DE2449834A1 - CEPHEMDER DERIVATIVES AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

Cephem derivatives and processes for their preparation

The invention relates to cephem derivatives.

The compounds are antibacterial agents that are used as animal feed additives, as therapeutic agents to combat infectious Diseases caused by gram-negative and gram-negative bacteria for the sterilization of hospital surfaces and the like, as well as new intermediates for their production. In particular, the antibacterial ones Compounds of the invention acylated derivatives VDn 7-Amino-3-substituted- <il -cephem compounds, the 5-tetrazolyl groups at the it position.

Although there are large numbers of cephem derivatives for use as antibacterial agents have been proposed, there is still a need for new agents.

The antibacterial compounds of the invention and the intermediates, from which they are produced by acylation are new and cannot be found in the prior art. In US Patents 3,427,3o2 and 3,465B B74, penam derivatives are used which contain a tetrazolyl group as part of the 6-acylamino substituent, and in Japanese

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-Z-

Patent publication 71-385o3 describes cephem derivative / ate, the one tetrazoly group as part of the 7-acylamine substituent contain. In addition, cephem derivatives are known which have a tetrazolylthiomethyl group at the 3-position (U.S. Patent 3,641 o21) · However, the compounds of the invention are novel in that they contain a tetrazolyl group., which is bound directly to the cephem nucleus.

About the biological and non-biological uses of tetrazoles is recently from Benson, "Heterocyclic Compounds, "Elderfield, Ed., Volume 8, John Wiley & Sons, Inc., New York, IM.Y., 1967, Chapter 1 reported during one Compilation of the Cephem lieter door in the US patent 3 766 176 is included.

Ea has now been found that certain 7-acylamina-3-Bubsti-

3 2

tuierte - ^ - Ctetrazol-S-yl) - - and - -cepeheme valuable intermediates that lead to the manufacture of these antibiotics.

A preferred group of compounds which are suitable as intermediates corresponds to the formula

RWH

wherein R is hydrogen or an amino protecting group selected from the group selected from Z.ZjZ-Trichloräthaxycarbonyl, 2,2,2-TribromMthoxycarbonyl, Benzyloxycarbonyl and

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where R ₃ , R and R _{5 are} each hydrogen, ChlDr, bromine, fluorine, methyl, methaxy or phenyl, A is hydrogen, acetaxy, 1-methyltetrazolylthio or 2-methyl-1,3, it-thiadiazalyl-5-thio and R "is a potential tetrazole protecting group selected from the group consisting of

wherein R; - hydrogen, alkyl having 1 to 3 carbon atoms or

Phenyl, R _{7 is} hydroxy, methoxy, alkanoyloxy with 2 to h carbon atoms or benzyloxy and R _{5 is} hydrogen, hydroxy, fluorine, chlorine, bromine, ÜDd, methyl, methoxy, alkynoyloxy with 2 to h carbon atoms, phenyl or benzyloxy, and

consists, marine R "and R ^ are each hydrogen or methyl and X Oxygen or Scuiefel is.

A second preferred class are intermediates of the formulas

and the salts thereof, wherein R is hydrogen or an amino protecting group is selected from the group consisting of 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, benzyloxycarbonyl and

R ₅

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consists, uiorin R-, R, and R ₁ . are each hydrogen, chlorine, bromine, fluorine, methyl, methoxy or phenyl, A is hydrogen, acetoxy, i-methyl-5-tetrazolylthio or 2-methyl-1 _T 3, £ f-thiadiazolyl-5-thio, R. hydrogen , AlkynoylDxyipethyl with 3 to 6 carbon atoms, 1- (alkynoyloxy) ethyl with k to 7 carbon atoms, methoxymethyl or phthalidyl and R _{11 is} hydrogen, alkanoyloxymethyl with 3 to 6 carbon atoms, 1-CAlkynoyloxy) ethyl with k to 7 carbon atoms, methoxymethyl, Is phthalidyl or a potential tetrazole protecting group selected from the group consisting of

8th
ujorin R _r hydrogen, alkyl with 1 to 3 carbon atoms or

Phenyl, R "is hydroxy, methoxy, alkynoyloxy with 2 to h carbon atoms or benzyloxy and R" is hydrogen, hydroxy, fluorine, chlorine, bromine, iodine, methyl, methoxy, alkanoyloxy with 2 to k carbon atoms, phenyl or benzyloxy, and

where Rg and R _{1 are} each hydrogen or methyl and X is sulfur or oxygen.

A third preferred class of cephem derivatives and salts of which correspond to the formulas

B R

Ar [Ch] ₁ cimh ^ s Ar / chL cimh

■ FQ

^and

NS WR.

N = N

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uorin Ar cyano, bromine, phenyl, mono- or disubstituted phenyl, ujorin every substituent liJasserstaff, fluorine, chlorine, Bom, amino, Methoxy is methyl, phenoxy, phenylthio, pyridylthio, Thienyl, 2-methyl-1,3,4-thiadiazol-5-ylthio or 1-tetrazolyl is, Q. hydrogen, hydroxy, azide, amino or carboxy is ^ η is an integer of ü or 1, A is hydrogen, acetoxy, i-methyltetrazal-5-ylthio or 2-methyl-1,3-4-thiadiazal-5-ylthia and R. is hydrogen, alkynoylaxymethyl with 3 to G Carbon atoms, methoxymethyl or phthylidyl, among the A prerequisite, however, that if Ar is pyridylthio, phenoxy, phenylthio, S-methyl-i ^ jA-thiadiazal-S-ylthiomethyl, cyano or bromine and η is 1, Q is hydrogen or carboxy.

The invention also includes compounds of the third preferred class, uiorin A, Q, η and R. have the meaning given above and Ar is selected from the group consisting of hydrogen, alkyl having 1 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms, Cyioalkyl with 3 to 7 carbon atoms, cycloalkenyl with 5 to 8 carbon atoms, cycloheptatrienyl, 1, * t-cyclohexydienyl, 1-aminocyclaalkyl with k to 7 carbon atoms, 5-methy1-3-pheny1-4-isoxazoly1, 5-methyl-3- (o-chloropheny1) -k isaxyzolyl, 5-methyl-3- (2,6-dichlorophenyl) - '+ - isaxyzolyl, 5-methyl-3- (2-chloro-6-fluorophenyl) -if-disoxazolyl, Z- Alkoxy-1-naphthyl with 1 to k carbon atoms in the alkoxy, sydnonyl, furuyl, pyridyl, thiazolyl, isothiazolyl, pyrimidinyl, triazolyl, imidazolyl, pyrazolyl, substituted phenoxy, substituted phenylthide, substituted pyridylthio, substituted thienyl, substituted pyridyl, substituted tetrazolyl, substituted thiazolyl, substituted isothiazo lyl, substituted pyrimidinyl, substituted triazolyl, substituted imidazolyl and substituted pyrazolyl, each substituted group can be substituted with up to 2 substituents selected from the group consisting of fluorine, chlorine, bromine, hydroxy, hydroxymethyl, amino, N , l \ l-dialkylamino with 1 to k carbon atoms in each alkyl group, alkyl with 1 to k carbon atoms, aminomethyl, aminoethyl,

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Alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to * t carbon atoms, 2-aminoethoxy and N-alkylamina with 1 to k carbon atoms.

As will be readily apparent to those skilled in the art, the o (carbon atom the side chain of the antibacterial cephem to which the amino or hydroxyl group (Q) is an asymmetrical ' Carbon atom that allows the existence of two optically active isomers, i.e. the D and L diastereoisomers, so the racemate form (DL form) also allows. In accordance with previous findings on the activity of such cephem compounds with asymmetric ^ carbon atoms the compounds of the invention with the D configuration are more active than those with the L configuration and constitute preferred compounds represent obujohl the L and DL forms of compounds of the invention belong to the subject matter of the invention.

With regard to the asymmetrical centers, it should be admonished that several of them in the Δ core, the basic block of which the Compounds of the invention derived are present. These enable further isomers are in the present case not of importance because the 7-amino-Δ-cephetrMtcarboxylic acid used, which leads to the products of the invention, is produced by fermentation and always has a configuration.

The term "tetrazole protecting group" or "tetrazolylcephem nitrogen protecting group" is intended to cover all groups which, as known to or apparent to those skilled in the art, (a) are used can be used to make the connections where-

2 rin R is an amino protecting group and R is said tetrazalylcephem nitrogen group is to enable a process that is derived from 7- (protected amino) -cephem-it-carboxylic acid, as described below, and (b)

2 from "said compounds, wherein R is said tetrazolylcephem nitrogen protecting group and R is selected from the group consisting of hydrogen and an amine protective group,

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using a method in which the cephemrine system is essentially preserved, can be removed. from More important for the invention is the ability of the TetrazDlylcephemsticksicffverbindungen protective group, perform a special function, as discussed in more detail below, than the exact chemical structure, and the novelty of the antibacterial Means of the invention does not depend on the structure the protecting group. The choice and identification of suitable Protecting groups can be easily and simply implemented by those skilled in the art met or carried out, and subsequently Examples of various suitable groups are given.

According to one embodiment of the invention, a method proposed for the preparation of such compounds in which the amino group is acylated in the 7-position.

According to another embodiment of the invention, intermediates in which the amino group in the 7-position is protected by an amino protective group by converted an amide at the Λ-position into a tetrazolyl group is, while at the same time the amide and the obtained tetrazolyl group by a tetrazolylcephem nitrogen protecting group to be protected.

The invention relates to new and novel compounds useful as antibacterial agents and as intermediates in the manufacture of these agents. For the sake of simplicity, these connections are referred to as / i. -Cephem derivatives. The term " / \> -Cephem" has been defined by Morin et al in the Journal of the American Chemical Society, Bk__, 3itoo (1962) so that underneath it the structure

is to be understood. Using this terminology, this becomes

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-B-

Known antibiotic CEphalospDrin G as 7- (5-Amino-5-carbaxyvaleramido) -3-acetoxymethyl - / \ -cephem-ff-carboxylic acid bs-ZBichriEt.

244983A

Many compounds of the invention are also 5-substituted Tetrazoles, which can exist in partly isomeric farms, namely

"No

As will be apparent to those skilled in the art, there are two forms ωεηπ the substitute L is hydrogen, in a dynamic, tautomeric equilibrium mixture. In that case, however, in which L means a substituent other than hydrogen, habsn the two forms have different chemical structures and do not transform into one another spontaneously.

In the case of the manufacture of the cephem admixture products and antibacterial Methods used in the invention are suitable for manufacturing. The first production is as follows:

C- (MHR ²

RIMH

/ IM-F

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NO

11

Il

Ar JtHi. CNH

IN THE

CH ₂ A

C -

NR ₁

NN 6

uiorin R, A, R ₂ , Ar, π and Q have the meanings given above and R. and R ^ are each hydrogen.

From an experimental point of view, the procedure is as follows: 7-carboxamida-3-substituted- ^ -cephem- ^ - carbanic acids (1), produced by acylation of the corresponding 7-aminocephem, ujenden into the it-carbamcyl compounds (2) by reaction of the

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4-carboxy part, activated in the form of the 2,4-dinitrophenol ester, with a suitable amine, R ^ IMhL, converted.

The compound 2, in which R is derived from triphenylmethyl, is either by alkylation of the 7-amino compound and subsequent Formation of the it-carbamoyl group, as stated above, or by selectively removing the R-acyl group from compounds of structure 2, such as removal of the 2,2,2-trihaloethoxycarbonyl group and use of acetic acid and zinc dust, and subsequent alkylation of the V-amino - ^ - carbarnoylcephem compound made with the required triphenylmethyl chloride.

The conversion of 2 to 3 requires the conversion of the 4-carbamoyl part of 2 into the corresponding iminochloride and then Implementation of the same with azide. The formation of the iminochloride will The easiest way is to use phosgene or phasphorus pentachloride in a reaction-inert solvent, uie e.g. chloroform, carried out during the reaction νση the imino chloride with the salt of hydrazoic acid and tetramethylguanidine to the Formation of the tetrazole ring leads. Lüie apparent to the expert many azide-yielding materials are available, which can also be used in this reaction, and such materials include salts of hydrazoic acid with inorganic bases, such as I sodium azide, lithium azide, Halium azide and ammonium azide. Because of the explosive nature of many Metal azides, it is advantageous, and in this case is preferred, to use azides formed from organic bases. Tetramethylguanidine hydrogen azide is particularly suitable for this purpose.

The subsequent process stage for converting 3 to 4 requires the removal of the "amino protecting group" R. The removal The reaction conditions applied to this group are determined by the nature of the group to be removed. As above is indicated, the 2,2,2-Trihalogenäthaxycarbonylteil in simply using zinc dust and acetic acid

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removed. The triphenylmethyl group is removed using formic acid and the benzoxycarbdenum group is removed by treating 3 with a mixture of trifluoroacetic acid / anisal (i +: 1, v / v) and trifluoromethylsulfanoic acid. It is advantageous if, in this last method the reaction at Eisbaritemperaturen ^(D 0 C) and for a limited period of time, in general, for ^ -6 minutes.The, tjird. If higher temperatures are used, such as 25-ka C, or if longer reaction times are used, e.g. 1-3 hours, it is possible to remove the "tetrazole blocking group" at the same time,

After the "amino protective group" has been removed, the selected FL group is removed by treating k or the p-taluenesulfonic acid salt thereof with the above-mentioned mixture of trifluoroacetic acid / anisole.

Acylation of 5 with the appropriate carboxylic acid, activated either in the form of an acid halide, activated ester, mixed Anhydride, or an acid with a carbodiimide, leads to the antibacterial compounds of the invention.

Uie to the skilled artisan will appreciate that other Uorhandensein funktianeller groups in the Acylierungssäure may require that these groups be blocked or masked in order to prevent so that these groups participate in exercises implementation. When the axylation is complete, the groups can be unblocked.

For example, for the preparation of compounds of the formula G, it is warin Q Amino is required for the amino group to block is, preferably with a tert-butoxycarbonyl group. the Blockierunosgruppe is then after completion of the acylation removed by treatment with acid. A similar procedure is required when Q is hydroxy. In this case a Formyl group used to block the hydroxy group.

Compounds of the formula G in which Ar is bromine, η is 1 and

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Q is hydrogen, have an antibacterial effect and can also be reacted with mercaptans to still to get more antibacterial compounds.

The starting materials for the process stages are either are available in the form of commercially available reagents or can according to methods described in the literature getting produced. E.g. the 7-amino-3-substituted

-cephem-if-carbon acids described in US Pat. No. 3,641,021, The amines RpNHr can be used after one or more Procedure, as described by Wagner and Zook in "Synthetic Organic Chemistry ", John Wiley and Sons, Inc., New York, IMW, 1956, Chapter 24, pages 653-727 are prepared and the triphenylmethyl chlorides used are prepared after the van Bachmann, Drg. Synthesis, 23, 100 (1943) Procedure received.

The second production route, which is used for the extraction of the antibacterial Compounds of the invention and the intermediates suitable for their preparation is illustrated as follows:

RNH ^ S. RNH S

TY ^X ] ■> - ■■ ι

jl \ l. ,. ^ - CH ₃ ■? ! ..- N- / CH ₃

D C0 ' ₂ HO CO ^ H

RNH D. N S. ck X ₁ Ni \ - / ^N \

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RNH,

RNH

10

RNH

N JT-H ₁ N

11

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H N

12th

N-N-R.

13th

ORIGINAL INSPECTED

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Ar

= äT N -N '-R

Ar

COKH

14th

.N

I.

-N -H:

ORIGINAL INSPECTED

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2U9834

[OHl _n O

Ar K) Hi ÜONH,

^ M

OH ₂ A

y \ -

^ Nt = T N

N ^Ν Ν

\-1

Ar

^ ^Ν \ ^ ^ CH _n A

f ^ Nh

- N

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-M-

in which R, A, Rp, Ar, π and Q have the meanings given above and R. is methoxymethyl.

In practice, the 7-acylamino-3-methyl-A is used -cephem - ^ - catboxylic acid 1 to the corresponding 7-acylamino-

2
3-methyl-A -cephem - ^ - carboxylic acid 7 isamerized, the activation of the 3-methyl group being taken into account in subsequent reactions.

The formation of the 4-carbamoy group in compounds of the formula B. It is accomplished by procedures similar to those described above are similar to the first manufacturing route.

The connections are made in a manner analogous to the first production method 8 in tetrazoles of the formula 9 according to the same l / experienced converted, the formation of the iminochloride and its subsequent reaction with azide contains.

Removal of the "tetrazole protecting group" from the compounds 9 with the formation of υαπ 1o tjird in the above in the first production meg carried out in the specified manner. The compounds 9 are grounded with trifluoroacetic acid / anisole at 3o-5o C for several Hours brought in touch.

Before the activated 3-methyl substituent is brominated the tetrazole group of 1o by alkylation with chloromethyl-methyl ether blocked. üJie is apparent to the expert, the Alkylation at the i \ L-position as well as at the I \ L-position occur. This also applies in practice, the alkylation predominantly taking place at the I \ L position. Because the blocking group is at a later stage in the process is removed, it is advisable not to separate the two isomers after the alkylation. Also serve both isomers have the same object and are therefore in the same way Way suitable.

The 3-methyl substituent of 11 is combined with N-bromosuccinimide in Presence of a peroxide by a known bromination method

ORIGIMAL INSPECTED

5 0 9 8 18/1173

- Ία -

brominated. When the bromination is complete, the 3-bromomethyl compound is formed not isolated, but with a special nucleophile Reactants, such as a mercaptan or an acetate salt, reacted to form 12.

The "amine protecting group" 12 is made according to the above in the first manufacturing route specified methods removed.

The acylation of 13 is carried out in the same way using the procedure given above, also with any functional group on the acylating acid protected or blocked if such a group Acylation reaction with the 7-amino group of A-Cephem (13) can disturb.

2 3

Risomerization of the Δ «bond of 14 to the Δ position is achieved by oxidizing the sulfur atom of the cephem molecule with a peracid, such as, for example, m-chloro overaoic acid, and a compound of the formula 15 is obtained. Treatment of 15 with tin (II) chloride and acetyl chloride leads to the formation of the desired / ± cephem of formula 16.

The IM. and I \ L blocking groups are made from 16 under application of Trifluoroessiqäure / Ani.sol, as indicated above, removed, urti the blocking groups from the acyl portion of the 7-acylamino group are also removed, if present.

A modification of the second preparation route allows the preparation of compounds in which R ^ is from phthalidyl or an alkynoyloxymethyl or 1- (alkynoyloxy) ethyl group. In the process leading to the preparation of these compounds, the tetrazole portion of 10 is mixed with an appropriate one Alkynoyloxymethyl halide or 1- (alkynaylaxy) -ethyl halide (Ulich et al., J. Am. Chem. Sac, 43, 66a (1921) and Euranto et al., Acta. Chem. Scand., 2t3, 1273 (1966) or phthalidyl halide instead alkylated by chloromethyl methyl ether. The phthalidyl,

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Alkynoyloxymethyl- and 1- (alkynnylaxy) ethyl-substituted tetrazoles of the end products represent proactive substance norms of the end products and, although they are inactive or have a relatively / low activity against microorganisms per se, are converted to the free tetrazole (R ₁ = H), when injected parenterally into an animal or human. The rate of metabolic conversion of these compounds to the free tetrazole is such that an ineffective and prolonged sustained concentration of the free tetrazole is present in the animal body. Such compounds therefore act as depot substances for the antibacterial agent having a free tetrazole group.

Regarding the antibacterial activity of these proactive substances it has been found that both the KL and I \ L substituted Isomers are active and suitable.

if with phthalidyl, alkynoyloxymethyl or i- (alkynoyloxy) Ethyl l \ L / l \ L-substituted tetrazoles by the second production route are obtained, the reaction step (16-6-) is omitted and only the blocking groups from the acyl moiety removed from the side chain.

Alternative methods for the production of these antibacterial products which carry a phthalidyl, alkynoyloxymethyl or 1- (alkynayloxy) ethyl group on the I \ L / I \ L position of the tetrazole part are available. One method involves alkylating the base salt of an appropriate 7-amino-3-substituted-£ f- (tetrazol-5-yl) -A-cephem and then acylating the 7-amino group as indicated above. In the second method, the base salt of a suitable 7-acylamino-3-substituted-if- (etrazol-5-yl-) -L • -cephem is alkylated. In both methods, the blocking groups are removed from the side chain if necessary.

The second sequence of reactions leading to the intermediates and the end product of the invention are preferred

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-Zd-

"AminoblckierunqsgruppEn" 2,2,2-trihaloethaxycarbonyl groups.

As indicated above, a characteristic feature of the acidic compounds of the invention, ie, those in which R. or R _{11 is} H or Q is carboxy, is their ability to form bffiLs salts. Acidic compounds of the invention are converted into basic salts by reacting said acidic compound with a suitable base in an aqueous or non-aqueous medium. Such basic reactants, which are suitable for the production of the said salts, can be of various types, including bases, including organic amines, ammonia, alkali hydroxides, carbonates, carbonates, hydrides and alkoxides, and also alkaline earth hydroxides and hydrides , alkoxides and carbonates. Typical of such bases are ammonia, primary amines, for example m-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethylamine, dctylamine, secondary amines, for example dicyclohexylamine, and tertiary amines, and for example diethy / aniline , IM-methylpyrrolidone, N-methylmorpholine and 1,5-diazabicyclo- £ if, 3, a7-5-nanes, sodium hydroxide, potassium hydroxide, ammonium hydroxide, I sodium ethoxide, halium methoxide, magnesium hydroxide, calcium hydride and barium hydroxide.

As will be apparent to those skilled in the art, there are some compounds of the invention sufficiently basic, and such end products in where Q is amino to form acid addition salts. These Acid addition salts, in particular the pharmaceutically suitable acid addition salts, are also a subject of the invention.

In addition, those admixtures of the invention which contain a free 7-amino group or a free tetrazole group (R ₁ , R ₁₁ = H) are also able to form acid addition salts and base salts. These salts are either suitable for characterizing these intermediates, for example the acid addition salts, or they are used in reactions, for example in the alkylation of the base salt of the tetrazoles.

S 0 9 8 1 8/1 1 7 3

In utilizing the chemotherapeutic activity of those compounds of the invention which form basic salts, it is of course advantageous to use pharmaceutically acceptable salts. Although water insolubility, high toxicity, or lack of crystallinity make some types of salt unsuitable or less suitable for direct use for a particular pharmaceutical application, the water-insoluble or toxic salts can be converted into the corresponding acids by decomposing the salts or, on the other hand, into any desired pharmaceutical form compatible basic salt are transferred. The pharmaceutically suitable salts include, preferably, the sodium, aluminum, potassium, calcium, magnesium, ammonium and substituted ammonium salts, such as, for example, of procaine, dibenzylamine, III, bis (dehydroabietyl) ethylenediamine, 1 -Ephenamine, M-ethylpiperidine, N-benzyl-B-phenethylamine, IM, IM ¹ -dibenzylethylenediamine, triethylamine and also the salts with other amines that have been bendzt to form salts with cephemones.

The new cephms described here show in vitro activity to many microorganisms, including gram positive and gram negative bacteria. The effectiveness of these compounds can easily be in vitro testing against various organisms in a brain-heart infusion medium with the standard two-fold serial dilution technique. The in vitro activity the connections described here does this for the local application in farm of ointments, creams and the like. ßder suitable for sterilization purposes, such as items in hospital rooms.

The new cephems of the invention are also effective in vivo antibacterial agents in animals and humans, not only for parenteral use but also for oral use.

The doctor will ultimately determine the dosage that is right for you is most suitable for specific patients. Such a dosage

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varies with the altar, dsm weight, and the sensitivity of the individual patient and also with the nature and extent of the Symptoms, the type of bacterial infection being treated and the pharmacodynamic properties of the individual too administering agent. It udrd commonly found that when the agent is administered orally, larger amounts of the active Constituents are required to give the same level as that achieved by smaller amounts in the case of parenteral administration achieved.

Taking into account the factors given above, it can be assumed that an effective daily oral dose of the compounds of the invention in humans corresponds to about 5-1,000 mg / kg per day, with a preferred range being 250-750 mg / kg per day in a single dose dider is in divided doses, and that a parenteral dose is 25-5od mg / kg per day with a preferred range of about 125- kaa mg / kg per day and such a dosage can be effective in alleviating the symptoms of the infection. These values are provided for illustrative purposes only and of course there may be individual cases in which higher or lower dosage ranges are of valuable service.

The preferred compounds of the invention which are useful as intermediates are 7- (2 ', 2 ^l , 2'-trichloroethoxycarboxamido) -3-methyl-'t- / 1- (p-methoxybenzyl) carbamoyl7 -Δ-cephem , 7- (Benzyloxycarboxamido) -3-methyl-it- tl \ J- (p-methoxybenzyl) carbamoyly - ^ -cephem, 7 - ((\ i-triphenylmethylamino) -3-methyl-4- I ^ IM-Cp- methaxybenzyDcarbamoyiy- ^ -cephem, & 7- (2 ·, 2 ', 2' »tri. chloroethaxycarboxamido) -3-acetoxymethyl) - ⁱ f- / l \ l- (p-methoxybenzyl) carbamoyl _ / - Δ -cephem, 7 - (Benzoyloxycarboxamido) -3-acetoxymethyl- -k- // iM-Cp-methoxybenzyDcarbamayl 7-Δ -cephem, 7- (l \ l-triphenyl-

methylamino) -3-acetoxymethyl-4- / "iM-Cp-methoxybsnzyDcarbamayll 3 * - J

-A -cephem, 7-2 ¹ , 2 ^l _l 2 ^I -Trichlorethoxycarboxamido) -3-methyl-

4-AlM-Cp-mEthoxybEnzyDcarbamoylJ-4 -cephem, 7- (2 ', 2', 2'-TrI-chlDrathoxycarboxamido) -3-methyl- ⁱ f- £ i- (p-methDxybenzyl) tetra- - / ^ - cephem, 7 - ((\ l-triphenylaniino) -3-methyl-4- / 1- (p-

S09818 / 1173

methyxybenzyl) tetrazol-5-yl7 ~ Δ-cephsm ,. 7-Amino-3-methyl- ⁱ t- ^ i-Cp-methoxybenzyOtBtrazol-B-yl- / -Δ -CEphem, 7- (BenzyloxynarbDxamidD) -3-acetnxymBthyl-ff- ^ i-Cp-methoxybenzyl) tetrazal-5 -yl / -Ä -cephem., 7- (2 ', 2' ^ '- TrichlaräthoxycarbaxamidoO-S-ÄcetüxymEthyl-4- £ 1-p-mBthaxybenzyl) tBtrazDl-5-yl_ / - Ä -cephem, 7-amineD ~ 3 ~ acetaxymethyl-if- ^ 1-p-mEthnxybenzyl) tetrazDl-5-yiy ~ Δ CEphem, 7-Benzyloxycarboxamido) -3- (i-methyltetrazol-5-ylthianiEthyD-it- / i ^ p-methDxybEnzyDtBtrazal-S-yl / -A -cephem, 7- (2 ^I , 2 ^l , 2 ^I -TrichlDrathaxycarbDxaniidD) -3- (2-methyl-1,3, itthiadiazcl-5-ylthiomethyl) -4- £ i- (p-niEthoxybenzyl) tEtrazole -5-yl / - ^ v -CEphEm, 7-Amina-3- (2-niethyl-1,3,4-thiadiazal-5-ylthiD-, ethyl) -l · - ^ (p-methoxybenzyl) tetrazDl-5 -yl / -A -cephem, 6- (2 ^!, 2 ', 2 ^I -TrichloräthGxycarbDxamidü) -3-mBthyl-'4- / i- (p-methoxybenzyl) tetrazQl-5-ylJ ~ Α -cephem, 7- (BEnzylDxycarbDxamidD) -3- (2-mEthyl) -i / Sj ^ -thiadiazol-S-ylthiDmEthyD-if- / i- (p-methoxybenzyl) tetrazal-5-yl_ / -Δ -CEphern, 7-aminD-3- methyl-4- (tEtrazDl-5-yl- _i ^ -cephem, 7-amineD-3-acetDxymEthyl-4- (tEtrazDl-5-yl) -A -cephem, 7-Amina-3- (2-mEthy 1-1,3, i + -thiadiazol-5-yl-thiomEthyl) -it- (iEtrazal-5-yl) - Δ . -cephEm, 7-AminD-3- (1-mEthyltetrazal-5-ylthiomEthyl) - ⁱ t- (tetrazDl-5-yl) -Δ-csphem, 7-C2 ¹ , 2 '^' - TrichlcräthDxycarboxamidD) -3-mBthyl -if- (tEtrazDl-5-yl) -A ² -cEphEm, 7- (Z », 2 ', 2'-TrichloräthaxycarbDxamido) -3-methyl-4- £ i-mBthcxymEthyl) -tetrazol-5-yl / - j ^ -CEphem, 7- (2 ^!, 2 ', 2 ^l -TrichloräthoxycarbDxamido) -3-methyl- ⁱ t-

r ι 2

/ 2- (mEthoxymEthyl) -tEtrazol-5-yl / -Δ -csphem, 7-amino-3-methyl-it-

ri- (mEthnxymEthyl) -tEtrazal-5-ylJ -Λ -cEphsm, 7-Amino-3-mEthyl-i * - £ 2- (rnethDxymEthyl) -tetrazQl-5-yl7 -Δ -cEphsm, 7-Amino-3- acEtDxymethyl-4- £ i- (mEthoxymethyl) tstrazal-5-yl7 - Δ -csphEiii, 7-amino-3-acEtaxymBthyl- ^ - £ i- (methaxymethyl) -tetrazal-5-yl_y-A -cephem, 7-amineD -3- (1-methyltetrazDl-5-ylthiDmBthyI) - ^ f- //! - (mEthc-xymethyl) -tetrazol-5-ylJ - / \ -cephem, 7 »AminG-3- (1-methyltetrazal-5- ylthiamethyl) - '+ - ^ 2- (methDxymBthyl) -tetrazal-5-yl7- A ² -7-AminD-3- (2-methyl-1,3, it-thiadia

7 2 * "-

mEthDxymethyl) tEtrazol-5-yl / - ^ -csphEm, 7-AminD-3- (2-methyl-1,3, it-thiadiazGl-5-ylthiDmethy l) -it- j_ 2- (methaxymethyl) tetrazol-5- ylJ-A ^Z -CBphEm, 7- (2 ', 2' ^ '

10 9 8 18/1173

bromoethyl-if- £ i-methoxymethyl) tetrazol-5-yl'7 - / \ -cephem and 7- (2, 2 ', 2 ^l -TrichlDrathDxycarbDxamida) -3-brammBthyl- ⁱ t- / ~ 2-

"7 2
methoxymethyl) tetrazol-5-yl / -Δ -CBphem.

The preferred antibacterial agents of the invention are 7-phenylacetamido-3-methyl-4- (tetrazol-5-yl) -A -cephem, 7-phenoxyacetamido-3-methyl- ^ - (tetrazol-5-yl) -A -cephem , 7- (2-Thienylacetamido) -3-methyl- ^£ f- (tEtrazal-5-yl) -Ä -cephem, 7-phenylacetamideD ^ -methyl-if- / 2- (pivalDylDxymethyl) tetrazDl-5-yl_y-Δ -cephem, 7-Phenaxyacetaniida-3-methyl-4- Z ^ 2- (pi \ / alDylDxy-Δ -cephem, 7-PhenDxyacä; aniida-3-methyl- ⁱ t - / "2- (pi \ / alDyloxymGthyl) ttitrazül-5-yly -Δ-cephem and 7- (2-thienylacetamideD) -3-methyl-4- ^ 2-pivalDylaxymethyl) tetrazDl-5-yl7 -A -cephem.

The values for the antibiotic effectiveness of a number of Compounds of the invention against Streptococcus pyoqenes are given in the table below. The tests were carried out under standardized conditions under which in a nutrient broth containing various concentrations of the Test material contained the specified specific organism inoculated and the minimum concentration (MIC) was determined and recorded at which a growth of the concerned Organism did not take place.

Table 1

R ¹ CDNH

609818/1173

-CD-

. In \ / itro

R A MIC (ng / ml) original; mcg./ml.)

C ₆ H ₅ DCH ₂ - ^ H H HC- N-CH -
/ 'I
N IM
V H DC _C H, -CH-
b D ι
DH H D-it-HOC ^ -H, CH-
6 k ι H

C _C H _C CH-b b »

H o, 78

3.1

6.2

1.5 1.5

1.5

N N

j- K

'■ ^ _S / ~ _SCH _ H o, 78

^D - ^C 6 ^H 5 ^Ch | - NN

OH -S- ^ A 3.12

^X IM —N ι CH ₃

[fX.CHg OCOCH ₃ 1.6

₄ N - IM

F -S- (I / _D , 1

^{N N} - N

509818/1173

-2G-

The novel antibacterial agents of the invention are in one A number of highly effective infections caused by vulnerable gram-negative and gram-positive bacteria in poultry and animals and humans are caused. For these purposes, the pure materials or mixtures thereof with other antibiotics be applied. They can be used alone or in combination with pharmaceutical carriers according to the chosen route of administration and administered in accordance with standard pharmaceutical practice, e.g., they can be administered orally in the form of tablets that contain excipients such as starch, milk sugar, certain clays, etc., or are used in capsules, alone or in admixture with the same or corresponding excipients. You can also take it orally in the form of Elixirs or suspensions that contain flavorings or colorings may be administered, or parenterally, i.e. intramuscularly or subcutaneously, injected. For parenteral Application, they are best used in the form of a sterile solution, which can either be aqueous, e.g. a solution in water, isotonic saline solution, isotonic dextrose solution, Ringer's solution, or non-aqueous, e.g. a solution in fatty oils of vegetable origin (cottonseed oil, Peanut oil, corn oil, sesame oil) or other non-aqueous carriers that affect the therapeutic effectiveness of the respective Do not affect the agent and are non-toxic in the volume or proportion used (glycerine, propylene glycol, Sorbitol). In addition, it is advantageous to prepare means necessary for preparation of solutions before administration on site and place are suitable, ^ all agents can be liquid diluents, such as propylene glycol, diethyl carbonate, glycerine, sorbitol, etc., agents for buffering and also local anesthetics and inorganic salts to provide the pharmacological desired To achieve properties included.

The following examples serve only to further illustrate the invention. The infrared spectra (IR spectra) are below Use of potassium bromide disks (KBr disks) or IMajol

509818/1173

Gauze measured, and the characteristic absorption bands

-1
are given in wave numbers (cm). The nuclear magnetic reaanance spectra (NMR) are determined at 60 MHz for solutions in deutero-chloroform, (CDCL :,), perdeuterodimethylsulfaxide (DMSO-dg) and the deuterium oxide (D "D), and the maximum digits are determined in parts per million (ppm) / falling from (downfield from) tetramethylsilane Dder sodium-ZjZ-dimethyl-Z-silapentane-S-sulfanate / expressed. The following abbreviations are used for the maximum farms: s-singlet, d = doublet, t = triplet, g = quartet, m = multiplet.

Example 1 .

7- (2 ', 2', 2 ^I -Trichloräthoxycarboxamido) -3-rnethyl- ^t t- £ [\ l- (p-methoxybenzyDcarbamoyl / -Δ -cephem

A. 7- (2 ', 2', 2'-Trichloräthoxycarboxamido) -3-methyl-A -cephem - ^ - carbon acid

In a suspension of 555 g of 7-Amina-3-methyl - / \ -cephem-it-carboxylic acid in 16.65 l of an acetone / water solution (1: 2) 600 ρ I sodium bicarbonate were added and the mixture at room temperature Stirred for 30 minutes, the resulting solution over a Period of 5 minutes. 600 g of 2,2,2-trichlara ethyoxycarbonyl chloride add and stir the mixture for a further 18 hours. The mixture was then extracted with methylene chloride, the aqueous layer separated and acidified to pH 2 with 5% hydrogen chloride solution, the acidified aqueous solution with fresh methylene chloride (3 χ 1.5 1 and 2 χ 500 ml) extracted and the combined organic Layers successively with 5 jU hydrochloric acid (2 500 ml) and Washed water (3 × 500 ml), then dried over magnesium sulfate. The thick Dl remaining after the solvent had been stripped off in vacuo was dissolved in 2 l of diethyl ether and dissolved in 1.5 1 petroleum ether added dropwise. The intermediate crystallized slowly out of the solution (yield 7o%)

NMR (DMSOd 6): I = 5, if (q) 1H;, 5.1 (d) 1H; ^, B5 (s) 1H; 3, i * 2 (s)

2H; 2, o (s) 3H.

509818/1173

-1
IR (HBr disk): / - = 1770 cm (β-lactam carbonyl).

9 max

The product was dissolved in a dioxane solution without further purification stored for further use.

B. 7- (Z ', 2'2'-Trichlorethoxycarboxamido ^ -methyl · - ^ - / * N-jjp-methoxybenzyD-carbamoyl · / -Δ -cephem

A solution H with 1.84 g of 2,4-dinitriophenol in 35 ml of methylene chloride and 4 g of 7- (2 ', 2 ^l , 2 ^l -trichloroethaxycarboxamido) -3-methyl-Δ. -cephem ^ -carboxylic acid treated in a minimum of dioxane, followed by a solution of 2.1 g of dicyclohexylcarbDdiimide in 20 ml of methylene chloride, After stirring at room temperature for 30 minutes, the dicyclahexylurea was filtered off, washed with methylene chloride, the filtrate and the washing liquid were added together and treated with 1.4 g of p-methoxybenzylamine in 14 ml of methylene chloride.

After 30 minutes at room temperature, the reaction mixture became with washed a saturated sodium carbonate solution and the organic Phase dried over magnesium sulfate. The thickness that remains after the solvent has been removed under reduced pressure Dl was triturated with PetrolSther and this crystallized Filtered product and dried to 4.0 g of a pale yellow solid.

WMR (DMSodg): 4 = 8.5 (t) 1H; 7, ο (q) 4H; 5.3 (q) and 4.95 Cu)

2H; 4.8 (s) 2H; 4.3 (d) 2H; 3.7 (s) 3H; 3.45 (broad) 2H and 2 (s) 3H.

IR (HBr disk); y ~ MIu cm " ¹ (B-lactam carbonyl).

Example 2

7- (2 ' _Ψ 2 ', 2 ^l -trichloroethoxycarboxamido) -3-methyl-4- / ip-methoxybenzylte t razol-5-yl-y * A -cephem

In a suspension of 100 g of 7- (2 ^!, 2 ', 2'-Trichloräthoxycarboxamido) -3-methyl-4- £ (\ l- £ -methoxybenzyl) carbamoyl7 - Δ-cephem in

509818/1173

2 l of chloroform were 250 ml of toluene with 3α g of phosgene over a Added dropwise over a period of 15 minutes. After a further 15 minutes a solution of 24 g of dry pyridine in 100 ml of chloroform added dropwise over a period of 45 min., uiarbei a solution is formed and carbon dioxide is slowly evolved. The solution was stirred for 90 minutes and then concentrated to half its volume in vacuo in order to add the excess phosgene remove. Then 2 l of chloroform and the stirred solution were further added 45 g of tetramethylguanidinium azide in 25 ml of chloroform added, the Chlarofarm solution after 2 hours in succession ' the one with water (2 χ 5οα ml), a saturated sodium carbonate solution (2 χ 3oo ml), 2.5 IN hydrochloric acid and water (1 χ 25α ml) washed, the organic phase dried over magnesium sulfate and concentrated in vacuo to give 1o2 g of a gummy solid. The product was chromatographed on a clay column (3oS g) with chloroform as solvent (4oB ml) and eluent (1.5 1) waiter cleaned and the eluate under Stir in 6 liters of petroleum ether, the product being a light brown Solid (79 g) precipitated.

(CDCl ₃ ): i = 6.9 (q) 4H; 5.4 (m) 3H; 4.9 Cd) 1H; 4.7 (s) 2H; 3.7 (s) 3H; 3.3 (q) 3H; and 1.4 (s) 3H.

IR (KBr disk): "f = 1770 cm" ¹ (β-lactam carbonyl).

In a corresponding lüeise 25 mg 7- (2 ", 2'X, 2'-Trichlaräthaxycarboxamida) 3-methyl- / [\ l- (p_-methoxybenzyl) carbamoyiy -Δ3-cephem, o, ao7 ml of pyridine and 2.6 mg of PhDsphorpentachlarid in 6 ml of chloroform the corresponding iminochloride. The treatment with tetramethylguanidinium azide (1g) in 2 ml of chloroform gives 22a mg. of the desired tetrazal, which in every respect with was identical to those obtained above.

Example 3

7-Amino-3-methyl-4- £ 1- (p-methoxybenzyl) tetrazol-5-yl-7- acephem .

To 73 g of 7- (2 ^l , 2 ^l , 2 ^l -Trichloräthoxycarboxamido) -3-methyl-4-

509818/1173

-w-

/ i- (p_-methoxybenzyl) tetrazol-5-yl-7a -cephem in 5oo ml of 95% strength Acetic acid was added to 25 g of zinc dust and the mixture was stirred vigorously for 3 hours at room temperature, filtered, and the filtrate appeared placed in a large amount of water and mixed with chloroform extracted, the organic layer washed with class and extracted the product with 1 W hydrochloric acid from the organic phase. The aqueous solution was washed with chloroform, with 2IM-Iodium hydride solution Basified to pH7 and extracted with chloroform, the chloroform layer dried over magnesium sulfate and reduced to a small volume under reduced pressure, when the concentrate was added to petroleum ether the product fell the end. The solids were filtered and dried; Yield 30 g.

IMMR (DMSDd ₆ ): S = 7 (2q) 8H; 5.5 (s) 2H; 5.4 (d) 1H; 5 [beta] (d) 1H;

3.7 (s) 3H; 3.6 (s) 2H; 2.2 (s) 3H and 1.4) s) 3H.

Example 4 7-Arriho-3-methyl-4- (tetrazol-5-vl) -A-cephem A mixture of 7. o g 7-amino-3-methyl-4- (1- / j> -methaxybenzyl7-tetrazole ~ 5-yl) -A -cephem in 5o ml Trifluoressiqsäure / anisole (4: 1) was 5 hours allowed to stand at 5o C ^D, the solution is then stirred into a large amount of diethyl ether was added and the precipitate filtered off.. The solids were dissolved in class, which was extracted several times with ethyl acetate, adjusted to pH 7.0 with aqueous 2IM-I \ latriumhydroxid and extracted again. The aqueous solution containing the product was freeze-dried to give 3.2 g of the desired compound (with a little sodium trifluoroacetate).

IMMR (DMSDd ₆ ): * = 5, ο (d) 1H; 4.6 (d) 1H; 3.4 (q) 2H; 1.9

(s) 3H and 1.3 (s) 3H.

Example 5

7- (Benzyloxycarboxamido) -3-methyl-A -cephem-4-carboxylic acid

609818/1173

Over a period of 45 minutes, I sodium bicarbonate (500 g) in portions into a stirred slurry of 7-amino-3-methyl -Δ. -cephem ^ -carboxylic acid (56a g) in cold water (5.6 1) and acetone (5.6 l). When the foaming was complete, benzyl chloroformate (49o g) was added and the solution at room temperature Stirred overnight, the reaction mixture then extracted with ethyl acetate (2 1 1) and the pH of the separated aqueous layer adjusted to 2 by adding 2IM hydrochloric acid. This mixture was then washed with ethyl acetate (2x11) extracted and the solvent in Uakkuum from the separated organic layer removed. The resulting remnant was dissolved in hot ethanol (2 l) and diluted with warm water (51); the product, 7 ~ (benzyloxycarboxamida) -3-methyl-A -cephem-4-carbdic acid, white solid (750 g) was dried in vacuo at 6 ° C.

(DMSDd ₆ ): & = 8.3 (d) 1H; 7.3 (m) 5H; 5.4 (q) 1H; 5.1

(d) 1H; 5 (s) 2H; 3.4 (q) 2H and 2.1 (s) 3H.

Example 6

7- (benzyloxycarboxamido) -3-methyl-4- [ M- (p-methoxybenzyl) -CARBAMDYL J -A ³

A mixture of 7- (benzyloxycarboxamido) -3-methyl-A -cephem ^ -carboxylic acid (34.8 g) and 2.4-0ΐηΐΐΓορπΒηα1 (18.4 g) were dissolved in dry DiDXan (7oo ml), dicyclohexylcarbodiimide (2o , 6 g) are added, the solution is stirred for 20 minutes at room temperature, then the dicyclohexyl urea precipitate is filtered off and the filtrate is treated with p-methoxybenzylamine (13.7 g), which is removed over a period of 10 minutes. admittedly. IMach further 15 min. Uurde the reaction mixture with dry ether (1, AD diluted, the IMiederschlag filtered off, geuiaschen with dry ether (5oo ml) and hn in Wakuum at 5o C g of the desired product as a white solid gstrocknet.

(DMSDd ₆ ): £ = B, k (m) 2H; 7 (q) 4H; 5.3 (q) 1H; 5.1 (s) 2H;

5 (d) 1H; 4.3 (d) 2H; 3.7 (s) 3H; 3.3 (s) 2H and 2 (s) 3H.

8 0 9 8 18/1173

Example 7

-if- / IM- (p-met hy ioxy benzyl) car bamoy IV - Δ -cephern

7- (Benzyloxycarboxamido) -3-meth / L-4- £ lM- (p-methoxy benzyl) carbamoyl / -A -cephem (2o g) was dissolved in 2oo ml of hydrogen bromide / Acetic acid dissolves the solution at room temperature until the end agitated the evolution of gas, the mixture then in a qrcBe Poured amount (approx. 2 1) of stirred ether and collected the resulting precipitate. The solid was dissolved in water, the aqueous solution washed with ethyl acetate (2 χ), with sodium bicarbonate adjusted to pH 7.5 and the suspension extracted with chloroform. The chloroform extract was dried (MqSo,) and under reduced pressure to the product in the form of a pale yellow solid (7.7 g). Evaporated.

IMMR (DMSOd ₆ ): & = 8, o (t) 1H; 7, ο (q) 4H; 4.8 (d) 1H; 4.6 (d) 1H;

4.4 (d) 2H; 3.7 (s) 3H; 3.2 (q) 2H; 2, Ks) 2H and 2, o (s) 3H.

Example B

7-4M-triphenylmethylamino) -3-methyl-4- / 1- (p-methoxybenzyl) -carbamoyl- · Δ -cephem.

To 2k g of 7-amino-3-methyl-4- / ~ N- (p-methoxybenzyl) -Δ cephem -carbamoyly in chloroform (äthanolfrei, 3oo ml) were Triphenylmethylchlarid (21, ο g) and triethylamine (.1, Gk g) given, the mixture left to stand in the dark at room temperature for 15 hours, the solution then diluted several times with chloroform and washed twice with water. The organic solution was dried (MgSG ^) and evaporated dry to the desired product as a foam. Trituration with light petroleum ether gave a pale yellow solid (40 g).

IMMR (CDCl ₃ ): j = S 7.2 9H; k, G (q) 1H; k, k (d) 2H; 4.1 (d) 1H; 3.7 (s) 3H; 3.0 3H and 2.0 (s) 3H.

509818/1173

Example 9

7- (IM-triphenylmethylamino) -3-methyl-4- L. i- (p-methoxybenzyl) -tetrazol-5-yiy-A-cephem

7- (l \ l-triphenylmethylamino) -3-methy 1-4- / ~ I \! - (p-methoxy benzyl) carbamoyl / -Δ-cephem (2, B g) in ethanol-free chloroform (7.5 ml) with pyridine (α, 6, q) was phasgen in Chlarofrom (3.7 ml, 1.7 M) treated the reaction mixture at room temperature Stirred for 3 a min., Excess phasing under reduced pressure removed and additional chloroform added until the solution was 10 ml in volume. Then tetramethylguanidine hydrogen azide was added (2.4 q) in chloroform (5 ml) was added to the above-mentioned solution, the reaction mixture a 2α min at room temperature stirred, then washed with water, dried (l? IgSD,) and evaporated to a Dl under reduced pressure. Rub in with Light petroleum gave 2.2 g of the desired product.

NMR (CDCL ₃ ): ί = 7.2, 19Hr 5.3 (s) 2H; k, k (q) 1H; k, 2 (d) 1H;

3.6 (s) 3H; 3, XD, 3H and 1,2 (s) 3H.

Example 1o

7-Amino-3-methyl-4 - / ^ 1-p-methoxybenzyl) tetrazol-5-yl / -Δ -cephem 7- (l \ l-Tripheny lmethylamina) -3-met hy 1-4- / i- (p-Methoxybenzyl) tetrazo 1-5-ylJ -Δ-cephem (1.5 g) was treated with formic acid (3d ml) and the solution was left to stand for 30 minutes at room temperature, then poured into 10 ml of water and the aqueous suspension washed with ethyl acetate. The aqueous solution was adjusted to pH 7.5 with aqueous 2IM-I \ latriumhydroxid and the mixture extracted with chloroform, the organic solution dried (MgSD,) and evaporated under reduced pressure to a foam, rowing with light petroleum ether gave 400 mg of the desired product in solid form.

NMR (CDCl ₃ ): £ = 7, α (q) 4H; 5.4 (s) 2H; 4.9 (d) 1H; 4.6 (d) 1H; 3.7 (s) 3H; 3.3 (q) 2H; 2, o (s) 2H and 1 _t 4 (s) 3H "

509818/1173

2U9834

Example 11

7- / P-oC- amino-O (-phenyl) acetamidq_ / -3 ~ methv / l-4 - (etrazal-5-vl) - Δ -cephem

A. 7- / d- (c <-t -butoxycarboxamido- o ^ -phenyOacetamidoJ -3- methyl-4- (tetrazol-5-yl) -A -cephem

D-C of-t-Butoxycarboxamido-oi-phenylacetic acid Co, 251 q) in Tetrahydrofuran (2 ml) was treated with triethylamine (o, 1o1 α) and ethyl chloroformate (α, 1οθ q) at -1o. After 15 min. at this temperature the sodium salt of 7-amino-3-methyl-4- (tetrazol-5-yl) -A -cephem (0.400 g) in water (3 ml) was added in one portion with stirring, the mixture with tetrahydrofuran (2 ml) diluted and allowed to warm up at room temperature. After one hour, the solution was treated with 2I \ I hydrochloric acid adjusted to pH 2, the suspension extracted with ethyl acetate, the ethyl acetate solution washed with water, dried (MgSD), concentrated in negative pressure and in a large amount Poured light petroleum ether; a white solid resulted. The compound was crystallized from chloroform (316 ml).

NMR (DMSOdg): ^ = 7, β (d) 1H; 7.2, 5H; S, o (d) 1H; 5.6 (q) 1H;

5.2 (d) 1H; 4.9 (d) 1H; 3.3 (q) 2H; 2, o (s) 3H -and 1.2 (s) 9H.

B. 7- / D- (o <-amino-o (-phenyl) acetamido7 -3-methyl-4- ( tetrazol-5-yl) -A -cephemtrifluoroacetate

7 - / "d- (o < -t-Butoxycarboxamido-oC-phenyDacetamido -3-methyl-4- (tetrazol-5-yl) -A Cephem (26 mg) was dissolved in trifluoroacetic acid (0.5 ml) and left to stand for 20 minutes at room temperature. Ether was added to the solution and the precipitate collected (24 mg).

NMR (DMSDd ₆ ): ^ = 7.4 (s) 5H; 5.6 (d) 1H; 5, Kd) 1H; 5, o (s)

1H; 3,4, 2H and 2, o (s) 3H.

509818/1173

2U9834

EXAMPLE 12

7 - ^ D - «/ - Amino - <? (- (p zol-5-yl -) - A -cephem

The experiences of examples 11A and 11B were repeated, starting from the required D - ^ <K -t-Butoxyvarboxamido-o (- (p- "hydroxyphEnyl) 7ESsiqsäurE instead of D - (<tf-t-Butoxycarboxamido-o (-phEhyl) ESsigsäurE. The desire was made Product.

IR (CHaCl "): T = 17Bo cm" ¹ (B-lactam carbonyl); 166o cm "" ¹

c. c- ΓΠ3Χ

(-CDnH-).

EXAMPLE 13

7 - (- (? (- HydroxyphEnylacEtamido) -3-mEthyl-it- (tEtrazol-5-yl) -A -

A. 7- (D- (X -formyloxyphEnylacEtamida) -3-i

3
5-yl) -A-csphem

D-G-Formy! Mandelic acid (1.8 q) in ether (15 ml) was mixed with Dxylyl chloride (2.5 ml) and one drop of dimethylformamide. After the vigorous reaction had ended (30 min.) Was the ether removed under reduced pressure and the residue in 1o ml Tetrahydrofuran (THF) in είπε stirred solution of 7-amino-3-methyl-it- (tEtrazol-5-yl) -Δ Add -cephsm (1g) in 2o ml of a water / THF mixture (1: 1) with excess sodium bicarbonate. After stirring for a further hour at room temperature, the mixture was adjusted to pH 2 with 2N hydrochloric acid and the pH Mixture extracted with ethyl acetate. The organic solution was washed with water, dried (mgSG,) and in the sub pressure evaporates; the desired product remained as a solid (35o mg).

NMR (DMSOd ₆ ): ί = 8.2 (s) 1H; 7.2 (s) 5H; 6, o (s) 1H; 5.5 (q) 1H;

5.1 (d) 1H; 3.5 (s) 2H and 2, o, 3H.

509 818/1173

B. 7- (D-ot-HydroxyphBnylacetamida) -3-methy] - '+ - (tetrazDl- 5-yl-A-cephem

7- (D - <? (- FDrmylDxy pheny! Acetamido) -3-methyl- £ + - (tetrazol-5-y I) - / 1 -cephem (d, 3k n) was dissolved in an excess aqueous sodium bicarbonate solution and 3 Let stand at 3 C for hours, then adjust the solution to pH 2 with 2IM hydrochloric acid and extract the suspension with ethyl acetate. The Omani solution was dried (MnSD,) and under reduced pressure to give the newly desired product as a solid (0.26 q) evaporates.

NMR (DMSDd ₆ ): ί = g, o, 1H; 7.3 (s) 5H; 5.6 (q) 1H; 5.2 (d (1H;

5.1 (s) 1H; 3.6 (s) 2H and 2, o (s) 3H.

Example 1 * t ? - (2 »Gyanoacetarnido) -3-methyl-4- (tetrazol-5-yl) -A-csphem

In a stirred suspension of 7-amino-3-methyl- ⁱ t- (tetrazol-5-yl) -A-cephem toxylate salt (576 q) in methylene chloride (20 ml) under nitrogen uiurde triethylamine (45o mq). After stirring for 2 minutes at room temperature, this solution was treated with one portion of the N-hydroxysuccinimide ester of cyanoic acid (^ 70 mo). After the reaction mixture had been stirred overnight under nitrogen, it was poured into 30 ml of water and the aqueous phase was adjusted to pH 8.0. The methylene chloride layer was separated off, the aqueous phase was acidified to pH 2 and then extracted with ethyl acetate, the ethyl acetate was washed with water and dried (sodium sulfate) and the solvent was removed in vacuo. Trituration of the residue with dry ether gave the product as a pale yellow solid (55 mg).

NMR (DMSDd ₆ ): & = 5.7 (q) 1H; 5.2 (d) 1H; 3.8 (s) 2H; 3.6 (s) 2H

and 2, o (d) 6H.

Example 15

7- (2-Carboxv

cephem sodium salt

7- (2-carboxyphenylacetamido) ~ 3-methyl - ^ - (tetrazol-5-yl) -Δ -

509818/1173

Phenylmalonic acid Co, 79 q) was dissolved in 25 ml of distilled water and the pH of the solution was adjusted to S, π by adding 2 I \ II \ latriumhydrnxidlösung. Then a solution of 7-Amina-3-methyl- ⁱ t- (tetrazal-5-yl) -A-cephem (0.65 g) in 10 ml of distilled water (pH adjusted to 6 by adding 2I \ II \ sodium hydroxide solution) was added and the reaction mixture was cooled to GC. 1-Ethyl-3 ~ (3-dimethylaminoprop-1-yl -) - carbodiimide (1.6 q) was added and the solution was stirred for 3.5 hours, during which the pH was increased by the dropwise addition of dilute hydrochloric acid within the range 6 , 1 ... 6.3 was held. At this point the pH was raised to 7.3 by the addition of saturated sodium bicarbonate solution, the reactant mixture was extracted with ethyl acetate and the extract was discarded. The aqueous phase was acidified to pH 3 with n, k M phosphoric acid, extracted again with ethyl acetate (two 50 ml portions) and the latter extract was dried and concentrated to a volume of about 25 ml. A solution of i \] atrium 2-ethylhexanaate (1 g) in 20 ml of ethyl acetate was then added to this solution, and the precipitate which formed was filtered off; it resulted in o, 75 g of the disodium amount of 7- (2-carboxy-2-phenylacetamido) -

A -cephem. The IR spectrum of the pro-

duct (HBr disk) showed absorption at 176o cm (ß-lactam carbonyl), 16

latcarbonyl).

g p

—1 —1

carbonyl), 166α cm (Amid -I-Band) and 16od cm (Carboxy-

ί = 7.4 (m) 5H; 5.7 (d) 1H; 5.2 (d) 1H; 3.4 (m) 2H and 3H.

Example 16
he use of 2-thienylmalanic acid instead of phenylmalonic acid

in example 15 leads to the synthesis of ! - (<£ - (2-thienyD-oC-carbDxyacetamido / -3-methyl - ^ - (tetrazol-5-yl) -A-cephem.

MMR (DßiSodg): / = 2, Ks) 3H; 3.3 Gn) 2H; 5 (s) 1H; 5.6 (m) 1H;

6, a-7.5 (m) 3H.

IR (HBr disk): y = 177d cm "(β-lactamcarbanyl);

max y.

167a cm (-CGMH-).

509818/1 173

2U9834

-3B-

Example 1 7

7-Phenylacetatnido-3-methyl - ^ - (tetrazol ~ 5-yl) -A -cephe m

Phenacetyl chloride (2.3 q) in acetone (5 ml) was at room temperature within 2α min. in a stirred solution of 7-Amina ~ 3-methyl - ^ - itetrazol-S-yl) -A -cephem-I sodium salt (1.31 q) in aqueous acetone (2a ml) added dropwise and at the same time with sodium hydroxide (2 IM) kept at pH-Lüert 8 + _ 0.5. (Do the encore the solution was stirred for a further 15 minutes, then the acetone was removed under reduced pressure and the pH of the aqueous solution was reduced 2-N hydrochloric acid adjusted to 2. The suspension was made with ethyl acetate extracted, the organic solution dried (MgSD,) and evaporated under reduced pressure. The remaining Dl solidified after trituration with ether (Mta mg).

(DMSDd ₆ ): ί = 9, α (d) 1H; 7.2 (s) 5H; 5.6 (g) 1H; 5.2 (d) 1H; 3.5 (s) 4H and 2.0 (s) 3H.

Example 18 7-phenoxyacetamido-3-methyl-4- (tetrazol-5-yl) -A-cephem

Phanoxyacetayl chloride (2.56 g) in acetone (5 ml) was added to a stirred solution of ^ -arnino-S-methyl-it-itetrazol-S-yl) - & cephem-I sodium salt (1.31 g) in aqueous acetone (3o ml) was added dropwise at room temperature within 20 minutes and simultaneously with Sodium hydroxide (2IM) is adjusted to pH 8 + 0.5 and the solution is then stirred for a further 15 minutes. The acetone was then under reduced pressure removed and the pH of the aqueous solution adjusted to 2 with hydrochloric acid (2N). The suspension was made with ethyl acetate extracted, and the organic solution dried (MqSD,). Evaporation and trituration of the residue gave the desired result Product as a solid (37o mg).

IMMR "(DMSDd ₆ ): i = 9, o (d) 1H; 7, o (m) 5H; 5.6 (g) 1H; 5.2 (d) 1H;

if, β (s) 2H >> 3, a (s) 2H; 2, o (s) 2H.

5 09818/1173

Example 19

Following the procedures of Examples 17 and 1B and beyond The following of the required reaction participants ^ "- Cßpheme synthesized:

7-bromoacetamido-3-methyl-i + - (tetrazol-5-yl) -A-cephem,

WMR (DMSDri _c ): S = 2.15 (s) 3H; 3.7 (m) 2H; i +, 1 (s) 2H; 5 / f (d) 1H

and 5.2 (tn) 1H; ■ ·

7- (o <-azido-c * -phenylacetamido) -3-methyl-'4- (tetrazol-5-yl) -Δ -cepheme,

NMR (DMSDd,.): S = 9.2 (s). 1H; 7.35 (s) 5H; 5.6 (s) 1H; 5.15 (q) 2H;

3.5B (s) 2H and 1.98 (s) 3H;

7- ^ o <-Ctetrazol-S-yDacetamido ^ -3-methyl ~ ^ - (tetrazol-5-yD-Δ -cepheme,

NMR (DMSDd.): / = 2, o (s) 3H; 3.6 (s) 2H; 5, o5 -5.15 (d) 1H;

5.15 (a) 2H; 5.5-5.8 (q) 1H and 9.5 (s) 1H;

V- (O ^ -phenylthioacetamido) -3-methyl-i + - (tetrazol-5-yl) -Δ -cepheme,

NMR (DMSGd _c ): / = 9.18 (d) 1H; 7, Z3 (m) 5H; 5.63 (q) 1H; 5.35 (d)

1H; 3.77 (s) 2H; 3.6 (m) 2H and 2.03 (s) 3H;

7_ / o (- (2, G-DimethDxyphenyl) carhoxamidoy -3-methyl-U- (tetra-Βο1-5-ν1) -Δ -cepheme,

NMR (DMSGd ₆ ): ί = 2, o (s) 3H; 3.6 (s) 2H; 3.7 (s) GH; 5, o5-5.15 (d)

1H; 5.5-5.8 (q) 1H; G, 5-6.7 (d) 2H and 7, o-7.3 (m) 1H;

7- (2-thienylqlyoxylamida) -3-methyl-i + - (tetrazol-5-yl) - L ~ CRphem,

(DMSDd ₆ ): i = 2, o (s) 3H; 3.6 (s) 2H; 5.1-5.15 (d) 1H; 5.4-5.7 (q) 1H; 7, o5-7.15 (m) 1H and 7.8-8, Km) 2H; and

509818 / Ί173

7- / e ^ - (2-thienyl) acetamido -3-methyl-4- (tetrazol-5-yl) -Δ -cepheme,

IMMR (DMSDd, -): I = 2, o (s) 3H; 3.6 (s) 2H; 3.8 (s) 2H; 5.1-5.15 (d)

1H; 5.5-5, B (q) 1H; 6.95-7, o (d) 2H and 7.1-7.2 Gn) 1H.

EXAMPLE 2o

7- / ö (-Hydroxy- (2-thiBnyl) ~ acetamidqy ^ -methyl-it-Ctetrazol- 5-yl) -A -cephem

7- (2-Thienylglyoxylamido) -3-methyl-4- (tetrazal-5-yl) -Δ-cephem (1.5 g) in water (30 ml) was reacted with 2IM-I \ latriumhydroxid to the sodium salt, the solution chilled on ice and added anhydrous sodium acetate (1.53 g). Sodium borohydride (276 mg) was then added in small amounts during k5 ming. added, kept at pH 8 by adding glacial acetic acid alternately with sodium borohydride and, after the addition, kept the pH value at 8 for 5 minutes with the ice bath removed. The solution was "layered" with ethyl acetate and the pH was adjusted to 2 with 40% phosphoric acid, then the organic layer was separated off, washed with water, dried (i \ la "SD,"), filtered and concentrated in vacuo until the solids crystallized. The product was filtered, washed with dry ether and dried in a vacuum. Yield 3Go mg.

NMR (DMSDd ₆ ): ζ - 7.2 (m) 1H; 7, o, 2H; 5.4 (,) 1H; 5, o (s) 2H;

3,5, 2 H and 2, o) s) 3H-

Example 21

7 - / "2 ~ (2-methyl-1,3 _s 4-thiadiazal ~ 5-yl-thia-acetamidD) J -3-methyl ^ - (tetrazol-S-yl) - ^ -cephem

Triethylamine (0.2 ml) was converted into a cold (D C) suspension of 7- (2-bromoacetamido) -3-methyl-4- (tetrazol-5-yl) -A -cephem (0.5 g) in methylene chloride (15 ml) and the resulting pale yellow solution was a slurry of 2-methyl-1,3,4-thiadiazole-5-thiol (o.19 g) added; this solution was at

50981 8/1173

D ⁰ C stirred. After 2 hours the product precipitate was filtered off (0.3 q).

NMR (DMSDd ₆ ): ^ = 9.3 (d) 1H; 5.2 (d) 1H; 4.15 (s) 2H; 5.6 (m) 1H;

3.6 (s) 2H; 2.7 (s) 3H and 2.05 (s) 3H.

Example 22

The procedure of Example 21 was based on 7- (2-BrDmacetamida) -3-methyl-it- (tetra2ol-5-yl) -Δ -cephem and 1-methyl-5-tnercaptatetrazdl (Lieber i.a. in Can. J. Chem. 3J7, 1q1 (1959) repeated, it surrendered

7- / of- (1-methyltetrazal-5-ylthia) acetaiTiidQ_ / -3-methyl-ittetrazol-5-yl) -A -cephem.

NMR (DMSOdg): & = 9.2B (d) 1H; 5.6 (q) 1H; £ 5.2 t (d) 1H; if, 13 (s) 2H;

3.95 (s) 3H; 3.59 (m) 2H and 2, o1 (s) 3H.

Example 23

The procedure of Example 21 was repeated starting from 4-mercaptopyridine and 7- (2-bromoacetamido) -3-methyl- ⁱ t- (tetrazol-5-yl) -Δ-cephem; 7- / ^ 2- (4-pyridylthio) acetamido / -3.methyl-if- (tetrazol-5-yl) -A -cephem resulted.

NMR (DMSOd ₆ ): £ = 9.32 (d) 1H; 8, AKm) 2H; 7.33 (m) 2H; 5.7 ~ 5.6 (q)

1H, 5.25 (d) 1H; 3.95 (d) 2H; 3, S (m) 2H and 2, o3 (s) 3H.

example 2k

7- (2 ', 2', ^ '- Trichloräthoxycarbaxamido ^ S-acetaxymethyl-i + -

methoxybenzyl) -carbamoyl_ / -Δ-cephem

A. 7- (2 ', 2', 2 ^! -Trichlorethoxycarboxamida) -3-acetaxymethyl- ^ -cephem- ^ - carboxylic acid

Sodium carbonate (300 g) was added portionwise to a stirred slurry of 7-aminocephalosporanic acid (408 g) in aqueous acetone (2: 1; 5 1: 2.5 liters). Then over a period of k5 min. 2 ¹ ^ '^' - Trichloräthylchloroforniat (35o g)

509818/1173

Dropped in and the mixture stirred at room temperature for a further 5 hours.

The acetone was then removed in vacuo, the aqueous solution diluted to 10 1 with distilled water, the pH of the solution adjusted to 2 with 5o% hydrochloric acid and the mixture with Ethyl acetate (to 5 χ 1.5 1) extracted. The combined organic layers were washed with water (2x21), dried (MgSD.) and the solution concentrated to 1.5 liters.

The concentrate was slowly poured into petroleum ether (boiling point So 8o C, 15 l) and the solid precipitate was washed with petroleum ether (boiling point 3o - Ua ⁰ C, 2 × 21). The precipitate was dried in vacuo at 45 ° C., 7- (2 ', 2', 2'-TrichlaräthoxycarbonyD-amino-O-acetoxymethyl-Δ-cephem-4-carboxylic acid was formed as a white solid (49a g).

NMR (DMSOd ₆ ): & = 1a (d) 1H; 5.5 (q) 1H; 5, Kd) 1H; 4.8 (q) 2H; "

4.8 (s); 3.5 (s) 2H and 2, o (s) 3H.

B. 7- (2 ', 2', 2 '-TrichlarethaxycarboxamidaXS-acetoxy ^ - LN- (p-methoxybenzyl) -carbamoyl7 - Δ -cephem

Based on the acid of the BÖBpiel 37A and according to the procedure of Example 1B, the desired product was obtained in moderate yield.

NMR (CDCl ₃ ): I = 2, o (s) 3H; 3.4 (s) 2H; 3.8 (s) 3H; 4.45 (d) 2H;

4.75 (s) 2H; 4.9 (m) 3H; 5.5 (q) 1H; 6.2 (b) 1H and 7.1 (q) 4H.

Example 25

7- (2x, 2 ', 2'-trichloroethaxycarboxamido) -3- (2-methyl-1,3,4-thiadiazDl-5-ylthio-methyl) -4- [ N- (p-methaxybenzyl) -carbamoyl] A -cephem

7- (2 ', 2 ·, 2i-trichloroethoxycarboxamido) -3- (2-methy1-1,3,4-thiadJ

carboxylic acid

1 ^, ^ - thiadiazol-S-yl-thiamethyl-Δ -cephem-4-

5 0 9 8 18/1173

Following the procedure of Example 24, aer with 7-amino-3- (2-methyl-1 ^^ - thiadiazol-S-ylthiomethyl) - ^ -cephem-4-carboxylic acid (US Pat. No. 3,641,021) as cephem became the desired product manufactured.

NFiR (CDCl ₃ ): ί 5.4 (m) 2H; 5, Kd) 1H; 4, B5 (s) 2H; 4.4 (q) 2H, 3.7 (s) 2H and 2.7 (s) 3H.

B. 7- (2 ^!, 2 ', 2 ^l -Trichloräthoxycarboxamido) -3- (2-methyl-1,3,4-thiadiazol-5-yl-thiomethyl) -4- / N- (p-methoxy-

benzyDcarbamoylj - A -cephem

Using the product of Example 25A and following the procedure of Example 24B, the desired intermediate was synthesized.

NMR (CDCL ₃ ): 4 = 7, o (q) 2H; 6.1 (m) 1H; 5.4 (q) LH; 4.9 (d) 1H;

4.7 (s) 2H; 4.4 (m) 4H; 3.75 (s) 3H and 3.6 (s) 2H.

Example 26

7- (2 ', 2', 2 ^I -Trichloräthoxycarboxamido) -3-acetoxymethyl-4- / i- (p-

inethoxybenzyl) tetrazol-5-yl J- Δ -cephem

Phosphorus pentachloride (1.68 g, B nmol) was added to a stirred solution of 7- (2 ', 2', 2'-Trichlaräthaxycarboxamido) -3-acetoxymethyl-4- / N- (p-methoxybenzyl) carbamoyiy-4-cephem ( 2.26 g, 4 nmol) and pyridine (0.64 g, B mmol) in dry, ethanol-free chloroform (3q ml) at o-5 ° C. were added. After 3 min., The nuclear magnetic resonance spectrum showed that the amide had completely reacted (disappearance of the 2-Protonendubletts at £ = 4.45) A solution of tetramethylguanidinium azide (6.3 g, 4o Jimai) in dry chloroform äthanalfreien (2o ml) was added dropwise over 10 min. to the cooled solution, after a further 10 min. the ice bath was removed and the reaction mixture was stirred at room temperature for 30 min. and water and washed over magnesium sulfate

509818/1173

2U9834

dried. Evaporation of the solvent gave the crude product as a pale brown solid (1.5 g). The product, pure according to thin layer chromatography, was obtained chromatographically on silica gel with the initial use of hexane as the eluent and the gradual addition of increasing amounts of ether and final elution with 100 % ether. (DMSDd _6): S = 1. ⁸ (s) 3H; 3.6 (q) 2H; 3.9 (s) 3H; 4.2 (s) 2H;

2H; 5.1 (d) 1H; 5.6 (m) 3H; 6.3 (d) 1H and 7.4 (q) W.

Example 27

7- (2 », 2 ', 2'-trichloroethoxycarboxamido) -3- (2-methyl-1,3-j4-thiadiazol-5-yl-thiomethyl) -4- / 1- (p-methoxyben3 / L) tetrazDl -5-yl J - A -cephem

Starting from the cephem of Example 25 and following the procedure of Example 26, the desired product was synthesized.

(CDCl ₃ ): ί = 7, o (q) 4H; 5.5 (s) 2H; 5.4 (m) 2H; 4.7 (s) 2H; if, Km) 2H; 5.75 (s) 3H and 5, G5 (m) 2H.

Example 28

7-amineα-3-acetoxymethyl-4- / i- (p-methoxyfflbenzyl) tetrazol-5-yiy -

Δ -cephem ^ ₁

Activated zinc dust (3αα mg) was poured into a stirred solution of 7- (2 ', 2', 2 '-TrichlDrathxycarboxamido-S-acetoxymethyl-it- /

1- (p-methoxybenzyl) -tetrazol-5-yiy-A -cephem (3oo mg, 0.5 mmol) in 9o% acetic acid (3 ml) and the suspension at Stirred at room temperature for 30 minutes, the reaction mixture filtered and evaporated to dryness. The resulting yellow foam was dissolved in chloroform, the solution twice with dilute Hydrochloric acid extracted, the aqueous extracts mixed with chloroform and the stirred mixture diluted sodium hydroxide until pH 7, o ffl added. The mixture was filtered,

509818/1 173

to remove the precipitate of inorganic salts that Layers separated and the aqueous solution extracted twice with chloroform. The combined organic extracts were with Washed with water and dried over magnesium sulfate. Evaporation of the solvent turned the product as a pale yellow Solid (110 mg) obtained in pure form by thin-layer chromatography.

I ¹ JMR (CDCl ₃ ): i = 1.9 (s) 'iH; 2, o (s) 3H; 3, WCq) 2H; 3, B (s) 3H; 4.3 (q) 2H; 3.8 (s) 3H; 4.3 (Sq) 2H; 4.65 (d) 1H; 4.95 (d) 1H; 5.5Cs) 2H and. 7, Kq) UW.

Correspondingly, starting from 7- (2 », 2 '^' - TrichloräthoxycarboKamida) -3- (2-methy1-1,3,4-thiadiazol-5-ylthiomethyl) -4- l_ 1- (p-methoxybenzyl) tetrazole- 5-yl / - Δ -cephem and, following the procedure of Example 28, the compound 7-amino-3- (2-methyl-1,3-4-thiadiazol-5-ylthiomethyl) -4-r / ip-methoxybenzyl) -tetrazol-5-yl - ^ / A -cephem .

NMR (CDCl ₃ ): i = 7, o Cq) ffH; 5.55Ca) 2H; 4.9 (d) 1H; i _t , 6 (m) IH; 3.8 (s) 3H; 3.65 cm) 2H and 2.7 (s) 3H.

Example 29

7-Amino-3- (2-methy1-1,3, i + -thiadiazol-5-ylthinmethyl) -4- (tetrazol -5-yl) -A -cephem

7-Amino-3- (2-methyl-i, 3, it-thiadiazol-5-ylthiomethyl) -it- / i- (methoxybenzyl) -tetrazol-5-yl7 -Δ- cephem (125 g) was dissolved in acetone ( 2 ml) and p-toluenesulfonic acid (60 mg) in acetone (1 ml) was added. The salt precipitated as a brown oil after the addition of ether to this mixture. The solvent was decanted and the residue was washed 3 times with ether (3o ml). The residual oil was dissolved in trifluoroacetic acid / anisole (4: 1 v / v; 2 ml) and kept in UassErbad in a sealed flask (25 ml) for 3 h at 38 ⁰ C..

Thereafter, the reaction mixture was poured into dry ether, the organic solvents from which

509818/1 173

2U9834

The end of the precipitate is decanted and the solid residues are washed with more ether (3 χ 3d ml). The cream substance separated from the protective group was taken up in acetone / Ldasser (pH 2.5), extracted with ethyl acetate, the aqueous phase was adjusted to pH 7.6 with aqueous sodium hydroxide (2IM) and then extracted with ethyl acetate. Concentrating the aqueous phase in vacuo to dryness gives a solid. This compound is characterized by the acylation of the sodium salt mentioned with 2 ', 2-1,2'-TrichloräthoxycarbonylchlDrid using the procedure of Example 1A to 7- (2', 2 ', 2'-Trichlaräthoxycarboxamido) -3- (2- methyl-1,3,4-thiadiazol-5-ylthiomethyl) -4- (tetrazol-5-yl) -Δ-cephem. (CDCl ₃ ): ί = 4.7 (d) 1H; 4.2Gn) 1H; 5, Ks) 2H; 5.35 (s) 2H;

6, o (m) 2H and 7.2 (s) 3H.

Example 3o

Sodium carbonate (42 g, 0.5 moles) was gradually turned into a vigorously stirred suspension of 7-amino-3-acetoxymethyl- ^ -cephem- ^ - carboxylic acid (50 g, α, 18 mol) in acetone: water (25α / 500 ml) and in the stirred solution over a period of 45 min. A solution of benzyl chloroformate (36 g, α, 21 mol) added dropwise in acetone (7o ml). After stirring for 6 hours, the acetone was removed in a rotary evaporator and the aqueous residue was also removed Washed ethyl acetate to remove impurities. The aqueous solution was covered with ethyl acetate and adjusted to pH 4, i.e. leavened. The combined ethyl acetate solutions from the extractions of the aqueous solutions were washed with water and washed over Dried magnesium sulfate. Evaporation of the ethyl acetate gave the product, 7-Benzylαxycarbαxamidα-3-acetoxymethyl-Δ -cephem- ^ t-carboxylic acid, as whitish, thin-layer chromatography pure solid (56 g).

NMR (DMSOd ₆ ): S = 2, o (s) 3H; 3.5 (s) 2H; 4.8-5.2 (m) 5H and

7.3 (s) 5H.

7-Benzyloxycarboxamido-3- (1-methylr-

609818/1173

- hi -

tetrazol-5-yl-thiomethyl) -Ä -cephem-if-catboxylic acid.

NMR (DMSDd ₅ ): i = 7.5 (s) 5H; 6.6 (d) 1H; 6.2 (s) 3H; k, k (b) 2H;

) 3H and 3.8 (s) 2H.

Example 31

7-Benzyloxycarboxamido-3-acetoxymethyl-tt- / N- (p-methoxybenzyl) carbamoyl / - ^ -cephem

A solution of 2, * + - dinitriaphenyl (22 g, 0.1 times) in methylene chloride (1ao ml) was converted into a solution of 7-benzyloxycarboxamido-3-acetoxymethyl- Δ- cephem - ^ - carboxylic acid (41 g, o, 1 time) in dry dioxane (.kna ml) and a solution of dicyclohexylcarbodiimide (21 g, 0.1 times) is added to this stirred solution. After 1.5 hours, the dicaclohexylurea precipitate was filtered off and a solution of p-methoxybenzylamine (13.7 g, 0.1 mol) in dioxane (100 ml) was added to the filtrate. After stirring for 6 hours, the precipitate was filtered off, washed with ether and ethyl acetate and dried. The product was present as a white solid (30 g) and was pure according to thin-layer chromatography.

NMR (DMSDd _c ): = 2, o (s) 3H; 3, if (s) 2H; 3.7 (s) 3H; k, 3 (u) 2H;

2H; 5, o (m) ^ H; 5.4 (q) 1H and 7, o (m) 9H.

7-Benzyloxycarboxamido-3- (1-methyltetrazol-5-yl-thiomethyl-it- / N- (p-methoxypenzyl) carbamDyl_ / -Δ cephem was prepared in a similar manner.

NMR (CDCl ₃ ): = 7, * t (s) 5tf; 7, Kq) ^ H; 7.7 (m) 2H; 5.25 (s) 2H;

5, if5 (d) 1H; 4.5 (m) 4H; if, o (s) 3H; 5.9 (s) 3H and 5.79 (s) 2H.

Example 32

Phosphorus pentachloride (k, 2 g, 2o mmol) were in a suspension of 7-beπzyloxy-caΓboxamido-3-acetoxymethyl-ί ^ - [ N- (p-methoxybenzyDcarbamoyl / -Δ-cephem (5.3 g, 10 mmol) in dry, ethanol-free

S09818 / 1173

ChlorofDrm (100 ml) containing pyridine (1.7 g, 20 mmol), given. After 30 minutes the IMMR spectrum indicated the reaction finished ujar.

The solution was cooled in an ice bath and her min over a period van Za., A solution of tetramethylguanidinium (16, ο g, 1oo mmol) added dropwise in dry äthanolfreiem chloroform. After a further 10 minutes, the ice bath was removed and the mixture was stirred for a further 30 min at room temperature. The solution was then washed with water, three times with an I sodium bicarbonate solution, three times with 6 liters of hydrochloric acid and again with water and dried over magnesium sulfate. Evaporation of the solvent gave the crude product as a brown solid (3.7 g) which was purified by silica column chromatography. Elute with dichloromethane / hexane (1: 1) and then remove impurities with ether / dichloromethane / hexane (2: 1: 1). Further elution with ether gave the product, 7-benzyloxycarboxamido-3-acetαxymethyl-4- / i- (p-methoxybenzyl) tetrazol-5-yl); / A -cephem, as a white solid pure by thin layer chromatography.

NMR (DMSDd _c ): ί = 1.9 (s) 3H; 3.65 (s) 2H; 3.6 (s) 3H; 4.3 (s) 2H; ta

5.15 (s) 2H; 5.35 (d) 1H; 5, G (m) 3H; 7.2 (m) 3 H, and 8.6 (d) 1H.

Similarly, 7-benzyloxycarboxamido-3- (1-methyltetrazol- 5-ylthiomethyl) -4 - ^ - ( p-methoxy benzyDtetrazol-S-yiy- Δ- cephem was prepared.

WMR (DMSDd ₆ ): = 7.3 (s) 5H;, 7, o5 (q) 4H; S, 5 (s) 3H; 6.2 (d) 1H;

5, o5 (s) 2H; 3.85 (s) 3H; 3.7 (s) 3H; 3.5-4cm) 2H and 3 _? 3 (s) 2H.

Example 33

7-Amino-acetoxymethoxymethylf-4- (iEtrazol-5-y I) -Δ -cephem 7-Benzyloxycarboxamido-S-acetDxymethy1-4- Ai- (p-methoxybenzyl) tetrazol-5-yly -Δ -cephem (100 mg) was dissolved in trifluoroacetic acid / anisole (4: 1, v / v; 0.5 cm) and this reddish brown

S09818 / 1173

2U9834

Solution of trifluoromethanesulfanic acid from a Pasteur pipette (25 Drops) added. The solution foamed up immediately and then turned a cherry-red color.

After 3 minutes at room temperature, the reaction mixture passed through Quenched addition of sodium-dried ether. It hit a brown gum settles down; the supernatant liquid was decanted and the residue washed again with ether.

The viscous gum again became methylene chloride in the minimum volume dissolved with 1% triethylamine and the solution on silica (2 mm, Zo χ 2o, silica gel G F254) with acetonitrile / water (6: 1 v / v) as Eluent chromatographed.

The band at RF o, h u was removed and extracted with 1% triethylamine / methylene chloride (3 χ 15α ml), the organic extracts extracted to dryness in vacuo; This produced a Lyeißer dye, namely a mixture of 7-amina-3-acetoxymethyl-4- (tetrazol-5-yl) -A cephem and triethylamine hydrochloride.

NMR: (CDCl ₃ ): S 5.25Cd) 1H; 4.9cm) 2H and 2, a5 (s) 3H.

Example 3k
V-Amino ^ -d-methyltetrazol-S-ylthiomethyD-if-itetrazol-S-yl) -

Δ -cephem

The procedure corresponding to Example 33 was carried out on the basis of V-Benzyloxycarboxamida ^ -d-methyltetrazal-S-yl-thiamethyD-if- / i- (p-methoxybenzyl) tetrazal-5-yl 7 -A -cephem made the raw product.

The Zuitterian was made by crystallizing the crude reaction mixture isolated after precipitation with dry ether from a minimal volume of aR potassium hydrogen phosphate as OH 7 buffer. After the crude reaction mixture has initially dissolved the zwitterion as a creamy yellow solid and is by thin-layer chromatography pure. \

5 09818/1173

- 5ο -

IMMR (DMSDd ₆ ): I = 5, Kd) 1Η; 4.8 (d) 1H; 4.3 (q) 2H; 3.9 (s) 3H

and 3.7 (s) 2H.

Example 35
7-2 ', 2 ", 2'-carbdic acid

7-2 ', 2', 2'-TrichlDrathDxycarboxaniidD) -3-methyl-A -cephem-4-

7- (2 ', 2', 2'-TrichlDrathoxycarboxamida) -3-methyl-z! \ -Cephem-4-carbdic acid (66.6 g) and N-hydroxysuccinimide (21.6 g) in dioxane (2αα ml) at room temperature were treated with dicyclohexylcarbodiimide (35,6) and the mixture for one hour at room temperature stirred, the mixture then filtered and the filtrate evaporated in negative pressure to a Gl, which is in pyridine (4οο ml) 7 C and then treated with aqueous sodium hydroxide (7.5 g in 100 ml) with vigorous stirring. The mixture was uiurde then allowed to warm to 25 C and stir for a further 1.75 hours, the pyridine then evaporated under reduced pressure and the residue up Poured ice. The PH-LUert was adjusted to 2 with 6IM-HCl and the precipitate extracted in Ethylea-plene *. The organic Solution was washed with 1N HCl and water and then under reduced pressure evaporated, the residue dissolved in an aqueous sodium carbonate solution and the resulting solution with ethyl acetate washed. The aqueous solution was treated with charcoal and filtered, the pH of the filtrate was adjusted to 2 with 6N HCl, the precipitate is extracted in ethyl acetate and the organic Solution treated with charcoal, filtered and dried (MgSO.) And the solution evaporated under reduced pressure; it happened the desired product as a foam, which solidifies when rubbed with petroleum ether (^ Β, ο g) and essentially chromatographically is pure.

IMMR (CDC13): £ = 7.5 (d) 1H; 6, a (q) 1H; 5.2 (m) 2H; 4.7 (s) 2H; 4.6 (s) 1H and 1.9 (a) 3H.

Example 36

7- (2>, 2 ', 2'-TrichlaräthoxycarbaxamidD) -3-methyl-it- / ~ N- (p-methoxy- benzyl) carbarnoyl7- & · -cephem

509818/1173

7 - (^ ¹ , 2 ', 2'-Trichloräthoxycarboxamido) -3-flJethyl-A -cephem-4-carboxylic acid C4b, 0 g) and N-hydroxysuocinimide (14.3 g) in dioxane (750 ml) were after a Treated hour with dicyolohexylcarbodiimide (24.3 g) at room temperature with stirring, the stirred solution of ji-methoxybenzylanxine (32.8 g) in dioxane (200 ml) was added, the mixture was stirred for a further hour at room temperature, then filtered and reduced to 300 ml concentrated. The concentrate was poured into a saturated aqueous Napco-z-solution (1: 2) and the precipitate separated, washed with water Iu-HCl and sohließlioh water and the solid is then in vacuum for 16 hours. Dried at 100 ⁰ C. 7- (2 ^f , 2 ·, 2'-trichloroethoxy-carboxamido) -3-methyl-4- / ~ N- (2.-methoxybenzyl) -carbamoyl7-A-oephem (58.6 g) was obtained. A sample was crystallized from acetone (melting point 219-220 ⁰ C *

NMR (DMSOd ₆ ) I ^ «7.0 (qJ 4Hj 6.0U) IHf 5.2 (m) 2Hj 4.7 (e) 2H |

4.6 (s) IHj 4.2 (d) 2Hj 3.7 (s) 3H and 1.7 (a) 3H

Example 37

7- (2 ■, 2 ·, 2 '-Trichloräthoxycarboxamido) -3-methyl-4-Z ~ l- (p_-methoxybenzyl) -tetrazol-5-yl7-A -oephem_ ,

7- (2 ', 2', 2'-trichloroethoxyoarboxamido) -3-methyl-4- /. N- £ -methoxybenzyl) -carbamoylZ-A-oephem (44.2 g) and pyridine (14.06 g) in chloroform (300 ml ethanol-free) at 40 ⁰ C were treated with phosphorus pentachloride (27.5 g) and the mixture Stirred at 40 ^° C. for 3 hours, then cooled to room temperature. Then tetramethylguanidinium azide (87.9 g) was added and the solution was stirred for 2 hours at room temperature, then washed with water, aqueous sodium bicarbonate, IN-HCl and water and dried (MgSO «). The organic solution was evaporated under reduced pressure; a gum remained which was dissolved in ithylacetate (200 ml) and sent down a column of alumina. The fraction containing the desired product was collected and the solution was evaporated to dryness under reduced pressure. The product resulted as a pale orange solid (42.4 g).

ORSGiNAL INSPECTED 5 0 9 8 18/1173

NMR (ODGl ₃ ) I ί = 7.0 (q) 4Hj 6, l (d) IH; 6, O (a) IHf 5.6 (q) 2H |

5.4 (8) IHj 5.2 (cl) IHj 4.8 (d) IHf 4.7 (e) 2Hf 3.7 (s) 3H and 1.5 (b) 3Η.

Example 38

7- (2, 2, 2 -trichloroethoxycarboxamido) -3-methyl-4- (tetrazole-5-

7- (2x, 2x, 2'-triohloroethoxycarboxamido) -3-methyl-4- / ~ 1- (£ -methoxybenzyl) tetrazol-5-yl7-A-oephem (40.7 g) in anisole (70 ml ) containing Irufluoreeaigeäur · (260 ml) was 6 hrs. at 5O ⁰ C, the solution was allowed to stand, then dissolved in 1 1 of water and extracted the resulting suspension with Äthylaoetat. The organic solution was extracted with saturated aqueous sodium bicarbonate, the aqueous solution was adjusted to pH 2 with 1 HCl, and the precipitate was extracted into ethyl acetate. The organic solution was dried (MgSO.) And reduced to 7- (2 ', 2',

'2

2 · -Triohloräthoxycarboxamido) -3-methyl-4- (tetrazol-5-yl) -Λ cephem (23 * 2 g) all pale brown solid evaporated. A sample was crystallized from chloroform (äthanolfrei) (m.p. 165-167 ⁰ C).

LMWH (DMSOd ₆ ) S S ■ 6.4 (q) IHf 5.8 (s) IHf 5.2 (m) 2Hj 4.8 (s) 2H

and 1.8 (s) 3H.

Example 39

7- (2 ', 2 ·, 2'-Trichloräthoxycarboxamido) -3 ~ methyl-4- (methoxy-

2
methyltetrazol-5-yl) -A-oephem

To a suspension of 7- (2 », 2 ', 2» -Trichloräthoxycarboxamido) -3-methyl-4- (tetrazol-5-yl) - / ^ "Oephm (8.27 g) in methylene chloride (50 ml) were successively triethylamine (2.22 g) and chloromethyl ether (1.76 g) were added and the solution was stirred at room temperature for 30 min., the solution was washed with water and aqueous sodium bicarbonate and dried (MgSO.). Evaporation under reduced pressure gave 7- (2 ', 2 », 2 • -Trichlorethoxycarboxamido) -3-methyl-4- (methoxymethyltetrazol-5-yl) -Λ oephem (7.3 g) as a cream-colored solid.

509318/1173 us

MMR (CDOl ₃ ): 6 = 6.4 (d) IH ₅ 6, O (cl) IH ₅ 5.8 (a) 2H | 4.7 (s) 2H |

3.4cm) 3H and 1.7 (e) 3H.

geample 4Q

7- (2 ' _f 2', 2 · -! Friciilorätlioxycarboxamido) -. 3- (l-nietliyltetrazol-5-

ylthiomethyl) -4 - (methoxymethyl-tetrazol-5-yl) -A-cephem

7- (2 ·, 2 ·, 2'-Triohloräthoxyoarboxamido) -3 «methyl-4- (methoxymethyltetrazol-5-yl) - ^ -oephem (8.0 g) Ia carbon tetrachloride (160 ml) and chloroform (16 ml) was deoxygenated, then N-Bromauooinimid (3.20 g) and benzoyl peroxide (200 mg) was added and the stirred Miaohung 10 - 15 ⁰ C for two hours with a 250 W tungsten filament lamp lit, while another of chloroform was added to to maintain a clear topcoat} Further benzoyl peroxide (200 mg) was added 30 minutes after the start of the lighting.

, 2.5 hours Bas suooinimide was filtered off, the Filtravat 45 C with the Treated triethylamine salt of 5-meroapto-l-methyltetrazole (3.40 g), the organic solution with water, aqueous sodium bicarbonate and finally water washed and then dried (MgSO.). The organic solution was trooken evaporated under reduced pressure and the residue ohromatographisoh (Kieselgelι Ethyl acetate / Leiohtpetroläther ItI) to the desired product (3.0 g) purified.

NMR (CDCl ₃ ) I 8 - 6.6 (s) IH? 6.2 (d) IHf 6.0 (s) IHι 5.9 (β) 2Η |

5.4Cm) 2Hj4.8 (s) 2111 4.2Cq) 2Hf 4.0 (s) 3H and 3.5 (β) 3Η.

Example 41

7- (2 \ 2 ', 2 -Trichloräthoxycarboxamido) -3- (2-methyl-1,3,4-thia-

diazol (5-ylthiomethyl) -methoxymethyltetrazol-5-yl) -A -cephem

7- (2 ', 2 ·, 2'-Triohloräthoxycarboxamido) -3-methyl-4- (methoxymethyltetrazol ~ 5 ~ ylthiomethyl) -A -cephem (4.0 g) in carbon tetrachloride (60 ml) and chloroform (8 ml ) was treated with N-bromosuooinimide and benzoyl peroxide, as in the example

509 ^ 18/1173

2449814

40 executed. The product was correspondingly with the triethylamine salt of 5 * Mereapto-2 ~ methylthiadiazole (2 g). treated »ea was found after column chromatography (silica, ethyl acetate / light petroleum ether IjI) the compound 7- (2 ', 2 ", 2" -Triohloräthoxycarboxamido) -3- (2-methyl-l, 3,4-Thhladiazol-5-ylt ^^ methyl) M-methoxymethyltetraatol-5-yl) - / f "» oephem (1.1 g).

NMR (ODCl ₅ ) I b «6.6 (e) 1H | 6.3 (d) 1H | 6, l (e) IHf 5.9 (·) 2H |

5.3-5.7U) 2Hf 4, β (β) 2H | 4, Kq) 2Hf 3.5 (·) 3Η) and 2.7 (β) 3Η.

Example 42
7- (2 ^l , 2 ^l , 2'-trichloroethoxyoarboxamido) -3- (l-methyltetrazole-5-

ylthiomethyl) -4- (methQxymethyltetrazol <-5-yl) -A -oephem (2.0 g) in a Essigaäure / Waaser-Misohung 7i3, 20 ml) -on O ⁰ C was stirred with activated zinc dust (2.0 g) treated, the mixture was filtered after one hour and the filtrate was diluted with water (100 ml), adjusted to pH 2 with IN-HOl and then washed twice with ethyl acetate. The clear aqueous solution was adjusted to pH 6 with sodium carbonate and extracted with chloroform. The organic solution was washed with a pH7 buffer, dried (MgSO /) and finally under reduced pressure to give 7-amino-3- (1-methyltetrAZOl-5-ylthiomethyl) -4- (methoxymethyltetrazol-5-yl) -A -cephem (0 * 9 g), an ohromatographically pure foam, evaporated.

NMR (CDCl ₃ ): S «6.6 (s) IHf 5.95 (») IHf 5.85 (s) 2Hf 5.25 (d) IHf

4.70 (d) IHf 4, K <i) 2Hf 3.95 (e) 3H and 3.5 (s) 3H,

7-Amino-3- (2-methyl-1,3t4-thiadiazol-5-ylthiomethyl) -4- (methoxymethyl-tetrazol-5-yl) - /! \ -Oephem was prepared in a similar manner.

NMR (CDCl ₃ ) J S «6.8 (s) IHf 6.4 (s) IHf 6.0 (s) 2Hf 5.4 (d) IHf

4.8 (d) IHf 4.2 (q.) 2Hf 3.7 (e) 3H and 3.2 (e) 2H.

509 ^ 18/1173

Example 43

7-Ietrazol-1-ylacetamido) ~ 3- (2-methyl-1,3,4-thiadiazol-5-ylthio · +

3 ι

methyl) -4- (tetrazol-5-yl) -A ~ ^ce P ^hem '

A. 7- (2etrazol-1-ylaoetamido) -3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) -4- (methoxymethyl-tetrazol-5-yl) -Λ -cephem

7-Amino-3- (2-methyl-lj3t4-thiadiazol-5-ylt] aiomethyl) -4- (met] ioxy methyltetrazol-5-yl) -A-oephem (430 mg) and Ietrazol-1-yllic acid (133 mg) in tetrahydrofuran (10 ml) and acetonitrile (10 ml) were treated with dioyolohexylcarboaiimide (215 mg) and let the hybrid stand for one hour at room temperature »then filtered and reduced to 7- (tetrazol-l-ylaoetamido) -3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) ~ 4- (methoxymethyltetrazole * -5-yl) -A -oephem (520 mg) ale thin layer chromatographically pure, cream color solid evaporated (520 mg)

NMR (CDOl ₃ ) J 6 »9, Ks) 1H | 6.6 (s) I 6.0 (s) 1H »5.9 (a) 2H |

5.4 (s) 2Hj 5.4U) 1H | 5.2 (d) 1H »4.0 (<i) 2Hj 3.4 (s) 3H and 2.6 (s) 3H.

B. 7- (Tetrazol-l-ylacetamido) -3- (2-methyl-1,3,4-thia-

diazol-5-ylthiomethyl) -4- (methoxymethyl-tetrazol-5-yl) / j -G ephem-1-oxide

7- (tetrazol-1-ylaoetamido) -3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) -4- (methoxymethyl-tetrazol-5-yl) -A. -oephem (500 mg) in chloroform (20 ml) was treated with stirring with m-chloroperbenzoic acid (219 mg) ^{, pyridine (40 mg) was added frequently for 1 hour at 0} ° C., the mixture was allowed to warm to room temperature and after a concentrated for another hour in the low pressure; Ethyl ether was added to the concentrate. The cream-colored solid precipitate was separated off, dried under reduced pressure and the desired product (410 mg) was obtained as a cream-colored solid which was pure chromatographically. HMR (DMSOd ₆ / Acetone d _& ) i S- 8.9 (s) IHf 6.0 (s) 2H | 6.0, IHf

5.6 (s) 2Hf 5.2 (d) IHf 4.5U) 2Hf 4.0 (s) 2Hf 5.5 (e). 3H and 2.7 (e) 3H.

SO 9 § 18/1173

- 56 -

C. 7- (Tetrazol-l ~ ylaoetamido) -3- (2 ~ methyl-1,3,4 ~ thiadiazol-5-ylthiomethyl) -4 - (methoxymethyltetrazol - 5-yl) -

• 2

/ f-cepheia

7- (Tetrazol-1-ylacetamido) -3- (2-methyl-1,3,4-thiadiazol ~ 5-ylthiomethyl) -4- (methoxymethyltetrazol-5-yl) - / \ - cephem-1-oxide, ( 400 mg) in dimethylformamide (10 ml) was treated with stirring with anhydrous tin (II) chloride (400 mg) and aoetylochloride (200 mg) at ⁰ ° C., the mixture was stirred for 1 hour and then poured into excess water. The aqueous mixture was extracted several times with chloroform and the organic solution was washed several times with water, the chloroform solution was then dried (MgSO.) And evaporated under reduced pressure to give the desired, thin-layer chromatographically pure compound in the form of a foam (250 mg).

IfMR (CDCl ₃ ): £ - 9.0 (s) IH; 8.7 (d) IH; 6.0 (s) 2H> 6.0, IH;

5.4 (e) SHj 5.2 (d) IHj 4.4 (aJ 2H | 3.7U) 2Hj 3.4 (s) 3H and 2.7 (s) 2H.

D. 7 - (^ etrazol-1-ylaoetamido) -3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) -4- (tetrazol-5-yl-A-cephem

7- (Ietrazol-1-ylacetamido) -3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) ~ 4- (methoxymethyltetrazol-5-yl) - / \ -cephem (70 mg) in trifluoroacetic acid . (2 ml) and anisole (0.5 ml) was 6 hours at 2O ⁰ C allowed to stand, after which the trifluoroacetic acid under reduced pressure removed; an oil remained. This residue was diluted with ethyl acetate and the resulting organic solution extracted with saturated aqueous sodium bicarbonate solution, the aqueous solution acidified to pH 2 with 2N HCl and the solution then extracted with ethyl acetate. The organic solution was dried (MgSO.) And evaporated under reduced pressure to give an oil which, when diethyl ether was added, crystallized into the desired product in the form of colorless needles (35 mg, ohromatographically pure).

509818/1173

LMWH (trifluorescent acid-d) » i> » 9.5 (s) IHi 5.8Cd) IHf 5.5C ») 2H |

5.2Cd) 1H | 4.5Ca) 2H | 3.6Ca) 2H and 2.8 (s) 3H.

Example 44

7- / D- (0 - Hydroxy - # - phenylaoetamido) -3-Cl ~ methyltetrazol ~ 5-ylthiomethyl) -4-Ctetrazol-5-yl) -A-otphem

A. 7-D-C (X -

Based on the appropriate substances and with the procedure · « way of example 4? became the familiar intermediate posed.

₃ ) J b - 8.2Cs) IHt 7.3Cs) 5H | 6.4Cs) IHj 6.2Ca) 1H »5.9Ce) 1H | 5.7C ») 2Hf 5.5Cq) IHf 5.2Cd) IHf 4.0Cq.) 2H» 3.9Cs) 3H and 3.4Cs) 3H.

B. 7-DC δ ^ -Formyloxy- o ⁱ -phen; ylaoetamido) -3-Cl-iaethyl-tetrazol-5-ylthiomethyl) -4-C-methoxymethyl-tetra-ol-5-yl) -ix -cephem-1-oxide

Using the above-mentioned intermediate of Example 44 and following the procedure of Example 43, the desired compound was obtained isolated and / of the next reaction without further purification used.

C. 7-DC ^ -S ¹ OrByIoXy- ^ct > -phenylacetamido) -3-Cl-iaethyl- · tetrazol-5-ylthiomethyl) -4-Caethoxymethyltetrazol-5-yl) -A - oephem

Starting from the appropriate compound of Example 44 and Using the procedure of Example 43, the desired product was made.

50 9 a 18/1173

2U9834

NMR (CDOL ₅₎ I h "8.3 (s) IHf 7.4 (s) 5H | 6.3 (s) IHj 6 _f 0 (s) 2H |

6.0, IHι 5.2 (d) IHn 4.5U) 2Hj 4.0 (b) 3Hj 3.8 (s) 2H and 3.5 («) 3H.

D. 7-D- (& -Formyloxy- ^ - phenylacetamido) -3- (1-methyltetrazol-5-ylthiomethyl) -4- (tetrazol-5-yl) -A -oephem

The trifluoroacetic acid-anisole treatment was based on the product of Example 44 Repeat Example 43 to produce the desired product.

LMWH (Aoeton ~ d ₆ / D ₂ 0) » i> * 8.3 (e) IHf 7.5 (m) 5H | 6.2 (e) IHf

5.9 (d) 1H | 5.3 (d) 1H »4.4 (e) 2H and 4.0 (HOD).

(Aoeton-d ^ / DgQ / ilxif luoresaetic acid-d) t

b - 4.4 (e) 2Hf 4.0 (s) 3H and 3.9 (a) 2H.

E. 7-D- (& -Hydroxy- ö ⁱ -. Phenylacetamido) -3- (1-methyltetrazol-5-ylthiomethyl) -4- (tetrazol-5-yl) -A ~

7_D- (C ^ -Formyloxy- ^ - phenylacetamido) -3- (1-methyltetrazol-5-ylthiomethyl) -4- (tetrazol-5-yl) -i! R- ^oe P ^il e ^ia (100 mg) in aqueous Sodium bicarbonate solution (5 ml) was left to stand for 3 hours at room temperature, the reaction mixture was then adjusted to pH with 2N HGl and extracted with ethyl acetate. The organic solution was dried (MgSO.) And evaporated under reduced pressure to give the desired product as a cream-colored solid (35 mg, essentially pure).

Example 45

- ^ÖC -phenylacetamido) -3- (1-methyl-tetrazol-5-ylthiomethyl) -4- (tetrazol-5-yl) -aoephem trifluoro acetate

A. 7- / ~ "D- 0 ^ - (jt-Butoxycarbonylamino) -phenylacetamide £ 7-

3- (l-methyltetrazol-5-ylthiomethyl) -4- (methoxymethyl-

tetrazol-5-yl) -A-cepiem
7-Amino-3- (l-methyltttrazol-5-ylthiomethyl) -4- (methoxymethyl-

50 9 a 18/1173

2U9834

tetrazol-5-yl) -A ² -oepkem (100 mg) and Ni-butoxycarbonylphenyl · glycine (65.4 mg) in ethyl acetate / acetone / trile (111.2 ml) were treated with dicyclohexylcarbodiimide (52 mg) at 15 ° G. After one hour the mixture was filtered, the filtrate diluted with ethyl acetate (10 ml) and the resulting solution washed with 1/1 of HCl, aqueous sodium bicarbonate and finally water. Drying (MgSO ^) and evaporation in the Unterdruok ergato the desired product (152 mg) as a pale yellow Feetetoff.

NMR (CDOl ₃ ) J b = 7.25 (8) 5Hj 6.5 (s) IHj 6.0 (s) IHj 5.8 (a) 2H |

. 5.6 (m) 2H | 5.3 (m) 2H; 4.1 (<ι / 2Ηϊ 3.9 (β) 3Η | 3.5 (s) 3H and 1.4 (a) 9H.

B. 7 - / "" D-O ^ - - (t-butoxycarbonylamino) phenylaoetamido7-3-. (1-methyltetrazol-5-ylthiomethyl) -4- (methoxymetliyltetrazol-5-yl) - ^^ '^ - cephem-1-oxide

7_ / ~ D -. 'X - (^ t-Butoxycarbonylamino) phenylacetamido7-3- (1-methyltetrazol-5-ylthiomethyl) -4- (methoxymethyltetrazol-5-yl) -A * cephem (140 mg, 0.22 mmol ) in chloroform (2 ml) was treated with m-chloroperbenzoic acid (51 mg, 85 ⁰ Io) at ^{0 0} C with stirring, the solution kept for one hour at Q ⁰ C and then pyridine (20 mg) was added; the solution was allowed to warm to room temperature and held at this temperature for a further two hours.

The reaction mixture was diluted with chloroform, with IN ^; Äfll and aqueous sodium bicarbonate and then dried (JIgSO ₄ ). Evaporation in vacuo gave the desired product as a cream-colored solid (120 mg).

This substance was used directly in the next reaction without further purification.

C. 7-Z D - ^ - (i-Butoxycarbonylamino) phenylaoetamido7-3- (l-methyltetrazol-5-yl-thiomethyl) -4- (methoxy, ethyltetrazol-5-yl) -Λ -cephem

l - / _ D- ' ^x - (i-Butoxycarboxylamino) phenylacetamido7-3- (l-methyl-

509 & 18/1173

■ ζ

tetrazol-5-ylthiomethyl) -4- (methoxymethyltetrazol-5-yl) -A cepheiii-1-oxide (120 mg) was suspended in dimethylformamide (0.3 ml) and acetonitrile (0.75 ml), the mixture with acetyl chloride (60 mg) and anhydrous tin-II-uhloria (3ö mg; ^{treated with stirring for one hour at 0 0} G, to room temperature

left to warm, stirred for another hour, then under reduced pressure concentrated and diluted with ethyl acetate. The organic, Solution was washed with water and aqueous sodium bicarbonate and finally dried (MgSO,). Evaporation in the lower i pressure gave an oil, which by preparative Dünnsohiohtohromato- j

graphie (silica, ethyl acetate / lent petroleum ether, 3 »2) to the j desired product was purified as pale yellow foam (60 mg).

NMR (ODCl ₅ ) I b = 7.4 (e) 5Hj 7.2 (d) IHf 5, Ö (m) 4Hj 5.3 (d) IH |

5.2 (d) IHf 4.5U) 2Hf 4 * 0 (e) 3Hj 3.8 (e) 2H | 3.6 (s) 3H and 1.5 (a) 9H.

D. 7-D- ( OC -amino- & -phenylacetamido) -3 ~ (l-methyltetra-

• 2

zol-5-ylthiomethyl ~ 4- (tetrazQl-5 ~ yl) -A -oephemtrifluoroacetate

7- / D- (oC - ^ - butoxycarbonylamine © ~ ^ -phenyl) acetamido7 ^w 3- (1-methyl-tetrazol-5-yl-thiomethyl) -4- (methoxymethyl-tetrazol-5-yl) - / y-cephem (55 mg ) in Trifluoraoetaäur «(2 ml) and Aniaol (0.5 ml) were left to stand at 20 C for 6 hours, then the l'rlfluoroacetic acid evaporated under reduced pressure and the residue treated with ether. The resulting solid was separated off, washed in portions with dry ether and dried in a high vacuum to give the desired product as trifluoroacetic acid.

NMR (E _fc

b x 7.4 (s) 5H | 5.8 (d) IHf 5.2 (d) IHf 5 ,. 4.2 (s) 2Hf 4.0 (s) 3H and 3.6 (s) 2H.

Example 46

The following ingredients were used in the specified oil

509818/1173

share vermieohti 2449834 - 61 - Sucrose, USP ifapioca strength Magnesium stearate 80.0 7-phenylacetamido-5-methyl-4- 13.5 (tetrazoi-5-yl) - "iAj ^ -oephem 6.5 100.0

After thorough mixing, the mixture was compressed into tablets, each tablet containing 100 mg of the cephem compound.

The same tablets were made with 50 and 250 mg of the active ingredient by choosing appropriate proportions of the cephem compound and excipients.

Example 47

The following ingredients were made into the indicated parts by weight marrying each other

Calcium carbonate. 17 »6

Dicalcium phosphate 18.8

Magnesium trisilioate 5 * 2

Lactose, USP 5.2

Potato starch - 0.8

7-phenoxyacetamido-3-methyl-
^ -Ctetrazol-ö'-yD- ^ -oephem 50.0

The thoroughly mixed pharmaceutical composition was filled into white gelatin capsules each containing 100 mg of the active ingredient.

The same capsules with 50 and 250 mg of the active ingredient were made by changing the proportions of the cephem compound and the excipi * entia mix prepared.

Example 48

The isodium salt of 7- (2-thienylaoetamido) -3-methyl-4- (tetrazol-5-yl) -A-oephem was thoroughly treated with sodium citrate (4% by weight) mixed and ground, the dry ground mixture sterilized and filled into sterile vials with serum caps

50 9 a 18/117 3

were ignored under sterile conditions. If this preparation is to be used »you inject sufficient sterile water; ser one that the contents dissolve aioh and a solution with 25 mg / ml of the active ingredient is formed. For the parenteral "administration, the solution is' off with a syringe from the _Pläschohen: pulled.

Correspondingly, by changing the added! Amount of water solutions with 10 »50» 100 and 200 mg / ml des Active ingredient produced.

Example 49

Potassium salt of 7- / D- # -Amlno - # - phenyl) aoetajaid ^ -3-methyl-4- (tetrazol-5-yl) -A -oephemes

In a stirred solution of 1.94 g of 7 ~ / D- ( OL -amino- CL -phenyl) acetamido7-3-methyl-4- (tetrazol-5-yl) -ia-oephem in 100 ml of methanol, which on - 30 ⁰ C was cooled, was a sufficient amount for the addition of equivalent base einee a 1.0N solution of potassium hydroxide in methanol are added dropwise "the Miβοhung to ⁰ ° C allowed to warm and then added dropwise with stirring in 700 ml of ether. The precipitate which formed was filtered off and dried in a high vacuum. The desired potassium salt was obtained in good yield *

When repeating this procedure, but with an equimolar amount of sodium hydroxide instead of potassium hydroxide, the product is the sodium salt of 7 -JTv- (amino-d -phenyl) aoetamido7-3-methyl-4- (tetrazol-5-yl) Ά ^ -oephem.

Example 50

Calcium salt of 7- £ ~ V ~ ^ -amino-ÖC - (^ .- hydroxyphenyl) acetamido / -3-methyl-4-tetrazol-5-yl) -A-cephem

In a stirred solution of 3 | 87 g of 7-Z ~ D - * - amino-Ä .- (j3-hydroxy phenyl) -aoetamido7-3-methyl-4- (tetrazol-5-yl) - ^^ - cephem in 40 ml of dimethylformamide became a cloudy solution of 370 mg

509.E1 8/1173

Calcium hydroxide min.eingegeben in the period of 5, the mixture at 35. «■ * 40 ⁰ C for one hour and then heated an additional 30 ml of dimethylformamide was added, the mixture an additional 30 min at 35 -. 40 ⁰ G held and the cooled solution then 700 ml of ether were added dropwise. An oil precipitated here. The solvent was poured off and the residue was poured into 100 ml of ethanol, followed by 400 ml of ether. The oil slowly solidified and was filtered off and dried under high vacuum. Ee resulted in the desired potassium salt.

Example 51

Hydrochloride salt of 7- / Td - (^ -amino- % -phenyl) aoetamido7-3-methyl-4- (tetrazol-5-yl) -A -eephem

A slurry of 50 mg / ~ b- ((X-Amino-ί ^ -phenyl) ao et ami do / · 3-me.thylr-4- (tetrazol-5-y ^ - ^^^ - oephem in 2 ml deionized Water was stirred for 5 minutes at room temperature, adjusted to pH 2.45 with dilute hydrochloric acid, and the solution thus obtained lyophilized immediately. The hydrochloride salt of the desired compound resulted as a white solid.

Claims

09818/1173

Claims (1)

P. Claims Cephem derivative of the formula HNH and the salts thereof, 'CH ₂ A wherein T is an 'i'etrazolyl precursor group iat that either N N-R-, or or a tetrazolyl • C ^ Ν "^ 'N-N R_ 5 0 9 8 18/1173 where R ^, R, and R _{5 are} each selected from the group consisting of hydrogen, chlorine, bromine, fluorine, methyl, methoxy and phenyl, and (3) an acyl group of the formula.-p 1 ^ _n AK juji | _η υ- where A is selected from the group consisting of hydrogen, acetylene, 1-methyl-5-tetrazolylthio, 2-methyl-1, 3,4-thiadiazolyl-5-thio and bromine, and R _{2 is} a tetrazolylcephem nitrogen protecting group or a Is a precursor group thereof and is selected from the group that is made up of -CH- / V-R wherein Rg is selected from the group consisting of alkyl having 1 to 3 Carbon atoms and phenyl, and R ^ is selected from the group which consists of hydroxy, methoxy, alkanoyloxy having 2 to 4 carbon atoms and benzyloxy, and Rq is from the group is chosen, the hydrogen, hydroxy, fluorine, chlorine, bromine, iodine, Is methyl, methoxy, alkanoyloxy of 2 to 4 carbon atoms, phenyl and benzyloxy, and -CH
J. ~ if V ^R io where Rq and R _{10 are} each selected from the group consisting of hydrogen and methyl and X is selected from the group consisting of oxygen and sulfur, R- is selected from the group consisting of Hydrogen, alkanoyloxymethyl with 3 to 6 carbon atoms, 1- (alkanoyloxy) ethyl with 4 to 7 carbon atoms, methoxymethyl and phthalidyl, and R ₁ - is selected from the group consisting of R-, and Rp, Ar from is selected from the group consisting of cyano, bromine, phenyl, mono- or substituted phenyl, in which each substituent is hydroxy, 5 0 9.8 18/11 7-3 Is fluorine, chlorine, bromine, amino, methoxy or methyl, phenoxy, Phenylthio, pyridylthio, thienyl, 2-methyl-l, 3,4-thiadiazol-5-ylthio, 1-tetrazolyl, alkyl with 1 to 12 carbon atoms, Alkenyl with 2 to 12 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, cycloalkenyl with 5 to 8 carbon atoms, Cycloheptatrienyl, 1,4-cyclohexadienyl, 1-aminocycloalkyl with 4 to 7 carbon atoms, 5-methyl-3-phenyl-4-isoxazolyl, 5-14ethyl-3- (o-chlorophenyl) -4-isoxazolyl, 5-methyl-3- (2,6-dichlorophenyiy-isoxazolyl, 5-methyl-3- (2-chloro-6-fluorophenyl) -4-isoxazolyl, 2-alkoxy-l-naphthyl with 1 to 4 üohxenstoffatomen in the Alkoxy group, sydnonyl, furyl, pyridyl, thiazolyl, isothiazolyl, Pyrimidinyl, triazolyl, imidazolyl, pyrazolyl, substituted Phenoxy, substituted phenylthio, substituted pyridylthio, substituted thienyl, substituted furyl, substituted Pyridyl, substituted tetrazolyl, substituted thiazolyl, substituted isothiazolyl, substituted pyrimidinyl, substituted Triazolyl, substituted imidazolyl and substituted pyrazolyl, each substituted part with is substituted up to 2 substituents from the group are selected from fluorine, chlorine, bromine, hydroxy, hydroxymethyl, Amino, Ν, Ν-dialkylamino with 1 to 4 carbon atoms in each alkyl group, alkyl with 1 to 4 carbon atoms, aminomethyl, aminoethyl, alkoxy with 1 to 4 carbon atoms, Alkylthio with 1 to 4 carbon atoms, 2-aminoethoxy and N-alkylamino with 1 to 4 carbon atoms, Q consists of the Group is selected which consists of hydrogen, hydroxy, azido, amino and carboxy, η is an integer of 0 or 1, A is selected from the group consisting of hydrogen, aoetoxy, l-methyltetrazol-5-ylthio and 2-methyl-1,3,4-thiadiazol-5-ylthio exists, provided, however, that when Ar is selected from the group consisting of pyridylthio, phenoxy, Phenylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio, bromine and cyano and η is 1, Q is selected from the group consisting of hydrogen and carboxy, and provided that when R 509818/1173 Ar _ is, I. 7 ^H ll or v \. and A is a group other than bromine, and when A is bromine T is a tetrazolyl group. 2. Compound according to claim 1, characterized in that that R is a group other than _ S, T "'is GHHH ₉ , Z.CH7 _n G- </ Q
Hp is p-methoxybenzyl and A is hydrogen or acetoxy. 3. 'Compound according to claim 2, consisting of 7- (2', 2 ', 2' - ^r J) richlorethoxycarboxaiaido) -5-methyl-4- £ N- (£ -methoxybenzyl) carbamoyl7- ^ -cephem 4.. A compound according to claim 2 consisting of 7-benzyloxycarboxamido) -3-methyl-4-Z N- (£. -Methoxybenzyl) carbamoyl / - ^ cephem 5. Compound according to claim 2, consisting of 7- (N-triphenylmethylamino) -3-methyl-4-Z N- (p_-methoxybenzyl) carbamoyl7- £ -cephem 6. A compound according to claim 2, consisting of 7- (2 ', 2', 2'-Trichloräthoxycarboxamido) -3-acetoxymethyl-4- / ~ N- (pmethoxybenzyl) carbamoyl7- ^ -cephem 7. A compound according to claim 2, consisting of 7- (benzyloxycarboxamido) -3-acetoxymethyl-4 - /. ~ N- (E.-methoxybenzyl) car- - / i -cephem 509818/1173 8. A compound according to claim 2 _f consisting of 7- (N-triphenylmethylamino) -3-acetoxymethyl-4-Z N- (p_-methoxybenzyl) carbamoyl - / \ - eephem 9. A compound according to claim 2, consisting of 7- (2 ', 2', 2 ^f -Trichloräthoxycarboxamido) -3-methyl-4-Z N- (p _, - methoxybenzyl) -carbamoyl7- * Z '-cephem 10. A compound according to claim 9 (formula I), characterized in that that E is a different group than -__ " Z7 and T is tetrazolyl, A is hydrogen, acetoxy, 1-methyl-5-tetrazolylthio and 2-methyl-1,3,4-thiadiazolyl-5-thio, and R _{11 is} p-methoxybenzyl. 11. Compound according to claim 10, consisting of 7- (2 ', 2', 2 · -Trichloräthoxycarboxamido) -3-methyl-4-Z ¹ ^ (p_-methoxybenzyl) -tetrazol-5-yl7 - '/ i - 12. A compound according to claim 10, consisting of 7- (N-triphenylmethylamino) -3-iaethyl-4-Z l- (£ .- ^> niethoxybenzyl) tetrazole -Z, -cephem 13. Compound according to claim 10, consisting of 7-amino-3-methyl-4-Z 1- (p_-methylbenzyl) tetrazol-5-yl7 ~ Z -cephem 14. Compound according to claim 10, consisting of 7- (benzyloxycarboxamido) -3-acetoxymethyl-4-Z ! - (p-Methoxybenzyl) tetrazol-5-yl7- / A -cephem 15. A compound according to claim 10, consisting of 7- (2 », 2 ', 2' -Trichlorathoxyearboxamido) -3-acetoxymethyl-4-Z ~ l ~ (l. methoxybenzyl) tetrazol-5-yl7-Z \ - 16. A compound according to claim 10, consisting of 7-amino-3-acetoxymethyl-4-Z 1- (£ -methoxybenzyl) tetrazol-5-yl7- / A -cephem 17 compound according to claim 10, consisting of 7- (Ben- S0981 8/1173 zyloxycarboxamido) -3- (1-methyltetrazol-5-ylthiomethyl) -4 ~ Z 1 - (^ - methoxybenzyl) tetrazol-5-yl7 ~ A -cephem 18. "A compound according to claim 10, consisting of 7-C2 ¹ , 2 ', 2'-Trichlorethoxycarboxamido) -3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) -4- / ~ 1- (£, -methoxybenzyl) tetrazol-5 «yl7-Zi -cephem 19. A compound according to claim 10, consisting of 7-amino-3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) -4-Z. 1- (p_-methoxy-benzyl) -tetrazol-5-yl / -Z \ -cephem 20. A compound according to claim 10, consisting of 7 ~ (2 ', 2 ', 2'- ^r Jirichloräthoxycarboxamido) -3-methyl-4-Zl- (£. -Niethoxybenzyl) -tetrazol-5-yl7-A-cephem 21. A compound according to claim 10, consisting of 7- (Ben ~ zyloxycarboxamido) -3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) - __ χ 4- / 1- (£ -methoxybenzyl) tetrazol-5 ~ yl / -A-cephem 22. Compound according to claim 11, characterized net that R is a group other than _ "and T is a ^ 7 Is tetrassyl group, H.-, and R -, -, are each hydrogen. 23. A compound according to claim 22, consisting of 7-amino-3-methyl-4- (tetrazol-5 »-yl) -A 24. A compound according to claim 22, consisting of 7-amino-3-acetoxymethyl-4- (tetrazol-5 ~ yl) -A -cephem 25. A compound according to claim 22, consisting of 7-amino-3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) -4- (tetrazol-5-yD- / ^ - cephem 26. Compound according to claim 22, consisting of 7-amino-3-Cl-methyltetrazol-5-ylthiomethyl) -4- (tetrazol-5-yl) - / ^ "G ethers 27 · Connection according to claim 22, consisting of 7- (2 ', 509818/1173 -70- 2A49834 2 ', 2 -Trichlorethoxycarboxamido) -3-methyl-4- (tetrazol-5-yl) - / Nj-cephem 28. A compound according to claim 11, characterized in that R is a group other than _ "iat and T is a group Z7 Q
Is tetrazoyl group and R ₁ and R _{11 are} each methoxymethyl. 29. A compound according to claim 28, consisting of 7- (2 ',
2 ', 2 ^l ~ irichloroethoxycarboxamido) -3-methyl-4-Z l- (methoxymethyl) · tetrazol-5-yl7- / A-cephem 30. A compound according to claim 28, consisting of 7- (2 ',
2 ', 2 ^l -Triohlorethoxycarboxamido) -3-methyl-4 ~ Z 2- (methoxymethyl) -tetrazol-5-yl7-A-cephem 31. The compound of claim 30 consisting of 7-amino-3-methyl-4-Z 1-methoxymethyl) tetrazol-5-yl / -A-cephem 32. Compound according to claim 30, consisting of 7-amino 3-methyl-4 ~ Z 2- (methoxymethyl) tetrazol-5-yl7 ~ A ** oephem 33. 'Compound according to claim 30, consisting of 7-amino -? 3-acetoxymethyl-4-Z 1- (methoxymethyl) tetrazol-5-yl7-A "" ^c ephem 34. A compound according to claim 30, consisting of 7 amino-3-aoetoxymethyl-4-Z 1- (methoxymethyl) tetrazol-5-yl7-A-cephem 35. Compound according to claim 30, consisting of 7-amino 3- (l-methyltetrazol-5-ylthiomethyl) -4 "-Z l- (methoxymethyl) tetrazol-5-yl7- / f-cephem 36. A compound according to claim 30, consisting of 7-amino-3- (l-methyltetrazol-5-ylthiomethyl) -4-Z 2- (methpxymethyl) tetrazo 1 - 5 -ylj-A "* 37. Compound according to claim 30, consisting of 7-amino-3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) -4 - / "1-X ^ ethoxymethyl) tetrazol-5-yl7- / \ ~ cepheia 509818/1173 38. Connection according to claim. 30, consisting of 7-amino 3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) -4-Z ~ 2- (methoxy- methyl) te trazol-5-yl7-Zl, -cephem 39. Compound according to claim 30, consisting of 7- (2 ', 2'-, 2' -tribromoethoxycarboxamido) -3-methyl-4-Z ~ l ~ ( ^me ' ^{tl: 10X} y ^me ' ^tii y ¹ ) tetrazole 5-yl7-Z ^ -cephem 40. Connection according to claim 30, consisting of 7- (2 *, 2 ♦, 2'-tribromoethoxycarboxamido) -3-methyl-4 ~ Z ~ 2- (methoxymethyl) tetrazol-5-yl7-'Ä -cephem 41. A compound according to claim 40, characterized in that R _ is P, and T is a tetrazolyl group, the Z7 is substituted by Ε-, Ar is selected from the group consisting of Phenyl, phenoxy and 2-ihienyl, Q is hydrogen, η is one is an integer of 1 and A is hydrogen. 42. A compound according to claim 41, wherein T is consisting of 7-phenylacetamido-3-methyl-4- (tetrazol-5-yl) - / f-cephem or 7-phenoxyacetamido-3-methyl-4- (tetrazol-5-yl) -Z: -cephem or 7- (2-Thienylacetamido) -3-methyl-4-tetrazol-5-yl) -12- cephem 45 · The compound of claim 41, wherein ΐ is composed of 7-phenylacetamido-3-methyl-4 ~ Z ~~ 2- (pivaloyloxymethyl) -tetrazol-5-yl7- / J-cephem, 7-phenoxyacetamido-3-methyl-4-Z 2- (pivaloyloxymethyl) tetrazol ~ 5-yl7-Ä ⁵ -cephem,
7- (2-Thienylacetamido) -3-methyl-4-Z ~ 2-pivaloyloxymethyl) tetra- 609818/1173 44. The compound of claim 1 wherein A is bromine consisting of . ^N and RNH CH ₂ Br wherein R is selected from the group consisting of 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxyoarbonyl, benzyloxycarbonyl, Hydrogen and ₌ c where R ^, R. and R ^ are each selected from the group consisting of hydrogen, chlorine, bromine, fluorine, methyl, methoxy and phenyl,
R _{1 is selected} from the group consisting of hydrogen, alkanoyl 509818/1173 oxymetliyl with 3 to 6 carbon atoms, 1- (alkanoyloxy) ethyl with 4 "to 7 carbon atoms, methoxymethyl and phthalidyl exists, and R _{11 is selected} from the group consisting of hydrogen, alkanoyloxymethyl with 3 to 6 carbon atoms, l- (alkanoyloxy) ethyl with 4 to 7 carbon atoms, methoxymethyl, phthalidyl, wherein Rg is selected from the group consisting of alkyl of 1 to 3 carbon atoms and phenyl, and Ry is selected from the group consisting of hydroxy, methoxy, alkanoyloxy of 2 to 4 carbon atoms and benzyloxy, and R _{Q is selected} from the group is selected, which consists of hydrogen, hydroxy, fluorine, chlorine, bromine, iodine, methyl, methoxy, alkanoyloxy with 2 to 4 carbon atoms, phenyl and benzyloxy and where Rq and R _{10 are} each selected from the group consisting of hydrogen and methyl, and X is selected from the group consisting of oxygen and sulfur. 45. Connection according to claim 44, characterized by that R is 2,2,2-trichloroethoxycarbonyl. 46. Compound according to claim 45 _f consisting of 7- (2 ·, 2 ', 2 ^l -trichloroethoxyearboxamido) -3-bromomethyl-4-Z 1- (methoxymethyl) tetrazol-5-yl7 ~ A-oephem 47. "Compound according to claim 4.5 1 consisting of 7- (2», 2 ', 2 ^l -Triohloräthoxycarboxamido) -3-bromomethyl-4 "-Z 2- ^ iethoxy- methyl) tetrazol-5-yl / -A'-oephem 5098 18/1173 48. Process for the preparation of a cephem derivative the formula SNH £
/ V / and the salts thereof, where T is a tetrazolyl precursor "2LCNHRp" or a tetrazolyl group is that either NH ₁₁ ^{or B} l is, in which H is selected from the group consisting of (1) hydrogen, (2) a Stiokatoffschutzgruppe, the 2,2,2-trichloroethoxycarbonyl, 2,2,2-50ribromoethoxycarbonyl, benzyloxycarbonyl or where R 1, R and R _{5 are} each selected from the group consisting of hydrogen, chlorine, bromine, fluorine, methyl, methoxy and phenyl, and (3) an acyl group of the formula O O consists, A is selected from the group consisting of hydrogen, acetoxy, 1-methyl-5-tetrazolylthio, 2-methyl-1,3,4-thiadiazolyl-5-thio 509818/1173 and bromine b., and Rp is a tetrazolyl cephemic protecting group or a precursor group for it is and is chosen from the group that made up wherein Rg is selected from the group consisting of alkyl with 1 to 3 carbon atoms and phenyl, and Ry from the group is selected from hydroxy, methoxy, alkanoyloxy having 2 to 4 carbon atoms and benzyloxy, and Rg is selected from the group selected from hydrogen, hydroxy, fluorine, chlorine, bromine, iodine, methyl, methoxy, alkanoyloxy with 2 to 4 carbon atoms, Consists of phenyl and benzyloxy, and -OH- / N where Rg and R _{1 are} each selected from the group consisting of hydrogen and methyl and X is selected from the group consisting of oxygen and sulfur, R _{1 is selected} from the group consisting of hydrogen, alkanoyloxymethyl with 3 to 6 carbon atoms, 1- (alkanoyloxy) ethyl having 4 to 7 carbon atoms, methoxymethyl and phthalidyl, and R _{11 is selected} from the group consisting of R-, and R ₂ is selected from the group consisting of Cyano, bromine, phenyl, mono- or disubstituted phenyl, in which each substituent is hydroxy, fluorine, chlorine, bromine, amino, methoxy or methyl, phenoxy, phenylthio, pyridylthio, thienyl, 2-methyl-1,3,4-thiadiazole 5-ylthio, 1-tetrazolyl, alkyl with 1 to 12 carbon atoms, alkenyl with 2 to 12 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, cycloalkenyl with 5 to 8 carbon atoms, cycloheptatrienyl, 1,4-cyclohexadienyl, 1-aminocyeloalkyl with 4 to 7 carbon atoms, 5-methyl-3-phenyl-4-isoxazolyl, 5-methyl-3- (o-chlorophenyl) -4-isoxazolyl, 5-methyl-3- (2,6-dichlorophenyl) -4-isoxazolyl, 5-methyl-3- (2-chloro-6-fluorophenyl) -4- .50 98 18/1173 isoxazolyl, 2-alkoxy-1-naphthyl with 1 to 4 carbon atoms in the alkoxy, sydnonyl, furyl, pyridyl, thiazolyl, isothiazolyl, pyrimidinyl, triazolyl, imidazolyl, pyrazolyl, substituted phenoxy, substituted phenylthio, substituted pyridylthio, substituted puridylthio , substituted pyridyl, substituted tetrazolyl, substituted thiazolyl, substituted isothiazolyl, substituted pyrimidinyl, substituted triazolyl, substituted imidazolyl and substituted pyrazolyl, each substituted part being substituted with up to 2 substituents selected from the group consisting of fluorine, chlorine , Bromine, hydroxy, hydroxymethyl, amino, N, N-dialkylamino with 1 to 4 carbon atoms in each alkyl group, alkyl with 1 to 4 carbon atoms, aminomethyl, aminoethyl, alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, 2 * -Aminoethoxy and N-alkylamino with 1 to 4 carbon atoms, Q is selected from the group i st, which consists of hydrogen, hydroxy, azido, amino, and carboxy.
η is an integer of 0 or 1, A is selected from the group consisting of hydrogen, acetoxy, l-methyltetrazol-5-ylthio and 2-methyl-l, 3,4-thiadiazol-5-ylthio exists, with the proviso that when Ar is selected from the group consisting of pyridylthlo, phenoxy, phenylthio, 2-methyll >> 3> 4-thiadiazol-5-ylthio, Consists of bromine and cyano, and Q is selected from the group consisting of hydrogen and carboxy exists, and on the further condition that if B. Q
is, T or W / and A is another group than bromine, and when A is bromine, T is a tetrazolyl group, characterized in that 50981 8/1173 at least one of the process stages in which (1) a compound of the formula given above, wherein R is hydrogen and T is a tetrazolyl group, with an organic acylic agent to form _ π for R acy- Ar / Cl7 _n C- Q is lated, (2) the amide group T, which is ^ 'CNHR ₉ , into a tetrazolyl group is converted for T, (3) a compound in which R is hydrogen or an amino protecting group is, T is tetrazolyl and R-, or R ^ -, is hydrogen, with a halide compound to form another group is alkylated as hydrogen for R- ^ or (4) a compound where R is hydrogen or an amino protecting group, T is tetrazolyl where R ₁ or R ₁ ^ is -CH ₂ -Q-CH * * and A is hydrogen, brominating to form a compound where A is bromine is and optionally then the methoxymethyl group is removed,
is carried out. 49 · The method according to claim 48 for producing a Compound of formula O
where R is the acyl group aWqjjT q_, ° ι E- Q
T is the tetrazolyl group of the formula . ¥. . 9 ~ ^R 11 or ¹ I, ^ H XT TT "F 509818/1173 is where R-, hydrogen, alkanoyloxymethyl with 3 to 6 carbon atoms, l- (alkanoyloxy) ethyl with 4 to 7 carbon atoms, methoxymethyl or phthalidyl, H ₁ -, R-. or a letrazolylcephem nitrogen protective group, A is hydrogen, acetoxy, 1-methyl-5-tetrazolylthio or 2-methyl * 1,3,4-thiadiazolyl-5-thio, characterized in that a compound of the formula T is acylated with an organic acid acylating agent. 50. The method of claim 48 for producing a connection of the IOrmel RNH CH ₂ A ¹ wherein R is the amino protecting group as defined in claim, T is a tetrazolyl group of the formula N NR ₂ I i N W wherein R _{2 is} the tetrazolylcephem ^{nitrogen protecting group, A 1 is} hydrogen, acetoxy, 1-methyl-5-tetrazolylthio or 2-methyl-1,3,4-thiadiazolyl-5-thio, characterized in that the amide group of a compound of the formula RNH S N s L-CHoA ^f ο- ⁷ / O-C-NHR, 509818/1173 where Rp is a potential tetrazolylcephem nitrogen protecting group pe is converted to the tetrazolyl group T. 51. The method of claim 48 for the preparation of a compound of the formula RNH ■ T where R is hydrogen or the amino protecting group, A 'is hydrogen, Acetoxy, 1 ~ M.ethyl-5 ~ tetrazolylthio or 2-methyl ~ 1,3,4-thiadiazolyl-5 ~ thio T is a tetrazolyl group of the formula ^{x ±} or N N ^N
|| is, in which R ₁₁ 'or R ₁ ' is alkanoyloxymethyl with 3 to 6 carbon atoms, l- (allcanoyloxy) ethyl with 4 to 7 carbon atoms, Met ho xymethyl or phthalidyl, characterized in that the corresponding tetrazolyl compound, in which R -, - , ', R ₁ * is hydrogen, is _{alkylated with R 1} ' halide. 52. The method of claim 48 for the preparation of a compound of the formula RNH fJH! wherein R is hydrogen or the amino protecting group, T "is one Tetrazolyl group of the formula 509818/1173 2U9834 IT N-GH _p -O-GH NN ⁵ or Il CH ₂ -O-CH ₃ , characterized in that a compound of the formula ÄNH lpt1 is brominated and optionally then the methoxymethyl group Will get removed. 5 0 9 8 18/1173