DD291561A5 - PROCESS FOR THE PREPARATION OF CEPHERNCARBONIC ACID ESTERS - Google Patents

Abstract

The invention relates to processes for the preparation of cephemcarboxylic acid esters of the general formula in which the substituents R 1 to R 3 have the meaning given in the description and their use for controlling bacterial infections. Formula {Cephemcarbonsaeureester production; pharmaceuticals; Infections, bacterial}

Description

Z-Ch ₉ -CC-COMH ¹ η I

0 N-OR ¹

(VIII)

CO ₂ -CHOCOR ³ I II

in which Z is halogen and R ¹ , R ² and R ³ have the abovementioned meaning, with thiourea to give compounds of general formula I and, if desired, the compounds obtained in a physiologically acceptable acid addition salt. 2. Use of Cephemcarbonsäureestern of the general formula I, characterized in that they are used for the preparation of medicaments for combating bacterial infections.

Field of application of the invention

This relates to processes for the preparation of new cephalosporin derivatives, which are particularly suitable as pharmaceuticals for oral administration.

Characteristic of the known state of the art

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

The previously known cephalosporin antibiotics do not meet all the requirements that must be placed on such a drug, namely a high antibacterial A! .iviii: against gram-positive (especially staphylococci) and gram-negative pathogens and at the same time a good absorption in the gastrointestinal tract,

In some cases, it has been possible to increase the absorption of a cephalosporin in the gastrointestinal tract by esterification of the 4-carboxy group. Since the cephalosporin esters generally have no per se antibiotic activity, the ester component must be chosen so that the ester after absorption by endogenous enzymes such as esterases, again quickly and completely split back to the cephalosporin with free carboxyl group.

The extent of enteral absorption of cephalosporins is largely dependent on the chemical structure of the cephalosporin and the respective ester component. Even small structural variations on the cephalosporin skeleton or in the ester component may influence the absorption. Finding suitable components is purely empirical.

For example, the introduction of acidic substituents into the 7-β-f = 3ite chain of aminothiazolyl cephalosporins, e.g. As in Cefixime, to an enterally absorbable compound, while compounds with neutral side chains, such as. B. in cefuroxime, enterally absorbed only in the form of prodrug esters. The dose-response propriety is not linear and the therapeutic serum levels achieved are not satisfactory. Carbonate esters from the series of aminothiazolyl cephalosporins are mentioned, for example, in EP 134420.

The invention provides processes for preparing antibiotically active cephamic acid esters which have sufficient chemical stability and are absorbed by balanced lipid and water solubility rapidly and to a therapeutically considerable extent in the gastrointestinal tract.

Explanation of the essence of the invention

The present invention is based on the object. To provide methods for the preparation of new pharmaceutically active compounds.

We have now systematically performed in vivo studies in various animal species, a close group of orally administered ceph-S-em-ii-carboxylic acid esters, which have sufficient chemical stability and balanced by lipid and water solubility rapidly and in a therapeutically significant extent be absorbed in the gastrointestinal tract.

The invention accordingly provides processes for the preparation of chephemcarboxylic acid esters of the general formula I.

COUCH-OC-OR I il CH ₃ 0

in which mean

R 'is hydrogen or methyl and

R ^{2 is} hydrogen or methoxy, wherein one of the two substituents R ¹ or R ^{2 is} always hydrogen; R ^{3 is} straight-chain or branched C ₁ -C ₆ -alkyl which may be substituted by C ₁ -C ₃ -alkoxy, C ₁ -C -cycloalkyl or C ₂ -C ₇ -cycloalkoxy; C 1 -C 6 cycloalkyl or C 1 -C ₇ cycloalkoxy,

wherein in the event that R ^{1 is} hydrogen and R ^{2 is} methoxy, R ³ can not be Ct-C ₄ alkyl and wherein the group-OR 'in syn position, as well as their physiologically acceptable acid addition salts

R ³ can thus stand

for C, -C ₆ alkyl, which may be straight or branched, such as. Methyl, ethyl, n -propyl, i -propyl, η-butyl, 2-butyl, 2-methylpropyl, t -butyl, n -pentyl, 2-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1 - dimethylpropyl, 1,2-dimethylpropyl or 2,2-dimethylpropyl, preferably C ₁ -C ₄ -, in particular Cj-C ₄ alkyl, such as n-propyl, i-propyl, η-butyl, 2-butyl, 2-methylpropyl, t-butyl, where those alkyl radicals still occupy a preferred position, which are substituted in the 1-position by methyl and wherein the alkyl radicals may also be substituted du.xh C, -C ₃ alkoxy, such as methoxy, ethoxy or propoxy, by C 3 -C ₈ -cycloalkyl, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, preferably by C ₆ -C ₇ -cycloalkyl, such as cyclopentyl, cyclohexyl or norbornyl, preferably cyclopentyl or cyclohexyl, in particular cyclohexyl , or by C ₂ -C ₇ -, preferably C ₄ -Cs-CyClOaIkOXy, such as tetrahydrofuranyl or tetrahydropyrans, in particular tetrahydropyranyl; for Cr-Ce-cycloalkyl, such as * .B. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, preferably Ce-CrCycloalkyl, such as. Cyclopentyl, cyclohexyl or norbornyl, preferably cyclopentyl or cyclohexyl, especially cyclohexyl; or

for C ₂ -C ₇ -, preferably C ₄ -C ₅ -CyClOaIkOXy, such as. For example, tetrahydrofuranyl or tetrahydropyranyl, in particular tetrahydropyranyl.

Preference is given to compounds of the general formula I in which R ^{1 is} methyl and R ^{2 is} hydrogen and R ^{3 has} the following meanings:

C ₁ -C ₅ -, preferably C ₃ -C ₄ -alkyl which may also be substituted by C 1 -C ₃ -alkoxy or by C 1 -C ₅ -cycloalkyl or by C ₄ -C ₅ -cycloalkyl;

C ₅ -C ₈ -, preferably C 1 -C 4 -cycloalkyl! or C ₄ -C ₅ -cycloalkyl,

these definitions given for R ^{3 are} as defined above in the discussion of the substituents of general formula I.

Of particular interest among the compounds with R ¹ = methyl and R ² = are hydrogen salts in which R ^{3 is} i-propyl, 2-butyl, 2-methylpropyl, 1-methoxy-2-propyl, cyclopentyl or cyclohexyl.

Preference is furthermore given to compounds of the general formula I in which R ^{1 is} hydrogen, R ^{2 is} methoxy and R ^{3 is} the group B

(B)

stands, in which mean

η = O or 1

m - Oodori and

R ^e = straight or branched C, -C ₃ alkyl which is ₇ -cycloalkoxy substituted by C ₁ -C ₃ -alkoxy, Cj-Ce-cycloalkyl, or Cr-C; C ₃ -C ₉ -cycloalkyl or C ₂ -C ₇ -cycloalkyl.

In the event that η = O, the following meanings are suitable for R ⁶ ; C ₁ -C ₆ -cycloalkyl, preferably C ₆ -C ₇ -cycloalkyl, such as cyclopentyl, cyclohexyl, norbornyl, preferably cyclopentyl or cyclohexyl, in particular cyclohexyl; C ₂ -C ₇ -CyClOaIkOXy, preferably C ₄ -C ₅ -CyClOaIkOXy such as tetrahydrofuranyl or tetrahydropyranyl, in particular tetrahydropyranyl.

Of particular interest for η = O are those compounds in which in group (B) R ^{6 is} cyclopentyl, cyclohexyl, tetrahydrofuranyl or tetrahydropyranyl, preferably cyclohexyl or tetrahydropyranyl.

For η = O R ⁰ may also stand for straight or branched C ₁ -C ₃ -alkyl, which is substituted by C, -C ₃ alkoxy, C 3 -C _e cycloalkyl, or Cj-CrCycloalkoxy, wherein said alkoxy, cycloalkyl and cycloalkoxy groups including theirs also here in

Considering preferred intervals as defined above for R ³ in the general formula I.

For R ⁶ , when η = O, the following substituted alkyl groups are of particular interest:

2-methoxyethyl, cyclopentylmethyl, cyclohexylmethyl and tetrahydropyranylmethyl.

If η = 1 in group (B), the same meanings for R ⁶ as for η = O come into consideration. Only in the case of the substituted C 1 -C ₃ -alkyl group is a substituted C 1 -C ₂ -alkyl group preferred at η = 1.

For R * in the meaning of a C _t -C ₃ -alkyl group substituted as indicated above, in particular when η = 1 and m = 0 or 1, mention may be made by way of example:

Methoxy-methyl 2-methoxyethyl 3-methoxy-propyl 2-methoxy- (2-methyl) -ethyl 2-methoxy- (1-methyl) -ethyl 1-methoxy- (1,1-dimethyl) -methyl

Ethoxy-methyl 2-ethoxy-ethyl 3-ethoxy-propyl 2-ethoxy- (2-methyl) -ethyl 2-ethoxy- (1-methyl) -ethyl 1 -ethoxy- (1,1-dimethyl) -methyl

(i-propyloxy) -methyl 2- (1-propyloxy) -ethyl 3- (1 -propyloxy-J-propyl 2- (1-propyloxy) - (2-methyl) -othyl 2- (1-propyloxy) - (1- methyl) -ethyl 1 - (1-propyloxy) - (1,1-dimethyl) -methyl

(2-propyloxy) -methyl 2- (2-propyloxy) -ethyl 3- (2-propyloxy) -propyl 2- (2-propyloxy) - (2-methyl) -ethyl 2- (2-propyloxy) - (1 -methyl) -ethyl 1- (2-propyloxy) - (1,1-dimethyl) -methyl

(Cyclopentyl) -methyl 2- (cyclopentyl) -ethyl 3- (cyclopentyl) -propyl 2- (cycloperyl) - (2-methyl) -ethyl a-f-cyclopentyl-d-methyll-ethyl 1- (cyclopentyl) - ( 1,1-dimethyl! methyl

(Cyclohexyl-methyl 2- (cyclohexyl) ethyl S -cyclohexyl-D-propyl 2- (cyclohexyl) - (2-methyl) -ethyl a -cyclohexyl-D-methyl-ethyl 1- (cyclohexyl) - (1,1-dimethyl )-methyl

(4-Tetrahydropyranyl) -methyl 2- (4-Tetrahydropyranyl) -ethyl 3- (4-Totrahydropyranyl) -propyl 2- (4-Tetrahydropyranyl) - (2-methyl) -ethyl 2- (4-Tetrahydropyranyl) - (1 -methyl) -ethyl 1- (4-tetrahydropyranyl! - (1,1-dimethyl) -methyl

preferably methoxy! 1,2-methoxyethyl, ethoxymethyl, 2-ethoxyethyl, cyclopentylmethyl, cyclic hexylmethyl and tetrahydropyranylmethyl, with particular preference being given to methoxymethyl, cyclopentylmethyl, cyclohexylmethyl or tetrahydropyranylmethyl.

If in the general formula IR 'is hydrogen and R ^{2 is} methoxy, then for R ³ very particularly preferred meanings are Cs-C ₇ -cycloalkyl, in particular cyclopentyl and cyclohexyl, C 1 -C -dicycloalkoxy, in particular tetrahydropyranyl and C 1 -C -alb Alkoxy substituted Ci-Cs-alkyl, such as 2-methoxy- (1-methyl) -ethyl.

al; Physiologically acceptable acid addition salts are the known for cephalosporin antibiotics salts, such as

z. As the hydrochloride, sulfate, maleate, citrate, acetate or formate. They are prepared in a conventional manner by combining the corresponding acid with I in an aqueous or organic solvent or a suitable solvent mixture.

The invention thus provides a process for the preparation of cephemcarboxylic acid esters of the general formula I.

C - CONH

ii

N-OR

COOCH-OC-OR-I II CH ₃ 0

wherein R 'is hydrogen or methyl and R ^{2 is} hydrogen or methoxy, where always the two substituents R ¹ or R ^{2 is} hydrogen, R ^{3 is} straight-chain or branched C ₁ -C ₆ -alkyl which may be substituted by C ₁ -C ₃ -Alkoxy, C ₃ -Ce-cycloalkyl or C ₂ -C ₇ -cycloalkyl, C ₃ -C ₈ -cycloalkyl or C ₂ -C ₇ -cycloalkyl, wherein in the event that R ^{1 is} hydrogen and R ^{2 is} methoxy R ³ can not be C 1 -C ₄ -alkyl and in which the group -OR ^{1 is} in syn position, as well as their physiologically tolerated acid addition salts, which is characterized in that a) a compound of the formula II

N-OR

CONH 5

J-

COOA

in which R ^{2 is} hydrogen or methoxy, R ^{4 is} hydrogen or an amino protecting group, R ^{5 is} methyl or a readily cleavable group and A is a cation, where R ⁴ can only be hydrogen when R ^{5 is} methyl, with a compound of general formula III

X-CH-OCO ₂ -R ³ (III)

CH ₃

wherein R ^{3 has} the above meaning and X is a leaving group to which reacts esters of general formula IV

"Τ

J) N-OR ¹

CONH

^K CO., - CH-OC-OR

CH ₃ 0

and the groups R ⁴ and R ⁵ in the meaning of a protective group or readily cleavable group removed in a conventional manner or b) a compound of general formula V

j- C JJ N-

-CO-Y

in which R ⁴ and R ^{5 have} the above meaning and Y is an activating group, with a compound of general formula Vl

T '3' ^(VI)

CO ₀ -CH-OC-OR

* I Il

CH ₃ 0

in which R ¹ and R ^{3 have} the abovementioned meaning or with a salt of this compound, to give a compound of general formula IV and the group R ⁴ and R ⁵ in the meaning of a protective group or a readily cleavable group cleaves in a conventional manner , or c) a compound of general formula VII

rC-C-CCNH

Il

O N-OR " .. ^ -. _{(v ||)}

CO ₀ -CHOCOR ³

* I Il

CH .. O

in which Z is halogen and R ¹ , R ² and R ^{3 have} the abovementioned meaning, with thiourea to give compounds of general formula I and - if desired - the compounds obtained are converted into a physiologically acceptable acid addition salt.

In general formulas II, IV and V, R ^{4 is} an amino protecting group known from poptide and cephalosporin chemistry, preferably formyl, chloroacetyl, bromoacetyl, trichloroacetyl, trifluoroacetyl, benzyloxycarbonyl, tert-butoxycarbonyl or trityl and R ^{5 is} also one from the peptide and Cephalosporinchemio known easily cleavable group, preferably benzhydryl, trityl, tetrahydropyranyl or 1-methoxy-i-methyl-ethyl. Particularly preferred for R ⁴ is trityl and chloroacetyl, for R ⁶ trityl and 1-metoxy-1-methyl-ethyl.

In formula III, X has the meaning of a generally known esterification groups, such as chlorine, bromine, iodine, phenylsulfonyloxy, p-toluene-sulfonyloxy or methylsulfonyloxy, preferably chlorine, bromine or iodine, especially iodine. As bases, which are based on the cation A in the general formula II, z. B. called sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, optionally substituted, alkylated amine bases, such as. Trimethylamine, triethylamine, diisopropylamine, ethyldiisopropylamine, Ν, Ν-dimethylaniline, Ν, Ν-dimethylbenzylamine, 1,5-diazabicyclo [4,3,0] non-5-ene (DBN), 1,8-diazabicyclo [5 , 4,0] -undec-7-ene (DBU), pyridine, picoline or 2,6-dimethylpyridine. Preferred bases are sodium or potassium bicarbonate, sodium or potassium carbonate, triethylamine, Ν, Ν-dimethylaniline, DBN or DBU.

By reacting the free carboxylic acids with these bases, the salts of the general formula II in which A is a cation, such as sodium or potassium, but also magnesium or calcium or an optionally substituted alkylated ammonium ion, such as ammonium, trimethylammonium, Triethylammonium, tetrabutylammonium, diisopropylammonium, ethyldiisopropylammonium, diazabicyclo [0,3,4] nonenium or diazabicycloOAoylundocenium. Preferred meanings of A are sodium, potassium, triethylammonium, N, N-Dimethylanilinii m, and the DBN and DBU-ion.

! Compounds of the formula VII Z is a halogen atom, preferably bromine or chlorine.

The reaction of the compounds of the formula II with the compounds of the formula III can be carried out in an organic solvent at about -2O ⁰ C to about + 5O ⁰ C, preferably at about O ⁰ C to room temperature. Examples of suitable solvents are ketones, for example acetone or methyl ethyl ketone, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidone or dimethylsulfoxide (DMSO). Preferred are DMF, DMA, N-methylpyrrolidone and DMSO. Particularly preferred is DMF.

The cleavage of the groups R ⁴ and R * from the resulting compounds of formula IV is carried out in a conventional manner by known methods of peptide and cephalosporin, eg with trifluoroacetic acid, dilute hydrochloric acid, preferably with t meisensäure with the addition of some water.

When a compound of the formula V is reacted with a compound of the formula VI, Y represents a carboxyl group-activating group, as is known from peptide and cephalosporin chemistry for corresponding reactions, for example a halide, preferably chloride, an activating agent Ester group, for example with 1-hydroxybenzotriazole or a mixed anhydride, for example with benzenesulfonic acid or toluenesulfonic acid. The activation of the carboxyl group is also known in the literature on dia addition of a condensing agent, such as. As a carbodiimide possible. The compound of the general formula VI can be used as such or in the form of a salt, for example the tosylate, hydrochlorides or hydroiodide, wherein the use of crystalline salts may be advantageous with regard to the purity of the products.

The reaction of compounds of the formula V with those of the formula VI can be carried out in an organic solvent such as methylene chloride, chloroform, acetone, methyl ethyl ketone, dimethylformamide, dimethylacetamide, or water, or in a mixture of these solvents.

The acylation reaction may conveniently be carried out at temperatures from about -5O ⁰ C to about + 5O ⁰ C, preferably -4O ⁰ C to + 3O ⁰ C, if desired in the presence of a base, such as triethylamine cder pyridine, performed. The base addition serves to bind the bac condensation-releasing acidic component.

The ring closure of compounds of the general formula VII with thiourea can be carried out by processes known per se, as described, for example, in EP-PS 134420. He succeeds z. B. smooth at temperatures of about O ⁰ C his 30 ⁰ C, preferably about 5 ⁰ C in organic solvents, preferably ap'otisch polar solvent, such as

Dimethylformamide, dimethylacetamide, acetonitrile or acetor

The compounds of formula III can be prepared in a conventional manner by ζ. Β 1-chloroethyl chloroformate

CkCH-OCO-CI CH ₃

with alcohols of the general formula VIII

R ³ -OH (VIII)

in which R ^{3 has} the meaning given above, is reacted.

The reaction is conveniently carried out in an organic solvent such as a halogenated hydrocarbon, for example methylene chloride or chloroform, optionally in the presence of a base, for example pyridine or triethylamine at a temperature of -2O ⁰ C to +30 ⁰ C.

Compounds of the formula III can also be prepared by halogen exchange. For example, a compound III in which X is iodo or bromo can be prepared by reacting the corresponding compound III in which X is chloro with an iodide or bromide salt such as sodium iodide or sodium bromide, optionally in the presence of a catalyst, for example zinc chloride , getting produced.

The preparation of the starting compounds of general formula II is described in EP-PS 34 536.

The preparation of starting compounds of the general formula V with the activated carboxyl group is carried out in a manner known from the literature, the esterification leading to the compounds of the formula VI in the same manner as described for the preparation of the esters of general formula IV.

The compounds of the general formula VII can be prepared by processes known per se. For example, it is possible (see EP-PS 134420) to react diketene with bromine, and then the intermediate obtained with a compound of the general formula VI, to give a precursor of the formula

Br-CH ₇ C-CH-CONH O

CO-CHOCOR '

ίIii CH ₃ O

in which R ^{2 is} hydrogen or methoxy, which is then converted by nitrosation (cf also EP-PS 134420) into a compound of general formula VII.

The ceph-3-em-4-carboxylic acid esters of general formula I have a number of physico-chemical and biological properties which make them valuable cephalosporin antibiotics for oral administration. They are stable, colorless and readily soluble in common organic solvents, which absorbs in the intestine, rapidly in serum to antibiotically active cephalosporin derivatives of the formula

N-j-C CONH

Xj

wherein R 'and R ^{2 have} the meanings given in formula I, are cleaved and therefore excellent for the treatment of bacterial infectious diseases such. As the infection of the respiratory or urogenital tract are. The compounds of the invention are administered orally in the form of conventional pharmaceutical preparations, such as. As capsules, tablets, powders, syrups or suspensions. The dose depends on the age, symptoms and body weight of the patient as well as the duration of the treatment. However, it lies in the cone between about 0.2 g and about 5 g daily, preferably between about 0.5 g and about 3 g daily. The compounds are preferably administered in divided doses, for example 2 to 4 times a day, whereby the single dose may contain, for example, between 50 and 500 mg of active ingredient.

The oral preparations may contain the usual carriers and / or diluents. For example, for capsules or tablets into consideration binders such. As gelatin, sorbitol, polyvinylpyrrolidone or carboxymethylcellulose, diluents, such as. As lactose, sugar, starch, calcium phosphates or polyethylene glycol, lubricants, such as. As talc or magnesium stearate, for liquid preparations z. As aqueous or oily suspensions, syrups or similar known preparation forms.

The following examples serve to further illustrate the invention, but do not limit it thereto.

Ausfuhrungsbelsplele

a) Preparation of Starting Materials Preparation Example 1 1-Chloroethyl (1-methoxy-2-propyl) carbonate

7.7 ml (70 mmol) of 1-chloroethyl chloroformate and 6.6 ml (70 mmol) of 1-methoxy-2-propanol were dissolved in 40 ml of dry methylene chloride and cooled to ⁰ ° C. Then added dropwise at 0-5 ⁰ C, a mixture of 5.8ml (72mmol) of pyridine and 20ml of dry methylene chloride, stirred for 2 hours under ice cooling and the resulting pyridinium hydrochloride sucked off. The filtrate was washed twice (H ₂ O) and distilled under reduced pressure in a water jet. This gave 8.8 g (64%) of the title compound (bp ₃₀ = 100-105 ⁰ C). 'H-NMR (CDCl ₃ ): = (ppm)

6,46 (q, CH-CI)

4.93 (m, CH-OCO ₂ )

3.63 (d, CH ₂ -O)

3.40 (s, OCH ₃ )

1.83 (0, CHR-CHCI)

1.46 (^ CH ₃ -CHOCO ₂ ).

Analogously to Preparation Example 1, the compounds compiled in Table 1 were prepared: TABLE 1

Ex. R ³ no.

Yield NMR (CDCl ₃ ) O = (ppm)

-CH

.CH ₂ OCH ₅

64%

CH,

6.46 (q, CH-CI) 4.93 (m, CH-OCO ₂ ) 3.63 Id ₁ CH ₂ -O) 3.40 (s, OCH ₃ ) 1.83 (d, CH ₃ -CHCl) 1.46 (d, CH ₃ -CHOCO _2).

/ \ 74% 6.48 (q, CH-CI) J \ 4.7 (m, CH-OCO ₂ ) ² \ / 2.2 to 1.0 (m, cyclohexyl-H) \ / 1.83 (d, CH ₃ -CHCl, obscured). 45% 6.83 (q, CH-CI) J ι 5.16 (m, CH-OCO ₂ ) ³ \ J 2.0-1.5 (m, CH ₂ ) \ - ** 1.83 Id ₁ CH ₃ -CHCI, obscured).

6.43 (q, CH-CI)

5.08-4.6 (m, CH-OCO ₂ )

47% 4.16-3.3 (m, (CH ₂ I ₂ O)

2,16-1,4 (m.CfCHjlj)

1.83 (d, CH ₃ -CHCl, concealed).

-CH

CH,

CH,

6.49 (q, CH-CI)

5.08-4.6 (m, CH-OCO ₂ )

57% 2.16-1.4 (m, C (CH ₂ I ₂ )

1.80 (d, CH ₃ -CHCl, obscured).

1.33 (d, CH (CH ₃ I ₂ )

-CH

^ C

CH ₅ (R, S)

6.43 (q, CH-CI)

4.78 (m, 0-CH-)

60% 1.83 (d, CH ₃ -CHCl, concealed).

, 1.5-1.8 (m, CH ₂ )

1.3 (2xt, 0-CH (CH ₃ ))

0.92 (2 xt, C H ₂ -CH _3).

6.48 (q, CH-CI)

4.16 (t, CH ₂ O)

62% 1.83 Id ₁ CH ₃ -CHCI, obscured).

1.67 (m, CH ₂ -CH ₂ -CH ₂ , obscured).

0.97 (t, CH ₃ )

-CH ₂ CH ₂ OCH ₃

6.48 (q, CH-CI)

4.3 in ₁ CH ₂ -OCH ₃ )

78% 3.6 in ₁ CO ₂ CH ₂ )

3.43 (s, OCH ₃ )

2.16-1.4 in ₁ C (CH ₂ J ₂ )

1.81 (d, CH ₃ -CHCl, obscured).

6.48 (q, CH-CI)

53% 4.17 (s, CH ₂ )

3.5-Al (m, CH ₂ OCH ₂ )

1.5-2.1 (m, CH ₂ CH ₂ ).

6.48 (q, CH-CI)

4.4-4.7 (m, CH-O)

40% 3.5-3.9 (m, CH) around 2.4 (m, CH)

1.81 ld, CH ₃ -CHCl, obscured).

1.0-1.9 (m, CH ₂ )

-CH

CHpCH-2

CH:

(R)

6.43 (q, CH-CI)

4.78 in ₁ O-CH-)

62% 1.83 Id ₁ CH ₃ -CHCI, obscured).

1.5-1.8 in ₁ CH ₂ )

1.3 (2Xt ₁ O-CH (CH ₃ )

0.92 (2 Xt, CH ₂ -CH ₃ ).

CH ₂ CH,

-CH

CH

(S)

6.43 (q, CH-CI)

4.78 in ₁ O-CH-)

58% 1.83 Id ₁ CH ₃ -CHCI ₁ masked).

1.5-1.8 in ₁ CH ₂ )

1.3 (2Xt ₁ O-CH (CH ₃ ))

0.92 (2Xt ₁ CH ₂ -CH ₃ ).

15 -CH ₂ CH ₂ CH ₂ OCH ₂ CH ₂ Ch ₃ 32%

6.48 (q, CH-CI)

4.33 (t.CHj)

3.53 (t, CO ₂ CH ₂ )

3.47 Iq, CH ₂ )

1.87 in ₁ CH ₂ )

1.81 Id ₁ CH ₃ -CHCI, obscured).

1.17 U ₁ CH ₃ )

16 -CH ₂ -CH

CH

6.48 (q, CH-CI)

4.03 (d, CH ₂ )

52% 3.6 in ₁ CO ₂ CH ₂ )

1.81 (d, CH ₃ -CHCl, obscured).

1.0 (q, CH ₃₎

B) exemplary embodiments

1. Compounds of general formula IV

example 1

7 - <(2- (2-tritylaminothiazole-4-yl) -2- (2) -1-methyl-1-methoxy-ethoximinoacetamido)> - 3-methoxymethyl-3-cephem-4-carboxylic acid-id-methoxyprop - ^ - yloxycarbonyloxylethylester

Step A

To a suspension of 560 mg (41 mmol) of anhydrous zinc chloride in 33 ml of carbon disulfide was added successively 4.3 g (28.3 mmol) of sodium iodide and 4.3 g (22 mmol) of 1-chloroethyl (1-methoxy-2-propyl) carbonate. The mixture was stirred for 2 hours under a nitrogen atmosphere, then the reaction mixture was poured into a mixture of 300 ml of 9% NaHCO ₃ solution and 300 ml of ether and the phases were separated. The organic phase was washed (NaHCO ₃ , sodium thiosulfate and NaCl solution) and dried (MgSO 4). The solvent was moved in vacuo at 2O ⁰ C and received crude 1-iodoethyl (1-methoxy-2-propyl) -carbonai was used further as a colorless oil which .igung without Reii immediately (step B).

steps

The crude product obtained from step A was taken up in 5 ml of dry DMF and added under ice-cooling to a solution of 3.8 g (5 mmol) of potassium 7 - <(2- (2-tritylaminothiazol-4-yl) -2- (Z) -1 -methyl-1-methoxy-ethoxyiminoacetamido)> - 3-methoxymethyl-3-cepham-4-carboxylate in 15 ml of dry DMF. After 10 minutes, the reaction mixture was stirred into a mixture

of 200ml 9% NaHCQ ₃ solution and 100ml Essigestar tin. The organic phase was washed (NaHCO ₃ and NaCl solution), dried (MgSO ₄ ) and the solvent removed in vacuo. The resulting oil was triturated under ice-cooling with 100 ml of ether and crystallized. The precipitate was filtered off with suction, washed with ether and gave 1.5 g of crystalline 7 - <(2- {2-tritylamolothiazol-4-yl) -2- (Z) -1-methyl-1-methoxy-ethoxyiminoacetamido)> 3-methoxymethyl-3-cephem-4-carbons8ure-1- (1-methoxyprop-2-yloxycarbonyloxy) -ethyl ester; From the filtrate was again treated by treatment with pentane 0.34g, 1.84 g (41%), the title compound.

¹ H NMR (U ₆ -DMSO): δ = (ppm)

9.54 (2 Xd, CONH, J = 8Hz) 8.85 (s, NH-trityl) 7.4-7.2 (m, phenyl-H) 6.85-6.8 (2 xq, O-CH- O) 6.7 (2xs, thiazole-H) 5.75 (2xq, J = 5Hz, C-7-H) 5.2 (2xd, C-6-H) 4.85 (m, OCOr-CH ) 4.15 (m, -CH ₂ -O)

3.55 (m, C-2-H)

3.4 (q, hidden, J = 5Hz ₁ CH ₂ -OCH ₃ ) 3.25 (s, CH ₂ -OCH ₃ ) 3.2 (s, 3-CH ₂ -OCH ₃ )

3.1 (s, 0-C-OCH ₃ )

1.5 (d, J = 6H ^ CO ₂ -CH (CH ₃ KCO ₂ ) 1.4 (s, C- (CH ₃ I ₂ )

1.2 (3 xt, J = 7 Hz, CH ₃ -CH-OCO _2).

Analogously to Example 1, Steps A and B, the compounds compiled in Table 2 were obtained as amorphous solids.

Tobel 2

.0-C-OCH N CH-z

CONH ^ ς

Vf

TrNH ^b h - ^Nv «

CO CHOCOR ³

* I Il

CH ₃ O

Ex. R ³ Yield NMR Jd ₆ -DMSO) δ = (ppm)

No.

CH ₂ OCH ₅

41%

9.54 (2xd, CONH, J = 8Hz) 8.85 (s, NH-trityl) 7.4-7.2 (m, phenyl-H) 6.85 to 6.8 (2 χ q, O-CH-O) 6.7 (2xs, thiazole-H) 5.75 (2xq, J = 5Hz, C-7-H) 5.2 (2χd, C-6-H) 4.85 Jm ₁ OCO ₂ -CH) 4.15 (m, 3 -CH ₂ -O) 3.55 (m, C-2-H) 3.4 (q, hidden, J = 5 Hz, CH ₂ -OCH ₃ ) 3.25 (5, CH ₂ -OCH ₃ ) 3.2 (8,3-CH ₂ -OCH ₃ ) 3.1 (s, O-C-OCH ₃ ) 1.5 (d, J = 6 Hz, CO ₂ -CH (CH ₃ K) CO ₂ ) 1.4 (s, C- (CH ₃ J ₂ ) 1.2 (3 xt, J = 7 Hz, CH ₃ -CH-OCO _2).

Table 2 (continued)

Ex. R ³ no.

Yield NMR Id ₆ -DMSO) δ = (ppm)

9.52 (2xd, CONH, J = 8Hz)

8.85 (s, NH-trityl)

7.4-7.2 (m, pheny! -H)

6.85-6.75 (2Xq ₁ O-CH-O)

6.7 (2xs, thiazole-H)

5.75 (2xq, J = 6Hz, C-7-H)

5.15 (2xd, C-6-H)

39% 4.55 (m, OCOr-CH)

4.15 (m, 3 -CH ₂ -O)

3.55 (2xAB, C-2-H)

3.2 (s, 3 -CHr-OCH ₃ )

3.1 (8.0-C-OCH ₃ )

1.85-1.25 (m, cyclohexyl-H)

1.5 (d, J = 6Hz, COr-CH (CHa) -OCO ₂ , obscured)

1.4 (S ₁ C- (CHi) ₂ , obscured)

9.55 (2 Xd ₁ CONH ₁ J = 8Hz)

8.85 (s, NH-trityl)

7.4-7.2 (m, phenyl-H)

6.8-6.75 (2Xq, 0-CH0)

6.7 (2xs, thiazole-H)

5.75 (2xq, J = 5Hz, C-7-H)

5.17 (2xd, C-6-H)

38% 5.05 (m, OCO ₂ -CH)

4.15 (m, 3-CH; r0)

3.55 (2xAB, C-2-H)

3.2 (8,3-CH ₂ -OCH ₃ )

3.1 (s, 0-C-OCH ₃ )

1.85-1.25 (m, cyclopentyl-H)

1.45 (2 xd, J = 6 Hz, CO ₂ -CH (CHs) -OCUj, obscured)

1.4 (s, C- (CH ₃ ) ₂ , obscured)

r ~ \

32%

9.5

8.85

7.4-7.2

6.92 to 6.77

6.69

5.75

5.18

4.77

4.15

3.75

3.55

3.2

3.1

1.59

1.5

1.4

(2xd, CONH, J = 8Hz) (s, NH-trityl) (m, phenyl-H) (2xq, 0-CH-0) (2xs, thiazole-H) (2xq, J = 5Hz, C-7 H) (2xd, C-6-H) (m, OCO ₂ -CH)

(m, (CH ₂ J ₂ O)

(C-2-H 2xAB,)

(s, 3-CH ₂ -OCH ₃ )

(3,0-C-OCH ₃ )

(m, CH (CH ₂ J ₂ )

(2xd, J = 6Hz _/ CO _r -CH (CH ₃ ) -OCO ₂ )

(s, C- (CH ₃ I ₂ )

Example 5

7 - <(2- (2-aminothiazol-4-yl) -2- (Z) -hydroxyiminoacetamido) -3-methoxymethyl-3-cephem-4-carboxylic acid 1- (1-methoxyprop-2-ethyl yloxycarbonyloxyj

1, C3g (2 mmol) of the cephalosporin obtained in Example 1 was dissolved at room temperature in 18 ml of 90% formic acid. The solution was diluted with 2 ml of water, stirred for 40 minutes at room temperature and filtered off the precipitated triphonylr-ethanol. The filtrate was concentrated with addition of toluene, the oily residue was taken up in acetone and the solution was clarified with addition of activated carbon. The clear filtrate was added under cooling with ice with n-pentane, whereupon the product separated as an oil. The solvent was decanted off and the oily residue was triturated with n-pentane to precipitate the amorphous product. Yield: 0.74 g (64%).

'H NMR (d ₆ -DMSO): δ = (ppm)

11.4 (s, NOH)

9.5 (d, J = 8Hz, CONH)

7.3 (S ₁ NH ₂ )

6.85-6.8 (2 x q, J = 6Hz, 0-CH-O)

6.7 (s, thiazole-H)

5.85 (2xq, J = 5Hz, C-7-H)

5.2 (3xd, C-6 - H) 4.85 (m, CHtOCO ₂ )

3.55 (AB, C-2-H)

3.25 (s, 3 -CH ₂ -OCH ₃ )

3.2 (s, CHj-OCH ₃ )

1.5 (2 xd, J = »6Hz, CO ₂ -CH (CH ₃ K) CO ₂ )

1,2 (3Xt ₁ CH ₃ -CH-OCO ₂ ).

As in Example 5, the compounds listed in Table 3 were obtained as amorphous solids.

Table 3

^ OH

N [Τ

XJ

CONH

CH ₂ OCH ₃

CO ₂ CHOCO ₂ R CH ₃

Ex. R ³ Yield NMR (d ₆ -DMSO) 5 = (ppm)

CH ₂ OCH ₅

11.4 (S, NOH) 9.5 (d, J = 8Hz, C0NH) 7.3 (s, NH ₂ ) 6.85 to 6.8 (2xq, J = 6Hz, O-CH-O) 6.7 (S, thiazole-H) 5.85 (2xq, J = 5Hz, C-7-H) 5.2 (3xd, C-6-H) 4.85 (m, CH-OCO ₂ ) 4.15 (8,3-CH ₂ -O) 3.55 (AB, C-2-H) 3.25 (s, 3-CH ₂ -OCH ₃ ) 3.2 (s, CH ₂ -OCH ₃ ) 1.5 (2 xd, J = 6 Hz, CO ₂ -CH (CHa) -OCO ₂ 1.2 (3Xt ₁ CH ₃ -CH-OCO ₂ ). 11.3 (S.NOH) 9.45 (d, J = 8Hz, CONH) 7.1 (s, NH ₂ ) 6.85 to 6.8 (2 Xq ₁ J = 6Hz ₁ O-CH-O) 6.65 (S, thiazole-H) 5.83 (2xq, J = 5Hz, C-7-H) 5.15 (2xd, C-6-H) 4.59 (m, CH-OCO ₂ ) 4.15 (s, 3 -CH ₂ -O) 3.55 (2 x A / B, C-2-H) 3.2 (s, 3-CH ₂ -OCH ₃ )

69% 1.85-1.25 (m, cyclohexyl-H)

1.5 (2 χ d, J = 6 Hz, COr-CH (CH ₃ J-OCO ₂ concealed)

11.3 (s, NOH)

9.45 (d, J = 8Hz, CONH)

7.15 (s, NH ₂ ) 6.85-6.75 (2xq, J = 6Hz, 0-CH-O)

6.65 (s, thiazole-H)

, 5.83 (2xq, J = 5Hz, C-7-H)

58% 5.2 (2xd, C-6-H)

5.05 (m, CH-OCO ₂ )

4.15 (s, 3 -CH ₂ -O)

3.55 (2 x A / B, C-2-H)

3.2 (5,3-CH ₂ -OCH ₃ ) 1.85-1.5 (m, cyclopentyl-H)

1.5 (2 χ d, J = 6 Hz, CO ₂ -CH (CH ₃ K) CO ₂ obscured)

Table 3 (continued)

Ex. R ¹ Yield NMR (d _e -DMS0) 5 = (ppm)

- (0 55%

11.3 (S, NOH) 9.45 (d, J = 8Hz, CONH) 7.12 (s, NH ₂ ) 6.91 to 6.75 (2xq, J = 6Hz, O-CH-O) 6.65 (S, thiazole-H) 5.85 (2xq, J = 5Hz, C-7-H) 5.19 (2xd, C-6-H) 4.79 (m, CH-OCO ₂ ) 4.15 (s, 3 -CH ₂ -O) 3.78 (m, (CH ₂ I ₂ O) 3.55 (2XAB.C-2-H) 3.2 (3,3-CH ₂ -OCH ₃ ) 1.6 (m, C (CHj) ₂ ) 1.5 (2 xd, J = 6 Hz, CO ₂ -CH (CHa) -OCO ₂ concealed)

Example 9

7- <2- (2-aminothiazol-4-yl) -2- (Z) -methoxyiminoacetamido> -3-methyl-3-cephem-4-carboxylic acid 1- (isopropoxycarbonyloxv) -ethyl ester

Step A To a suspension of 200 mg (1.5 mmol) of anhydrous zinc chloride in 10 mM carbon disulfide was added sequentially 1.5 g (100 mmol) of sodium iodide and 1.2 g (7.5 mmol) of i-chloroethyl isopropyl carbonate. The mixture was stirred for 2 hours under a nitrogen atmosphere, the reaction mixture was poured into a mixture of 9% NaHCO ₃ solution and ether and the phases were separated. The organic phase was washed (NaHCO ₃ , sodium thiosulfate and NaCl solution) and dried (MgSO ₄ ). The solvent was distilled off in vacuo at 20 "C to give crude 1-iodoethyl isopropyl carbonate as a colorless oil, which was used immediately without purification (step B).

Step B The crude product obtained from step A was taken up in 18 ml of dry DMF and added with ice-cooling to a solution of 1.3 g (3 mmol) of potassium cofetamet in 10 ml of dry DMF. After 75 minutes, the reaction mixture was stirred into a mixture of 9% NaHCO 3 ₃ solution and ethyl acetate. The organic phase was washed (NaHCO ₃ and NaCl solution), dried (MgSO ₄ ) and the solvent removed in vacuo. The crude product was chromatographed on 100 g of silica gel with ethyl acetate. 300 mg of the title compound were obtained.

'H NMR (d _e -DMS0): 5 = (ppm)

9.6 (2 xd, CON H, J = 8Hz) 7.23 (br, 8, NH ₂ ) 6.78 and 6.83 (2 xq, 0-CH-O) 6.73 (2xs, thiazole) H) 5.77 (2xQ, J = 5Hz, C-7-H) 5.13 (2 xd, C-6-H) 3.85 (s, OCH ₃₎ 3.4 to 3.68 (m, C-2-H) 2.03 (s, CH ₃ )

1.5 (d, J = 6Hz, CO ₂ -CH (CH ₃ I-OCO ₂ ) 1.25 (d, (CHs) ₂ -CH).

Analogously to Example 9, the compounds listed in Tabello 4 were obtained as amorphous solids. Table 4

OCH ₃

 CONH

J _x CH 0 T

CO ₀ CHOCOR I ι η

CH ₃ O

Ex. R ³ No. Yield NMR (d _e -DMS0) 5

9.6 (2 xd, CONH, J = 8Hz)

7.23 (brs, NH ₂ )

6.78 and 6.83 (2 x q, 0-CH-O)

-CH- '

CH,

6.73 (2xs, thiazole-H) 5.77 (2xq, J = 5Hz, C-7-H) 5.13 (2xd, C-6-H) 3.85 (S ₁ OCH ₃ ) 3.4 to 3.68 (M, C-2-H) 2.03 (see CH ₃ ) 1.5 (c, J = 6 Hz, COr-CH (CH ₃ K) CO ₂ ) 1.25 ((1, (CH ₃ I ₂ -CH).

9.6 (2xd, CONH, J = 8Hz)

7.23 (brs, NH ₂ )

6.78 and 6.83 (2 x q, 0-CH-O) 6.73 (2xs, Thiazo! -H)

5.77 (2xq, J = 5Hz, C-7-H)

42% 5.13 (2xd, C-6-H)

4.58 and 4.4 (m, 1H, O-CH) 3.85 (s, OCH ₃ )

3.38 to 3.68 (m, C-2-H) 2.03 (s, CH ₃₎

1.5 (d, J = 6Hz, CO ₂ -CH (CH ₃ K) CO ₂ )

1.05-1.9 (m, 10H, cyclohexyl-H).

9.57 (2xd, CONH, J = 8Hz)

7.20 (brs, NH ₂ )

6.78 and 6.83 (2 x q, 0-CH-O)

-CH

CH ₂ CH,

6.73 (2xs, Thiczol-H) 5.73 (2xq, J = 5Hz, C-7-H) 5.13 (2xd, C-6-H) 4.62 (M, 1H, CH-0) 3.82 (s, OCH ₃ )

3.38-3.68 (m, C-2-H)

2.03 (s, CH ₃ )

1.5 (d, J = 6Hz, COz-CH (CHj) -OCO ₂ )

1,58,1,2,0,85 (111,8H, -CH ₂ -UiId-CH ₃ )

-CHCH ₂ OCH

9.6 (2xd, CONH, J = 8Hz) (2xs, thiazole-H) (d, CH ₂ ) (2xs, thiazole-H) 7.23 (brs, NH ₂ ) (2xq, J = 5Hz, C-7-H) (s, 3H, OCH ₃ ) (2xq, J = 5Hz, C-7-H) 6.78 and 6.83 (2 x q, 0-CH-O) (2xd, C-6-H) (S ₁ CH ₃ ) (2xd, C-6-H) 6.73 (M, 1H, O-CH) (d, J = 6 Hz, CO ₂ -CH (CH ₃ K) CO ₂ ) (2 xt, 2 H, _0-CH2) 5.77 (s, N-OCH ₃ ) (m, 3 H, _CH3) (s, OCH ₃ ) 5.15 3.4-3.68 (m, C-2-H) (brs, NH ₂ ) 4.82 3.4 6.78 and 3.83 (2 χ q, 0-CH-O) 3.85 3.25 6.73 2.03 5.7-5.8 1.5 5.13 1.2 4.09 7.23 3.85

13 -CH ₂ CH ₂ CH ₅

3.38-3.68 (m, C-2-H)

2.03 (s, CH ₃ )

1.62 (m, 2H, -CH ₇ -)

1.5 (d, J = 6Hz, CO ₂ -CH (CH ₃ K) CO ₂ )

0.89 (t, -CH ₃ ).

Table 4 (continued)

Example no.

R ³ yield NMFUd ₆ -DMSO) δ = (ppm)

9.59 (2 xd, CONH ₁ J = SHz)

7.23 (br s, NH ₂ )

6.78 and 6.83 (2 x q, 0-CH-O)

-CH ₂ CH ₂ OCH ₃

6.73 (2xs, thiazole-H) 5.77 (2xq, J = 5Hz, C-7-H) 5.13 (2 xd, C-6-H) 4.25 (m, 2H, O-CH ₂ ) 3.85 (s, N-OCH ₃ ) 3.4 to 3.68 (M, C - 2-H) 3.52 (m, 2H, O-CH ₂ ) 3.25 (s, 3H ₁ OCH ₃ ) 2.03 (8, CH ₃₎ 1.5 {d, J = 6Hz, C0r-CH (Ci

9.6 (2 xd, CONH ₁ J = 8Hz)

7.23 (br s, NH ₂ )

6.78 and 6.83 (2 x q, 0-CH-O)

6.73 (2xs, thiazole-H) 5.77 2 x q, J = 5Hz, C-7-H) 5.13 (2 xd, C-6-H) 3.85 (S ₁ OCH ₃ ) 3.4 to 3.68 (m, C-2-H! 2.03 (s, CH ₃ ) 1.5 (d, J = 6 Hz, CO ₂ -CH (CH ₃ K) CO ₂ )

CH ₂

9.6 (2xd, CONH, J = 8Hz)

7.23 (brs, NH ₂ ) 6.78 and 6.83 (2 X q, 0-CH-O)

6.73 (2xs, thiazole-H)

5.77 (2xq, J = 5Hz, C-7! H)

31% 5.13 (2xd, C-6-H)

4.09 (m, 3 H, 0-CH ₂ and 2'-H)

3.85 (s, OCH ₃ )

3.4-3.68 (m, C-2-H)

2.03 (s, CH ₃ )

1.8 (m)

1.5 (d, J = 6Hz, COr-CH (CH ₃₎ -OCO ₂₎

9.6 (2xd, CONH, J = 8Hz)

7.22 (brs, NH ₂ )

6.78 and 6.82 (2 x q, 0-CH-O)

6.73 (2xs, thiazole-H) 5.75 (2xq, J = 5Hz, C-7-H) 5.13 (2 xd, C-6-H) 4.5 (M, 1H, 2'-H) 3.85 (s, OCH ₃ ) 3.4 to 3.68 (m, C-2-H) 2.03 (8, CH ₃₎ 1.5 (d, J = 6 Hz, CO ₂ -CH (L ¹ H ₃ K) CO ₂ )

9.6 (2xd, CON; «, J =

7.21 (brs, NH ₂ ) 6.79 and 6.88 (2 xq, O-CH-0)

6.73 (2xs, thiazole-H)

5.76 (2xq, J = 5Hz, C-7-H)

35% 5.13 (2xd, C-6-H)

4.8 (m, 1H, 4'-H)

3.85 (s, OCH ₃ )

3.4-3.68 (m, C-2-H)

2.03 (s, CH ₃ )

1.5 IdJ = OHz ₁ CO ₂ -CH (CH ₃ K) CO ₂ )

Table 4 (continued)

Ex. No. Yield NMR {d "-DMS0) 6 = (ppm)

- £ H-CH ₂ CH ₃ (R)

-CH

CH;

9.55 (2xd, CONH, J = 8Hz) (2xs, thiazole-H) (2xs, thiazole-H) 7.20 (brs, NH ₂ ) (2xQ, J = C-7-H * 5Hz,) (2xq, J = 5Hz, C-7-H) 6.78 and 6.83 (2 x q, O-CH-0) (2xd, C-6-H) (2Xd, C-O-H) 6.73 (q, 2H, CH ₇ -CH ₃ ) (2xQ ^ H ₁ CH ₂ -CH ₃₎ 5.74 (s, OCH ₃ ) (S ₁ OCH ₃ ) 5.13 (M, C-2-H) (M, C-2-H) 4.63 (s, CH ₃ ) (s, CH ₃ ) 3.85 (d, J = 6 Hz, CO ₂ -CH (CH ₃ J-OCO ₂ ) (d, J = 6 Hz, CO ₂ -CH (CHa) -OCO ₂ ) 3.4 to 3.68 (2 χ 1,3H ₁ O-CH (CH ₃ I-CH ₂ -) (2 X t, 3 H, O-CH (CH ₃ J-CH ₂ -) 2.03 (t, 3H ,, CH ₃₎ (2 X t, 3 H, _CH3) 1.51 (2xd, CONH, J = 8Hz) 1.2 (br s, NH ₂ ) 0.83 6.78 and 6.83 (2 x q, O-CH-0) 9.55 6.73 7.20 5.74 5.13 4.63 3.85 3.4 to 3.68 2.03 1.51 1.2 0.83

-CHjCHjCHj CH ₃ (S)

9.57 (2xd, CONH, J = 8Hz)

7,20 (brs.NHj)

6.78 and 6.83 (2 x q, 0-CH-O)

-CH ₂ CH ₂ CH ₂ OCH ₂ CH ₃

6.73 (2xs, thiazole-H) (2xs, thiazole-H) 5.74 (2xq, J = 5Hz, C-7-H) (2xq, J = 5Hz, C-7-H) 5.13 (2χd, C-6-H) (2 xd, C-6-H) 4.19 (m, 2H, CO ₂ CH ₂ ) (2xd, 2H, OCH ₂ CH) 3.85 (S ₁ OCH ₃ ) (s, OCH ₃ ) 3.4 to 3.68 (M, C-2-H) (M, C-2-H) 3.4 (m, 2H, O-CH ₂ CH ₃ ) (s, CH ₃ ) 2.03 (s, CH ₃ ) (m, 1 H, -CH (CH ₃ ) ₂ ) 1.84 (m, 2H, CH ₂ CH ₂ CH ₂ ) (d, J = 6 Hz, CO ₂ -CH (CH ₃ J-OCO ₂ 1.5 (d, J = 6 Hz, COz-CH (CH ₃₎ -OCO ₂₎ (2 xd, CH (CH ₃ I ₂ ) 1.1 (1.3H ₁ CH ₃ ) 9.57 (2 xd, CONH, J = 8Hz) 7.21 (brs, NH ₂ ) 6.78 and 6.83 (2 x q, 0-CH-O) 6.73 5.74 5.13 3.92 3.85 3.4 to 3.68 2.03 1.9 1.5 0.89

22 -CH2CH

Claims (1)

claims: COOCH-OC-ORCH ₃ 0 in which mean R ^{1 is} hydrogen or methyl and R ^{2 is} hydrogen or methoxy, where always one of the two substituents R ¹ or R ^{2 is} Hydrogen stands,
R ³ straight or branched C ₁ -C ₆ -alkyl, which may be substituted by C ₁ -C ₃ -alkoxy, C ₃ -C ₈ -CyClOaIkyl or C ₂ -C ₇ -CyClOaIkOXy, C3-C ₈ -cycloalkyl OdOrC ₂ -C ₇ -CyClOaIkOXy, wherein for the case that R ¹ is hydrogen and R ² is methoxy, R ³ is not Ci- C ₄ alkyl and in which the group -OR ¹ in syn position, as well as their physiologically acceptable acid addition salts, characterized in that a) a compound of formula II N -. C-CONH - j 1) N-OR ⁵ J 0
«· COOA in which R ^{2 is} hydrogen or methoxy, R ^{4 is} hydrogen or an amino-protecting group, R ^{5 is} methyl or a readily cleavable group and A is a cation, where R ⁴ can only be hydrogen if R ^{5 is} methyl,
with a compound of general formula III X-CH-OCO ₂ -R ³ (III) CH ₃ in which R ^{3 has} the abovementioned meaning and X represents a leaving group to which esters of general formula IV are reacted Il κ  OR XY ^Ä - (IV) ⁿ CO.-CH-OC-OR I I Il CH ₃ O and the groups R ⁴ and R ⁵ removed in the meaning of a protecting group or readily cleavable group in a conventional manner or
b) a compound of general formula V N i-C CO-Y -OR R ⁴ in which R ⁴ and R ^{5 have} the above meaning and Y is an activating group, with a compound of general formula Vl (Vl) CO - CH-OC-OR * I Il CK ₃ O in which R ² and R ^{3 have} the abovementioned meaning or with a salt of this compound, to give a compound of general formula IV and the groups R ⁴ and R ⁵ in the meaning of a protecting group or a readily cleavable group cleaves in a conventional manner , or
c) a compound of general formula VII