PH27125A

PH27125A - Cephalosporin derivatives

Info

Publication number: PH27125A
Application number: PH39900A
Authority: PH
Inventors: Jurgen Blumbach; Friedlhelm Adam; Norbert Klesel; Gerd Fischer; Walter Durckheimer; Burkhard Mencke; Dieter Isert; Gerhard Seibert
Original assignee: Hoechst Ag
Priority date: 1989-01-19
Filing date: 1990-01-17
Publication date: 1992-03-16
Also published as: NO900252L; CN1044280A; HUT54165A; EP0379132A2; PT92890A; FI900270A0; CA2008059A1; IL93086A0; AU4853690A; NZ232135A; TNSN90006A1; ZA90361B; DD291561A5; DE3901405A1; JPH02229196A; EP0379132A3; HU205936B; HU900172D0; NO900252D0

Description

E ,! i

HOECHST AKTIENGESELLSCHAFT HOE 89/F 016 Dr. KA/rh

Description

Cephalosporin derivatives and processes for their 5S preparation

The invention relates to novel cephalosporin derivatives which are particularly suitable for oral administration, a process for their preparation and pharmaceutical form- ulations containing such compounds.

OL

Although many clinically relevant cephalosporins with a broad antibacterial spectrum have been developed, most of them are suitable only for parenteral administration, . 15 since they are absorbed only very inadequately, if at all, following oral administration. In many cases, however, - it is desirable to give the patient highly active anti- biotics in oral form.

The cephalosporin antibiotics known to date do not meet all the requirements which have to be imposed on such a

J medicament, that is to say a high antibacterial activity against Gram-positive (specifically Staphylococci) and

Gram-negative pathogens and at the same time a good absorp- ’ 25 tion in the gastrointestinal tract.

In some cases, it has been possible to increase the absorp- tion of a cephalosporin in the gastrointestinal tract by esterification of the 4-carboxyl group. Since the cephal- } 30 osporin esters as a rule have no antibiotic activity in themselves, the ester component must be chosen so that after absorption, the ester is split back again into the cephalosporin with a free carboxyl group rapidly and com- pletely by endogenous enzymes, such as esterases.

The degree of enteral absorption of cephalosporins depends decisively on the chemical structure of the cephalosporin A and the particular ester component. Even small structural rE Ry RSE rl Cle Te To ld Gl wh 30

Foe Ry rr CU i

REGRET BR SE be i CL a ee I TS EROSIONS, . / > 4 . 2h 2h ! ' - 2 - ’ bi variations on the cephalosporin basic skeleton or in the ) 2

Fs ester component can influence the absorption. The dis- a covery of suitable components is purely empirical. Thus, Hi . . is for example, the introduction of an acid substituent._into Hi;

S the 7 B-side chain of aminothiazolyl-cephalosporins, such A as, for example, in cefixime, Leads to a compound which %

Ba can be absorbed enterally, whereas compounds with neutral 4 : . . . i side chains, such as, for example, in cefuroxime, are ab- % . A sorbed enterally only in the form of prodrug esters. The o # 10 dose/effect relationship is thereby often non-linear and b IY . Wy the therapeutic serum levels achieved are not satisfactory. ;

Rice - Carbonate esters from the aminothiazolyl-cephalosporin , 3 series are mentioned, for example, in European Patent £4 134,420. . 4 15 - &

By in vivo studies carried out systematically on various x : - Yuk animal species, we have now found a narrow group of ceph- ¥ 3-em-4-carboxylic acid esters which can be administered i: pS4s orally, have a sufficient chemical stability and due to Es 20 a balanced Lipid- and water-solubility are absorbed rapidly 3 and in a therapeutically substantial degree in the gastro- i 12 intestinal tract. ti

The invention accordingly relates to cephemcarboxylic 3 ai 25 acid esters of the general formula I iy “, y

N C - CONH ie 0" (1) Fi

HN 1 N_ ch, -Rr? by : 5 N-OR d 277 LE

COOCH-0C-0R” | He " cE

CH, lo] IL in which i } rR! denotes hydrogen or methyl and x, ’ EL r2 denotes hydrogen or methoxy, one of the two sub- 3 pl ’ stituents R' or RZ always representing hydrogen; VE . . by *

R> denotes straight-chain or branched Cq-Cs-alkyl, £7 which can be substituted by Cq-C3-alkoxy, C3-Cg-~ b cyclolakyl or Cp-Cy-cycloalkoxy; A . 7.

Cy-Cg-cycloalkyl or I get

Ca-Cy-cycloaltkoxy, it ee a af a i : IE:

NOWELL E Bs hea Cir, “Ok SVMS EN TREN +0 i Lar BU a pitt) 3 TTT Tor eB SR ERS i =< _

RE Ee : BN REN ci Srv ce AS I oc

EC

! - 3 - i in which, in the case where j is hydrogen and RZ is meth- iH oxy, RS cannot be Cq-C4-alkyl, and in which the group . 2 oR’ is in the syn-position, and physiologically toler- it ated acid addition salts thereof. By

R” can thus represent yt

Cq1-Cs-alkyl, which can be straight-chain or branched, such ge as, for example, methyl, ethyl, n-propyl, i-propyl, n- 4 butyl, 2-butyl, 2-methylpropyl, t-butyl, n-pentyl, 2- Be 10 pentyl, 2-methylbutyl, I-methylbutyl, 1,1-dimethylpropyl, * & 1,2-dimethylpropyl or 2,2-dimethylpropyl, and preferably gr oe represents Cq-Cg4-alkytl, and in particular represents : i

C3-C4-alkyl, such as, for example, n-propyl, i-propyl, A n-butyl, 2-butyl, 2-methylpropyl or t-butyl, wherein = J) 15 those alkyl radicals which are substituted in the 1- pin position by methyl are also preferred, and wherein the & alkyl radicals can also additionally be substituted by §4 } €q-C3-alkoxy, such as, for example, methoxy, ethoxy 4 or propoxy, by Cz-Cg-cycloalkyl, such as, for example, i 20 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo- 2 heptyl or cyclooctyl, preferably by Cs5-Cp-cycloaltkyl, . * such as, for example, cyclopentyl, cyclohexyl or nor- B - bornyl, preferably cyclopentyl or cyclohexyl, in parti- 5 cular cyclohexyl, or by €Cp-C7-cycloalkoxy, preferably 25 C4,-Cs-cycloalkoxy, such as, for example, tetrahydro- & ' furanyl or tetrahydropyranyl, in particular tetrahydro- Lt pyranyl; © , or represent C3-Cg-cycloalkyl, such as, for example, JE. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo- Lh 30 heptyl or cyclooctyl, preferably Cs-C7-cycloalkyl, such 4 as, for example, cyclopentyl, cyclohexyl or norbornyl, He } preferably cyclopentyl or cyclohexyl, in particular He cyclohexyl; or 35 represents Cp-Cz-cycloatkoxy, preferably C4-Cg-cyclo- 5 alkoxy, such as, for example, tetrahydrofuranyl or tetra- Ie hydropyranyl, in particular tetrahydropyranyl. y i

Preferred compounds of the general formula I are those in $2 7 pA tee ants slg RPIne J va bal Cag DEL - Ca es Lakh Vath ei bi i

EREESGA Tp a RE eT

SRI 0630 sv dR ni oh Sr RRA INTER HE IE ERIN I SEI IR CE 0

Lo Lie

Ah ook ‘ - 4 - A ‘ i a which rR! represents methyl and RZ represents hydrogen ay and R> has the following meanings: ig

Be 1 1A A

Ci1-C5-alkyl, preferably C3-C4-alkyl, which can also wo ¥ og additionally be substituted by C4-C3z-alkoxy or by Cg-Cy- £1 cycloalkyl or by C4-Cs-cycloalkoxy; id “ bot

Ho

Cs-Cg-cycloalkyl, preferably Cg-Cy-cycloalkytl, or 55 on

C4-Cg-cycloalkoxy, 5 = in which these definitions mentioned for R> have the mean- . % A ings given above in the discussion of the substituents of gr i # 3 #1 the general formula I. . FS in ra fe afi

Amongst the compounds where rR = methyl and RZ = hydrogen, 58 those in which R3 represents i-propyl, 2-butyl, 2-methyl- h propyl, 1-methoxy-2-propyl, cyclopentyl or cyclohexyl, ge : are of particular interest. ’ Ge ’ Compounds of the general formula I in which R' repre- bk sents hydrogen, RZ represents methoxy and RS represents [3 vo rat 2 ida

CH -D R6 (8) f o wo re

Hn ' HC

Eo

Wa dv wherein ____. . . .. i wi n = 0 or 1 i 5 fou - 30 m = 0 or 1 and be ye EL

RS = straight-chain or branched Cq-C3-alkyl, which i - is substituted by Cq-Cz-alkoxy, Cz-Cg-cyclo- i: alkyl or Cp-Cp-cycloalkoxy; gr {A

C3-Cg-cycltoalkyl or 5 3s Cp-Cz-cycloalkoxy, 4

IE are furthermore preferred. RUE oc

I) it

In the case where n is 0, the following meanings are pos- a sible for RS: ie - ’ i & pc

DER ae Cran 3

ORI cr ine sb hc vv Amgen Cpe iiapve SARC REY

C3-Cg-cycloalkyl, preferably Cg-Cz-cycloalkyl, such Fo as, for example, cyclopentyl, cyclohexyl or norbornyl, Hi preferably cyclopentyl or cyclohexyl, in particular de cyclohexyl; 5 $i 2

Cp-C7-cycloalkoxy, preferably C4-Cs-cycloalkoxy, i 5 such as, for example, tetrahydrofuranyl or tetrahydro- fo pyranyl, in particular tetrahydropyranyl. vo 1f n = 0, those compounds in which RO in the group (8B) . wl represents cyclopentyl, cyclohexyl, tetrahydrofuranyl or i - tetrahydropyranyt, preferably cyclohexyl or tetrahydro-~ : vr pyranyl, are of particular interest. i 1f n= 0, R® can also represent straight-chain or branched i

C4-C3-alkyl, which is substituted by €1-C3-alkoxy, 5

Cy-Cg-cycloalkyl or C,-Cy-cycloalkoxy, the alkoxy, 25 ¢ cycloalkyl and cycloalkoxy groups, including their pre- £7 ferred ranges which are also suitable here, being as de- a fined above for R3 in the generat formula 1.

If n = 0, the following substituted alkyl groups are of 4 ; ~. particular interest for RS: L 2-methoxyethyl, cyclopentylmethyl, cyclohexylmethyl and i tetrahydropyranylmethyl. i po

If n in the group (B) = 1, suitable meanings for RS are 4 - the same as for when n = 0. Only in the case of the sub- 7 stituted Cq-Cz-alkyl group is a substituted C4-Co- = © 30 alkyl group preferred when n = 1. ! g

Examples which may be mentioned of R® in the meaning of : B a Cq-Cz-alkyl group substituted as described above, especially if n = 1 and m = 0, are: 1 1. methoxy-methyl yi 2-methoxy-ethyl 1 3-methoxy-propyl pi 2-methoxy-(2-methyl)-ethyl 5 2 2 iE

Th eb Sho EA EL at ert ere oe rb Ca HE AE SEE Sb

BN bv bret or sh Crien Lr & . ‘ i ; 2-methoxy-(1-methyl)-ethyl 5 4 1-methoxy-(1,1-dimethyl)-methyl bl ethoxy-methyl ig 2-ethoxy-ethyl Ea 3-ethoxy-propyl be 2-ethoxy-(2-methyl)-ethyl : ; 2-ethoxy-(1-methyl)-ethyl 3 ’ 1-ethoxy-(1,1-dimethyl)-methyl io pt (1-propyloxy)-methyl 2 7, 2=(1-propyloxy)-ethyl : I 3 3-(1-propyloxy)-propyl $ 2-(1-propyloxy)-(2-methyl)-ethyl big 2-(1-propyloxy)-(1-methyl)-ethyl bd 1-(1-propyloxy)=-(1,1-dimethy()-methyl i 2-(propyloxy)-methyl : 4 : 2-(2-propyloxy)-ethyl ;F 3-(2-propyloxy)-propyl Li 2-(2-propyloxy)-(2-methyl)-ethyl bY 2-(2-propyloxy)-(1-methyl)-ethyl i 1-(2-propyloxy)-(1,1-dimethyl)-methyl % (cyclopentyl)-methyl FC 2-(cyclopentyl)-ethyl : co 3-(cyclopentyl)-propyl Cl 2-(cyclopentyl)-(2-methyl)-ethyl Bi 2-(cyclopentyl)-(1-methyl)-ethyl “i 1-(cyclopentyl)-(1,1-dimethyl)-methyl {(cyctohexyl)-methyl w . 2-(cyclohexyl)-ethyl a 3-(cycltohexyl)-propyl ov 2-(cyclohexyl)-(2-methyl)-ethyl . 2-(cyclohexyl)-(1-methyl)-ethyl EX 1-(cyclohexyl)-(1,1-dimethyl)-methyl gh a (4-tetrahydropyranyl)-methyl Bi 2-(4-tetrahydropyranyl)-ethyl gs 3-(4-tetrahydropyranyl)-propyl i ch ¥

A So ER i! to -7- Eo 2-(4-tetrahydropyranyl)-(2-methyl)-ethyl : x 2-(4-tetrahydropyranyl)-(1-methyl)-ethyl i 1-(4-tetrahydropyranyl)-(1,1-dimethyl)-methyl i

S preferably methoxymethyl, 2-methoxyethyl, ethoxymethyl, hi 2-ethoxyethyl, cyclopentylmethyl, cyclohexylmethyl and ha tetrahydropyranylmethyl, methoxymethyl, cyclopentylmethyl, , cyclohexylmethyl or tetrahydropyranyimethyl being parti- i cularly preferred. go 10 LB 1¢ rR! in the general formula I represents hydrogen and i

RZ represents methoxy, especially preferred meanings La } of R3 are accordingly Cg-Cy-cycloalkyl, in particular i cyclopentyl and cyclohexyl, C4-Cs-cycloalkoxy, in par- . ag 15 ticular tetrahydropyranyl, and Cq-C3z-alkyl which is sub- 5 } stituted by Cq-C3z-alkoxy, such as, for example, -2-meth- Hl oxy-(1-methyl)-ethyl. | i

Possible physiologically tolerated acid addition salts J 20 are the salts known for cephalosporin antibiotics, such He . as, for example, the hydrochloride, sulfate, maleate, b. citrate, acetate or formate. They are prepared in a man- ES ner which is known per se by bringing the corresponding Ln - acid together with I in an aqueous or organic solvent or i 25 a suitable solvent mixture. bi

The invention furthermore relates to a process for the i preparation of cephemcarboxylic acid esters of the gene- gl ral formula I i 30 Fo go \ J C - CONH Be npn on! Ta -r? Er $ N-OR ° 2" (n bo

COOCH-0C-OR fe vo. EP iy 0 i

Ee oh wherein R' denotes hydrogen or methyl and RZ denotes ae hydrogen or methoxy, one of the two substituents rR gh or RS always representing hydrogen, R3 represents de

ECE raed RAE ole ab . TTT IE Te TT TER ERR.

BEVIN RP CCW 5 oh » oo Cos Don Mn ERE TiN el

I vc emt cE am ————— he . a ry

F. « ; ’ ee - 8 - i : a straight-chain or branched Cq4-Cg-alkyl, which can be 5) 5 substituted by Cq-C3z-alkoxy, C3-Cg-cycloalkyl or C2- bo oy 3,

Cs-cycloalkoxy, or represents C3-Cg-cycloalkyl, or bi + represents Cp-Cp-cycloalkoxy, in which, in the case Lo fr CR

S where R1 is hydrogen and R2 is methoxy, RS cannot be Ie i

Cq-C4-alkyl, and in which the group -oR" is in the Lo wR syn-position, and of physiologically tolerated acid FI a addition salts thereof, which comprises bo

Eo a) reacting a compound of the formula 11 * 4

Ck -~ 5 RY f NET C — CONH 1 7

J "5 2 3 n=l N-OR J _Lcu.r 14S of NT 2 (11) Le " COOA i ’ } ¥ By in which R® represents hydrogen or methoxy, R repre- A

EL sents hydrogen or an amino-protective group, RS repre- A sents methyl or a group which can easily be split off and i B

A represents a cation, in which RY can only represent hyd- ds rogen if RS is methyl, i R with a compound of the general formula III B . {7 X - CH - 0CO, - R3 a. tig (111) yo

Yo } in which RS has the above meaning and X represents a leav- : ing group, to give the ester of the general formula IV : — CONH : - 30 Ny 5 (1v). un | N-OR A= cH Rr? v

R 4 Ss 0 2 7

Co,- CH-0-C-OR> e n .

CH, 0 and removing the groups R* and R%, in the meaning of a 2 protective group or a group which can easily be split off, 4 4 in a manner which is known per se, or 2 ao pad i b) reacting a compound of the general formula V Ro remem LL : 3 i a oS TEE FER Ri T EE Ceo - TERRE Ln ORNE da. CE Te : EE Sr Bo lle RGR ;

EER fh itl Ca Coe nan REC AR SBR ;

RRERER I A Co nde ani BRE CRE LL &

Ce EE olay ER ANRC REGIA

IU abe dco vpst nian a ofr tein son Ee AC NI 44 3 . ' -9 - ; % 3 Bo

Lb

N ¢ ——CO-Y (Vv) ’ A } " 5 ol

N I | N-OR Bol

H i i rd #0 in which R® and R® have the above meaning and Y repre- i } nh sents an activating group, with a compound of the general { ; formula VI y - ol nN ——" 2 2 ob

J——N = CH,R (vl) ho , 2 . En ~~ 0 3 §

CO.,-CH-0C-OR LR . CHy © bi - 3. + : . . 2 3 . . in which RS and R” have the above meaning, or with a he: . salt of this compound, to give a compound of the general fo formula IV, and splitting off the groups rR and RS, in Pa : the meaning of a protective group or a group which can ol easily be split off, in a manner which is known per se, = or ER c) reacting a compound of the general formula VII " 2-08,-C-C-CoH r > , ho : & OY

CO,-CHOCOR’ 9 " ! a, 0 in which Z represents halogen and RY, r2 and RS have 5 the above meaning, with thiourea to give compounds of the A i general formula I and - if desired - converting the re- "e sulting compounds into a physiologically tolerated acid i addition salt. -

Sy

In the general formulae II, IV and V, R* stands for an 5 amino-protective group which is known from peptide and i cephalosporin chemistry, preferably formyl, chloro- A acetyl, bromoacetyl, trichloroacetyl, trifluoroacetyl ar 8 “ ok a B fa tel = : BIE so Aang AT ER A A #0

Wn

Co - 10 - a benzyloxycarbonyl, tert.-butoxycarbonyl or trityl, and i Is

R> stands for a group which can easily be split off and er ~ is Likewise known from peptide and cephalosporin chemistry, a ™ preferably benzhydryl, trityl, tetrahydropyranyl or 1- on methoxy-li-methylethyl. Trityl and chloroacetyl are par- 5 " ticularly preferred for RY, and trityl and 1-methoxy-1- v : methyl-ethyl are particularly preferred for rR. po

In formula 111, X denotes a leaving group which is gen- £1 " erally known for esterification reactions, such as, for \ 5 . example, chlorine, bromine, iodine, phenylsulfonyloxy, . p-toluene-sulfonyloxy or methylsulfonyloxy, preferably : be chlorine, bromine or iodine, in particular iodine. £0

Examples which may be mentioned of bases on which the i cation A in the general formula Il is based are sodium i bicarbonate, potassium bicarbonate, sodium carbonate, ’ bo potassium carbonate and optionally substituted, alkylated “© amine bases, such as, for example, trimethylamine, tri- i ) ethylamine, diisopropylamine, ethyldiisopropylamine, N,N- CH : dimethylanil ine, N,N-dimethylbenzylamine, 1,5-diazabicy- i clol4,3,0lnon-5-ene (DBN), 1,8-diazabicyclol5,4,0lundec-7~- fs —- ene (DBU), pyridine, picoline or 2,6-dimethylpyridine. Lo

Preferred bases are sodium bicarbonate or potassium bicar- on bonate, sodium carbonate or potassium carbonate, triethyl- bs Bh . amine, N,N-dimethylaniline, DBN or DBU. :

Reaction of the free carboxylic acids with these bases : gives the salts of the general formula II in which A stands ¥ for a cation, such as, for example, sodium or potassium, but also magnesium or calcium or an optionally substituted Eo ’ alkylated ammonium ion, such as, for example, ammonium, y . trimethylammonium, triethylammonium, tetrabutylammonium, ro diisopropylammonium, ethyldiisopropylammonium, diazabi- v : cyclol0,3,4Inonenium or diazabicyclol[0,4,5]undecenium. uo

Preferred meanings of A are sodium, potassium, triethyl- gp ammonium, N,N-dimethylanilinium and the DBN and DBU ion. i hn

In compounds of the formula VII, Z stands for a halogen k bt

EE I OR ls TT a aw TERT

RRERER LIOR SERN Re E30 7 : co oat AER TIER iy EB NRB tss ate Wmpa2 H s N E e onts a a 4 gow . Se atom, preferably chlorine or bromine. © !

The reaction of the compounds of the formula Il with the z ) fF compounds of the formula III can be carried out in an HE organic solvent at about -20 to about +50°C, preferably a at about 0°C to room temperature. Examples of solvents t i which can be used are ketones, such as, for example, ace- HS tone or methylethyl ketone, N,N-dimethylformamide (DMF), ! t

N,N-dimethy(acetamide (DMA), N-methylpyrrolidone or di- a methylsulfoxide (DMSO). OMF, DMA, N-methylpyrrolidone \ vl and DMSO are preferred. OMF is particularly preferred. boy

The groups rR and R? are split off from the resulting com- in pounds of the formula IV in a manner which is known per se i 5 by methods known from peptide and cephalosporin chemistry, i for example with trifluoroacetic acid, dilute hydrochloric Lo ’ acid or preferably with formic acid, with the addition of a + ul

Little water. § i 1f a compound of the formula V is reacted with a compound Lo of the formula VI, Y represents a group which activates § - the carboxyl group, such as is known for corresponding 3 ~ reactions from peptide and cephalosporin chemistry, for : example a halide, preferably chloride, an activating ester y group, for example with 1-hydroxybenzotriazole, or a mixed : anhydride, for example with benzenesulfonic acid or tol- i uenesul fonic acid. The activation of the carboxyl group is also possible in a manner which is known from the

Literature via the addition of a condensing agent, such as, for example, a carbodiimide. Co ’ The compound of the general formula VI can be used as such or in the form of a salt, for example the tosylate, hy- drochloride or hydriodide, and the use of crystalline Lo salts may be advantageous in respect of the purity of the Fo products. : .

The reaction of compounds of the formula V with those of : the formula VI can be carried out in an organic solvent, 4 i ; bi

I IRENE 20:0 cosinor URNS, i j? - 12 - RE such as, for example, methylene chloride, chloroform, ace- vn tone, methylethyl ketone, dimethylformamide, dimethylacet- "i - amide or water, or in mixtures of these solvents. be

The acylation reaction can advantageously be carried out at temperatures from about -50°C to about +50%c, prefer- iy . ably -40°C to +30°%c, if desired in the presence of a 7 base, such as, for example, triethylamine or pyridine. z

The addition of a base serves to bond the acid component = : liberated during the condensation. i .

The cyclization of compounds of the general formula VII ‘ i . with thiourea can be carried out by processes which are no known per se, such as are described, for example, in J 7

European patent 134,420. For example, it is achieved od i smoothly at temperatures of about 0 to 30°C, preferably hi Bb about 5°¢, in organic solvents, preferably aprotic polar Lo solvents, such as, for example, dimethylformamide, dimethyl - - acetamide, acetonitrile or acetone. -

L?

The compounds of the formula III can be prepared in a : manner which is known per se, for example by reacting ; ~~ t1-chloroethylchloroformate )s C1 - CH - 0CO - C1

CH4 : with alcohols of the general formula VIII

RS - OH (VIII) i in which RS has the abovementioned meaning. g

The reaction is advantageously carried out in an organic ; solvent, such as a halogenated hydrocarbon, for example methylene chloride or chloroform, if appropriate in the presence of a base, for example, pyridine or triethyl- bo amine, at a temperature of -20% to +30°%c. -

Compounds of the formula I!I can also be prepared by ! .

HS i i

Be INTER EE Gi gE Co cof een WR pe :

I CER chp syd ar ve os HR PN I ABR i, 2 hi ir

Fr SE £0 peo rr . . - 13 - ve v rE: halogen replacement. For example, a compound 11! in which 3 : - X represents bromine or iodine can be prepared by reacting “ .

H the corresponding compound II! in which X represents LIA chlorine with an iodide or bromide satt, such as, for i! i example, sodium iodide or sodium bromide, if appropriate ve . in the presence of a catalyst, for example zinc chloride. El . po

The preparation of the starting compounds of the general ro formula II is described in European Patent 34,536. 5 - : 3

The starting compounds of the general formula V with the 3 : - activated carboxyl group are prepared in a manner which , Lo is known from the Literature, and the esterification to be give the compounds of the formula VI is carried out in : . : the same manner as has beeri described for the preparation - of the esters of the general formula IV. . i -

The compounds of the general formula VII can be prepared ’ i by processes which are known per se. Thus, for example (compare European patent 134,420), diketene can be reacted : with bromine and the resulting intermediate can then be . reacted with a compound of the general formula VI, a pre- : - {iminary product of the formula

Br-CH,C-CH,~CONH jg

Oo ~/— CH RZ 0 F 2

CO,CHOCOR

CH, 0 in which r2 denotes hydrogen or methoxy being obtained and subsequently being converted by nitrosation (compare also g

European Patent 134,420) into a compound of the general formula VII. oo -

The ceph-3-em-4-carboxylic acid esters of the general . formula I have a number of physicochemical and biological go properties which make them useful cephalosporin antibiotics r . for oral administration. They are stable, colorless oo yo { v

ER Cm

REE Ee OE np : RE DERERGAA Ci a e L esten e v og j Co - 14 - Ch compounds which are readily soluble in the customary organic : ; solvents, are absorbed in the intestine, are rapidly split Eo in the serum to give antibiotic cephalosporin derivatives oo p of the formula SE. 3 N C —— CONH ~S :

MN | N-0R1 A

HN 0 z= LF 1 2 a ) Lo in which R' and R™ are as defined in formula 1, and are 10 therefore outstandingly suitable for the treatment of ’ bacterial infection diseases, such as, for example, in- ss fection of the respiratory tract or of the urogenital ’ tract. : So 15 The compounds according to the invention are administered orally in the form of customary pharmaceutical formulations, for example, capsules, tablets, powders, syrups or suspen- sions. The dose depends on the age, symptoms and body weight of the patient and on the duration of treatment. 20 However, it is as a rule between about 0.2 g and about . g per day, preferably between about 0.5 g and about 3 g per day. The compounds are preferably administered in _. divided doses, for example 2 to 4 times daily, and the . individual dose can contain, for example, between 50 and 500 mg of active compound.

The oral formulations can contain the customary excipients and/or diluents. Thus, for example, binders, such as, for example, gelatin, sorbitol, polyvinylpyrrolidone or car- boxymethyl cellulose, diluents, such as, for example, lactose, sugar, starch, calcium phosphates or polyethylene glycol, and lubricants, such as, for example, talc or magnesium stearate are possible for capsules or tablets, and aqueous_or oily suspensions, syrups or similar known formulation forms, for example, are suitable for liquid formulations. aE

The following examples serve to further illustrate the invention, but do not Limit it to them. hu

EE ae : TE eee

N acid BELA of AB: <2 1 cn Lee TT : p - 15 - Co f A. Preparation of starting substances ~

Preparation example 1 1-Chloroethyl 1-methoxy-2-propyl carbonate 7.7 mL (70 mmol) of 1-chloroethylchloroformate and 6.6 ml (70 mmol) of 1-methoxy-2-propanol were dissolved in 40 ml of dry methylene chloride and the solution was cooled to 0°C. A mixture of 5.8 mL (72 mmol) of pyridine and 20 ml ' Co of dry methylene chloride was then added dropwise at 0 ~- : sc, the mixture was stirred for a further 2 hours, while cooling with ice, and the pyridinium hydrochloride formed was filtered off with suction. The filtrate was washed twice (Hp0) and distilled under a water pump vacuum. 8.8 g (64%) of the title compound were obtained (boiling pointzg = 100 - 105°C). 6.46 (q, CH-C1) 4.93 (m, CH-0COp) 3.63 (4, CH5-0) i. 3.40 (es, OCHg) 1.83 (4, CH5-CHC1) 1.46 (a, CH3-CHOCO,) .

The compounds summarized in the Table 1 were prepared } analogously to Preparation Example 1: ! {i i i l

Lo i

I i. lh nee CR

RRR Be 7% Artie. oc oo CL CT DARREL RL i - 16 -

Table 1 0

C1 - CH - olor’ bh,

Example R3 Yield NMR (CDCLlz) § = (ppm) 3

NO ————— 6.46 (gq, CH-C1)

J CH,0CH3 } 4.92 (m CH-DCO., ) 1 -CH 64 % 3.63 (dg, CHy-O) t

AN 3.40 (s, OCH) i

CH4 1.83 (d, CH,-CHC1) 1.446 (a, CH, =CHDCOD, ).

TT 6.48 (gq, CH-C1) 4.7 (m, CH-DCOD,) * 2 < 74% 2221.0 (m, Cyclohexyl =H) 1.83 (d, CH,=CHC1, masked t

I

6.83 (q, CH-C1)

S.16 (m, CH-DCO;) 3 <] 45% 2.0-1.8 (m, CHy) 1.83 (d, CH; ~CHC1, masked ¢ i 3.00-4.6 (a, CH-0CD,;) { 4 0 47 % 4.16-3.3 (m, (CH), O) 1.83 (dd, CH;=CHC1, pasked

Eo } - {

CH 6.49 (gq, CH-C)) 3 57 % S.08-4.4 (a, CH-OCOD,) 6 ~ 2. 16-1.4 (», C(CHy 14) i

CHy 1.80 (d, CM; -CHC1, masked 1.33 (go, CH(CH; 4) i

Vs

- I a RNR ro rove. cn a A SPANAIR

CA . . - PE 3 fos . . - 17 - j i Table 1 (continuation) y- Example RS Yield NMR (CDCLl3) 6= (ppm) oo No. : . [I . : CHoCHy 4.76 (m, 0-CH-) 7 “CH 60 % 1.83 (dy, CHy=CHC1, 2ckeq

CH (R,S) 1.8 - 1.8 (m, CHy) 3 1.3 (2 x t, D-CHI(CH,) ee No 6.48 (q, CH-C)) 4.16 (t, CH, 0) 9 =CH,CH, CH 62 £ 1.83 (dg, CHy =CHC1 , masked 1.67 (m, CHy-CHy~CH, - . 6.48 (q, CH-C1) : 4.3 (m, CHy; =OCH, ) seh -CH,CH,0CH 8% 3.6 (em, CO, CH, ) oo 2.16-1.4 (m, C(CHy)4) 1.81 (go, CH =CHC1, packed -_— mmm —————_ é.48 (q, CH-C)) 3.5 - 4.1 (m, CH, DOCH, . CH, © | 1.5 = 2.1 (m, CHyCH,). -— f 6.48 (Qa, CH-C1) : od - 4,7 (» CH-D) Ci 12 40 £ 3.3 - 3.9 (m, CH) um 2.4 (m, CH) 1.81 (gd, CM; —CHC1 , masked 1.0 - 1.9 (am, CH) : ¥

EE ES EE. b a l i}

a CEE sid RNs stb ee £5 A ge Ch SO SA nS z hl - to aR : Co ;: - 15 - !

J Table 1 (continuation) ; + Do

J.” Example R3 Yield NMR (CDCLl3) 5 = (ppm) ange bs 2 3 . m, = H=) 13 cs” 62 % 1.85 (0, CH; CHCl. masked ~ 1.5 - 1.8 (m, CH,)

CH, (R) 1.3 (2 x t, D-CHI(CH,) : 0.92 (2 x t, CHy=CH;). ee 6.43 (q, CH-C1) ps CH,CHy 3-28 (mm, 0=CH=-) ; 14 CH 58 1s ee Bi, Che + masked ‘, LL . ’ a

CHy (8s) 1.3 (2 x t, O-CH(CH;) - 0.92 (2 x t, CHy=CH;). ——— etna : 6.48 (q, CH-C1) 4.33 (t, CH,) -CH,CH,CH,OCH,CH,CHy 32 % 30 (Je. LOCH) . Q 2 1.87 (m, CHy) 1.81 (d, CH,;-CHC} ,masked 1.17 (t, CHy) - 6.48 (q, CH-C1) - Hs 4.03 (d, CH,) 16 -CH,-CH 52 % 3.6 (ma, CO,CH,)

Nop. 1.81 (d, CH,-CHC1 , masked 3 1.0 tq, CH;) - i ] » 1 rn

TTT TL re na Em

J PW vast OR ) A ey ns Lh

EE IREDELL oe wer ss mie 00 CE Kami ENE yy y 4 ;

Eb 3

J: . . - 19 - yr B) Embodiment examples

E

I 1. Compounds of the general formula IV ] : 5 Example 1 1-(1-Methoxyprop-2-yloxycarbonyloxy)ethyl 7-(2-(2-trityl- aminothiazol-4-yl)-2-(Z)-1-methyl-1-methoxy-ethoxyimino- acetamido)-3-methoxymethyl-3-cephem-4-carboxylate

C10 i

Step A i = 4.3 g (28.3 mmol) of sodium iodide and 4.3 g (22 mmol) of 1-chloroethyl 1-methoxy-2-propyl carbonate were added in succession to a suspension of 560 mg (41 mmol) of an- i hydrous zinc chloride in 33 mL of carbon disulfide. The reaction -mixture was stirred under a nitrogen atmosphere in for 2 hours and then poured into a mixture of 300 mL of 9X strength NaHCO3 solution and 300 mL of ether and : the phases were separated. The organic phase was washed ts (NaHCO3 solution, sodium thiosulfate solution and NaCl I solution) and dried (MgS0,). The solvent was stripped b off in vacuo at 20°C to give crude 1-iodoethyl-(1-meth- vi ‘\.loxy-2-propyl carbonate as a colorless oil, which was fur- f . ther used immediately without purification (Step B). : i

Step B s jit

The crude product obtained from Step A was taken up in l 5 mL of dry dimethyl formamide and the mixture was added ii to a solution of 3.8 g (5 mmol) of potassium 7-(2-(2- i tritylaminothiazol-4-yl)-2-(2)-1-methyl-1-methoxy-ethoxy- i iminoacetamido)-3-methoxymethyl-3-cephem-4-carboxylate i in 15 mL of dimethylformamide, while cooling with ice. i

After 10 minutes, the reaction mixture was stirred into I a mixture of 200 mL of 9% strength NaH(CO3 solution and i! 100 mL of ethyl acetate. The organic phase was washed (NaHCO3 solution and NaCl solution) and dried (MgsS0y,) I and the solvent was stripped off in vacuo. The resulting i

I hi co

RE BR “ Se

Se | | Ce _ : RR IA RNG cdl ni sre he pkey ip pb Ee OT

Ing ’ : : ae - 20 - 8 : 7. oil was triturated with 100 ml of ether, while cooling Lo pe with ice, and made to crystallize. The precipitate was - 18 filtered off with suction and rinsed with ether to give 1.5 g of crystalline 1-(1-methoxyprop-2-yloxycarbonyloxy)-

S ethyl 7-(2-(2-tritylaminothiazol-4-yl)=-2-(2Z)-1-methyl~- v r 1-methoxy-ethoxyiminoacetamido)-3-methoxymethyl-3-cephem- 4L-carboxylate. A further 0.34 g, making 1.84 g (41%) to- gether, of the title compound was obtained from the fil- trate by treatment with pentane. "H-NMR (dg-DMS0): & = (ppm) 9.54 (2 x 4, CONH, J = B Hz) : i 8.85 (s, NH-trityl) 7.4-7.2 (m, phenyl-H) 6.85-6.8 (2 x q, 0-CH-0) 6.7 (2 x B, thiazole-H) 5.75 (2 x q, J = 5 Hz, C-7-H) . 5.2 (2 x 4, C-6-H) 4.85 (m, 0C0,-CH) 4.15 (o, -CH,-0) 3.55 (m, C-2-H) 3.4 (q, masked , J = 5 BZ, CE,-OCHs) 3,25 (s, CH,-O0CHs3) — 3.2 (8, 3-CH,-0CHz) ', 3.1 (8, 0-C-OCHz) 1.5 (4, J = 6 Bz, CO,-CH(CHs)-0COp) ] 1.4 (s, C-(CHs),) 1.2 (3 x t, J = 7 Hz, CHx~CH-0COp). :

The compounds summarized in Table 2 were obtained as amorphous solids analogously to Example 1, steps A and B. i !

I so Gow CO

BEE LEER

I ENE pi Situs CURT ATL he es en areal SI ¥

JY

TR

TEER ' .

Fa - 21 -

Table 2 pt * »

Jc. £ THs 0-C-0CH4

N CH

N CONH s

AAT

TrNR 5 Zz OCH, Co 0 co, CHOCOR? 1 “

Ci CH40 | . f

Example rR yield NMR (dg-DMSO) s = ppm

No. 9.54 (2 x d, CONM, J=8 Hz) : 7.4-7.2 (mn, phenyl =H) $.83-6.8 (2 xX Qs D-CH-D) ‘cu é&.7 (2 x 8, thiazole -“H)

EN Bh Che eit S.2 (2 x d, C=é~-M)" i

CHy0CHy 4.85 (m, OCO,=-CH) 41 % 4.13 (wm, 3-CHy=D) 3 3.4 tq, masked, J=S MHz, CH, ~0CH;) . 3.25 (=, CH, -0DCH3 L , 3.2 (s, 3=CHy =OCH;) b

S.t (s, O-C-OCH;) . 1.8 (d, J=é Mz, COy=-CH(CH;)-DCO,) i 1.2 (3 x t, J=7 Hz, CH; -CH-0CO, ) . ' i

BE 2 CE ASL ar nT

ES Cha Lr La

ET eA : SE

Cy ERR EL 4 Lid r fT ; } ie i

EE AR ASM I benim 4 one nr Ness hte pry oh PRET “ol A

I . ‘I 4 3 ' y - 22 -

Fk: Table 2 (continuation) a Example RO Yield NMR (dg-DMSO) 5 = ppm f. No. 4 9.52 (2 x d, CONH, J=B Hz) ” 0.05 (s, NH=trityl) 7.4-7.2 (my, phenyl=H) 6.805-46,78 (2 x q, D-CH-D) 6.7 (2 x 8, thiazoleH) = 8.73 (2 x q, J»S Hz, C=7-M) 39 3 S.15 (2 x d, C-b6-H) 2 4.33 (m, DCO, -CH) 4.15 (m, 3-CHy=0) 3.35 (2 x AB, C-2-H) — 3.2 (s, 3~CHy=-0DCH;) a 3.1 (s, O-C-DCH;) 1.905-1.25% (m, cyclohexyl =H) : . 1.3 (d, J=é Hz, CO, =CHI(CH,)-DCO,, ‘ “ masked) i g 1.4 (8, C~(CH;)y, masked) i: A — 1 9.85 (2 x d, CONH, J=B Hz) i 9.85 (3, NH-trityl)

A 7.4-7.2 (m, p hanyl=H) 8 6$.0-6.7% (2 x q, 0O=CH-O) i 6.7 (2 x s,thiazole =H) pe 8.75 (2 x q, J=5 Hz, C-7~H) 4 s.17 (2 x d, C=6-H) 3 in 38 ¢ 8.05 (m, DCO, ~CH) i or 4.15 (a, 3-CH, =D) 3 3.85 (2 x AP, C-2-H) 4 3.2 (8s, 3-CHy=DCH;) i 3.1 (s, 0-C-DCH;)

FI 1.85-1.2%5 (m, Cyclopentyl=H) 1.45 (2 x d, J=b Hz, COy=CH(CH;)- 4. 0CO, , masked) 1.4 (8, C=-(CH;)g, masked) ; ee 1 4 i i 4

Ne

I TT FE DE OR A vy 3% fi TINA —

RR Rasta : E Ce : } boa PL aon 1: ie ods RA : ; Ho i In IRR fe op deme an ester ATRL AN EATEORT A

Br

Ho ae : - - 23 - : oe

Fed Table 2 (continuation)

FRE

PR

#3 f yr Example R> Yield NMR (dg-DMSO) g = ppm

F No. ¥ 5 » 9.3 (2 x d, CONH, J=8 Hz) 9.85 (8s, NH-trityl) 7.4-7.2 (m, phenyl=H) ’ &.92-6.77 (2 x Qe O=-CH=-0D) é.6% (2 nu 8,thiazole =H) 4.77 (a, OCD; -CH) 3.835 (2 «x AB, C-2-H) 3.1 (s, O-C-0DCH;) 1.99 (m, CH(CH;) 3)

To 1.3 (2 x d, Jmé Hz, CO3~CHI(CH; I~ : 0co,) 3 1.4 . (s, C=-(CH; 14) : a i 20 Example 5 ’ 1-(1-Methoxyprop-2-yloxycarbonyloxy)-ethyl 7-(2-(2- : aminothiazol-4-yl)=-2-(2)-hydroxyiminoacetamido)-3-meth- { oxymethyl-3-cephem-4-carboxylate : ; 1.83 g (2 mmol) of the cephalosporin obtained according i to Example 1 were dissolved in 18 ml of 90X strength for- . 1 mic acid at room temperature. The solution was diluted 3 with 2 mL of water and stirred at room temperature for ; 30 40 minutes and the triphenylmethanol which had precipi- : tated was filtered off with suction. The filtrate was

E concentrated, with the addition of toluene, the oily resi- due was taken up in acetone and the solution was clari- ? fied by addition of active charcoal. n-Pentane was added ; 35 to the clear filtrate, while cooling with ice, whereupon i the product separated out as an oil. The solvent was 3 decanted off and the oily residue was triturated with n-

Ek) { pentane, whereupon the amorphous product precipitated. { Yield: 0.74 g (64%). 2

Ll ; ‘ 7

IER RRR te : Co NE : RON if Dn

EERE EI FN SL a dnt Bn, iv ‘ a een Ai Tn etn sie . - q Er . } - 24 ~-

BE H-NMR (dg-DMSO): = (ppm)

Fr » 11.4 (s, NOH) » 9.5 (a, J = 8 Hz, CONH) at ’ 7 . 3 (8 + NH, :- 6.85-6.8 (2 x gq, J = 6 Hz, 0-CH-0) " 6.7 (8s, thiazole -H)

E 5.85 (2 x q, J = 5 Hz, C-7-H) 5.2 (3 x a, C-6-H)

TT 4.85 (m, CH-0CO,) 4.15 (8, 3-CH,-0) 3.55 (A/B, C-2-H) 3.25 (8, 3-CH,-OCHz) ) ] 3.2 (8, CH,-OCH4) 1.5 (2 x 4, J = 6 Hz, CO,-CH(CHg)-0CO) "1.2 (3 x t, CHz-CH-0CO,). - 3 The compounds Listed in Table 3 were obtained as amor- 1 phous solids analogously to Example 5. 1 . i Ye 4 4 . 4 i

A i :

= n v BR RL sp TTT To TTT . ) Ca 5 a RRA Ayn : CTD Is i!

BIR er wo I

Re tg frm ret a :

RA BEREAN Si dls) ae SERRE aT Cent eral Cael bt SON up td ne ce 2

Fa i a. - 25 - a Table 3

Pe NE py _OH . % — cont —— 2 J — CH OTH;

Fy CI 0 2 y €0,CHOCO, _—

CH 3

Example R3 Yield NMR (dg-DMSO) 5 = ppm

No. -— eee. on a Lr i 5 i 11.4 (8, NOH) : 9.5 (d, J=B Hz, CONH) - l33 (8, NH) . § CH,OCH b&.7 (es, thiazole=H) es 5.85 (2 x q, J=S Hz, C=7-H) i 5 “CH 64 £ 8.2 (3 x d, C=é-H) g CH 4.85 (nm, CH-DCO;) 3 4.15 (s, 3-CH,=O) 3.55 (A/B, C-2-H) oo g 3.235 (s, 3=-CH, =0CH; ) oN 3.2 (sm, CHy; =DCH3 ee 1.3 (2 x d, IJ=& Hz, CO,~-CHI(CH,)=-0CO, i — i { : 11.3 (as, NOH) ; 9.4% (d, J=B Hz, CONM) 7.1 (s, NH) 1 &.05-4.09 (2 x Q Jeb Hz ’ 0-CH-D) 6.65 (s, thiazole=H) i S.83 (2 x q, JS Hz, C=7=-M) 1 4.359 (m, CH-0CO,) ; 4.15 (8, 3-CH;-D) { 3.55 (2 x AB, C-2-H) : { 3.2 (®, 3-CHy =0CH;, ) i 1.8 (2 x d, Jes Mz, CD, -CH (CH; Y=0CO, ’ ; masked) me ———_—— ore A———————— eet? S—————e ae eee :

E or fis i Cn CL a - 26 - } fe

A Table 3 pe Example R° Yield NMR (dg-DMSO) ¢ = ppm x 11.3 (s, NOW)

FF 9.45 (d, J=B Hz, CONH) wy 7.15 (a, NHy) 1 . 95-6.7% (2 x q, J=b Hz, D-CH-O) 6.65 (8s, thiazole=H)

S.0% (m, CH-DCO,) 4.15% (s, 3-CH,-0) 3.85 (2 x AB, C-2-H) 3.2 (8, 3-CH,y =0DCHg) 1.05-1.5 (m, cyclopentyl =H)

A 1.5 (2 x d, J=é Hz, COy=CHI(CH;)=0CO,. 4 masked? o . : 4

We 11.3 (sm, NOH) - 5g 9.45 (d, J=8 Hz, CONH) . 4 7.12 (s, NH, ) 5

He 6.91-6.75 (2 x qe Jeb Hz, O-CH-D)

B( 6.65 (s, thiazole «py

CER ot (2 x qy J=S Hz, C=7-H) 1 8 { 55% 4.79 (m, CH-DCO,) id 4.15 (8, 3-CHy-0) 3 3.78 (m, (CH) gD) vy 3.88 (2 x AB, C-2-H) od . 1.6 © fm, C(CHy dg?

Ae 1.5 (2 x dy Jub Hz, COy =CH (CHy ) =0CO, masked) or i ‘

” Ty NCEE eT J rid TTT } - EREER - . .

A a RCE AN egress Torn soe CL mde eed alee haere 4 ) Sm : A ; ov v Ce + 3 BR 4 SA ‘ .

N - 27 -

Ro ;

By Example 9 ne :

Si git 1-(Isopropoxycarbonyloxy)-ethyl 7-2-(2-aminothiazol-4-yl)- pi 2-(1)-methoxyiminoacetamido-3-methyl-3-cephem-4-carboxy- 1 se 5 Late ] Step A : 1.5 g (10 mmol) of sodium iodide and 1.2 g (7.5 mmol) of 10 1-chloroethylisopropyl carbonate were added in succession’ to a suspension of 200 mg (1.5 mmol) of anhydrous zinc chloride in 10 mL of carbon disulfide. The reaction mix- ture was stirred under a nitrogen atmosphere for 2 hours = and poured into a mixture of 9% strength NaHCO3 solution 3 15 and ether and the phases were separated. The organic 2 phase was washed (NaHCO03 solution, sodium thiosulfate solution and NaCl solution) and dried (MgS0,). The solvent # . . . fi was distilled off in vacuo at 20°C to give crude 1-iodo- iy ethyl isopropyl carbonate as a colorless oil which was i] 20 further used immediately without purification (Step B). 1 k

LE | Step B 2 ~ ¥ 1 The crude product obtained from Step A was taken up in 3 25 18 ml of dry dimethylformamide and the mixture was added ; to a solution of 1.3 g (3 mmol) of potassium cefetamet § in 10 mL of dry dimethylformamide, while cooling with ice.

After 75 minutes, the reaction mixture was stirred into a mixture of 9% strength NaHCO3 solution and ethyl acetate. . 30 The organic phase was washed (NaHCO3 solution and NaCl : solution) and dried (MgS0y,) and the solvent was stripped i off in vacuo. The crude product was chromatographed on 100 g of silica gel using ethyl acetate. 300 mg of the title compound were obtained. oo cod i ee

DE SEER i a ———

RL cn

SER SE

. TEE ir Apt Dt EL fn fT te EE OA

BR i a - 28 - a 1H-NMR (dg-DMSO): 4 = ppm gy & 9.6 (2 x 4, CONH, J = BHz) yy 7.23 (br, 8, NH) i 6.78 ang 6.83 (2 x q, 0-CE-0) "A 6.73 (2 x 8, thiazote-H) 3 5.77 (2 x q, J = 5 Hz, C-7-B) oo 5.13 (2 x 4, Cc-6-H) 3.85 (e, OCHz) 3.4-3.68 (m, c-2-H) 2.03 (s, CHy) 1.5 (a, J = 6 Bz, Co,-CH(CHz)-0C0p) i ’ 1.25 (4, (CH4),-CH).

The compounds listed ‘in Table 4L were obtained as amor- Co } phous solids analogously to Example 9. 1 Table 4 i 2 ER OCH

X 3 ie Nn" 3 Nil —con s i J hy: HN A £ ~~ CH v3 o 3 3 iN C0.,CHOCOR fi 3 1 2, n

A | CHO : 1 : Example RS Yield NMR (dg-DMSO) é = ppm ! No. 9.6 (2 x d, CONH, J=B Hz) ot 7.23 (br ss, NM;) i CH 6.78 ;:nd 6.83 (2 x q, O~CH-O) 3 6.73 (2 x 8, thiazole-M) 9 CH; 47 £ 8.77 (2 x q, J=5 Hz, C-7-H) 3 3.85 (s, OCH;) ‘3.4 - 3.68 (m, C=2-M) : ‘2.03 (se, CHy) .1.8 (d, J=é Hz, COy ~CH(CH;)=0C0,) 1.28 (d, (CH; 0g ~CH) « ! : i

Came ee tr trate rot Ai I SU i

” DEEN sy TT i i = ir RH PL ane 0k Si CET So o . Te | . . o So 3 Pa pie firth A v hs - :

EE ENE SA ita urinate wr RE re gE Sn ee i ih! ’ a Co - 29 - i Table 4 (continuation) gy Example R° Yield NMR (dg-DMSO) § = (ppm) 3 No. 3 N ee # | 9.6 (2 x d, CONH, J=B Hz)

A 7.23 (br s, NH3) - 6.78 and 6.B3 (2 x qr 0-CH-D? > 6.73 (Zz x =, thiazole -p)

S.77 (Z x q, J=5 Hz, C-7-H) {) 42 3% 4.58 and 4.4 (m, 1H, O-CH) 3.85 (s, OCH;) 3.38 - 3.68 (m, C-2-H) ; 2.03 (s, CH3) 1.5 (d, J=é Hz, CO; =CHI(CH;)~DCO,) iz ®.57 (2 x d, CONM, J=8 Hz) i 7.20 (br 8, Ni, ) } }

Ke 6.78 and ¢ B83 (2 x q, D-CH-0) ~~ 4 CH 6.73 (2 x 8, thiazole =H) jg 3 85.73 (2 x q, J=5 Hz, C-7-H) oe 11 =CH{_ 46 v 8.13 (2 x d, C=6~H)

Bq CH. CH 4.62 (m, 1H, O-CH) fi 2¥73 3.82 (s, OCH;) ig 2.03 (ss, CH;) biol 1.9 (d, J=é Hz, CO, ~CH(CH,)=0COD,) 44 fri 1g 5 . ee ———— rf

Fuad a 4 “f “

Cod

EE

;

BN i oo ER RT : RI SPE Lt abn i RARE vs “pms

A

: ! ’ - 30 - 3 Table 4 (continuation) 3 Example RS Yield NMR (dg-DMSO) 45 = (ppm)

No.

Ne. 4 9.6 (2x d, CONH, J=8 Hz) 7.23 (br s, NH) : 4.78 and 4.83 (2 x q, O-CH-D)» 6.73 (2 x su, thiazole =H)

S.77 (2 x qo J=5 Hz, C=-7~H) 4.82 (m, 1H, DO-CH) 12 ~CHCH,0CH3 43% 5.85 (8, N-OCH;) ’ 3.4 (dg, CH) Co ET 3. 3 (s v 3H, OCH, ) : 2.03 (s, CH) 1 . 2 (m . SH , CH, ) © 1 i 7.23 (br 8, NHy) a ’ } . é. 78 and 6. 83 (2 x Q. O-CH-D) ind 6.73 (2 x 8, thiazole=H) sit S5.7 - 5.8 (2 x q, I=5 Hz, C~-7-H) 3 5.13 (2 x d, C~6-H) i 13 =CH,CH,CHy 47 % 4.09 (2 x t, 2H, O-CH,) oY 3.85 (s, OCH,) or 3.38 - 3.68 (m, C-2-H) ing 2.03 (s, CHy)

Rid 1.62 (mm, 2H, =CH3 =) .

It 1.8 (d, J=é Hz, CO,-CH(CH;)=-DCO,) 0.89 (t, ~CH;). by i 4 —_—nmnm mm m— — —_—_—mn mn -- - i | 9.59 (2 x d, CONH, J=B Mz) ; " 7.23 (br 8, NH; ) wg 6.78 and 46.03 (2 x q, D=-CH-D) +4 6.73 (2 x 8, thiazole=-H) i 8.77 (2 x qy J=3 Hz, C-7-H) £4) 14 ~CH,CH,0CHz 39 § 5.13 (2 x d, C-é-H)

Ped 4.2% (m, 2H, O=CH,) 4 3.4 ~- 3.680 (ma, C~2-H)

Sy 3.32 (m, 2H, O=-CM;) +3 2.03 ts, CH) : 1.3 (d, Job Hz, CO, -CH(CH;)~DCOD;) : — ee ————————r } tid a had NE iil EE TE a RE : hia E.. gies aveliie nl ad

HR PRE ae ge

IRM A lr 0 hi Tn Sl

EER STN X ta ar al ar SU CT He ) ; : - 31 - ! § Table 4 (continuation)

Example R> Yield NMR (dg-DMSO0) ; = (ppm) & No. q 9.6 (2 x d, CONH, J=B Hz) : 7.23 (br s, NH) 6.768 and 4.83 (2 x q, O-CH-D) : 6.73 (2 x s, thiazole-H) 42 % 8.77 (2 x q, J=S Hz, C=7-H) > S.13 (2 x d, C=b-H) 3.85 (s, OCH) 3.4 = 3.68 (m, C-2-H) ~ 2.03 (s, CH;) : : / 1.9 (d, J=é Hz, COs ~CH(CH;)-0CD,)

Ce ————————————————————————————————————— : 9.6 (2 x d, CONH, J=B Hz) 7.23 (br s, NH) 6.78 and 6.83 (2 x q, O-CH-O) 0) 6.73 (2 x s, thiazole=H)

Cu . S.77 (2 x qy J*3 Hz, C~-7-H) 16 0 31% s.13 (2 x d, C-6-H)

CH; 4.09 (m, 3H, O-CH, and 2'=H) 3.85 (s, OCH)

S.4 - 3.68 (m, C-2-H) 2.03 (s, CH; — 1.8 (m) v 1.3 (d, J=é6 Hz, CO,=CH(CH;)=-0CO;) mm 9.6 .(2 x d, CONH, J=B Hz) 7.22 (br 8, Wy) : 6.76 2nd 4.82 (2 x q, O-CH-O) 17 38 4 6.73 (2 x s, thiazole -H) 5.75 (2 x qy J=S Hz, C-7-H) : 4.5 (m, iH, 2'=H) 3.4 - 3.48 (a, C-2-H) : 2.03 (ss, CH;) 3 1.5 (d, J=é Hz, CO, =CH(CH;)-DCO;) a4

I me NEE — oo Sie

IEE RR Er SL ' - 32 -

Table 4 (continuation)

Example R> Yield NMR (dg-DMSO) 45 = (ppm)

No. - 9.46 (2 x od, CONH, J=B Hz) 7.21 (br 8, NH) 6.79 and 4.88 (2 x q, O-CH-O) 6.73 (2 x s, thiazole =H) 5.76 (2 x q, J=% Hz, C-7-H) 18 { 0 35 8 5.13 (2 x d, C-6-H) 4.8 (m, IH, 4°=H) 3.85 (s, OCH; i 3.4 — 3.68 (m, C-2-H)

TL 2.03 (ss, CH3) ; ; 1.5 (d, J=b& Hz, C0, -CH (CH; )=DCO,) 9.55 (2 x o, CONH, J=B Hz) . 7.20 (br s, NH) 6.78 and 6.83 (2 x q, O-CH-D) 6.73 (2 x 8, thiazole-y) -CH-CH 45 5.74 (2 x q, J=S Hz, C-7-H) 19 i 2CHs 5.13 (2 x d, C-6-H)

CH (R) 4.63 (q, 2H, CH, -CH;) 3.85 (s, OCH) 3.4 - 3.68 (m, C-2-M) 2.03 (s, CH;) 1.91 (d, J=é Hz, CO; ~CH (CH, )=-0DC0,) — 1.2 (2 x t, 3H, O-CH(CH;)~CH, -) 9.55 (2 x d, CONH, J=8 Hz) ] 7.20 (br Ss, NH, ) &.73 (2 x wu, thiazole =H) 5.74 (2 x qy J=% Hz, C-7-H) -CH CH CH 45 % S.13 (2 x d, C=6=H) oH (s) 4.63 (2 x q, 2H, CH, =CH;) 3.4 - 3.48 (ma, C-2-H) 2.03 (ss, CH; 1.81 (d, J=é Hz, CO,=CH(CH,)-0COs) 1.2 (2 x t, SH, O=CH(CH;)-CH;") 0.83 (2 x t, 34, CM;) ee

EE Cr

BRAC x : BERR: 1A pF RERRAE aL ps INN nL

BE RAN teases vn ee - 33 - / Table 4 (continuation) f

Example RS Yield NMR (dg-DMSO) , = (ppm)

No. 9.57 (2xd, CONH, J = 8 Hz) 7.20 (br ®, NH) 6.78 and 4.83 (2 x q, O-CH-D) 6.73 (2 x 8, thiazole op) 21 -CH,CH,CH,0CH,CH3 ag Ss. 13 (2 x d, Cm&=H) 4.19 (m, 2H, CO,CH,) 3.85 (ss, OCH;) 3.4 - 3.68 (m, C-2-H) 3.4 (m, 2H, 0-CH;y; CH; )

Te 2.03 (ss, CHy) 1.84 (m, 2H, CH; CH CH, 1.5 (d, J=é Hz, CO,~-CH(CH;)-0CO," } 1.1 (t, 3H, CH)

Aq 3 ?.37 (2 x d, CONH, J=B Hz)

A 7.21 (br s, NH) ; 6.73 (2 xs, thiazole pn) 5, CH S.74 (2 x q, J»S Hz, C-7-H) 03 5.13 (2 x d, C-6-H) 22 -CH,CH 40 ¢ 3.92 (2 x d, 2H, OCH, CH)

Neh 3.85 (s, OCHy) 3 3.4 - 3.48 (m, C-2-H) —- 2.03 (s, CH;) . 1.9 (m, 1H, =CH(CH;),) 0.89 (2 x d, CHICH;),)

Claims

ee ————————————— — ee * ' 27125 Patent Claims: Co

1. A cephemcarboxylic acid ester of the general formula S i EN £ N-OR : cH, -R” . 0 3 . COOCH-OL-OR CH, 0 ’ in which rR denotes hydrogen or methyl, and RZ denotes hydrogen or methoxy, one of the two substi- tuents rR or RZ always representing hydrogen; g3 denotes straight-chain or branched C,_Cg-alkyl, i 10 which can be substituted by ¢,-Cy-alkoxy, C;-Cg- cycloalkyl or C,-C,-cycloalkoxy; C4-Cg-cycloalkyl or C,-C,-cycloalkoxy, in which, in the case where rR is hydrogen and RZ is methoxy, R3 cannot be C,~Cg-alkyl, and in which the group or! is in the syn-position, and physiologically tolerated acid addition salts thereof.

2) A pharmaceutical formulation which is active against bacterial infections, which comprises a cephemcarboxylic acid ester of the formula TI.

3) A method for combating bacterial infections in a patient comprising administering to said patient Pant . , . { an effective amount of a compound as claimed 1n ) claim 1}.