DD232495A5 - PROCESS FOR THE PREPARATION OF CARBAPENEM ANTIBIOTICS - Google Patents

Abstract

The invention relates to a new and more efficient method for the production of carbapenem antibiotics which have a substituent of the general formula in the 2-position. Where A is a straight or branched alkylene chain having 1 to 6 carbon atoms; R5 is an optionally substituted, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, araliphatic, heteroaraliphatic or heterocyclylaliphatic group or an optionally substituted aryl, heteroaryl or heterocyclyl group; and the rest of the formula a nitrogen-containing aromatic heterocycle having a ring carbon atom attached to the alkylene group A and quaternized by the substituent R5. formulas

Description

Field of application of the invention

The invention relates to a process for the preparation of carbapenem antibiotics which in the 2-position a radical of the formula

in which A is a straight or branched C, C-alkylene chain, R ^ is an optionally substituted, aliphatic, cycloaliphatic ^ cycloaliphatic-aliphatic, araliphatic, heteroaraliphatic and heterocyclyl-aliphatic radical or an aryl, heteroaryl and heterocyclyl radical, and the Remainder of the formula

N-20

means which is ternated with a ring carbon atom to the alkylene group A gebi.

a nitrogen-containing aromatic heterocycle

i 1 5 lengruppe A and by the substituent R qua-

Characteristic of the known technical solutions

The carbapenem derivatives obtainable according to the invention are described in US application Ser. No. 425,755, filed September 28, 1982, by Choung J. Kim and in the continuation-in-part application filed September 9, 1983. The entire disclosure of these applications is hereby incorporated by reference.

Application 425,755 and its continuation-in-part application describes the preparation of carbapenem

Antibiotics of the formula

.15.

COOR

wherein

R represents a hydrogen atom and

1 R is selected from hydrogen.

substituted and unsubstituted: alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; Cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl radicals; phenyl; Aralkyl, aralkenyl and aralkinyl, wherein the aryl radical is phenyl and the aliphatic part has 1 to 6 carbon atoms; Heteroaryl, heteroaralkyl, heterocyclyl and Heteroeyelylalkyl, wherein the heteroatom or heteroatoms in the heterocyclic radicals are selected from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl radicals of the heterocyclic

Radicals 1 to 6 carbon atoms; and wherein the substituent or the substituents of the above radicals are selected from C 1-6 -alkyl radicals which are optionally substituted by amino, halogen, hydroxy or carboxyl

are substituted, halogen, -OR- ',

0 0 ^ NR ³

, -SO ₂ NR ³ R ⁴ , NR ³ R ⁴

0 0 0 0

-NHCNR ³ R ⁴ , R ³ CNR ⁴ -, -CO ₂ R ³ , = O, -OCR ³ , -SR ³ , -SR ⁹ ,

0 0 0

-SR ⁹ , -CN, -N ,, -OSO.R ³ , -OS-R ⁹ , -NR ³ SR ⁹ , -OP (O) (OR ³ ) -

ηD. J xl ft

δ οο

(OR ⁴ ), -NR ³ C = NR ⁴ , -NR ³ CO ₂ R ⁴ ,

wherein the radicals R- 'and R are independently selected from hydrogen; Alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; , Cycloalkyl, cycloalkylalkyl and alkylene-alkyl of 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl radicals; phenyl; Aralkyl, aralkenyl and aralkinyl, wherein the aryl radical is phenyl and the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl, wherein the heteroatom or heteroatoms in the heterocyclic groups are selected from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl groups of the heterocyclic groups are 1 to 6 carbon atoms

τ. λ

or wherein R and R together with the nitrogen atom to which at least one of these radicals is bonded form a 5- or 6-membered nitrogen-containing heterocyclic ring; R the for

R ^ has given meanings, but no water

18 s to ff atom can be; or wherein R and R together represent hydroxy-substituted C2_ j are _<O alkylidene; R is selected from substituted and unsubstituted radicals such as alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; Cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl moieties; phenyl; Aralkyl, aralkenyl and aralkinyl, wherein the aryl moiety is a phenyl radical and the aliphatic moiety has from 1 to 6 carbon atoms; Heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or heteroatoms in the above-mentioned heterocyclic moieties are selected from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moieties attached to said heterocyclic moieties are 1 to 6 carbon have atoms; wherein the radicals listed for R are optionally substituted by 1 to 3 substituents which are independently selected from:

C 1-6 alkyl optionally substituted by amino, fluoro, chloro, carboxy, hydroxy or carbamoyl; Fluorine, chlorine or bromine; OR ³ ; -OCO ₂ R ³ ; -OCOR ³ ; -OCONR ³ R ⁴ ;

-OS-R ⁹ ; oxo; -NR ³ R ⁴ ; R ³ CONR ⁴ -; -NR ³ CO ₉ R ⁴ ; -NR ³ CONR ³ R ⁴ ; 0

0 0 O ^ 0

0 O ^ -SR ^y ·; -SR

• χ A

-CONR- ^ R; -CN; or phenyl, optionally substituted by 1 to 3 fluoro, chloro, bromo, C 1-6 alkyl. -OR ³ , -NR ³ N ⁴ , -SO, R ³ , -CO ₉ R ³ or -CONR ³ R ⁴ , wherein R ³ , R and R in these R radicals have the meanings given above;

or in which

5 R ^ also to another atom of the ring

may be bonded to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional heteroatoms selected from O, S and N;

R 15 is selected from hydrogen and the following substituted and unsubstituted groups: alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; Cycloalkyl, cycloalkylalkyl and alkylcycloalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl moieties; SpiroeyeIoalkyl having 3 to 6 carbon atoms; phenyl; Aralkyl, aralkenyl and aralkinyl, wherein the aryl moiety is a phenyl group and the aliphatic moiety has 1 to 6 carbon atoms; Heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl, wherein the heteroatom or heteroatoms in the above-mentioned heterocyclic units are selected from 1 to 4 oxygen, nitrogen and sulfur atoms and. the alkyl moieties attached to said heterocyclic moieties have 1 to 6 carbon atoms;

wherein the substituent or substituents of the abovementioned radicals are selected from: amino, mono-, di- and trialkylamino, hydroxy, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chlorine, bromine, fluorine, cyano and carboxy ;

and wherein the alkyl moieties of the above listed substituents have 1 to 6 carbon atoms; A represents a straight or branched C g alkylene chain;

2 ^{v. Chr}

R is a hydrogen atom, an anionic charge or a common, easily removable carboxyl protective group .

with the proviso that there is also a counterion

when R represents a hydrogen atom or a protecting group; and the rest of the formula

O ⁹

a substituted or unsubstituted mono-, M- or polycyclic aromatic heterocyclic radical containing at least one nitrogen atom in the ring, said ring being bonded to A via a ring carbon atom and having a ring nitrogen atom quaternized by a group R 1 is; or the pharmaceutically acceptable salts thereof. This process is shown in the following reaction scheme:

COOR

2 ¹

III

R ⁸ HR ¹⁵

A- "

-COOR ² '

, iv

15

 N

'COOR

R ^c -L

R ⁵ -X '

\ 7

II R ⁸ H

15

15

COOR ^-

.S-A + - N-R "

COOR '

possibly

Deblockie- ^ tion

The preferred variant of the process described above proceeds according to the following reaction scheme:

15

deblocking

R ⁵ -X '

COO

In this process, a starting compound III in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide is added with about an equimolar amount of a compound such as p-toluenesulfonic anhydride, p-nitrobenzenesulfonic anhydride, 2,4,6 Tris isopropylbenzene sulfonic acid anhydride, methanesulfonic acid anhydride, trifluoromethane sulfonic acid, diphenyl chlorophosphate, toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride or the like. In this case, L represents a leaving group, such as toluenesulfonyloxy, p-nitrobenzene sulfonyl, diphenoxyphosphinyloxy and other leaving groups which can be introduced by customary processes and are generally known. The reaction to introduce the leaving group into the 2-position of the intermediate compound III is advantageously carried out.

in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine or the like. At a temperature of about -20 to + 40 ⁰ C, most preferably at O ⁰ G, by. The leaving group L of the intermediate IV may also be a halogen atom which may be obtained by reacting the intermediate III with a halogenating agent such as,, PCl ₂ , PBPBr ₂ , (OO), PBr ₂ , oxalyl chloride or the like, in a solvent, such as CH ₂ Cl ₂ , CH ₂ CN, THF or the like, in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine or the like. Intermediate compound IV can be isolated if desired, but usually used without further isolation or purification.

The intermediate compound IV is then converted by means of a customary displacement conversion into the intermediate compound II. It is thus possible to prepare the intermediate compound IV with about an equimolar amount of a heteroaralkyl mercaptan of the formula

HS-A k · N

where A is a straight or branched C 1-6 alkylene chain and the rest of the formula

" Denotes a mono-, bi- or polycyclic aromatic heterocyclic radical which contains a quaternizable nitrogen atom in the ring, this ring being bonded to A via a ring carbon atom in an inert organic solvent such as dioxane, dimethylformamide, dimethylsulfoxide or acetonitrile , and in the presence of a Baje, such as diisopropylethylamine,

Triethylamine, sodium bicarbonate, potassium carbonate or 4-dimethylaminopyridine, implement. The temperature for the displacement reaction is not critical. An advantageous temperature range is about -40 to 25 ⁰ C. Most conveniently the reaction is carried under cooling, ie, about 0 to -10 ⁰ C.,.

The quaternization of the ring nitrogen atom in the heteroaralkyl group of the intermediate II is carried out by reacting the intermediate II in an inert organic solvent with at least one equivalent (up to about a 50% ± molar molar excess) of an alkylating agent of the formula

R ⁵ -X '

implements. In this case, Br has the abovementioned meanings and X ¹ denotes a customary leaving group, such as halogen (chlorine, bromine or iodine, most preferably iodine), or a sulfonate ester moiety, such as a mesylate, tosylate or triflate. Suitable non-reactive organic solvents may be chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethyl sulfoxide and dimethylformamide. The temperature of the alkylation reaction is not critical, and it is preferably carried out at temperatures of about 0 to 40 ° C. Most suitably, the reaction is carried out at room temperature.

Intermediate compound I 'is connected to a counterion X' (ζ.

Derived from the alkylating agent used). This counterion may be at this time or later, e.g. after deblocking, by another counterion, e.g. a pharmaceutically acceptable, be substituted by conventional methods. Alternatively, the counterion can then be removed during deblocking.

The deblocking to remove the carboxyl-protecting group R of the intermediate compound I ^f is carried out by conventional methods, such as solvolysis, chemical reduction or hydrogenation. If the protective group used is p-nitrobenzyl, benzyl, benzhydryl or 2-naphthyl methyl, which can be removed by means of catalytic hydrogenation, then the intermediate compound I ^! in a suitable solvent such as dioxane-water-ethanol, tetrahydrofuran-aqueous dipotassium hydrogenphosphate-isopropanol or the like, at a hydrogen pressure of 1 to 4 atmospheres in the presence of a hydrogenation catalyst such as palladium on carbon, palladium hydroxide, platinum oxide or the like a temperature of O to 5O ⁰ C for 0.24 to 4 hours. If it is 2 'to the radical R, for example, an o-nitrobenzyl group, then you can perform the deblocking by means of photolysis. Protecting groups, such as 2,2,2-trichloroethyl, can be removed by mild reduction with zinc. The allyl group can be removed using a catalyst comprising a mixture of a palladium compound and triphenyphine in a suitable aprotic solvent such as tetrahydrofuran, methylene chloride or diethyl ether. Similarly, other common carboxyl protecting groups can be removed by methods known to those skilled in the art. Compounds of the formula I ',

2 ¹

wherein R is a physiologically hydrolyzable ester such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc., can be administered directly to the host without first deblocking since such esters are hydrolyzed in vivo under physiological conditions.

The above method has several disadvantages. Thus, this process proceeds through various stages, the number of which can advantageously be reduced. Die- Gesamtaus * -

Prey is quite low and the quaternization step is carried out with the carbapenem compound per se.

The aim of the invention The aim of the invention is to provide a novel process for preparing the compounds of formula I, which comprises on the one hand less steps and higher yields results than the known processes and in which the other hand, the quaternized amine may first be prepared, which is then later in a Synthesis stage is bound to the carbapenem nucleus. In addition, it should be possible with this method to produce quaternary amine compounds with a wide variety of amines, such as sterically hindered amines and those with low pKb values in a simpler manner.

13 Presentation of the essence of the invention

The invention relates to a novel process for the preparation of carbapenem derivatives of the formula

R ¹⁵ _R ⁸

S-A

COOR ²

, τ ι

 * i

wherein

R represents a hydrogen atom and

R ^{1 is} selected from hydrogen and the following substituted and unsubstituted radicals: alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; Cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl moieties; phenyl; Aralkyl, aralkenyl and aralkinyl, wherein the aryl moiety is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; Heteroaryl heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) e) in the abovementioned heterocyclic units are selected from 1 to 4 oxygen, nitrogen or sulfur atoms and which have 1 to 6 carbon atoms with the said heterocyclic units ; wherein the substituent or substituents of the above radicals are independently selected from the group consisting of:

C ₁ c-alkyl, optionally substituted by amino, halogen, hydroxy or carboxyl;

Halogen;

3 o

-OR Hq

SiC

O Il

Il 3 4 O

-OCNR R

CN

-OSO ₃ R

O ir g

-OS-R

,

3 '' 9

-NR S-R

-OP (O) (OR ³ ) (OR ⁴ )

-rsiiiL. «« λ -NR ³ C = NR ⁴

O

R ³ CNR ⁴ - '.

-CO ₂ R ³ ; -NR ³ CO ₂ R ⁴

^{= O-} NO-

- O

Il 3 -OCR -SR ³

O Il 9

-SR ³

wherein in the abovementioned substituents the groups

-χ λ R and R are independently selected

are under hydrogen; Alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; Cycloalkyl, cycloalkylalkyl and alkylcycloalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 bi3 6 carbon atoms in the alkyl moieties; phenyl; Aralkyl, aralkenyl and aralkinyl, wherein the aryl moiety is a phenyl moiety and the aliphatic moiety has from 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclyl

alkyl, wherein the heteroatom or heteroatoms in the above-mentioned heterocyclic moieties are selected from 1 to 4 nitrogen, oxygen and sulfur atoms and the alkyl moieties attached to said heterocyclic moieties have from 1 to 6 carbon atoms, or

R '' and R together with the nitrogen atom to which at least one of these groups is bonded form a 5- or 6-membered nitrogen-containing heterocyclic ring;

R has the meanings given for R 1, but can not be a hydrogen atom; or in which

R and R together represent a hydroxy substituted C _2-1 Q-alkylidene group;

r5 is selected from the following substituted and unsubstituted radicals: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; Cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl moieties; phenyl; Aralkyl, aralkenyl and aralkinyl, wherein the aryl moiety is a phenyl radical and the aliphatic moiety has from 1 to 6 carbon atoms; Heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or heteroatoms in the above-mentioned heterocyclic units are selected from 1 to 4 oxygen, nitrogen and sulfur atoms and the alkyl moieties linked to said heterocyclic units have 1 to 6 carbon a have tome;

wherein the radicals listed for R- ⁵ are optionally substituted by 1 to 3 sub-substituents independently selected from: C, g-alkyl optionally substituted by amino, fluoro, chloro, carboxy, hydroxy or carbamoyl; Fluorine, chlorine or bromine;

ι 3 O

-Or -ail q

3 -NR S-R

-OCO _R 7 Il

² o

-OCOR ³ 7 -SR ³ 7

-OCONR ³ R ⁴ ; _O

O -SR ⁹ ;

-OS-R ^ 7 OO

O -S-R * 7

-OXO 7 -SO-R ³ 7

D 3 4 -3

^1U- NR- ³ R ^ 7 ^r

R ³ CONR ⁴ - 7 *.

-NR ³ CO ₂ R ⁴ 7 -CONR ³ R

3 3 4 "CN;

-NR CONR R 7

or phenyl, optionally substituted with 1 to fluoro, chloro, bromo, C 1-6 alkyl, -OR ³ , -NR ³ R ⁴ , -SO ₃ R ³ , -CO ₂ R ³ or -CONR ³ R ⁴ , wherein R ³ , R ⁴ and R ⁹ in these R ⁵ radicals have the meanings given above; or in which

R ^ also to another atom of the ring

O·-

may be bonded to form a fused, heterocyclic or heteroaromatic ring, which ring may contain additional heteroatoms selected from O, S and N;

R ^ 'is selected from hydrogen and the following substituted and unsubstituted groups: alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; Cycloalkyl, cycloalkylalkyl and alkylcycloalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl moieties; Spirocycloalkyl having up to 6 carbon atoms; .Phenyl; Aralkylv ^ Äralkenyl and

Aralkynyl "wherein the aryl moiety is a phenyl group and the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocycloalkyl, wherein the heteroatom or heteroatoms in the above-mentioned heterocyclic moieties are selected from 1 to 4 oxygen, Nitrogen and sulfur atoms and the alkyl moieties attached to said heterocyclic moieties have 1 to 6 carbon atoms;

wherein the substituent or substituents of the abovementioned radicals are selected from: amino, mono-, di- and trialkylamino, hydroxy, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidines, nitro, chlorine, bromine, fluorine, cyano and carboxy ;

and wherein the alkyl moieties of the substituents listed above have 1 to 6 carbon atoms;

A is a straight or branched C, g-alkylene

chain means;

ρ R represents a hydrogen atom, an anionic charge or a common, easily removable carboxyl-protecting group, provided that a counterion is also present when R represents a hydrogen atom or a protecting group; and the rest of the formula

a substituted or unsubstituted, mono-, bi- or polycyclic, aromatic, heterocyclic radical containing at least one nitrogen atom in the ring, the ring being bound to A via a ring carbon atom and having a ring nitrogen atom which is quaternized by a group R ⁵ is;

or, a pharmaceutically acceptable salt thereof,

1, characterized in that an intermediate of the formula

15

COOR

2 ¹

18 15

10 in which R, R and R ^{J have} the meanings given above,

2 '

R is a common, easily removable carboxyl

Protecting group means and

L is a common leaving group, such as toluenesulfonyl fonyloxy, p-nitrobenzenesulfonyloxy, diphenoxyphosphinyloxy or halogen, with a thiol compound of the formula

HS-A h NR ⁵

VII.

where A and the rest

N-R the above

Have 25 meanings and X "means a counter anion,

in an inert. Solvent and in the presence of a base to a carbapenem compound of formula I ^1st

COOR "

1 in which R ¹ , R ⁸ , R ¹⁵ , R ² ', A,

N- R ^v and X

have the meanings given above, and if desired, the carboxyl-protecting group

2 '

R to obtain the corresponding deblocked compound of formula I or a pharmaceutically acceptable salt thereof.

According to the invention, the intermediates of formula VII are also provided.

The carbapenem compounds of formula I are effective antibacterial agents or intermediates useful for the preparation of such agents.

The compounds of formula I contain the carbapenem nucleus

1 6

and are therefore referred to as 1-carba-2-penem-3-carboxylic acid derivatives. It can also be assumed that the compounds have the following basic structure

4 '6

and are therefore referred to as 7-0xo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid derivatives. According to the invention, such compounds are included in which the protons in the 5- and 6-position are both ice and trans. The preferred compounds have a 5R, 6S (tranS) -

Configuration, as is the case with thienamycin.

The compounds of the general formula I can be unsubstituted in the 6-position or substituted by substituents previously described for other carbapenem derivatives.

8 be. In particular, R may be a hydrogen atom and R may be a hydrogen atom or a substituent other than hydrogen, as described in European Patent Application 38,869 (see the definition of R /).

8 1 be. Alternatively, R and R together may signify a Cp-O-alkylidene or a substituted, for example, hydroxy, C 1-12 -alkylidene radical.

The compounds of general formula I may be unsubstituted in the 1-position (R = H) or substituted by substituents previously described for other carbapenem derivatives. In particular, R may be a hydrogen atom or a 1-substituent other than hydrogen, as described in European Patent Application 54,917 (see the definition of R or R ² therein) or in US Pat. No. 4,350,631. Preferred substituents R, which are not a hydrogen atom, are, for example, C 1-6 -alkyl, in particular preferably methyl, phenyl and phenyl- (C- _1- C ) -alkyrenes.

15 The substituent R, which is not a hydrogen atom, can

have either α or β configuration. The present invention encompasses both the individual α and β isomers as well as their mixtures

 30

The definitions for R ¹ , R and R ¹ - ⁵ are to be specified as follows:

(a) The aliphatic "alkyl", "alkenyl" • and "alkynyl" groups may be straight or branched chain having 1 to 10 carbon atoms; preferred are groups of 1 to 6, most preferably groups of 1 to 4 carbon atoms; when the alkyl, alkenyl and alkynyl groups are part of other substituents, such as in cycloalkylalkyl or heteroaralkyl or aralkenyl, they preferably contain 1 to 6, most preferably 1 to 4 carbon atoms.

(b) "heteroaryl" includes mono-, bi- and polycyclic, aromatic, heterocyclic groups having 1 to 4 O, N or S atoms; preferred are 5- or 6-membered heterocyclic rings, such as thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl,

Pyridazinyl, pyrrolyl, pyrazolyl, etc. 20

(c) "heterocyclyl" includes mono-, bi- and polycyclic, saturated or unsaturated, non-aromatic, heterocyclic groups having 1 to 4 O, N or S atoms; preferred are 5- or 6-membered,

heterocyclic rings such as morpholinyl, piperazinyl, piperidyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, etc.

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

The term "common, readily cleavable carboxyl-protecting group" refers to known ester groups which have been used to block a carboxyl group during a chemical reaction sequence and which,

if desired, can be removed by methods which do not result in the destruction of the remaining part of the molecule, e.g. 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 are benzhydryl, p-nitrobenzyl, 2-naphthylmethyl, allyl, benzyl, trichloroethyl, silyl, such as trimethylsilyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl, 4-pyridylmethyl and C, g-alkyl such as methyl, ethyl or t-butyl.

Such protecting groups also include groups which are hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl. A particularly advantageous carboxyl-protecting group is p-nitrobenzyl, which can be easily removed by catalytic hydrogenation.

Include the pharmaceutically acceptable salts of non-<toxic acid addition salts, for example salts with mineral acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, etc. and salts with organic acids such as maleic, acetic, citric, Bernstein , Benzoic, tartaric, fumaric, almond, ascorbic, lactic, gluconic and malic acids. Compounds of formula I in the form of the acid addition salts can be represented by the formula

¹⁵

R = H or a protecting group

wherein X is the acid anion

indicated. The counter anion X can be selected to provide pharmaceutically acceptable salts for therapeutic administration, but in the event that the compounds of the formula I

X may also be a toxic anion. In such a case, the ion may then be removed or substituted with a pharmaceutically acceptable anion to obtain an efficacious end product useful for therapeutic use. When acidic or basic groups in the groups R or R ⁵ or in the rest

are present, the invention also includes suitable base or acid salts of these functional groups, e.g. Acid addition salts in the case of a basic group and metal salts (eg, sodium, potassium, calcium and aluminum salts), ammonium salts and salts with non-toxic amines (eg trialkylamine, procaine, dibenzylamine, 1-ephenamine, N-benzyl-ßphenäthylamin -, N, N'-Dibenzylathylendiaminsalze, etc.) in the case of an acidic group.

2

Compounds of the formula I in which R represents a hydrogen atom, an anionic charge or a physiologically hydrolyzable ester group and their pharmaceutically acceptable salts are useful as antibacterial agents. The other compounds of formula I are useful as intermediates which can be converted to the above-mentioned biologically active compounds.

A preferred embodiment of the invention comprises compounds of the formula I in which R is a hydrogen atom and R is a hydrogen atom, CH ^ CHp-,

OH OH ι ι

C- or CH ₃ CH- stands. Below are

those compounds in which R is for

Oh T

CH, CH-, and most preferably the compounds are of the absolute configuration 5R, 6S, 8R.

CH ₃ ^ CH, CH ₃ ^ CH ₃ / CH-

Another preferred embodiment comprises

1 8 compounds of the formula I, in which R and R together represent an alkylidene radical of the formula - HOCH ₂

CH ₃ stand.

The alkylene radical (ie, the substituent "A") in the compounds of general formula I may be a straight or branched chain and may contain from 1 to 6 carbon atoms. Preferred compounds are those in which A represents - (CH ₂ ) -, where η is 1 or 2. Particular preference is given to those compounds in which A is -CH ₂ -.

The alkylene unit "A" is via a ring carbon atom to the N-substituted, quaternized, aromatic heterocycle of the general formula

G * - * ⁵

bound, in which

the substituent R preferably represents one of the following, optionally substituted, radicals:

C ₂ _ ₁₀ alkenyl, C ₂ _ ₁₀ alkynyl, C - ^ - cycloalkyl, -C ₁ _g-alkyl, phenyl, phenyl-C ^ alkyl, phenyl-Cpc-alkenyl, phenyl-Cp ^ alkynyl, heteroaryl Heteroaralkyl, wherein the alkyl moiety has 1 to 6 carbon atoms, heterocyclyl or heterocyclylalkyl, wherein the alkyl moiety has 1 to 6 carbon atoms. The heteroaryl group of the substituent R (or the heteroaryl part of the heteroaralkyl radical) may be a mono-, bi- or polycyclic aromatic heterocyclic group containing 1 to 4 O, N or S atoms; preferred are 5- or 6-membered heterocyclic rings such as thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl and pyrazolyl. The heterocyclic group of the substituent R (or the heterocyclyl portion of the heterocyclylalkyl group) may be a mono-, bi- or polycyclic, saturated or unsaturated, non-aromatic, heterocyclic group containing 1 to 4 O, N or S atoms; preferred are 5- or 6-membered heterocyclic rings such as morpholinyl, piperazinyl, piperidyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl and pyrrolidinyl.

The substituent R may be optionally substituted by 1 to 3 substituents independently selected from:

(a) C _1-6 -alkyl, optionally substituted by preferably 1 to 3 amino, fluoro, chloro, carboxy, hydroxy or carbamoyl groups;

(B) Fluorine, cnio (C) -OR ³ ; (d) (e) -OCO ₂ R ³ ; -OCOR ³ ; , (F) -OCONR ³ R ⁴ ; (G) O Ii 9 -OS-R; Il (H) -Oxo; (I) -NR ³ R ⁴ ; (J) R ³ CONR ⁴ -; 00 (1) -NR ³ CO "R ⁴ ; 3 3 4 -NR CONR R (Ro) O 3 ^JI 9 -NR ^ SR *; ti o

(O) -SOR "; (P) O Ii η -SR ⁵ ; H O (q) (r) (s) -SO ₃ R ³ ; -CO ₂ R ³ ; -CONR ³ R ⁴ (T) -CN;

or

(u) phenyl, optionally substituted by 1 to 3 substituents independently selected from fluoro, chloro, bromo, C ₁ / -alkyl, -OR,

-ζ Ι. τ τ I ~ V

-NR ³ R ⁴ ,

-CO ₉ R

or -C0NR3r ^z »·, where in the

above-mentioned substituents R, the groups R and R are independently selected from hydrogen; Alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; Cycloalkyl, cycloalkylalkyl and alkylcycloalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl moieties; phenyl; Aralkyl, aralkenyl and aralkinyl, wherein the aryl moiety is a phenyl radical and the aliphatic moiety has from 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl, wherein the heteroaryl and heterocyclyl group or the corresponding part of a group is the group

1 has the meanings given above for the substituent R, and the alkyl moieties attached to said heterocyclic units have 1 to 6 carbon atoms; or

-ζ. λ

R- 'and R together with the nitrogen atom to which at least one of these radicals is bonded signify a ίof the 6-membered nitrogen-containing heterocyclic ring (as indicated above for R? ); and

R has the meanings given for the radical R, but can not denote a hydrogen atom. The substituent R ⁵ particularly preferably denotes a C 1-6 -alkyl group, in particular a methyl group.

The substituent R may additionally be reacted with another ring atom of the radical of the formula

form a fused, heterocyclic or heteroaromatisehen ring, said ring may additionally contain, preferably 1 or 2, heteroatoms selected from 0, N and S atoms. So the rest of the formula means

for example

or.

28 The group of the formula

/ """ _{I ffi}

preferably represents a substituted or unsubstituted mono-, bi- or polycyclohexyl aromatic heterocycle containing at least one nitrogen atom in the ring and 0 to 5 additional ring heteroatoms selected from 0, S and N atoms, said hetero-cyclic ring via a ring carbon atom is bonded to A and. having a quaternized with the group R ring nitrogen atom.

The heteroaromatic ring of formula 15

may optionally be substituted on free ring carbon atoms by preferably 1 to 5, more preferably 1 to 3, substituents independently selected from the following groups: C _1-6 alkyl; C 1-8 -alkyl substituted by, preferably 1 to 3, hydroxy, amino, C ₁ -4 -alkylamino, di (C ₁ -4) -alkylamino, C 1-8 -alkoxy, carboxy, halogeno (These are understood below chlorine, bromine, fluorine or iodine groups, preferably chlorine, bromine or fluorine groups) or Sulforeste; C, g cycloalkyl; C, gG -cycloalkyl- (C ₁ -C 4) -alkyl, optionally substituted by 1 to 3 of the substituents mentioned above in connection with C ₁ -C 4 -alkyl; C ^^ - alkoxy; C, ._ ^ - alkylthio; amino; C ₁ _ ^ - alkylamino; Di- (C ₁ -C 4) alkylamino; Halogen; C _1- ^ - alkanoylamino; C ^^ - alkanoyloxy; carboxy; SuIfο; 0

-COC ₁ _ ^ - alkyl; hydroxy; amidino; guanidino; phenyl; Phenyl substituted by 1 to 3 substituents * - the -

alkoxy, Cj ^ alkylamino, di- (C ₁ _ _Zf) alkylamino, - C _1-4 alkyl, C ^^ are independently selected from amino, halo, hydroxy, trifluoromethyl, Carboxy and sulfonic groups; Phenyl (C _1-4) alkyl, wherein the phenyl moiety may optionally be substituted by 1 to 3 of the above in connection with phenyl and the alkyl substituents optionally substituted by 1 to 3 of the above in connection with C ₁ _ ₄ alkyl substituent can be; and

Heteroaryl or heteroaralkyl, wherein the heteroatom or. the heteroatoms are selected from 1 to 4 O, S and N atoms and the alkyl moiety linked to the heteroalkyl radical has 1 to 6 carbon atoms, the heteroaryl and heteroaralkyl groups being optionally substituted on the heterocyclic ring moiety by 1 to 3 substituents are independently selected from hydroxy, amino, halogen, trifluoromethyl, C _{1 -4} alkyl, C _1-4 alkoxy, C ^^ - alkylamino, di (C ₁ λ) alkylamino, carboxy and sulfo and on the Alkyleinheit are optionally substituted by 1 to 3 'substituents which are selected from hydroxy, amino, C ^ ^ - alkylamino, di (C _1-4 ) alkylamino, C ₁ ^ alkoxy, carboxy, halogen and SuIfο. In addition, free ring nitrogen atoms may be substituted (other than the quaterciisierte nitrogen atom) by 1 to 3 substituents independently selected from C ₁ _r- alkyl; C ^^ - alkyl substituted by, preferably 1 to 3, hydroxy, amino, C ₁ _ ^ - ^A - y ^{llc lami 3: l} o-, di- (. C ^) - alkylamino, C ₁ ^ Alkoxy, carboxy, halogen or sulfo groups; C ^ g-cycloalkyl; C _3-6 cycloalkyl (C _1-4 ) alkyl; if desired, substituted by 1 to 3 of the substituents mentioned in connection with C. Λ-alkyl; phenyl; Phenyl substituted by 1 to 3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, _C1-C12 alkyl, C _1-4

oxy, C ₁ Λ -alkylamino, di- (C ₁ -alkylamino, carboxy and sulfo; phenyl- (C 1 -C 4) -alkyl, wherein the phenyl moiety is optionally substituted by 1 to 3 of phenyl substituents mentioned may be substituted and the alkyl part may, if desired, be substituted by 1 to 3 of the substituents mentioned in connection with C., / -alkyl;

Heteroaryl or heteroaralkyl wherein the heteroatom or heteroatoms are selected from 1 to 4 O, S or N atoms and the alkyl moiety attached to the heteroalkyl group has from 1 to 6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally attached to the heterocyclic ring moiety are substituted by 1 to 3 substituents which are independently selected from hydroxy, amino, halogen, trifluoromethyl, C ^^ - alkyl, C ^^ - alkoxy, Cj .4-alkylamino, di-CC ^^ - alkylamino, carboxy and SuIfo, and are optionally substituted on the alkyl moiety with 1 to 3 substituents selected from hydroxy, amino, Cj _ ^ - alkylamino, di (C, j _ ^) - alkylamino, C _1. ^ - alkoxy, carboxy, halogen and SuIfo. The most preferred substituents of the ring carbon and ring nitrogen atoms are C 1-6 alkyl groups, especially methyl groups.

In the preferred embodiment described above, preference is given to those compounds in which A is - (CH ₂ ) _n -, where η is 1 or 2, particular preference is given to those compounds in which A is

-CH ₂ - and wherein HIGH

(a) R and R together for ^. C = stand

or

CH, ^

8 1

(b) R is a hydrogen atom and R is for

a hydrogen atom, CH ₃ 31 CH ₃ ^ CH CH ₃ CH ₃ - OH or 1 OH > C- CH-cCH- stands. CH-, CH ₃ ^ 5

Especially preferred are the compounds wherein R

OH

1 '

is a hydrogen atom and R is CH ₃ CH-, in particular compounds having the absolute configuration 5R, 6S _f 8R.

In a preferred embodiment, the group is of the formula

an aromatic, 5- or 6-membered, nitrogen-containing, heterocyclic ring containing from 0 to 3 further heteroatoms selected from O, S or N. This aromatic heterocycle may, wherever possible, be fused to another ring. This other ring may be a saturated or unsaturated carboylene ring, preferably a C ^ _- -? carbocyclic ring, an aromatic carbocyclic ring, preferably a phenyl ring, a 4- to 7-membered heterocyclic ring (saturated or unsaturated) having 1 to 3 heteroatoms selected from O, S, N or NR ¹¹ , wherein R ¹¹ a hydrogen atom, a C ,, g-alkyl radical, if desired, substituted by 1 to 2 substituents which are selected independently from -OR, -NR 1 R, -CO ₂ R, oxo, phenyl, fluorine, chlorine, bromine, -SO ₃ R- ⁵ and -CONR ^ R ^, or a phenyl radical which is desirably substituted by 1 to 3 substituents independently selected from C 1 -C 4 alkyl. .OR,. -NR ^ R, fluorine, chlorine, bromine, -SO, R- \ -C0JR3 and -CONR- ⁵ R, wherein R ⁵ and

4 11

R in these substituents R have the meanings mentioned in connection with the substituent R,

1 or a 5-Ms 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, S, N or

11 11

R, wherein R has the meaning given above. The 5- or 6-membered aromatic quaternized ring or, wherever possible, the carbocyclic, heterocyclic or heteroaromatic ring fused thereto, or both of these rings, may optionally be attached to free ring atoms through, preferably up to a total of 5, substituents for the entire ring system that are above related to the group of formula

may be substituted. In the preferred embodiment described above, preferred compounds are those wherein A is - (CH ₂ ) -, where η is 1 or 2. Especially preferred are those compounds wherein A is -CHp- and wherein HOCH ₉ (a) R and R together are C =

CH,

or

(b) R is a hydrogen atom

CH, OH

(b) R ^{8 represents} a hydrogen atom and R ^{1 represents}

a hydrogen atom, CH ₃ CH ₂ -, ^ CH-, Q, - or

OH CH ₃ CH ₃

CH ₃ CH- stands.

Particularly preferred are compounds wherein R is a hydrogen atom and R is the group OH

CH ₃ CH-, in particular compounds with the absolute configuration 5R, 6S, 8R.

Another preferred embodiment of the invention relates to compounds in which the rest of the formula

represents a radical which is selected from the following groups:

_R 7 (a) _φ ^R

R ⁵ -N ^ 5V_ ρ6

τ] ^Λ

R ^{10 /}

wherein R, R and R are independently selected from hydrogen; C ^^ - alkyl; C 1-4 -alkyl, substituted by, preferably 1 to 3, hydroxy, C ₁ -alkylamino, di- (C ₁ -alkyl) -amino, C 1 -alkoxy, amino, sulfo, carboxy or halogen (chlorine, Bromine, ioruor or iodine, preferably chlorine, fluorine or bromine); Cz g -cycloalkyl; C ₁ ^ - alkoxy; C ₁ _ _Zf alkylthio; amino; C ₁ _ ^ - alkylamino; Di (C _1- ) alkyl) amino; Halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine); C ₁ ^ alkanoylamino; C ₁ _ ^ - alkanoyloxy; carboxy;

0 -C-OC _1- ^ -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, C ₁ -alkyl or C ₁ _ ₂ - alkoxy groups; Phenyl-i-C 1-4 alkyl, in which the phenyl part is optionally substituted by 1 to 3 of the substituents mentioned in connection with phenyl and the alkyl part is desirably substituted by 1 to 3 of the substituents mentioned in connection with C ₁ λ-alkyl; and heteroaryl and heteroaralkyl, wherein the heteroatom or heteroatoms in the above-mentioned ^^ heterocyclic

Units are selected from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moiety attached to said heteroaralkyl moiety has 1 to 6 carbon atoms; or

wherein two of R, R or R together represent a saturated condensed carbocyclic ring, a fused aromatic carbocyclic ring, a fused non-aromatic heterocyclic ring or a fused heteroaromatic ring, said condensed rings being optionally substituted by 1 or 2 of the substituents defined in connection with R, R and R may be substituted;

, 5

(b) nf, r Tl or

which are optionally substituted on a carbon atom by 1 to 3 substituents independently selected from C 1-10 alkyl; C ,, ^ alkyl substituted by preferably 1 to 3 hydroxy, C ₁ ^ alkylamino, di- (C ₁ _ ^ - alkyl) -amino, SuIfο-, C ₁ _ _- ^ alkoxy, Amino, carboxy or halogen groups (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine); £ -z- cycloalkyl; _1- C ^ -alkoxy; C ₁ _ ^ - alkylthio; amino; C _1-8 alkylamino; Di- (C _1- ^ aIlCyI) amino; Halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine); C ₁ α-alkanoylamino; C ₁ _.- alkanoyloxy; carboxy; 0

-COC ₁ _ ^ - alkyl; hydroxy; amidino; guanidino; phenyl; Phenyl substituted with one, or three zwai Anino-, halogen (chlorine, bromine, fluorine or iodine; preferably chlorine, fluorine or bromine), hydroxy, trifluoromethyl, Cj ^ alkyl or C ^ -alkoxy _1- ; Phenyl (C ₁ -Zf) -alkyl, wherein the phenyl part is optionally replaced by 1 to 3 of the

may be substituted with substituents mentioned phenyl and the alkyl part may be optionally substituted by 1 to 3 of the substituents mentioned in connection with C ^ alkyl; and heteroaryl or heteroaralkyl wherein the heteroatom or heteroatoms in the above-mentioned heterocyclic moieties are selected from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moiety attached to said heteroaralkyl moiety has from 1 to 6 carbon atoms, or if so substituted, that they form a fused, carbocyclic, heterocyclic or heteroaromatic ring, which is optionally substituted by 1 or 2 of the abovementioned substituents;

R ⁵

or

which are optionally substituted on a carbon atom by one or two substituents independently selected from C ₁ u -alkyl; C, r alkyl substituted by, preferably by 1 to 3 hydroxy, C ^ alkylamino, di- _(C1 ^ alkyl) amino, _C1 ^ - alkoxy, SuIfο-, amino, carboxy - or halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine) groups; C, g -cycloalkyT; C ^ alkoxy; C ₁ -Zf alkylthio; amino; C ₁ λ-alkylamino; Di- (C _1- / -alkyl) -amino; Halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine); C ₁ α-alkanoylamino; C ^ - alkanoyloxy;

0 η carboxy; -COC ₁ _ ^ - alkyl; Hydroxy, amidino, guanidino, phenyl; Phenyl substituted by one, two or three amino, halogen (chlorine, bromine, fluorine or iodine; preferably chlorine, fluorine or bromine) -, hydroxy, trifluoromethyl, C _1- ^ -AIlCyI- or C ^^ - alkyl ; Phenyl- (C ₁ -C 4) -alkyl, it being possible for the phenyl part to be substituted by 1 to 3 substituents mentioned in connection with phenyl, and the alkyl part optionally substituted by 1 to 3 of the substituents mentioned in connection with C ₁ Λ-alkyl can be; and heteroaryl or heteroaralkyl wherein the heteroatom or heteroatoms in the above-mentioned heterocyclic moieties are selected from 1 to 4 O, N or S atoms and the alkyl moiety attached to said heteroaralkyl moiety has from 1 to 6 carbon atoms or, if desired are substituted so as to form a fused, carbocyclic, heterocyclic or heteroaromatic ring, which is optionally substituted by 1 or 2 of the abovementioned substituents;

(D)

or

, optionally substituted on a carbon atom by a substituent selected from

C ^ - alkyl. C ^^ - alkyl substituted by, preferably by 1 to 3 hydroxy * -, C ^^ - alkylamino, di- _(C1 ^ alkyl) amino, C, ^ alkoxy, SuIfο-, amino -, carboxy or halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine) groups; C 1-4 cycloalkyl; C ^ _ ^ - alkoxy; C ₁ _4_-alkylthio; amines; C ₁ _ ^ - alkylamino; Ci- (C 1-8 alkyl) amino; Halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine); C ^^ - alkanoylamino ;. C _1- ^ -Al-

kanoyloxy; Carboxy; - = -COC ₁ _ ^ - alkyl; Hydroxy, amidino, guanidino, phenyl; Phenyl, substituted by one, two or three amino, halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine), hydroxy, trifluoromethyl, C ₁ __ ^ -alkyl or C ₁ _ ^ - alkoxy groups; Phenyl-iCj a) -alkyl, wherein the phenyl part, if desired. may be substituted by 1 to 3 of the said additives in a mmenhang with phenyl substituents, and the Al

if desired, by 1 to 3 of the combined

can be substituted by C.sub.1-C.sub.3-alkyl substituent; and

Heteroaryl or heteroaralkyl, wherein the heteroatom or heteroatoms in the above-mentioned heterocyclic moieties are selected from 1 to 4 O, N or S atoms and the alkyl moiety bonded to said heteroaralkyl moiety has from 1 to 6 carbon atoms;

(E)

or

J.

wherein X is Ό, - S or NR, wherein R is the following radicals: C 1-4 alkyl; C ^^ - alkyl, substituted (C _1- ^) by 1 to 3 hydroxy, amino, C _1- ^ alkylamino, di - alkylamino, C, ^ alkoxy, carboxy, halogen or SuIfοgruppen ; C, g -cycloalkyl; C, _g cycloalkyl (C ₁ _ _Zf) alkyl, optionally substituted by 1 to 3 in connection with C ^ - said alkyl substituents. phenyl; Phenyl substituted by 1 to 3 substituents independently selected from amino, halogen, hydroxy, trifluoromethyl, C ₁ _ ^ - alkyl, C ₁ ^ -alkoxy, _C1 ^ alkylamino, di- (C ₁ ^) - alkylamino, carboxy and sulfo;

Phenyl "^ - ^) - alkyl in which the phenyl moiety can be substituted, if desired, by 1 to 3 of the substituents mentioned in connection with phenyl and the alkyl moiety, if desired, by 1 to 3 of the substituents mentioned in connection with C ₁ λ-alkyl may be substituted;

Heteroaryl and heteroaralkyl wherein the heteroatom or heteroatoms are selected from 1 to 4 O, S or N atoms and which are linked to the heteroaralkyl group

Alkyleinheit having 1 to 6 carbon atoms, wherein the heteroaryl and heteroaralkyl groups are optionally substituted on the heterocyclic ring moiety by 1 to 3 substituents independently selected from hydroxy, amino, halogen, trifluoromethyl, C _1- ^ -AllCyI, C ₁ ^ alkoxy, C ^ alkylamino, di- (C ₁ ^) - alkylamino, carboxy and SuIfο and may be substituted on the alkyl moiety with 1 to 3 substituents selected from hydroxy, amino, C ₁ λ-alkylamino, di- (C ₁ -C 4 -alkyl) amino, C 1 -C 4 -alkoxy, carboxy, halogen and sulfo,

said heteroaromatic radical being optionally on a carbon atom by one or more substituents may be substituted, are independently selected from C _1- ^ -alkyl; C ₁ _, alkyl substituted by, preferably ^ by 1 to 3, hydroxy, C ₁ alkylamino, di- (C ₁ _ ^ - alkyl) amino, C _1- ^ -AIkOXy-, amino , Sulfonic, carboxy or halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine) groups; C- ^ g-cycloalkyl "C _1- ^ -alkoxy; C ^^ - alkylthio; amino; C _{1 to} C alkylamino; Di- (C ₁ -Zf -alkyl) -amino; Halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine); C ₁ _ _Zf alkanoylamino; C ^^ - alkanoyloxy; carboxy; - 0

-COC ₁ _4_ alkyl; hydroxy; amidino; guanidino; phenyl; Phenyl substituted by one, two or three amino, halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine), hydroxy, trifluoromethyl, C 1-4 -alkyl or C ₁ _ _> 2 ₄ ~ ^Alkoxy yg ^ru PP ^en ; Phenyl- (C ₁ -C 4) -alkyl, in which the phenyl moiety may, if desired, be substituted by 1 to 3 of the substituents mentioned in connection with phenyl, and the alkyl moiety, if desired, substituted by 1 to 3 of the substituents mentioned in connection with C ₁ -C 4 -alkyl can be; and

Heteroaryl or heteroaralkyl, wherein the heteroatom or heteroatoms in the above-mentioned heterocyclic moieties are selected from 1 to 4 O, N or S atoms and the alkyl moiety linked to the heteroaralkyl moiety has 1 to 6 carbon atoms or is desirably all substituted in that it results in a fused, carbocyclic, heterocyclic or heteroaromatic ring, which is optionally substituted by one or two of the substituents defined above;

(f) - I

N-

X

NO"

or

wherein X is O, S or NR, wherein R is the following radicals: C ₁ r -alkyl; C ^ alkyl substituted by 1 to 3 hydroxy, amino, C ^ λ-alkylamino, di- (CL λ) alkylamino, C ^ _1- -AIkOXy-, carboxy or halogen SuIfο groups; C, _g cycloalkyl; C ^ _g-Cycloalky1- (C _1- ^) - _alkyl,: optionally substituted by 1 to 3 of the above in connection with Cj ^ alkyl substituent; phenyl; Phenyl substituted by 1 to 3 substituents / independently selected from amino, halo

gen, hydroxy, tri-fluorines thy 1, C _{1 -Zf} -alkyl, CL ^ alkoxy, C ₁ _.- alkylamino, di (C ₁ -) alkylamino, carboxy and sulfo;

Phenyl- (C ₁ -Zf) -alkyl, wherein the phenyl moiety may be optionally substituted by 1 to 3 of the substituents mentioned in connection with phenyl and the alkyl moiety optionally substituted by 1 to 3 of the substituents mentioned in connection with C ₁ λ-alkyl can; and

Heteroaryl and heteroaralkyl, wherein the heteroatom or heteroatoms are selected from 1 to 4 O, S or N atoms and the alkyl moiety attached to the heteroaralkyl radical has from 1 to 6 carbon atoms, the heteroaryl and heteroaralkyl groups being optionally attached to the heterocyclic Ring unit are substituted by 1 to 3 substituents which are independently selected from hydroxy, amino, halogen, trifluoromethyl, Cj ^ alkyl, C _1- Zf alkoxy, C ₁ ^ alkylamino, di (C ₁ ^) - alkylamino , carboxy and SuIfο and may be substituted on the alkyl moiety with 1 to 3 substituents selected from hydroxy, amino, C _1- r alkylamino, di- _(C1 ^ alkyl) amino, C ^ -alkoxy _1- Carboxy, halogen and sulfo, said heteroaromatic radical optionally being substituted on a carbon atom by a substituent selected from C ₁ l -alkyl; C ₁ λ-alkyl substituted by, preferably by 1 to 3, hydroxy, Cj ^ alkylamino, di- (C ₁ ^ alkyl) amino, C ₁ λ-alkoxy, amino, SuIfο-, Carboxy or halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine) groups; C, ^ - cycloalkyl; C _1- Zt -alkoxy; C ₁ _ _Zf alkylthio; amino; C _{1 to} C alkylamino; Di- (C ₁ _ ^ - alkyl) amino; Halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine); C ^^ - alkanoylamino;

Cj __ / - alkanoyloxy; carboxy; -C-O-C, λ-alkyl ·; hydroxy; amidino; guanidino; phenyl; Phenyl substituted by one, two or three amino, halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine), hydroxy, trifluoromethyl, C 1-12 alkyl or C 1-8 alkoxy groups; Phenyl (C 1-4) alkyl, in which the phenyl moiety may be substituted, if desired, by 1 to 3 of the substituents mentioned in connection with phenyl, and the alkyl moiety may be replaced by 1 to 3 of the substituents mentioned in connection with C.sub.1-6-alkyl may be substituted; and

Heteroaryl or heteroaralkyl, wherein the heteroatom or heteroatoms in the above-mentioned heterocyclic units are selected from 1 to 4 O, N or S atoms and the alkyl moiety linked to the heteroaralkyl moiety has 1 to 6 carbon atoms; and

N 'NR ⁵ R ⁵ θ

N -.N

I j

N-R 'j j »

NO

'N / - * J-R

NR ⁵ 'β

R ⁵ © - '

l \ IN NO

N or '' f ''

^or R ⁵ -Nv. ^ N

wherein R is one of the following radicals: C 1-8 alkyl; C, λ-alkyl substituted by 1 to 3 hydroxy, amino,. Cj ^ -Alkyiamino-, di- (C ₁ _ ^) - alkylamino, C ₁ ^ -AIkOXy-, carboxy, halo or sulfo groups; C ^^ - cycloalkyl; Cz g -cycloalkyl- (C ₁ _r) -alkyl, optionally substituted by 1 to 3 of the substituents mentioned in connection with C 1 -C 4 -alkyl; phenyl; Phenyl substituted by 1 to 3 substituents independently of one another selected from amino, halogen, hydroxy, trifluoromethyl, C ₁ -C 4 -alkyl, C ₁ -C 4 -alkoxy, C ₁ -C 4 -alkylamino, di- (C ₁ _.) - alkylamino, carboxy and sulfo; Phenyl (C ₁ _r) alkyl, wherein the phenyl moiety is optionally substituted by 1 to 3 of the above in connection with phenyl and the alkyl substituents substituted if desired, by 1 to 3 substituents of said above in connection with C _1- r alkyl substituents is; and heteroaryl and heteroaralkyl wherein the heteroatom or heteroatoms are selected from 1 to 4 O, S or N atoms and the alkyl moiety attached to the heteroaralkyl has from 1 to 6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally at the heterocyclic ring moiety by 1 to 3 substituents independently selected from hydroxy, amino, halogen, trifluoromethyl, C ₁ λ alkyl, C _1- ^ -alkoxy, C ^ alkylamino, di- (C _1- ^) - alkylamino, Carboxy and sulfo, and on the alkyl moiety by 1 to 3 substituents selected from hydroxy, amino, C ₁ _ ^ - alkylamino, di (C ₁ _ ^) - alkylamino, C ₁ ^ alkoxy, carboxy, halogen and Sulfo, are substituted.

The groups R and R together may also form a fused, heterocyclic or heteroaromatic ring.

In the compounds described above, preferred are those in which A is - (CH ₂ ) _n -, where η is 1 or 2. Particularly preferred are compounds in which A is -CH ₂ - and in which

HIGH ₀

(a) R and R together represent ^ C = or

CH ₃

O Λ

(b) R is hydrogen and R is CH, CH, OH OH

Hydrogen atom, CH ₃ CH-, ^ CH-, "C- or CH ₃ CH- stands.

CH ₃ CH ₃

Especially preferred are compounds wherein R is a

OH

1 '

Is hydrogen atom and R is CH-zCH-, especially compounds with the absolute 5R, 6S, 8R configuration

 20

Particular preference is given to compounds of the general formula I in which the radical of the formula

a radical of the general formula

® r7 R iR ⁶ R ¹ 0 ^^

means, in which

R, R and R independently of one another are selected from hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, carboxyl and carbamoyl and

R has the meanings given above and is preferably C.g-alkyl, particularly preferably -CH- *.

Preferred among these preferred compounds are those in which A is - (CHp) -, in which η is 1 or 2. Most preferred are those compounds in which A is -CHp- and in which HOCH ₀ (a) R and R together are C =

CH ₃

or (b) R is a hydrogen atom and R ^{1 is} a

CH, CH, OH OH 3 _X 3,

Hydrogen, CH ₃ CH ₂ -, CH-, C- or CH ₃ CH-

CH ₃ ^ CH ₃ is.

Particularly preferred are compounds in which R is a Was-OH hydrogen atom and R is CH ₃ CH-, in particular compounds having the absolute configuration 5R, 6S and 8R.

Further preferred are compounds of general formula I, wherein the radical of the formula

N ⁸ -R ⁵

a group of the general formulas (a)

wherein R is a C. ^ alkyl, particularly preferably a methyl radical, and R is a hydrogen atom or a C ₁ ^ -Alkylrest'mit; (B)

wherein R ^ is a C _{1 A-} alkyl radical, particularly preferably a methyl radical, and R and R represent a hydrogen atom or a C 1-4 -alkyl radical; (C)

RN ^X NR ^P

where B? a C, ^ alkyl, especially a methyl radical, and R represents a C ^^ j ₊ alkyl or phenyl (C _1- ^) - alkyl radical;

R ⁵

wherein R is a C. ^ - alkyl radical, preferably a methyl radical and R is a C ^ ^ - alkyl radical, in particular a methyl radical;

(e) R ⁵

®

wherein R ^ is a C ^ _-if "Alky" ¹¹ * ⁸ ^ "preferably a methyl radical, and R is a C ₁ , Λ-alkyl radical, preferably a methyl radical; or

N® - R ⁵

wherein R is a C ₁ ^ -alkyl radical, in particular'für a methyl radical, means.

Of these compounds described above, preferred are those in which A is - (CH ₂ ) -, wherein η is 1 or 2. In particular, those in which A is -CH ₂ - and wherein

HIGH ₉

1 8 \

(a) R and R together for £, = stand drier

CH,

(b) R represents a hydrogen atom and R represents a

CH ₃ CH ₃ OH OH hydrogen atom, CH ₃ CH ₂ -, ^ CH-, ^ C- or CH ₃ CH-.

stands.

CH ₃ CH _x

Particularly preferred are compounds wherein R is a Was-OH

1 '

is hydrogen atom and R is CH ₃ CH-, in particular compounds with the absolute configuration 5R, 6S, 8R.

Particular preference is given to those compounds of the general formula I in which the radical of the formula

^ N - R ^{v represents} a group of the following formulas:

CE ₃

/ Ve

_(d) - ^ N-CS ₂ CH ₂ CH ₃

(E)

(G)

CH

3 CH.

N I

CH.

(F)

(H)

CH.

CH.

(I)

N- "" I

CH-

(J)

(K)

(M)

CH j θ

CH.

-N

; or

(1)

¹ H.

CH

CH.

(Η)

CH.

Of these compounds described above, preferred are those in which A is - (CH ₂ ) J ₁ - and η is 1 or 2. Particular preference is given to those compounds in which A is - (CH ₂ ) - and in which

(a) R and R together for

C = stand or

CH

 ζ

O- J Λ

(b) R is a hydrogen atom and R is an

CH ₃ CH ₃ OH · OH 10.Hydroxy, CH ₃ CH ₂ -, ^ CH-, ^ C- or CH ₃ CH-

CH ₃ CH ₃ is.

Particularly preferred are compounds wherein R is a Was-OH

1 '

is hydrogen atom and R is CH ₃ CH-, in particular compounds with the absolute configuration 5R, 6S, 8R.

Particularly preferred according to the invention are the following compounds of the general formula

OH

(R)

-N

r- "S A-

-R '

t: OOR '

wherein R represents a hydrogen atom, an anionic charge or a common, easily removable carboxyl-protecting group, with the proviso that a counterpart

2 ion when R represents a hydrogen atom or a protecting group, and wherein the radical of the formula

For

(a) -SCH

N-CH

(B)

SCH

(D)

SCH.

CH. "V

SCH CH ₂

CH. Y

(G)

SCH.

CH.

(I)

SCH.

(f) -SCH

- CH ₂ CH ₂ CH.

CH.

( ^h > -SCH ₂ - / " ^:: sy-cH ₃

CH Θ ⁰ N

-S CH

2 \ S

ik)

-SCH

CH

(M)

-SCH

SCH.

(η) -SCH.

CH

-J-f ^N

CH.

CH.

wherein the H-NMR (D ₂ O) spectrum shows characteristic peaks at ο: 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 (1OH, m), 8.19 (1H, s) j

wherein the H-NMR (D ₂ O) spectrum shows characteristic peaks at ei: "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 (1OH, m), 8.62 (1H, s);

(R)

SCH.

(S)

-SCH

(Ν)

N-CH ₂ COO

/ ^H 3

CH.

stands.

SCH.

CH. JJS '

or

N-

CH.

Most preferred are those compounds of general formula I wherein the radical of formula

/ ~ N

a remainder of the formula

N '

- <IO

represents.

Of these compounds, particular preference is given to those in which A is - (CHp) - and η is Ί or 2. Particularly preferred are those in which A is -CHpsteht and wherein.

HOCHp

(a) R and R together are C = or

CH,

8 Λ

(b) R represents a hydrogen atom and R represents a

CH, CH, OH OH

CH, CH,

Hydrogen atom, CH ₅ CH ₂ -, CH-, C- or CH, CH-.

Particular preference is given to compounds in which R is a

Especially preferred are compounds

OH

means hydrogen and R is CH, CH-, in particular.

other connections with the absolute configuration 5R, 6S, 8R.

The process according to the invention proceeds via an intermediate compound of the formula

R ⁸ H *

COOR

2 '

IV

which is described, for example, in European Patent Applications 38 869 and 54 917. This compound can be prepared according to the general procedures described therein. L is a common leaving group (referred to as "X" in European Patent Application 38,869), such as chlorine, bromine, iodine, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, methanesulfonyl, trifluoromethanesulfonyloxy, diphenoxyphosphinyloxy or di (trichloroethoxy) phosphinyloxy. The preferred leaving group is the diphenoxyphosphinyloxy group. The intermediate compounds of formula IV are generally prepared in situ by reacting an intermediate of formula

COOR

III

wherein R ¹ , R ⁸

15 2 'R. and R have the meanings given above

gene, reacted with a suitable acylating agent R ° -L. The preferred intermediate IV where L is the diphenoxyphosphinyloxy group can be prepared by reacting a ketoester 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, 4-dimethylaminopyridine or the like, at a temperature of about -20 to + 40 ⁰ C, most preferably at about ^{0 0} C, is reacted. If desired, it is possible to isolate the intermediate compound IV, but they are usually used without isolation or purification as starting compound for the process according to the invention.

In the process according to the invention, a carbapenem intermediate IV is reacted with a quaternary amine thiol compound of the formula

HS-A h ^S N ^Φ - R ⁵

X ⁹

15 VII

in which the rest of the formula

Ν ^β -

has the meaning given above and X represents a counter anion. The reaction is carried out in an inert solvent such as acetonitrile, acetonitrile-dimethylformamide, tetrahydrofuran, tetrahydrofuran-HpO, acetonitrile-HpO or acetone, in the presence of a base.

The type of base is not critical. Examples of suitable bases are sodium hydroxide, diisopropylethylamine, 1,8-diazabicyclo [5.4..0] undec-7ren, 1,5-diazabicyclo [4.3-0] non- 5-ene and tri (C ^^) alky! amines, such as triethylamine, tributylamine or tripropylamine. The reaction of the intermediate compound IV and the thiol VII can be carried out in a wide temperature range, for example from -15 ° C to room temperature. Preferably, one works at a temperature of about -15 to +15 ⁰ C, most be

preferably at about 0 ⁰ C.

The carbapenem products obtained by reacting the quaternary aminethiol VII with the intermediate IV are associated with a counter anion [e.g. (CrHcO) "PO",

Cl or the anion associated with the quaternary thiol]. This counteranion may be substituted at this time by conventional methods by another counter anion, e.g. by one which is more pharmaceutically acceptable. Alternatively, one can remove the counter anion during the subsequent deblocking step. If the quaternized carbapenem compound and the counteranion are an insoluble product, then the product may crystallize out as it forms. You can win it by filtering.

After preparation of the desired carbapenem compound, the carboxyl-protecting group R of the compound I 'can optionally be removed by conventional methods, eg solvolysis, chemical reduction or hydrogenation. If the protective group used is a p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl group which can be removed by catalytic hydrogenation, then the intermediate compound I 'can be dissolved in a suitable solvent, for example dioxane-water-ethanol, tetrahydrofuran-diethyl ether buffer, tetrahydrofuran-aqueous dipotassium hydrogen phosphate-isopropanol or the like., at a hydrogen pressure of about 1 to 4 atmospheres in the presence of a hydrogenation catalyst such as palladium on carbon, palladium hydroxide, platinum oxide or the like., at a temperature from 0 to 5O ⁰ Treat C for about 0.24 to 4 hours.

2 '

If R is an o-nitrobenzyl group, then you can also deblocking medium? Perform photolysis. Protecting groups, such as 2,2,2-trichloroethyl, can be removed by mild reduction with zinc. The allyl protecting group can be removed by using a catalyst comprising a mixture of a palladium branch and triphenyl-

having phosphine. In this case one works in a suitable aprotic solvent, e.g. Tetrahydrofuran, methylene chloride or diethyl ether. Similarly, one can remove other common carboxyl protecting groups by known methods. Finally you can do that

2 '

Compounds of formula I ^f wherein R is a physiologically hydrolyzable ester such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl or methoxymethyl ester, administered directly to the host without deblocking these esters since they are in vivo under physiological conditions be hydrolyzed.

18 5 15 Contain the substituents R, R, R or R or the

substituent A bonded, quaternized, heteroaromatic group, a functional group that could interfere with the intended course of reaction, then this group can be protected by a common blocking group and then deblocked to recover the desired functional group. Suitable blocking groups and methods for introducing and removing such groups are well known to those skilled in the art.

As with other β-lactam antibiotics, the compounds of general formula I can be converted by known methods into pharmaceutically acceptable salts which for the purposes of the invention substantially correspond to the non-salt compounds. For example, you can connect

of the formula I in which R is an anionic charge, dissolved in a suitable inert solvent and then adding one equivalent of a pharmaceutically acceptable acid. The desired acid addition salt can be obtained by customary processes, for example precipitation with solvents, lyophilization, etc.

herds. When other basic or acidic functional groups are present in the compounds of formula I, pharmaceutically acceptable base and acid addition salts can similarly be prepared by known methods.

The compounds of the formula I in which R is a hydrogen atom or an anionic charge, or their pharmaceutically acceptable salts, can also be converted into the corresponding compounds by conventional methods.

be converted fertilize, where R is a physiologically hydrolyzable ester group. An agreement

2 compound of the formula I, in which R denotes a customary carboxyl protective group, can also be converted into a

2 speaking compound in which R is a hydrogen atom,

means an anionic charge or a physiologically acceptable ester group, or a pharmaceutically acceptable salt thereof are transferred. 20

It is readily apparent that some of the compounds falling within Formula I can be obtained as both optical isomers and epimer mixtures. According to the invention, all such optical isomers and Epimerenmischungen are included. For example, if the 6-position substituent is a hydroxyethyl radical, then this substituent may have either R or S configuration. Both the resulting isomers and their Epimerenmischungen are included according to the invention.

The thiol intermediate compounds of the formula VII can be prepared by, for example, the corresponding thioacetate of the formula

CH ^ CS-A

wherein A has the meaning given above and the rest of the formula

a mono-, bi- or polycyclohexyl, aromatic, heterocyclic radical which contains a quaternizable nitrogen atom in the ring, this ring being bonded to A via a ring carbon atom, used as starting compound. The thioacetate is quaternized by reacting it in an inert organic solvent such as diethyl ether, dichloroethane, methylene chloride, dioxane, benzene, xylene, toluene or mixtures thereof with a suitable alkylating agent of the formula "

R ⁵ - X '

wherein R has the meanings given above 'and X ^{1 is} a common leaving group, such as halogen (chlorine, bromine or iodine, most preferably iodine) or a sulfonate ester moiety, such as mesylate, tosylate or triflate, means. The temperature for the alkylation reaction is not critical. It is preferably carried out at temperatures of about 0 to 40 ⁰ C.

Before reacting with the carbapenem intermediate rv, the quaternized thioacetate is hydrolyzed acidic or basic to liberate the quaternary thiol intermediate VII. This hydrolysis is preferably carried out immediately before coupling with IV in order to minimize the decomposition of the relatively unstable quaternary thiol VII.

Substituting suitable solvents, then one can the reaction of the intermediate III to the final product I without isolation of the various intermediate compounds, i. in a "one-pot" process. Such a method is described, for example, below in Example 7.

The carbapenem derivatives of general formula I, wherein

ρ R represents a hydrogen atom, an anionic charge or a physiologically hydrolyzable carboxyl-protecting group, or their pharmaceutically acceptable salts are strong antibiotics effective against various Gram-positive and Gram-negative bacteria. They may be used, for example, as additives to animal feed to promote growth, as preservatives in foods, as bactericides in industrial applications, e.g. in water-based paints and white water of paper mills, for inhibiting the growth of harmful bacteria and as a disinfectant for killing and inhibiting the growth of harmful bacteria on medical or dental equipment. However, the compounds of the invention are particularly useful for the treatment of human and animal infectious diseases caused by Gram-positive or Gram-negative bacteria.

The pharmaceutically active compounds according to the invention may be used alone or in the form of pharmaceutical agents which, in addition to the carbapenem active ingredient, contain a pharmaceutically acceptable carrier or diluent. The compounds can be administered in a variety of ways. Of particular interest are: oral, topical or parenteral (intravenous or intravenous)

muscular injection) administration. The pharmaceutical agents may be in solid form, such as capsules, tablets, powders, etc., or in liquid form, such as solutions, suspensions or emulsions. Agents for injection, which are the preferred mode of administration, can be prepared in unit dosage form in vials or in multi-dose containers and may contain formulatory agents such as suspending, stabilizing and dispersing agents. The compositions of the invention may be in ready to use form or in the form of a powder for reconstitution with a suitable carrier, such as sterile water, at the time of use.

The dose to be administered depends largely on the compound used, the formulation, the route of administration, the nature and condition of the patient and the particular site and the organisms to be controlled. The choice of a suitable, preferred dosage and the mode of administration is therefore up to the physician. In general, the compounds of the invention may be administered parenterally or orally, but to mammals, including humans, in an amount of from about 5 to 200 mg / kg / day. Administration is generally in divided doses, e.g. 3 to 4 times a day.

The following examples illustrate the invention without, however, limiting it.

example 1

Preparation of 3- [4- (N, N-dimethyl-1,2,3-triazolium) methylthio] -6a [i (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.O] hept-2-ene-2-carboxylate

A. Preparation of Isomer A

20

SAc

me

ε) MeOTf

b) aq. NaOH

d) H ₂ / Pd-C

CO-PNB

25 30

OH

35

0.58 ml (5.16 mmol) of methyltrifluoromethanesulphonate are added dropwise under nitrogen to a stirred, ice-cooled solution of 590 mg (3.52 mmol) of 4- (methanethiolacetate) -1-methyl-1,2,3-triazole in 2 ml of dry methylene chloride. After 0.5 h, the bath is removed and the solvent is siphoned off after 1 h. The remaining oil is dissolved in a few ml of water, this solution is cooled in an ice bath, a cold solution of 305 mg (7.59 mmol) of sodium hydroxide in a few ml of water and stirred for 0.75 h. The solution is diluted with 25 ml of water, the pH is adjusted to 7.5 by addition of solid sodium dihydrogenphosphate monohydrate, then 14 ml of this solution (about 1.9 mmol of triazoliumthiol) are added to an ice-cooled, stirred solution of 1.0 g (1.72 mmol) of enol phosphate in 10 ml of tetrahydrofuran (THF) and stirred for 0.75 h (during the reaction settles some crystalline material, probably Na ₂ HPOr). Transfer the suspension to a pressure bottle with a little THF (20 mL) and water (20 mL), add 30 mL of ether and 1.0 g of 10% palladium on carbon, and hydrogenate the mixture at 2.7 6 "for 1 h. The organic phase is separated off, washed twice with 5 ml of water, the combined aqueous phases are filtered and the filtrate is concentrated in a high vacuum (about 0.5 mm, 1.5 hours) and the yellow solution is chromatographed (reverse phase column for medium pressure, 35 × 90 mm, H ₂ O as eluent) to give, after lyophilization, 395 mg of the carbapenem compound which is slightly contaminated with inorganic material, purified by means of HPLC (10 × 300 mm Waters Microbondapack C-18 Column, multiple injections, HpO as eluant) to give 310 mg (57%) of isomerone A as a dark yellow colored powder.

¹ H-NMR (D ₂ O) O: 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 (1OH, m), 8.46 (1H, s)

64

1 IR (Nujol): 1760 cm

-1

UV (phosphate buffer, pH 7.4, M = O, 05) λ x 296 (£ = 7500).

IucLA.

B. Preparation of isomer B and isomer C

SAc

N-Me

(assumed structure).

a) MeOTf

b) aq. NaOH

d) H ₂ / Pd-C

OP (O ^).

ti

CO ₂ PNB

1.60 ml (14.0 mmol) of methyltrifluoromethanesulphonate are added dropwise under nitrogen to an ice-cooled solution of 1.20 g (7.02 mmol) of 4- (methanethanol acetate) -2-methyl-1,2,3 triazole in 6 ml of dry methylene chloride, allowed to warm to room temperature, stirred for 16 h, added additional methyltrifluoromethanesulfonate (0.40 ml, 3.56 mmol) and after 3 h at room temperature the solvent removed with a aspirator. The remaining oil is triturated with ether, the resulting gummy product is dissolved in 5 ml of water, cooled in an ice-bath and a solution of 844 mg (21.1 mmol) of sodium hydroxide in 5 ml of water is added. The mixture is stirred for 0.75 h, diluted to 60 ml with a solution of water and the pH is adjusted to .8 by the addition of solid potassium dihydrogenphosphate. Then you give

40 ml of this solution (about 4.7 mmol of a mixture of the isomeric triazolium thiols) to an ice-cooled, stirred solution of the enol phosphate (2.00 g, 3 »45 mmol) in 60 ml of THF. This mixture is stirred for 0.5 h in an ice bath, 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 hydrogenated for 1 h at 40 psi (2 , 76bar) separates the organic phase and washed twice with 10 ml of water. The combined aqueous phases are filtered, the filtrate is concentrated in a high vacuum (about 0.5 mm, 1.5 h), the resulting solution is chromatographed (reverse phase column for medium pressure, 45 × 130 mm, HpO as eluent) and After lyophilization, receives 595 mg of a mixture of isomeric carbapenem compounds contaminated with little inorganic material. These are separated and purified by HPLC (10 χ 300 mm Waters Microbondapack C-18 column, multiple injections, HpO as eluant) and obtained in the order of elution;

Isomer B, 153 mg (13%)

¹ H-NMR (D ₂ O) S : 1.23 (3H, d, J = 6.4Hz), 3.12 (2H, q, J = 1.4, 8.9Hz), 3.39 ( 1H, q, J = 1.7, 6.0 Hz), 4.07 4.68 (10, m), 8.19 (1H, s) IR (Nujol) 1755 cm ^-1

UV (phosphate buffer, pH = 7.4, M = O, 05) λ: 296 nm (£ = 6700);

and isomer C, 284 mg (24%)

¹ H-NMR (D ₂ O) ε: 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 (1OH, m), 8.62 (1H, s) IR (nujol) 1750 cm ^-1 UV (phosphate buffer, pH 7.4, M = 0.05) ^ _mQV : 298 nm (£ = 7600)

Example 2

(5R, 6S) -6- (1R-hydroxyethyl) -3- (2-methyl-1,2,3-thiadiazolium-4-yl-methylthio) -7-oxo-i-azabicyclo [3 · 2.0jhept-

2-ene-2-carboxylate

OH

"-V

0 ^

ir-N

• N ^w - CH, COO " ^ö '^

A. Ethyl 1,2,3-thiadiazol-4-yl carboxylate ¹

NHCOEt

0 η

ICC

N "SOCl ₂

_{Ί c} CH, COEt 15 3 "

A solution of ethyl cc-N-carbethoxyhydrazonopropionat (31.2 g, 0.154 mol) in 80 ml of thionyl chloride is stirred for 3 h at 23 ° C, heated for 20 min at 70 ⁰ C, the thionyl chloride evaporated and the residue is triturated in hexane ( 4 x 30 ml). Dissolve the red solid in 150 ml of dichloromethane, wash the solution with saturated sodium bicarbonate solution and water, dry over Na 2 SO 4, and concentrate the solution until the compound crystallizes. It is allowed to stand for a certain time at 23 ° C and filtered from the crystals; 16.8 g, mp. 86 ° C, 69%. The filtrate is concentrated and purified by chromatography on a silica gel column with dichloromethane as a solvent for elution. This gives 3.17 g, mp. 86 ° C, 13%

IR (KBr) 0 ^ _0v : 1720 (ester) cm ' ¹

¹ H-NMR (CDCl ₃ ) S s.1.52 (3H, t, J = 7.1 Hz, CH ₃ CH ₂ O), 4.57 (2H, q, J = 7.1 Hz, CH ₃ CH ₂ O), 9.47 (1H, s, H of thiadiazole).

¹ CD. Hurd and RIMori, J. Am. Chem. Soc., 77, 5359 (1955)

1. B. 1,2,5-Thiadiazol-4-yl-methanol ¹

Lt

To a suspension of ethyl 1,2,3-thiadiazol-4-yl-carboxylate (18.35 g, 0.116 mol) in 400 ml of ether is added portionwise 2.47 g (0.065 mol) of lithium aluminum hydride over a period of 1 h , the reaction mixture is stirred for 7 h at 23 ° C and treated with 2/47 g (0.065 mol) of lithium aluminum hydride. The mixture is stirred for a further 24 h, then successively 7 ml of water, 7 ml of 15% sodium hydroxide solution and 21 ml of water, stirred for 15 min, decanted the .Etherlösung and extracted the rubbery product with ether (5 x 100 ml). The ethereal extracts are combined, dried (MgSO 4) and concentrated (5.4 g). The crude material is purified on a silica gel column (120 g, 4 × 16 cm) using ether as a solvent for elution. This gives 1.3 g (7%) of ethyl 1,2,3-thiadiazol-4-yl-carboxylate and 2.45 g (1896) of 1,2,3-thiadiazol-4-yl-methanol. IR (FiIm) J .: 3380 (OH) cm ^-1

- IHCLX.

¹ H-IIMR _(CDCl3) ti: 2.31 (1H, s, OH), 5.22 (2H, s, 8.50 (1H, s, H of thiadiazole).

S.I.Ramsby, S.O. Ögren, S.B.Ross and N. E. Stjernström, Acta Fnam.Succica., 22 »285-96 (1973); CA. , 72, 137052W (1973).

68 1. C. 1 , 2, 5-thiadiazol-4-yl-methanol-methanesulfonate

CH ₂ OH ^CH 2 ^0Ms

MsCl

A solution of 1,2,3-thiadiazol-4-yl-methanol (0.75 g, 6.5 mmol) in 20 ml of di chlorine than is cooled under nitrogen to 5 ⁰ C, "treated with 1.018 ml (7, Triethylamine and 0.565 ml (7.3 mmol) of methanesulfonyl chloride, the ice bath is removed after 15 minutes, and the reaction mixture is stirred for 2 hours, the solution is washed with a 1N hydrochloric acid solution (2 × 2, ml) and water, dried ( The residue is purified by chromatography (silica gel column .1.5 × 21 cm) using ether as solvent for the elution, giving 0.90 g (7190) of 1,2,3-dichloromethane. thiadiazol-4-yl-methanol methanesulfonate

IR (film) v>: 1350 (SO ₉₎ and 1172 (SO ₉₎ cm ^{"1 1}

¹ H-NMR _(CDCl3) S: 3.09 (3H, s, CH _3), 5.75 (2H, s, CH _£),

8.72 (1H, s, H of thiadiazole) UV (CH ₂ Cl ₂ ) λ _max : 251 (£ 1990) Analysis: for CgHgN ₂ O ₃ S

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

and 0.13 g (19%) of di- (1,2,3-thiadiazol-4-ylmethyl) ether IR (FiIm) N? "·. 1272, 1242, 1200, 986, 805, 728 cm ^{-1 1} H-NMR (CDCl ₃ ) £: 5.16 (s, 4H, CH ₂ ), 8.42 (s, 2H, H atoms of thiadiazole) ,

69 D. 4-Acetylthiometh-1,2,5-thiadiazole

CHoSCCH,

CH ₃ CSNa

To a solution of 1,2,3-thiadiazol-4-yl-methanol-methanesulfonate (0.90 g, 4.6 mmol) in 9 ml of tetrahydrofuran is added 2 ml of an aqueous solution of sodium thioacetate [prepared from 0.38 ml (5.3 mmol) of thiolacetic acid and 0.445 g (5.3 mmol) of sodium bicarbonate], the resulting mixture is stirred for 1 h at 23 ° C and diluted with 75 ml of ether. The organic solution is washed with water (3 x 3 ml), dried (MgSO 4) and concentrated. The crude mixture is purified by chromatography (silica gel column: 1.4 × 19 cm), using 50% ether in hexane as eluent. 0.60 g (75%) is obtained

IR (movie)>? ·. 1675 (C = O) cm " ¹

H-NMR _(CDCl3) J: 2.37 (3H, s, CH _3), 4.58 (2H, s,

8.44 (1H, s, H of thiadiazole) Analysis: for C ₅ HgN ₂ OS ₂

Calculated: C 34.47% H 3.47% N 16.08% S 36.80% Found: 34.48 3.83 16.28 36.80. E. 4-Acetylthiomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-acetylthiomethyl-3-methyl- 1,2,3-thiadiazolium trifluoromethanesulfonate

CHo SC CH -

CF, SO, Me

-7 // \\

CF ^ SO

, 0

CH ₂ SCCH,

CF ₃ SO ₃

To a solution of 0.60 g (3.44 mmol) of 4-acetylthiomethyl-1,2,3-trthiadiazole in a mixture of 4 ml of ether and 0.4 ml of dichloromethane, a few crystals of the title compound and trifluoromethanesulfonate 0/407 are added over 5 minutes 'ml (3 ^ 6LmMoI) .The reaction mixture was stirred for 6 h under nitrogen at 23 ⁰ C. the white solid which is filtered and washed with ether a mixture of the two title compounds. This gives 1.05 g * 90%

IR (KBr) ^ _max : 1675 (C = O) cm " ¹ "

¹ H-NMR (DMSO, d-6) S: 2.43 (3H, s, CH ₃ COS), 3.33 (s, CH ₃ on N-3), 4.57 (s, CH ₃ on N -2), 4.66 (2H, s, CH ₂ ), 9.55 (H on thiadiazolium-N-2), 9.66 (H on thiadiazolium-N-3)

Analysis: for C ₇ HgN ₂ O ^ S ₃ F ₃

Calculated: C 20.27% H 2.38% N 9.45% S 32.46% Found: 24.61 2.57 8.47 28.21. .

F. 4-mercaptomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-mercaptomethyl-3-methyl-1,2,3- thiadiazolium trifluoromethanesulfonate

0 CH ₂ SH

CH ₂ SCCH ₃

Me ^ /? ΓΛ ^{: HC1} ' ^6N

\, Λ ,, η-! 'S CF ^ SO

A solution of a mixture of 4-acetylthiomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-acetylthiomethyl-3-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate (1.05 g, 3 , 1.m mol) in 10 ml of 6N hydrochloric acid is heated to 65 ⁰ C under nitrogen for 1.75 h, the solvent is evaporated off under reduced pressure and receives 0.91 g of a yellow syrup. This compound is used without further.Cleaning for the next. Step.

G. (5R, 6S) -6- (iR -Hydroxyethyl) -3- (2-methyl-1,2,3-thiadiazolium-4-yl-methylthio) -7-oxo-i-azabicyclo [3.2.0] - he-pt-2-ene-2-carboxylate

OH

0 OP (OPh),

CX) ₂ PNB

CH ₂ SH

CF ₃ SO ₃ "

pH 7.2

10% Pd / C

15>

Ether, THF, H ₂ O

COO

A cold (5 ⁰ C) solution of 1.7 g (2.92 mmol) of (5R, 6S) -p-nitrobenzyl 6- (iR-hydroxyethyl) -3- (diphenylphosphono) -7-oxo-1-azabicyclo [3 x 2.0] hept-2-ene-2-carboxylate in 10 ml of tetrahydrofuran is treated with a solution of a crude mixture of 4-mercaptomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and ^ mercaptomethyl-methyl 1,2,3-thiadiazolium trifluoromethanesulfonate (0.9 g) in a mixture of a phosphate buffer (pH 7.2, 0.3 M, IfLmI) and 5 ml of tetrahydrofuran. The reaction mixture is stirred for 1 h and the pH is maintained at 7.2 with a 2N sodium hydroxide solution. The mixture is stirred for a further hour, then 50 ml of ether and 1 g of 1096 palladium on carbon, the resulting mixture hydrogenated for 2 h at a pressure of 3.1 bar and 23 ° C 'and filtered through a pad of Celite. The organic phase is separated off, diluted with 50 ml of ether and 20 ml of phosphate buffer (pH 7.2, 0.3 M) and hydrogenated for 2 h

at 3.5 bar (2 g 10% palladium on carbon). The aqueous phases (from the first and second hydrogenolysis) are combined, washed with ether and purified by chromatography on a PrepPak 500-C / 18 using water as eluent. This gives 0.22 g of a crude product, which in turn is purified by HPLC, using water as the eluent. After lyophilization, 0.040 g (h%) of the title compound are obtained. IR (KBr) V? _maY : 3400 (br, OH), 1745 (C = O of β-lactam),

1580 (carboxylate) cm

¹ H-NMR (D ₂ O) /: 1.23 (3H, d, J = 6.3 Hz, CH ₃ CHOH), 3.04, 3.05, 3.16 (2H, m, 'H- 4), 3.38 '(1H~dd, J = 2.8Hz, J = 6.0Hz, H-6), 3.9-4.6 (2H, m, H-5, CH ₅ CHOH ), 4.51, 4.53 (2 "s", 'SCH ₂ ), 4.61 (s, N ⁺ CH ₃ )

UV (HpO) λ: 224 (£ 4345), 262 (έ 4980), 296 (£ 6885) [α] 23 _{= 18} ο (c = ο, 18,

T. / ρ = 9.8 (measured at a concentration of 10 in phosphate buffer of pH 7.4 at 36.8 ⁰ C) h.

example

Potassium 3- [5- (i-carboxylatomethyl-3-methyl-1,2,3-triazolium) methanethio] -6a [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [5 «2.0] hept-2-ene-2-carboxylate

CO,

It

73

^C N

ν '2) MsCl / NEt

KSCOCH

AcS

BrCH ₂ COEt

AcS

CO ₂ Et

br "

a) KOH

OP (O ^).

CO ₂ PNB

c) H ₂ / Pd-C

co.

2.83 g (70.9 mmol) of lithium aluminum hydride are added in small portions to a stirred suspension of 9.00 g (70.9 mmol) of 1-methyl-1,2,3-triazole-4-carboxylic acid [C. Pederson , Acta. Chem. Scand., 1959, 13, 888] in 200 ml of dry THF, the mixture is stirred for 15 h at room temperature, then carefully added to 20 ml of 20% aqueous sodium hydroxide solution in about 1 ml aliquots, filtered the granular suspension and wash the solid with more THF (5 x 75 ml). Dry the combined THF solutions (MgSO 4), remove the solvent, flash chromatograph the residual yellow oil over a silica gel column (90χ35 mm) [100 ml portions of hexane, mixtures of ethyl acetate-hexane (1: 1). and (1: 3) and finally ethyl acetate-methanol (9: 1) as the eluent] to give 4-hydroxymethyl-i-methyl-1,2,3-triazole (3.18 g, 40%) as a colorless oil.

¹ H-NMR (CDCl,) 6 ι 4.07 (3H, s), 4.73 (2H, d), 7.52 (1H, s) IR (neat): 3320 cm.

3.82 ml (49.6 mmol) of methanesulfonyl chloride are added dropwise to an ice-cooled stirred solution of 4.67 ml (41.3 mmol) of the alcohol and 7.47 ml (53.7 mmol) of triethylamine in 20 ml Methylene chloride, the solvent removed after 0.5 h and takes the remaining solid in 30 ml of acetonitrile. Then, 7.06 g (62.0 mmol) of potassium thioacetate are added and the suspension is stirred for 3 hours at room temperature. An additional amount of potassium thioacetate (3.0 g, 26.3 mmol) is added, the suspension is stirred for a further 16 h, then the dark-colored suspension is concentrated and 10 ml of water are added. The mixture is extracted with methylene chloride (5 x 40 ml), the combined extracts are dried (MgSO 4) and the solvent is removed. , The residual oil is flash chromatographed on a silica gel column (90 χ 36 mm) [hexane is used as the eluent and then one. Mixture of. hexane

Ethyl acetate (1: 1)]. This gives 4- (methythioacetate) -1-methyl-1,2,3-triazole (5.95 g, 84%) as a slightly rosage-colored residue

¹ H-NMR _(CDCl3) 6i 2.40 (3H, s), 4.10 (3H, s), 4.20 (2H, s), 7.53 (1H, s)

IR (Nujolmull): 1675 cm " ¹ .

A solution of 1.00 g (5.85 mmol) of triazole and 1.48 ml (13.3 mmol) of ethyl bromoacetate in 10 mL of dry acetonitrile is heated to 60 ° C under nitrogen for 90 h, the solvent is removed and the residual oil is triturated with ether (4 x 25 ml) to give 1-methyl-3- (ethylcarboxymethyl) -4-methanethioacetate-1,2,3-triazolium bromide as a brownish, gummy product which is used directly.

A cold solution of 0.66 g (12 mmol) KOH in 5 ml of water is added to an ice-cooled, stirred solution of triazolium bromide in 20 ml water, diluted to 35 ml after 20 min, and sufficient solid dihydrogen phosphate added to adjust the pH to adjust this solution to 8.0. This is then added to an ice-cooled, stirred solution of the enol phosphate in 35 ml of THF, transferred this mixture after 0.5 h in a 35 ml of ether and 1.5 g of 10% palladium-on-carbon pressure vessel and hydrogenated for 55 min at 2 , 75; bear. The organic phase is then separated off, washed twice with 5 ml of water, the combined aqueous phases are filtered and the filtrate is concentrated in a high vacuum. The remaining material is chromatographed on a reverse phase column (35 x 120 mm) using water as the eluent. After lyophilization of the fractions containing the carbapenem compound, 1.20 g of a green-colored solid are obtained. This is again chromatographed on a Waters Prep.

"3'5 500 HPLC column (PrCpPAK-SOOZC ₁₈ ), giving 2% acetone

nitrile-water used as eluent. The fractions containing the carbapenem compound are combined, lyophilized, rechromatographed by HPLC (10 × 300 mm Waters Microbondapack C-18 column) using water as the eluent, and after lyophilization the pure title compound is obtained (190 mg, 17%). ) as a light yellow solid.

¹ H-NMR (D ₂ O) 6 : 1.24 (3H, d, J = 6.4 Hz), 3.07 (2H, d, J = 9 Hz), 3.38 (1H, q, J = 2.7, 6.0 Hz), 4.02-4.30 (3H, m), 4.29 (3H, s), 5.23 (2H, s), 8.52 (1H, s) IR (Nujolmull): 1750 cm ^-1 UV (phosphate buffer, pH 7.4) X.-296 mn (£ = 7520).

IHcLA.

Example 4

Potassium-3- [4- (i-carboxylatomethyl-3-methyl-1,2,3-triazolium) -methanthio] -6a - [ 'I- (R) ^ - hydroxyethyl] -7-oxo-1-azabi cyclo ·3 · 2.0 "jhept-2-ene-2-carboxvlate

~ e

- ^C0 '

ι ο

HO-CC = CH ⁺ 0

ti

77 0

HOC

CO ₂ Et

N N

a) EtOCCl, NEt

b) NaBH

10

HO ^ ^ p = - N

^C0 2 ^Et

Il

OC-N =)

HSCCH,

H

AcS '> = ^ 20 _Ν ν-

OH

a) MeOTf

b) KOH

d) H ₂ / Pd-C

CO ₂ PNB

A mixture of 30.0 g (0.23 mol) of ethyl azidoacetate and 14.3 ml (0.23 mol) of propargylic acid in 75 ml of toluene is stirred at room temperature. The reaction is slightly exothermic for 1.5 h, but then becomes rapidly strongly exothermic, so that one must cool with an ice bath. After this exothermic phase is over, the reaction mixture is refluxed for 0.5 h. After cooling in an ice bath, the crystalline material is filtered off and washed with a little toluene. The crude material thus obtained (33.3 g 72%) consists of a single isomer [1 H-NMR (DMSO-dg) S: 1.20 (3H, t, J = 7 Hz), 4.15 (2H, q, J = 7Hz), 5.42 (2H, s), 8.67 (1H, 3)], which is likely to be 1- (ethylcarboxymethyl) -1,2,3-triazole-4-carboxylic acid, wherein this in analogy to earlier work (C. Pederson, Acta.

Chem. Scand., 1959, 2A> 888).

A solution of 5.00 g (25.1 mmol) of the carboxylic acid and 3.68 ml (26.4 mmol) of triethylamine in 50 ml of dry methylene chloride is added to an ice-cooled, stirred solution of 2.52 ml (26.4 mmol ) Ethyl chloroformate in 50 ml of dry methylene chloride, the purple-colored solution stirred for 0.5 h, then washed with 10 ml of water, dried (MgSO 4) and the solvent was removed. The mixed, crude anhydride is dissolved in 50 ml of THF and added slowly to an ice-cooled suspension of 0.72 g (18.9 mmol) of sodium borohydride in 50 ml of THF. After stirring for 0.5 h additional sodium borohydride (0.30 g, 7.9 mmol) is added and allowed to react in the ice bath for 1 h. Then 5 ml of water and after 10 min 3 ml of 1Obigen aqueous HCl solution.

After the evolution of gas has subsided, 2 g of solid potassium carbonate are added with stirring, the organic phase is removed and the remaining white paste is extracted with further THF. The combined aqueous phases are dried over MgSO 4, the solvent is removed and flash-chromatographed on a silica gel column, with hexane,

Eluted mixtures of ethyl acetate-hexane and finally ethyl acetate. 1- (Ethyl-carboxymethyl) -4-hydroxymethyl-1,2,3-triazole (2.04 g, 44%) is obtained as a crystalline solid.

¹ H-NMR (CDCl ₃₎ ^: 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 (20.8 mmol) of diisopropyl azodicarboxylate are added dropwise under nitrogen to an ice-cooled solution of 5.47 g (20.8 mmol) of triphenylphosphine in 100 ml of dry THF, and after 0.5 h an ice-cooled solution of 1, 93 g (10.4 mmol) of the alcohol and 1.49 ml (20.8 mmol) of thioacetic acid in 50 ml of dry THF under nitrogen to this mixture, allowed to stand for 2 h in an ice bath and then for a further 2 h at room temperature and removed then the solvent. The reaction mixture is flash chromatographed on silica gel (40 g, eluting with 100 ml portions of hexane, 5%, 10%, 15%, ... 50% ethyl acetate-hexane). The fractions containing the thioacetate are combined and rechromatographed on silica gel (60 g), with 200 ml portions of hexane, 5%, 10%, 15%, 20% ethyl acetate-hexane and 22.5%, 25%, 27.5%, ... 35% ethyl acetate-hexane eluted. This gives 1.24 g (49%) of 1- (ethylcarboxymethyl) -4-methanethioacetate-1,2,3-triazole as a crystalline solid [ ¹ H NMR]: 1.28 (3H, t, J = 7 Hz) , 2.37 (3H, s), 3.87 (2H, s), 3.90 (2H, q, J = 7Hz), 5.12 (2H, s), 7.63 (1H, s) ; IR (Nujolmull): 1735, 1780 cm ^-1 and another 1.40 g of a triphenylphosphine oxide contaminated material.

0.51 ml (4.53 mmol) of methyl trifluoromethanesulfonate are added dropwise to an ice-cooled, stirred solution of the triazole (1.00 g, 4.12 mmol) in 5 ml of dry methylene chloride, the bath is removed after 0.5 h after a further 0.5 b, the solvent is removed by means of an air-suction

Pump, and we obtain a white solid, which is suspended in 15 ml of water. This mixture is then stirred while cooling in an ice bath, a solution of 0.69 g (12.4 mmol) of KOH in 5 ml of water is added, the reaction mixture is stirred for 1 h, then diluted to 30 ml with water and solid potassium dihydrogen phosphate is added to adjust the pH to 8.0. A portion of this solution (22 mL, 3.0 mmol of the thiocarboxylate) is added to an ice-cooled stirred solution of the enol phosphate (1.60 g, 2.76 mmol) in 30 mL of THF and taken in after 0.5 h High vacuum to the reaction mixture to remove THF. The yellow solution is then chromatographed on a reverse phase column (35 × 120 mm), eluting with 300 ml of water and then 100 ml portions of 5, 10, 15, ... 30% acetonitrile-water. After lyophilization of the desired fractions, the p-nitrobenzyl ester is obtained as a yellow solid (930 mg). This is then transferred to a 25 ml of ether, 25 ml of THF and 25 ml of phosphate buffer [prepared by dissolving 1.36 g (0.01 mol) of potassium dihydrogen phosphate in 100 ml of water and adjusting the pH to 7.4 by adding 45%. iger aqueous KOH] and 900 mg 10%. Palladium-carbon-containing pressure bottle, hydrogenated for 1 h at 2.75 bar, then separating the organic phase and washed twice with 5 ml of water. The combined aqueous phases are filtered and then concentrated under high vacuum. The remaining solution is re-chromatographed on a reverse phase column (35 × 120 mm), eluting with water. The fractions containing the carbapenem compound are combined and lyophilized to give 1.21 g of a light greenish solid. This is purified by HPIC (10 χ 300 mm Waters Microbondapack C-18 column, HpO as eluent) to give the pure title compound (480 mg, 41%). ¹ H NMR (D ₂ O) <5: 1.23 (3H, d, J = 6.4Hz), 3.11 (2H, d, J = 9Hz), 3.37 (1H, q, J = 3.0, 6.1 Hz), 4.02 (7H, m),

5.18 (2H, s), 8.53 (1H, s), IR (Nujolmull): 1750 cm ^-1 UV (phosphate buffer, pH 7.4) λ: 205 m ( I = 7810).

Example 5

3- [5- (i, 4-dimethyl-i, 2,4-triazolium) -methanthio] -6a- [i- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept- 2-en-2- carboxylate

0% H

CO ₂ '

A. 1 ~ methyl 5-methanethioacetate 1, 2,., 4-triazole

b)

0.46 ml (6.0 mmol) of methanesulfonyl chloride are added dropwise to an ice-cooled, stirred solution of 565 mg (5.0 mmol) of 1-methyl-5-hydroxymethyl-1,2,4-triazole (RG Jones and C. Chem. Ainsworth, J.Amer.Chem.Soc., 1955, 77, 1938) and 0.91 ml (6.5 mmol) of triethylamine in 5 ml of methylene chloride, after 20 mins another 1.05 ml (7.5 mmol) of triethylamine and then 0.53 ml (7.5 mmol) of thioacetic acid and stirred for 45 min. The reaction mixture is then diluted with methylene chloride, washed with water, the aqueous phase extracted with methylene chloride (3x5 ml), the organic phases are combined, dried (MgSO.sub.4) and the solvent is removed. Column chromatography on silica gel

pure i-methyl-5-inethanthioacetat-i, 2,4-triazole (570 mg) as a yellow oil [in addition, 200 mg of an impure fraction, which in turn is chromatographed (preparative TLC, silica gel), with further 100 mg of pure material (total yield 85%)].

H-NMR (CDCl ₃₎ Ci: 2.38 (3H, s), 3.90 (3H, s), 4.25 (3H, s), 7.80 (1H, s).

B. 3- [5- (i, 4-Dimethyl-1,2,4-triazolium) -methanthio] -6a [i- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept ~ 2-ene

2-carboxylate.

SAc

a) MeOTf

b) NaOH

d> H ₂ / Pd-C

1.20 ml (10.7 mmol) of methyltrifluoromethanesulphonate are added dropwise to an ice-cold solution of 730 mg (4.27 mmol) of 1-methyl-5-methanethioacetate-1,2,4-triazole in 7 ml of methylene chloride. The reaction mixture is allowed to warm slowly to room temperature over 3 hours, then concentrated and the residual oil is triturated with ether to leave crude 1: 1-dimethyl-S-methanthoacetate-1,2,4-triazolium trifluoromethanesulfonate (1.46 g) used directly.

A solution of 512 mg (12.8 mmol) of sodium hydroxide in 5 ml of water is added to an ice-cooled solution of the triazolium salt (1.45 g, 4.35 mmol) in 5 ml of water, diluted after 45 min with 25 ml of water and adjusted the pH with solid potassium dihydrogen phosphate to 7.6. This solution is then added to an ice-cold, stirred solution of the

Enol phosphate (2.00 g, 3.45 mmol) in 25 ml of THF, the reaction mixture transferred after 30 min in a pressure bottle containing 40 ml of ether and 2.0 g of 10% palladium on carbon, hydrogenated for 1.2 h at 3.1 bar and the reaction mixture is then diluted with 25 ml of ether and filtered. The organic phase is separated off, washed twice with 5 ml of water, the combined aqueous phases are washed with 3 × 25 ml of ether and then concentrated in vacuo. Column chromatography (reverse phase, 45 x 130 mm, water as eluent) and subsequent lyophilization of the fractions containing the carbapenem compound gives 650 mg of the crude material. This is chromatographed again to give the pure title compound (450 mg, 39%). ¹ H-NMR (D ₂ O) .l: 1.24 (3H, d, J = 6.4 Hz), 3.19 (2H, q, J = 2.6, 9.2'Hz), 3.45 (1H, q, J = 2.8, 6.0 Hz), 3.91

(3H, s), 4.06 (3H, s), 4.08-4.36 (2H, m), 4.54 (2H, d, J = 2.8Hz), 8.71 (1H, s) IR (Nujolmull): 1755 cm ^-1 UV (phosphate buffer, pH 7.4) λ _Μαν : 294 nm (E = 8202)

Fifa, X.

T ₁ ^ ₂ = 9.1 h (phosphate buffer, pH 7.4, M = O, 067, T = 37 C).

Example 6

(1 ^f R, 5 R, 6 S) -3 - [(i, 3-dimethyl-5-tetrazolium) methylthio] -6- (1-hydroxyethyl) -7-OXO-1-azabicyclo [3.2.0] hept 2-en-2

carboxylate £

CH-,

CB ₃ -

A. 5-Carbethoxy-2-methyltetrazole and 5-carbethoxy-1'- methyltetrazole

io

CO ₂ Et ^{2 2} ν f? \\ - or * N ^. /) ₂ SO ₄ ^N

CH,

CH ₃

1a. Methylation with diazomethane

A solution of 9.17 g (0.064 mmol) of 5-carbethoxytetrazole [D.Moderhack, Chem. Ber., 108, 887 (1975)] in 80 ml of ethyl ether (the use of a mixture of ethanol and ether leads to the same isomer ratio). It is cooled to ^{0 0} C and treated dropwise (15 min) with a solution of 3 g (0.071 mmol) of diazomethane in 200 ml of ether. The pale yellow solution is stirred for 30 min, excess diazomethane is destroyed by addition of 1 ml of acetic acid, the solvent is evaporated off and the residue is distilled to give a clear oil, bp 95-100 ° C / 0.5 torr; 9.64 g (96-6). The ¹ H-NMR spectrum indicates that the 1-methyl and 2-methyl isomers are present in a ratio of 6: 4. The separation of these two isomers is not possible by distillation or by HPLC. IR (film) 0 · 1740 cm ^"1 (C = O of ester) ¹ H-NMR _(CDCl3) O: 1.53 (3H, two overlapping t, J = 7.0, CH ₂ CH _3), 4 , 46 and 4.53 (3H, 2s, CH ₃ of 1-methyl- and 2-methyltetrazoles, ratio 6: 4.

The methyl signal of the 2-isomer is at lower field. The 2-isomer is present in lesser amounts), 4.5 ppm (2H, two overlapping q, CH ₂ CH ₃ ).

85. 5-carbethoxy-2-methyltetrazole

N Vy-CO ₉ Et + V V-COpEt - Z-) γ V-CO ₅ Et

XT // έ ^_7nO,.

CH,

* V ^ ~ V ^150C / V /

CH *

A mixture of 5-carbethoxy-2-methyltetrazole and 5-carbethoxy-1-methyltetrazole (0.252 g, 1.61 mmol, ratio of the two isomers = 1: 1) in 0.5 ml of Me.thyljodid was enclosed in a glass tube and 15 h at 100 ⁰ C and 6 h at 130 ° C heated. After distillation of the reaction mixture, the title compound is obtained as a light yellow oil. (0.139 g, 55%), b.p. 95 to 100 ° C / 0.5 torr (air bath temperature).

IR (film) vV ·. 1740 cm ^-1 (C = O of the ester) ¹ H-NMR (CDCl ₃ ) O: 1.46 (3H, t, J = 7.0, CH ₃ CH ₂ ), 4.53 (3H, s, CH ₃ -2), 4.5 (2H, q, J = 7.0, CJ ₂ CH ₃ ).

2. Methylation with Dimethyl Sulfate A solution of 1.42 g (0.01 mol) of 5-carboethoxytetrazole in 20 ml of dry acetone is treated with 1.38 g (0.01 mol) of anhydrous potassium carbonate and 1.26 g (0.01 Mol) dimethyl sulfate, the mixture is refluxed for 12 h, the carbonate is filtered off and the solvent is evaporated off under reduced pressure. The residue is diluted with 30 ml of dichloromethane, washed with 10 ml of saturated sodium bicarbonate solution, 10 ml of brine and dried over anhydrous sodium sulphate. After

evaporation of the solvent and distillation in vacuo gives a clear oil (1.45 g, 93%), Kp.85 to 110 ⁰ C / 0.5 Torr. The H-NMR shows the presence of 2.two isomers in a ratio of 1: 1.

86 B. 5-hydroxymethyl-2-methyltetrazole

LiBH ₄ > ι,) - CH ₂ OH

1 ♦ By reduction of the ester mixture A mixture of 5-carbethoxy-1-methyltetrazole and 5-carbethoxy-2-methyltetrazole (ratio 6: 4) (7.60 g, 0.49 mol) in 50 ml of dry tetrahydrofuran is cooled to 0 ⁰ C, treated with 1.06 g (0.049 mmol) of lithium borohydride, which is added over 15 min in small portions, the mixture is kept for a further 30 min at 1O ⁰ C and then stirred for 4 h at 20 ⁰ C. The mixture is cooled O ⁰ C, carefully destroying excess hydride by addition of 6N HCl (pH = 7, after evolving no gas), concentrate the solvent in vacuo, dilute the residual oil with 200 ml of dichloromethane, wash with 10 ml of brine, and finally dry Na ₂ SO ₄ . After concentration of the solvent and distillation of the residue in vacuo, 1.83 g (33%) of a clear oil are obtained. The ¹ H-NMR spectrum of this material shows that it is 5-hydroxymethyl-2-methyltetrazole.

2. By reduction of 5-carbethoxy-2-methyltetrazole

To a solution of 0.139 g (0.89 mmol) of 5-carbethoxy-2-methyltetrazole obtained by isomerization of the mixture of the esters in methyl iodide in 1 ml of dry tetrahydrofuran is added at 10 ° C 0.019 g (0.87 mmol solid lithium borohydride, the mixture is warmed slowly to room temperature and stirred for 4 h. Excess borohydride is destroyed by careful addition of 6N HCl at ⁰ ° C. (pH 7). The solvent is evaporated off, the residue is dissolved in 25 ml of dichloromethane and dried over anhydrous water.

a sodium sulfate. After evaporation of the solvent, the title compound is obtained as a clear oil (0.092 g, 91%), b.p. 90 to 120 ° C / 0.5 torr (dec.) IR (film) v? · 3350 cm ^-1 (broad, OH) ¹ H-NMR (CDCl ^) 0: 4.4 (2H, s, CH, -2), 4.93 (2H, s, CH ₀ -5).

C. 5-Acetylmercaptomethyl-2-methyltetrazole

"? VcH ₂ 0H DM ₅ Cl, Et ₃ N Τ \ __ ο

^{1U W}

2) CH, COSK

CH ₃ ^ CH ₃

To a solution of 1.83 g (11.7 mmol) of 5-hydroxymethyl-2-methyltetrazole in 25 ml of dry dichloromethane is added dropwise at ⁰ ° C. over a period of 5 minutes to 1.47 g (12.9 mmol) of methanesulfonyl chloride and then 1.30 g (12.9 mmol) of triethylamine, the mixture is stirred for 1 h at ⁰ ° C, then treated with a solution of 1.60 g (14, O mmol) of potassium thioacetate in 10 ml of dry N, N-dimethyl ! Formamide, the resulting gel is stirred for 3 h at ^{0 0} C, the reaction mixture is diluted with 200 ml of dichloromethane, washed with 20 ml of brine and dried over anhydrous sodium sulfate. After evaporation of the solvent in vacuo and chromatography of the resulting oil on silica gel (2 × 15 cm, eluted with dichloromethane and dichloromethane-acetone 5%) , the title compound is obtained as a clear oil (1.31 g, 6596).

IR (film) ^ _max : 1696 cm ^-1 (C = O of the thioester)

¹ H-NMR (CDCl ₃₎ ^: 2.43 (3H, s, SAc), 4.36 (3H, s, 2-CH _3), 4.38 ppm (2H, s, 5-CH _2).

D. 5-Mercaptomethyl-i, 3-dimethyltetrazolium trifluoro methane sulfonate

^ .CH-7 γ, τι ςό -

MS ^ N _x CF, SO, CH, NaOH _M - ^ N _N ^D ^ 3 ^ 3? VCH ₉ SAc -2-2-2 ^ ¹ J * ^ V-CH ₅ SH

, <"^ N ^ ^W ~ -N

CH ₃ CH ₃

A solution of 0.400 g (2.32 mmol) of 5-acetylmercaptomethyl-2-methyltetrazole in 3 ml of dry dichloromethane is treated with 0.76 g (4.64 mmol) of methyl triflate and stirred for 16 h at 22 ⁰ C. After evaporation of the solvent in Vacuum gives a red oil. This salt is dissolved in 5 ml of cold, oxygen-free water and treated with 0.8 ml (3.2 mmol) of 4 M sodium hydroxide. The mixture is stirred for 40 min at ^{0 0} C, diluted with 7 ml of water and the pH adjusted to 7.3 with saturated KH ₂ PO ^ solution. The resulting clear solution is kept under nitrogen and used immediately for the subsequent step.

  ·.

E. (1'R, 5R, 6S) -3- [i, 3-dimethyl-5-tetrazolium) -methylthio] -6- (1-hydroxyethyl) -7-0X0-1-azabicyclo [3.2.0] - hept-2-ene-2-carboxylate

CO ₂ PNB

CF ₃ SO ₃

CH ₂ SH

SCH

CO ₂ PNB

CF ₃ SO ₃

CH,

, CH

H ₂ Pd / C

A solution of 0.915 g (1.58 mmol) of enol phosphate in 8 ml of tetrahydrofuran is cooled to ⁰ ° C. and treated dropwise over 20 minutes with a solution of 5-mercaptomethyl-1,3-dimethyltetrazolium trifluoromethanesulfonate (2.32 mmol as prepared above). During the addition, the pH of the reaction mixture remained stable, ie at 6.5. 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 vessel, diluted with 10 ml of THF. 20 ml of ether and 20 g of ice and hydrogenated the carbapenem compound with 10% palladium on charcoal at a pressure of 3.1 bar, while slowly raising the temperature to 22 ⁰ C for 90 min. The catalyst is filtered off and washed with 5 ml of water and 20 ml of ether. The aqueous phase is washed with 20 ml of ether and a vacuum is applied for 20 minutes to remove traces of the organic solvent. Chromatography on PrePak 500-C / 18 and elution with water and lyophilization gives 0.266 g (h9%) of the title compound as a white powder; [oc] jp = + 13 ° (c = 1.04, H ₂ O). - ---

UV (H ₂ O, pH 7.4) ^A _max : 294 nm (= 7500)

_Max

IR (KBr) v>: 1755 (C = O of β-lactam), 16ΟΟ cm " ¹ (wide,

XucL2 £

C = O of the carboxylate)

¹ H-NMR (D ₂ O) 6: 1.24 (3H, d, J = 6.4 Hz, CH ₃ CHOH), 3.0-3.3 (2H, m, H-4), 3, 42 (1H, dd, J = 5.8, 2.9 Hz, H-6), 4-4.2 (2H, m, H-5 and _CH3 CHOH), 4.34 and 4.57 (2 χ 3H, 2s, CH ₃ -I and -3 of the tetrazole), 4,49 and 4,51 (2H, 2s, CH ₂ S).

The product has a half-life of 10.5 h at 27 ^° C. (c = 10 M in a pH 7.4 phosphate buffer).

example

Preparation of 3- (N-methylpyridin-2-yl-methanethio) -6a [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3 · 2.0] hept-2-ene- 2-carboxylate by means of a one-pot procedure

CO ₂ PNB

SAc

CH ₃ CN

5 min, ⁰ ° C

ClP (O ^)

EtN (iP r)

NaOH

H ₂ O, O ⁰ C, 1h

O ₂ PNB

PH 6.5-7.5

THF, H-O!

OH

CO ₂ PNB

ch, g Ι ³ ώΠ

operating room

H ₂ Pd-C 10% 5 ° C, 2 h.

A. Preparation of Enol Phosphate (2)

CO ₂ PNB

CO ₂ PNB

An ice-cooled solution of ketone 1 (3 g, 8.62 mmol) in 30 mL acetonitrile is treated with 1.57 mL (9 mmol, 1.04 eq). Ethyldiisopropylamine (addition time about 2 minutes) and 1.87 ml (9 mmol, 1.04 equiv.) Of chlorodiphenyl phosphate (addition time about 2 minutes). The reaction mixture is stirred for 45 min. The solution is diluted with 60 ml of ethyl acetate, washed with 2 × 50 ml of cold water and brine, dried over sodium sulfate and concentrated (bath temperature below 20 ^° C.) ), whereby a foam is obtained, which is used in this way.

93 1 B. Preparation of Thiol (4)

SAc

NaOH / H ₂ O 0 °, 1 h.

'2)

An ice-cooled solution of thioacetate 3 (3.31 g, 10 mmol) in water is purged with nitrogen for 5 minutes and treated dropwise over about 5 minutes with a cooled solution of 0.7 g (17.5 mmol, 1.75 eq .) Sodium hydroxide in 8 ml of water. The mixture turns yellow. After 75 minutes under nitrogen, adjust the pH to 7.4 with saturated aqueous KH 2 PO 4. The reaction mixture was diluted with 15 ml of water and used this aqueous solution of the thiol 4 (50 ml, 0.2 mmol / ml) for the following reaction.

C. Coupling CO, ρ OH PNB

THF-H ₂ O pH 6.5-7.5 0% 1 h.

OH

An ice-cooled solution of 2 (crude, prepared in A, 8.62 mmol) in 50 ml of tetrahydrofuran is treated dropwise with an aqueous solution of the thiol 4 prepared in B (5 ml of the solution every 5 min). During the reaction, the pH of the reaction mixture is maintained at about 6.5 to 7.5 (preferably 7) by addition of a cooled 2N sodium hydroxide solution. The reaction is monitored by TLC (a) silica gel, ethyl acetate; (b) reverse phase Analtech RPSF, CH ₃ CN pH 7 buffer (4: 6).

Total used 1.15 eq. Thiol (50 ml of solution). The reaction was complete after 1 h at ⁰ ° C. The mixture is used as such for hydrogenation after the pH is adjusted to 7.

D. Hydrogenation

CH.

CO ₂ PNB

45 psi (3.1 bar) H ₂ / Pd-C 10%

THF-H ₂ O ether 0 ⁰ C, 2 h.

CH-

The reaction mixture containing compound 5 (prepared in C) is transferred to a Parr bottle with 10 ml of THF, 10 ml of phosphate buffer (pH 7, 0.1 M), 75 ml of ether and 5 g of 10% Pd-C and hydrogenated for 2 h at a pressure of 3.1 bar and a temperature of 3 to 10 ° C. The catalyst is then filtered off, washed with 3 x 10 ml of water and

ίο

carefully adjust the pH to 6.2 with cold 2N NaOH solution. Ether is added, the aqueous phase is separated off and washed again with ether. The aqueous phase is freed from the organic solvent in vacuo and then purified on a Bondapak C-18 column (100 g, 4.5 x 13 mm) using cold, distilled water. The pale yellow fractions containing the product (lyophilized and TLC monitored) are lyophilized to give 1.46 g (50% yield calculated from the bicyclic ketone) as a yellow powder; 293 '( t = 9000), X 271 ( 1 = 11 064).

Example 8

CH.

CO ₂ PNB

O ClP (00)

(00)

CO-PNB

CF ₃ SO ₃ ^

SAc

CF ₃ SO ₃ ^

35

Q

OP (00)

If, in the process of Example 7, the keto intermediate compound 1 used there is replaced by an equimolar amount of the corresponding 1β-methyl intermediate, the abovementioned carbapenem compound (end product) is obtained.

example

If, in the process of Example 7, the keto intermediate compound 1 used there is replaced by an equimolar amount of the corresponding 1α-methyl intermediate compound, the carbapenem compound (final product) indicated above is obtained.

Claims (2)

97 Claim for invention 1. A process for the preparation of compounds of the formula 15 R " S-A COOR ' NO" wherein R is a hydrogen atom and, 1 R is selected from hydrogen and the following substituted and unsubstituted radicals: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; Cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl moieties; phenyl; Aralkyl, aralkenyl and aralkinyl, wherein the aryl moiety is a phenyl radical and the aliphatic moiety has from 1 to 6 carbon atoms; Heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom (s) in the above-mentioned heterocyclic units are selected from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moieties attached to said heterocyclic moieties have 1 to 6 carbon atoms ;
wherein the substituent or substituents of the above radicals are independently selected from the group consisting of: C ₁ / -alkyl, optionally substituted by amino, halogen, hydroxy or carboxyl;
Halogen; 3 o -OR // q -SR O Il ¹¹ 3 AO -OCNR R CN ~ ^N 3 3 -OSO-R "9 -OS-R / i , ^{NR R.} ο 3 ^{f /} 9 -NR S-R -OP (D) (OR ³ ) (OR ⁴ ) O \ -NHCNR ³ R ⁴ . -NR ³ C = NR ^{4 [} OI ₃ : ι 3 "4 R R- ³ CNR-. · -CO R ³ : -NR ³ CO ₂ R ⁴ ι ⁼ O'-NO ₂ - O Ii 3 -OCR -SR ³ - -SR> wherein in the abovementioned substituents the groups R and R are independently selected from hydrogen; Alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; Cycloalkyl, cycloalkylalkyl and alkylcycloalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl moieties; phenyl; Aralkyl, aralkenyl and aralkinyl, wherein the aryl moiety is a phenyl moiety and the aliphatic moiety has from 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclyl alkyl, wherein the heteroatom or heteroatoms in the above-mentioned heterocyclic units are selected from 1 to 4 nitrogen, oxygen and sulfur atoms and the alkyl moieties attached to said heterocyclic moieties have 1 to 6 carbon atoms, or • ζ. λ
R and R together with the nitrogen atom, on at least one of these groups is attached to form a 5- or 6-membered nitrogen-containing heterocyclic ring; Q -7. R has the meanings given for R ^ but can not be a hydrogen atom; or in which R and R together represent a hydroxy-substituted Cp * Q-alkylidene radical; r5 is selected from the following substituted and unsubstituted radicals: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; Cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl ring. and 1 to 6 carbon atoms in the alkyl moieties; phenyl; Aralkyl, aralkenyl and Ar alkynyl, wherein the aryl moiety is a phenyl radical and the aliphatic part has · 1 to 6 carbon atoms; Heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl, wherein the heteroatom or heteroatoms in the above-mentioned heterocyclic units from 1 to 4 oxygen, nitrogen and. Sulfur atoms are selected and the alkyl moieties attached to said heterocyclic moieties have from 1 to 6 carbon atoms; wherein the radicals listed for R are optionally substituted by 1 to 3 substituent independently selected from: C 1-6 alkyl optionally substituted by amino, fluoro, chloro, carboxy, hydroxy or carbamoyl; Fluorine, chlorine or bromine; -CN 7
-NR ~ CONR "R '7 · -.'' or phenyl, if desired substituted by 1 to fluorine, chlorine, bromine, C 1 -4 -alkyl, -OR ³ , -NR ³ R ⁴ , -SO ₃ R ³ , or rCONR R, where R, R and R in these R- Radicals have the meanings given above; or in which R ^ also to another atom of the ring may be bonded to form a fused, heterocyclic or heteroaromatic ring, which ring may contain additional heteroatoms selected from O, S and N; R 1 is selected from hydrogen and the following substituted and unsubstituted groups: alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; Cycloalkyl, cycloalkylalkyl and alkylcycloalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl moieties; Spiro eye Ioalkyl having "up to 6 carbon atoms, phenyl, aralkyl, aralkenyl and Aralkinyl, wherein the aryl moiety is a phenyl group, the aliphatic part has 1 to 6 carbon atoms; Heteroaryl, heteroaralkyl, heterocyclyl and heterocycloalkyl wherein the heteroatom or heteroatoms in the above-mentioned heterocyclic moieties are selected from 1 to 4 oxygen, nitrogen and sulfur atoms and the alkyl moieties attached to said heterocyclic moieties have 1 to 6 carbon atoms; wherein the substituent or substituents of the abovementioned radicals are selected from: amino, mono-, di- and trialkylamino, hydroxy, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chlorine, bromine, fluorine, cyano and carboxy ; and wherein the alkyl moieties of the substituents listed above have 1 to 6 carbon atoms; A is a straight or branched C, / alkylene chain means; R represents a hydrogen atom, an anionic charge or a common, easily removable carboxyl-protecting group, provided that also a counterion 2
is present when R represents a hydrogen atom or a protective group; and the rest of the formula a substituted or unsubstituted, mono-, bi- or polycyclic, aromatic, heterocyclic radical which contains at least one nitrogen atom in the ring, which ring is bonded to A via a Rirvgl: ohlenstoffatom and has a ring nitrogen atom which is represented by a group R is quaternized; or a pharmaceutically acceptable salt thereof, characterized in that an intermediate of the formula 2 ' IV 10 wherein R ¹ , R and sit, the meanings given above R ² 'represents a common, easily removable carboxyl-protecting group and L is a common leaving group,
with a thiol compound of the formula HS-A- VII. where A and the rest N-R the above Have meanings and X ~ means a counter anion, in an inert solvent and in the presence of a base to a carbapenem compound of formula I ¹ S-A COOR " 103
wherein R ¹ , R ⁸ , R ¹⁵ , R ² ', A, Cn ⁹ - R ⁵ and X " have the meanings given above, or a pharmaceutically acceptable salt thereof, if desired, removing the carboxyl-protecting group R to obtain the corresponding deblocked compound of formula I. 2. The method according to item 1, characterized in that sodium hydroxide is used as the base. 3. The method according to item 1, characterized in that one carries out the reaction at a temperature of about -15 ° to +15 ⁰ C. 4. The method according to item 1, 2 or 3, characterized in that the leaving group L is a chlorine, bromine, iodine, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, diphenoxyphosphinyloxy or di- (trichloroethoxy) -phosphinyloxy group. 5. The method according to item 1, 2 or 3, characterized in that the leaving group L used is a diphenoxyphosphinyloxy group. 6. The method of item 1 for the preparation of a compound of formula WORM 104 R is a hydrogen atom, an anionic charge or a common, easily removable carboxyl-protective With the proviso that, when R represents a hydrogen atom or a protecting group, there is also a counterion, or a pharmaceutically acceptable salt thereof, characterized in that an intermediate compound of the formula OH COOR wherein L represents a common leaving group and R represents a common, easily removable carboxyl-protecting group, with a ThiO! compound of the formula CH. HS-CH wherein X ~ is a counter anion, in an inert solvent and in the presence of a base to a carbapenem compound of the formula CH. wherein R and X ~ have the meanings given above, or a pharmaceutically acceptable salt thereof, and Optionally, the protecting group R is removed to obtain the corresponding deblocked compound of formula I. 5 7. The method according to punctuation of a compound of formula OH H ^CH 3 SCH "COOR ' for the manufacture wherein FU is a hydrogen atom, an anionic charge or a common, easily removable carboxyl protective 2 group, with the proviso that if R is a hydrogen atom or a protective group, a counterion is also present, or a pharmaceutically acceptable salt thereof, characterized in that an intermediate of the formula CH. H N: ooR ² ' wherein L represents a common leaving group and R represents a common, easily removable carboxyl-protecting group, with a ThiO! compound of the formula HS-CH wherein X "represents a counter anion, in an inert solvent and in the presence of a Base to a carbapenem compound of the formula H. in which R and X have the meanings given above sit, or a pharmaceutically acceptable salt " of which reacts and, if desired, the protecting group R removed to obtain the corresponding deblocked compound of formula I.