AT387574B - METHOD FOR PRODUCING NEW CARBAPENEM DERIVATIVES - Google Patents

Abstract

Process for the preparation of novel carbapenem derivatives of the formula I in which R<1> is a hydroxyethyl group, R<15> is hydrogen or methyl, A is a C1-C2-alkylene group, R<5> is a C1-C3-alkyl or -alkylene group or a carboxylatomethyl group and the radical IV is an optionally substituted pyridinium, imidazolinium, thiazolium, triazolium, tetrazolium or thiadiazolium radical, by reacting the compound II with a thiol of the formula III. <IMAGE>

Description

  

    <Desc / Clms Page number 1>
 



   The invention relates to a process for the preparation of new carbapenem derivatives of the general formula
 EMI1.1
 in which R represents a 1-hydroxyethyl group, R 15 represents hydrogen or methyl, which can be in either the a- or S-position, A represents a -C-alkylene group, R represents a C1-C3-alkyl or -alkenyl group or a carboxylatomethyl group, the rest
 EMI1.2
 represents a pyridinium, imidazolium, thiazolium, triazolium, tetrazolium or thiadiazolium radical which is optionally substituted by one to three methyl or benzyl groups, this ring being bonded to A via a ring carbon and containing a ring nitrogen which is group R5 is quaternized, and R2 is hydrogen, an anionic charge or a conventional,

   represents easily removable carboxyl protective group, with the proviso that when R2 2 is hydrogen or a protective group there is also a counterion X-present or of pharmaceutically usable salts thereof.



   A number of ss-lactam derivatives which describe the carbapenem nucleus are described in the literature
 EMI1.3
 contain. It is reported that these carbapenem derivatives can be used as antibacterial agents and / or ss-lactamase inhibitors.



   The original carbapenem compounds were natural products such as thienamycin of the formula
 EMI1.4
 obtained by fermentation of Streptomyces cattleya (U.S. Patent No. 3,950,357). Thienamycin is an extremely effective broad-spectrum antibiotic, which is particularly effective against various Pseudomonas species, organisms which are known to be resistant to ss-lactam antibiotics.



   Other natural products containing the carbapenem core include olivic acid derivatives such as the antibiotic MM 13902 with the following formula

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 EMI2.1
 described in U.S. Patent No. 4, 113, 856, the antibiotic MM 17880 of the formula
 EMI2.2
 described in U.S. Patent No. 4, 162, 304, the MM 4550A antibiotic of the formula
 EMI2.3
 described in U.S. Patent Nos. 4, 172, 129 and the 890Ag antibiotic of the formula
 EMI2.4
 described in US Pat. No. 4,264,735. In addition to the natural products, the compound desacetyl 890A 10 of the formula
 EMI2.5
 in US Patent No. 4,264,734 and the preparation by enzymatic deacylation of the corresponding N-acetyl compound.

   Likewise, various derivatives of the naturally occurring olivic acids have been synthesized, e.g. B. Compounds of formula

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 EMI3.1
 wherein CO 2 Rl represents a free, salted or esterified carboxyl group, n is 0 or 1 and R represents an H atom, an acyl group or a group of the formula RgOS, where R3 represents a salt-forming ion or a methyl or ethyl group, such as described in EP-A 8885.



   US Pat. No. 4,235,922 (see also EP-A 2058) describes the carbapenem derivative of the formula
 EMI3.2
 while GB-PS No. 1, 598, 062 the isolation of the connection
 EMI3.3
 from a Streptomyces fermentation mixture.



   Carbapenem compounds that are unsubstituted at the 6-position have also been synthesized. For example, U.S. Patent No. 4,210,661 describes compounds of the formula
 EMI3.4
 wherein R2 represents a phenyl or substituted phenyl group, and U.S. Patent No. 4,267, 177 describes compounds of the formula
 EMI3.5
 wherein R. represents a substituted or unsubstituted pyridyl group, and U.S. Patent No. 4,255,441 describes compounds of the formula
 EMI3.6
 

  <Desc / Clms Page number 4>

 wherein R2 and R3 are an H atom or an alkyl group and R4 represents the group NH-CO, in which R6 represents an alkyl, phenyl or substituted phenyl group and n is 1 or 2; and U.S. Patent No. 4,282,236 describes compounds of the formula
 EMI4.1
 
 EMI4.2
 
2 means, in which R represents an H atom, an alkyl, aryl or aralkyl group.



   Carbapenem compounds of the general formula
 EMI4.3
 are described in US Pat. Nos. 4,218,463, wherein R 1 is an H atom or an acyl group and R8 is an H atom or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, Alkylcycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl mean. There are no descriptions of any heteroaralkyl-R substituents of the type
 EMI4.4
 where A is an alkylene group and
 EMI4.5
 is a quaternized nitrogen-containing aromatic heterocycle attached to the alkylene group with a ring carbon atom.



   The natural product thienamycin has the absolute configuration 5R, 6S, 8R. This isomer, like the other seven thienamycin isomers, can be obtained according to US Pat. No. 4,234,596 by total
 EMI4.6
 is crucial intermediate compounds of the syntheses described
 EMI4.7
 where pNB means p-nitrobenzyl.



   Because of the exceptional biological effectiveness of thienamycin, a large number of derivatives have been produced and described in the literature. So among other things

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   (1) N-Formimidoyl-thienamycin of the formula
 EMI5.1
 described in EP-A 6639j (2) N-heterocycle derivatives of thienamycin of the formula
 EMI5.2
 and
 EMI5.3
 the bifunctional ring can additionally be unsaturated in the ring; and
 EMI5.4
 represents an alkyl or an aryl group; and Z is an imino, oxo function
H atom represents an amino or alkyl group described in U.S. Patent Nos. 4, 189, 493;

   (3) substituted N-methylene derivatives of thienamycin of the formula
 EMI5.5
 where X and Y represent an H atom, R, OR, SR or NRl R 2, where R is a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, Heteroaralkyl, heterocyclyl or heterocyclylalkyl group
 EMI5.6
 
No. 4, 194, 047; (4) Compounds of the formula

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 EMI6.1
 
 EMI6.2
 independently of one another mean either an H atom or an acyl group (including acyl groups of the type
 EMI6.3
 where R can be an alkyl group substituted by a quaternary ammonium group, e.g.

   B.
 EMI6.4
 described in U.S. Patent Nos. 4,226,870; (5) Compounds of the formula
 EMI6.5
 where R3 is an H atom, an acyl group or a monovalent substituted or unsubstituted hydrocarbon group, Rl is a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, Heteroaryl or heteroaralkyl group, and R2 is an acyl group (including acyl groups of the type
 EMI6.6
 
 EMI6.7
 
 EMI6.8
 
 EMI6.9
 

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 EMI7.1
 
 EMI7.2
 or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
Mean cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl group, described in US Pat. No. 4,235,920;

   (7) Compounds of the formula
 EMI7.3
 
 EMI7.4
 and together with the nitrogen atom to which they are attached, a substituted or unsubstituted monocyclic or bicyclic heteroaryl or heterocyclyl group having 4 to 10 ring atoms, one or more of which can be an additional heteroatom from the group consisting of oxygen, sulfur and nitrogen; form ; R means
 EMI7.5
 
Q-Cycloalke's heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl group having 4 to 10 ring atoms, one or more of which is a heteratom from the group consisting of oxygen, sulfur and nitrogen, and in which the alkyl radical is the heteroalkyl or heterocyclylalkyl group 1 to Contains 6 carbon atoms; the substituent (s) on R, R, R or on the ring by connecting R and R are chlorine; Bromine; Iodine; Fluorine; Azido;

   C1-4 alkyl; Mercapto; Sulfo; Phosphono; Cyanothio (-SCN);
 EMI7.6
 contains atoms; a monocyclic or bicyclic heteroaralkyl or heterocyclylalkyl group with 4 to 10 ring atoms, 1 to 3 carbon atoms in the alkyl radical and 1 to 4 heteroatoms from the group consisting of oxygen, sulfur and / or nitrogen; a

  <Desc / Clms Page number 8>

 nucleus-substituted aralkyl or heteroaralkyl group in which the substituent is chlorine, fluorine, bromine, iodine or C 1-4 alkyl; an aryl or nucleus-substituted aryl group having 6 to 10 ring carbon atoms in which a nucleus substituent is hydroxy, C 1-6 alkyl, chlorine, fluorine or bromine; an aralkoxyalkyl group;

   C 2-12 alkylthioalkyl;
 EMI8.1
 or unsubstituted C 1 - "- alkyl group; a C -alkenyl or alkynyl group; a ring-substituted or unsubstituted cycloalkyl, cycloalkenyl, cycloalkenylalkyl or cycloalkylalkyl group with 3 to 6 ring carbon atoms and up to 6 carbon atoms in the chains; a C 6 10 Aryl group; an aralkyl group with 6 to 10 ring carbon atoms and 1 to 6 carbon atoms in the alkyl chain; a monocyclic or bicyclic heteroaryl or heteroaralkyl group with 4 to 10 ring atoms, one or more of which are oxygen, nitrogen or sulfur, and with 1 to 6 Carbon atoms in the alkyl chain;

   and the ring or chain substituents are chlorine, bromine, iodine, fluorine, azido, cyano, amino, Ce alkylamino;
 EMI8.2
 
 EMI8.3
 -alkyl) -amino- OM, OQ, or, if the compound is in the zwitterion form, -0-, in which case A- is not present; A, if the compound is not in the zwitterion form, is a counter ion;

   M is a pharmaceutically usable cation; and Q is a blocking group as defined herein as described in GB-PS Ni.1,604,275; (8) Compounds of the formula
 EMI8.4
 the group associated with the amino nitrogen group of thienamycin
 EMI8.5
 is a mono- or polycyclic nitrogen-containing heterocyclic group and R is an H atom, a substituted or unsubstituted alkyl, aryl, alkenyl, heterocycliclalkenyl, aralkenyl, heterocyclylalkyl, aralkyl, -NR2-, -COOR- , CONR2 - or CN group, as described in EP-A 21082. Among the compounds described in US Pat. No. 4,235,920 is

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 EMI9.1
 where A is a pharmaceutically acceptable anion.

   The above-mentioned quaternary amine derivative is also described in Recent Advances in the Chemistry of SS-Lactam Antibiotics, Royal Society of Chemistry, London, 1981, pages 240-254, the antibacterial activity being 1/2 to 2/3 on average that of thienamycin is given.



  Carbapenem derivatives with various substituents in the 6-position,
 EMI9.2
 
 EMI9.3
 wherein R 1 is an H atom, a methyl or hydroxyl group and R51 is a monovalent organic group such as a heterocyclylalkyl group; (2) EP-A 8514 describes compounds of the formula
 EMI9.4
 where R. is a substituted or unsubstituted pyrimidinyl group and R2 is
Is H atom or a group CR, R, Rg, where R3 is an H atom or a hydroxyl group, R4 is an H atom or an alkyl group and R5 is an H atom, an alkyl, benzyl or phenyl group, or R5 and R4 together form a carbocyclic ring;

   (3) EP-A 38869 describes compounds of the formula
 EMI9.5
 
 EMI9.6
 tuiert or unsubstituted: alkyl, alkenyl and alkynyl groups with 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 half; Aryl groups such as phenyl;

   Aralkyl, aralkenyl and aralkynyl, the aryl half being phenyl and

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 EMI10.1
 
 EMI10.2
 

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 EMI11.1
 
 EMI11.2
 
 EMI11.3
 
 EMI11.4
 

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 EMI12.1
 where R is an H atom or an organic group bonded to the carbapenem ring via a carbon atom, n is 0 or 1, X is a saturated or unsaturated hydrocarbon
 EMI12.2
 a positively charged nitrogen atom that is not bound to a hydrogen atom.



   The above-mentioned EP-A 38869 describes the synthesis of carbapenem derivatives via intermediates
 EMI12.3
 
 EMI12.4
 
 EMI12.5
 
 EMI12.6
 , where X is referred to as a leaving group.



   At the Gordon Research Conference on Medicinal Chemistry in New London, New Hampshire, 2-6. August 1982, a publication was distributed describing a number of carbapenem antibiotics. Among the compounds described on page 9 of this document is the carbapenem of the formula
 EMI12.7
 which differs from the compounds prepared according to the invention in that the quaternized heteroaromatic ring in the 2-substituent is bonded directly to the sulfur atom instead of to the carbon atom of an alkylene group.



   EP-A 50334 describes carbapenem derivatives of the general formula

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 EMI13.1
 
 EMI13.2
 Hydrogen, alkyl, alkenyl, aryl and aralkyl; A is a direct single bond that connects the S and C atoms listed, or A is a cyclic or acyclic linking group selected, among others, from the group alkyl, cycloalkyl, aryl, heteroaryl or heteroalkyl;
 EMI13.3
 selected from each other from the group hydrogen, alkyl or aryl; in addition, the carbamimidoyl mentioned is characterized by cyclic structures which are formed by the connection of the two nitrogen atoms via their substituents and their connection to the connecting group A; In addition, carbamimidium compounds are described by quaternizing one of the nitrogen atoms of the carbamimidoyl mentioned.

   On page 12 of this EP-A the group is a possible 2-substituent
 EMI13.4
 , where R is defined as hydrogen, one of the following substituted or unsubstituted groups: alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl and where the two nitrogen atoms are involved in cyclic structures, which are indicated by the dashed line are. No cyclized carbamimidoyl groups with a quaternized nitrogen atom are specifically described, but on page 22 a cyclized carbamimidoyl group of the formula
 EMI13.5
 described.



   On the basis of the stated definitions of the substituent R1, it can be assumed that EP-A 50334 does not describe a compound whose preparation falls within the scope of the invention. However, since the linguistic description in this EP-A is so vague as to the intended cyclic structures, reference has been made to it.



   While, as stated above, carbapenem derivatives have been described according to the prior art which have a 2-substituent of the general formula
S-A-Het, where A is an alkylene group and Het is a heterocyclic or heteroaromatic group, there is no description known to the patent applicants of carbapenem compounds in which Het is a radical of the formula:

  <Desc / Clms Page number 14>

 
 EMI14.1
 wherein R is a substituted or unsubstituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclic or heterocyclylaliphatic group and
 EMI14.2
 means its quaternary nitrogen-containing aromatic heterocycle which is bonded to the alkylene carbon via a ring carbon atom.

   As mentioned above, the carbapenem was with
 EMI14.3
 as the 2-substituent, as well as the carbapenem with a quaternary heteroaromatic ring bonded directly to the sulfur - 2-substituent.



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



   According to the invention, new carbapenem derivatives of the general formula (I) should therefore be prepared in which the 2-substituent has the formula
 EMI14.4
 in which A, and the grouping
 EMI14.5
 have the meaning given above.



   The process according to the invention is characterized in that a compound of the formula
 EMI14.6
 

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 EMI15.1
 represents protecting group, with a thiol compound of the formula
 EMI15.2
 where A and
 EMI 15.3
 and R5 are as defined above and X "is a counter anion, is reacted in an inert solvent and in the presence of a base, in particular sodium hydroxide solution, whereupon the counter ion J: 3 is optionally replaced by another counter ion, an alkenyl group present as R5, if appropriate hydrogenated to the corresponding alkyl group and, if necessary, the carboxyl protecting group was split off in order to obtain the desired unblocked compound of the formula (I) or a pharmaceutically acceptable salt thereof.



   The compounds of formula (I) are effective antibacterial agents or intermediates which can be used to prepare such agents.



   The compounds of general formula (I) prepared according to the invention contain the carbapenem core
 EMI 15.4
 and can thus be named as 1-carba-2-penem-3-carboxylic acid derivatives. On the other hand, the structure of the connections
 EMI15.5
 
 EMI15.6
 derivatives are named. While the invention encompasses the compounds in which the relative stereochemistry of the 5,6 protons can be cis or trans, the preferred compounds have the 5R, 6S (trans) configuration as in the case of the thienamycin.



   The term "easily removable carboxyl protecting group" means a known ester group which has been used to block a carboxyl group during the chemical reaction steps described below and which, if desired, can be removed by methods which do not cause substantial destruction of the molecular residue, e.g. B. by chemical or enzymatic hydrolysis, treatment with chemical reducing agents under mild conditions, irradiation with UV light or catalytic hydrogenation.

   Examples of such protective ester groups include benzhydryl, allyl, p-nitrobenzyl, 2-naphthylmethyl, benzyl, trichloroethyl, silyl such as trimethylsilyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl, 4-pyri-

  <Desc / Clms Page number 16>

 dylmethyl, and C g-alkyl such as methyl, ethyl or tert. Butyl. Included among these protecting groups are those that 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 hydrogenolysis.



   The pharmaceutically acceptable salts mentioned above include the addition salts with non-toxic acids, e.g. B. salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, etc., and salts with organic acids such as maleic acid, acetic acid, citric acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid and malic acid. Connections of the For-
 EMI16.1
 
 EMI16.2
 
 EMI 16.3
 receives pharmaceutically usable salts for therapeutic use, but in the case of intermediates of the formula (I) X "can also be a toxic anion.

   In this case, the anion can be subsequently removed or replaced by a pharmaceutically usable anion, so that an effective end product is obtained which can be used therapeutically. If in groups R or R5 or in the group
 EMI 16.4
 acidic or basic groups are present, the invention is also intended to include suitable basic or acidic salts of these functional groups, e.g. B. Acid addition salts in the case of a basic group and metal salts (eg sodium, potassium, calcium and aluminum), the ammonium salt
 EMI 16.5
 



   Compounds of formula (I) in which R represents hydrogen, an anionic charge or a physiologically hydrolyzable ester group, as well as pharmaceutically usable salts thereof, can be used as antibacterial agents. The remaining compounds of formula (I) are valuable intermediates which can be converted into the biologically active compounds mentioned above.



   The starting compounds of the formula (II) for the process according to the invention are obtained from the compounds of the formula
 EMI 16.6
   1 15 2 'where R, R and R are as defined above, by reaction with diphenyl chlorophosphate. For this purpose, the ketoester (IV) is in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with an approximately equimolar amount of diphenyl chlorophosphate in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethyl

  <Desc / Clms Page number 17>

 aminopyridine, or the like, at a temperature of about -20 to +40 C, preferably at about OOC.

   If desired, the intermediate (II) can be isolated, but it is advantageously used as the starting substance for the process according to the invention without isolation or purification.



   The carbapenem product (II) is quaternary amine thiol of the formula
 EMI17.1
 reacted, whereby
 EMI17.2
 is as defined above and X "is a counter anion. The reaction is carried out in an inert solvent such as acetonitrile, acetonitrile-dimethylformamide, tetrahydrofuran, tetrahydrofuran-HO, acetonitrile-HO or acetone in the presence of a base. The type of base is not of critical importance. Suitable bases include sodium hydroxide, diisopropylethylamine, 1, 8-diaza-bicyclo (5, 4, 0) undec-7-ene, 1, 5-diaza-bicyclo (4, 3, 0) non -5-ene and tril 4) -alkylamines such as triethylamine, tributylamine or tripropylamine The reaction of the product (II) with the thiol (V) can be carried out over a wide range of temperatures, e.g.

   B. from -15 C to room temperature, but is preferably carried out at a temperature in the range of about -15 to +15 C, especially at about OOC.



   The carbapenem product obtained by reacting the quaternary aminthiol (V) with the compound (II) contains a counter anion [e.g. (CgHgOLPO ", Cl, or the anion associated with the quaternary thiol], which can be replaced in this step by another counter anion, for example by one that is more pharmaceutically usable. This substitution is carried out by conventional methods. On the other hand, the counter anion can also be removed during the deblocking step, and if the quaternized carbapenem compound and the counter anion form an insoluble compound, the product can crystallize out during its formation and be obtained pure by filtration.



   After the formation of the desired carbapenem product, the carboxyl protecting group can
R21 of compound (I) can optionally be removed by conventional methods such as solvolysis, chemical reduction or hydrogenation. If a protecting group is used which can be removed by catalytic hydrogenation, such as p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl, the intermediate can
 EMI17.3
 in a suitable solvent, such as dioxane-water-ethanol, tetrahydrofuran-diethyl ether buffer, tetrahydrofuran-aqueous dipotassium hydrogenphosphate-isopropanol or the like, under a hydrogen pressure of 1 to 4 bar in the presence of a hydrogenation catalyst, such as palladium on charcoal, palladium hydroxide, platinum oxide or similar, at a temperature of 0 to 50 ° C for about 0.24 to 4 hours.

   If R21 is a group such as o-nitrobenzyl, photolysis can also be used to unblock. Protecting groups such as 2, 2, 2- - trichloroethyl can be removed by gentle zinc reduction. The allyl protection group

  <Desc / Clms Page number 18>

 can be removed with a catalyst consisting of a mixture of a palladium compound with triphenylphosphine in a suitable aprotic solvent such as tetrahydrofuran, diethyl ether or methylene chloride. In the same way, other conventional carboxyl
 EMI18.1
 hydrolyzable esters, such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc., can be used directly without deblocking, since such esters are hydrolyzed in vivo under physiological conditions.



   The thiol compounds of formula (V) z. B. from the corresponding thiol acetate compounds of the formula
 EMI18.2
 are produced, where A and
 EMI18.3
 are as defined above. The thiol acetate compound is quaternized by reacting it in an inert organic solvent such as diethyl ether, dichloromethane, methylene chloride, dioxane, benzene, xylene, toluene or mixtures thereof with a suitable alkylating agent of the formula R5 -X ', as defined above and X 'represents a conventional leaving group such as halo (chlorine, bromine or iodine, preferably iodine) or a sulfonate ester half such as mesylate, tosylate or triflate.

   The temperature for the alkylation reaction is not critical and temperatures in the range of about 0 to 40 ° C are preferred.



  Before the reaction with the carbapenem intermediate (II), the quaternized thiol acetate compound is subjected to acidic or basic hydrolysis to obtain the quaternary thiol intermediate (III). This hydrolysis is preferably carried out immediately before the coupling with (II) in order to keep the decomposition of the relatively unstable quaternary thiol (III) as low as possible.



   The reaction can proceed from product (IV) to
 EMI18.4
 explained in more detail.



   As in the case of other ss-lactam antibiotics, compounds of the general formula (I) can be converted by means of known processes into pharmaceutically usable salts which, for the invention, are to be kept basically equivalent to the compounds not in salt form. For example, a compound of formula (I) in which an anionic charge is present can be dissolved in a suitable inert solvent and then an equivalent of a pharmaceutically acceptable acid can be added. The desired acid addition salt can be isolated by conventional methods, e.g. B. by solvent precipitation, lyophilization, etc.

   If other basic or acidic functional groups are present in the compound of formula (I), pharmaceutically usable base and acid addition salts can be prepared by known methods.



   It goes without saying that certain substances in the context of the formula (I) can be formed both as optical isomers and as epimeric mixtures thereof. The invention is intended to encompass all such optical isomers and epimeric mixtures. If e.g. B. the 6-Substi-

  <Desc / Clms Page number 19>

 tuent hydroxyethyl, it can be in either the R or S configuration, and the corresponding isomers as well as an epimeric mixture thereof are included in the invention.



   Likewise, the methyl group can be in the 4-position in the a- or 6-position, which two compounds are equally important.



    A compound of formula (I) in which R2 represents hydrogen or an anionic charge, or a pharmaceutically acceptable salt thereof, can also be used by conventional means
 EMI19.1
 bare ester group, or in a pharmaceutically acceptable salt thereof.



   The novel carbapenem derivatives of the general formula (I), in which R2 denotes hydrogen, an anionic charge or a physiologically hydrolyzable carboxyl protecting group, or their pharmaceutically usable salts, are strong antibiotics which are active against various gram-positive and gram-negative bacteria, and they can e.g. B. as animal feed additives to improve growth, as preservatives in food, as bactericides in industrial applications, for. B. for water-based paints and in the white water of paper mills to prevent the growth of harmful bacteria, and as a disinfectant to destroy or prevent the growth of harmful bacteria on medical or dental equipment.

   However, they are particularly suitable for the treatment of infectious diseases in humans and animals which are caused by gram-positive or gram-negative bacteria.



   The pharmaceutically active compounds prepared according to the invention can be used alone or in pharmaceutical preparations which, in addition to the carbapenem, contain a pharmaceutically acceptable carrier or diluent. The compounds can be administered in a wide variety of ways; Of particular interest are: Orally, topically or parenterally (e.g. intravenous or intramuscular injection). The pharmaceutical preparations can be in solid form, such as capsules, tablets, powders, etc., or in liquid form, such as solutions, suspensions or emulsions.

   Preparations for injections, the preferred mode of administration, can be prepared in the form of single doses in ampoules or in multi-dose containers and can contain adjuvants such as suspending, stabilizing and dispersing agents. The formulations may be in a ready-to-use form or in powder form for fresh preparation prior to administration with a suitable solvent, such as sterile water.



   The dose to be administered depends largely on the particular compound used, the particular preparation, the route of administration, the type and condition of the recipient and the specific location and the organism being treated. The choice of the special preferred dosage and type of application is left to the treating doctor.



  In general, however, the compounds can be used parenterally or orally in mammals in amounts of about 5 to 200 mg / kg / day. Usually it is used in divided doses, e.g. B. three or four times a day.



   The following examples serve to illustrate the invention without restricting it.



   example 1
Preparation of 3- [4- (N, N-dimethyl-l, 2,3-triazolium) methylthio] -6a - [l- (R) -hydroxyethyl] - - 7-oxo-l-aza-bicyclo (3rd , 2, 0) hept-2-en-2-carboxylate
 EMI19.2
 

  <Desc / Clms Page number 20>

 a) Preparation of the isomer A
 EMI20.1
 
 EMI20.2
 

  <Desc / Clms Page number 21>

 B) Preparation of Isomer B and Isomer C
 EMI21.1
 
Methyl trifluoromethanesulfonate (1, 60 ml, 14.0 mol) was added dropwise to an ice-cooled solution of 4- (methanethiol acetate) -2-methyl-1, 2, 3-triazole (1, 20 g, 7.02 mol) in dry methylene chloride (6 ml) added under nitrogen. The mixture was then allowed to warm to room temperature and stirring was continued for 16 h.

   Additional methyl trifluoromethanesulfonate (0.40 ml, 3.56 mol) was added and after 3 h at room temperature the solvent was suctioned off. The remaining oil was triturated with ether and the resulting gum was dissolved in water (5 ml). This solution was cooled in an ice bath and a solution of sodium hydroxide (844 mg, 21.1 mmol) in water (5 ml) was added. After stirring for 0.75 h, this solution was diluted with 60 ml of water and the pH was adjusted to 8 by adding solid potassium dihydrogen phosphate.



  Then 40 ml of this solution (about 4.7 moles of a mixture of the isomeric triazolium thiols) was added to an ice-cooled, stirred solution of the enol phosphate (2.00 g, 3.45 moles) in THF (60 ml). This mixture was stirred in an ice bath for 0.5 h, after which it was transferred to a pressure bottle which contained a suspension of palladium on activated carbon (10% strength; 2.00 g) and ether (60 ml). The mixture was hydrogenated at 27.6 N / cm 2 for 1 h. The organic phase was separated and washed with water (2 x 10 ml). The combined aqueous phases were filtered and the filtrate was concentrated under high vacuum (about 67 Pa, 1, 5 h).

   The remaining solution was then chromatographed (medium pressure reversed phase column, 45 x 130 mm, water as eluent) and, after lyophilization, gave 595 mg of a mixture of the isomeric carbapenem compounds which were contaminated with little inorganic material. It was separated and purified by high pressure liquid chromatography (10 x 300 mm Waters Microbondapak C 18 column, multiple injection, water as eluent) and gave in the order of elution: Isomer B 153 mg (13%);
HNMR (D20) ö: 1, 23 (3H, d, J = 6.4 Hz), 3, 12 (2H, q, J = 1, 4, 8, 9 Hz), 3.39 (1H, q, J = 2, 7, 6, 0 Hz), 4, 07-4, 68 (10H, m), 8, 19 (1H, s).



   IR (Nujol): 1755 cm.



   UV (phosphate buffer, PH = 7.4, M = 0.05) I.: 296 nm (e = 6700) j and isomer C; 284 mg (24%);
HNMR (D20) S: 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).

  <Desc / Clms Page number 22>

 
 EMI22.1
 
 EMI22.2
 
 EMI22.3
 
 EMI22.4
 
 EMI22.5
 the crystals were filtered off; 16.8 g, melting point 86 C, 69%.

   The filtrate was concentrated and purified by chromatography on a silica gel column with dichloromethane as the eluting solvent to give 3.17 g, 13%, melting point 86 C.
 EMI22.6
    -1.B) 1,2,3-thiadiazol-4-ylmethanol2
 EMI22.7
 
Lithium aluminum hydride (2.47 g, 0.065 mol) was added portionwise to a suspension of ethyl 1,2,3-thiadiazol-4-ylcarboxylate (18.35 g, 0.16 mol) in ether (400 ml) during a Period of 1 h added. The reaction mixture was stirred at 23 C for 7 h and with lithium 1 C. D. Hurd and R.I. Mori, J.Am.Chem.Soc., 77, 5359 (1955).



   2 S. I. Ramsby, S. O. Ogren, S. B. Ross and N. E. Stjernstrom, Acta Pharm. Succica., 10, 285-296 (1973) j C. A. 79, 137052W (1973).

  <Desc / Clms Page number 23>

 treated aluminum hydride (2, 47 g, 0, 065 ml). The mixture was then stirred for a further 24 h before water (7 ml), 15% sodium hydroxide solution (7 ml) and water (21 m) were added in succession.



  After stirring for 15 min, the ether solution was decanted and the gummy residue was extracted with ether (5 x 100 ml). The ether extracts were combined, dried (MgSO 4) and concentrated (5.4 g). The crude material was purified over a silica gel column (120 g, 4 x 16 cm) using ether as the eluent. 1.3 g (7%) of ethyl 1,2,3-thiadiazol-4-ylcarboxylate and 2.45 g (18%) of 1,2,3-thiadiazol-4-ylmethanol were obtained.
 EMI23.1
 \) diazols).



    C) l, 2,3-thiadiazol-4-ylmethanol methanesulfonate
 EMI23.2
 
A solution of 1,2,3-thiadiazol-4-ylmethanol (0.75 g, 6.5 mmol) in dichloromethane (20 ml) was cooled to 5 C under a nitrogen atmosphere and with triethylamine (1,018 ml, 7.3 mmol) and methanesulfonyl chloride (0.556 ml, 7.3 mmol) were treated. After 15 minutes the ice bath was removed and the reaction mixture was stirred for 2 hours. The solution was washed with 1N hydrochloric acid solution (2 x 2 ml) and water, dried (MgSO, and MgO) and concentrated.

   The residue was purified by chromatography (silica gel column 1, 5 x 21 cm) with ether as the eluting solvent and gave 0.90 g (71%) 1,2,3-thiadiazol-4-ylmethanol methanesulfonate;
 EMI23.3
 
1172 (SO,) cm Analysis: Calculated for CHOgS: C 24, 73, H 3, 11, N 14, 42, S 33, 02; found: C 24, 78, H 3, 09, N 14, 66, S 31, 94; and 0.13 g (19%) di (1,2,3-thiadiazol-4-ylmethyl) ether;
 EMI23.4
 
 EMI23.5
 
 EMI23.6
 in tetrahydrofuran (9 ml) was added an aqueous solution (2 ml) of sodium thiol acetate prepared from thiolacetic acid (0.38 ml, 5.3 mmol) and sodium bicarbonate (0.445 g, 5.3 mmol)].



  The resulting mixture was stirred at 23 C for 1 h and diluted with ether (75 ml). The organic solution was washed with water (3 x 3 ml), dried (MgSO.) And concentrated. The crude mixture was purified by chromatography (silica gel column: 1.4 × 19 cm) with 50% ether in hexane as the eluting solvent and gave 0.60 g (75%).
 EMI23.7
 

  <Desc / Clms Page number 24>

 
 EMI24.1
 
 EMI24.2
 
 EMI24.3
 Mixture of ether (4 ml) and dichloromethane (0.4 ml), some crystals of the title compound and trifluoromethanesulfonate (0.407 ml, 3.6 mmol) were added over a period of 5 minutes.
 EMI24.4
    ; 1, 059, 66 (H on thiadiazolium N-3).



  Analysis: Calculated for C7H9N2O4S3F3: C 20.27, H 2, 38, N 9, 45, S 32, 46; found: C 24, 61, H 2, 57, N 8, 47, S 28, 21.
 EMI24.5
 
 EMI24.6
 
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 mmol ) in 6N hydrochloric acid (10 ml) was heated for 1.75 h at 65 C under a nitrogen atmosphere. The solvent was evaporated under reduced pressure and a yellow syrup of 0.91 g remained.

   This compound was used for the next step without purification.

  <Desc / Clms Page number 25>

 
 EMI25.1
 
 EMI25.2
 
 EMI25.3
 

  <Desc / Clms Page number 26>

 
Example 3
Potassium 3- [5- (l-carboxylatomethyl-3-methyl-l, 2,3-triazolium) methanthio] -6 a- [l- (R) -hydroxyethyl] -7-oxo-1-aza bicyclo (3, 2, 0) hept-2-en-2-carboxylate
 EMI26.1
 
 EMI26.2
 was added in approximately 1 ml aliquots. The resulting granular suspension was filtered and the solid washed with additional THF (5 x 75 ml). The combined THF solutions were dried (MgSO4) and the solvent removed.

   The remaining yellow oil was flash chromatographed on a silica gel column (90 x 35 mm) [100 ml amounts of hexane, mixtures of ethyl acetate-hexane (1: 1 and 1: 3) and finally ethyl acetate-methanol

  <Desc / Clms Page number 27>

 
 EMI27.1
 stirred solution of the alcohol (4.67 ml, 41.3 mol) and triethylamine (7.47 ml, 53.7 mol) in methylene chloride (20 ml) was added. After 0.5 h the solvent was removed and the remaining solid was taken up in acetonitrile (30 ml). Potassium thiol acetate (7.06 g, 62.0 mol) was then added and the suspension allowed to stir at room temperature for 3 hours. A further amount of potassium thiol acetate (3.0 g, 26.3 mol) was added and the suspension was left to stir for a further 16 h.

   The dark colored suspension was then concentrated and water (10 ml) was added. The mixture was extracted with methylene chloride (5 x 40 ml). The combined extracts were dried (MgSO.) And the solvent removed. The remaining oil was flash chromatographed on a silica gel column [(90 x 36 mm); hexane served as eluant, followed by a mixture of hexane and ethyl acetate (1: 1)]. This yielded 4- (methanethiolacetate) -I-methyl-1, 2, 3-triazole (5, 95 g, 84%) as a pale pink solid.



   HNMR (CDClg) ô: 2.40 (3H, s), 4.10 (3H, s), 4.20 (2H, s), 7.53 (1H, s).



   IR (Nujol Mull): 1675 cm
A solution of the triazole (1.00 g, 5.85 mol) and of ethyl bromoacetate (1.48 ml, 13, 3 mmol) in dry acetonitrile (10 ml) was heated to 600C under nitrogen for 90 h. The solvent was separated and the remaining oil was triturated with ether (4 x 25 ml) to leave the 1-methyl-3- (ethylcarboxymethyl) -4-methanethiol acetate-1,2,3-triazolium bromide as a brownish gum, which was used directly has been.



   A cold solution of KOH (0.66 g, 12 mmol) in water (5 ml) was added to an ice-cooled, stirred solution of the triazolium bromide in water (20 ml). After 20 minutes it was diluted to 35 ml and a sufficient amount of solid potassium dihydrogen phosphate was added to bring the pH of this solution to 8.0. Then this solution was added to an ice-cooled, stirred solution of the enol phosphate in THF (35 ml). After 0.5 h, this mixture was transferred to a pressure bottle containing ether (35 ml) and 10% palladium-on-carbon (1.5 g). It was hydrogenated at 27.6 N / cm 2 for 55 minutes. The organic phase was then separated and washed with water (2 × 5 ml). The combined aqueous phases were filtered and the filtrate was concentrated under high vacuum.

   The remaining material was chromatographed on a reverse phase column (35 x 120 mm) with water as the eluent.



  Lyophilization of the carbapenem-containing fractions left 1.20 g of a green-colored solid. This was chromatographed again, u. on a Waters Prep. 500 HPLC (PrepPAK- 500 / C 18) column with 2% acetonitrile water as eluent. The fractions containing the carbapenem were pooled and lyophilized. This material was again chromatographed by high pressure liquid chromatography (10 x 300 mm Waters Microbondapak C-18 column) with water as the eluent and after lyophilization gave the pure title compound (190 mg, 17%) as a pale yellow solid.
 EMI27.2
 q, J = 2, 7, 6, 0 Hz), 4, 02-4, 30 (3H, m), 4, 29 (3H, s), 5, 23 (2H, s), 8, 52 (lH , s).



  IR (Nujol Mull): 1750 cm-1.



  UV (phosphate buffer, PH 7, 4) I: 296 nm (e = 7520).

  <Desc / Clms Page number 28>

 



   Example 4
Potassium-3- [4- (1-carboxylatomethyl-3-methyl-1,2,3-triazolium) methanthio] -6 (1- [1- (R) -hydroxyethyl] -7-oxo-1- aza-bicyclo (3, 2, 0) hept-2-en-2-carboxylate
 EMI28.1
 
A mixture of ethyl azido acetate (30.0 g, 0.23 mol) and propiolic acid (14.3 ml, 0.23 mol) in toluene (75 ml) was stirred at room temperature. The reaction remained slightly exothermic for 1.5 hours.

  <Desc / Clms Page number 29>

 
 EMI29.1
 
 EMI29.2
 



  The crude material obtained in this way (33.3 g, 72%) consisted of a single isomer [HNMR (DMSO-d6) S: 1.20 (3H, t, J = 7 Hz), 4.15 (2H, q, J = 7 Hz), 5, 42 (2H, s), 8, 67 (1H, 3)],
 EMI29.3
 
A solution of the carboxylic acid (5.00 g, 25.1 mol) and the triethylamine (3.68 ml, 26.4 mol) in dry methylene chloride (50 ml) became an ice-cooled, stirred solution of ethyl chloroformate (2.52 ml , 26.4 mol) in dry methylene chloride (50 ml). The purple colored solution was allowed to stir for 0.5 h, after which it was washed with water (10 ml), dried (MgSO4) and the solvent removed.

   The crude mixed anhydride was dissolved in THF (50 ml) and slowly added to an ice-cooled suspension of sodium borohydride (0.72 g, 18.9 mol) in THF (50 ml). After a stirring time of 0.5 h, further sodium borohydride (0.30 g, 7.9 mol) was added and the reaction was left in an ice bath for 1 h. Then water (5 ml) was added and after 10 min 3 ml of 10% aqueous HC1 was added.



  After gas evolution ceased, solid potassium carbonate (2 g) was added with stirring.



  The organic phase was then separated and the remaining white dough-like mass was extracted with further THF. The combined organic phases were dried (MgSO 4) and the solvent was removed. Flash chromatography on silica gel eluting with hexane, mixtures of ethyl acetate-hexane and finally ethyl acetate yielded 1- (ethylcarboxymethyl) -4- - hydroxymethyl-1,2,3-triazole (2.04 g, 44%) as a crystalline solid:
HNMR (CDClg): 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).



   Diisopropyl azodicarboxylate (4.11 ml, 20.8 mol) was added dropwise to an ice-cooled solution of triphenylphosphine (5.47 g, 20.8 mol) in dry THF (100 ml) under nitrogen. After 0.5 hours, an ice-cooled solution of the alcohol (1.93 g, 10.4 mol) and of thiolacetic acid (1.49 ml, 20.8 mol) in dry THF (50 ml) was added to this mixture under nitrogen. The mixture was left in an ice bath for 2 h and then at room temperature for a further 12 h; then the solvent was removed. The reaction mixture was flash chromatographed on silica gel (40 g; elution with 100 ml portions of hexane, 5%, 10%, 15% ... 50% ethyl acetate-hexane).

   The fractions containing the thiol acetate were combined and again on silica gel (60 g; elution with 200 ml portions of: hexane, 5%, 10%, 15%, 20% ethyl acetate-hexane and 22.5%, 25%, 27, 5% ... 35% ethyl acetate-hexane). This yielded 1.24 g (49%)
 EMI29.4
 q, J = 7 Hz), 5, 12 (2H, s), 7, 63 (1H, s);
IR (Nujol mull): 1735.1780 cm and a further 1.40 g of a material contaminated with triphenylphosphine oxide.



   Methyl trifluoromethanesulfonate (0.51 ml, 4.53 mol) was added dropwise to an ice-cooled, stirred solution of the triazole (1.00 g, 4.12 mol) in dry methylene chloride (5 ml).



  After 0.5 h the bath was removed and after a further half an hour the solvent was suctioned off in vacuo. What remained was a white solid which was suspended in water (5 ml) and this stirred mixture was cooled in an ice bath. A solution of KOH in water (0.69 g, 12.4 mol; 5 ml) was added and the reaction was left under stirring for 1 h. It was then diluted to 30 ml with water and solid potassium dihydrogen phosphate was added to bring the pH to 8.0. A portion of this solution (22 ml, about 3.0 moles of the thiol carboxylate) was added to an ice-cooled, stirred solution of the enol phosphate (1.60 g, 2.76 moles) in THF (30 ml). After 0.5 h, the reaction mixture was removed in a high vacuum to remove the THF.

   The yellow solution was then chromatographed on a reverse phase column (35 x 120 mm) with elution with water (300 ml) and subsequent 100 ml quantities of 5%, 10%, 15% ... 30% acetonitrile water. Lyophilization of the desired fractions yielded the p-nitro

  <Desc / Clms Page number 30>

 benzyl ester as a yellow solid (930 mg). This was placed in a pressure bottle, the ether (25 ml), THF (25 ml) and phosphate buffer [25 ml, prepared by dissolving potassium dihydrogen phosphate (1.36 g, 0.01 mol) in water (100 ml) and adjusting the PH value at 7.4 by adding 45% aqueous KOH] and 10% palladium on activated carbon (900 mg). The hydrogenation was carried out at 27.6 N / cm 2 for 1 h, after which the organic phase was separated off and washed with water (2 × 5 ml).

   The combined aqueous phases were filtered and concentrated under high vacuum. The remaining solution was chromatographed on a reverse phase column (35 x 120 mm) and eluted with water. The fractions containing the carbapenem were combined and lyophilized to give 1.21 g of a pale green solid. This was then purified by high pressure liquid chromatography (10 x 300 mm Water Microbondapak C-18 column, water as eluent) and gave the pure title product; 480 mg (41%):
HNMR (D2O) 5: 1, 23 (3H, d, J = 6.4 Hz), 3, 11 (2H, d, J = 9 Hz), 3.37 (lH, q, J = 3, 0, 6, 1 Hz), 4, 02 (7H, m), 5, 18 (2H, s), 8, 53 (1H, s).



   IR (Nujol mull): 1750 cm
UV (phosphate buffer, PH 7, 4) I.: 205 nm 7810).



   Example 5
 EMI30.1
 
 EMI30.2
 
 EMI30.3
 
 EMI30.4
 
 EMI30.5
 Lich thiolacetic acid (0.53 ml, 7.5 mmol) added and stirring continued for 45 min. The reaction mixture was then diluted with methylene chloride and washed with water. The aqueous phase was extracted with methylene chloride (3 × 5 ml) and the combined organic phases
 EMI30.6
 as a yellow oil [in addition, an impure fraction (200 mg) was chromatographed again (preparative DSC, silica gel) to give a further 100 mg of pure material (overall yield 85%)]: 'HNMR (CDCl) ô:

   2, 38 (3H, s), 3, 90 (3H, s), 4, 25 (3H, s), 7, 80 (1H, s).

  <Desc / Clms Page number 31>

   B) 3- [5- (1,4-Dimethyl-1,2,4-triazolium) methanthio] -6a- (1- (R) -hydroxyethyl] -7-oxo-1-aza-bicyclo ( 3, 2, 0) hept-2-en-2-carboxylate
 EMI31.1
 
Methyl trifluoromethanesulfonate (1, 20 ml, 10.7 mol) was added dropwise to an ice-cooled solution of 1-methyl-5-methanethiol acetate-1, 2, 4-triazole (730 mg, 4.27 mol) in methylene chloride (7 ml) . The reaction mixture was allowed to warm slowly and remained at room temperature for 3 hours, after which it was concentrated.

   The remaining oil was triturated with ether to give crude 1,4-dimethyl-5-methanethiol acetate-1,2,4-triazolium trifluoromethanesulfonate (1,46 g) which was used directly.



   A solution of sodium hydroxide (512 mg, 12.8 mol) in water (5 ml) was added to an ice-cooled solution of the triazolium salt (1.45 g, 4.35 mol) in water (5 ml). After 45 minutes the mass was diluted to 25 ml with water and the pH was adjusted to 7.6 with solid potassium hydrogen phosphate. This solution was then added to an ice-cooled stirred solution of the enol phosphate (2.00 g, 3.45 mol) in THF (25 ml). After 30 minutes, the reaction mixture was placed in a pressure bottle containing ether (40 ml) and 10% palladium on activated carbon (2.0 g). The mass was hydrogenated for 1.25 h (30.9 N / cm 2). Then the reaction mixture was diluted with ether (25 ml) and filtered off.

   The organic phase was separated and washed with water (2 x 5 ml). The combined aqueous phases were washed with ether (3 x 25 ml) and then concentrated under vacuum. Column chromatography (reverse phase, 45 x 130 mm, water as eluent) and subsequent lyophilization of the fractions containing carbapenem yielded 650 mg of the crude material. This was chromatographed again to provide the pure title product (450 mg, 39%).



   1HNMR (D ô: 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 to 4, 36 (2H, m), 4, 54 (2H, d, J = 2.8 Hz), 8.81 (1H, s).



   IR (Nujol mull): 1755 cm
UV (phosphate buffer, PH 7, 4) I: 294 nm (e = 8202).



   T1 / 2 (phosphate buffer, PH 7.4, M = 0.067, T = 37 C): 9.1 h.

  <Desc / Clms Page number 32>

 
 EMI32.1
   [(l, 3-Dimethyl-5-tetrazolium) methylthio] -6- (l-hydroxyethyl) -7-oxo-l-aza - bicyclo (3, 2, 0) hept-2-ene-2-carboxylate
 EMI32.2
 A) 5-carbethoxy-2-methyltetrazole and 5-carbethoxy-l-methyltetrazole
 EMI32.3
 la) methylation with diazomethane
A solution of 5-carbäthoxytetrazole [D. Moderhack, Chem. Ber., 108, 877 (1975); 9.17 g, 0.064 mmol] in ethyl ether [the use of a mixture of ethanol and ether gave the same isomer ratio; 80 ml] was cooled to 0 ° C. and treated dropwise (15 min) with a solution of diazomethane (3 g, 0.071 mmol) in ether (200 ml).

   The light yellow solution was stirred for 30 min and the excess diazomethane was destroyed by adding acetic acid (1 ml). Evaporation of the solvent and distillation of the residue gave a clear oil: bp 95 to 100 C / 67 Pa; 9.44 g (96%).



   HNMR indicated a mixture of 1-methyl and 2-methyl isomers in a ratio of 6: 4.



  The two isomers could not be separated either by distillation or by HDFC.



   IR (film) #max: 1740 cm-1 (C = O of the ester).



   HNMR (CDCI3) ô '; 1, 53 (3H, two overlapping t, J = 7, 0, CH CHg), 4, 46 and
4, 53 (3H, 2S, CH3 of 1-methyl and 2-methyltetrazoles, ratio
6: 4; the methyl of the 2-isomer is in the lower field and is the weaker product), 4, 5 bpm (2H, two overlapping q,
CH2CH3).



   Ib) 5-carbethoxy-2-methyltetrazole
 EMI32.4
 

  <Desc / Clms Page number 33>

 
A mixture of 5-carbäthoxy-2-methyltetrazole and 5-carbäthoxy-1-methyltetrazole (0.252 g, 1.61 mol, ratio of isomers 1: 1) in iodomethane (0.5 ml) was sealed in a glass tube and Heated to 1000C for 15 h and 130 C for 6 h. Distillation of the reaction mixture gave the title compound as a light yellow oil: 0, 139 g (55%); Bp 95 to 100 C / 67 Pa (air bath temperature).
 EMI33.1
 q, J = 7, 0, CH2CH3) '
2nd

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



   HNMR indicated the presence of two isomers in a 1: 1 ratio.



     B) 5-hydroxymethyl-2-methyltetrazole
 EMI33.2
 
1. By reducing the ester mixture
A mixture of 5-carbäthoxy-1-methyltetrazole and 5-carbäthoxy-2-methyltetrazole (ratio 6: 4; 7, 60 g, 0, 049 mol) in dry tetrahydrofuran (50 ml) was cooled to 0 C and treated with lithium borohydride ( 1, 06 g, 0.049 mole) in small portions over a period of time
 EMI33.3
 
Hydride was carefully destroyed by the addition of 6N HCI (PH = 7 after gas evolution ceased). The solvent was evaporated in vacuo and the remaining oil was diluted with dichloromethane (200 ml), washed with brine (10 ml) and finally dried over Na, SO.

   Evaporation of the solvent and distillation of the residue under vacuum gave 1.83 g (33%) of a clear oil.



   HNMR of this material indicated that the product was 5-hydroxymethyl-2-methyl-tetrazole.



   2. By reducing 5-carbäthoxy-2-methyltetrazole
To a solution of 5-carbäthoxy-2-methyltetrazole (0, 139 g, 0.89 mol), which had been obtained by isomerizing the ester mixture with methyl iodide, in dry tetrahydrofuran (1 ml) was added lithium borohydride solid at 10 C ( 0.019 g, 0.87 mmol) was added. The mixture was slowly allowed to warm to room temperature and stirred for 4 hours. The excess borohydride was destroyed by carefully adding 6N HC1 at OOC (PH 7). The solvent was evaporated and the residue dissolved in dichloromethane (25 ml) and dried over anhydrous sodium sulfate.

   Evaporation of the solvent gave the title compound as a clear oil: 0.092 g (91%); Bp 90 to 120 C / 67 Pa with decomposition.



   IR (film) ,,: 3350 cm -1 (broad, OH).



   HNMR (CDClg) S: 4.4 (2H, s, CH3-2), 4.93 (2H, s, CH2-5).

  <Desc / Clms Page number 34>

   C) 5-Acetylmercaptomethyl-2-methyltetrazole
 EMI34.1
 
To a solution of 5-hydroxymethyl-2-methyltetrazole (1.83 g, 11.7 mmol) in dry dichloromethane (25 ml) was added methanesulfonyl chloride (1.47 g, 12.9 mmol) at 0 C and then triethylamine (1 , 30 g, 12.9 mmol) was added dropwise over 5 min. The mixture was stirred at 0 C for 1 h and then treated with a solution of potassium thioacetate (1.60 g, 14.0 mmol) in dry N, N-dimethylformamide (10 ml). The resulting gel was stirred at 0 C for 3 h.

   The reaction mixture was diluted with dichloromethane (200 ml), washed with brine (20 ml) and dried over anhydrous sodium sulfate. Evaporation of the solvent under vacuum and chromatography of the oil obtained on silica gel (2 x 15 cm, elution with dichloromethane and dichloromethane-acetone 5%) gave the title compound as a clear oil: 1.31 g (65%).



   IR (film) 9maux 1696 cm -1 (C = O of the thioester).



   HNMR (CDClg) #: 2.43 (3H, s, SAc), 4.36 (3H, s, 2-CHg), 4.38 tpm (2H, s, 5-CH 2).



   D) 5-mercaptomethyl-1,3-dimethyltetrazolium trifluoromethanesulfonate
 EMI34.2
 
A solution of 5-acetylmercaptomethyl-2-methyltetrazole (0.40 g, 2.32 mmol) in dry dichloromethane (3 ml) was treated with methyl triflate (0.76 g, 4.64 mmol) and stirred at 22 C for 16 h . Evaporation of the solvent in vacuo gave a red oil. This salt was dissolved in cold, oxygen-free water (5 ml) and treated with 4M sodium hydroxide (0.8 ml, 3.2 mmol). The mixture was stirred at 0 C for 40 min, diluted with water (7 ml) and the pH value with saturated KH. PO. set to 7, 3.

   The clear solution formed was kept under nitrogen and immediately used for the following stage.
 EMI34.3
 
 EMI34.4
 

  <Desc / Clms Page number 35>

 
 EMI35.1
 
A solution of the enol phosphate (0.915 g, 1.58 mmol) in tetrahydrofuran (8 ml) was cooled to 0 C and added dropwise with the solution of 5-mercaptomethyl-1,3-dimethyltetrazolium-tri-
 EMI35.2
 at 6.5. After a further 20 min, the pH of the solution was adjusted to 7.0 with saturated sodium bicarbonate. The mixture was placed in a hydrogenation bottle, with THF (10 ml),
 EMI35.3
 
9 N / cm2 hydrogenated, (20 ml) washed. The aqueous phase was washed with ether (20 ml) and kept under vacuum for 20 min to remove all traces of the organic solvent.

   Chromatography on PrepPak 500-C / 18 and elution with water gave the title compound as a white powder after lyophilization; 0.26 g (49%).
 EMI35.4
 
04, H20) .buffer).



   Example 7
Production of. 3- (N-Methylpyridin-2-yl-methanthio) -6α - [1- (R) -hydroxyethyl] -7-oxo = 1-aza-bicyclo (3, 2, 0) hept-2-ene -2-carboxylate according to the "one-pot" process
 EMI35.5
 

  <Desc / Clms Page number 36>

 
 EMI36.1
 

  <Desc / Clms Page number 37>

 
 EMI37.1
 A) Preparation of the enol phosphate (2)
 EMI37.2
 
An ice-cold solution of the ketone (1) (3 g, 8.62 mol) in acetonitrile (30 ml) was treated with ethyldiisopropylamine (9 mmol, 1.04 eq., 1.57 ml; addition time about 2 min) and chlorodiphenyl phosphate (9 mmol, 1, 04 eq., 1, 87 ml; addition time about 2 min) treated.

   The reaction mixture was stirred for 45 min and DSC (ethyl acetate, silica gel) showed the disappearance of the ketone (1). The solution was diluted with ethyl acetate (60 ml), washed with cold water (2 x 50 ml) and brine, dried over sodium sulfate and concentrated (bath temperature below 20 ° C) to give a foam which was used as such.



   B) Preparation of the thiol (4)
 EMI37.3
 
An ice-cooled solution of the thioacetate (3) (3.31 g, 10 mmol) in water, cleaned with nitrogen for 5 min, was added dropwise (about 5 min) with a cooled solution of sodium hydroxide (1.75 eq., 17.5 mol , 0.7 g) in water (8 ml). The mixture turned yellow. After 75 min under nitrogen, the pH was adjusted to 7.4 with saturated aqueous solution of Kt-LPO.

   This aqueous solution of thiol (4) (50 ml, 0.2 mmol / ml) was used as such.

  <Desc / Clms Page number 38>

   C) clutch
 EMI38.1
 
An ice-cooled solution of (2) (crude, prepared according to A, 8.62 mol) in tetrahydrofuran (50 ml) was treated dropwise with the aqueous solution of the thiol (4) prepared according to B) (5 ml every 5 min). During the course of the reaction, the pH of the reaction mixture was maintained at about 6.5 to 7.5 (preferably 7) by adding cooled 2N sodium hydroxide solution. The reaction was followed by DSC (a) silica gel, ethyl acetate; (b) Reverse phase Analtech RPSF, CH3CN buffer PH 7 (4: 6).



   Finally, 1, 15 eq. Thiol used (50 ml of the solution). The reaction was complete after 1 h at 0 C and the mixture was used as such for the hydrogenation after the pH had been adjusted to 7.



   D) hydrogenation
 EMI38.2
 

  <Desc / Clms Page number 39>

 
The reaction mixture containing the compound (5) (prepared according to C) was placed in a Parr flask with THF (10 ml), phosphate buffer (PH 7, 0, 1 mol; 10 ml), ether (75 ml) and Pd-C 10 % (5 g) and hydrogenated at 3 to 10 C and 30, 9 N / cm2 for 2 h. The catalyst was then filtered off, washed with water (3 × 10 ml) and the pH was carefully adjusted to 6.2 with cold 2N NaOH. After the addition of ether, the aqueous phase was separated off and washed again with ether. The aqueous phase was freed from the organic solvent under vacuum and then purified on a Bondapak C-18 column (100 g, 4.5 x 13 cm) with cold distilled water.

   The light yellow fractions containing the product (checked by UV and DSC) were lyophilized and gave 1.46 g (50%; yield calculated from the bicyclic ketone) of (6) as a yellow powder.



     # 293, e = 9000, # 271, # = 11064.



   Example 8
 EMI39.1
 
 EMI39.2
 
The preparation was carried out in an analogous manner to that in Examples 1 to 7. The title compound was obtained as a pale yellow solid with the following data:
HNMR (D2O) #: 1.25 (3H, d, J = 6.0 Hz), 2, 7-3, 2 (2H, m), 3.40 (1H, q,
 EMI39.3
 Example 9
 EMI39.4
 
The preparation was carried out in an analogous manner to that in Examples 1 to 7. The characteristic data of the compound obtained were as follows:
 EMI39.5
 

  <Desc / Clms Page number 40>

 
 EMI40.1
 : 175cyclo (3,2,0) hept-2-en-2-carboxylate
 EMI40.2
 When the procedure was analogous to Examples 1 to 7, the title compound was in the form
 EMI40.3
 



  IR (KBr) #max: 3400, 1750 and 1580 cm UV #max (H2O): 298 nm (E = 8058).



  Analysis: Calculated for C15H18N4O2S1 # 2 H2O: C 51, 87, H 5, 44, N 7, 56; found: C 51, 95, H 5, 66, N 7, 56.



  Example 11
 EMI40.4
 
 EMI40.5
 
 EMI40.6
 [1- (R) -hydroxyethyl] -7-oxo-l-aza-bi analysis: calculated for C16H28N2O4S1 # 2 H2O: C 51, 87, H 5, 44, N 7, 56; found: C 51, 37, H 5, 69, N 7, 37.

  <Desc / Clms Page number 41>

 
 EMI41.1
 
 EMI41.2
 
 EMI41.3
 
 EMI41.4
   (N-MeUV #max (H2O): 300 nm (# = 8108).



  Example 13
 EMI41.5
   (1-Propylpyridin-4-ylmethanthio) -6a- [1- (R) -hydroxyethyl] -7-oxo-l-aza-bi-cyclo (3, 2, 0) hept-2-en-2-carboxylate
 EMI41.6
 
When the procedure was analogous to Examples 1 to 7, the title compound was obtained as a yellow powder.
 EMI41.7
 and 7.80 (2H, d, J = 6.0 Hz).



  IR (KBr) 9 maux 3400, 1750 and 1590 cm Analysis: calculated for C18 H22N204S. 2 H20: C 54, 52, H 6, 10, N 7, 07; found: C 54, 32, H 6, 03, N 6, 99.



  Example 14
 EMI41.8
 
 EMI41.9
 

  <Desc / Clms Page number 42>

 
When the process was carried out analogously to Examples 1 to 7, the title compound was obtained as a yellow solid with the following characteristics:
HNMR (D2O) #: 1.24 (3H, d, J = 7.0 Hz), 2, 62 (3H, s), 3, 2-3, 5 (3H, m),
 EMI42.1
 
ABq, J = 12, 6 Hz), 7, 82 (lH, q, J = 7, 0 Hz, 6.5 Hz), 8, 35 (lH, d, J = 7, 0 Hz) and 8, 65 (1H, d, J = 6.5 Hz).



  IR (KBr) v maux 3400.1750 and 1580 cm-1.



  UV #max (H2O); 296 nm (# = 8014).



  Analysis: Calculated for C17H20N2O4S1 # 1/4 H2O: C 57, 85, H 5, 85, N 7, 94; found: C 58, 60, H 5, 86, N 7, 87.



  Example 15
 EMI42.2
 (2-Me-1-aza-bicyclo (3,2,0) hept-2-ene-2-carboxylate
 EMI42.3
 
When the process was carried out analogously to Examples 1 to 7, the title compound was obtained in the form of a pale yellow powder with the following characteristics:
HNMR (CDCl3) #: 1.20 (3H, d, J = 7 Hz), 2.92 (3H, s), 3.08 (lH, d, J = 3.5 Hz,
3, 20 (1H, d, J = 3 Hz), 3, 44 (1H, dd, J = 1 Hz, J = 3, 5 Hz),
4, 00 (3H, 5), 4, 20 (3H, m), 4, 36 (2H, m) and 7, 88 (1H, s).
 EMI42.4
 
9 mau aza bicyclo (3,2,0) hept-2-en-2-carboxylate
 EMI42.5
 
When the process was carried out analogously to Examples 1 to 7, the title compound was obtained as a yellow solid with the following characteristics:

   
 EMI42.6
 

  <Desc / Clms Page number 43>

 
 EMI43.1
 
 EMI43.2
 
 EMI43.3
 
1, 12-aza-bicyclo (3,2,0) hept-2-ene-2-carboxylate
 EMI43.4
 
When the process was carried out analogously to Examples 1 to 7, the title compound was obtained as a yellow solid with the following characteristics:
 EMI43.5
 
6 1, 253, 30 (3H, m), 3, 90 (3H, s) and 4, 1 - 4.4 (4H, m).



  IR (KBr) vs max 3400.1750 and 1580 cm UV #max (H2O): 297 nm (# = 8994).



  Analysis: calculated for C15H19N3O4S. 2 H20: C 48.25, H 6.09, N 7.79; found: C 47, 96, H 5, 83, N 7, 89.



  Example 18
 EMI43.6
 [2- (-bicyclo (3,2,0) hept-2-en-2-caroxylate
 EMI43.7
 
When the process was carried out analogously to Examples 1 to 7, the title compound was obtained as a yellow amorphous solid with the following characteristics:
 EMI43.8
 

  <Desc / Clms Page number 44>

 
 EMI44.1
 
1,28-oxo-1-azabicyclo (3,2,0) hept-2-en-2-carboxylate
 EMI44.2
 
When the process was carried out analogously to Examples 1 to 7, the title compound was obtained as a yellow amorphous solid with the following characteristics:
HNMR (D2O): 1, 32 (3H, d, J = 7, 0 Hz), 1, 63 (3H, d, J = 7, 2 Hz), 2, 5-4, 6 (6H, m), 4, 32 (3H, s) and 8, 2-8, 9 (4H, m).



   IR (KBr) max 3400, 1750 and 1590 cm
UV Àmax (H2O): 296 nm (# = 7573).



   Analysis:
 EMI44.3
 



   Example 20
Preparation of 3- (N-methyl-N'-benzylimidazol-2-ylmethanthio) -6α - [1- (R) -hydroxyethyl] -7-oxo-1-aza-bicyclo) 3, 2, 0) hept -2-en-2-carboxylate
 EMI44.4
 
When the process was carried out analogously to Examples 1 to 7, the title compound was obtained as a pale yellow amorphous solid with the following characteristics:
 EMI44.5
    1, 404, 0-4, 2 (2H, m), 4, 23 (2H, broad s), 5, 57 (2H, s) and 7, 2 to 7, 65 (7H, m).



  IR (KBr) -: 3400.1760 and 1590 cm -
 EMI44.6
 xmas analysis: calculated for C21H23N3O4S1 # 1 1/2 H2O: C 57.25, H 5.94, N 9, 54, S 7, 28; found: C 56.66, H 5, 70, N 9, 49, S 8, 30.

  <Desc / Clms Page number 45>

 
 EMI45.1
 
 EMI45.2
 
 EMI45.3
 
 EMI45.4
 
 EMI45.5
 

  <Desc / Clms Page number 46>

 
 EMI46.1
 
 EMI46.2
 

  <Desc / Clms Page number 47>

 
 EMI47.1
 m), 3.42 91H, 1, J = 6, 0 and 2, 2 Hz), 3, 85 (6H, s), 4, 2-4, 6 (4H, m) and 7, 40 (2H, s).



    22e) Yellow powder IR (KBr) 9 maux 3410, 1750 and 1600 cm.
 EMI47.2
    : 8, 40 (1H, d, J = 8.5 Hz) and 8, 72 (1H, d, J = 6.3 Hz).



    22f) Yellow powder
 EMI47.3
 m), 3, 48 (1H, q, J = 6, 0 and 1, 8 Hz), 3, 90 (3H, s), 4, 05 (3H, s), 4, 2-4, 4 (4H , m) and 8, 80 (lH, s).



  Example 23
 EMI47.4
 
 EMI47.5
 26A R = H 26B R = CH3 A) Preparation of 4-hydroxymethyl-3-methylpyridine
 EMI47.6
 
Boekelheide's general procedure [B. Boekelheide, W. J. Linn, JACS, 1286 (1954)] for the preparation of hydroxymethylpyridine was used. Here was a solution of fresh
 EMI47.7
 

  <Desc / Clms Page number 48>

 Maintained at 75 C for 3 h. The solution was concentrated to about 100 ml under a water jet vacuum, 50 ml of H 20 was added and the mixture was concentrated to about half its volume. The resulting mixture was cooled (0 to 5 C) and made basic (cold about 10) using cold 40% aqueous NaOH. The mixture was extracted with methylene chloride (5 times) and the extract dried (NaCO, + Na SO,).

   Concentration on the rota vap gave a yellow solution. Dilution of this solution with hexane gave a solid which was separated by filtration and dried in vacuo. 48.0 g (83%) of 3,4-lutidine - N-oxide were obtained as a dirty-white solid.



   The N-oxide was added portionwise to 60 ml of acetic anhydride and the resulting dark orange solution was heated to about 90 ° C. for 1 hour (water bath). The excess acetic anhydride was then distilled off under reduced pressure and the material boiling at 90 to 120 ° C./13.3 Pa (39.0 g) was collected. Chromatography of this oil (silica gel / ethyl acetate-petroleum ether 2: 3) gave pure 4-acetoxymethyl-3-methylpyridine (19.0 g, 30%) in the form of an oil.



   IR (clear): 1745 cm-
 EMI48.1
 washed (brine), dried (Na2 SO.) and evaporated to give 11.0 g of an off-white solid, melting point 70 to 72 C. The solid was triturated with cold ether and gave pure 4-hydroxymethyl-3-methylpyridine (9, 5 g, 67%) as a white solid, melting point 77 to 80 C [W. L.F. Armarego, B.A. Milloy, S.C. Sharma, JCS, 2485 (1972); Melting point 81 to 82 C]:
HNMR (CDClg) ô: 8, 27, 7, 41 (ABq, J = 5 Hz, 2H), 8, 18 (s, 1H), 5, 63 (br s, -OH), 4, 67 (s, CH2), 2, 20 (s, CH3).



   IR (Nujol): 3170 cm
B) Preparation of 4- (acetylthiomethyl) -3-methylpyridine
 EMI48.2
 
Diisopropylazodicarboxylate (12.8 ml, 0.065 mol) was added to an ice-cold, mechanically stirred solution of triphenylphosphine (17.04 g, 0.065 mol) in 250 ml of dry THF and the resulting slurry was stirred at 0 C for 1 h. A solution of 4-hydroxymethyl-3-methylpyridine (4.0 g, 0.0325 mol) in 100 ml of dry THF and then freshly distilled thioacetic acid (4.64 ml, 0.065 mol) was added dropwise to this mixture. The resulting mixture was stirred at 0 C for 1 h and then at room temperature for 1 h, an orange solution being formed.



  The solution was concentrated (rotary evaporator) and then diluted with petroleum ether. The resulting mixture was filtered and the filtrate was then evaporated to give an orange oil. Chromatography (silica gel / hexane, then 10 to 50% ethyl acetate-hexane) of this oil gave 7.0 g of an oil which was distilled (Kugelrohr) and the pure product (6.0 g, 100%)
 EMI48.3
 

  <Desc / Clms Page number 49>

 C) Preparation of 4- (acetylthiomethyl) -1,3-dimethylpyridinium triflate
 EMI49.1
 
To an ice-cold solution of the thioacetate (2.95 g, 0.016 mol) in 10 ml of methylene chloride, methyl trifluoromethanesulfonate (4.60 ml, 0.04 mol) was added dropwise and the mixture was stirred under nitrogen at 0 ° C. for 1 h. The reaction mixture was then evaporated to dryness and the residue triturated with ether.

   The resulting solid was separated by filtration and dried in vacuo. There were 4.0 g, 72% of the product as a white solid.



   HNMR (CDCI3) ô: 8, 72 (s, 1H), 8, 58, 7, 87 (ABq, J = 6 Hz, 2H), 4, 39 (s, N-CH3), 4, 17 (s, Ci 2), 2, 53 (s, Chug), 2, 36 (s, CH3).



   IR (pure): 1700 cm
 EMI49.2
 
 EMI49.3
 
 EMI49.4
 

  <Desc / Clms Page number 50>

 eluted with water and then 10% acetonitrile water. Lyophilization of the relevant fractions gave 0.9 g of an orange solid. This was chromatographed again using water and then 2% acetonitrile water as the eluent. Lyophilization revealed
 EMI50.1
 



   UV (phosphate buffer, PH 7): 295 nm (e = 7180).



   In order to illustrate the strong antibacterial broad-spectrum activity both in vitro and in vivo and the low toxicity of the carbapenem compounds according to the invention, biological data which relate to the currently preferred carbapenem compounds according to the invention are given below.



   Efficacy in vitro
Samples of carbapenem compounds, which were prepared according to Examples 8 and 9, showed the following minimum inhibitory concentrations (MIC) in I1g / ml compared to the stated microorganisms after solution in water and dilution with nutrient solution, determined by incubation
 EMI50.2
 Antibacterial activity in vitro of the carbapenem derivative from Example 8
 EMI50.3
 
 <tb>
 <tb> organisms <SEP> MIC <SEP> (p. <SEP> g / ml) <SEP>
 <tb> new ones <SEP> connection <SEP> N-formimidoyl-
 <tb> - <SEP> thienamycin <SEP>
 <tb> S. <SEP> pneumoniae <SEP> A-9585 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 004 <SEP>
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 001 <SEP>
 <tb> S. <SEP> aureus <SEP> A-9537 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 004 <SEP>
 <tb> S.

    <SEP> aureus <SEP> + <SEP> 50% <SEP> serum <SEP> A-9537 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 016 <SEP>
 <tb> S. <SEP> aureus <SEP> (pen. <SEP> res.) <SEP> A-9606 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 008 <SEP>
 <tb> S. <SEP> aureus <SEP> (meth. <SEP> res.) <SEP> A-15097 <SEP> 4 <SEP> 0, <SEP> 5 <SEP>
 <tb> S. <SEP> faecalis <SEP> A-20688 <SEP> 0, <SEP> 5 <SEP> 0, <SEP> 5 <SEP>
 <tb> E. <SEP> coli <SEP> (10-4 <SEP> dil.) <SEP> A-15119 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 016 <SEP>
 <tb> E. <SEP> coli <SEP> (10 ' <SEP>) <SEP> A-15119-0, <SEP> 03 <SEP>
 <tb> E. <SEP> coli <SEP> (10 ' <SEP>) <SEP> A-15119-0, <SEP> 06 <SEP>
 <tb> E. <SEP> coli <SEP> (10) <SEP> A-20341-1 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 03 <SEP>
 <tb> E.coli <SEP> (10-3) <SEP> A-20341-1 <SEP> - <SEP> 0.03
 <tb> E.coli <SEP> (10-2) <SEP> A-20341-1 <SEP> - <SEP> 0.13
 <tb> K.

    <SEP> pneumoniae <SEP> A-9664 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 13 <SEP>
 <tb> K. <SEP> pneumoniae <SEP> A-20468 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 06 <SEP>
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 06 <SEP>
 <tb> P. <SEP> vulgaris <SEP> A-21559 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 03 <SEP>
 <tb>
 

  <Desc / Clms Page number 51>

 continuation
 EMI51.1
 
 <tb>
 <tb> organisms <SEP> MIC <SEP> () <SEP> ig / ml) <SEP>
 <tb> new ones <SEP> connection <SEP> N-formimidoyl-
 <tb> - <SEP> thienamycin <SEP>
 <tb> P. <SEP> morganii <SEP> A-15153 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 13 <SEP>
 <tb> P. <SEP> rettgeri <SEP> A-22424 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 25 <SEP>
 <tb> S. <SEP> marcescens <SEP> A-20019 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 03 <SEP>
 <tb> E. <SEP> cloacae <SEP> A-9569 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 06 <SEP>
 <tb> E.

    <SEP> cloacae <SEP> A-9656 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 06 <SEP>
 <tb> P. <SEP> aeruginosa <SEP> A-9843A <SEP> 4 <SEP> 1
 <tb> P. <SEP> aeruginosa <SEP> A-21213 <SEP> 1 <SEP> 0, <SEP> 25 <SEP>
 <tb> H.influenzae <SEP> A-9833 <SEP> 16 <SEP> 16
 <tb> H.influenzae <SEP> A-20178 <SEP> 32 <SEP> 32
 <tb> H. <SEP> influenzae <SEP> A-21518 <SEP> 16 <SEP> 32
 <tb> H. <SEP> influenzae <SEP> A-21522 <SEP> 8 <SEP> 32
 <tb> B. <SEP> fragilis <SEP> A-22862 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 016 <SEP>
 <tb> B. <SEP> fragilis <SEP> A-22053 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 06 <SEP>
 <tb> B. <SEP> fragilis <SEP> A-22696 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 13 <SEP>
 <tb> B.

    <SEP> fragilis <SEP> A-22863 <SEP> 0, <SEP> 03 <SEP> 1 <SEP>
 <tb>
 Antibacterial activity in vitro of the carbapenem derivative from Example 9
 EMI51.2
 
 <tb>
 <tb> organisms <SEP> MIC <SEP> (µg / ml)
 <tb> new ones <SEP> connection <SEP> N-formimidoyl-
 <tb> - <SEP> thienamycin <SEP>
 <tb> S. <SEP> pneumoniae <SEP> A-9585 <SEP> 0, <SEP> 001 <SEP> 0, <SEP> 002 <SEP>
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 0, <SEP> 001 <SEP> 0, <SEP> 002 <SEP>
 <tb> S. <SEP> aureus <SEP> A-9537 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 004 <SEP>
 <tb> S. <SEP> aureus <SEP> + <SEP> 50% <SEP> serum <SEP> A-9537 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP>
 <tb> S. <SEP> aureus <SEP> (pen. <SEP> res.) <SEP> A-9606 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 008 <SEP>
 <tb> S. <SEP> aureus <SEP> (meth. <SEP> res.) <SEP> A-15097 <SEP> 8 <SEP> 4
 <tb> S.

    <SEP> faecalis <SEP> A-20688 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 5 <SEP>
 <tb> E. <SEP> coli <SEP> A-15119 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP>
 <tb> E. <SEP> coli <SEP> A-20341-1 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 03 <SEP>
 <tb> K. <SEP> pneumoniae <SEP> A-9664 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 06 <SEP>
 <tb> K. <SEP> pneumoniae <SEP> A-20468 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 13 <SEP>
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 06 <SEP>
 <tb>
 

  <Desc / Clms Page number 52>

 Continuation)
 EMI52.1
 
 <tb>
 <tb> organisms <SEP> MIC <SEP> (yg / ml)
 <tb> new ones <SEP> connection <SEP> N-formimidoyl-
 <tb> - <SEP> thienamycin <SEP>
 <tb> P. <SEP> vulgaris <SEP> A-21559 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 03 <SEP>
 <tb> P. <SEP> morganii <SEP> A-15153 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 13 <SEP>
 <tb> P.

    <SEP> rettgeri <SEP> A-22424 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 13 <SEP>
 <tb> S. <SEP> marcescens <SEP> A-20019 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 03 <SEP>
 <tb> E. <SEP> cloacae <SEP> A-9659 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 06 <SEP>
 <tb> E. <SEP> cloacae <SEP> A-9656 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 06 <SEP>
 <tb> P. <SEP> aeruginosa <SEP> A-9843A <SEP> 8 <SEP> 1
 <tb> P. <SEP> aeruginosa <SEP> A-21213 <SEP> 2 <SEP> 0, <SEP> 25 <SEP>
 <tb>
 
Effectiveness in vivo
The in vivo therapeutic efficacy of the compound of Example 8 and of N-formimidoyl- thienamycin after intramuscular use in mice which had been experimentally infected with various organisms is given in the following table. The PD50 is given (dose in mg / kg needed to protect 50% of the infected mice).
 EMI52.2
 
 <tb>
 <tb>



  Protective effect <SEP> at <SEP> the <SEP> intramuscular <SEP> treatment <SEP> infected <SEP> mice
 <tb> PD50 / treatment <SEP> (mg / kg) <SEP>
 <tb> organism <SEP> infection <SEP> connection <SEP> N-formimidoyl-
 <tb> (number <SEP> the <SEP> organisms) <SEP> off <SEP> example <SEP> 8-thienawycin
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 3, <SEP> 6x10 <SEP> 3, <SEP> 3 <SEP> 3 * / 15 *
 <tb> P. <SEP> aeruginosa <SEP> A-9843a <SEP> 5.5 <SEP> x <SEP> 104 <SEP> 0.3 <SEP> 0.5 *
 <tb> P. <SEP> aeruginosa <SEP> A-20481 <SEP> 5, <SEP> 4x10 <SEP> 0, <SEP> 63 <SEP> 0, <SEP> 4 * <SEP>
 <tb> P. <SEP> aeruginosa <SEP> A-20599 <SEP> 1, <SEP> 4 <SEP> x <SEP> 105 <SEP> 0.7 <SEP> 0.16 *
 <tb> S. <SEP> aureus <SEP> A-9606 <SEP> 6, <SEP> 6x108 <SEP> 0, <SEP> 09 <SEP> 0, <SEP> 07 * <SEP>
 <tb> S. <SEP> faecalis <SEP> A-20688 <SEP> 2, <SEP> 3 <SEP> X <SEP> 108 <SEP> 3, <SEP> 3 <SEP> 2, <SEP> 8 * <SEP>
 <tb> E.

    <SEP> coli <SEP> A-15119 <SEP> 6, <SEP> 2x10 <SEP> 0, <SEP> 6 <SEP> 2, <SEP> 5 * <SEP>
 <tb> K. <SEP> pneumoniae <SEP> A-9964 <SEP> 5, <SEP> 1x106 <SEP> 2, <SEP> 5 <SEP> 2, <SEP> 2 * <SEP>
 <tb>
 * Data from the literature
Treatment regimen
Except in the case of E. coli A-15119 and K. pneumoniae A-9964, the mice were treated with the drugs 0 and 2 h after infection i. m. treated. For E. coli and K. pneumoniae treatment 1 and. 3, 5 h after infection. 5 mice per dose were used for each test.



   toxicity
The toxicity of the compound from Example 8 after intracranial administration to mice was investigated and the results are shown in the following table.

  <Desc / Clms Page number 53>

 
 EMI53.1
 
 <tb>
 <tb>



  toxicity <SEP> after <SEP> intracranial
 <tb> application <SEP> at <SEP> mice
 <tb> connection <SEP> * LDgo <SEP> highest <SEP> dose <SEP> (mg / kg)
 <tb> (mg / kg) <SEP> without <SEP> clinical <SEP> characters
 <tb> from <SEP> toxicity
 <tb> connection <SEP> off
 <tb> example <SEP> 8 <SEP> 14 <SEP> 5
 <tb> N-formimidoyl-
 <tb> -thienamycin <SEP> 32 <SEP>
 <tb>
 * Average of 25 mice per compound
Blood levels in mice after intramuscular use
The table below shows the blood levels and the half-life of the compound from Example 8 after intramuscular use of 20 mg / kg in mice.
 EMI53.2
 
 <tb>
 <tb>



  Blood levels <SEP> (pg / ml)
 <tb> connection <SEP> 10 <SEP> 20 <SEP> 30 <SEP> 45 <SEP> 60 <SEP> 90 <SEP> * t1 / 2 <SEP> ** FK <SEP>
 <tb> (min) <SEP> (ugh / ml) <SEP>
 <tb> minutes <SEP> after <SEP> application
 <tb> connection <SEP> off
 <tb> example <SEP> 8 <SEP> 14 <SEP> 10.8 <SEP> 6.8 <SEP> 2.6 <SEP> 0.6 <SEP> <0.6 <SEP> 10 <SEP> 6, <SEP> 3 <SEP>
 <tb> N-fornimidotyl
 <tb> -thienanycin <SEP> 12.6 <SEP> 9.9 <SEP> 7.3 <SEP> 2.6 <SEP> 0.7 <SEP>> 0.3 <SEP> 9 <SEP> 6
 <tb>
 * tl / 2 means the half-life in minutes ** FK means the area under the curve
The compounds were solubilized in 0.1 M phosphate buffer PH 7. The values come from a single test, 4 mice were used per connection.



   Excretion in the urine
The following table shows the cumulative excretion in the urine of the compound from Example 8 after intramuscular use (20 mg / kg) in mice.
 EMI53.3
 
 <tb>
 <tb>



  excretion <SEP> in <SEP> urine
 <tb> intramuscular <SEP> application <SEP> from <SEP> 20 <SEP> mg / kg <SEP> at <SEP> mice
 <tb> percentage <SEP> the <SEP> found again <SEP> dose
 <tb> connection <SEP> 0 <SEP> - <SEP> 3 <SEP> 3 <SEP> - <SEP> 6 <SEP> 6 <SEP> - <SEP> 24 <SEP> 0 <SEP> - <SEP> 24
 <tb> hours <SEP> after <SEP> the <SEP> application
 <tb> connection <SEP> off
 <tb> example <SEP> 8 <SEP> 26.1 <SEP> 0.5 <SEP> 0.1 <SEP> 26.7¯6.7
 <tb> N-F <SEP> ormimidoy <SEP> 1- <SEP>
 <tb> -thienanycin <SEP> 12.1 <SEP> 0.1 <SEP>> 0.1 <SEP> 12.2¯3.6
 <tb>
 

  <Desc / Clms Page number 54>

 
The compounds were solubilized in 0.1 M phosphate buffer PH 7. The values come from a single test, 4 mice per connection were used.



   More biological data
Efficacy in vitro
Samples of the carbapenem compounds listed below (identified by the numbers of Examples 10 to 21 and 1 to 6), after dissolving in water and diluting with nutrient solution, showed the following minimum inhibitory concentrations (MIC) in llg / ml compared to those listed
 EMI54.1
 
 EMI54.2
 
 <tb>
 <tb>



  MIC <SEP> (g / ml)
 <tb> organism <SEP> example <SEP> example <SEP> example <SEP> example <SEP> example <SEP> MK <SEP> 0787 *
 <tb> 10 <SEP> 11 <SEP> 12 <SEP> 13 <SEP> 14
 <tb> S. <SEP> pneumoniae <SEP> A-95B5 <SEP> 0, <SEP> 002 <SEP> 0, <SEP> 002 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 002 <SEP>
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 0, <SEP> 002 <SEP> 0, <SEP> 001 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 002 <SEP>
 <tb> S. <SEP> faecalis <SEP> A-20688 <SEP> 0, <SEP> 5 <SEP> 0, <SEP> 5 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 5 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 5 <SEP>
 <tb> S. <SEP> aureus <SEP> A-9537 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 004 <SEP>
 <tb> S.

    <SEP> aureus <SEP> + <SEP> 50% <SEP> serum <SEP> A-9537 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 016 <SEP>
 <tb> S. <SEP> aureus <SEP> (pen. <SEP> res.) <SEP> A-9606 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 008 <SEP>
 <tb> S. <SEP> aureus <SEP> (meth. <SEP> res.) <SEP> A-15097 <SEP> 4 <SEP> 4 <SEP> 8 <SEP> 4 <SEP> 2 <SEP> 4
 <tb> E. <SEP> coli <SEP> A-15119 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 016 <SEP>
 <tb> E. <SEP> coli <SEP> A-20341-1 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 03 <SEP>
 <tb> K.

    <SEP> pneumoniae <SEP> A-9664 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 06
 <tb> K. <SEP> pneumoniae <SEP> A-20468 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 13 <SEP>
 <tb> E. <SEP> cloacae <SEP> A-9659 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 06 <SEP>
 <tb> E. <SEP> cloacae <SEP> A-9656 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 06 <SEP>
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 025 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 06 <SEP>
 <tb> P.

    <SEP> vulgaris <SEP> A-21559 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 03 <SEP>
 <tb> P. <SEP> morganii <SEP> A-15153 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 13 <SEP>
 <tb> P. <SEP> rettgeri <SEP> A-22424 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 13 <SEP>
 <tb> S. <SEP> marcescens <SEP> A-20019 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 03 <SEP>
 <tb> P. <SEP> aeruginosa <SEP> A-9843a <SEP> 2 <SEP> 2 <SEP> 4 <SEP> 8 <SEP> 1 <SEP> 0, <SEP> 25 <SEP>
 <tb> P. <SEP> aeruginosa <SEP> A-21213 <SEP> 0, <SEP> 5 <SEP> 0, <SEP> 13 <SEP> 2 <SEP> 1 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 25 <SEP>
 <tb> H.

    <SEP> influenzae <SEP> A-9833 <SEP> 2 <SEP> 2 <SEP> 4 <SEP>> <SEP> 32 <SEP>> <SEP> 32 <SEP> 16
 <tb> H. <SEP> influenzae <SEP> A-21518 <SEP> 2 <SEP> 2 <SEP> 4 <SEP>> <SEP> 32 <SEP>> <SEP> 32 <SEP> 16
 <tb> B. <SEP> fragilis <SEP> A-22B62 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 06 <SEP>
 <tb> B. <SEP> fragilis <SEP> A-22696 <SEP> 0, <SEP> 5 <SEP> 0, <SEP> 5 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 13 <SEP>
 <tb>
 * N-formimidoyl-thienamycin

  <Desc / Clms Page number 55>

 
 EMI55.1
 
 <tb>
 <tb> MIC <SEP> (ng / ml)
 <tb> organism <SEP> example <SEP> 15 <SEP> example <SEP> 16 <SEP> example <SEP> 17 <SEP> example <SEP> 18 <SEP> HK0787 *
 <tb> S.

    <SEP> pneumoniae <SEP> A-9585 <SEP> 0, <SEP> 002 <SEP> 0, <SEP> 001 <SEP> 0, <SEP> 001 <SEP> 0, <SEP> 002 <SEP> 0, <SEP> 002 <SEP>
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 0, <SEP> 002 <SEP> 0, <SEP> 001 <SEP> 0, <SEP> 001 <SEP> 0, <SEP> 002 <SEP> 0, <SEP> 002 <SEP>
 <tb> S. <SEP> faecalis <SEP> A-20688 <SEP> 0.5 <SEP> 0.13 <SEP> 0.25 <SEP> 0.5 <SEP> 0.25
 <tb> S. <SEP> aureus <SEP> A-9537 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 002
 <tb> S. <SEP> aureus + 50X <SEP> serum <SEP> A-9537 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP>
 <tb> S. <SEP> aureus <SEP> (pen. <SEP> res.) <SEP> A-9606 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 008 <SEP>
 <tb> S. <SEP> aureus <SEP> (Heth. <SEP> res.) <SEP> A-15097 <SEP>
 <tb> E.

    <SEP> coli <SEP> A-15119 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP>
 <tb> E. <SEP> coli <SEP> A-20341-1 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 016 <SEP>
 <tb> K. <SEP> pneumoniae <SEP> Ä-9664 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 03 <SEP>
 <tb> K. <SEP> peneumoniae <SEP> A-20468 <SEP> 0.13 <SEP> 0.034 <SEP> 0.13 <SEP> 0.13 <SEP> 0.13
 <tb> E. <SEP> cloacae <SEP> A-9659 <SEP> 0.13 <SEP> 0.03 <SEP> 0.13 <SEP> 0.06 <SEP> 0.13
 <tb> E. <SEP> cloacae <SEP> A-9656 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 06 <SEP>
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 0.13 <SEP> 0.016 <SEP> 0.13 <SEP> 0.03 <SEP> 0.03
 <tb> P.

    <SEP> vulgaris <SEP> A-21559 <SEP> 0.03 <SEP> 0.008 <SEP> 0.016 <SEP> 0.03 <SEP> 0.016
 <tb> M. <SEP> morganii <SEP> A-15153 <SEP> 0.13 <SEP> 0.03 <SEP> 0.13 <SEP> 0.06 <SEP> 0.06
 <tb> P. <SEP> rettgeri <SEP> A-22424 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 13
 <tb> S. <SEP> marcascens <SEP> A-20019 <SEP> 0.06 <SEP> 0.016 <SEP> 0.06 <SEP> 0.06 <SEP> 0.03
 <tb> P. <SEP> aeruginosa <SEP> A-9843A <SEP> 1 <SEP> 2 <SEP> 32 <SEP> 0, <SEP> 5 <SEP> 1
 <tb> P.aeruginosa <SEP> A-21213 <SEP> 0.25 <SEP> 0.13 <SEP> 2 <SEP> 0.13 <SEP> 0.13
 <tb>
 
 EMI55.2
 

  <Desc / Clms Page number 56>

 
 EMI56.1
 
 <tb>
 <tb> HIC <SEP> (fg / ml) <SEP>
 <tb> organism <SEP> example <SEP> 19 <SEP> example <SEP> 20 <SEP> example <SEP> 21 <SEP> MK <SEP> 0787 * <SEP>
 <tb> S.

    <SEP> pneumoniae <SEP> A-9585 <SEP> 0, <SEP> 002 <SEP> 0, <SEP> 0005 <SEP> 0, <SEP> 0005 <SEP> 0, <SEP> 002 <SEP>
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 0005 <SEP> 0, <SEP> 0005 <SEP> 0, <SEP> 002 <SEP>
 <tb> S. <SEP> faecalis <SEP> A-20688 <SEP> 0, <SEP> 5 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 25 <SEP>
 <tb> S. <SEP> aureus <SEP> A-9537 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 002 <SEP>
 <tb> S. <SEP> aureus <SEP> + <SEP> 50% <SEP> serum <SEP> A-9537 <SEP> 0.016 <SEP> 0.016 <SEP> 0.03 <SEP> 0.008
 <tb> S. <SEP> aureus <SEP> (pen. <SEP> res.) <SEP> A-9606 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 008 <SEP>
 <tb> S. <SEP> aureus <SEP> (Heth. <SEP> res.) <SEP> A-15097 <SEP>
 <tb> E.

    <SEP> coli <SEP> A-15119 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 016 <SEP>
 <tb> E. <SEP> coli <SEP> A-20341-I <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 016 <SEP>
 <tb> K. <SEP> pneumoniae <SEP> A-9664 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 03 <SEP>
 <tb> K. <SEP> pneumoniae <SEP> A-20468 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 06 <SEP>
 <tb> E. <SEP> cloacae <SEP> A-9659 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 06
 <tb> E. <SEP> cloacae <SEP> A-9656 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 06 <SEP>
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP>
 <tb> P.

    <SEP> vulgaris <SEP> A-21559 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP>
 <tb> H. <SEP> morganii <SEP> A-15153 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 06 <SEP>
 <tb> P. <SEP> rettgeri <SEP> A-22424 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 13
 <tb> S. <SEP> marcescens <SEP> A-20019 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 03
 <tb> P. <SEP> aeruginosa <SEP> A-9843A <SEP> 16 <SEP> 32 <SEP> 8 <SEP> 1 <SEP>
 <tb> P. <SEP> aeruginosa <SEP> A-21213 <SEP> 2 <SEP> 2 <SEP> 0, <SEP> 5 <SEP> 0, <SEP> 13 <SEP>
 <tb>
 
 EMI56.2
 

  <Desc / Clms page number 57>

 
 EMI57.1
 
 <tb>
 <tb> MIC <SEP> (µg / ml)
 <tb> organism <SEP> example <SEP> 1 <SEP> example <SEP> 1 <SEP> example <SEP> 1 <SEP> MK <SEP> 0787 *
 <tb> isomer "A" isomer "B" <SEP> isomeric "C" <SEP>
 <tb> S.

    <SEP> pneumoniae <SEP> A-9585 <SEP> 0, <SEP> 0005 <SEP> 0, <SEP> 0005 <SEP> 0, <SEP> 0005 <SEP> 0, <SEP> 002 <SEP>
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 0, <SEP> 0005 <SEP> 0, <SEP> 001 <SEP> 0, <SEP> 0003 <SEP> 0, <SEP> 002 <SEP>
 <tb> S. <SEP> faecalis <SEP> A-20688 <SEP> 0.13 <SEP> 0.5 <SEP> 0.5 <SEP> 0.25
 <tb> S. <SEP> aureus <SEP> A-9537 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 004 <SEP>
 <tb> S. <SEP> aureus + SOX <SEP> serum <SEP> A-9537 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 008 <SEP>
 <tb> S. <SEP> aureus <SEP> (pen. <SEP> res.) <SEP> A-9606 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 008 <SEP>
 <tb> S.aureus <SEP> (Neth.res.) <SEP> A-15097
 <tb> E. <SEP> coli <SEP> A-15119 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 008 <SEP>
 <tb> E.

    <SEP> coli <SEP> A-20341-1 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 016 <SEP>
 <tb> K. <SEP> pneumoniae <SEP> A-9664 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 03 <SEP>
 <tb> K. <SEP> pneumoniae <SEP> A-20468 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 06 <SEP>
 <tb> E. <SEP> cloacae <SEP> A-9659 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 13 <SEP>
 <tb> E. <SEP> cloacae <SEP> A-9656 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 13 <SEP>
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 06 <SEP>
 <tb> P. <SEP> vulgaris <SEP> A-21559 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 016 <SEP>
 <tb> M.

    <SEP> morganii <SEP> A-15153 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 13
 <tb> P. <SEP> rettgeri <SEP> A-22424 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 25 <SEP> 0, <SEP> 13 <SEP>
 <tb> S. <SEP> marcescens <SEP> A-20019 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 016 <SEP>
 <tb> P. <SEP> aeruginosa <SEP> A-9843A <SEP> 0, <SEP> 5 <SEP> 2 <SEP> 8 <SEP> 0, <SEP> 5 <SEP>
 <tb> P. <SEP> aeruginosa <SEP> A-21213 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 5 <SEP> 0, <SEP> 13 <SEP>
 <tb>
 * N-formimidoyl-thienamycin

  <Desc / Clms Page number 58>

 
 EMI58.1
 
 <tb>
 <tb> MIC <SEP> (pg / ml)
 <tb> organism <SEP> example <SEP> 2 <SEP> example <SEP> 3 <SEP> MK <SEP> 0787 *
 <tb> S. <SEP> pneumoniae <SEP> A-9585 <SEP> 0, <SEP> 002 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 001
 <tb> S.

    <SEP> pyogenes <SEP> A-9604 <SEP> 0, <SEP> 003 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 001 <SEP>
 <tb> S. <SEP> faecalis <SEP> A. <SEP> 20688 <SEP> 1 <SEP> 4 <SEP> 0, <SEP> 25 <SEP>
 <tb> S. <SEP> aureus <SEP> A-9537 <SEP> 0.008 <SEP> 0.25 <SEP> 0.001
 <tb> S. <SEP> aureus <SEP> + <SEP> 50% <SEP> serum <SEP> A-9537 <SEP> 0.03 <SEP> 1 <SEP> 0.008
 <tb> S. <SEP> aureus <SEP> (pen. <SEP> res.) <SEP> A-9606 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 5 <SEP> 0, <SEP> 002 <SEP>
 <tb> S. <SEP> aureus <SEP> 9Meth.res.) <SEP> A-15097
 <tb> E. <SEP> coli <SEP> A-15119 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 6 <SEP> 0, <SEP> 008 <SEP>
 <tb> E. <SEP> coli <SEP> A-20341-1 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 6 <SEP> 0, <SEP> 008 <SEP>
 <tb> K. <SEP> pneumoniae <SEP> A-9664 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 03 <SEP>
 <tb> K.

    <SEP> pneumoniae <SEP> A-20468 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 5 <SEP> 0, <SEP> 06 <SEP>
 <tb> E. <SEP> c10acae <SEP> A-9659 <SEP> 0, <SEP> 06 <SEP> 2 <SEP> 0, <SEP> 06 <SEP>
 <tb> E. cloacae <SEP> A-9656 <SEP> 0.06 <SEP> 2 <SEP> 0, <SEP> 06 <SEP>
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 016 <SEP>
 <tb> P. <SEP> vulgaris <SEP> A-21559 <SEP> 0, <SEP> 03 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 008 <SEP>
 <tb> M. <SEP> morganii <SEP> A-15153 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 5 <SEP> 0, <SEP> 06 <SEP>
 <tb> P. <SEP> rettgeri <SEP> A-22424 <SEP> 0, <SEP> 25 <SEP> 2 <SEP> 0, <SEP> 06 <SEP>
 <tb> S. <SEP> marcescens <SEP> A-20019 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 016 <SEP>
 <tb> P. <SEP> aeruginosa <SEP> A-9843A <SEP> 0, <SEP> 25 <SEP> <63 <SEP> 0, <SEP> 5 <SEP>
 <tb> P.

    <SEP> aeruginosa <SEP> A-21213 <SEP> 0, <SEP> 13 <SEP> 16 <SEP> 0, <SEP> 13 <SEP>
 <tb>
 * N-formimidoyl-thienamycin

  <Desc / Clms Page number 59>

 
 EMI59.1
 
 <tb>
 <tb> MIC <SEP> (g / ml)
 <tb> organism <SEP> Example <SEP> 4 <SEP> example <SEP> 5 <SEP> example <SEP> 5 <SEP> MK <SEP> 0787 *
 <tb> S. <SEP> pneumoniae <SEP> A-9585 <SEP> 1 <SEP> 0, <SEP> 002 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 001
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 2 <SEP> 0, <SEP> 002 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 002 <SEP>
 <tb> S. <SEP> faecalis <SEP> A-20688 <SEP> 63 <SEP> 0, <SEP> 5 <SEP> 16 <SEP> 0, <SEP> 25 <SEP>
 <tb> S. <SEP> aureus <SEP> A-9537 <SEP> 32 <SEP> 0, <SEP> 004 <SEP> 0, <SEP> 5 <SEP> 0, <SEP> 002 <SEP>
 <tb> S. <SEP> aureus <SEP> + <SEP> 50% <SEP> serum <SEP> A-9537 <SEP>> <SEP> 63 <SEP> 0, <SEP> 008 <SEP> 2 <SEP> 0, <SEP> 004 <SEP>
 <tb> S.

    <SEP> aureus <SEP> (pen. <SEP> res.) <SEP> A-9606 <SEP>> <SEP> 125 <SEP> 0, <SEP> 016 <SEP>> <SEP> 125 <SEP> 0, <SEP> 004 <SEP>
 <tb> S. <SEP> aureus <SEP> (Heth. <SEP> res.) <SEP> A-15097 <SEP>
 <tb> E. <SEP> coli <SEP> A-15119 <SEP> 16 <SEP> 0, <SEP> 008 <SEP> 1 <SEP> 0, <SEP> 016 <SEP>
 <tb> E. <SEP> coli <SEP> A-20341-1 <SEP> 16 <SEP> 0, <SEP> 008 <SEP> 2 <SEP> 0, <SEP> 016 <SEP>
 <tb> K. <SEP> pneumoniae <SEP> A-9664 <SEP> 32 <SEP> 0, <SEP> 03 <SEP> 4 <SEP> 0, <SEP> 03 <SEP>
 <tb> K.Pneumoniae <SEP> A-20468 <SEP> 63 <SEP> 0, <SEP> 06 <SEP> 4 <SEP> 0, <SEP> 06 <SEP>
 <tb> E. <SEP> cloacae <SEP> A-9659 <SEP> 63 <SEP> 0, <SEP> 03 <SEP> 8 <SEP> 0, <SEP> 06 <SEP>
 <tb> E. <SEP> cloaeae <SEP> A-9656 <SEP> 125 <SEP> 0, <SEP> 03 <SEP> 16 <SEP> 0, <SEP> 06 <SEP>
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 32 <SEP> 0, <SEP> 03 <SEP> 4 <SEP> 0, <SEP> 016 <SEP>
 <tb> P.

    <SEP> vulgaris <SEP> A-21559 <SEP> 32 <SEP> 0, <SEP> 016 <SEP> 4 <SEP> 0, <SEP> 016 <SEP>
 <tb> M. <SEP> mor9anii <SEP> A-15153 <SEP> 32 <SEP> 0, <SEP> 06 <SEP> 8 <SEP> 0, <SEP> 06 <SEP>
 <tb> P. <SEP> rettgeri <SEP> A-22424 <SEP> 32 <SEP> 0, <SEP> 13 <SEP> 8 <SEP> 0, <SEP> 13 <SEP>
 <tb> S. <SEP> marcescens <SEP> A-20019 <SEP> 32 <SEP> 0, <SEP> 03 <SEP> 4 <SEP> 0, <SEP> 03 <SEP>
 <tb> P. <SEP> aeru9inosa <SEP> A-9S43A <SEP> 63 <SEP> 0, <SEP> 5 <SEP> 32 <SEP> 0, <SEP> 5 <SEP>
 <tb> P.

    <SEP> aeruginosa <SEP> A-21213 <SEP> 63 <SEP> 0, <SEP> 06 <SEP> 16 <SEP> 0, <SEP> 13 <SEP>
 <tb>
 * N-formimidoyl-thienamycin
Effectiveness in vivo
The therapeutic efficacy in vivo of certain compounds produced according to the invention and of N-formimidoyl-thienamycin (MK 0787) after intramuscular use on mice which had been experimentally infected with various organisms is shown below. The PD50 (dose in mg / kg) that is necessary to protect 50% of the infected mice is given.

  <Desc / Clms Page number 60>

 



  Protective effect during intramuscular treatment of infected mice
PD50 / treatment (mg / kg)
 EMI60.1
 
 <tb>
 <tb> example <SEP> 13 <SEP> example <SEP> 15 <SEP> example <SEP> 16 <SEP> example <SEP> 19 <SEP> example <SEP> 21 <SEP> example <SEP> 1 <SEP> example <SEP> l)) <SEP> K0787 <SEP>
 <tb> isomer <SEP> "A" <SEP> isomer <SEP> "B"
 <tb> S. <SEP> aureus <SEP> A-9606 <SEP> - <SEP> 0.21 <SEP> - <SEP> 0.89 <SEP> 0.07 <SEP> - <SEP> - <SEP> 0.07
 <tb> E. <SEP> celi <SEP> A-15119 <SEP> - <SEP> 0.86 <SEP> 1.2 <SEP> - <SEP> - <SEP> - <SEP> - <SEP> 2
 <tb> K. <SEP> pmeumeniae <SEP> A-9554 <SEP> - <SEP> 1.8 <SEP> 1.8 <SEP> - <SEP> - <SEP> - <SEP> - <SEP> 3
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> - <SEP> 1.4 <SEP> 7.1 <SEP> - <SEP> - <SEP> - <SEP> - <SEP> 9
 <tb> P.

    <SEP> aeruginosa <SEP> A-9843A <SEP> 0, <SEP> 4 <SEP> 0, <SEP> 19 <SEP> 0, <SEP> 19 <SEP> 1, <SEP> 8 <SEP> 0, <SEP> 45 <SEP> 0, <SEP> 39 <SEP> 0, <SEP> 89 <SEP> 1 <SEP>
 <tb> P. <SEP> meraginosa <SEP> A-24081 <SEP> - <SEP> 0.33 <SEP> 0.19 <SEP> - <SEP> - <SEP> - <SEP> - <SEP> 0.4
 <tb> example <SEP> 10 <SEP> example <SEP> 11 <SEP> example <SEP> 14 <SEP> HK <SEP> 0787 <SEP>
 <tb> S. <SEP> aureus <SEP> A-9606 <SEP> 0, <SEP> 07 <SEP> 0, <SEP> 1 <SEP> 0, <SEP> 2 <SEP> 0, <SEP> 07 <SEP>
 <tb> E. <SEP> coli <SEP> A-15119 <SEP> 1 <SEP> 0, <SEP> 4 <SEP> 0, <SEP> 2 <SEP> 3
 <tb> K. <SEP> pneumoniae <SEP> A-9664 <SEP> 3 <SEP> 3 <SEP> 1 <SEP> 3
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 2 <SEP> 4 <SEP> 2, <SEP> 4 <SEP> 9
 <tb> P. <SEP> aeruginosa <SEP> A-9843A <SEP> 0, <SEP> 5 <SEP> 0, <SEP> 2 <SEP> 0, <SEP> 2 <SEP> 0, <SEP> 5 <SEP>
 <tb> P.

    <SEP> aeruginosa <SEP> A-24081 <SEP> 0, <SEP> 8 <SEP> 0, <SEP> 2 <SEP> 0, <SEP> 1 <SEP> 0, <SEP> 4 <SEP>
 <tb> example <SEP> 12 <SEP> HK0787
 <tb> S. <SEP> aureus <SEP> 0, <SEP> 2 <SEP> 0, <SEP> 07 <SEP>
 <tb> E. <SEP> coli <SEP> 4 <SEP> 2, <SEP> 2 <SEP>
 <tb> K. <SEP> pneumoniae <SEP> 3 <SEP> 2.3
 <tb> P. <SEP> mirabilis <SEP> 10 <SEP> 9
 <tb> P. <SEP> aeruginosa <SEP> A-9843A <SEP> 1, <SEP> 6 <SEP> 0, <SEP> 5 <SEP>
 <tb>
 

  <Desc / Clms Page number 61>

 
Blood levels in mice after intramuscular use
The blood levels and the half-life of various compounds produced according to the invention after intramuscular use of 20 mg / kg in mice are shown below.
 EMI61.1
 
 <tb>
 <tb>



  connection <SEP> C <SEP> * T1 / 2 <SEP> ** AUC
 <tb> max
 <tb> (g / ml) <SEP> (min) <SEP> (g.h / ml)
 <tb> example <SEP> 8 <SEP> 14 <SEP> 10 <SEP> 6, <SEP> 3 <SEP>
 <tb> example <SEP> 9 <SEP> 13, <SEP> 9 <SEP> 9 <SEP> 5.3
 <tb> example <SEP> 10 <SEP> 14, <SEP> 5 <SEP> 10 <SEP> 6, <SEP> 9 <SEP>
 <tb> example <SEP> 11 <SEP> 15, <SEP> 5 <SEP> 11 <SEP> 7, <SEP> 7 <SEP>
 <tb> example <SEP> 12
 <tb> example <SEP> 13 <SEP> 17, <SEP> 7 <SEP> 9 <SEP> 8, <SEP> 5 <SEP>
 <tb> example <SEP> 14 <SEP> 19, <SEP> 2 <SEP> 11 <SEP> 11, <SEP> 8 <SEP>
 <tb> example <SEP> 15 <SEP> 18, <SEP> 8 <SEP> 11 <SEP> 10.5
 <tb> example <SEP> 16 <SEP> 16, <SEP> 7 <SEP> 12 <SEP> 8.5
 <tb> example <SEP> 17 <SEP> 20, <SEP> 1 <SEP> 11 <SEP> 9.5
 <tb> example <SEP> 18 <SEP> 14, <SEP> 9 <SEP> 11 <SEP> 7, <SEP> 4 <SEP>
 <tb> example <SEP> 20 <SEP> 14.8 <SEP> 11 <SEP> 6.4
 <tb> example <SEP> 21 <SEP> 15.8 <SEP> 13 <SEP> 7,

    <SEP> 6 <SEP>
 <tb> example <SEP> 1 <SEP> isomer <SEP> "A" <SEP> 16, <SEP> 7 <SEP> 12 <SEP> 9, <SEP> 5 <SEP>
 <tb> example <SEP> 1 <SEP> isomer <SEP> "B" <SEP> 15, <SEP> 9 <SEP> 10 <SEP> 7, <SEP> 4 <SEP>
 <tb> example <SEP> 1 <SEP> isomer <SEP> "C" <SEP> 15, <SEP> 1 <SEP> 10 <SEP> 7, <SEP> 3 <SEP>
 <tb> MK <SEP> 0787 <SEP> 14.6 <SEP> 10 <SEP> 6
 <tb> example <SEP> 3 <SEP> 11 <SEP> 8 <SEP> 3.4
 <tb> example <SEP> 4 <SEP> 14, <SEP> 9 <SEP> 6 <SEP> 3, <SEP> 9 <SEP>
 <tb> example <SEP> 5 <SEP> 27 <SEP> 16, <SEP> 7 <SEP> 15, <SEP> 1 <SEP>
 <tb> example <SEP> 6 <SEP> 28.4 <SEP> 14 <SEP> 15.6
 <tb>
 
 EMI61.2
 The compounds were solubilized in 0.1 M phosphate buffer PH 7.



  The values come from a single test, 4 mice were used per connection.

 

Claims (1)

 PATENT CLAIM: Process for the preparation of new carbapenem derivatives of the general formula  EMI61.3    <Desc / Clms Page number 62>    in which R represents a 1-hydroxyethyl group, R15 represents hydrogen or which can be in both a and ss positions, A represents a C.-C-alkylene group, R represents a C1-C3-alkyl or alkenyl group or one carboxylatomethyl group, the rest  EMI62.1  represents a pyridinium, imidazolium, thiazolium, triazolium, tetrazolium or thiadiazolium radical optionally substituted by one to three methyl or benzyl groups, this ring being bonded to A via a ring carbon and containing a ring nitrogen,  EMI62.2  represents a common, easily removable carboxyl protecting group, with the proviso  that when R2 is hydrogen or a protective group there is also a counter ion X "or pharmaceutically acceptable salts thereof, characterized in that a compound of the formula  EMI62.3    EMI62.4  represents protecting group, with a thiol compound of the formula  EMI62.5  where A,  EMI62.6  and R are as defined above and X "is a counter anion, is reacted in an inert solvent and in the presence of a base, in particular sodium hydroxide solution, whereupon the counter ion X) is optionally replaced by another counter ion, an alkenyl group present as R optionally hydrogenated to the corresponding alkyl group and, if necessary, the carboxyl protecting group is split off to give the desired unblocked compound of the formula (I)    or to obtain a pharmaceutically acceptable salt thereof.