DE1951012A1 - Esters of 7- (alpha-amino-alpha-phenylacctamido) -3-methyl-delta? -Cephem-4-carboxylic acid - Google Patents

Description

Esters of 7- (^ -amino- <* - phenylacetamido) -3-methyl-Δ-cephem-4-carboxylic acid

The invention relates to a group of novel esters of 7 - (<* - amino- oC -phenylacetamido) -3-methyl-Δ cephem-4-carboxylic acid with the following general formula:

C ₆ H ₅ -CH-CO-NH-CH

-CH CH,

NHo O = CN ^ ^ C-CH ₅

(D

COOCH ₀ OCO-R

where R stands for a hydrogen atom, an alkyl radical, a cycloalkyl radical, a cycloalkyl-alkyl radical, an aryl radical or an aralkyl radical »and salts of these compounds with non-toxic, pharmaceutically acceptable acids.

In particular, R can stand for a lower alkyl radical, like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. Butyl, pentyl and the like; also for a monocyclic one

0 0 9 8 17/1911

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Cycloalkyl radical with 3 to 7 carbon atoms; for a bicyclic Cycloalkyl radical, such as a 1-bicyclo (2,2,2) octyl or adamantyl radical; for a monocyclic aryl radical, e.g. an optionally substituted phenyl radical; for a bicyclic aryl radical, such as a 1-naphthyl, a 2-naphthyl or a substituted naphthyl radical; for a mono- or bicyclic Aralkyl radical, e.g. for a benzyl or phenylethyl radical or for a naphthyl-low. alkyl radical, such as naphthylmethyl and the like.

Examples of substituents in the above ring systems which form part of R include lower alkyl radicals, lower alkoxy radicals, lower alkyl mercapto radicals, lower haloalkyl radicals, such as mono-, di-, or trihaloalkyl radicals, in which the halogen can be fluorine, chlorine or bromine, as well as nitro groups.

As examples of acids with which the invention Compounds that can form salts, such as inorganic acids such as chlorine, bromine and hydroiodic acid, sulfuric acid and the like, and organic acids such as acetic, citric, tartaric and maleic acids and the like.

Due to the asymmetric carbon atom in the side chain of the compounds according to formula (I), which is marked in the form by an asterisk, these compounds exist in two epimeric forms, and the invention includes both forms as well as mixtures thereof.

The compounds according to the invention can be derived are derived from the heterocyclic substance cepham with the following Formula?

009817/1911

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7 < -cn ^XcH 2 "CH ₂ 2 CH ₂ - -N CH ₂ - O = C - 3 8 5

of which they the 7-amino-3-methyl- £ k ^ -cephem-4-carboxylic acid derivatives are.

7- (οι -amino- od-phenylacetamido) -3-methyl-A -cephem-4-carboxylic acid has a broad range of antibiotic activity in vitro and is absorbed to a certain extent after oral administration; however, the absorption is far from complete, and it is therefore the purpose of the invention to provide new derivatives of 7- (»<L-amino-oC-phenylacetamido) -3-methyl-Δ cephem-4-carboxylic acid which are easier to use in the organism be absorbed and dispersed as the original compound. Experiments made in this direction showed that the above disadvantage can be overcome if the 7- (° * - Απιΐηο- <* i-phenylacetamido) -3-methyl-Δ-cephem-4-carboxylic acid in the form of its ester administered according to formula (I); the Es.ter are easily absorbed and distributed in the organism, and one obtains an extraordinarily high concentration of 7- {oC -amino-c * i-phenylacetamido) -3-methyl- in the blood and in the tissues due to the enzymatic cleavage of the ester bonds Δ "'-cephem-4-carboxylic acid.

The compounds according to formula (I) are well tolerated substances, which are also enterally in any known form the pharmaceutical preparations usable for antibiotics can be administered, whereby, however, the oral administration, e.g., in the form of tablets or capsules, is preferred.

009817/1911

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Another object of the invention is to provide methods

for the preparation of the compounds according to formula (I).

One of these methods comprises a first stage in which -R ¹ -ot-phenylacetamido) -3-methyl-A -cephem-4-carboxylic acid or one of its salts according to formula (II) is reacted with a compound according to formula (ill), according to ^{1 of the} following reaction scheme:

C ₆ H ₅ = CH-CO-NH-CH

O = C

(II)

X-CH ₂ OCOR (III)

0, Hc-CH-CO-NH-CH-6 5,!

R 'O = C-

-CH Xl i I

COOCH ₂ OCOR

(IV)

• In the Forael scheme, R has the above meaning, R ¹ is an optionally protected amino group or a group which can be converted into an amino group after the above reaction has been carried out, for example an azido or nitro group, or a halogen atom; Y represents hydrogen or a cation, such as an alkali metal or a tertiary amine, and X represents a halogenated, preferably chlorine or bromine, an acyloxy radical or an alkyl or arylsulfonyloxy radical. - 5 - ■ ·

0 0 9 8 17/1911

INSPECTED

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Compounds according to formula "(IV) formed by the above reaction are esters of 7 - (. Oi.-R '- <^ - Phenylacetainido) -3-methyl-A -cephem-4-carboxylic acid and as such are new compounds. when R ¹ is an amino group, compounds of the invention can be immediately obtained and if R ¹ is not an amino group, is obtained interesting intermediates in the synthesis of the compounds of the invention, as such, are also part of this invention. as a common characteristic of the substituents R ¹ may be said that it is selected from groups which can be converted into an amino group with the aid of mild methods in which the molecules on the ester group or on the lactam ring are not destroyed. In particular, the substituent R 'can have the formula Z-NH- where Z is a benzyloxycarbonyl radical, a p-halo, p-nitro or p-methoxybenzyloxycarbonyl radical, an allyloxycarbonyl radical or a sulfur-containing radical, such as a tri-tylsulfenyl radical, an arylsulfenyl radical st, for example an o-nitrophenylsulfenyl radical, / In addition, Z can be a triphenylmethyl radical (also referred to as trityl radical), a tertiary butoxycarbonyl radical, a β, β, β-trichloroethyloxycarbonyl radical and an enamine or a Schiff base. In general, any group or radical which can be split off by catalytic hydrogenation or by mild acid hydrolysis is suitable, since tests have shown that the esters according to formula (I) are stable under such conditions.

It will be understood that the methods for preparing the compounds of formula (i) from the compounds of formula (IV) depend on the substituent R '. The conversion of the substituent R 'into a free amino group can be effected are made using methods known from peptide chemistry.

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Some of the starting compounds according to formula (II) were mentioned in the synthesis of T- (U- amino-c * - -phenylacetamido) -3-methyl-A -cephem-A-carboxylic acid. Others can be prepared by methods known from peptide chemistry by acylation of 7-amino-3-methyl-Δ-cephem-4-carboxylic acid. The starting compounds of the formula (III) are mostly known and the new compounds can be prepared in the same manner as the known ones, using methods which are generally customary for this type of compound. Among these processes, mention should be made of the reaction of an acid halide with paraformaldehyde (described, for example, in JAGS »53, 660 (1921)) or the halogenation of methyl esters (described, for example, in Acta Chem. Scand. 20, 1273 (1966)). The reaction of the compounds according to formula (II) with the compounds according to formula (III) can be effected at or below room temperature or by careful heating to the boiling point of the solvent in question, depending on the meaning of Y and X. A wide variety of organic solvents can be used here , optionally mixed with water, can be used, for example acetone, dioxane, tetrahydrofuran, methylene chloride, dimethylformamide.

The reaction gives partly oily products which are used for the next stage without further purification can be. By dropping them several times they can be considered amorphous Powder can be obtained.

The following reaction step in which the R 'group is converted into an amino group, can be carried out according to various methods known from peptide synthesis, the method depending on which group R 'represents.

009817/1911. '

ORIGINAL INSPECTED

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When R ^{1 has} the formula Z-NH- and Z is benzyl oxy carbonyl, and its related derivatives or trityl, the preferred process is catalytic hydrogenation, which is preferably carried out at room temperature and at normal or slightly elevated pressure in a solvent, which can be an irreducible organic solvent, possibly mixed with water. Preference is given to noble metal catalysts such as palladium or platinum or Raney nickel as catalysts, but others can just as well be used. If Z stands for a sulfur-containing group, an enamine or, for example, a Schiff base, mild hydrolysis at pH = 2 in a dilute solution of hydrochloric acid in aqueous acetone is preferred. If Z is a tertiary butoxycarbonyl or a β-dicarbonyl radical introduced for protection, treatment with formic acid at room temperature is particularly suitable for removing the Z radical the sulfur atom of the sulfenamide group takes place. In the present case the best yields are obtained with sodium or potassium iodide, sodium thiosulfate, sodium hydrogen sulfide, sodium dithionite and potassium thiocyanate. Other sulfenamide groups can be split off in the same way * If R 'is an azido or nitro group or a halogen atom, in particular a bromine atom, these groups or atoms can be converted into the free amino group in a known manner, the azido and the nitro group by reduction with a noble metal catalyst and hydrogen or with Raney nickel and the halogen atom by amination with, for example, hexamethylenetetramine.

8-7 / 1911

WQINAL INSPECTE0

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Another suitable method of making those of the present invention Compounds consists in the conversion of a reactive derivative of an oi-substituted phenylacetic acid according to formula (V) with an ester of 7-amino-3-methyl - / ^ - cephem-4-carboxylic acid according to formula (VI), whereby a product according to the above formula (IV) is obtained:

- CH - CO - Y '- Hi ₂ N - CH CH CH ₂

- ~ - O = i

CHCH

1 ]

C N.

COO-CH ₂ -OCO-R (IV) -

In formula (V), R «has the same meaning as in formula (II); in formula (VI), R has the meaning defined under formula (I); -CO-Y 'represents a radical which _{can react with the NH 2} group in the compound according to formula (VI) to form a CO-NH bond, resulting in a compound according to formula (IV). For example, -CO-Y ^{1 can be} an acid halide, such as an acid chloride or bromide; or it is an anhydride, a mixed anhydride with '. an alkyl carboxylic acid such as isobutyl carboxylic acid or a carboxylic acid, an inorganic acid or a sulfonic acid; the group can also be a derivative of the reaction of a carboxylic acid with a carbodiimide or N, N'-carbonyldiimidaz.ol or a compound with a similar function.

The reaction can be carried out at a low or slightly elevated temperature in an organic, optionally mixed with water Solvent to be carried out. Suitable solvents are methylene chloride, chloroform, acetone, dimethylformamide or dimethylacetamide, ether, tetrahydrofuran, dioxane or similar inert solvents. "_ q _

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ORIGINAL INSPECTED

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The reaction products according to formula (IV) (or (I), if p) can be isolated in the usual way, e.g. by Falling over or by removing the solvent and subsequent Recrystallization from a solvent, and can be converted into compounds using the methods described above Formula (I) are converted.

The starting compounds of the formula (V) are known and can be prepared using the standard methods known from peptide chemistry getting produced.

The compounds according to formula (VI) are novel compounds and are interesting intermediates in the synthesis of the compounds according to formula (i); insofar they are Part of the invention. The intermediates can be prepared by treating 7-amino-3-methyl- & cephem-4-carboxylic acid in the form of one of its salts, e.g. an alkali salt or the triethylammonium salt with a halomethyl ester of Formula Rp-CHp-OCO-rR, where Rp is a halogen, preferably a Represents chlorine or bromine atom and R has the above meaning.

3 can

The 7-amino-3-methyl-ε y -cephem-4-carboxylic acid / can be used as such, or the 7-amino group can be protected, for example with a triphenylmethyl radical or another radical which is suitable for the amino group during the esterification to protect. Only protective radicals that can be easily removed without damaging the lactam ring or the ester group are suitable for this purpose. The reaction is carried out in the usual way in an inert organic solvent such as acetone, dimethylformamide or methylene chloride, at room temperature or at a slightly elevated temperature. If the amino group has been protected, the protective group can be removed again with the aid of methods known from the literature.

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00981 7/1911

• ίο -

1A-36843

The reaction products according to formula (VI) are customary Way isolated as acid addition salts, for which, for example, p-toluenesulfonic acid or other inorganic or organic Acids such as sulfuric acid, phosphoric acid, hydrochloric acid, acetic acid, maleic acid, tartaric acid and the like can be used can.

As already mentioned, the esters of 7 - (^ - Amino-O <-phenylacetamido) -3-methyl- ^ -cephem-4-carboxylic acid according to formula (I) can be obtained in a single step with the aid of the free amino compounds according to the formulas (II) and (V) in the reactions described above. The reaction can take under a wide variety of conditions. Various organic solvents, such as acetone, dimethylformamide, Tetrahydrofuran or Methylenchlorld, possibly with small Quantities of water can be mixed, can be used, The reaction temperature is below or at room temperature, but the mixture can, depending on the solvent used, also-be warmed up easily.

According to another method, the invention Compounds are prepared according to the following reaction scheme j

-CHCONH-CH-R ¹ CO-

• CHCONH-CK-

I i

R ¹ CO-

-N-

CH

(VII)

-CH-COOCH ₂ OCOr

■ ^CH

(IV) - »(I)

CH-COuCH ₉ OCOR

(VIII)

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Here, R and R ^{1 have} the above meaning. The starting materials for this process are the acyloxymethyl esters of the ÖC-R'-substituted benzylpenicillin, which have already been described earlier. For example, the compounds according to formula (VII) can be prepared by esterifying an ot-R'-substituted benzylpenicillin with a compound according to formula (III). The protected compounds (VII) are converted into the sulfoxide compounds (VIII) in a manner known from the chemical literature by treating them with an oxidizing agent, for example with hydrogen peroxide in acetic acid or with metaperiodic acid. By heating in an inert
Solvents, such as xylene, in the presence of an acid catalyst, such as p-toluenesulfonic acid, these sulfoxides rearrange themselves into the compounds of the formula (IV), which can then be converted into the compounds according to the invention in the form of the described y / s.

The following examples explain the invention in more detail,
without restricting them.

example 1

A. Pivaloyloxymethyl-D (-) - ot-azidobenzyl penicillinate sulfoxide

To a solution of pivaloyloxymethyl-D (-) - c ^ -azidobenzylpenicillinate (6.0 g) in glacial acetic acid (60 ml) became 30% hydrogen peroxide (6 ml) was added and the mixture was stirred at room temperature for 3 hours.

Ethyl acetate (100 ml) was then added and the acids
removed by extraction -with water, saturated sodium bicarbonate solution and water until a neutral reaction. the
The ethyl acetate layer was separated, dried over magnesium sulfate and evaporated in vacuo to leave the desired compound as an amorphous powder. / ~ ^ _7τ) = +51> 8

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(c = 1, CHOI,). The NMR spectrum (10 96 in CDCI, with TMS as internal standard) showed signals at cf = 1.23 (representative of 4 methyl groups) 1.7O (s), 4.71 (s), 5, O7 (d), 5.11 (β), 5.75 (a), 5.98 (d), 6.00 (dd), 7.4O (s), 8, O (d).

The IR spectrum (5 1 ° in CHGl,) had strong bands at 2140, 1814, 1760, 1698, 1515, 1280, 1107 ^ 033 and 975 cm " ¹ .

B. Pivaloyloxymethyl-7- / ~ D (-) - <^ -azido-phenylacetamido 7-3-methyl-A -cephem-4-carboxylate

A solution of 2.0 g of pi valoyloxymethyl-D (-) - <> £ -azidobenzylpenicillinate sulfoxide and 150 mg p-toluenesulfonic acid in 50 ml of xylene was refluxed for 1 hour and then evaporated to dryness in vacuo. The residue was dissolved in ethyl acetate (25 ml) yellow and the solution washed with aqueous sodium bicarbonate and water. After drying, the Lo = -

solvent driven off in vacuo and the residue through

Chromatographed 100 g of silica. By eluting with a mixture of cyclohexane and ethyl acetate (7-3), fractions were obtained which contained the desired compound and were evaporated to dryness together. The residue was recrystallized from ether to give the desired compound as white crystals, melting at 111-112 ⁰ C.

UV spectrum λ. ^ 2 ^H = 263m / U (£ = 6400)

IBaA /

The IR spectrum ( $ 0.3> in KBr) showed strong bands at 2120, 1782, 1742, 1730, 1697, 1530, 1375, 1250, 1140, 1125, 1040 and

970 cm " ¹

= -21, "β ⁰ (c = T, CHCl ₃ )

D ₃

The HMR spectrum ( $ 10> in CDCl ₃ , TMS as internal standard) contained signals at cf = 1.21 (s); 2.13 (s); 3.25 (d) J = 17; 3.45 (d) J = 17; 4.98 (d) J = 5; 5.12 (s); 5.72 (dd) J = 5, J = 10; 5.88 (s), x 7.15 (d) J = 10 and 7.42 (s). '-

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0098 17/1911

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C; Pivaloyloxymethyl-7- / ~ "D (-) - ° <- aminophenylacetamido 7-3-

methyl-Δ-cephem-4-carboxylate hydrochloride

■ To a solution of pivaloylmethyl-7- / ~ D (-) - cxi-azidophenylacetamido J-Ji-methyl- Δ ^ -cephem-4-carboxylate (2.0 g) in ethyl acetate (30 μl) _ were added water (30 ml) and 1 g of a catalyst with 10 fo palladium on charcoal were added, working in a flask equipped with a powerful stirrer, a gas inlet, a gas outlet, an electrode made of a combination of glass and calomel and one by an automatic Titrator controlled burette.

The system was flushed with nitrogen, after which a stream of hydrogen was passed through the suspension with stirring, the aqueous phase being kept at a pH of 3> 0 by adding 1N hydrochloric acid via the automatic titrator. When the acid consumption ceased, the flask was again purged with nitrogen until all hydrogen was removed and the catalyst filtered off. The filtrate was in two phases which were separated, whereupon the aqueous phase was washed with ether and subjected to freeze-drying. The desired compound was obtained as a colorless amorphous powder which easily dissolved in water. The UV spectrum showed a Λ ÜgS *> ei ² 58 m / U (£ = 5830). The NMR spectrum (D ₀ O) showed signals at cf = 1.17 (s); 2, O5 (s); 3.22 (d) J = 16; 3.42 (d) J = 16; 5, 05 (d) J = 5; 5.27 (s); 5.65 (d) J = 5; 5.82 (d) J = 6; 5.95 (d) J = 6; 7.57 (s).
(TMS used as external standard).

Example 2

A. Pivaloyloxymethyl-7-amino-3-methyl-Δ-cephem-4-carboxylate hydrochloride

To a suspension of 7-amine-3-methyl-acephem-4-carboxylic acid (11.0 g) in N, N-dimethylformamide (100 ml)

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Triethylamine (9.8 ml) and chloromethyl pivalate (14.8 ml) were added. After stirring for 6 hours at room temperature, ethyl acetate (300 ml) was added and the mixture was added three times with 50 ml of water each time washed.

After drying, the solution was concentrated to about 100 ml and 100 ml of water was added, followed by 2N hydrochloric acid was added with stirring until the pH of the aqueous phase was 3.0. The phases were then separated and off the aqueous phase was obtained by freeze drying the desired Compound as a colorless powder that was used without further purification.

B. Pivaloyloxymethyl ~ 7- / ~ D (-) - ^ - aminophenylacetamido_7-3-methyl-Δ -cephem-4-carboxylate hydrochloride

Pivaloyloxymethyl-7-amino-3-methyl-Δ-cephem-4-carboxylate hydrochloride (7.4 g) was suspended in dry, ethanol-free chloroform (100 ml) at 0 ° C. with vigorous stirring. Sodium bicarbonate (4.3 g) and then D (-) - c * - phenylglycyl chloride hydrochloride (5.0 g),. manufactured according to J.Org.Chem. 31, 897 (1966) added.

After stirring for a further 3 hours at ⁰ ° C., the mixture was filtered through diatomaceous earth and the clear filtrate was concentrated in vacuo, the desired product remaining as an amorphous powder, which is identical to the end product obtained in Example 1.

Example 3

A. Potassium 7- / 3D (-) - ^ - azidophenylacetamido_7-3-methyl- Δ cephem-4-carboxylate

3 To a suspension of 7-amino-3-methyl-A ^ -cephem-4-

carboxylic acid (7.1 g) in water (53 ml) was added sodium bicarbonate (7.0 g) with stirring. After adding acetone (13 ml) to the resulting solution, the mixture was reduced to 6-80

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cooled and a solution of D (-) - o £ -azidophenylacetyl chloride (6.2 g) in acetone (13 ml) was added over 5 minutes. After 40 min While stirring, the mixture was washed with ether and adjusted to a pH of 2.0 with dilute hydrochloric acid. The acidified The mixture was then washed twice with 30 ml of ether each time and the combined extracts mixed with 15 ml v / water, whereupon 2M aqueous potassium bicarbonate was added with vigorous stirring until the pH of the aqueous phase was 7.0. The layers were then separated and the aqueous layer with Washed with ether and subjected to freeze-drying, the desired compound being obtained as a colorless amorphous powder which was used for the following step without further purification.

B. Pivaloyloxymethyl-7- / ~ D (-) - ot-azidophenylacetamido 7-3-methyl- Δ-cephem-4-carboxylate

To a suspension of potassium T- ^ di- ·.] _- oi-azidophenylacetamido 7-3-methyl- Λ -cephem-4-carboxylate (4.14 g) and potassium bicarbonate (1.5 g) in acetone (100 ml) and 10% aqueous sodium iodide (2 ml) were added chloromethyl pivalate (2.7 ml) and the mixture was refluxed for 2 hours. After cooling, the suspension was filtered and the filtrate was evaporated to dryness in vacuo. The residue was washed repeatedly by decantation with petroleum ether in order to separate off the unreacted chloromethyl pivalate. The oily residue was taken up in ethyl acetate (100 ml) and the resulting solution was washed with aqueous sodium bicarbonate and water / water. After drying and evaporation in vacuo, the desired compound, which was identical in every respect to that in Example 1B, was initially obtained as a yellowish oil.

The compound was based on that described in Example 1C Way into the pivaloyloxyn: ethyl-7- / ~ D (-) - ^ - air.inophenylacetamido 7-3-diethyl-Δ ^ -cephem-4-carboxylate hydrochloride converted.

8647 * claims

0 0 9 8 17/1311

BATH ORIGINAL

Claims (18)

Dec. 1, 1969 Claims 1. Ester of 7 - (<^ -amino- oL -phenylacetamido) -3-methyl- ^^ - cephem-4-carboxylic acid of the general formula - CH-CO-NH-ClI CH NH ₂ O = CM / C-CH ₃ (I) COOCH ₀ OCO-R where * denotes an asymmetric carbon atom and R denotes hydrogen, an alkyl radical, "a cycloalkyl or cycloalkylalkyl radical, represents an aryl or an aralkyl radical, and salts of these esters with non-toxic, pharmaceutical permissible acids. 2. Stereoisomers of the compounds according to claim 1 and mixtures thereof of the general formula } A C ₆ H ₅ -CH-CO-NHp-O C CH ₂ NH ₂ O = C -N J> CH ₃ COOCH ₂ OCO-U where R has the above meaning. 009817/1 91 1 ORIGINAL IMSPECTED - t - -1A-36 843 4 3 .. Compounds according to claim 1 and 2, wherein R is an aliphatic radical with a straight or branched chain from 1 "to 6 carbon atoms, and their pharmaceutical permissible 'salts. 4. Acetoxymethyl-7- (o ^ -amino - «^ - phenylacetamido) -3-methyl-Δ-ceph <
permissible salts. 3-methyl-Δ-cephem-4-carboxylate and its pharmaceutical 5., Acetoxymethyl-7- (DC -) - ⁰ ^ - amino- <* - phenylacetamidο) ■ 3-methyl-Λ -cephem-4-carboxylate and its pharmaceutically acceptable salts. 6. Pivaloyloxymethyl-7- (o £ -amino- <? 6 ~ phenylacetamido) -3-methyl-Δ-ceph
permissible salts. 3-methyl-Δ-cephem-4-carboxylate and its pharmaceutical 7. Pivaloyloxymethyl-7- / D (-) - <? ^ - amino-σί-phenylacetamido 7-3-methyl- & -cephem-4-carboxylate and its pharmaceutical permissible salts. 8. Compounds according to claim 1 and 2, wherein R is an alicyclic Radical with 3 to 10 carbon atoms as ring members. 9. Compounds according to claim 1 and 2, wherein R is an aromatic carbocyclic radical. 10. Process for the preparation of the compounds according to Claim 1 to g , characterized in that • ζ one is a 7 - (^ - R'-. ^ - Phenylacetamido) -3-methyl-Δ -cephem-4-carboxylic acid or one of its salts of the formula (II) 0 0 9 8 17/1911 - y - ^ ■ · 1A-36 843 wherein R ^{1 represents} an amino group, a substituted amino group or a group which can be converted into an amino group and Y represents hydrogen or a ketone, reacts with a compound according to formula (III) X-CH ₂ OCOR (III) wherein R has the meaning defined in claim 1 and X is a halogen atom, an acyloxy, an alkylsulfonyloxy or an arylsulfonyloxy radical, where, if R 'is an amino group, the compounds according to Claim 1 and, if R ^1, a substituted amino group or a group to be converted into an amino group, as an intermediate is a compound of the formula (IV) CrHc-CH-CO-NH-CH OT \ h _o I Il R ¹ O = CN COOCH ₀ OCOR (IV) then ■ '- - obtained in which one / the substituent R * in the usual way converted into an amino group. 11. Alternative method for the preparation of the compounds according to claim 1 to 9 »marked z-eicbnet, that one e ^ -R'-substituted phenylacetic acid or one their derivatives with a 7-amino-3-methyl- Δ -cephem ~ 4- _ 4 _ 0 0 9 8 17/1911 - r - / J5 1A-36 843 carboxylic acid ester or one of its derivatives according to the Reaction scheme -CH-CO-Y '+ H ₀ N-CH CH CH ₀ I'll H CH ₀ - Ill ^ r O = CN .C-CH- ^ * f \ y ^J \ ^ ι I ^^ (IV) (V) (VI) COO-CH ₂ -OCO-R reacted, where in the above formulas R and R ^{1 have} the above meaning and -CO-Y ^{1 stands} for a radical which is capable of reacting with the NHp group in compound VI to form a -CO-NH bridge, so that, if R ^{1 is} an amino group, a compound according to Claim 1 and, if R ^{1 is} not an amino group, a compound according to formula (IV) is obtained as an intermediate in which the substituent R 'is then converted into a Amino group transferred .. 12. Alternative process for the preparation of the compounds according to claim 1 to 9t characterized in that an ester of a ^ -R ¹ -substituted benzylpenicillin according to formula (VIl) CHCOXH-CII CH ^ - "/" _ττ λ j J j 1 ^ ^η -χ . (VII) R «CO N. wherein R and R ^{1 have} the above meaning - -2u of a compound of the formula (VIII) <t »V- N, CHCONU-CH CIl C ^ _n (VIII) ^l 3 R ¹ CO ft OH-COOCiUOCOR ί. 009817 / 1911- _ ₅ _ BATH ORIGINAL - IT - _% 1A-36 843 Ao oxidized and this by heating in an inert solution medium rearranged in the presence of an acid catalyst to a compound of formula (IV) as an intermediate, whereupon The substituents R <of this intermediate product are converted into an amino group in the usual way. 13 «Method according to claim 11, characterized in that as represented by the formula (V) Reactant D (-) - «* - Phenylglycyl chloride hydrochloride is used. 14. The method according to claim 11, characterized in that a mixed anhydride as a reactant represented by the formula (V)
Enamine of o ^ -henylglycine is used. 15 «Method according to claim 10, 11 and 12, characterized
characterized in that the substituents R ^{1 of} the compounds of formula (IV) by reduction into a
Amino group transferred. 16. The method according to claim 10, 11 or 12, characterized
characterized in that the substituent R ¹ in compounds of formula (IV) by hydrolysis into a
Amino group transferred. 17. The method according to claim 12, characterized in that the oxidation of the compound
according to formula (VII) since hydrogen peroxide is carried out. 18. The method according to claim 12, characterized in _{that v} that the oxidation of the compound
carries out according to formula (VII) with metaperiodic acid. 009817/191 1