DE2537558A1 - CEPHALOSPORIN ANTIBIOTICS - Google Patents

Description

Dr. F. Zumstein Sr. - Dr. E. Assmann - Dr. R. Koenigsberger {Mpt.-Phys. R. Holzbauer - Dipl.-Ing. F. Klingseisen - Dr. F. Zumstein jun.

TELBF = ON: COLLECTIVE NO. 2283-41 β MUNICH 2, TELEX 529Θ7 »BRAUHAUSSTRASSE * TELEGRAMS: ZUMPAT CHECK ACCOUNT:

{MUNICH 91139-809. Bank code 70010080

«ACCOUNT: BANKHAUS H. AUFHÄUSER

- «Rl-NR. 3979Θ7. Bank code 7ΟΟ3Ο6ΟΟ

Ceph 197 12/10 / bs

GLAJO LiBORATORIES LIMITED Greenford, Middlesex / England

Cephalosporin antibiotics

The invention relates to improvements in the field of antibiotics of the cephalosporin series.

The cephalosporin compounds are referred to in the present description with reference to "Cepham" (J. Amer. Chem. Soq., 1962, 84, 3400). The term "cephem" refers to the basic cepham structure with a double bond.

Many cephalosporin compounds are known which have antibacterial activity, which have & ⁵ unsaturation and are usually substituted at the 3-position by a methyl group or substituted methyl group and at the 7ß-position by an acylamido group. It has now been found that the antibiotic properties of a specific Ceph-3-em-4-carboxylic acid are mainly determined by the nature of both its 7β-acylamido group and the substituent in the 3-position of the compound. A great deal of research has been carried out to find combinations of such groups that lead to antibiotics with particular properties.

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Cephalosporin antibiotics are used to treat medical conditions which are caused by pathogenic bacteria in humans and humans, for example in treatment diseases caused by bacteria, which are resistant to other antibiotics, such as penicillin! Terbindungen, are used in the treatment of patients who are sensitive to penicillin. In many areas of application it is desirable to use a cephalosporin antibiotic, which has activity against both gram-positive and gram-negative microorganisms, and great efforts have been made ' taken eephalosporin antibiotics with an improved "wide range to develop.

The practicality of a considerable number of well-known Commercially available and experimental Cephalqsporin antibiotics are characterized by their relatively high sensitivity to the ß-lactamases, produced by many bacteria, restricted will. Therefore, one desirable property of a broad spectrum cephalosporin antibiotic is one "Considerable resistance to β-lactamases including those produced by gram negative microorganisms.

Another difficulty encountered with many cephalosporin antibiotics occurs that is intended for therapeutic purposes is because they degrade in vivo. It has been found that a considerable number of known cephalosporin antibiotics has the disadvantage that after administration it is often rapidly activated by enzymes (e.g. esterases) which are present in the body, are deactivated. ■

It has now become a hater of cephalosporin antibiotics with one special combination of 7β-acylamido group and substituent found in the 3-position, which give the compounds a good effectiveness with a broad spectrum, and with the above

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described desirable properties, a high ß-lactamase stability and a good stability in vivo is paired .

The present invention therefore provides antibiotic compounds or antibiotics of the general formula

CH ₂ O.CO.NH.R ^S (I) COOH

(where R is a! "uryl, thienyl or phenyl group; R ^{a is} a Cj-C ^ -alkyl group, a GP-O.-alkenyl or -alkynyl group, a CU-CU-cycloalkyl group or a phenyl group and R ^{s represents} a C 1-4 alkyl group, a C ₂ -C ₂ alkenyl or alkynyl group, a C 1 -C 12 -cycloalky group, a benzy group or a phenyl group) and their non-toxic derivatives , the compounds being syn isomers or being present as mixtures of syn and anti isomers which contain at least 905ε of the syn isomer The compounds syn isomers which are essentially free of the corresponding anti isomers are particularly preferred.

The compounds according to the invention are defined as having the syn (cis) isomeric form with regard to the configuration of the group OR ^a with regard to the carboxamido group. In the present description, the syn configuration is structurally defined as follows:

981 n / 1 non

The syn configuration is based on the work of Ahmad and Spenser in Can. J. Chem 1961, 39, 1340 assigned.

The expression "non-toxic ¹¹ , which is applied to derivatives of the compounds according to the invention, means that these derivatives are physiologically acceptable in the dose in which they are administered. Such derivatives can, for example, salts, biologically compatible esters, 1-oxides and solvates (especially hydrates).

Salts which, if applicable, can be formed from the compounds according to the invention include salts of inorganic bases, such as alkali metal (e.g. sodium and potassium), alkaline earth metal (e.g. calcium) salts and salts of organic bases (e.g. of procaine, phenylethylbenzylamine, dibenzylethylenediamine, Ethanolamine , diethanolamine, iriethanolamine and N-methylglucosamine). The salts can also be in the form of resinates, which are formed, for example, with a polystyrene resin or a crosslinked polystyrene-divinylbenzene copolymer resin containing amino or quaternary amino groups.

If R in the above formula I is a furyl group, it can be a fur-2-yl or fur-3-yl group and if it is a thienyl group, so it can be an Ihien-2-yl or Ihien-3-yl group. Preferably the group R is a fur-2-yl group.

As indicated above, the group R ^a in formula I represents an alkyl group having 1 to 4 carbon atoms, for example a methyl or ethyl group; an alkenyl or alkynyl group having 2 to 4 carbon atoms, for example vinyl, allyl or propargyl; a cycloalkyl group having 3 to 7 carbon atoms such as a cyclopentyl group; or a phenyl group.

The group R ^s in the formula I can, if the definition so permits, be the same as or different from ^{the group R a.} It can be an alkyl group with 1 to 4 carbon atoms,

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e.g. a methyl or ethyl group; a Cp-C.alkenyl group, e.g., a vinyl or allyl group; a C ^ -C ^ cycloalkyl group, e.g. represent cyclopentyl.

The group R is preferably a] Pur-2-yl group and the Group R ^ is a methyl group.

The antibiotic compounds of the invention are through Their high antibacterial effectiveness against a range of gram-positive and gram-negative organisms, their particularly high Stability against ß-lactamases by various gram-negative Organisms are created, characterized, properties that make them useful in treating a variety of diseases that are caused by pathogenic bacteria in humans and animals.

An important "compound falling under the general formula I is due to its broad-spectrum antibiotic properties, its stability in the presence of human serum, its high stability against β-lactamases produced by a variety of organisms, and its resistance against the action of mammary esterases the syn isomer of (6R, 7R) -7- [2- ^ ¹ ur-2-yl) -2-methoxyiminoacetamido] -3-li-methylcarbamoyloxymethylceph-3-em-4-carboxylic acid with the Pormel

H H

"• CONH 'ry"

N J__Ji-J CH ₂ O. CO.NHCH ₃ (II)

OCH ₃ °

for example in the form of the sodium or potassium salt.

The compounds of the invention can be prepared by any convenient method.

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According to one embodiment of the invention, there is a method for the preparation of an antibiotic compound of the general Formula I (as defined above.) And the non-toxic derivative thereof, which consists of either A) a compound of the formula

CH ₂ O.CO.NH.R ^s (III) COOR ¹ .

(where B has the meaning of ^ S or ^ S-> 0, R is hydrogen or a carboxyl-blocking G group or carboxy1-protecting group, R ^{s has} the meaning defined above and the broken line that lines the 2-, 3 - and 4-positions of the formula II bridged, indicates that the compound can be a Ceph-2-em or a Ceph-3-em compound), or an acid addition salt or H-SiIy! derivative thereof, with an acylating agent condense that of the acid

R.CCOOH

\O.

(IV)

(wherein R and R ^{a have} the meanings indicated above) corresponds to, or condensed with an acylating agent which corresponds to an acid which is a precursor for acid IV; or
B) a compound of the formula

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HH

Acyl.NH-

CH ₂ OH (V)

(where acyl represents the group R.C.CO

Il

0R ^a

or is a precursor thereof; B, R and the broken line have the meanings ^{indicated above) with an isocyanate of the formula R s} ITCO (where R ^{s has} the meaning indicated above), after which, if necessary and desired, any of the following reactions are carried out in each case

C) in any suitable sequence of reactions,

i) Conversion of a gate runner of the desired group

R.C.CO-

Il

ir

\> R ^a

in this group,

ii) converting a Δ isomer to the desired Δ isomer, iii) removing any carboxyl blocking groups, and iv) reducing a compound wherein B is

^ S - * - 0 has to form the desired connection with B => S; and

D) the desired compound of the formula I, if necessary after separation of the syn and anti isomers and, if desired, after Converting the compound to a non-toxic derivative thereof wins.

If R is a carboxyl blocking group, the remainder can do so

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an ester-forming alcohol (aliphatic or araliphatic), Phenol, silanol, or stannanol, or a symmetrical or mixed anhydride group that is different from a suitable acid derives, be.

Hicht-toiische derivatives of the compounds of the formula I can be found in formed in any convenient way. For example, salts with bases by reacting the cephalosporic acid with Sodium or Ealium-2-ethylhexanoat can be produced. Biologically Compatible ester derivatives can be formed using conventional esterifying agents. 1-oxides can by treating the corresponding cephalosporin sulfide with a suitable oxidizing agent, for example with a peracid such as metapesriodic acid, peracetic acid, monoperphthalic acid or m-chloroperbenzoic acid, or with t-butyl hypochlorite, Usually in the presence of a weak base such as pyridine, are formed. ■

An acylating agent corresponding to the acid of the formula IT can be used with an amino compound of the formula IE. where B and cthe broken line denote the above Have meanings and R is hydrogen or a carboxyl blocking group or a carboxyl protective group or a derivative thereof, for example a salt such as a tosylate or an IF-SiIylderivat, condense, whereby the condensation optionally carried out in the presence of a condensation agent and, if necessary, the carboxyl-blocking group E is then removed.

In this way, compounds of the formula I can be produced by using an acid halide, in particular an acid chloride or bromide, corresponding to the acid It. Such acylations könnet 5O ⁰ C at temperatures from -50 to +, preferably -20 rt .to +30 ⁰ C, & durchgefi. The acylation can be carried out in an aqueous or non-aqueous medium.

Acylation with an acid halide can be carried out in the presence of an acid binding agent such as a tertiary amine such as

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friethylamine or dimethylaniline, an inorganic base, like calcium carbonate or sodium bicarbonate or an oxirane, which serve to bind hydrogen halide released during the acylation reaction. Becomes an oxirane used for this purpose, it is preferably a lower 1,2-alkylene oxide, such as ethylene oxide or propylene oxide.

The free acid form of a compound of the formula HT can be themselves can be used as acylating agents. Such acylations are desirably in the presence of, for example, a carbodiimide such as H ^ IP-diethyl-, -dipropyl- or -diisopropylcarbodiimide, Hjlf'-dicyclohexylcarbodiimide or ff-A ^ hyl-IP-Y-dimethylaminopropylcarbodiimide, a carbonyl compound, such as carbonyldiimidazole or an isoxazolinium salt, such as N-iithyl-S-phenylisoxazolinium - ^ '- sulfonate or F-t-butyl-S-methylisoxazolinium perchlorate. the Condensation reaction is desirably carried out in an anhydrous reaction medium, e.g., methylene chloride, dimethylformamide or acetonitrile.

The acylation can also be carried out with other amide derivatives the free acid IT, such as "for example a symmetrical anhydride or mixed anhydride, e.g. with pivalic acid or formed with a haloformate, such as a lower alkyl haloformate, be performed. The mixed or symmetrical anhydrides can be generated in situ. For example For example, a mixed anhydride can be generated using H-A * thoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. Mixed anhydrides can also be mixed with phosphorus-containing acids (for example phosphoric acid or phosphorous acid), sulfuric acid or aliphatic or aromatic. Sulfonic acids (e.g. p-coluenesulfonic acid).

If desired, one can first use a compound of the formula

60981Ü / 10OfI

R.C0.C0.RH.

.CH ₂ 0.C0.NH.R ^S

(VI)

wherein B, R, R ¹ , R ^s and the broken line are as defined above, and then form the reaction of the compound of the formula Y with an etherified hydroxylamine of the formula R ^a 0.1H ₂ , (where R ^{a is} as defined above possessed), followed - if necessary - by a removal of the group R. The reaction product can be separated off before or after the removal of R with formation of the certain syn isomer.

The reaction of the 3-hydroxymethyl-cephalosporin V with the isocyanate of the formula R ^S .M "CO (where R ^{s has} the meaning indicated above) is preferably carried out in the presence of a lower- (C ₁ -O.) -Trialkylamine. The reaction can at a (temperature ranging from -50 to +105 ⁰ C, are suitably carried out from 0 to +25 ⁰ C.

The reaction can be carried out in a substantially inert organic solvent such as an H ", H-disubstituted amide, a halogenated one Hydrocarbon or an ether. Reactions of this ü? Yps are for example in the U.S. Patent 3,355,452.

That for use in the method of this embodiment of FIG 3-hydroxymethyl starting material used in the invention can, for example prepared according to the methods described in British Patent 1,121,308 and Belgian Patent 783 44-9 will.

As indicated above, starting materials of the formula III, if desired in the form of acid addition salts, e.g. B with hydrochloric acid, hydrobromic acid, sulfuric acid, saline

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pitric acid, phosphoric acid, toluene-p-sulfonic acid or methanesulfonic acid can be used.

Protecting groups or "blocking groups, the 4-carboxy group Clay compounds of Formula III, "V or TI substitute, are." preferably groups which can easily be split off at a later stage in the reaction sequence and are advantageous Groups containing 1-20 carbon atoms. Suitable blocked carboxyl groups are known and are described, for example, in the above Belgian patent specification 783,449. Preferred blocked carboxyl groups include aryl lower alkoxy carbony groups, such as p-methoxybenzyloxycarbonyl, p-nitro- "benzyloxycarbonyl and diphenylmethoxycarbonyl; lower alkoxycarbonyl groups, such as t-But oxy carbonyl; and low-haloalkoxycarbonyl groups, such as 2,2,2-irichloroethoxycarbonyl. The carboxy blocking group can then be added after each in the literature described or the usual suitable method can be removed. For example, it is acidic or basic catalyzed hydrolysis is applicable in many cases, as are the enzymatically catalyzed hydrolyses.

If, at the end of a given reaction sequence, compounds are obtained in which B has the meaning of ^ S - * 0 and if a compound is desired in which B has the meaning of> S, a conversion into a sulfide, for example by reducing the correspondingly, is obtained Acyloxy sulfonium or alkyloxysulfonium salt, prepared in situ, by reaction with, for example, acetyl chloride in the case of an acetoxysulfonium salt, the reduction being carried out, for example, with sodium dithionite or iodide ions, such as in a solution of potassium iodide in a water-miscible solvent, e.g. acetic acid,! Tetrahydrofuran, dioxane, dimethylformamide oderDimethy! acetamide is carried out. The reaction can be carried out at a temperature of -20 to +50 ⁰ C.

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ρ ■■ - · -

- 12 -

If the resulting compound is a Ceph-Z-em ^ -carboxylic acid ester, so the desired ceph-3-em compound can be obtained by treatment of the former can be obtained with a base.

The antibiotic compounds according to the invention can be administered in any convenient or customary manner in inalogy with other antibiotics to be formulated and the invention therefore includes a pharmaceutical composition containing an antibiotic compound of formula I or a non-toxic derivative, e.g., salts or biocompatible Eaters thereof adapted for use in human or veterinary medicine. Such compositions can be used formulated in the usual manner with the aid of any necessary pharmaceutical carrier or excipient.

The antibiotic compounds of the invention can be formulated for injection and can be in unit dose form in ampoules or in multi-dose containers with one added Preservatives can be formulated. The compositions can take such forms as suspensions, solutions, emulsions in oily or aqueous vehicles, and can be formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient can be in Powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

The compositions can be used for veterinary medicine, for example be formulated as intramammary preparations in either long-acting or quick-release bases.

In general, the compositions can range from $ 0.1 upwards, preferably from $ 10-60 of the active material, depending on the Administration method included. When the compositions comprise unit dose forms, each unit preferably contains

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50-1500 mg of the active ingredient. The dose for treatment of adults in human therapy is preferably in the range of 500 to 4000 mg per day depending on the route and the frequency of administration.

The compounds according to the invention can be used in combination with other compatible therapeutic agents, such as antibiotics, for example penicillins or other cephalosporins or letracyclines are administered.

- The following examples serve to illustrate the invention. All temperatures are in ⁰ C. The melting points of Examples 1 to 6 were determined on a Kofler block. For Examples 7 to 13, the melting points in open capillaries were determined on a Mettler device and assume the form (M *), where χ represents the rate of heating in ⁰ C per minute and y represents the switch-on temperature. Rotations were measured in the temperature range from 18 to 24 ^{° C.} Ultraviolet spectra were measured in a pH 6 phosphate buffer. The structures were also confirmed by infrared spectroscopy and nuclear magnetic resonance spectroscopy.

In summary, it can be said that new cephalosporin antibiotics in which the 7β-acylamido group is a syn-2-ary1-2- (etherified imino) acetamido group and the substituent at the 3-position is an alkyl, alkenyl, etc. substituted carbamoyloxymethyl group. These connections show a great antibacterial activity against a wide area

of gram-positive and gram-negative organisms, in particular a high level of stability against ß-lactamazene, which is produced by various Organisms are generated and have stability in vivo. The compounds are syn isomers or come as mixtures of syn- and anti isomers that contain at least $ 90 of the syn isomer .

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-H-

example 1

(6R, 7f!) - 7-r2- (Far-2-yi) -2 - metlioxyiminoacetaniiao] -5-3ür-phenylcarbamoyloxymethyleeph-3-a-4 - carboxylic acid (syn-isomer)

A solution of 1.00 g of the syn isomer of (6R, 7R) -7- [2 -]? Ur-2-yl) -2-methoxyiniinoacetamido] -3-hydroxymethyleeph-3-em-4-carboxylic acid in 20 ml !!, !! - dimethylformamide (purified by filtering through basic aluminum oxide) was cooled to 5 ° C. and treated with 0.73 ml triethylamine and 2.85 ml phenyl isocyanate. The mixture was stirred at 5 ^° C. for 1 hour and then the ice bath was removed and the mixture was stirred at 20 ^° C. for a further 1.5 hours. The solution was partitioned between 100 ml of 3 percent aqueous sodium bicarbonate solution and 100 ml of ethyl acetate. The layers were separated and the aqueous solution was washed 3 × 100 ml of ethyl acetate and then covered with 100 ml of ethyl ether and acidified to pH 1.8 with concentrated hydrochloric acid.

The layers were separated and the aqueous layer was extracted with 4 x 100 ml more ethyl acetate. The combined organic extracts were washed with 5 × 150 ml of water and 100 ml of saturated fiatrium chloride solution and dried (MgSO.) And the solvent was removed in vacuo to give a yellow foam which was triturated with 50 ml of ether, 905 ^{mg of the title compound} obtained, [a] _D + 27 ° (c 1, DMSO) X pH6 max 255nm (£ 23500) and 270nm (€ 19500). ;

Example 2

Sodium (6R, 7R) -7- [2- (fur-2-yl) -2-methoxyiminoacetamido1-3-W-methylcarbaemoyloxymethylceph-3-em-4-carboxylate (syn-isomeres)

By treating 1.525 g of the syn isomer of (R, 7R) -7- [2- (Fur-2-yl) -2-methoxyiminoacetamido] -3-hydroxymethylceph-3-em-4-carboxylic acid in 60 ml Ν, Ν-dimethylformamide with 1.12 ml triethylamine nM 2.0 ml of methyl isocyanate, as in Example 1,

6 0 98 10 / 1ClG 0

0.803 g of the syn isomer (6R, 7R) -7- [2- (Pur-2-yl) -2-methoxyiminoacetamidoj ^ -N-methylcarbamoyloxymethylceph ^ -em-4-carboxylic acid are melted. A 0.726 g portion thereof was dissolved in 2 ml of acetone and a solution of 1.6 mmol of sodium Dl-2-ethylhexanoate in 1.6 ml of acetone was added and the solution was cooled overnight. The product was filtered off, washed with chilled acetone and dried in vacuo to give 282 mg of the title compound, [a] ^ + 59 ° (C 1, H ₂ O); \ ^pH6 max 274- nm (£ 17600).

Example 3

(6R. 7R) -3- (N-ethylcarbamoylox yme thy 1) -7-Γ.2- C for-2-y1) -2-methox y iminoacetamido1-ceph ~ 3-em-4-carboxylic acid (syn -Isomer)

By reacting 1.54 g of the syn isomer (6R, 7R) -7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-hydroxymethylceph-3-em-4-carboxylic acid in 60 ml of H. ", H-dimethylformamide with 2.0 ml of ethyl isocyanate and 1.12 ml of triethylamine, as in Example 1, resulted in 622 mg of the title ^compound _{, [cc] D} + 68 ° (C 1, DMSO); λ ρΗ6 max 273 nm (e 16350).

Example 4

(6R, 7R) -3- (N-t-Butylcarbamoy1oxymethy1-7-Γ2- (fur-2-y1) -2-methoxylminoacetamido] -ceph-3-em-4-carboxylic acid (syn-isomer)

By reacting 2.00 g of the syn isomer of (6R, 7R) -7- [2-pur-2-yl) -2-methoxyiminoacetamido] -3-hydroxymethylceph-3-em-4-carboxylic acid in 60 ml of N. , N-dimethylformamide with 5.20 g of t-butyl isocyanate and 2.92 ml of triethylamine, as in Example 1, gave 1.58 g of the title compound, [a] _D + 77 ^P (c 1, DMSO); ^ ^pH6 275nm (<f 16400).

Example 5

(6R.7R) -3- (N-Allylcarbamoyloxymethyl) -7-r2- (fur-2-yl) -2-meth oxyiminoacetamido] -ceph-3-em-4-carboxylic acid (syn isomer)

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By treating 2.00 g of the syn isomer of (6R, 7R) -7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-hydroxymethylceph-3-em-4-carboxylic acid in 100 ml Ν, Ν-dimethylformamide with 2.0 ml of triethylamine and 4.42 g of allyl isocyanate, as in Example 1, gave 1.63 g of the title compound, [a] _D + 32 ° (c_ 1, 1, DMSO); ^ ^pH6 rnax 274nm (ε 13100).

Example 6

(6R _< 7R) -7-f2- (Fur-2-yl) - 2-methoxyiiiiinoacetainidol-3-H-methylcarbamoyloxymethylceph-3-em-4-carboxylic acid (syn-isomer)

A suspension of 1.00 g of the syn isomer of (6R, 7R) -7- [2- (Pur-2-yl) -2-methoxyiminoacetamido] -3-hydroxymethylceph-3-em-4-carboxylic acid 0.871 g of tri-n-butyltin oxide were added in 50 ml of dry methylene chloride and the mixture was kept at 21 ° for 30 minutes stirred under nitrogen, the suspension going into solution. 0.60 g (10.50 mmol) of methyl isocyanate was added and it was stirred for a further 3 hours. 30 ml of ethyl acetate and 30 ml of water were added and the methylene chloride was removed in vacuo removed. The volume of the ethyl acetate was brought to about 30 ml and the pH of the solution was adjusted with aqueous sodium bicarbonate solution set to 8.5. The aqueous solution was washed with 3 × 30 ml of ethyl acetate, then with 30 ml Covered with ethyl acetate and adjusted to pH 1.9 with hydrochloric acid. The phases were separated and the aqueous Phase extracted with a further 3 x 50 ml of ethyl acetate. The combined ethyl acetate extracts were washed with saturated sodium chloride solution washed and dried (magnesium sulfate) and the solvent removed in vacuo to give 0.962 g the title carboxylic acid received as an almost white foam; [ctjjj + 47 ° (c 0.57, DMSO); λ ™ ,. 273nm (€ 15450).

Example 7

(6R _t 7R) -3-N-Cyclohexylcarbamoyloxymethyl-7-r2-methoxy-2- (fur-2-yl) -acetamidol-ceph ^ -em ^ -carboxylic acid (syn-isomeres)

G 0 9 8 1 0/1 Π 0 Γι

A suspension of 1.00 g of the syn isomer of (6R, 7R) -3-hydroxymethyl-7- [2-methoxyimino-2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid 0.870 g of tri-n-butyltin oxide were added in 50 ml of dry benzene under nitrogen and this was obtained a solution after stirring for 30 minutes. 1.318 g of cyclohexyl isocyanate were added and stirring was continued for an additional 3½ hours after which time the reaction was essentially complete.

By adding 50 ml of water to the reaction mixture, a precipitate of dicyclohexylurea was obtained (which is filtered off became). The benzene layer was separated, stirred and 50 ml of 0.1M hydrochloric acid was added, with a white gelatinous precipitate was obtained which was filtered off.

The precipitate was dissolved in aqueous sodium bicarbonate solution and extracted with 50 ml of ethyl acetate. The aqueous phase was acidified with 2 m hydrochloric acid and with 2 χ
• 80 ml of ethyl acetate extracted. The organic layer was washed with 2 × 150 ml of water, dried over magnesium sulfate and evaporated in vacuo to give 396 mg of the vanity compound as an off-white solid, F (Mq ₀ ) = 162 °, 0] ^ ⁰ ' ⁵
+ 38.0 °, (c. 1.0 DiOXaU) JX _1110x (pH6 phosphate buffer) 274nm
(€ 16930).

Example 8

(6R, 7R) -3-N-n-Butylcarbamoyloxymethyl-7- [2-methyloxyimino-2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer)

A suspension of 2.00 'g of the syn isomer of (6R, 7R) -3-hydroxymethyl-7- [2-methoxyimino-2- (fur-2-yl) acetamido] -ceph-3-em-4- carboxylic acid in dry benzene (under nitrogen) was treated with 1.74 g of tri-n-butyltin oxide and obtained
a solution after stirring for 1 hour. 2.08 g of n-butyl isocyanate were added and stirring was continued for 4 hours.
100 ml of water were added to the reaction mixture and the

6 0 9 8 10/1000

stirred, separated benzene sent was treated with 100 ml of 0.1 M hydrochloric acid to give a gelatinous precipitate which was filtered off and dissolved in 100 ml of saturated aqueous sodium bicarbonate solution, once the aqueous solution was washed with 2 × 100 ml of ethyl acetate the aqueous phase was acidified with 2 m hydrochloric acid under a layer of 100 ml of ethyl acetate. The organic phase was separated and the aqueous layer was extracted again with 100 ml of ethyl acetate. The combined organic extracts were washed with 2 × 200 ml of water, dried over magnesium sulfate and evaporated in vacuo, 1.124 g of the title compound being obtained as a pale yellow plague of I "149.6 °; [α]? ⁰ * ⁵ +42 , 6 ° (c 1.03, DMSO) ^ phate buffer 274nm (£ 16960).

Example 9

(6R _t 7R) -7- [2-methoxyimino-2- (thien-2-yl) acetamido] -3-N-methylcarbamoyloxymethylceph-3-em-4-carboxylic acid (syn-isomer)

A solution of 926 mg of the syn isomer of 2-methoxyimino-2- (thien-2-yl) acetic acid in 30 ml of dry methylene chloride was cooled to about 0 ° under dry nitrogen. These solution was at about 0 ° with 0.7 ml of triethylamine, 0.43 ml of oxalyl chloride and a drop of dry Ν, Η-dimethylformamide, Stirred for 1.25 hours, with slight foaming and discoloration occurring.

The solution was evaporated and dried in vacuo for 1.25 hours, the corresponding acid chloride being obtained in the form of almost white crystals. A 'solution of approximately 5 mmol of the acid chloride in 50 ml of dry acetone was added dropwise over 15 minutes at about 1 ⁰ C to a solution of 862 mg of (6R, 7R) -7-amino-3-F-methylcarbamoyloxymethylceph-3- em-4-carboxylic acid and 756 mg of sodium hydrogen carbonate in 60 ml of water and the reaction mixture was stirred for a further 1.25 hours, during which the reaction proceeded completely, as the thin-layer omatogram showed

60 9 8 1 (1/10 00

The solution with a pH of about 7 was 3 x 100 ml Washed ethyl acetate and the combined washings were washed with 2 χ 50 ml of water back-extracted.

The aqueous phase was coated with a layer of 150 ml of ethyl acetate and acidified to pH 1.9 with concentrated hydrochloric acid. The aqueous phase was extracted with a further 2 × 100 ml of ethyl acetate, the organic extracts were combined, washed with 2 × 150 ml of water and 75 ml of saturated salt solution, dried (magnesium sulfate) and evaporated in vacuo, giving 1.503 g of a semicrystalline white solid received. Trituration of the crude product with 30 ml of ether gave 863 mg of the title compound in the form of a white pesticide of P (Mg ₀ ) = 144 °; [a] ^ ² + 57.3 ° (c 1.14, DMSO),

Phosphate buffer) 263 nm (e 16300) with an inflection at 295 nm (β 10650).

Example 10

(6R, 7R) -7-r2-ethoxyimino-2-phenylacetamido] -3-N-methylcarbamoyloxymethy1-c eph-3-em-4-carboxylic acid (syn-Is omeres)

The method of making this connection was the same as in Example 9, except that the acid chloride was prepared from 561 mg of the syn isomer of 2-ethoxyimino-2-phenylacetic acid and the crude acid chloride was isolated as a yellow crystalline plague.

Add dropwise the acid chloride in 28 ml dry acetone to a solution of 500 mg (6R ^ R) -7-amino-3-l * -methylcarbamoyloxymethylceph-3-em-4-carboxylic acid and 439 mg sodium hydrogen carbonate in 35 ml water over 10 minutes at about 10 ⁰ C, followed by stirring for 3 1/2 hours at 5 to 10 ° resulted in acylation of the amino compound, as evidenced by the thin-film ore omatogramm yielded. The reaction mixture was then worked up in essentially the same manner as in Example 9, giving 480 mg of the title compound in the form of a

6 o 9 81 η / 1 η ο η

gave white powder of F (m | _q ) = 138 °; [a] | ² + 58.0 ° (£ 1.0, DMSO), X “, _eT (pH6 phosphate buffer) 259nm (£ 20150).

Example 11

(6R, 7R) -5 ~ y-methylcarl3ainoyloxyinethyl-7-r2-phenox7imino - 2-phenylacetamido 1-cepfa.-3-em-4-carboxylic acid (syn-isomer)

700 mg of the acid chloride of 2-phenoxyimino-2-phenylacetic acid (syn-isomeres) were described in the same manner as in Example 9 manufactured. The crude acid chloride was isolated as a "pale brown gummy mass.

A solution of this crude acid chloride in 28 ml of dry acetone was added dropwise to a cooled to 10 ° solution of 500 mg of (6R, 7E.) - 7-amino-3-l ⁱ r-methylcart) amoyloxymethylceph-3-em-4-carboxylic acid , '35 ml of water and 439 mg Natriumhydrogencarbonst for 10 minutes and the reaction was added after 3 hours of stirring at 5 completely to 1O ⁰ C (DünnschichtchromatograTmii). The reaction mixture was then worked up in essentially the same way as in Example 9, 453 mg of the title compound being obtained as a white powder before F (Mg ₀ ) = 165 °; [α] £ ⁴ + 78.8 ° (c 1.23, DMSO), Λ (ρΗ6 phosphate buffer) 260 nm (£ 20050) with inflections at 265.5 nm (£ 18685) and 282 nm (l 13300).

Example 12

(6R.7R) -7-T2-cyclopentyloximino-2- (fur-2-yl) -acetamidoΊ-3-Ν-methylcarbamoylo: x3nnethylceph-3-eni-4-carboxylic acid (syn-isomer)

The procedure for preparing the acid chloride was the same as that of Example 9, except that the starting acid was 556 mg 2-CycloPentyloximino-2- (fur-2-yl) acetic acid (syn isomer) were used. The acid chloride subsequently became more crystalline Solid isolated.

609810/10 GO

An I solution of the above acid chloride in 25 ml of dry acetone was at about 10 ⁰ C to a solution of 500 mg (6R, 7R) -7-amino-3-If-methylcarbamoyloxymethylceph-3-em-4-carboxylic acid and 439 mg added dropwise in 35 ml of water for 10 minutes. After the course of the reaction for 2 hours at 5 ° to 10 °, the thin-layer chromatogram indicated that the reaction was complete. The reaction mixture was worked up in essentially the same way as in Example 9, 608 mg of the title compound being obtained as a white powder of I ¹ (Mg ₀ ) = 126 °; [α] ²² + 68.5 °

(c 1.06, OMSO), λ _ΜΜ . (ρΗ6 phosphate buffer) 276.5 nm (e 19400). ■ "" max

Example 13

(6R, 7R) -3-M "-Methylcarbamoyloxymethyl-7- [2-methoxyimino - 2- (fur-2-yl) -acetamidο] -ceph-3-em-4-carboxylic acid (syn-isomer)

The preparation of the acid chloride proceeded in the same way as described in Example 9, except that 282 mg of the syn isomer were used of 2-methoxyimino-2- (fur-2-yl) acetic acid were used as starting material. The acid chloride was in shape isolated from almost white crystals.

A solution of about 1.67 mmol of the acid chloride in 17 ml of dry acetone was at about 10 ° to a solution of 287 mg of (6R, 7R) -7-amino-3-N-methylcarbamoyloxymethylceph-3-em-4-carboxylic acid and 252 mg of sodium hydrogen carbonate in 20 ml of water were added dropwise over the course of 15 minutes. The mixture was kept at 5 to 10 ° for 1 hour, after which the reaction in a thin layer chromatograph was found to be complete. The mixture was worked up in the same way as described in Example 9, 258 mg of the title compound being obtained as a solid of P (Mg ₀ ) = 159; [α] ²² + 58.9 ° (c 1.08, DMSO), X _n , (pH6 phosphate buffer)

273nm (ε 17360) with inflections at 260.5 (ε 15300) and 285nm (L 15825).

609810/1000

Manufacturing

(6R, 7R) -7-Amino-3-N-methylcarbamoylo: methyl ceph-3-em-4-carboxylic acid

A suspension of 1.029 g of (6R, 7R) -7-amino-3-hydroxymethylceph-3-em ~ 4-carboxylic acid in 50 ml of dry dichloromethane was treated under nitrogen with 0.436 g of iriethylamine and with 1.25 g of tri-butyltin oxide and the Mixture was stirred for 30 minutes. 0.570 g of methyl isocyanate in 5 ml of dry dichloromethane was added and the mixture was stirred at 22 for 4 hours. The insoluble matter was filtered off and 2 ml of water was added. The solution was cooled and the pH adjusted to 3.1 with formic acid. The resulting suspension was stirred for 30 minutes at about 5 ° and the precipitate was filtered off, washed with cold water and dried in vacuo, 0.482 g of the title amino acid being obtained j [a] -n + 34 ° (c. 0.70, DMSO), Λ max (P ^{H 6} buffer) 263nm (C 7100), A _inf 246nm (£ 6300).

• 609810/1000

Claims (22)

Claims -.a wherein R is a furyl, thienyl, or phenyl group; R is a C. to C. alkyl group, a C. to C. alkenyl or alkyny group, a C. to C. cycloalkyl group or a phenyl group and R ^{3 is} a C. to C. alkyl group, a Gp - C.-alkenyl or alkynyl group, a C ^ - C ^ cyeloalkyl group, a benzyl group or a phenyl group, and non-toxic derivatives thereof, the compounds being syn isomers or as mixtures of syn and anti -Isomers are present which contain at least 90 $ of the syn isomer. 2. A compound according to claim 1 in the form of the syn isomer, essentially free from the anti isomer. 3. (6R, 7R) -7- [2- (Fur-2-yl) -2-methoxyiminoacetamido] -3- N -phenylcarbamoyloxymethylceph-3-em-4-carboxylic acid (syn-isomeres) and non-toxic derivatives thereof. 4. (6R, 7R) -7- [2- (Fur-2-y1) -2-methoxyiminoacetamido] -3- N -methylcarbamoyloxymethylceph-3-em-4-carboxylic acid (syn-isomeres) and non-toxic derivatives thereof. 5- Sodium (6R, 7R) -7- [2- (fur-2-y3) ~ 2methoxyiminoacetamido] -3-N-methylcarbamoyloxymethyl ceph-3-em-4-carboxylate (syn isomer) l Β ti q R10 / 1 η π η 6. (6R, 7R) -3- (N-ethylcarbamoyloxymethyl) -7- [2- (fur-2-y1) -2- methoxyiminoacetamido] -eeph-3-em-4-carboxylic acid (syn isomer). and non-toxic derivatives thereof. 7. (6R, 7R) -3- (li-t -Butylcarbamoyloxymethyl) -7- [2- (ftir-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid (syn-isomeres) and non-toxic derivatives thereof. 8. (6R, 7R) -3- (N-allylcarbamoyloxymethyl) -7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid (syn-isomeres) and non-toxic derivatives thereof. 9. (6R, 7R) -3 -. (N-Cyclohexylcarbamoyloxymethyl) -7- [2- (fur-2-yl) · 2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid (syn isomer) and non-toxic derivatives thereof. 10. (6R, 7R) -3- (N-n-Butylcarbamoyloxymethyl) -7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid (syn-isomeres) and non-toxic derivatives thereof. 11. (6R, 7R) -7- [2-methoxyimino-2- (thien-2-yl) acetamido] -3- N -methylcarbamoyloxymethylceph-3-em-4-carboxylic acid (syn-isomeres) and non-toxic derivatives thereof. 12th (6R, 7R) -7- [2-Ethoxyimino-2-phenylacetamido] -3-N-methylcarbamoyloxymethyl-ceph-3-em-4-carboxylic acid (syn-isomeres) and non-toxic derivatives thereof. 13. (6R, 7R) -3- N -methylcarbamoyloxymethyl-7- [2-phenoxyimino-2-phenylacetamido] -ceph-3-em-4-carboxylic acid (syn-isomeres) and non-toxic derivatives thereof. 14. (6R, 7R) -7- [2-Cyclopentyloximino-2- (fur-2-yl) acetamido] -3_lf_ _m ethylcarbamoyloxymethylceph-3-em-4-carboxylic acid (syn isomer) and non-toxic derivatives thereof. ■ 609810/1 -Π 0 0 15. Method of making an antiMotic compound of the general formula I according to claim 1 and the non-toxic derivatives thereof, characterized in that either A) a connection of the general order COOR CH ₂ O. CO. (III) wherein B has the meaning of > ~ S or S->0; R is hydrogen or a carboxyl blocking group or carboxyl protecting group; R ^{s has} the meaning given in claim 1; and the broken line spanning the 2, 3 and 4 positions of the molecule indicates that the compound can be a ceph-2-em or ceph-3-em compound; or an acid addition salt or ΪΤ-silyl derivative thereof is condensed with an acylating agent that of the acid R- CCOOH It ^N ε OR (IV) corresponds to, in which R and R ^{a have} the meanings given in claim 1, or condensed with an acylating agent which corresponds to an acid which is a precursor of the acid (IV); or B) a compound of the formula 6 0 9 8 10/1 0 0) 0 Acyl.HH COOR ^j CH ₂ OH wherein acyl represents the group R.G.CO or one of them means and B, R and the interrupted Line have the meanings shown above; with an isocyanate of the formula R .FCO, in which R represents the has indicated meanings, implements, whereupon, if necessary and / or desired in each case one or any of the following reactions (C) can be carried out in any suitable sequence: (i) Conversion of a goal runner of the desired group R.C.CO- in this group, (ii) Conversion of a Λ -isomer into the desired δ -isomer, (iii) removal of any carboxyl blocking groups and (iv) reduction of a cephalosporin sulfoxide product to form of the corresponding sulfide and D) Finally, the desired compound of the formula I, if necessary after separating the syn and anti isomers and, if desired, after converting the compound into a non-toxic one 10/1000 Derirate of it wins. 16. The method according to claim 15, characterized in that the compound III condensed with an acid halide., .. das corresponds to acid IV. 17 · The method according to claim 16, characterized in that the condensation in the presence of an acid-binding agent comprising tertiary amine, an inorganic base or a Oxirane. 18. The method according to claim 15, characterized in that a compound III is condensed with a free acid IV in the presence of a condensing agent which is a carbodiimide, Carbonyldiimidazole or an isoxazolinium salt. 19 · The method according to claim 15, characterized in that reaction B is carried out at a temperature in the range from -50 to 4105.degree. 20. The method according to claim 15, characterized in that the reaction B at
is carried out. reaction B at a temperature in the range from 0 ° to + 25 ° C 21. The method according to claim 16, characterized in that a compound V is reacted with an isocyanate of the formula R ^S .ITCO, wherein R ^{s has} the meaning given in claim 15 and is carried out in the presence of a lower trialkylamine. 22. The method according to any one of claims 15 to 20, characterized characterized in that a product of the general formula I is converted into its sodium salt by reaction with sodium 2-ethylhexanoate is converted. 609810/1000 23 · Pharmaceutical composition containing an antibiotic A compound as claimed in any one of claims 1 to 14 in a compound suitable for use in human or veterinary medicine or adapted form, or with customary auxiliaries and carriers. 24 · Pharmaceutical composition according to claim 23, formulated for administration by injection. * Ci 9 η ι ο / 1 η η ο