AU602131B2 - Cephalosporin derivatives and a process for their preparation - Google Patents

Abstract

Cephalosporin derivatives of the formula <IMAGE> pharmaceutical preparations active against bacterial infections and which contain such cephem derivatives, process for the production of the pharmaceutical preparations and use of the cephem derivatives for combating bacterial infections.

Description

Te the Commissioner of Patents Hoechst PAT 510 Ahollurist Aulnorized ppa. Reuter i.V. Lapice '0 2 13 1rm.

COMMONWEALTH OF AUSTRALIA' PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

Class I t. Class v0 Application Nkimber: Lodged: Complete Specification Lodged: Accepted- Published: Priority: Related Art: t I This doMuImrit contains the amendments made under Section ',and is correct for printing 4 4 $4 4 N.me of Alplicant; 44a Address of Applicant: ,Actjial Inventor Adiress for Service HOECHST AKTIENGESELLSCHAFT Bruningstrasse, D-6230 Frankfurt/Main Federal Republic of Germany RUDOLF LATTRELL, WALTER DUROKHEIMER, REINER KIRRSTETTER and GERHARD SEIBERT EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 300.

~'CompI'ate Specification for the invention entitled: CEPHALOSPORIN DERIVATIVES AND A PROCESS FOR THEIR

PREPARATION

The following statemn,-.t a full description of this invention, Iricludin4 the best m-lthod of performing it known to 1, US I I S. -la-' HOECHST AKTIENGESELLSCHAFT Dr.KA/gm HOE 85/F 254 Cephalosporin derivatives and a process for their preparation The invention relates to novel cephalosporin derivatives which are substituted in the 3'-position of the cephem ring by an imidazole ring bonded via the nitrogen and which have a very good antimicrobial action against Grampositive and Gram-negative bacteria and are therefore suitable as medicaments for the treatment of microbial infections, and to a process for their preparation.

The invention therefore relates to cephalosporin derivatives of the general formula I C -CONH S)T t 2N R CH2R3

COOR

4 and physiologically acceptable acid addition salts thereof, in which R denotes hydrogen or halogen,

R

2 denotes hydrogen,

C

1

-C

6 -alkyl, which can be mono- or polysubstituted by identical or different substituents from the group comprising halogen, aryl, heteroaryl, C 1

-C

4 -alkylthio,

C

1

-C

4 -alkoxy, nitrile and carbamyl, in which the amino group can be mono- or disubstituted by identical f or different substituents from the group comprising C1-C 6 -alkyL, hydroxy-(C 1 -C2)-alkyl, hydroxyl and S' methoxy, C2-C6-alkenyl, which can optionally be mono- or polysubstituted by identical or different substituents from the group comprising halogen,

C

2

-C

6 -alkynyL, which can be optionally substituted by halogen, -2-

C

3 -C7-cycLoaLkyL, which can be optionally substituted by halogen,

C

4

-C

7 '-cycLoaLkenyL,

C

3

-C

7 -cycLoaLkyLmethyL, the group -CH 2

=CH-R

7 or-(H -CmR in which mn and n each represent 0 or 1 and

R

5 and Rcan be identical or different and denote hydrogen, aryt or a Cl-CII-aLkyL group, or together with the carbon atom to which they are bonded form a uethyLene or a C3-C 7 -cycLoaLkyLidene group,

R

7 denotes an HOOC- or Cl-C 4 -aLkyLQOC- group, R 3 denotes an imidazoL-1-yL radical which can be mono- or poLysubstituted by identical or differ- 'lot* ent substituents from the group comprising C 1

-C

6 o 15 atkyL, which can be mono- or poLysubstituted by hydroxyL, acetoxy, carbamyloxy, chlorine, carboxyL, 0.:C I-C 6 -a Lkoxyc arbony L, f o riy L C I-C 6 -a Lky Lc arbony L 0:1. cyano, carbamyL, amino and Cl-C 6 -aLkoxy and in which 2 adjacent alkyL groups can also be closed to form a di- to decainethyLene ring which is optionally substituted by Cl-C 6 -aLkyt, haLogen, hydroxyl, oko, carboxyL V or carbainyt and in which one carbon atom can be repLaced by ~i an oxygen or sulfur atom and which can also contain one or two double bonds, or by C 2

-C

6 -atkenyL. which can be substituted by hydroxyL, *by C 2

-C

6 -aLkynyL, by C 3

-C

6 -cycloaLkyL, by C 3

-C

6 -cyctoaLky~methyL.

by phenyL or benmyt., wh ich can be subst ituted by C 1 C-a~ikyt, NaLogen, hydroxyL or Cl-C 4 -atkoxy, by Cl-C 6 -aLkoxy or by C 1 -C6-aLkyLthio, by hatogen, trifLuoromethyL. cyano, hydroxyt or mercapto, -3by carboxyL, Cl-C 6 -aLkoxycarbonyt or carbamyL, which can be mono- or disubstituted on the nitrogen by C 1

C

6 -aLkyL, hydroxyt or methoxy; by carbazoyt, which can be mono- or disubstituted on the nitrogen by Cj-

C

4 -aLkyt, by nitro, amino or di-(C 1

-C

2 )-aLkyLamino, or by formyl, Cl-C 4 -aLkyLcarbonyL or aryLcarbonyL, Rdenotes hydrogen, Cl-C 6 -aLkyt, benzhydryL, aLLyl, propargyL, methoxymethyl, C 1

-C

6 -aL kanoyLoxy-C 1

-C

6 idaLkyl, Cl-C 6 -atkoxycarbonyLOxy-n 1

-C

6 -a.kyL, phthaL idyL or 5-methyL-1,3-dioxoLen-2-on-4-yL-methyL, and in which the R group is in the syn-position.

The following substituents, for example, are possible Particularly preferred subst ituents: R hydrogen, fluorine, chlorine or bromine 4 R 2 a Cl-C 4 -aLkyL radical, such as, for example, methyl, ethyl, propyl, isopropyL or butyL, which can be mono- or polysubstituted, preferably mono-, di-, tri- or tetrasubstituted, in particular mono- or disubstituted, for example by fluorine, such as, in particular, monofLuoromethyl, difluoromethyl, triftuoromethyL, 1,1,2,2tetrafluoroethyl, 1,1,1-trifLuoroethyL or 1,1,2,2-tetrafluoropropyl; aLkyl which is substituted by aryL, such as, for example,~ 425 by phenyL, 3- or 4-toLyL or 2- or 3- or 4-chtorophenyL, in particular benzyL; aLkyL which is substituted by heteroaryL, such as, for example, 1,3-thiazot-4-yt-substituted aLkyL, in particular 1,3-thiazoL-4-yL-methyL, or alkyl which is substituted by imidazolyL, such as, for example, imidazoL-1-yL-ethyL, aLkyL which is substituted by Cl-C 4 -atkyLthio, such as, in particular, methylthiomethyt; aLkyL which is substituted by CI-C 4 -alkoxy, such as, in particular, methoxymethyL, ethoxymethyl or ethoxyethyl; alkyl which is substituted by -4 nitrile or carbamyt, it also being possihble for the amino group to be further mono- or disubstituted, for example by Cl-C 4 -aLkyl, such as, in part icular, 'N-methyl-, Nethyl- or N-propyL-carbamyL-methyL, N,N-dimethyL-carbamyLmethyl, N-hydroxy- or N-methoxy-carbaniyt-methyL, N-methyl- N-hydroxy-carb-amyL-methyl or N-hydroxymethyL-carbamyLmethyt, a C2-Cd,-aLkenyL radical, such as, in particular, 2propenyL dr 2-butenyt, which can be mono- or poLysubstituted, preferably mono- or disubstituted, by halogen, such as, in particular, 3-chLoro-2-propenyL or 2-bromo-2-propenyL,

C

2

-C

6 -aLkynyL, such as, in particular, prnpargyL, C3-C7-cYctoaLkyL, such as, in particular, cycLopropyL, cycLobutyL, cyctopentyt or cycLohexyi, C3-C7-cycloaLkyLmethyL, such as, in particular, cycLoprOpyL- or cycLobutytmethyL, C4-C7-cycLoaLkenyt, such as, in particular, cycLopenten-1-yL; the g'roup -(CH 2 -R ,in which R 7 denotes the 6m jfgroup COOH and R~ and Rca'n be identical or different and can denote hydrogen, aryL, preferably phenyL; Cl-C 4 aLkyL, such as, for example, methyl, ethyl, propyl, isopropyL, butyL or sec.-butyL, preferably methyL or ethyl and in particular methyl, or 5 6 in which R and R together with the carbon atom to which they cre bonded, can form a methyl group or a C 3 -1 C7-cycLoaLkyLidene group, such as, for example, cycLopropyL, cycLobutyL, cycLopentyL, cycLohexyt or cycLoheptyl, preferably cycLopropyt, cycLobutyL, cycLopentyL or cyc tohexyL, m =0 or 1 and n 0 or 1, the sum of m and n representing 1 or 2.

Preferred examples of the group I.c are the foL lowing:P in the case where n is 0 and mi is 1:

CH(CH

3

CCCH

3 2

CH(COH

5

CHC

2

H

5 or CH(CH 2 9

CH

3 in the case where m is 0 and n is 1: -CH 2 and if n and mi are 1: -CH 2

-C(=CH

2 R: an imidazoL-1-yL radical, which can be mono- or polysubstituted, preferably mono-, dli- or trisubstituted, in particular mono- or disubstituted, for example by Cl-C 4 aLkyL which is optionally mon~o- or disubstiftuted, preferably optionally monosubstituted, such as, in particular, methyL, ethyl, propyL, isopropyL, n-butyL, sec.-butyL or tert.-butyL, or aLso by in each case two methyl or ethyl groups, by three methyL groups, or by methyl in combination with ethyl, propyl or isopropyl, 15 hydroxy-Cl-C 4 -aLkyL, such as, in particular, hydroxymethyl, hydroxyethyL, hydroxypropyL, hydroxyisopropyL, hydroxybutyL, hydroxy-sec.-butyL or hydroxy-tert.-butyL, and in which, for example, there may also be two hydroxyL groups on the alkyl radical; acetoxy-Cl-C 4 -aLkyL, such as, in particular, acetoxymethyL;., carbamyLoxy-Cl-C 4 -aLkyL, such as, in particular, carbamyLoxymethyL; chLorine-Cl-C 4 -aLkyL, such as, in particular, chLoromethyl; carboxy-Cl-C 4 -aLkyL, such as, in particular, carboxymethyl and carboxyethyt; Cl-C 4 -aLkoxycarbonyL-Cl-C4-aLkyL, such as, in particular, methoxycarbonyLmethyL, ethoxycarbonyLmethyL or methoxycarbonyLethyt; formyL-Cl-C4-aLkyL, such as, in particular, formylmethyL;

C

1

-C

4 -aLkyLcarbonyL-Cl-C4-aLkyL, such as, in particul ar, methiyLcarbonyLmethyL, ethyLcarbonyLmethyL, -6methyLcarbonyLethyL and ethyl carbonyLethyL; cyano-Cl-C 3 -alkyL, such as, in particular, cyanomethyL and cyanoethyl; carbamyl-Cl-C 4 -aLkyl, such as, in particular, carbamyLmethyl or carbamyLethyL; amino-Ci-C 4 -aLkyL, such as, in particular, aminomethyl or aminoethyL, l -C4-aLkoxy-Cl-C 4 -aLkyL, such as, in particular, methoxymethyL, ethoxyinethyl, propoxymethyL, isopropoxymethyl, methoxyethyL, ethoxyethyL, methoxypropyL and methoxyisopr-npyL; C3-C4-aLkenyL, such as, in particular, aLLyL, 2-retliylaLLyL and buten-3-yL, which can also be further substituted by hydroxyl such as, in part icul ar, hydroxyal LyL and hydroxybutenyL; C3-aLkynyL, such as, in particular, propargyL, ij C 3

-C

6 -cycLoalkyL and C 3

-C

6 -cycLoaLkyL-methyt, the carbon number relating to the cycLoalkyL part, such as, in particular, cyctopropyt, cycLobutyL, cycLopentyt, cyclohexyL cyc L c.ropyLme thy L and cyc LopentyL me thyL p ref erabl y cycLopropyL and cycLohexyt, phenyl and benzyl, which can also be substituted, for example by halogen, in particular chLorine and fluorine, such as, for example, 4-chLorobenzyL-4-fLuorophenyL; Cl!;4-a~koxy, such as, in particular, methoxy, ethoxy, propxyisopropoxy, butoxy, isobutoxy and tert.-butoxy, preferably methoxy;

C

1 -C4-aLkyLthio, such as, in particular, methyLthio, eth~thopropytthio and 'isopropylthio; halogen, such as, in particular, fluorine, chlorine, 4 4 bromine or iodine, trifluoromethyL, cyano, hydroxyL, mercapto or carboxyt; Cl-C 4 -aLkoxycarbonyL, such as, for example, methoxycarbonyL or ethoxycarbonyl; carbamyL, which can be mono- or disubstituted on the nitrogen atom by Cl-C4-aLkyL, sv.ch as, in particular, -7 N-methyl-, N-ethyl- or N,N-dimethyLcarbamyL, by hydroxyl or methoxy, such as, for CvxampLe, N-hydroxy- or N-methoxycarbamyL; nitro; amino; or dlimethylamino; carbazoyL, which can be mono- or dlisubstituted on the nitrogen by Cl-C 4 -aLkyL, preferably methyl, such aS, in particuLar, N 1-methyl- or N 1,N 1 -dimethyLcarbazoyL; formyL; Cl-C 4 -aLkyLcarbonyL, in particular acetyt and propionyL; or aryLcarbonyL, such as, in particular, benzoyL.

lf R3repr3sents an imidazoL-1-yL radlical which is substituted by two adjacent aLkyl groups which are cLosed to form a dli- to decamethyLene ring, preferably to form a tri-, tetra- or pentamethyLwene ring, it also being possible for a carbon atom in these fused-on rings to be replaced by an oxygen or sulfur atom and also for thiese rings to contain one or two dloubLe bonds, possible examples of this are:

NG

R 4 hydrogen, Cl-C 4 -aLkyL, such as, in particular, methyl, ethyl or tert.-butyl; benzhydryL, aLLyl, prOpargyL, methoxymethyt, C 1 -C5-aL kaioyLoxy-C 1

-C

3 -aLkyL, such as, in particular, acetoxymethyL, propionyloxymethyL, isopropionyLoxymethyL, n-butyryLoxymethyL, isobutyryLoxymethyl, pivaLoyLoxymethyL, isovaLeryLoxymethyL, 1-acetoxyethyl, 1-n-propionyLoxyethyL or 1-acetoxypropyL; or Cl-C 5 -aLkoxycarbonyLoxy-Cl-C 3 -aLkyLp~ such as, in part icut ar, 1-methoxycarbonyLoxyethyL, 1-ethoxycarbony IoxyethyL, 1-isopropoxycarbonytoxyethyL, methoxycarbonyLoxymethyl, phthaL idyL or 5-methyL-1,3-dioXoLen-2-on-4-yLmethyl.

The invention furthermore relates to a process for the preparation of compounds of the formula I and their S 8 physiologically acceptable acid addition salts, which comprises a) reacting a compound of the general formula II

(II)

or salts thereof, in which R 1

R

2 and Rhave the meaning given in formula 1, the amino group can also be protected and R denotes a group which can be replaced by imidazole or that imidazole derivative which corresponds to the radicals R 3 of formula I, with imidazole or this imidazole derivative, a) splitting off any protective group present and B) if necessary, converting the resulting product into a physiologically acceptable acid addition salt, 4i 14 44 4 4 44 4i 4 Itt or b) 444444 t 4,44 4a44I 4li reacting a compound of the general formula III

R

9 H

H(III)

R 4 2 in which R and R 8 have the meaning given above for formula II and R represents hydrogen or an aminoprotective group, with imidazole or the imidazole derivative on which the radical R 3 defined in formula I is based, to form the compound of the general formula IV 9 R NH ,1 1 (IV) N 4H 2R 3 002 in which R R 4 and R 9 have the abovementioned meaning and a) splitting off any amino-protective group present and 0) reacting the compound IV in which R 9 denotes hydrogen, either as such or in the form of a reactive derivative, with a 2-syn-oxyiminoacetic acid of the general formula V N -C-COOH I

(V)

OHR

f t 1 2R v in which R and R have the meaning given and the amino group can also be in the protected form, or with a derivative of this compound activated on the carboxyl group and a) splitting off any protective group present, 8) if necessary, converting the resulting product of the general formula I into a physiologically acceptable acid addition salt and y) if esters are to be obtained, converting the com- ,pounds of the formula I in which R represents hydrogen obtained by process variants a) or b) into the esters mentioned under R in a manner which is known per se.

If the preparation of the compound of the general formula I by process variant a) is to be carried out by nucleophilic replacement of R8 in the compounds of the general formula II by imidazoLe or one of the imidazole derivatives mentioned, possible radicals R are, in particular', acyloxy radicals with lower aliphatic carboxylic acids, preferably with 1 to 4 carbon atoms, such as, for example, acetoxy or propionyloxy, in particular acetoxy, which can be optionally substituted, such as, for example: chloroacetoxy or acetylacetoxy. Other groups are also possible for R 8 such as, for example, carbamyloxy or a halogen atom, such as, for example, chlorine, Lromine or iodine.

The nucleophitic replatement reaction on compounds of the general formula It can be effected by a procedure in which the reaction is carried out in the presence of imidazole or the imidazole derivatives corresponding to the radicals R and tri-Cl-C4-alkyliodosianes, such as, for example, trimethyL- or triethyLiodosiLane. A procedure can be followed here in which the compound II in which R represents acetoxy is first reacted with trimethyliodosilane under the reaction conditions mentioned below, and the compound 11 formed, where R8 I, is isolated and then reacted with imidazoLe or the imidazole derivative, or the 3-lH 2 1 compound is reacted in situ by addition of the imidazoLe or imidazote derivative. Instead of trimethyLiodosiane, it is also possible, for example, to use a reaction mixture of iodine and hexamethyldisiane which has first been reacted at telaperatures between and 120 0 C in a manner which is known from the literature, trimethyliodosilane being formed, Instead of trimethyiodosilane, triethyliodosiLane, which is prepared in m manner which is known from the literature, can also be used with the same good result.

The reaction is carried out at temperatures between abotk aiid '+100 0 C, prsferably between +10 0 C and +80 0

C,

Exampltes of suitable tinert aprotic solvents ted hydrocarbonso such aS methylene chloridS AnW dichioroethane, trichtoroethane and carbon tetrachLoridle, or Lower al.kyLiitrites, such as acetonitriLe or propionitrite, or frig-ens; methyisne chtoride is a particularly outstanding soLvent.

Thi imidlazoLe or irdidazote derivative cor-esponding to the radicaL R 3 is~ added in at Least the sto~iciometric amount up to a twenty-foLd excess, and the reaction is preferabLy carried out with amounts such that the amount of hydrogen iodide Liberated is bonded and at Least another moL, preferably 1.5 5 moL, of imidazole or imidazoLe derivative are avaiLabLe for the replacement react ion.

Since other functionat groups in the starting compound II, such as, for example, the amino group or the carboxyL group, in addition to the group P, to be replaced, also react with trimethyLiodositane,, the Latter is added in at Least a two-fold to a fifteen-fold excess, preferably in a three-fold to ten-fold excess.

Such functional, groups can aLso be presiLyLated by addi- $ion of a siLyLating agent, such as, for example, bistriklethyigiLyLacetamide, N-i-,ethyL-N-trimethyLsitLtrifLuoroucetamidej bistr hnethytsiLyLtrifluoroacetamide, tr imiethyL~chLoro i lane, hexcmethyLdisitazane or bistrimethyLsiLyLurea, in either the presenice or the absence of a base, preferabLy the desired imidazoLe or iridazoLe derivative on which the group Ris based, in the amoun'cu described above. Trimethytiodositane is then added in at least the stoichiometric amount or in excess, prefer-ably in a twofoLd to ten-fold excess.

If the amino group in the formulae 11 and V is in the protected form, suitabLe amino-protective groups are, for exampLe, optionally substituted atkyL, such as, for exapmpLep tert.-butyL or ttrt.-amyt; enzyL, p-methoxybenzyt, trityL or benzt,,-"vL, preferabLy trityL; triatkyt- 12 silyl, such as, for example, trimethyLsiLyL; optionally substituted aliphatic acyl, such as, for example, formyL, chloroacetyl, bromoacetyL, trichloroacetyl or trifluoroacetyL, preferably formyl; or optionally substituted aLkoxycarbonyl, such as, for example, trichloroethoxycarbony, benzytxycarbony or tert.-butoxycarbonyL, preferably tert.-butoxycarbony or benzyLoxycarbonyl; or dimethylaminomethyLene.

After the replacement reaction, the protective group caz be split off in a manner which is known per se, for example the trityL group can be split off by means of a carboxylic acid, such as, for example, acetic acid, trifluoroacetic acid or formic acid, or the benzyloxycarbony group can be split off hydrogenolytically.

After addition of water or aqueous mineral acids, for example dilute HCL, HBr, HI or H 2 S0 4 the reaction products of the formula I can, for example, be isolated from the aqueous phase in the customary manner, for example by freeze-drying the aqueous photse, chromatography or precipitation by addition of organic solvents. The reaction products are preferably isolated by precipitation from the reaction solution in the form of a sparingly soluble salt, for example a hydriodide salt.

In the case where R represents a carbamyoxy group, the replacement reaction is carried out analogously. If R 8 represents bromine, the repacement is carried out in a manner which is known from the literature.

According to process variant the compounds of the general formula I are obtained by acyLation of compounds of the general formula IV or addition salts thereof, for example with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid or an organic acid, such as, for example, methanesulfonic acid or toluenesulfonic acid, with carboxylic acids of the genera c r WIU~I( IPl~_rl I ii 13 formula V or with a reactive derivative of such an acid.

It is not necessary here for the compounds of the general formula IV to be isolated. The reaction can also be carried out by a process in which compounds of th2 general formula III, for example 7-aminocephalosporanic acid or 3 -iodomethyL-7-amino-ceph-3-em-4-carboxylic acid or reactive derivatives thereof, are reacted with the imidazole or imidazole derivative corresponding to the radical R 3 in the general formula IV in a suitable solvent and the compound of the general formula IV formed is acylated in situ to give the compounds of the general formula I.

According to the invention, starting compounds of the general formula III in which R 8 represents iodine are employed in this reaction. Suitable solvents are chlorinated hydrocarbons, such as, for example: methylene chloride and chloroform; ethers, such as, for example: diethyl ether, tetrahydrofuran and dioxane; and acetonitrile and amides, such as, preferably, dimethylformamiide and dimethylacetamide. It may also prove to be advantage- 20 ous to use mixtures of the solvents mentioned.

If the compounds of the general formula III are in the form of a reactive derivative, particularly suitable derivatives are slLyl derivatives, which are formed by reacting compounds of ch general formula III with silyl compounds, such as, for e-ample, trimethylchlorosilane, bis-(trimethylsilyl)-trifluoiroacetamide and the like.

The base corresponding tt the radical R3 is used in at least th stoichiometric amount up to a ten-fold excess, preferably in an amount of 1.5 to 5 equivalents. The reac- 30 tion is carried out at temperatures between about -50 and +100 0 C, preferably between +20 and +50 0

C.

II

*r 4 4 'itr it 4,t t t 1 4 The compounds of the general formula IV can he prepared from compounds of the general formula III wherein R 8 represents acetoxy in a manner analogous to that described above for the compounds of the general formula II.

1 11 IUUWI I is. d lull oesurplton OT 1 ns unventlon, inclualng Ine DU im imluu 14 If the carboxyLic acids of the general formula V and their derivatives protected on the amino group are employed themselves as the acylating agent, the reaction bs advantageously carried out in the presence of a condensing agent, for example a carbodiimide, such as, for example, N,N'-dicycLohexycarbodiimide.

CarboxyLic acids of the general formuLa V can be activated in a particularly advantageous manner by treatment with certain carboxylic acid amides and, for example, phosgene, phosphorus pentachloride, tosyL chloride, thionyL chloride or oxalyL chloride, such as is described, for example, in German Patent 2,804,040.

Further particularly suitable activated derivatives of the carboxylic acids of the general formuLa V are halides, preferably chlorides, which are obtained in a known manner by treatment: with halogenating agents, such as, for example, phcsphorus pentachloride, phosgene or thionyL chloride, under the gentle reaction conditions known from the Literature for cephaLosporin chemistry.

Suitable activated derivatives of the carboxyl c acids of the general formula V are furthermore the anhydrides and mixed anhydrides, azides, activated esters and thioesters.

Particularly suitable mixed anhydrides are those with Lower alkanoic acids, such as, for example, acetic acids, and particularly preferably those with substituted acetic acids, such as, for example, trichLoroacetic acid, pivalic acid and cyanoacetic acid. However, the mixed anhydrides with crbonic acid half-esters, which are obtained, for example, by reaction of the carboxytic acids of the formula V, in which the amino group is protected, with benzyL, p-nitrobenzyL, iso-butyL, ethyl or allyl chLoroformate are also particularly suitable.

Suitable activated esters are preferably those with pnitrophenol, 2,4-dinitropheno methyLcyanohvdrin, N- Li: .I -s 15 hydroxysuccinimide and N-hydroxyphthalimide, and especially those with 1-hydroxybenzotriazole and 6-chloro-1hydroxybenzotriazole. Particularly preferred thioesters are, for example, those with 2-mercaptobenzothiazole and 2-mercaptopyridine. The activated derivatives can be reacted as isolated substances or also in situ.

The reaction of the cephem derivatives of the general formula IV with a carboxylic acid of the general formula V or an activated derivative thereof is in general carried out in the presence of an inert solvent. Particularly suitable solvents are chlorinated hydrocarbons, such as, preferably, methylene chloride and chloroform; ethers, such as, for example, diethyl ether and, preferably, tetrahydrofuran and dioxane; ketones, such as, preferably, acetone and butanone; amides, such as, preferably, dimethylformamide and dimethylacetamide, or pyridine. It may also prove to be advantageous to use mixtures of the solvents mentioned. This is frequently the case if the cephem compound of the general formula IV is reacted with S 20 an activated derivative produced in situ from a carboxylic t acid of the formula V.

The reaction of cephem compounds of the formula IV with carboxylic acids of the formula V or activated derivatives thereof can be carried out in a temperature range from about -80 to about +80oC, preferably between about and room temperature.

l The reaction time depends on the reactants, the temperature and the solvent or solvent mixture and is usually between 1/4 and about 72 hours.

If appropriate, the reaction with acid halides can be carried out in the presence of an acid-binding agent to bond the hydrogen halide Liberated. Suitable acid-binding agents are, in particular, tertiary amines, such as, for example, triethylamine or dimethylaniline, inorganic bases, by halogen, trifluoromethyl, cyano, hydroxyl or mercapto, 16 such as, for example, potassium carbonate or sodium carbonate, or alkylene oxides, such as, for example, propylene oxide. The presence of a catalyst, such as, for example, dimethylaminopyridine, can, if appropriate, also be of advantage. If the amino group in the compounds of the general formula IV is in the form o'f a reactive derivative, this derivative can be a derivative such as is known from the literature for amidation reactions.

Suitable derivatives are thus, for example, silyl derivatives, which are formed by reacting compounds of the general formula IV with a silyl compound, such as, for example, trimethylchlorosilake or bis-(trimethylsilyl)acetamide. If the reaction is carried out with such a compound activated on the amino group, it is advantageous to carry out the reaction in an inert solvent, such as, for example, methylene chloride, tetrahydrofuran or dimethylformamide.

D4 t If compounds of the general formula I in which R represrsi ents Cl-C6-alkanoyloxy-Cl-C 6 -alkyl, Cl-C 6 -alkoxy- 20 carbonyloxy-C 1

-C

6 -alkyl, phthalidyl or 5-methyl-1,3dioxolen-2-on-4-ylmethyl are to be obtained, the compounds of the general formula I in which R 4 denotes hydrogen are reacted with a compound of the general formula VI X CHO Rb

(VI)

Ra o in which Ra denotes hydrogen or a C 1

-C

5 -alkyl group and Rb denotes a C 1

-C

6 -alkyl or a Cl-C 6 -alkoxy group, rJ^ 1or VII or VIII (UI

XCH

2 CN 3 S(VI) 2 0 17 t" °sr^ 0

I

in which as also in formula VI X represents halogen, t/r: ~4LL :I 17preferably chlorine, bromine or iodine, in a manner which is known per se. Processes such as are known for esterification reactions are used. If R 4 represents CI-C 6 alkyl, benzhydryl, allyl or propargyl, the esterification methods known from the Literature for these groups are used. Protective groups can be removed in a known manner, as described above.

Examples which may be mentioned of physiologically acceptable acid addition salts of the compounds of the general formula I are those with hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid or organic acids, such as, for example, methanesulfonic acid, Sp-toluenesulfonic acid or maleic acid.

The imidazoles used according to the invention and other starting compounds are known from the literature or can I't"t be obtained by processes which are known from the litera- I ture.

t c SThe compounds of the general formula I obtained according t to the invention and their physiologically acceptable acid addition salts exhibit a remarkably good antibacterial activity against both Gram-positive and Gram-negative bacterial germs.

The compounds of the formula I also have an unexpectedly good action against bacteria which form penicillinase and cephalosporinase. Since they also have favorable toxicological and pharmacological properties, they are useful chemotherapeutics.

''"The invention thus also relates to medicament products for the treatment of microbial infections, which contain one or more of the compounds according to the invention.

The products according to the invention can also be used ~il~i L r iii. i. r _I i: i- i i(nrri 18 in combinations with other active compounds, for example from the series comprising penicillins, cephalosporins and aminoglycosides.

The compounds of the general formula I and their physiologically acceptable acid addition salts can be administered orally, intramuscularly or intravenously.

Medicament products which contain one or more compounds of the general formula I as the active substance can be prepared by a process in which the compounds of the formula I are mixed with several pharmacologically acceptable excipients or diluents, such as, for example, fillers, emulsifiers, lubricants, flavor correctants, colorants or buffer substances, and the mixture is brought into a suitable galenical formulation form, such as, for example, tablets, coated tablets, capsules or a suspension or solution suitable for parenteral administration.

Examples of excipients or diluents which may be mentioned are tragacanth, Lactose, talc, agar-agar, polyglycols, ethanol and water. Buffer substances are, for example, S 20 organic compounds, such as, for example, N,N'-dibenzylethylenediamine, diethanolamine, ethylenediamine, Nmethylglucamine, N-benzylphenethylamine, diethylamine and tris-(hydroxymethyl)aminomethane, or inorganic compounds, S. such as, for example, phosphate buffer, sodium bicarbonate or sodium carbonate. Suspensions or solutions in water h with or without buffer substances are preferably suitable for parenteral administration. It is also possible to administer the active compounds as such in a suitable ro 1 form, for example in capsules, without an excipient or diluent.

Suitable doses of the (ompounds of the general formula I or their physiologically acceptable acid addition salts are about 0.4 to 20 g/day, preferably 0.5 to 4 g/day, for an adult with a body weight of about 60 kg.

19 Individual or in general multiple doSes can be administered, it being possible for the individual dose to contain the active compound in an amount of about 50 to 1,000 mg, preferably about 100 to 500 mg.

The following embodiment examples of syn-compounds which can be prepared according to the invention serve to further illustrate the invention, but do not limit it 'hereto.

Example 1: 7-[2-(2-AminothiazoL-4-yL)-2-syn-methoxyimino-acetamido]- 3-[(2-methylimidazol-1-yl)methyl]-ceph-3-em-4-carboxytic acid Process a) 11.8 g (26 mmol) of 7-E2-(2-aminothiazol-4-yl)-2-synmethoxyimino-acetamido3-cephaLosporanic acid are suspended in 50 mL of chloroform, 16.25 ml (88 mmol) of N-methyl-Ntrimethylsilyltrifluoroacetamide (MSTFA) are added and the mixture is stirred at room temperature for 1 hour. The mixture is cooled to 18 0 C, 10 ml (79 mmoL) of iodotrimethylsilane are added and the mixture is stirred at room temperature (23 0 C) for a further 20 minutes. It is concentrated in vacuo, the oily residue is dissolved in 50 ml of acetonitrile and 2.1 ml of tetrahydrofuran are added.

This solution is added all at once to a mixture of 2.63 g (32 mmol) of 2-methylimidazole and 11 ml (59 mmol) of MSTFA in 26 mL of acetonitrile and the dark-colored solution is left at room temperature for 1.5 hours. 3.1 mL of water are then added, while cooling with ice and shaking.

After 10 minutes, the precipitate formed is filtered off with suction, washed twice with acetonitriLe and then with ethanol and ether and dried. Yield of hydriodide salt of the title compound: 13.8 g (88% of theory). The crude hydriodide is dissolved in aqueous sodium bicarbonate I- 20 solution and chromatographed over silica gel (5 x 55 cm column) with acetone:water After freeze-drying fractions 8-14 (800 ml), 1.1 g of the A 2-compound are obtained, and fractions 15-24 (1.2 liters) give 7.5 g of the title compound as a yellowish-colored amorphous solid.

1 H-NMR (DMSO-d 6 6 H-NMR (DMSO-d6) 6 2.33 3H, IM-CH 3 3.02 and 3.26 (AB,I 18Hz, 2H, SCH 2 3.82 3H, OCH 3 4.90 (AB, 2H, CH 2 5.02 J 5Hz, 6-H); 5.60 (dd, J 5 and 9Hz, 6.70 1H, thiazole-H); 6.78 (cd, J 2Hz, 1 imidazole-H); 7.20 (bs, 3H, NH 2 and 1 imidazole-H); and 9.52 ppm J 9Hz, 1H, CONH).

Process b, variant a 3.39 g (10 mmol) of 7-amino-3-iodomethy-ceph-3-em-4carboxyic acid are suspended in 80 ml of tetrahydrofuran and, after addition of 5 mL (20 mmol) of bis(trimethytsilyl)acetamide (BSA), the mixture is stirred at room temperature for 1.5 hours. 1.23 g (15 mot) of 2-methyLimidazoe are then added, while cooling, and the mixture is stirred at room temperature (23 0 C) for 4.5 hours.

1 mL of water is then added, while cooling, and the precipitate formed is filtered off with suction and washed with ethanol, acetone and ether. 4.5 g of the monohydriodide salt of 7-amino-3-E(2-methyimidazo-1-yL)methyl]ceph-3-em-4-carboxyic acid are obtained. The crude salt is introduced into a solution of 2.86 g (9 mmol) of the active hydroxybenzotriazoe ester of 2-(2-aminothiazoL-4yl)-2-syn-methoxyiminoacetic acid in 60 mL of N',N-dimethylformamide and 2 mL of water. The mixture is left at 5 0

C

for 8 hours. The dimethylformamide solution is poured into 1 liter of ether, the precipitate which has separated out is dissolved in aqueous sodium bicarbonate solution The invention furthermore relates to a process for the preparation of compounds of the formula I and their L-CUI ICIUtYIC"-_I-~ gl IIFL~III-~. :~IIC 21 and the dark-colored solution is chromatographed over a "Lobar-C" silica gel column (Merck-Darmstadt) with acetone:water After freeze-drying the product fractions, 990 mg (23% of theory) of an amorphous solid are obtained. The solid is identical in all its properties to that of the product obtained by process a).

Process b, variant B 7-Amino-3-[(2-methylimidazo-1-yl)methyt]-ceph-3-em-4carboxylic acid monohydriodide 2.96 g (10.8 mmol) of 7-aminocephalosporanic acid and mI (9.7 g, 37.8 mmol) of N,0-bis(trimethylsilyl)-trifluoroacetamide (BSTFA) in 25 ml of methylene dichloride are kept under reflux for 1 hour. The solution is cooled to 20°C and 4 ml (28 mmol) of iodotrimethylsilane are added. The mixture is kept at room temperature for minutes and concentrated in vacuo and the oily residue is dissolved in a mixture of 20 ml of acetonitrile and 0.8 ml of tetrahydrofuran. The solution is cooled to 15°C and a solution of 1.07 g (13 mmol) of 2-methylimidazole and 5.0 M1 of BSTFA in 10 ml of acetonitrile is added. The dark-colored mixture is left at room temperature for hours and is then hydrolysed by addition of 1 ml of water, while cooling. After 1 hour, the precipitate formed is filtered off with suction, washed twice with acetonitrile and then with ethanol and ether and dried. 4.2 g (10 mmol, 92% of theory) of the title compound are obtained.

NMR (CF 3

CO

2 D) 6 2.81 3H, CH3); 3.60 (AB, 2H,

SCH

2 5.1 5.8 4H, 21actam- H and CH2N); and 7.2 7.55 ppm S 30 2 imidazole-H) By acylation with the activated hydroxybenzotriazole ester of 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetic acid in dimethylformamide/H20, 7-E2-(2-aminothiazol-4-yt)-2syn-methoxyimino-acetamido3-3-[(2-methy imidazot-1-yl)-

IYPI~-~CC~

^Llrr~-~-lrrr-r~~ 22 methyl3-ceph-3-em-4-carboxyic acid is obtained as an amorphous solid, after chromatography, as described above in variant a. The compound is identical in all its properties to that obtained by process a).

Example 2: 7-E2-(2-Aminothiazot-4-yL)-2-syn-(2-carboxyprop-2-yLoxyimino) acet amido J-3-E C 2-met hy L-imidaz oL-1-yL) me t hyL3-c eph 3 -em-4-carboxyic acid Ii i* 1.1 g (2 mmol) of 2-syn-(2-tert.-butoxycarbony-prop-2-yLoximino)-2-(2-trityLaminothiazoL-4-yL )-acetic acid are stirred together with 0.32 g of 1-hydroxy-1H-benzotriazoLe hydrate and 0.5 g of N,N'-dicyclohexycarbodiimide in 9 ml of dimethytformamid, at room temperature for 3 hours.

The dicyclehexyure, which has precipitated out is filtered off and 760 mg (1.8 mmoL) of 7-amino-3-E(2-methyimidazo-1-yl)methyL -ceph-3-em-4-carboxyLic acid monohydriodide (Example 1, process b, variant B) are added to the solution of the active ester. After 17 hours at room temperature, the mixture is stirred into 800 mL of ether and the product which has precipitated out is filtered off with suction and dried in vacuo. The crude product is dissolVed in 20 ml of 90 percent strength trifluoroacetic acid. After 20 minutes, the solution is concentrated in vacuo and the oily residue is evaporated twice with toluene. The residue is dissolved in aqueous sodium bicarbonate solution and chromatographed over a "Lobar B" silica gel column (Merck, Darmstadt) with ethyl acetate/isopropanoL/water (20:15:10). After freeze-drying of the product fractions, 306 mg (28% of theory) of the title compound are obtained as a paLe yellow amorphous solid.

SH-MR (DMSO-d 6 i 1.42 CS, 3H, CH 3 1.47 3H, CHI); 3.00 and 3.18 (AB, J 18Hz, 2H, SCH 2 4.75 and 4.95 (AB, 2H, CH 2 4.99 J 23 5.58 Cdd, J 5 ard 8Hz, 6.70 1H, thiazoLe-H); 6.82 1 imidazote-H); 7.15 Cbs, 3H, NH2 and 1 imidazote-H); and 10.55 ppm J 8Hz, 1H, CONH).

The examples Listed below are obtained anaLogoiusLy to ExampLe 1, process a) as amorphous solids which correspond to the generaL formula I where R4= hydrogen, and in which R 1 R 2 and R 3 have the meaning given in Table 1.

I

I

~IJ

I

tI

I

It

I

14 41: 1 It 4 t

II

1(4 I

II

I

II It 14 24 Table 1 Example-* R 2 I H-NMR (solvent) 6 (pprn)

I-

3 4

H

H

H

CH

3

CH

3

CH

3

=N

-NJ

CWF

3 C0OD) 3.52 and'3.80 CAB, J3 18 Hz, 2H, SCH 2 4.24 Cs, 3H, VCH 3 5.20 and 5.70 CAB, 3 101, 0 2 5.36 M. 3 a 5Hz, 6-H) 6.11 3 7.43 Cs, 1H, Thiazole-H); 7.53; 7.66 and 8.92 (in each case one bs, 3 Imidazoll-H),

WCF

3 COOH) 2.46 Cs, 3H, CH 3 3.50 and' 3.75 CAB, J 18Hz, 2H, SCH 2 4.25 CS, 3H. OCHi 3 5."18 and 5.65 (AB, 3 14Hz, CH 2 5.35 Cdo 3 64H) 6.05 (do 3 5Hz, 7-H); 7.35 Cm, 2H, Thiazole- andlmldazole-H) 8.71 CbS,1 lmidazo-i&'4.)

(CF

3 COOD) 1,52 Ct, 3H, CH 2

CH

3 3.13 Cq, 2H. CWCH 3 3.41 and 3.70 (AB, 3 18Hz, 2H. SCH 2 4.24 Cs, 3H, OCH 3 5.20 and' 5.58 CAB, 3 CH 2 5.38 Cd, 3 5Hz, 6-H); 6.08 Cd, 3 5Hz, 7M); 7.2 7.55 CK 3H., Thlazole-H and2 Imidazole-H) 1 25 TabLe 1 (Continuation) IH-NMR (solvent) ExampLe 8 (ppm).

CH

3 4 t

I

S

S

CF020): 2.70 Cs, 3H, CH 3 2.79 CS, 3H, CH 3 3.42 and 3.70 J.

1BHz, 2H, SCH 2 4.27 Cs, 3H, DCH); 5.10and' 5.50 CAB, J a 15Hz, CH 2

N);

5.37 Cd, J a Hz, 6.28 3 LIS Cs, 1 Imidazole-H); 7.41 CS, I Thiazole-H); CDMSO-d 6 2.36 Cs, 3H, CH 3 3.10 and 3.30 (AB. 31-H z, 2H, SCH 2 3.83 s, 3H, OCH 3 4.89 (AB, 2H,

CH

2 5.05 Cd, J 5Hz; 5.65 (dd, 3-5 and 8Hz, 6.92 Cbs, 1 nidazol elH) 7.22 (bs, I Imidazole-H),7,32 (bs, NH 2 9.45 Cd, 3.;1z, CONH); (DMS0-d 6 1.30 Ct. 3H, CH 2 2H 3 236 Cs, Bh, CH 3 3.20 (AB, 2H.

SCH1 2 3.64 Cs, ,0CHP 3 );4.15 (q, 2H CH CH 3 4.95 CAB, 2H, CH N); 5Hz, 5.55 (ddl -',and BHz, 6.62 Cs, Thazole-H) 7,96 bs,1-mmidazole-H) 943 3 8Hz, CONH).

(DMSO-d 6 2.33 Cs, 3H, CH 3 3.35 CAB, 2H, SCH 2 3.S Is, 3H, OCH 3 4.65 (AS, 2H, CH 2 4.92 Cd, 3a 5Hz, 5.50 Cdd, J-5 and BHz 6.70 Cs, 1 Cm3H$ andl I Wdazole-H);9.42 KCd. ft, 3. Uk

CH

3 C

M

3 c0 2

C

2

HS

#4 '4 4

A

3 sutfonic acid, with carboxyLic acids of the generaL

K

4 26 Table 1 (Continuation) P H-Nt4R Example C'soLv.ent): 8iCppm) 12

CH

3

CH

3 CH 3 CH 2 0H Ii NO2 (DMS0-d 6 2.28 AS, 3H. CH 3 3.05 (AB, 2H, SCH 2 4.31 Cbs, 2H, GC1 2 4.80 (AB, 2H, CH 2

N);

4.98 Cd, 3 5Hz,6i-H); 5.56 (dd, 3 m 5 and 8Hz, 6.70 (S.

1 ThiazolenH),,6.78 1 Imldazole- 7.0 7.3 CK 1 Imldazole-H and NH 2 11.10 3 8Hz, CONH); (CF0C 2 2.47 CS, 3HACHP) 3.62 CAB, 2H, SCH 2 4.22 Cs, 3H, OCH 3 5.00 CS, 2H, CH 2 OH); 5.32 and 5.63 (AB, J',14Hz, CH 2 5.33 Cd, J a 6-H) 6.05 Cd, J3-5Hz, 7 7.40 'Thia?7,,1e-H);8.72 Cs, ImidaZol e-H);

MC

3 OPD): 2.42 Cs, 3H, CH 3 3,65 CAB, 2H, SCH 2 4.25 Cs, 3H, OCHP) 5.22 WS 2H1, CH 2 N) 5.39 Cd, J3m SH'z, 6.20 Cd. J3a5Hz, 7H).

7.43 Cs, Thlmzole-H);7.50 Cs, Imi dazole- H) i~.

t 1 above for the compounds of the general formula II.

-27- ExampLe 13: 7-(2-(2-AminothiizoL-4-yL -2-syn-hydroxy im ino-acetam idol- 3-U(2-methyl -im icdazoL-1 -y I)methyl J-ceph-3-em-4-carboxyL i c acid A solution of the act ive ester is prepared f rom 671 mg CI imol) of 2-(2-trity aminothiazoL-4-yL)-2-trityLoxyiminoacetic acid, 160 zwf; of 1-hydroxy-1H-benzotriazote hydrate and 250 mg of N,N'-dicycLohexytcarbodiimide in mi of dimethytfo;-mamide analogously to Example 2.

After addition of 380 mg (0.9 mmoL) of 7-amino-3-U(2methyL imidazoL-1-yL )met hytLJ-ceph-3-em-4-carboxyL ic acid monohydriodide, the mixture is Left at room temperature for 4 hours and at 5 0 C f or 17 hours. -The dicycLohexyLurea which has precipitated out is f iltered off and the 15 solution is concentrated in vacuo. The oily residue is t 41 dissolved in 20 mLt of 90 percent strencn trifLuoroacetic acid. The solution is Left at rooi, temperature for t minutes and concentrated in vacuo and the residue is Vevaporated twice with toLuene. The residue is then suspended in ether, filtered off with suction and washed with ether. Yield: 0.35 g. 7his crude product is dissolved in aqueous sodium bicarboitate solution and chromatographed over a "Lobar B" siLica geL column with ethyL acetate/ isopropanoL /water (20: 15: 10). After ,reeze-drying the product fractions, 80 mg of the title compound are obtained as a yellowish-colored amorphous soL id.

ktH-N'R (CF 3

CO

2 D) :2.80 3H, CHQ); 3.40 and 3.65 CAB, J 18Hz, 2H, SCH 2 5.05 5.72 Cm, 3H, AB of CH 2 N and 6-H); 6.29 Cd, J 5Hz, and 7.3 7.6 3H1, 2 imidazole-H, 1 tlaoLe-H).

The examples shown beLow are obtained analogously to Example 1, process variant 8) from 7-amino-3-t(2- P reTeraoLy those with p- nitrophenoL,

Z,

4 -dinitrophenot, thyLcyanogvdr in,

N-

r: 4 -1 ,i r

B

ii: _i -_ltllC*I~_l

L

28 methyl imidazo-1-yL )methyLJ-ceph-3-em-4-carboxytic acid monohydriodide and the corresponding active HOST esters, as amorphous solids which correspond to the generaL formula I where R1 and R 4 z hydrogen and R and in which R 2 has the meaning given in Table 2.

Table 2 1

H-NMR

Example Csolvent) :8(ppM).

U

.C

2

H

5

-CH

2

CONH

2

.CH

2

MKH

3

CF

3 COOD) 1.45 Ct, 3H, CH 2

CH

3 2.83 Cs, 3H, CH); 3.43 and 3.73 CAB, J 18Hz, 2H, SCH 2 4.55 2H, CH 2

CH

3 5.22 and 5.55 CAB, 3. 15Hz, CHN); 5.38 6.10 3 SHz, 7.2 7.6 Cm, 311, Thiszole-Hand 2 Imidazole-H).

(CF

3

CO

2 2.83 Cs, 3H, CH 3 3.42 and 3.69 (AB, 3J18Hz- 2H, SCH 2 )t 5.02 (s, 2H, CH 2

CONH

2 5.1 -5.7 m, 3H, AB of

CH

2 Nanid 6.23 3.5Hz, 7.2-7.65 (Mn, 3H, 2 Imidazole-H) and 1 Thiazol e-H) ftCSW 6 2.31 (h,3HaF, 3 2.63 3H* KHM, 3.05ard 3.29 (AB, =l17Hz,2H, 4.4 2H, C2=IC3)1 4.85 ad 4.95 COD, 3.15Hz, QR 5.07 J.Hz, 6-N) 5.71 (dri, J-5 and 8f, 6.82 17hiazole-H); 6.93 lzmidazole 7.22 bS, 11 jkdazOle-fO,7.2R (bs, 2H, NH2); 7.43 id. J5H7.

%N"

3 9.70 J4WZ, Coll').

agents are, in particuLar, tertiary amines, such as, for exampte, triethytamine or dimethytanitine, inorganic bases, 4 29 Table 2 (Continuation) Example

IR

I 1 .WMR C~olventY Dr8 I HNR (s1et

-CH

2 -K1

-CH

2 CnCH OCF 3

C

2 0.2-1.5 Cm. 5H, Cyclopropyl); 2.80 Ca. 3H, 3.148 and 3.67 CAB* J-28 Hz, 2H. SCM 2 11.26 Cdo Us, 0CM 2 5.0-5.6 CM. 3M, CH 2

N

and 6H); 6.10 Jn5Hz, 7.26- 7.55 Cmo 3M. Thlazole-H) and2 Imidazole OCF 3

C

2 2.60 (to IHO inCH); 2.81 (as 3Ms CM 3 3.145 a.nd 3.65 (AB, 2H,

SCH

2 4.8-5.8 Cm. 5H. 0CM 2

CH

2

N

and 6.08 Jw5Hz. 7-H); 7.15-7.6 3H. Thlazole-H arfd2 Imidazole-)..

OCF 3

C

2 2.81 (as 3Ms CH 3 3.143 and 3.68 (AB 2H. SCH 2 4.7-4.9 (mn, 2H, 0 2 CHwCH 2 5.1-6.2 7H.

CH

2

CMUOCH

2 0 CM 2 N and 2 Lac'tam-H); 7.1-7.6 Cm. 3H. Thiazole-HAnd 2 Imidazole-91.

OCF 3

C

2 2.80 Cs 3Hs CH 3 3.142 and 3.75 CAB, 2H, SCM 2 4.9-5.7 Cm. 3M, CH 2 N and 6.11 Cdo J! 6.72 Ct, Jft70Hz, 1H.

CM?

2 7.2-7.6 Cmo 3M. Thiazole-H) and 2 ImIdazole-HI.

-CM

2

CH-CH

2

-CM?

2 C in which as also in formula VI X represents halogen, Example 21: PivaLoyLoxymethyL 7-[2-(2-am inot h i azoL -4-yL )-2-syn-methoxyiminoacetamido)-3-E(2-methyL-imidazoL-1-yL)methyLJ-ceph-3em-4-carboxyL ate A mixture of 954 mg (2 mmoL) of 7-E2-(2-aminothiazoL-4yI. -2-syn-methoxy im inoace tam ido3 (2-methyl imidazot -1yL)methyLJ-ceph-3-em-4-carboxyLic acid (Example 1) and 200 mg (2 mmoL) of potassium bicarbonate in 10 nil of water is LyophiL ized and the residue is evaporated twice with toluene and dlissolved in 10 mL of dry N,N-dimethyLformamidle (DPIF). A solution of 2 mmot of iodomethyL pivaLate in 0.5 mL of dlimethyLformamidle is added at 5 0 C, while s t ir r ing, the mixture is stirred for 2 hours, a further mL of iodomethyl pivaLate solution is added and the mixture is stirred for a further hour. After addition of [4 20 mL of water, the mixture is extracted three times with ml of ethyl acetate each time, the organic phase is dried with sodium sutfate and the solvent is removed in vacuo. The oily residue is chromatographed over a "Lobar C" silica gel column with ethyl acetate: isopropanoL :water 0:20: 5) The product fractions are evaporated and the residue is triturated with ether, the title compound being obtained as an amorphous solid (140 mg).

1 H-NMR (DMSO-d 6 6 1.16 9H, (CH 3 3 2.25 3H, CHQ); 3.22 and 3.38 (AB, J=18Hz, 2H,

SCH

2 3.83 3H, OCH 3 4.88 Cbs, AB, CH 2 5.19 (dl, J=5Hz, 5.56 (ddc, J=5 and 9Hz, 5.88 and 5.96 (AB, J=7Hz, 2N, CH 2 OCO); 6.80 (s, 1 thiazoLe-H); 6.95 and 7.06 (in each case one d, J=2Hz, 2 imidazoLe-H); 7.22 Cbs, 2H, NH 2 and 9.66 ppm (Cd; J=9Hz, 1H, CONH).

The compounds shown below, which correspond to the general 4 ft 31 formula I where R 1and R 4= hydrogen and in which R 2 and R 3have the meaning given in Table 3, are obtained analogously to ExampLe 1, process variant'j9) and Examples 14 20 of Table 2.

Table 3 Example H3

N

-NJ

1 H-NMR '(solvent) S (ppm) t ~f

I

I

I

Ii

N

-(CH

2 3

CH

3 -C C

(CF

3 CO 2 D) :1.03 Ct, 3H, CH 3 1.86 Cm, 2H, CH 2 2.82 Cs, 3H, CH ;3.43 and 3.60 (AB, 2H, SCH 2 4.45 Ct, 2H, OCH 2 4.9 5.6 (m, 3H, 6-H and CH 2 6.10 J 1H, 7.22 and 7.55 Cm, 3H, Thiazote-H and 2 ImidlazoLe-H)

(CF

3

CO

2 D) 0.95 3H, CH 3 1.15 1.95 Cm, 4H, CH 2 CH 2 2.80 Cs, 3H, CH 3 3.40 and 3.73 CAB, 2H,

SCH

2 4.34 t, 2H, OCH 2 4.95 5.90 Cm, 3H, 6-H and CH 2 6.13 Cd, 1H, J =5Hz, 7.25 7.51 Cm, 3Hi, Thiazole-H)andi'21midazo-Le-H).

(CF

3 CO 2 D) :2.82 Cs, 3H, CH 3 3.26 and 3.43 CAB, 2H, SCH 2 5.1 5.6 Cm, 3H, 6-H and CH 2 5.45 2H,

OCH

2 6.03 Cd, 1H, J =5Hz, 7-H); 7.2 7.6 Cm, 8H, Thiazote-HID 2 Imidazole-Hh,-Phenyl -H) 4- C I are about 0.4 to 20 glday, preferabLy 0.5 to 4 g/day, for an aduLt with a body weight of about 60 kg.I

U

I

-32- Table 3 (Continuation) Example I H-NMR (solvent) :I(ppm) 4- I.

-CH2T-

-NJ

CH 3 N-c CH 3 CF 3

CO

2 D) :2.80 3H, CH 3 3.45 an,d 3.65 (AB, 2H, SCH 2 5.60 (s, 2H, OCH 2 5.0 5.8 (mn, 3H, 6-H) and CH 2 5.95 1H, 7.25 1K, Thiazole-H); 7.6 7.9 (mn, 2H, Inidazole-H); 8.20 and 9.85 2H, Thiazole-H).

(DMSO-d 6 1.3 2.0 (mn, 8H, Cyclopentyl); 2.33 3H, CH 3 3.1- 3.4 (mi, 2H, SCH 2 4.4 5.4 (mn, 4H, 6-H, CH 2 N,=OCH); 5.6 (dd,3= 8Hz, 6.63 1K, Thiazole-H); 6.8 -7.3 (mn, 4H, 2 Imiidazole-H)jlK 2 9.40 J 8HZ, 1H, CONK) (CF3CO 2 1.5 -2.2 (mn, 8H, Cyclopentyl); 2.43 3H, CH 3 3.6 (bs, 2H, SCH 2 4.9 5.6 (in, 4H, 6-H, CH 2 N, =OCH); 6.03 1KH, J= 7.1 7.4 (in, 2H, Thiazobe-H?) Iiidazole-H);8.55 (bs, 1K, Iinidazole-H)

I.

Ctr"OruuL CFiU WLISUT OFOU Ul- IVU. I UL~U Ut iyuriouioe SaLT OT the title compound: 13.8 g (88% of theory). The crude hydriodide is dissolved in aqueous sodium bicarbonate -33 The compounds of the examples shown below are obtained analogously to Example 1, process a) as amorphous solids which correspond to the general formula I where R1and R4 hydrogen, and in which R 2 and R 3 have the meaning given in Table 4.

Table 4 ExampLe 1

H-NMR

(solvent) 4 (ppm) t I

CH

3

CH

3 CH 3

CH

3 UH)2 (DMSO-d 6 1.16 3H, CHCH) 2.12 3H, CH 3 2.71 2H, LH2C3);2.84 and 3.04 (AB, J 18Hz, 2H, SCH 2 3.82 3H, 0C11 3 4.95 5.10 (mn, 3H, CH 2 N and 6-H); 5.64 (dd, J =5 and 8Hz, 6.67 Iiidazole-H);6.72 Thiazole-H); 7.22 (bs, NH 2 9.58 J =81z,

CONH)

(DMSO-d 6 1.15 and 1.20 (in eachi case one d, J =7Hz, 2 x CH 3 2.96 amnd 3.26 (AB, J3=18Hz, 2H1, SCH 2 3.16 (dq,

CH(CH

3 2 3.81 3H, OCH 3 4.91 (bs, 2H, CH 2 5.03 J 5,64 (dd, 0=5and[,7-H);6.72 Thiazole-H);6.81 and 7.13 (in each case I sJlidazole-0);7.22 (bs, NH 2 9.57 J3=8Hz, CONH) (DMS0-d 6 0.75 0.93 (Kn 4 Cyclopropyl-H); 1.92 2.08 (in, 1 Cyclopropyl 3.07 and 3.28 (AB, J= Tor a noIurs. ine aimetflYLTormamiae S0LUtiofl is poureo into 1 Liter of ether, the precipitate which has separated out is dissoLved in aqueous sodium bicarbonate soLution 34' Table 4 (Continuation) ExampLe R 2 R3 1 H-NMR (s~oLvent.? :JCpm 18Hz, 2H, SCH 2 3.82 3H, OCH 3 4.94 aind 5.04 (AB, J =15Hz, 2H,

CH

2 5.05 J =5Hz, 5.66 (dd, J =5 and 8Hz, 64.69 Cs, Imidazole-H);6.71 Cs, Thiazole-H); 7.13 Imidazole-H); 7.22 Cbs, NH 2 9.57 J =8Hz, CONH) 31 CH 3 -NJ (DMSO-d 1.1 1.8 (iM, 10 Cyclohexyl-H); 2.4 2.6 (mn, 1 Cyclohexyl-H); 2.97 and 3.24 (AB, J= 18Hz, 2H, SCH 2 3.82 3H, OCH 3 4.89 And 4.94 (AB, J 15Hz, 2H, CH 2

N)

5.03 J =5Hz, 5.65 (dd, J =5 And 8Hz, 6.72 Thiazole- 6.80 and 7.120in each easel1 s, 2 imidlazole-H);7.22 (bs, NH 2 9.55 (d, tIJ J=8Hz, CONH) 32 CH 3 (DMSO-d 6 2.72 and 3.16 (AB, .J 18Hz, 2H1, SCH 2 3.82 Cs, 3H, OCH 3 4.82 and 5.04 (AB, J 15Hz, 2H, CH 4.96 J =5Hz, 6-0 5.49 (dd, J 5 and 8Hz, 6.71 (s, Thiazole-H);6.98 Cs, Iinidazole-H); 7.21 (bs, NH 2 7.4 7.64 Cm, 6H, 1 Inidazole-H)5 Phenyl-H); 9.53 J -8Hz, CONH)

I.

35 TabLe 4 (Continuation) Example I H-NMvR (solvent) :(ppm) 33

N

-16

/IVN

L (DMSO-d 6 1.6 -1.8 (bs, 4 Cyclohexene--H); 2.3 -2.5 (bs, 4 Cyclohexene-H); 3.08 and 3.25 (AB, J 18Hz, 2H, SCH 2 3.82 3H, OCH 3 4.81 and 4.88 (AB, J 15Hz, 2H, CH 2 5.04 J =5Hz, 5.65 (dd, J 5 and 8Hz, 6.72 Thiazole-H); 7.22 (bs, NH 2 7.64 Iiidazole-H); 9.58 J 8Hz, CONH) (DMSO-d 6 2.25 2.65 (mn, 6 Cyclopentene-H);3.10 and 3.31 (AB, J3= 18Hz, 2H, SCH 2 3.82 3H, OCH 3 4.81 and 4.88 (AB, J =15Hz, 2H, CH 2 5.08 J3=5Hz, 5.68 (dd, J =5 aind 8Hz, 6.72 Thiazole-k); 7.22 (bs, NH 2 7.51 1Imidazole-); 9.60 J

CONH)

(DMSO-d 6 3.33 aind 3.49 (AB, 3J 18Hz, 2H1. SCH 2 3.82 3H, OCH 3 3.94 and 4,22 (AB, J 15Hz, 2H, CH 2 4.97 J3=5Hz, 6-H); 5.58 (dd, J =5 a;nd 8Hz, 6.74 Thiazole-7H); 7.21 (bs, NH 2 7.62 Iidazol 9.51 J 8Hz, CONH); 12.9 (bs, COGH); 19..72 (bs,

COON)

co 2

H

36 Table 4 (Continuation) R3 ExaMple I H-NMR o LYe n t) Cppm) I 4 I

CH

2 CO 2

H

CH 2 CO 2

H

C(CH

3 2 C0 2

H

C CCH 3 )2 2 C0 2

H

(DMSO-d 6 2.98 and 3.30 CAB, J 18Hz, 2H, SCH 2 4.34 Cs, 2H, OCH 2 4.74 and 4.92 CAB, J =lSHz, 2H, CH 2 5.01 Cd, J 5Hz, 5.63 (dd, J =5 and 8Hz, 6.81 (s, Thiazole-H);6.85 7.28 and 7.73 (in each case 1 3 Imidazole-H);7.22 Cbs,

NH

2 10.83 Cd, J =8Hz, CONH)

CWF

3 CO 2 2.50 Cs, 3H, CH 3 3M4 and 3.72 CAB, ~J 18Hz, 2H, SCH 5.11 Cs, 2H, OCH 5.21 n CAB. J =15Hz, 2H, CH 2 5.41 Cd, J =5Hz, 6.14 Cd, J 7.30 Cs, Iniidazole-7H),; 7.46 Cs, Thiazole-H*; 8.77 Cs, Inidazole-H) CDMSO-d 6 1.43 Cbs, 6H, CH 3 3.00 and 3.33 CAB, J =lBHz, 2H, SCH 2 4.71 and 4.94 CAB, J =15Hz, 2H, CH 2

N)

5.05 Cd, J =5Hz, 5,68 (dd, J 5 and 8Hz, 6.71 Cs, Thiazole- 6.85 Cs, 1jidazole-H);7.28 Cbs, 3H, NH 2 and 1 Imidazole-H)I 7.72 Cs, Imidazole-H?;9.58 Cd, J =BHz, CONH) CDMSO-d 6 1.88 and 1.95 (in each case 1 s, 2 x CH 3 2.11 Cs, 3H, CH 3 2.95 imd 3.03 CAB, J =lBHz, 2H, SCH 2 4.71 and 5,02 CAB, J 15Hz, 2H,

CH

2 4.96 Cd, J =5Hz, 5.61 Cdd, J -5 and 8Hz, 6.58 Cs,

CH

3

I

37 Table 4 (Continuation) Example R2R H-NMR (solvent) f ppm) Imidazol1i); 6.70 Thiazole-H); 7.21 (bs, NH 2 7.61 Imidazole-

H)

JH2

PN

CH

2 C C0 2 H -NIu (DMSO01 6 2. 91 a nd 3. 32 (AB, 3= 18Hz, 2H, SCH 2 4.63 and 4.93 (AB, J =15Hz, 2H, CH 2 4.70 2H, OC2;5.01 J =5Hz, 5.60 (dd, J =5 and 8Hz, 7-H) 5.80 and 6.12 (in-each caseli, =CH 2 6.72 Cs, Thiazole+H );6.83 7.28 and 7.71 (in each case 1 s, 3 rImidazole-H);7.21 (bs,

NH

2 9.61 Cd, 3=8Hz, CONH)

CH

2

CH

3 41 CH 2 C C0 2 H -NI (DMSO-d 6 2,26 Cs, 3H, CHP) 2.93 and 3.18 CAB, J3=18Hz, 2H, SCH 2 4.73 2H, OCHP) 4.80 and 4.89 (AB, J =_15Hz, 2H, CH 2 N) 5. 00 (do 5.58 Cdd, J3=5 and 8Hz, 5.63 and 6. 00Cmn each case 1 bs, 2H, =CH 2 6.6and 7.16 (in each case 1 s, 2 Imidazole-HW; 6.71 Cs, Thiazole-H); 7.24 (bs, NH 2 9.61 (do J3=8Hz,

CONH)

4 H t4 mH 42 CH C CO H -N (DMSO-d 6 )h 2.11 3H, CH 2.94 and 3.12 CAB, J ulBHz, 2H, SCH 2 C 4.72 2H, OCH 2 4.80 and 4.90 CAB, J -15Hz, 2H, CH 2 5.00 (do J S, 5.60 Cdd, J3-5 and -38- TabLe 4 (Continuation) E xamp It R 2 R3 1 1 H-NMR (.soLvent) :(PPM) r1Co 2

H

CH

3

CH

3

-NJ

CH2CN2 8Hz, 5.80 and 6.12(in each case 1 s, 2H,9 =CN 2 6. 58 and 7.63mn each case 1 s, 2 Imidazole-H); 6.72 Thiazole-H)-*3 7.22 (bs, NH 2 9.62 J =8Hz,

CONH)

(CF

3 CO 2 1.8 2.7 (mn, 8H, Cyclopentyl); 2.81 3H, CH 3 3.46 and 3. 66 (AB, J =18Hz, 2H, SCH 2 5.55 07n, 3H, 6-H an~d CH 2

N);

6.10 J 5Hz, 7.24 795 (mn, 3H, ThIazole-H andg 2 Ini dazole-H) (DMSO-d 6 3.22 and 3.43 (AB, 2H,

SCH

2 3.80 2H, CH 2 CN); 3.82 3H, OCH 3 4,78 and 4.94 (AB, 2H, CH 2 5.02 J =5Hz, 6 5.57 (dd, J =5 and 8Hz, 6.74 Thi azole-H);6.86 and 7.74 in each case I s, 2 Imidazole-H);7.21 (bs, NH 2 9.50 J 8Hz, CONH) (DMSO-d 6 3.25 and 3.36 (AB, 2H, SCH 2 3.80 2H, CH 2

CO

2 H);3.82 3H, OCH 3 4.81 4nd 4.94 (AB, 2H, CH 2 5.02 J=iz 6-H); 55 (dd, J=S5aind 8Hz, 6.74 Thiazole-H); 6.86 a,nd 7,74(ineach case 1 s,2 rnidazole-H);7. 20 (bs, NHa) 9..48 Jr. 8Hz, CONH); 444444 4 4 I$S 4 4 .4,44 4

II

I I ii\ I- ii 39 Table 4 (Continuation) Example 2 R IH-NMR (solvent), a (ppm)= I I.

CH

3

CH

3

CH

3 CONHCH 3 H3 KH3 CONH' 3 C ON H NHCM (DMSO-d 6 2.30 3H, CH 3 3.18 and 3.48 (AB, SCH 2 3.81 3H, OCH 3 4.85-5.05 3H, 6-H and CH 2 5.58 (dd, J =5 and 8Hz, 6.77 Thiazole-H);7.20 (bsNH 2 7.62 Imidazole-H); 9.48 J=8Hz, NH) (DMSO-d 6 2.42 3H, CH 3 1; 2.70 J 7Hz, 2 x CH 3 3.22 and 3.42 (AB, SCH 2 3.81 (s, 3H, OCH 3 4.82 5.03 (mn, 3H, 6-H and CH 2 5.51 (dd, Ji a~nd 8Hz, 6.71 (s, Thiazole-H); 7.18 (bs, NH 2 7.72 Inidazole-H); 9.48 (i, J 8Hz, NH) (DMSU-d 6 2.40 3H, CH 3 3.21 and 3.46 (AB, SCH 2 3,81 3H, OCH 3 4.8-5.1 3H, 6-H and CH 2 5.61 (dd, J and 8Hz, 6.71 (s, Thiazole-H);7.21 (bs, NH 2 7.68 Imidazole-H);9.50

NH)

(CF

3

CO

2 2.30 3H, CH 3 2.80 3H, 3.88 and 3.99 (AB,2118fHz, 2N, SCH 2 4.26 3H, OCH 3 4,65 and k tEL 4;C 40 TabLe 4 (Continuation) Example I H-NMR (solvent) 6 a ppm)= 4. I.

C 2 H 5

CH

2 C -=CH C3H

CN

Nq 4.92 (AB, J 15Hz, 2H,CH 2

N);

5.36 J 5Hz, 6.10 (d, J 5Hz, 7.44 Thiazole- 8.83 Cs, Imidazole-l) (DMSO-d 6 1.20 3H, CH 2

CH

3 2.25 2.68 (in, 6 Cyclopentene-H); 3.02 'and 3.28 (AB, J3= 18Hz, 2H,

SCH

2 3 .95 q, 2H CH 2 CH 3 4.88 (AB, 2H, CH 2 N ;-ST04 (d J3 5.61 (dd, J3= 5 and 8Hz 6.70 Thiazole-H); 7.22 C bs NH 2 7 .49 s, Imi dazol e-H) 51 J3 8Hz NH) DMSO -d 6 1 .6 18 C bs, 4 Cyclohexene-Hi); 2.3-2.6 (mn, CH and 4 Cyclohexene-H);3.02 and 3.20 (AB, J3 18Hz, 2H, SCH 2 4.57 (bs, 2H, OC-H 2 4.75 4.90 (AB, 2H, CN 2 N)2N 03 d, 13 5Hz 5 .61 (dd, J=5 Sand 8Hz, 6.76 Cs, Thiazole-H); 7.24 (bs, NH 2 7.58 Cs, Imidazole-H,; 9.63 (d, 3= 8Hz, CONH) (CF 3 C0 2 D) 1.1 3H, 0H 3 1.7 2.3 (mn, 6H, CH 2 and 4 Cyclohexerie-H); 2.6-2.9 Cbs, 4 Cyclohexene-H); 3. 45 and 3. 76 CAB 2ZH, SCI-17 i 4. 50 C t, 2H OCH 2 Example 1, process varianit B) from 7 -amino-3-E(2- 2.

41 Table 4 (Continuation) Example* 2 R 3 1 I-NMR (solvent) :8 (PPM)= I I C3H -CH j0

-N

CH

3 C3 4.90 and 5.85 (mt, 3H, 6-Hand CH 2 N) 6.13 1H, 7-H) 7.50 Thiazole-.H);8.67 Imid a zole -H) (CF 3 COOD): 1.6 2.4 (in, 12H, 8 Cyclopentyl-H and 4 Cyclohexene-H); 2.6-2.95 (mn, 4H, 4 Cyclohexene-H.); 3.50 and 3.68 (AB, 2H, SCH 2 5.05 5.55 (mn, 4H,Lac~tarn-H, CH 2

N

and OCH); 6.14 1H, 7-H); 7.50 Thiazole-H);8.66 (CF 3 COOD):1.04 3H, CH~) 1.83 (mn, 2H, CH 2 2.5 3H, C3;3.62 (bs, 2H, SCH 2 4.50 2H, OCH 2 5.15 5.60 (in, 3H, 6-H and CH 2

N);

6.14 1H, 7.23 {bs, ImidazoleNIM); 7.50 Thiazole-

(CF

3 COO-) 2. 50 s, 3H CH 3 3.28 a nd ,.46 (AB, 2H, SCrH 2 5.1-5.65 (mn, 5H, Lactam-H, CH 2 N and OCH 2 6.08 IH, 7.21 (bs, Imidazole-H); 7.30-7.60 %(ni 1 5 Benzyl -H and 1 Thiezolo.-r,; 8.59 (bs, Imldazole-H' it,? U C 42 TabLe 4 (Continuation) Exaip Le R 3 I H-NMR (solvent) 5 (pp'i)= I I C H2

CH

3

CH

3

CH

3

NH

(CF 3 C000) 0. 2-1.-5 (in, 5H Cyclopropyl-H); 2.48 3H, CH ;3.60 (bs, 2H, SCH 2 4.40 2H, OCH 2 5.05- 5.65 (mi, 3H, 6-H and CH 2

N);

6.13 1H, 7.20 Cbs, 1H, Imidazole-H);7.50 (r, Thiazole-H);8.78 Im~dazole-H)

(CF

3 CO0D): 3,70 (bs, 2H,

SCH

2 4,30 Cs, 3H, OCH 3 5,15 5,80 Cm, 3H, 6-H and

CH

2 6,15 Cd, 7,50 Cs, Thiazole'-H ;8,30 and 9,03 Cbs, 2 Imidazole-P)

(CF

3 COOD): 3.55 and 3.78 CAB, 2H, SCH 2 4.25 3H,

OCH

3 5.05 5.50 Cm, 3H, 6-H and CH 2 6.15 1H, 7.50 Thiazole-H); 8.48 Imidazole-H) (CF 3 COOD): 2.83 3H, CH 3 3.60 (bs, 2H, SCH2; 4 .25 Cs, 3H, UZH 5.05 5,60 Cm, 3H, Lactam-H and CH 2 6.13 (d, 1 H, 7-H) 7 .51 C s, I H, Thi azol e-

H)

NA

4Br 2 43 Table 4 (Continuation) E xamp L-e I H-N

MR

(so vent) 1: 8 (ppm) 1.

CH

3

CH

3

CH

3 (R I.Cl) -N rN I

I

I ~I~tt I I NqOC

H

3

(CF

3 COOD) 3. 75 bs 2H, SCH 2 4. 30 s, 3H OCH 3 5.0 (in, 3H, Lac tam-H and CH 2 N) 6.15 1H, 7.50 (s, Thiazole-H).; 7.55 nd 8.50 (bs,* Imidazole-H) (CF 3 COOD): 1.48 3H, CH 3 2.75 3H, CH 3 2.95 (s, 3H, SCH 3 3.62 (bs, 2H, SCH 3.83 2H, OCH 2 4.28 (s, 3H, OCH 3 5.0 5.55 3H ,6-H and CH 2 6.08 1H, 7-H) 7.50 Thi azole-H)

(CF

3 COOD): 3.46 and 3.70 (A, 2H, SCH 2 4.15 3H, OCH 3 4.25 NOCH 3 5.00 5.65 (mn, 3H, 6-H @nd CH 2

N);

6.13 1H, 7.15 (bs, Iinidazole-H),; 7.50 Thiazole- H) 8.72 XImidazole-H,) (DMSO-d 6 1.6-1.8 (bs, 4- Cyclohexene-H); 2.35-2.6 (bs, 4 Cyclohexene-H); 2.98 and 3.18 (AB J 18Hz, 2H, SCH 2 3.82 (s, 3H,OCH 3 4.78 and 4.85 (AB, J 2H, CH 2 N) 4.98 J 5.60 (dd, J =5 and 8Hz, 7-H); 7.38 (bs, NH 2 7.56 Imidazol e-H); 9.48 J 8Hz, CONH) III S S ''St I S .5 The compounds shown beLow, which correspond to the generaL 44 Table 4 (Continuation) Example R 3 I H-NMR (solvent) (PPM) 4 4 CH 2

COOH

c(CH 3 2

CO

2

H

CH

2

CO

2

H

(DMSO-d 6 2.25-2.65 (in, 6 Cyclopentene-H; 2498 and 3.18 (AB, J 18Hz, 2H, SCH 2 4.22 2H, OCH 2 4.71 and 4.93 (AB, J 15Hz, 2H, CH 2 N) 4.95 J 5Hz, 6-H) 5.57 (dd, J 5 anid 8Hz, 6.81 (s, Thiazole-H);7.16 (bs, NH 2 7.47 Iiidazol-e.-H);10.90 3 =8Hz, CONH) (DMSO-d 6 ):l1.45 (bs, 6H, CH 3 2 .20 2 ,60 (mi, 6 Cycl opentene-H); 3.00 and 3.28 (AB, 3=18Hz, 2H,

SCH

2 4 .70 and 4.-92 (AB J 2H, CH 2 N) 5.01 J 6-H) ;5.62 (dd, J Sa nd 8Hz, 6.82 Thiazole-H); 7.15 (bs, 7.49 InidazOle-H);1O.i2 J 8Hz, CONH) (DMvSO-d 6 (bs, 4Cyclohexene-H); 2. 3-2. 55 bs 4 Cycl ohexene-H); 3. 02 and 3. 15 (AB J 18Hz, 2H, SCH 2 4.34 2H, OCH 2 4.-72 and 4.94 (AB,j 2H, CH 2 5.01 J 5.62 (dd,J 5 and 8Hz 6.82 Thiazole-H); 7.20 (bs, NH 2 7.57 Imidazole-H) 11. 10 d, J 8Hz, CONH 45 Example R 3 I H-NMR C solvent) (ppm) 4. i i c(CH 3 2 c0 2

H

C2 C2

PN

3

CH

3 44 I 4 4 4~ V 4 4 I 4 44 4,, .444 44 $4 4 44 4 4-t 4 4 4 4 44 4 44 .44 4"4 4 4 4 4 4 44 4 4 4*44 4 4 4444, 4 4 DMS0- d 6 1.4 5 b s, 6 H, CH 3 1 .6 1.8 (b s 4Cycl1o h ex e ne-H); 2 .3-2.6 (bs 4 Cycl ohexene-H); 3.01 and 3.19 (AB, J 18Hz, 2H, SCH 4.72 and 4.94 (AB, J 2H, CH 2 N) 5'.00 J 5.60 (dd, J 5 and 8Hz, 6.81 Thiazole-H); 7.20 (bs, NH 2 7.55 Imidazole'-H);11.05 J 8Hz, CONH) (DMSO-d 6 3H, CH 2 iH 3 1 .6-1 .8 bs 4 Cycl ohexene-H); 2.3-2.5 (in, 4 Cyclohexene-H); 2.97 and 3.16 (AB, J 18Hz, 2H,

SCH

2 4 .06 2H ,CH 2

CH

3 4.77 and 4.86 (AB, J 15Hz, 2H, CH 2 5 .00 d, J 5Hz 6-H) 5.58 (dd, J =5 and 8Hz, 7-H); 6.70 s, Thi azole-,H) 7 .20 (bs,

NH

2 7.-52 s, Imi dazole-H; 9.48 J 8Hz, CONH) (DMSO-d 6 1.20 3H, CH 2

CH

3 2.11 3H, CH 3 2,92 and 3.13 J 18Hz, 2H, SCH 2 4.06 2H, CH 2

CH

3 4.78 and 4.89 (AB, J 15Hz, 2H, CH 2

N)

4.98 (d J 5Hz 6-H 5.,57 (dd, J S and 8Hz, 6.56 Imidazole-H); 6.69 (s, Thlazole-HI;7.18 (bs, NH 2 7.62 Imidazole-:wf)-9.47 (d, J =8Hzt, CONH) -46- Example R' R' IH-M (solvent) 8(ppni)= CH 2

CH

2

NJ

CH

3 -NJz (DMSO-d 6 2.27 3H, CH 3 2.92 and 3.21 J 18Hz, 2H, SCH 4.23 (bs, 4H, QCH,.CH 2 4.81 and 4.88 J 2H, CH 2 5.01 J 5.58 (dd, J= 5 and 8Hz, 6.68 Imidazole- 6.76 Thiazobe-H); 6.84, 7.16, 7.18 and 7.6O(in each case 1 s, 4 Imidazole-H); 7.24 (bs, NH 2 9.59 J= 8 Hz CONH 46a

R

3 Ilu~-NMR (solvent) 6(ppm). Exampt e I C H 3

CH

3 rNt iCtI

CCF

3 COOD): 2.90 3N, CH 3 3.25 and 3.48 CAB, 2H, scI1 2 4.25 (so 3H,

'OCH

3 5.05-5.65 3H, tactam-H and'CH2N); 6.12 1H, J=SHz, tactam-H); 7.48 Cs, 18, thiazote-H); 7.52 Cs, IN, imidazote-H) It

IC

t~ I -I I I

IC

4 C I C

CCF

3 COOD): 2.84 3H,

CH

3 3.45 Cbs, 2H,

SCH

2 4.27 (so 3H, OC8 3 5.0? 4H..

C1420H), 5.20-$.85 Cm, 3HO Lactam-H and CH 2

N);

6.05 J=5Hz, I14, tac-.

tam-H); 7.48 Cs, 1I4, thiazoLe-H)

(CF

3 COOD): 1.5-2.2 Cm, 8H, CYC(Opentyt); 3.50 and 3.90 CAB, 214, SCH 2 .5.9 Ow, 4H, lactam-H, C14 2 1, OCH); 6.16 J= 1I4, Lactam-Il); 7.50 Cs, IN, thiazote-H); 7.55; 7.70 and 9.00 (in each case bs, 3 imidazote-H) I 4 4 4 46b ExampLeJ Rr I 74 CH 2 CONH2 CH2CONHCH 3 N6.

NI--

I 1-NMR (solvent) d(ppm)= (DMSO-d 6 1.6-1.8 Cbs, 4 ;yctohexene-H); 2.3-2.6 (bs, 4 cyctohexene-H)s 2.96 and 3.21 (AB, Jz18Hz, 2H,

SCH

2 4.39 2H,

CH

2

CONH

2 4.76 and 4.88 (AS, J=15Hz, 2H, CH 2

N);

5.02 td, j- Hz, 5.63 (ddo J=5 and 8Hz, 7-H); 6.82 Cs, thiazote-H); 7.10 1H, NHZCO); 7.29 (s, 2H, NH 2 7.48 1N,

NH

2 CO); 7.52 1 imidarote-H); 9.73 JP8Hz,

CONH)

(DMSO-d 6 1.6-1.75 Cbs, 4 cyctohexene-H); 2.45-2.5 (bs, 4 cyctohexene-H); 2.64 and 2.66 (2s, 3H, NICH3); 2.98 and 3.18 (AB, P18Hz, 2H, SCH 2 4.43 Cs, 2HO ICH2CONHCH3); 5.26 and 5.88 CAB, 2H, CH2N); 5.02 Cd, J= 5.61 (dd, and 8Hz, 6.83 Cs, thiazote-H); 7.30 Cs, 2H,

NH

2 7.42 and 7.44 (2s, IH, NHCH 3 7.49 1 imidozote-H); 9.68 Jz 8Hz, CONH) We"W"!1W M4" 47 Example 76: 7-E2-(2-AminothiazoL-4-yL)-2-syn-methoxyimino-acetamido)- 3-E(2-methyLimidazoL-1-yl)methyLJ-ceph-3-em-4-carboxyLic a c id Process variant 8 Tert.-butyL 7-amino-3-E(2-methyLimidazoL-1-yL)methytjceph-3-em-4-carboxyL ate 1.77 g (5.4 mmoL) of tert.-butyL 7-aminocephaLosporanate and 5 mL (18.7 mmol) of BSTFA in 12 ml of methyLene dichLoridle are heated at the boiling point for 1 hour.

After cooling, 2 ml (15 mmoL) of trimethyLiodosiLane are added and the mixture is Left at room temperature for 20 minutes. It is concentrated, the oily residue is dissolved in 10 ml of acetonitrile and a solution of 524 mg (6.4 mmoL) of 2-methyL-imidazoLe in 5.2 ml of acetonitriLe and 2.6 ml of BSTFA is added. The mixture is Left at room temperature for 3 hours. After addition of 0.6 ml of water, a small amount of a dark precipitate forms, and is fiLtered off with suction (140 mg) and discarded. The mother Liquor is concentrated and the residue is chromatographed over a silica gel column with methyLene dichLoride/methanoL/aqueous ammonia (90 10 Fractions 3-5 (130 ml are eviarated and 310 mg of the title compound remain as an amorphous, brownish soLid.

1 H-NMR (DMSO-d 6 6 =1.50 9H, CH 3 3 2.29 3H, lm.-CH3); 3.18 and 3.27 (AB, J 18Hz, 2H, SCH 2 5.78 and 5.88 (AB, J

CH

2 4.80 and 5.01 (in each case 1 dl, J 5Hz, 2 tactam-H); 6.90 and 7.12 ppm (2 s, in each case 1 imidazoLe-H) -48 2. Tert.-butyL 7-[2-C2-aminothiazoL-4-YL )-2-syn-methoxyimino-acetamidoJ-3-t(2-methyLimidazoL-1-yL)methytlceph-3-em-4-carboxX'Late A solution of 190 mg (0.54 mmoL) of the product from ExampLe 76 /1 in 2 ml of dlimethyLformamidle is added to a solution of 0.5 mmol of the active hydroxybenzotriazoLe ester of 2-(2-aminothiazoL-4-yL )-2-syn-methoxyiminoacetic acid, prepared from 100 mg (0.5 mmoL) of acid, 90 mg of hydroxybenzotriazote and 110 mg of dlicyclohexylcarbodiimide in 2.5 mL of N,N-dimethyLformamidle (DPIF). After 4 hours at room temperature, the dlicycLohexylurea is filtered off with suction and the solution is diluted with 150 ml of ethyl acetate and washed twice with aqueous sodium bicarbonate solution and twice with water. After drying with MgSO 4 the solvent is removed in vacuo and the partly solid residue is digested with ether. The undissoLved solid is filtered off with suction, washed with ether and dried.

YieLd: 150 mg 1 H-NMR (DMSQ-d 6 6 =1.48 Cs, 9H1, (CH 3 3 2.28 3H, C11 3 3.28 and 3.39 CAB, J 18Hz, ZH, SCH 2 3.84 Cs, 3H, OCH 3 4.82 and 4.93 (AB, J 15Hz, 2H, CH2N); 5.28 J =5Hz, 5.60 (Cdd, J 5 and 8Hz, 7-H); 6.74 Cs, thiazoLe-H); 6.86 Cs, imidazoLe-H); 7.21 Cbs, 3H, NH 2 and 1-imidazole-H); w~ql9.60 pIpm Cd, J =8Hz, CONH) 3. Preparation of the title compound mg of the compound from Example 76/2 are dissolved in 3 ml of trifluoroacetic acid. After 30 minutes, the sokution is evaporated in vacuo and the residue is .4 -49triturated severaL times with ether. 25 m~g of a co(, Less sotid which is identical in all its, properties (RF value, NMR spectrum) to the compound~ from ExampLe 1 are obtained.

IL~

Claims (3)

1. A cephalosporin derivati;e of the formula I C-CONN T 1(1 H N R 1 TO 2 0 1 CH R 3 COOR 4 or a physiologically acceptable acid addition salt thereof, in which R' denotes hydi 'gen or halogen, R2 denotes hydrogen; C -C 6 al kyl, which can be mono- or polysubstituted by identical or different substituents from the group comprising halogen, aryl, C -C -alkylthio, C 1 -C 4 -al koxy, n itrile and carbamyl, in which the amino group can be mono- or disubstituted by identical or different substituents fromthe group comprising C-C 6 -alkyl, hydroxy-(C -C 2 )-alkyl, hydroxyl and methoxy; -l enl, which can optionalliy bemono- orpoy substituted by identical or different substituents fronm the group comprising halogen; C,-C,-al kynyl, which can be optionally substituted by halogen; C 4 -C 7 -cycloalkeil; C -C72 cclalj Ylth Lhegrup-CH 2 =CH-R 7 or -(CH 2 )~CmR in which m and n each represent 0 or l and R5 and R. 6 can be identical or different and denote h'ycroo:. aryl or a C~ CC, -a ikyl group, or togethcr with the carbon atom to which the- are bonded form a methylene or a S 5T41 z 1j, 'I -51 C 3 C 7 cycloalkylidene group, R 7denotes an HOOC- or C -C 4 alkylOOC- group, R 3 denotes an imidazol-.l-yl radical -N which can be mono- or polysubstituted by identical or different substituents from the group comprising C 1 -2 6 -alkyl, which can be mono- or polysubstituted by hydroxyl, acetoxy, carbamyloxy, chlorine, C -C 6 -alkoxycarbonyl, forrrrl, C -C -alkylcarbonyl, cyano, carbamyl, and C -C 6 -alkoxy and in which 2 adjacent alkyl group. can also be closed to form a di- to decamethylene ring which is optionally substituted by C 1 -C 6 -alkyl, halogen, hydroxyl, oxo or carbamyl and in which one carbon atom can be replaced by an oxygen or sulfur atom and which can also contain one or two double I bonds; or by 2 6 2,~yi 1 which can be substituteid by hydroxyl; by -al kynyl; by C 3 -C 6 -cycloalkyl; by C 3 -_C 6 cycloalkylmethyl; by phey Lor bnzyl, which can be substituted by C 1 _C 4 alkylo halogen, hydroxyl or C 1 _C-alkoxy, by C 1 oro by g,-.q,-alkylthio: by halogen, trifluoromethyl, cyano, hydroxyl or mer- byC 1 -C 6 -al koxycarbonyl or carbamyl, which can be mono- or dJ.s'bstituted on the nitrogen by C -Q-alkyl; by nitro or di-(C 1 7 2 )-alkylamino; R 4 denotes hydrogen, C 1 -C 6 -alkyl; benzhydryl, allyl, propargyl, methoxymethyl, C 1 -C 6 -alkanoyloxy-C,,- -C -alkyl, C 1 -C 5 -alkoxycarboniyloxy-C 1 -C 6 -4Akyl,

7.30-7.60 5 Benzyl-H and 1 Thiazole-h); 8.59 (bs, Imidazole-~) I' 52 phthalidyl or 5-methyl-1,3-dioxolen-2-on-4-yl-methyl, and in which the R 2 group is in the syn-position. 2. A process for the pr. ,aration of a cephalosporin C' MA t derivative of the fo-'ula I or a physiologically acceptable acid addition salt thereof, which comprises a) reacting a compound of the formula II HjI1- C- CONN /\S'iR8k OR HPN (II) or a salt thereof, in which R R 2 and R have the meaning given in formula I, the amino group can also be protected and R denotes a group which can be replaced by imidazole or that imidazole derivative which corresponds to the radicals R 3 of formula I, with imidazole or this imidazole derivative, a) splitting off any protective group present and 8) if necessary, converting the resulting product into a physiologically acceptable acid addition salt, reacting a compound of the formula III SS CHR 2 (III) io which R and R have the meaning given above for formula II and R 9 represents hydrogen or an amino- protective group, with imidazole or the imidazole derivative on which the radical R 3 defined in formula 1Ttl_~*: il. i 53 I is bLsed, to form the compound of the formula IV R NH Si (IV) NS H2R3 0 I A 02 in which R 3 R 4 and R 9 have the abovementioned meaning and a) splitting off any amino-protective group present and B) reacting the compound IV in which R 9 denotes hydrogen, either as such or in the form of a reactive derivative, with a 2-syn-oxyiminoacetic acid of the general formula V N -C-COOH (V) HZN R OR 2 in which R 1 and R 2 have the meaning given and the amino group can also be in the protected form, or with a derivative of this compound activated on the carboxyL group and a) splitting off any protective group present, 0) if necessary, converting the resulting product of the formula I into a physiologically acceptable acid addi- tion salt and y) if an ester is to be obtained the compound of the formula I in which R 4 represents hydrogen obtained by process variant a) or b) is converted into the ester mentioned under R in a manner which is known per se. 3. A pharmaceutical product which is active dgainst bac- 2H,CH 2 4.98 J= 5.60 (dd, J= 5 and 8Hz,7-H); 7.38 (bs, NH 2 7.56 Imidazole-rH);

9.48 J=8Hz, CONH) 54 terial infections, which contains a cephalosporin derivative of the formula I as calimed in claim 1 in adjunct with a pharmaceutically acceptable carrier or expedient. 4. A process for the preparation of a pharmaceutical product which is active against bacterial infections, which comprises bringing a cephalosporin derivative of the formula I as claimed in claim 1 into a pharmaceutically suitable administration form, if appropriate with pharmaceutically customary excipients or diluents. A method of combating bacterial infections comprising administering to a patient suffering therefrom a pharmacologically effective amount of a cephalosporin derivative of the formula I as claimed in claim 1. DATED this 7th day of June 1990 HOECHST AKTIENGESELLSCHAFT WATERMARK PATENT TRADEMArK ATTORNEYS THE ATRIUM 290 BURWOOD ROAD HAWTHORN, VICTORIA 3122 AUSTRALIA DBM/KS/CH (1.35)