DE2646305A1 - CEPHALOSPORIN TYPE ANTIBACTERIAL AGENTS - Google Patents

Description

Case

- ■ ir

Syntex (USA) Inc., Palo Alto (Calif., USA)

Cephalosporin-type antibacterial agents

Background of the Invention ;

1. The invention

The invention relates to compounds of the cephalosporin type having antibiotic "activity, and to intermediates and processes for the preparation of such compounds. According to a further embodiment, the invention relates to 3 ~ B- (1 ~ methyl * tetrazol-5-ylthio) -prop-1 - (t) -enyl] ~ 73-acetamido ~ ceph-3-em-l | -carboxylic acids with α-substituted Acetamido ™ group 5 70-acetamido-3- [3- (l> 2, ⁱ l-triazole ~ 5 -ylthio) -

15-9.76 / Dr.PB / gVvw

709816/1207

prop-l- (t) -enyl] -ceph-3-em-4-carboxylic acids with α-substituted Acetamido group, and esters and salts thereof and methods of making such compounds. According to another embodiment relates the invention relates to pharmaceutical preparations and antiseptic agents containing such compounds and methods of destroying and / or inhibiting them the growth of gram-negative and / or gram-positive bacteria.

2. State of the art

Since it was first discovered that certain derivatives of Cephalosporin C are potent antibiotic Having activity, a large number of cephalosporin-type compounds have been recognized for their possible improved or different antibiotic activity and selectivity synthesized; please refer e.g. USA patents 3 * 769,277, 3,630,700, 3,853,860, 3.859.274, 3-864.338, 3.867.380 and 3.88O.851. A general A discussion of the cephalosporins can be found in "'Cephalosporins and Penicillins Chemistry and Biology * Editor E.H. Flynn, Academic Press, Inc. (1972),

Summary In summary, the inventive

Compounds by the following general formula such as -709816 / 1207

are given:

R ³ -CH ₂

! (trans)

wherein R is l-methyltetrazol-5-yl or l, 2, l | -triazol-5-yl

, R is hydrogen or one of the following protecting groups: diphenylmethyl, benzyl, o-nitrobenzyl, p-nitro ~ benzyl, 3 ₃ 5-dinitrobenzyl _s p-methoxybenzyl, ter-t-butyl, Pivaloyloxymethylj phenacyl or polyhaloalkyl of up to 6 carbon atoms, e.g. 2 _{5 is} 2,2-trichloroethyl ₅ and R is thiophen-2-yl, trifluoromethylthio, phenoxy, phenylthio, (1H) -tetrazol-1-yl or sydnon-3-yl,

2 3

where R is hydrogen when R is thiophen-2-yl represents.

The invention also includes the pharmaceutically acceptable salts of the above compounds. Also, as can be seen from formula I, the steric configuration of the propenyl double bond is trans ₄ and the substituent of the formula: ₀

R ⁵ CH ₂ CNH- in the 7-position is ß-position.

In summary, one of the inventive

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mass method characterized in that one Compound of the formula:

1 " ⁵ S 2 ·

in which R and R have the above meanings and R is defined as R above, but is different from hydrogen _? hydrolyzed *

In summary, another method according to the invention is characterized in that one Compound of the formula:

or a pharmaceutically acceptable salt thereof,

1 2
wherein R and R have the above meanings, acylated.

In summary, a third method according to the invention is characterized in that optionally a free acid into the corresponding 709816/1207

transferred to a pharmaceutically acceptable salt or, if appropriate, a pharmaceutically acceptable salt converted into the corresponding free acid or optionally a free acid or a pharmaceutical harmless salt thereof converted into the ester of a suitable protective group.

In summary, these pharmaceutical preparations and antiseptic agents are according to the invention characterized in that they are the * l-carboxylic acids of the formula I and / or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable one Contain carrier or antiseptic carrier.

In summary, this is according to the invention Method for reducing or inhibiting bacterial infections, characterized in that mammals, suffering from such infections, an effective amount of the carboxylic acids of formula I or their pharmaceutically acceptable salts administered or, in the case of undesired bacterial growth, on inanimate ones Articles an effective amount of the above-mentioned compounds in an antiseptic carrier upon them Applies objects.

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Further description of the invention and preferred embodiments

The compounds of the invention can be represented by the following sub-forms;

II

III

N ^ H Ti \ Il H j J, N-CH ^ -CN ^, \ s "

R ¹ ₀ ^ ~ " ^N

IV

VI

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! 45

I -

I.
i

where R ^{1 is} l-methyltetrazol-5-yl or! ^, 'J-triazole-S j R is hydrogen or one of the following protective groups: diphenylmethyl, benzyl, o-nitrobenzyl, p-nitrobenzyl, 3,5-dinitrobenzene, p- Methoxybenzyl, tert-butyl, pivaloyloxymethyl, phenacyl or polyhaloalkyl having 2 to 6 carbon atoms, for example 2,2,2-trichloroethyl, is and X is oxygen or sulfur.

The pharmaceutically acceptable salts of the above compounds are also within the scope of the invention includes.

Furthermore, as noted above, the amino or carbonylamino substituent on carbon atom 7 j3 position and the propenyl double bond is a trans double bond.

Typical examples of compounds of the formula II can be found in the following examples 3? 3A 3B, ₅ and 4a.

Typical examples of compounds of the formula III can be found in Examples 11 and below Typical examples of compounds of the formula IV can be found in Examples 7-8 9 and 10j typical examples of the compounds of the formula V can be found in Examples 5 and 6; typical examples of compounds of the formula VI can be found in Examples 13 and

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With regard to the antibiotic activity, those compounds of the formula I are preferred in which R is 1-methyltetrazol-5-yl; the preferred substituents R ^ are (1H) -tetrazol-1-yl, trifluoromethylthio and sydnon-3-yl. The particularly preferred compounds of the formula I are 7β ~ fa ~ (1H) -tetrazol-lylacetamido] -3 ~ [3- (1 "" methyltetrazol ~ 5 ~ ylthio) -prop-1- (t) -enyl] -ceph- 3-em-4-carboxylic acid ₅ 73- (a-trifluoromethylthioacetamido) -3- [3- (l-methyltetrazol-5-ylthio) -prop-1- (t) -eny1] -ceph-3 ~ em-Η - carboxylic acid, 7β ~ (a ~ sydnon-3-ylacetamido) -3- [3 ~ (1-methyltetrazol-5 ~ ylthio) -prop-1- (t) -enyl] -ceph-3-em- ¹ l-carboxylic acid and their pharmaceutically acceptable salts "

The sodium salts are preferred for convenience; accordingly are the particularly preferred Salts the sodium salts of the preferred and particularly preferred compounds of the formula L.

The process for the preparation of the inventive Compounds can be represented schematically by the following series of overall reaction equations:

709816/1207

c

O IJH

(A)

Cl) '

asene-catalyzed / anhydrous rearrangement

C2)

oxidative rearrangement

COPY

709816/1? 07 ORiQlMAL INSPECTED

f?

Hydrolysis (7)

Cn)

Hydrolysis (6)

(E)

Cl ")

12 * "5

wherein R _9, R and R have the above meanings

71 -τ

and R is defined the same as R, but different from thiophen-2-yl is _a while R is the group of the formula;

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represents.

Step 1 of the above process can conveniently be carried out by reacting the starting material of the formula A with a suitable vinyl Grignard compound, preferably in a suitable inert organic solvent. In the typical case of this treatment is preferably conducted at temperatures ranging from -100 to -20 ⁰ C ₃ about -60 to -80 ⁰ C, about 0.25 to 2.0 hours, preferably about 0.25 to * 0 , For 5 hours. Typically, a molar ratio of Grignard compound to compound of formula A of about 3 to 10, preferably about k to 5, is used. Typically, and preferably, the treatment is carried out under anhydrous conditions and under an inert atmosphere, for example under nitrogen. Suitable inert organic solvents which can be used are, for example, tetrahydrofuran, dimethoxyethane, dioxane and the like and mixtures thereof. Suitable Grignard compounds,

which can be used are e.g. Vinylmagnesium-709816/1207

Chloride, vinyl magnesium bromide and the like. The resulting product is a mixture of α- and (3 ~ hydroxy ~ isomer, which, if desired, can be cleaved by conventional methods. <

The starting materials of the formula A are known compounds and can be prepared by known processes, as for example in US Pat. No. 3 »864 * 338 and in the preparations described below, or by obvious modifications of these processes, e.g. by replacing protective groups will.

Stage 2 of the procedure can be carried out in two weeks. be carried out by the compound of formula B (either the individual α- or β-hydroxy isomers or mixtures thereof) with a mercapto-substituted heterocycle corresponding to the desired substituent SR in the presence of a small amount of a strong acid (typically approx. 0 * 01 to 0 _s l mol per mole of the compound of formula B) treated. In the typical case, this treatment is conducted at temperatures in the range of about 0 to 50, preferably ⁰ C to about 35 ₉ '15 ⁰ C * approx for 2 to 24 hours, preferably about 6 to 8 hours is carried out to give Molar ratios of mercaptoheterocycle to compound of formula B of approx.

1.0 to 5.0, preferably about 1.1 to 1.5 * applies. 70S816 / 1207

Suitable inert organic solvents that can be used are e.g. tetrahydrofuran, Direthoxyethane, dioxane, chloroform, methylene chloride and the same. Suitable strong acids that can be used are e.g. perchloric acid, hydrochloric acid, Hydrobromic acid, sulfuric acid and the like " Suitable organic acids that can be used are, for example, p-toluenesulfonic acid, trifluoroacetic acid and the same. Typically, p-toluenesulfonic acid will give better results obtain.

Stage 3a, the rearrangement of the cepheine double bond and the orientation of the ester group on carbon atom 4, can conveniently be carried out by treating the compound of formula C with a catalytic amount of triethylamine in pyridine. Typically, this treatment is carried out under anhydrous conditions at temperatures in the range from approx. 0 to kO ⁰ C, preferably approx. 20 to 25 ⁰ C, for approx. 10 to 72 hours, preferably for approx. 24 to 36 hours, where molar ratios of triethylamine to compound of formula C of about 0.01 to 1.0, preferably about 0.05 to 0.1, are used. Suitable organic solvents that can be used are, for example, pyridine, quinoline, Ν, Ν-dimethylaniline and the like

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as well as mixtures thereof. The following reagents could also be used instead of triethylamine: Diisopropylethylamine _s 1,6-diazabicyclo- [5 ** 4,0] - undecajnon-1-en, 1,5-diazabicyclo ^ - [ ⁱ l _s 3iO} ~ non ~ l-en and the like. This rearrangement can also be carried out in two stages (3a and 3b) via the intermediate product D '. The stage 3a can be conveniently carried out by treating the compound of formula C in a suitable inert organic solvent with m-chloroperbenzoic acid * In the typical case, this treatment is conducted at temperatures in the range of about -10 to +25 ⁰ C, preferably ca ₃ , 0 to 5 ° C, about O _{3 for} 5 to 24 hours, preferably about 3 to 5 hours, performed, with molar ratios of m-chloroperbenzoic acid to compound of the formula C of about 1.0 to 1.2 applies. This molar ratio should preferably be close to 1 (approx. 1 _s 05 to 1.1) in order to prevent further oxidation of the thio group to the sulfonyl group. Suitable inert organic solvents that can be used include methylene chloride, chloroform and the like, and mixtures thereof. Instead of m-chloroperbenzoic acid, the following reagents could also be used: perbenzoic acid, peracetic acid, hydrogen peroxide,

Sodium metaperiodate, ozone and the like. Level 3b 709816/1207

can conveniently be carried out by treating the sulfoxide of the formula D ¹ in a suitable inert organic solvent, preferably under an inert atmosphere, with a mixture of stannous chloride and acetyl chloride. In the typical case, this treatment is conducted at temperatures in the range of approximately, -10 to +25 ⁰ C, preferably about 0 to 5 ⁰ C, ca, 0.25 to 5> O long hours, preferably about 1.0 to 2 ,, running 0 hours to give molar ratios of Stannoehloriö to compound of formula D ¹ of about 1.5 to 5.0, preferably about 2.0 to 3 ₉ 0, applies. Instead of 'stannous chloride and acetyl chloride, the following reagents could be used \ Phosphortr-iehlorid, phosphorus and the like and mixtures thereof "

Step 4 of the process can conveniently be carried out by treating the compound of the formula in an inert organic solvent in the presence of pyridine with phosphorus pentachloride. This part of stage 4 is typically carried out under anhydrous conditions and under an inert atmosphere at temperatures in the range from approx. 10 to 30 ^° C. for approx. 2.0 to 4.0 hours, 1.1 to 1, 3 moles of pyridine and about 1.1 to 1.2 moles of phosphorus pentachloride per mole of the compound of the formula II 'are used. After the resulting reaction practically turned into 709816/12 07

Is the end, about 2 to moles of isobutyl alcohol, preferably about 5 moles of isobutyl alcohol, per mole of compound of the formula II ^{f are} added to the mixture produced,

whereupon the treatment at temperatures in the range from approx. -20 to + 30 ^° C., preferably approx. 0 to 5 ^° C., for approx. 0.25 to 2.0 hours, preferably approx. 0.5 to 1.0 For hours, continues. A small amount of water is then added to effect the final reaction in this treatment. This last step is typically the case at temperatures in the range of -20 to +30 ⁰ C, preferably about 0 to 5 ⁰ * C, about O ₅ I to 1.0 hours, preferably about 0.25 to 0, For 5 hours. Suitable inert organic solvents which can be used for this treatment are, for example, chloroform and the like. The following compounds, for example, could also be used instead of pyridine: quinoline, N, N-dimethyl aniline and the like. Instead of isobutyl alcohol, other lower alkanols could also be used, for example methanol, ethanol and the like or mixtures thereof.

The next two steps in the process i.e. acylation of the amino group and if desired the removal of the ester group can be carried out in any order. So first can the ester group are cleaved (step 7) and then

70 9816/1207

the amino group can be acylated (step 8) or vice versa (ie steps 5 and 6). Step 7 or 6 and step 4a can be carried out according to conventional methods used by those skilled in the art to cleave ester groups, the corresponding free acid being obtained; For example, benzhydryl and p-methoxybenzyl esters can be conveniently prepared by treatment with a mixture of trxfluoroacetic acid and anisole (typically in a molar ratio of 2: 1 to 6: 1) at ~ 50 to + 50 X _f, preferably at 0 to 5 ⁰ C, about 2 to For 60 minutes, preferably for 2 to 5 minutes, in an inert solvent such as methylene chloride, benzene and the like, are cleaved.

Steps 5 and 8 can be carried out using conventional methods for acylating amino groups will. For example, stages 5 and 8 can conveniently be carried out by adding the compounds of the formula D or E with about 1.1 to 1 * 5 stoichiometric Equivalents of an acyl halide with the desired R -Methylene carbonylacyl group in an inert organic solvent (e.g. dichloromethane, chloroform, etc.) in the presence of an organic or inorganic base (e.g. sodium bicarbonate, pyridine, triethylamine and the like) at temperatures ranging from -20 to

+60 ⁰ C, preferably from 0 to 5 ⁰ C, about 0.5 to 1 hour 709816/1207

long treated. Typically about 2 to stoehiometric equivalents of the base are used. The acylation can also be carried out by treatment with a ^{carboxylic acid with the desired R- 5} radical (ie, a carboxylic acid of the formula R ^ COOH) and a suitable coupling agent, for example dicyclohexy lcarbodiimide or N-ethoxycarbonyl-2-ethoxy-l _a 2-dihydroquinoline _{i can be carried out} in a suitable inert solvent, for example diehlomethane.

It is generally preferred that the individual products of each of the process steps described above are separated off and / or isolated before they are used as starting material for subsequent steps Evaporation, crystallization, column chromate ο graphi e _s thin layer oraat ο graph ie, distillation, etc. Specific explanations of typical separation and isolation processes can be found in the corresponding examples below, but other equivalent separation processes could also be found It should also be noted that where typical reaction conditions (e.g. temperatures, molar ratios and reaction times)

conditions have also been given above both above 709816/1207

as well as below these areas can, although they are generally less expedient, bulky. .. - .- · .., ·

The pharmaceutically acceptable salts according to the invention can be prepared by processes well known to those skilled in the art _{: i.} For example, by simple. Treatment of the free .Acid of the formula I with an inorganic or organic base ₅ which forms the cation desired for the salt, for example ..- ■ - .. sodium hydroxide, potassium hydroxide, - triethylamine ,; Ethanolamine, tris (- hydroxyme. "& Hyl) -. Aminoinethane, etc. The sodium salts can also be conveniently prepared by treating a solution of the acid in ethyl acetate with an excess of sodium 2-ethylhexanoate.

The acids and salts of the present invention have a broad spectrum of antibacterial activity against both gram-positive and gram-negative organisms such as Staphylococcus aureus, Proteus vulgaris, Escherichia coli, Streptococcus pyogenes, Klebsiella pneumoniae and Shigella sonnei. The compounds can be used to treat infections of this type Combat humans and mammals or prophylactically prevent, and can be administered in the same way as cephalothin or gephalosporin

derivatives are generally administered (typically 709816/1207

XL

Case parenterally or orally). The connections can be in the most varied. Dosage forms are administered either alone or in combination with other pharmaceutically acceptable medicaments in the form of pharmaceutical preparations which are suitable for oral or parenteral administration. The dosage forms typically contain the compounds (typically as pharmaceutically acceptable salts) and a pharmaceutical carrier and are preferably formulated in the form of dosage units for easy administration and precise administration. To facilitate dosing. The pharmaceutical carrier can be either a solid material or a liquid in which the compound is dissolved, dispersed or suspended. The dosage form may optionally contain other compatible _drugs} preservatives, emulsifiers, wetting agents and / or pH buffering agents. Suitable preservatives that can be used are e.g. Benzyl alcohol and the like. Suitable buffering agents are, for example, sodium acetate and pharmaceutical phosphoric acid salts and the like. Liquid forms of administration include, for example, solutions, suspensions, emulsions, syrups, elixirs, etc. Liquid carriers

include e.g. water, saline, etc. Solid Dar-7 0 9 3 16/1207

Dosage forms are e.g. tablets, powder, capsules, Pills etc. Suitable solid carriers are e.g. pharmaceutical grades of starch, lactose, sodium saccharin,

Sodium bisulfite and the like "

The compounds according to the invention are typically used in dosages of about 10 to 100 mg per kg of body weight and administered per day. The exact effective dosage depends of course on the type of treatment administration, the condition being treated and the patient.

The compounds can also be used as antiseptic agents in cleaning agents or disinfectants, im typical case in the form of a solution or suspension

in a liquid carrier or in an aerosol spray, be used.

Definitions

The following terms in this description mean the following, if not expressly that The opposite is indicated: the expression. "Lower alkyl" refers to alkyl radicals with 1 to 6 carbon atoms and includes both straight and branched alkyl radicals, such as methyl, ethyl, Isopropyl, tert-butyl, pentyl, n-hexyl, isohexyl and like that. The term "lower alkoxy" refers to -alkoxy groups with 1 to 6 carbon atoms, the

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can be defined as a group -OR ¹ , in which R. ^f means lower alkyl as defined above. The term "halogen" or "halide" relates to fluorine, chlorine, bromine and iodine or the corresponding halides. The term "pharmaceutically acceptable salts" refers to those salts of the parent compound which do not significantly adversely affect the pharmaceutical properties (e.g., toxicity, efficacy, etc.) of the parent compound, such as are conventionally used in the pharmaceutical field. Salts according to the invention are salts with pharmaceutically acceptable cations with respect to the acid and sulfo groups of the compounds of the formulas III and IV; in the case of compounds of the formula III in which R is carboxyl or sulfo, both mono- and bis-salts can be prepared. Suitable pharmaceutically acceptable cations are, for example, the alkali metal ions, for example sodium / potassium, etc., the alkaline earth metal ions, for example calcium, etc., and also ammonium ions and organic cations of tri-ethylamine, diethylamine, tris (hydi * oxymethyl) -amino-methane, ethanolamine , Choline, caffeine and the like. The term "l-methyltetrazol-5-yl" refers to the remainder of the formula:

709816/1207

and the term ⁿ i ₃ 2 _a ⁱ } -triazol-5 ~ yl "refers to the remainder of the formula:

The expression "KaXm ₁ temperätür" relates. to about 20 ^° C .; all temperatures and temperature ranges are ¹ "given in degrees C. All percentages are overall. weight percent, and the term" equimolar "refers to an amount which is the other reactant stoichiometrically equivalent in the relevant reaction.

The expression. "Benzhydryl" refers to the phenylmethyl radical of the formula:

1207

The term "sydnon-3-yl" refers to the Remainder of the formula:

The following preparations and examples illustrate the invention. In the examples, the magnetic proton resonance spectra (NMR) are determined at 100 mHz (the signs of the coupling constants are not labeled), and the signals are given as singlets (s), broad singlets (bs), _s doublets (d) _s double doublets (dd) _? Triplets (t), double triplets (dt), quartets (q) and multiplets (ra).

Manufacturing 1

3-acetoxymethyl-7ß- (thiophen ~ 2-yl ~ äc'etami ^^ carboxylic acid

In this preparation, k2 g of cephalothin [ie 3-acetoxy / methyl-7β- (thibphen-2-ylacetamido) -ceph ~ 3 ~ em-4-carboxylic acid] are dissolved in 130 ml of pyridine with heating and the solution is then brought to approx ⁰ C cooled. 13 ml of acetic anhydride are added and the resulting mixture is allowed to stand for 2 hours at room temperature, during which time a crystalline precipitate is formed. Then who-709816/1207

the 250 ml of a mixture of ethyl ether and ethyl acetate in a volume ratio of 65:35 are added, whereupon the resulting mixture is stirred for 1 hour and then filtered * The crystals obtained are ground with 65 ml of a mixture of ethyl acetate and ethyl ether in a volume ratio of 65? 35 washed and dried in vacuo _s giving> 41 g of the pyridinium salt of 3-acetoxymethyl-7β- (thiophene-2-ylacetamido) 'ceph-2-em-4-carboxylic acid. This salt is added to a mixture of 65O ml of water and 650 ml of ethyl acetate, which is then acidified to pH = 2 using 20% aqueous hydrochloric acid. The ethyl acetate layer is separated off and the aqueous layer is extracted further with 400 ml of ethyl acetate. The combined ethyl acetate extracts are washed twice with sodium chloride solution and dried over anhydrous sodium sulfate, whereupon the solvent is removed under reduced pressure; 3 * 1 g of 3-acetoxymethyl-7β- (thiophene-2-ylaeetamido) -ceph-2 ~ em ~ 4-carboxylic acid are obtained.

■ Manufacturing "2

3-Hydroxymethyl-7ß- (thiopheri-2- ^ y ^ l · ^ a ^ c ^ e · t · amide. · O ·) · - · e ^ eph "^ 2 ^ - ^ em '' ^/ l" - carboxylic acid

In this preparation 3 * 1 g of 3-acetoxymethyl-7β- (thiophen-2-ylacetamido) -ceph-2-em-4-carboxylic acid are used

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added to a solution of 8.4 g of lithium hydroxide monohydrate in 1000 ml of water. The mixture is stirred under nitrogen for 2 hours at room temperature and then layered with 600 ml of ethyl acetate. The pH of the mixture is then brought back to ~ 2 by adding about 50 ml of 20? Aqueous hydrochloric acid. The ethyl acetate layer is separated off and the aqueous layer is extracted twice with 500 ml of ethyl acetate each time. The combined ethyl acetate extracts are washed twice with sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure ₃ , 24 _f 2 g of 3 "hydroxyinethyl ~ 7i5- (thiophan-2-ylacetamido) -ceph-2-em-4 ~ carboxylic acid.

Manufacturing 3

3-Hydroxymethyl-7ß- (thiophen-2 "ylacetamido) - ^: ceph" 2-em- ^j l "carboxylic acid benzhydryl ester

In this preparation, 2 * 1.2 g of 3-hydroxymethyl-7β- (thiophen-2-ylaceta.mido) -ceph-2-em- ¹ l -carboxylic acid are dissolved in 800 ml of tetrahydrofuran and then mixed with 15 g of diphenyldiazomethane, whereupon the resulting mixture is stirred for 3 hours at room temperature. The mixture is evaporated to dryness under reduced pressure and the residue with 250 ml of a mixture of ethyl ether and

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After the mixture has ^{been stirred for one and a} half hours, the pesticide is recovered by filtration, washed with 100 ml of a mixture of ethyl ether and methylene chloride in a volume ratio of 90:10 and then dried> whereby one receives .. 28.5 g of 3 = hydroxymethyl ~ 7P- (thiophene-2--ylacetaiTi3.do) "ceph-2-'ejri'- ⁱ 4-carboxylic acid benzhydryl ester"

Manufacture k '■.

5-Formyl-7β ~ (thiophen-2-ylacet amido) -cep'h-2 "Bm- ^ t-carboxylic acid benzhydryl ester

In this preparation, 31 g of dried chromium trioxide are added to a mixture of 51 g of dry pyridine and 800 ml of dry Met hy "Ie nc hl id or added, followed .The mixture is stirred under nitrogen for 20 minutes at 15 ⁰ C. 26 g of 3- Benzhydryl hydroxymethyl-7β- (thiophene-2-y! Acetamido) -eeph-2-em-4-carboxylate in 250 ml of dry methylene chloride are added all at once, the resulting mixture is stirred for 30 minutes and then filtered through diatomaceous earth The reaction flask and the diatomaceous earth are mixed with 500 ml of methylene chloride

this

washed and / combined with the previous piltrate j this liquid is mixed with ^ 00 ml of a 5? Potassium hydroxide solution, 500 ml of 20% aqueous hydrochloric acid

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and washed twice with 400 ml of saline each time. The aqueous washing liquids are back-extracted with 500 ml of methylene: chloride and the extracts are added to the previously washed methylene chloride filtrate, whereupon the liquid is dried over sodium sulfate and then stirred for 1 hour with 30 g of silica gel. The mixture is filtered and the silica gel is ^{washed with 1} 100 nil of a mixture of ethyl acetate and methylene chloride in a volume ratio of 1: 1. The combined filtrates are evaporated to dryness under reduced pressure, whereupon the resulting residue (26 g) is recrystallized from a mixture of ethyl ether and methylene chloride and 21.1 g of 3-formyl-7ß ~ (thiophene ·· * 2-ylacetamido) - ceph-2-em - ^ - carboxylic acid benzhydryl ester gives.

Example 1 -

This example explains step 1 of the process for the preparation of the compounds according to the invention of anhydrous tetrahydrofuran under nitrogen at -70 ⁰ C and stirred during 5 minutes dropwise with 10 ml of a 2 molar solution of ₃ 5-Viny! magnesium chloride was added. After 15 minutes, 50 ml of a buffer solution of pH = 7

709816/1207

Isomer 2 (lower Rf value), NMR (CDCl3,) J: 3.79s, 2H (CH ₂ -J [^ jI); 4.63m, IH (HC-OH); 5.0-5.8m, 6H (H-6, H-7, H-4 + CH = CH ₂ ); 6.25s, IH (H-2); 6.8-7.5m, 14H (CH25 ₂ + Ό!)

Example 2

This example illustrates step 2 of the process for the preparation of the compounds according to the invention. In this example, 2.7 g of 3- (1-hydroxyprop-2-enyl) ~ 7β- (thiophen-2-ylacetamido) -ceph-2-em- ⁱ l-carboxylic acid benzhydryl ester dissolved in 30 ml of tetrahydrofuran and stirred at ⁰ C * IO ₅ whereupon 0.6 g of 5-mercapto-l-methyltetrazole and 50 mg of p-toluenesulfonic acid are added. The mixture is ^{stirred for 5 hours at 1} JO ⁰ C, then poured into 200 ml of saturated aqueous sodium bicarbonate solution and extracted twice with 200 ml of ethyl acetate each time. The ethyl acetate extracts are combined and washed with brine, dried over sodium sulfate and evaporated to dryness under reduced pressure, giving 2.8 g of an orange oil. This is chromatographed over 200 g of silica gel, eluting with a mixture of ethyl acetate and hexane in a volume ratio of 6: H. The fractions, which are homogeneous according to thin-layer chromatography, are combined, 2.1 g of 3- [3- (1-methyltetrazol-5-ylthio) -prop-1- (t) -enyl] -70- (thiophene-2 -ylacetamido) -ceph-2-em-4-carbon-709816/1207

ι St.

benzhydryl ester as pale yellow glass contains j [a] _D (CHCl ₃ ) "+ 321 °; UV (EtOH) 284 ran (£ 21,600); IR (KBr) 1780, 17 ¹ K), 1675 cm"¹; NMR (CDCl _7): 3 ₅ 80s _s 3H (N-Me); 3.82s, 2H (CH ₂ -IL ₃ Jl); / »3.8, 2H (CH ₂ -S ₅ covered by the previous signals); 5.2, 2H (H-6 + H-4); 5.56dd, J 4.8 Hz, IH (H-7); 5.7at, J 7, 16Hz _s IH (H-2 ») j 6.2d, J βΗζ, IH (HI ¹ ); 6.27s, IH (H-2); 6.51d, J 8Hz, IH (NH); 6.8-7.4m, 14H (CHo ₂ + I ^ _g J)).

Similarly, 3- [3- (l * 2,1-Triazol ~ 5-ylthio) -prop-l- (t) -enyl] -7ß- (thiophen-1-y! Acetamido) -ceph-2- eiD-4-carboxylic acid benzhyd] - ⁱ y: i ester [OeI, NMR (CDCl ₇ ): 3 ^ 60d _? J 7Hz, 2H (3'-CH ₂ ), 3.82 s, 2H (C 1-4 CH ₂ ); 5 ₅ 16d ₅ J 4 IH (H-6); 5.20s, IH (H-4); 5 _? 49dd, J 4.5, 8Hz, IH (H-7) 5.69dt, J 16.7 Hz, IH (H-2 ^f ); 5> 98d, J 16Hz, IH (H-I ') 6.14s, IH (H-2); 6.83s, 1H (CHi5 ₂ ); 6.9-7, ^ m, 13H («5 ₂ + U ^ ₃ Jj);

N — Yy ^ -
8.02s, IH (Ji 'Λ)] using the same procedure

H
divides, but 5-mercapto-l, 2,4 ~ triazole instead of

5-mercapto-l-methyltetrazole used "

Example 3

This example illustrates step 3 of the invention Process for the production of the invention Links. In this example a solution of 0.9 g

709816/1207

i
Benzhydryl 3- [3- (1-methyltetrazol-5-ylthio) -prop-1- (t) -enyl] -7β- (thiophen-2-ylacetamido) -eeph-2-em-4-carboxylate in 5 ml of dry pyridine treated with 0.1 ml of triethylamine. The mixture is left to stand at room temperature for 20 hours and then evaporated to dryness under reduced pressure. The resulting residue is chromatographed over 100 g of silica gel eluting with 15 _s Vol .--? Benzene containing ethyl acetate is eluted and 300 mg of 3 ~ [3- (l ~ methyltetrazol-5-ylthio) ~ prop-l- (t) -enyl] -7i3- (thiophen ~ 2 ~ yl ~ acetamido) -ceph- 3-em-4-carboxylic acid benzhydryl ester and 500 mg of the starting material 3 ~ [3 ~ (l "Methyltetj ' ⁱ azol-5" y3-thio) -propl ~ (t) -enyl] -7P- (thiophen-2-ylacetamido) "Ceph-2-em - ^ - carboxylic acid benzhydryl ester is obtained. The recovered starting material is treated in the same manner as above,

Further
where / 150 mg of 3- [3- (l-methyltetrazol ~ 5-ylthio) -prop-l ~ (t) -enyl] -7ß- (thiophen-2-ylacetamido) "ceph-3 ~ em- ⁱ l" benzhydryl carboxylate and 250 mg of recovered 3 "[3" ^c (l ~ 'methyitetrazol-5-ylthio) -prop-1- (t) -enyl] ~ 7β ""(thiophen-2-ylacet'-amido) -ceph-2 -em-4-carboxylic acid benzhydryl ester received as a white solid substance; . Mp 90-95 ⁰ C (dec.); [α] _β "158 ^ο _(CHCl3); UV (EtOH): 301 nm (£ 19 ¹ IOO); IR (KBr): 1785, 1720 _P I68O cm"^1; NMR (CDCl): 3.4m, 2H (2-CH _2); 3.8Os ₅ 2H

₂ g); 3.83s ₃ 3H (N-Me); 3.9Id ₃ J 7-, 5Hz ₅ 2H (3 '4.95d, J 4.5Hz, IH (H-6); 5.79dd, J 4.5, 9 Hz ₃ IH (H-7)

6, O8dt, J 16, 7.5Hz, IH (H-2 ¹ ); 6.63d, J 9Hz, IH (NH); 7 098 1 "B / 120 7

6.8-7.5m, 15H (CHo ₂ + E [gjl + H-I ');

Analysis for ^C 3i ^H 28 ^N 6 ° 4 ^S 3 ^: Calc .: C 57.75; H 4.38; N, 13.03 % Found: C-58.06; H 4.65; N 12.58 55 «

Similarly, benzhydryl 3 "" ^ ylthio) -prop-1- (t) -enyl] -70 - (thiophen-2-ylacetamido) -ceph-3-em-4-carboxylate C Srap. I83-185 ⁰ Cj [ a] _D -87 ° (dioxane); UV (EtOH) 306 nra (£ 19.10O); IR (KBr) 179O ₅ I705, 1665 cm "¹; NMR- (DMSO-dg); 3.33bs, 2H

J 7Hz, 2H (3 ^f -CH ₂ ) ₅ 3.79s, 2H (ζΧ. _0Η ) ί J 4.5Hz _s IH (H-6); 5.75dd _s J.4.5.8 Hz, IH (H ~ 7); 6 _i 22dt J 16.7 Hz, IH (H-2 ·); 6.69d _A J 16Hz, ih (HI ¹ ); 6.9-7.61

τι — π ^Ν ™ 1ι

13H (O ₂ + ¹ IgA); 8.39s, IH (U ^ N). Analysis for C,., H "N ^ OnS,:

jx c. [j ^ j H

Calc .: C 59.12; H 4.32; N 11.12 % Found: C 58.93; H 4.55; N 10.96 %] by the same process, but using 3- [3- (l ₅ 2,4-triazol ~ 5-ylthio) -prop-1- (t) -enyl] -7ß- (thiophene- 2-ylacetamido) -ceph-2-em-4-carboxylic acid benzhydryl ester instead of 3 ~ [3 ~ (l ~ methyltetrazol-5-ylthio) -prop-1- (t) -enyl] -70- (thiophen-2-ylacetamido ) -ceph-2-em-4-carboxylic acid benzhydryl ester is used

709816/1207

Example 3A

This example explains step 3a of the process according to the invention for the preparation of the compounds according to the invention. In this example I ₅ O g 3 ~ [3- (1-methyltetrazol-5-ylthio) -prop-1- (t) -enyl] ~ 7β- (thiophen-2-yiacetamido) -ceph-2-em- ⁱ -carboxylic acid benzhydryl ester was ^{stirred at 0 °} C. in 25 ml of methylene chloride and 0.3 g of m-chloroperbenzoic acid was added in individual portions over the course of 2 hours. The mixture is further diluted with methylene chloride and washed with excess dilute aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a yellow foam. This is chromatographed over silica gel, eluting with a mixture of acetone and methylene chloride in a volume ratio of 15:85. The pure fractions are combined and yield 0.6 g of 3- [3- (l-methyltetrazol-5-ylthio) -prop-l- (t) -enyl] -7 / 3- (thiophen-2-ylacet amido) - ceph ^ -em - ^ - carboxylic acid benzhydryl ester-1-oxide as a white crystalline solid substance; . Mp 125-127 ⁰ C; [cx] _D -204 ° (CHCl ₃ ); UV (EtOH) 307 nm (6 20.200); IR (KBr) 1790, 1720, 1680 cm "¹; NMR (CDCl3) 3, 06d, 3.95d _s J 19Hz, 2H (H-2a and H-2β); 3.82s, 2H (CH ₂ -JL ₃ J); 3.85s, 3H (N-Me); 3.92d, J 7Hz (3'-CH ₂ ); M7d, JH, 5Hz (H-6); 5.9-6.3m, 2H (H. -7 and H-2 *); 6.8-7.6m, ΙβΗ (CHc5 '+ iLj) H-I' + NH). 709816/1207

Analysis for ^C 3 ₁ ^H 28 ^N 6 ° 5 ^S 3 ^:

Calc .: C 56.35; H 4.27; N 12.72 %

Found: C, 56.16; H 4.18; N 12.49 %.

Similarly, 3- [3- (1,2,4-triazol-5-ylthio ) -prop-1- (t) -enyl] -7β - (thiophene-2-y! acetamido) -ceph-3-em-4-carboxylic acid benzhydryl ester-1-oxide prepared by the same process, but using 3- [3 ~ (1,2,4-triazol-5-ylthio) -prop-1- (t) -enyl] -7β- (thiophen-2-y ! acetamido) -ceph-2-em-4-carboxylic acid benzhydryl ester used as starting material .

Example 3B

This example illustrates step 3b of the process according to the invention for the preparation of the compounds according to the invention. In this example, 0.5 g of 3 ~ [3- (l ~ Methy It etrazol-5-ylthio) -prop-1- (t) -enyl] ~ 7β- (thiophene ~ 2 ~ ylacetamido) -ceph-3- em-4-carboxylate-l-oxide dimethylformamide is dissolved, followed by stirring the solution at 0 ⁰ g under nitrogen in 10 ml of dry, while 0.5 g of stannous chloride and 1 ml of acetyl chloride are added; the mixture is ^{stirred at 0 °} C. for 15 minutes. One continues to stir
while the solution is warmed to room temperature, and
stirs for a further 20 minutes. The mixture is then with
Diluted water and extracted twice with ethyl acetate. -

709816/1207

The combined extracts v / ground twice with water and Washed brine, dried over sodium sulfate and evaporated under reduced pressure, giving 0.6 g of a

• *

yellow oil. This is chromatographed over silica gel, with a mixture of acetone and methylene chloride in a volume ratio of 5; 95 eluted and 0, * »0'g 3-D" (1-Methyltetrazol-5-ylthio) -prop-1- (t) -enyl] -73- (thiophen-2-ylacetamido) -ceph-3-em-4-carboxylic acid benzhydryl ester obtained as a white crystalline powder substance.

Similarly, 3- [3 "(I _A 2 _> '4 ~ Triazol ~ 5- · ylthio) -prop-1- (t) -enyl} = 73- (thiopben-2 ~ y! Acetamido) -cepjb- 3-em-4-carboxylic acid benzhydryl ester prepared by the same process, but using 3- [3 ~ (l _J 2, ⁱ l ~ Triazol ~ 5-yl'-thio) -prop-1- (t) -enyl] - 70- (thiophen-2-ylacetamido) -ceph-: 3-em-4-carboxylic acid benzhydryl ester-1-oxide was used as the starting material.

example H

This example explains stage ^ i of the process according to the invention for the preparation of the compounds according to the invention. In this example, 0.25 g of 3 ~ C3- (I-methyltetrazol-5-ylthio) -prop-l- (t) -enyl] -73- (thiophen-2-ylacetamido) -ceph-3- em- ⁱ l-carboxylic acid also hydrylest in 6 ml

under
dry methylene chloride / nitrogen at room temperature ge-r

709816/1207

stirred and treated with 60 ^ uI pyridine and 100 mg phosphorus pentachloride. The mixture is stirred for 2 · door hours at Räumtempera *, then cooled to 0 ⁰ C, treated with 0.1 ml of isobutyl alcohol and stirred for a further ¹ JO minutes. Then 0.5 ml of water are added and the mixture is stirred vigorously for 15 minutes. The mixture is then diluted with excess dilute aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The combined extracts are washed with water and sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure, crude 3 ~ i3- (1 ~ Methyltetra ™ = zol-5-ylthio) -prop-1- (t) -enyl] - T / 3 -aminoceph-J-em- ^ -carboxylic acid benzhydryl ester is obtained as a brown oil; NMR (CDCl-,) 3,51m, 2 H (2-CH _2); 3.85s, 3H (N-Me); ^ 3.9, 2H (3 ^f ~ CH _2S overlapped by N-Me); 3.75d, 3>95d> J "51Hz, 2H (H-6 + H-7) j 6, ldt, J 16, 7.5Hz, IH (H-2 ^r ) i 6.880, J 16Hz, IH (H. -I ') j 7, O4s, IH (CH «5 ₂ ); 7.1-7.6m, 1OH (c5 ₂ ).

In a similar way 3 ~ ß- (l, 2,4-triazol-5-ylthio) -prop-l- (t) -enyl] -7ß-aminoceph-3-em-4-carboxylic acid benzhydryl ester is prepared by the same process, with 3- [3- (1,2,4-triazol-5-ylthio) ~ prop-l (t) ~ enyl] ~ 7β - (thiophen-2-yiac et amido) -ceph-3 ~ em- ⁱ Benzhydryl i-carboxylate is used as the starting material.

709816/1207

example HA

This example illustrates step 4a of the process according to the invention. In this example, 0.2 g of 3-C3- (l-methyltetrazol-5-ylthio) -prop-l- (t) -enyl] -7β - »(athiophen-2-ylacetamido) -ceph-3 ~ em- ^'i} -carbonsäurebenzhydrylester and 0.5 ml of anisole stirred together at 0 ⁰ C and treated with 2.5 ml trifluoroacetic acid. The mixture is stirred vigorously for 2 minutes and then quickly evaporated to dryness under reduced pressure. The resulting crude 3- [3- (l-methyltetrazol-5-ylthio) -prop-l- (t) -enyl] -7ß- (a-thiophen-2-ylacetamido) -ceph-3 ~ eni ~ ⁱ i- carboxylic acid is dissolved in tetrahydrofuran and the solution is then filtered. The resulting filtrate is treated with an excess of a solution of sodium 2-ethylhexanoate in tetrahydrofuran and then evaporated to dryness. The residue is mixed with isopropanol and stirred at room temperature for 1 hour. The resulting solid substance is isolated by filtration, washed three times with isopropanol and dried in vacuo, 0.11 g of sodium 3 - * [3- (lm.ethyltetrazol-5-ylthio) -prop-l- (t) -enyl ] -7ß- (a-thiophen-2-ylacetamido) -ceph-3-em-4-carboxylate is obtained as an off-white powder which decomposes before melting; UV (water) 296 nm (£ 20,100); IR (KBr) 17660, 1660, 1600 cm "¹;

NMR (DMS0-d ₆ ) 3, ¹ JbS, 2H (2-CH ₂ ); 3.75s, 2H "CCH ₂ -CgJJ) j *

3.92s, 3H (N-Me); 4.00d, J 7.5Hz, 2H (3'-CH ₉ ); 4.97d, J 5Hz,

709816/1207

2846305 SO

IH (6-H); 5.47dd, J5.9Hz, IH (7-H); 5.71dt, J 7.5, 15Hz, IH (2'-H); 6.8-7, Om, 2H (thiophene); 7.1Od, J 15Hz, IH (1'-H); 7.25-7, ¹ Jm, IH (thiophene); 9> O6d, J 9Hz, IH (NH).

The sodium salt of 7ß- (a-Thiophen-2-ylacetamido) -3- [3- (1,2,4-triazol-5-ylthio) -prop-1- (t) -enyl] -ceph-3-- era-i | - carboxylic acid is prepared by adding a mixture of 80 mg of 3- [3- (l-methyltetrazol-5-ylthio) -prop-l- (t) -enyl3-7ß- (a-thiophene-2- ylacetamido) ^ceph-3-em-i} -carbonsäurebenzhydrylester and 0.5 ml anisole at 0 ⁰ C is stirred and then adding 2.5 ml of trifluoroacetic acid. The mixture is stirred vigorously for 2 minutes and then quickly evaporated to dryness under reduced pressure. The resulting crude 7β ~ (a ~ thio ~ phen-2-ylacetamido) -3- [3- (1 _? 2,4-triazol-5-ylthio) -prop-lit) -enyl] -ceph-3-em -4-carboxylic acid is mixed with ethyl ether, resulting in a white solid substance which separates out and is then isolated by filtration. The solid substance is dissolved in tetrahydrofuran, the solution filtered and the filtrate with an excess of a solution of sodium 2- Treated ethyl hexanoate in tetrahydrofuran. The mixture is evaporated to dryness and the residue is mixed with isopropanol. A white solid substance separates out and is then isolated by filtration, washed several times with isopropanol and dried in vacuo, k2 mg of sodium 7β- (a-thiophen-2-ylacetamido) ~ 3- [3- (1,2 , 4-triazol-5-ylthio) prop-1 (t) -enyl] ceph-3 em ~ ⁱ i-709816/1207

carboxylate is obtained, which also decomposes before melting; UV (water) 297 nm (£ 19,000); IR (KBr) 1755, 1660, 1610 cm " ¹ · NMR (DMSO-dg): 3.4 ¹ Is, 2H (2-CH ₂ ); 3.78s, 2H (CK ₂ -C ~ P); 3, 8bd, 2H (3'-CH ₂ ); * J, 98d, J 5Hz, 1-H (6-H)

., J 5, 9Hz, IH (TH); 5.7Mt, 'J 7, 15Hz ₅ IH (2'-H) j 6.8-7, Om, 2H (thiophene); 7, O7d / J 15Hz, IH (l ^f -H); 7 ₅ 3-7 ₅ 5m _? IH (thiophene); 8.22s, IH ( ¹ J ^ J-); 9.08 (1, J. 9Hz, IH (NHCO).

Example 5 .

This example illustrates the acylation steps in the process for preparing the compounds of the invention. In this example, a mixture of 0.15 g of 7β-amino-3- [3- (1-methyltetrazol-5-ylthio) -prop-1- (t) -enyl] -ceph-3-em-4-carboxylic acid diphenylmethyl ester and 0.5 ml of pyridine in 5 ml of chloroform at room temperature and stirred with 0.1 g of 1H-tetrazol-1-ylacetyl chloride in 2 ml of chloroform was added. The mixture is stirred for 30 minutes, then further diluted with chloroform, with dilute aqueous hydrochloric acid and brine, dried over anhydrous sodium sulfate and then under reduced pressure evaporated to give 0.25 g of a brown oily residue. The residue is obtained using thick layer chromatography Purified on silica gel, whereby one

with a mixture of acetone and dichloromethane in the ratio 7 0 9 8 16/1207

si

1: 4 eluted uHd 0.12 g 7 £ ~ Ea- (IH) -

3-13- (l-methyltetrazOl-5-ylthio 5 -pröp-l- (15 -eiiyl) -ceph-3-em ~ 4-carboxylic acid diphenylffiethyl ester as white glass; »(CDCl ₃ ): 3.45bs, 2H (2-CH ₂ ) j 3.78s *

J? Hz, 2H (3'-CH ₂ ); 4.92 (3, J "5Hz, IH (6-Ή) ;. 5.19s, 2H

(i ^ i-CH ^ COJi 5, T7dd, J 5, 9Hs ^ IH (7-H); 6,12dt, J 7,

IB (2'-H) j 6.8-7.6m, (CHc ^ + 1H) ; 8,89S, IH (Z. ^) _t

Similarly, 7i! - [ä- (1H) -tetrazol-1 «yl-" acetamido] -3- (1,2,4-triazol-5-ylthio) -prop ~ 1- (t) -enyl] -ceph-3-eiH-4-carboxylic acid diphenylmethyl ester prepared by the same process, but using 70-amino-3- [3 - "(1» 2,4- ■ fcriazol - 5-ylthio) -prop-l- (t ) -enyl] -ceph-J-era - ^ - carboxylic acid diphenylmethyl ester used as raw material,

Example 6

This example illustrates the hydrolysis of the carboxylic acid ester protecting group and the preparation of the salts according to the invention.

In this example, a mixture of 0.11 g of 70- [a- (1H) -Tetrazol-ly! Acetamido] -3- [3- (1-methyltetrazol-5-ylthio) -prop-1- (t) - enyl] -ceph-3-em-lJ-carbönsäurediphenylmethylester and 0.5 ml of anisole at 0 ⁰ C and then mixed with 2.5 ml of trifluoroacetic acid. The mixture is stirred vigorously for 2 minutes and then under reduced pressure 70 9816/1207

evaporated to dryness quickly. The resulting crude 70- [öt- (1H) -tetrazol-1-ylacetainido] -3- [3- (1-ynethyltetra2; ol-5-ylthio) -prop-1- (t) -enyl] -ceph-3 -em- ¹ l-carboxylic acid is treated with ethyl ether. A white pest substance separates out and is isolated by filtration, then dissolved in tetrahydrofuran and the solution filtered, whereupon the filtrate is treated with an excess of a solution of sodium 2-ethylhexanoate in tetrahydrofuran The dry substance is evaporated and the resulting residue is mixed with isopropanol.A white solid substance separates out and is isolated by filtration, washed three times with isopropanol and dried in vacuo, giving 4.5 mg of sodium 7β- [α- (1H) -tetrazole-1 -ylacetamido] -3-C3- (lr methyltetrazol-5-ylthio) -prop-l- (t) -enyl] ~ ceph-3-em- ⁱ l-carboxylate can be obtained as a white powder which can be obtained without melting above 170 ⁰ C decomposes; UV (water) 296 nm (£ 21,000); IR (KBr) 1775, 1700, 1615 cm "¹; NMR

(DMSO-dg): 3, ¹ I ¹ Is, 2H (2-CH ₂ ); 3.92s, 3H (N-Me): 3.99d, J 7Hz, 2H (3'-CH ₂ ); 4.99d, J 5Hz, IH (6-H); 5.37s, 2H (1 N-CH ₂ CO); 5.51dd, J 5, 9Hz, IH (7 ~ H); 5.73dt, J7, 16Hz, IH (2'-H); 7, Hd, J 16Hz, IH (l ^r -H); 9.37s, IH ( ¹ J ^ N), 9.5d, J 9Hz, IH (NH). . " ^H

Similarly, sodium 7β- [α- (1H) -tetrazol-ly / acetamido] -3- [3- (1,2, iJ-triazol-iJ-ylthio) -prop-1- (t) -enyl ] ceph-3-em-t ^{1-carboxylate} by the same procedure 709816/1207

prepared, but 7β- [a- (1H) .- ⁱ tetrazol-1-ylacet ~ amido] -3- [3- (1,2,4 -.triazol-5-ylthio) -prop-1 - (t) -enyl] -ceph-3-em-4-carboxylic acid diphenylmethyl ester used as starting material. ", ...

Example 7

This example illustrates the acylation steps for the preparation of the compounds according to the invention. In this example, a mixture of 0.15 g of 7β-amino-3- [3- (imethyltetrazol-5-ylthio) -prop-1- (t) -enyl] ~ eeph-3-em-4- carboxylic acid and Oj.5 ml of pyridine is stirred in 5 ml chloroform at 0 ⁰ C and then added with 0.1 ml Phenoxyaeetylchlorid, followed by stirring the mixture for 30 minutes. The mixture is then diluted with ethyl acetate and washed successively with dilute aqueous hydrochloric acid, dilute aqueous sodium bicarbonate solution and brine. The mixture is dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure to give 0.25 g of a brown oil. The oil is purified by thick layer chromatography over silica gel, eluting with a mixture of acetone and dichloromethane in a ratio of 1:20 and adding 0.12 g of 3 ~ [3-Cl-methyltetrazol-5-ylthio) -prop-l- (t) -enyl] -7 [beta] "phenoxy" acetamidoceph-3-em-4-carboxylic acid diphenylmethyl ester is obtained as a pale yellow oil;

709818/1207

nmr p _y ^ ₂ )%, ys _f y

C6-H) ;: '5,9' ¹ Kt ^ J 5, 9fe, -Iff (T-if) j

In an ätoXicher way w-ii * ä-. Tß (1,2 j 4-tr ia «ol-5-yl € hio) -p-rop-l-- (t)" .- bonsäurediph ^ nylraetliylestep after aera same procedure produced, whereby one, however, ■ Tß ~ AminQ-3 - f3 ~ i t, 2r4 ^ triä-. ; zol-5-ylthio) -ppop-1- (t) -eny1} -ceph ^ -em-ft-carboxylic acid-. phenylraethyl ester used as the starting material.

- ".- ■ Example 8. ..'...

This example illustrates the hydrolysis of the carboxylic ester protective group and the preparation of the salts according to the invention. In this example, a mixture of 80% 3- [3- (l- * methyltetrazol "! 5-ylthio) ~ prop-l- (t) -enyl" -7ß- (a-phenoxyacetamido) -eeph-3- Em- ⁱ l -earbpnsäurediphenylme- methyl ester and 0.5 ral anisole at ⁰ ° C. and then mixed with 2.5 ml of trifluoroacetic acid. The mixture is Minu 2 · ⁴ th vigorously stirred and then evaporated under reduced pressure quickly to dryness. The resulting crude 3- [3- (1-methyltetrazol-5-ylthio) -prop-1- '(t) -enyl] -7β- (aphenoxyacetamide) -ceph-3-em - ^ - carboxylic acid which remains as a residue , is treated with ethyl ether and delivers ■

7098 16/1207

a pale yellow pest substance which is then isolated by filtration. The pest substance is dissolved in tetrahydrofuran, the solution filtered and the filtrate treated with an excess of a solution of sodium 2-ethylhexanoate in tetrahydrofuran. The mixture is evaporated to dryness. Isopropanol is added to the residue, giving a white solid which separates out and is then isolated by filtration, washed several times with isopropanol and dried in vacuo, 35 mg of sodium 3- [3- (l-methyltetrazole -5-ylthio) ~ propl- (t) -enyl] -7β- (a-phenoxyacetamido) -ceph-3-em-4-carboxylate is obtained, which decomposes without melting; UV (water) "293 nm (£ 15,900); IR (KBr) 1765, 1675, 1600 cm" * ¹ ; NMR (DMS0-d ₆ ): 3.4bs, 2H (2-CH ₂ ); 3.92s, 3.H (N-Me); 3.99d, J 7Hz, 2H (3'-CH ₂ ); 4.60s, 2H (OCH ₂ CO); 5.00d, J 5Hz, IH (6-H); 5.5Odd, J 5.9Hz, IH (7-H); 5.72dt, J 7, 15Hz, IH (2'-H); 6.8-7.4m, 6H (<z5 + 1 • -H); 9.00d, J 9Hz, IH (NH); Similarly, sodium 7ß- (a-phenoxyacetamido) -3- [3- (1,2,4-triazol-5-ylthio) -prop-1- (t) -enyl] -ceph-3- em-4-carboxylate prepared by the same process, but using 7β- (cc-phenoxyacetamido) -3- [3- ( _1,2> 4-triazol-5-ylthio) -prop-1- (t) -enyl] -ceph-3-em- ⁱ l -carboxylic acid diphenylmethyl ester used as starting material.

709816/1207

Example 9 -

This example explains the acylation steps for the preparation of the compounds according to the invention _. In this example, a mixture of 0.15 g of 73-amino-3- [3 ~ (1-methyltetrazol-5-ylthio) -prop-1- (t) -enyl ] -ceph-3-era-iiearboxylic acid diphenylmethyl ester and 0.5 ml of pyridine in 5 ml of chloroform at 0 ⁰ C and then stirred with 0.1 ml of phenylthio

acetyl chloride is added and the mixture is stirred for 30 minutes. The mixture is then diluted with ethyl acetate and washed successively with dilute aqueous hydrochloric acid, dilute aqueous sodium bicarbonate solution and brine. The mixture is dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue is purified by thick layer chromatography over silica gel, eluting with a mixture of acetone and dichloromethane in a ratio of 1:20 and giving 3- [3- (l-methyltetrazol-5-ylthio) -prop-l- (t) -enyl] ~ 7ß-phenylthioacetamidoceph-3-em- ⁱ l-carboxylic acid diphenylmethyl ~ ester is obtained.

In a similar way, 7β-phenylthioacetamido-3- [3- (1,2, ^ - triazol-5-ylthio) -prop »l- (t) ~ enyl3-ceph-3-em" 4-carboxylic acid diphenylmethyl ester is made by the same process prepared, but 7β-amino-3- [3- (1,2,4-triazol-5-ylthio) -prop-1- (t) -enyl] -ceph-3-em- ^i- i-carboxylic acid diphenyl

methyl ester used as the starting material. 7098Ί671207

Example 10

This example explains the hydrolysis of the carbonic ester protective group and the preparation of the salts according to the invention. In. In this example, a mixture of 80 mg of 3- [3- (1-methyltetrazol-5-ylthio) ~ prop-1- (t) ™ enyl] ".7β- (a-phenylthioacetamido) -ceph-3-em- ⁱ stirred} -carbonsäurediphenyl "methylester and 0.5 ml of anisole at 0 ⁰ C and then treated with 2.5 ml trifluoroacetic acid. The mixture is stirred vigorously for 2 minutes and then quickly evaporated to dryness under reduced pressure. The residue consisting of crude 3- [3- (1-methyltetrazol-5-ylthio) ~ prop-1- (t) -erjyl3-7β "(a-phenylthio ^; -acetamido) -ceph-3-em-4-carboxylic acid is treated with ethyl ether and then filtered off. The isolated plague substance is dissolved in tetrahydrofuran, the solution is filtered and the piltrate is treated with a solution of sodium 2-ethylhexanoate in tetrahydrofuran. The mixture is evaporated to dryness. The residue is mixed with isopropanol and then filtered. The isolated Pestsubstanz is several times washed with isopropanol and then dried in vacuo to give sodium 3- [3- (l- ^rae thyltetrazol-5-ylthio) -prop-l- (t) ~ enyl] ~ 7ß ~ (aphenylthioacetamido) -ceph-3-em-4-carboxylate receives *

Similarly, sodium 7β- (a-phenylthioacetamido) -3- [3- (1,2,4-triazol-5-ylthio) -prop-1- (t) -enyl] T

709818/1207

ceph-3-em- ¹ ! -carboxylate prepared by the same process, using 7β- (oc-phenylthioacetamido) -3- [3- (1,2, jj ~ triazol-5-ylthio) -prop-1- ( t) -enyl] -ceph-3-em- ⁱ l -carboxylic acid diphenylmethyl ester is used as the starting material.

Example 11

This example explains the acylation steps of the process for the preparation of the inventive Vex "-:" ties.

In this example, a solution of 0.25 g of 7β-amino-3- [3- (1-methyltetrazol-5-'ylthio) -prop-1- (t) -enylceph-3-em-4-carboxylic acid diphenylmethyl. ^< 3rd treated in 10 ml of chloroform with 0.15 g of trifluoromethylthioacetic acid and 0.2 g of dicyclohexylcarbodiimide. The mixture is stirred for 2 hours at room temperature and then filtered to remove the dicyclohexylurea. The filtrate is evaporated to dryness and the residue is purified using thick-layer chromatography over silica gel, eluting with a mixture of acetone and dichloromethane in a ratio of 1:20 and adding 3- [3- (l-methyltetrazol-5-ylthio) -prop -l- (t) -enyl] -7ß- (a-trifluoromethylthioacetamido) -ceph-3 · "em-4-carboxylic acid diphenylmethyl ester obtained".

3- C3- (1,2,4-Triazol ~ 5-ylthio) -prop-1- (t) -enyl] -70- (a-trifluoromethylthioacetamido.) Ceph-3-em- ⁱ t-carboxylic acid diphenylmethyl ester according to the same

709816/12 07

Articles made of said _s-man but 7.beta.-amino-3- [3- (1,2,4-triazol - 5-ylthio) prop-1 (t) -enyl] -eeph-3-em-Jl-earbonsäurediphenylmethylester used as starting material.

Example 12

This example explains the hydrolysis of the carboxylic acid ester protective group and the preparation of the salts according to the invention. In this example, a mixture of 80 mg of 3- [3 - (l-methyltetrazol-5-ylthio) ~ prQp-l- (t) -enyl] -7ß- (a-trifluoromethylthioacetamido) -ceph ~ 3-em- ^f l-carboxylic acid diphenylmethyl ester and 5 ml of anisole for _{0 s} ^{at 0} ° C. and then mixed with 2.5 ml of trifluoroacetic acid. The mixture is stirred vigorously for 2 minutes and then quickly evaporated to dryness under reduced pressure. The crude 3- [3- (1-methyltetrazol-5-ylthio) -prop-1- (t) -enyl] -70 - (a-trifluoromethylthioacetamido) ~ ceph-3 ~ em-4-carboxylic acid obtained as residue is with Treated ethyl ether and then filtered off. The isolated solid is dissolved in tetrahydrofuran ₉ the solution is filtered and treated the Piltrat with an excess of a solution of sodium 2-ethylhexanoate in tetrahydrofuran. The mixture is evaporated to dryness. The residue is mixed with isopropanol and then filtered off. The isolated solid substance is washed several times with isopropanol and dried in vacuo, sodium 3- [3 ~ (1-njehtyltetrazol-5-ylthio) -prop-1- (t) -enyl] -7ß-

7 09o16 / 1207

(α-trifluoromethylthioacetamido) -ceph-3-em - ^ - carboxylate .

Similarly, sodium 3- [3- (1,2,4-triazol-5-ylthio) -prop-1- (t) -enyl] ^ ß-Ca-trifluoromethylthioacefcamido) -ceph-3 ~ em-4 carboxylate prepared by the same process, but using 3- [3- (1,2,4 ~ triazol-5-ylthio) ~ prop-1- (t) -enyl] -70- (a-trifluoromethylthioacetamido) -ceph-3-em-4-carboxylic acid diphenylmethyl ester used as starting material.

Example 13

This example explains the acylation stages of the process for the preparation of the compounds according to the invention. ' .

In this example, a solution of 0.25 g of 70 ~ amino-3- [3- (1-methyltetrazol ~ 5-ylthio) -prop ~ 1- (t) -enyl3 ~ ceph-3-em-4-carboxylic acid diphenylmethyl ester and 0.2 g sydnone-3-acetic acid treated in ethyl acetate with 0.20 g of dicyclohexylearbodiimide. The mixture is left for 2 hours at room temperature stirred, then filtered and evaporated to dryness. The residue is subjected to thick-layer chromatography over silica gel, being treated with a mixture of acetone and dichloromethane eluted in a ratio of 1:10 and 3-D- (I-methyltetrazol-5-ylthio) -prop-1- (t) -enyl] -70- (sydnon-3-yl-.

acetamido) -ceph ~ 3-em-4-carboxylic acid diphenylmethyl ester

709818/1207

Similarly, 7ß- (Sydnon-3-ylacetamido) -3- [3- (1,2,4-triazol-5-ylthio) -prop-1- (t) -enyl] -ceph-3-em- i | - Diphenylmethyl carboxylate prepared by the same process _a but using 7ß-amino-3- [3 - (: i, 2, .4-triazol-5-ylthio) -prop-l - (t) -enyl] -ceph ^ -em-ll-carboxylic acid diphenyl methyl ester used as starting material.

Example 14

This example illustrates the hydrolysis of the carboxylic ester protective group and the preparation of the salts according to the invention. In this example a mixture of 80 mg of 3- [3- (l-methyltetrazol ~ 5-ylthio) -prop-l ~ (t) -enyl] ~ 7J3 - (a-sydnon-3-ylacet amido) -c eph stirred -3 ~ em-4 -carboxylic acid and 0.5 ml anisole at 0 ⁰ C and then treated with trifluoroacetic acid 2,5.ml. The mixture is stirred vigorously for 2 minutes and then quickly evaporated to dryness under reduced pressure. The crude 3- [3- (l-methyltetrazol-5-ylthio) -prop-l- (t) -enyl] -7β - (a-sydnon-3-ylacetamido) -ceph-3-em- ^{i obtained as residue} L-carboxylic acid is treated with ethyl ether and then filtered off. The isolated pest substance is dissolved in tetrahydrofuran, the solution filtered and the piltrate treated with an excess of a solution of sodium 2-ethylhexanoate in tetrahydrofuran. The mixture is evaporated to dryness. The residue

709816/1207

is mixed with isopropanol and then filtered off. the isolated plague substance is washed several times with isopropanol and then dried in vacuo, sodium 3- [3- (l-methyltetrazol-5-ylthio) -prop-1- (t) -enyl] -7β ~ (α » sydnon-3-ylacetamido) -ceph-3-em-4-carboxylate

Similarly, sodium 7ß- (a ~ sydnon ~ 3-yl ~ acetamido) -3- [3- (1 * 2 _s 4-triazol-5-ylthio) "prop-l ~ (t) ~ enyl3" - ceph-3-em-4-carboxylate prepared by the same process, but using 7ß- (a-sydnon-3-ylaeetamido) ~ 3-t3- (1,2,4-triazol-5-ylthio) -prop- 1- (t) -enyl] -ceph ~ 3-em-4-carboxylic acid diphenylmethyl ester used as starting material "

Example 15

To purify and isolate the free acid, a small portion (10 mg) of each of the sodium salts prepared according to Examples * IA, 6, 8, 10, 12 and 1 * 1 is converted back into the 4-carboxylic acid by adding the salt to water dissolves, adjusts the pH to 1.5 using dilute hydrochloric acid and extracted twice with ethyl acetate. The combined extracts are washed with brine, dried and evaporated to dryness. The residue is mixed with ethyl ether and the purified H -carboxylic acid product is isolated by filtration «

7 0 9 8 16 · / 120 7

Example l6

The antibacterial activity of certain compounds according to the invention is determined in the following tests explained in vitro and in vivo.

A. In vitro test

Test Organisms:

1. Streptococcus pyogenes (ATCC 8668) "- S.p.

2. Escherichia coli (ATCC 25922-1) - E.c.

Minimum Inhibitory Concentrations (MIC) were determined for various test compounds and for Cephalothin Sodium'C (a commercially available cephalosporin antibiotic) using an Arnes Handititer 2 to make two-fold serial dilutions from 200 µg / ml to 0.0008 µg / ml. Culture media were dispensed in volumes of 0.05 ml each into dishes in a dilution trough, and 0.05 ral dilution loops were used to transfer fluid for serial dilution. Each dish was inoculated with 1 μl of inoculum which had been produced by a 1:10 dilution in brain-heart infusion broth from the bacterial culture which had been grown in brain-heart infusion broth ^{at 37 ° C. for 18 hours.} After the inoculation, the troughs were ^{incubated in a stationary position at 37 °} C. for 16 hours.

After incubation, the troughs were placed on a red low

709816/1207

cc

and the endpoints were determined using a redox indicator dye (O _s 33 ml of a 2 5% solution of tetrazolium chloride per 100 ml of nutrient medium). 3 troughs were used for each test compound or each standard against each bacterium. If more than one endpoint was found for the multiple trials, the mean dilution was assumed to be the endpoint. The bacteriostatic endpoints, i.e. the concentrations _f at which growth is prevented, are given as minimum inhibitory concentrations (MIC) in ng / ml,

MIC , OOO8 ¹ ^ g / ml) , 0125 Test Organisms Test connection , 12 ² S.p. <o , OO16 ³ Cephalothin Sodium , 0125 E.c. 3 , OO625 ¹¹ 0 .0125 S.p. O '. 25th S.p. O 0 0

Pussnote:

1 = Sodium 3- [3- (1-methyltetrazol-5-ylthio) -prop-1- (t) ~

enyl] -7β- (a-thiophen-2-ylacetamido) -ceph -3-em- * l-carboxy-. lat;

2 = Sodium 7β- [a- (1H) -tetrazol-1-ylacetamido] -3- [3- (1-me ~

ethyl tetrazol-5-ylthio) prop-1- (t) -enyl] ~ ceph-3-em- ⁱ } -carboxylate;

3 = sodium 7β- (a-thiophen-2-ylacetamido) -3- [3- (1,2, U-tria "

zol-5-ylthio) prop-l- (t) -enyl] -ceph-3-em- ⁱ l-carboxy lat;

709816/1207.

4 = Natriura-3- [3- (l-methyltetrazol-5-ylthio) -prop-l- (t) "enyl] -7β- (a-phenoxyacetamido) -ceph-3-em- ⁱ l-carboxylate

B. In vivo test

Test organism = Staphylococcus aureus

Female Swiss Webster mice weighing 19-21 g were housed in groups of 10, with putters and water being available ad libitum. Staphylococcus aureus Smith strain obtained from Sterling-Winthrop Research Institute, Rensselaer, New York, was inoculated into tubes containing brain-heart infusion broth and grown l8 hours at 37 ⁰ C with shaking at 220 rpm. The cultures were diluted 1 × 10 fold in 5% sterile gastric mucin for administration by injection to mice. Each mouse was injected intraperitoneally

-4

0.5 ml of the 10% dilution administered 0.2 ml of a solution of the test compound in sterile water was injected subcutaneously into the area between the shoulder blades of the mice at 30 minutes and 4 hours after challenge, using * 1 different doses and 10 mice used per dosage. The untreated control animals and the test animals were observed twice daily and the deaths recorded per observation period up to 72 hours after challenge. The EDj- ₀ for 72 hour survival was determined using probit analysis or the Reed method

709816/1207

and Muench to America! .. Journal of Hygiene 'calculated 27_ _s ^ 93- ^ 97 C ". (1938). Each test was a commercially available cephalosporin (ie, cephalothin' Sodium and / or cefazolin sodium _s concomitantly so a direct comparison with the test compound could be made.

ED ₅₀ (mg / kg)

Test connection

<O, 5

Cephalo thin Sodium ' Cefazolin Sodium

1.48

O _s 53 0.45

Footnote:

1 = sodium 3- [3- (l-methyltetrazol ~ 5 ~ ylthio) -prop ~ l- (t) -

enyl] -7β ~ (ot-thiophene-2 ~ ylacet amido) ~ ceph ~ 3-em- ⁱ l-carboxy lat;

2 = sodium 7β-Co- (IH) -tetrazol-1-ylacetamido] -3- [3- (l-me

ethyltetrazol-5-ylthio) prop-l ~ (t) ~ enyl3-ceph ~ 3-em- ⁱ lcarboxylate.

The acute oral toxicity (i.e. LDr--,) of sodium 7ß- [a- (1H) -tetrazol-l-ylacetamido] ~ 3 ~ [3- (l-methyltetrazol-5-ylthio) -prop-l- ( t) enyl] ceph-3-em-4-carboxylate in mice, j is found to be greater than 512 mg / kg.

ORIGINAL INSPECTED

709816/1207

Claims (48)

264630S. Claims , IV compound of the formula: in which the propeny! double bond is trans, R. ■ l-methyltetrazol-5-yl or 1 _ί 2 _? '· Ι · -Ίνίαζο1 ~ 5'-γ1 means ^ R is hydrogen, diphenylmethyl, p ~ methoxybenzyl _; p-nitrobenzyl, o-nitrobenzyl, benzyl, tert-butyl, 2.2 _S 2-trichloroethyl, phenacyl or pivaoioyloxymethyl and Rr denotes thiophen-2-yl, trifluoromethylthio, phenoxy, phenylthio, (1H) -tetrazol-1-yl or sydnon ~ 3 ~ yl, and their pharmaceutically acceptable salts, where, if R ^ is thiophen-2-yl, R ^{2 is} hydrogen or a pharmaceutically acceptable cation «. 2) compound according to claim 1, characterized in that that they are of the formula 709816/1207 - 98- CO ₂ H II 1 2 corresponds, in which R and R are as defined in claim 1, and their pharmaceutically acceptable salts, - 3) Compound according to claim 2 _f, characterized in that R is 1-methyltetrazol ~ 5 ~ yl. 4) Compound according to claim 3 * characterized in that it looks around 3 "[3 ~ (l ~ methyltetrazole ~ 5-ylthio) -prop-1- (t) -enyl'J -7β- (a-thiophene-2-y! Acetamido ) -ceph-3-em-4-carboxylic acid and its pharmaceutically acceptable salts. 5) Compound according to claim 'I _5, characterized in that it was the sodium salt 6) Compound according to claim 2, characterized in that R is l, 2,4-triazol "5-yl. 7) Compound according to claim 6 _5, characterized in that it is 7ß ~ (a ~ thiophene-2 ~ yl ~ acetamido) -3- [3- (l _a 2, U-triazol-5 ~ ylthio) "prop-l ~ (t) -enyl] -ceph-3-em-4-carboxylic acid and its pharmaceutically acceptable salts «, 8) Connection according to claim 7 ₅ thereby ge ~ 709816/1207 indicates that it is the sodium salt. 9) A compound according to claim 1, characterized in that they are _the: formula: III 1 7 corresponds to, wherein R and R vde are defined in claim 1, and pharmaceutically acceptable thereof
Salts. 10) connection according to claim 9, characterized indicates that R is diphenylmethyl, 11) connection according to claim 9 _S characterized by indicates that R is hydrogen or a pharmaceutically acceptable cation. 12) Connection according to claim 9> characterized in that that R is l-methyltetrazol-5-yl. 13) Compound according to claim 12, characterized in that it is J5- [3- (l ~ methyltetrazol-5 ~ ylthio) -prop-1- (t) -enyl] -7ß- (a-trifluoromethylthio- 8 ^ 18/1207 acetamido) -ceph-3-em-4-carboxylic acid and its pharmaceutical contains harmless salts. 14) compound according to claim 13 _5, characterized in that
marked that it is the sodium corn. 15) connection according to claim 9> thereby
characterized in that R is 1,2.i4-triazol-5-yl, 16) compound according to claim 15, characterized
characterized in that it is 3- [3- (l _s 2,4-triazol-5-ylthio) -prop-l- (t) -enyl] -7ß- (a-trifluoromethylthioacetamido) -ceph-3-em- ⁱ } -carboxylic acid and its pharmaceutically acceptable salts. 17) compound according to claim 16, characterized
indicated that it is the sodium salt. 18) connection according to claim 1 _? through this
characterized by having the formula: Hh? ¥ IV 709816/1207 corresponds to, wherein X is oxygen or sulfur and R and R are as defined in claim 1, and their pharmaceutically acceptable salts. 19) compound according to claim 18, characterized characterized in that R is diphenylmethyl. 20) compound according to claim 18, characterized characterized in that R was hydrogen or a pharmaceutically acceptable cation 21) Compound according to claim 18, characterized in that R is l-methyltetrazol-5-yl. * 22) Compound according to claim 21, characterized in that it is 3- [3-Cl-methyltetrazol '5-ylthio) -prop-l- (t) -enyl] -7ß- (a-phenoxyacetamido) -ceph-3 -em- ⁱ l-carboxylic acid and its pharmaceutically acceptable salts, 23) Compound according to claim 22, characterized in that it is the sodium salt. 2k) Compound according to claim 21, characterized in that it is 3- [J5- (l * -Methyltetrazol-5-ylthio) -prop-1- (t) -enyl] ~ 7ß- (a-phenylthioacetamido) -ceph -3-em-4-carboxylic acid and its pharmaceutically acceptable salts. 25) compound according to claim 2 * 1, characterized 709816/1207 indicated that it is the sodium salt. 26) compound according to claim 18, characterized τ ♦ indicated that R means 1,2,4-TrIaZoI-S-JTl » 27) Compound according to claim 26, characterized in that it is 7ß ~ (a-Phenoxyacetamido) -3- [3- (l _a 2, A-triazol-5-ylthio) "prop ~ l- (t) -enyl3 -ceph-3 ~ eni- ⁱ {-carboxylic acid and its pharmaceutically acceptable salts. 28) Compound according to claim 27, characterized in that it is the sodium salt. 29) Compound according to claim 26, characterized in that it is 7ß ~ (ot-phenylthioacetamido) -3- [3- (l ₅ 2,4-triazol-5-ylthio) -prop ~ l- (t) ~ enyl ] -ceph-3-em-4-carboxylic acid and its pharmaceutically acceptable salts. 30) compound according to claim 29, characterized indicated that it is the sodium salt. 31) Compound according to claim I _5, characterized in that it has the formula: 709616/1207 r \ H ? ?
N-CH "-CR -C- 1 2 corresponds to wherein R and R are as defined in claim 1, and pharmaceutically acceptable thereof Salts. . 32) connection according to claim 31> thereby indicated that R means dipheny! methyl. 33) connection according to claim 31 * thereby characterized in that R is hydrogen or a pharmaceutical means harmless cation. 34) Connection according to claim 31 »thereby characterized in that R means l-methyltetrazol-5-yl .. 35) Compound according to claim 3 * 1 * characterized in that it is 7ß ~ [a- (1H) -Tetrazol ~ iylacetamido] -3- [3- (l-methyltetrazol-5-ylthio) -propl- (t) - enyl] -ceph-3-em- ⁱ -carboxylic acid and its pharmaceutically acceptable salts. 36) Compound according to claim 35 > characterized in that it is the sodium salt. 7 0 9 8 16/1207 37) Compound according to claim 31 * characterized in that R l _{a is} 2,4-triazol-5-yl. 38) Compound according to claim 37, characterized in that it is Jß- [ot- (1H) -Tetrazol ~ 1-ylacetamido] -3- [3- (1,2,4-triazol-5 ~ ylthio) prop -1- (t) -enyl] -ceph-3-em-4-carboxylic acid and its pharmaceutically acceptable salts; 39) Compound according to claim I _5, characterized in that it has the formula: I VI 1 2 wherein R and R are as defined in claim 1 and their pharmaceutically acceptable salts. 40) compound according to claim 39, characterized characterized in that R is diphenylmethyl. 41) compound according to claim 39, characterized characterized in that R is hydrogen or a pharmaceutically acceptable cation. ' ■ 709818/1207 42) Compound according to claim 39 *, characterized in that R is l-methyltetrazol-5-yl . 43) Compound according to claim 42, characterized in that it is 7ß- (a ~ sydnon-3 ~ ylacetamido) -3- [3- (l-methyltetrazol-5-ylthio) -prop-1 * - (t) -enyl] -ceph-3-em-4-carboxylic acid and pharmaceuticals thereof contains harmless salts. 44) connection according to claim 43 j thereby indicated that it is the sodium salt. 45) connection according to claim 39? through this characterized in that R l, 2,4 ~ triazol-5-yl. . 46) Compound according to claim 45, characterized in that it is 7ß- (a-sydnone ~ 3 ~ ylacetamido) -3- [3- (1,2,4-triazol-5-ythio) -prop-1- (t) -enyl] -ceph-3-em-4-carboxylic acid and their pharmaceutically acceptable salts. 47) Compound according to claim 1, characterized in that it is 7ß- (a ~ (1H) ~ tetrazoll-ylacetamido) -3- [3- (l-methyltetrazol ~ 5 ~ ylthio) -prop "l- (t) -enyl] -ceph-3-em-4-carboxylic acid, 7ß- (oc-trifluoromethylthioacetamido) -3- [3- (l-methyltetrazol ~ 5-ylthio) ~ prop-1- (t) -enyl] -ceph- 3 ~ em-4-carboxylic acid, 7β- (ct-sydnone- . 709816/1207 / ο 3-ylacetamido) -3- [3- (1-methyltetrazol ~ 5 ~ ylthio) -prop-1- (t) -enyl] -ceph-3-em-4-carboxylic acid and their pharmaceutically acceptable salts, 48) Process for the preparation of new compounds of the formula: R ³ -CH in which the propeny! double bond is trans, R 1-methyltetrazol-5-yl or 1,2,4-triazol-5-yl 2
R means hydrogen, diphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl ,. Benzyl, tert "~ butyl, 2,2,2-trichloroethyl, phenacyl or pivaloyloxymethyl and R 1 is thiophen-2-yl _{3 is} trifluoromethylthio, phenoxy, phenylthio, (1H) -tetrazol-1-yl or sydnon-3-yl means, and their pharmaceutically acceptable salts, where, if R p. Thiophen-2-yl means to compounds with R equal Hydrogen and its pharmaceutically acceptable salts are, characterized in that one 709816/1207 JJl (A) a compound of the formula: R ³ -CH _O -CN. τ -z pt wherein R and R have the above meanings and R one of the meanings given above for R with Exception of water has, hydrolyzed or (B) a compound of the formula: 12 · wherein R and R are as defined above, or acylated a pharmaceutically acceptable salt thereof and (C) optionally converting a free acid obtained into the corresponding pharmaceutically acceptable one Salts transferred or ''. (D) optionally converting a pharmaceutically acceptable salt obtained into the corresponding one free acid transferred or 7 0 9 8 16/1207 (E) any received free * Acid or a pharmaceutically acceptable obtained "." "" Lich salt converted into a corresponding compound with a suitable ester protection group. ~ " kB) Pharmaceutical "preparation" characterized in that it contains a pharmacologically effective, non-toxic amount of a compound according to one of the preceding claims, "* '.._"'; 7098 1 G / 12Ö7