DE2612760A1 - CEPHALOSPORIN DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THESE - Google Patents

Description

DR.A.VAN DERWERTH DR.FRANZ LEDERER REINER F MEYER

DIPL-ING. (1934-1974} DIPL-CHEM.DlPL-ING.

8000 MUNICH 80 LUCILE-GRAHN-STRASSE 22

TELEPHONE: (089) 472947 TELEX: 524624 LEATHER D TELEGR .: LEATHER PATENT

February 27, 1976

PLC. 255 / A (PC. 5672 / A)

PFIZER CORPORATION Calle 15 1/2, Avenida Santa Isabel, Colon, Panama

Cephalosporin derivatives, processes for their preparation and Medicinal products containing them

The invention relates to antibacterial agents in iorui of Cephalosporin derivatives having a wide range of antibacterial activity, a process for their preparation and medicinal products containing such cephalosporin derivatives *

The compounds of the invention form a number of 7- (α-aminophenylacetamido or α-hydroxyphenylacetamido) -Δ ^ -cephem compounds or of derivatives thereof which have an oxadiazolyl, thiadiazolyl or triazolylthiomethyl ring in the 3-position which may have one of a specific range of substituents.

609841/0996

2 612 7 6 Π

The cephalosporin derivatives according to the invention have the following general formula:

COOZ

wherein: E = H or OH;

Ji Λ

Y = ϊίΗρ »° S or OE, where B is a lower alkanoyl-> lower alkoxycarbonyl or benzoyl group;

X = 0, S, HH or KHe is 5

Z = hydrogen, a lower alkyl, benzhydrylphenyl, indan-5-yl group or a group of the following formulas -CHpOCO-C-lower alkyl), -CH (CH ₅ ) OCOO- (lower alkyl) or

is; and

E ¹ = -CH ₀ OCH ₀ COOH, -CH _o 0CH _o C00- (nieaalkyl), -CH ₀ QCH ₀ -

52 ^ 2 3 dd

CONE E ^, where E and E ^ are independent of each other

Are hydrogen or a lower alkyl group, or -COHB Ε- ⁷ , in which E and E ^ have the meaning given above,
as well as pharmaceutically acceptable salts thereof.

Among the expressions used in the description "lower Alkyl "or" lower alkyl ".," Lower alkoxy "and" lower & lkanoyl " are to be understood as alkyl, alkoxy or alkanoyl groups which contain up to 4 carbon atoms. It should be noted that the term "lower alkanoyl" includes the eormyl radical. Me means methyl.

609841/0996

Lower alkyl or alkoxy groups containing 3 or 4 carbon atoms contain, and lower alkanoyl groups which are 4-carbon Containing atoms can be straight-chain or branched-chain. Preferred alkyl groups have 1 or 2 carbon atoms, with the exception of the group of the formula -CHpOCO- (lower alkyl), wherein the lower alkyl group is preferably a methyl or t-butyl group.

The pharmaceutically acceptable salts of the compounds of the invention include the non-toxic metal salts, in particular _s of lithium, sodium, potassium, calcium, aluminum, and ammonium and substituted ammonium salts, eg. £. Salts of trialkylamines, N-ethylpiperidine, procaine, dibenzylamine, N-benzyl ~ ß-phenylethylamine, 1-ephenamine, N ₁ N ¹ -dibenzylethylenediamine, dehydroabietylamine, Ν, Ν'-bis-dehydroabietylamine and other amines that have hitherto been used Formation of salts with benzylpenicillin were used · Sufficiently basic compounds of the invention, e.g. B. those in which Y is an -NH ₂ group can also form acid addition salts. The invention therefore includes salts formed with acids which form non-toxic, acid addition salts containing pharmaceutically acceptable anions, e.g., hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or acid phosphate, acetate -, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, trifluoroacetate and p-toluenesulfonate salts. It should also be noted that compounds in which Y »-NB ^ can exist in a zwitterionic form.

Preferred compounds according to the invention contain R ¹ -CH ₂ OCH ₂ CONH ₂ , -CONH ₂ J-Ch ₂ OCH ₂ COOH or -CHgOCHpCOO-lower alkyl) as the best. Y is preferably -NH ₂ or -OH.

609841/099 6

When R = -OH, it is preferably in the para position of the phenyl ring. X is preferably -KH ₂ when E is para-hydroxy. X is preferably NH or S and Z is preferably hydrogen.

Preferred, individual compounds are those in which R, R, X, X and Z are the following radicals:

R. Y ethyl si X Z H OH -COKH ₂ KH H ρ-OK NH ₂ -CFl ₂ OCn ₂ CO ₂ H NK K j p-OH NH ₂ -Qi ₂ OCH ₂ CONH ₂ NH K i p-OH ; ^m 2 -CONH ₀
Ut KH H H '■ OH -CK ₀ CCH ₀ COOH KH H H OH -CH ₂ OCH ₂ COOEt S. H H OH -CH OCH COOH S. H H OH -CK ₀ OCH COOH 0 H I. Et =

These preferred compounds are preferably in the D form

It should be pointed out that in the compounds according to the invention, in which X = UH, an OJautomerism between the Structure in which the hydrogen atom is in the 4 ~ position is present, and the structures in which the hydrogen atom is in the 1 or 2 position, is possible.

The cephalosporin ^{derivatives according to the invention can exist in epimeric 11} D "or" L ⁿ forms, and the invention relates to both the cleaved D and L epimers and their mixtures. However, the D compounds are preferred.

609841/0996

The compounds of the invention can act on a number of Ways to be made, these include the following possibilities;

(1) The compounds can be obtained by acylation of a 7-Ä-mino-3-heterocyclic-thiomethyl-Δ - cephem derivatives of the following general formula:

(II)

COOZ

with an acylating agent of the following general formula:

COOH

(III)

wherein T is a protected amino group or a protected hydroxyl group or a group of the formula -OE, or with its functional equivalent as an acylating agent, e.g. B. an acid chloride or bromide, an "activated" ester or a mixed anhydride and then removing the protecting group at Y. The acylating agent (III) is preferably in the D-form.

The acid chloride or bromide can be obtained by conventional methods. For example, the acid chloride by reacting the acid (III) in a suitable solvent with oxalyl or thionyl chloride or with Phosgene can be produced.

609841/0 9 96

The preferred "activated" ester has the following formula:

CH

coo

- (IV)

and it can be made by reacting the acid (III) with N-hydroxysuccinimide in the presence of a dehydrating agent, e.g. B. Dicyclohexylcarbodiimide.

Suitable mixed anhydrides have the following formula:

CO-0-C0OR ^J

- (ν)

where ~ B? is a lower alkyl group and particularly preferably the isobutyl group. The mixed anhydride is typically prepared by reacting a solution of the acid (III) in a suitable solvent, e.g. B. dry tetrahydrofuran containing about 1 equivalent of a suitable base, e.g. B. triethylamine contains, with a lower alkyl chloroformate, for. B · isobutyl chloroformate. The reaction should take place at low temperature, e.g. B. -10 ⁰ C to 0 ⁰ C, are carried out, and it is generally completed in a few minutes.

It should be noted that the term "functional Equivalent as acylating agent "provided it refers to the Compound (III) also refers to the "internally protected" dione of the following formula:

609841/0996

26127B0 - 7 -

(VI)

includes.

The dione can be obtained by reacting phosgene with a compound of the following general formula:

getting produced.

Suitable protecting groups at Y are those which commonly used for this purpose. The preferred protecting group for an amino group is one t-butoxycarbonyl group, and for a hydroxyl group a formyl or dichloroacetyl group. In making the Acid chlorides or bromides, HCl or HBr is released, which contains any free -NHp groups represented by Y. will, protonate. The proton can act as a suitable "protective group" and it cannot introduce it a t-butoxycarbonyl group may be required as the solution containing the protonated acid chloride or bromide can be coupled directly to the compound (II).

When the acylation is carried out by reacting the free acid (III) with the compound (II), it is generally required to protect any free carboxyl groups in the compound (II) from the reaction. the Reaction should take place in the presence of a dehydrating agent,

609841/0996

e.g. of dicyclohexylcarbodiimide (DCC) or 1-ethyl-3- (3-diniethylaiainoprop-1-yl) -carbodiimide hydrochloride, be performed.

Protection of any free carboxyl groups, e.g. B. by trimethylsilyl groups is generally absolutely necessary when using IXJC, but it may not be necessary when using 1-ethyl-3- (3-diraethylaminoprop-1-yl) -carbodiimide hydrochloride. In a typical reaction, compound (II) and a base, e.g. B. triethylamine, in a suitable solvent, e.g. B. dry methylene chloride, this is followed by the addition of trimethylsilyl chloride if there are any free carboxyl groups in the compound (II). After stirring for about one hour, a solution of the compound (III) and a dehydrating agent, e.g. B. of dicyclohexylcarbodiimide, in a suitable solvent, e.g. B. methylene chloride, added, and the resulting solution is stirred for several hours. After filtering off, the organic filtrate can be washed with an aqueous acid, e.g. B. hydrochloric acid, be shaken to remove any protective trisiethylsilyl groups, and after separation, the organic phase can be dried over anhydrous magnesium sulfate. Although the reaction can be carried out at room temperature, it is preferably carried out at a low temperature, e.g. B. -5 ⁰ C to O ⁰ C carried out. The product obtained after evaporation of the reaction mixture to dryness is of course a cephalosporin which has a protected amino group or a protected hydroxyl group. Such protective groups can be removed using conventional procedures. For example, a t-butoxycarbonyl group can be removed by acid hydrolysis, e.g. B. formic acid or anhydrous trifluoroacetic acid is used at about O ⁰ C, and

609841/0996

the desired product of formula (I) is in the case of trifluoroacetic acid in the form of its trifluoroacetate addition salt after evaporation of the reaction mixture in vacuo and trituration of the oil obtained with dry Ether obtained · The trifluoroacetate salt can be in its zwitterionic form or in a pharmaceutically acceptable one Acid addition salts thereof can be converted by methods conventional in the art. For example, if Z is hydrogen, the zwitterionic form of the compound can be obtained by treating a suspension of the trifluoroacetate salt in water with a sodium hydroxide solution while adjusting the pH to about 7> 5 »then Filter and then add hydrochloric acid to lower the pH to about 3.55 to precipitate the zwitterionic product can be obtained. Protective Formyl and dichloroacetyl groups can be treated with an aqueous base, e.g. B · aqueous sodium bicarbonate solution, are removed, wherein when Z is hydrogen, the sodium salt of the cephalosporin is formed. The free acid can be obtained by acidification. In a typical way of working becomes the cephalosporin protected on the hydroxyl group dispersed in aqueous sodium bicarbonate solution, and the solution is mixed with a suitable, water-immiscible, organic solvents, e.g. B. ethyl acetate, layered. After acidification of the aqueous phase to about pH a 2, the organic phase is separated off, dried and evaporated in vacuo, leaving an oil which with dry ether to form the desired oc-hydroxycephalosporin can be triturated in the form of the free acid.

In a typical procedure which comprises the reaction of a mixed anhydride (V) with the compound (II),

609841/0996

the compound (II), optionally with the aid of a base such as triethylamine, in a suitable solvent, ζ. B. aqueous tetrahydrofuran, dissolved and then with a solution of the anhydride in ζ. Β. Tetrahydrofuran mixed. Each mixing for about an hour, preferably at a temperature of -10 ⁰ C to 0 ⁰ C, the coolant is removed and the solution is left to stand for several hours, followed by dilution with water and extraction with a suitable, with Water-immiscible, organic solvents, e.g. B. ethyl acetate, followed by the removal of impurities in the organic phase. After the separation, the aqueous phase can with a suitable, water-immiscible, organic solvent, e.g. B. ethyl acetate, and then on z. B. pH = 2 can be acidified by adding hydrochloric acid in order to induce the extraction of the desired product into the organic phase. After separation, the organic phase can be dried over anhydrous magnesium sulfate, evaporated in vacuo and the oil obtained can be crystallized by trituration with dry ether. The product is of course the protected cephalosporin and the protecting groups can be removed as previously described. The reaction of the activated ester (IV) with the compound (II) can be carried out in a similar manner.

In a typical reaction which involves acylation of the compound (II) with an acid chloride, will the acid chloride in a suitable solvent, e.g. B. dry acetone, and it becomes a solution the compound (II) in z. B. aqueous acetone, which is sodium bicarbonate contains, added. Each mixing for about

609841/0996

one hour at low temperature, e.g. B. O C, can Coolant must be removed and stirring continued for several hours. Water and one with water not Miscible solvents such as ethyl acetate are then added and the pH of the aqueous phase is adjusted to about 2.0 with z. B. hydrochloric acid adjusted. After this The organic phase can be separated off by filtration and the aqueous phase extracted with fresh ethyl acetate. The organic phases can be combined, evaporated in vacuo and triturated with dry ether. That The product is in turn a cephalosporin with a protected amino group or a protected hydroxyl group, and the Protective groups can be removed as previously described. The acid bromide can be reacted in a similar manner will.

The acylation with the "internally protected" dione (VI) can be carried out in a manner similar to the reaction with the acid chloride be performed. The product goes without saying a cephalosporin in which Y ■ is -OH »

The compounds of the formula (II) in which Z is hydrogen can be obtained by methods analogous to the prior art be e.g. B. as follows:

N N

OAc-r-HS ,.

(VIIIl

H ₂ O, 50 -75 C ₁ 1-2 hours pH 6.5- ^ 7.5

609841/0996

or alternatively

(ii) CHC.KH

OAc -t- HS

N N

(VIII)

OHC * NM

Pho sphatpuf f it 50-75 ⁰ C, pH 6.5 - 8.0

In some cases, the second synthetic route gives the purer one Source material. The compounds of formula (VIII) are new compounds and they are in the British patent application 40447/75. They are also identified in the applicant's patent application with the Title "Substituted heterocyclic thiols and process for their preparation" filed on the same day was described.

The compounds of formula (II) in which Z is a radical other than hydrogen, i.e. H. such connections, in where Z completes an ester group

609841/0996

likewise using methods analogous to the prior art be produced, e.g. B. by esterification of the corresponding compound (II) protected on the amine radical, in which Z is a hydrogen atom or an alkali metal atom, e.g. B «a potassium atom, means to be produced, typically as follows:

(iii) EUNH

coo (lower alkyl)

suitable, protective] group]

COOCH (Ph),

CJ.

B.Ntf

DCCD ₅ and

Phenol or indan-5-ol

-N

If Il.

y or

Indan-5-yl

B098A 1/0996

or (iv)

B.NIi

coocH ocoC-lower alkyl)

does

B. NH

N N

A.

CM = alkali metal atom, preferably potassium atom J.

COOCH (CH,) 0C0 _o (lower- ^ ^ alkyl)

The corresponding bromine compounds can instead of chlorine compounds specified in the aforementioned schemes (iii) and (iv) are used

BO 98 4 1/0996

It may also be necessary to have any free

SI

Carboxyl groups in the radical R before reactions (iii) and (iv) to protect. Following the reaction, the protective group or groups can be conventional Working methods are removed.

It is known per se that in reactions of the type described above under (iv) a certain isomerization of the Double bond in the cephem ring to the 2-position occur can. This can be reversed in a known manner by forming the S-oxide of the product and subsequent reduction be made.

(2) The compounds according to the invention in which Y is »OH or _{Έ & ο} and Z ■ is hydrogen can also be prepared by reacting a cephalosporin derivative of the following general formula:

- (VII)

COOK

where Y = OH, NHg or a protected hydroxyl group or a protected amino group and R is a group which can be easily split off, for example a chlorine, bromine, iodine or particularly preferably an acetoxy group, means with a heterocyclic thiol of the following general formula:

HS

(VIII)

609841/0996

or with a metal or ammonium salt thereof and -

if necessary - removal of any protective

ρ
Groups from Best Y are made.

The compound (VII) is preferably in the D-form. The metal salt is preferably an alkali metal salt and particularly preferably a sodium or potassium salt, e.g. B. from the following general formula:

N ■ N

(VIIIA)

R ¹

If the radical R ^{1 contains} a -COOH group, the thiol can be converted in the form of its dimetal salt, e.g. B.

_N N (VIIIB)

KS / ^ CH ₀ OCH ₁ COOK;

Y is preferably a protected amino group, e.g. Legs t-butyloxycarbonylamino group, or a free hydroxyl group. Unprotected amino groups tend to with the ß-lactam system of cephalosporins under the reaction conditions to react. In most cases, however, there is no need to protect an α-hydroxyl group.

The reaction is typically carried out in a phosphate buffer solution carried out at a pH of 6.5 to 8.0 to establish the existence of the anion:

N "N y

- (vine);

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ensure, and also at a temperature of 50 ⁰ C to 75 ⁰ C. After several hours, the reaction mixture can be cooled and mixed with a suitable, water-immiscible, organic solvent, for. B. ethyl acetate, to extract impurities in the organic phase. After separation, the aqueous phase can be covered with fresh ethyl acetate and then treated with aqueous hydrochloric acid to bring the pH to a low value, κ. B. pH = 2, to induce extraction of the product into the organic phase. After separation, the organic phase can be washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The oil obtained can be made to crystallize by trituration with dry ether. Any protecting groups for amino or hydroxy groups in the cephalosporin product can be removed according to the procedure described under method (1) above.

The starting materials of the formula (VII) are either known compounds or they can be according to the prior art analog methods can be produced.

(3) The compounds of the formula (I) in which Z is a radical other than hydrogen can, by esterification of corresponding Compounds of the formula (I) in which Z is hydrogen or an alkali metal atom (preferably a potassium atom) is, where any free hydroxyl or amino groups represented by X, and any free carboxyl groups in the R radical, if any protected from the esterification reaction and then freed from the protective residue.

609841/0996

The esterification reactions can, for example, using the reagents as described in route (1) under (iii) and (iv) can be performed.

(4) Salts of the compounds according to the invention can, if desired, be prepared by standard procedures will. For example, the production of a sodium or potassium salt by dissolving a compound in which Z = H in a suitable solvent and adding a solution of the appropriate alkali metal acetate in the same solvent. After Reaction is typically made to the salt by concentrating the reaction mixture by partial evaporation in vacuo and adding the concentrate to a large volume of a suitable solvent to precipitate the salt isolated. Acid addition salts of those compounds according to the invention in which Y is an amino group can be obtained by Dispersing the cephalosporin in water, acidifying to a low pH, e.g. B. pH = 2, with the appropriate one Acid, e.g. B. hydrochloric acid, evaporating the product to dryness, preferably by freeze drying will.

The investigation of the compounds according to the invention in vitro as antibacterial agents was carried out so that the minimum inhibitory concentration (M, I.C.) of the test compound in one suitable medium in which the growth of the microorganism in question no longer occurred. In practice were agar plates (brain / heart infusion agar), each of which contained the test compound in a certain concentration a standard number of cells of the test microorganism and each plate was then incubated for 24 hours at 37 ° C. the

609841/0996

Plates were then checked for the presence or absence of bacterial growth and the corresponding M.I.C. value was determined. The microorganisms used in these examinations, against which the compounds were active included strains of Escherichia coli, Klebsieila pneumoniae, Aerobacter aerogenes, Serratia marcescens, Proteus mirabilis, Proteus vulgaris, Staphylococcus aureus and Streptococcus pyogenes.

The M.I.G. values in micrograms / milliliter for the inventive Compounds are listed in Table I below.

The compounds according to the invention can be applied on their own, but they are generally used as a mixture applied with a pharmaceutical carrier, taking into account the intended route of administration under the standard pharmaceutical practice is selected. For example, they can be taken orally in the form of tablets, which are carriers or Contain diluents such as starch or lactose, or in capsules either alone or in admixture with diluents, or in the form of elixirs or suspensions containing flavorings or coloring agents. You can also injected parenterally, e.g. B. intravenous, intramuscular or subcutaneous. For parenteral administration, they are available on best used in the form of a sterile aqueous solution which may contain other solutes, e.g. B. a sufficient one Amount of salts or glucose to make the solution isotonic.

A suitable total daily dose (oral or parenteral) for An average adult human of 70 kg is in the range of 125 mg to 1 g of the active compound, which is 2 to Taken 4 times a day is to be expected. In any case, can

609841/0996

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however, the appropriate dose will be determined by the doctor, which will depend on the age, weight and response of the patient is.

The invention therefore also relates to a pharmaceutical composition or a medicament which comprises a compound of the formula (I) as defined above or a pharmaceutically acceptable one Containing salt thereof together with a pharmaceutically acceptable diluent or carrier. The invention further relates to a method of treating animals and humans to prevent them from being gram-positive or gram-negative To cure bacteria caused diseases, the animal or the human being an antibacterially effective amount of a A compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition or a Medicines, as previously defined, are applied.

The invention is illustrated by the following examples, as is the preparation of the starting materials. The connections were checked for purity by means of thin layer chromatography (t.l.c, examined for silica gel (silica gel) and / or by high pressure liquid chromatography. The IR spectra were recorded as Solutions in a suitable solvent, e.g. B. chloroform, in the form of KBr disks or mixed with Nujol, added.

The nuclear magnetic resonance spectra (Ii.MR) were measured at 60 MHz with the exception of Example 2, which was recorded at 100 MHz, on solutions of the compounds in e.g. B. perdeuterodimethyl sulfoxide (DMSOd ₆ ) or deuterium oxide (D ₂ O) using a suitable internal calibration standard, e.g. B. added by tetramethyl silane. The protons responsible for the signals are underlined.

609841/0996

example 1

A solution of 4-, 25 S 3-acetoxymethyl-7 - (Da - tert-butoxycarbonylamino-p-hydro ^ phenylacetamido) -ceph-J-em-A-carboxylic acid and of 1.53 S 3-carboxymetho ^ methyl-1,2,4-triazole-5-thiol in 100 ml of phosphate buffer of pH = 7.0 was adjusted to pE = 7.2 by addition of aqueous 2N Hatriumhydroxidlösung, and the resulting solution was then 5 hours at 70 ⁰ C. The reaction mixture was cooled to room temperature, extracted once with ethyl acetate, and the organic layer was discarded. The aqueous layer was overlaid with fresh ethyl acetate and the pH was adjusted to 2.5 by the addition of 2N aqueous hydrochloric acid. The organic phase was separated, washed with brine, separated again and finally dried over sodium sulfate. Evaporation of this dried extract and trituration of the residue obtained with dry ether gave the product, namely 7- (Da-tert-butoxycarbonylamino-p-hydroxyphenylacetamido) -3- (3-carboxymetho23rmethyl) -1,2,4-triazole- 5-yl) -thioBiethylceph-3-em-4 ~ carboxylic acid, as a white solid in a yield of 1.6 g.

b2_7- (D-a-Amino - ^ - hydrosiyghenjlacetamido) -3- (^ -carboxyme thosj-

1.5 S äes of the product obtained previously under a) were stirred in 12 ml of ice-cold irifluoroacetic acid for 10 minutes. This solution was then added to 200 ml of dry ether, and the off-white precipitate thus obtained was filtered off and dried in vacuo. This product was prepared by triturating with 50 ml of 5: Λ v / v. Ethyl acetate / ethanol

609841/0996

cleaned for an hour. The yield of the dried product, namely the trifluoroacetate salt of 7- (D-a-amino-p-hydroxyphenylacetamido) -3- (3-carboxymethoxyiaeth; yl-1, 2,4-triazol-5-yl) -thiomethylceph-3-eni-4-carboxylic acid, was 1.1 g.

ΙΕ spectrum (KBr) ») _max « 1.765 cm ""' ¹ (ß-lactam carbonyl) MIR spectrum (DfISOd ₆ ) S = 3, ^ - 2 (broad singlet, 2-CH ₂ )

4.0 (singlet) , «", γ, ττ _rn tt \ 4> (singlet) (-CH ₂ OCH ₂ -CO ₂ H)

4.82 (multiplet, 6-H and a-H)

5.55 (unresolved multiplet, 7-H)

6.64 (doublet, T = 7 c / s, 2 aromatic Protons)

7.15 (doublet, T = 7 c / s, 2 aromatic Protons)

9.3 (doublet, Γ = 8 c / s, CO-HH) ppm

Examples 2 and 3

The following (drifluoroacetate salts were prepared using similar procedures, as described in Example 1, using the same cephalosporin as in Example 1 and the corresponding thiol was assumed.

CONH

609841/0996

E.g. E characteristic values

-COIiH ₀ IR spectrum (KBr) \) _v = 1760 cm " ¹

(ß-lactam carbonyl) 1660 ca "" ¹ (amide carbonyls) HMR spectrum (DHSOd ₆ )

^ - 7.35, doublet (T- 8 c / s, aromatic protons)

6.85, doublet (T- 8 c / s, aromatic protons)

5.68, broad singlet, (7-H)

4.96, multiplet (6-H and aH) 3.54-, broad singlet (2-CE ₂ ) ppm

IR spectrum (KBr) ^ - 1760 cm "" ¹

(ß-lactam carbonyl)

. «1660 cm" * ¹

(Amide carbonyl)

HMB spectrum (DHSOd ₆ )

i = 7.26, doublet (aromatic. Protons)

6.77, doublet (aromatic protons)

5.62, broad singlet (7-H)

4.97, doublet (T = 5 c / s), (6-H) 4.80, singlet (a-H)

4.46, singlet (one CH ₂ )

4.32, singlet (one CH ₂ )

4.08, singlet (one CH ₂ )

3.48, broad singlet (2-CH ₂ ) ppm

Example 4

ZzL ^D : ^ il2 ^ £ 2- ^ 2liS52i§ £££ §! I§22z3r £ ^
thiomethylcegh-J-em ^ -carboxylic acid

Aqueous 2U sodium hydroxide solution became a solution of 27.6 g 5-acetoxymethyl-7- (D-α-hydroxyphenylacetamido) -ceph-3-em-4-carboxylic acid and'10 g of the ammonium salt of

609841/0996

3-Carbamo; yl-1,2,4-triazole-5-thiol give au 7.0 in phosphate buffer at pH ~ uai the pH to 7 O ₅ increases and Diose solution was then heated for 5 hours at 70 ⁰ C. . The reaction mixture was then cooled to room temperature and acidified to pH 2.0 by adding aqueous 2E hydrochloric acid. Extraction of the reaction mixtures using ethyl acetate and evaporation gave 3 g of yellow solid. It was found to be about 50% pure by high pressure liquid chromatography (HPLC) and was discarded. The remaining, aqueous portion contained a guüimi-like residue, which was washed well with water and finally triturated with a solution of isopropanol / ethyl acetate * The residue from this trituration was 15 g. By high pressure liquid chromatographic analysis it was found that it was about 70 % pure. Evaporation of the isopropanol / ethyl acetate filtrate gave a 5 % 7% solid that was about 80% pure. This latter material was chromatographed on silica gel, xfo a 95 % pure (hplc) sample eluting with a 6% solution of methanol in Chloroform was obtained in a yield of 1.56 g, which was obtained from 7- (D ~ a ~

thiomethylceph ~ 3 ~ eai-4 ~ carbonic acid.

IR spectrum (KBr) i) _max = 1.765 cm "" ¹ (ß-Lactaiacarbonyl) HME spectrum (DHSOi ₆ ) S = 3.6 (broad singlet, 2-

4.0 (doublet, T = 13 c / s) ,, - CH -S- "

4.35 (doublet, T = 13 c / s) ~ " ²

5.0 (multiplet, 6-H and a-H)

5.55 (doublet, T = 5 c / s) _? ^ _H

5.70 (doublet, T = 5 c / s) "*"

7.25 (multiplet, aromatic protons]

8.55 (doublet, T = 8 c / s, CO-NH), ppm

609841/0996

Examples 5 "to 12

The following connections were made in a similar way of working xtfie described in Example 4, manufactured by the same cephalosporin as in Example 4 and the corresponding one Thiol or an a. Salt assumed vrarde:

com

coca

Table H.

characteristic values

-CH ₂ OCH ₂ COOH

-CH ₂ OCH ₂ COM ₂ ΙΕ spectrum (KBr) y>"" = 1? 60 cm ¹

(ß-Lactaaearbon ^ l MIR-Spectrumi (DHSOd ₆ )
= 5.68 (broad singlet, 2-CH ₂ )

4.2 (singlet + non-resolved quartet, 3-CH ₂ -S + one CH ₂ )

4.65 (singlet, one CH ₂ ) 5.06 (multiplet, 6-H and aH) 5.65 (doublet, Γ »5 c / s) 7-H 5.80 (doublet, T = 5 c / s ) 7-H

7.42 (multiplet, aromatic protons)

8.73 (doublet, T = 9 c / s, -COIiH), ppm

IR-Spelctrua (Mujol) ύ ^ _ν «1.775 chT '

(ß-Lactaacarbonjl = 1.670 cnT (amide carbonyl)

609841/0996

26-2760

Ex. X characteristic values

-CH ₂ OCH ₂ CO ₂ Et

8 HMe HHE spectrum (:

£ - 7.3 (broad singlet (aromatic protons)

5.65 (wide 3 singlet, 7 ~ H) 5.04 (center of the doublet,

3 "= 4.5 c / s, 6-H) 4.90 (singlet, a-H)

3.95 (broad singlet,

2 methyl-an)

3.64 (broad singlet, 2-CH ₂ , ppm)

IR spectrum (KBr) ti ^ ₃₃ . = ■■ 1,775 cm "" ¹

(ß-Lactanresbonyl) ESJB spectrum (DHSOd ₆ )
S- 1.15 center of the triplet,

<j = 6.5 c / s, -COoCH ^ CH ^) 3.6 (broad singlet, 2-CH ₂ ) 4.18 (complex pattern,

-CO ₂ CH ₂ CH ₅ and 5-CH ₂ and a CH ₂ )
4.90 (singlet, ei: a CH ₂ )

4.96 (multiplet, 6-H and a-H) 5.6 (poorly resolved

Doublet, 7-H)
7.25 (multiplet, aromatic

Protons)
8.52 (doublet, T = 9 c / s, C03S1H,

exchanges with D ₂ O), ppm

IR spectrum (KBr) ι / _χ «1,770 cm" ¹

(ß-Lactamcarbonyl) β 1,670 cm " ¹ (Amidcarbony1)

NME spectrum (DMSOd ₆ )

S = 7.45 multiplet (aromatic protons)

609841/0

- 23 -

BSD. X

characteristic fourth

HMe -

, COOH O -CH ₂ OCH ₂ COOH = 4.75 (singlet, methylene) 4.15 (singlet, methylene) 5.70 (singlet, N-CH,) 3.55 (broad singlet, 2-CH

IR spectrum (Nujol suspension) = 1.775 cm " ¹ (ß-lactam carbonyl)

Nuclear Magnetic Resonance Spectrum (DHSOd ₆ )
^ = 3.6 (multiplet, 2-Cg ₂ and N-CH ₅ ) 4.2 (multiplet, -CH ₂ -S and a

CH ₂ )

4.7 (broad singlet _r Cg ₂ ) 5.1 (hultiplet, 6-H and oc-H) 5.7 (poorly split doublet,

7-1)

7.38 (broad singlet, aromatic protons)
8.74- (doublet, T = 8 c / s, CONH) ppar

ΙΕ spectrum (KBr)

= 1,775

(ß-lactaiacarbonyl)

Nuclear Magnetic Resonance Spectrum (DMSOd ₆ )
<$ = 9.62 (doublet, T = 7.5 c / s, CONg)

7.30 (singlet, aromatic protons)

5.65 (broad singlet, 7-g) 5.05 (multiplet, 6-H and aH) 4.76 (singlet, a Cg ₂ ) 4.15 (singlet, a Cg ₂ ) 3.55 (multiplet, 2 -Cg ₂ ) ppm

6098 41/0996

Ex. X

characteristic values

11 NMe -COiIH,

12 S -CH ₂ OCH ₂ COOH ΙΕ spectrum (EfUjöl suspension)

$ 1,770 cdi "' ¹ (ß-lactaracarbonyl)

-1
1,680 cm (amide carbonyl)

_nnv

MB spectrum ₆
<£ = 8.55 (BublettjT = 9 c / s,

7.80 (doublet, X «18 c / s, amide-ITH) 7.28 (broad singletfc, aromatic protons)

5.00 (multiplet, 6-H and cx ~ H) 4.15 (broad singlet, 3-Cli ₂ -S) 3.70 (center of multiplet, U-CH ₅ and 2-CH ₂ ) ppm

ΙΕ spectrum (KBr)

1,665 cm

(ß-lactaacarbonyl) (Aniide carbon ^ l)

KME-Sp3ktruia (D ₂ O)

«5 = 7, ^ 2 (singlet, aromatic Protons)

5.58 (doublet, T- 4 c / s, 7-H) 5.25 (singlet, Ph.CH (OH) -) 5.00 (multiplet, 6-H and one CH 4.05 (singlet, a CH ₂ ) 3.66 (doublet, 3 "« 18 c / s, 2 3.25 (doublet, J * 18 c / s, 2-ppm

609841/0996

example

2_Zz ^ Si52z2 21 ■> 3- em-4- carb on acid

10og 7-i ^{i orraaDiidocephalosporansaure!} Were dissolved in 1600 ml of a phosphate buffer solution with pH = 7 dissolved »0, and the pH was adjusted to 7 with ₅ O 21T HatriumhydroxidlÖsung. Then 48 g of 3 ™ carbaiaoyl-5 - & ercapto-1,2,4-tria2ol were added and the pH was readjusted to 7> 0 with 2N sodium hydroxide solution. The mixture obtained was ^{heated to 70 °} C. for 5 hours; and then cooled to room temperature and adjusted its pH to 0.5 with concentrated hydrochloric acid. The mixture was diluted with 1500 ml of methanol and stirred at room temperature for 3 hours before being cooled to 5 ° C. The pH was then adjusted to 3.9 with ammonium hydroxide solution and, after stirring for 2 hours at 5 ° C, stirred, and 4-7> 9 S precipitate of 7-amino-3- (3-carbamoyl-1, 2, ^/ ! - triasol ~ 5-3 ^f l) -thioraeth7lceph-3-ea-4-carboxylic acid filtered off, washed first with water and then with acetone and ether and finally dried in a yakuuai at room temperature.

72 g of D-0- (dichloroacetyl) -mandeloyl chloride in 120 ml of acetone were added to a solution of 45% of the 7-AEiino-3- (3-carbamoyl-1,2,4-triasol-5 prepared under a) for 45 minutes -yl) -thiomethylceph-3-em-4-carboxylic acid and 27 g BTatriumbicarbonat in 720 ml of water and 600 ml acetone at 0 ⁰ C was added, the pH was maintained by adjusting with 235Γ Natriumhydrosidlösung during the addition to 7 ». 5 The mixture was allowed to warm to room temperature and then stirred for one hour. The acetone was removed in vacuo, the pH was raised to 9.5 by adding sodium carbonate solution, and after 30 minutes the pH was adjusted to 2 with concentrated hydrochloric acid. The reaction mixture was then with

609841/0998

a mixture of 310 ml of tetrahydrofuran and 310 ml of ethyl acetate extracted.

The organic phase was washed with water and brine and then evaporated to dryness. The received oil was triturated with ither, leaving 7- (D-α-hydroxyphenylacetamido) -3- (3-carbamoyl-1,2,4-triazol-5-yl) -thiomethylceph-3-em-4-carboxylic acid as an off-white solid in a yield of 23.3 g. By high pressure liquid chromatography (hplc) it was found that the product was identical to the product of Example 4.

Example 14

Using a similar procedure as in Example 13 »b) was 7- (D-a-hydroxyphenylacetamido) -3- (2-carbamoyl-1,3,4-oxadiazol-5-yl) -thiomethyl-ceph ^ -eni ^ -carboxylic acid from 7-amino-3- (2-carbamoyl-1,3,4-oxydiazol-5-yl) -thiomethylceph-3-em-4 ~ carboxylic acid and D-O-pormylmandeloyl chloride.

ΙΕ spectrum (Nujol suspension) 0 "_ = 1770 cm (ß-lactam carbonyl) NMR spectrum (DMSOd ₆ ) & = 7.25 (singlet, aromatic protons)

5.58 (multiplet, 7-H) 5.00 (multiplet, 6-H and aH) 4.30 (broad singlet, 3-CH ₂ -S) 3.55 (multiplet, 2-CH ₂ ) ppm

Example 15
) -thiomethjlcegh-

Solutions of 5 »^ 6 7-aminocephalosporanic acid and 3.19 g 2-carbamoyl-1,3,4-oxadiazole-5-thiol in dilute, aqueous Sodium hydroxide solution at pH about 7.0 (total volume

ß09841 / 0996

mixing from about 75 ml), and the resulting mixtures in a water bath vmrden "at 70 ⁰ C for one hour, stirred and heated. During the reaction the pH of the solution to 6.5 to 7> O by addition of aqueous 2N After this time the reaction mixture was rapidly cooled to room temperature, 2N hydrochloric acid was added to adjust the pH to 3 »5, and the resulting brown precipitate was collected by filtration - (2-carbamoyl-1,3,4-oxadiazol-5-yl) -thiomethylceph-3-em-4-carboxylic acid was washed well with acetone to give 3.1 g of a brownish yellow powder.

b) _7- (D-a-tert-Butox2carbon2lamino2-2hen2lacetamido-3 - (. 2-_

1.9 g of D-lT-tert-Butoxycarbonylphenylglycin were dissolved in 25 ml of dry tetrahydrofuran (THF), and the solution was cooled to 5 ⁰ C. Then, 0.76 g of triethylamine were added with stirring, the reaction mixture was cooled to -10 ⁰ C and treated for 2 minutes with 1.0 g of isobutyl chloroformate. The solution of the Mischanhydrides was stirred at -10 ⁰ C for 15 minutes.

1.8 g of the cephalosporin product from a) were added to an ice-cooled solution of 13 ml of THF and 13 ml of water which contained 0.5 g of triethylamine, and the mixture was stirred to bring about dissolution. The resulting solution was added over 7 minutes with stirring to the solution of the Mischanhydrides at -5 ⁰ C. After a further 30 minutes at this temperature, the reaction mixture was left to stand for 2 hours, during which time the coolant was removed.

60 9 8 41/0996

2612 7 6

25 ml of water were added and the reaction smell was extracted once with ethyl acetate. The ethyl acetate extract was dried over anhydrous magnesium sulfate, evaporated in vacuo and the product obtained was dried with dry Ether rubbed in, taking 530 mg of a dirty-white pest received as the first serving. The aqueous phase was covered with a layer of ethyl acetate, the pH was increased to 2.0 Aqueous 2N hydrochloric acid was added and the organic layer was separated and dried over magnesium sulfate. The solvent was evaporated in vacuo and the obtained

A product was triturated with dry ether, 800 mg of an off-white solid being obtained as portion 2. By thin-layer chromatographic analysis it was found that portions 1 and 2 were identical, namely from 7- (D-atert.-Butoxycarbonylamino) -phenylacetamido-3- (2-carbamoyl-1,3 »4-oxadiazol-5- * yl) -thiomethylceph ^ -eni - ^ - carboxylic acid passed. The parts were joined together.

500 mg of the product from b) were added to 5 ml ice-cold with stirring Trifluoroacetic acid added. After 6 minutes it was the brown solution was evaporated in vacuo and the oily residue was triturated with dry ether. The product, namely 7- (D-a-aminophenylacetamido) -3- (2-carbamoyl-'l, 3 »4- oxadiazol-5-yl) thiomethylceph-3-em-4-oarboxylic acid trifluoroacetate salt was filtered, washed well with dry ether and dried in vacuo. The yield of the off-white solid was 500ng.

5-yl) -thiometh2lcegh-3-em-4-carboxylic acid

To get the zwitterionic form of the desired product, were 400 mg of the trifluoroacetate salt previously prepared under c) suspended in 5 nil of water, and the pH of the

H0 9 8 4 1/0996

The mixture was adjusted to 7 * 5 by adding 2N sodium hydroxide solution set.

The solution was filtered to remove insoluble material, and the pH of the filtrate was increased to 3 * 5 by adding adjusted by 2N hydrochloric acid. Avenge for two days of storage at 5 ° C. the product, namely 7- (D-oc-aminophenylacetamido) -3- (2-carbamoy1-1,3,4-oxadiazol-5-yl) -thiomethylceph-3-em-4-carboxylic acid in the zwitterionic form, collected by filtration, washed with a small amount of water, and im Vacuum dried. The yield of the off-white solid was 110 mg. The product was determined by means of thin layer chromatography, Characterized IR spectrum and NMR spectrum.

IR spectrum (Nujol) J = 1760 cm

"" ¹

Max

= 1690 cm "

(β-lactam carbonyl) (4-carboxyl).

Examples 16 to 28

The following cephalosporanic acid derivatives were prepared using a procedure similar to that described in Example 1.5, 7-Aminocephalosporanic acid and the corresponding heterocyclic thiol were assumed. The products were obtained in the form or forms indicated, in most cases the trifluoroacetate salt (TFA) not converted to the zwitterionic form as in Example "15. The products were determined by thin layer chromatography or high pressure liquid chromatography as well as by IR spectra and HMR spectra.

CONIf

N

CO ₂ H

B098A 1/0996

Table III

E.g. R. X R ¹ -CONII ₀
£ λ isolated |
Form j 16 HO- 0 -CO ^ HCH zwitterionic!
Form \ ind I ¹ FA-I
Salt ' 17th H 0 -COK (He) ₀ ΤϊΆ salt 18th H 0 -CON (Ma) ₂ H 19th HO- 0 -CONHEt Il 20th H 0 -COlClIEt Il 21 HO- 0 -CHgOCHgCOgEt It 22nd HO- 0 -CONHCIi ti 23 H S. -CONH ₀ It 24 H NXH ₃ -CONHg Il 25th HO- N. CH ₃ -CHgOCHgCOgEt 26th HO- N.CH ₃ -CHgOCHgCOgH It 27 HO- N-CH ₃ -CHgOCHgCOgH It 28 HO- S. Il

The trifluoroacetate salts can optionally be converted into the zwitterionic Form of the cephalosporin according to the example 15 »d) specified method.

The characteristic values of the compounds of Examples to 28 are summarized below:

6098A 1/0996

26127B0

Example 16

IR spectrum (KuJoI suspension) v_. _ev = 1750 cm "(ß-lactaiacarbonyl)

- 16? 0 ca "(Aiaidcarbonyl)

Example 17

IR spectrum l) ".. ^ ~ 1775 cm (ß-lactanecarbonyl)

= 1675 ca (amide carbonyl)

KMR spectrum

S β 9.6 (doublet, J «8 c / s, amide-MH) 9.12 (doublet, J = 5 c / s, CONHCK ₇ ) 7.5 (singlet, aromatic protons) 5.76 (unresolved Multiplet, 7 ~ H)

5.05 (multiplet, 6-H and α-Η)

4.58 (doublet, J- 13 c / s,) 4.25 (doublet, T = 13 c / s, 3-CH ₂ -S) 3.57 (multiplet, 2-CH ₂ ) 2.82 (doublet , T = 5 c / s, COMCH ₅ ) ppm

Model .18

IE-Spektruai (KBr))) _rn ^. _r = 1775 cm " ¹ (ß-lactaacarbonyl)

= 1660 cm (amide carbonyl)

HME Spectruia (DiISOd ₅ )

^ = 7.5 (singlet, aromatic protons) 5.8 (broad singlet, 7 ~ -H) 5.1 (multiplet, 6-H and α-Η) 4.35 (broad singlet, 3-CH ₃ -S )

3.6 (multiplet, 2-CH ₂ ) 3.3 (singlet, U-CH ₅ ) 3.05 (singlet, N-CH ₅ ) ppm

Example 19

IR spectrum (KBr) v ' _mo ^ «1770 cm" ¹ (ß-Lactaacarbonyl

= 1660 cm "(amide carbonyl)

MMH spectrum £ «7.32 (doublet, 3T» 7 c / s, amide-KH)

7.25 (doublet, T = 8 c / s, aromatic protons)

6098 41/0996

S «6.72 (Dublstt, Z = 8 c / s, aromatic protons) 5.70 (unresolved multiplet, 7-H) 4.95 (unresolved multiplet, 6-H and α-H) 4.30 ( broad singlet, 3-CH ₂ -S-) 3.58 (broad singlet, 2-CH ₂ ) 5.36 (singlet, M-CH ₅ ) 3.00 (singlet, N-CH ₅ ) ppm

Example 20

IR spectra (JOr) i _n ^ _r - 1780 cm " ¹ (ß-lactam carbonyl)

= 1670 cm (amide carbonyl)

CMR spectrum ( ₆

^ = 7 ■) ¹³ T (singlet, aromatic protons)

5.7 (broad singlet, 7-H)

5.0 (multiplet, 6-H and a-H)

4.3 (broad singlet, 3-CH ₂ -S)

3.4 (complex cultiplet, 2-CH ₂ and COMCH ₂ CH ₃ )

1, -1 (center of triplets, 3 "» 7 c / s, CONHCH ₂ CH ₇ ) ppm

jjLJ-g? I "51.

IE-SpsktruBi (IiBr) j “. _v = 1775 cm '"' ¹ (ß-lactam carbonyl)

~ I67O ca "(aaidcarbonyl)

Example 22

IH spectrum (KBr) | J _{1? 80 Cm} -1 _(ß " _{LactaKlcarlDOnyl)}

- 1760 cm "(33stercarbonyl)

= 1675 cm (amide carbonyl)

MMR spectrum ₆

& ~ 3 »3 (doublet, $ - 8 c / s, aromatic protons) 4.75 (doublet, 3" ~ 8 c / s, aromatic protons) 5.70 (broad multiplet, 7-H) 3.60 ( broad singlet, 2-CH ₂ ) 1.20 (center of triplet, T = 7 c / s, ppm)

609841/0996

Example 2 ^

ΙΕ spectrum (KBr) ύ «1775 csf ¹ (ß-lactaincarbonyl)

= 1665 cm "" (Aiaidcarbon; /!)

EMR spectrum ( ₆

5 «9.18 (doublet, T = 5 c / s, amide-HH)

7, ^ 7 (singlet, aromatic protons)

5.77 (broad multiplet, 7-H)

5.00 Olul-ciplett, 6-H and α-Η)

4.30 (multi-plet, 5-CH ₂ -S)

3.55 (Haltiplott, 2 ~ CH _O )

2.76 (center of the bublet, T5 c / s, ΟΟϊΕίΟΠ ^) ppa.

Example 24-

IR spectrum (Nujol suspension) } , _r = 1775 cli ™ '(ß ~ Lactaracarbonjl

«1680 cn" (amide carbonyl)

MIR spectrum (D ₆

ο- 7.4- (singlet, aromatincäe protons)

5.65 (unresolved multiplet, 7-H)

4 »95 (not av.fgalösbe.o Kultiplott, 6-Ji and K-H

4.15 ("broad singlet, 3-CK ₂ -S)

3.75 (singlet, M-CK ₅ )

3.6 (multiplet, 2-CH ₉ ) ppc

BaisDial 25

lE-Spekferuri (KJIr) \) ^. ^ «1775 cn '' (ß-Lücta

~ 1S75 en "* (amide carbon ^ 'l)

IfrlR spectrum

& - 7i25 (doublet, 3 "= 8 c / s, aromatic protons) 6.75 (doublet, 2T = 8 c / s, aromatic protons) 5.65 (multiplet, 7-H) 4.90 (cultiplet, 6 -H and α-Η) 4.10 (broad singlet, 3-CE ₂ -S) 3.70 (singlet, H-CH) 3.55 (KuItipietc, 2-CH ₂ ) ppm

BO 984 1/0996

Example ^ 26

IH-Sp ektrun (KBr) ι) "= 1780 cm" * ¹ (ß-lactam carbonyl)

1765 cm * "(ester carbonyl)

1630 cm (amide carbonyl)

HMR Sp ectruia

<£ »7» 45 (doublet, J 8 c / s, aromatic protons)

6.76 (doublet, Cf8 c / s, aromatic protons)

5.75 (broad singlet, 7-H)

4.96 (multiplet, 6-H and α-Η)

4.70 (singlet, one CH ₂ )

4.10 (multiplet, two CH ₂ )

3.58 (broad singlet, N-CH ₅ and 2-CH ₂ )

1.00 (center of the triplet, T = 6 c / s,

Example 27

IS spectrum (KBr) |) _mnv - 1775 ca "" ¹ (ß-lactanicarbonyl)

1675 cm "'(amide carbonyl)

MlH sp ect rum

= 7j28 (doublet, T- 8 c / s, aromatic protons)

6.75 (doublet, T- 8 c / s, aromatic protons)

5.68 (broad singlet, 7-H)

4.95 (multiplet, 6-H and a-H)

4.68 (singlet, one CH ₂ )

4.03 (singlet, one CH ₂ )

3.55 (singlet, N-CH ₅ )

3.35 (multiplet, 2-CH ₂ ) ppm

Example 28

IR spectrum (ICBr) | / _mev «1765 cm" ¹ (ß-lactam carbonyl)

1670 cm ~ (amide carbonyl)

NTIR spectrum ₆

6 «9.55 (doublet, tr = 8 c / s, amide-N-H)

7 »35 (center of the doublet, ^" = 8 c / s, aromatic Protons)

609841/0996

6.83 (center of the doublet, T- 8 c / s, aromatic protons)

5.80 (unresolved cult triplet, 7-H)

4.96 (Kultiplett, 6-H and a-H)

4.18 (singlet, methylene)

3.62 (broad singlet, 2-CH ₂ ) ppm

Example 29

a) _ £ D) -5

? A solution of 56 9 6 phosgene in.500 ml of toluene was for 1 hour to 45.6 g of (D) -a ~ Eydro: xyphenyl83sigsäure in 450 ml (tetrahydrofuran were added at room temperature, then the mixture was for 6 hours at 45 ⁰ C. The organic solvent was removed in vacuo and the residue was recrystallized from carbon tetrachloride, giving 49.4 g of (D) -5-phenyl-1,3-dioxolane-2,4-dione as a white solid with F. = 76 - 77 ⁰ C were obtained.

Analysis for CqIL-O ^:

calculated: C = 60.67 H = 3.39 %

found: C = 60.37 E = 3.68 %

50.4 g of (D) -5-bienyl-1,3-dioxolane-2 _i 4-dione are added over 15 minutes to a solution of 84.0 g of 7- ^ mino-3-C (3-carbamoyl-1 , 2,4-triazol-5-yl) - ~ thicaiethyl] -ceph-3-em-4-carboxylic acid in 1075 parts of an aqueous buffer of pH 6.8 was added. The solution was stirred for 45 minutes at ZiiMasrteaiperatur, and 840 ral of a 1: 1 mixture of ethyl acetate and tetrahydrofuran were added. The pH of the aqueous phase was reduced to 2.0 with concentrated hydrochloric acid. The organic layer was separated, washed with 800 ml of water, dried and

60 9841/099 6

evaporated under reduced pressure. The residue was triturated with ether, the crude product being obtained in the form of 80.2 g of pale yellow solid. Chromatography on silica gel using up to 10% methanol in chloroform as the eluant gave the pure product, namely 7- (D-a-Hydro3cyphenylacetamido) -5- (3-carbamoyl-1,2,4-triazol-5-y1) -

^ - ^ _ _/ -ceph-3-.em-4-carboxylic acid

thiomethyV, dais in chromatographic and spectrographic Examination proved to be identical to the product prepared according to Example 4.

Example ^ O

100 mg of the product of Example 4 was added to an ice-cold, stirred solution of 45.1 mg of diphenyldiazomethane (Ph ₂ CHN ₂ ) in 15 ml of ethyl acetate and the reaction mixture was kept cooling for about 20 hours. The reaction mixture was then washed with aqueous sodium bicarbonate solution and then water, the organic layer was separated and dried over magnesium sulfate. The organic layer was evaporated in vacuo and the residue triturated with dry ether to give the diphenylmethyl ester of 7- (Da-hydroxyphenylacetamido) -3- (3-carbamoyl-1,2,4-triazol-5-yl) -thiomethylceph -3-em-4-carboxylic acid in the form of 99 white solid with a ^{temperature of 133-135 °} C. were obtained. A sample recrystallized from isopropanol gave the following analytical values:

Analysis for CZ ₀ H ₀ QNcOcS ₀ :

calculated: C = 58.52 H = 4.30

found: C = 58.56 H = 4.32

IR spectrum \> _mev «= 1778 cm" ¹ (ß-lactam carbonyl)

B09841 / 0996

example

800 mg of N, 0-bis- (vrimethylsilyl) -acetami & vmrden to a suspension of ² MDO of the product of Example 13? a) added in 9 BiI dry TSF and the mixture was heated to 50 C for 20 minutes, after this time a clear solution was obtained. This solution was cooled to room temperature, and a solution of 0.23 S DQ-iOrmyltaandeloylchlorid ( prepared according to the description in German Offenlegungsschrift 2 506 622) added in 1 ml of dry THE, Nach. With stirring for 2 hours, 10 ml of ethyl acetate and 5% of water were added thereto, and this mixture was stirred for an additional 10 minutes. The organic phase was separated, washed twice with water, separated again, dried over 1% SO ^ _ and evaporated in yolcuuia to give 0.5 g of Eohpro & uk-c, trituration of this raw material with dry. Acetone gave the desired product, 3 ~ - (3-carbamoyl-1,2,4-triaol-5 ~ yl) -thioethyl-7- (da-iormyloxypheny / acetamido) -coph-3-gas 4-carboxylic acid as an opaque white solid. The Aurib rate was 140 ag.

IE spectrum t ^ = 1770 cm (ß-lactam carbonyl) UV spectrum. (EtOH) E ^ j = 169 (at 270 na) EHR spectrum (DHSOd ₆ )

fj- 3.5 (broad singlet, 2-CH ₂ )

3.95 (center of doublet, Zf- 13 c / s)

4-, 3O (center of the doublet, T- 13 c / s j ^

4.95 (doublet, T --- 5 c / s, H-6)

5.60 (very broad multiplet, K-7)

6.03 (Singulstt, a-H)

7i35 (broad singlet, aromatic protons)

7.76 (porous singlet, -COIiH ₂ )

8.26 (sharp singlet, -OoCHO)

9.20 (doublet, T = 7 c / s, -COHH), ppm

609841/0996

'92 ^ $ :: ί2: ΐ £ ^^

28 rag of sodium bromide was added to a stirred solution of 4-0 mg of the chloroethyl ether of pivalic acid in 1.5 ml of dry dimethylformamide. After 15 minutes, 123 & S of the product from Example 4 were added, and after 10 minutes a solution of 50 ml of dicyclohexylamine in 0.5 dl of dry DMP was added dropwise over approximately 15 minutes of kinutane. The reaction mixture obtained was stirred for 17 hours at the same time as it was quoted, after which time water and ethyl acetate were added. The organic layer was separated and washed successively with aqueous sodium bicarbonate solution, water / water, 1N hydrochloric acid and water again, and finally dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, xm & the residue was triturated with dry ether, v / obei the product, pivaloyloxymethyl-3- (3-carbamoyl-i, 2,4-triaao3.-5-yl) -thioin3th7l-7- ( Da-hydroxyphen3 ^r lacetaaido) -ceph-3-eüi ~ ^z i-carbo: xy'JLat obtained as achrautaig-white Fe3t vrcirde. The yield was yv ng.

ΙΕ spectrum (KBr) V _1110x - 1755 cm ", broadened (ß-Lactara and

Etbl)

(Estsrcarbonyle)

KllR spectrum (DMSOd ₆ )

A = 1.18 (sharp singlet, t-butyl)

3) 95 (center of a doublet, 3 = 13 c / s) na q

4-, 4O (center of a doublet, J = 13 c / s)

5.10 (multiplet, 6-H and cc-H)

5.80 (multiplet, 7-H and methylene from ester group) 7.30 (broad singlet, aromatic protons)

7.86 (multiplet, -COIm ₂ )

8.68 (doublet, T = 7 c / s, -COM-), ppm

'6 09841/0996

Claims (1)

Claims wherein; E = H or OH; Y = NH ₂ , OH or OR, where R ⁴ "is lower Alkanoyl, a lower alkoxycarbonyl or is a benaoyl group;
X = 0, S, KH, or HMe;
Z = hydrogen, a lower alkyl, a benzhydryl phenyl, an indan-5-yi group or a group of the following formulas -CHpOCO-C-lower alkyl), -CH (CH,) OCOO-C-lower alkyl) or is; and
R ¹ β -CH ₂ OCH ₂ COOH, -CI ^ OCHgCOO-C-lower alkyl), ² R ^, wherein R ² and R ^{5 are} independent of each other hydrogen or a lower alkyl group 2 3 2 3, or -COIiR R, where R and R ^ are as before have given meaning is as far as pharmaceutically acceptable salts thereof. 2. A compound according to claim 1, characterized in that Y = or OH, and Z = hydrogen. 6098 41/0996 5. A compound according to claim 2, characterized in that the radical R ^{1 is} -CH ₂ OGH ₂ COM ₂ . 4. A compound according to claim 2, characterized in that the radical R ^{1 is} -COIiH ₂ , -CH ₂ OCH ₂ COOH or -CHgOCHgCOOC-lower alkyl). 5. A compound according to any one of claims 2 to 4, characterized in that that R »H and Y = OH. 6. A compound according to any one of claims 2 to 4, characterized in that the radical R is para-OH and Y = NH ₂ . 7. A compound according to any of claims 2 to 6, characterized in that that X = HH or S. 8. A compound according to any one of claims 2 to 7> characterized in that it is in the D-shape. 9. A compound according to claim 1, characterized in that R = H, Y = OH, R ¹ = COIiIi _2,:
the D-shape is present. Y = OH, R ¹ = COIiIi ₂ , X »HH and Z = H, and that they are in 10. A compound according to claim 1, characterized in that R = p-OH, Y »1IH ₂ , R ¹ = -CH ₂ OCH ₂ COOH, X = Mi and Z = H, and that it is in the D-Fora » 11. A compound according to claim 1, characterized in that R = p-OH, Y = NH ₂ , R ¹ a -CH ₂ OCH ₂ CONH ₂ , X = NH and Z = H, and that they are in the D-form is present. 12. A compound according to claim 1, characterized in that R = p-OH, Y = NH ₂ , R ¹ = -CONH ₂ , X = HH and Z = H, and that it is in the D-form. 609841/0996 13. Compound according to Claim 1, characterized in that E is H, X - OH, R ¹ = -CH ₂ OCH ₂ COOH, X = MH and Z = H, and that it is in the D form. 14. A compound according to claim 1, characterized in that R H, X = OH ₁ R ¹ «-CH ₂ OCH ₂ COOEt, X = S and Z = H, and that it is in the D form. 15 · Compound according to claim 1, characterized * that R H, X = OH, R ¹ β -CH ₂ OCH ₂ COOH, X * S and Z = H, and that it is in the D-form =. 15. A compound according to claim 1, characterized in that R H, X = OH, R ¹ = -CH ₂ OCH ₂ COOH, X
that it is in the B-3? orai * H, X = OH, R ¹ = -CH ₂ OCH ₂ COOH, X = O and Z * H, and 17- Procedure for establishing a connection between the 33'ornel (i) according to claim 1, characterized in that a 7-amino-J-heterocyclischas-thioüiethvl- ^ -cepheme derivative of the following general formula: 11 ο ι COOZ wherein R _1, X and Z have the meaning given in claim 1, with an acylating agent of the following general formula: 609841/0996 26Ί27ΒΠ wherein E has the meaning given in claim 1 and J is a protected amino group or a protected hydroxyl group or a group of the formula -OR, in which E has the meaning given in claim 1, or is reacted with its functional equivalent as acylating agent, and then the protecting group of Y is removed, with any free carboxyl groups in the compound (II) optionally being protected before the reaction and being freed from the protecting group after the reaction. 18. The method according to claim 171, characterized in that the functional equivalent used as acylating agent is an acid chloride or bromide, an activated ester or a mixed anhydride of the compound of formula (III). 19. The method according to claim 18, characterized in that the activated ester has the following general formula: (IV) wherein E and Y have the meaning given in claim 17. 20. The method according to claim 18, characterized in that the mixed anhydride has the following general formula: - (V) CO-O-COOR- ⁷
/ wherein E and Y have the meaning given in claim 17 and B? is a lower alkyl group. 6,99841 / 0996 21. The method according to any one of claims 17 to 20, characterized in that characterized in that Y is a protected amino group odsr is a protected hydroxyl group and that Z is a hydrogenator is. 22. The method according to claim 17, characterized in that the functional equivalent used as acylating agent has the following general formula: - (VI) in R has the meaning given in claim 17. 2Y. Process for the preparation of a compound of the Forrael (I) according to claim 1, in which Y ~ OH or MIp and Z »signifies hydrogen, characterized in that a cephalosporin derivative of the following general formula: ; 0i! H (VII) COOH wherein R has the meaning given in claim 1, Y = OH, HH ₀ or a protected amino group or a means protected hydroxyl group and R means a readily cleavable one Group, with a heterocyclic triol of the following general formula: N- ι ¹ H - (viii) 609841/0996 26127GÜ or one. Metal or ammonium salt thereof, v; orin H and X have the B specified in claim 1, is reacted, which may be the Distance closes. v; orin H and X have the meaning given in claim 1 ο removal of any protective groups on Y 24. The method according to claim 25, characterized in that p Y - OH or aif> is t-butoxycarbonylamino group. 25 »Method according to claim 25 or 24, characterized in that that the compound (VIII) in the form of its alkali metal sals is implemented. 26. The method according to any one of claims 25 to 25 »thereby characterized in that the easily removable group is a chlorine, bromine, iodine or acetoxy group. 27. A process for the preparation of a compound of the formula (I) according to claim 1, wherein Z is a group other than hydrogen according to the definition of claim Λ , characterized in that a compound of the formula (I), wherein Z is hydrogen, optionally after Conversion to their alkali metal salt form is esterified, with any free hydroxyl or amino groups passing through Y, and any & soft free carboxyl groups in the remainder E protected from the esterification and after Esterification to be freed from the protective group 28. Medicament, characterized in that it contains a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to one of claims Λ to 16, optionally together with a pharmaceutically acceptable diluent or carrier. 609841/0996