to give a yellow amorphous powder which was purified on a C18 "Bonda-pak (Waters Associates) column (30 g)" was eluted

2,4-dimethyl-5-mercaptomethyl-thiazo!

To a solution of 4.8 g (26.0 millimoles) of chlorine compound 40 46 [prepared by the method described in J. Amer. Chem. Soc., 104, 4461 (1982)] in 50 ml of absolute ethanol

2.4 g (30 millimoles) of thiourea were added. The reaction mixture was heated under reflux for 18 hours. The precipitate was collected by filtration and washed with ether (20 ml)

Wash 45 to give the isothiouronium salt, which was dissolved in 22 ml of 1 normal sodium hydroxide solution and heated at 100 ° C under a nitrogen atmosphere for 4 minutes. The reaction mixture was then cooled to room temperature, the pH was adjusted to 7.0, extracted with 1-normal-50 hydrochloric acid and with ether (3 × 50 ml). The combined ether phases were washed with water and brine and over MgS04.

Evaporation of the dried solution gave 780 mg (49% yield) of thiol 47 as a colorless oil which was used for the next 55 step without further purification.

NMR (DC13) 8: 2.05 (3H, s), 2.35 (3H, s) and 3.60 (2H, d, J =

6.5 Hz).

IF

X

ci P (o «.

■>

.CH.0

4S

656130

44

P-nitrobenzyl-3- [2,4-dimethyl-thiazol-5-yl-methylthio] -6a- [1- (RJ-hydroxyethyl) -7-oxo-I-azabicyclo (3.2.0) hept-2-ene -2-carboxylate

To a chilled (0 ° C) solution of 1.4 g (4.0 millimoles) of keto intermediate 5 in 25 ml acetonitrile was added 610 mg (4.7 millimoles) diisopropylethylamine in 1 ml acetonitrile, followed by 1.15 g (4.3 millimoles) of diphenyl chlorophosphate in 1 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred at 0 C for 20 minutes and then a solution of 610 mg (4.7 millimoles) of diisopropylethylamine in 1 ml of acetonitrile was added, followed by 750 mg (4.7 millimoles) of thiol 47 in 2 ml of acetonitrile. The reaction mixture was stirred at 0 ° C for 3 hours. The precipitate was collected by filtration and washed with methylene chloride (20 ml) to give 1.14 g (61% yield) of the title compound as a white solid.

NMR (DMSO-d6) 5: 1.25 (3H, d, J = 6.4 Hz), 2.30 (3H, s), 2.65 (3H, s), 3.1-3.4 ( 3H, m), 4.10 (1H, broad s), 4.0-4.5 (3H, m), 5.25 and 5.50 (1H each ABq, J = 4 Hz), 7.68 ( 2H, d, J = 8.5 Hz) and 8.25 (2H, d, J = 8.5 Hz).

IR (KBr) ymax: 3500, 1770 and 1690 cm "1.

Analysis for C22H23N3OäS2:

Calc .: C 53.73 H 4.71 N 8.57 S 13.44%

Found: C 53.97 H 4.74 N 8.58 S 13.10%

OH

.CH.

ai.

CH.

48

OH

.CH.

CH.

CO.

SO

3- (2,3,4-Trimethyl-thiazol-5-yl-methylthio) -6a- [I- (R) -hydroxy-ethyl] -7-oxo-azabicyclo (3.2.0) hept-2-en- 2-carboxylate

To a solution of 1.97 g (4.0 millimoles) of the compound in 180 ml of methylene chloride was added a solution of 0.98 ml (13 millimoles) of methyl fluorosulfonate in 2 ml of methylene chloride. The reaction mixture was stirred at room temperature for 70 minutes. The reaction mixture was poured into a solution of ether (400 ml) and n-pentane (100 ml). The precipitate was collected by filtration and washed with ether (20 ml) to give 1.6 g (65.5% yield) of the quaternized thiazole 49 as a white amorphous powder.

NMR (DMSO-d6) 5: 1.25 (3H, s, J = 6.5 Hz), 2.45 (3H, s), 2.80 (3H, s), 3.2-4.5 ( 6H, m), 3.90 (3H, s), 5.30 (2H, broad s), 7.60 and 8.2 (1H each d, J = 8.5 Hz).

IR (KBr) ymax: 3400, 1770 and 1690 cm-1.

Analysis for C23H26N309S3F- '/ 2H20:

Calc .: C 45.09 H 4.44 N 6.86%

Found: C44.50 H 4.38 N6.58%

To a solution of 1.0 g (1.72 millimoles) of compound 49 in 100 ml of tetrahydrofuran and 100 ml of ether was added 100 ml of pH = 7.0 buffer solution, followed by 1.0 g of 10% palladium on carbon. The mixture was hydrogenated at 2.72 MPa pressure on a Parr shaker for 40 minutes. The mixture was filtered through "Celite" and the catalyst was washed with water (2x10 ml). The combined filtrates and wash water were extracted with ether (3 x 100 ml) and lyophilized to give a yellow powder which was obtained from a C18 " Bondapak (Waters Associates) column (40 g) ", eluting with 10% acetonitrile in water under a pressure of 545 kPa.

Each 15 ml fraction was subjected to high pressure liquid chromatography and fractions with UV absorption at Xmax 300 nm were collected and freeze dried to give 315 mg (50% yield) of the title compound as a yellow solid.

NMR (D20) S: 1.25 (3H, d, J = 7.0 Hz), 2.25 (3H, s), 2.90 (3H, s), 3.0-3.30 (3H, m), 3.90 (3H, s) and 4.1-4.4 (4H, m).

IR (KBr) ymax: 3400, 1750 and 1580 cm-1.

UV Xmax (H20): 297 nm (e = 8994).

Analysis for CI5H19N304S-2H20:

Calc .: C 48.25 H 6.09 N7.79%

Found: C 47.96 H 5.83 N7.89%

0H

i

»V

-SCH:

Example II

Preparation of 3- [2- (N-methylthiazolium) methylthio] -6a- [1- (R) -hydroxyethyl] -7-oxo-I-azabicyclo (3.2.0) hept-2-ene-2-carboxylate

L / \) H SOCI, L // XC1 <■

2— »">

HCT 1 HCT?

2-mercaptomethyl thiazole

To a chloroform solution (30 ml) of thionyl chloride (3.8 ml, 52 millimoles) was added 3.60 g (26 millimoles) of hydroxymethylthiazole 1 at room temperature, followed by heating to 50 ° C for 2 hours. The chloroform was evaporated in vacuo to leave a brown solid which was dissolved in 30 ml of absolute ethanol. 2.04 g (26 millimoles) of thiourea were then added. The mixture was then heated under reflux for 18 hours. The precipitate was collected by filtration and ethanol and ether washed to give 3.4 g (75% yield) of the isothiouronium salt 3. The isothiouronium salt 3 was dissolved in 30 ml of water and then N2 was passed through for 20 minutes. 1.10 g (27 millimoles) of sodium hydroxide was added and the mixture was heated to 100 ° C over 2 minutes. The pH of the cooled (0 ° C.) solution was adjusted to 6.0 with acetic acid and then extracted with ethyl acetate (2 × 35 ml). The organic phase was dried (MgSO 4) and was evaporated in vacuo to give 0.75 g (42% yield) of the thiol 4 as a yellow oil which was used without further purification.

NMR (CDC13) 8: 2.1 (1H, t), 4.0 (2H, d, J = 10 Hz), 7.27 (1H, d, J = 3.0 Hz) and 8.85, d , J = 3.0 Hz).

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

45

656 130

C02PNB 3)

F

"W 'Vr \

HS / \ (

COgPNB

\

p-Nitrobenzyl 3 - [(2-thiazole) methylthio] -6a- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate

To a chilled 0 ~ "C solution of 1.4 g (4.0 millimoles) of keto intermediate 5 in 8 ml of acetonitrile was added 0.79 ml (4.4 millimoles) of diisopropylethylamine, followed by 1.17 g (4.4 Millimoles) of dipheriyl chlorophosphate under a nitrogen atmosphere The solution obtained was stirred at 0 ° C. for 30 minutes, during which p-nitrobenzyl-3- (diphenyl-phosphoryloxy) -6- [l- (R) -hydroxyethyl] -7-oxo-l -azabicyclo (3.2.0) hept-2-en-2-carboxylate to which a solution of 0.79 ml (4.4 millimoles) of diisopropyl-ethylamine in 2 ml of acetonitrile was added, followed by a solution of 0.72 g of thiol 4 in 2 ml of acetonitrile The reaction solution was stirred for 60 minutes at 0 ° C. and then diluted with 50 ml of methyl acetate and washed with 30 ml of water, 20 ml of 10% aqueous H3P04 and 30 ml of brine. Evaporation of the dried (MgS04) solution gave a crystalline solid, which was triturated with ether 782 mg (42% yield) of the title compound 6 as white crystalline material resulted. Melting point 158-160 ° C.

NMR (CDClj) 5: 1.32 (3H, d, J = 7.0 Hz), 3.28 (3H, m), 4.20 (2H, m), 4.36 (2H, s), 5 , 40 (2H, q), 7.40 (1H, d, J = 4.0 Hz), 7.64 (2H, d, J = 8 Hz), 7.76 (1H, d, J = 4, 0 Hz) and 8.24 (2H, d, J = 8 Hz).

IR (KBr) ymax: 3500, 1770 and 1700 cm-1.

Analysis for C2oHi9N306S2:

Calc .: C 52.05 H 4.15 N9.10 S 13.89%

Found: C 52.35 H 4.40 N 8.72 S 13.90%

was hydrogenated at 2 MPa pressure on the Parr shaker for 35 minutes. The mixture was then filtered and the catalyst was washed with water (2 x 10 ml). "The combined filtrates and wash water were extracted with ether (2 x 150 ml) and lyophilized to give a yellow powder. The crude yellow powder on a Cls "Bondapak Reverse Phase Column" (7 g) (Water Associates), eluting with 5% acetonitrile in water at a pressure of 545 kPa. Each 15 ml fraction was subjected to high pressure liquid chromatography and the fractions with UV absorption at Xmax-300 nm were collected and lyophilized to give 23 mg (5% yield) of the title compound as a yellow amorphous solid.

NMR (DzO) 8: 1.28 (3H, d, J = 7.0 Hz), 3.12 (2H, d, J = 7.0 Hz), 3.44 (1H, dd, J = 1, 0 Hz and 3.0 Hz), 4.20 (3H, s), 4.24 (2H, m), 4.76 (3H, m), 8.12 (1H, d, J = 4 Hz) and 8; 24 (1H, d, J = Hz).

IR (KBr) ymax: 3400, 1740 and 1580 cm "1.

UV Xmax (H20) 292 nm (s = 7285).

Example 12

30 Preparation of 3- [l- (RS) -methyl-N-methyl-pyridin-3-yl-methyl-thio] -6a- [l- (R) -hydroxyethyl] -7-oxo-I-azäbicyclo (3.2 .0) hept-2-en-2-carboxylate

15 8

! _0 Cl-P (Oi02

0H

CH,

3- [2- (N-Methylthiazolium) methylthio] -6a- [I- (R) -hydroxyethylJ-7-oxo-I-azabicyclo (3.2.0) hept-2-ene-2-carboxylate

0.5 ml of methyl fluorosulfonate was added to a solution of 782 mg (1.36 millimoles) of compound 6 in 55 ml of methylene chloride and the mixture was stirred at room temperature for 90 minutes. The precipitate was collected by filtration and washed with methylene chloride (30 ml) and ether (20 ml) to give 630 mg of the crude quaternized thiazole 7, which was used for the next step without further purification.

Then, to a solution of Compound 7 in 140 ml of tetrahydrofuran and 120 ml of ether, 140 ml of pH = 7.0 buffer solution was added, followed by 650 mg of 10% palladium on carbon. The mixture p-nitrobenzyl-3- [l- (R, S) methyl-pyridin-3-yl-methylthio] -6a- [I- (R) -hydroxyethyl] -7-oxo-l-azabicyclo (3.2.0 ) hept-2-en-2-carboxylate

To a cooled (0 ° C) solution of 1.85 g (5.3 millimoles) of keto intermediate 5 in 20 ml of acetonitrile was added 754 mg of so (5.8 millimoles) of diisopropylethylamine in 1 ml of acetonitrile, followed by a solution of 1.57 g (5.84 millimoles) of diphenylchlorophosphate in 2 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred at 0 ° C for 15 minutes, and then a solution of 754 mg (5.8 millimoles) of diisopropyl-55 ethylamine in 1 ml of acetonitrile was added, followed by 814 mg (5.8 millimoles) of thiol 27 in 2 ml acetonitrile. The mixture was stirred at 0 ° C for 3 hours and then the reaction mixture was diluted with 200 ml of ethyl acetate and with ice-cold brine (200 ml), water (200 ml), aqueous bicarbonate (100 ml) and 60 brine (100 ml ) washed. Evaporation of the dried (MgS04) solvent gave a yellow oil which was purified by silica gel column chromatography, eluting with 50% acetone-50% methylene chloride. 1.65 g of the title compound were obtained as a yellow solid.

65 NMR (CDC13) 6: 1.22 and 1.25 (3H each d, J = 7.0 Hz), 1.46 and 1.50 (3H each d, J = 7.2 Hz), 2.4 -3.3 (3H, m), 3.8-4.2 (3H, m), 5.35 (2H, ABq, J = 14.5 Hz) and 7.2-8.6 (8H, m ).

IR (KBr) vmax: 3400.1765 and 1690 cm-1.

656130

46

Analysis for G ^ H ^ NjC ^ S,:

Calc .: C 58.83 -H 4.94 N 8.95 S 6.83%

Found: C 57.15: H 5.04 N 8.28 S 6.78%

V '

X

k-,

SOCI,

KaOH

■ SH 27

N

25 _

4- (r-mercaptoethyl) 'pyridine

To a solution of: 25 g of 1- (4-pyridyl) ethanol 25 [prepared by the method described in J., Chem. Soc., Perkin II, 1462 (1974)] in 500 ml of chloroform, 50 g of thionyl chloride were added. The mixture was refluxed for 2 hours. The evaporation of the solvents in vacuo gave the chlorine compound 26 as a semi-solid, which was used for the next step without further purification. A hot solution of 14.4 g of thiourea in 75 ml of ethanol was added to a solution of 26 in 1,60 ml of ethanol. The reaction mixture was heated under reflux for 18 hours. The ethanol was evaporated and the residue was dissolved in 100 ml of water and the pH was adjusted to 10 by the addition of 2-normal sodium hydroxide solution. The mixture was stirred at room temperature for 90 minutes, adjusted to pH 6.0 by adding 6 normal hydrochloric acid and extracted with ether (2 x 200 ml). Evaporation of the dried (MgS04) solvent gave a yellow oil which was distilled at a pressure of 666 Pa and collected in the boiling range 60-65 ° C; 11.0 g (38% yield) of pure thiol 27 were obtained as a colorless oil. •;

NMR (CDCy 5: 1.70 (3H, d, J-6.0 Hz), 2.05 (1H, d, J = 5.8 Hz), 4.20 (1H, t, J = 6.0 Hz, 5; 8 Hz), 7.20 (2H, d, J = 6.2 Hz) and 8.5 (2H, d, J = 6.2 Hz) =;

OH OH-

Analysis for C24H26N306S, I,:

Calc .: C 47.14 H 4.29 N 6.87 S 5.24%

Found: C 47.19 H 4.78 N 6.11 S 5.41%

5 To a solution of 1.45 g (2.37 millimoles) of compound 29 in 120 ml of tetrahydrofuran and 120 ml of ether was added 120 ml of pH = 7.0 buffer solution, followed by 1.5 g of 10% palladium on carbon. The mixture was hydrogenated at 3 MPa pressure on the Parr shaker for 60 minutes. The mixture was filtered io through "Celite" and the catalyst was washed with water (2 x 15 ml). The combined filtrates and wash water were extracted with ether (2 x 200 ml) and lyophilized to give a yellow solid which was obtained from a C1S "Bondapak" (Waters Associates) reverse phase column (50 g) was purified, eluting with 5% 15 acetonitrile in water under a pressure of 545 kPa. Each 20 ml fraction was subjected to high pressure liquid chromatography and the fractions with UV absorption at> .max 300 nm were collected and lyophilized to give 200 mg (24% yield) of the title product as a yellow amorphous solid.

NMR (D20) 5: 1.32 (3H, d, J = 7.0 Hz), 1.63 (3H, d, J = 7.2 Hz), 2.5-4.6 (6H, m) , 4.32 (3H, s) and 8.2-8.9 (4H, m).

IR (KBr) vmax: 3400, 1750 and 1590 cm "1.

UV Xmax (H, 0): 29.6, nm (s = 7573).

20th

25th

30th

35

Analysis for C17H2 calc .: C 54.38

3N204S, • 1! 4H20: H 5.77 N 7.46%

Found: C 54.39 H 5.98 N 7.68% 0H.

r * Vi t *, ®

^ Example 13

Preparation before 3- (N-methyl-N'-benzyl-imidazol-2-yl-methylthio) -6a- [l- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3.2.0) hept- 2-en-2-carboxylate fl "

1) H2N - "- N-AC

M '

2) EtOH.

A

~ N HCl 42

• SH

3- [l- (RS) rMethyl-N-methyl-pyrìdin-3-yl-methylthio] -6a- [l- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3.2.0) hept- 2-en-2-carboxylate

10 ml of methyl iodide was added to a solution of 1.1 g (2.34 millimoles) of compound 28 in 100 ml of acetone. The reaction mixture was stirred at room temperature for 18 hours. The precipitate was collected by filtration and washed with methylene chloride (10 ml) to give 1.4 g (100% yield) of the quaternized pyridine 29 as a yellow powder.

NMR (DMSO-d6) 5: 1.10 (3H, d, J = 6.5 Hz), 1.62 (3H, d, J = 7.5 Hz), 2.6-4.2 (6H, m), 4.39 (3H, s), 5.42 (2H, ABq, J = 13.6 Hz) and 7.9-9.2 (8H, m).

IR (KBr) vmax: 3400, 1770 and 1190 cm- '.

N-benzyl-2-mercaptomethyl-imidazole

'• To a solution of 3.23 g (13.0 millimoles) of the chlorine compound 55 ^ / [prepared according to J. Amer. Chem. Soc., 71, 383 (1949)] in 80 ml of acetonitrile, 1.72 g (14.5 millimoles) of N-acetylthiourea were added. The reaction mixture was heated under reflux for 3 hours. The precipitate was collected by filtration and washed with acetonitrile (10 ml) to give the isothiouro-60 nium salt, which was then dissolved in 80 ml of absolute ethanol and heated for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated in vacuo to about 30 ml volume and the precipitate was removed by filtration. Evaporation of the filtrate in vacuo gave 3.5 g (97% yield) of thiol 42 as a thick yellow syrup.

NMR (CDC13) 8: 2.1 (1H, t, J = 4.5 Hz), 3.80 (2H, s), 5.20 (2H, s) and 6.8-7.5 (7H, m).

47

656130

P-nitrobenzyl-3- [N-benzylimidazol-2-yl-methylthio] -6a- [l- (R) -hydroxyethyl] -7-oxo-l-azabicyclo (3.2.0) hept-2-ene carboxylate

To a cooled (0 ° C) solution of 3.03 g (8.5 millimoles) of keto intermediate 5 in 70 ml acetonitrile was added 1.17 g (9.0 millimoles) diisopropylethylamine in 2 ml acetonitrile followed by 2.4 g (9.0 millimoles) of diphenyl chlorophosphate in 2 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred at 0 ° C for 20 minutes and then a solution of 1.17 g (9.0 millimoles) of diisopropylethylamine in 2 ml of acetonitrile was added, followed by 4.8 g (15 millimoles) of thiol 42. An additional 1.93 g (15 millimoles) of diisopropylethylamine was added and the reaction mixture was stirred at 0 ° C for 2 hours. The precipitate was collected by filtration and washed with cold methylene chloride (20 ml) to give 2.5 g (55% yield) of the title compound as a white solid.

NMR (DMSO-d6) S: 1.23 (3H, d, J = 7.2 Hz), 2.5-4.1 (6H, m), 4.25 (2H, s), 5.20 ( 2H, s), 5.20 and 5.45 (1H each, d, 1 = 14.5 Hz) and 6.9-8.3 (11H, m).

IR (KBr) ymax: 3400.1775 and 1690 cm "1.

V4

CO-PNB

ÌX> -0

1+

CH,

r *

To a solution of 1.11 g (1.71 millimoles) of the compound ^ in 100 ml of tetrahydrofuran and 100 ml of ether was added 120 ml of pH = 7.0 buffer solution, followed by 1.0 g of 10% palladium on carbon. The mixture was hydrogenated at 3 MPa pressure on the 5 pair shaker for 45 minutes. The mixture was filtered through "Celite" and the catalyst was washed with water (2 x 10 ml). The combined filtrates and wash water were extracted with ether (2 x 10 ml) and lyophilized, giving a yellow powder, which was purified to C18 " Bondapak "(Waters Associates) -io column (40 g), eluting with 10% acetonitrile in water under a pressure of 545 kPa.

Each 15 ml fraction was subjected to high pressure liquid chromatography and the fractions with UV absorption at Xmax 300 nm were collected and lyophilized to give 305 mg 15 (43% yield) of the title compound as a light yellow amorphous solid.

NMR (DMSO) S: 1.40 (3H, d, J = 7.0 Hz), 2.9-3.4 (3H, m), 3.98 (3H, s), 4.0-4, 2 (2H, m), 4.23 (2H, broad s), 5.57 (2H, s) and 7.2-. 7.65 (7H, m).

20 IR (KBr) ymax: 3400, 1760 and 1590 cm "'.

UV Xmax (HzO): 299 nm (s = 8807).

Analysis for C ^ H ^ NjC ^ S, • 1 '/ 2H20:

Calc .: C 57.25 H 5.94 N 9.54 S 7.28%

25 Found: C 56.66 H 5.70 N 9.49 S 8.30%

OH

30th

35

Example 14

Preparation of 3- (2-methyl-N-methylpyridin-3-yl-methylthio) -6- [l- (R) -hydroxyethyl] -7-oxo-l-azabicyclo (3.2.0) hept-2-en- 2-carb-40 oxylate

, C02 Et L A H

lì

"CH,

«Socl *)

CH.

u

1 .

CK,

3- (N-Methyl-N'-benzyl-imidazol-2-yl-methylthio) -6a- [l- (R) -hydr-oxyethyl] -7-oxo-l-azabicyclo (3.2.0) hept-2 'en-2-carboxylate

To a solution of 1.76 g (3.3 millimoles) of compound 43 in 1.1 liters of methylene chloride was added 1.15 ml (13.4 millimoles) of methyl fluorosulfonate. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to about 15 ml volume. The precipitate was collected by filtration and washed with methylene chloride (10 ml) to give 1.58 g (74% yield) of the quaternized imidazole 44 as a white solid.

NMR (DMSO-d6) 8: 1.15 (3H, d, J = 7.0 Hz), 3.2-4.4 (6H, m), 4.70 and 5.0 (1H each ABq, J = 10.8 Hz), 5.24 and 5.46 (1H each, ABq, J = 14 Hz), 5.50 (2H, s) and 7.4-8.4 (11H, m).

IR (KBr) ymax: 3500, 1770 and 1700 cm "'.

Analysis for C28H29N4.O9S2F:

Calc .: C 51.48 H 4.47 N8.67 S 10.20%

Found: C 51.84 H 4.52 N 8.65 S 9.87%

45

12

13

no

1) H2NANH2

2) NaOH

H CH-HCI 14

rr-

15

2-methyl-3-mercaptomethyl-pyridine

Ester 12 was prepared according to the procedure described in J. Org. Chem., 21, 800 (1956). To a cooled (0 ° C) suspended solution of 2.86 g of lithium aluminum hydride in 50 ml of 60 dry tetrahydrofuran was added dropwise a solution of 6.23 g (38 millimoles) of the ester 12 in 15 ml of tetrahydrofuran over a 15 minute period . The mixture was stirred at 0 ° C for 60 minutes and then 50 ml of ethyl acetate was added. The precipitate was filtered and washed with aqueous saturated ammonium chloride solution. The organic phase was dried over MgSO4, filtered and evaporated in vacuo to give 3.2 g (70% yield) of hydroxymethylpyridine 13 as a yellow oil.

656130

48

NMR (CDCI3) of compound 13 8: 2.46 (3H, s), 4.73 (2H, s), 5.1 (1H, broad), 7.2 (1H, dd, J = 8 Hz), 7.8 (1H, dd, J = 8 Hz, J = 1 Hz) and 8.3 (1H, dd, J = 7 Hz, J = 1 Hz) and 8.3 (1H, dd, J = 7 Hz , J = 1 Hz).

To a chilled solution of 4 ml of thionyl chloride in 10 ml of methylene chloride was added dropwise a solution of 3.2 g (26 millimoles) of alcohol 13 in 10 ml of methylene chloride over a 15 minute period under a nitrogen atmosphere. The cooling bath was removed and the reaction mixture was stirred at room temperature for 3 hours. All solvents were evaporated in vacuo leaving compound 14 as a brown solid which was used for the next step without further purification. The crude brown solid was dissolved in 30 ml of absolute alcohol. Then 2.5 g (32 millimoles) of thiourea was added and the mixture was heated to 65-70 ° C over 18 hours. The mixture was cooled to room temperature. The residue was collected by filtration and washed with ethanol (20 ml) and ether (50 ml) to give 30 g of isothiouronium salt. This salt was dissolved in 10 ml of water and then a solution of 640 mg (16 millimoles) of sodium hydroxide in 10 ml of water was added under nitrogen. The reaction mixture was warmed to 100 ° C over 2 minutes and then cooled to 0 ° C. The pH was adjusted to 6.0 with acetic acid and then extracted with chloroform (2 x 35 ml). Evaporation of the dried (MgS04) chloroform would give 941 mg (46% yield) of the thiol 15 as a yellow oil.

NMR (COCI3) of thiol 15 8: 1.8 (1H, t), 2.60 (3H, S), 3.73 (2H, d, J = 10 Hz), 7.13 (1H, dd, J = 8 Hz), 7.57 (1H, dd, J = 8 Hz) and 8.43 (1H, dd, J = 8 Hz, 3 Hz).

0H

A

OH

1 1 // ä ~ \

—K-f \

C0zpNB CH,

CH30S02F

0

%

f ra3 \ ^ I I a

16

OH

COjPNB CH3

17th

©

Pd / C, H,

FSO3O

C ° 2GCK, 1

20th

18th

CH

I ©

25th

0H

"eq-

C02pNB

HS

e

15

C02pNB

35

16

p-nitrobenzyl-3- (2-methylpyridin-3-yl-methylthio) -6a- [l- (R) -hydro-xyethyl] -7-oxo-l-azabicyclo (3.2.0) hept-2-en- 2-carboxylate

To a cooled (0 ° C) solution of 1.52 g (4.37 millimoles) of keto intermediate 5 in 5 ml of acetonitrile was added 0.86 ml (4.80 millimoles) of diisopropylethylamine, followed by a solution of 1 17 g (4.37 millimoles) of diphenyl chlorophosphate in 3 ml of acetonitrile under a nitrogen atmosphere. The solution obtained was stirred at 0 ° C. for 30 minutes, during which p-nitrobenzyl-3- (diphenylphosphoryloxy) -6a- [l- (R) -hydroxyethyl] -7-oxo-1-azabi-cyclo (3.2.0) hept-2-en-2-carboxylate was obtained. To this solution was added a solution of 0.86 ml (4.80 millimoles) of diisopropyl-ethyl-amine in 2 ml of acetonitrile, followed by a solution of 940 mg (6.76 millimoles) of thiol 15 in 2 ml of acetonitrile. The reaction mixture was stirred at 0 ° C for 60 minutes. The precipitate was collected by filtration and washed with 30 ml ether to give 1.12 g (55% yield) of the title product as a pale yellow solid. Mp 186-188 ° C (cer.).

NMR (DMSO-d6) 8: 1.20 (3H, d, J = 7 Hz), 2.60 (3H, S), 3.40 (m, 2H), 4.16 (m, 2H), 4 , 32 (2H, S), 5.16 (1H, d, J = 5 Hz), 5.44 (2H, q, J = 14 Hz), 7.32 (2H, m), 7.8 (2H , d, J = 8 Hz), 8.36 (2H, d, J = 8 Hz) and 8.48 (1H, dd, J = 5.5 Hz, 1.5 Hz).

IR (KBr) ymax: 3500, 1770 and 1750 cm-1.

Analysis for C23H24N306S:

Calc .: C 58.83 H 4.94 N8.94 S 6.83%

Found: C 58.63 H 4.99 N9.06 S 6.58%

3- (2-Methyl-N-methylpyridin-3-yl-methylthio) -6 a- [l- (R) -hydroxy-ethyl] -7-oxo-1-azabicyclo (3.2.0) hept-2- en-2-carboxylate

To a solution of 697 mg (1.19 millimoles) of compound 16 in 100 ml of methylene chloride, 0.5 ml (6.18 millimoles) of methyl fluorosulfonate was added dropwise at 10 ° C. over a period of 10 minutes. The mixture was stirred at room temperature for 2.5 hours. The precipitate was collected by filtration and washed with 30 ml of methylene chloride to give 777 mg (90% yield) of the quaternized pyridine 17 as a yellow solid.

NMR (COCL3) of compound 17 5: 1.20 (3H, d, J = 7 Hz), 2.82 (3H, s), 4.36 (3H, s), 4.16 (2H, m), 4.60 (2H, s), 5.20 (1H, m), 5.42 (2H, q, J = 14 Hz), 7.80 (2H, d, J = 8 Hz), 8.04 ( 1H, dd, J = 7 Hz, 6.5 Hz), 8.32 (2H, d, J = 8 Hz), 8.64 (1H, d, J = 7.5 Hz) and 9.08 (1H , d, J = 7.5 Hz).

IR (KBr) vmax: 3500 and 1765 cm-1.

40 Analysis for C24H26FN3OqS:

Calc .: C48.91 H 4.55 N 7.23 S 11.04%

Found: C 49.39 H 3.97 N7.20 S 10.98%

To a solution of 1.10 g (1.88 millimoles) of compound 17 in 45 80 ml of tetrahydrofuran and 80 ml of ether was added 80 ml of pH = 7.0 buffer solution, followed by 800 mg of 10% palladium on carbon. The mixture was hydrogenated at 2 MPa pressure on the Parr shaker for 40 minutes. The mixture was filtered through "Celite" and the catalyst was washed with water (2 x 10 ml) 50. The combined filtrates and wash water were washed with ether (2 x 100 ml) and lyophilized to give a yellow powder which was obtained by HP-20 column chromatography was purified eluting with water followed by 5% acetonitrile in water. Each 15 ml fraction was subjected to high-55 pressure liquid chromatography and fractions with ultraviolet absorption at Xmax 300 nm were collected and lyophilized, whereby 614 mg (42% yield) of the title compound was obtained as a pale yellow powder.

NMR (D20) 8: 1.28 (d, 3H, J = 7 Hz), 2.86 (3H, s), 3.20 (2H, dd, 60 J = 10 Hz, 3.5 Hz), 3 , 42 (1H, dd, J = 5.4 Hz, 3.5 Hz), 4.20 (3H, m), 4.32 (3H, s), 4.35 (2H, S), 9.88 (1H, dd, J = 7.2 Hz, 6.5 Hz), 8.5 (1H, d, J = 8 Hz) and 8.70 (1H, d, J = 8 Hz).

IR (KBr) ymax: 3400.1760 and 1590 cm-1.

UV tanax (H20): 298 nm (s = 8391).

65

Analysis for C17H20N2O3S • H20:

Calc .: C 55.73 H 5.46 N7.65 S 8.74% "

Found: C 55.50 H 6.05 N7.74 S 8.65%

49

656 130

Example 15

Preparation of 3- [4- (N, N-dimethyl-l, 2,3-triazolium) methylthio] -6a- [l- (R) -hydroxyethyl] -7-oxo-l-azabicyclo (3.2.0) hept-2-en-2-carboxylate oh ch s

e co

2nd

A. Preparation of Isomer A

0.58 ml of methyl trifluoromethanesulfonate (5.16 millimoles) was added dropwise to an ice-cooled, stirred solution of 590 mg of 4- (methanethiol acetate) -l-methyl-l, 2,3-triazole (3.52 millimoles) in 2 ml of dry methylene chloride added under nitrogen. After 0.5 h the bath was removed and after 1 h the solvent was removed with an aspirator. The remaining oil was dissolved in a few ml of water and this solution was cooled in an ice bath. Then a cold solution of 305 mg of sodium hydroxide (7.59 millimoles) in a few ml of water was added and the reaction was stirred for 0.75 h. The solution was then diluted with 25 ml of water and the pH was adjusted to 7.5 by adding solid sodium dihydrogen phosphate monohydrate. Then 14 ml of this solution (approx. 1.9 millimoles of the triazolium thiol) became an ice-cooled stirred solution of 1.0 g of enol phosphate (1.72 millimoles) in 10 ml of tetrahydrofuran (THF).

This was allowed to stir for 0.75 h (some crystalline material, presumably Na2HP04 settled in the course of this reaction). The suspension was transferred to a pressure bottle using a little THF (20 ml) and water (20 ml). Then 30 ml of ether

1.0 g of 10% palladium on carbon was added to the mixture and stirred at a pressure of 2.7 MPa for one hour. The organic phase was separated and washed with water (2x5 ml). The combined aqueous phases were filtered and the filtrate was concentrated under a high vacuum (approx. 70 Pa, 1.5 h). The yellow solution was then chromatographed (medium pressure reverse phase column, 35 x 90 mm, H20 as eluent), whereby after freeze-drying 395 mg of the carbapenem, which was slightly contaminated with some organic material, were obtained. It was purified by high pressure liquid chromatography (10 x 300 mm "Waters Microbondapack" C-18 column, multiple injection, H20 as eluent) to give 310 mg (57% yield) of isomer A as a brown colored powder.

HNMR (D20) 5: 1.23 (3H, d, J = 6.4 Hz), 3.10 (2H, d, J =

9.1 Hz), 3.24 (1H, q, J = 2.7, 6.1 Hz), 4.03-4.71 (10H, m), 8.46 (1H, s).

IR "(Nujol) 1760 cm-1.

uv (phosphate buffer, pH 7.4, M = 0.05) Xmax: 296 (s = 7.500).

B. Preparation of Isomer B and Isomer C

OH

a) MeOTf SAC b) aq. NaOH

OH

in — me

CO

(tentative structure)

1.60 ml of methyltrifluoromethane sulfonate (14.0 millimoles) was added dropwise to an ice-cooled solution of 1.20 g of 4- (methylthioacetate) -2-methyl-l, 2,3-triazole (7.02 millimoles) in 6 ml of dry methylene chloride added under nitrogen. This was allowed to warm to room temperature and stir for 16 hours. Additional methyl trifluoromethane sulfonate (0.40 ml, 3.56 millimoles) was added and after 3 hours at room temperature the solvent was removed with an aspirator. The remaining oil was ground with ether and the gum obtained was dissolved in 5 ml of water. It was then cooled in an ice bath and a solution of 844 mg sodium hydroxide (21.1 millimoles) in 5 ml water was added. It was stirred for 0.75 h and then diluted with water from 60 ml and the pH was adjusted to 8 by adding solid sodium dihydrogen phosphate. Then 40 ml of this solution (approx. 4.7 millimoles of a mixture of isomers triazolium thiols) were placed in an ice-cooled stirred solution of 2.00 g of enol phosphate (3.45 millimoles) in 60 ml of THF. This mixture was stirred in an ice bath for 0.5 h and then transferred to a pressure bottle containing a suspension of 2.00 g of 10% palladium on carbon and 60 ml of ether. The mixture was hydrogenated at a pressure of 2.72 MPa for one hour. The organic phase was separated and washed with water (2x10 ml). The remaining solution was then chromatographed (medium pressure reverse phase column, 45 x 130 mm, H20 as eluent), whereby after lyophilization 595 mg of a mixture of isomers carbapenem was obtained which was contaminated with some inorganic material. These were separated and purified by high pressure liquid chromatography (10 x 300 mm "Waters Mi-cronondapack" C-18 column, multiple injection, H20 as eluent), whereby, in the order of elution, the following compounds were obtained with the analysis data given were: Isomer B; 153 mg (13%).

'HNMR (D20) 5: 1.23 (3H, d, J = 6.4 Hz), 3.12 (2H, q, J = 1.4, 8.9 Hz), 3.39 (1H, q , J = 2.7, 6.0 Hz), 4.07-4.68 (10H, m), 8.19 (1H, s).

IR (Nujol) 1755 cm '.

uv (phosphate buffer, pH = 7.4, M = 0.05) Xmax: 296 nm (g = 6.700); and isomer C; 284 mg (24%).

• HNMR (D20) 5: 1.23 (3H, d, H = 6.4 Hz), 3.15 (2H, q, J = 3.7, 9.0 Hz), 3.37 (1H, q , J = 2.6, 6.0 Hz), 3.95-4.65 (10H, m), 8.62 (1H, s).

IR (Nujol) 1750 cm "'.

uv (phosphate buffer, pH = 7.4, M = 0.05) Xmax: 298 nm (8 = 7.600).

Example 16

(5R, 6S) 6- (1 R-hydroxyethyl) -3- (2-methyl-1,2,3-thiadiazolium-4-yl-methylthio) -7-oxo-l-azabicyclo [3.2.0] hept- 2-en-2-carboxylate

OH

, N CH.

A. Ethyl l, 2,3-thiadiazol-4-yl carboxylate

CD. Hurd and R.I. Mori, J. Am. Chem. Soc., 77, 5359 (1955).

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

656130

50

• NHCOEt

SOCI.

CK.

: oEt

0

A solution of 31.2 g of ethyl cc-N-carbethoxyhydrazole propionate (0.154 mol) in 80 ml of thionyl chloride was stirred at 23 ° C. for 3 hours and heated to 70 ° C. for 20 minutes. The thionyl chloride was evaporated and the residue was triturated in hexane (4 x 30 ml). The red solid was dissolved in 150 ml di-chloromethane and the solution was washed with saturated sodium carbonate solution and with water. After drying over NajSO ^. the solution was concentrated until the compound crystallized. After standing at 23 "C for some time, the crystals were filtered off; 16.8 g, mp 86" C, 69%. The filtrate was concentrated and purified by chromatography on silica gel acid with dichloromethane as an eluent to give a yield of 3.17 g (13%); Mp 86 ° C.

IR (KBr) vm ": 1720 (ester) cm-1.

'Hmr; 'Hmr (CDC13) 5: 1.52 (3H, t, J = 7, 1 Hz, CH3CH20), 4.57 (2H, q, J = 7, 1 Hz, CH3CH20), 9.47 (IH, s, H of thiadiazole).

B. 1,2,3-Thiadiazol-4-yl-methanol

S.I. Rämsby, S.O. Ögren, S.B. Ross and N.E. Stjerenstrom, Acta Pharm. Succica., 10, 285-96 (1973); C.A., 79, 137052W (1973).

ö

o n

.cost

LiJilH.

J * <

S

CHjOH

ti

GHjOB

KsCi

Ö

CK ^ OKs ir (film) vmas: 1350 (S02) cm-1, 1172 (SOq) cm "1.

1 Hmr (CDCI3) 5: 3.09 (3H, s, CH3), 5.75 (2H, s, CH2), 8.72 (1H, s, H from thiadiazole).

uv (CH2Cl2) Xmax: 251 (1990).

5 Analysis for C6H6N203S:

Calc .: C 24.73 H 3.11 N 14.42 S 33.02% Found: C 24.78 H 3.09 N 14.66 S 31.94%

and 0.13 g (19%) of di (1,3,3-thiadiazol-4-ylmethyl) ether.

ir (film) vraax: 1272, 1242, 1200, 986, 805, 728 cm '

-I

'Hmr (CDClj) 5: 5.16 (s, 4H, CH2), 8.42 (s, 2H, H's from thiadiazole).

D. 4-acetylthiomethyl-l, 2,3-thiadiazole

ö

CF ^ Ois ch csnft

IT '

To a solution of 18.35 g of ethyl l, 2,3-thiadiazoI-4-yl-carboxy-lat (0.116 mol) in 400 ml of ether was added in portions 2.47 g of lithium aluminum hydride (0.065 mol) over a period of one hour admitted. The reaction mixture was stirred at 23 ° C for 7 hours and treated with lithium aluminum hydride (2.47 g, 0.065 ml). Stirring was continued for 24 hours before successively adding 7 ml of water, 7 ml of 15% sodium hydroxide solution and 21 ml of water. After stirring for 15 mm. the ether solution was decanted and the gum was extracted with ether (5 x 100 ml). The ether extracts were combined, dried (MgSO4) and concentrated (5.4 g). The raw material was purified on a silica gel column (120 g, 4 × 16 cm) using ether as the eluent, 1.3 g (7%) of ethyl 1, 2,3-thiadiazol-4-ylcarboxylate and 2.45 g (18 %) l, 2,3-thiadiazol-4-ylmethanol were obtained.

ir (film) vmax: 3380 (OH) cm-1.

'Hmr (CDC13) 5: 2.31 (IH, s, OH), 5.22 (2H, s, CH20), 8.50 (1H, s, H from thiadiazole).

C. l, 2,3-thiadiazol-4-ylmethanol methanesulfonate

A solution of 0.75 gl, 2,3-thiadiazol-4-ylmethanol (6.5 millimoles) in 20 ml dichloromethane was cooled to 5 ° C. under a nitrogen atmosphere and with 1.018 ml triethylamine (7.3 millimoles) and with 0.565 ml of methanesulfonyl chloride (7.3 millimoles) treated. After 15 minutes the ice bath was removed and the reaction mixture was stirred for 2 hours. The solution was washed with 1N hydrochloric acid (2x2 ml) and water, dried (MgSO4 + MgO) and concentrated. The residue was purified by chromatography (silica gel column 1.5 x 21 cm) with ether as the eluent, giving 0.90 g (71%) of the 1,2,3-thiadiazol-4-ylmethanol methanesulfonate.

To a solution of 1,3,3-thiadiazol-4-ylmethanol methanesulfonate (0.90 g, 4.6 millimoles) in 9 ml of tetrahydrofuran was added 2 ml of an aqueous solution of sodium thioacetate (Herge-25 represents 0 , 38 ml thioacetic acid [5.3 millimoles] and 0.445 g sodium bicarbonate [5.3 millimoles]). The mixture obtained was stirred at 23 ° C. for one hour and diluted with 75 ml of ether. The organic solution was washed with water (3x3 ml), dried (MgSO4) and concentrated. The crude mixture was purified by chromatography (silica gel column: 1.4 x 19 cm) using 50% ether in hetane as eluent. 0.60 g (75%) of the title compound were obtained.

ir (film) vmax: 1675 (C = 0) cm "1.

35 'Hmr (CDC13) 8: 2.37 (3H, s, CH3), 4.58 (2H, s, CH2), 8.44 (1H, s, H, from thiadiazole).

Analysis for C5H6N2 = S2:

Calc .: C 34.47 H 3.47 N 16.08 S 36.80% 40 Found: C 34.48 H 3.83 N 16.28 S 36.80%

E. 4-Acetylthiomethyl-2-methyl-l, 2,3-thiadiazolium trifluoromethane sidfonate and 4-acetylthlomethyl-3-methyl-l, 2,3-thiadiazolium trifluoromethanesulfonate ch. s

; L:

3 CT.SCyse glscch v.

-.0

cs2scck3 cr.so ~

To a solution of 0.60 g of 4-acetylthiomethyl-l, 2,3-thiadiazole (3.44 millimole) in a mixture of 4 ml of ether and 0.4 ml of dichloromethane, a few crystals of the title compounds and 0.407 ml of trifluoromethanesulfonate (3, 6 millimoles) over a period of 55 minutes. The reaction mixture was stirred for 6 hours at 23'C under a nitrogen atmosphere. The white solid, which was a mixture of the two title compounds, was filtered and washed with ether. The yield was 1.05 g (90%).

60

ir (KBr) vraas: 1675 (C = 0) cm-1.

1 Hmr (DMSO, d-6) S: 2.43 (3H, s, CH3COS), 3.33 (s, CH3 in N-3), 4.57 (s, CH3 in N-2), 4, 66 (2H, s, CH2), 9.55 (H at thiadiazolium N-2), 9.66 (H at thiadiazolium N-3).

Analysis for C7H9N204S3F3:

Calc .: C 20.27 H 2.38 N 9.45 S 32.46%

Found: C 24.61 H 2.57 N 8.47 S 28.21%

51

656130

F. 4-Mercaptomethyl-2-methyl-l, 2,3-thiadiazolium trifluoromethane sulfonate and 4-mercaptomethyl-3-methyl-l, 2,3-thiadiazolium trifluoromethane sulfonate

SE

CF SO.

3 3

A solution of a mixture of 4-acetylthiomethyl I-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-acetylthiomethyl-3-methyl-l, 2,3-thiadiazolium trifluoromethanesulfonate (1.05 g, 3.1 millimoles ) in 6N hydrochloric acid (10 ml) was heated under a nitrogen atmosphere for 1.75 h to a temperature of 65 ° C. The solvent was evaporated under reduced pressure, leaving 0.91 g of a yellow syrup. This compound was used in the next step without cleaning.

G. (5R, 6S) 6- (1R-hydroxyethyl) -3- (2-methyl-l, 2,3-thiadiazolium-4-ylmethylthio) -7-oxo-l-azabicyclo [3.2.0] hept-2 -en-2-carboxylate o:

J.

9

o? (CPh).

«E ^ K-

S> CF3S03

COOPNB

pK 7.2

Example 17

Potassium-3- [5- (l-carboxylatomethyl-3-methyl-l, 2,3-triazolium) me-

thanthio] -6a- [l- (R) -hydroxyethyl] -7-oxo-l-azabicyclo [3.2.0] hept-2-

en-2-carboxylate eoo

A cold (5 ° C) solution of (5R, 6S) paranitrobenzyl-6- (lR-hydroxyethyl) -3- (diphenylphosphono) -7-oxo-l-azabicyclo [3.2.0] -hept-2-en-2 Carboxylate (1.7 g, 2.92 millimoles) in 10 ml of tetrahydrofuran was treated with a solution of the crude mixture of 4-mercapto-methyl-2-methyl-1, 2,3-thiadiazolium trifluoromethanesulfonate and 4-mercaptomethyl-3 -methyl-l, 2,3-thiadiazolium trifluoromethanesulfonate (0.9 g) in a mixture of phosphate buffer (pH 7.2, 3.3 molar, 15 ml) and tetrahydrofuran (5 ml). The reaction mixture was stirred for one hour and the pH was kept at 7.2 with 2 normal sodium hydroxide solution. Stirring was continued for an additional hour before adding 50 ml of ether and 1 g of 10% palladium on carbon. The mixture obtained was hydrogenated at 23 ° C. under a pressure of 3 MPa for 2 hours and filtered through "Celite". The organic phase was separated off and mixed with 50 ml of ether and 20 ml of phosphate buffer (pH 7.2, 0.3 Molar) and hydrogenated for 2 hours under a pressure of 3.4 MPa (2 g of 10% palladium on carbon). The aqueous phases were cleaned (from the first and the second hydrogenolysis), washed with ether and chromatographed on "PrepPak "500-C18 purified, eluting with water and obtaining 0.22 g of the raw material. This was further purified by high pressure liquid chromatography to give 0.040 g (4%) of the title compound after freeze-drying.

ir (KBr) vmiK: 3400 (br, OH), 1745 (C = ^ 0 from β-lactam), 1580 (carboxylate) cm "1.

'Hmr (D20) 5: 1.23 (3H, d, J = 6.3 Hz, CH3CHOH), 3.04, 3.05, 3.16 (2H, m, H-4), 3.38 ( 1H, dd, J = 2.8 Hz, J = 6.0 Hz, H-6), 3.9-4.6 (2H, m, H-5, CH3CHOH), 4.51, 4.53 ( 2 "S", SCH2), 4.61 (s, N + CH3).

uv (H20) 244 (s4345), 262 (s4980), 296 (e6885), [a] "18 ° (c 0.18 H20); T, / i = 9.8 h measured at a concentration of 10 ~ 4 M in phosphate buffer pH 7.4 at 36.8 ° C).

2.83 g of lithium aluminum hydride (70.9 millimoles) were added in small portions to a stirred suspension of 9.00 g of 1-methyl-l, 2,3-triazole-4-carboxylic acid (70.9 millimoles) (C. Pederson, Acta Chem. 30 Scand., 1959, 13, 888) in 200 ml dry THF. The mixture was stirred for 15 hours at room temperature and then 20 ml of 20% aqueous sodium hydroxide solution was carefully added in approximately 1 ml portions. The resulting granular suspension was filtered and the solid was washed with an additional 35 THF (5 x 75 ml). The combined tetrahydrofuran solutions were dried with magnesium sulfate and the solvent was removed. The remaining yellow oil was "flash" chromatographed on a silica gel column (90 x 35 mm) (100 ml portions of hexane, mixtures of ethyl acetate-hexane (1: 1) and 40 (1: 3) and finally ethyl acetate-methanol (9: 1) as eluent), giving 4-hydroxymethyl-l-methyl-1,2,3-triazole (3.18 g, 40%) as a colorless oil.

'HNMR (CDCI3) 8: 4.07 (3H, s), 4.73 (2H, d), 7.52 (1H, s).

IR (pure) 3320 cm "1.

45 3.82 ml of methanesulfonyl chloride (49.6 millimoles) was added dropwise to an ice-cooled stirred solution of 4.67 ml of alcohol (41.3 millimoles) and 7.47 ml of triethylamine (53.7 millimoles) in 20 ml of methylene chloride. After 0.5 h the solvent was removed and the remaining solid was taken up in 30 ml of Acetoni-50 tril. Then 7.06 g of potassium thioacetate was added and the solution was stirred for 3 hours at room temperature. In addition, 3.0 g of potassium thioacetate (26.3 millimoles) was added and the suspension was stirred for an additional 16 hours. The dark colored suspension was then concentrated 55 and 10 ml water was added. The mixture was washed with methylene chloride (5 x 40 ml). The combined extracts were dried with magnesium sulfate and the solvent was removed. The remaining oil was flash chromatographed on a silica gel column (90 x 36 mm) (hexane followed by a mixture of hexane-ethyl acetate (1: 1) was used as the eluent). 4- (acetylthiomethyl) -l- methyl-l, 2,3-tri-azole (5.95 g, 84%) as a pale pink solid.

• HNMR (CDCI3) 5: 2.40 (3H, s), 4.10 (3H, s), 4.20 (2H, s), 7.53 (1H, s).

65- IR (Nujol) 1675 cm "1.

A solution of 1.00 g triazole (5.85 millimoles) and 1.48 ml ethyl bromoacetate (13.3 millimoles) in 10 ml dry acetonitrile was heated to 60 ° C under nitrogen over 90 hours. The

656130

52

Solvent was removed and the remaining oil was triturated with ether (4 x 25 ml) to give l-methyl-3- (ethoxycarbo-nylmethyl) -4-acetylthiomethyl-l, 2,3-triazolium bromide as a brownish gum, which was obtained directly was used further.

A cold solution of 0.66 g KOH (12 millimoles) in 5 ml water 5 was added to an ice-cooled stirred solution of the triazolium bromide in 20 ml water. After 20 minutes this was diluted to 35 ml and enough hard potassium dihydrogen was added to adjust the pH to 8.0. This was then added to a stirred, ice-cooled solution of the enol phosphate in 10 THF (35 ml). After 0.5 h this mixture was placed in a pressure bottle containing 35 ml ether and 1.5 g 10% palladium on carbon. The mixture was hydrogenated at a pressure of 2.72 MPa for 55 minutes. The organic phase was then separated and washed with water (2x5 ml). The combined aqueous phases were filtered and the filtrate was concentrated under high vacuum. The remaining material was chromatographed on a reverse phase column (35 x 120 mm) with water as the eluent. Freeze-drying of the fractions containing carbapenem gave 1.20 g of a green colored solid. This was chromatographed on a "Waters Prep." 500 HPLC (PrepPak-500 / Cls column) with 2% acetonitrile water as the eluent. The fractions containing carbapene were combined and freeze-dried. This material was re-chromatographed by high pressure liquid chromatography 25 (10 x 300 mm Waters Microbondapack C-18 column) using water as the eluent and after freeze-drying the pure title compound was obtained (190 mg, 17%) as a pale yellow solid.

'HNMR (DzO) 8: 1.24 (3H, d, J = 6.4 Hz), 3.07 (2H, d, J = 30 9 Hz), 3.38 (1H, q, J = 2, 7.6.0 Hz), 4.02-4.30 (3H, m), 4.29 (3H, s), 5.23 (2H, s), 8.52 (1H, s).

IR (Nujol) 1750 cm ~ '.

UV (phosphate buffer, pH 7.4) A. max 296 nm (e = 7.520).

35

Example 18

Potassium-3- [4- (l-carboxylatomethyl-3-methyl-l, 2,3-triazolium) -methylthio] -6a- [l- (R) -hydroxyethyl] -7-oxo-l-azabicyclo [ 3.2.0] -hept-2-en-2-carboxylate

I © ß

d) Kj / Pä-C

A mixture of 30.0 g azidoacetate (0.23 mol) and 14.3 ml propionic acid (0.23 mol) and 75 ml toluene was stirred at room temperature. The reaction remained mildly exothermic for 1.5 h and then quickly became strongly exothermic and cooling with an ice bath became necessary. After this exothermic phase, the reaction mixture was heated under reflux for 0.5 h. After cooling in an ice bath, the crystalline material was collected by filtration and washed with a little toluene. The raw material thus obtained (33.3 g, 72%) consisted of a single isomer ['HNMR (DMSO-dö): 1.20 (3H, t, J = 7 Hz), 4.15 (2H, q, J = 7 Hz), 5.42 (2H, s), 8.67 (1H, 3)], probably l- (ethoxycarbonylmethyl) -l, 2,3-triazole-4-carboxylic acid by analogy to a previous work (C. Pederson, Acta Chem. Scand., 1959, 13, 888).

A solution of 5.00 g of the carboxylic acid (25.1 millimoles) and 3.68 ml of triethylamine (26.4 millimoles) in 50 ml of dry methylene chloride became an ice-cooled stirred solution of 2.52 ml of ethyl chloroformate (26.4 millimoles) placed in 50 ml of dry methylene chloride. The purple solution was stirred for 0.5 h, after which it was washed with 10 ml of water, dried with magnesium sulfate and the solvent and the crude mixed anhydride was dissolved in 50 ml of THF and slowly to an ice-cooled suspension of 0.72 g of sodium borohydride (18.9 millimoles) in 50 ml of THF. After stirring for half an hour, an additional 0.30 g of sodium borohydride (7.9 millimoles) was added and the reaction mixture was left to stand in an ice bath for one hour. Then 5 ml of water was added and after 10 minutes 3 ml of 10% aqueous hydrochloric acid followed. After gas evolution ceased, 2 g of solid potassium carbonate was added with stirring. The organic phase was then removed and the remaining white paste was extracted with additional tetrahydrofuran. The combined organic phases were dried with magnesium sulfate and the solvent was removed. "Flash" column chromatography on silica gel, eluting with hexane, mixtures of ethyl acetate-hexane and finally with ethyl acetate, gave l- (ethoxycarbonylmethyl) -4-hydroxymethyl-1,2,3-triazole (2.04 g, 44%) as a crystalline solid.

'HNMR (CDCI3) 5: 1.28 (3H, t, J = 7 Hz), 4.23 (2H, q, J = 7 Hz), 4.75 (2H, s), 4.85 (2H, s), 7.73 (1H, s).

4.11 ml of diisopropylazodicarboxylate (20.8 millimoles) was added dropwise to an ice-cooled solution of 5.47 g of triphenylphosphine (20.8 millimoles) in 100 ml of dry THF under nitrogen. After 0.5 h, an ice-cooled solution of 1.93 g of the alcohol (10.4 millimoles) and 1.49 ml of thioacetic acid (20.8 millimoles) in 50 ml of dry THF was added to the above mixture under nitrogen. This was left to stand in an ice bath for 2 hours and then at room temperature for a further 12 h; the solvent was then removed. The reaction mixture was subjected to "flash" chromatography on silica gel (40 g; eluted with 100 ml portions of hexane, 5%, 10%, 15% ... 50% ethyl acetate-hexane). The fractions containing thiolacetate were combined and poured onto silica gel ( 60 g) rechromatographed [elution with 200 ml portions of hexane, 5%, 10%, 15%, 20% ethyl acetate-hexane and 22.5, 25, 27.5 ... 35% ethyl acetate-hexane], giving 1 , 24 g (49%) 1- (ethoxycarbonylmethyl) -4-acetylthiomethyl-l, 2,3-triazole as a crystalline solid ['HNMR 5: 1.28 (3H, t, J = 7 Hz), 2.37 ( 3H, s), 3.87 (2H, s), 3.90 (2H, q, J = 7 Hz), 5.12 (2H, s), 7.63 (IH, s); IR (Nujol) , 1735.1780 cm-1] and an additional 1.40 g of material which was contaminated with triphenylphosphine oxide.

0.51 ml of methyl trifluoromethane sulfonate (4.53 millimoles) was added dropwise to an ice-cooled stirred solution of 1.00 g of the triazole (4.12 millimoles) in 5 ml of dry methylene chloride. The bath was removed after half an hour and after another half an hour the solvent was removed with a vacuum pump. The remaining solid was suspended in 15 ml of water and this mixture was stirred with cooling in an ice bath. A solution of 0.69 g KOH (12.4 millimoles) in 5 ml water was added and the reaction mixture was stirred for one hour. It was then diluted to 30 ml with water and solid potassium dihydrogen phosphate was added.

53

656130

given to adjust the pH to 8.0. A 22 ml portion of this solution (approximately 3.0 millimoles of the thiol carboxylate) became the ice-cooled, stirred solution of the enol phosphate (1.60 g, 2.76 millimoles) in 30 ml of THF. After 0.5 h the THF of the reaction mixture was removed under high vacuum. The yellow solution was then chromatographed on a reverse phase column (35 x 120 mm), eluted with 200 ml water followed by 100 ml portions of 5, 10, 15 ... 30% acetonitrile water. Freeze-drying of the desired fractions gave the p-nitrobenzyl ester as a yellow solid (930 mg). This was transferred to a pressure bottle containing 25 ml ether, 25 ml THF and 25 ml phosphate buffer (prepared by dissolving 1.36 g potassium dihydrogen phosphate [0.01 mol] in 100 ml water and adjusting the pH to 7.4 by adding of 45% aqueous KOH) and 900 mg of 10% palladium on carbon The hydrogenation was carried out under a pressure of 2.72 MPa for one hour and then the organic phase was separated off and washed with water (2x5 ml) Combined aqueous phases were filtered and concentrated under high vacuum. The remaining solution was chromatographed on a reverse phase column (35 x 120 mm) eluting with water. The carbapenem-containing fractions were combined and freeze-dried to give 1.21 g of a slightly greenish solid. This was then purified by high pressure liquid chromatography (10 x 30 mm "Water microbondapack" C-18 column, H20 as eluent), the pure Ti tel product was obtained, 480 mg (41%).

'HNMR (DjO) 5: 1.23 (3H, d, J = 6.4 Hz), 3.11 (2H, d, J = 9 Hz), 3.37 (1H, q, J = 3.0 , 6.1 Hz), 4.02 (2H, m), 5.18 (2H, s), 8.53 (1H, s).

IR (Nujol) 1750 cm- '.

UV (phosphate buffer, pH 7.4) ^ max 205 nm (s = 7.810).

Example 19

3- [5- (1,4-Dimethyl-l, 2,4-triazolium) methylthio] -6a- [1- (R) -hydroxyethylJ-7-oxo-I-azabicyclo [3.2.0] hept- 2-en-2-carboxylate

A. I-Methyl-S-acetylthiomethyl-1,2,4-triazole -N PS e) HsCl / NEt r \

-V

b) CH3ÇSB / N £: 3

B. 3- [5-f 1,4-Dimethyl-l, 2,4-triazolium) methylthio] -6a- [l- (R) -hydroxyethyl] -7-oxo-l-azabicyclo [3.2.0] hept -2-en-2-carboxylate

0.46 ml of methanesulfonyl chloride (6.0 millimoles) was added dropwise to an ice-cooled stirred solution of 565 mg of 1-methyl-5-hydroxymethyl-1,2,4-triazole (5.0 millimoles) (made according to RG Jones and C. Ainsworth, J. Amer. Chem. Soc., 1955, 77, 1938) and 0.91 ml triethylamine (6.5 millimoles) in 5 ml methylene chloride. After 20 minutes, an additional 1.05 ml of triethylamine was added followed by 0.53 ml of thioacetic acid (7.5 millimoles) and stirring was continued for 45 minutes. The reaction mixture was then diluted with methylene chloride and washed with water. The aqueous phase was washed with methylene chloride (3x5 ml) and the combined organic phases were dried with magnesium sulfate and the solvent was removed. Column chromatography on silica gel gave pure l-methyl-5-acetylthiomethyl-1,2,4-triazole (570 mg) as a yellow oil. (In addition, an impure fraction (200 mg) was rechromatographed (preparative thin layer chromatography on silica gel), a further 100 mg of the pure material being obtained (total yield: 85%).)

HNMR (CDCLj) 8: 2.38 (3H, s), 3.90 (3H, s), 4.25 (3H, s), 7.80 (1H, s).

r \ -r y

&) MeOTf b) HaOH

o Jjf n d) K2 /? d-C

oé> dead.)

C02? NB

1.20 ml of methyl trifluoromethanesulfonate (10.7 millimoles) was added dropwise to an ice-cooled solution of 730 mg of l-methyl-5-is acetylthiomethyl-1,2,4-triazole (4.27 millimoles) in 7 ml of methylene chloride. The reaction mixture was slowly warmed to room temperature over 3 hours and then concentrated. The remaining oil was triturated with ether to give crude 1,4-dimethyl-5-acetylthiomethyl-1,2,4-triazolium-20 trifluoromethanesulfonate (1.46 g) which was used directly.

A solution of 512 mg of sodium hydroxide (12.8 millimoles) in 5 ml of water was added to an ice-cooled solution of 1.45 g of the tri-azolium salt (4.35 millimoles) in 5 ml of water. After 45 min. 25 this was diluted to 25 ml with water and the pH was adjusted to 7.6 with solid potassium dihydrogen phosphate. The solution was then added to an ice-cooled stirred solution of 2.00 g of enol phosphate (3.45 millimoles) in 25 ml of THF. After 30 minutes, the reaction mixture was placed in a pressure bottle containing 40 ml of 30 ether and 2.0 g of 10% palladium on carbon. This was hydrogenated under a pressure of 3 MPa for 1.2 h. The reaction mixture was then diluted with 25 ml ether and filtered. The organic phase was separated and washed with water (2x5 ml). The combined aqueous phases were washed with 35 ether (3 x 25 ml) and then concentrated under vacuum. Column chromatography (reverse phases, 45 x 120 mm, water as eluent), followed by freeze-drying of the carbapenem-containing fractions gave 650 mg of the crude material. This was rechromatographed to give the pure title product 40 (450 mg, 39%).

'HNMR (D20) 5: 1.24 (3H, d, J = 6.4Hz), 3.19 (2H, q, J = 2.6, 9.2 Hz), 3.45 (1H, q, J = 2.8.6.0 Hz), 3.91 (3H, s), 4.06 (3H, s), 4.09-4.36 (2H, m), 4.54 (2H, d , J = 2k8 Hz), 8.71 (1H, s).

IR (nujol) 1755 cm-1.

45 UV (phosphate buffer, pH 7.4) Àmax 294 nm (e = 8.202); T * (phosphate buffer, pH 7.4, M = 0.067, T = 37 ° C) 9.1 h.

Example 20

(l'R, 5R, 6S) 3 - [(l, 3-dimethyl-5-tetrazolium) methylthio] -6- (1-50 hydroxyethyl) -7-oxo-l-azabicyclo [3.2.0] hept- 2-en-2-carboxylate ce

ço y

4-

CE

"-H'

I.

CH

3rd

A. 5-carbethoxy-2-methyltetrazole and 5-carbethoxy-l-methyltetrazole

"V CK-H,

\ V — CC ^ Et

1>

\

-K2 N- "O

II W + | V_c;

\ x.

, cv2sc <

la. Methylation with diazomethane

A solution of 9.17 g of 5-carbethoxytetrazole (0.064 millimole) (obtained from D. Moderhack, Chem. Ber., 198, 887 [1975]) in 80 ml

656130

54

Ethyl ether (a mixture of ethanol and ether gave the same ratio of the isomers) was cooled to 0 ° C and treated dropwise (15 min) with a solution of 3 g diazomethane (0.071 millimoles) in 200 ml ether. The pale yellow solution was stirred for 30 minutes and the excess diazomethane was destroyed by adding 1 ml of acetic acid. Evaporation of the solvent and distillation of the residue gave a clear oil: bp 95-100 'C / 67 Pa; 9.64 g (96%). 'Hmr indicated a mixture of 1-methyl and 2-methyl isomers in a ratio of 6: 4. The two isomers could not be separated either by distillation or by high pressure liquid chromatography.

ir (film) vmax: 1740 cm-1 (C = 0 of the ester).

1 Hmr (CDC13) 5: 1.53 (3H, two overlaps t, J = 7.0, CH2CH3), 4.46 and 4.53 (3H, 2S, CH3 of 1-methyl and 2-methyl-tetrazole, Ratio 6: 4. The methyl of the 2-isomer is in the second field and is present in smaller amounts), 4.5 ppm (2H, two overlaps q, CH2CH3).

1 b. 5-carbethoxy-2-methyltetrazole

N "" *.

Ji V-CO „2t lî ^ K

+ 1

ch.

>

ce.

iT 2 130 * C

o washed with 10 ml brine and finally dried with dry sodium sulfate. Concentration of the solution and distillation of the residue under vacuum gave 1.83 g (33%) of a clear oil. This material showed that the product was 5-5 hydroxymethyl-2-methyltetrazole.

2. By reducing 5-carbethoxy-2-methyltetrazole

To a solution of 0.139 g of 5-carbethoxy-2-methyltetrazole (0.89 millimole, obtained by isomerizing the mixture of the 10 esters with methyl iodide) in 1 ml of dry tetrahydrofuran at 10 ° C., 0.019 g of solid lithium borohydride (0.87 millimole) given. The mixture was slowly warmed to room temperature and stirred for 4 hours. The excess of borohydride was destroyed by careful addition of 6 normal hydrochloric acid at 0 ° C (pH 7). The solution was evaporated and the residue was dissolved in 25 ml dichloromethane and dried over anhydrous sodium sulfate. Evaporation of the solvent gave the title compound as a clear oil: 0.092 g (91%); SDP 90-120 ° C / 667 Pa, with decomposition.

20 ir (film) vmax: 3350 cm-1 (wide, OH).

'Hmr (CDC13) 8: 4.4 (2H, s, CH3-2), 4.93 (2H, s, CH2-5).

COjSt.

A mixture of 5-carbethoxy ~ 2-methyltetrazole and 5-carb-ethoxy-l-methyltetrazole (0.252 g, 1.61 millimoles, ratio of the two isomers 1: 1) in 0.5 ml iodomethane was melted in a glass tube and applied 100 ° C for 15 h and heated to 130 ° C for 6 h.

Distillation of the reaction mixture gave the title compound as a slightly yellow oil: 0.139 g (55%); Sdp 95-100 ° C / 67 Pa (air bath temperature).

ir (film) vmax: 1749 cm-1 (C = 0 of the ester).

'Hmr (CDC13) 8: 1.46 (3H, t, J = 7.0, CH3CH2), 4.53 (3H, s, CH3-2), 4.5 (2H, q, J = 7.0 , CH2CH3).

2. Methylation with dimethyl sulfate

A solution of 1.42 g of 5-carbethoxytetrazole (0.01 mol) in 20 ml of dry acetone was treated with 1.38 g of anhydrous potassium carbonate (0.01 mol) and 1.26 g of dimethyl sulfate (0.01 mol) . The mixture was heated under reflux for 12 hours. The carbonate was filtered and the solvent was evaporated under reduced pressure. The residue was diluted with 30 ml dichloromethane, washed with 10 ml sodium bicarbonate, 10 ml brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and distillation under vacuum gave a clear oil: 1.45 g (93%). Bp 85-110 ° C / 67 Pa. 'Hmr confirmed the presence of both isomers in a 1: 1 ratio.

B. 5-hydroxymethyl-2-methyltetrazole

CE3-îf

CO ^ z + liBK <

r.

3rd

s2ok

C. 5-Acetylmercaptomethyl-2-methyltetrazole

25th

Vf

I.

H

H":

OH.

1) MsCl, £ t3N

2) CH3COSK

CHi l ^

-N

: h2sac or.

30 To a solution of 1.83 g of 5-hydroxymethyl-2-methyltetrazole (11.7 millimoles) in 25 ml of dry dichloromethane was added 1.47 g of methanesulfonyl chloride (12.9 millimoles) at 0 ° C, followed by 1.30 g Triethylamine (12.9 millimoles) added dropwise over 5 minutes. The mixture was stirred at 0 ° C for 1 hour and then 3S treated with a solution of 1.60 g of potassium thioacetate (14.0 millimoles) in 10 ml of dry N, N-dimethylfonpamide. The resulting gel was stirred at 0 ° C for 3 hours. The reaction mixture was diluted with 200 ml dichloromethane, washed with 20 ml brine and dried over anhydrous sodium sulfate. Evaporation of the solvent under vacuum and chromatography of the resulting oil on silica gel (2 x 15 cm eluted with dichloromethane and dichloromethane-acetone 5%) gave the title compound as a clear oil: 1.31 g (65%).

ir (film) vmM: 1696 cm-1 (C = 0 of the thioester). 45 'Hmr (CDC13) 8: 2.43 (3H, s, SAc), 4.36 (3H, s, 2-CH3), 4.38 ppm (2H, s, 5-CH2).

D. 5-mercaptomethyl-l, 3-dimethyltetrazolium trifluoromethane sulfonate

50 jjss »

CH.

/ -

\ CR, SO, CS,

"-CS" SAc ^ ^

Oh OH

55

1. By reducing the mixture of esters

A mixture of 5-carbethoxy-l-methyltetrazole and 5-carb-ethoxy-2-methyltetrazole (ratio 6: 4) (7.60 g, 0.049 mol) in 50 ml of dry tetrahydrofuran was cooled to 0 ° C. and 06 g of lithium borohydride (0.049 millimoles) treated, which was added in small portions over 15 minutes. The mixture was kept at 10 ° C. for a further 30 minutes and then stirred at 20 ° C. for 4 hours. The mixture was cooled to 0 ° C and the excess hydride was carefully destroyed by adding 6 normal hydrochloric acid (the pH was 7 after no more gas escaped). The solution was concentrated under vacuum and the remaining oil was diluted with 200 ml dichloromethane,

CH. «

©

CH2SH

A solution of 0.400 g of 5-acetylthiomethyl-2-methyltetrazole (2.32 millimoles) in 3 ml of dry dichloromethane was treated with 0.76 g of 60 methyl triflate (4.64 millimoles) and stirred at 22 ° C. for 16 hours. Evaporation of the solvent in vacuo gave a red oil. This salt was dissolved in 5 ml of cold oxygen-free water and treated with 0.8 ml of 4 molar sodium hydroxide (3.2 millimoles). The mixture was treated at 0 C for 65 40 min, diluted with 7 ml of water and the pH was adjusted to 7.3 by saturated KH2P04 solution. The clear solution obtained was kept under nitrogen and immediately used for the following step.

55

656 130

E. (l'R, 5R, 6S) 3 - [(1,3-dimethyl-5-tetrazolium) methylthio] -6- (1-hydroxyethyl) -7-oxo-l-azabicyclo [3.2.0] hept -2-en-2-carboxylate OH

• Ì5 ^

\ CO .PIE 3

In a 2 1 reaction vessel equipped with a magnetic stirrer, a Vigreaux column for distillation, a heating element and an N2 feed, 4.0 mol (432 ml) of methyl acetoacetate and 8.0 mol (464.6 g ) Allyl alcohol. The reaction mixture 5 was distilled at 92 ° C. for 12 hours. 136 ml (2.0 mol) of allyl alcohol was added and the mixture was distilled for 23 hours. Then 136 ml (2.0 mol) of allyl alcohol was added and the mixture was distilled for 16 hours. The reaction mixture was then distilled in vacuo and the product was obtained at a temperature of 105-110aC / 4.67 kPa. 414 g of the allylacetoacetate were obtained (73% yield).

A solution of 0.915 g of the enol phosphate (1.58 millimoles) in 8 ml of tetrahydrofuran was cooled to 0 ° C and prepared dropwise with a solution of 5-mercaptomethyl-l, 3-dimethyltetrazolium trifluoromethanesulfonate (2.32 millimoles) as indicated above over 20 min. The pH of the reaction mixture was kept stable at 6.5 during the addition. After a further 20 minutes the pH of the solution was adjusted to 7.0 with saturated sodium bicarbonate. The mixture was transferred to a hydrogenation bottle, diluted with 10 ml THF, 20 ml ether and 20 g ice. The carbapenem was hydrogenated over 10% palladium on activated carbon under a pressure of 3 MPa while the temperature was slowly raised to 22 ° C over 90 minutes. The catalyst was filtered off and washed with 5 ml of cold water and 20 ml of ether. The aqueous phase was washed with 20 ml ether and treated under a vacuum for 20 min to remove traces of organic solvents. Chromatography on "PrePak" 500-C / 18, eluting with water, gave the title compound as a white powder after freeze-drying 0.266 g (49%); [ag + 13 °

(c 1.04, H20).

UV (H20, pH 7.4) X,

ir (KBr) vmax: 1755 (C =

C = O of the carboxylate).

'Hmr (D20) 5: 1.24 (3H, d, J = 6.4 Hz, CH3CHOH), 3.0-3.3 (2H, m, H-4), 3.42 (1H, dd, J = 5.8, J = 2.9, H-6), 4-4.2 (2H, m, H-5 and CHjCHOH), 4.34 and 4.57 (2 x 3H, 2S, CH3- 1 and 3 of tetrazole), 4.49 and 4.51 (2H, 2s, CH2S).

The product has a half-life of 10.5 h at 37 ° C (c of 10 ~ 4 M in pH 7.4 phosphate buffer).

Example 21

Alternative process for the preparation of 3- (N-methylpyridin-2-yl-

methylthio) -6a- [l '(R) -hydroxyethyl] -7-oxo-l-azabicyclo [3.2.0] -

hept-2-en-2-carboxylate x: 294 nm (e7,500).

= 0 of the ß-lactam), 1600 cm- '(broad,

A.

COjCBJ

To a solution of 226.5 g of the allylacetoacetate (1.594 moles) in 3 liters of acetonitrile and 243.4 ml of triethylamine (1.753 moles) was added 20 345.3 ml of p-toluenesulfonyl azide (1.753 moles) over an hour while maintaining the temperature was kept at about 20 ° C. by a cooling bath. The reaction mixture turned yellow. The reaction mixture was then stirred at room temperature under a nitrogen atmosphere for 18 hours. The mixture was concentrated on a rotary evaporator. The residue was dissolved in 2.61 diethyl ether and 1 molar aqueous KOH (800 ml). The organic phase was washed 5 times with 500 ml of 1 molar KOH and once with 400 ml of brine. After drying over magnesium sulfate under concentration in a rotary evaporator (temperature <30 ° C.), 260.2 g (97%) of the title product were obtained.

302 ml (1.315 mol) of t-butyldimethylsilyl triflate 40 were added to a stirred suspension of 203 g of allyl diazetoacetate (1.195 mol) in 2 l of methylene chloride and 199 ml (1.434 mol) of triethylamine at 5 ° C. over a period of 45 min. admitted. The mixture was stirred at 5 ° C for one hour and then for another hour without cooling. The reaction mixture was washed 4 times with 500 ml H20 and then once with 500 ml brine. It was dried over sodium sulfate and concentrated to 344 g of an orange-45 oil. This oil was used directly for the next step.

W

d ^ ~

To a mixture of (1 'R, 3R, 4R) -3- (l'-tert-butylimethylsi-60 lyloxyethyl) -4-acetoxy-azetidin-2-one (28.7 g, 0.1 mol) and 6 , 8 g of freshly melted ZnCl2 (0.05 mol) in 700 ml of dry methylene chloride, a solution of 33.84 g of allyl-2-diazo-3-tert-butyldimethylsilyloxy-3-butenoate (0.12 mol) in 50 ml was added dropwise Methylene chloride added over 5 hours. The mixture was stirred at room temperature for 65 hours when TLC (thin layer chromatography) detected a small amount of residual starting material. An additional amount of 4.23 g allyl-2-diazo-3-tert-butyldimethylsilyloxy-3-butenoate (0.015 mol) in 10 ml

656130

56

Methylene chloride was added over a one hour period and stirring was continued at room temperature for 10 hours. The reaction mixture was then diluted with 750 ml ethyl acetate, washed (2 x 300 ml saturated NaHCO 3, 300 ml brine), dried over magnesium sulfate and evaporated to give 62.5 g of a dark orange oil, which was dissolved in 500 ml methanol and washed with 1 normal aqueous hydrochloric acid (110 ml) was treated. The resulting mixture was stirred at room temperature for 2 hours and then 10 ml of 1-normal hydrochloric acid was added, followed by further stirring for 2 hours. The reaction mixture was concentrated to half volume and poured into a mixture of ethyl acetate (800 ml) and Poured water (800 ml). The organic phase was separated, washed with 800 ml and the combined aqueous extracts were washed with 400 ml of ethyl acetate. The combined organic extracts were washed with brine (2 x 400 ml), dried with magnesium sulfate and concentrated to 32 g of a dark orange-red oil. "Flash" chromatography gave 9.33 g (33% yield) of the title compound as a golden yellow oil, which solidified to a pale yellow solid.

'H-nmr (CDC13) 8: 6.20-5.72 (m, 2H), 5.48-5.21 (m, 2H), 4.74 (dt, J = 5.8, J' = 1.2 Hz, 2H), 4.30-3.88 (m, 2H), 3.30-3.20 (m, 2H), 2.89 (dd, J = 7.3, J '= 2 , l, lH), 2.18 (s, 1H), 1.32 (d, J = 6.2, 3H).

E. CSi-

co:

NE

OH

A mixture of a-diazoester prepared in Step D above (9.2 g, 32.7 millimoles) and rhodium acetate [Rh2 (0Ac) 4] in benzene (1 Ì) was refluxed for one hour. The solution was treated with activated carbon and filtered through "Celite". The "Celite" was washed with 100 ml of hot benzene. The concentration of the filtrate gave 8.08 g (97% yield) of the title product as a pale brown crystalline solid.

1 H-nmr (CDC13) 8: 6.15-5.68 (m, 1H), 5.45-5.18 (m, 2H), 4.71-4.60 (m, 2H), 4, 40-4.05 (m, 2H), 3.17 (dd, J = 7, 1, J '= 2.0, 1H), 2.95 (dd, J = 6.9, J' = 18, 9.1H), 2.42 (dd, J = 7.6, J '= 18.8, 1H), 1.88 (s, 1H), 1.39 (d, J = 6.3, 3H) .

OH

F.

co:

OH

'CO;

To a solution of 7.5 g of the keto ester, prepared in step E

(0.03 mol) 6.08 ml diisopropylamine (0.035 mol) was added at 0 * C under an N2 atmosphere followed by diphenylphosphoryl chloride. After 15 minutes, thin layer chromatography showed no remaining starting material. 6.26 ml of diisopropylamine (0.036 mol) and a solution of 4.5 g of freshly distilled 2-mercaptomethylpyridine (0.036 mol) in 5 ml of acetonitrile were then added to the reaction mixture. After stirring at 0 ° C for two hours, the mixture was poured into 1 liter of ethyl acetate, washed with water (2 x 150 ml), saturated NaHCO 3 (150 ml), H20 (150 ml) and brine (200 ml). The organic phase was dried with magnesium sulfate and turned to a dark orange-yellow

Concentrated rubber. "Flash" chromatography gave the product as a golden yellow oil. The product was dissolved in diethyl ether and cooled to 0 C. The filtration gave 4.8 g (44% yield) of the purified title product as cream-colored crystals.

'H-nmr (CDClj) 8: 8.6-8.4 (m, 1H), 7.85-7.15 (m, 3H), 6.20-5.74 (m, 1H), 5, 54-5.15 (m, 2H), 4.80-4.66 (m, 2H), 4.29-4.03 (m, 1H), 4.19 (s, 2H), 3.69- 2.85 (m, 1H), 2.97 (s, 1H), 1.32 (d, J = 6.2, 3H).

OH

G.

OE

To a solution of 1.79 g of the allyl ester prepared in step F (4.97 millimoles), 175 mg of tetrakistriphenylphosphine palladium (0.15 millimoles) and 175 mg of triphenylphosphine (0.67 millimoles) in 25 ml of methylene chloride was added a solution of 1.085 g of potassium -2-ethyl hexanoate (5.96 millimoles) in 12 ml of ethyl acetate was added.

After stirring at room temperature for one hour, thin layer chromatography showed only traces of the starting material. The reaction mixture was diluted with anhydrous diethyl ether (150 ml) and the precipitate was collected by filtration, washed with ethyl acetate and then with ether, giving a light brown solid. This solid was dissolved in 10 ml of water and purified by reverse phase chromatography, giving 1.85 g of the title product as an off-white solid. This material was further purified by slurrying in acetone to give 1.47 g (42%) of the pure title compound.

'H-nmr (D20) 8: 8.45-8.36 (m, 1H), 7.92-7.22 (m, 3H), 4.78-3.91 (m, 2H), 4, 69 (s, 2H), 3.34-2.71 (m, 3H), 1.19 (d, J = 6.4, 3H).

H,

OH

CO,

27.6 mg of toluenesulfonic acid (0.16 millimoles) were added to a cooled (0 ° C.) suspension of 53.8 mg of potassium 6-hydroxyethyl-2- (2-pyridylmethylthio) carbapenem-3-carboxylate (0.15 millimoles ) given. The mixture was stirred at 0 ° C. for 20 minutes and then treated with 0.02 ml of methyl triflate. After stirring at 0 ° C for 60 min, LA-1 resin was added, followed by 6 ml of hexane. The mixture was extracted with water (4 x 0.5 ml) and the combined aqueous phases were purified by reverse phase high pressure liquid chromatography to give 10 mg of the title compound.

Example 22

Preparation of 3- (N-methylpyridin-2-yl-methylthio) -6a- [l- (R) -hydroxyethyl] -7-oxo-la: a6icyclo [3.2.0] hept-2-en-2-carboxylate the "one-pot" process

OH.

CK,

CO.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

656 130

1) Na0K / H, 0 ÇK3

2 n c \ | J

O *, 1 h. Tf ^

yj EH

2) KH2? 04

4th

57

C02? N3

© 1

CF, SO © CH3 3 3

SAc ch3cn

O '' C, 45 min.

CH,

NaOH

HjO, O C, 1 h.

r> T "3 CF.SO.® 15

U U. - ■ »J

© 1 J ß »

H2 Pd-C 10% 5 "C, 2h.

OH

A

30th

O

0? (Opf).

C02? N3

A. Preparation of enol phosphate (2) OH OH

An ice-cooled solution of 3 g of ketone 1 (8.62 millimoles) in 30 ml of acetonitrile was treated with ethyl-diisopropylamine (9 millimoles, 1.04 eq, 1.57 ml) (addition time approx. 2 min.) And chlorodiphenylphosphate ( 9 millimoles, 1.04 eq, 1.87 ml) (addition time approx. 2 minutes). The reaction mixture was stirred for 45 minutes and thin layer chromatography (ethyl acetate, silica gel) indicated the disappearance of ketone 1. The solution was diluted with 60 ml of ethyl acetate, washed with cold water (2 x 50 ml) and brine, dried over sodium sulfate and concentrated (bath temperature below 20 ° C) to give a foam which was used as such.

An ice-cooled solution of 3.31 g of thioacetate 3 (10 millimoles) in water, through which nitrogen was bubbled for 5 minutes, was added dropwise (about 5 minutes) with a cooled solution of 0.7 g of sodium hydroxide (1.75 eq, 17.5 millimoles) in 8 ml of water. The mixture turned yellow. After 75 min the pH was adjusted to 7.4 with saturated aqueous solution of KH2P04. The reaction mixture was diluted with 15 ml of water. This aqueous solution of thiol 4 (50 ml, 0.2 millimoles / ml) was used as such.

C. clutch

A_

TKr-H20 '

pH 6.5-7.5 0 ", Ì h.

^ CH. %! <

CO-.PNE

An ice-cooled solution of 2 (crude, made in A, 8.62 millimoles) in 50 ml of tetrahydrofuran was treated dropwise with an aqueous solution of thiol 4 made in B (5 ml of solution every 5 minutes). During the course of the reaction, the pH of the reaction mixture was maintained at about 6.5 to 7.5 (preferably 7 by adding chilled 2 normal sodium hydroxide solution). The reaction was followed by thin layer chromatography (a) silica gel, ethyl acetate; (b) Reverse phase "Analtech" RPSF, CH3CN - pH 7 buffer (4: 6).

Finally, 1.15 eq thiol (50 ml of the solution) was used. The reaction was complete after one hour at 0 C and the mixture was used as such for the hydrogenation after the pH was adjusted to 7.

D. Hydrogenation

The reaction mixture, which contained 5 (made in C), 65 was placed in a Parr bottle with 10 ml of tetrahydrofuran, 10 ml of phosphate buffer (pH 7, 0.1 molar), 75 ml of ether and 5 g of PD-C 10 % transferred and hydrogenated at a pressure of 3 MPa at 3-10 ° C for 2 hours. The catalyst was then filtered off, with water (3 ×

OH

A

656130

58

10 ml) and the pH value was carefully adjusted to 6.2 with lesser 2 normal sodium hydroxide solution. Ether was added and the aqueous phase was separated and washed again with ether. The aqueous phase was cleaned of organic solvent under vacuum and then cleaned on a "Bondapak" C-18 column (100 g, 4.5 x 13 cm) with cold distilled water. The pale yellow fractions containing the product ( detected by UV and thin layer chromatography), were freeze-dried, 1.46 g (50% yield, calculated based on the bicyclic ketone) of 6 as a yellow powder. * .293, s = 9000, X271, e = 11064.

Example 23

Preparation of (5R, 6S) -3 - [[(1,3-dimethylpyridinium-4-yl) methyl] thio] -6- [l- (R) -hydroxyethylJ-7-oxo-J-azabicyclo [3.2. 0] hept-2-en-2-carboxylate (23A)

and

(4R, 5R, 6S) -3 - [[(1,3-dimethylpyridinium-4-yl) methyl] thio] -6- [1- (R) -hydroxyethyl] -4-methyl-7-oxo-I- azabicyclo [3.2.0] hept-2-en-2-carboxylate (23B)

OH R

CH | 3rd

Ol ©

'CH,

CO.

23A R = H

23B R = CH3 A. Preparation of 4-hydroxymethyl-3-methylpyridine

CHOH

CH

CH

CH

Boekelheide1's general procedure for the use of hydroxymethylpyridines was used. As a result, a solution of freshly distilled 3,4-lutidine (46.0 g, 0.43 mol) in 1.20 ml of glacial acetic acid was cooled to 0 ° C. and then 64 ml of 30% H202 were added dropwise heated to 75 "C (oil bath temperature). Then another 20 ml of 30% H202 was added and heating continued for 18 hours. Finally, 20 ml of 30% H202 were again added and the reaction was continued at 75e1 C for a further 3 h. The solution was then concentrated to 100 ml under a water jet vacuum, then 50 ml of HzO was added and the mixture was concentrated to half the volume. The resulting mixture was cooled (0-5 "C) and basified to pH 10 using cold 40% aqueous NaOH. The mixture was then extracted with CH2C12 (5X) and the extract was dried (Na2C03 and Na2S04) and concentrated on a rotovap to give a yellow solution. Dilution of this solution with hexane gave a white solid which was collected by filtration and dried in vacuo to give 3,4-lutidine-N-oxide (48.0 g, 83%) as an off-white solid.

• The N-oxide was added dropwise to 60 ml of acetic anhydride and the resulting dark orange solution was warmed (water bath) at 90 ° C. for 1 h. The excess acetic anhydride was then distilled off under reduced pressure and the material (39.0 g) boiling at 90-120 ° C / 13 Pa (0.1 Torr) was collected. Chromatography of this oil (silica gel / ethyl acetate: petroleum ether, 2: 3) gave pure 4-acetoxymethyl-3-methylpyridine (19.0 g, 30%) as an oil.

IR (pure) 1745 cm "1.

The acetate was then taken up in 100 ml of 10% aqueous HCl and heated under reflux for 1 h. The resulting solution was cooled to 0 C, basified with solid K2C03 and then extracted with CH2C12 (3 x 100 ml). The organic extract was washed (brine), dried (Na2S04) and evaporated to give 11.0 g of an off-white solid, F. 70-72 "C. This solid was triturated with cold ether, with pure 4-hydroxymethyl 3-methylpyridine (9.5 g, 67%) was obtained as a white solid, F. 77-80 "C (Lit.2 F. 81 -82 C).

'HNMR (CDC13) 5: 8.27, 7.41 (ABq, J = 5 Hz, 2H), 8.18 (s, 1H), 5.63 (br s, -OH), 4.67 (s , CH2), 2.20 (s, CH3).

ir (Nujol) 3170 cm "1.

'' V. Boekelheide, W.J. Linn, JACS, 76, 1286 (1954). 2 W.L.F. Armarego, B.A. Milloy, S.C. Sharma, JCS, 2485 (1972).

B. Preparation of 4- (acetylthiomethyl) -3-methylpyridine

CH.

CH.OH

• CH.

To an ice-cooled, mechanically stirred solution of tri-phenylphosphine (17.04 g, 0.065 mol) in 250 ml of dry THF was added dropwise diisopropyl azodicarboxylate (12.8 ml, 0.065 mol) and the resulting slurry was kept at 0 ° C for Stirred for 1 h. To this mixture was added dropwise a solution of 4-hydroxymethyl-3-methylpyridine (4.0 g, 0.0325 mol) in 100 ml of dry THF, followed by freshly distilled thiolacetic acid (4.64 ml, 0.065 mol). The resulting mixture was stirred at 0 ° C for 1 hour and then at room temperature for 1 hour to obtain an orange solution. The solution was concentrated (rotary evaporator) and then diluted with petroleum ether. The resulting mixture was filtered and the filtrate was evaporated to give an orange oil. Chromatography (silica gel / hexane, then 10% → 50% ethyl acetate / hexane) of this oil gave 7.0 g of an oil which was distilled (Kugelrohr) and gave the pure product (6.0 g, 100%) as a yellow oil, K. (air bath temperature) 95-100 0 C / 13 Pa (0.1 Torr).

HNMR (CDCI3) 5: 8.40, 7.20 (ABq, J = 5 Hz, 2H), 8.37 (s, IH), 4.08 (s, CH2), 2.35 (s, CH3 ), 2.32 (s, CH3).

ir (pure) 1695 cm "1.

C. Preparation of 4- (acetylthiomethyl) -! J3-dimethylpyridinium triflate

CH.

CH.

3rd

CH,

To an ice cold solution of thioacetate (2.95 g, 0.016 mol) in 10 ml of methylene chloride was added dropwise methyl trifluoromethane sulfonate (4.60 ml, 0.04 mol) and the mixture was stirred at 0 ° C and N2 for 1 h. The reaction mixture was then evaporated to dryness and the residue was triturated with ether. The resulting solid was collected by filtration and dried in vacuo to give the product (4.0 g, 72%) as a white solid.

'HNMR (CDCI3) 5: 8.72 (s, 1H), 8.58, 7.87 (ABq, J = 6 Hz, 2H), 4.39 (s, N-CH3), 4.17 (s , CH2), 2.53 (s, CH3), 2.36 (s, CH3). ir (pure) 1700 cm "1.

'D. Preparation of (5R, 6S) -3 - [[(I, 3-dimethylpyridinium-4-yl) meriniJ thio 7-6- / l- (R) -hydroxyethylJ-7-oxo-I-azabicyclo- [3.2.0 ] hept-2-en-2-carboxylate

5

10th

IS

20th

25th

30th

35

40

45

50

55

60

65

59

656130

Cr3S 3

CO ^ NB

3} H2. Pd / C

To an ice-cold solution of NaOH (0.324 g, 0.008 mol) in 10 ml H20, into which N2 was introduced, thioacetate (1.4 g, 0.004 mol) was added and the mixture was stirred at 0 ° C and under N2 for 1 h touched. After adjusting the pH to 7.2-7.3 using 10% aqueous callium dihydrogen phosphate solution, the solution obtained was added dropwise to an ice-cold solution of the enol phosphate "(1.45 g, 0.0025 mol) in 20 ml of THF were added and the mixture was stirred for 1 h at 0 ° C. and then placed in a pressure bottle, to which 20 ml of ether, 25 ml of 0.1 M phosphate buffer (pH 7.4) and 1.4 were added 10% palladium-on-carbon was added, the mixture was then hydrogenated at 45 psi for 1 hour, the reaction mixture was filtered through Celite, and the filter material was washed with additional ether and phosphate buffer with a pH 7.4 washed. The aqueous phase was separated and the remaining solvents removed in vacuo. The resulting aqueous solution "was applied to a reverse phase column (C18 BondaPak) which was eluted with water and then with 10% acetonitrile / water . Freeze-drying of the relevant fraction gave 0.9 g of an orange solid. This material was rechromatographed using water and then 2% acetonitrile / water as the eluent. Lyophilization gave pure 23A (0.25 g, 57%) as a yellow solid.

»HNMR (D20) 5: 8.55 (s, 1H), 8.53, 7.96 (ABq, J = 6.8 Hz, 2H), 4.30-3.99 (m, 2H), 4 , 27 (s, 5H), 3.35 (dd, yes = 2.8 Hz, J2 = 6.0 Hz, 1H), 3.05 (d, J = 8.8 Hz, 2H), 2.50 (s, 3H), 1.23 (d, J = 6.3 Hz, 3H). ir (KBr) 1755, 1590 cm-1.

uv (phosphate buffer, pH 7) 295 nm (s7180).

E. Preparation of (4Rr5R, 6S) -3 - [[(1,3-Dimethylpyridinium-4-yl) methyl] thio] -6- [l- (R) -hydroxyethyl] -4-methyl-7-oxo l-azabi-cyclo [3.2.0] hept-2-en-2-carboxylate o

CO-PNB

1) (POJjPCl

2)

3) H2. Pd / C

25th

30th

washed. The organic phase was dried (Na2SO4) and evaporated at room temperature, the enol phosphate being obtained as an off-white foam. This foam was taken up in 20 ml of THF, cooled to -30 ° C under nitrogen and then treated with an aqueous solution of the thiolate (prepared as previously made from 0.3 g NaOH (7.5 mmol) and 1.3 g of the thiolate (3.76 mmol) in 10 ml H20). The reaction mixture was stirred at -30 ° C for 30 minutes and then at 0 ° C for 75 minutes and finally it was transferred to a pressure bottle containing 20 ml ether, 30 ml 0.1M phosphate buffer (pH 7.4) and 1.5 g of 10% palladium on activated carbon contained. After hydrogenation at 45 psi for 1 h, the mixture was filtered through Celite and the aqueous phase was separated and concentrated in vacuo. The resulting solution was applied to a reverse phase column (C18 BondaPak) which was eluted with water. Freeze-drying of the relevant fractions gave 1.2 g of a yellow solid. This material was rechromatographed (elution with H20 to 4% acetonitrile / H20), whereby pure 23B (0.250 g, 28%) was obtained as a yellow solid after freeze-drying.

»HNMR (D20) 5: 8.53 (s, 1H), 8.49, 7.81 (ABq, J = 6.2 Hz, 2H), 4.38-3.98 (m, 4H), 4 , 27 (s, 3H), 3.49-3.18 (m, 2H), 2.51 (s, 3H), 1.25 (d, J = 6.7 Hz, 3H), 1.16 ( d, J = 7.6 Hz, 3H).

ir (KBr) 1750.1595 cm-1.

uv (philosophy buffer, pH 7, 292 nm (s7930).

Example 24

Preparation of (5R, 6S) -3 - [[(1,2-dimethylpyridinium-4-yl) methyl] thio] -6- [l- (R) -hydroxyethyl] -7-oxo-l-azabicyclo [ 3.2.0 Jhept-2-en-2-carboxylate (24A)

and

(4R, 5R, 6S) -3 - [[(1,2-dimethylpyridinium-4-yl) methyl] thio] -6- [1- (R) -hydroxyethyl] -4-methyl-7-oxo-l- azabicyclo [3.2.0] hept-2-en-2-carboxylate (24B)

OH R

24A R = H 24B R = CH3

A. Preparation of 4-hydroxymethyl-2-methylpyridine

An ice-cold solution of the bicyclic ketone (0.906 g, 0.0025 mol) in 10 ml acetonitrile was successively treated with diphenylchlorophosphate (0.544 ml, 0.00263 mol) diisopropylethylamine (0.457 ml, 0.00263 mol) and 4-dimethylaminopyridine (0 , 3 mg) treated. After 50 minutes the reaction mixture was diluted with cold ethyl acetate and then with cold water and brine

45

3 3

■ A solution of methyl 2-methylisonicotinate 1 (14.0 g, 0.093 mol) in 50 ml of anhydrous ether was added to a suspension of 95% lithium aluminum hydride (2.4 g, thus 0.06 mol) in 150 ml of anhydrous ether added at - 5 ° C under N2. The resulting mixture was stirred at room temperature for 30 minutes and then heated under reflux for 2 hours. Another addition of 1.2 g of 55 (0.03 mol) lithium aluminum hydride was made in portions and refluxing continued for 1 h. The reaction mixture was then cooled to 0 ° C. and treated successively with 3.75 ml of H20, 3.75 ml of 15% aqueous NaOH and finally with 11.25 ml of HzO. This suspension was then filtered and the filter cake was washed with ether and then with ethyl acetate. The filtrate was evaporated to give a dark yellow oil which was taken up with acetonitrile and then filtered through silica gel (elution with acetonitrile and then acetone). This gave the product (7.7 g, 67%) as a yellow

65 oil.

»HNMR (CDC13) S: 8.30, 7.10 (ABq, J = 5 Hz, 2H), 7.17 (s, 1H), 5.42 (s, - OH), 4.70 (s, CH2), 2.50 (s, CH3).

10. Efimovsky, P. Rumpf, "Bull. soc. chim. Fr. ", 648 (1954).

656130

B. Preparation of 4- (A cetylthiomethyl) -2-methylpyridine

CH OH

CH

To a solution of triphenylphosphine (31.4 g, 0.12 mol) in 200 ml dry THF at -5 ° C under N2 was added dropwise di-isopropyl azodicarboxylate (23.6 ml, 0.12 mol) and the mixture was added stirred for 1 h at -5 ° C. To the resulting slurry, a solution of 4-hydroxymethyl-2-methylpyridine (7.60 g, 0.062 mol) and freshly distilled thioacetic acid (8.60 ml, 0.12 mol) in 40 ml of dry THF was added over 10 minutes. The reaction mixture was stirred at 0 ° C for 30 min and then at room temperature for 1 h. The resulting suspension was filtered and the filtrate was concentrated to give an orange-yellow liquid which was diluted with ether and filtered. The filtrate was evaporated and the remaining oil was chromatographed (silica gel / ethyl acetate / hexane (1: 1)) to give the thioacetate (8.87 g, 79%) as a yellow oil.

1 HNMR (CDC13) 5: 8.45, 7.03 (ABq, J = 5 Hz, "2H), 7.08 (s, 1H), 4.04 (s, CH2), 2.55 (s, CH3 ), 2.39 (s, CH3).

ir (pure) 1695 cm-1.

C. Preparation of 4-mercaptomethyl-2-methylpyridine

To 15 ml of ice-cold IN NaOH, into which N2 was introduced, 4- (acetylthiomethyl) -2-methylpyridine (1.358 g, 0.0075 mol) was added all at once. After stirring for 15 min at 0 ° C, the reaction mixture was washed with ether (2x5 ml), neutralized with concentrated HCl and extracted with methylene chloride (3 x 10 ml). Evaporation of the methylene chloride solution gave the thiol (0.89'g; 96%) as a pale yellow oil which gradually turned pink when standing.

»HNMR (CDCI3) 5: 8.43, 7.37 (AB q, J = 5 Hz, 2H), 7.43 (s, 1H), 3.63 (d, J = 7.5 Hz, CH2) , 2.55 (s, CH3), 1.81 (t, J = 7.5 Hz,

SH).

D. Preparation of Allyl- (5R, 6S) -3 - [[(2-methylpyridin-4-yl) methyl] thio] -6- [l- (R) -hydroxyethyl] -7-oxo-1-azabicyclo - [3.2.0] hept-2-en-2-carboxylate co.

co.

Diphenylchlorophosphate (0.653 ml, 0.00315 mol), diisopropylethylamine (0.550 ml, 0.00315 mol) and dimethylaminopyridine (0.8 mg.) Were gradually added to an ice-cold solution of the bicyclic ketone (0.760 g, 0.003 mol) in 8 ml of acetonitrile ) added. After stirring the mixture at 0 ° C for 1 h, it was cooled to -20 ° C and 4-mercaptomethyl-2-methylpyridine (0.620 g, 0.00446 mol) followed by diisopropylethylamine (0.550 ml, 0.00315 mol) was added. The reaction was stirred at -20 ° C for 1.5 hours and then allowed to stand at room temperature. The resulting mixture was diluted with 50 ml of ethyl acetate, washed (HzO, saturated NaHCO 3 and saturated NH 4 Cl solution), dried (Na 2 SO 4) and evaporated. The remaining material was chromatographed on silica gel (eluted with ethyl acetate and then with acetonitrile) to give a solid which, triturated with ether, gave the pure product (0.820 g, 73%) as a white solid:

• HNMR (CDCI3) 5: 8.45, 7.09 (ABq, J = 5 Hz, 2H), 7.15 (s, IH), 6.25-5.80 (m, IH), 5.60 -5.20 (m, 2H), 4.82-4.68 (m, 2H), 4.55-4.05 (m, 2H), 3.97 (s, 2H), 3.16-2 , 93 (m, 3H), 2.55 (s, 3H), 1.84 (br s, 1H), 1.32 (d, J = 6 Hz, 3H).

ir (neat) 1777, 1695 cm-1.

E. Preparation of (5 R, 6S) -3- [[(1,2-Dimethylpyridinium-4-yl) methyl-tliio] -6- [l- (R) -hydroxyethyl] -7-oxo-l- azabicyclo [3.2.0] hept-2-ene-2-carboxylate

■ ch.

co.

• ch.

CO.

A solution of the allyl ester (0.350 g, 0.936 mmol) in 6 ml of dry acetonitrile was cooled to -5 ° C and treated with methyl trifluoromethanesulfonate (0.111 ml, 0.983 mmol). After 15 min, a solution of tetrakis (triphenylphosphine) palladium (0.027 g, 2.5 mol%) and triphenylphosphine (0.027 g) was added. After stirring, pyrrolidine (0.082 ml, 0.983 mmol) was added dropwise to the reaction mixture over 5 minutes. A solid slowly began to separate from the resulting brown solution. The mixture was stirred vigorously for 20 min at 0 ° C and then 15 ml of cold (0 ° C) acetone was added slowly and stirring continued for 20 min at 0 ° C. The resulting suspension was filtered and the residue was washed with cold acetone and then dried under vacuum to give 0.345 g of a beige powder. This material was taken up in a small portion of phosphate buffer with a pH of 7 (0.05M) and applied to a short reverse phase column (CI8 BondaPak). Elution with H20 and freeze-drying of the relevant fractions gave 0.255 g of a light yellow solid. This material was rechromatographed as before to give pure 24A (after freeze drying) (0.195 g, 60%), slightly yellow solid:

»HNMR (D20) 8: 8.58, 7.83 (ABq, J = 6.4 Hz, 2H), 7.87 (s, 1H), 4.32-3.95 (m, 2H), 4 , 22 (s, 2H), 4.17 (s, 3H), 3.32 (dd, J, = 2.6 Hz), J2 = 6, I Hz, 1H), 3.06-2.93 ( m, 2H), 2.74 (s, 3H), 1.22 (d, J = 6.4 Hz, 3H).

ir (KBr) 1757.1590 cm-1.

uv (phosphate buffer, pH 7.4) 296 nm (s7446).

F. Preparation of Allyl- (4R, 5Rj6S) -3 - [[(2-methylpyridin-4-yl) methylthio] -6- [l- (R) -hydroxyethyl] -4-methyl-7-oxo- l-azabicyclo- [3.2.0] hept-2-ene-2-carboxyiat

CH.

OH

, CH.

CO.

CH.

OH

HK

CO.

A solution of a-diazoester (1.50 g, 0.00508 mol) in 12 ml of ethyl acetate / hexane (3: 1) was heated to a moderate reflux under nitrogen and then 0.020 g of rhodium octanoate was added all at once. Rapid N2 evolution was observed over 5 min and after further heating under reflux for a further 10 min the reaction was terminated (TLC). The solvents were then removed under reduced pressure and the remaining gum was taken up in 15 ml of acetonitrile. The solution was cooled to -5 ° C and treated with diphenyl chlorophosphate (1.10 ml, 0.00533 mol), diisopropylethylamine (0.927 ml, 0.00533 mol) and 4-dimethylaminopyridine (0.6 mg, 0.1 mol %) treated. The reaction mixture was stirred for 1 h

60

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

61

656 130

stirred at 0e C and then cooled to -20 "C and treated with a solution of 4-mercaptomethyl-2-methylpyridine (0.656 g, 0.00533 mol) in 1 ml acetonitrile and then with 0.927 ml (0.00533 mol) diisopropylethylamine The resulting mixture was stirred at -10 ° C for 1.5 h and then treated with additional thiol (0.066 g, 0.53 mmol) and diisopropylethylamine (0.093 ml, 0.53 mmol) and the reaction mixture was stirred for 1 h Heated the toilet and then diluted with 75 ml of cold ethyl acetate, washed (H20, brine), dried (Na2S04) and evaporated (bath temperature <30 ° C.) The resulting gum was chromatographed on silica gel. Elution with ethyl acetate removed the contaminants and a subsequent one Elution with acetonitrile gave the product (1.04 g, 53%), which was obtained as a pale yellow foam: • HNMR (CDC13) 5: 8.43, 7.07 (ABq, J = 5 Hz, 2H), 7, 10 (s, 1H), 6.20-5.75 (m, 1H), 5.51-5.29 (m, 2H), 4.81-4.69 (m, 2H), 4.29- 4.03 (m, 2H), 3.96 (s, 2H), 3.35-3.05 (m, 2H), 2.53 (s, 3H), 2.16 (br s, 1H), 1.33 (d, J = 6.3 Hz, 3H), 1.22 (d, J = 7.3 Hz, 3H) .

ir (neat) 1770, 1705 cm-1.

G. Preparation of (4R, 5R, 6S) -3 - [[(1,2-dimethylpyridinium-4-yl) methyl] thio] -6- [l- (R) -hydroxyethyl] -4-methyl-7- oxo-l-azabi-cyclo [3.2.0] hept-2-en-2-carboxylate

A solution of the allyl ester (0.582 g, 0.0015 mol) in 15 ml of dry acetonitrile was treated with trifluoromethanesulfonate (0.178 ml, 1.575 mmol) at -5 ° C. and under nitrogen. After 15 min, a solution of tetrakis (triphenylphosphine ) Palladium (0.035 g, 2 mol%) and triphenylphosphine (0.035 g) in 1 ml of methylene chloride were added, followed after 5 min by 0.131 ml (1.575 mmol) of pyrrolidine, the resulting mixture was stirred at 0 ° C for 20 min and then 30 ml of cold (0 ° C.) acetone was added, the mixture was stirred vigorously for 15 min at 0 ° C. and then the precipitate was collected by filtration, washed with cold acetone and dried in vacuo to give 0.520 g of a beige powder A further 0.041 g of the crude product could be obtained by diluting the filtrate with ether The combined solids were dissolved in a small proportion of phosphate buffer (0.05M), pH 7.4 and applied to a reverse phase column (C18 BondaPak) Elution with H20 and then with 2% acetonitrile / H20 after freeze-drying gave 24B (0.413 g, 76%) as a yellow solid:

»HNMR (D20) 5: 8.55, 7.76 (ABq, J = 6.3 Hz, 2H), 7.81 (s, 1H), 4.4-3.7 (m, 2H), 4th , 19 (s, 2H), 4.16 (s, 3H), 3.47-3.14 (m, 2H), 2.73 (s, 3H), 1.24 (d, J = 6.4 Hz, 3H), 1.16 (d, J = 7.3 Hz, 3H).

ir (KBR) 1750, 1595 cm- '.

uv (phosphate buffer, pH 7.4) 293 nm (s7170).

Example 25

Preparation of (5R, 6S) -3 - [(1,6-dimethyl-pyridinium-2-yl) methylthio J-6- (1 R-hydroxyethyl) -4 R-methyl-7-oxo-1-azabicy clo [3.2.0] hept-2-en-2-carboxylate

A. (1,6-dimethylpyridinium-2-yl) methylthiol, trifluoromethane sulfonate salt

CH,

HeOTf

S?

SCCH

3rd

HCl, 61!

Ether

SH, TfO

A solution of (6-methylpyridin-2-yl) methylthioacetate (1.0 g, 5.52 mmol) in dry ether (5 ml), under a nitrogen atmosphere, was treated with methyl triflate (0.74 ml, 6.5 mmol) treated and stirred at 23 C for 15 h. The ether was decanted and the white solid was washed twice with ether and dissolved in hydrochloric acid solution (15 ml, 6N, 90.0 mmol). The resulting mixture was heated at 70 ° C. for 4 h under a nitrogen atmosphere, and then concentrated under reduced pressure to a yellow syrup. Traces of hydrochloric acid were removed by codistillation with water (2 × 10 ml). The crude product was purified by reverse phase chromatography purified (2.2 x 13.0 cm, PrePak C-18) with water as eluent, the appropriate fractions were combined and freeze-dried to give a white powder 25; 1.43 g, 85.4%:

ir (KBr) vmax: 2565 (SH), 1626 (pyridinium), 1585 (pyridinium)

-1

cm

30th

uv (H, 0) Xm.M: 278 (67355).

Analysis for C9H12N03S2F3: Calc .: C 35.64 H 3.99 N 4.62 Found: C 35.49 H 4.05 N 4.56

S 21.14% S 20.99%

B. (5R, 6S) -3 - [(1,6-Dimethylpyridinium-2-yl) methylthio] -6- (1R-hydroxyethyl) -4 R-methyl-7-oxo-I-azabicyclo [3.2.0Jhept- 2-en-2-carboxylate

1- (PhO ^ PCl

2- HEt (iPrJ2

3- Thiol t 4- HEt (iPr) z

^ COOPNB

H2, M / C

COO ©

45 buffer 7.0

Ether THF

To a cold (5 "C) solution of (5R, 6S) p-nitrobenzyl-3,7-dioxo-6- (IR-hydroxyethyl) -4RS-methyl-1-azabicyclo [3.2.0] heptane-2- 50 R-carboxylate (1.11 g, 3.06 mmol, R / S: 86/14) in dry acetonitrile (90 ml) were simultaneously under a nitrogen atmosphere diphenylchlorophosphate (0.68 ml, 3.3 mmol) and Diisopropylethylamine (0.57 ml, 3.3 mmol) was added over a period of 10 min. The cold (5'C) mixture was stirred for 1 h, cooled to -30 ° C 55 and simultaneously with a solution of (1, 6-dimethylpyridium-2-yl) methylthio, trifluoromethanesulfonate salt (1.03 g,

3.4 mmol) in dry acetonitrile (2 ml) and diisopropylethylamine (0.59 ml, 3.4 mmol) were added over a period of 15 min. The resulting mixture was at -30 ° C for 0.5 h

60 stirred and warmed to 0 '' C and stirred for 1 h before the solution was diluted with cold water (35 ml). The resulting emulsion was applied to a reverse phase column (PrePak C-18,

2.5 x 18 cm), which was then eluted with a mixture of 25-50% acetonitrile in water. A closing freeze skirt

When the appropriate fractions were obtained, a yellow powder gave 0.17 g, 15.3%.

ir (KBr) vroax: 1750 (C-O of β-lactam), 1625 (pyridinium), 1600 (C = 0) of the carboxylate cm-1.

656 130

62

'HMR (D2) S: 1.12 (d, J = 7.2 Hz, CH3 from C-4), 1.24 (d, J = 6.4 Hz, CHjCHOH), 2.80 (s, CH3 from C-6 of pyridinium), 4.18 (CH3 from N of pyridinium), 4.41 (center of the AB quartet, CH2S), 7.5-8.4 (H from pyridinium).

uv (buffer 0.05M, pH 7.0) Xmax: 278 (si 1504); [ag -256.4 "(c0.22, H, 0); t.,. = 20.8 h measured at 37 'C in the buffer (pH 7.4) for a concentration of 10_4M.

Example 26

Preparation of (5R, 6S) -3 - [(1,6-dimethylpyridinium-2-yl) -inethylthio] -6- (1R-hydroxyethyl) -7-oxo-1-azabicyclo [3.2.0] hept-2-en-2-carboxylate

Sodium hydroxide solution. The mixture was stirred for 0.5 h and poured into a reverse phase column (4.0 x 18 cm, PrePak C-18) at the top. The column was eluted with a mixture of 25-50% acetonitrile in water. Freeze-drying the appropriate fractions gave the title compound as a yellow powder, 2.82 g (51% (Ph0) 2P02 ~, 49%, CF3S03 ~), 80%.

ir (KBr) vraax: 3700-3000 (OH), 1772 (C = 0 of the β-lactam), 1700 (C = 0 of the ester), 1625 (pyridinium), 1590 (pyridinium) cm "'.' HMR (DMSO , d-6) S: 1.15 (d, J = 6.2 Hz, CH3CHOH), 2.84 (s, 10 CH3 at C-6 of the pyridinium), 4.16 (s, CH3 at N of the pyridinium ), 4.79 (s, SCH2), 6.6-7.5 ((Ph0) 2P02 ~), 7.5-8.7 (H on the pyridinium and H on the PNB ester).

B. (5R, 6S) -3 - [(lj6-dimethylpyridinium-2-yl) methylthio] -6- (1R-15 hydroxyethyl) -7-oxo-l-azabicyclo [3.2.0] hept-2-en- 2-carboxylate

A.

COO ©

(5R, 6S) -paranitrobenzyl-3- [(1,6-dimethylpyridinium-2-yl) methylthio] -6- (lR-hydroxyethyl) -7-oxo-I-azabicyclo [3.2.0] hept-2 -en-2-carboxylate, trifluoromethanesulfonate and diphenyl phosphate salt coopnb

, 0

H ,, Pd / C CH'3

CF3S03 0.3

(PhO ^ PO ^ buffer ch.

O

scch "

CH

Oh

A

HeOTf

Ether

1- NaOH

2- KH PO

1- (PhO ^ POCl coo

2- HEt (iPr)

3_Thi01

35

4- KEt (iPr).

COOPNB OH

<ß

COOPNB

, Tf <(PhOlPo ©

To a cold (5e C) solution of (5R, 6S) -paranitrobenzyl-6- (lR-hydroxyethyl) -3,7-dioxo-l-azabicyclo [3.2.0] heptane-2R-carboxy-lat (2, 14 g, 6.14 mmol) in dry acetonitrile (18 ml) under a nitrogen atmosphere were diphenyl chlorophosphate (1.37 ml, 6.6 mmol), diisopropylethylamine (1.15 ml, 6.6 mmol) in such an amount that the temperature was kept at 5 ° C (7- 10 min) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) was added. The mixture was stirred at 5 ° C for 1.5 h and used as such; this mixture is hereinafter referred to as "Solution A". A solution of (6-methylpyridin-2-yl) methylthioacetate (1.23 g, 6.8 mmol) in dry ether (10 ml) under a nitrogen atmosphere was treated with methyl triflate (0.85 ml, 7.5 mmol) and stirred for 1.5 h at 23 ° C. The ether was decanted and the white powder was washed twice with ether (2 x 10 ml) and diluted with water (20 ml) The resulting aqueous solution was cooled to 0 ° C. under an oxygen-free atmosphere and treated with sodium hydroxide (4N, .3.4 ml, 13.6 mmol). The mixture was stirred at 2 ° C for 1 h and then the pH was adjusted to 7.6 by adding potassium dihydrogen phosphate. This mixture is referred to below as "Solution B". The cold (5 ° C.) "Solution A" was treated with "Solution B" for a period of 0.5 h, the pH between 7.25-7. 35 was held by dropwise addition of 4N

To a solution of (5R, 6S) -paranitrobenzyl-3 - [(l, 6-dimethyl-pyridinium-2-yl) methylthio] -6- (lR-hydroxyethyl) -7-oxo-azabicyclo- [3.2.0] hept-2-en-2-carboxylate, trifluoromethanesulfonate and diphenyl phosphate (49:51), salt (0.87 g, 1.27 mmol) in wet tetrahydrofuran (50 ml) became ether (50 ml), potassium dihydrogen phosphate / sodium hydroxide buffer (0.1M, 40 ml, pH 7.0) and 10% palladium on activated carbon (0.87 g). The mixture was hydrogenated at a pressure of 248 kPa (36 psi) and at 23e C for 2 h and then filtered with Celite. The two phases were separated and the aqueous phase was washed with ether (2 x 15 ml), concentrated to 30 ml under high vacuum and poured into a reverse phase column at the top (PriPak C-18, 2.2 x 13 cm). The column was eluted with water. The appropriate fractions were combined and freeze drying gave a yellow powder, 0.179 g, 40%.

ir (KBr) Xmax: 1755 (C = 0β-lactam), 1628 (pyridinium), 1590 (C = 0 carboxylate) cm-1.

'HNMR (DzO) 5: 1.25 (d, J = 6.4 Hz, CH3CHOH), 2.82 (s, CH3 at C-6 of the pyridinium), 3.12 (, dd \ J = 9.2 Hz, J = 2.9 Hz, H-4), 3.39 (dd, J = 6.0 Hz, J = 2.8 Hz, H-6), 3.7-4.4 (CH3CHOH, H -5, CH3 at the N of the pyridinium), 4.48 (s, CH2S), 7.6-8.4 (H at the pyridinium).

uv (H20) Xm,%: 279 (s9628) with shoulder at 296; [ccg 55.0 "C (c, 0.63, HzO); t ... = 12.5 h measured at 37 ° C in buffer pH 7.4 for a concentration of 10_4M.

Example 27

Preparation of 3- [2- (N-methylpyridinium) methanthio] -6a- [l- (R) -hydroxyethyl] -a-methyl-7-oxo-l-azabicyclo [3.2.0Jhept-2-en-2- carboxylate

60

65

HIGH

fO- * 0

A

63

656130

C02PNB.

cojpnb

A. p-nitrobene: yl-2-diazo-3-oxo-n-valerate (4)

A solution of 50 g (0.35M) of ethyl 3-oxo-n-valerate and 54 g (0.35M) of p-nitrobenzyl alcohol in 400 ml of toluene was heated to BONO "C without a reflux condenser for 18 h. Evaporation of the solvent gave a yellow, crystalline material which was recrystallized from diethyl ether / pentane to give 75 g (86% yield) of p-nitrobenzyl-3-oxo-n-valerate (3), mp 33-34-C.

IR (KBr) y 1740 and 1705 cm "1.

NMR (CDC13) 5: 1.20 (3H, t, J = 7.0 Hz), 2.65 (2H, q, J = 7.0 Hz), 3.60 (2H, s), 5.28 (2H, 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 CH3CN was added 45 g (0.44M) of TEA at 0 ° C, followed by 50 g (0.22M) of p-carboxybenzenesulfonyl azide. The ice bath was removed and the mixture was stirred for 90 minutes. The precipitate was filtered with CH3CN and the filtrate was concentrated to 100 ml volume and diluted with 800 ml EtOAc. The organic solution was washed with aqueous sodium hydrogen carbonate and brine and dried (MgS04). Evaporation of the dry solvent gave 55 g (90% yield) of compound 4 as pale yellow crystals, mp 96-97 ° C.

IR (KBr) y 2120 and 1710 cm-1.

NMR (CDC13) 5: 1.20 (3H, 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,

C. 4β-l-methyl-3-diazo-3-p-nitrobenzyloxycarbonyl-2-oxo-propyl-

3a- [l- (R) -t-butylimethylsilyloxyethyl) azetidin-2-one

60.4 g (0.21M) of compound 5 6 were added to a suspended solution of 12.5 g (0.1 M) of anhydrous ZnCl2 in 700 ml of CH2C12 and the mixture was stirred at 23 ° C. for 15 min and then to 0 ° C cooled. A solution of 106 g (0.27M) of compound 5 in 200 ml of CH2C12 was added dropwise to the above reaction solution over 90 minutes and then stirred for 120 minutes without a cooling bath. The reaction mixture was washed with aqueous NaHC03 10 (4 x 150 ml), water and brine and dried (MgS04). Evaporation of the dry solvent gave a dark oil, which was purified by an SiO 2 column; elution of the column was carried out with ethyl acetate / methylene chloride (1: 9) and gave 51.5 g (54%) of compound 7 as a white crystalline material, mp 112-114 ° C.

'IR (KBr) y 2130.1760 and 1720 cm-1. The * 360 MHz NMR spectrum of compound 7 showed that compound 7 was present as a mixture in the 1-methyl position in a ratio of 2: 1.

NMR (CDC13) 5: 0.3-0.6 (6H, 2s), 0.8Z (9H, 2S), 1.05-1.15 (6H, 20 m), 2.68 (0.66H, 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 (1H , m), 4.09 (1H, m), 517 (2H, two), 5.84 (0.66H, s), 5.95 (0.34H, s), 7.52 (2H, d, J = 8.5 Hz) and 8.23 (2H, d, J = 8.5 Hz).

25 osi + l oh

X

■ co-jpnb

X jij?

} AfNCO -PNB

£ * °

J = 8.0 Hz).

co2pnb n-

I.

. OSi co2pnb

35

B. l-p-nitrobenzyloxycarbonyl-l-diazo-2-t-butyldimethylsilyloxy-2-

butane (5)

To a chilled (0 ° C) solution of 54 g (0.2M) of Compound 4 in 400 ml CH2C12 was added 41.4 g (0.4M) TEA followed by 56 g (0.21M) t-butyldimethylsilyl chloride in 30 ml CH2C12 for 40 min. The solution was stirred for 120 minutes and then washed with ice water. The CH2C12 was dried (MgS04), filtered and evaporated in vacuo to give 68 g (89% yield) of compound 5 as a yellow solid. F. 54-55 ° C.

IR (KBr) y 2080 and 1695 cm-1. The NMR spectrum of Compound 5 indicated that Compound 5 was obtained in the form of an E / Z mixture of the olefinic position in a 9: 1 ratio.

NMR (CDC13 major isomer) 8: 0.15 (6H, s), 0.90 (9H, 's), 1.58 (3H, d, J = 7.0 Hz), 5.15 (2H. S) , 7.30 (2H, d, J = 9.0 Hz) and 8.0. (2H, d, J = 9.0 Hz).

I.

OSi +

!. '

/

\

r in oac

D. 4a- (l-methyl-3-diazo-3-p-nitrobenzyloxycarbonyl-2-oxo-propyl) -3a- [l- (R) -hydroxyethyl] -azetidin-2-one (8)

150 ml of 1N-HCl were added to a solution of 30 g (59.5 mmol) of compound 7 in 400 ml of MeOH at 23 ° C. and the mixture was stirred for 18 h. The reaction mixture was concentrated to approximately 200 ml in volume and extracted with ethyl acetate (3-200 ml). The combined ethyl acetate extracts were washed with water, 40 aqueous NaHCO 3 and brine. Evaporation of the dried (MgS04) solution gave 22.3 g (96%) of compound 8 as a white, crystalline material, mp 147-148 ° C.

IR (KBr) y 3400.2135 and 1750 cm "" 1. The NMR spectrum at 360 MHz of compound 8 showed that compound 8 was a mixture of isomers in the 4-position in a ratio of 2: 1.

NMR (DMSO-d) 8: 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 (2H, s), 7.70 (2H, d, J = 9.0 Hz), 8.05 (0.66H, s), 8.10 (0.34H, s) and 8.27 (2H, d, J = 9.0 Hz).

50 oh

I N2 SH CH

C02PNB

co2pnb

COjPNB

60

OS £ '+ \

CH, N.

ÜV-

o 7

c02pnb

E. p-nitrobenzyl-6a- [1- (R) -hydroxyethyl] -4-methyl-3-, 7-dioxo-l-cizcibicyclo [3.2.0] heptane-2-carboxylate (9)

A solution of 14.0 g (35.86 mmol) of compound 8 and 70 mg of rhodium (II) octanoate in ethyl acetate was heated under reflux for 20 minutes under a nitrogen atmosphere. The mixture was evaporated in vacuo to give a form of compound 9-65.

IR (CHC13) y 3400 and 1750 cm "1.

The NMR spectrum at 360 MHz of compound 9 showed compound 9 as a mixture of isomers in the 4-position in the

656130

64

ratio 2: 1. The "Nuclear Overhauser Effects" (NOE) were used to determine the configuration of the 4-methyl. When Hs of the main isomer is irradiated, a 7% increase in the signal for the 4-methyl protons can be observed, which shows the cis relationship of the Hs and the On the other hand, when the Hs of the minor isomer is irradiated, no signal increase for the 4-methyl can be observed, indicating the relationship of H5 and 4-methyl for the minor isomer.

NMR (CDC13) for the main isomer 5: 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, q, J = 8.0 and 2.2 Hz), 4.18 (1H, m), 4 , 82 (1H, s), 5.24 (1H, d, J = 6.3 Hz), 6.18 (1H, d, J = 6.3 Hz), 7.60 (1H, d, J = 8.5

The reaction mixture was diluted with ethyl acetate, washed with ice water and brine, and dried (MgS04). Evaporation of the solution in vacuo gave a yellow oil which was purified on an SiO 2 column; elution of the column with 20% ethyl acetate in methylene chloride gave 375 mg (40% yield) of compound 11 as a white amorphous foam.

IR (KBr) y 3400, 1775 and 1710 cm-1.

NMR (CDCI3) 5: 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 (IH, d, J = 7.6 Hz), 4 , 18 (IH, q, J = 6.7 and 2.0 Hz), 4.25 (1H, m), 5.25 (IH, d, J = 11.3 Hz), 5.40 (IH, d, J = 11.3 Hz), 7.15-8.2 (4H, m).

10th

F. p-Nitrobenzyl-3-diphenoxyphosphinyl-6a- [l- (R) -hydroxyethylJ-4ß-methyl-7-oxo-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (10) zu 7.18 g (55 mmol) of diisopropylethylamine was added to a cold (0 "C) solution of 20.0 g (55.2 mmol) of keto intermediate 9 in 150 ml of CH3CN, followed by 14.85 g (55 mmol) Diphenylchlorophosphonate in 20 ml CH3CN for 5 min The resulting solution was stirred at 0 ° C for 60 min and then diluted with 600 ml ethyl acetate, washed with ice cold 10% H3P04 and brine, and evaporation of the dried (MgS04) solution gave a crude oil which was purified on a Si02 column; elution of the column with 10% ethyl acetate in methylene chloride gave 3.7 g (11.5%) of the phosphonate 10 in white form.

IR (CHCI3) y 3400, 1790 and 1720 cm "'.

NMR (CDCI3) 5: 1.20 (3H, d, J = 7.2 Hz), 1.38 (3H, d, H = 7.3 Hz), 3.35 (IH, 1, J = 6, 7 and 2.0 Hz), 3.50 (1H, m), 4.2-4.25 (2H, m), 5.20 (1H, d, J = 10.5 Hz), 5.37 ( 1H, d, J = 10.5 Hz), 7.1-7.4 (10H, m), 7.56 (1H, d, J = 9.0 Hz) and 8.10 (1H, d, J = 9.0 Hz). The "Nuclear Overhauser Effects" were used to determine the configuration of the 4-methyl of compound 10. When the H5 was irradiated, no signal increase for the 4-methyl could be observed, which showed the trans relationship of the H5 and the 4-methyl.

OH

hs

COjPNB

10th

$ ■

COjPHB 11

H. 3- [2- (N-Methylpyridinium) methanthio] -6a- [I- (R) -hydroxy-ethyl] -4ß-methyl-7-oxo-l-azabicyclo [3.2.0] hept-2-ene -2-carboxy-

lat

450 mg (3.3 mmol) of methyl trifluoromethanesulfonate were added to a solution of 1.0 g (2 mmol) of compound 11 in 10 ml of CH2C12 and the mixture was stirred at 23 ° C. for 90 min. Evaporation 30 of the CH2CI2 in vacuo gave the quaternized pyridine as

Foam which was hydrogenated immediately without further purification. The crude pyridinium salt was dissolved in a mixture of TMF / ether / buffer solution with pH 7 (1: 1: 1, 100 ml each) and then 600 mg of 10% palladium on activated carbon were added. The mixture was hydrogenated at 241 kPa (35 psi) for 45 minutes on a shaker. The mixture was filtered with Celite and the catalyst was washed with water (2 x 10 ml). The combined filtrate and wash water were extracted with ether (2 x 100 ml) and lyophilized to give a yellow Pul-40 which was purified on a C18 Bondpak reverse phase column (10 g) using 5% CH3CN was eluted in water at 55.2 kPa (8 psi). Each 15 ml fraction was tested by high pressure liquid chromatography and fractions with UV absorption at a tanax of 300 nm were collected and dried to give 58 mg (11% yield) of the title compound as a pale yellow powder.

IR (KBr) y 3400.1750 and 1590 cm-1. Xmax (H2) 292 nm (£ 7081).

NMR (D20) 5: 1.13 (3H, d, J = 6.5 Hz), 1.23 (3H, d, J = 6.5 Hz), 50 3.18 (1H, m), 3, 45 (1H, q, J = 6.0 and 2.1 Hz), 4.0-4.4 (4H, m), 4.65 (3H, s), 7.79 (2H, m), 8 , 30 (1H, m) and 8.60 (1H, m).

Example 28

55 Preparation of 3- [2- (1,4-dimethylpyridinium) methanthioJ-6a [1- (R) -hydroxyethyl] -4ß-methyl-7-oxo-l-azabicyclo (3.2.0) hept-2-ene -2-carboxylate

45

CH,

G. p-nitrobenzyl-3- [pyridin-2-yl-methanthio] -6a- [l- (R) -hydroxy-ethylJ-4ß-methyl-7-oxo-l-azabicyclo [3.2.0 Jhept-2- en-2-carboxy-lat (ll)

390 mg (3 mmol) of diisopropylethylamine and then 370 mg (3 mmol) of 2-mercapto-methylpyridine under N2 were added to a cooled (−15 ° C.) solution of 1.2 g (2 mmol) of the phosphonate 10 in 10 ml of CH3CN . The reaction mixture was stirred at -15 ° C for 60 min and a further 60 min at 0 ° C.

cs

H 0 "P ^ 2 2) CF-jSOgO ^

>

10th

3)? M2

C «3 ^

° co © 4

13

65

656130

3- [2- (1,4-dimethylpyridinium) metlumthio] -6a- [1- (R) -hydroxyethyl] -4ß-methyl-7-oxo-l-azabicvcio [3.2.0] hept-2-ene -2-carboxylate (13)

This compound was obtained as a yellow powder in 17% yield from compound 10 in the same manner as described in Example 27.

IR y 3400, 1755 and 1600 cm'1.

UV (H20) 300 nm (e7600).

NMR (D20) 5: 1.20 (3H, d, J = 6.7 Hz), 1.28 (3H, d, J = 6.7 Hz), 2.60 (3H, s), 3.4 -3.5 (2H, m), 4.2-4.4 (4H, m), 4.52 (3H, s), 7.82 (1H, t, J = 6.5 and 4.2 Hz ), 8.32 (1H, d, J = 6.5 Hz) and 8.60 (1H, d, J = 4.2 Hz).

Example 29

Preparation of 3- [4- (l-methylpyridinium) methanothio] -6a- [I- (R) -

hydroxyethyl] -4ß-methyl-7-oxo-I-azabicyclo [3.2.0] hept-2-en-2-

carboxylate

1) HS

ai

C02PNB

10th

3} £> <Y / H_

C02 © ® CK

\

Example 31

Preparation of 3- [3- (1,2-dimethylpyridinium) methane-thio) -6a- [1- (R) -hydroxyethyl] -4ß-methyl-7-oxo-l-azabicyclo [3.2.0] hept-2 -en-2-carboxylate

CH

A

OH

2) CF3S03CH3

C02PN3

10th

3) Pd / H,

15

© -CH.

3- [4- (l-methylpyridinium) methane-thio] -6a- [l- (R) -hydroxyethyl] -4ß-methyl-7-oxo-l-azabicyclo [3.2.0] hept-2-en-2 -carboxylate (14)

This compound was obtained as a yellow powder in 15% yield from compound 10 in the same manner as described in Example 27.

IR (KBr) y 3410.1750 and 1650 cm- '.

UV lmax (H20) 293 nm (e7295).

NMR (D20) 8: 1.15 (3H, d, J = 6.5Hz), 1.20 (3H, d, J = 6.5 Hz), 3.20 (1H, m), 3.45 ( 1H, q, J = 6.0 and 2.0 Hz), 4.11 (IH, q, J = 8.0 and 2.0 Hz), 4.20 (1H, m) and 4.35 (3H , s), 7.95 (2H, d, J = 5.2 Hz) and 8.72 (2H, d, J = 5.2 Hz).

Example 30

Preparation of 3- [3- (1-methylpyridinium) methane-thio] -6a- [l- (R) -hydroxyethyl] -4ß-methyl-7-oxo-l-azabicyclo [3.2.0] hept-2-ene -2-carboxylate

1> hsAÖ œ

2) CF.SO.CH_ 1

. »...) .1 /> -

3- [3- (1,2-Dimeth \ ipyridinium) methane-thioJ-6a- [l- (R) -hydroxy-ethyl] -4ß-methyl-7-oxo-l-azabicyclo [3.2.0Jhept-2- en-2-carboxylate (16)

This compound was obtained as a yellow powder in 14% yield 20 from compound 10 in the same manner as described in Example 27.

IR (KBr) y 3410, 1750 and 1600 cm "1.

UV Xmm (H20) 296 nm (s8500).

NMR (D20) 8: 1.25 (3H, d, J = 6.5 Hz), 1.30 (3H, d, J = 6.5 Hz), 25 2.95 (3H, 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 (1H, t, J = 8.5 and 6.3 Hz), 8.40 (1H, d, J = 8.5 Hz) and 8.72 (1 H, d, J = 6.3 Hz ).

Example 32

30 Preparation of [3- (2,4-dimethyl-l, 2,4-triazolium) methane thio] 6a- [l- (R) -hydroxyethyl] -4ß-methyl-7-oxo-l-azabicyclo [ 3.2.0] hept-2-en-2-carboxylate ch

V

©

^ 3

ï

CO © ra3

10th

3) p £ ^ a2

17th

15

3- [3- (1-Methylpyridinium) methane-thio] -6a- [I- (R) -hydroxyethyl] -4ß-methyl-7-oxo-l-azabicyclo [3.2.0] hept-2-en-2 -carboxylate (15)

This compound was obtained as a yellow powder in 27% yield from compound 10 in the same manner as described in Example 27.

IR (KBr) y 3420, 1750 and 1610 cm-1.

UV (H20) 295 nm (e8750)

NMR (D20) 8: 1.10 (3H, d, J = 6.9 Hz), 1.25 (3H, d, J = 6.9 Hz), 1.27 (IH, m), 1.43 (1H, q, J = 6.2 and 1.8 Hz), 4.1-4.35 (4H, m), 4.39 (3H, s), 8.0 (IH, t, J = 8 , 5 and 6.2 Hz), 8.45 (1H, d, J = 8.5 Hz), 8.70 (IH, d, J = 6.2 Hz) and 8.82 (IH, s).

Analysis for C17H20N2O4S • 2 '/ Ì H20:

Calc .: C 51.90 H 6.36 N 7.12%

Found: C 51.92 H 5.71 N 6.88%

[3- (2,4-Dimethyl-1,2,4-triazolium) methane-thio] -6a- [I- (R) -hydroxy-eth \ iJ-l-4ß-methyl-7-oxo-l- azabicyclo [3.2.0] hept-2-en-2-carboxylate

45 (17)

This compound was obtained as a yellow powder in 9% yield from compound 10 in the same manner as described in Example 27.

IR (KBr) y 3420, 1756 and 1605 cm-1.

see UV Xm, x (H20) 291 nm (e7850).

NMR (D20) 8: 1.15 (3H, d, J = 6.3 Hz), 1.22 (3H, d, J = 6.3 Hz), 3.35 (IH, m), 3.48 (1H, q, J = 6.0 and 1.8 Hz), 3.90 (3H, s), 4.05 (3H, s), 4.2-4.4 (4H, m) and 8, 80 (1H, s).

55 Example 33

Preparation of 3- [2- (1,3-dimethylimidazolium methane-thio] -6a- [1- (R) -hydroxyethyl] -4ß-methyl-7-oxo-I-azabicyclo [3.2.0] hept-2 -en-2-carboxylate ^

CH,

1) HS

-VA *

° "P (O0) 2 2} ^ 2 ^ 2

COjPHB

10th

3)

18th

656130

66

3- [2- (1,3-DimethyUmidazolìum) methane-thio] -6a- [! - (R) -hydroxy-ethyl] -4ß-methyl-7-oxo-I-azabicyclo [3.2.0] hept-2 -en-2-carboxylate (18)

This compound was obtained as a yellow powder in 32% yield from compound 10 in the same manner as described in Example 27.

IR (KBr) y 3400, 1758 and 1600 cm-1.

UV Xra; lx (H20) 294 nm (87194).

NMR (D20) 5: 1.10 (3H, d, J = 6.3 Hz), 1.25 (3H, d, J = 6.3 Hz), 3.30 (IH, m), 3.42 (IH, 1, J = 6.0 and 2.2 Hz), 3.85 (6H, s), 4.2-4.6 (4H, m) and 7.40 (2H, s).

Example 34

Following the general procedure of Examples 1-33, the following carbapenem products were prepared using the intermediates of the formula

C02pNB

5

-A-H-N-R

cocß

Example No.

A

/ - \ © 5

O"-*

34a

-ch2-

O*.

34b

-ch2ch2-

e3

34c

-ch2-

cb3

34d

-ch2-

CE3ffl

- \

-O

34e

-ch2ch2-

c \ ©

N v

34f

-ch2-

- ^ n-ch2ch2ch3

C \ ©

• 34g

-ch2-

■ P

67

656130

Example No.

A

(_ / - R

'34h

-ch2-

ch ©

tir3

34i

-ch2-

&

- <j f

CE3

34j

-ch2-

ch © ua3-t n-cïï-

X> CH3

34k

-ch2-

-Q

© T

ch3

341

ch3 1

-ch3-

^ 7 ^ 3

34m

-ch2-

/ ch2-0

tjl '

ch ^

34n

-ch2-

y -Ä

y ch3

34o

-ch2-

_ ^ N © 1 \ j ^> L (mixture of ^ Î <^ CH 3 possible isomers)

ch3 3

34p

-ch2-

-in _

| il ©

! I.

656 130

68

Example No.

A

S ~ \ © 5

CN-R

34q

-ch2-

^ cocP

^ h3

34r

-ch2-

f3 ©

"H fi

1 N

ch2-cocP

34s

-ch2-

ch,

4 ©

fìl

N N

1

CH3

34t

-ch2-

n-n-ch,

<1 © |

ch3

Example 35

According to the general procedures of Examples 1 to 33, the following carbapenem compounds are prepared using the intermediates of the formula oh ch j h? 3rd

w fl

0 ^ - N *

C02pNB

oh ch

1 h i 5

CH) | |

he eoo®

Example No.

A

Q®5

35a

-ch2ch2-

<3 ^

69

656 130

Example No.

A

/ ~ \ © 5

U * - *

35b

-ch2ch2-

C \ ©

xn V

35c

-ch2-

-V n-ch2ch2ch3

35d

-ch2-

CE®

35e

-ch2-

CK ®

n-ch,

35f

-ch2-

<]

© î

ch3

35g ch3 1

-ch-

-Q &.,

35h

-ch2-

/ C * 2-Q)

tj © / '

ch3

35i

-ch2-

1 (mixture of

3 possible isomers)

ch3 3

35j

-ch2-

Ii n ©

WN "CH3

656130

70

Example No.

A

35k

-ch2- -

? H2

f "* T *

L! n

1

CH3

351

-ch2-

Jt2 ® • pi ^

N

ce2-co <P

35m

-ch2-

CH,

rS0

K S

d,

35n

-ch2-

N — N-CH-

<1

© f- *

CK3

In the procedure of Example 22, when the keto intermediate '1 is replaced by an equimolar amount of the corresponding la-methyl-45 intermediate, the above-mentioned carbape-nem end product is obtained.

R

Claims (102)

656 130 2nd PATENT CLAIMS O 1. Compound of the formula S — A- COOK' (I) 5 NO wherein R8 is hydrogen and R1 is selected; hydrogen or a substituted or unsubstituted radical from the group consisting of alkyl, alkenyl and alkynyl having 1-10 C atoms; Cycloalkyl and cycloalkylalkyl with 3-6 C atoms in the cycloalkyl ring and 1-6 C atoms in the alkyl radical; Phenyl; Aralkyl, aralkenyl and aralkynyl, the aryl radical being phenyl and the aliphatic part having 1-6 C atoms; Heteroaryl. Heteroaralkyl, heterocycly] and heterocyclyl-alkyl, where the heteroatom or the heteroatoms; in the heterocyclic esters are selected from the group; consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl radical which is linked to the heterocyclic radicals mentioned has 1-6 C atoms, the substituent or the substituents of the radicals mentioned above being selected independently of one another from the group, consisting of C, -C6-alkyl, optionally substituted by amino, halogen, hydroxy or carboxy, -OR3 O II -OCNR3R4 O II - CNR3R4 • -NR3R4 .. .NR3., VNR3R4 O Ii; —S-NR3R4 II 0 O. II -—NHCNR3R4 O II R3CNR4— -CO, R3 = 0 O II -OCR3 -SR3 O II -SR9 O II -SR9 II 0 -CN -n3 -OS-R9 O O II - NR3S -R9 II 0 -OP (0) (OR3) (OR4) —NR3C = NR4 1 R3 -N02 wherein the groups R3 and R4 of the above substituents 20 are independently selected from the group hydrogen; Alkyl, alkenyl and alkynyl with 1-10 C atoms; Cycloalkyl, cycloalkylalkyl and alkylcycloalkyl with 3-6 C atoms in the cycloalkyl ring and 1-6 C atoms in the alkyl part; Phenyl; Aralkyl, aralkenyl and aralkynyl, wherein the aryl part is phenyl and the aliphatic 25 part has 1-6 C atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocyclylalkyl, in which the heteroatom or the heteroatoms in the said heterocyclic radicals are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl radicals which are associated with the said hetero-30 rocyclic radicals are connected, have 1-6 C atoms, or R3 and R4 together with the nitrogen atom to which at least one of them is bonded form a 5- or 6-membered nitrogen-containing heterocyclic ring; R9 is defined the same as R3 * with the exception of hydrogen, or in which R1 and R8 taken together mean C2-C, 0-alkylidene or C2-C10-alkylidene which is substituted by hydroxy; R5 is a substituted or unsubstituted substituent from the group consisting of alkyl, alkenyl and alkynyl with 1-10 C atoms; Cycloalkyl and cycloalkylalkyl with 3-6 C atoms in the cycloalkyl ring and 1-6 C atoms in the alkyl-40 radical; Phenyl; Aralkyl, aralkenyl and aralkynyl, in which the alkyl radical is phenyl and the aliphatic part has 1-6 C atoms; Heteroaryl, heteroaralkyl, heterocyclyl and heterocyclyl, in which the heteroatom or the heteroatoms in the heterocyclic radicals mentioned are selected from the group consisting of 1-4 acidic acid, nitrogen or sulfur atoms and the alkyl radicals attached to the said heterocyclic radicals are bonded, have 1-6 C atoms, where the abovementioned Rs radicals are optionally substituted by 1-3 substituents which are selected independently of one another from Cj-C6-alkyl, optionally substituted by 50 amino, fluorine, chlorine, carboxy , Hydroxy or carbamoyl; fluorine, chlorine or bromine; -OR3 -0C02R3; 55 - OCOR3; - OCONR3R4; O II 60 -OS-R9; II O -OXO; 65 - NR3R4; R3C0NR4—; -NR3C02R4; - NR3CONR3R4; 3rd 656 130 O II - NR3S -R9; II O -SR3; O T -S-R9; 0A- 0 V -S-R9; -S03R3; -C02R3; - CONR3R4; -CN; or phenyl, which is optionally substituted by 1-3 fluorine, chlorine, bromine, CrC6-alkyl, -OR3, - NR3R4, -S03R3, -C02R3 or - CONR3R4, where R3, R4 and R9 in such R5 substitutes such as are defined above; or R5 to another point on the ring Q ». is bound so that a condensed heterocyclic or heteroaromatic ring is formed, which ring may contain additional heteroatoms selected from O, S and N; R15 is selected from hydrogen or from the group consisting of the following substituted and unsubstituted substituents; Alkyl, alkenyl and alkynyl with 1-10 C atoms; Cycloalkyl, cycloalkylalkyl and alkylcycloalkyl with 3-6 C atoms in the cycloalkyl ring and 1-6 C atoms in the alkyl radical; Spirocycloalkyl with 3-6 C atoms; Phenyl; Aralkyl, aralkenyl and aralkynyl, the aryl radical being phenyl and the aliphatic part having 1-6 C atoms; Heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl, the heteroatom or the heteroatoms of the heterocycles mentioned being selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl radicals which are linked to the heterocyclic radicals mentioned, 1- 6 have C atoms, wherein the substituent or the substituents of the abovementioned radicals are selected from the group; Amino, mono-, di- and trialkylamino, hydroxy, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chlorine, bromine, fluorine, cyano and carboxy; and wherein the alkyl radicals of the above-mentioned substituents have 1-6 C atoms; A is straight or branched Q-Q alkylene; R2 is hydrogen, an anionic charge or a carboxy protecting group, provided that when R2 is hydrogen or a protecting group there is also a counter ion; and a substituted or unsubstituted mono-, di- or polycyclic aromatic heterocyclic radical which contains at least 1 nitrogen in the ring, the ring being bonded to A via a ring carbon atom and which has a ring nitrogen atom which is quaternized by the group R5 ; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 of formula I, wherein R15 is hydrogen, or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 2 of formula 1, wherein Gœ- is an aromatic mono-, bi- or polycyclic N-containing heterocyclic ring which has 0-5 additional heteroatoms selected from the group O, S or N, the heterocyclic ring being bonded to A via a ring carbon atom and s contains a ring nitrogen atom which is quaternized by the group Rs, and the heterocyclic ring is optionally substituted on a free ring carbon atom 1-5 substituents which are independently selected from the following group: C, -C4-alkyl; C, -C4 alkyl. substituted by 1-3 hydroxy, amino, io C 1-4 alkylamino, di (C, -C4) alkylamino, C, -C4 alkoxy, carboxy, halogen or sulfo: C3-C <s-cycloalkyl; C3-C6-cycloalkyl (C, -C4) alkyl, optionally substituted by 1-3 of the substituents mentioned in connection with C, -C4-alkyl; C, -C4 alkoxy; Cr C4 alkylthio: amino; CrC4 alkylamino; Di (Ci-C4) alkylamino; 15 halogen; CrC4 alkanovlamino; C, -C4 alkanoyloxy; Carboxy; O H Sulfo; - C — O — C | —C4 —alkyl; Hydroxy; Amidino; Guanidino; Phenyl; Phenyl. substituted by 1-3 substituents which are selected independently of one another from the group, amino, halogen, 20 hydroxy, trifluoromethyl, C, -C4-alkyl, C, -C4-alkoxy, CrC4-alkylamino, di (C1-C4) alkylamino , Carboxy and sulfo; Phenyl (C [-C4) alkyl, in which the phenyltcil is optionally substituted by 1-3 substituents as mentioned above in connection with phenyl, and the alkyl part is optionally substituted by 1-3 substituents 25 as described above in connection with C, -C4 -Alkyl are mentioned; and heteroaryl or heteroaralkyl, in which the hetero atom or heteroatoms are selected from the group consisting of 1-4 O, S or N atoms and the alkyl part which is connected to the heteroalkyl has 1-6 C atoms, which The heteroaryl and hetero-30-roaralkyl groups mentioned are optionally substituted in the heterocyclic ring by 1-3 substituents which are selected independently of one another from: hydroxy, amino, halogen, trifluoromethyl, C, -C4-alkyl, CrC4-alkoxy, C, -C4 Alkylamino, di (Ci-C4) alkylamino, carboxy and sulfo and 1-3 substituents in the alkyl radical are from the group hydroxy, amino, QQ-alkylamino, di (C, -C4) alkylamino, C, -C4-alkoxy, carboxy, halogen and sulfo and the heterocyclic ring mentioned is optionally substituted on a free nitrogen atom by 1-3 substituents which are independently selected from the group Cr-C4-40 alkyl; C [-C4 alkyl, substituted by 1-3 hydroxy, amino, CrC4 alkylamino, di (C, -C4) alkylamino, C, -C4 alkoxy, carboxy, halogen or sulfo groups; C3-C6 cycloalkyl; C3-C <5-cycloalkyl (C, -C4) alkyl, optionally substituted by 1-3 substituents as mentioned above in connection with C] -C4-alkyl; Phenyl, 45 phenyl, substituted by 1-3 substituents which are independently selected from amino, halogen, hydroxy, trifluoromethyl, C, -C4-alkyl, C] -C4-alkoxy, Q-Ct-alkylamino, di (Ct- C4) alkylamino, carboxy and sulfo; Phenyl (CI-C4) alkyl, in which the phenyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with phenyl, and the alkyl part is optionally substituted by 1-3 substituents, as described above in connection with C , -C4-alkyl are mentioned, substituted; and heteroaryl or heteroaralkyl, in which the heteroatom or heteroatoms are selected from the group consisting of 1-4 O, S-55 or N atoms and the alkyl radical which is combined with the heteroaralkyl has 1-6 C atoms , the heteroaryl and heteroaralkyl groups mentioned optionally substituted in the heterocyclic ring by 1-3 substituents which are selected independently of one another from hydroxy, amino, halogen, trifluoromethyl, C, -60 C4-alkyl, CrC4-alkoxy, C, -C4- Alkylamino, di (C, -C4) alkylamino, carboxy and sulfo and in the alkyl part are substituted with 1-3 substituents which are selected from hydroxy, amino, Ci-C4-alkylamino, di (C, -C4) alkylamino, C 1 -C 4 alkoxy, carboxy, halogen and sulfo; or a pharmaceutically acceptable salt thereof. 65 4. A compound according to claim 2 of formula I, wherein ■ o , © "5 656 130 4th is an aromatic 5- or 6-membered N-containing heterocyclic ring which contains 0-3 additional heteroatoms selected from N, S and O, and the heterocyclic ring may be substituted on a free ring carbon atom by 1-5 substituents which are selected from the group: Ci-Cj-alkyl; C1-C4-alkyl, substituted by 1-3 hydroxy, amino, CrC + -alkylamino, di (CrC4) alkylamino, C, -C4-alkoxy, carboxy, halogen or sulfo; C3-C6 cycloalkyl; C3-C0-cycloalkyl (C, -C4) alkyl, optionally substituted by 1-3 substituents as mentioned above in connection with C, -C4-alkyl; Ci-C4-alkoxy; C1-C4 alkylthio; Amino; C, -C4 alkylamino; Di (C, -C4) alkylamino; Halogen; C, -C4 alkanoylamino; C1-C4 alkanoyloxy; O II Sulfo; —C — O — Ci — C4 — alkyl; Hydroxy, amidino: guanidino; Phenyl; Phenyl substituted by 1-3 substituents which are independently selected from amino, halogen, hydroxy, trifluoromethyl, Ct-C4-alkyl, C, -C4-alkoxy, C, -C4-alkylamino, Di ^ -GJalkylamino, carboxy and Sulfo; Phenyl (C, -C4) alkyl, in which the phenyl part is optionally substituted with 1-3 substituents, as mentioned above in connection with phenyl, and the alkyl part optionally with 1-3 substituents, as described above in connection with CrC4- Alkyl are mentioned, substituted; and heteroaryl or heteroaralkyl, in which the heteroatom or heteroatoms are selected from the group consisting of 1-4 O, S or N atoms and the alkyl part which is combined with the heteroaralkyl has 1-6 C atoms, where the heteroaryl and hetero-roaralkyl groups are optionally substituted in the heterocyclic ring radical by 1-3 substituents which are selected independently of one another from: hydroxy, amino, halogen, trifluoromethyl, C, -C4-alkyl, QQ-alkoxy, CrC4-alkylamino, di (C, -C4) alkylamino, carboxy and sulfo and in the alkyl radical have 1-3 substituents which are selected from: hydroxy, amino, C, -C4-alkylamino, di (C1-C4) alkylamino, C, -C4-alkoxy , Carboxy, halogen and sulfo and said heterocyclic ring is optionally substituted on a free ring nitrogen atom by 1-3 substituents which are independently selected from the group: C, -C4-alkyl; C1-C4-alkyl, substituted by 1-3 hydroxy, amino, C, -C4-alkylamino, di (C1-C4) alkylamino, C1-C4-alkoxy, carboxy, halogen or sulfo; C3-C6 cycloalkyl; C3-Cö-CycIoalkyl (Ci-C4) alkyl, optionally substituted by 1-3 substituents, as mentioned above in connection with CrC4-alkyl; Phenyl; Phenyl substituted by 1-3 substituents which are independently selected from amino, halogen, hydroxy, trifluoromethyl, C, -C4-alkyl, QQ-alkoxy, C, -C4-alkylamino, di (CrC4) alkylamino, carboxy and sulfo ; Phenyl (C, -C4) alkyl, in which the phenyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with phenyl, and the alkyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with Cl-C4 Alkyl are mentioned, is substituted; and heteroaryl or heteroaralkyl, in which the heteroatom or the heteroatoms are selected from the group 1-4 O, S or N atoms and the alkyl part which is combined with the heteroalkyl has 1-6 C atoms, the heteroaryl and the heteroaralkyl groups in the heterocyclic ring are optionally substituted by 1-3 substituents which are selected independently of one another from hydroxy, amino, halogen, trifluoromethyl, Cr-C4-alkyl, C, -C4-alkoxy, C, -C4-alkylamino, Di (C [-C4) alkylamino, carboxy and sulfo and in the alkyl part 1-3 substituents selected from hydroxy, amino, Cj-C ^ alkylamino, di (C1-C4) alkylamino, Cl-C4-alkoxy, carboxy, halogen and sulfo; or a pharmaceutically acceptable salt thereof. 5. A compound according to claim 4, wherein the heterocyclic ring -O , © "5 is substituted with 5 substituents independently selected from lower alkyl and wherein A is as defined in claim 1 and is preferably -CH2 -, -CH2CH2- or -CH (CH3) -. s 6. A compound according to claim 2 of the formula I, in which is a radical which is selected from group a) , 10 ' wherein Rô, R7 and R10 are independently selected from hydrogen; C, -C4 alkyl, Q-Q alkyl substituted by hydroxy. C, -C4 alkylamino, di (C, -C4 alkyl) amino, C, -C4 alkoxy, amino, sulfo, carboxy or halogen; C3-C6 cycloalkyl; Q-Cr alkoxy; 20 C, -C4 alkylthio; Amino; C, -C4 alkylamino; DifCVQ alkyl) ami-no; Halogen; Cj-Q-alkanoylamino; C, -C4 alkanoyloxy; Carbo-O II xy; - C-O-C! - C4 alkyl; Hydroxy; Amidino; Guanidino; Phenyl; Phenyl substituted by one, two or three amino, halogen, hydroxyl, trifluoromethyl, Q-C ^ alkyl or Ct-Q-alkoxy; Phenyl (C, -C4) alkyl, in which the phenyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with phenyl, and the alkyl part is optionally substituted by 1-3 sub-30 substituents, as mentioned in connection with Cj-Q-alkyl are mentioned, substituted; and heteroaryl and heteroaralkyl, wherein the heteroatom or the heteroatoms in the group consist of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl radical which is combined with the heteroalkyl radical has 1-6 carbon-3J atoms; or wherein 2 of Rö, R7 or R10 together form a condensed saturated carbocyclic ring, a condensed aromatic carbocyclic ring, a condensed non-aromatic heterocyclic ring or a condensed heteroaromatic ring, the condensed 40 rings optionally being substituted by 1 or 2 of the substituents, which are defined above for R6, R7 and R10 are substituted; b) or r optionally on free ring carbon or nitrogen atoms up to optionally substituted on a C atom by 1-3 substituents, which are independently selected from: C, -C4-alkyl; C 1 -C 4 alkyl substituted by hydroxy, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, sulfo, Q-Q alkoxy, amino, carboxy or halogen; C3-C6 cycloalkyl; CrC4 alkoxy; C, -C4 alkylthio; Amino; C, -C4 alkylamino; Di (CrC4 alkyl) amino; Halogen; C, -55 C4 alkanoylamino; C, -C4 alkanoyloxy; Carboxy; O II —C — O — Cj — C4 alkyl; Hydroxy; Amidino; Guanidino; Phenyl; Phenyl substituted by one, two or three amino, halogen, hy-60-hydroxyl, trifluoromethyl, C1-C4-alkyl or C1-C4-alkoxy; Phenyl- (C, -C4) alkyl, wherein the phenyl part is optionally substituted with 1-3 substituents, as mentioned above in connection with phenyl, and the alkyl part is optionally substituted with 1-3 substituents, as described above in connection with C ^ C * alkyl is 65, is substituted; and heteroaryl or heteroaralkyl, in which the heteroatom or the heteroatoms in the heterocyclic radicals mentioned are selected from the group consisting of 1-4 O, N or S atoms and the alkyl radical which is associated with the said heterocyclic radicals. 5 656 130 lerocyclic residues is combined, has 1-6 C atoms, or is optionally substituted to form a fused carbocyclic, heterocyclic or heteroaromatic ring which is optionally substituted by 1 or 2 of the above-mentioned substituents; _ c) R iL R5 © | RJ A S? N - II H R ^ © / ■ N ■ or IN. optionally substituted on a C atom by 1 or 2 substituents which are selected independently of one another from: CrC .- alkyl; C 1 -C 4 alkyl substituted by hydroxy, C 1 -C 4 alkylamino, di (CrC4 alkyl) amino, CrC4 alkoxy, sulfo, amino, carboxy or halogen; C3-C6 cycloalkyl; Cj-Cr alkoxy; Ct-C4 alkylthio; Amino; C, -C4 alkylamino; Di (CrC4 alkyl) amino; Halogen; Cr C4 alkanoylamino; Cx-C4 alkanoyloxy; Carboxy; O I! - C - 0 - C1 - C4 alkyl; Hydroxy, amidino, guanidino, phenyl; Phenyl substituted with one, two or three amino, halogen, hydroxy, trifluoromethyl, C1-C4-alkyl or Q-Q-alkoxy; Phenyl (C, -C4) alkyl, in which the phenyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with phenyl, and the alkyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with QC ,, Alkyl are mentioned, is substituted; and heteroaryl or heteroaralkyl, in which the heteroatom or the heteroatoms in the abovementioned heterocyclic radicals are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl radical which is combined with the heteroalkyl mentioned, 1-6 C -Atoms, or is optionally substituted so that a fused carbocyclic, heterocyclic or heteroaromatic ring is formed, which is optionally substituted by 1 or 2 of the substituents defined above; d) V? R5 e! R II N R5 © I v. II r il SK. or optionally substituted on a C atom by a substituent selected from Cj-Q-alkyl; C 1 -C 4 alkyl substituted by hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 4 alkoxy, sulfo, carboxy or halogen; C3-Cö-CycIoaIkyl; CrC4 alkoxy; Ci-C4 alkylthio; Amino; CrC4 alkylamino; Di (C, -C4 alkyl) amino; Halogen; CrC4 alkanoylamino; C, -C4-O if it is substituted by 1-3 substituents as mentioned above in connection with phenyl and the alkyl part is optionally substituted by 1-3 substituents as mentioned above in connection with C 1 -C 4 -alkyl; and heteroaryl or heteroaralkyl, wherein the heteroatom or the heteroatoms in the above-mentioned heterocyclic radicals are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms, and the alkyl radical, which is combined with the heteroaralkyl mentioned, 1-6 Has C atoms; e) © 5 -K, - K or . NO 15 wherein X is O, S or NR, wherein R is C, -C4 alkyl; C 1 -C 4 alkyl substituted by 1-3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halogen or sulfo; C3-C <j-cycloalkyl; C3-Cö-cycloalkyl (C, -C4) alkyl, optionally substituted by 1-3 substituents, as mentioned above in connection with 20 with C, -C4-alkyl; Phenyl: phenyl, substituted by 1-3 substituents which are independently selected from amino, halogen, hydroxy, trifluoromethyl, CrC4-alkyl, C, -C4-alkoxy, C | -C4-alkylamino, di (C, -C4) alkylamino, carboxy and sulfo; Phenyl (CrC4) alkyl, in which the phenyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with phenyl, and the alkyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with C, -C4- Alkyi are mentioned, substituted: and heteroaryl and heteroaralkyl, wherein the hetero atom or the heteroatoms are selected from 30 of the group consisting of 1-4 O, S or N atoms and the alkyl part, which is combined with the heteroaralkyl, Has 1-6 C atoms, the heteroaryl and heteroaralkyl groups mentioned in the heterocyclic ring are optionally substituted by 1-3 substituents which are selected independently of one another from 35 from the group hydroxyl, amino, halogen, trifluoromethyl, C 1 -C 4 -alkyl, C, -C4 alkoxy, Cl-C4 alkylamino. Di (C, -C4) alkylamino, carboxy and sulfo and in the alkyl part is substituted by 1-3 substituents which are selected from hydroxy, amino, C, -C4-alkylamino, di (C, -C4) alky! Amino , CrC4-alkoxy, carboxy, halogen 40 and sulfo, the radicals mentioned are optionally substituted on a C-Alom by one or more substituents which are independently selected from Ci-C4-alkyl; C, -C4-alkyl, substituted by hydroxy, C, -C4-alkylamino, di (C, -C4 alkyl) a-mino, C, -C4-alkoxy, amino. Sulfo, carboxy or halogen; C3-C6-45 cycloalkyl; C, -C4 alkoxy; C, -C4 alkylthio; Amino; C, -C4 alkylamino; Di (C, -C4 alkyl) amino; Halogen; Cj-C4-Alkanoy! Amino; O II C, -C4 alkanoyloxy; Carboxy; -C-O-C, -C4-alkyl; Hydro-50 xy; Amidino; Guanidino, phenyl; Phenyl substituted with one, two or three amino, halogen, hydroxy, trifluoromethyl, Cj-C * alkyl or C, -C4 alkoxy; Phenyl (C, -C4) alkyl, in which the phenyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with phenyl, and the alkyl part optionally 55 by 1-3 substituents, as mentioned in connection with C, -C4-alkyl are mentioned, substituted; and heteroaryl or heteroaralkyl, in which the heteroatom or the heteroatoms in the abovementioned heterocyclic radicals are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl part which is combined with the heteroaralkyl radical mentioned, 1 -6 has C atoms or is optionally substituted such that it forms fused carbocyclic, heterocyclic or heteroaromatic rings, which are optionally substituted by 1 or 2 of the substituents defined above: Alkanoyloxy; Carboxy; -C-O-Q-C4-alkyl; Hydroxy; Amid 65 dino; Guanidino, phenyl; Phenyl substituted by one, two or 0 three amino, halogen, hydroxy, trifluoromethyl, C, -C4-alkyl or C, -C4-alkoxy; Phenyl (CrC4) alkyl, in which the phenyl part is given © 5 ■ N © ■ 5 656 130 6 c © I ** t u © 5 -N-R or in which X is O, S or NR, in which R is a radical from the group C, -C4-alkyl; C1 -C4 alkyl substituted by 1-3 hydroxy, amino, C1 -C4 alkylamine, di (C1 -C4) alkylamino, C1 -C4 alkoxy, carboxy, halogen or Sullo: C3 -Ca cycloalkyl; C3-C0-cycloalkyl (Ci-Cjalkyl, optionally substituted by 1-3 substituents as mentioned above in connection with C1 -C4-alkyl; phenyl; phenyl substituted by 1-3 substituents, which are selected independently of one another from Amino, halogen, hydroxy, trifluoromethyl, C, -C4-aikyl, C, -C4-alkoxy, C | -C4-alkylamino, di (Ct-C4) alkylamino, carboxy and sulfo; phenyl (Cl-C4) alkyl, wherein the phenyl part may optionally be substituted by 1-3 substituents as mentioned above in connection with phenyl, and the alkyl part may optionally be substituted by 1-3 substituents as mentioned above in connection with C 1 -C 4 -alkyl; and Heteroaryl and heteroaralkyl, in which the heteroatom or the heteroatoms are selected from the group consisting of 1-4 O, S or N atoms and the alkyl part which is combined with the heteroaralkyl has 1-6 C atoms which mentioned heteroaryl and heteroaralkyl groups optionally in the heterocyclic ring by 1-3 substituents are substituted, which are independently selected from hydroxy, amino, halogen, trifluoromethyl, C, -C4-alkyl, C, -C4-alkoxy, CrC4-alkylamino, di (C, -C4) alkylamino, carboxy and sulfo and in the alkyl radical are substituted by 1-3 substituents which are selected from hydroxy, amino, CrC4-alkylamino, di (C, -C4) alkylamino, C, -C4-alkoxy, carboxy, halogen and sulfo, the heteroaromatic radicals mentioned optionally substituted on a C atom by a substituent selected from C 1 -C 4 alkyl; C 1 -C 4 alkyl substituted by hydroxy, C 1 -C 4 alkylamino, di (CrC4 alkyl) amino, Q-Q alkoxy, amino, sulfo, carboxy or halogen; C3-C6 cycloalkyl; Q-Cr alkoxy; C, -C4 alkylthio; Amino; C, -C4 alkylamino; Di (C, -C4) alkylamino; Halogen; C: -C4-Alkanoylamino, - Ci-C4-Alkanoyl-O II oxy; Carboxy; —C — O — C, —C4 — alkyl; Hydroxy; Amidino; Guanidino; Phenyl; Phenyl substituted with 1, 2 or 3 amino, halogen, hydroxy, trifluoromethyl, C, -C4 alkyl or C, -C4 alkoxy; Phenyl (C, -C4) alkyl, in which the phenyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with phenyl, and the alkyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with Ci C4-alkyl are mentioned, is substituted; and heteroaryl or heteroaralkyl, in which the heteroatom or the heteroatoms in the abovementioned heterocyclic radicals are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl part which is combined with said heteroaralkyl, 1-6 C- Has atoms; and substituted by 1-3 substituents as mentioned above in connection with Q-C ^ -alkyl; Phenyl; Phenyl, substituted by 1-3 substituents which are independently selected from amino, halogen, hydroxy, trifluoromethyl, C, -C4-alkyl, C, -C4-5 alkoxy, Ci-C4-alkylamino, di (C1-C4) alkylamino, carboxy and sulfo; Phenyl (C1-C4) alkyI, in which the phenyl part is optionally substituted by 1-3 substituents, as mentioned above in connection with phenyl, and the alkyl part optionally by 1-3 substituents, as described above in connection with C, -C4 -Alkyl io are mentioned, is substituted; and heteroaryl and heteroaralkyl. wherein the heteroatom or the heteroatoms are selected from the group consisting of 1-4 O, S or N atoms and the alkyl part. which is combined with the heteroaralkyl, has 1-6 C atoms, the heteroaryl and heteroaralkyl groups mentioned are optionally substituted on the heterocyclic ring by 1-3 substituents which are selected independently of one another from hydroxy, amino, halogen, trifluoromethyl, Q-Gt-alkyl, C, -C4-alkoxy, C, -C4-alkylamino, di (C1-C4) alkylamino, carboxy and sulfo and in the alkyl part have 1-3 substituents which are selected 20 from hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halogen and sulfo; or a pharmaceutically acceptable salt thereof. 7. A compound according to claim 6, wherein _0> "N —— R5 represents a radical selected from the group; »7 a) 30th , 10th wherein R5 is Cj-C ^ alkyl and R6, R7 and R10 independently of one another -35 the hydrogen or C! -C4 alkyl; b) 40 or wherein Rs is C [-C6-alkyl and in which ring carbon atoms present are optionally substituted by 1-3 substituents which are independently selected from CrC4-alkyl; c) so-called) © 5 -N-R © • N- K-R NO -.5 © IÏ-R -NO R -H ; © l K ^ N R5 © I R © f ^ n r '! R J N or -NO NO © ^ or R -K v. ^ 60 wherein R5 is C, -C6 alkyl and wherein ring carbon atoms present are optionally substituted by 1 or 2 substituents independently selected from CrC4 alkyl; d) wherein R is a residue selected from: C, -C4 alkyl; Q-Q-alkyl substituted by 1-3 hydroxy, amino, CrC4-alkylamino, di (C, -C4) alkylamino, C, -C4-alkoxy, carboxy, halogen or sulfo; C3-Q-cycloalkyl; C3-C6-cycloalkyl (C, -C4) alkyl, optionally sub- R ' ®K 1 R Œ I K II N N Ü 656 130 11. The compound of claim 9, wherein V ' ®K. or K X wherein R5 is C, -C6-alkyl and in which ring carbon atoms present are optionally substituted by C, -C4-alkyl; O is. e) 5 -K-.H or X . K-K 12. A compound according to claim 9. wherein R © | O * 8 wherein R5 is C, -C6-alkyl, X is O, S or NR, wherein R is C1-C4-alkyl 15 and wherein 1 or more ring carbon atoms present are optionally substituted by C, -C4-alkyl; 0 II © 5 M-S < FT- X K-R is. N " © | l tJ © 5 -N-R \ N or 13. A compound according to any one of claims 9-12, wherein A 20 is -CH, - or -CH, CH, - and R 'CH3-CH (OH) - and the absolute configuration is 5R, 6S, 8R. 14. A compound according to claim 6 of formula 1, wherein O "* 5 as defined in claim 6 under c), or a pharmaceutically wherein R5 is C, -C6 alkyl, X is O, S, or NR, wherein R is Cj-C ^ alkyl acceptable salt thereof. and in which 1 or more ring carbon atoms present are 15. A compound according to claim 6 of the formula 1, in which are optionally substituted by C 1 -C 4 -alkyl, and g) © 5 -N-R K-R .NO © ■ N- N- N-H © © .Jï-R -NO 5 © I I R —K ^^ iv-R -MR Y or 5 IT R -N wherein R5 is C, -C6 alkyl and R is C, -C4 alkyl. 8. A compound according to claim 6 of formula I, wherein "O" * 5 as defined in claim 6 under a); or a pharmaceutically acceptable salt thereof. 9. A compound according to claim 6 of formula I, wherein as defined in claim 6 under b); or a pharmaceutically acceptable salt thereof. 10. A compound according to claim 9, wherein -Cy-j as defined in claim 6 under d), or a pharmaceutically acceptable salt thereof. 16. A compound according to claim 6 of formula I, wherein as defined in claim 6 under e), or a pharmaceutically acceptable salt thereof. 17. A compound according to claim 6 of formula I, wherein as defined in claim 6 under f), or a pharmaceutically acceptable salt thereof. 18. A compound according to claim 6 of formula I wherein 50 as defined in claim 6 under g), or a pharmaceutically acceptable salt thereof. 19. A compound according to claim 2 of formula I, wherein a radical of the formula is. , 10th 65, in which R6, R7 and R10 are selected independently of one another from the group hydrogen, C, -C4-alkyl, C, -C4-alkoxy, carboxy and carbamoyl; or a pharmaceutically acceptable salt thereof. 656 130 20. A compound according to claim 2 of the formula S — A — r N — S c? N \ 2 o mrm COOK wherein A and R2 are as defined in claim 1 and "Oh ~ r5 means a radical of a formula of the following group: (a) (c) io (e) \ ^ xr6 a) wherein R5 is C, -C4-alkyl and R6 is hydrogen or Q-Q-alkyl; R5, N® R b) (i) wherein R5 is C, -C4 alkyl and Rfi and R7 are hydrogen or C, -C4 alkyl; c) 30th wherein Rs is C, -C4-alkyl and R is C, -C4-alkyl or phenyl (C, -C4) alkyl; d) (G) (k) a3 T » CH. (m) \\ S / N®-CS. wherein R5 is C 1-4 alkyl and R6 is C 1 -C 4 alkyl; e) ■ Ti (b> / e N-XCH- Nv \ ®-CH2CH2CH3 (d) CH, • e3 N. (f) -c -CH. CH. // / Ci, 3rd CH. (H) jD CH_ I 2 0 ") i. " CH. or (1) (n) or a pharmaceutically acceptable salt thereof. H N / R wherein R5 is C, -C4 alkyl and R C, -C4 alkyl; or N, 0 45 22. A compound according to claim 2 of the formula OH -X. S — A- ^ ~~ V-R5 COOK wherein Rs is Ci-C4-alkyl or a pharmaceutically acceptable salt thereof. 21. A compound according to claim 2 of the formula S — A- c: oor2 NO wherein A and R2 have the meaning given in claim 1 and is a radical of the formula from the following group: wherein R2 is hydrogen, an anionic charge or a carboxy protecting group, provided that if R2 is hydrogen 55 or a protecting group there is also a counter ion and wherein -O 60 represents a remainder of the following group: ®-R5 (a) -SCH - / Vc 2 \ = J CH3 -SCE2CH2 Kft-CH, (b) 65 (c) -SCE rQ I® CE, • r3 (d) 656 130 (e) "n—, -SCH2CH2 - \ = y CH (G) wherein R2 is as defined in claim 1 and (R) indicates the configuration / -CH2CH2CH3 (f) of the hydroxyethyl group, or a pharmaceutically acceptable salt thereof. 24. A compound according to claim 2 of the formula 0H - î ^ -crn rv _— // v> (R) CH. N • sch2ck2- CH, »I 3 (i) (k) (m) -SCH. -SCE -SCH V * ' ^ i \ -CE, Ci) I. CE. O '"eoo ?. 3 10 wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 25. A compound according to claim 2 of the formula OH E. (R) ! "C3 S | CH. -SCE (1) (n) // s ch 2 ck 2 (n.-c2 - coor wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 26. A compound according to claim 2 of the formula m [ CH. (O) ? H3 -SCH 2 ^ & CH. "SCH2 ~ V JL SCH COOR (p) wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 27. A compound according to claim 2 of the formula wherein the 'HNMR (D, 0) spectrum shows the following characteristic peaks at S: 1.23 (3H, d, J = 6.4 Hz), 3.12 (2H. Q , J = 1.4, 8.9 Hz), 3.39 (1H, q, J = 2.7, 6.0 Hz), 4.07-4.68 (10H, m), 8.19 ( IH, 35 s); e yA n -j— n 3 (») I —— '<. -SCH q) CH. COOR "* 3 wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 3 28. A compound according to claim 2 of the formula wherein the 'HNMR (D20) spectrum shows characteristic peaks OH at 5: 1.23 (3H, d, J = 6.4 Hz), 3.15 (2H, q, J = 3.7, 9.0 Hz), 3.37 (IH, I - ('N-CH2CH2CH3 q, J = 2.6, 6.0 Hz), 3.95-4.65 (10H, m), 8.62 (1H, s); (r) -SCEf -n '/ NS-CH, r '3 .eoo CH e fs 'e -SCE «- (S) -O Irl .N 2 w CH. wherein R: is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 29. A compound according to claim 2 of the formula (o -scE ^ - ^ y oh or (v) ■ CE 2 COO / ch3 CH. La (R) _J. (U) 55 7 -SCH- • N - N / CH_ n / CH. sh 'COOR ^ 3 or a pharmaceutically acceptable salt thereof. 23. A compound according to claim 2 of the formula OH H (R), J sh 2- ^ p-cs, wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 30. A compound according to claim 2 of the formula ch3 SCE2-YNVCB3 COOR '\ J COOR 656 130 10th wherein R2 is as defined in claim I, or a pharmaceutically acceptable salt thereof. 31. A compound according to claim 2 of the formula wherein R2 is delined as in claim 1, or a pharmaceutically acceptable salt thereof. 32. Compound according to claim 2 of the formula ch, oe ch (R) i - ■ —V sce. OOR e / ch. wherein R2 is as defined in claim 1 or a pharmaceutically acceptable salt thereof. ; 33. Compound according to claim 2 of the formula (R) __J. sh. 'coor JN I. ce. <»-J- ,. sce, '/ coor wherein R- is as defined in claim I. or a pharmaceutically acceptable salt thereof. m 38. Compound according to claim 2 of the formula COO e sce. / ch N L / 'cook • N " I. ce. wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 39. Compound according to claim 2 of the formula sce. 'coor ch, V \\. L> ■ n ' 1 ch2-coo wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 40. A compound according to claim 2 of the formula wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 34. Compound according to claim 2 of formula oe <R) 1 ——V oh (R) l 35 ■ ce, f. © sce. 'coor / y E3C : oor ' wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 35. Compound according to claim 2 of the formula 40 wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 41. Compound according to claim 2 of the formula ° H "» «^ -Sce. '/ "N- -n 'coor ce. wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 36. Compound according to claim 2 of formula oe (R) 1 sch coor wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 37. A compound according to claim 2 of the formula such that R2 is as defined in claim 1 or a pharmaceutically acceptable salt thereof. 42. Compound according to claim 2 of the formula 0h - ch, (R) J 55 60 wherein R2 is as defined in claim I, or a pharmaceutically acceptable salt thereof. 43. Compound according to claim 2 of the formula 65 sce. coo —N ch 11 656 130 wherein the 1 HNMR (D20) spectrum shows the following characteristic peaks at 5: 1.23 (3H, d, J = 6.4 Hz), 3.12 (2H, q, J = 1.4, 8.9 Hz), 3.39 (1H, q, J = 2.7, 6.0 Hz), 4.07-4.68 (10H, m), 8.19 (1H, s), or a pharmaceutically acceptable salt or esters thereof. 44. Compound according to claim 2 of the formula 53. Compound according to claim 45 of the formula OE w —l ,. SCH. Ctcf-c * No" COOR "^ COO6 N-N CH wherein the 1 HNMR (D20) spectrum shows the following characteristic peaks at 8: 1.23 (3H, d, J = 6.4 Hz), 3.15 (2H, q, J = 3.7, 9.0 Hz), 3.37 (1H, q, J = 2.6, 6.0 Hz), 3.95-4.65 (10H, m), 8.62 (1H, s), or a pharmaceutically acceptable salt or esters thereof. 45. A compound according to claim 1 of formula I, wherein R15 is as defined in claim 1 but is different from hydrogen, or a pharmaceutically acceptable salt thereof. 46. The compound of claim 45, wherein Q # - as defined in claim 3, or a pharmaceutically acceptable salt thereof. 47. The compound of claim 45, wherein "O" 2- * 5 as defined in claim 4, or a pharmaceutically acceptable salt thereof. 48. The compound of claim 47, wherein the heterocyclic ring is optionally substituted on an existing ring carbon atom with up to 5 substituents independently selected from lower alkyl. 49. The compound of claim 48, wherein A is - CH2—, -CH2CH2- or -CH (CH3) -. 50. The compound of claim 45, wherein - €> ' as defined in claim 6, and pharmaceutically acceptable salts thereof. 51. The compound of claim 50, wherein - €> as defined in claim 7. 52. A compound according to claim 51 of the formula O »®-R5 as defined in claim 21, or a pharmaceutically acceptable salt thereof. 15 54. Compound according to claim 45 of the formula ■■ -o ch. O'COOR wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 55. A compound according to claim 45 of the formula 30th 0 COOR "* -" 3 wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 56. Compound according to claim 45 of the formula CH, (R) oe> ... scalca V N coor wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 57. Compound according to claim 45 of the formula CS "CEj \. = <L IW -— L W COOR 55 wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 58. A compound according to claim 45 of the formula <*> __L as defined in claim 20. wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 656 130 12 59. Compound according to claim 45 of the formula OE “CH- wherein R- is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 66. A compound according to claim 45 of the formula N — CH2CH2Ca3 COOR wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 60. Compound according to claim 45 of the formula COOK2 C = 3 wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 61. A compound according to claim 45 of the formula (R) V CH, SCH. 'COOR "V) CH, wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 62. Compound according to claim 45 of the formula approx. (JO _J, 63. Compound according to claim 45 of the formula <M -L SCH CH. CH, e / 3 x \ CH, COOR wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 64. Compound according to claim 45 of the formula »—U. SCH. COOR CH. SCH. V // "N -2 CH, COOR ' wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 67. Compound according to claim 45 of the formula <a _J., 25 wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 68. A compound according to claim 45 of the formula wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 69. Compound according to claim 45 of the formula so wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 70. Compound according to claim 45 of the formula «_J.,. SCH.- CH, 'm K® \\. : L> • N / CE2-COO wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 65. Compound according to claim 45 of the formula COOR wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 71. Compound according to claim 45 of the formula 13 656 130 wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 72. Compound according to claim 45 of the formula sce. // ce. / 3rd coor ce. wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 73. A compound according to claim 45 of the formula wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 74. Compound according to claim 45 of the formula sce. 3rd coor ce. wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 75. A compound according to claim 45 of the formula scs coor wherein R2 is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 76. Compound according to one of claims 2, 3, 6, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18 and 19, wherein R1 is hydrogen, CH3CH2 -, (CH3) 2CH -, (CH3 ) 2C (OH) - or CH3CH (OH) -. 77. Compound according to one of claims 2, 3, 6, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18 and 19, wherein R1 and R8 together HIGH, ch; : c = mean. 82. Compound according to one of claims 2, 3, 7, 8, 14, 15, 16, 17, 18, 19, 45, 46, 50, 76, 77, 78, 79, 80 and 81, wherein A-CH, -or —CH2CH2—. 83. A compound according to any one of claims 23 to 44, wherein R2 5 is p-nitrobenzyl. 84. A compound according to any one of claims 23 to 42, wherein R2 is an anionic charge. 85. Process for the preparation of a compound of formula I ' where R \ R5, R8, R15, A and / "" "N © 20th as defined in claim 1, and R2 'is a carboxy protecting group, or a pharmaceutically acceptable salt thereof, characterized in that the following reaction steps are carried out: 25 (a) reacting a compound of formula III r8 e , 15th <y XCOOR2 wherein R \ R8, R2 and Rls are as defined above in an inert organic solvent with a reagent capable of introducing the cleavable group L to the compound of formula III, an intermediate of formula IV where R1, R8, R1S and R2 are as defined above and 45 L is a cleavable group; (b) reaction of the intermediate IV in an inert organic solvent in the presence of a base with a mercaptan reagent of the formula es-a- where A is as defined above and n 78. A compound according to any one of claims 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18 and 19, wherein R1 is CH3CH (OH) -. 79. Compound according to one of claims 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 14, 15, 16. 17, 18 and 19, wherein R1 is CH3CH (OH) - and the absolute Configuration is 5R, 6S, 8R. 80. A compound according to any one of claims 45, 46 and 51, wherein R 'is CH3CH (OH) - and R15 is methyl. 81. A compound according to any one of claims 45, 46, 47, 48, 49 and 51, wherein R1 is CH3CH (OH) -, Rls is methyl and the absolute configuration is 5R, 6S, 8R. is a mono-, bi- or polycyclic aromatic heterocyclic radical which contains a quaternizable nitrogen atom in the ring, the ring being bonded to A via a ring carbon atom, an intermediate of the formula II is obtained, wherein R ", R8, R15, A, R2 and 656 130 i4 contains, wherein the ring is bonded to A via a ring carbon atom, an intermediate of the formula as defined above; 5 (c) reaction of the intermediate of step (b) in an inert organic solvent with an alkylating agent of the formula R5 - X ' wherein R5 is as defined above and X 'is a cleavable group, the rest S-A COOR (ii) is obtained, wherein R1, R8, R'5, A, R "and 15 are as defined above; quaternized on a ring nitrogen atom with the radical R5, another () is replaced by (c) reacting the intermediate of step (b) in an inert manner in order to obtain a pharmaceutically acceptable organic solvent with an alkylating agent of the formula bare salt. D5 Y ' 86. Process for the preparation of a compound of formula 20 wherein R5 is as defined above and X 'is a cleavable group, _ the rest (H a A N © R5 30th o "" '"COOH wherein R1, R5, Rs, R15, A and -C- as defined in claim I, characterized in that the following reaction steps are carried out: (a) reacting a compound of formula is 35 R8 H l ("D is quaternized on a ring nitrogen atom with the radical Rs, the carboxy protective group R2 being removed before or after the quaternization step (c) and, if appropriate, the compound obtained being converted into a pharmaceutically acceptable salt. 87. A process for the preparation of a compound of the formula I 'according to claim 85, in which R1, Rs, R8, R15, A and _ / 7 N • 'COOR are as defined in claim 1 and R "is a carboxy protecting group or a pharmaceutically acceptable salt thereof, characterized in that a compound of formula 15 8 - (II) wherein R1, R8 and R1 s are as defined above and R "is a carboxy protecting group, in an inert organic solvent with a reagent capable of introducing the releasable group L into the double position of the compound of formula III, a 45 Intermediate of the formula , 15th (IV) , L 50 COOR COOR wherein R1, R8, R15 and A, which are as defined above and R2 is a carboxy protecting group and means a mono-, bi- or polycyclic aromatic heterocyclic radical which will maintain a quaternizable nitrogen ring atom, wherein R ', R8, Rls and R2 are as defined above and have, wherein said ring on A via a ring carbon atom L is a cleavable group; 55 is bound in an inert organic solvent with a (b) Reaction of intermediate IV in an inert organic alkylating agent of the formula see reacting solvents in the presence of a base with a mercaptan reagent of the formula wherein Rs is as defined above and X 'is a leaving group 60, the ring Rs — X ' HS-A where A is as defined above and G the compound of formula II is quaternized with a radical Rs 65 and the compound obtained is optionally converted into a pharmaceutically acceptable salt. a mono-, bi- or polycyclic aromatic heterocyclic 88. Process for the preparation of a compound of formula I ", Radical means which has a quaternizable nitrogen atom in the ring wherein R1, R5, R8, R15, A and 15 656 130 O © as defined in claim 1 or a pharmaceutically acceptable salt thereof, characterized in that a compound of the formula II, in which R1, R8, R's and A, as defined above and R ~ is a carboxy protective group and a mono-, means bicyclic or polycyclic aromatic heterocyclic radical which has a quaternizable nitrogen ring atom, the said ring being bonded to A via a ring carbon atom, in an inert organic solvent with an alkylating agent of the formula R5 -X ' where R5 is as defined above and X 'is a leaving group, the ring usually having broad spectrum antibiotic activity which is remarkable activity against various Pseudomonas species, organisms notoriously resistant to beta-lactam antibiotics. Other natural products containing the carbapenem core include the olivic acid derivatives, such as the antibiotic MM 13902 of the formula scs = cenhcoce. the compound of formula II is quaternized with a radical R5, the carboxy protective group R2 being removed before or after the quaternization step and the compound obtained being optionally converted into a pharmaceutically acceptable salt.